OPTIMAL MANAGEMENT OF HEPATITIS B VIRUS INFECTION

Transcription

OPTIMAL MANAGEMENT
OF HEPATITIS B VIRUS
INFECTION
PROGRAMME
& ABSTRACTS
www.easl.eu/athens2014
www.easl.eu
CONTENTS
Welcome Message
3
Committees
4
Acknowledgements / Sponsors
5
General Information
7
Scientific Programme
11
Poster Boards
19
Invited Speakers’ Abstracts
33
Poster Abstracts
111
2
Programme & Abstracts • Optimal Management of Hepatitis B Virus Infection
WELCOME MESSAGE
On behalf of the European Association for the Study of the Liver (EASL) and the Asian
Pacific Association for the Study of the Liver (APASL), we are delighted to welcome you
to Athens for the EASL Special Conference «Optimal Management of Hepatitis B Virus
Infection».
The management of chronic HBV infection has improved substantially over the last 15
years, but still remains suboptimal as the virus cannot be usually eradicated. The variability
of viral strains and heterogeneous course of disease in different regions of the world, together with the absence of curative treatment options, impose a number of dilemmas and
challenges in every day clinical practice.
This two-day meeting will focus on all clinical aspects of the management of chronic HBV
infection, but will also cover some basic topics of HBV virology and immunology that will
inform future therapeutic advances. Experts from both Europe and Asia-Pacific areas and a
few guests from North America will provide the latest data and expert opinions. Some of the
key topics to be covered will include HBV epidemiology, virology, immunopathogenesis, natural history, treatment indications and end-points, optimal current treatment approaches
and their challenges in chronic hepatitis B patients, including special groups, and finally
innovative prospective treatment options.
The format of the program aims to generate active discussions and interactions, to reveal
similarities and differences between different patient populations, to reach widely accepted
conclusions that will improve patient management, to highlight the unmet medical needs
and ultimately to guide preclinical and clinical research in this field. Thus, all clinicians and
scientists are encouraged to actively participate in the discussions during the round table
sessions as well as to submit and present their data in the poster sessions.
We hope that you will enjoy this conference and your stay in Athens, with all the history and
culture it has to offer.
With warm regards
SCIENTIFIC ORGANISING COMMITTEE
Pietro Lampertico
Mala Maini
EASL Special Conference • Athens, Greece • September 25–27, 2014
George Papatheodoridis
3
SCIENTIFIC ORGANISING COMMITTEE
Pietro Lampertico, Milan, Italy
Mala Maini, London, UK
George Papatheodoridis, Athens, Greece
EASL GOVERNING BOARD
SECRETARY GENERAL
Markus Peck-Radosavljevic, Vienna, Austria
VICE-SECRETARY
Laurent Castera, Paris, France
TREASURER
Mauro Bernardi, Bologna, Italy
SCIENTIFIC COMMITTEEE MEMBERS
Alessio Aghemo, Milan, Italy
Tom Karlsen, Oslo, Norway
Helen Louise Reeves, Newcastle-upon-Tyne, UK
Cecília Rodrigues, Lisbon, Portugal
Frank Tacke, Aachen, Germany
EDUCATIONAL COUNCILLORS
Jean-François Dufour, Bern, Switzerland
Cihan Yurdaydin, Ankara, Turkey
EU POLICY COUNCILLOR
Patrizia Burra, Padua, Italy
4
ACKNOWLEDGEMENTS
PREMIUM SPONSORS
EASL thanks its Premium Sponsors for their generous contributions and support of all the
2014 EASL educational activities with an unrestricted educational grant.
CONFERENCE SPONSORS
EASL acknowledges the following companies’ dedication and generous support for the
EASL Special Conference “Optimal Management of Hepatitis B Virus Infection”.
BRONZE SPONSOR
OTHER SPONSORS
EXHIBITORS
5
PA
TO
LO
GY
HE
OF
AR
S
YE
www.easl.eu
50
Get Notified
GENERAL
INFORMATION
GENERAL INFORMATION
GENERAL INFORMATION
VENUE
CLIMATE
Hilton Athens
46 Vassilissis Sofias Avenue
Athens 115 28
Greece
The warm weather continues into
September, although a drop in temperature
does occur in this month, leading the way
for the cooler autumnal weather. The
average daily temperature for Athens
in this month can reach highs of 29°C
(84°F) or drop to an average minimum
temperature of 19°C (66°F).
INFORMATION ABOUT ATHENS
The enchanting capital of Greece has
always been a birthplace for civilization.
It is the city where democracy and most
of the wise men of ancient times were
born. This important civilization of
ancient world flourished in Athens and
relives through some of the world’s most
formidable edifices.
The City of Athens is today a European
metropolis with world-class cultural
attractions complemented with modern
amenities, diverse entertainment and
natural beauty, always hospitable to its
guests and enjoyable to its visitors. Having
hosted the 2004 Olympic Games, Athens
can evidently meet the requirements of
the most demanding of events, always
delivering an impeccable result.
All participants are kindly requested to
wear their name badges throughout the
EASL Special Conference in order to be
admitted to the lecture halls and other
scheduled activities.
REGISTRATION
Registration Desk
The onsite registration desk at the
conference venue will be opened:
Thursday, Sept. 25
Friday, Sept.26
Saturday, Sept. 27
16:00 - 20:00
8:00 - 19:00
8:00 - 13:00
CME ACCREDITATION
City Web Site:
www.greece-athens.com
LANGUAGE
The official language of the conference is
English.
8
NAME BADGES
The ‘EASL Special Conference: Optimal
Management of Hepatitis B Virus
Infection’ accredited by the European
Accreditation Council for Continuing
Medical Education (EACCME) to provide
the following CME activity for medical
specialists. The EACCME is an institution
of the European Union of Medical
Specialists (UEMS), www.uems.net
Upon completion of all mandatory online
evaluations, the EASL Office will send you
an electronic version of your certificate by
e-mail.
Through an agreement between the
European Union of Medical Specialists
and the American Medical Association,
physicians may convert EACCME credits
to an equivalent number of AMA PRA
Category 1 Credits™. Information on the
process to convert EACCME credit to
AMA credit can be found at www.amaassn.org/go/internationalcme
TRANSPORT TO THE VENUE
Live educational activities, occurring
outside of Canada, recognized by the
UEMS-EACCME for ECMEC credits are
deemed to be Accredited Group Learning
Activities (Section 1) as defined by the
Maintenance of Certification Program
of The Royal College of Physicians and
Surgeons of Canada.
EVALUATION FORMS
CME Events Evaluation Form - The
session evaluation forms will be available
onsite in the registration area on the last
day of the conference. Please note that a
completed CME Events Evaluation Form
is a pre-requisite in order to receive a
Certificate of Attendance.
Session Evaluation Forms
Session evaluation forms will be available
through the conference mobile application.
By bus
Take Bus Route X95 and get off at «Ilissia»
station, which is right across the hotel.
By metro
Take the blue line towards Aigaleo and
get off at «Evangelismos» station, which
is situated at a 3-minute walking distance
from the hotel.
The cost of the ticket is at 8 EUR per
person
Hotel Parking
The Hilton Athens hotel features an onsite 170-space parking lot, with secure,
covered and self-parking facilities available.
Address
The Hilton Athens Hotel
46 Vassilissis Sofias Avenue
Athens
Greece 11528
Tel: 30-210-7281000
Fax: 30-210-7281111
9
GENERAL INFORMATION
The ‘EASL Special Conference: Optimal
Management of Hepatitis B Virus
Infection’ is designated for a maximum
of (or ‘for up to’) 12 hours of European
external CME credits. Each medical
specialist should claim only those hours
of credit that he/she actually spent in the
educational activity.
GENERAL INFORMATION
LIST OF PARTICIPANTS
To be displayed on the notice board
located in the registration area.
DRESS CODE
Informal for all occasions.
SMOKING POLICY
This will be a non-smoking event.
BANKING
The official currency in Greece is the Euro (€)
Greek banks have limited hours: MondayThursday from 8:00 to 14:30 and Friday
from 8:00 to 14:00. Some branches are
open extra hours in the evenings and on
Saturday mornings.
CURRENCY EXCHANGE
Foreign currency can be exchanged at
banks, bureau de change and automatic
currency exchange machines.
SAFETY & SECURITY
Please do not leave bags or suitcases
unattended at any time, whether inside or
outside the session halls. Hotels strongly
recommend that you use their safety
deposit boxes for your valuables.
LIABILITY & INSURANCE
The EASL Office cannot accept liability
for personal accidents or loss of or
damage to private property of participants.
Participants are advised to take out their
own personal travel and health insurance
for their trip.
10
SCIENTIFIC
PROGRAMME
SCIENTIFIC PROGRAMME
GET THE PROGRAMME & ABSTRACTS
ON YOUR MOBILE DEVICE
Download the Conference app
THURSDAY, SEPTEMBER 25
16:00 – 20:00
REGISTRATION
FRIDAY, SEPTEMBER 26
09.00 - 09.05
INTRODUCTION
George Papatheodoridis, Greece
09.05 - 11.00
SESSION 1 – EPIDEMIOLOGY, PUBLIC HEALTH AND BURDEN OF DISEASE
Chairs: Angelos Hatzakis, Greece
Daniele Prati, Italy
09.05 – 09.20
The changing epidemiology
Alfredo Alberti, Italy
09.20 - 09.40
Hepatitis B immunization: Impact and the way to go in Europe
Jean-Pierre Van Damme, Belgium
09.40 - 10.00
Barriers to diagnosis and treatment in Europe
Emmanuel Tsochatzis, UK
10.00 - 10.20
Barriers to diagnosis and treat chronic hepatitis in Asia
Sang-hoon Ahn, South Korea
10.20 - 10.40
Can HBV be eradicated globally?
Mark Thursz, UK
10.40 - 11.00
Discussion
11.00 - 11.30
Coffee Break
12
11.30 - 13.30
SESSION 2 – VIROLOGY AND IMMUNOPATHOGENESIS
11.30 - 11.50
New insights into HBV entry and replication
Maura Dandri, Germany
11.50 - 12.10
HBV genotypes and mutations: from lab to clinical practice
Stephen Locarnini, Australia
12.10 - 12.20
Discussion
12.20 - 12.40
Immune response in HBV infection
Carlo Ferrari, Italy
12.40 - 13.00
Interactions between HBV, host immunity and the liver
Percy Knolle, Germany
13.00 - 13.20
Age-dependent immune events during HBV infection
Antonio Bertoletti, Singapore
13.20 - 13.30
Discussion
13.30 - 14.30
Lunch
14.30 - 16.40
SESSION 3 – NATURAL HISTORY
Chairs: Mala Maini, UK
Jean-Michel Pawlotsky, France
Chairs: Ferruccio Bonino, Italy
Geoffrey Dusheiko, UK
14.30 - 14.45
Natural course of chronic hepatitis B and predictors of disease
progression and HCC in Western countries
Giovanna Fattovich, Italy
14.45 - 15.00
Natural course and predictors of disease progression and HCC
in Eastern countries
Yun Fan Liaw, Taiwan
15.00 - 15.20
Host genomics and natural course
Jia-Horng Kao, Taiwan
15.20 - 15.30
Discussion
13
14.30 - 16.40
SESSION 3 – NATURAL HISTORY (Cont.)
Chairs: Ferruccio Bonino, Italy
Geoffrey Dusheiko, UK
15.30 - 15.50
The role of non-invasive markers in chronic HBV infection
Laurent Castera, France
15.50 - 16.10
HCC surveillance: indications and cost/effectiveness
Massimo Colombo, Italy
16.10 - 16.30
Occult HBV infection: is there any clinical significance?
Giovanni Raimondo, Italy
16.30 - 16.40
Discussion
16.40 - 17.10
Coffee Break
17.10 - 19.00
SESSION 4 – TREATMENT INDICATIONS, END-POINTS & OPTIONS
Markus Peck, Austria
17.10 - 17.30
Summary of international CPGs optimal follow-up of untreated
patients, treatment indications and therapeutic end-points
Spilios Manolakopoulos, Greece
17.30 - 18.00
Treatment for HBeAg+ with normal ALT immunotolerant
patients: pros and cons
Thomas Berg, Germany
Teerha Piratvisuth, Thailand
18.00 - 18.20
Mechanisms of actions of IFNs-NAs
Georgios Germanidis, Greece
18.20 - 18.40
Is clearance of HBsAg and cccDNA a realistic target?
Massimo Levrero, Italy
18.40 - 19.00
Discussion
19.00 - 19.05
First day closing
Mala Maini, UK
19:05 - 20:00
Cocktail Reception
14
SATURDAY, SEPTEMBER 27
09.00 - 11.10
SESSION 5 – OPTIMAL TREATMENT FOR CHB
09.00 - 09.20
Treatment of HBeAg positive Hepatitis B with Pegylated
Interferon: Clinical Significance of HBVDNA and HBsAg
Quantitative Testing
Harry Janssen, Canada
09.20 - 09.40
Optimal use of Peg-Interferon for HBeAg negative Chronic
Hepatitis B
Maurizia Rossana Brunetto, Italy
09.40 - 10.00
NAs as first-line therapy for CHB
Seng Gee Lim, Singapore
10.00 - 10.10
Discussion
10.10 - 10.25
Management of NAs failures
Fabien Zoulim, France
10.25 - 10.40
Safety and monitoring during long-term NAs therapy
Maria Buti, Spain
10.40 - 11.00
Cost-effectiveness of current therapeutic options of CHB
Kostas Athanasakis, Greece
11.00 - 11.10
Discussion
11.10 - 11.40
Coffee Break
Chairs: Michael Manns, Germany
Patrick Marcellin, France
15
11.40 - 13.30
SESSION 6 – CHALLENGES FOR THE CURRENT TREATMENT OPTIONS
Chairs: Rafael Esteban, Spain
George Papatheodoridis, Greece
11.40 - 12.00
Can nucleos(t)tide analogue therapy be discontinued?
Anna Lok, USA
12.00 - 12.15
Can cirrhosis be really reversed?
Pierre Bedossa, France
12.15 - 12.30
Challenges in the management of decompensated cirrhosis
Cihan Yurdaydin, Turkey
12.30 - 12.40
Discussion
12.40 - 13.00
Does treatment reduce the HCC risk in Western countries?
Ray Kim, USA
13.00 - 13.20
Does treatment reduce the HCC risk in Eastern countries?
Henry Chan, Hong Kong
13.20 - 13.30
Discussion
13.30 - 14.30
Lunch
14.30 - 16.40
SESSION 7 - SPECIAL GROUPS
Chairs: Mario Rizzetto, Italy
Stefan Zeuzem, Germany
14.30 - 14.50
Optimal HBV prophylaxis in HBsAg+ or HBsAg-/anti-HBc+
patients under immunosuppression
Evangelos Cholongitas, Greece
14.50 - 15.10
Optimal prevention of post-transplant HBV recurrence
Didier Samuel, France
15.10 - 15.25
HBV and pregnancy
Ulus Akarca, Turkey
15.25 - 15.35
Discussion
16
Optimal management of patients with severe acute hepatitis B
Bulent Degertekin, Turkey
15.50 - 16.10
The optimal current and potential future therapeutic options
for HBV+HDV infection
Heiner Wedemeyer, Germany
16.10 - 16.30
HBV and HCV co-infection
Stanislas Pol, France
16.30 - 16.40
Discussion
16.40 - 17.10
Coffee Break
17.10 - 18.50
SESSION 8 - FUTURE TREATMENT OPTIONS
15.35 - 15.50
Chairs: Pietro Lampertico, Italy
David Mutimer, UK
17.10 - 17.30
Is there a role for PegIFN and NA combination?
Jörg Petersen, Germany
17.30 - 17.50
Is there a role for NA and NA combination?
Markus Cornberg, Germany
17.50 - 18.10
Myrcludex B, an NTCP-specific Inhibitor of HBV
and HDV Entry
Stephan Urban, Germany
18.10 - 18.30
Novel immunological approaches for treatment
of chronic hepatitis B
Michael Roggendorf, Germany
18.30 - 18.50
Discussion
18.50 - 18.55
Meeting closing
Pietro Lampertico, Italy
17
THE LEADING LIVER ASSOCIATION IN EUROPE
APPLY FOR AN EASL
FELLOWSHIP PROGRAMME!
• Post-Doc Research Fellowships
Application is open from September 30 - November 30
• Entry-Level Research Fellowships
Application is open from September 30 - November 30
• Physician Scientist Fellowships
• Andrew K. Burroughs Short-Term Fellowship
• EASL Mentorships 2014
Application available at the end of November
The Dame Sheila Sherlock EASL Fellowship programmes aim to enhance the mobility
of investigators within different European institutions, actively promote scientific
exchange among research units in Hepatology, and enable physician scientists to
take leave from clinical duties to spend 6-12 months in a research laboratory.
EASL EDUCATIONAL ACTIVITY
•
•
•
No restrictions on applicant’s nationality
Leading European hosting institutions
Open to all registered EASL members
arded
Up
000 aw
to €40’
For application conditions, deadlines and details visit www.easl.eu/_fellowship
POSTER
BOARDS
POSTER BOARDS
POSTER BOARDS
Abstract
Poster Title
P01 YI
QSAR STUDY OF NON-NUCLEOSIDE ANTIReza Aalizadeh
HEPATITIS B VIRUS AGENTS BY MLR AND SVM
METHODS
P02 RENAL FUNCTION DURING 2 YEARS
TREATMENT WITH TELBIVUDINE IN REALLIFE CLINICAL PRACTICE (CLDT600AGR01)
Konstantinos
Mimidis
P03 YI
THE APPLICATION OF DATA MINING
TECHNIQUES TO EXPLORE PREDICTORS OF
DELTA VIRUS (HDV) IN EGYPTIAN PATIENTS
WITH CHRONIC HBV
Abubakr Awad
P04 YI
THE ROLE OF AN INTERVAL LIVER BIOPSY IN
PATIENTS WHO REMAIN UNTREATED FOR
HEPATITIS B AFTER AN INITIAL BIOPSY
Victoria Kronsten
P05 YI
TO STUDY THE EFFECT OF ENTECAVIR
AND INTERFERON COMBINATION WITH
INTERFERON AND ENTECAVIR ALONE IN
MANAGEMENT OF HBE ANTIGEN POSITIVE
CHRONIC HEPATITIS B
Hira Bashir
P06 YI
TO ASSESS THE VACCINATION STATUS AND
ITS IMMUNOLOGICAL RESPONSE, UP TO
SEVEN YEARS AFTER VACCINATION AMONG
MEDICAL COLLEGE STUDENTS.
Hira Bashir
P07 RELATIONSHIP BETWEEN VIRAL LOAD AND
HBSAG LEVEL IN PREGNANT WOMEN WITH
CHRONIC HEPATITIS B VIRUS INFECTION
Maria Belopolskaya
P08 YI
COMBINING HEPATITIS B SURFACE ANTIGEN Saurabh Bhargava
WITH TETANUS FOR A SINGLE ORAL VACCINE
20
Abstract Presenter
Poster Title
Abstract Presenter
P09 EVALUATION OF LIVER FUNCTION IN
PATIENTS WITH HEPATITIS B INFECTION
– ACUTE, CHRONIC HEPATITIS AND LIVER
CIRRHOSIS
Yana Boyanova
P10 YI
LOSS OF HEPATITIS B SURFACE ANTIGEN IS
NOT COMMON AMONG PATIENTS INFECTED
WITH HIV AND HEPATITIS B VIRUS
Anders Boyd
P11 YI
EFFECT OF IMMUNOSUPPRESSION AND
ANTIVIRAL THERAPY IN PERSISTENT
INTRACELLULAR REPLICATION AMONG
HEPATITIS B VIRUS AND HIV-CO-INFECTED
PATIENTS
Anders Boyd
P12 THE RISK OF HEPATOCELLULAR CARCINOMA Fabrizio Bronte
IN HBV CIRRHOSIS IS AFFECTED BY
POLYMORPHISMS OF THE MERTK GENE
P13 NUTRITIONAL ASSESSMENT IN PATIENTS
WITH CIRRHOSIS FROM VIRAL AND NONVIRAL ETIOLOGIES
Chalermrat
Bunchormtavakul
P14 BONE MINERAL DENSITY AND RENAL
FUNCTION IN CHRONIC HEPATITIS B
PATIENTS RECEIVING NUCLEOTIDE
VERSUS NUCLEOSIDE ANALOGS: A PILOT
PROSPECTIVE STUDY
Chalermrat
Bunchormtavakul
P15 EFFICACY OF HBV DNA AND HBSAG
QUANTIFICATIONS AND LIVER STIFFNESS
MEASUREMENT IN IDENTIFYING INACTIVE
HBV CARRIERS AT A SINGLE TIME POINT
EVALUATION.
Gaia Caccamo
POSTER BOARDS
Abstract
21
POSTER BOARDS
Abstract
Poster Title
Abstract Presenter
P16 MXA GENE EXPRESSION IS DOWNREGULATED IN CHRONIC HEPATITIS B
PATIENTS WITH HBV CORE GENE I97L
MUTATION
Ivana Carey
P17 CHRONIC HEPATITIS B IN TUNISIAN
PREGNANT WOMEN.
Rym Ennaifer
P18 PREDICTIVE FACTORS OF SIGNIFICANT
HISTOLOGICAL LESIONS IN CHRONIC
HEPATITIS B
Myriam Cheikh
P19 THE DIAGNOSTIC VALUE OF APRI AND FIBMyriam Cheikh
4 SCORE FOR THE ASSESSMENT OF LIVER
FIBROSIS IN CHRONIC HEPATITIS B TUNISIAN
PATIENTS.
P20 VIROLOGIC AND HISTOLOGIC FEATURES OF
TUNISIAN HBV CARRIERS WITH NEGATIVE
HBEAG AND NORMAL ALT
P21 YI
LOW RISK OF SEVERE COMPLICATIONS
Heng Chi
AFTER LIVER BIOPSY IN CHRONIC HEPATITIS
B PATIENTS
P22 YI
GOOD PREDICTIVE FACTORS OF THE LONGJae Young Choe
TERM THERAPEUTIC RESPONSE OF CHRONIC
HEPATITIS B IN PEDIATRIC PATIENTS
P23 DEEP SEQUENCING TO EXPLORE ARCHIVED
HBV DRUG RESISTANCE MUTATIONS IN
COMPARISON WITH TRADITIONAL SANGERBASED SEQUENCING
22
Myriam Cheikh
Yoon-Seok Chung
Poster Title
Abstract Presenter
P24 TENOFOVIR-INDUCED FANCONI SYNDROME
IN CHRONIC HEPATITIS B MONOINFECTED
PATIENTS SUCCESSFULLY RESCUED BY
ENTECAVIR
Mauro Viganò
P25 ENTECAVIR MONOTHERAPY IMPROVES
RENAL FUNCTION IN LAMIVUDINE
RESISTANT PATIENTS DEVELOPING RENAL
SIDE EFFECTS DURING LONG-TERM
TENOFOVIR EXPOSURE
Pietro Lampertico
P26 LOW RISK OF HEPATITIS B VIRUS
REACTIVATION IN HBSAG NEGATIVE/ANTIHBC POSITIVE CARRIERS UNDERGOING
RITUXIMAB FOR RHEUMATOID ARTTHRITIS
Mauro Viganò
P27 PORTAL HYPERTENSION BUT NOT HCC
RISK IS ATTENUATED IN COMPENSATED
CIRRHOTICS FOLLOWING 12 YEARS OF
TREATMENT WITH NUCLEOS(T)IDE
ANALOGS
Pietro Lampertico
P28 YI
HEPATITIS B CORE-RELATED ANTIGEN
Benjamin Maasoumy
(HBCRAG) LEVELS IN THE NATURAL HISTORY
OF HEPATITIS B VIRUS INFECTION IN A
LARGE EUROPEAN COHORT
P29 A SURVEY OF DOCTOR’S KNOWLEDGE,
ATTITUDE AND PRACTICE WITH INFECTION
CONTROL GUIDELINES IN SUEZ CANAL
REGION HOSPITALS, EGYPT
POSTER BOARDS
Abstract
Hesham El-Sayed
23
POSTER BOARDS
Abstract
Poster Title
Abstract Presenter
P30 EFFECTIVENESS AND SAFETY OF THERAPY
SIMPLIFICATION FROM LAMIVUDINE +
ADEFOVIR TO TENOFOVIR MONOTHERAPY
IN VIROLOGICALLY SUPPRESSED HBEAGNEGATIVE CHRONIC HEPATITIS B PATIENTS
Massimo Fasano
P31 CROSS-SECTIONAL STUDY TO EVALUATE
HEPATITIS B VIRUS (HBV) INFECTION
SCREENING PRACTICES AND OUTCOMES
IN PATIENTS WITH INFLAMMATORY
RHEUMATIC DISEASES (REBIB-I STUDY)
Montserrat GarciaRetortillo
P32 UPDATING HEPATITIS B VIRUS (HBV) STATUS
IN ARMENIA
Hasmik Ghazinyan
P33 ARFI ELASTOGRAPHY – HOW MANY
George Gherlan
MEASUREMENTS ARE NEEDED FOR THE BEST
PERFORMANCE?
P34 ACOUSTIC RADIATION FORCE IMPULSE IN
HEPATITIS B VIRUS INACTIVE CARRIERS - A
COMPARISON WITH OTHER CONDITIONS
George Gherlan
P35 YI
REASSESSMENT OF HEPATITIS B AND DELTA
IN CENTRAL AFRICA REPUBLIC (CAR) 25
YEARS AFTER A FULMINANT HEPATITIS
OUTBREAK (ANRS 12202)
Sumantra Ghosh
P36 YI
FUNCTIONAL INNATE IMMUNE RESPONSES
ARE RESTORED WITH SEQUENTIAL NUC
THERAPY FOLLOWING PEGYLATED
INTERFERON–ALPHA EXPOSURE AND NOT
WITH NUC MONOTHERAPY IN CHRONIC
HEPATITIS B.
Upkar Gill
24
Poster Title
Abstract Presenter
P37 HIGH LEVELS OF HEPATITIS B SURFACE
ANTIGEN (HBSAG) CAN EXCLUDE
SIGNIFICANT FIBROSIS AND DISTINGUISHES
TRUE ‘IMMUNE-TOLERANCE’ IN CHILDREN
AND YOUNG ADULTS WITH CHRONIC
HEPATITIS B
Navjyot K. Hansi
P38 QUANTITATIVE HEPATITIS B SURFACE
ANTIGEN (QHBSAG) CAN DEFINE LOWRISK INACTIVE CARRIERS OF CHB: IS IT
CLINICALLY APPLICABLE ACROSS ALL AGEGROUPS?
Navjyot K. Hansi
P39 YI
PROLONGED USE OF TENOFOVIR AND
ENTECAVIR IN HBV RELATED CIRRHOSIS- AN
APPRAISAL FROM TERTIARY CARE CENTER.
Sundeep Goyal
P40 YI
TRANSIENT ELASTOGRAPHY AND LIVER
FIBROSIS SERO-MARKERS FOR ASSESSMENT
OF LIVER FIBROSIS IN EGYPTIAN PATIENTS
WITH CHRONIC HEPATITIS "B"
Mohamed Hassany
P41 A NEW ALGORITHM CONVENIENT FOR A
COMPUTERIZED PHYSICIAN ORDER ENTRYBASED (CPOE) SYSTEM TO PREVENT HBV
REACTIVATION IN PATIENTS TREATED WITH
BIOLOGIC AGENTS.
Javier Cresop
P42 TENOFOVIR DF PREVENTS HBV
REACTIVATION IN ANTI-HBC POSITIVE
PATIENTS WITH HEMATOLOGIC
MALIGNANCIES TREATED WITH RITUXIMAB:
12-MONTHS RESULTS OF A RANDOMIZED
STUDY (PREBLIN STUDY).
Maria Buti
POSTER BOARDS
Abstract
25
POSTER BOARDS
Abstract
Poster Title
P43 CHARACTERIZATION OF HBSAG LOSS IN
Emilio Suarez
PATIENTS WITH CHRONIC HEPATITIS B (CHB)
TREATED WITH NUCLEOS/TIDE ANALOGS
(NUCS): A RETROSPECTIVE MULTICENTER
STUDY (HEBESAS).
P44 EVALUATION OF 2012 EASL CLINICAL
Jose Luis Calleja
PRACTICE GUIDELINES IN UNTREATED
PATIENTS WITH CHRONIC HEPATITIS B VIRUS
INFECTION IN SPAIN. A RETROSPECTIVE
CROSS-SECTIONAL STUDY (HEBEST).
P45 YI
TRAINED IMMUNITY IN NEONATES OF
CHRONIC HBV-INFECTED MOTHERS
Michelle Hong
P46 YI
NKG2D-DEPENDENT INTERACTIONS
BETWEEN CD4 T CELLS AND NK CELLS IN
THE HBV-INFECTED LIVER
Wei-Chen Huang
P47 CORRELATION BETWEEN QUANTIFICATION
Sae Kyung Joo
OF HEPATITIS B SURFACE ANTIGEN AND HBV
DNA LEVELS IN PATIENTS WITH COMBINED
CHRONIC HEPATITIS B AND STEATOSIS
P48 YI
LACTATE SERUM CONCENTRATIONS
DURING TREATMENT WITH POLYMERASE
INHIBITORS IN PATIENTS WITH CHRONIC
HEPATITIS B WITH OR WITHOUT CIRRHOSIS.
A PROSPECTIVE STUDY.
Maria Kalafateli
P49 ESTABLISHING A NEW VIRAL SET-POINT
IN CHRONIC HBV INFECTION: CLINICAL
EVIDENCE OF IMMUNE RECONSTITUTION
AFTER PROLONGED HBV DNA SUPPRESSION
WITH TENOFOVIR
Melissa Kelley
26
Abstract Presenter
Poster Title
Abstract Presenter
P50 COMPARISON OF THE EFFICACIES OF
ENTACAVIR 0.5 AND 1.0 MG COMBINED WITH
ADEFOVIR IN PATIENTS WITH MULTIPLEDRUG-REFRACTORY CHRONIC HEPATITIS B
INFECTION
Yoon Jun Kim
P51 ASSESSMENT OF CURRENTLY ACCEPTED
CRITERIA FOR VIROLOGIC BREAKTHROUGH
IN CHRONIC HEPATITIS B PATIENTS
RECEIVING ENTECAVIR THERAPY
Yu Seung Kim
P52 IMMUNOLOGICAL PARAMETERS FOR
PREDICTION OF SUSTAINED RESPONSE (SR)
AFTER NUCLEOS(T)IDE ANALOGS (NAS)
DISCONTINUATION IN PATIENTS WITH
HBEAG-NEGATIVE CHRONIC HEPATITIS B
Charikleia Kranidioti
P53 HEPATITIS B IN SUBSTANCE USERS IN EAST
LONDON
Jan Kunkel
P54 IS PEGINTERFERON AN OPTION IN THERAPY
OF ROMANIAN PATIENTS WITH HEPATITIS B?
Dana Valentina
Obretin
P55 EXCELLENT SURVIVAL AFTER HEPATITIS
B RELATED LIVER TRANSPLANTATION:
ANALYSIS IN TWO SPANISH CENTERS.
Sabela Lens
P56 EFFICACY OF TENOFOVIR SWITCH THERAPY
FOR NUCLEOS(T)IDE-EXPERIENCED
PATIENTS WITH CHRONIC HEPATITIS B
Angeline Lo
POSTER BOARDS
Abstract
27
POSTER BOARDS
Abstract
Poster Title
Abstract Presenter
P57 YI
COMPARISON OF RESPONSE RATES OF
PEGINTERFERON, TENOFOVIR AND
ENTECAVIR IN MONO & MIXED HBV
GENOTYPIC INFECTION WITH DIFFERENT
BASELINE FACTORS IN PAKISTANI PATIENTS
Majid Mahmood
P58 YI
COMPARISON OF PEGINTERFERON,
TENOFOVIR AND ENTECAVIR IN TREATMENT
OF CHRONIC HBV PATIENTS HAVING MIX
INFECTION WITH GENOTYPES A AND D
Majid Mahmood
P59 A NEW THERAPEUTIC OPTION FOR TREATING Mamun Mahtab
CHRONIC HEPATITIS B: OUTCOME OF A
PHASE III CLINICAL TRIAL
P60 YI
HBV DNA LEVELS IN LAMIVUDINE
RESISTANCE PATIENTS VERSUS
UNDETECTABLE LAMIVUDINE RESISTANCE
CASES DURING HBV RECURRENCE PERIOD
AFTER LIVER TRANSPLANTATION
Abdorrasoul
Malekpour
P61 YI
EFFECT OF GENOTYPE AND SUBGENOTYPE
IN HBV RECURRENCE AMONG LIVER
TRANSPLANT PATIENTS
Abdorrasoul
Malekpour
P62 YI
ASSESSMENT OF TOTAL ECONOMIC BURDEN
OF CHRONIC HEPATITIS B (CHB)-RELATED
DISEASES IN IRAN
Abdorrasoul
Malekpour
P63 YI
COMPUTATIONAL IDENTIFICATION OF RCC
IN PROTEINS STRUCTURE OF HEPATITIS B
VIRUS
Abdorrasoul
Malekpour
28
Abstract
Poster Title
Abstract Presenter
P64 EFFECT OF NUCLEOSIDE AND NUCLEOTIDE
ANALOGUES ON RENAL FUNCTION
IN CHRONIC HEPATITIS B VIRUS
MONOINFECTION
Stanislas Pol
P65 ADD ON PEGINTERFERON TO ADEFOVIR
ENHANCES HBSAG LOSS IN INACTIVE HBV
CARRIERS.
Michelle Martinot
Peignoux
P66 A MODEL FOR ASSESSING MODERATE OR
Michelle Martinot
ADVANCED FIBROSIS, IN CHRONIC HEPATITIS Peignoux
B PATIENTS
P67 CONSOLIDATING DIVERSE CLINIC DATA ON
HEPATITIS B PATIENTS TO CREATE UNIFIED
RECORDS FOR REAL-TIME PATIENT AND
CLINIC MANAGEMENT AND OUTCOMES
REPORTING USING EXISTING SYSTEMS,
OPEN SOURCE SOFTWARE AND HEP-PRO
PROPRIETARY SOFTWARE
P68 IS ANTIVIRAL PROPHYLACTIC TREATMENT
Nikolaos
NECESSARY IN HBSAG (-), ANTIHBC (+) AND
Papadopoulos
ANTIHBS (+) ONCO-HEMATOLOGIC PATIENTS
WITH HIGH OR MODERATE RISK FOR HBV
REACTIVATION?
P69 LACK OF USEFULNESS OF SERUM MAKERS
FOR ASSESSMENT OF SIGNIFICANT LIVER
FIBROSIS IN INACTIVE CARRIERS OF
HEPATITIS B INFECTION
POSTER BOARDS
Dominic Morgan
Mar Riveiro-Barciela
29
POSTER BOARDS
Abstract
Poster Title
Abstract Presenter
P70 INSULIN RESISTANCE IS ASSOCIATED WITH
HIGHER LIVER STIFFNESS AND INCREASED
IMMUNE RESPONSE IN INACTIVE CARRIERS
OF HEPATITIS B
Mar Riveiro-Barciela
P71 SAFETY AND EFFICACY OF TENOFOVIR IN
TREATMENT HEPATITIS B PATIENTS IN
CLINICAL PRACTICE
Teresa Moreira
P72 YI
INVOLVEMENT OF TNF-ALPHA IN IMMUNE
REACTION ASSOCIATED WITH VIRAL
HEPATITIS B
Alexandra Rosu
P73 INFLUENCE OF PREDICTOR VARIABLES ON
DEGREE OF FIBROSIS IN CHRONIC HBVINFECTION MEASURED BY FIBROTEST
Narina Sargsyants
P74 YI
SINGLE CENTER EXPERIENCE: EFFICACY
AND SAFETY OF LONG TERM THERAPY WITH
NUCLEOS(T)IDE ANALOGS IN CHRONIC
HEPATITIS B (CHB) PATIENTS
Elisaveta Sidorova
P75 NONINVASIVE PREDICTION OF
HEPATOCELLULAR CARCINOMA
DEVELOPMENT : FIB-4 INDEX IN PATIENTS
WITH CHRONIC HEPATITIS B Goktug Sirin
P76 REAL-LIFE DATA ON LONG-TERM
Joo Hyun Sohn
VIROLOGICAL RESPONSE TO ORAL
ANTIVIRAL THERAPY FOR TREATMENT-NAÏVE
PATIENTS WITH CHRONIC HEPATITIS B: A
KOREAN MULTICENTER, RETROSPECTIVE
COHORT STUDY
30
Poster Title
Abstract Presenter
P77 YI
DESIGNING ENHANCED PATHWAYS OF CARE
FOR PATIENTS WITH CHRONIC HEPATITIS B
USING HEPBASE, A PROPRIETARY DATABASE
USED TO STRATIFY PATIENTS.
Ankur Srivastava
P78 YI
A NEW CLINICAL DATABASE TOOL TO
IMPROVE IDENTIFICATION OF HEPATITIS
B AND C VIRUSES IN THE PRIMARY CARE
SETTING
Ankur Srivastava
P79 IFNL3 (IL28B) AND IFNL4 POLYMORPHISMS
ARE NOT ASSOCIATED WITH TREATMENT
RESPONSE TO PEGYLATED INTERFERONBASED THERAPY IN THAI PATIENTS WITH
Pisit Tangkijvanich
P80 THE DRAGON PROJECT – A COMMUNITY
APPROACH TO DELIVERING HEPATITIS B
SCREENING FOR THE CHINESE COMMUNITY
IN MANCHESTER, UK
Alison Uriel
P81 YI
DETERMINANTS OF HBSAG RESPONSE
Margo van
INDUCED BY ADDITION OF PEGINTERFERON Campenhout
TO ENTECAVIR IN HBEAG-POSITIVE CHRONIC
HEPATITIS B
P82 ANTIBODY TO HEPATITIS CORE ANTIGEN
LEVELS IN THE NATURAL HISTORY OF
CHRONIC HEPATITIS B
P83 QUANTITATIVE HEPATITIS B CORE ANTIBODY Gui-Qiang Wang
LEVEL IS A NEW BASELINE PREDICTOR FOR
TREATMENT RESPONSE IN HBEAG-POSITIVE
CHRONIC HEPATITIS B PATIENTS RECEIVING
PEGINTERFERON THERAPY
POSTER BOARDS
Abstract
Gui-Qiang Wang
31
POSTER BOARDS
Abstract
Poster Title
Abstract Presenter
P84 SERUM GAMMA-GLUTAMYLTRANSFERASE
IS USEFUL FOR MONITORING NATURAL
COURSE AND PREDICTING TREATMENT
OUTCOME OF CHRONIC HEPATITIS B VIRUS
INFECTION
Chao Wu
P85 YI
ACCUMULATION OF PLATELETS IN
Rui Huang
THE LIVER MAY BE AN IMPORTANT
CONTRIBUTORY FACTOR TO LIVER INJURY IN
CHRONIC HEPATITIS B VIRUS INFECTION
P86 EFFICACY OF PROPHYLACTIC ANTIVIRAL
Winnie Yeo
THERAPY IN PREVENTING HEPATITIS
DURING RITUXIMAB-BASED CHEMOTHERAPY
IN PATIENTS WITH LYMPHOMA AND PRIOR
RESOLVED HEPATITIS B
P87 SEROPREVALENCE AND RISK FACTORS OF
HEPATITIS B VIRUS INFECTION IN BIRJAND,
IRAN: A POPULATION-BASED STUDY
Masood zZaee
P88 YI
HBV GENOTYPES IN CHILDREN WITH
CHRONIC HEPATITIS B IN BELARUS
Yana Zinovich
P89 DEFINING NORMAL VALUES OF LIVER AND
SPLEEN STIFFNESS USING SHEAR WAVE
ELASTOGRAPHY (SWE)
Pavlos Zoumpoulis
P90 FIBROSIS QUANTIFICATION IN CHRONIC
LIVER DISEASE (CLD): A PROSPECTIVE
STUDY COMPARING TWO ELASTOGRAPHIC
METHODS: VIBRATION CONTROLLED
TRANSIENT ELASTOGRAPHY (VCTEFIBROSCAN) AND SHEARWAVE
ELASTOGRAPHY (SWE)
Pavlos Zoumpoulis
32
INVITED SPEAKERS’
ABSTRACTS
O01
THE CHANGING EPIDEMIOLOGY
Alfredo Alberti1
1
Dept of Histology Microbiology and Medical Biotechnologies, Universita Degli Studi Di Padova,
Padova, Italy
SPEAKERS’ ABSTRACTS
Corresponding author’s email: [email protected]
Seroprevalence of hepatitis B in the general population in European Countries is not jet
well defined and updated. A recent systematic review found general population estimates
available from 13 out 0f 34 countries, ranging from 0.1% to 5.6%. The survey confirmed
that countries in the south and east of the European Union and in Turkey have a much
higher prevalence than those in northwestern Europe. Some countries have data obtained
mainly from blood donor or antenatal screening, with prevalences that are expected to
underestimate substantially those of the general population. On the other hand, data obtained
among PWID, MSM and migrants are usually much higher than the corresponding figures
in the general population, with few exceptions. Several factors have contributed and still are
contributing to dynamic changes in HBV epidemiology, prevalence and incidence rates in
different countries. These include : HBV vaccination and to a much less extend treatment,
improvement in blood screening and safety, higher standard of living and reduced family
size, education on prevention of parenteral transmission by unsafe sex, illicit drug use and
iatrogenic routes. These factors obviously have been and are affecting HBV epidemiology
with different impact in different countries. One example relates to immigration, as the entity
of migratory flows, together with the delta differences in prevalence between immigration
and emigration countries is changing considerably the HBV incidence and prevalence in
several European countries. Better understanding of these changes at the regional level is
essential to build a rational strategy for better HBV control.
34
O02
HEPATITIS B IMMUNIZATION:
IMPACT AND THE WAY TO GO IN EUROPE
Pierre Van Damme1
1
University of Antwerp, Antwerpen, Belgium
Despite the availability of safe and effective hepatitis B virus (HBV) vaccines for more
than 30 years, the burden of hepatitis B disease still is substantial. In 1992, the World
Health Organization recommended the inclusion of HBV vaccination in all national
vaccination programmes. As of 2014, 47 of the 53 European countries (89%) implemented
a universal hepatitis B vaccination programme. The most recent countries to follow the
recommendation were Ireland (in 2008) and The Netherlands (in 2011). Still, six countries
(Denmark, Finland, Iceland, Norway, Sweden and the United Kingdom) adopt risk-group
targeted vaccination only, instead of adding a universal vaccination program. However,
changing demography, increasing immigration and the current vaccine costs make the cost/
benefit ratios in these remaining low endemicity countries strongly in favor of universal
HBV vaccination. Global efforts, including a cohesive European vaccination policy, are
essential to control and prevent hepatitis B.
35
Grant: Pierre Van Damme acts as chief and principal investigator for vaccine trials
conducted on behalf of the University of Antwerp, for which the University obtains research
grants from vaccine manufacturers; speakers fees for presentations on vaccines are paid
directly to an educational fund held by the University of Antwerp. PVD receives no personal
remuneration for this work.
O03
BARRIERS TO DIAGNOSIS AND TREATMENT IN EUROPE
Emmanuel Tsochatzis1
1
Sheila Sherlock Liver Unit, Royal Free Hospital, London, United Kingdom
In Europe, according to the estimations of the European Region of the World Health
Organization, there are approximately 14 million people chronically infected with HBV and
around 36,000 related deaths each year with the number of deaths reported to be increasing.
Over the last 15 years, the efficacy of the therapeutic options for chronic HBV infection has
dramatically improved. Practically all chronic HBV infection can now achieve at least ontherapy virological remission which is associated with improved liver histology, reduction
of need for liver transplantation and eventually improved survival. Despite the availability
of effective therapies, however, the morbidity and mortality from chronic hepatitis B is
increasing as only a small proportion of such patients actually receive treatment. Barriers to
care and treatment can arise at multiple levels, which often differ widely among countries
within Europe. I will discuss these barriers and suggest ways of addressing them.
36
O04
BARRIERS TO DIAGNOSIS AND TREAT CHRONIC
HEPATITIS B PATIENTS IN ASIA
Sang Hoon Ahn1
1
Internal Medicine,Yonsei University College of Medicine, Seoul, Korea, South
First of all, there is a characteristic biologic feature of Asian HBV infection represented
as long lasting immune tolerance phase resulting in immune-mediated liver injuries and
subsequent liver disease progression, and high prevalence rate of genotype C, which
is associated with a more progressive disease course and less responsiveness to antiviral
therapy. Second, a lack of awareness of HBV infection among patients, governments, and
healthcare practitioners is another cause to prevent to identify unrecognized victims of
CHB infection. Lastly, even if the society and the government recognizes the necessity of
secondary prevention such as active screening, most Asian countries are lack of medical care
systems, sensitive laboratory tests, and liver specialists. Moreover, the costs of screening,
monitoring, and therapy are beyond the threshold of willingness-to-pay. In addition, there
are no adequate insurance coverage and reimbursement system nationwide.
Treatment of chronic HBV infection in Asia is also a major challenge. There have been great
advanced in the development of antiviral therapy in the past decade, and many important
studies and experience for antiviral treatment were gained in Asian populations. Moreover,
a better understanding on the natural history of HBV infection and non-invasive assessment
of liver fibrosis enable to stratify the risk of CHB patients for adverse clinical outcomes.
However, treatment of chronic HBV infection is a complex task that requires individualized
assessment and the high cost of medical care.
37
Chronic hepatitis B virus (HBV) infection is a major global health problem especially in
the Asia-Pacific region where more than 40 countries are encompassing a wide geographic
area with a large population. In many Asian countries, the prevalence of chronic hepatitis
B (CHB) is highly endemic due to high occurrence of perinatal transmission and infection
of HBV during early childhood. About 300 million chronic HBV carriers live in Asia, and
15-25% of them will eventually die of HBV-related end stage liver disease. During the past
decade, the introduction of universal vaccination has significantly reduced the incidence
of perinatal infection in most Asian countries. However there is still large population of
old adult patients with HBV infection. Moreover, in managing patients with CHB, great
obstacles and challenges lie ahead for most of Asian countries.
An access to antiviral drugs is the most critical obstacle in many of Asian countries, which
have low-income economies. Lack of adequate reimbursement for treatment and diagnostic
testing is common in Asia, and antiviral agent with low genetic resistance barrier such as
lamivudine is still being widely used rather than recently developed higher potent antiviral
agents.
To overcome the difficult situation in this part of the world, there should be an effort to
develop active screening programs and to perform educational activities such as publication
of guideline of CHB. Additionally, technical and financial support from other Western
countries and reduction of prices for both diagnostic testing such as HBV DNA assays
and nucleot(s)ide analogues by international agencies may help these undeveloped Asian
countries to enhance the facilities and infra to treat patients with CHB. As for individual
practitioner, careful selection of patients for treatment and application of road-map concept
during treatment should be needed.
The effective management of HBV infection in Asians requires a comprehensive
understanding for cultural, socio-economic, and accessibility issues. Moreover, clinical
practice for treatment of CHB patient requires both insights for nation-wide scope and
optimization for individual patient treatment.
38
O05
CAN HBV BE ERADICATED GLOBALLY?
Mark Thursz1
1
Imperial College, London, United Kingdom
Eradication of an infectious disease, which requires elimination in all geographic regions,
is an enormous ambition. The historical success of smallpox eradication achieved through
immunisation gives artificial optimism to those planning elimination and eradication
campaigns. The more recent, WHO led, programme to eliminate polio gives a more
realistic picture of the clinical, epidemiological, and political challenges that may be faced.
There are a number of reasons to be both optimistic and pessimistic about the potential
elimination of hepatitis B virus (HBV). On the positive side we have good diagnostic tests,
an effective vaccine and good drugs to suppress viral replication. On the negative side the
disease is asymptomatic in the majority of cases, the burden of disease is concentrated in
resource limited settings and there is currently no political momentum to address HBV.
The impressive impact of vaccination has been best illustrated by the Taiwanese programme
which began in 1984 and has seen the childhood HBsAg prevalence drop from 10% to
0.9% with > 95% vaccine coverage and a comprehensive antenatal screening system.
Unfortunately, this level of coverage is not replicated worldwide: WHO data suggests
that vaccine coverage is only 70% on average. In many countries there is no antenatal
HBV screening and birth dose vaccination is impossible. Alternative interventions to
avoid vertical transmission are therefore essential to support an elimination strategy.
HBsAg testing is cheap, sensitive and specific but the key diagnostic for treatment decisions
is the HBV DNA which is unavailable or too expensive for use in resource limited settings.
There are a number of novel initiatives to develop cheap, reliable and robust point of care
viral load measurements which should overcome this barrier in the foreseeable future.
The asymptomatic nature of chronic HBV infection is a barrier to patients being
diagnosed and treated as well as making it difficult to monitor the impact of public health
interventions. In West Africa we have recently evaluated screening strategies to identify HBV
carriers in the community. Uptake of screening and linkage into care rates are very high
and cost effective. When coupled with a vaccination programme, screening and treatment
should have a major impact on both the burden of disease and the prevalence of infection
Whilst the necessary clinical tools (diagnostics, vaccination and treatment) are potentially
available the most important barrier to HBV eradication remains; absence of political will.
Global fund decline to provide antiviral drugs for viral hepatitis and GAVI will not provide
birth dose vaccination. HBV is not seen as a major infectious disease by UN institutions or
Gates foundation. It also does not count as a neglected disease. Until the political situation
changes HBV cannot be considered as an eradicable disease.
39
O06
NEW INSIGHTS INTO HBV ENTRY AND REPLICATION
Maura Dandri1
1
Virus Hepatitis Research Unit, I. Department of Internal medicine, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany
Liver disease associated to chronic infection with hepatitis B virus (HBV) continues to be
a major health problem of global impact that elevates the risk of developing liver cirrhosis
and hepatocellular carcinoma. Approved therapeutic regimens efficiently suppress HBV
replication, but they generally don’t cure infection, because HBV deposits its viral genome,
the cccDNA, as a nuclear persistence form. As a consequence, relapse of viral activity is
commonly observed after cessation of treatment with polymerase inhibitors. The narrow
host range of HBV and the need of high differentiated primary hepatocytes have hindered
progresses in understanding specific steps of HBV entry and replication. HBV infection
establishment is a multistep process which involves attachment, internalization, uncoating,
nuclear translocation and cccDNA formation. These processes appear to depend on complex
interactions with specific host factors determining both tissue and species tropism of HBV.
The identification of the cellular factors involved in these processes as well as in cccDNA
maintenance is necessary to uncover novel antiviral targets and for the development of more
effective therapeutic strategies.
Using primary cells from humans and Tupaia belangeri, as well as HepaRG cells, important
determinants of viral infection could be recently found. Among these, the recognition of the
sodium taurocholate co-transporting polypeptide (NTCP) as the bona fide HBV and HDV
entry receptor has been a major breakthrough and has enabled the establishment of cell lines
supporting HBV and HDV infection. These studies revealed that the viral binding to NTCP
is mediated by the preS1-domain of the HBV envelope protein. NTCP is a transmembrane
transporter localized to the basolateral membrane of highly differentiated primary
hepatocytes and mediates most of the hepatocellular Na+-dependent uptake of bile salts.
Myrcludex-B, which is an optimized synthetic lipopeptide consisting of the myristoylated
2–48 aa region of the HBV preS1 envelope protein, was shown to strongly inhibit HBV
entry. Previous infection studies in human liver chimeric mice also permitted to evaluate the
in vivo capacity of Myrcludex-B to prevent de novo HBV and HDV infection, as well as viral
spreading post infection. Notably, administration of the entry inhibitor during the rampup phase of HBV infection hindered not only the increase of HBcAg-positive hepatocytes
but also hindered amplification of the cccDNA pool in initially infected hepatocytes. Thus,
agents targeting NTCP are expected to be potent candidates that act as anti-HBV drugs.
40
The elimination of the viral genome from the infected livers is very challenging since it
appears to require either immune mediated destruction of the infected hepatocytes or the
induction of cccDNA destabilization and loss. To this regard, activation of specific innate
immune signaling pathways was shown to suppress cccDNA activity and also to induce its
partial degradation. Moreover, recent studies with human-liver chimeric mice have shown
that in the milieu of compensatory liver regeneration, hepatocyte proliferation induces
strong reduction of intrahepatic cccDNA levels, leading to the formation of cccDNA-free
hepatocytes. The drastic cccDNA reduction induced by cell division underscores a weak
point in HBV persistence, while the use of entry inhibitors possibly in combination with
other therapeutic strategies may be fundamental to maintain viral clearance in cccDNA-free
or “cured” hepatocytes.
41
Little is known about the mechanisms regulating cccDNA biogenesis, except that they
require distinct host enzymes involved in DNA repair. When the rcDNA is converted
to a cccDNA form that is associated with histones and non-histones proteins, cccDNA
transcriptional activity, and hence viral replication, is regulated by various liver-enriched
transcription factors and by the acetylation status of the histones bound to the cccDNA
minichromosome. Moreover, the viral HBx protein has been shown to be essential for
cccDNA-driven HBV transcription. Cellular factors also appear to be needed to export the
pregenomic RNA (pgRNA) from the nucleus to the cytoplasm, where pgRNA is translated
to HBV core protein and polymerase and serves as template for the reverse transcription
of the viral genome within the immature nucleocapsids. rcDNA containing mature capsids
are then assembled with viral surface proteins in the endoplasmic reticulum to form viral
particles that are released from the hepatocyte. The multivesicular body (MVB) machinery
has been involved in budding and release of HBV virions. Knowledge in this area may also
lead to the development of a new class of antiviral agents.
O07
HBV GENOTYPES AND MUTATIONS:
FROM LAB TO CLINICAL PRACTICE
Stephen Locarnini1
1
Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia
Ten genotypes of HBV (A to J) have now been described, which have an essentially
geographical distribution (Europe/USA/Africa: genotypes A, D and E; Asia: genotypes B
and C; South America: genotypes F and H). The clinical significance of these different
genotypes has only recently become apparent with the recognition that there is more
accelerated progression to cirrhosis/hepatocellular carcinoma (HCC) in those patients
infected with genotypes C or F whilst genotypes A, B and C respond better to therapy with
interferon than genotype D.
The common HBV mutants of clinical interest include those that affect: 1) the HBeAg
phenotype (basal core promoter [BCP] A1762T/G1764A and precore stop codon G1896A
[pcW28*] mutants); 2) HBsAg secretion and expression (envelope variants such as vaccine
escape [sG145R], HBIG escape [sD144A/E] and diagnostic escape (mini-loop 1 of the
‘a’ determinant), and 3) Antiviral Drug Sensitivity (polymerase changes: rtL180M =
rtM204V/I for L-nucleosides [lamivudine/telbivudine]; rtL180M + rtS184G + rtS202I
+ rtM204V/I + rtM250V for cyclopentane group (entecavir); rtA181T/V +/- rtN236T
for acyclic phosphonates (adefovir and tenofovir). The HBeAg and HBsAg variants are
generally selected out over the natural history of chronic hepatitis B (CHB) as a consequence
of the host’s immune response attempts, both humoral (anti-HBe and anti-HBs) as well
as cellular, to control and eliminate HBV from the liver. Of particular importance is the
emergence of HBVs lacking the ability to make or secrete HBeAg or HBVs containing
defects in Pre-S2 protein synthesis or even deletions in the Pre-S2 region itself. These
HBVs have been strongly linked to the development of advanced liver disease including
HCC as have the BCP mutants A1762T/G1764A. A proportion of >45% BCP mutants
in patients infected with either genotype B or C HBV significantly increases the risk of
liver cirrhosis development, and could actually provide another important pathogenomic
viral biomarker along with quantitative HBV DNA and HBsAg. Other specific changes in
regulatory domains of the HBV genome such as the selection of novel HNF-1 binding sites
in the BCP region have been associated with extremely high HBV replication levels, leading
to fulminant hepatitis.
The identification of these SNPs using next generation sequencing technology may very
well provide the framework and molecular genetic basis for a personalised management
approach to patients with CHB.
42
O08
IMMUNE RESPONSE IN HBV INFECTION
Carlo Ferrari 1
1
Unità Operative di Malattie Infettive ed Epatologia, Azienda Ospedaliero-Universitaria di
Parma, Parma, Italy
In the face of this poor induction of intracellular innate immunity, adaptive responses are
efficiently and timely induced immediately after the start of the active virus replication and
cytokines released by liver infiltrating HBV-specific T cells, especially CD8 cells, at the site
of infection are believed to be the main responsible for the early non-cytolytic clearance of
HBV (5,6). In contrast to the timely activation of T cells, NK cell activation seems to be
delayed because the peak of NK cell frequency and function generally follows the peak of
viremia. (7).
Both HBV-specific CD8 cells and NK cells are then responsible for the cytolytic elimination
of residual infected cells and for permanent control of infection. At the time of the ALT
peak, HBV-specific T cells appear to be highly activated but almost totally inhibited in their
function, as a likely effect of soluble factors, such as arginase released by necrotic liver cells.
This is believed to be a protective mechanism to protect the liver from excessive immune
pathology. This functional inhibition is only transient, because resolution of infection is
associated with a decline of activated T cells and a restoration of the T cell function, leading
to the maturation of long-lasting protective T cell responses, which are typical of HBV
infection and that are maintained by the occult persistence of HBV, which is never totally
eliminated from the infected host, even after successful resolution of acute hepatitis (8).
43
In HBV infection acquired in the adult life, levels of viremia remain generally low for several
weeks before the start of an active and exponential phase of virus replication, which can lead
to the infection of virtually all hepatocytes. When infection is self-limited this is followed by
a rapid decline of viremia which generally starts before maximal ALT elevation and is likely
sustained by non-cytolytic mechanisms. Early intracellular immune responses (which lead
to type I IFN production following engagement of toll-like and RIG-I receptors by viral
PAMPs) are poorly induced by HBV which would behave as a stealth virus poorly sensed
by the innate immunity (1,2,3). In addition, HBV is also able to actively inhibit innate
responses, for example affecting type I IFN production and suppressing TLR expression
by its structural and non-structural proteins, further impairing initial anti-viral control (4).
When acute infection becomes chronic, a progressive impairment of the HBV-specific T cell
function is observed and chronic virus persistence is associated with the lack of protective
T cell memory and with an exhaustion of HBV-specific T cells ranging from functional
inhibition to physical T cell deletion, depending upon quantity of viral antigen and duration
of T cell exposure to high antigen loads. This functional T cell inhibition is deeper within the
liver than in the circulation and it is more severe in the presence of high viremia levels (9, 10).
Exhausted T cells express high levels of co-inhibitory molecules, such as TIM3, CTLA4,
2B4 and PD1, and can be more or less severely inhibited in their anti-viral function with
either a total or a partial loss of anti-viral cytokine production, cytolytic activity and capacity
to expand following antigen encounter (11-15). The importance of these mechanisms of
T cell inhibition is indicated by the partial restoration of the T cell function upon decline
of antigen and prolonged suppression of HBV replication in nucleoside analogue treated
patients (16) and by the possibility to improve the anti-viral T cell function by in vitro
blockade of co-inhibitory pathways using specific blocking antibodies, such as anti-PD-L1
(11-17). In addition to exhaustion by exposure to high antigen doses, different mechanisms
operating within the infected host can simultaneously contribute to T cell inhibition in
chronic HBV infection, including high intrahepatic levels of arginase and indoleamine
2,3 dioxygenase that can metabolize amino acids that are essential for T cell function; upregulation of the pro-apoptotic protein Bcl2-interacting mediator (Bim); hyper-activity of
regulatory T cells and inhibitory cytokines, such as IL10 and TGF beta (18-21).
Based on this knowledge, future therapeutic strategies to reduce the time of NUC
administration by accelerating HBsAg clearance should combine different compounds
contributing to T cell restoration by a synergistic activity on the different mechanisms
implicated in T cell inhibition (4). Since T cell functional restoration can be difficult to
achieve in vivo because of the deep energetic and metabolic HBV-specific T cell impairment
(Fisicaro P. et al, personal communication), T cell receptor re-directed T cells engineered
through transfer of HBV-specific T cell receptors represent a potential and alternative way
to provide patients with functionally efficient T cells reconstituted in their specificity (22).
In addition, innovative therapeutic strategies have been proposed to target intrahepatic
innate immunity through the development of T cell receptor like antibodies, conjugated
with IFN-α, which are able to recognize HLA class I peptide complexes on infected liver
cells, thereby increasing intrahepatic IFN-α delivery (23). To exploit the protective role of
the innate immunity, specific strategies based on the administration of TLR agonists are also
under investigation in light of the evidence that TLR9 agonists can induce efficient CTL
expansion in mice (24), that TLR7 agonists can induce intrahepatic IFN-α production in
HBV infected chimpanzees (25) through their capacity to stimulate plasmocitoid dendritic
cells and that a strong intrahepatic production of IFN-γ can be induced by TLR8 agonists
in an IL12- and IL18-dependent manner (26).
44
45
References
1. Wieland S, Chisari FV. Stealth and cunning: hepatitis B and hepatitis C viruses. J Virol
2005;79:9369e80.
2. Wieland S, Thimme R, Purcell RH, et al. Genomic analysis of the host response to
hepatitis B virus infection. Proc Natl Acad Sci USA 2004;101:6669e74.
3. Bertoletti A, Maini MK, Ferrari C. The host pathogen interaction during HBV
infection: immunological controversies. Antiviral Ther 2010; 15:15e24
4. Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis
B virus infections: towards restoration of immune control of viral infection. Gut
2012;61:1754e64.
5. Webster G, Reignat S, Maini M, et al. Incubation phase of acute hepatitis B in man:
dynamic of cellular immune mechanisms. Hepatology 2000;32:1117e24
6. Fisicaro P, Valdatta C, et al. Early kinetics of innate and adaptive immune responses
during hepatitis B virus infection. Gut 2009;58:974e82.
7. Dunn C, Peppa D, Khanna P, et al. Temporal analysis of early immune responses in
patients with acute hepatitis B virus infection. Gastroenterology 2009;137:1289e300.
8. Sandalova E, Laccabue D, Boni C, et al. Increased levels of arginase in patients with
acute hepatitis B suppress antiviral T cells. Gastroenterology 2012;143:78-87
9. Bertoletti A, Ferrari C. Kinetics of the immune response during HBV and HCV
infection. Hepatology 2003;38:4e13
10. Rehermann B, Nascimbeni m. Immunology of hepatitis B virus and hepatitis C virus
infection. Nat Rev Immunol 2005;5:215e29
11. Boni C, Fisicaro P, Valdatta C, et al. Characterization of hepatitis B virus (HBV)specific T-cell dysfunction in chronic HBV infection. J Virol 2007;81:4215e25
12. Fisicaro P, Valdatta C, Massari M, et al. Antiviral intrahepatic T cell responses
can be restored by blocking programmed death-1 pathway in chronic hepatitis B.
Gastroenterology 2010;138:682e93
13. Schurich A, Khanna P, Lopes AR, et al. Role of the cohinibitory receptor cytotoxic
T lymphocyte antigen-4 on apoptosis-Prone CD8 T cells in chronic hepatitis B.
Gastroenterology 2010;138:682e93
14. Raziorrouh B, Schraut W, Gerlach T et al. The immunoregulatory role of CD244 in
chronic hepatitis B infection and ist inhibitory potential on virus-specific CD8+ T-cell
function. Hepatology 2010;52:1934e47
15. Nebbia G, Peppa D, Schurich A, et al. Upregulation of the TIM-3/Galectin-9 pathway
of T cell exhaustion in chronic hepatitis B virus infection. Plos One 2012;7:e47648
16. Boni C, Laccabue D, Lampertico P, et al. Restored function of HBV-specific T
cells after long term effective therapy with nucleos(t)ide nalogues. Gastroenterology
2012;143:963e73.
17. Fisicaro P, Valdatta C, Massari M, et al. Combined blockade of programmed death-1
and activation of CD137 increase responses of human liver T cells against HBV, but
not HCV. Gastroenterology 2012;143:1576e85
18. Lopes AR, Kellam P, Das A, et al. Bim-mediated deletion of antigen-specific CD8+ T
cells in patients unable to control HBV infection. JCI 2008;118,1835e45
19. Das A, Hoare M, Davies N, et al. Functional skewing of the global CD8 T cell
population in chronic hepatitis B virus infection. J Exp Med 2008;205:2111e24
20. O’Shea JJ, Paul E. Mechanisms underlying lineage commitment and plasticity of helper
CD4+ T cells. Science 2010;327:1098e102.
21. Protzer U, Maini MK, Knolle PA. Living in the liver: hepatic infections. Nat Rev
Immunol 2012;12:201e13
22. Koh S, Shimasaki N, Suwanarusk R, Ho ZZ, Chia A, et al. (2013) A practical approach
to immunotherapy of hepatocellular carcinoma using T cells redirected against hepatitis
B virus. Mol Ther Nucleic Acids 2: e114.
23. Ji C, Sastry KS, Tiefenthaler G, et al. Targeted delivery of interferon-alpha to hepatitis
B virus-infected cells using T-cell receptor-like antibodies. Hepatology 2012; 56: 2027–
2038.
24. Huang LR, Wohlleber D, Reisinger F, et al. Intrahepatic myeloid-cell aggregates enable
local proliferation of CD8(+) T cells and successful immunotherapy against chronic
viral liver infection. Nat Immunol. 2013;14:574-83.
25. Lanford RE, Guerra B, Chavez D, et al. GS-9620, an oral agonist of Toll-like receptor-7,
induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees.
Gastroenterology 2013; 144: 1508–1517
26. Jo J, Tan AT, Ussher JE, Sandalova E, et al. Toll-like receptor 8 agonist and bacteria
trigger potent activation of innate immune cells in human liver. PLoS Pathog. 2014
26;10(6):e1004210.
46
O10
AGE-DEPENDENT IMMUNE EVENTS DURING HBV
INFECTION
Antonio Bertoletti1
1
Duke-Nus Medical School, Singapore, Singapore
Chronic HBV infection progresses through distinct disease phases that are strongly
associated with patient age. The so-called immune tolerant (IT) phase represents the
classical early phase of infection and it is associated with high levels of HBV replication
and lack of clinical signs of liver Inflammation. Whether this HBV infection phase is also
associated with immunological features of “tolerance’ has been recently challenged. Here,
I will review the data that dispute this concept of immune tolerance. I will also show the
results of a recent study of cord blood of neonates born to mothers chronically infected by
HBV that show that HBV exposure in utero appeared to induce a state of trained immunity,
characterized by increased monocyte maturation and enhanced Th1 development. An
alternative interpretation of the immunopathological events that take place during this early
phase of CHB infection will be proposed.
47
O11
NATURAL COURSE OF CHRONIC HEPATITIS B
AND PREDICTORS OF DISEASE PROGRESSION
AND HEPATOCELLULAR CARCINOMA IN WESTERN
COUNTRIES
Giovanna Fattovich1, Elena Raffetti2, Bettina E Hansen3, Francesco Donato2
1
Department of Medicine, University Hospital Verona,Verona, 2Institute of Hygiene, Epidemiology
and Public Health, University of Brescia, Brescia, Italy, 3Gastroenterology and Hepatology,
Erasmus MC University, Medical Center Rotterdam, Rotterdam, Netherlands
The natural course of chronic hepatitis B virus (HBV) infection varies from one individual
to another and from one geographical area to another (1,2). We review the natural history of
chronic hepatitis B (CHB) in Western countries with emphasis on disease progression and
prognostic factors.
Chronic hepatitis B
Vertical HBV transmission is rare and HBV infection is mainly transmitted horizontally
during infancy or childhood. The duration of the early replicative phase (HBeAg positive
CH) is usually short, but can result in disease evolution to cirrhosis. Long term studies
in Caucasian patients with HBeAg positive CH show that most of them become inactive
carriers after spontaneous HBeAg seroconversion, but progression to HBeAg negative CH
may occur (1,3). HBeAg negative CH predominates in European, African and Middle East
countries of the Mediterranean Basin, where genotype D prevails.
Inactive HBsAg carriers
HBeAg negative patients with normal ALT at presentation should be followed closely for
the first year and then they can be classified into inactive carriers (alanine aminotransferase
(ALT) ≤ upper limit of normal (ULN) and serum HBV-DNA persistently ≤ 2000 IU/mL),
low viremic active carriers (ALT ≤ ULN and HBV-DNA 2.000-20.000 IU/mL) and HBeAg
negative CH (ALT > ULN and/or HBV-DNA > 20.000 UI/mL). The natural history of
inactive carriers is benign: reactivation of hepatitis is rare and the risk of developing HCC
and liver-related mortality is negligible in Western countries (1).
48
Spontaneous HBsAg clearance
A constant rate of spontaneous HBsAg loss occurs at a rate of 1-2% per year in Caucasian
carriers (1). A relevant predictor is advanced age at diagnosis. Western studies have indicated
that HBsAg seroclearance is consistently associated with a favourable long term prognosis in
the absence of concurrent hepatitis C virus (HCV) or hepatitis delta virus (HDV) infection,
provided that HBsAg loss occurs before the development of cirrhosis.
Incidence of hepatocellular carcinoma
In an updated systematic review and meta-analysis of the studies performed in Europe
and North America, the summary point estimates of HCC incidence rates were 0.07 per
100 person-years in asymptomatic carries, 0.02 in inactive carriers, 0.2 in subjects with
chronic hepatitis without cirrhosis, and 2.0 in subjects with compensated cirrhosis (Table
1), with 5-year cumulative risks of 0.3%, 0.1%, 1% and 10%, respectively. The summary
incidence rates were lower in Europe and North America than East Asia and Japan for all
clinical categories. In the above mentioned longitudinal study of untreated Italian patients
with CHB without cirrhosis at diagnosis, substantial differences in HCC risk were observed
between subjects who developed and those who did not develop cirrhosis during follow-up,
with an incidence rate of 2.0 and 0.06 per 100 person-years, respectively (4).
Incidence of liver-related death
The inactive carrier has a low risk of liver-related mortality (incidence rate 0.03 per 100
person-years) compared with persons with chronic hepatitis with and without cirrhosis (1).
Survival in these patients is comparable with non infected persons in Western studies. In
patients with compensated cirrhosis B at diagnosis, the summary liver-related death rates
were 3.3 per 100 person-years in Europe, with a 5-year cumulative risk of 15% (1).
49
Incidence rate of disease progression
Incidence of cirrhosis
In some European studies, the incidence of cirrhosis was found to be negligible in inactive
carriers (0.01 per 100 person-years) but substantial in patients with CHB, with values about
2-fold higher in HBeAg negative compared to HBeAg positive CH. In a recently published
cohort study of 105 untreated Italian patients with CHB without cirrhosis at diagnosis,
cirrhosis occurred in 32 patients with an incidence of 1.56 per 100 person-years (21% and
33% at 10 and 25 years of follow-up), with the highest incidence observed in the 48 patients
with HBeAg persistence or detectable serum HBV DNA in HBeAg negative CH (4.49 per
100 person years) (4). A higher incidence of cirrhosis were reported in Western compared
to Eastern studies (1).
In Italian patients with CHB without evidence of cirrhosis at diagnosis life expectancy is
relatively long, but the 25-year cumulative incidence of liver-related mortality was higher in
the subgroup of patients who developed cirrhosis during follow-up compared with patients
without cirrhosis (20% and 2%, respectively, p = 0.0005) (4).
Factors predicting disease progression
Host related factors
Western studies have demonstrated that older age, male gender and disease expression have
an impact on the rate of developing severe liver disease, HCC and liver-related mortality
(1). In Caucasian patients living in the Mediterranean area with CHB and without cirrhosis at
diagnosis, cirrhosis occurrence increased the risk of developing HCC and liver-related mortality
20- and 16-fold respectively, compared with the absence of cirrhosis development (4).
In an updated analysis of 161 untreated European cirrhotic patients (6), only age (hazard
ratio, HR, for every 10 year increase of age: 2.42, 95% CI 1.36-4.29, p=0.003) and platelet
count (HR for <150 vs >=150 per 109/L: 6.27 95%CI 1.42-27.72,p= 0.02) at baseline were
associated independently with HCC. A linear increase of risk with increasing age was found
when also stratifying for platelet count (Figure 1). A risk score combining age and platelet
count assessed the long-term HCC risk with very good performance (C-statistic=0.82, 95%
CI 0.75-0.89) among patients with compensated cirrhosis B (personal communication).
Viral related factors
Viral load and serum HBsAg levels
Among European studies, a prospective cohort study of CHB patients reported that high
levels of HBV replication (HBeAg persistence or HBV-DNA positivity in HBeAg negative
patients) increase the risk of cirrhosis occurrence about 7-fold, compared to inactive
carriers (4). A 25-year longitudinal study of Italian patients with HBeAg positive CHB
at diagnosis showed that the risk for liver-related death was increased 33-fold in patients
who remained HBeAg positive and 38-fold in those with HBeAg negative CH or HBeAg
reversion compared to inactive carriers (3). European patients with compensated cirrhosis
B and serum HBV-DNA detectable (HBeAg positive or negative) are at increased risk of
decompensation and liver related death with respect to HBV-DNA negative patients (1).
HBsAg levels have been demonstrated to be clinically useful to diagnose the clinical phase
of infection with more accuracy (5). European studies, mainly in genotype D patients,
have proposed cut-off levels of HBsAg and HBV-DNA that, when used together, help to
distinguish true inactive carriers from patients with HBeAg negative CHB (5). A large
cohort study of CHB patients from Europe reported an association between lower serum
HBsAg levels and the presence of moderate to severe fibrosis (stages F2-F4) in HBeAg
positive patients, but this association was not observed in HBeAg negative patients (5).
HBV genotypes
The severity of HBV related liver disease has been found to differ by HBV genotype (1,2).
This has been shown with genotypes B and C, and genotype A and D. Genotype B and C
50
are the most prevalent in Asia. Genotype D is widely spread across Southern and Eastern
Europe, Northern Africa, the Middle East, India and the Arctic. Genotype A is found in
Northwest Europe, North America and Southern and East Africa. Genotype D infection is
associated with more active liver disease and advanced liver fibrosis compared with genotype
A infection. In the case of genotype A there are significant differences between subgenotype
A2 that prevails in Europe and North America and subgenotype A1 that predominates
in sub-Saharan and South Africa. Genotype A1 has been associated with very high risk
of HCC in sub-Saharan Africa. The rate of complications, including HCC, for patients
infected with genotype A2 appear to be lower than that found in patients infected with
genotype D, C or F1.
Other factors
Western cohort studies have indicated that concurrent HBV/HDV or HBV/HCV infections
or alcohol abuse increases the risk of cirrhosis and HCC (1).
References
1. Fattovich G , Bortolotti F, Donato F. Natural history of chronic hepatitis B: Special
emphasis on disease progression and prognostic factors. J Hepatol 2008;48:335-352.
2. Hadziyannis SJ. Natural history of chronic hepatitis B in Euro-Mediterranean and
African Countries. J Hepatol 2011;55:183-191.
3. Fattovich G, Olivari N, Pasino M, D'Onofrio M, Martone E, Donato F. Long-term
outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years. Gut.
2008;57:84-90.
4. Ieluzzi D, Covolo L, Donato F, Fattovich G. Progression to cirrhosis, hepatocellular
carcinoma and liver-related mortality in chronic hepatitis B patients in Italy. Dig Liv
Dis 2014; 46: 427-432.
5. Martinot-Peignoux M, Lapalus M, Asselah T, Marcellin P. HBsAg quantification:
useful for monitoring natural history and treatment outcome. Liver Int 2014; 34 (Suppl
1): 97-107.6. Fattovich G, Pantalena M, Zagni I, et al. Effect of hepatitis B and C
virus infections on the natural history of compensated cirrhosis: a cohort study of 297
patients. Am J Gastroenterol 2002; 97:2886-95.
51
In conclusion, several studies indicate that incidence of cirrhosis is higher and HCC risk is
lower in Western countries than in East Asian countries. The discrepancies in the natural
history of chronic HBV infection in the different case-series and geographical areas may be
due to the different distribution of the main factors influencing disease progression, such
as age at infection, age at entry, gender, proportion of HBeAg seropositivity, predominant
HBV genotype, fibrosis stage and environmental factors.
Figure 1:
Hazard ratio of hepatocellular carcinoma according to age (continuous variable) and platelet
values (≤150 or > 150/109/L)
52
O12
NATURAL COURSE AND PREDICTORS OF DISEASE
PROGRESSION AND HCC IN EASTERN COUNTRIES
Yun-Fan Liaw and Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung
University College of Medicine, Taipei, Taiwan
Following HBeAg seroconversion, most patients enter a “residual inactive phase” with
sustained normal serum ALT, HBV-DNA < 2000 IU/ml and HBsAg level < 1000 IU/mL
and minimal risk of disease progression. Those with serum HBsAg level <200 IU/mL plus a
precipitous decline > 0.5 log10 IU/mL per year have a NPV of 100% and 92% and a positive
predictive value of 97% and 100% for HBsAg seroclearance within 1 and 3 years, respectively.
In contrast, active hepatitis may relapse after HBeAg seroconversion in those with a serum
HBV-DNA > 2000 IU/mL, HBsAg level > 1000 IU/mL, males, genotypes C infected and
those with HBeAg seroconverted after age 40.
The frequency of flares, the extent, the severity and the duration of hepatic lobular alterations
are the factors for development of cirrhosis. Age, gender, HBeAg serostatus, serum ALT,
HBV-DNA and HBsAg levels, genotype and basal core promoter mutations are factors for
cirrhosis and HCC development. Based on these factors, normograms have been developed
to predict 3-, 5- and 10- year risk of cirrhosis and HCC.
In conclusion, serum HBeAg status, ALT (hepatitis B flare, AFP level), HBV-DNA and
HBsAg levels are changing during the natural course of chronic HBV infection. Various
combinations of these markers are able to predict HBeAg seroconversion, sustained remission,
HBsAg seroclearance, reactivation and disease progression to cirrhosis or HCC.
53
Chronic hepatitis B virus (HBV) infection is prevalent in Eastern countries, where the infection
is mostly acquired perinatally or in early childhood and has a long “immune tolerant phase”.
“Immune clearance phase” usually starts during adolescent or adulthood, and is associated
with hepatitis activity and alanine aminotransferase (ALT) elevation. The clinical course is
characterized by episodic acute hepatitis B flares with an abrupt rise of serum ALT levels
over 5x upper limit of normal. Hepatitis B flares are considered to be the results of immune
response against HBV, occur more frequently during hepatitis B e antigen (HBeAg) positive
phase than in HBeAg negative reactive phase. Hepatitis B flares with declining serum HBVDNA level usually reflect “effective immune clearance” of HBV and may eventually lead to
HBeAg seroconversion and/or HBV-DNA seroclearance, at a much higher incidence than in
patients without flare. Of the hepatitis B flares with serum alphafetoprotein (AFP) elevation >
100 ng/mL, >80% are associated with bridging hepatic necrosis (BHN). Both AFP and BHN
during hepatitis B flare are predictive for HBV-DNA/HBeAg seroclearance/seroconverison
within one year in up to 60-70% of the patients. In contrast, hepatitis B flares with rising or
stably high HBV-DNA represent “ineffective immune clearance” and may lead to further
heaptocytolysis. Furthermore, hepatitis B flares with increasing serum HBV-DNA over 3x108
IU/mL may develop hepatic decompensation, with a negative predictive value (NPV) of 99%.
O13
HOST GENOMICS AND NATURAL COURSE
OF HBV INFECTION
Jia-Horng Kao1
1
National Taiwan University College of Medicine, Taipei, Taiwan
Chronic hepatitis B virus (HBV) infection is a global health problem, leading to cirrhosis,
hepatocellular carcinoma (HCC) and liver-related deaths. The natural course of chronic
HBV infection is orchestrated by the interaction between the virus, hepatocytes and host
immune responses. A typical course after perinatal infection consists of three chronological
phases: ‘immune tolerant’, ‘immune clearance’ and ‘inactive residual’ phases. A significant
proportion of patients in the inactive residual phase experience HBV reactivation with
hepatitis flare, and therefore enter the fourth ‘reactivation’ phase or a variant form of
‘immune active’ phase. Several host and viral factors including sex, age, ALT level, HBeAg
status, HBV DNA level, HBsAg level, and precore/core promoter mutants have been clearly
shown to affect liver disease progression in HBV carriers. However, little is known about
the impact of host genomics on the natural course of chronic HBV infection. HLA-DPB1
is a member of the major histocompatibility complex (MHC) class II molecules, which are
glycoproteins attached to the cell membrane of predominantly B-lymphocytes, dendritic
cells and macrophages. GWAS studies from Japan and China suggested that variants of
the HLA-DP locus (HLA-DPA1 A allele and HLA-DPB1) protect against progression of
chronic hepatitis B (CHB) and HCC development. Another GWAS study from Taiwan also
indicated HLA-DPB1, HLA-DQA2 and HLADQB2 loci are associated with persistent HBV
infection in males. We recently genotyped 3 candidate SNP identified from previous GWAS
studies, including rs9275319 at HLA-DQ region, rs7574865 at STAT4 and rs17401966 at
KIF1B in 706 HBV-related HCC patients as cases and 805 inactive HBV carriers as controls.
The positive association was further validated in 391 HBV-related cirrhotic patients. We
found that rs9275319 and rs7574865, but not rs17401966, were associated with HCC
development. Using additive model, the minor alleles of rs9275319 and rs7574865 were
associated with lower risks of HCC with odds ratio (95% confidence interval) of 0.56 (0.440.70) and 0.80 (0.68-0.94), respectively. In addition, the minor allele of rs9275319 was also
shown to be associated with lower risks of cirrhosis with odds ratio of 0.54 (95% confidence
interval: 0.40-0.72). Our data suggested the minor allele of rs9275319, which is at HLADQ region, was associated with lower risks of HCC and cirrhosis development in Asian
HBV carriers. Whether these HLA polymorphisms are also protective against chronicity
of acute HBV infection or associated with disease progression in Caucasian HBV patients
awaits further studies. In conclusion, host genomics may have an important influence on
the progression of chronic hepatitis B. However, most of these genetic polymorphisms have
not entered the clinical practice yet but allow a better understanding of the pathophysiology
of chronic HBV infection.
54
O14
THE ROLE OF NON-INVASIVE MARKERS
IN CHRONIC HBV INFECTION
Laurent Castera1
1
Service d’Hépatologie Hôpital Beaujon Assistance Publique-Hôpitaux de Paris, Clichy, France
Liver biopsy, which was traditionally considered to be the gold standard for the staging of
fibrosis, has been challenged in the past decade by non-invasive markers. These methods
rely on two distinct but complementary approaches: a ‘biological’ approach, based on the
quantification of biomarkers of fibrosis in serum, and a ‘physical’ approach, based on the
measurement of liver stiffness using elastography-based technologies. Advantages of serum
biomarkers include their high applicability (> 95%) and good reproducibility. However, as
none are liver specific their results can be influenced by comorbid conditions (risk of false
positive results with FibroTest! in patients with Gilbert’s syndrome or with APRI in case of
acute hepatitis). Transient elastograpy has the advantages of being a user’s friendly procedure
that can be performed at the bedside or in an outpatient clinic with high performance for
detecting cirrhosis. However, its applicability is lower (80%) than that of serum biomarker
(particularly in case of ascites, obesity and limited operator experience) with the risk of false
positive results in case of ALT flares. Although these non-invasive methods were initially
developed and validated in patients with chronic hepatitis C, they are now increasingly used
in patients with hepatitis B, reducing the need for liver biopsy.
55
O15
HCC SURVEILLANCE:
INDICATIONS AND COST/EFFECTIVENESS
Massimo Colombo1
1
Fondazione IRCCS Maggiore Hospital, University Of Milan, Milan, Italy
Surveillance of at risk patients like those with chronic liver disease is an effective strategy to
improve treatment of hepatocellular carcinoma (HCC). Not surprisingly the international
societies EASL, AASLD and APASL released recommendations, with some nuances mainly
in radiological algorithms where global advancements in the contrast imaging techniques
have progressively encouraged non-invasive diagnosis of HCC in avoidance of liver biopsy,
which is now regarded mostly as a means to restore sensitivity. The two Western societies
identify cirrhotics and non cirrhotic patients with chronic hepatitis B as ideal candidates for
screening, AASLD focusing on Asian males older than 40 years of age and Asian females
older than 50 years together with all HBV carriers with a family history of HCC and African/
north American blacks older than 20 years, since these patient categories are at increased
risk of liver cancer as a consequence of early exposure to the hepatitis B virus. EASL suggests
screening for all patients with clinically active hepatitis B as well for those with a family
history of HCC (understudied in the West compared to EASL). While AASLD identifies
patients with NAFLD as an additional target of screening, EASL recommends screening
of chronic hepatitis C patients with bridging fibrosis (Metavir F3), too, given the increased
prevalence of HCC in these patients. However, bridging fibrosis is frequently misdiagnosed
with either a percutaneous liver biopsy or such non invasive approaches, as Fibrotest and
Transient elastography. Abdominal US is the standard of care for surveillance, whereas the
serum alpha-fetoprotein (AFP) assay is no longer considered for screening (and diagnosis)
by the western societies due to its poor accuracy and the lack of a standardized recall policy.
A meta-analysis of studies of surveillance indicated that the semiannual combination of
US+AFP has no added value compared to US alone for the early diagnosis of HCC. This
notwithstanding, the AFP assay still holds a place in the recommendations by APASL, where
high risk patients with chronic viral hepatitis or cirrhosis, will receive the test in combination
with serum des-gamma-carboxy-prothrombin (DCP), an abnormal prothrombin protein
elaborated by the neoplastic liver cells and AFP-L3, a fucosylated variant of AFP that most
hepatologists in the West are reluctant to adopt for both screening and diagnosis of HCC.
All societies share the same recommendation for semiannual surveillance with abdominal
US, as the intervals of screening are not dictated by the level of cancer risk, but rather by
the growth rate of the tumor, which in fact takes 6 months to double its volume, on average.
56
57
The effectiveness of more aggressive screening (every 3 months) is not evidence based.
The 3-month screening leads to higher five-year cumulative incidence of liver nodules
and a greater economic burden to reach a final diagnosis which negatively impacts on
morbidity and cost utility ratio of the strategy of intensified screening. The diagnostic
algorithm of a nodule detected during surveillance is framed by a standardized recall
policy, which in the West varies according to the size of the nodule whereas in the
APASL world depends on the pattern of arterial uptake of the contrast. Owing to the
fact that a less than 10 mm HCC is difficult to diagnose by contrast CT scan or MRI as
a consequence of immature arterialization of the nodule, an enhanced follow-up with US
every 3 months to detect any increase in size or change in echo pattern may guide further
investigations with radiology or echo-guided liver biopsy. Conversely, nodules greater
than 10 mm in diameter, which represent 80% of tumors detected during surveillance,
can be diagnosed by CT or MRI imaging whenever the specific pattern of an intense
contrast uptake during the arterial phase (wash-in) is seen together with a contrast washout during the venous/delayed phase. Contrast-enhanced US is not recommended by
AASLD and EASL to diagnose HCC, because it may fail to distinguish intrahepatic
cholangiocarcinoma from HCC in cirrhosis. This is not the policy of APASL which
suggests US enhanced by hepatospecific contrast to diagnose hypovascular tumors.
While a typical “wash-in + wash-out” pattern suffices to diagnose an HCC >10 mm
using a single imaging technique in a sequential study, a liver biopsy is deemed necessary
to confirm the diagnosis of nodules which do not display these characteristic features at
contrast imaging. It should be borne in mind, however, that non-invasive diagnosis of a
de novo HCC is recommended in cirrhotic patients and patients with chronic hepatitis
B, only. A debate is still ongoing over the level of existing evidence and cost effectiveness
ratio of screening for HCC. In a systematic review of 4 randomized controlled studies
and 16 observational studies aimed to evaluate the effect of screening on mortality, the
overall effect of screening on mortality in patients with chronic liver disease was judged
to be very low. Undoubtedly, screening was able to identify early stage tumor yet the
survival advantage of screening compared with clinical diagnosis in incident cases was
uncertain. In the absence of a specifically designed randomized controlled study, it is
difficult to appreciate the economic consequences of screening for liver cancer, and
therefore this issue has been analyzed through modeling. Analysis of cost efficacy of
screening, indeed, differs in many details that have been included in the model, but all
studies found that some form of screening strategy is cost effective. The incidence of
HCC is a critical factor determining whether screening is cost effective or not, with the
cut off being an incidence of HCC between equal or above 1.5% per year. All societies
acknowledge that surveillance is a cost-effective standard of care for HCC. Future efforts
should be geared toward removing the barriers to universal surveillance of at risk patients
by concentrating on improving access to testing and consequent treatment.
References
1. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology
2011;53:1020-2. Review.
2. Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging
classification. Semin Liver Dis. 1999;19:329-38.10.
3. Omata M, Lesmana LA, Tateishi R, Chen PJ, Lin SM, Yoshida H, et al. Asian Pacific
Association for the Study of the Liver consensus recommendations on hepatocellular
4. Kansagara D, Papak J, Pasha AS, O'Neil M, Freeman M, Relevo R et al. Screening for
Hepatocellular Carcinoma in Chronic Liver Disease: A Systematic Review. Ann Intern
Med. 2014 in press.
58
O16
OCCULT HBV INFECTION: IS THERE ANY CLINICAL
SIGNIFICANCE?
Giovanni Raimondo1
1
Division of Clinical and Molecular Hepatology, University Hospital of Messina, Messina, Italy
The European guidelines on management of chronic HBV infection identify the occult
HBV infection (OBI) as one of the five - not necessarily sequential and stable – phases
in the natural history of chronic hepatitis B [1]. Actually, OBI defines the long-lasting
persistence of HBV genomes in the liver (with detectable or undetectable HBV DNA
in the serum) of individuals testing negative for the HBV surface antigen (HBsAg) [2].
Apart from a minority of cases in which the lack of HBsAg detection is the consequence of
the infection with viral genetic variants (S-escape mutants) producing a modified HBsAg
undetectable by diagnostic kits, in most cases OBI is due to replication-competent viruses
that are strongly suppressed in their replication activity and gene expression [reviewed
in 3]. Although the causes of HBV suppression are not yet well clarified, much evidence
suggests that the host’s immune-surveillance and epigenetic mechanisms are likely involved
[4-8]. The molecular basis of OBI is related to the long-lasting persistence of free viral
genomes - as HBVcccDNAchromatinizedepisomes - in the nuclei of infected hepatocytes.
The stability and long-term persistence of cccDNA molecules together with the long halflife of hepatocytes imply that HBV infection, once it has occurred, may continue for life
even in conditions of strong inhibition of viral functions[9]. Of note, in vitro studies have
demonstrated that the replication, transcription, and protein synthesis capabilities of HBV
isolates from the liver of OBI individuals can be fully restored once the viruses are taken out
of the host’s microenvironment [10]. This observation is of great relevance not only from
the biological point of view but also because it may explain some of the clinical scenarios in
which OBI may be implicated. In fact, it is well known that the occult infection may reactivate
in patients undergoing immune- and/or chemo-therapies (thus, losing the immunological
control of viral replication) with consequent development of hepatitis showing the typical
serological profile of acute hepatitis B (HBsAg (re)-appearance and even HBeAg positivity)
[3]. In analogy, HBV-naive patients undergoing liver transplantation may develop typical
hepatitis B if the donor is OBI positive [3].
59
Finally, OBI is responsible for many of the residual cases of transfusion-transmitted HBV
hepatitis that is a rare event in most developed countries but is still a quite serious problem in
areas where the high HBV endemicity and the elevated costs of NAT diagnostic approaches
hamper a totally efficient check of all transfusion blood units [11-13].
A widely debated aspect of the possible clinical implications of OBI concerns its possible
involvement in the progression toward cirrhosis of patients with chronic hepatitis C or other
known causes of liver disease as well as with cryptogenic chronic hepatitis. Indeed, a metaanalysis has confirmed that OBI is a risk factor for cirrhosis occurrence [14]. Moreover,
a recent long-term observational cohort study has shown that OBI is associated with the
most severe complications of cirrhosis in HCV patients even independently of the HCC
development, and that HCV subjects with OBI have a significantly increased risk of liverrelated death compared to OBI-negative patients [15]. Of note, the histological evaluation of
liver tissues from individuals who have recovered from self-limited acute hepatitis (who may
persistently carry HBV genomes) showed the presence of a mild necroinflammation up to
30 years after the resolution of the acute hepatitis [16,17], in analogy to what was observed
in woodchucks convalescent from acute WHV hepatitis [18]. Another important aspect that
should be mentioned is that the occurrence of ALT flares in patients with chronic hepatitis
C and OBI corresponds to the reappearance of circulating HBV DNA, thus suggesting that
a transient HBV reactivation might be involved in the hepatocyte damage in these patients
[19, 20]. Altogether, these data could suggestthat the long-lasting persistence of the virus in
the liver of OBI patients may provoke a very mild but continuing necroinflammation that –
if other causes of liver damage co-exist - may contribute over time to the progression of the
chronic liver damage toward cirrhosis.
HBV is a well known oncogenic virus and a major causative agent of liver cancer worldwide.
Much evidence indicates that it may maintain its pro-oncogenic capabilities (i.e., HBV
DNA integration into the host’s genome; production of proteins with potential transforming
properties) also in cases of occult infection [21]. OBI appears to exert its pro-oncogenic
role in HCV infected patients as well as in alcoholics and in individuals with cryptogenic
liver disease [22],and a recent meta-analysis confirms that OBI is a risk factor for HCC
development [23].
60
61
References
1. EASL Clinical Practice Guidelines: management of chronic hepatitis B virus infection.
J Hepatol 2012;57:167-185.
2. Raimondo G, Allain JP, Brunetto MR, Buendia MA, Chen DS, Colombo M et al
Statements from the Taormina expert meeting on occult hepatitis B virus infection. J
Hepatol 2008;49:652-657.
3. Raimondo G, Caccamo G, Filomia R, PollicinoT OccultHBV infection.
SeminImmunopathol 2013;35:39-52
4. Zerbini, A., Pilli, M., Boni, C., Fisicaro, P., Penna, A., Di, V. P., Giuberti, T., et al. The
characteristics of the cell-mediated immune response identify different profiles of occult
hepatitis B virus infection. Gastroenterology, 2008;134:1470-1481.
5. Bes, M., Vargas, V., Piron, M., Casamitjana, N., Esteban, J. I., Vilanova, N., et al. T
cell responses and viral variability in blood donation candidates with occult hepatitis B
infection. J Hepatol 2012;56:765-774.
6. Guidotti LG, ChisariFV. Noncytolytic control of viral infections by the innate and
adaptive immune response.Annu Rev Immunol 2001;19:65-91.
7. Levrero, M., Pollicino, T., Petersen, J., Belloni, L., Raimondo, G., & Dandri, M. Control
of cccDNA function in hepatitis B virus infection. J. Hepatol., 2009;51, 581-592.
8. Pollicino T, RaimondoG OccultHBV infection (Snapshot). J Hepatol 2014, in press
9. Zoulim F. New insight on hepatitis B virus persistence from the study of intrahepatic
viral cccDNA. J Hepatol 2005;42:302-8.
10.Pollicino T, Raffa G, Costantino L, Lisa A, Campello C, Squadrito G, et al. Molecular and
functional analysis of occult hepatitis B virus isolates from patients with hepatocellular
carcinoma. Hepatology 2007;45:277-285.
11.Stramer, S. L., Wend, U., Candotti, D., Foster, G. A., Hollinger, F. B., Dodd, R. Y.,
Allain, J. P., & Gerlich, W. Nucleic acid testing to detect HBV infection in blood donors.
N. Engl. J. Med, 2011;364, 236-247.
12.Hollinger, F. B. & Sood, G. . Occult hepatitis B virus infection: a covert operation. J.
Viral Hepat, 2010; 17, 1-15.
13.Allain, J. P. & Cox, L. Challenges in hepatitis B detection among blood donors. Curr.
Opin. Hematol., 2011;18, 461-466.
14.Covolo L, Pollicino T, Raimondo G, Donato F. Occult epatiti B virus and risk for
chronic liver disease: A meta-analysis. Dig Liv Dis 2013;45:238-24
15.Squadrito G, Cacciola I, Alibrandi A, Pollicino T, Raimondo G. Impact of occult epatiti
B virus infection on the outcome of chronic hepatitis C. J Hepatol 2013;59:696-700.
16.Blackberg J, Kidd-Ljunggren K. Occult hepatitis B virus after acute self-limited infection
persisting for 30 years without sequence variation. Journal of hepatology 2000;33:992-7.
17.Yuki N, Nagaoka T, Yamashiro M, Mochizuki K, Kaneko A, Yamamoto K, et al. Longterm histologic and virologic outcomes of acute self-limited hepatitis B. Hepatology
(Baltimore, Md 2003;37:1172-9.
18.Michalak TI, PardoeIU, Coffin CS, Churchill ND, Freake DS, Smith P, et al. Occult
lifelong persistence of infectious hepadnavirus and residual liver inflammation in
woodchucks convalescent from acute viral hepatitis. Hepatology, 1999;29:928-38.
19.Kannangai, R., Vivekanandan, P., Netski, D., Mehta, S., Kirk, G. D., Thomas, D. L.,
& Torbenson, M. Liver enzyme flares and occult hepatitis B in persons with chronic
hepatitis C infection. J. Clin. Virol.,2007;39, 101-105.
20.Chemin, I., Guillaud, O., Queyron, P. C., & Trepo, C. Close monitoring of serum HBV
DNA levels and liver enzymes levels is most useful in the management of patients with
occult HBV infection. J. Hepatol, 2009;.51, 824-825.
21.Pollicino T., Saitta, C., & Raimondo, G. Hepatocellular carcinoma: the point of view of
the hepatitis B virus. Carcinogenesis,2011;32, 1122-1132.
22.Donato F, Gelatti U, LiminaRM, Fattovich G. Southern Europe as an example
of interaction between various environmental factors: a systematic review of the
epidemiologic evidence. Oncogene 2006;25:3756-70.
23.Shi Y, Wu YH, Wu W, Zhang WJ, Yang J, Chen Z. Association between occult hepatitis
B virus infection and the risk of hepatocellular carcinoma: a meta-analysis. Liver Int
2012;32:231-24.
62
O17
SUMMARY OF INTERNATIONAL CPGs OPTIMAL FOLLOWUP OF UNTREATED PATIENTS, TREATMENT INDICATIONS
AND THERAPEUTIC END-POINTS
Spilios George Manolakopoulos1, Hara Kranidioti1
1
2nd Department of Internal Medicine, Athens University Medical School, Athens, Greece
Acute and chronic hepatitis B virus (HBV) related liver disease remains a global and serious
health problem. There are approximately 400 million people with chronic HBV infection
being at risk for cirrhosis, hepatocellular carcinoma (HCC) and death in the near future.
Although HBV was recognized in mid-60’s, it still remains one of the most challenging
issues in hepatology for both basic and clinical research. Nevertheless, a tremendous
progress in our understanding of the pathogenesis and natural history of the disease has been
achieved, while the availability of commercial sensitive and reliable assays for HBV DNA
determination and a number of potent anti viral agents have improved the management of
patients with HBV-related chronic liver disease.
All these guidelines underline that HBV is a complex condition with a dynamic course.
The ultimate goal of therapy is to prevent the progression of liver disease to cirrhosis, liver
failure, HCC and death. This can only be achieved when viral replication is suppressed
at a level associated with biochemical and histological remission. This is a realistic goal
as HBV eradication can be achieved infrequently with the available drugs. Therefore,
all guidelines agree that antiviral treatment should be offered in patients with active or
advanced liver disease, while those patients at immune tolerant or inactive carrier phase
should be under close monitoring. Although International guidelines agree that the decision
to initiate treatment should be based on ALT, serum HBV DNA levels and liver histology,
the proposed cut-off values vary among them.
63
The scientific associations for the study of the liver disease in Europe, Asia-Pacific and
USA (EASL, APASL, AASLD) have developed clinical practice guidelines in order to assist
physicians on the optimal management for patients with HBV infection. EASL and APASL
published the last version of HBV guidelines in 2012 and AASLD in 2009.
For non-cirrhotic patients, AASLD suggests HBV DNA levels of 20,000 IU/mL, while
APASL suggests HBV DNA levels of 20,000 IU/mL for HBeAg positive and 2,000 IU/
mL for HBeAg negative patients. EASL guidelines recommend an HBV DNA threshold
of 2,000 IU/mL for all patients. In addition, EASL guidelines recommend treatment when
ALT levels are just above the upper limit of normal (40 U/L), while APASL and AASLD
recommend treatment when ALT levels are greater than twice the upper limit of normal. In
addition, AASLD guidelines suggest that the upper limit of normal for ALT should better
be 30 and 19 U/L for men and women respectively. The EASL guidelines seem simpler
and combine the need for liver biopsy with the decision for treatment initiation in specific
groups of patients where the biochemistry and HBV DNA could not clarify the decision;
on the other hand, AASLD and APASL societies rely primarily on ALT levels. For patients
with cirrhosis and decompensated liver disease, EASL guidelines recommend treatment
initiation in all patients with detectable HBV DNA even with normal ALT, while AASLD
and APASL guideline recommend treatment in cases with compensated cirrhosis only when
HBV DNA is greater than 2,000 IU/mL. APASL and EASL guidelines mention the role
of non-invasive modalities for liver fibrosis assessment. It is noteworthy, that all guidelines
agree that close monitoring is essential before treatment initiation as HBV infection has
a dynamic course; decision for treatment should also take account age, family history of
HCC, general health status and extrahepatic manifestations.
Regarding the treatment options, all guidelines agree that there are two different strategies:
the finite duration therapy and the long-term treatment with nucleos(t)ides analogues. As
not all agents have been licensed in all countries, there are some differences among the
societies in the list of available agents against HBV, while APASL society clearly mention
the importance of cost-effectiveness of drug therapy for each country as a guide to which
one should be finally chosen. Regarding the first-line treatment options, EASL and AASLD
agree that pegylated interferon, entecavir and tenofovir should be the first option, while
APASL guideline suggests that conventional interferon, pegylated interferon, lamivudine,
adefovir, telbivudine, thymosin-α, entecavir and tenofovir can all be considered for initial
therapy in patients without cirrhosis. All guidelines agree that interferon should not be used
in patients with severe hepatitis flares, decompensation and liver failure.
64
All guidelines agree that treatment with nucleos(t)ides analogues can be stopped 12 months
after HBeAg seroconversion in patients with HBeAg positive chronic hepatitis B. However,
for HBeAg negative patients, EASL and AASLD guidelines suggest that treatment should
be continued until HBsAg clearance, while APASL guidelines suggest that treatment can
be stopped after 2 years of virological remission with undetectable HBV DNA on three
occasions.
Recommendations of the three guidelines vary slightly in the surveillance for HCC,
the monitoring during treatment and the approach of patients with HBV infection and
malignancies who are going to start immunosuppressive therapy.
Although the management of an individual patient should be flexible and cover all his/her
needs and preferences, the guidelines summarize the existing data, improve the knowledge of
the physicians and exercise the clinical judgment. Overall, all clinical practice guidelines are
in the same line, while the slight variation among them could be explained by the differences
in time of development, the evolution of knowledge, the differences in the availability of
drugs among countries and the differences in resources.
65
O20
MECHANISMS OF ACTIONS OF IFNS-NAS
Georgios Germanidis1
1
Aristotle University of Thessaloniki, Thessaloniki, Greece
The goal of therapy for CHB is preventing progression of the disease to cirrhosis,
decompensated cirrhosis, end-stage liver disease, HCC and death. This goal can be achieved
if HBV replication can be suppressed in a sustained manner. Then, the accompanying
reduction in histological activity of CHB lessens the risk of cirrhosis and decreases the risk
of HCC, particularly in non-cirrhotic patients. However, chronic HBV infection cannot be
completely eradicated due to the persistence of covalently closed circular DNA (cccDNA)
in the nucleus of infected hepatocytes. Recently, cccDNA as a reservoir for HBV infection
serves as a central target in the development of novel antiviral strategies towards a “cure” of
the infection. Moreover, the HBV genome integrates into the host genome and might favour
oncogenesis and the development of HCC.
Two different types of drugs are currently used in the treatment of CHB: pegylated interferon
alpha (PEG-IFNα) and nucleoside/nucleotide analogues referred to collectively as NAs.
NAs efficiently block the HBV replication pathway by acting as inhibitors of the viral
polymerase , but they do not target cccDNA transcription, having only modest effects on the
production of circulating viral antigens (HBsAg, HBeAg). As a consequence, monotherapy
with NAs can be a life commitment, during which immunological control is rarely achieved.
At present, the two first line NAs are entecavir (ETV) and tenofovir (TDF). Recently ,
characterization of the structure of the HBV RNase H by computing a 3-dimensional
molecular model, paves the way for functional and structural studies for the development
of new inhibitors of HBV replication specifically targeting RNase H activity, which is an
essential enzyme to the HBV life cycle. It is intriguing to note that HBV-specific CD8+
T-cell functions could be restored, at least in part, after long-term treatment with NAs. It
is reported that HBV-specific T cells isolated from NAs-treated patients that had achieved
complete control of infection displayed efficient responses after in vitro expansion.
Virus-specific CD8+ T cells isolated from the peripheral blood of chronically HBV-infected
patients are functionally impaired and seem to have lost most of their ability to proliferate
and to produce cytokines, like IFN-γ. The reported CD8+T cell failure has been attributed
to high levels of persisting viral antigens.
66
The other option, Pegylated IFN-α (PegIFNα) has been shown to have both immunemodulatory and direct antiviral effects. Reduction of serum HBsAg is more marked in patients
treated with PegIFNα. Since HBsAg loss and seroconversion represent the closest outcome
to clinical cure, IFN-α treatment remains a valuable anti-HBV therapeutic approach.
Yet, only a minority of HBV patients responds to IFNα therapy and the mechanisms that
drive viral antigen decline and sustained virological responses in IFN-α-treated patients
are not entirely understood. IFN-α has been shown to induce a complex network of
intracellular signaling on the infected hepatocytes. While studies in HBV-transgenic mice
have reported its capacity to accelerate pgRNA degradation and core particle decay , recent
studiesperformed in vitro and in HBV-infected humanized mice showed that IFN-α can
reduce the levels of both pregenomic and subgenomic HBV-RNAs by inducing epigenetic
modifications of the histones bound to the cccDNA minichromosome.
67
Soluble HBV surface antigen (HBsAg) along with HBeAg may drive chronic T cell
stimulation and tolerance. Particularly, the latter has been implicated in altering the
reactivity of virus-specificCD8+ T cells. Moreover, accessory HBsAg seroconversion has
been reported to induce a more potent restoration of CD8+ T cell responses than HBV
viral load reduction alone. Highly viremic HBV-infected patients show a more severely
impaired CD8+ T cell phenotype and T cell dysfunction is more profound in the liver
than in the blood. CD8+ T cell dysfunction in chronic HBV infection follows a wellestablished pattern with elevated expression of inhibitory molecules such as programmed
death-1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), Tim-3, and 2B4 (CD244)
on T cells. Blockade of these inhibitory pathways may at least partially restore HBVspecificCD8+ T cell functionality, as it has been shown in vitro. A recent study could show
that in vivo blockade of the PD-1/PD-L1 pathway, together with entecavir treatment and
DNA vaccination, enhances virus-specific CD8+ T cell responses in the woodchuck model,
leading to sustained immunological control of viral infection. Increased regulatory T cell
numbers , together with immune-suppressive cytokines such as IL-10 and TGF-β impair
virus-specific CD8+ T cell responses. Collectively, several mechanisms may contribute to
the diminished frequency and function of virus- specificCD8+ T cells in CHB and that
combined modulation of different pathways may lead to a restoration of HBV-specific T cell
responses and permanent immunological control of infection. Recently, a DNA multivalent
synthetic plasmid vaccine expressing genotype A and C HBV surface and consensus core
antigens, was found to generate robust cytotoxic and antibody responses across multiple
antigenic epitopes in mice and Rhesus macaques.
Silencing of the cccDNA can be achieved through IFN-α or epigenetic manipulations.
Destruction or degradation of cccDNA can be achieved by IFN-α ,TNFα, or lymphotoxins/
LTβR agonists through APOBEC3A/B via cytidine deamination that results in extensive
nucleotide changes [guanine (G) to adenine (A)] in cccDNA. Thus, it is conceivable that
IFN-α directly contributes to the decline of viral antigen amounts (HBeAg, HBsAg) by
targeting cccDNA transcription and degradation.
On the other hand, the effectiveness of the immune status is known to be essential to achieve
control of HBV infection and treatment outcome may be mostly triggered by the immune
modulatory effects of PegIFNα on the innate and adaptive immune responses. Treatment
with PegIFNα leads to a significant induction of the cytokine IL-15 and an expansion of
natural killer (CD56bright NK) cells that correlated with the peak of virological responses,
suggesting a direct involvement of NK cells to the IFN-α-mediated antiviral effects. The
receptor involved in the regulation of apoptosis/ necrosis, TRAIL, may play an important
role in this setting, since patients with a strong increase in NK cell TRAIL expression
showed significantly greater reductions in viral load and a trend to greater reductions
in HBsAg compared to patients without an increase in TRAIL expression, suggesting a
dominance of cytolytic TRAIL mediated effector functions. Treatment with PegIFNα also
led to an increased IFN-γ production of NK cells and an increase in the expression of the
activatory receptor NKp46. In contrast to the significant PegIFNα mediated functional
augmentation of NK cells, quite different effects were observed on T cells. Indeed, PegIFNα
therapy led to a striking reduction of CD8+ T cells, an effect that was most pronounced on
predominantly end-stage effector cells. Even more importantly, HBV-specific CD8+ T cells
remained at low frequency and no restoration of their effector functions was observed. Most
likely, IFN-a suppresses T cell responses by its strong antiproliferative effect. However, it
is also possible that indirect effects, such an NK cell mediated inhibition of T cells, may
contribute to the IFN mediated inhibition of T-cell responses. Indeed, elevated expression
of TRAIL receptor2 (TRAIL-R2) renders HBV-specific CD8+ T cells more susceptible to
apoptosis by TRAIL-expressing NK cells. In contrast, therapy with NAs was not shown to
lead to a functional recovery of NK cells. Finally, immunotherapeutic approaches might be
able to restore the innate and/or adaptive immunity to HBV infection. Indeed, a toll-like
receptor (TLR) 7 agonist has been shown to significantly reduce viral loads in HBV infected
chimpanzees.
In conclusion, PegIFNα and NAs have differential effects on the innate and adaptive
immune responses, and, both drugs have shown some capabilities to restore impaired
immune functions in chronic HBV infection.
68
These results may have important clinical implications since they provide the rationale for
a re-evaluation of combination therapy with PegIFNα and NAs in CHB. Indeed, it should
be the goal of combination therapy to restore both arms of the immune system, together
with HBV DNA and a more rapid HBsAg decline, to improve the possibility of complete
virus control.
One of the major unmet challenges in the field of viral hepatitis that have been identified
during the EASL Monothematic Conference on Translational Research in Viral Hepatitis, is
to improve the impact of NAs and Peg-IFNα therapies. Still, the reason for the disappointing
response to IFN-α–based HBV therapy remains unclear. The high concentrations of IFN-α
used in experimental conditions to achieve maximal cccDNA degradation might suggest
that clinically acceptable concentrations are not sufficient. Alternatively, the finding that the
expression of APOBEC3A is only transient after IFN-α treatment in patients underscores the
fact that hepatocytes rapidly become refractory to the cytokine. In experimental conditions
also it was shown that addition of potent NAs that suppress viral replication enhance the
effect of IFN-α on cccDNA. However, this does not agree with the disappointing, albeit
limited, clinical trial results obtained thus far. It may be that preexisting cccDNA is more
resistant to that action of APOBEC compared to cccDNA that is newly generated by
reverse transcription. Alternatively, the extent of deamination in response to IFN-α may be
insufficient to irreversibly damage every molecule of cccDNA. However, combining newer
analogs with IFNs that do not elicit a refractory state, or with LTβR agonists, may be worth
testing in the future.
Further defining the precise mechanisms of the anti-HBV effect of IFN-α and other
cytokines on cccDNA degradation may open up potential new avenues for more effective
HBV elimination.
69
Hypothetically, a late add-on therapy of PegIFNα to an ongoing NA administration might
be most beneficial. According to this scenario, NA therapy would first lead to strong
suppression of viremia, thereby inducing restoration of HBV-specific CD8+ T cells and,
subsequently, PegIFNα will be added to accelerate the decline of circulating and intrahepatic
viral antigens and to allow expansion of NK cells and enhancement of TRAIL-mediated
cytotoxic effector functions against the infected hepatocytes. Compensatory hepatocyte
proliferation, in turn, may increase the fraction of cccDNA-free hepatocytes and promote
cccDNA destabilization.In a pilot recent small study with monotherapy and combination
arms, PegIFNα-induced innate immune activation and subsequent refractory effect, directly
benefits from the suppression of HBV replication with concomitant NA treatment.
O22
TREATMENT OF HBEAG POSITIVE HEPATITIS B WITH
PEGYLATED INTERFERON: CLINICAL SIGNIFICANCE OF
HBVDNA AND HBSAG QUANTITATIVE TESTING
Harry Janssen1
1
University of Toronto, Toronto, Canada
•
•
•
•
•
•
•
•
70
Monitoring HBVDNA in combination with quantitative HBsAg will likely help us to
decide when an HBV patient is in remission of disease. Both markers have also been
associated with the likelihood of developing hepatocellular carcinoma.
In HBeAg positive patients pegylated interferon therapy can be given in treatment
naïve patients to achieve sustained off-treatment immune control with finite treatment.
Sustained immune control is a key step towards HBsAg clearance. Approximately 30% of
the patients will respond to therapy. Baseline viral genotype, the presence for pre-core and
core promotor mutations, viral load and ALT values determine the likelihood of response.
Pegylated interferon could also be given as an add-on strategy in order to achieve
HBeAg- and/or HBsAg seroconversion after long-term therapy with nucleoside analogs.
Studies are ongoing to investigate both this treatment concept.
Monitoring response early during pegylated interferon therapy potentially allows early
differentiation between responders and non-responders, and raises the possibility of
individualized, response-guided therapy in CHB.
Early favorable results demonstrating on-treatment decline in HBsAg could motivate
patients to continue therapy with PEG-IFN and achieve sustained immune control.
Early indications of failing therapy could allow alterations to treatment regimen.
In HBeAg-positive disease, HBsAg decline and actual HBsAg values at week 12 and 24
help as a guide to management decisions.
Given the valuable information it provides, HBsAg monitoring is, in combination with
HBVDNA measurement, likely to play a role in future studies undertaken to improve
the management of CHB and in developing a response-guided therapy approach for
individual patients.
Since pegylated interferon and nucleoside analogs are both potent in targeting HBV, but
with different modes of action, different strategies of combination therapy have been
investigated. Although it does not seem beneficial to simultaneously start pegylated
interferon and nucleoside analogs, observations of the effects of HBV on the immune
system have led to new hypotheses for other combination regimens.
O23
OPTIMAL USE OF PEG-INTERFERON FOR HBEAG
NEGATIVE CHRONIC HEPATITIS B
Maurizia Rossana Brunetto1, Ferruccio Bonino2
1
Liver Unit, Reference Centre for Chronic Liver Disease and Hepatocellular Carcinoma of
the Tuscany Region, 21General Medicine 2- Liver and Digestive Disease Unit, Clinical and
Experimental Medicine Department, University Hospital of Pisa, Pisa, Italy
HBeAg-negative chronic hepatitis B (HBeAg-neg-CHB) represents the most prevalent
form of CHB worldwide, because of changing HBV epidemiology and aging of HBVinfected population [1]. HBeAg-neg-CHB results from the inability of the host's immunesystem to effectively control viral replication, whose persistence is favored by the selection
of viral variants (HBeAg-defective HBVs) that escape the immune-system more efficiently
than wild-type-HBV [2-3]. Spontaneous resolution of HBeAg-neg-CHB is uncommon and
liver damage persists progressing slowly towards cirrhosis and its complications in spite of
temporary remissions of viral replication and biochemical disease activity, that characterize
the disease profile of a significant proportion of patients [1,4]. As a consequence, the
differential diagnosis between HBeAg-neg-CHB from Inactive-Carriership (IC) is not
always straightforward and requires a stringent, prolonged monitoring of serum HBV-DNA
and ALT. Recently, the evidence that serum HBsAg levels decline significantly with the
achievement of an effective immune-control, contributed, to simplify the identification of
IC (at least in genotype B, C and D infections) combining quantification of both serum
HBsAg and HBV-DNA [5-6].
Antiviral treatment is mandatory for the management of HBeAg-neg-CHB in the attempt
to halt a disease otherwise progressive and both Interferon-α(IFN) and nucleos(t)ide
analogues (NA) appear to improve the outcome of CHB [1]. The treatment is much more
cost-effective when therapy is started earlier during the pre-cirrhotic phase and induces the
off-therapy control of the infection [7]. On the contrary, in presence of cirrhosis the cure of
CHB reduces the mortality rate, but does not eliminate the HCC risk [1]. Both currently
available therapeutic approaches inhibit viral replication in the majority of treated patients,
but IFN only appears able to switch CHB into inactive or even occult HBV-infection with
a time limited treatment course. Unluckily, only 20-30% of IFN treated patients will have a
transition to IC and about 12% will clear serum HBsAg [8].
71
The reasons why IFN is fully effective only in about 1/3-1/4 of treated patients are not
known: a better understanding of the complex interplay between the different activities
of IFN and virus and host's heterogeneity would warrant the amelioration of current
therapeutic strategies and new therapeutic approaches. Nevertheless, already to-day, the
careful reading of the results of clinical trials and the study of on treatment dynamics of
HBV-infection by the combined quantitative monitoring of serum HBV-DNA and HBsAg
warrant a better cost-effective treatment tailoring at the single patient level.
At the end of '80, standard IFN was the 1st treatment option for CHB and 5–10 MU everyother-day for 16-24 weeks induced a progressive decline of serum HBV-DNA and ALT in
about 70% of treated patients [9]. The extremely high relapse rates (70-90%) prompted
longer treatment courses (12-24 months), that were associated with higher sustained
response rate (22-30% vs 10-15%) [9]. Interestingly among patients with sustained
response, independently of treatment duration, the IFN-induced HBsAg clearance 4-7 years
post-treatment ranged from 31.6 to 66.6% [9-11], a much higher rate than spontaneous
HBsAg loss in IC. Early in this century, standard IFN has been substituted by pegylated
formulations, where the conjugation of IFN with polyethylene glycole (Peg) molecules
prolongs the half-life of IFN and warrants the once weekly administration. In the Phase
III trial up to 80% of HBeAg neg patients achieved HBV-DNA <2000 IU/ml after 48
weeks of Peg-IFN, but only 25% maintained the virologic response at 5 years and 12%
cleared HBsAg [8]. The rates of HBsAg loss after Peg-IFN are significantly higher than in
virologic responders to NA, which maintain a pharmacologically induced IC status, that is
rapidly lost once NA are withdrawn[1]. On the contrary, the evidence that HBsAg loss and
anti-HBs seroconversion can be reached progressively during the post-treatment follow-up
provides a strong evidence of the ability of IFN to induce high levels of immune control and
the curative switch from active CHB into the inactive infection.
However, in spite of an ideal clinical outcome, responders to Peg-IFN are a minority among
treated patients, thus there is a compelling need for treatment optimization by a response
guided treatment and by identifying new options where both Peg-IFN and NA are used in
combination or sequential schedules.
Viral load had been for years the only available diagnostic tool to monitor the efficacy of
IFN, only recently, the evidence that the extent of HBsAg decline from baseline to the end
of treatment correlated with HBsAg loss 3 years post-treatment, proposed the on-treatment
serum HBsAg kinetics as an additional viral tool useful for response guided therapy [12].
The available data suggest that HBsAg serum levels are produced by transcription of specific
viral mRNAs and mirror the complex equilibrium between virus and immune system rather
than viral replication. Overall, in HBeAg neg carriers HBsAg serum levels appear to be the
indirect expression of transcriptionally active cccDNA [13]. Accordingly, serum HBsAg
kinetics were shown to well correlate with both direct or immune mediated antiviral activity
of IFN and the HBsAg serum levels decline after 48 weeks of treatment was significantly
72
Studies aimed to optimize the combined use of Peg-IFN and NA were discouraged by the
results of Phase III trial, where Peg-IFN and Lamivudine did not show sustained response
rates higher than monotherapy [17]. Actually, a sub-analysis showed an interaction between
genotype and the type of treatment, with higher response rate in genotype D patients treated
with the combination as compared to monotherapy, whereas the opposite was true for
genotype B [18]. In light of these observations combined or sequential Peg-IFN and NA
therapy needs to be revisited to capitalize much better the higher antiviral potency of new
generation NA and eventually shortening their treatment duration.
In conclusion, the integrated use of molecular and immunometric diagnostic tools warrant
a personalized use of Peg-IFN, maximizing its benefits in responder patients, avoiding
ineffective treatments for patients who are IFN-non sensitive and, possibly, accelerating
the serum HBsAg decline in subgroups of responder to NA reducing treatment duration.
73
higher in patients who achieved a sustained viral response as compared to non-responders.
In addition EOT HBsAg levels £10 IU/mL were associated with 52% probability of HBsAg
clearance after 3 years of post-treatment follow-up, compared to only 2% in patients with
higher HBsAg levels [12]. The predictive value of EOT HBsAg levels was better than
that of HBV-DNA since HBsAg clearance was achieved only in 15% of the patients with
undetectable HBV-DNA at EOT. However, HBV genotypes influence HBsAg serum levels
both prior to and during Peg-IFN and the on-treatment timeframe where the HBsAg
decline is more likely to be significantly predictive of long-term response differs among viral
genotypes [14]. Consequently, HBsAg genotype-specific algorithms are required to warrant
a response-guided therapy. In addition, as in the differential diagnosis between active and
inactive HBV infection, the combined use of both HBV-DNA and HBsAg improved the
prediction: the absence of any HBsAg decline together with <2 log IU/ml reduction of
HBV-DNA after 12 week of Peg-IFN identifies non responders with high accuracy (95 to
100% negative predictive value) [15]. Thus, at present, quantitative HBsAg and HBV-DNA
monitoring warrants the early identification of non-responders to IFN [16]; whereas EOT
serum-HBsAg may identify patients with high chance of HBsAg-clearance or sustainedvirologic-response [12, 14]. Overall, the characterization of the on treatment serum HBsAg
kinetics allows different treatment strategies with improved cost-efficacy, where patients can
benefit from the earlier shift to NA in case of non-response or prolonged Peg-IFN-therapy
in case of slow HBsAg decline. Finally, HBsAg monitoring could help to identify NA treated
patient in whom adding on or shifting to Peg-IFN could warrant the sustained control of
HBV with an earlier HBsAg to anti-HBs serconversion [16].
References
1. EASL Clinical Practice Guidelines: management of CHB. JHep 2012 vol. 57:167–185
2. Brunetto MR, Stemler M, Schodel F et al Identification of HBV variants which cannot
produce precore derived HBeAg and may be responsible for severe hepatitis. Ital J Gastr
1989;21:151-154
3. Brunetto MR, Giarin E, Saracco G et al HBV unable to secrete HBeAg and response to
interferon. Gastroent. 1993;105:645-650
4. Brunetto MR, Oliveri F, Coco B, et al. Outcome of anti-HBe positive CHB in alphaIFN treated and untreated patients: a long term cohort study. J Hep 2002; 36: 263-270.
5. Brunetto MR, Oliveri F, Colombatto P, et al..HBsAg serum levels help to distinguish
active from inactive hepatitis B virus genotype D carriers. Gastroent. 2010;139(2):48390.
6. Tseng T,Liu C Yang H et al Serum HBsAg levels help predict disease progression in
patients with low HBV loads. Hepatology 2013; 57(3):441-50
7. Iannazzo S, Coco B, Brunetto MR et al. Individualized treatment of HBeAg-neg CHB
using Peg-IFN as first-line and week-12 HBV DNA/HBsAg stopping rule: a costeffectiveness analysis. Antivir Ther. 2013;18(4):623-33.
8. Marcellin P, Bonino F, Yurdaydin C et al. HBsAg levels: association with 5-year
response to Peg-IFN-2a in hepatitis B e-antigen-negative patients. Hepatol Int. 2013
Mar;7(1):88-97
9. Brunetto MR, Oliveri F, Colombatto P et al. Treatment of HBeAg-neg CHB with
interferon or Peg-IFN. J Hep. 2003;39 Suppl 1:S164-7.
10.Manesis EK, Hadziyannis SJ. Interferon alpha treatment and retreatment of HBeAg.neg
CHB . Gastroent. 2001; 121: 101-109.
11.Lampertico P, Del Ninno E, Vigano M, et al. Long-term suppression of HBeAg-neg
CHB by 24-month interferon therapy. Hepatology. 2003 Apr;37(4):756-63.
12.Brunetto MR, Moriconi F, Bonino F, et al. HBsAg levels: a guide to sustained response
to Peg-IFN-2a in HBeAg-neg CHB . Hepatology 2009;49:1141-50.
13.Brunetto MR A new role for an old marker J. Hep. 201o; 52 (4): 475-477
14.Brunetto MR, Marcellin P, Cherubini B et al. Response to Peg-IFN alfa-2a (40KD)
in HBeAg-negative CHB: On-treatment kinetics of HBsAg serum levels vary by HBV
genotype. J Hep. 2013 Dec;59(6):1153-9.
15.Rijckborst V, Hansen BE, Ferenci P et al. Validation of a stopping rule at week 12 using
HBsAg and HBV DNA for HBeAg-negative patients treated with Peg-IFN-2a. J Hep.
2012 May;56(5):1006-11.
16.Ouzan D, Penaranda G, Joly H et al.. Add-on Peg-IFN leads to loss of HBsAg in patients
with HBeAg-neg CHB and HBV DNA fully suppressed by long-term NA. J Clin Virol.
2013 Dec;58(4):713-7.
17.Marcellin P, Lau GK, Bonino F et al. Peg-IFN alfa 2a alone, Lamivudine alone and the
2 in combination in patients with HBeAg neg CHB. NEJM 2004; 351:1206-17.
18.Bonino F, Marcellin P, Lau GK et al Predicting response to Peg-IFN-2a, lamivudine
and the two combined for HBeAg-neg CHB. Gut. 2007 May;56(5):699-705.
74
O24
NUCLEOS(T)IDE ANALOGUES AS FIRST LINE THERAPY
Seng Gee Lim1
1
National University Health System, Singapore, Singapore
All major guidelines recommend either nucleos(t)ide analogues (NAs) or immunomodulators
as first line therapy for chronic hepatitis B (CHB). Initially, one year therapy was shown to
be efficacious with regards to improvements in serology, biochemistry and histology, but
the early NAs were found to rapidly lead to resistance due to their low genetic barrier.
Management of drug resistance was a major issue until the arrival of the high genetic barrier
drugs, entecavir and tenofovir. Concerns about development of multi-resistant HBV have
subsided somewhat with no evidence of resistance to tenofovir after 6 years of therapy is truly
remarkable. A number of studies have now examined the long-term benefits of NA therapy.
Consistently, these studies have shown accrual of benefits over time with progressive HBeAg
seroconversion, maintained ALT normalisation and sustained viral suppression. Moreover,
stronger evidence is now emerging of regression of cirrhosis and fibrosis. NA as first line
therapy covers the full spectrum of manifestations of CHB, from flares to cirrhosis and acute
on chronic liver failure. In all these settings, NAs have shown genuine benefits in terms of
survival and endpoints. However, NA therapy has not shown a substantial improvement
in HBsAg seroclearance despite many years of continuous therapy, and the benefits with
regards to reduction in HCC is not based on strong evidence. Consequently, patients who
start on CHB therapy are likely to be stuck on long-term therapy for the foreseeable future.
One major problem is compliance over the long-term, which can lead to reactivation, flares
and even liver failure and death. This is particularly true for HBeAg negative CHB, as
stopping rules for HBeAg seroconverters is well established, but over the long term can
lead to increasing frequency of HBeAg negative CHB. An important question is whether
there are differences in efficacy between the different NAs? A recent meta-analysis of RCTs
showed that telbivudine was able to lead to almost twice as many seroconversions compared
to entecavir, a rather novel finding, but differences in NAs are mainly related to safety.
Overall safety has been excellent but nucleotide analogues are known for problems with
nephrotoxicity although this seems to be quite low with tenofovir.
In conclusion, NAs are now a mainstay of therapy, with well established efficacy and safety
profiles. They can be used to treat a full spectrum of CHB cases. As we move towards a
higher objective of HBV eradication, it does appear that such an objective is beyond what
current NAs are able to achieve. Whether combination therapy can go some way towards
achieving this objective remains to be seen.
75
O25
MANAGEMENT OF NUCLEOS(T)IDE ANALOGUE
FAILURES
Fabien Zoulim1
1
Unit 1052, INSERM, Lyon, France
The management of NAs failure has been improved dramatically with the development
of antivirals exhibiting a high barrier to resistance and a good cross-resistance profile. The
development of drug resistance begins with mutations in the polymerase gene, followed by
an increase in viral load, an increase in serum ALT levels several weeks to months later, and
progression of liver disease. Typically, the development of NA resistance depends on the
following factors:
1.
2.
3.
4.
5.
6.
7.
8.
Rate of virus replication;
Complexity and diversity of the viral quasi-species;
Selective pressure exerted by the NA (potency);
Viral replication space in the liver;
Replication fitness of the emerging NA resistant HBV;
Genetic barrier to resistance of the NA;
Previous treatment history and archiving of drug resistant strains;
Treatment observance/compliance.
All patients receiving NA therapy for CHB should be closely monitored for virologic response
and breakthrough during treatment. In a compliant patient, it is important to distinguish
between primary nonresponse, partial virologic response, and virologic breakthrough, as
it has implications for treatment adaptation .Good adherence to anti-HBV therapies is
important for maintaining maximal suppression of HBV replication. Treatment adaptation
should be made according to cross-resistance. The initial drug choice and subsequent rescue
therapies should be based on the knowledge of cross-resistance, so that the second agent has
a different resistance profile to the initial failing agent. This is particularly important since
drug resistant mutants that have been selected by previous treatments are archived in viral
cccDNA reservoirs in the liver. The add-on strategy with NAs having complementary crossresistance profiles is mandatory when using drugs with a low barrier to resistance. In case of
viral breakthrough associated with drug resistance, an appropriate rescue therapy should be
initiated as soon as possible. Some mutants are associated with slow decline of viral load and
may require an add-on strategy. Furthermore, the switch strategy does not apply to patients
who have been exposed to multiple alternating mono-therapies; these patients should be
enrolled in add-on strategies in order to minimize the risk of subsequent treatment failure,
especially in the presence of underlying cirrhosis.
Following these recommendations allows to maximize treatment efficacy and achieve viral
suppression, even in patients who failed a previous line of antiviral therapy.
76
O26
SAFETY AND MONITORING DURING LONG-TERM NAS
THERAPY
Maria Buti1
1
Liver Unit, Hospital Universitario Valle Hebron, Barcelona, Spain
Nucleos(t)ides analogs (NAs) have become the mainstay of CHB treatment because they can
be administered orally and have potent antiviral activity and very few side effects. However,
the majority of patients with chronic hepatitis B infection need prolonged treatment
with NAs until disease remission and serological endpoints have been achieved (1-2).
Among the five approved NAs, lamivudine, adefovir, telbivudine, entecavir and
tenofovir, only two are currently recommended by guidelines, entecavir and tenofovir
due to the high potency and minimal risk of resistance. All of them are generally safe
and well-tolerated (1-3). NAs are eliminated by the kidneys and dose adjustments
are needed in patients with impaired renal function. Renal impairment is common in
patients with decompensated cirrhosis and in liver transplant recipients. Therefore,
renal safety is an important factor in deciding which NAs is most appropriate for
patients with hepatitis B, particularly those who have other risk factors for renal impair.
A major drawback with earlier NAs was the high rate of antiviral drug resistance; however,
entecavir and tenofovir have high barriers to resistance, with rates of antiviral drug resistance
reported to be 1.2% and 0% after 5 and 7 years of treatment, respectively, in phase 3 trials of
NAs-naive patients (4-7). The risk of entecavir resistance is much higher, 51% after 5 years
of treatment, in patients with lamivudine-resistant HBV (8). Continued treatment with
entecavir or tenofovir for up to 5 and 7 years respectively resulted in undetectable serum
HBV DNA levels in more than 95% of patients, HBeAg seroconversion in 40% to 41% of
HBeAg-positive patients, and HBsAg loss in 3% to 10%. Long-term viral suppression has
been shown to reverse fibrosis and cirrhosis (6).
Side Effect Monitoring
Several of the NAs drugs can also cause side effects that require monitoring. Data of
adefovir-associated nephrotoxicity exist, but they have predominantly involved patients in
earlier trials who received a higher daily adefovir dose (30 mg) than the currently used
daily dose (10 mg) (9). Tenofovir can also cause nephrotoxicity, but the reports have mainly
involved the use of tenofovir to treat HIV infection. Among HIV-infected patients on
tenofovir, approximately 1% will develop renal insufficiency, including some with Fanconi's
syndrome (10).
77
Toxicity can manifest as weakness, glycosuria, proteinuria, hypophosphatemia, and elevated
creatinine. In a large clinical trial involving patients with chronic HBV monoinfection,
none of the 426 patients treated with tenofovir developed renal insufficiency (11). Of
these, nephrotoxicity associated with adefovir or tenofovir has received the most attention.
Nephrotoxicity manifesting as decrease in glomerular filtration rate (GFR) is more
common in patients who are >50 years old, have baseline renal insufficiency, hypertension
and/or diabetes mellitus.7 Proximal renal tubular injury-resembling Fanconi syndrome
with hypophosphatemia, hypouricemia, aminoaciduria, and glycosuria-had also been
reported in patients coinfected by HBV and HIV (12). In most instances, nephrotoxicity is
reversible after dose reduction or discontinuation of treatment. The postulated mechanisms
of nephrotoxicity associated with adefovir and tenofovir treatment include increased
intracellular influx through organic anion transporters and/or a defect in its luminal
excretion through multidrug-resistance-associated proteins, or mitochondrial toxicity in the
proximal tubular cells of the kidney. Lamivudine and entecavir have not been reported to be
associated with nephrotoxicity but need to be adjusted to renal function. Nevertheless, since
patients receiving adefovir or tenofovir can potentially develop renal insufficiency, monitoring
of creatinine every 3 months is warranted for patients on chronic adefovir or tenofovir
therapy (1-2). Telbivudine has been associated with peripheral neuropathy, particularly
when given with peginterferon (13), and myositis. Therefore, patients on telbivudine should
be asked for signs and symptoms of neuropathy and have a creatine kinase level drawn
every 3 to 6 months. In a recent study, an improvement in eGFR was observed in chronic
hepatitis B patients treated with telbivudine. The improvement in eGFR was maintained
during continuous treatment of telbivudine for up to 6 years and was observed in various
subpopulations (14). However, improvement in renal function has not been systematically
examined in patients receiving other HBV NAs. Reports of some telbivudine trials provided
data on improvement in eGFR but did not specify whether any patient had deterioration in
renal function. The key question is whether improvement in renal function outweighs the
risk of antiviral drug resistance and other adverse effects of telbivudine to justify its use as a
first-line antiviral agent for hepatitis B. Despite its potent antiviral activity, telbivudine has a
low barrier to antiviral drug resistance and shares similar resistance mutations as lamivudine.
A phase III clinical trial of telbivudine found that viral resistance was observed in 25.1% and
39.5% of HBeAg-positive patients and in 10.8% and 25.9% of HBeAg-negative patients after
2 years of telbivudine and lamivudine, respectively (12).
By contrast, phase III trials of entecavir and tenofovir in nucleoside-naive patients showed
genotypic resistance rates at 5 years of 1.2% and 0%, respectively (1-2). The mechanism
responsible for the improvement of renal function during long-term telbivudine therapy is
still under investigation.
Patients receiving NAs should have their renal function checked initially to ensure
appropriate dosing. Patients receiving NAs require more frequent clinical and laboratory
monitoring during the first year.
78
Monitoring Treatment
All patients starting on hepatitis B therapy should have monitoring for medication-related
side effects and for response to therapy. The exact monitoring and duration of treatment
differ based on the patient's baseline HBeAg status and whether the patient is taking an
interferon-based regimen or a NAs. The most important measures of response to therapy
consist of normalization of serum ALT levels, a decrease in serum HBV DNA level, loss of
HBeAg (in patients HBeAg-positive at baseline), and loss of HBsAg (in patients HBeAgpositive and HBeAg negative at baseline).
Monitoring and Management of HBeAg-Positive Patients
For HBeAg-positive patients receiving a NAs, the most important factor that determines
duration of therapy is whether HBeAg seroconversion takes place (HBeAg changes from
positive to negative and anti-HBe changes from negative to positive). One-year HBeAg
seroconversion rates are similar (12 to 30%) for all NAs and interferon-based therapies
(1-3). With nucleos(t)ide analogues, the HBeAg seroconversion rates tend to increase by
5 to 10% with each subsequent year of therapy. For HBeAg-positive patients, the AASLD
and EASL guidelines recommend administering oral antiviral therapy until the following
conditions are met: (1) HBeAg seroconversion occurs (HBeAg loss and anti-HBe detection
on two occasions 1 to 3 months apart), and (2) the patient completes at least 6-12 months
of therapy after anti-HBe has appeared. Close monitoring of relapse should occur after
treatment is withdrawn.
79
Guidelines recommend monitoring patients receiving NAs therapy with blood test including
a liver and renal panel and HBV DNA concentration every 3 months initially and then every
3-6 months (1-3). For patients who initially were HBeAg positive, HBeAg and hepatitis B e
antibody (anti-HBe) should be tested every 24 weeks during treatment and HBsAg once a
year 1-3). Patients who are at risk of impaired renal function should have their renal function
monitored regularly, particularly if they are receiving adefovir or tenofovir because of the risk
of nephrotoxicity. A phase 3 trial of tenofovir showed that only 1% of patients had an increase
in serum creatinine level after 5 years treatment (6) Prolonged use of tenofovir has also been
reported to lead to reduced bone mineral density in patients with human immunodeficiency
virus infection, but prospective studies in patients with HBV infection are lacking.
In addition, all NAs approved for HBV have a “black box” warning because of their
potential for inhibition of human DNA polymerase gamma involved in mitochondrial
DNA replication. A reduction in intracellular mitochondrial DNA levels can lead to varying
clinical manifestations of mitochondrial toxicity (i.e.: neuropathy, myopathy, lactic acidosis)
but these side effects are rarely reported with the oral antiviral agents active against HBV.
There have been few prospective studies on the safety of nucleoside analogs during
pregnancy. According to the Antiretroviral Pregnancy Registry, the incidence of birth
defects associated with lamivudine and tenofovir use during pregnancy is not increased.
Entecavir is contraindicated during pregnancy due to its potential teratogenicity (15). This
issue will be discussed in a specific topic.
For patients who are HBeAg-positive at baseline, HBeAg and anti-HBe should be assessed
at the end of 1 year of therapy, and every 3 to 6 months thereafter (1). If therapy is
discontinued, the liver function tests and HBV DNA should be checked every 3 months in
the first year and then every 6-12 months thereafter. Extending the duration of consolidation
therapy after seroconversion to a minimum of 12 months is more and more recommended,
particularly considering nucleoside analogue therapy is generally safe and well tolerated,
and recent data suggest higher sustained response rates with a longer duration of post
seroconversion therapy (16). Patients who have persistently undetectable HBV DNA levels
and convert to HBeAg negative should have HBsAg checked every 6 to 12 months (1-2).
Patients who do not achieve HBeAg seroconversion are quite unlikely to have continued
HBV DNA suppression after stopping therapy; thus therapy should continue until this
endpoint is reached.
Monitoring and Management of HBeAg-Negative Patients
For HBeAg-negative patients, the recommendation is to continue therapy until clearance
of HBsAg occurs, which unfortunately happens in an extremely low proportion of patients.
For patients who are HBeAg-negative at baseline, the HBV DNA level should be followed
every 12 to 24 weeks and if it becomes undetectable, a surface antigen (HBsAg) should
subsequently be obtained every 6 to 12 months. The duration of therapy with nucleoside
analogue therapy for HBeAg-negative patients has not been established, but generally
requires more than several years. A long duration of therapy is required because of the high
relapse rates, even in patients who achieve sustained on-therapy undetectable HBV DNA
levels (1). If, however, HBsAg clearance occurs, therapy can be discontinued (1-3). When
therapy is discontinued, the liver function tests and HBV DNA should be checked every 3
months in the first year and then every 6 to 12 months thereafter.
In conclusion, despite the favorable safety profile of these drugs, guidelines recommend all
patients should be monitored closely during treatment to evaluate response, tolerability,
and adherence.
80
81
References
1. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661–662.
2. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J
Hepatol 2012;57:167–185.
3. Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statement on the
management of chronic hepatitis B: a 2012 update. Hepatol Int 2012;6:531–561.
4. Chang TT, Lai CL, Kew YS, Lee SS, Coelho HS, Carrilho FJ, et al. Entecavir treatment
for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.
Hepatology 2010;51:422–430.
5. Yuen MF, Seto WK, Fung J, Wong DK, Yuen JC, Lai CL. Three years of continuous
entecavir therapy in treatment-naive chronic hepatitis B patients: viral suppression, viral
resistance, and clinical safety. Am J Gastroenterol 2011;106:1264–1271.
6. Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with
tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up
study. Lancet 2013;381:468–475.
7. Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus
resistance to entecavir in nucleosidenaive patients is rare through 5 years of therapy.
Hepatology 2009;49:1503–1514.
8. Sherman M, Yurdaydin C, Sollano J, et al. Entecavir for treatment of lamivudinerefractory, HBeAg-positive chronic hepatitis B. Gastroenterology 2006;130:2039–2049.
9. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir
dipivoxil for the treatment of hepatitis B antigen-positive chronic hepatitis B. N Engl J
Med 2003;348:808–816.
10.Soriano V, Puoti M, Bonacini M, Brook G, Cargnel A, Rockstroh J, et al. Care of patients
with chronic hepatitis B and HIV co-infection: recommendations from an HIV–HBV
International Panel. Aids 2005;19:221–240.
11.Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, et al. Tenofovir
disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med
2008;359:2442–2455.
12.Mauss S, Berger F, Filmann N, et al. Effect of HBV polymerase inhibitors on renal
function in patients with chronic hepatitis B. J Hepatol 2011;55:1235–1240.
13.Liaw YF, Gane E, Leung N, et al. 2-Year GLOBE tria lresults: telbivudine is superior to
lamivudine in patients with chronic hepatitis B. Gastroenterology 2009;136:486–495.
O27
COST-EFFECTIVENESS OF CURRENT THERAPEUTIC
OPTIONS FOR CHB
Kostas Athanasakis1
1
Department of Health Economics, National School of Public Health, Athens, Greece
In the context of “scarce resources vs. infinite healthcare needs” in which health care systems
are (constantly) obliged to operate, resource allocation decisions and, especially, insurance
coverage and funding of available medical interventions, are of utmost importance. For that
purpose, Health Technology Assessment and one of its core components, Cost-Effectiveness
Analysis, can substantially contribute to the rational and efficient allocation of healthcare
budgets, by analyzing and comparing the costs and outcomes of existing or forthcoming
medical treatments.
Chronic hepatitis B virus infection has been a field of intense research by health economists
during the last two decades, partly as a result of the significant disease and economic
burden that is associated with CHB, as well as due to the continuous developments in the
treatment armamentarium against the disease and the subsequent need to investigate the
pharmacoeconomic value of available options.
This speech will attempt to provide a narrative review of the evolution of health economics
evidence for the therapeutic options against CHB in the last 20 years, as reported by the
international literature. Following a brief presentation of the theoretical background of
pharmacoeconomics, the speech will provide a “bird’s eye view” of the early works of health
economics in CHB and focus especially on current therapeutic alternatives, by presenting
and commenting on the most recent published evidence. Interventions against CHB that
do not focus solely on treatment, such as vaccination and screening, will also be (briefly)
covered.
82
O28
CAN NUCLEOS(T)TIDE ANALOGUE THERAPY BE
DISCONTINUED?
Anna SF Lok1
1
University of Michigan, Ann Arbor, MI, United States
Although drug resistance is extremely rare with the new NUCs: entecavir and tenofovir,
costs, adherence and risks of adverse events remain a concern. AASLD, APASL and EASL
guidelines all recommend that for patients who had cirrhosis at the start of treatment, NUCs
should be continued indefinitely to prevent the risk of severe hepatitis flares associated with
virological relapse. For non-cirrhotic patients, all three guidelines recommend that HBeAg+
patients who have achieved HBeAg seroconversion and completed at least 6 months of
consolidation therapy may discontinue treatment. Given that only 40-50% patients achieve
HBeAg seroconversion after 5 years of continuous NUC therapy, median duration of
treatment is expected to be at least 5-6 years.
Clinical studies have reported durability of response varying from 20% to >80%. Because
of the low durability in some high profile studies and the persistence of HBV in the liver
even in patients with durable HBeAg response, many experts have argued that HBeAg
seroconversion is not an indicator to stop treatment. AASLD and EASL guidelines
recommend that non-cirrhotic HBeAg- patients should continue treatment until they have
achieved HBsAg loss. Given that only 1-5% of patients achieve HBsAg loss after 5 years of
continuous NUC therapy, most patients will require lifelong treatment. APASL guidelines
recommended that treatment may be discontinued after completion of 2 years treatment
with undetectable serum HBV DNA on at least 3 occasions 6 months apart.
83
Nucleos(t)ide analogues (NUCs) are effective in suppressing HBV replication but they do
not eradicate the virus. Cessation of treatment even in patients who have had many months
and even years of undetectable HBV DNA in serum is usually followed by virological
relapse. In some patients, virological relapse is followed by hepatitis flare which may lead
to hepatic decompensation. This has prompted many experts to recommend indefinite
treatment when NUCs are used for hepatitis B; however, long-term therapy is associated
with high costs, risks of adverse events, and potential for antiviral drug resistance.
A recent study in Taiwan showed that cessation of entecavir in HBeAg-patients per APASL
guidelines was associated with clinical relapse in 45% within 1 year of stopping treatment.
On the other hand, a study of 33 Greek patients who discontinued adefovir after 4-5 years
treatment found that while all patients had virological relapse, 18 patients had durable
remission and 13 patients lost HBsAg. Despite guideline recommendations, there is no
consensus among experts regarding if and when NUC can be discontinued. Robust data
of patients carefully monitored in standardized protocols are urgently needed to provide
evidence-based guidance. These studies should also address important unresolved
questions including: for HBeAg+ patients is there a difference between stopping treatment
after HBeAg loss vs. HBeAg seroconversion, is there a clear benefit of 12 vs. 6 months
consolidation; for HBeAg- patients, what is the rate of durable virologic remission and
what is the rate of HBsAg loss when treatment is discontinued after 4-5 years; for patients
with compensated cirrhosis, is it safe to stop treatment in those who have achieved HBeAg
seroconversion or HBsAg loss?
84
O29
CAN CIRRHOSIS BE REALLY REVERSED?
Pierre Bedossa1
1
Hôpital Beaujon, University Paris-Diderot, Paris, France
The end point of liver fibrosis in almost all chronic liver diseases is cirrhosis. Cirrhosis
which is characterized by annular fibrosis surrounding hepatocyte nodules is accompanied
by vascular remodeling and regeneration with important functional and hemodynamic
consequences that include development of portal hypertension and eventually
decompensation and death. The dogma prevailing in the literature until recently was that
fibrosis, and even cirrhosis, was irreversible and the best hope therapeutically would be to
halt progression. Subsequent mounting evidence both in animal models and in humans have
provided further support that liver fibrosis and even cirrhosis can regress or even completely
revert to normal architecture on cessation of the cause of liver injury. Indeed, isolated reports
have initially been published with biopsy-proven regression of cirrhosis of various origins.
There are now well-documented studies analyzing large cohorts of patients with hepatitis C
virus (HCV) or hepatitis B virus (HBV) cirrhosis effectively treated with antiviral regimens.
In several of these studies, patients have been followed with serial liver biopsies performed
with a sufficient time interval with as much as 75% of biopsies in hepatitis B or C having
a decreased in their stage of fibrosis after viral eradications and whatever the initial score
of fibrosis. Cirrhosis may also regress in a lower percentage although the return to a fully
normal liver is rarely observed and difficult to prove. Interestingly, few studies have shown
that histological regression of cirrhosis is clinically relevant since patients with cirrhosis
regression have less liver-related events (decompensation, hemorrhage, transplantation) in
their follow-up than those that did not regressed. Furthermore, in addition to a decrease
of the amount of extracellular matrix, regression of fibrosis/cirrhosis is associated to a
restauration of the lobular architecture and parenchymal specialized functions as shown
by immunohistochemistry, which is an additional proof of reversal to a normal lobular
architecture.
However, it is obvious that not all cirrhosis may revert, even after definite viral eradication
or suppression. For fibrosis/cirrhosis regression to occur, several mechanisms needs to be
present. At first, the process of chronic inflammation must be stopped. Such is the case after
viral eradication in viral hepatitis. The stopping of the chronic inflammatory reaction is a
necessary event for liver regeneration to occur.
85
However, even if this condition is reached, liver cell regeneration may not be possible such
as in atrophic cirrhosis where the potential for hepatocyte to duplicate is exhausted due to
major telomere atrition. In this case, reversion of cirrhosis is unlikely.
The vanishing of fibrous septa is another important issue. It is linked to enzymatic digestion
of extracellular matrix that will allow the progressive return to a normal architecture. The
activated hepatic stellate cells will either reverse to a quiescent phenotype or cells will dye by
apoptosis. However, a high degree of collagen cross-linking or the presence of elastic fibers
in abundance within extracellular matrix may limit fibrosis resorption.
Finally, cirrhosis reversion is associated to resurgence of portal tracts and restoration of a
lobular vascularisation with a hepatic vein outflow. These portal tracts which usually emerge
after fibrous septa resorption may be inefficient because of portal vein thrombosis which
may impair the reshaping of portal tract and the regression of cirrhosis.
Finally, one major issue pertaining to the reversion of cirrhosis is the reliability of methods
to measure changes in fibrosis longitudinally. Although assessment of liver fibrosis with
liver biopsy remains the current reference standard for quantifying fibrosis, it is, as such,
an imperfect gold standard. Another issue regarding evaluation of regression of cirrhosis
pertains to most common fibrosis scoring systems have been developed before the idea
of fibrosis regression gained importance and are not equipped for assessing this aspect,
in which peculiar histologic features may be observed. The Laennec scoring system is a
recent histological scoring system of cirrhosis which are divided in 3 substages (4A, 4B,
4C) according to thickness of fibrous septa and nodule size. Stage 4C with thick septa and
small nodules is probably not accessible to regression while the other stages have more
potential to regress. Nevertheless and based on the current limitation of liver biopsy, a key
requirement for future diagnostics of cirrhosis regression assessment is the development of
reliable and accurate noninvasive biomarkers of liver fibrosis. Although these approaches
have progressively gained acceptance as an adjunct for diagnosing cirrhosis, these have
not been fully validated for assessing the dynamics of liver fibrosis, especially longitudinal
evaluation of fibrosis regression.
86
O30
CHALLENGES IN THE MANAGEMENT OF
DECOMPENSATED CIRRHOSIS
Cihan Yurdaydin1
1
Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey
Nucleos(t)ide analog (NA) treatment have extended treatment indications in patients
with liver disease due to HBV infection. One very good example of this is treatment of
patients with decompensated cirrhosis (DC). Patients with DC due to hepatitis B virus
(HBV) when left untreated have a 5 year survival rate of only 14-35%. Current guidelines
on the management of HBV infection recommend therefore immediate treatment with
NAs. Pegylated interferon treatment of patients with DC is contraindicated in the era of
NAs. Optimal treatment of treatment-naïve patients with DC consist of the use of NAs
with high potency and high genetic barrier to resistance. Hence, entecavir and tenofovir are
recommended as first line treatment options also for patients with DC. Several studies have
shown that NA treatment in DC leads to clinical and biochemical improvement reflected in
amelioration of the Child Pugh and MELD scores, serum albumin, bilirubin and ALT and
may lead to removal of a patient awaiting liver transplantation from the transplantation list.
Experience from the lamivudine area has shown that the majority of mortal cases under NA
treatment occur in the first 6 months after treatment commencement. Survival depends on
the severity of liver disease at initiation of NA treatment and appears to be independent of
the pace of HBV DNA decline. Thus, immediate commencement of treatment is crucial in
patients with DC. Similarly, careful assessment of the patient with DC at the time of initial
assessment is of importance in identifying the chances of a patient for rescue with NAs
without liver transplantation. A theoretical concern in the treatment of a patient with DC
could be impaired pharmacokinetics of the drug given due to porto-systemic shunting, lower
protein binding, decreased bioactivation due to impaired metabolism. However, at least in
one study no difference between compensated and decompensated cirrhosis in the context
of the slope of HBV DNA decline was observed. Overall, NAs represent a valid option for
the treatment of HBV-induced DC leading to improved hepatic function and decreased
morbidity. Still, concerns regarding safety of NAs such as lactic acidosis, nephrotoxicity
and metabolic bone disease may be especially valid in the context of advanced liver disease
patients and the need for assessment in this regard continues. Finally, patients with high
Child Pugh scores should be carefully followed in the early months of NA treatment and
those with suboptimal ameliorations in hepatic reserve need to be seriously assessed and
liver transplantation in such patients should not be delayed.
87
O31
DOES TREATMENT REDUCE THE HCC RISK
IN WESTERN COUNTRIES?
W. Ray Kim1
1
Division of Gastroenterology and Hepatology, Stanford University, Stanford, United States
An increasing body of data is accumulating to indicate that long term therapy with effective
antiviral agents against hepatitis B virus (HBV) is able to alter the natural history of liver
disease associated with chronic HBV infection, including regression of fibrosis and cirrhosis,
prevention and reversal of hepatic decompensation and reduction in the incidence of new
and recurrent hepatocellular carcinoma (HCC). While much of these data have originated
from Asia, there have been at least four studies conducted in Western countries that included
large enough number of patients treated with modern antiviral agents while being followed
for a duration sufficiently long to allow assessment of long term end points, such as HCC.
These studies include (1) a multicenter European network (‘Virgil’) study (Zoutendijk, Gut
2013:760 and Arends, Gut 2014;ePub), (2) a Greek multicenter study (Papatheodoridis,
EASL 2013 Abst 766), (3) an Italian multicenter study (Lampertico EASL 2013 Abst 755),
and (4) the global registration trial for tenofovir (Kim, EASL 2013). The table in Figure
1 compares the four studies – they were heterogeneous with regard to racial distribution,
proportion of cirrhosis and hepatic decompensation and prior antiviral exposure.
Figure 2 compares the 5-year incidence of HCC among the four studies. In patients without
cirrhosis, the incidence was low (1-2%) and similar to one another. Much larger variability
was seen in cirrhotic patients with the lowest incidence in the TDF global study and the
highest in the Greek study. Overall, however, the absolute number of patients developing
HCC was small. None of the four studies included a placebo arm to determine whether
HCC incidence was reduced with antiviral therapy. In the Greek study, which did include a
lamivudine comparison group, there was no difference in HCC incidence between the two
agents. In the TDF study, the observed incidence of HCC was compared to what would be
expected based on a prediction model derived in Taiwanese patients.
It is difficult to draw a firm conclusion based on these studies about the extent to which
antiviral therapy reduces HCC incidence in Western countries. However, as advanced
fibrosis and cirrhosis constitute a major risk factor for HCC and reversal of fibrosis should
occur in all races, it is likely that antiviral therapy has a favorable impact on HCC incidence
in Western populations.
88
Furthermore, Western patients tend to have a shorter duration of infection, decreasing the
probably of insertion of viral DNA into the host genome – which should make the risk of
HCC more reversible. However, higher prevalence of concomitant liver disease such as
alcoholic and/or non-alcoholic steatohepatitis or hepatitis C may make the risk to reverse
less readily. Taken altogether, in patients that meet treatment eligibility, antiviral therapy
should be instituted regardless of its impact on HCC risk. Even in patients whose HCC
risk is significantly altered, there is no data to suggest that surveillance of HCC be lessened.
Table 1:
Figure 1:
89
O32
DOES TREATMENT REDUCE HCC RISK IN EASTERN
COUNTRIES?
Henry Chan1
1
Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
Chronic hepatitis B is the major cause of hepatocellular carcinoma (HCC) in Eastern
countries. In Asia Pacific regions, approximately 80% of HCC are related to hepatitis B
virus (HBV) infection. A multi-center Asian trial comparing lamivudine versus placebo
among patients with advanced fibrosis and early cirrhosis has confirmed the benefit of
lamivudine in retarding the progression of hepatic complications [1]. However, the benefit
of lamivudine in HCC reduction is still controversial. Subsequent meta-analysis suggests an
approximate 80% reduction of HCC risk by antiviral therapy, but most of these trials are
based on lamivudine treatment [2].
Entecavir and tenofovir are the recommended first line therapies for chronic hepatitis B
by all regional management guidelines. As tenofovir is registered relatively late in Eastern
countries, most of the experiences in HCC risk reduction are based on cohorts receiving
entecavir. In 3 studies in Taiwan and Japan comparing antiviral drug treated versus
untreated controls with propensity score matching, the adjusted hazard ratio of HCC is
between 0.23 and 0.37 [3-5] (Figure 1). Benefit of antiviral therapy in HCC risk reduction
among cirrhotic patients can be clearly demonstrated by studies in Hong Kong, Taiwan and
Japan, but the benefit in non-cirrhotic patients is controversial [3,4,6].
Complete viral suppression during antiviral therapy is important to maximize the risk
reduction of HCC development. This is shown both in cohorts in Hong Kong and in Korea
[7,8]. Patients who fail to achieve undetectable HBV DNA at month 12 of entecavir therapy
have only 45% to 74% chance of complete viral suppression at the end of 3 years [9-11].
Tenofovir switch is an effective means to bring down the HBV DNA for entecavir partial
responders, but the management of tenofovir partial responders is uncertain.
90
References:
1. Liaw YF et al. N Engl J Med 2004; 351: 1521-31.
2. Sung JJ, et al. Aliment Pharmacol Ther 2008;28:1067-77.
3. Wu CY, et al. Gastroenterology 2014;147:143-51.
4. Hosaka T, et al. Hepatology 2013;58:98-107.
5. Kumada T, et al. J Hepatol 2013;58:427-33.
6. Wong GL, et al. Hepatology 2013;58:1537-47.
7. Wong GL, et al. Gastroenterology 2013;144:933-44.
8. Cho JY, et al. Gut 2014 (Epub ahead of print).
9. Wong GL, et al. Aliment Pharmacol Ther 2012;35:1326-35.
10.Bang SJ, et al. Dig Dis Sci 2013;45:600-5.
11.Kwon DH, et al. Gut Liver 2013;7:712-8.
Figure 1:
Estimated annual incidence of HCC based on 5-year follow-up [3-5]
91
O33
OPTIMAL HBV PROPHYLAXIS IN HBSAG+ OR HBSAG-/
ANTI-HBC+ PATIENTS UNDER IMMUNOSUPPRESSION
Evangelos Cholongitas1
1
4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration
General Hospital of Thessaloniki, Thessaloniki, Greece
Individuals with a previous exposure to HBV may be at risk of HBV reactivation when they
receive immunosuppressive therapy. The precise factors associated with the risk of HBV
reactivation are not well understood, but the latter seems to depend on the serological
profile of the patient, the underlying disease and the immunosuppressive therapy that
will be used(1). HBV reactivation is usually reported in patients receiving chemotherapy
for haematological malignancies and/or bone marrow transplantation(2). Theoretically,
any type of immunosuppressive therapy can lead to HBV reactivation, but rituximab, a
monoclonal antibody targeting the CD20 receptor, has been associated with severe HBV
reactivations in HBsAg positive as well as HBsAg negative/antiHBc positive patients(2,3). It
is highly recommended that the HBV markers (HBsAg, anti-HBc and anti-HBs) should be
screened in all candidates for immunosuppressive therapy(4).
In HBsAg-positive candidates pre-emptively nucleos(t)ide analogues [NA(s)] (regardless of
HBV DNA levels) should be received during immunosuppressive therapy and for 12 months
after its cessation. Pre-emptive treatment with lamivudine is proposed for patients with low
(<2000 IU/ml) HBV DNA levels when a finite and short duration of immunosuppression is
scheduled, otherwise entecavir or tenofovir is recommended(4).
In HBsAg negative/antiHBc positive patients, no standard management to prevent HBV
reactivation has been established. Based on current recommendation, close monitoring or
lamivudine prophylaxis are considered reasonable options for HBsAg negative/anti-HBc
positive patients who require immunosuppression providing that baseline serum HBV DNA
is undetectable(4). Based on literature data (Cholongitas et al, unpublished data), it could
be suggested the use of anti-HBV prophylaxis in HBsAg negative/anti-HBc positive patients
with haematological diseases and/or those who are going to receive rituximab containing
regimens regardless of their anti-HBs and serum HBV DNA status.
92
On the other hand, HbsAg negative/anti-HBc positive patients with non-hematological
diseases and/or those who are going to receive rituximab free regimens seem to require antiHBV prophylaxis only if they have baseline detectable HBV DNA. However, further studies
may be needed in specific subgroups, such as those with solid tumors. Although the optimal
duration of prophylaxis for HBsAg negative/antiHBc positive patients is unknown, it seems
that clinicians should continue anti-HBV prophylaxis and/or the follow-up for at least 12
months after discontinuation of immunosuppression. Finally, regarding the management of
HBV reactivations, an agent with a high genetic barrier (i.e. entecavir or tenofovir) seems
clinically more appropriate choice.
References:
1. Hwang JP, Lok AS. Management of patients with hepatitis B who require
immunosuppressive therapy. Nat Rev Gastroenterol Hepatol. 2014;11(4):209-19.
2. Evens AM, Jovanovic BD, Su YC, et al. Rituximab-associated hepatitis B virus (HBV)
reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA
safety reports. Ann Oncol. 2011;22(5):1170-80
3. Roche B, Samuel D. The difficulties of managing severe hepatitis B virus reactivation.
Liver Int. 2011;31 Suppl 1:104-10
4. European Association for the Study of the Liver. EASL clinical practice guidelines:
Management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167-85
93
O35
HEPATITIS B AND PREGNANCY
Ulus Salih Akarca1
1
Ege University, Izmir, Turkey
Hepatitis B virus (HBV) persistently infects at least 350 million people in the world. It is
the main cause of liver cirrhosis and hepatocellular carcinoma worldwide. Mother to child
transmission (MTCT) is the most common way of infection in high HBV endemic areas.
Because of young age, most of the mothers are HBeAg positive and highly replicative during
pregnancy. High viral load is the main determinant of MCTC of HBV infection. Therefore,
HBV infection in pregnancy concerns both individual health of pregnant women and public
health.
When hepatitis B and pregnancy are reviewed, the following issues should be considered.
1) Effect of HBV on pregnancy and fetus; 2) Changes in the course of HBV infection
during pregnancy; 3) Treatment of chronic hepatitis B in pregnant women; 4) Precautions
to reduce the transmission rate of HBV to infants.
Effect of HBV on pregnancy: The impact of HBV infection on pregnancy and fetus
has not been clearly defined. A higher rate of low birth weight and prematurity has been
reported during acute infection than in the general population [1]. Advanced liver disease
decrease the fertility and increase the rate of preterm labour, intrauterine infections and
low birth weight [2]. Although increased prevalence of gestational diabetes, preterm labour,
antepartum haemorrhage, and low birth weight were reported in HBV infected pregnants,
their clinical significances are unknown [3]. Although inactive carrier state has no impact on
fetus and newborn, cirrhosis may increase the rate of prematurity and fetal loss. Fulminant
hepatitis was reported in early 90s in babies born to HBeAg negative replicative mothers
[4]. They were attributed to the lack of immunosuppressive effect of HBeAg in newborn.
Changes in the course of HBV infection during pregnancy: Clinical feature of acute
HBV infection in pregnancy is not different from those in non-pregnant women. However,
HBsAg serocoversion seems to be delayed and lower in pregnant women. In one study
conducted in China, prodromal symptoms were found to be milder and ALT levels were
lower comparing to non-pregnant women [5]. Mostly, chronic HBV infection goes well
during pregnancy. Because of the immune suppressive state and higher cortisol levels, HBV
DNA is more likely to be increased and ALT decreased.
94
Treatment of HBV infection in pregnants: When making treatment decisions, probability
of future pregnancies should be considered in women with childbearing potentials. If the
liver disease is mild in a patient planning conception within a couple of years, treatment
may be deferred. Treatment of the patient with interferons may be an alternative, because of
their finite duration. In patients with advanced liver disease, treatment decision is made as
in general. When pregnancy is planned, the risk of hepatitis flare after cessation of the drug
and probable fetal toxicity of the drugs should be discussed with the patients. The rates of
birth defects are similar in babies born to mothers who were treated with lamivudine or
tenofovir and those not received any of these drugs [8], [9], [10]. Although lamivudine,
tenofovir and telbivudine are considered safe in pregnancy, their long-term effects on babies
are not known. In addition, their experiences in pregnant women have inadequate data
related to certain complications. Considering every aspect, EASL guideline recommends
not to stop treatment when a patient with advanced liver disease becomes pregnant [11].
The risks of probable hepatitis flares on the mother and on fetus are considered to be higher
than the risk of toxicity of the drugs. If the patients with mild to moderate fibrosis become
unexpectedly pregnant, cessation of the drugs should be discussed with the patients. The
probability of hepatitis flares and its outcomes, the data related to the fetal effects of the
drugs should be reviewed. In fact, there is no sufficient data for outcome after cessation
of antivirals in pregnant women. Elevation of HBV DNA is universal and ALT elevation
usually ensues, however most of the patients experience spontaneous decline in HBV DNA
and ALT levels and hepatic decompensation rarely reported [12].
Precautions to reduce the transmission rate of HBV: The recommended
immunoprophylaxis for newborns is active immunization with hepatitis B vaccine and
administration of hepatitis B immunoglobulin. Although there are data, which HBIG does
not increase the prevention rate in babies born to HBeAg negative/HBsAg positive mothers
[13], combined prophylaxis is universally recommended for all newborns of HBsAg positive
mothers. Despite vaccine and HBIG, 5-10% of babies born to HBV carrier mothers
become HBsAg positive. Intrauterine transmission of HBV accounts for almost 15-40% of
newborn HBV infection. Placental disintegration, which can be seen in threatened abortion
and TORCH infection, may increase the risk of intrauterine transmission [14]. A very few
examples indicate that infected oocyte can cause intrauterine HBV infection.
95
Because of immune restoration, ALT may increase after delivery [6]. This elevation is usually
mild, however severe exacerbation and fulminant course has been described. Therefore, the
pregnant women with chronic hepatitis B should be monitored closely after term.
In women with liver cirrhosis, probability of decompensation and variceal bleeding may
increase in the late pregnancy and during labour. Management of the complication of
cirrhosis is not different from non-pregnant women. Endoscopic screening and intervention
to varices may be performed [7]. However, beta-blockers and octreotide should not be used
to avoid the side effects.
Ascending infection from vaginal secretions during pregnancy may result in HBV infection.
Intrauterine infection usually persists despite active-passive immunoprophylaxis after
birth, while persistent infection can be prevented in cases of perinatal and postpartum
transmission. Ineffectiveness of immunoprophylaxis is related to HBV DNA levels during
delivery. Several studies indicated that HBV infection could be completely prevented in
infants born to women with HBV DNA <106 IU/ml by active-passive immunoprophylaxis.
However, success rate of these prophylaxis are conversely related to HBV DNA levels of
mothers. The higher HBV DNA levels, the lower protection rate of HBV infection in infants.
Zou et al stratified the mothers according to their pre-term HBV DNA levels [15]. They
found that among 869 infants born to HBsAg positive mothers, 27 (3.1%) became HBsAg
positive, despite immunoprophylaxis. The rates of immunoprophylaxis failure were found to
be 0%, 3.2%, 6.7%, and 7.6% in infants whose mothers’ HBV DNA levels were <6, 6-6.99,
7-7.99, and ≥ 8 log copies/ml, respectively. Since high level of viremia in mothers is related
to failure of immunoprophylaxis, several studies have been conducted to investigate the
effects of oral antivirals on viremia in pregnant women and their protective role on MTCT.
Although the number of patients was low, lamivudine, telbivudine, and tenofovir were
found to be safe and effective to reduce the rate of immunoprophylaxis failure. Therefore,
international guidelines allow giving abovementioned antivirals in the last trimester of
pregnancy in HBsAg-positive women with high levels of viremia. If only purpose of giving
antivirals is prevention of MCTC, the drugs may be stopped within 3 months after delivery.
In the patients who have to be treated, there are insufficient data related to the use of
oral antivirals during breastfeeding period. However, tenofovir may be safe at this period.
Although it is detected in breast milk, because of its lower per oral bioavailability, it has
extremely low concentration in infant’s plasma.
Several studies demonstrated that breast-feeding does not increase the rate of maternal to
child transmission. Yet, breast care for abrasions and infections are advised.
The impact of the mode of delivery on mother to child transmission of HBV DNA is not
clear. Generally, it is believed that mode of the delivery has no impact on MCTC, although
caesarean section may decrease the rate of intrapartum HBV transmission. However,
most of the studies do not have sufficient data related to mother’s viral load, mode of
immunoproflaxis against HBV, and urgency of the procedures. A recent study from China
demonstrated that babies born by elective caesarean section had a lower rate of HBsAg
positivity at 7-12 months old, comparing to those born by vaginal delivery, especially in the
population whose mother’s HBV DNA >106 copies/ml [16]. In fact, several other studies
found no difference in HBsAg positivity of infants born by caesarean section and vaginal
delivery.
96
References:
1. Sookoian S. Liver disease during pregnancy: acute viral hepatitis. Ann Hepatol.
2006;5:231-6.
2. Tse KY, Ho LF, Lao T. Theimpact of maternal HBsAg carrier status on pregnancy
outcomes: a case-control study. J Hepatol 2005;43:771–775.
3. Reddick KL, Jhaveri R, Gandhi M, James AH, Swamy GK. Pregnancy outcomes
associated with viral hepatitis. J Viral Hepat 2011;18:e394–e398.
4. Bahn A, Hilbert K, Martiné U, Westedt J, von Weizsäcker F, Wirth S. Selection of a
precore mutant after vertical transmission of different hepatitis B virus variants is
correlated with fulminant hepatitis in infants. J Med Virol 1995;47:336-41.
5. Han YT, Sun C, Liu CX, Xie SS, Xiao D, Liu L, Yu JH, Li WW, Li Q. Clinical features
and outcome of acute hepatitis B in pregnancy. BMC Infect Dis. 2014;14:368.
6. ter Borg MJ, Leemans WF, de Man RA, Janssen HL. Exacerbation of chronic hepatitis
B infection after delivery. J Viral Hepat 2008; 15: 37-41.
7. Borgia G, Carleo MA, Gaeta GB, Gentile I. Hepatitis B in pregnancy. World J
Gastroenterol. 2012;18:4677-83.
8. Yu M, Jiang Q, Ji Y, Jiang H, Wu K, Ju L, Tang X, Wu M. The efficacy and safety of
antiviral therapy with lamivudine to stop the vertical transmission of hepatitis B virus.
Eur J Clin Microbiol Infect Dis. 2012;31:2211-8.
9. Yi W, Liu M, Cai HD. Safety of lamivudine treatment for chronic hepatitis B in early
pregnancy. World J Gastroenterol 2012;18:6645-50.
10.Greenup AJ, Tan PK, Nguyen V, Glass A, Davison S, Chatterjee U, Holdaway S,
Samarasinghe D, Jackson K, Locarnini SA, Levy MT. Efficacy and safety of tenofovir
disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus.
J Hepatol. 2014. Article in press.
11.European Association For The Study Of The Liver. EASL clinical practice guidelines:
Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-85.
12.Kim HY, Choi JY, Park CH, Jang JW, Kim CW, Bae SH, Yoon SK, Yang JM, Lee CD,
Lee YS. Outcome after discontinuing antiviral agents during pregnancy in women
infected with hepatitis B virus. J Clin Virol. 2013;56:299-305.
97
Conclusions: HBV infection in pregnant women is a special issue for the mother, fetus and
public health. Acute and chronic HBV infections do not impact on pregnancy in general.
However, fulminant course in acute hepatitis B and several complications in chronic HBV
infection have been described. Particularly, advanced liver disease may be associated
with preterm labour, low birth weight, prematurity, and fetal loss. Active and passive
immunoprophylaxis of babies born to highly viremic HBsAg positive mothers have reduced
the rate of MCTC from 90% to 5-10%. In order to further decrease the MCTC rate, oral
antivirals are allowed to be used in the late pregnancy. Hopefully, universal vaccination will
make these issues unnecessary in the future.
13.Chen HL, Lin LH, Hu FC, Lee JT, Lin WT, Yang YJ, Huang FC, Wu SF, Chen SC,
Wen WH, Chu CH, Ni YH, Hsu HY, Tsai PL, Chiang CL, Shyu MK, Lee PI, Chang
FY, Chang MH. Effects of maternal screening and universal immunization to prevent
mother-to-infant transmission of HBV. Gastroenterology. 2012;142:773-781.
14.Ma L, Alla NR, Li X, Mynbaev OA, Shi Z. Mother-to-child transmission of HBV:
review of current clinical management and prevention strategies. Rev Med Virol. 2014
Jun 23, online publication.
15.Zou H, Chen Y, Duan Z, Zhang H, Pan C. Virologic factors associated with failure to
passive-active immunoprophylaxis in infants born to HBsAg-positive mothers. J Viral
Hepat 2012;19:e18–e25
16.Pan CQ, Zou HB, Chen Y, Zhang X, Zhang H, Li J, Duan Z. Cesarean section reduces
perinatal transmission of hepatitis B virus infection from hepatitis B surface antigenpositive women to their infants. Clin Gastroenterol Hepatol. 2013;11:1349-55.
98
O37
THE OPTIMAL CURRENT AND POTENTIAL FUTURE
THERAPEUTIC OPTIONS FOR HBV+HDV INFECTION
Heiner Wedemeyer1
1
Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover,
Germany
Suppression of HDV RNA replication is the primary goal of treatment of hepatitis delta
which is usually associated with normalization of liver enzymes and histological improvement
of liver disease. Ideally, antiviral therapy induces serological cure from hepatitis B defined
by HBsAg loss and development of anti-HBs antibodies, simultaneously also leading to
recovery from HDV infection.
Possible future treatment options include novel therapies leading to clearance of HBsAg.
In addition, post-translational modification steps of hepatitis delta antigens including
methylation, acetylation, phosphorylation and isoprenylation are potential therapeutic
targets. Clinical trials are ongoing investigating prenylation inhibitors to treat HDV infection.
The second possibility to interfere the infection with hepatitis delta is to block HDV entry
by HBV entry inhibitors these methods have been successfully tested in humanized mice
and are currently in early clinical development.
Current therapy should be individualized based on the stage of liver disease, the status
of both HBV and HDV replication and response kinetics during therapy, in particular
concerning quantitative HBsAg levels to identify subjects who benefit from PEG-IFNa
maintenance treatment. For patients with end-stage liver disease liver transplantation
remains the only treatment option.
In summary, treatment of hepatitis delta remains a major challenge with very limited options
to induce cure from HDV infection.
99
Treatment of hepatitis delta remains a major challenge with very limited options to induce
cure from HDV infection. Nucleoside and nucleotide analogues used for the treatment
of HBV infection have been shown to be ineffective against HDV because HDV does not
encode for any viral enzyme but uses host polymerases for replication. Thus, pegylated
Interferon alpha remains the only effective treatment.
O38
HBV AND HCV CO-INFECTION
Stanislas Pol1
1
Unité d’Hépatologie, Hôpital Cochin, Paris, France
Co-infection in Hepatitis B Virus (HBV)-infected patients by Hepatitis C Virus (HCV)
has been less extensively studied than Hepatitis D virus (HDV) infection. HBV/HCV
coinfection is observed in around 5% of patients, is associated with a risk of more severe
liver disease (cirrhosis and/or hepatocellular carcinoma -HCC-) and will require an antiviral
therapy against both HCV and HBV infection.
1. Prevalence of HBV/HCV infection
Given the similar routes of transmission (at least regarding the parenteral risk), the coinfection in Hepatitis B Virus (HBV)-infected patients by Hepatitis C Virus (HCV)
is reported in around 5% of the patients (1). In the EPIB studies (which compared the
characteristics of HBV infection according to HIV-status, the prevalence of HCV coinfection
varies from 3.5% in HIV-negative to 12.5% in HIV-positive patients (figures for HDV
infection are 9.7 and 5.0%, respectively) and varied according to the risk factor for HBV
infection (geographical, intravenous drug use or sexual transmission)(2).
2. HBV/HCV infection is associated with a more severe disease
HBV/HCV co-infection (like HDV super-infection) accelerates liver disease progression and
increases the risk of HCC (1,3-4). In the EPIB studies, even though the stage of fibrosis in
HIV-positive patients at the last visit was not different from that in HIV-negative patients, it
was more severe in HCV-seropositive than in HCV-seronegative patients, whatever the HIV
status (mean last METAVIR fibrosis stage 2.7 +/- 1.4 vs. 1.5 +/- 1.2, respectively, p<10-3):
29.4% of the 51 HCV-positive patients had clinical cirrhosis compared with 11.1% of the
641 HCV-negative patients (p<10-3)(2). Similarly, although liver fibrosis remained roughly
stable during the follow-up in the whole study population, there was a significant increase
in HCV-seropositive patients but not in HCV negative patients (mean METAVIR fibrosis
increase +1.1 +/- 1.4 vs. 0.0 +/- 1.1, respectively, p=0.002). The prevalence of cirrhosis
was also higher in HDV-positive patients (23.1% vs. 12.1%, p=0.05. In multivariate
analysis, age (OR + 1 year 1.06, 95%CI 1.04-1.09, p<10-3), male gender (OR 1.78, 95%
CI: 0.93-3.41, p=0.08), daily alcohol intake>40g (OR 1.78, 95% CI: 1.14-2.78, p=0.01),
and positive HCV (OR 2.64, 95% CI: 1.11-6.26, p=0.03) and HDV (OR 2.61, 95% CI:
1.07-6.36, p=0.03) serological status were associated with cirrhosis at the end of follow up.
100
These results evidence in more than 700 chronically HBV-infected that HCV (and HDV
combined infection unlike HIV co-infection) worsens HBV-induced fibrosis in HAARTtreated patients.
4. Treat HCV then HBV infection
Given the absence of virologic interference between HBV and HCV replication, HBV-HCV
co-infected patients should usually receive, as recommended by the EASL guidelines, a first
line interferon-including treatment for HCV (6-10). Half of HBV DNA-positive patients
may achieve a significant decline of HBV DNA titers but HBs Ag loss is rare with a risk of
HBV reactivation. Sustained virological response rates for HCV are broadly comparable
with those reported in HCV mono-infected patients (8-10). Clearance of HCV is associated
during treatment or after with a potential risk of HBV post-treatment reactivation (9).
Therefore, HBV DNA monitoring is mandatory during treatment and after HCV treatment.
Any HBV reactivation must then be treated with nucleos(t)ides analogues according to
the guidelines (6). The new oral combination of direct-acting antivirals may modify the
therapeutic recommendations: after sustained virologic response which is achievable now in
up to 95% of HCV-infected patients, the recommendations for HBV therapies will probably
follow those of HBV-infected patients according to the different phases of HBV infection,
immune tolerance, chronic active hepatitis or inactive carriage.
101
3. No clear virologic interference in HBV/HCV co-infection
HBV and HCV replicate in the same hepatocyte but not at the same subcellular location
(nuclear and cytoplasmic, respectively) why may explain the absence of interference (5).
By opposition with HDV infection which results in a decline in HBV replication, HCV/
HBV co-infection has no clear impact on the HCV viral load while a proportion of these
patients may have fluctuating serum HBV DNA levels, as in any HBV-infected patients:
this evidences the need for longitudinal evaluation of viral loads before starting any antiviral
therapy in order to clarify the pathogenic role of both viruses (1). Nevertheless, HBV DNA
level may be often low or undetectable and HCV is responsible for the activity of chronic
hepatitis in most patients, although this is variable probably due to indirect mechanisms
mediated by innate and/or adaptive host immune responses (6).
References:
1. Chu CJ, Lee SD. Hepatitis B virus/hepatitis C virus coinfection: Epidemiology, clinical
features, viral interactions and treatment. J Gastroenterol Hepatol 2008;23:512-20.
2. Piroth L, Pol S, Lacombe K, Miailhes P, Rami A, Rey D, et al. Management and
treatment of chronic hepatitis B virus infection in HIV positive and negative patients:
the EPIB 2008 study. J Hepatol 2010,53:1006-1012.
3. Jamma S, Hussain G, Lau DT. Current concepts of HBV/HCV coinfection: Coexistence,
but not necessarily in harmony. Curr Hepat Rep 2010;9:260-9.
4. Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological studies on the
combined effect of hepatitis B and C virus infections in causing hepatocellular
carcinoma. Int J Cancer 1998;75:347-54.
5. Bellecave P, Gouttenoire J, Gajer M, Brass V, Koutsoudakis G, Blum HE, et al. Hepatitis
B and C virus coinfection: a novel model system reveals the absence of direct viral
interference. Hepatology 2009;50:46-55.
6. European Association for the Study of the Liver. EASL clinical practice guidelines:
Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-185.
7. Potthoff A, Wedemeyer H, Boecher WO, Berg T, Zeuzem S, Arnold J, et al. The HEPNET B/C co-infection trial: A prospective multicenter study to investigate the efficacy
of pegylated interferon-alpha2b and ribavirin in patients with HBV/HCV co-infection.
J Hepatol 2008;49:688-94.
8. Liu CJ, Chen PJ, Lai MY, Kao JH, Jeng YM, Chen DS. Ribavirin and interferon is
effective for hepatitis C virus clearance in hepatitis B and C dually infected patients.
Hepatology 2003;37:568-76. 9. Zhou J, Dore GJ, Zhang F, Lim PL, Chen YMA.
Hepatitis B and C virus coinfection in the TREAT asia HIV observational database. J
Gastroenterol Hepatol 2007;22:1510-8.
9. Saitta C, Pontisso P, Brunetto MR, Fargion S, Gaeta GB, Niro GA, et al. Virological
profiles in hepatitis B virus/hepatitis C virus coinfected patients under interferon plus
ribavirin therapy. Antivir Ther 2006;11:931-4.
102
O39
IS THERE A ROLE FOR PEGIFN AND NA COMBINATION?
Jörg Petersen1
1
IFI Institute at the Asklepios Klinik St Georg Hamburg, University of Hamburg, Hamburg,
Germany
Although combination of lamivudine plus PegIFN failed to demonstrate benefit when
evaluated at the end of follow-up in most pivotal studies, a more pronounced on-treatment
virologic response (week 48) was observed with combination therapy as compared to
lamivudine or PegIFN alone (2,3). This more profound HBV DNA suppression induced by
the combination regimen was associated with a lower incidence of lamivudine resistance.
However, concern for HBV associated drug resistance has decreased significantly over
the last years with newer, high-potency NAs such as entecavir and tenofovir, even when
administered alone. Thus, whether combination therapy confers an additional benefit
compared to mono-therapy for treating chronic hepatitis B remains unclear from those
studies. Interestingly, from a more virological point of view, the combination of PegIFN and
adefovir induced a stronger cccDNA reduction and HBsAg loss compared to single therapy
(4, 5). However, combination therapies using PegIFN and more potent NAs, entecavir and
tenofovir, may be even more attractive, but the efficacy remains to be comprehensively
evaluated. Recently, a switch treatment from entecavir to PegIFN after 36 months of
continuous treatment with complete response to entecavir was superior to continuation of
entecavir treatment by measuring HBeAg seroconversion and HBsAg loss rates (6). Several
studies are currently being undertaken investigating combination treatment of PegIFN and
entecavir or tenofovir using simultaneous or add-on approaches.
103
Currently available antiviral treatment for chronic hepatitis B virus infection can be divided
into two classes of therapeutic agents: Peg interferon (PegIFN) and nucleos(t)ide analogues
(NAs). The major advantages of NAs are good tolerance and potent antiviral activity
associated with high rates of on-treatment response to therapy; the advantages of PegIFN
include a finite course of treatment, absence of drug resistance, and an opportunity to
obtain a post-treatment durable response to therapy. The use of these two antiviral agents
with different mechanisms of action in combination is theoretically an attractive approach
for treatment, either in a simultaneous way or as a sequential combination therapy (addon), or even as an immediate switch from one agent to the other. As of now, combination
treatments with PegIFN plus NAs are not indicated and not supported by the recent EASL
CPG 2012 (1).
Due to the preliminary character of the results so far, a combination treatment of nucleos(t)ide
analogs plus PegIFN is not recommended. Finally, combination treatment with telbivudine
and PegIFN should not be conducted. In a recent study, peripheral neuropathy was described
in 7 out of 50 patients who received combination therapy of PegIFN and telbivudine,
compared to only in 1 out of 54 patients who received telbivudine mono-therapy (7).
The efficacy and place of potent and appropriate HBV therapies must be determined,
but this requires large and expensive trials. Thus, the efficacy of potent mono-therapies
including interferon versus the combination of interferon and a nucleos(t)ide analog in
several ways will need to be gleaned from direct clinical experience in the next few years.
EASL is considering combination therapy as a still unmet need and is supporting a further
assessment of safety and efficacy of the combination of PegIFN with a potent NA such as
entecavir or tenofovir to increase anti-HBe or anti-HBs seroconversion rates (1).
References:
1. EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection.
European Association for the Study of the Liver. J Hepatology 2012;57:167-185
2. Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa 2a HBeAg-positive chronic
Hepatitis B study group. Peginterferon alfa 2a, lamivudine, and the combination for
HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682-95
3. Marcellin P, Lau GK, Bonino F, et al: Peginterferon alfa 2a HBeAg-negative chronic
Hepatitis B study group. Peginterferon alfa 2a alone, lamivudine alone, and the two
in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med
2004;351:1206-17
4. Wursthorn K, Lutgehetmann M, Dandri M, et al: Peginterferon alpha 2b plus adefovir
induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis
B. Hepatology 2006;44:675-84
5. Takkenberg RB, Jansen L, de Niet A, et al. Baseline hepatitis B surface antigen (HBsAg)
as predictor of sustained HBsAg loss in chronic hepatitis B patients treated with
pegylated interferon alpha 2a and adefovir. Antivir Ther 2013;18:895-904.
6. Ning Q, Han M, Sun Y, et al. Switching from entecavir to PegINf alfa-2a in patients
with HBeAg-positive chronic hepatitis B: A randomized open-label trial (OSST trial). J
Hepatology 2014 Jun7.pii: S0168-8278(14)00392-4. doi: 10.1016/j.jhep.2014.05.044.
[Epub ahead of print]
7. Marcellin P, Wursthorn K, Wedemeyer H, et al. Telbivudine plus pegylated interferon
alfa-2a in a randomized study in chronic hepatitis B was associated with unexpected
high rate of peripheral neuropathy. J Hepatology 2014 (in press)
104
O40
IS THERE A ROLE FOR NA AND NA COMBINATION?
Michael Cornberg1
1
Hannover Medical School, Hannover, Germany
Cure of chronic hepatitis B virus (HBV) infection is at this stage not easy to achieve due
to the persistence of covalently, closed circular DNA (cccDNA) in the nucleus of infected
hepatocytes. Therefore, the goal of current antiviral therapies for chronic HBV infection
is to prevent progression to cirrhosis, decompensated end-stage liver disease, HCC and
death [1, 2]. Prevention of progression and even reversal of fibrosis or early cirrhosis can be
achieved by sustained suppression of HBV replication by targeting the reverse transcriptase
with nucleoside and nucleotide analogues (NA) [1, 3, 4]. Monotherapy with the most
potent NA entecavir and tenofovir is usually sufficient and result in >95% suppression of
HBV DNA after 5 years in adherent patients and resistance is not a major issue anymore
[1, 2]. Thus, is there any role for NA and NA combination? Indeed, some patients may
fail to achieve complete viral suppression after 12 months of therapy and are referred to as
partial responders. These patients may have an increased risk of developing HCC compared
to patients with complete and maintained suppression [4, 5]. This could be of relevance
for patients with advanced liver fibrosis or cirrhosis. Petersen et al., have retrospectively
analyzed 57 difficult to treat patients with resistant HBV strains or partial response to
preceding therapies who have been treated with a rescue combination regimen of entecavir
and tenofovir. In this setting, NA and NA combination was highly efficient and safe [6].
However, in most cases switching to another NA without cross-resistance may be sufficient.
Tenofovir monotherapy can be effective in HBV patients with partial response to ETV
[7]. As viral suppression is the key element to prevent progression, patients with extremely
high HBV DNA may benefit from NA and NA combination? Lok et al. suggested that the
combination of entecavir and tenofovir was superior to entecavir monotherapy in HBeAg
positive patients with HBV DNA >109 IU/ml, but there was no direct comparison of the
combination therapy with tenofovir alone [8]. Some in vitro studies indicating synergistic
antiviral effects of combining different NA [9, 10]. However, at that point it was unclear
if two potent NA with the same antiviral mechanism can have synergistic effects on HBV
DNA suppression in patients? Recently, a randomized controlled trial in 126 HBeAg positive
individuals with high viremic inactive or so-called immune-tolerant HBV infection showed
that a combination of tenofovir and emtricitabine (Truvada) over 192 weeks suppressed
HBV replication more than tenofovir alone [11].
105
Emtricitabine is considered as less potent NA. Thus, NA and NA combination may indeed
have synergistic antiviral effects which could be beneficial in difficult to treat situations.
Now that highly effective and well-tolerated therapies are available, one might also discuss
if treatment in high viremic inactive individuals could lower the risk of HCC and reduce
HBV transmission.
However, suppression of HBV DNA is not cure! The combination of tenofovir and
emtricitabine did not result in higher rates of HBeAg seroconversion or HBsAg loss rates
[11]. In fact, those end-points were achieved less often. In general, inhibition of the reverse
transcriptase has no direct effect on cccDNA, which is reflected by the slow decline of
HBsAg levels during NA treatment. If HBsAg decline occurs during NA therapy, this
may have other reasons such as an activated immune system (i.e. high IP-10 [12, 13])
or restoration of the immune response [14]. Compared with the rapid developments in
the hepatitis C field, treatment for HBV has been stable in recent years. We should not be
satisfied with NA that only maintain long-term viral suppression, but they rarely lead to
HBsAg loss which should be the most important goal [15]. The field needs to evolve toward
a cure. One promising field may be the development of therapeutic vaccines. Here it may
be still essential to suppress HBV DNA sufficiently. If cure is possible, we will treat also
the so-called immune tolerant patients. Thus, there may be still a role for NA and NA in
combination with immune modulation in the future. At present, I see only a role for NA and
NA combination in few patients with very high viral load or partial response and advanced
liver disease.
References:
1. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J
Hepatol. 2012; 57:167–85.
2. Cornberg M, Protzer U, Petersen J et al. [Prophylaxis, diagnosis and therapy of hepatitis
B virus infection - the German guideline]. Z Gastroenterol. 2011; 49:871–930.
3. Marcellin P, Gane E, Buti M et al. Regression of cirrhosis during treatment with
tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up
study. Lancet. 2013; 381:468–75.
4. Wong GL, Chan HL, Mak CH et al. Entecavir treatment reduces hepatic events and
deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology. 2013;
5. Zoutendijk R, Reijnders JG, Zoulim F et al.Virological response to entecavir is associated
with a better clinical outcome in chronic hepatitis B patients with cirrhosis. Gut. 2012;
6. Petersen J, Ratziu V, Buti M et al. Entecavir plus tenofovir combination as rescue therapy
in pre-treated chronic hepatitis B patients: an international multicenter cohort study. J
Hepatol. 2012; 56:520–6.
106
107
7. Pan CQ, Hu KQ, Yu AS, Chen W, Bunchorntavakul C, Reddy KR. Response to
tenofovir monotherapy in chronic hepatitis B patients with prior suboptimal response to
entecavir. J Viral Hepat. 2012; 19:213-9.
8. Lok AS, Trinh H, Carosi G et al. Efficacy of entecavir with or without tenofovir disoproxil
fumarate for nucleos(t)ide-naive patients with chronic hepatitis B. Gastroenterology.
2012; 143:619–28.e1.
9. Delaney WE, Yang H, Miller MD, Gibbs CS, Xiong S. Combinations of adefovir with
nucleoside analogs produce additive antiviral effects against hepatitis B virus in vitro.
Antimicrob Agents Chemother. 2004; 48:3702–10.
10.Schinazi RF, Bassit L, Clayton MM et al. Evaluation of single and combination
therapies with tenofovir disoproxil fumarate and emtricitabine in vitro and in a robust
mouse model supporting high levels of hepatitis B virus replication. Antimicrob Agents
Chemother. 2012; 56:6186–91.
11.Chan HL, Chan CK, Hui AJ et al. Effects of tenofovir disoproxil fumarate in hepatitis
B e antigen-positive patients with normal levels of alanine aminotransferase and high
levels of hepatitis B virus DNA. Gastroenterology. 2014; 146:1240–8.
12.Jaroszewicz J, Ho H, Markova A et al. Hepatitis B surface antigen (HBsAg) decrease
and serum interferon-inducible protein-10 levels as predictive markers for HBsAg loss
during treatment with nucleoside/nucleotide analogues. Antivir Ther. 2011; 16:915–24.
13.Papatheodoridis G, Goulis J, Manolakopoulos S et al. Changes of HBsAg and interferoninducible protein 10 serum levels in naive HBeAg-negative chronic hepatitis B patients
under 4-year entecavir therapy. J Hepatol. 2014; 60:62–8.
14.Boni C, Laccabue D, Lampertico P et al. Restored function of HBV-specific T cells
after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology. 2012;
143:963–73.e9.
15.Cornberg M, Honer Zu Siederdissen C. HBsAg seroclearance with NUCs: rare but
important. Gut. 2014
O41
MYRCLUDEX B, AN NTCP-SPECIFIC INHIBITOR OF HBV
AND HDV ENTRY
Stephan Urban1
1
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Im
Neuenheimer Feld, Heidelberg, Germany
For almost three decades after the discovery of Hepatitis B Virus (HBV) the early events of
infection (attachment, receptor binding and fusion) remained entirely unresolved. Although
the extraordinary hepatotropism of HBV and its peculiar host specificity were supposed
to be linked to specific receptor binding, it stayed unclear which domain(s) within the
viral envelope protein(s) are essential for mediating entry and which cellular receptor(s)
are addressed. One reason was the sustained lack of suitable in vitro infection systems.
Following the establishment of the susceptible HepaRG cell line and primary hepatocytes
from humans (PHH) and tupaia belangeri (PTH) as reliable in vitro infection systems,
systematic analyses allowed the identification of a myristoylated preS1- subdomain as
essential for specific hepatocyte binding.
Using a different approaches sodium taurocholate co-transporting polypeptide (NTCP/
SCL10A1) could recently be identified as this highly specific hepatic receptor for the
myristoylated preS1 subdomain. The development of peptidic ligands of this receptor
as potent inhibitors of viral entry opened a novel therapeutic option to treat acute and
chronically infected patients. The exclusive targeting of the lead substance of such
lipopeptides (Myrcludex B) to NTCP in the liver and the remarkable inhibitory potential
at picomolar concentrations makes it a promising novel drug which successfully passed a
phase Ia clinical safety trial. It entered a phase IIa efficacy trials in chronically HBV and
HDV infected patients, which are currently running. Moreover, the identification of NTCP
as the long sought receptor for HBV allows the establishment of robust cell culture systems
and animal models for future approaches aiming at the identification of host dependency
and restriction factors, the identification of novel drugs and the development of immune
competent small animal models.
108
O42
NOVEL IMMUNOLOGICAL APPROACHES FOR
TREATMENT OF CHRONIC HEPATITIS B
Michael Roggendorf 1
1
Institute for Virology, Technical University Munich, München, Germany
Induction of HBV-specific T cells by therapeutic vaccination or immunomodulation may
be an innovative strategy to overcome virus persistence. Vaccination with commercially
available HBV vaccines in patients with or without reduction of viral load did not result in
effective control of HBV infection, suggesting that new formulations of therapeutic vaccines
are needed. The woodchuck (Marmota monax) is a useful preclinical model for developing
the such new therapeutic approaches in chronic hepadnaviral infections. Several innovative
approaches combining nucleos(t)ide analogues, with prime boost vaccination using DNA
or recombinant adenoviral vectors have been successfully tested in the woodchuck model.
In recent years several mechanisms have been characterized which interfere with an
adaptive immune response resulting in chronic outcome of viral infection. One of these
mechanisms, the interaction of programmed death receptor 1 (PD-1) with its receptor PDL1 has been shown to be activated in chronic hepatitis B infection. Thus, it is important to
study the role of PD-1/PD-L1 system in woodchucks as a preclinical model .By using PDL1 polyclonal antibodies the effects of PD-1/PD-L1 pathway blockade on enhancing WHVspecific immunity in chronically WHV infected animals was investigated. In vivo blocking
PD-1/PD-L1 pathway in combination with antiviral treatment and therapeutic vaccination
synergistically enhances the function of virus specific CD8 T cell, and improves viral control
in woodchucks chronically infected with WHV. About 30% of the treated animals eliminated
the virus from blood and liver and developed antibodies to the surface protein anti-WHs.
These results indicate that PD-1/PD-L1 system plays a very important role in the regulation
of virus-specific CD8 T cell responses during the chronic hepadnaviral infection. These
findings may be useful for the design of new immunotherapeutic strategies in patients with
chronic hepatitis B.
109
It is estimated that approximately 400 million people are chronically infected with HBV
worldwide. There are two types of antiviral therapies currently available for chronic HBV:
treatment with pegylated interferon alpha (PEG-IFNα) and nucleot(s)ide analogues.
However, treatment with PEG-IFNα leads to a sustained antiviral response in only about
30% patients and is associated with side effects.The introduction of PEG-IFNα in combination
with nucleoside analogues did not significantly increase the rate of sustained responders.
Although treatment with nucleoside analogues improves the clinical condition of chronic HBV
patients, it is hampered by emergence of drug resistance mutations, and rebounding viremia
after cessation of antiviral therapy, due to the persistence of the viral cccDNA in the liver.
Therefore, alternative strategies to treat chronic HBV infection are needed.
110
POSTER
ABSTARCTS
P01 - YI
QSAR STUDY OF NON-NUCLEOSIDE ANTI-HEPATITIS B
VIRUS AGENTS BY MLR AND SVM METHODS
Reza Aalizadeh1, Navid Moghadam Jamei 2, Javad Shadmanesh3
1
Laboratory of Analytical Chemistry, Department of Chemistry, University of Athens,
Panepistimiopolis Zografou, 157 71 Athens, Greece, 2Young Researchers and Elite Club, Ardabil
Branch, Islamic Azad University, Ardabil, Iran, 3Laboratory of Inorganic Chemistry and
Technology, Department of Chemistry, University of Athens, Panepistimiopolis Zografou, 157 71
Athens, Greece
Aims: The aim of this work is to investigate the correlation of the molecular structures of
the HBV surface antigen (HBsAg) inhibitors with their inhibition activities so as to identify
molecular structure requirements for designing of some active inhibitors.
POSTER ABSTRACTS
Methodology: A dataset consisted of35 compoundsdivided into training and test subsets
using hierarchal clustering technique. Stepwise method was applied to screen the most
respected molecular descriptorsin order toconstruct the predictive modelbased on training
set, and then the built predictive model was evaluated using test set compounds. The models
were validated by leave-one-out cross validation, external test set, applicability domain,
modified r2 and concordance correlation coefficient values, and employing evaluation set
from different experimental data set available in literatures. Euclidean based applicability
domain was employed to find out the structural diversity between evaluations set and
training set for prediction purpose.
112
Results: Performing the above work follow leaded to generation of a linear predictive model
for obtaining the inhibition activities of taken inhibitors was as follows:
Exp. = 17.119(±2.81)-20.043(±5.15)PW2 -2.944(±0.620) MATS5v -2.322 (±0.444)
Mor28p -0.4951(±0.1362) L2p +1.42371(±0.4850) R8e (eq.1)
The results were listed in Table 1 as follows:
TRAINING
TEST
R2
RMSE
F
CCC
R2
RMSE
F
CCC
r2m
MLR
0.868
0.167
28.89
0.929
SVM
0.976
0.086
97.06
0.980
0.866
0.125
1.053
0.888
0.684
0.905
0.094
0.665
0.899
0.688
Finally, to evaluate the acceptance of model the Golbraikh and Tropsha acceptable model
criteria’s were performed and the all given conditions by the validation rules, were confirmed
by built models.The selected descriptors were PW2, MATS5v, Mor28p, L2p, and R8e,
where the effect of PW2 (path/walk 2 - Randic shape index) is dominant.Based on these
results 35 new inhibitors were designed and their activities were predicted.
POSTER ABSTRACTS
Conclusions: The predictive ability of the proposed model was found to be satisfactory and
since the provided results were validated by different validation methods, therefore, they can
be used to predict the inhibition activities of subsequent new inhibitors with high reliability.
113
P02
RENAL FUNCTION DURING 2 YEARS TREATMENT
WITH TELBIVUDINE IN REAL-LIFE CLINICAL PRACTICE
(CLDT600AGR01)
Konstantinos Mimidis1, Ioannis Ketikoglou2, Maria Raptopoulou-Gigi3,
Konstantinos Kaligeros4, Ioannis Elefsiniotis5, Nikolaos Antonakopoulos6
1
1st Department of Internal Medicine, University Hospital of Alexandroupolis, Alexandroupolis,
2
Department of Internal Medicine, Ippokrateio Hospital, Athens, 32nd Medical Department,
Aristotle University Medical School, Thessaloniki, 43rd Department of Internal Medicine,
Sismanoglio Hospital, 5University Internal Medicine Clinic, General & Oncology Hospital
Athens “Agioi Anargyroi”, 6Medical Department, Novartis Pharmaceuticals, Athens, Greece
Introduction: Renal function during HBV treatment is of growing importance as recorded
at the latest EASL guidelines.
Aims: The aim of this study is to analyze renal function evolution in chronic HBV patients
under Telbivudine monotherapy in real-life clinical practice.
POSTER ABSTRACTS
Methodology: We report an interim analysis of an ongoing real-life study in CHB. 90 HBeAg
positive and negative, nucleos(t)ide-naive patients from 6 Greek tertiary Hepatology centers
were followed up for 2 years under Telbivudine monotherapy. Renal function was recorded
at Day 1, months 6, 12 and 24, assessing both serum creatinine and eGFR (Cockroft-Gault,
MDRD4, CKD-EPI).
Results: Mixed-model regression analysis showed a significant decrease of serum creatinine
levels over time (β=-0.02, SE=0.01, P=0.027) and a significant increase of eGFR levels
(Cockcroft-Gault) levels over time (β=2.35, SE=0.85, P=0.006). Moreover, the significant
increase of eGFR levels was confirmed with the MDRD4 (β=2.45, SE=0.88, P=0.005) and
CKD-EPI formula as well (β=1.32, SE=0.59, P=0.024).
Telbivudine’s “reno-protective effect” was also observed at the subgroup of patients over
50 years, as assessed with an increase in eGFR with CKD-EPI formula (β=1.92, SE=0.88,
P=0.029) 71.4% (10/14) of patients with baseline eGFR (CKD-EPI) 60- 90 ml/min/1.73m2
shifted to >90 ml/min/1.73m2 at year 2.
114
Conclusions: Renal function was significantly improved after 24 months treatment with
telbivudine. This beneficial effect was applicable in the subgroup of patients over 50 years
old, adding to the growing literature of this finding.
POSTER ABSTRACTS
Figure:
115
P03 -YI
THE APPLICATION OF DATA MINING TECHNIQUES TO
EXPLORE PREDICTORS OF DELTA VIRUS (HDV) IN
EGYPTIAN PATIENTS WITH CHRONIC HBV
Abubakr Awad1, Rabab Fouad2, Mahasen Mabrouk2, Dina Sabry3, Mira Atef2, Naglaa Zayed2
1
Computer Science, Faculty of Computers and Information - Cairo University, 2Endemic
Medicine and Hepatology, 3Medical Biochemistry and Molecular Biology, Faculty of Medicine Cairo University, Giza, Egypt
Introduction: Between 15 and 20 million persons are infected with delta virus (HDV)
globally, particularly in the Mediterranean basin and is associated with severe liver disease.
These findings emphasize the need for an innovative, economic, reliable, non-invasive
technique for prediction of HDV diagnosis utilizing simple clinical, and laboratory data.
Data mining is a method of predictive analysis, which can explore tremendous volumes
of rich information found in electronic health records to discover hidden patterns and
relationships.
Aims: To develop an economic, reliable, easy to apply and acceptable algorithm for
prediction of HDV prevalence in chronic HBV patients to restrict un-necassary screening
for HDV.
POSTER ABSTRACTS
Methodology: The study included 121 chronic HBV patients attending outpatient clinic at
Cairo-Fatemic Hospital, Ministry of Health and Population, Egypt. Patients were subjected
to clinical assessment, routine laboratory investigations, HBsAg, HBeAg (ELISA), HBcAb
(IgM, IgG), HBV-DNA qPCR (Real Time PCR), IgG for HDV and qPCR for HDV RNA.
Using the data mining analysis, we constructed decision tree learning algorithm (REP
TREE) to predict HDV using 25 clinical, laboratory, and serological attributes.
Results: The prevalence of HDV in chronic HBV patients was 8.3% by HDV IgG and
9.9% by HDV-PCR. Decision tree algorithm was able to predict HDV with high sensitivity
and specificity (table 1). Out of 25 attributes, the decision-tree model showed that HBV
viraemia at an optimal cutoff value 229 IU/Ml was selected as the best predictor, and to
a less extent Hb levels < 14.3g/dl (figure 1). Delta patients with negative HBeAg status
(90.9%) were associated with low HBV viremia, which could be represented by prevalence
of inactive carrier state in 66.7% among them.
Conclusions: Serum level of HBV-DNA and Hb levels are simple variables that have
the prospective for prediction of prevalence HDV in chronic HBV patients. The proposed
prediction model can help physicians by restricting the use of screening methods only to
patients presenting a high probability of HDV. This is especially beneficial in clinical settings
in countries with limited resources as Egypt.
116
POSTER ABSTRACTS
117
P04 - YI
THE ROLE OF AN INTERVAL LIVER BIOPSY IN PATIENTS
WHO REMAIN UNTREATED FOR HEPATITIS B AFTER AN
INITIAL BIOPSY
Ashley Barnabas1, Victoria Kronsten1, Matthew Bruce1, Mary Horner1,
Kosh Agarwal1, Ivana Carey1
1
Institute for Liver Studies, King’s College Hospital, London, United Kingdom
Introduction: In untreated chronic hepatitis B (CHB) infection, the utility of repeat liver
biopsy is unknown, when an initial biopsy does not identify significant liver damage. We
hypothesised that in patients with persistently elevated HBV DNA levels despite such initial
histological findings, an interval liver biopsy is indicated
Aims: 1.To assess if repeating a liver biopsy, after an interval, in patients who remain
untreated for CHB after an initial biopsy is clinically useful when markers of active CHB
persist.2. To identify markers at initial biopsy that predict progressive liver disease.
POSTER ABSTRACTS
Methodology: Retrospective review of our liver biopsy database and casenotes was
performed. Plasma IP10, HBsAg, AST and HBV DNA levels were measured by ELISA [pg/
ml], Abbott ARCHITECT® assay [log10IU/ml], AutoAnalyser [IU/l] and real-time TaqMan
PCR [log10IU/ml] at time of initial and repeat liver biopsy.
Results: We identified 21 patients (95% HBeAg negative, 10 males, median age 37.5 years)
with persistent laboratory markers of active HBV disease (HBV DNA >2000IU/ml) after the
first biopsy. In the first biopsy median necro-inflammatory grade was 2 and median fibrosis
stage was 1 by Ishak scoring system. The median interval between biopsies was 4.2 years.
9 patients had a 1-2 stage increase in fibrosis on Ishak score. 12 patients had no change
or regression in fibrosis score. One HBeAg positive patient progressed from stage 1 to
stage 4 fibrosis. 6 patients developed moderate inflammation (grade>3) at repeat biopsy. 7
patients started antiviral treatment due to disease progression. HBsAg, HBV DNA and liver
transaminases levels at time of the first biopsy were similar in patients with and without liver
disease progression in repeated biopsy (HBsAg: 4.02 vs.3.8; HBV DNA: 3.93 vs.3.49, AST:
22 vs.27; all p>0.05). IP10 levels at time of the first biopsy were higher in patients with disease
progression on the second biopsy than in patients without progression (222 vs.134 pg/ml,
p=0.004). No HBeAg negative patient progressed by more than two stages in fibrosis.
Conclusions: Repeat biopsy is needed to reassess disease in this patient group as 43% of
patients demonstrated features of significant liver injury at interval biopsy. As no HBeAg
negative patients developed advanced fibrosis, a four year interval seems appropriate in this
group. IP10 plasma levels > 200 pg/ml at the time of initial biopsy is helpful in predicting
disease progression (PPV 78%).
118
P05- YI
TO STUDY THE EFFECT OF ENTECAVIR AND INTERFERON
COMBINATION WITH INTERFERON AND ENTECAVIR
ALONE IN MANAGEMENT OF HBE ANTIGEN POSITIVE
CHRONIC HEPATITIS B
Hira Bashir1, Shamail zafar2, Gulsena Masood Khan2
1
Medicine & Gastroenterology, 2Medicine, Lahore Medical & Dental College, Lahore, Pakistan
Introduction: Two types of therapies are available for treatment of CHB i.e. Nucleos(t)ide
analogues and Interferon. NUC’s inhibit HBV polymerase thus inhibiting HBV replication
while Interferon has both antiviral and immunomodulatory effects.
Aims:We planned this study to combine Entecavir with Pegylated Interferon and to see combination
effect of these two medicines in comparison with Entecavir and PEG interferon alone.
Methodology: It was randomized, comparative study. Patients were assigned following groups
1. PEG-Interferon 2a once weekly for one year. (Group A)
2. PEG-Interferon 2a in combination with Entecavir 0.5 mg OD for one year (Group B)
followed by Entecavir only.
3. Entecavir 0.5 mg OD for 104 weeks. (Group C)
Results: At time of evaluation i.e. week 104, proportion of patients with HBeAg
Seroconversion was 50% (7 out of 14 patients) for Group A, 36 % (5 of 14 patients)
for Group B and 27% (4 of 15 patients) for Group C. (95% CI: 1.7-25.6 %; p=0.022).
Similarly suppression of HBV DNA to not detected levels was 86% (12 out of 14 Patients)
for the combination group while it was 50% (7 out of 14 patients) for Group B, whereas it
was 47% for Group C (7 out of 15 Patients). (95% CI: 4.4-31.5%; p=0.012). Biochemical
response i.e. ALT normalization was 57% (8 out of 14 patients) for the combination group,
50% (7 out of 14 Patients) for the PEG group and 53 % (8 out of 15 Patients) for the
Entecavir group. (95 % CI: 5.7-35.5%; p=0.011). HBsAg seroconversion was 14% (2 out
of 14 patients) in the combination group while it 0 % for both Groups B and C.
Conclusions: One year therapy with combination of PEG interferon2a in combination with
Entecavir proved better thanusing both therapies alone for not only early viral suppression
and ALT normalization but also for HBe and HBs seroconversion.
119
POSTER ABSTRACTS
HBeAg, Anti HBe, HBeAg, Anti HBsAg and HBV DNA Quantitative essay were done
every 12 weeks for 104 weeks. Primary treatment comparison was HBs seroconversion.
Other efficacy measures were disappearance of HBV DNA, HBeAg seroconversion and
normalization of ALT.
P06 - YI
TO ASSESS THE VACCINATION STATUS AND ITS
IMMUNOLOGICAL RESPONSE, UP TO SEVEN YEARS
AFTER VACCINATION AMONG MEDICAL COLLEGE
STUDENTS.
Hira Bashir1, Shamail zafar2, Gulsena Masood Khan2
1
Medicine & Gastroenterology, 2Medicine, Lahore Medical & Dental College, Lahore, Pakistan
Introduction: Immunization with Hepatitis B vaccine is the most effective means, of
preventing this infection and its consequences. In fact, the number of reported cases among
Health care workers has declined from 1990 onwards due to courtesy of this vaccine. Due
to lack of followup vaning immunity levels can render a subject vulnerable to Hepatitis B.
Aims: We conducted the present study, in order to declare our institution as fully immunized
against Hepatitis B and to determine the level of immunity among students who have been
immunized previously.
POSTER ABSTRACTS
Methodology: Four hundred and eighty medical students were interviewed after verbal
consent. The particulars of students were entered in self administered questionnaires by
convenience sampling. Blood samples were drawn and checked for hepatitis B antibodies
and hepatitis B surface antigen.
Sample size of 480 was calculated using 5% level of significance, margin of error as 5%.
Descriptive statistics like percentages, mean and range were calculated. Subjects were
grouped as years after vaccination and data compiled according to their anti HBs status.
Odds ratio and 95% confidence interval were presented as the risk factor. Data was entered
in SPSS software and analysis was done using student t-test.
Group – I: “Immune by vaccination”
Group – II: “Waning protective antibody after vaccination”
Group – III:“No immunity”
Group – IV: “Immune by natural infection”
Group – V: “Chronic infection”
120
Results: There were a total of 480 medical students, 290(60.4%) were female while 190
(39.6%) were male. Ages ranged from 17 to 25 years with a mean age of 20.47 years (SD
=1.64). 236 students (49.2%) were found to be positive for Anti HBs while 244 (50.8%)
were found to be negative for Anti HBs. Out of those who were negative for Anti HBs, 34
(7.1%) claimed that they were previously vaccinated (p-value <0.01). 13 students (2.7%)
were found positive for HBs Ag (p-value <0.01). Students were found to have a statistically
significant drop of vaccination cover as the years elapsed since completion of vaccination
course.197 (41%) were those who never had previous vaccination and were offered full
three doses of vaccination.
POSTER ABSTRACTS
Conclusions: In a time range of one to seven years post vaccination 34 (7.1%) of students
lost the protective cover of antibodies and required to receive a booster dose to achieve
antibodies level of 10mIU/ml.
121
P07
RELATIONSHIP BETWEEN VIRAL LOAD AND HBSAG
LEVEL IN PREGNANT WOMEN WITH CHRONIC HEPATITIS
B VIRUS INFECTION
Maria Belopolskaya1,Viktor Avrutin2, Sergey Firsov3, Alexey Yakovlev3,4
1
Polyclinic, Botkin Infection Disease Hospital, St.-Petersburg, Russia, 2institute for system theory,
University of Stuttgart, Stuttgart, Germany, 3Botkin Infection Disease Hospital, 4St. Petersburg
State University, St.-Petersburg, Russia
Introduction: Viral load and HBsAg level are important markers used to diagnose hepatitis
B and to determine its phase. The viral load’s measurement is necessary to estimate
mother-to-child transmission risk for women with chronic hepatitis B (CHB). Recently,
the relationship between hepatitis B virus (HBV) viral load and other markers has been
investigated by many authors.
Aims: The present study was undertaken to investigate the relationship between the levels
of HBV DNA and HBsAg in CHB pregnant women and to estimate potential applications
of HBsAg level monitoring.
POSTER ABSTRACTS
Methodology: 85 patients with CHB were included in the study. Three groups of CHB
patients were considered: the main group of 31 pregnant women and 2 control groups:
26 non-pregnant women and 28 men. HBV DNA was measured by real-time polymerase
chain reaction. HBsAg level was measured by chemiluminiscent immunoassay method.
Relationship between viral load and HBsAg level was determined by the Spearman rank
correlation rho.
Results: In the group of all patients we obtain rho=0.3762 (P<0.0005; n=85). This confirms
the significance of the correlation between the levels of HBsAg and HBV DNA. By contrast
to control groups, the group of pregnant women included a large number of patients with
an unmeasurable value of HBV DNA between 50 and 150 IU/ml. In this group we get the
value rho=0.1871 (P<0.25; n=31). This value, corresponding to a weak (but still present)
correlation between HBsAg and HBV DNA levels can be explained by a large number
of patients with identical ranks caused by an unmeasurable value of HBV DNA. Indeed,
excluding the patients with an unmeasurable value of HBV DNA from consideration, we
obtain the value rho=0.4211 (P<0.05; n=18) which is much closer to the results obtained
for control groups: rho=0.4728 (P<0.01; n=26) for non-pregnant women and rho=0.4812
(P<0.01; n=28) for men. In patients with a high HBsAg level both high and low level of viral
load can be observed, while a low level of HBsAg correlates with a low HBV DNA level.
Conclusions: 1. Correlation between HBsAg and HBV DNA levels is significant.
2. In the group of pregnant women a low HBV DNA level is observed more frequently than
in other groups. This leads to a decrease of the Spearman rank correlation coefficient rho
in this group. 3.A low level of HBsAg indicates a low HBV DNA level, a high HBsAg level
does not always correspond to a high viral load.
122
P08 - YI
COMBINING HEPATITIS B SURFACE ANTIGEN WITH
TETANUS FOR A SINGLE ORAL VACCINE
Mani Bhargava1, Saurabh Bhargava2,Vishal Bhargava3
1
ICFAI University, 2Manav Bharti University, 3KRV Hospitals Pvt. Ltd., Kanpur, India
Introduction: The desirability of combination vaccines has intensified recently with
declining vaccine coverage and growing public concern about new virulent disease outbreaks.
Moreover, oral immunization induces both mucosal and systemic immune responses,
whereas mucosal responses are not generally observed following systemic immunization.
Aims: The goal of the present study was to investigate the potentials of Archaeosomes as a
carrier for oral combination vaccine. Recombinant hepatitis B surface antigen (HBsAg) and
Tetanus Toxoid (TT) were chosen as the candidate antigens.
Results: TEM photomicrographs indicate stable, multilamellar vesicles. CLSM
photomicrographs revealed localized fluorescence in the GALT region was much higher
compared to control indicating effective uptake of archaeosomes. Prepared formulations
produced comparable specific IgG levels to those observed in the case of Intramuscular
(IM) administration of alum adsorbed antigens. Also they elicited measurable sIgA in
mucosal secretions, while alum adsorbed antigens failed to elicit such responses.
123
POSTER ABSTRACTS
Methodology: Archaeosomes containing HBsAg & TT were prepared by using polar
lipid extracted from T. acidophilum using lipid cast film method. The morphological
study of archaeosomes was done by transmission electron microscope, mean particle size
determined by Malvern Zetasizer. The amount of entrapped antigen was determined using
Bicinchoninic Acid method. CLSM was carried out to confirm the uptake of archaeosomes.
Stability studies were performed in simulated gastric fluid (SGF), simulated intestinal fluid
(SIF). In-vivo studies were performed on female BALB/c mice by immunizing them orally
and IgG response in serum and sIgA was determined in various body secretions using
specific ELISA.
Conclusions: When HBsAg & TT were given in combination in archaeosomes orally, the
system produced anti-HBsAg and anti-TT antibody comparable to the IM given preparations.
This can be due to antigen competition or self-adjuvating effect of archaeosomes. The
combination of HBsAg & TT loaded archaeosomes produced both systemic as well as
mucosal antibody responses upon oral administration. Thus, archaeosomes are a promising
carrier for oral combination vaccines. This approach could be adapted for human use
because the mucosal surfaces are the initial sites of infection and it therefore seems logical
to attempt to develop vaccination strategies that evoke appropriate localized responses to
counteract the early events of pathogenesis
POSTER ABSTRACTS
Figure:
124
P09
EVALUATION OF LIVER FUNCTION IN PATIENTS WITH
HEPATITIS B INFECTION – ACUTE, CHRONIC HEPATITIS
AND LIVER CIRRHOSIS
Yana Boyanova1, Krasimir Antonov1, Asen Aleksiev1, Olga Kosseva 1, Deian Jelev1,
Lyudmila Mateva1, Zahariy Krastev1, Christian de Mey2
1
Clinic Of Gastroenterology, St Ivan Rilski University Hospital, Sofia, Bulgaria, 2
ACPS - Applied Clinical Pharmacology Services, Mainz-Kastel, Germany
Introduction: Fluorescein Lisicol (NRL972, Norgine, UK), a fluorescent-labelled bile
salt is cleared via biliary excretion without entero-hepatic recycling or biotransformation.
Its plasma-concentration ratio 30/10 minutes after a 2 mg i.v. injection NRL972
(CR=C(30):C(10)) is an investigational marker of the severity and progression of hepatic
functional impairment.
Aims: The study aims to evaluate NRL972 CR in acute hepatitis B (AHB), chronic
hepatitis B (CHB) and HBV-associated liver cirrhosis (HBCIR).
Results: Upon hospitalisation, AHB-patients showed severely impaired NRL972elimination (median CR: 0.84; range: 0.71 to 0.88), which improved markedly after 4
(median CR: 0.37; range: 0.19 to 0.77) and 8 weeks (median CR: 0.27; range: 0.16 to
0.57) on average, but at 8 weeks almost half of the patients (47%) retained a CR > 0,30
and 18% were with impaired function: CR > 0,40. Prior to treatment, CHB-patients had
a median CR of 0.33; on-treatment, NRL972-elimination tended to become slower, but a
small improvement was seen 3-6 months after treatment (median CR: 0.26 for both). In
HBCIR-patients, NRL972-elimination was impaired more in Child-B&C-patients (median
CR: 0.76; range: 0.68 to 0.87) than Child-A (median CR: 0.62; range: 0.36 to 0.81). CR in
early-onset AHB was well comparable with severe HBCIR; also, 22% of the CHB-patients
had a dysfunction similar to that otherwise seen in severe HBCIR, whereas 36% of the
HBCIR-patients had CR-values in the range (0,36 to 0,63) seen in CHB.
Conclusions: NRL972-testing provides useful information pertinent to disease within and
across different HB-disease forms in a way essentially different from viral load, enzymes
and histology.
125
POSTER ABSTRACTS
Methodology: Patients with AHB (N:19), CHB treated with Peg-IFN or entecavir (N:23)
and HBCIR-patients (N:11) were investigated. In AHB, NRL972-testing was performed
upon hospitalization and 1, 4, and 8 weeks later. CHB were tested before, every 3 months
on-treatment and 3- 6 months later.
P10 - YI
LOSS OF HEPATITIS B SURFACE ANTIGEN IS NOT
COMMON AMONG PATIENTS INFECTED WITH HIV AND
HEPATITIS B VIRUS
Anders Boyd1, Joël Gozlan2, Patrick Miailhes3, Caroline Lascoux-Combe4,
Hayette Rougier5, Pierre-Marie Girard5, Karine Lacombe5
1
Inserm UMRS_1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique,
2
Laboratoire de Virologie, Hôpital Saint-Antoine, Paris, 3Infectious Diseases Department,
Hospices Civils de Lyon, Lyon, 4Department of Infectious Diseases, Hôpital Saint-Louis,
5
Service des maladies infectieuses et tropicales, Hôpital Saint-Antoine, Paris, France
Introduction: Among patients coinfected with HIV and hepatitis B virus (HBV), hepatitis
B surface antigen (HBsAg)-loss and, among hepatitis B “e” antigen (HBeAg)-positive
patients, HBeAg-loss have only been described retrospectively or during antiviral treatment
with a finite range of potency.
Aims: The objective of this study was to examine the rates and determinants of HBsAg- and
HBeAg-loss in a large, contemporary, prospective cohort of HIV-HBV infected patients.
POSTER ABSTRACTS
Methodology: 290 patients with HBsAg-positive serology (>6 months) were followed.
Complete HBV serological battery (HBeAg, anti-HBe antibodies, HBsAg, and anti-HBs
antibodies) was taken at inclusion and every yearly visit. Piecewise exponential survival
models were used to determine risk-factors associated with HBeAg- and HBsAg-loss.
Results: During a median 7.4 years (IQR: 3.1-8.0) of follow-up, rates of undetectable
HBV-DNA viral load (<60 IU/mL) substantially increased from 39.1% at inclusion to
90.6% at the end of follow-up. Accordingly, tenofovir use became more frequent, with
19.0% at inclusion and 85.5% towards the end of follow-up, while 35 (12.1%) patients
received concomitant pegylated-interferon therapy at some point during follow-up.
In HBeAg-positive patients (N=151), the incidence rate of HBeAg-loss was 8.4/100
person·years after a median 3.0 years (IQR: 2.0-4.9) of follow-up. In multivariable
analysis, higher cumulative HIV-RNA (HR=0.84, 95%CI: 0.71-0.99, p=0.04) and HBVDNA replication (HR=0.73, 95%CI: 0.67-0.79, p<0.001) were significantly associated
with decreased rates in HBeAg-loss.
126
Overall, the incidence rate of HBsAg-loss was 1.0/100 person·years after a median 4.6 years
(IQR: 2.1-7.2) of follow-up. HBsAg-loss occurred at a consistent rate, with cumulative
proportion of patients remaining HBsAg-positive at 99.3%, 97.8%, 95.8%, and 94.6% after
1, 3, 5, and 7 years of follow-up, respectively. Again, rates of HBsAg-loss were much lower
with increased cumulative HIV-RNA (HR=0.52, 95%CI: 0.31-0.87, p=0.01) and HBVDNA replication (HR=0.75, 95%CI: 0.55-1.02, p=0.06). Longer cumulative periods of
anti-HBV treatment were not associated with HBeAg- or HBsAg-loss.
POSTER ABSTRACTS
Conclusions: Despite high rates of HBV virological suppression and increased use of
potent anti-HBV therapy, HBsAg-loss remains uncommon in HIV-HBV co-infected
patients. Suppression of HIV and HBV are pivotal in increasing the rate of this important
therapeutic outcome.
127
P11 - YI
EFFECT OF IMMUNOSUPPRESSION AND ANTIVIRAL
THERAPY IN PERSISTENT INTRACELLULAR REPLICATION
AMONG HEPATITIS B VIRUS AND HIV-CO-INFECTED
PATIENTS
Anders Boyd1, Karine Lacombe2, Fabien Lavocat3, Sarah Maylin4, Patrick Miailhes5,
Caroline Lascoux-Combe6, Constance Delaugerre4, Pierre-Marie Girard2, Fabien Zoulim3
1
Inserm UMRS_1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique,
2
Service des maladies infectieuses et tropicales, Hôpital Saint-Antoine, Paris, 3Inserm,
U1052, UMR CNRS 5268, Centre de Recherche en Cancérologie de Lyon, Lyon,
4
Laboratoire de Virologie, Hôpital Saint-Louis, Paris, 5Infectious Diseases Department, Hospices
Civils de Lyon, Lyon, 6Department of Infectious Diseases, Hôpital Saint-Louis, Paris, France
Introduction: Covalently closed circular DNA (ccc-DNA) of hepatitis B virus (HBV) acts
as a reservoir for reactivation of viral replication and whose quantification can be used as a
marker of persistent intracellular replication.
Aims: The determinants of intracellular levels of replication have rarely been evaluated in
HBV-human immunodeficiency virus (HIV) co-infected patients.
POSTER ABSTRACTS
Methodology: Sixty HIV-HBV co-infected patients with at least one liver biopsy during
follow-up in the French HIV-HBV cohort were included. HBV ccc-DNA and total
intracellular HBV-DNA were extracted from biopsies and quantified by real-time PCR.
Risk-factors of intracellular replication were determined using mixed-effect linear regression
models.
Results: At the time of biopsy, 35 (61.4%) patients were HBeAg-positive and 23 (46.9%)
had detectable serum HBV-DNA (median: 3.10 log10 IU/mL, IQR:2.75-5.38). Among
the 22 patients undergoing tenofovir (TDF)-containing antiretroviral therapy, cumulative
TDF-duration was at a median 17.8 months (IQR:5.7-31.0). Overall, median HBV cccDNA was -1.10 log10 copies/cell (IQR:-1.70, -0.29) and total intracellular HBV-DNA was
0.27 log10 copies/cell (IQR:-0.39, 2.00).
128
In multivariable analysis, patients with HBeAg-positive serology had significantly higher
levels of HBV ccc-DNA (+0.76 log10 copies/mL; 95%CI:0.39, 1.13; p<0.001), whereas
those with a nadir CD4+ cell count above 250/mm3 had significantly lower HBV ccc-DNA
levels (-0.57 log10 copies/mL; 95%CI:-0.95, -0.19; p=0.004). Furthermore, patients with
longer than 3 years of cumulative TDF-duration had significantly lower HBV ccc-DNA
levels after adjustment (-0.88 log10 copies/cell: 95%CI:-1.40, -0.35; p=0.001). Accordingly,
when focusing on patients undergoing TDF with a biopsy at TDF-initiation and sometime
during therapy (median duration: 35.3 months, range: 20.2-56.6), most exhibited strong
declines in HBV ccc-DNA (median change in log10 copies/cell/year:-0.46, range:-0.67, 0;
n=7). HBV ccc-DNA levels did remain detectable at the end of follow-up for all patients, yet
at very low levels (median: 0.04 copies/cell, range:0.01, 0.31). The results above were similar
when using total intracellular HBV-DNA levels as an end-point.
POSTER ABSTRACTS
Conclusions: In coinfected patients, severe immunosuppression is associated with
intracellular HBV replication. Treatment with TDF is linked to large declines in ccc-DNA,
yet replication within the hepatocyte still persists after long periods of treatment.
129
P12
THE RISK OF HEPATOCELLULAR CARCINOMA IN HBV
CIRRHOSIS IS AFFECTED BY POLYMORPHISMS OF THE
MERTK GENE
Fabrizio Bronte1, Rosaria Maria Pipitone1, Stefania Grimaudo1, Donatella Ferraro2,
Vincenza Calvaruso1, Sandro Sferrazza1, Giulia Pecoraro1, Antonio Craxì1,Vito Di Marco1
1
Sezione di Gastroenterologia, Di.Bi.Mi.S, 2Sezione di Virologia Dip.PRO.SA.M.I,
University of Palermo, Palermo, Italy
Introduction: Patients with chronic HBV infection who have long term viral suppression
on NUCs are still at risk of developing hepatocellular carcinoma (HCC) at an yearly rate
from 2.8% to 4.8%. Single nucleotide polymorphisms (SNPs) of the MERTK gene are
known to modulate tumor-associated macrophages and may influence angiogenesis and
carcinogenesis.
Aims: We assessed the potential association between allelic polymorphism of the rs4374383
SNP in the MERTK gene and the risk of development of HCC among patients who had
active HBV replication and in patients who achieved a virological suppression on long term
NUCs treatment.
POSTER ABSTRACTS
Methodology: Enrollment cohort of 327 consecutive patients with chronic HBV infection
at first presentation (169 chronic hepatitis; 133 cirrhosis; 25 HCC) on clinical and US
6-monthly surveillance. Two hundred and forty-eight were given long term treatment
with NUCs (entecavir or tenofovir). SNPs were tested by TaqMan SNP genotyping allelic
discrimination (Applied Biosystems, Foster City, CA-USA) on stored sera.
Results: The overall distribution of SNP rs4374383 alleles was: AA 14.8%, AG 44.4%,
GG 40.8%. Among 25 patients with HCC at baseline (mean age 62 years, 72% male), 3
(12%) were GG and 22 (88%) GA or AA. Among the remaining 302 patients with chronic
hepatitis or cirrhosis (mean age 51 years, 78% male), 131 (43.3%) were GG and 131
(56.6%) AG or AA genotypes (OR: 5.62; 95%CI: 1.65-19.17 p 0.002). In the group on
long term NUCs, all 248 patients had reached HBV undetectability by PCR (< 20 IU)
within one year of therapy.
130
Thirty of these patients developed HCC during follow-up (median 36.2 months; range
8.8-82). These patients had the GG polymorphism in 8 cases (26.7%) and the GA or AA
in 22 (73.3%). Among the 218 who did not develop HCC, 101 (46.3%) were GG and 117
(53.7%) GA or AA (OR: 2.37; 95%CI: 1.01-5-56 p 0.041). Patients on NUCs with chronic
hepatitis had a lower risk of HCC than those with cirrhosis (OR: 0.13; 95%CI: 0.04-0.40;
p=0.0001) and cirrhotic patients with GG genotype had a lower risk of HCC than patients
with AG or AA genotypes (OR: 0.35; 95%CI: 0.13-0.96; p=0.036).
POSTER ABSTRACTS
Conclusions: The AG or AA genotypes of rs4374383 SNP of the MERTK gene confers
a significant additional risk of developing HCC to patients with chronic HBV infection,
especially in the presence of cirrhosis. Testing patients on NUCs suppressive treatment for
this SNP may allow to tailor surveillance for HCC.
131
P13
NUTRITIONAL ASSESSMENT IN PATIENTS WITH
CIRRHOSIS FROM VIRAL AND NON-VIRAL ETIOLOGIES
Chalermrat Bunchorntavakul1, Kanokpoj Chanpiwat1
1
Gastroenterology and Hepatology, Rajavithi Hospital, MInistry of Public Health,
Bangkok, Thailand
Introduction: Malnutrition is an important prognostic factor among in patients with
cirrhosis. The prevalence of malnutrition in this population varies according to several
factors including the etiology and the severity of liver disease, as well as the method of
nutritional assessment used.
Aims: To evaluate nutritional status among patients with cirrhosis from viral and non-viral
etiologies by several assessment methods.
POSTER ABSTRACTS
Methodology: This cross-sectional study was conducted at Rajavithi Hospital, Bangkok,
Thailand, between Oct 2013 and Jan 2014. Patients with cirrhosis at outpatient clinic were
assessed for their nutritional status several methods including subjective global assessment
(SGA), anthropometry (body mass index, triceps skinfold thickness and mid-arm muscle
circumference; MAMC), hand grip strength dynamometry (HGS), and bioelectrical
impedance analysis (BIA). Malnutrition was defined by standard cut-point for general
population of each method. Patients with hepatocellular carcinoma, overt encephalopathy,
and severe other comorbidities were excluded.
Results: Eighty-five patients were evaluated, 54% were male and the mean age was 54.4
± 11.6 years. Most patients were Child-Pugh class A (80%) and the common etiologies of
cirrhosis were hepatitis B (35%), hepatitis C (27%), and alcohol (21%). The prevalence of
malnutrition was varied according to the assessment methods used; 44.7% by SGA, 51.8%
by MAMC, and 36.5% by HGS, and 15.3% by BIA. There was a strong correlation between
skeletal muscle mass measured by BIA and MAMC (k=0.4036, p<0.0001); and HGS
(k=0.736, p<0.0001). SGA showed slightly agreement with HGS (k=0.298, p <0.05); and
BIA (k=0.291, p<0.05). The prevalence of malnutrition were 49% vs 38% by SGA, 34%
vs 41% by HGS, and 51% vs 53% by MAMC in viral vs non-viral etiologies of cirrhosis,
respectively. There was no significant difference in each nutritional parameter between viral
and non-viral etiologies of cirrhosis [table], as well as between viral hepatitis B and C.
132
Conclusions: Although the prevalence is varied according to the assessment methods used,
malnutrition is common (15-52%) in patients with cirrhosis even in those with Child-Pugh
class A. There were no differences in the prevalence of malnutrition and the nutritional
parameters between viral and non-viral etiologies of cirrhosis.
POSTER ABSTRACTS
Table:
133
P14
BONE MINERAL DENSITY AND RENAL FUNCTION
IN CHRONIC HEPATITIS B PATIENTS RECEIVING
NUCLEOTIDE VERSUS NUCLEOSIDE ANALOGS: A PILOT
PROSPECTIVE STUDY
Chalermrat Bunchorntavakul1,Vitoon Taweewattanakitbavorn1
1
Gastroenterology, Rajavithi Hospital, Bangkok, Thailand
Introduction: Nucleotide analogs (tenofovir and adefovir) are associated with negative
impact on bone mineral density (BMD) and renal function, which is mainly explained by
proximal tubular dysfunction and hypophosphatemia. However, prospective data assessing
bone and renal safety of these agents are limited.
Aims: To evaluate the prevalence of bone disease among patients with non-cirrhotic CHB
receiving antiviral therapy and to evaluate changes in BMD and glomerular filtration rate
(GFR) between CHB patients receiving nucleotide (NTA) versus nucleoside analogs
(NSA).
POSTER ABSTRACTS
Methodology: Data of CHB patients without established cirrhosis who had been treated
with oral antiviral therapy for <1 year in a single tertiary center (Rajavithi Hospital, Bangkok)
were prospectively collected between 2012-2014. Patients with significant comorbidities or
receiving the treatment for bone disease (other than calcium supplement) were excluded.
BMD assessment was performed by dual x-ray absorptiometry at the lumbar spine (LS)
and the femoral neck (FN). The results of BMD were compared with mean BMD from ageand sex- matched controls from Asian database and expressed as SD of the mean (Z-score).
Osteopenia and osteoporosis were defined as BMD between 1 and 2.5 and more than 2.5
SD below the mean BMD for young adults (T-score), respectively. The GFR was estimated
by Cockcroft-Gault method.
Results: Fourteen patients were included; 86% were men, 43% were HBeAg positive, and
the median age was 41.1 (25.6-63.5) years. Eight patients had been treated with NTA (5
tenofovir, 3 adefovir) and 6 patients had been treated with NSA (4 lamivudine, 2 entecavir),
with a median follow-up period of 1.5 years (1.2-1.6). At baseline, the overall prevalence of
osteoporosis and osteopenia were 7.1% and 35.7%, respectively and the median GFR was
95.4 (47-144) ml/min.
134
LS-BMD in CHB patients was slightly lower than age-matched population with median
Z-scores of -0.2 (-2.6 to 2.0) at LS and 0.1 (-1.6 to 2.1) at FN region. Baseline characteristics
and changes in BMD and GFR over years of follow up were summarized in the table.
There was a trend toward a decrease in LS-BMD and GFR in patients who received NTA
compared to those who received NSA, however this was not statistically significant.
Conclusions: Osteopenia is relatively common in CHB patients without cirrhosis receiving
oral antiviral therapy. There was a non-significant trend toward a reduction in LS-BMD
(representing trabecular bone) and GFR in patients receiving NTA.
POSTER ABSTRACTS
Table:
135
P15
EFFICACY OF HBV DNA AND HBSAG QUANTIFICATIONS
AND LIVER STIFFNESS MEASUREMENT IN IDENTIFYING
INACTIVE HBV CARRIERS AT A SINGLE TIME POINT
EVALUATION
Sergio Maimone1, Gaia Caccamo1, Giovanni Squadrito2, Angela Alibrandi3,
Francesca Saffioti2, Rosaria Spinella2, Giuseppina Raffa1, Teresa Pollicino4, Giovanni Raimondo2
1
Division of Clinical and Molecular Hepatology, 2Department of Clinical and Experimental
Medicine, Azienda Ospedaliera Universitaria “G. Martino” di Messina, 3Department of
SEFISAST, University of di Messina, 4Department of Pediatric, Gynecologic, Microbiological,
and Biomedical Sciences, Azienda Ospedaliera Universitaria “G. Martino” di Messina,
Messina, Italy
Introduction: According to the international guidelines, a narrow longitudinal evaluation
of HBV DNA and ALT levels is required to identify inactive HBV carriers (ICs). Recently,
HBsAg quantification (qHBsAg) as well as liver stiffness measurements (LSM) have been
proposed as useful diagnostic tools in chronic HBV infection.
POSTER ABSTRACTS
Aims: Aim of this study was to evaluate the efficacy of HBV DNA quantification, qHBsAg
and LSM in identifying the IC status at a single time point investigation.
Methodology: 57 well characterized ICs followed up for a median time of 7.6 years (range
6-22.5 years) were included in the study. In addition, 90 HBsAg/anti-HBe positive patients
with histologically proven chronic hepatitis B (CHB) were enrolled as control group. All the
ICs were tested for HBV DNA, qHBsAg and LSM at three time points (baseline, 6 and 12
months) whereas the CHB patients were investigated at a single time point before starting
any anti-HBV therapy. HBV-DNA ≤2,000 IU/mL, LSM ≤6 kPa and qHBsAg ≤1,000 IU/
mL were used as cut offs to evaluate sensitivity, specificity, negative predictive value (NPV),
positive predictive value (PPV) and diagnostic accuracy (DA) to identify the IC status at a
single time point.
Results: The mean HBV DNA, qHBsAg, LSM values at baseline were statistically lower
in ICs than in CHB cases (910±1,383 vs 22,732,019±49,084,261 IU/mL p<0.0001; 2,250
±8,798 vs 6,117±13,897 IU/mL p=0.04; 5.4±2.1 vs 16.1±23 kPa p<0.0001, respectively)
and were stable in ICs at the three different time points.
136
At baseline, HBV DNA quantification showed 86% sensitivity, 91% specificity, 81% NPV,
94% PPV, and 88% DA; qHBsAg showed 81% sensitivity, 58% specificity, 66% NPV, 75%
PPV and 72% DA; LMS showed 84% sensitivity, 75% specificity, 75% NPV, 84% PPV, and
81% DA. Combined HBV DNA and qHBsAg showed 94% sensitivity, 96% specificity, 87%
NPV, 98% PPV, 95% DA in identifying IC, whereas coupled HBV DNA and LSM analysis
showed 97% sensitivity, 97% specificity, 95% NPV, 98% PPV, 97% DA. The combination
of LSM and qHBsAg showed 95% sensitivity, 78% specificity, 89% NPV, 89% PPV, 89%
DA. The evaluation of the 3 parameters together showed 96% sensitivity, 100% specificity,
100% PPV; 92% NPV, and 97% DA. These data were confirmed at months 6 and 12.
POSTER ABSTRACTS
Conclusions: Combined HBV DNA quantification and LSM appears to be a highly
reliable approach for identifying HBV inactive carriers at a single time point evaluation. The
qHBsAg as third, additional parameter does not improve the diagnostic accuracy.
137
P16
MXA GENE EXPRESSION IS DOWN-REGULATED IN
CHRONIC HEPATITIS B PATIENTS WITH HBV CORE GENE
I97L MUTATION
Ivana Carey1, Kate Childs1, Sanjay Bansal1, Diego Vergani1, Kosh Agarwal1,
Giorgina Mieli-Vergani1
1
Institute of Liver Studies, King’s College Hospital, London, United Kingdom
Introduction: The myxovirus resistance protein A (MxA) gene is interferon-stimulated
gene (ISG) and its product is involved in the inhibition of HBV replication by using
interaction with HBV core antigen (HBcAg). HBcAg is often subject of hot-spot mutations.
Only one in-vitro study demonstrated impact of core I97L mutation on interaction with
MxA gene.
Aims: We aimed to investigate relationship between liver MxA gene mRNA and protein
expression, HBV core gene mutations in liver/plasma and liver HBcAg expression in chronic
hepatitis B (CHB) patients prior to antiviral therapy and assess their impact on predicting
therapy response.
POSTER ABSTRACTS
Methodology: Patients: 23 immunotolerant CHB patients (8 males, median age 10.2
yrs) were treated for 52 weeks [lead-in LAM (3mg/kg/d) for 9 weeks; add-on IFN-α (5MU/
m2TIW) from week 9], were divided according to response: 5 responders (R=HBsAg loss)
and 18 non-responders (NR).
Materials & Methods: Pre-treatment liver biopsy and plasma samples were used. Total
RNA was extracted from pre-treatment biopsies and liver samples obtained from 5 healthy
controls. HPRT1 and MxA genes mRNA expression was measured by quantitative realtime RT-PCR. HBV core gene non-synonymous mutations including codon 97 were
evaluated by the direct sequencing of pre-treatment liver/plasma samples. Immunostaining
assessed liver HBcAg expression [positive cells/1000 hepatocytes] and location of MxA
protein expression in the liver tissue. The results were compared between responders and
non-responders and healthy controls.
138
Results: MxA protein expression in liver was predominantly in hepatocytes and did not
differ between R, NR and healthy controls. MxA mRNA expression was similar in R and
NR, but was lower in CHB patients than in healthy controls (0.06 vs. 0.04 vs. 1, p<0.05).
Baseline number of non-synonymous mutations in liver/plasma were similar in R and NR
(liver: 8 vs. 8; plasma: 9 vs. 9). Core I97L mutation in liver and plasma was present only in
NR (liver: 33% vs. 0%, p=0.07 and plasma: 39% vs. 0, p<0.05). MxA mRNA expression
was lower in patients with core I97L mutation than in wild-type patients (0.01 vs.0.07,
p<0.05). R and NR had similar liver HBcAg expression (7.7 & 12, p=0.93).
POSTER ABSTRACTS
Conclusions: MxA mRNA expression was down-regulated in CHB immunotolerant
patients in particular in antiviral therapy non-responders with core I97L mutation. Further
studies investigating the interaction of HBcAg and MxA gene including MxA promoter on
HBV replication are needed to elucidate detailed mechanism involved.
139
P17
CHRONIC HEPATITIS B IN TUNISIAN PREGNANT WOMEN
Rym ennaifer1, Myriam cheikh2, Haifa Romdhane1, Rania Hefaiedh1,
Houda Ben nejma1, Najet Bel Hadj1
1
hepatogastroenterology, 2Mongi Slim university Hospital, Tunis, Tunisia
Introduction: HBV infection in pregnancy has several particularities that complicate the
management of infection in this setting. The major risk is perinatal viral transmission.
Aims: The aim of this study was to determine clinical, biochemical and viral features of
chronic HBV infection during pregnancy in Tunisian patients.
Methodology: Retrospective study including all pregnant women seen in our department
for CHB. Liver function test and viral load were evaluated.
Results: Twenty-eight females with a mean age of 32 +/-6 years old screened for HVB
at the first trimester of pregnancy were included. All patients were HBeAg-negative.
Aminotransferase (ALT and/or AST) level were <40 IU/l (upper limit of normal) in 26
cases (93%). Mean level of ALT and AST were respectively 20+/-12 IU/l and 21 +/-9 IU/l.
Mean serum viral load was 26140 IU/ml +/-72873, 10 patients had DNA level >2000IU/
ml and 4 patients had DNA level >20000UI/ml. Antiviral therapy during the last trimester
of pregnancy was not indicated. All the children received passive-active immunoprophylaxis
at birth. Regarding mothers, nineteen were diagnosed as inactive CHB carrier. After the
delivery, 9 females were treated for active chronic hepatitis B (Peg INF n=8; entecavir n=1).
POSTER ABSTRACTS
Conclusions: In this Tunisian study, CHB screened pregnant women are mostly HBeAgnegative with low viral load and normal ALT level. However, screening during early
pregnancy and passive-active immunoprophylaxis as well as quantification of HBV DNA at
the end of the second trimester remains mandatory in order to reduce perinatal transmission.
140
P18
PREDICTIVE FACTORS OF SIGNIFICANT HISTOLOGICAL
LESIONS IN CHRONIC HEPATITIS B
Myriam Cheikh1, Rym ennaifer2, Haifa Romdhane2, Rania Hefaiedh2,
Wassila Bougassas2, Houda Ben nejma2, Najet Bel Hadj2
1
Mongi Slim university Hospital, Tunis, Tunisia, 2hepatogastroenterology,
Mongi Slim university Hospital, Tunis, Tunisia
Introduction: Liver biopsy is considered as the gold standard for assessing histological
lesions in chronic hepatitis B (CHB), however it is an invasive procedure.
Aims: The aim of our study was to determine predictors of significant histological lesions
in CHB among demographic characteristics and serum laboratory tests.
Methodology: Retrospective study including patients with CHB who underwent liver
biopsy. Correlation of age, sex, laboratory tests [aminotranferase (ALT and AST; upper
limit of normal ULN=40IU/l), gammaglutamyl transpeptidase (GGT), platelet and white
blood cell count, serum DNA level] and activity or fibrosis >=A2/F2 according to Metavir
were studied using Chi-square and Student test.
Conclusions: In CHB, significant histological lesions can be predicted using routine
laboratory parameters such as aminotransferases, platelet count and serum DNA level.
Lower ULN for aminotransferase should be used for clinical decision.
141
POSTER ABSTRACTS
Results: One hundred and thirteen patients with CHB were included, mean age 37 +/-11
years and 59.3% females. Only one patient was HBeAg-positive. Male gender (OR: 4.7 CI
[1.1-18.6], p=0.023), ALT >32 IU/l (OR: 9 CI [1.5-45], p=0.005), AST >20IU/l (OR: 21
CI [2.3-26], p=0.001), GGT>25.5 IU/l ( OR: 12.5 CI [1.3-16], p=0.045), platelet count
<196000/mm3 (OR: 6 CI [1.2-37], p=0.034) and serum DNA level >10 300 IU/ml (OR:
12.5 CI [2.5-60], p=0.001) were significantly correlated with significant histological lesions
(>= A2 and/or F2 ).
P19
THE DIAGNOSTIC VALUE OF APRI AND FIB-4 SCORE
FOR THE ASSESSMENT OF LIVER FIBROSIS IN CHRONIC
HEPATITIS B TUNISIAN PATIENTS
Myriam Cheikh1, Rym ennaifer2, Rania Hefaiedh2, Haifa Romdhane2,
Wassila Bougassas2, Houda Ben nejma2, Najet Bel Hadj2
1
Mongi Slim university Hospital, Tunis, Tunisia, 2hepatogastroenterology,
Mongi Slim university Hospital, Tunis, Tunisia
Introduction: Liver biopsy, which is considered the gold standard for the evaluation of
hepatic fibrosis in patients with chronic hepatitis B (CHB), has certain limitations.
Aims: The aim of this study was to investigate the diagnostic performance of non-invasive
markers of hepatic fibrosis as potential alternatives to liver biopsy.
POSTER ABSTRACTS
Methodology: Retrospective study including patients with a diagnosis of CHB who
underwent a liver biopsy were reviewed. Non invasive tests based on biochemical markers
were evaluated for the prediction of fibrosis. They included the following: the aspartate
aminotransferase to platelet ratio index (score APRI= [AST / NUS] / platelet count x 100;
the fibrosis index based on the four factors (FIB-4=age x AST/ (platelet x ALT)). Diagnostic
adequacy of these indices was evaluated by receiver operating characteristic curve analysis.
Results: Thirty two patients were collected. There were 18 males (54.5%) and 15 females
(45.5%) with a mean age of 39±8.7 year-old. A statistically significant positive correlation
was found between Metavir fibrosis score and APRI and FIB-4 (p = 0.041; p=0.026,
respectively). Area under the receiver operating characteristic curves for the APRI and
FIB-4 were 0.76 and 0.77 respectively. The cut-off with a positive correlation between
significant fibrosis (>=2) was >=0.207 for APRI [OR=30.6; p=0.001] and >=0.695 for
FIB-4 [OR=13.7; p=0.025].
Conclusions: Our results suggest that APRI and FIB-4 index may be useful in estimating
the extent of fibrosis in patients with CHB. There is a need for more comprehensive
prospective studies to help determine the diagnostic value of non-invasive tests for liver
fibrosis.
142
P20
VIROLOGIC AND HISTOLOGIC FEATURES OF TUNISIAN HBV
CARRIERS WITH NEGATIVE HBEAG AND NORMAL ALT
Rym ennaifer1, Myriam Cheikh2, Rania Hefaiedh1, Haifa Romdhane1,
Houda Ben nejma1, Najet Bel Hadj1
1
hepatogastroenterology, 2Mongi Slim university Hospital, Tunis, Tunisia
Introduction: The HBeAg-negative chronic hepatitis B (CHB) is generally differentiated
from the inactive carrier state by persistently or transiently elevated aminotransferase and
high serum HBV DNA levels. However, patients with HBeAg-negative and normal alanine
aminotransferase (ALT) may have high serum HBV DNA levels and significant histological
liver damage.
Aims: The aim of this study was to determine the prevalence of significant liver disease
and serum HBV DNA levels in HBeAg-negative patients with persistently normal ALT
(PNALT).
Results: Fifty-three patients with HBeAg-negative CHB were included, 45 females, mean
age 36 +/-10 years. Significant fibrosis and activity were present in respectively 11 patients
(20%) and 5 patients (10%), significant histological lesions in 20%. DNA level >=20000IU/
ml were seen in 7 patients (13.2%) and between 2000 and 20000 IU/ml in 13 patients
(24.5%). In patient with DNA level <2000IU/ml (n=33), 5 had significant histological
lesions (15%).
Conclusions: In this Tunisian study, 20% of HBeAg-negative CHB and PNALT have
significant histological lesions. Even in the subgroup with low DNA level, significant lesions
were seen in 15%. Our findings suggest than neither ALT level, neither serum HBV DNA
is accurate in predicting histologically significant liver disease. Liver biopsy should be
considered in this subgroup of patients.
143
POSTER ABSTRACTS
Methodology: Retrospective study including patients with HBeAg- negative CHB followed
at least 12 months with PNALT (<40IU/L in at least 3 determinations). Serum HBV
DNA was determined by PCR and liver biopsies were scored with the Metavir system for
inflammation and fibrosis. Significant inflammation and fibrosis were considered when
Metavir score was respectively >=A2 and >=F2, significant histological lesions if >=A2
and/or >=F2.
P21 - YI
LOW RISK OF SEVERE COMPLICATIONS AFTER LIVER
BIOPSY IN CHRONIC HEPATITIS B PATIENTS
Heng Chi1, Bettina E Hansen1, Harry L.A. Janssen1,2, Robert J de Knegt1
1
Gastroenterology and Hepatology, Erasmus MC University Medical Centre Rotterdam,
Rotterdam, Netherlands, 2Toronto Centre for Liver Disease, Toronto Western and General Hospital,
Toronto, Canada
Introduction: A liver biopsy (LB) can assist on whether or not to start antiviral therapy in
chronic hepatitis B (CHB) patients. Ideally, biopsy specimen needs to be ≥25 mm in order
to assess fibrosis accurately. For this size, additional biopsy passes are needed.
Aims: We aimed to investigate the complication rate of LB in CHB.
POSTER ABSTRACTS
Methodology: This retrospective cohort consisted of all consecutive LBs performed between
2005 and 2011. LBs were done or supervised by experienced hepatologists with cutting
needles (Angiotech tru-cut 14G16cm) according to an institutional protocol. Complication
was defined as an event where the patient returned to the hospital for further examinations
due to biopsy-related complaints (e.g., pain). Complications followed by hospitalisation ≥2
days or intervention (e.g., blood transfusion, surgery) were considered as severe.
Results: We enrolled 1382 consecutive LBs of which 368 (26%) were done in CHB patients.
Baseline characteristics of CHB patients were as follows: median age of 35 years, 67% males,
60% HBeAg-negatives, median HBV DNA of 5.5 log10 IU/mL, 17% advanced fibrosis
(Metavir F3 or F4), 6% cirrhosis. Two or more biopsy passes were performed in 97% of the
patients. Mean biopsy specimen length was 29 mm with 76% of the specimens being ≥25
mm. The only factor associated with the acquirement of specimens ≥25 mm was additional
biopsy passes (≥25 mm specimens were acquired in 9% with one pass vs. 78% with two
or more passes; p<0.001). Twenty-one patients (5.6%) developed a complication (mostly
pain). One complication (0.3%) was severe: intraparenchymal bleeding and hospitalisation
for 3 days. Compared to patients with other liver diseases (1014), CHB patients (368) had
a similar complication rate (5.6 vs. 5.6%; p=0.98), but a lower severe complication rate (0.3
vs. 2.1%; p=0.016). Logistic regression modelling showed that LB in CHB patients was
associated with reduced risk of severe complications compared to other liver diseases when
adjusted for platelet count (OR 0.13; 95% CI 0.02-0.95; p=0.044), INR (OR 0.15; 95%
CI 0.02-1.09; p=0.06), or additional biopsy passes (OR 0.13; 95% CI 0.02-1.01; p=0.051).
Conclusions: In CHB, two or more passes with a cutting needle are needed to collect
sufficient specimen for accurate fibrosis assessment. Despite the increase in invasiveness of
additional passes, the risk of severe complications was very low. CHB patients may have a
lower risk of severe complications compared to patients with other liver diseases.
144
P22 - YI
GOOD PREDICTIVE FACTORS OF THE LONG-TERM
THERAPEUTIC RESPONSE OF CHRONIC HEPATITIS B IN
PEDIATRIC PATIENTS
Jae Young Choe1, Suk Jin Hong2, Byung-Ho Choe1
1
Pediatrics, Kyungpook National University School of Medicine, 2Pediatrics, Daegu Catholic
University College of Medicine, Daegu, Korea, South
Aims: For children with chronic hepatitis B (CHB), higher pretreatment ALT and
histologic activity index score, lower HBV DNA and HBe Ag level, longer duration of
lamivudine therapy and good compliance are known as predictors of better response to
lamivudine. However, most of previous studies on this topic were assessed at the end of 52
weeks duration of treatment. The predictors for the long-term treatment response were to
be evaluated in this study.
Methodology: Seventy two (38 male; range: 0.7~16.4 years, mean age 6.0 years) treated
with lamivudine had been followed-up for at least 36 months (range: 36~109 months,
mean 59.0 months). Complete remission (CR) was defined as the state of normalization
of ALT, HBV DNA negativization (< 300 IU/mL), and HBe Ag seroconversion after
treatment. Univariate and multivariate analyses were used to identify the effects of patient’s
demographic and pretreatment laboratory data.
Results: After 3 years of treatment, CR and HBs Ag loss occurred in 54 (75%) and 23
(32%) of the 72 patients, respectively. Regression analyses showed that age of less than 6
years is good predictor for both CR and HBs Ag loss (p ≤ 0.005). The CR rate was also
significantly higher in pretreatment ALT (> 5 times of upper limit of the normal range),
and lower HBV DNA level (<300 pg/mL). All were genotype C.
POSTER ABSTRACTS
Conclusions: Younger age is a good predictor for long-term response to lamivudine
treatment in children with CHB. Pretreatment ALT and HBV DNA levels are also
significant predictors to CR.
145
P23
DEEP SEQUENCING TO EXPLORE ARCHIVED HBV
DRUG RESISTANCE MUTATIONS IN COMPARISON WITH
TRADITIONAL SANGER-BASED SEQUENCING
Yoon-Seok Chung1, Jae-Min Han1, Hui-Seong Kim1, Byeong-Sun Choi1, Chun Kang1
1
Division of AIDS, National Institute of Health, Cheongwon-gun, Korea, South
Introduction: HBV drug resistance testing is routinely performed prior to antiretroviral
treatment. Long durations of therapy are required and often lead to the emergence of drug
resistance. While population Sanger-sequencing (PS) detects variants with frequencies above
15–20% of the viral quasispecies, deep sequencing (DS) strategies allow for sensitivities
of 1% and below. However, these strategies have not yet entered the daily routine in a
widespread manner.
Aims: Here, we present data of the clinical samples, analyzed with both PS and DS in
daily routine to obtain insights in sensitivity, accuracy and the putative impact of minority
variants on resistance interpretation.
POSTER ABSTRACTS
Methodology: PS and DS on polymerase were performed from specimen for whom
resistance testing was longitudinally collected for 1~3 years. For deep sequencing, the
same PCR products were used for Nextera XT® library preparation and sequenced using
Illumina’s Hiseq 2500 sequencing system. Bioinformatics analyses were performed using an
automated customized pipeline. Several clinical guidelines including SeqHepB, the largest
HBV drug resistance database, and geno2pheno, assessed anti-HBV drugs sensitivity levels.
Results: DS resulted in a total of 205,683 sequence reads, with a median reads of 11
332, 10 655 and 7 553 for patients #1, #2 and #3, respectively. A number of significant
multi-drug drug resistant mutations were found in the all 8 patients with long term therapy
including S202G, N236T, M250V, L180M, M204I, A181T, T184L, and M250V. In
addition, clinically relevant minority multi-drug resistance mutations were detected by DS
but not by Sanger in 26 out of the 32 subjects evaluated (81.3%), all of them at frequencies
<35% in the virus population.
Conclusions: This study showed the impact of minority variants in drug resistance
assessment which still needs to be correlated with clinical utilities. DS is a powerful tool
for routine drug resistance testing. Applying a generalized PS derived cutoff of 15–20% to
Deep Sequencing data may result in the non-consideration of clinically relevant mutations.
Thus, it is important to determine meaningful clinical cutoffs.
146
P24
TENOFOVIR-INDUCED FANCONI SYNDROME IN CHRONIC
HEPATITIS B MONOINFECTED PATIENTS SUCCESSFULLY
RESCUED BY ENTECAVIR
Mauro Viganò1, Alessandra Brocchieri2, Angiola Spinetti3, Serena Zaltron3,
Giampaolo Mangia4, Floriana Facchetti4, Alessandro Fugazza2, Francesco Castelli3,
Massimo Colombo4, Pietro Lampertico4
1
Liver Unit, Ospedale San Giuseppe, Università degli Studi di Milano, Milan,
2
Medicine Unit, Ospedale Maggiore di Lodi, Lodi, 3University Division of Infectious
and Tropical Diseases, University of Brescia and Brescia Spedali Civili General Hospital,
Brescia, 4Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca’ Granda
Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
Aims: Despite the excellent safety records of Tenofovir disoproxil fumarate (TDF), a few
cases of Fanconi syndrome have been reported among human immunodeficiency virus
(HIV) positive patients, and recently two cases of TDF-associated Fanconi syndrome have
been reported in chronic hepatitis B (CHB) patients from Australia.
Results: A 68 year-old CHB male who had been previously exposed to Adefovir dipivoxil
(ADV) for 2 years, but without risk factors for renal dysfunction and normal baseline
renal function, developed an increased serum creatinine (1.32 mg/dL, eGFR 57 mL/
min/1.73m2), hypophosphatemia (2.1 mg/dL), normoglycemic glycosuria and proteinuria
indicative for Fanconi syndrome after 42 months of TDF. By switching TDF to Entecavir
(ETV), glomerular and tubular function rapidly normalized while serum HBV DNA
remained undetectable during the subsequent 15 months of ETV treatment. The second
was a 67-year-old CHB NUC naïve male with arterial hypertension under pharmacological
control and normal renal function who developed a Fanconi syndrome (serum creatinine
3.35 mg/dL, eGFR 18 mL/min/1.73m2, hypophosphatemia 1.7 mg/dL, proteinuria and
normoglycemic glycosuria) after 45 months of TDF administration. Following TDF
withdrawal and ETV start, glomerular and tubular function progressively improved and
serum HBV DNA remained persistently undetectable. Both patients were homozygous for
the C allele at position -24 in the ABCC2 gene (rs717620 of MRP2), a polymorphism which
has been associated with the genetic predisposition to accumulate TDF within tubular cells.
Conclusions: Though the overall risk of TDF associated severe renal toxicity in HBV
patients appears to be negligible, both glomerular and tubular function should be carefully
monitored in patients exposed to TDF, especially when other renal risk factors such as arterial
hypertension, history of previous exposure to ADV or older age, are present. Proactive dose
reductions of TDF may prevent the development of severe renal complications.
147
POSTER ABSTRACTS
Methodology: Here, we describe two additional CHB patients who developed a Fanconi syndrome.
P25
ENTECAVIR MONOTHERAPY IMPROVES RENAL
FUNCTION IN LAMIVUDINE RESISTANT PATIENTS
DEVELOPING RENAL SIDE EFFECTS DURING LONG-TERM
TENOFOVIR EXPOSURE
Giampaolo Mangia1, Pietro Lampertico1, Mauro Viganò2, Floriana Facchetti1,
Invernizzi Federica1, Roberta Soffredini1, Massimo Colombo1
1
Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca Granda - Ospedale
Maggiore Policlinico, Università degli Studi di Milano, 2Liver Unit, Ospedale San Giuseppe,
Università degli Studi di Milano, Milan, Italy
Introduction: Tenofovir (TDF) is a recommended first-line therapy for both naïve and
experienced chronic hepatitis B patients because of its efficacy and favorable safety profile,
though selected patients may have to stop treatment because of renal side effects.
Aims: To assess the efficacy and safety of Entecavir (ETV) in patients switched from TDF
for hypophosphatemia or hyperphosphaturia.
POSTER ABSTRACTS
Methodology: 18 chronic hepatitis B patients (63 years, 94% males, 56% cirrhotics,
94% HBeAg-negative, 94% Adefovir+Lamivudine exposed, 100% with normal ALT and
undetectable HBV DNA) who have been treated with TDF monotherapy for 39 months
(range: 7-52), were switched to ETV monotherapy (1.0 mg or 0.5 mg according to eGFR
by MDRD) due to renal side effects. HBV DNA, ALT, serum creatinine, eGFR, serum
phosphate levels and tubular phosphate re-absorption (TmPO4/eGFR) were assessed at
baseline (start ETV) and every 3 months. Hypophosphatemia was defined as grade 1 (<2.5
mg/dL), grade 2 (<2.3), grade 3 (<2.0), whereas hyperphosfaturia (TmPO4/eGFR) was
classified as grade 1 (<0.80), grade 2 (<0.60) and grade 3 (<0.40).
Results: At baseline, 6 (33%), 7 (39%) and 5 (28%) patients had grade 1, 2 or 3
hypophosphatemia, whereas 12 (67%) and 6 (33%) patients had grade 2 or grade 3
hyperphosphaturia, respectively.
148
During 6 months (range: 5-12) of ETV therapy (1.0 mg in 8 patients and 0.5 in 10 patients),
median serum creatinine remained unchanged (1.20 vs 1.17 mg/dL), whereas eGFR (60 vs
62 mL/min, p=0.004), serum phosphate levels (2.2 vs 2.4 mg/dL, p=0.046) and TmPO4/
eGFR (0.42 vs 0.57 mmol/L, p=0.004) significantly increased. After ETV switch, 7 (39%)
patients achieved normal phosphatemia levels (≥2.5 mg/dL) as well as either normal
phosphaturia or grade 1 iperphosphaturia.
POSTER ABSTRACTS
As far virological responses are concerned, 13 patients (72%) maintained a virological
response whereas 5 patients (28%) (3 treated with 0.5 mg/24h) had a mild virological
breakthrough (HBV DNA: 10, 17, 20, 27, 79 IU/mL) without ALT increase, occurring
between month 3 and 6. In one of the 2 patients in whom ETV dose was increased to 1 mg,
HBV DNA was cleared from serum. In 2 patients who had a further increase of HBV DNA
(from 27 to 244; from 79 to 109 IU/mL) ETV was topped and TDF restarted
Conclusions: Switching to ETV monotherapy patients who developed renal side effects
during long-term TDF treatment, improved kidney tubular function with minimal risk of
virological rebounds.
149
P26
LOW RISK OF HEPATITIS B VIRUS REACTIVATION IN
HBSAG NEGATIVE/ANTI-HBC POSITIVE CARRIERS
UNDERGOING RITUXIMAB FOR RHEUMATOID
ARTTHRITIS
Mauro Viganò1,Valentina Varisco2, Alberto Batticciotto2, Pietro Lampertico3,
Antonio Marchesoni4, Patrizia Gibertini4, Raffaele Pellerito5, Guido Rovera5, Roberto Caporali6,
Monica Todoerti6, Michele Covelli7, Antonella Notarnicola7, Massimo Colombo3, Piercarlo Sarzi Puttini2
1
U.O. Epatologia, Ospedale San Giuseppe, Università degli Studi di Milano, 2UOC
Reumatologia, Ospedale L. Sacco, 3Division of Gastroenterology and Hepatology, Fondazione
IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, 4UOC DH
di Reumatologia, Istituto Ortopedico G. Pini, Milan, 5UO Reumatologia, Ospedale Mauriziano,
Torino, 6Divisione di Reumatologia, IRCCS Fondazione San Matteo, Università di Pavia, Pavia,
7
Reumatologia Universitaria, AOU Policlinico, Bari, Italy
Aims: B cell-targeted therapy using rituximab (RTX) is an effective treatment for
rheumatoid arthritis (RA). However, the risk of hepatitis B virus (HBV) reactivation in
hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc)
positive RA patients undergoing RTX is unknown.
POSTER ABSTRACTS
Methodology: We retrospectively reviewed 306 RA treated with RTX in 5 Italian outpatient
rheumatologic Clinics. Complete serological screening for HBV status before RTX was
available in 33 HBsAg negative/anti-HBc positive patients affected by RA and treated with
RTX without anti-HBV prophylaxis from August 2006 to December 2011 underwent
sequential clinical and laboratory examinations during follow-up. These patients (73% female,
60 yrs, disease duration 8 yrs, 100% serum HBV DNA negative by PCR assay, 90% antiHBs positive) have been treated with RTX, administered for 3 cycles (range: 1-8) lasting for
22 months (range: 0-62) in 14 patients and ongoing in the remaining cases) plus diseasemodifying anti-rheumatic drugs (DMARS). Laboratory examinations, including serum
HBsAg and serum HBV DNA were assessed at least every 6 months, whenever alanine
aminotransferase (ALT) flared above the upper limit of normal and at the last follow-up.
Results: During 45 months (range: 12-80) of follow-up, anti-HBs titers dropped in 6
(28%) patients including two who became seronegative. One patient (3%) only showed a
slight elevation in serum HBV DNA (44 IU/mL) that became detectable 6 months after the
first RTX administration but was not associated to either HBsAg seroreversion or ALT flare
and was promptly suppressed by lamivudine treatment.
Conclusions: In HBsAg negative/anti-HBc positive RA patients, administration of
RTX+DMARS poses a negligible risk of HBV reactivation thereby calling for HBsAg or
HBV DNA monitoring, only.
150
P27
PORTAL HYPERTENSION BUT NOT HCC RISK IS
ATTENUATED IN COMPENSATED CIRRHOTICS
FOLLOWING 12 YEARS OF TREATMENT WITH
NUCLEOS(T)IDE ANALOGS
Federica Invernizzi1, Pietro Lampertico1, Giampaolo Mangia1, Massimo Iavarone1, Mauro
Viganò2, Massimo Primignani1, Roberto de Franchis3, Massimo Colombo1
1
Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca’ Granda Ospedale
Maggiore Policlinico, Università degli Studi di Milano, 2U.O. Epatologia, Ospedale San Giuseppe,
Università degli Studi di Milano, 3Division of Gastroenterology, Ospedale Luigi Sacco, Università
degli Studi di Milano, Milan, Italy
Aims: Whether long-term HBV suppression by nucleos(t)ide analogs (NUC) modifies
the course of esophageal varices (EV) is currently unknown. To gain more insights on the
response of portal hypertension to NUC therapy in this setting, we started this prospective
single center cohort study.
Results: During 12 (2-17) years of treatment, pre-existing EV regressed in 18 (67%)
patients, remained unchanged in 8 (29%) and increased in size in 1 (4%), whereas de-novo
EV developed in 6 (7.5%) (5 F1 and 1 F2) of the 80 EV-free patients at baseline. Overall,
the 12-year rates of EV regression and worsening were 83% and 9%, respectively.
151
POSTER ABSTRACTS
Methodology: A standardized protocol (Baveno) including 414 upper gastrointestinal (GI)
endoscopies was applied to 107 consecutive HBeAg-negative compensated cirrhotic patients
(93% Child-Pugh A) receiving oral analogs from 2 to 17 (median 12) years. Beginning with
lamivudine (LMV) 100 mg daily, resistant patients (LMV-R) were rescued with add-on
adefovir or switched to tenofovir. Check-up including serum HBV DNA was performed
every 3 months; abdominal ultrasounds scan every 6 months. Starting from 2006 all patients
alive and hepatocellular carcinoma (HCC) free (n=79) were tested by Fibroscan on yearly
basis and a total of 392 liver stiffness measurements (LSM) were performed until 2013. As
previously reported in untreated patients with chronic HBV infection, a cut-off value ≤9.4
kPa and >13.1 kPa had a high (>90%) sensitivity and specificity to exclude and confirm the
histological diagnosis of cirrhosis, respectively.
Six of 7 (86%) EV progressors had either a clinical breakthrough due to LMV-R and/or
developed HCC. None of the patient bled from ruptured EV. Overall, 36 patients developed
HCC with a 12-year cumulative probability of 34%. Twelve patients (11%) died, 9 for HCC
progression, 2 for extra-hepatic neoplasia and one for stroke, while 15 (14%) underwent LT,
(13 for HCC, 2 for end stage liver disease due to LAM-R). The 12-year cumulative rate of
overall survival was 76%. Median LSM values progressively declined from 7.6 (2.5-22) kPa
after 6.3 years of therapy to 5.9 (3.4-22) kPa after 12 years of NUC therapy. The proportion
of patients with values >13 kPa decreased from 14% to 8% while those with values ≤9.4 kPa
increased from 64% to 78%.
POSTER ABSTRACTS
Conclusions: Long-term suppression of HBV by nucleos(t)ide analogs minimizes the
risk of de-novo EV and EV progression in compensated cirrhotics, leaving however HCC
incidence rates unaffected.
152
P28 - YI
HEPATITIS B CORE-RELATED ANTIGEN (HBCRAG)
LEVELS IN THE NATURAL HISTORY OF HEPATITIS B
VIRUS INFECTION IN A LARGE EUROPEAN COHORT
Benjamin Maasoumy1,2, Steffen Wiegand1,2, Jerzy Jaroszewicz1,3, Birgit Bremer1,
Patrick Lehmann1,2, Katja Deterding1, Michael P Manns1,2, Heiner Wedemeyer1,2, Markus Cornberg1,2
1
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover,
2
German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany, 3Department of
Infectious Diseases and Hepatology, Medical University in Bialystok, Bialystok, Poland
Introduction: Serological markers are the key tools to understand and manage chronic
hepatitis B virus (HBV) infection. HBV core-related antigen (HBcrAg) has been suggested
as another interesting serological marker of HBV infection. HBcrAg contains HBV core
antigen and HBeAg, which share an identical 149-amino-acid-sequence. Low levels of
HBcrAg may indicate a safe stop of nucleotide analogues, while high levels were identified
as an independent risk factor for HCC. We here aimed to analyze HBcrAg levels in the
different phases of HBV-infection in European patient with HBV infection.
Results: The highest HBcrAg levels were documented in the IT and IC phase (mean
5.45 and 4.71 log10 U/ml, respectively), lower in ENH (mean 1.72 log10 U/ml) but only
-0.49 in LRC and -0.38 (mean log 10 U/ml) in HRC patients. LRC and HRC patients
were HBcrAg <1U/ml or negative in 80% and 73%, respectively. In contrast, only 11%
of the ENH (although HBeAg negative) and none in the IT and IC had levels <1U/
ml. HBcrAg showed a high correlation with HBV DNA in AHB (Spearman correlation:
r=0.81; p<0.0001), IC (r=0.68; p<0.0001) and ENH patients (r=0.77; p<0.0001) and a
moderate correlation in the IT (r=0.47; p<0.01) but no in the LR group. In contrast, there
was a moderate correlation between HBcrAg and HBsAg in all phases. Only in the ENH
phase we documented a correlation between ALT or AST levels and HBcrAg (r=0.43 and
0.52, respectively; p<0.01). LRC patients with HBcrAg levels >1 IU/ml experienced HBV
reactivation in 38% compared to only 10% among those with levels <1 IU/ml (mean followup 32 months).
Conclusions: HBcrAg levels vary significantly between the different phases of HBVinfection. In HBeAg negative patients HBcrAg levels may indicate active disease. HBcrAg
may be a useful marker in addition to HBV-DNA and qHBsAg to further classify the natural
course of HBV-infection and monitor HBV patients.
153
POSTER ABSTRACTS
Methodology: HBcrAg levels were determined in a European cohort of 291 patients in
different phases of HBV infection: HBeAg positive immune-tolerance (IT) (n=41), HBeAg
positive immune-clearance (IC) (n=73), HBeAg negative hepatitis (ENH) (n=54), HBeAg
negative low-replicative phase (LRC) (n=85) and HBeAg negative high-replicative phase
(HRC) (n=30) and acute Hepatitis B (AHB) (n=8).
P29
A SURVEY OF DOCTOR’S KNOWLEDGE, ATTITUDE AND
PRACTICE WITH INFECTION CONTROL GUIDELINES IN
SUEZ CANAL REGION HOSPITALS, EGYPT
Hesham El-Sayed1, Sohair Mehanna2, Nermine El-Maraghy3, Soha Younis4, Zeinab Khedr2
1
Pediatrics, Faculty of Medicine, Suez Canal Univeristy, 2Social Research Center, American
Univeristy, 3Microbiology & Immunology, 4Clinical Pathology, Faculty of Medicine, Suez Canal
Univeristy, Cairo, Egypt
Introduction: Doctors are at high risk of infection and transmission of hepatitis B and
C and HIV following exposure to infected blood and body fluids. Doctors are exposed to
high incidence of accidental needle-stick and splash with blood and body fluids. Lack of
experience, education and skills may increase the risk of exposure
Aims: To assess the knowledge, attitude and practice of doctors regarding infection control
guidelines in the Suez Canal region (Ismailia, Port-Said and Suez governorates) in Egypt
POSTER ABSTRACTS
Methodology: A cross sectional study was conducted on a random sample of doctors from
6 hospitals in the Suez Canal region. Doctors were classified in 3 categories according to
their years of experience (<5 years; 5-<10 years; and >10 Years). A structured questionnaire
was administered during the period October – December 2013
Results: A total of 376 doctors participated in the study. Fifty six percent of respondents
reported that they had suffered a needle-stick injury with a used needle, While 79% of the
doctors reported exposure to blood or body fluids Splash. More than 75% of doctors did
not report their exposures. Furthermore, the more experienced doctors were less likely to
report their exposures (p=0.024). Infection control measures are generally good, but not
optimal, in most of hospitals. However, training for infection control measures was very low
(35%).
Conclusions: In the present study, years of experience of doctors are not correlated with
increased knowledge, attitude and practice in infection control. Furthermore, the high level
of exposure of doctors to blood and body fluids highlights the need for improvement in health
safety to prevent transmission of infections. Education, monitoring, improved availability of
resources and disciplinary measures are necessary to improve infection control in hospitals.
154
P30
EFFECTIVENESS AND SAFETY OF THERAPY
SIMPLIFICATION FROM LAMIVUDINE + ADEFOVIR
TO TENOFOVIR MONOTHERAPY IN VIROLOGICALLY
SUPPRESSED HBEAG-NEGATIVE CHRONIC HEPATITIS B
PATIENTS
Massimo Fasano1, Paolo Maggi2, Armando Leone2, Chiara Bellacosa2, Anna Volpe2,
Angarano Gioacchino2, Teresa Antonia Santantonio1
1
Department of Clinical and Experimental Medicine, Clinic Of Infectious Diseases, University of
Foggia, Foggia, 2Clinic of Infectious Diseases, University of Bari, Bari, Italy
Introduction: In Lamivudine resistant (LAM-R) chronic hepatitis B (CHB) patients,
Tenofovir (TDF) monotherapy has demonstrated the same efficacy of the combination
with a nucleoside analogue.
Methodology: 60 consecutive patients with HBeAg-negative CHB (median age 58 yrs,
80% males, 38% cirrhosis) successfully treated with LAM + ADV due to LAM- resistance
(median duration 63 months, range 20-96) were enrolled. In all patients, the combination
therapy has been replaced by TDF monotherapy. Currently, the median period of TDF
treatment is 38 months (range 10-41). During the first year after switching, transaminases,
renal and liver function tests, HBV DNA quantitative (real-time PCR, the sensitivity limit of
12 IU/ml) were assessed every 3 months, and every 6 months thereafter. Patients underwent
two dual energy X-ray absorptiometry (DEXA) of the lumbar spine (LS) and femoral neck
(FN) performed at enrollment and after 12 months.
Results: During TDF monotherapy, all patients maintained virologic response and none
had a virologic breakthrough. HBsAg clearance was observed in 3 patients (5%), who
subsequently discontinued therapy. Monitoring of renal function showed no changes in
median levels of serum creatinine, eGFR and phosphate.
155
POSTER ABSTRACTS
Aims: To evaluate the effectiveness and safety of simplification from combination therapy
Adefovir + Lamivudine (ADV + LAM) to TDF monotherapy, in a cohort of virologically
suppressed CHB patients.
Two patients (3.3%) had to reduce TDF dose, one for a significant eGFR decline (<50
ml/min) and one due to serum phosphate levels <2 mg/dL. All patients, except 4, had
25(OH)-vitamin D insufficiency and received supplementation with cholecalciferol. At the
first DEXA, osteoporosis (T-score <-2.5), osteopenia (T-score between -1 and -2.5) and
normal bone mineral density (BMD) were observed at FN in 2%, 27.4% and 70.6% and at
LS in 3.7%, 42.6% and 53.7% of patients, respectively. After 1 year of TDF therapy, 57/60
patients repeated DEXA, overall 8 patients with normal BMD progressed to osteopenia and
2 patients with osteopenia worsened to osteoporosis and 47 patients remained unchanged.
Despite the stable virologic suppression, 4 patients developed hepatocellular carcinoma
(HCC) and 4 had a recurrence of HCC.
POSTER ABSTRACTS
Conclusions: In patients with LAM-R and prolonged exposure to ADV, monotherapy with
TDF was able to maintain suppressed viral replication, without major renal safety issues,
while BMD worsened in a minority of patients.
156
P31
CROSS-SECTIONAL STUDY TO EVALUATE HEPATITIS
B VIRUS (HBV) INFECTION SCREENING PRACTICES
AND OUTCOMES IN PATIENTS WITH INFLAMMATORY
RHEUMATIC DISEASES (REBIB-I STUDY)
Montserrat Garcia-Retortillo1, Joana Villaverde1, Blanca Sampedro2, Joaquin Cabezas2,
Albert Pardo3, Ramon Fontova4, Tarek Carlos Salman5, Maria Pilar Lisbona5, Joan Maymó5,
Blai Dalmau6, Eduard Graell7, José Inciarte8, Raimon Sanmartí8, Javier Crespo2, Ricard Solà1
1
Gastroenterology Department, Hospital del Mar, Universitat Autònoma der Barcelona,
Barcelona, 2Gastroenterology Department, Hospital de Valdecilla, Santander, 3Gastroenterology
Department, 4Rheumatology Department, Hospital Joan XXIII , Tarragona, 5Rheumatology
Department, Hospital del Mar, Universitat Autònoma der Barcelona, Barcelona,
6
Gastroenterology Department, 7Rheumatology Department, Hospital Parc Taulí, Sabadell,
8
Rheumatology Department, Hospital Clínic, Barcelona, Spain
Introduction: In the Spanish general population the prevalence of HBsAg-positive is 0.7%
whereas of HBsAg-negative and anti-HBc-positive is 8.9%.
Aims: We assessed HBsAg and Aanti-HBc prevalence in patients with inflammatory
rheumatic diseases before starting immunosuppressives, as well as the screening practices
performed.
Results: Final analysis in 746 patients, median of 57 years (19-90), predominantly female
(66%), and mostly Spanish (91%). The most prevalent inflammatory rheumatic diseases
were rheumatoid arthritis (62%), psoriatic arthropathy (22%) and spondyloarthropathies
(12%). Anti-TNF use was reported in 403 (54%) patients and rituximab use in 20 (2.7%)
patients.
157
POSTER ABSTRACTS
Methodology: Epidemiological, cross-sectional, multicenter study involving rheumatology
and/or hepatology departments evaluating patients with an inflammatory rheumatic
condition.
HBsAg was available in 559 patients and positive in 4 (0.7%). Anti-HBc was available
in 474 patients, 36 (7.6%) of whom were HBsAg-negative/anti-HBc-positive. In 471 out
of 743 patients (63.4%) HBV screening was based on HBsAg and anti-HBc. Among the
40 patients with any positive serologic marker (HBsAg and/or anti-HBc), none received
rituximab or infliximab, and only 6 (15%) of them were referred to a gastroenterologist.
Three patients (all of them HBsAg-positive) received oral antiviral treatment and one
of them because of HBV reactivation. This patient had been treated with etanercept,
corticosteroids and antimalarials. Reactivation was successfully controlled with tenofovir.
None of the other two HBsAg-positive patients who received antiviral treatment had been
treated with anti-TNF or biologic agents.
POSTER ABSTRACTS
Conclusions: Our results in this subpopulation confirm the prevalence reported in
the general Spanish population for both HBsAg and anti-HBc. The rate of appropriate
HBV screening was somewhat lower than previously reported by rheumatologist surveys,
suggesting the need for better screening education.
158
P32
UPDATING HEPATITIS B VIRUS (HBV) STATUS IN ARMENIA
Hasmik Ghazinyan1, Aregnaz Mkhitaryan1, Gayane Melik-Andreasyan2, Ara Asoyan 1
1
Hepatology, Nork Clinical Hospital, 2Epidemiology, Research Institute of Epidemiology,
Yerevan, Armenia
Introduction: Over 350 million or 1 in 20 people worldwide have chronic hepatitis B
infection, which is characterized by geographic prevalence. The chronic infection can
cause significant liver disease ranging from hepatitis, to the development of cirrhosis and
hepatocellular carcinoma as well as liver failure.
Aims: Description of updating HBV status in Armenia.
Results: As area of intermediate endemisity 30% of the general population of Armenia
has serological evidence of current or resolved HBV infection. In general healthy Armenia
population the prevalence of HBsAg is median 2-2.5 %.The predominant genotype of
HBV in Armenia is genotype D. The previously risk factors of transmission were medical
procedures, hemotransfusion and probably perinatal. Among infected children likelihood
of developing chronic infection was 30-90%.Chronic HBV associated with 25% of lifetime
risk of HCC. The incidence of acute hepatitis B in Armenia from 1993 to 2012 had a
pronounced tendency to decrease from 11.5%ooo to 2.1%ooo. At the period between 1993
and 2000, the incidence in the group of children less than 14 years and adults decreased an
average of 4 folders. HBV vaccination program was launched in Armenia (1999 -2002) with
an overall coverage rate of >95% achieved HBV vaccination course. In subsequent years
(2001 -2012.), among people older than 14 years the incidence decreased 1.5folder (4, 1-2,
7%ooo), whereas among children 15 (3,1-0, 2%). According to recent data among infected
patients with acute HBV infection was 80 % of the age-group 20-40, among which 60%
were men. The main route of transmission of HBV infection was horizontal (i.e.sexual).
Conclusions:
• Armenia was and remains intermediate endemic region of HBV infection.
• Vaccination against HBV effectively prevents transmission of HBV and developing of
acute and chronic HB.
• The age distribution of acute HBV cases had significantly shifted to older age groups
peaking among 20-40 years old.
• The main route of infection becomes horizontal i.e. sexual.
159
POSTER ABSTRACTS
Methodology: A retrospective epidemiological analysis of long-term (1993-2013)
morbidity was done according to official statistics (morbidity) of hepatitis B.
Over 10000 people of healthy population were enrolled in this study.
The mean age of them was 30.5 (ranged 1-60); male/female ratio was 3:1.
The following serological markers (HBsAg, anti-HBc, anti-HBs, HBeAg, anti-HBe) were
used for assessment of dynamic hepatitisB virus infection by ELISA methods.
P33
ARFI ELASTOGRAPHY – HOW MANY MEASUREMENTS
ARE NEEDED FOR THE BEST PERFORMANCE?
George Sebastian Gherlan1, Petre Iacob Calistru1
1
Infectious Diseases, “Dr.Victor Babes” Center for Diagnostics and Treatment, Bucharest, Romania
Introduction: After 10 years of elastography in liver fibrosis evaluation, we learned that
quality factors are important. For Virtual Touch Tissue Quantification (VTTQ) / Acoustic
Radiation Force Imaging (ARFI), the quality factors are not yet clearly established. When it
comes to the number of measurements, the more, the better, but because of time limitations
only a finite number can be performed.
Aims: We aimed to establish the minimum number of ARFI measurements that guarantee
the best performance.
POSTER ABSTRACTS
Methodology: 113 patients with liver diseases (chronic B or C hepatitis, nonalcoholic fatty
liver) or with no hepatic pathology were included. All patients underwent ARFI examination
and 20 consecutive measurements were performed at the same site in the right lobe. We
tried to establish the minimum number of measurements that have the same performance
as 20 measurements. We calculated the median values for 2 to 10 measurements and for 20
measurements and verified their correlations. For staging purposes we used cut-offs of 1.31
m/s for significant fibrosis and 1.80 m/s for cirrhosis.
Results: 20 measurements were feasible in all 113 patients, but 12 patients (10.6%)
had IQR<30% of liver stiffness value. If only one (the first) measurement was taken in
consideration, the correlation coefficient with the median of 20 measurements was 0.893;
for 5 measurements, 0.972; for 10, 0.992, all with p<0.0001. With only one measurement
we misidentified significant/insignificant fibrosis as compared to the median of 20
measurements in 22 patients (19.4%), with 5 measurements in 10 (8.8%) and with 10
measurements in only 3 patients (2.6%). In the identification/exclusion of cirrhosis the
disagreement between 1 and 20 measurements occurred in 5 patients (4.4%), between 5
and 20 measurement in 2 (1.7%) and for 10 measurements in the same 2 (1.7%) patients.
Conclusions: In our group, ARFI/VTTQ was feasible in all patients, but unreliable results
based on IQR were found in 10.6% of the patients. Based on the presented data, for an
optimal evaluation of the stage of fibrosis, we recommend performing 10 consecutive
measurements, as the results are in this case almost similar with the median of 20
measurements. For cirrhosis identification, if a median of over 1.8 m/s is obtained we can
stop at 5 measurements, because making more measurements is statistically unlikely to
change the result.
160
P34
ACOUSTIC RADIATION FORCE IMPULSE IN HEPATITIS
B VIRUS INACTIVE CARRIERS - A COMPARISON WITH
OTHER CONDITIONS
George Sebastian Gherlan1, Petre Iacob Calistru1, Cristina Voinea2, Cristian Szabo2
1
Infectious Diseases, 2Laboratory, “Dr.Victor Babes” Center for Diagnostics and Treatment,
Bucharest, Romania
Introduction: Inactive hepatitis B virus (HBV) carriers are defined as HBs antigen
positive, HBe negative patients that have persistently normal transaminase levels and low
or undetectable HBV DNA levels. Usually they are not subjected to liver fibrosis evaluation
(either invasive or noninvasive) especially if their viral load is below 2000 IU/ml.
Aims: In this study, we tried to compare the differences between the results of Acoustic
Radiation Force Impulse (ARFI) measurements in inactive HBV carriers and in patients
with other liver diseases or with no known liver afection.
Results: In HBV inactive carriers the mean ARFI result was 1.34±0.34 m/s, in HCV
patients 1.84±0.77 m/s, in FL patients 1.02±0.24 m/s, and in healthy patients 1.08±0.21
m/s. ARFI results in HBV carriers are significantly higher than in healthy or FL patients
(mean differences: 0.262 m/s, CI95% = 0.118 – 0.407, p=0.001 respectively 0.321 m/s,
CI95% = 0.141 – 0.502, p=0.001). The stiffness in HCV patients was significantly higher
than in HBV carriers, as denoted by a speed of propagation of shear waves of 0.502 m/s,
CI95% = 0.348 – 1.037, p<0.001. Transaminase levels were not significantly different
between HBV carriers and healthy patients, but they were significantly higher in FL patients
(although normal) than in HBV carriers - mean difference = 24.84 IU/l for ALT and 14.77
IU/l for AST, with p=0.001 and 0.013 respectively.
Conclusions: Liver stiffness measured by ARFI is significantly increased in HBV inactive
carriers compared to patients with no liver disease or with fatty liver disease and normal
transaminase. This fact is probably related to a mild necroinflammatory process that may be
sometimes present in “inactive HBV carriers” and is not reflected by ALT elevation.
161
POSTER ABSTRACTS
Methodology: 159 patients (43 inactive HBV carriers, 52 randomly selected patients with
chronic hepatitis C virus (HCV) infection, 25 patients with ultrasound aspect suggesting
fatty liver (FL) but normal transaminase and 39 patients with no evidence of any liver
disease) were included in the analysis. We performed 10 consecutive ARFI measurements
in the right liver lobe of each patient. In all included patients, interquartile range (IQR) was
less than 1/3 of the median of the 10 measurements.
P35 - YI
REASSESSMENT OF HEPATITIS B AND DELTA IN
CENTRAL AFRICA REPUBLIC (CAR) 25 YEARS AFTER A
FULMINANT HEPATITIS OUTBREAK (ANRS 12202)
Sumantra Ghosh1, Dulce Alfaiate1, Natali Abeywickrama Samarakoon1,
Ségolène Brichler2, Gina Laghoe3, Mariama Abdou-Chekaraou1, Ikram Amri1,
Jean-Omer Ouavene3, Christian Trepo1, David Durantel1, Fabien Zoulim1, Emmanuel Gordien2,
Jean-Claude Cortay1, Narcisse P Komas3, Paul Deny1,2
1
U1052, INSERM, INSERM Lyon France, Lyon, 2Laboratoire associé au CNR
des hépatites B, C et delta, Service de Bactériologie,Virologie - Hygiène, Hôpital Avicenne,
GHUPSSD, Université Paris 13, Bobigny, France, 3Institut Pasteur de Bangui, Bangui,
Central African Republic
Introduction: An estimated 5% of individuals infected with hepatitis B virus (HBV) are
also infected with Hepatitis delta virus (HDV). Little is known about intertropical delta
fulminant hepatitis (FH) outbreaks and the role of HDV in the liver damage. In Amazonas,
delta FH outbreaks are mostly linked to HDV genotype 3 and HBV genotype F; but HBV/A
or HBV/D may also be the helper. From 1983 to 1987, FH outbreak occurred in CAR,
killing 88% of hospitalised severe acute cases.
POSTER ABSTRACTS
Aims: To approach HDV pathogenesis in FH, we aimed to characterize HDV strains
obtained from ancient outbreak samples (AS) and compare them to recent HDV strains
obtained in 2010 among asymptomatic students in Bangui.
Methodology: From the AS cohort, we studied 92 patient samples along with 41 samples
of there close relatives and/or health care workers; from the 2010 cohort, we studied 115
HBs Antigen (Ag) positive students to check HDV. HDAg and Anti-HD Antibodies (Ab)
were screened by ELISA and nucleic acids (NA) were extracted from serum samples by
manual or automated techniques. Viral RNA detection relied on RT-PCR of 400 bp (R0
region) and SHD gene (585 bp). HBV genotyping was also performed. Amplified PCR
product were cloned and/or sequenced. Phylogenetic analyses were assessed by sequence
alignment and Bayesian approaches.
162
Results: We obtained 12 FH-associated HDV R0 and 3 SHD sequences from the whole AS
cohort and 7 HDV R0 sequence from recent CAR cohort. Phylogenetic studies indicated
that these CAR HDV1 strains were associated to HBV/E during the FH outbreak. We could
not differentiate FH AS strains from recent CAR strains on the tree topology. By using
5’SHD specific primer, full length SHD gene could be amplified in only 3 samples out of 12
advocating RNA hydrolysis in AS or genetic variability of HF HD gene. Comparison of AS
FH S-HDAg to 2009 CAR S-HDAg did not reveal AS FH specific SHD patterns.
POSTER ABSTRACTS
Conclusions: FH delta in Bangui was linked to different HDV1 strains in a HBV/E
background. CAR HDV1 viral RNA could only be found in 12 cryopreserved (-20°C) sera
from the mid-eighties, confirming the sturdiness of the viral pseudo double stranded RNA.
HDV-specific serological markers (HDAg and/or Anti-HD Ab) were not constantly positive
indicating the importance of NA testing in FH. Larger HDV genome amplification was very
difficult to obtain from AS samples. Interestingly, different HDV/HBV genotypes in CAR
and Amazonas can lead to similar histopatological features in intertropical area.
163
P36 - YI
FUNCTIONAL INNATE IMMUNE RESPONSES ARE
RESTORED WITH SEQUENTIAL NUC THERAPY
FOLLOWING PEGYLATED INTERFERON–ALPHA
EXPOSURE AND NOT WITH NUC MONOTHERAPY IN
CHRONIC HEPATITIS B.
Upkar Singh Gill1, Dimitra Peppa2, Harsimran D Singh2, Lorenzo Micco2,
Graham R Foster1, Patrick T F Kennedy1, Mala K Maini2
1
Hepatology Unit, Centre for Digestive Diseases, Blizard Institute, Barts and The London SMD,
QMUL, 2Division of Infection & Immunity, University College London,
London, United Kingdom
Introduction: Treatment strategies in Chronic Hepatitis B (CHB) are now focused
on achieving sAg loss; thus greater consideration is being given to combined/sequential
therapeutic approaches comprising Pegylated-Interferon (PEG-IFN) and nucleot(s)ide
analogues (NUCs), to achieve this goal. We previously demonstrated boosting of NK cell
responses in eAg- patients treated with PEG-IFN and postulated that this effect could
be maintained with sequential NUC therapy, representing a superior strategy to NUC
monotherapy.
POSTER ABSTRACTS
Aims: To assess differential NK cell responses in patients receiving a sequential NUC in
comparison to patients on NUC monotherapy to determine if there is a treatment advantage
with PEG-IFN exposure.
Methodology: PBMC from 18 eAg+ patients during PEG-IFN therapy were utlised. 10/18
patients considered PEG-IFN non-responders progressed to sequential NUC therapy and
were followed until virally suppressed. NUC monotherapy patients, without prior PEG-IFN
exposure, were analysed for comparison. Phenotypic and functional analysis of NK cell
subsets was performed by multicolour flow-cytometry.
Results: PEG-IFN expanded CD56bright NK cells by 3-fold (p=0.0001); this was maintained
on sequential therapy but not seen with NUCs alone (p=0.03). NK cell expression of
C-Type lectin and natural cytotoxicity receptors was analysed.
164
All receptors, except NKG2D, were expressed at significantly higher levels on sequential
NUCs vs. NUC monotherapy (p=<0.05), with marked augmentation in the expression
of NKp30 and NKp46 on CD56bright NK cells (p=0.0001 & 0.002 respectively). The
proportion of CD56bright NK cells expressing TRAIL was 3-fold higher on sequential NUC
therapy compared with NUC monotherapy (p=0.007). These NK cells during sequential
therapy demonstrated ability to degranulate and produce IFN-γ; functional restorations
not achieved on NUCs alone (p=0.0001 & 0.002 respectively). These changes were more
dramatic in patients demonstrating eAg seroconversion +/- sAg decline on sequential NUCs.
POSTER ABSTRACTS
Conclusions: The potent expansion of activated CD56bright NK cells induced by PEGIFN is sustained on sequential NUC therapy, with high expression of NKp30, NKp46 and
TRAIL when compared to NUCs alone. Restoration of NK cell cytotoxic/effector functions
on sequential therapy is demonstrated. PEG-IFN non-responders exhibit innate boosting
which is maintained with functional innate restoration on sequential NUC therapy. Further
work is being undertaken to see if this priming effect is present with shorter courses of
PEG-IFN.
165
P37
HIGH LEVELS OF HEPATITIS B SURFACE ANTIGEN
(HBSAG) CAN EXCLUDE SIGNIFICANT FIBROSIS
AND DISTINGUISHES TRUE ‘IMMUNE-TOLERANCE’
IN CHILDREN AND YOUNG ADULTS WITH CHRONIC
HEPATITIS B
Navjyot K Hansi1, Upkar Singh Gill1, Amrita Banerjee1, Neelan Sunendraraj1,
Chandni Patel1, Sandhia Naik2, Graham R Foster1, Patrick T F Kennedy1
1
QMUL, 2Paediatric Gastroenterology & Hepatology, Barts Health NHS Trust, London,
United Kingdom
Introduction: Immune tolerant (IT) Chronic Hepatitis B (CHB) is synonymous with
disease in young people and characterised by normal serum ALT and high HBV DNA.
We demonstrated the limitations of this clinical definition; reporting evidence of immune
activity indistinguishable between disease phase and comparable to that found in older
patients. Recent studies have reported an inverse correlation between quantitative HBsAg
(qHBsAg) and the degree of liver fibrosis in eAg+ patients.
Aims: To investigate qHBsAg and its relationship with disease phase; we propose the
inclusion of qHBsAg to characterise IT disease.
POSTER ABSTRACTS
Methodology: Children and young adults were followed in a dedicated young people’s
clinic. Ninety consecutive treatment naïve, eAg+ patients were included for analysis;
(female=48), median age 23 (range 6-30). Data on longitudinal ALT, HBV DNA & fibrosis
stage were documented. HBsAg levels were quantified in all patients to determine any
correlation with IT disease.
Results: We probed whether qHBsAg correlated with clinical variables, delineating disease
phase. There was no correlation of qHBsAg with age or ALT levels. High HBV DNA
correlated with high qHBsAg; HBV DNA >8log, (p=0.02); HBV DNA >9log (p=<0.001).
68/90 patients underwent liver biopsy. Patients with Ishak fibrosis (F) stage 0/1, indicating
no or minimal liver damage demonstrated higher qHBsAg compared to patients with a
higher fibrosis stage (F≥2, p=0.04).
166
Considering this, we observed patients deemed IT (ALT <40, HBV DNA >8log, F0/1) have
significantly higher qHBsAg compared to non-IT eAg+ patients (p=0.001). qHBsAg varied
highly in the cohort; mean 88,638IU/ml (4.9log). However, all patients considered IT had
qHBsAg >10,000IU/ml (4log), but only true IT patients (F0/1) demonstrated qHBsAg
>1,000,000IU/ml (6log); a theoretical qHBsAg threshold for further modelling analysis
in a larger cohort to identify true IT patients. Binary logistic regression analysis suggested
qHBsAg has high specificity (94%) to exclude significant liver damage, with 63% sensitivity.
POSTER ABSTRACTS
Conclusions: A proportion of young adults considered to have IT CHB based on ALT and
HBV DNA have significant liver damage not consistent with immunological tolerance. On
the contrary, high qHBsAg can distinguish those with IT disease confirmed histologically
with minimal or no fibrosis. We propose that qHBsAg should be used in combination with
serum ALT and HBV DNA to accurately define the IT disease phase.
167
P38
QUANTITATIVE HEPATITIS B SURFACE ANTIGEN
(QHBSAG) CAN DEFINE LOW-RISK INACTIVE CARRIERS
OF CHB: IS IT CLINICALLY APPLICABLE ACROSS ALL
AGE-GROUPS?
Navjyot K Hansi1, Upkar Singh Gill1, Amrita Banerjee1, Neelan Sunendraraj1,
Louise Payaniandy2, Josephine Schulz2, Deva Payaniandy2, Sandhia Naik3,William Tong4,
William Alazawi1, Janet Dearden2,Yiannis N Kallis2, Paul Kooner2, Richard Marley2,
Graham R Foster1, Patrick T F Kennedy1
1
QMUL, 2Department of Hepatology, 3Paediatric Gastroenterology & Hepatology, 4Department of
Virology, Barts Health NHS Trust, London, United Kingdom
Introduction: Inactive carriers (IC) defined as those with low serum ALT and HBV DNA
represent a significant proportion of e-antigen negative chronic hepatitis B (CHB) under
follow-up in secondary care. Recent data proposes that quantitative Hepatitis B surface
antigen (qHBsAg) can define a low-risk IC profile. Patients with qHBsAg levels (<1,000IU/
ml) are at reduced risk for disease progression and the development of HCC; conversely
qHBsAg levels (>1,000IU/ml) significantly increases the risk of disease progression (Tseng
et al, Hepatology 2013). Identification of low-risk IC’s would allow less stringent follow-up
and reduce the need for HCC screening in selected patients.
POSTER ABSTRACTS
Aims: To investigate whether a qHBsAg threshold (<1,000IU/ml) can be applied to
children and young adults with an IC disease profile.
Methodology: Forty-one consecutive treatment naïve eAg negative young patients (<30
years) considered IC’s (ALT<40, HBV DNA <2,000IU/ml) over longitudinal followup were included for analysis; female=27, median age=26 (range 12-30). Twenty-five
consecutive older patients (>30 years) defined as ICs based on the same parameters were
included for comparison; female=10, median age=42 (range 31-61). HBsAg levels were
quantified in all patients to determine any correlation between the qHBsAg threshold
(<1,000 IU/ml) and age.
168
Results: In line with an IC disease profile, serum ALT and HBV DNA levels in both
cohorts were similar (p=ns), however, qHBsAg levels were significantly higher in the <30
vs. >30 cohort; mean qHBsAg 11,025 IU/ml vs. 4,546 IU/ml (p=0.003). In keeping with
this, we detected a significant negative correlation with age and qHBsAg (Spearman Rho
rs =-0.33, p=0.006). Significantly more >30‘s had qHBsAg <1,000IU/ml, (40% vs. 10%;
p=0.04), consistent with low-risk ICs; a disease profile associated with reduced risk for
disease progression and the development of HCC.
POSTER ABSTRACTS
Conclusions: No robust model exists for disease stratification and HCC risk in ICs of
CHB. The utility of qHBsAg in addition to serum ALT and HBV DNA can enhance
risk stratification. However, the natural decline in qHBsAg with advancing age precludes
a threshold level (<1,000 IU/ml) to define low-risk IC in younger patients. These data
suggest a higher level of qHBsAg may still be compatible with low-risk IC in young patients.
Furthermore, our data highlight the need to define an age limit above which this qHBsAg
level can be used to identify low-risk ICs.
169
P39 - YI
PROLONGED USE OF TENOFOVIR AND ENTECAVIR
IN HBV RELATED CIRRHOSIS- AN APPRAISAL FROM
TERTIARY CARE CENTER.
Sundeep Goyal1, Ashok Kumar Jain1,Vinod Kumar Dixit1, Sunit Kumar Shukla1,
Jayant Ghosh1
1
Gastroenterology, Institute of Medical Sciences, BHU,Varanasi, India
Introduction: Limited data is available from India on outcome and efficacy of tenofovir
and entecavir in hepatitis B–related cirrhosis when used from prolonged time.
Aims: We investigated the long-term efficacy and outcome of these antiviral drugs in patients
with chronic hepatitis B virus (HBV) infection, with compensated or decompensated
cirrhosis.
POSTER ABSTRACTS
Methodology: We retrospectively analyzed laboratory and clinical data of 400 HBV related
cirrhotic patients without access to liver transplantation, which were treated with tenofovir/
entecavir therapy at University hospital’s gastroenterology services beginning from January
2007. 210 (52.5%) patients had at least one of the components of decompensation at
baseline. 220 (55%) and 180 (45%) patients were initiated tenofovir and entecavir,
respectively. Median follow-up period was 45(12-68) months for tenofovir and 36 (11-60)
months for entecavir.
Results: At end of 1-year HBV DNA level less then 20 IU/ml was achieved in 91.88% and
88.88 % of patients and alanine aminotransferase normalized in 54.54% and 55.55% of
patients who received tenofovir and entecavir, respectively. At last visit, Child–Turcotte–
Pugh scores improved among 29.5% of patients who received tenofovir, 25% who received
entecavir, and remains stable in 61.9% and 65% patients respectively in both groups. Mean
MELD score improved by 0.21 ±2.5 and 0.19 ±1.1 per year in tenofovir and entecavir
treated patients. The 5-year cumulative rate of liver decompensation, hepatocellular
carcinoma and cirrhosis related complications were 3.1%, 1.9% and 2.1% with annual
incidence of 0.88%, 0.35% and 0.55% per person-year respectively.
Conclusions: Tenofovir and entecavir are effective and potent drugs for prolonged
treatment of HBV cirrhosis patients and improve over all clinical course too.
170
P40 - YI
TRANSIENT ELASTOGRAPHY AND LIVER FIBROSIS
SERO-MARKERS FOR ASSESSMENT OF LIVER FIBROSIS
IN EGYPTIAN PATIENTS WITH CHRONIC HEPATITIS “B”
Mohamed Hassany1 and Tropical Medicine Department, National Hepatology & Tropical
Medicine Research Institute, Cairo, Egypt
1
Tropical Medicine Department, National Hepatology & Tropical Medicine Research Institute,
Cairo, Egypt
Introduction: Chronic viral hepatitis B (CHB) is a global public health problem; nearly
2 to 3 million Egyptians are chronic carriers of hepatitis B virus (HBV).An accurate
assessment of liver fibrosis in patients with CHB is mandatory to begin specific antiviral
therapy. As liver biopsy (LB) is an invasive procedure, alternative non-invasive tests have
been developed to reliably assess the stages of liver ﬁbrosis as transient elastography (TE,
Fibroscan)-and other sero-markers as APRI Score, FIB-4 and Fibro-α score.
Aims: Evaluate the accuracy of the liver stiffness measurement (LSM) by TE and indirect
serum scores in assessment of liver fibrosis in patients with chronic hepatitis B in comparison
to the liver biopsy.
Results: A fair agreement between the APRI score, FIB4 score, fibroαscore and the results
of liver biopsy (Kappa=0.23) and moderate agreement between fibroscan and the results of
liver biopsy (Kappa=0.528).
Conclusions: Liver biopsy still considered the golden standard for assessment of liver
fibrosis and necro-inflammation in CHB, use of non -invasive methods like sero-markers
and transient elastography could be reliable to certain extent in making decisions for
treatment.
171
POSTER ABSTRACTS
Methodology: 30 patients with CHB, were assessd for liver fibrosis using: APRI score =
{(AST level (U l−1)/40 (upper limits of normal))/ (platelet count × 109 l−1)} × 100 .FIB-4
score = Age (years) × AST [U/L]/ (platelet count [109/L] × (ALT [U/L]).Fibro-α score =
(1.35 (numeric constant) + AFP (IUml˗) × 0.009584 + (AST)/ (ALT) × 0.243 - platelet
count (× 109 l−1) ×0.001624) . Liver stiffness measurement using the transient elastography
(Fibroscan) then liver biopsy was performed in the same day.
P41
A NEW ALGORITHM CONVENIENT FOR A COMPUTERIZED
PHYSICIAN ORDER ENTRY-BASED (CPOE) SYSTEM TO
PREVENT HBV REACTIVATION IN PATIENTS TREATED
WITH BIOLOGIC AGENTS
Javier Crespo1, Candido Hernandez2, Blanca Sampedro3, Maria Buti4, Pau Abrisqueta5,
Maria J Carreras6, Anna Farriols6, Elena Gonzalez-Colominas7, Jose Antonio Carrion8
1
Gastroenterology, Hospital Valdecilla, Santander, 2Medical Affairs, Gilead Sciences, Madrid,
3
Gastroenterology, Hospital Galdakao, Galdakao, 4Hepatology, 5Hematology, 6Pharmacy,
Hospital Vall Hebron, 7Pharmacy, 8Hepatology, Hospital del Mar, Barcelona, Spain
Aims: In the last years several algorithms for screening and preventing HBV reactivation
in patients receiving immunosuppressive therapies have been published. However, the
application of these algorithms in a CPOE system has practical limitations. We try to find
the most desirable algorithm which could be purposely applied to any CPOE system to
improve screening rates and data analysis.
POSTER ABSTRACTS
Methodology: The feasibility of implementing a CPOE system that allows increasing
the rate of HBV screening has been demonstrated by our group previously (Sampedro
et al. Hepatology 2014). With this background a multidisciplinary team of hepatologists,
hematologists, clinical pharmacologist, and hospital pharmacists look for the most desirable
algorithm.
Results: The key points agreed by the multidisciplinary team which should contain any
desirable algorithm are: 1) It is able to capture both HBsAg and anti-HBc parameters,
independently; 2) In cases positive for HBsAg/anti-HBc markers the HBV DNA should
be tested; 3) In HBsAg positive subjects, results crucial an alert requiring an assessment of
the liver disease status; 4) It should deal with the likely “No Answer” outcome; 5) It should
take into account the fact that medical specialists will use the CPOE over the time and
consequently should be able to provide with memory messages accordingly to the latter
serology status. Taking into account former key points an algorithm was established (See
Figure) which includes four questions and five alert messages (in cursive letter), in addition
to several internal instructions (in capital letter) to assure the re-assessment of the patient
status during upcoming prescriptions.
172
POSTER ABSTRACTS
Conclusions: A purposely algorithm has been created for countering to the CPOE
system requirements which will allow to improve the HBV screening in patients receiving
immunosuppressive therapies.
173
P42
TENOFOVIR DF PREVENTS HBV REACTIVATION IN
ANTI-HBC POSITIVE PATIENTS WITH HEMATOLOGIC
MALIGNANCIES TREATED WITH RITUXIMAB: 12-MONTHS
RESULTS OF A RANDOMIZED STUDY (PREBLIN STUDY)
Maria Buti1, Maria Luisa Manzano2, Rosa Morillas3, Montserrat Garcia-Retortillo4,
Leticia Martin5, Martin Prieto6, Maria Luisa Gutierrez7, Emilio Suarez8, Mariano Gomez9,
Javier Lopez10, Francisco Gea11, Manuel Rodriguez12, Juan Manuel Zozaya13,
Miguel A Simon14, Albert Pardo15, Luis Enrique Morano16, Jose Luis calleja17, Rafael Esteban1
and PREBLIN study group
1
Hepatology, Hospital Vall Hebron, Barcelona, 2Gastroenterology, Hospital Doce de Octubre,
Madrid, 3Hepatology, Hospital Germans Trias, Badalona, 4Hepatology, Hospital del Mar,
Barcelona, 5Gastroenterology, Hospital de Donostia, San Sebastián, 6Hepatology, Hospital
U.P. La Fe; CIBERehd,Valencia, 7Gastroenterology, F.U. Fundacion de Alcorcon, Alcorcon,
8
Hepatology, Hospital de Valme, Sevilla, 9Gastroenterology, Hospital de Getafe, Getafe,
10
Hematology, Hospital Ramon y Cajal, 11Hepatology, Hospital La Paz, Madrid, 12Hepatology,
Hospital Central de Asturias, Oviedo, 13Gastroenterology, Hospital de Navarra, Pamplona,
14
Hepatology, Hospital Clinico Lozano Blesa, Zaragoza, 15Gastroenterology, Hospital Joan
XXIII, Tarragona, 16Infectious Disease, Hospital do Meixoeiro,Vigo, 17Gastroenterology, Hospital
Puerta de Hierro, CIBERehd, Majadahonda, Spain
Introduction: Patients positive for HBsAg or anti-HBc are at risk of severe HBV
reactivation due to immunosuppressive treatment with rituximab (RTX). In Spain, 8.7% of
the population is anti-HBc positive. Lamivudine prophylaxis reduces but does not eliminate
the risk of HBV reactivation.
POSTER ABSTRACTS
Aims: It is important to assess the safety and efficacy of more potent antivirals, such as
tenofovir DF (TDF) in prevention of HBV reactivation of this subpopulation.
Methodology: Randomized, prospective, open-label, multicenter, parallel-group clinical
trial from 17 hospitals throughout Spain. HBsAg negative, anti-HBc-positive patients with
undetectable HBV-DNA were randomized before starting RTX to receive TDF or to 18
months of observation (tests every 2 months). HBV reactivation was defined as HBV-DNA
elevation ≥ 1 log10 IU/mL above baseline and/or HBsAg reappearance.
174
Results: A total of 62 anti-HBc positive patients were recruited. At baseline, 4 patients
had detectable HBV-DNA and received open-label TDF. The remaining 58 patients were
randomized to receive TDF (n=30) or to observation (n=28). Fifty-eight percent of patients
were male, median age 70±1.4 years, with non-Hodgkin lymphoma (56.5%), chronic
lymphocytic leukemia (22.6%), and other (20.9%). At 12 months, 10 subjects withdrew
(4 due to malignancy-related death). HBV reactivation was not observed in TDF patients
0/34, compared to 2/28 (7.1%) with observation. The 2 HBV reactivations, both at month
4 of RTX, were identified by HBV-DNA elevation, without ALT elevations or HBsAg
seroreversion. No patients had clinical symptoms of hepatitis, and both were rescued with
TDF, becoming HBV-DNA undetectable at 6 months.
POSTER ABSTRACTS
Conclusions: The results from this study in anti-HBc-positive patients treated with RTX
demonstrate that prophylaxis with TDF is effective in preventing HBV reactivation.
175
P43
CHARACTERIZATION OF HBSAG LOSS IN PATIENTS
WITH CHRONIC HEPATITIS B (CHB) TREATED WITH
NUCLEOS/TIDE ANALOGS (NUCS): A RETROSPECTIVE
MULTICENTER STUDY (HEBESAS)
Emilio Suarez1, Miguel Angel Simon2, Maria Buti3, Martin Prieto4, Juan M Pascasio5,
Manuel Rodriguez6, Teresa Casanovas7, Javier Crespo8, Juan Arenas9, Rafael Gomez10,
Blanca Figueruela11, Moises Diago12, Rosa Morillas13, Juan Manuel Zozaya14,
Jose Luis Calleja15, Marta Casado16, Esther Molina17, Javier Fuentes18
1
Hepatology, Hospital de Valme, Sevilla, 2Hepatology, Hospital Clinico Lozano Blesa, Zaragoza,
3
Hepatology, Hospital Vall Hebron. CIBERehd, Barcelona, 4Hepatology, Hospital U.P. La
Fe; CIBERehd,Valencia, 5Gastroenterology, Hospital Virgen del Rocio, Sevilla, 6Hepatology,
Hospital Central de Asturias, Oviedo, 7Hepatology, Hospital de Bellvitge, Hospitalet de
Llobregat. Barcelona, 8Gastroenterology, Hospital M. de Valdecilla, Santander, 9Gastroenterology,
Hospital de Donostia, San Sebastian, 10Gastroenterology, Hospital Virgen de la Salud, Toledo,
11
Gastroenterology, Hospital de Valme, Sevilla, 12Hepatology, Clinica Quiron-Universidad Catolica
de Valencia,Valencia, 13Hepatology, Hospital Germans Trias i Pujol.CIBERehd, Badalona,
14
Gastroenterology, Hospital de Navarra, Pamplona, 15Gastroenterology, Hospital Puerta
de Hierro, CIBERehd, Majadahonda, 16Gastroenterology, Hospital Torrecardenas, Almeria,
17
Hepatology, Hospital Complex of Santiago, Santiago de Compostela, 18Hepatology, Hospital
Miguel Servet, Zaragoza, Spain
Introduction: HBsAg loss is the optimal goal of CHB treatment but it is difficult to achieve
in patients treated with NUCs, mainly in HBeAg negative patients.
POSTER ABSTRACTS
Aims: The aim of this study was to investigate the patient characteristics associated with
HBsAg loss.
Methodology: Retrospective multicenter study of CHB patients treated with NUCs that
lost HBsAg after 2007. Exclusion criteria were spontaneous HBsAg loss or occurred during
IFN/PEG-IFN therapy, HCV, HDV or HIV coinfection, liver transplantation or HBV
reactivation due to immunosuppressive therapies.
176
Results: A total of 86 patients were included, 91% male and 94% Caucasian, median age of
51 years at the time of HBsAg loss. 54% (45/83) were HBeAg positive at the start of NUCs.
Genotype was available in 32 patients, the majority being D (44%) and A (34%). Severe
fibrosis or cirrhosis was present in 22% (6/27).
HBV DNA was persistently undetectable in 69% patients before HBsAg loss: median
duration 1.19 yr in HBeAg positive and 3.00 yr in HBeAg negative patients (p=0.014).
Upon HBsAg loss, HBV DNA was detectable (52 IU/ml) only in one patient and 34%
(25/73) had developed antiHBs. The time between diagnosis of CHB and HBsAg loss was
significantly longer in HBeAg negative than in HBeAg positive patients: median, 10.5 vs.
3.1 yr, respectively (p <0.0001). Although the time from NUCs initiation to HBsAg loss
differed between HBeAg negative and HBeAg positive patients (median, 3.2 vs. 1.9 yr,
respectively), it did not reach statistical significance (p=0.120).
HBsAg loss occurred in 62.8% patients treated with TDF (39.5%) or ETV (23.3%),
followed by LAM (15.1%) and ADV (9.3%). The mean time from NUCs initiation to
HBsAg loss was 1.8 yr with ETV/TDF and 6.6 yr with ADV/LAM (difference was 4.8 yr,
CI: 3.9-5.7, p<0.0001).
Treatment was discontinued in 75.6% patients after HBsAg loss (median, 8.7 months).
HBV DNA was undetectable in all patients and 60% (36/60) had developed antiHBs at
the time of NUCs discontinuation. No HBsAg seroreversion occurred during a median of
12 months follow-up (range, 2-55 months). No patient developed hepatic complications or
hepatocellular carcinoma.
POSTER ABSTRACTS
Conclusions: These data suggest the time between the diagnosis of CHB and HBsAg
loss is longer in HBeAg negative than in HBeAg positive patients. In addition, HBsAg loss
occurred faster with TDF/ETV than with LAM/ADV. HBsAg loss was maintained in all
patients after discontinuation of NUCs.
177
P44
EVALUATION OF 2012 EASL CLINICAL PRACTICE
GUIDELINES IN UNTREATED PATIENTS WITH
CHRONIC HEPATITIS B VIRUS INFECTION IN SPAIN. A
RETROSPECTIVE CROSS-SECTIONAL STUDY (HEBEST)
Jose Luis Calleja1, Emilio Suarez2, Ricard Sola3, Miguel Fernandez-Bermejo4,
Juan M Pascasio5, Maria Luisa Manzano6, Javier Crespo7, Maria Buti8,
Javier Garcia-Samaniego9, Martin Prieto10, Jose Carlos Erdozain11, Jose Luis Castro12,
Beatriz de Cuenca13, Miguel Angel Simon14, Francisco Jorquera15, Paz Valer16, Francisco Gea17,
Maria Luisa Garcia-Buey18, Raquel Gonzalez19
1
Gastroenterology, Hospital Puerta de Hierro, CIBERehd, Majadahonda, 2Gastroenterology,
Hospital de Valme, Sevilla, 3Hepatology, Hospital del Mar, Barcelona, 4Gastroenterology,
Hospital San Pedro de Alcantara, Caceres, 5Gastroenterology, Hospital Virgen del Rocio, Sevilla,
6
Hepatology, Hospital 12 de Octubre, Madrid, 7Gastroenterology, Hospital M. de Valdecilla,
Santander, 8Hepatology, Hospital Vall Hebron. CIBERehd, Barcelona, 9Hepatology, Hospital
Carlos III, Madrid, 10Hepatology, Hospital U.P. La Fe; CIBERehd,Valencia, 11Gastroenterology,
Hospital Infanta Sofia, San Sebastian de los Reyes, Madrid, 12Gastroenterology, Hospital
Severo Ochoa, Leganes, Madrid, 13Gastroenterology, Hospital Infanta Cristina, Parla,
Madrid, 14Hepatology, Hospital Clinico Lozano Blesa, Zaragoza, 15Gastroenterology, Complejo
Hospitalario de Leon, Leon, 16Gastroenterology, Hospital de Fuenlabrada, Fuenlabrada, Madrid,
17
Hepatology, Hospital La Paz, 18Hepatology, Hospital La Princesa, Madrid, 19Gastroenterology,
Hospital de Mostoles, Mostoles, Madrid, Spain
POSTER ABSTRACTS
Aims: To study the proportion of untreated chronic hepatitis B (CHB) patients in a
Spanish cohort that would require treatment according to the 2012 EASL-Clinical Practice
Guidelines (EASL-CPGs): i.e., ALT ≥ 40 IU/L, HBV DNA ≥ 2,000 IU/mL, and significant
liver necroinflammation/fibrosis. A second analysis was performed using more restrictive
ALT cut-offs (ALT ≤30 IU/L in males and ≤19 IU/L in females).
Methodology: All untreated CHB patients in 19 hospitals in Spain with at least two HBV-DNA
and ALT assessments were included retrospectively between February 2009-September 2012.
Patients with HCV or HIV co-infection, or diagnosis of hepatocellular carcinoma were excluded.
Significant liver damage was defined as evidence of at least moderate necroinflammation and/or
fibrosis on liver biopsy (LB grade ≥A2 and/or stage ≥F2 on the METAVIR scale or equivalent)
and/or significant fibrosis on transient elastometry (TE >9.4 kPa).
178
Results: A total of 475 patients were evaluated, 54% males, 96% HBeAg-negative, mean
HBV-DNA 5.94±7 IU/mL, mean ALT 26.8±15.7 IU/L, 69% inactive carriers according
to the EASL-CPGs. Assessment of liver damage was performed in 322 (68%) patients
with LB (25%) and/or TE (60%). Of the 322 patients, 103 (32%) did not have any of
the three EASL-CPGs treatment criteria whereas the remaining 219 patients have at least
one criteria, that is, 167 (76%), 48 (22%) and 4 (2%) had one, two, and three criteria,
respectively. Among those 219 patients (See Figure), 40 (18%) had ALT ≥ 40 IU/L and
DNA ≥ 2,000 IU/mL, 135 (66%) exhibited ALT < 40 IU/L and DNA ≥ 2,000 IU/mL, and
37 (17%) had ALT ≥ 40 IU/L and DNA < 2,000 IU/mL. Twelve patients (6%) fulfilled
the current treatment criteria according to the EASL-CPGs (4 showing all three criteria
and 8 with DNA≥ 2,000 IU/mL and significant liver necroinflammation/fibrosis), the same
number when 30/19 IU/L ALT cut-off was applied (10 with all three criteria and 2 with
DNA≥ 2,000 IU/mL and significant liver necroinflammation/fibrosis).
Conclusions: Only 4% (12/322) of untreated CHB patients in Spain would require therapy
when the 2012 EASL-CPGs are applied, and using lower ALT cut-offs does not appear to
make difference.
POSTER ABSTRACTS
Figure:
179
P45 - YI
TRAINED IMMUNITY IN NEONATES OF CHRONIC HBVINFECTED MOTHERS
Michelle Hong1, Elena Sandalova1, Diana Low2, Adam J. Gehring1,Yap-Seng Chong3,
Ernesto Guccione2, Antonio Bertoletti1,4
1
Singapore Institute for Clinical Sciences, 2Institute of Molecular and Cell Biology, 3Department
of Obstetrics & Gynaecology, National University of Singapore , 4Emerging Infectious Diseases
(EID) Program, Duke-NUS Graduate Medical School, Singapore, Singapore
Introduction: Neonatal susceptibility to infections is largely ascribed to immaturity of the
newborn immune response. Hepatitis B virus (HBV) is thought to hijack the newborns’
defective host defence and induce an immunotolerant state leading to the establishment
of chronic infection, However, the extent to which the neonatal immune system is exposed
to HBV antigens and whether this can cause a global alteration of adaptive and innate
immunity have never been characterized.
Aims: We aim to characterize the phenotypic and functional profile of immune cells present
in the cord blood (CB) of neonates born to chronic HBV-infected mothers.
POSTER ABSTRACTS
Methodology: We obtained cord blood samples from 20 chronic HBV-infected mothers
and tested the presence of intracellular HBsAg by immunofluorescence. We analyzed the
phenotypic and functional profile of CB immune cells using a systemic approach comprising
flow cytometry, Nanostring, and Luminex technologies.
Results: We show that HBV exposure in utero did not trigger virus-specific adaptive
immunity but instead induced a state of trained immunity, characterized by increased
monocyte activation/maturation and enhanced Th1 development. Importantly, acquisition
of this trained immunity status results in a better ability of the HBV-exposed cord blood
immune cells to respond to bacterial infection. The observed changes in immune maturation
status was likely a result of immuno-modulation of the neonatal cytokine environment,
since we detected higher production of plasma IL-12p40 and IFN-alpha in the cord blood
of HBV-exposed neonates than controls.
Conclusions: Our data challenge the current dogma of immunotolerance in HBV vertical
infection and suggest the presence of a novel and potentially symbiotic relationship between
HBV and its natural host at birth. From a clinical perspective, our results call for a more
precise re-evaluation of the immunological events that are occurring in the early phases of
HBV infection.
180
P46 - YI
NKG2D-DEPENDENT INTERACTIONS BETWEEN CD4 T
CELLS AND NK CELLS IN THE HBV-INFECTED LIVER
Wei-Chen Huang1, Dimitra Peppa1, Nicholas Easom1, Xin-Zi Tan1, Harsimran Singh1,
Guiseppe Fusai2,William Rosenberg2, Indrajit Ghosh3, Richard Gilson3, Eleni Nastouli4,
Upkar Gill5, Patrick Kennedy5, Chi-Wen Chang6, John Trowsdale6, Mala Maini1 and Maini Group
1
Division of Infection and Immunity, 2Institute for Liver and Digestive Health , 3Centre for Sexual
Health and HIV Research, 4Department of Clinical Microbiology and Virology, University College
London, 5Barts and the London Hospital, London, 6Department of Pathology, University of
Cambridge, Cambridge, United Kingdom
Introduction: NK cells are emerging as potent regulators of adaptive immunity; we have
recently shown that they can kill hepatitis B virus (HBV)-specific T cells in a contactdependent manner (Peppa JEM 2013). The TRAIL pathway was involved in NK cell
deletion of T cells but blocking studies implicated additional pathways.
Aims: In this study we explored the role of NKG2D-dependent interactions between NK
cells and T cells.
Results: The activatory receptor NKG2D was maintained at high levels on NK cells
from patients with HBV and further increased on intrahepatic NK cells. NKG2Dligands (NKG2D-L) are not usually expressed on T cells but were upregulated on T cells
(CD4>CD8) in CHB patients, particularly those with liver inflammation. NKG2D-L were
preferentially expressed on activated and HBV-specific T cells, and strikingly enriched on
T cells in the CHB liver compared to their circulating counterparts or to T cells in control
livers without inflammation. Following NKG2D pathway blockade in vitro, there was a
small but consistent rescue of circulating and intrahepatic HBV-specific CD4 T cells from
CHB patients with ongoing liver inflammation.
181
POSTER ABSTRACTS
Methodology: We evaluated peripheral blood from healthy individuals and patients with
chronic hepatitis B (CHB). Intrahepatic lymphocytes were isolated from liver tissue of
biopsies (CHB) or resections (controls). A MICA-transfected B lymphoblast cell line, C1R
MICA, was used to assess NK cell activation and cytotoxicity. Global, activated and HBVspecific T cells from the circulation and liver were stained with NKG2D-L mAb. NK cell
depletion and NKG2D-blocking mAb were used for functional experiments.
(NKG2D-L)-expressing cells were able to trigger activation and cytotoxicity of NK cells
from patients with CHB in an NKG2D-dependant manner. We therefore concluded that
the NKG2D pathway allows bidirectional cross-talk between T and NK cells. In support of
this, the NKG2D+ fraction of NK cells were more activated (HLA-DR+) in patients with
CHB than controls, particularly in the infected liver.
Conclusions: These results imply that NKG2D-L expressing T cells drive activation and
cytotoxicity of NK cells in the HBV-infected liver, promoting deletion of HBV-specific
T cells. Thus NKG2D-dependent CD4 T cell/NK cell interactions may support innate
immunity at the expense of the adaptive arm in CHB.
POSTER ABSTRACTS
Figure:
182
P47
CORRELATION BETWEEN QUANTIFICATION OF
HEPATITIS B SURFACE ANTIGEN AND HBV DNA LEVELS
IN PATIENTS WITH COMBINED CHRONIC HEPATITIS B
AND STEATOSIS
Sae Kyung Joo1
1
Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul,
Korea, South
Introduction: Quantitative hepatitis B surface antigen (HBsAg) is a surrogate marker that
can be used to monitor patients with chronic hepatitis B (CHB) who are being treated,
and HBsAg titer is related to HBV DNA level. However, the correlation between HBsAg
quantification and HBV DNA level in patients with combined CHB and steatosis is not
well established.
Aims: The aim was to investigate the relationship between HBsAg titer and HBV DNA
level in CHB patients combined with non-alcoholic fatty liver disease (NAFLD).
Results: Of 69 patients, 47 were male (68.1%) and 22 were female (31.9%); the mean age
was 42.45±11.7 years. Median body mass index was 25.95 kg/m2 and median homeostasis
model assessment (HOMA-IR) was 2.76. Baseline HBeAg was negative in 36 patients
(52.2%), and median serum HBV DNA level was 1290 IU/mL. Median HBsAg titer was
7969. By Mann-Whitney test, HBsAg titer differed significantly between HBeAg-positive
and -negative patients (P<0.001), as did HBV DNA level (P<0.001). By Spearman test,
significant correlations were observed between HBsAg and HBV DNA levels (P<0.001 and
r=0.418).
Conclusions: HBeAg-negative patients have higher levels of HBsAg and lower levels of
HBV DNA. HBsAg has significant correlation with HBV DNA levels in patients with
combined CHB and NAFLD.
183
POSTER ABSTRACTS
Methodology: This study included a total of 69 consecutive CHB patients without
significant alcohol consumption or other known liver diseases, who showed evidences
of hepatic steatosis on ultrasonography. Patients demographics and data on serum liver
biochemistries, platelet count, and serologic and virologic status were collected. HBV DNA
was measured by real-time polymerase chain reaction, and serum HBsAg was quantified by
electrochemiluminescence assay (Roche Diagnostics, Basel, Switzerland).
P48 - YI
LACTATE SERUM CONCENTRATIONS DURING
TREATMENT WITH POLYMERASE INHIBITORS IN
PATIENTS WITH CHRONIC HEPATITIS B WITH OR
WITHOUT CIRRHOSIS. A PROSPECTIVE STUDY
Maria Kalafateli1, Christos Triantos1, Martha Mandellou2, Konstantinos Zisimopoulos1,
Paraskevi Tselekouni1, Dimitra Taprantzi1, George Tsiaoussis1, Konstantinos Thomopoulos1,
Evangelos Anastasiou3, Chryssoula Labropoulou-Karatza4,Vasiliki Nikolopoulou1
1
Department of Gastroenterology, 2Department of Biochemistry, 3Department of Microbiology,
4
Department of Internal Medicine, University Hospital of Patras, Patras, Greece
Introduction: Lactic acidosis has been reported in patients with chronic hepatitis B (CHB)
and impaired liver function, treated with polymerase inhibitors (PIs). However, this issue
remains controversial.
Aims: To evaluate the clinical implications of lactate serum concentrations’ changes
in patients with chronic hepatitis B (both with and without cirrhosis) during treatment
with PIs.
POSTER ABSTRACTS
Methodology: One-hundred seven consecutive patients with CHB (males: 69 (64.5%),
median age: 57years (24-85)) were prospectively included. Lactate concentrations were
measured at 6, 12, 24, 36, 48 and 60 months following initiation of treatment with PIs:
lamivudine (n=8, 7.5%), tenofovir (n=38, 35.5%), entecavir (n=34, 31.8%), lamivudine
plus tenofovir (n=21, 19.6%), lamivudine plus adefovir (n=3, 2.8%), adefovir plus entecavir
(n=2, 1.9%) and entecavir plus tenofovir (0.9%). Cirrhosis was present in 37 (34.6%)
patients (HCC: 9 (24.3%), median Child-Pugh (CP) score: 6 (5-12), MELD score: 8 (628), CP A/B/C: 23/8/6 (62.2/21.6/16.2%)). Arterial blood gas analysis was performed when
elevated lactate was measured.
Results: None of the patients developed lactic acidosis during follow-up (median: 38.5
(4-132) months). There were no changes in lactate concentrations in cirrhotics versus noncirrhotics following 6, 12, 24, 36, 48 and 60 months of treatment (6 months: 11±2.95 vs
11.6±3.57, 12 months: 10.95±3.29 vs 11.1±3.56, 24 months: 11.35±4.22 vs 11.2±3.41, 36
months: 10±4.11 vs 11.6±3.75, 48 months: 9.1±4.27 vs 12.6±4.54, 60 months: 11.6±5.32
vs 12.7±4.8, respectively; all p=ns).
184
No difference in lactate was observed in cirrhotic patients with advanced liver disease
assessed by CP staging (p=ns for all time points). No lactate changes were observed among
patients treated with entecavir or tenofovir or lamivudine alone, or between patients treated
with combination treatment and monotherapy for all time points, either cirrhotics or not
(p=ns for all comparisons). Moreover, no lactate changes were observed across time for
both groups of patients (p=ns for all comparisons). Six patients had elevated levels of lactate
(median: 22.75±1.57, 2 CPA cirrhosis, MELD scores: 12 and 16) during treatment, but no
lactic acidosis.
POSTER ABSTRACTS
Conclusions: In this prospective study we did not observe significant lactate serum
concentrations’ changes during treatment with PIs in patients with CHB with or without
cirrhosis. None of the patients included developed lactic acidosis.
185
P49
ESTABLISHING A NEW VIRAL SET-POINT IN CHRONIC
HBV INFECTION: CLINICAL EVIDENCE OF IMMUNE
RECONSTITUTION AFTER PROLONGED HBV DNA
SUPPRESSION WITH TENOFOVIR
Melissa Kelley1, David Wong1
1
Toronto Western Hospital, Toronto, Canada
Introduction: Short term suppression of hepatitis B virus (HBV) DNA with nucleos(t)
ide analogues for 1-2 years is mostly unsuccessful as most relapse: HBV DNA rebounds
to pre-treatment levels unless those who were initially HBeAg positive seroconvert to antiHBe positive status or those who were initially HBeAg negative become HBsAg negative.
Since these outcomes are rare events, current guidelines effectively recommend lifelong
therapy. Studies of HBV-specific immunity show weak responses in chronic HBV infection
but suggest reconstitution of immunity when HBV DNA is suppressed with nucleos(t)ide
analogue therapy. Clinical correlates of immune reconstitution are lacking.
Aims: To explore the possible development of clinically significant HBV immunity after
long term nucleotide therapy by comparing the pre-treatment viral set-point to the posttreatment viral set-point.
POSTER ABSTRACTS
Methodology: This retrospective study examines patients enrolled in the Gilead LongTerm Tenofovir studies (GS-US-174-0102 and GS-US-174-0103) at the Toronto Western
Hospital who stopped treatment after 8 years. Patients were randomized to Tenofovir or
Adefovir for 48 weeks followed by open-label Tenofovir for the next 7 years. Post-treatment,
patients were monitored with blood tests every 4 weeks (including HBV DNA testing,
LLQ 29 IU/mL) for 24 weeks. The decision to re-start antiviral therapy was joint decision
between the treating physician and the patient.
Results: Twenty-three patients stopped treatment. Four were HBeAg-positive at the
beginning of treatment. All three who remained HBeAg-positive at the end of treatment
failed to achieve a new lower viral set-point and were re-treated. One patient seroconverted
to anti-HBe positive status after 4.3 years of treatment. The viral set-point diminished from
7-8 log IU/mL pre-treatment to 4 log IU/mL post-treatment. An additional 19 patients
were HBeAg-negative/anti-HBe-positive prior to treatment. 15/19 (78.9%) established a
new viral set-point as HBV DNA diminished from 4-8 log IU/mL pre-treatment to <29-3
log IU/mL post-treatment. The remaining 4 patients failed to achieve a new lower viral setpoint. Two were retreated and two continue to be monitored.
Conclusions: Long term suppression of HBV DNA with Tenofovir resulted in a new viral
set-point in the majority of those who were HBeAg-negative/anti-HBe-positive, suggesting
clinically significant immune reconstitution. This phenomenon was not observed in those
who were HBeAg positive, suggesting an ongoing immunomodulatory role of HBeAg.
186
P50
COMPARISON OF THE EFFICACIES OF ENTACAVIR 0.5
AND 1.0 MG COMBINED WITH ADEFOVIR IN PATIENTS
WITH MULTIPLE-DRUG-REFRACTORY CHRONIC
HEPATITIS B INFECTION
Yoon Jun Kim1,Yuri Cho1, Jeong-Hoon Lee1, Su Jong Yu1, Byeong Gwan Kim2,
Jung-Hwan Yoon1, Hyo-Suk Lee1
1
Department of Internal Medicine and Liver Research Institute, Seoul National University
College of Medicine, 2Department of Internal Medicine , Seoul National University Boramae
Hospita, Seoul, Korea, South
Introduction: Entecavir (ETV) plus adefovir (ADV) combination therapy is a useful
treatment option for patients with multiple-drug-refractory chronic hepatitis B (CHB)
virus infection. However, it is unclear if the dose of ETV affects the treatment outcomes of
combination therapy.
Aims: The purpose of this study was to evaluate and compare the efficacies of the
combinations of ETV 0.5 mg plus ADV and ETV 1.0 mg plus ADV in patients with
multiple-drug-refractory CHB infection.
Results: The efficacy of ETV 0.5 mg + ADV was not inferior to that of ETV 1.0 mg
+ ADV. At 12 months, the rate of non-response in the ETV 0.5 mg + ADV group was
not significantly different than that in the ETV 1.0 mg + ADV group (3.7 % vs. 6.4 %,
respectively; P = 0.095). Further, at 12 months, the change in serum HBV DNA level in
the ETV 0.5 mg + ADV group was not different than that in the ETV 1.0 mg + ADV group
(-3.67 ± 2.11 log10IU/mL vs. -3.22 ± 1.68 log10IU/mL, respectively; P = 0.302).
Conclusions: No significant difference was noted in the efficacies of ETV 0.5 mg + ADV
and ETV 1.0 mg + ADV in patients with CHB refractory to both lamivudine and ADV
monotherapy. Therefore, in order to reduce systemic exposure and possible side effects of
ETV, ETV 0.5 mg + ADV might be an option for rescue combination therapy in patients
with multiple-drug-refractory CHB.
187
POSTER ABSTRACTS
Methodology: We conducted a retrospective analysis of 148 patients with CHB infection.
Thirty-seven patients were treated with ETV 0.5 mg plus ADV 10 mg/day (ETV 0.5 mg +
ADV) and 111 patients were treated with ETV 1.0 mg plus ADV 10 mg/day (ETV 1.0 mg +
ADV). The virological and biochemical responses were compared between the two groups.
P51
ASSESSMENT OF CURRENTLY ACCEPTED CRITERIA FOR
VIROLOGIC BREAKTHROUGH IN CHRONIC HEPATITIS B
PATIENTS RECEIVING ENTECAVIR THERAPY
Hee Yeon Kim1, Yu Seung Kim1, Chang Wook Kim1
1
The Catholic University of Korea, Seoul, Korea, South
Introduction: Current guidelines suggest testing for genotyping resistance in compliant
patients with virologic breakthrough.
Aims: We investigated whether the concept of virologic breakthrough suggested by current
guidelines is appropriate for treatment with entecavir (ETV) in the era of sensitive HBV
DNA PCR assays.
POSTER ABSTRACTS
Methodology: We retrospectively reviewed medical records of 894 consecutive patients
with chronic hepatitis B or HBV-associated cirrhosis receiving ETV from 2007 to 2013
in Uijeongbu St. Mary’s Hospital. Patients with a history of previous nucleoside analogue
treatment (n=77), hepatocellular carcinoma (n=135), and Child B or C (n=27), treatment
duration < 6 months (n=168) were excluded. Inclusion criteria for evaluating virological
breakthrough was defined by an increase in HBV DNA level of >1 log copies/ml compared
to nadir for patients in non-virological response group, or HBV DNA levels increasing to
>200 copies/ml for patients in virological response group (HBV DNA <112 copies/ml)
Results: Among 487 patients, 84 subjects met the inclusion criteria at median of 24
months. Thirty-one of 84 patients had demonstrated poor compliance. Ten patients who
had not been followed up at least twice after meeting the inclusion criteria were excluded.
Among remaining 45 patients, six were non-virological response group (detectable HBV
DNA), and 39 patients were virological response group (undetectable HBV DNA). In the
non-virological response group, four out of 6 (66.7%) with an increase in HBV DNA >1
log copies/ml revealed resistance during a median 31 months. In the virological response
group, three patients developed resistance during a median 44 months. Patients developing
resistance showed an increase of HBV DNA of >10,000 copies/ml at 3-month follow up.
Remaining 36 patients in the virological response group had not revealed resistance during
a median 22 months of follow-up.
188
Thirty-four out of these 36 patients finally achieved complete virological response, and two
patients remained partial virological response during a follow-up of 20 month.
POSTER ABSTRACTS
Conclusions: Currently-accepted criteria for virologic breakthrough does not accurately
predict development of resistance in chronic hepatitis B patients with ETV therapy,
especially for patients who had achieved virological response. On-treatment chronic
hepatitis B patients, whose HBV DNA temporarily increase not up to 10,000 copies/ml,
generally leads to a complete virological response.
189
P52
IMMUNOLOGICAL PARAMETERS FOR PREDICTION OF
SUSTAINED RESPONSE (SR) AFTER NUCLEOS(T)IDE
ANALOGS (NAS) DISCONTINUATION IN PATIENTS WITH
Hariklia Kranidioti1,2, Spilios Manolakopoulos2, Michael S Breen1,
Rocio T Martinez-Nunez1, George Kontos2, Tilman Sanchez-Elsner1, Christopher H Woelk1,
George Papatheodoridis3, Salim I Khakoo1
1
clinical and experimental sciences, Faculty Medicine, University of Southampton, Southampton,
United Kingdom, 22nd Academic Department of Internal Medicine, Hippokration General
Hospital, 3Academic Gastroenterology Department, Laiko General Hospital, Athens, Greece
Introduction: The optimal NAs treatment duration of patients with HBeAg-negative
chronic hepatitis B (CHB) is not well defined.
Aims: The aim of our study was to define the immunological parameters associated with
SR following cessation of NA(s) therapy.
Methodology: We performed whole genome gene expression analysis (oligo microarrays)
on PBMCs from three groups of patients with HBeAg-negative CHB:
•
•
•
POSTER ABSTRACTS
•
•
5 inactive Carriers (IC)
3 patients undergoing NAs therapy for >5 years, who relapsed after NAs cessation
(Relapsers: R) PBMCs were analysed at the end of treatment
3 patients with SR for ≥6 months after NAs cessation; PBMCs were analyzed at 2 time
points:
End of treatment (SR-EOT)
Six months after EOT (SR-6m)
The microarrays results were validated using qPCR on PBMCs from 9 IC, 10 R and 7 SREOT (HBV DNA < 10000 IU/ml for ≥ 12 months) for five key genes (IL1A, IL1B, TNF,
IRAK3, IL1RN).
190
Results: The number of differentially expressed genes (p-value<0.05 after Bonferoni
correction), between R and SR-EOT; SR-EOT and SR-6m; SR-EOT and IC were
respectively 1649, 730, 2231. Clustergram analysis suggested that SR-EOT was an outgroup to the others. KEGG pathway analysis demonstrated common immune pathways.
Key genes in these pathways which are down-regulated in SR-EOT compared to R include
members of the IL-1 (5.35 fold-change, p=0.004) and TNF (3.1 fold-change, p=0.03) and
chemokine families (4.5 fold-change, p=0.02). qPCR confirmed the results of the whole
genome gene expression analysis in the same patients for some of the tested key genes as
IL1A and TNF (p=0.05). qPCR revealed low levels of IL1A, IL1B and TNF expression in 6
of 7 SR-EOT and high levels in 6 of 10 R-EOT. Moreover, expression of IL1A in SR-EOT
had negative correlation (p=0.028, r=-0.672) with the decline of HBsAg levels during the
off-treatment follow up.
POSTER ABSTRACTS
Conclusions: Patients with HBeAg-negative CHB who had SR during off-treatment
period had distinct immunological parameters from those who relapsed. These data may
help to define individuals who are candidates for safely stopping NA therapy.
191
P53
HEPATITIS B IN SUBSTANCE USERS IN EAST LONDON
Jan Kunkel1, Mandie Wilkinson2, Graham R Foster1
1
Hepatology, Queen Mary University of London, 2Blood Borne Virus Team, East London NHS
Foundation Trust, London, United Kingdom
Introduction: Whereas infection with Hepatitis C Virus (HCV) is a well-established comorbidity in substance users, infection with Hepatitis B Virus (HBV) remains understudied
in this population.
Aims: The aim of this study was to assess and characterise infection with HBV in patients
of a substance misuse service over time.
Methodology: In January 2013 and June 2014 HBV-infected patients registered with the
East London based Blood Borne Virus Team were identified by database search. Data on
demographics, virology, severity of liver disease, co-infections, co-morbidities and treatment
was retrieved and analysed.
POSTER ABSTRACTS
Results: 49 HBV-infected patients were under the care of the service in 2013. 18
months later, 24 of these had left the service while 26 HBV patients had newly registered.
Characteristics of the HBV-infected service users are shown in the table. Co-infection
with HCV was common, and co-infection with Hepatitis D Virus (HDV) and Human
Immunodeficiency Virus (HIV) occurred in a significant proportion. Of note, one patient
had acquired Hepatitis B after failing to respond to several courses of HBV vaccination and
subsequently developed hepatocellular carcinoma.
Conclusions: HBV prevalence among substance users is high and remains stable over
time despite a high fluctuation of patients. A significant proportion of patients is cirrhotic,
with alcohol consumption and co-infection with HCV and HDV being major contributing
factors. Vaccination failures require close follow-up in this high-risk group. The current
guidelines on monitoring and treatment are difficult to implement in this population due
to the high fluctuation.
192
POSTER ABSTRACTS
Table:
193
P54
IS PEGINTERFERON AN OPTION IN THERAPY OF
ROMANIAN PATIENTS WITH HEPATITIS B?
Dana Valentina Obretin1, Stefan Dragos Lazar1,2, Adriana Motoc1, Emanoil Ceausu1,2
1
“Victor Babes” Infectious Diseases Hospital, 2“Carol Davila” University of Medicine, Bucharest,
Romania
Introduction: Infections with HBV (hepatitis B virus) in Romania has a prevalence of
2-6%, and represents 22% of chronic liver diseases. In some Romanian studies genotype
D, the most resistant to Interferon was found in 80% of cases and genotype A in 13%.
Interferon is indicated in pacients with viral load over 2000 significant necroinflammation
and/or fibrosis.
Aims: Analysis of a group of patients with chronic HBV infection without Delta coinfection
treated with pegInterferon α2A (peg IFN).
POSTER ABSTRACTS
Methodology: retrospective study on 101 patients with chronic HBV treated in hospital of
Infectious Diseases “Dr Victor Babes” Bucharest, between 2007-2014.
Results: We treated 57 men and 44 women, of which 57% were aged between 30 and
40 years. In 20% of cases we found the presence of infection in other family members. In
65% of cases we found normal or slightly elevated transaminase <2XUNL( upper normal
limit). At the start of the treatment 20 patients were HBeAg positive and 40% had viral
load> 10 6 IU / L. In 85% of patients we found significant necroinflammation ≥ A2 and in
65% medium-severe fibrosis F2-F3. Before the therapy with peg-IFN 20 patients received
other therapies (standard IFN, lamivudine, entecavir, combinations). Treatment with
interferon was interrupted due to adverse events in 5 cases (1 case of TB meningitis, 2
cases of pulmonary tuberculosis, 1 case of very elevated ALT, 1 case of severe anemia due
metrorrhagia). After the treatment we noticed some cases of severe illneses: gastric cancer,
malignant melanoma, mixedema with pericarditis, renal failure. In 50% of cases treated with
pegIFN pacients received a new antiviral therapy with nucleoside analogues. After treatment,
15 patients did seroconverted to Anti HBe antibodies and two of them in HbS antibodies.
Four HBeAg negative patients seroconverted to HBs antibodies. Eight patients received
combinations (peg IFN and nucleoside analogues) with favorable response in 4 cases.
Conclusions: Although patients treated with pegIFN had probably the unfavorable
genotype, the results of this study show that 45% of patients no longer required long-term
oral therapy.
194
P55
EXCELLENT SURVIVAL AFTER HEPATITIS B RELATED
LIVER TRANSPLANTATION: ANALYSIS IN TWO SPANISH
CENTERS.
Sabela Lens1, María García-Eliz2, Martin Bonacci1, Angel Rubin2, Carmen Vinaixa2,
Antoni Mas1, Xavier Forns1, Martin Prieto2
1
Liver Unit, Hospital Clínic, Barcelona, 2Liver Unit, Hospital La Fe,Valencia, Spain
Introduction: Hepatitis B virus (HBV) –related cirrhosis or fulminant hepatitis is an
indication of liver transplantation (LT) worldwide. Since the establishment of combined
immunoglobulin (HBIG) and nucleoside analog prophylaxis, the rate of HBV recurrence
is very low.
Aims: To analyse the factors related to HBV recurrence and to transplant-free survival in
HBV-related liver transplantation
Results: 241 LT were performed (82% male, median age 52 years). Indications for LT were
decompensated cirrhosis (64%), hepatocellular carcinoma (25%) or fulminant hepatitis
(11%). HDV coinfection was present in 19%, HCV in 11% and HIV in 4%. Eighty-five
(35%) patients were not receiving antiviral treatment before LT. Most patients (82%) had
undetectable HBV-DNA at the time of LT; only 28 (12%) were HBeAg positive. During
follow-up, HBsAg became positive in 18 (7%, median 2 years after LT): positive HBeAg
at LT, hepatocellular carcinoma and resistance to lamivudine were associated to HBV
recurrence. Patient and graft survival 5 and 10 years after LT were 81% and 76% and 80%
and 75%, respectively. Factors associated to lower survival were positive HBeAg or DNA at
LT, fulminant hepatitis and hepatitis C coinfection.
Conclusions: Survival after LT for patients with HBV-related liver disease is excellent.
Since the introduction of antivirals, hepatitis B recurrence is very low. Nevertheless, it is
higher in patients with HBeAg at LT, hepatocellular carcinoma and lamivudine resistance.
195
POSTER ABSTRACTS
Methodology: Retrospective data from adult LT patients receiving low-dose HBIG plus
nucleoside analog after LT in two Spanish Transplant centres were recorded. Patients were
followed up a mean of 6±4.6 years.
P56
EFFICACY OF TENOFOVIR SWITCH THERAPY FOR
NUCLEOS(T)IDE-EXPERIENCED PATIENTS WITH
CHRONIC HEPATITIS B
Angeline Oi-Shan Lo1,Vincent Wai-Sun Wong1, Grace Lai-Hung Wong 1,Yee Kit Tse1,
Hoi Yun Chan1, Henry Lik-Yuen Chan1
1
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong,
Hong Kong, China
Introduction: Tenofovir disoproxil fumarate has been used in chronic hepatitis B patients
with suboptimal virologic response to nucleos(t)ide analogs. However, the efficacy of
tenofovir switch therapy in nucleos(t)ide-experienced patients has not been well studied in
a prospective manner.
Aims: We aimed to evaluate the efficacy of tenofovir switch therapy in nucleos(t)ideexperienced patients, and identify the factors associated with treatment response of tenofovir
switch therapy.
POSTER ABSTRACTS
Methodology: This study was conducted in a university hospital in Hong Kong from
2009 to 2013. All nucleos(t)ide-experienced hepatitis B e antigen (HBeAg) positive and
negative patients prescribed with tenofovir were identified and recruited for prospective
follow-up and analysis. Hepatitis B virus (HBV) DNA and other biochemical parameters
were monitored in regular 3-6 monthly follow-up visits. Primary efficacy endpoint was
maintained virologic response with tenofovir switch therapy, defined as undetectable HBV
DNA (<20 IU/ml) until the last follow-up visit.
Results: An overall of 214/252 (84.9%) patients achieved maintained virologic response
after 22 (7-55) months of tenofovir switch therapy. HBeAg seroconversion was achieved in
11/82 (13.4%) of HBeAg positive patients after 25 (14 - 53) months of tenofovir therapy.
Hepatitis B surface antigen (HBsAg) seroclearance was achieved in 4 (1.6%) patients.
The majority of patients switched to tenofovir due to drug resistance. The commonest
was lamivudine resistance which was found in 168 (66.7%) patients, with 56 (22.2%)
patients had proven genotypic YMDD mutants, and 112 (44.4%) suffered from virologic
breakthrough clinically.
196
On multivariate analysis by Cox proportional hazard model, a lower HBV DNA level at the
time of switching to tenofovir was the only independent factor associated with treatment
efficacy. Maintained virologic response after switching to tenofovir was achieved in 177/190
(93.2%) patients with HBV DNA < 20,000 IU/ml versus 37/62 (59.7%) patients with HBV
DNA ≥ 20,000 IU/ml (p <0.001). Absence of genotypic resistance to lamivudine or adefovir
dipivoxil did not affect treatment outcome.
POSTER ABSTRACTS
Conclusions: Tenofovir switch therapy is an effective treatment strategy in nucleos(t)ideexperienced chronic hepatitis B patients. However, in patients with HBV DNA ≥ 20,000 IU/
ml at the time of switching to tenofovir, the chance of achieving maintained undetectable
HBV DNA would be significantly reduced.
197
P57 - YI
COMPARISON OF RESPONSE RATES OF
PEGINTERFERON, TENOFOVIR AND ENTECAVIR IN MONO
& MIXED HBV GENOTYPIC INFECTION WITH DIFFERENT
BASELINE FACTORS IN PAKISTANI PATIENTS
Majid Mahmood1, Asim Anwar2, Zahid Azam3
1
Department of Zoology, PMAS Arid Agriculture University, Rawalpindi, 2Department of
Medicine, PAEC General Hospital, Islamabad, 3Natioanal Institute of Liver & GI Diseases
(NILGID), Dow University of Health Sciences, Karachi, Pakistan
Introduction: HBV treatment response is dependent on choice of treatment along with
virological and host factors.
Aims: The aim of this study was to compare treatment response of Tenofovir, Entecavir and
Peginterferon for their response in Pakistani chronic HBV mono & mixed genotypic infected
patients and to analyze the influence of HBV genotype, baseline HBV DNA, HBeAg status,
ALT, age and gender on the response rate.
POSTER ABSTRACTS
Methodology: Total 162 patients received three treatments viz. Tenofovir (n=57), Entecavir
(n=51) for two years and Peg-Interferon (n=54) for 1 year. Patients were followed up and
monitored for virological response (Undetectable HBV DNA), combined virological &
biochemical response (Undetectable HBV DNA + normal ALT), HBsAg clearance and
HBeAg clearance. Logistic regression analysis was used to analyze the data
Results: Peginterferon had a greater rate of combined response than tenofovir (p=0.045)
while tenofovir treated patients shown a higher rate of virologic response than peginterferon
treated patients (p=0.004). Genotype A had higher rate of virologic response (p=0.004) and
HBsAg clearance (p=0.012) than the mix genotype infection (A+D). Genotype D also had
higher rates of combine response (p=0.017) and HBsAg clearance (p=0.010) than the mix
infection (A+D). HBeAg negative infection was strongly associated with higher rates of
virologic response (p=0.000), combine response (p=0.018) and HBsAg clearance (p=0.000)
as compared to HBeAg positive infection. Patients with low baseline HBV DNA showed
higher rates of virologic (p=0.005), combine (p=0.000) and HBsAg (p=0.000) response
than high baseline HBV DNA. High baseline ALT had greater rate of virologic response
(p=0.018) in tenofovir group but it was significantly associated with lower rates of virologic
response in both entecavir (p=0.006) and peginterferon treated patients (p=0.012).
Conclusions: Genotype A or D alone, low viral load and negative HBeAg were significant
predictors of high response rate in all treatments. Tenofovir had higher rate of virologic
response as compared to peginterferon while peginterferon had higher rate of combined
response than both of the nuclos(t)ide analogues.
198
P58 - YI
COMPARISON OF PEGINTERFERON, TENOFOVIR AND
ENTECAVIR IN TREATMENT OF CHRONIC HBV PATIENTS
HAVING MIX INFECTION WITH GENOTYPES A AND D
Majid Mahmood1, Asim Anwar2, Zahid Azam3
1
Department of Zoology, PMAS Arid Agriculture University, Rawalpindi, 2Department of
Medicine, PAEC General Hospital, Islamabad, 3Natioanal Institute of Liver & GI Diseases
(NILGID), Dow University of Health Sciences, Karachi, Pakistan
Introduction: Treatment responses are differrent among different HBV genotypes. Most
studies have addressed monogenotypic infection. Mix infection with genotypes A and D
in chronic HBV patients is associated with an overall low response rate of the patients in
Pakistani Population.
Aims: This study was aimed to compare tenofovir, entecavir and peginterferon treatments
for response rate of the patients who were infected with both genotypes A and D
simultaneously.
Results: The proportion of HBeAg negative and positive patients was not different
statistically among the treatment groups. Patients treated with Tenofovir showed significantly
high response rate as compared to both Entecavir and Peginterferon treated patients
(p=0.001). The response rate of the patients treated with Tenofovir was 86 % while 38 %
of the patients were responded to Entecavir and 25 % to Peginterferon. No difference was
found in combined response and HBsAg clearance of the patients among the treatments
groups.
Conclusions: Patients infected with both genotype A and D simultaneously respond better
to Tenofovir as compared to Entecavir or Peginterferon regardless of HBeAg status.
199
POSTER ABSTRACTS
Methodology: A total of 51 such patients were enrolled and received three types of
treatments i.e. Tenofovir (n=14), Entecavir (n=13) for two years and Peg-Interferon (n=24)
for 1 year. Patients were followed for virological response (Undetectable HBV DNA),
combined response (Undetectable HBV DNA + normal ALT), HBsAg clearance and
HBeAg clearance. Their response rates were compared by Pearson Chi square test
P59
A NEW THERAPEUTIC OPTION FOR TREATING CHRONIC
HEPATITIS B: OUTCOME OF A PHASE III CLINICAL TRIAL
Mamun Al Mahtab1, Sheikh Mohammad Fazle Akbar2, Julio Cesar Aguilar Rubido3
1
Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh, 2Medical
Sciences, Toshiba General Hospital, Tkyo, Japan, 3Trials and Hepatitis B, Center for Genetic
Engineering and Biotechnology, Havana, Cuba
Introduction: There is a pressing need to develop evidence-based therapy for patients with
chronic hepatitis B (CHB)
Aims: To assess the utility of a therapeutic vaccine containing both HBsAg/HBcAg versus
pegylated interferon (PegIFN) for treating patients with CHB.
POSTER ABSTRACTS
Methodology: A randomized and open phase III clinical trial was designed for a total of
160 patients. The study received the permission from the Institutional Review Board and
a written consent was obtained from patients. A total of 74 patients with CHB completed
the therapeutic schedule of immunization with 100 microgram of both antigens (HBsAg/
HBcAg) (CIGB, Havana, Cuba). Patients were vaccinated once in every two weeks in two
cycles of 5 doses; the first cycle by nasal route and the second by simultaneous nasal and
subcutaneous routes. Seventy-six patients with CHB completed the treatment with PegIFN
(180 microgram, once weekly, subcutaneously for 48 consecutive weeks [CIGB]). The
levels of HBV DNA, alanine aminotransferase (ALT), and hepatitis B e antigen (HBeAg)
were checked periodically during treatment and for 24 and 48 weeks after end of treatment
(EOT).
Results: Vaccinated patients did not show any severe or serious adverse event during the
treatment or follow up period. However, 7 patients receiving PegIFN exhibited severe
adverse events. According to the analysis per protocol, 62.2% (46 out of 74 patients) treated
with the vaccine reduced the level of HBV DNA below 250 copies/ml at the EOT and a
similar proportion (60.8%) remained below 250 copies/mL at 24 weeks of treatment-free
follow up. A proportion of 76.9% of patients receiving PegIFN reduced the HBV DNA
level below 250 copies/mL at EOT, however, only 38.4% remained under the same level
at 24 weeks after EOT (p<0.05). The levels of HBV DNA at 48 weeks of follow-up were
still lower in vaccinated patients compared to PegIFN group. Normalization of ALT was
comparable between two groups at the EOT and during follow up period. However the
HBeAg loss and or seroconversion evidenced a comparatively higher and more sustained
response after the end of follow-up in vaccinated patients.
Conclusions: HBsAg/HBcAg-based therapeutic vaccine represents a safe and effective
immune therapeutic approach for CHB patients. The clinical evaluation of the therapeutic
vaccine in combination with the current drugs also deserves further attention.
200
P60 - YI
HBV DNA LEVELS IN LAMIVUDINE RESISTANCE
PATIENTS VERSUS UNDETECTABLE LAMIVUDINE
RESISTANCE CASES DURING HBV RECURRENCE PERIOD
AFTER LIVER TRANSPLANTATION
Mohammadreza Fattahi1, Rahim Rahimi1, Abdorrasoul Malekpour1
1
Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Introduction: Drug resistance to nucleoside analogue remains main drawback of therapy
for HBV related liver transplant which finally induce virus recurrence.
Aims: Here the state of HBV DNA level in confirmed lamivudine resistance patients and
undetectable lamivudine resistance cases evaluated during HBV recurrence period after
liver transplantation.
Conclusions: Our finding showed that recurrence rate of HBV among liver transplant is
dependent on duration of therapy. Critical Mutation inside the polymerase gene appeared
in near half of the recurrent cases and risk of natural mutation to other nucleside analogue
like entecavir also remain major shortcoming associated with lamivudimne resistance. Here
the data proposed a significant correlation between drug resistance and increasing of viral
DNA level when compared to recurrent but not-mutated group. HBV DNA level would be
helpful as a predictor parameter in managing the liver transplant patients under nucleoside
analogue for add-on or replacing therapy. Key words: HBV, Drug resistance, DNA level,
Transplantation.
201
POSTER ABSTRACTS
Methodology: Based on our aims 32 patients with HBV related liver transplantation
selected for this study. All patients had received a combination of lamividuine/IgG
therapy for 2-6 years. The virus DNA level was under detection limit of 50 IU/ml before
transplantation. In all patients HBV DNA presence evaluated by PCR assay. In recurrent
HBV cases quantification of viral genome were performed by commercial Real-Time PCR.
In this group polymerase gene mutations relevant to nucleoside analogues assessed also by
sequencing analysis after amplification of polymerase gene by PCR.
Results: Among 32 enrolled patients 13 cases had detectable HBV viral genome as
confirmed by PCR assays. Polymerase sequence analysis showed the presence of critical
M204I mutation as a proof for resistance to lamivuidne and telbevudine among 6 out
of 13 recurrent cases. These results also indicated that entecavir resistance among this
group as one out of 6 cases harbour S202 mutation before entecavir consumption. HBV
quantification of viral genome showed higher viral titre (mean of 5.7×105) in lamidudine
resistant group when compared to those group with undetectable drug resistance (mean of
3.7×104).
P61 - YI
EFFECT OF GENOTYPE AND SUBGENOTYPE IN HBV
RECURRENCE AMONG LIVER TRANSPLANT PATIENTS
Abdorrasoul Malekpour1, Mohammadreza Fattahi1, Rahim Rahimi1
1
Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Introduction: Although the importance of some factors in HBV recurrence revealed,
genotype or subgenotype roles in this situation remain unclear.
Aims: In this study, HBV drug resistant patients who received lamivudine/IgG for 2-6 years
evaluated more for mutation of surface gene sequence and genotype.
Methodology: Totally 13 HBV recurrent patients after liver tranasplantation enrolled
for this study. A Gap-PCR method employed for discrimination between genotpe D and
Non-D among patients, Polymerase/surface sequence of HBV genome amplified by PCR
then introduced into sequencing analysis. Sequence retrieved from data aligned by the help
of reference sequences and phylogenetic analysis evaluated by mega4 software. Related
vaccine escape mutants rather than subgenotype predicted after submitting the sequences
into online software.
POSTER ABSTRACTS
Results: All the 13 patients with HBV recurrence had HBV genotype D by Gap-PCR
assay, as expected in our area. Phylogenetic analysis of polymerase sequence also confirmed
the dominancy of D genotype. Point mutation analysis revealed presence of critical vaccine
escape mutant among some persons. Interestingly among 13 recurrent cases 7 cases was
infected by subgenotpe D3 and others were infected by D1 subgenotype which only this later
group harbour critical M204I mutation as sign of Lamivudine/telbevudine drug resistance.
Conclusions: Our data suggest a close correlation between HBV D genotype and higher
rate of recurrence. Also subgenotype D1 induced more mutation occurrence among
polymerase gene in compare to D3 which didn’t report previously. Albeit we need more
patients to confirm the concept, correlation of drug resistance with subgenotype remain a
suggestion before subsequent evaluation in a bigger group of patients.
202
P62 - YI
ASSESSMENT OF TOTAL ECONOMIC BURDEN OF
CHRONIC HEPATITIS B (CHB)-RELATED DISEASES IN IRAN
Mohammadreza Fattahi1, Fatemeh Zareh1, Abdorrasoul Malekpour1
1
Gastroentrohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Introduction: Viral hepatitis is the most prevalent liver disease in the world wide. Among
the human diseases that are major health concern, Hepatitis B infection is a serious problem
for the World Health.
Aims: To estimate the total annual cost due to Chronic Hepatitis B(CHB)-related diseases
imposed on each patient and his/her family in Iran.
Methodology: Economic burden of CHB-related diseases (CHB, cirrhosis and
hepatocellular carcinoma) were examined. A retrospective 100 patients in Iran were identified
to obtain their socioeconomic status, utilizationand costs of treatment, and work loss days
due to illness with a structured questionnaire. Costs of hospitalization were extracted from
databases of Namazi hospital in Shiraz, respectively. The outpatient expenditure per patient
was measured through the rate of outpatient visits and average cost per visit reported by the
patients, while the inpatient cost was calculated through annual rate of hospitalization and
average expenditure. Self-medication and direct nonmedical cost were also reported. The
Human Capital Approach was employed to measure the work loss cost.
Conclusions: This study confirms that CHB-related diseases impose a substantial
economic burden on patients, families, and the society in Iran. The study demonstrates
increasing health-care costs related to disease progression and provides useful information
on cost of treatment and work loss for different disease states, which can be further utilized
in cost-effectiveness evaluation.
203
POSTER ABSTRACTS
Results: The total annual cost per patient for CHB, cirrhosis and hepatocellular carcinoma
were US$ 3094.5, US$ 17483, and US$ 32958 in Iran, respectively.
P63 - YI
COMPUTATIONAL IDENTIFICATION OF RCC IN PROTEINS
STRUCTURE OF HEPATITIS B VIRUS
Mohammadreza Fattahi1, Mojtaba Mortazavi2, Abdorrasoul Malekpour3
1
Gastroenterohepatology Research Center (GEHRC),, Shiraz University of Medical
Sciences, Shiraz, 21Department of Biotechnology, Institute of Science and High Technology
and Environmental Science, Graduate University of Advanced Technology, Kerman,
3
Gastroenterohepatology Research Center (GEHRC),, Shiraz University of Medical Sciences,
Shiraz, Iran
Introduction: Degeneracy of codons is the redundancy of the genetic code, exhibited as
the multiplicity of three-codon combinations specifying an amino acid. The degeneracy
of the genetic code is what accounts for the existence of synonymous mutations. One of
the accepted theories explaining the biological importance of such non-uniform codon
selection is that codons are translated at different speeds.
POSTER ABSTRACTS
Aims: Thus, varying codon placement along a message may confer variable rates of
polypeptide emergence from the ribosome, which may influence the capacity to fold toward
the native state.
Methodology: Decreasing of tRNAs concentration, effect on ribosomes to pause at rare
codons until the rare activated tRNA brings the next amino acid to the growing polypeptide.
It was observed that distribution of rare triplets along mRNAs is definitely non-uniform.
The rare codons are not randomly distributed, but rather organized in large clusters across
species. Recent studies suggest that rare codon clusters (RCC) are functionally important
for protein activity. Here, for the first time we analyzed and reported rare codon clusters
in HBV genome and then identified location of these rare codon clusters in the structure
of HBV protein. The virus has 4 overlapping open reading frames (ORFs) including large
S region (PreS/S), PreC/C, × and P and regulatory elements of transcription, replication
and encapsidation within these ORFs. This analysis was performed using the Sherlocc
program that detects statistically relevant conserved rare codon clusters. The protein family
accession number (Pfam) of mature HBV proteins were identified and analyzed in Sherlocc
program. Results of these studies show that L-HBsAg, HBx, HBeAg and DNA-directed
DNA polymerase have a rare codon clusters. To investigate position of rare codon clusters in
structure of HBV proteins, 3D structures of the HBV proteins and locations of rare codon
clusters were visualized and studied using Swiss PDB Viewer software.
Conclusions: The results of these studies gives us a new insights toone hidden layer of
codon usage information lie in the rare codon clusters and we believe studying rare codon
clusters may in future help in development a new and effective drug.
204
P64
EFFECT OF NUCLEOSIDE AND NUCLEOTIDE ANALOGUES
ON RENAL FUNCTION IN CHRONIC HEPATITIS B VIRUS
MONOINFECTION
Vincent Mallet1, Michaël Schwarzinger2, Anaïs Vallet-Pichard3, Hélène Fontaine3,
Marion Corouge3, Philippe Sogni3, Stanislas Pol3
1
nstitut Cochin, Université Paris Descartes, Sorbonne Paris Cité, (Unité Mixte de Recherche
S1016), Centre National de la Recherche Scientifique, Unités Mixtes de Recherche 8104,
Institut National de la Santé et de la Recherche Médicale Unité 1016, Assista, Paris, , 2THEN
“Translational Health Economics Network», 3nstitut Cochin, Université Paris Descartes, Sorbonne
Paris Cité, (Unité Mixte de Recherche S1016), Centre National de la Recherche Scientifique,
Unités Mixtes de Recherche 8104, Institut National de la Santé et de la Recherche Médicale
Unité 1016, Assista, Paris, France
Introduction: The relation between exposure to nucleoside and nucleotide analogues and
renal impairment is controversial in chronic HBV infection.
Aims: To determine the factors that impact renal function in chronic HBV infection,
including exposition to nucleoside and nucleotide analogues.
Intervention: None
Measurements: Variation of estimated glomerular filtration rate (eGFR) with time under
nucleoside or nucleotide analogue monotherapy or nucleoside/nucleotide analogue
combination adjusted to age, sex, Asian origin, high blood pressure, metabolic syndrome,
and to the presence of the following characteristics at baseline: extensive fibrosis or cirrhosis,
HBV DNA > 5 logIU/ml, and eGFR < 90 ml/min/1.73 m2 or not.
205
POSTER ABSTRACTS
Methodology: Design: Longitudinal prospective and retrospective observational study.
Setting: Hepatology unit of a tertiary care center in France
Patients: 214 patients (median age 43 years, 69.2% men, 25.2% from Asian origin) with
compensated chronic HBV infection without coinfection, without immunodepression and
without more than one condition included in the Charlson/Deyo index treated with 291
lines of nucleos(t)ide analogues (198 monotherapies, 89 combinations) during a median
(interquartile range) time period of 2.8 (1.4, 4.3) years.
Results: Adefovir dipivoxil (ADV) given as a monotherapy or a combination decreased
eGFR over time (P<0.0001 and p<0.002, respectively) and remained stable under tenofovir
disoproxil fumarate (TDF) and entecavir (ETV). Age, male sex, south Asian ethnic origin,
HBV DNA > 5logIU/ml and baseline eGFR< 90 ml/min/1.73 m2 influenced eGFR variation
over time (P<0.0001). Patients with extensive fibrosis or cirrhosis tended to improve eGFR
over time (P=0.056). eGFR decreased in patients with a baseline eGFR < 90 ml/min/m2,
regardless of treatment. eGFR remained stable or tended to improve under ETV or TDF,
respectively. Patients from Asian origin, with an initial HBV DNA > 5logIU/ml and with an
initial eGFR >90 ml/min/1.73 m2 exposed to TDF or ETV were more prone to increase
eGFR over time (P=0.015 for TDF and P<0.0001 for ETV).
Limitation: No sensitive (TmPO4/eGFR) exploration of renal tubular function was done.
POSTER ABSTRACTS
Conclusions: In this real-life study, eGFR improved or remained stable over time in
patients with chronic HBV infection with a baseline eGFR > 90 ml/min/1.73 m2 treated
with a second-generation nucleos(t)ide analogue. Patients from south Asian ethnic origin or
with an initial HBV DNA > 5logIU/ml were more prone to improve eGFR under treatment.
206
P65
ADD ON PEGINTERFERON TO ADEFOVIR ENHANCES
HBSAG LOSS IN INACTIVE HBV CARRIERS
Patrick Marcellin1, Feryel Mouri1, Nathalie Boyer1, Emilie Estrabaud2, Tarik Asselah1,
Michelle Martinot Peignoux3
1
Service d’hépatologie, 2CRI Paris Montmartre UMR1149 inserm, Hôpital Beaujon, 3CRI Paris
Montmartre UMR1149 inserm, Hopital Beaujon, Clichy, France
Introduction: HBsAg loss, considered to be the ideal outcome of HBV infection, occurs
spontaneously at low rate in inactive HBV carriers not candidates for therapy.
Aims: We investigated the ability of treatment to achieve accelerate incidence of HBsAg
loss in inactive carriers
Results: At baseline; ALT were 24±7 and 23±7 (ns), HBV genotypes A, B-C, D, E
observed in 33%, 15%, 33%, 19% in untreated and 37%, 20%, 37%, 6% in treated patients
(ns). HBsAg levels 3.24±1.0 and 3.34±0.92 log IU/ml (ns), HBV DNA levels 2.57±0.97
and 2.90±0.84 log IU/ml (ns), in untreated and treated patients, respectively. At the end of
follow up, HBV DNA was undetectable in 12/69 (17%) of untreated and 9/22 (41 %) of
treated patients (p<0.02), an HBsAg loss was observed in 10/69 (15%) of untreated and
7/22 (32%) of treated patients, (p=0.06). A baseline HBsAg levels > 3.3 log IU/ml shows a
negative predictive value (NPV) of 92% for HBs loss. Among the treated patients a HBs loss
was observed in 0/6 (0%) receiving adefovir and 7/16 (44%) receiving add-on peginterferon,
(p=0.04). Baseline HBsAg levels were 3.50 ±0.99 and 2.88±1.16 log IU/ml in adefovir and
add-on peginterferon therapy patients, respectively (ns). In the 16 patients receiving add-on
peginterferon therapy, baseline HBsAg levels were 1.97 ±0.83 and 3.59±0.74 log IU/ml in
patients with or without HBsAg loss, respectively (p<0.001). An HBsAg titer >3.3 log IU/
ml shows a NPV 100% for HBsAg loss. No patient relapsed.
207
POSTER ABSTRACTS
Methodology: 91 inactive carriers from a well phenotyped cohort (Journal of Clinical
Virology 2013;58:401) were followed for a 2 years period. At that time point 69 remained
untreated, 22 underwent therapy (Figure) All the patients ended therapy at 5 years. All the
patients were followed for at least 2 years after treatment cessation.
Conclusions: In inactive HBV carriers treated with adefovir add-on peginterferon
dramatically accelerates the HBsAg decline and rate of HBsAg loss (44%), in comparison
to untreated patients (17%).
POSTER ABSTRACTS
Figure:
208
P66
A MODEL FOR ASSESSING MODERATE OR ADVANCED
FIBROSIS, IN CHRONIC HEPATITIS B PATIENTS
Michelle Martinot Peignoux1,2, Cédric Laouénan3, Martine Lapalus2, Emilie Estrabaud2,
Tarik Asselah2,4, Patrick Marcellin4,5
1
Centre Abrami, 2Hôpital Beaujon, CRI paris Montmartre UMR1149 inserm, 3INSERM,
IAME, UMR1137 Univ Paris Diderot, Sorbonne Cité, Paris, Département de Biostatistics
Hôpital Bichat, AP-HP, Paris France, 4Service d’hépatologie , Hôpital Beaujon AP-HP, 5CRI
Paris Montmartre UMR1149 inserm, Hôpital Beaujon, Clichy, France
Introduction: Fibrosis assessment is essential in patients with chronic hepatitis B (CHB).
Little is known about the association between fibrosis, host and viral factors
Aims: We evaluated the association between fibrosis and ethnicity, demographical and
clinical data, IFNL3 polymorphism, HBsAg titer, HBV-DNA load, genotypes, Precore and
basal core-Promoter variants, in a population of naïve HBeAg positive or negative CHB
patients with an available liver biopsy and serum sample the same day -2) to develop a
prediction model based on non invasive markers for the identification of patients with
moderate to advanced fibrosis, suitable candidates for therapy.
Results: 101 HBeAg(+), 305 HBeAg(-) genotypes A to E patients were included. Mild
fibrosis stages (F0-1) and moderate to advanced fibrosis (F2- F4) were found in 61% and
39% of patients, respectively. In univariate analysis, advanced age (p<0.001), male (p=0.01),
HBeAg(+) (p=0.06), ALT >2xN (<0.0001), HBV-DNA >4.3 log10IU/ml (p<0.0001),
1762T/1764A (<0.0001) and 1762T/1764A/1896A (p=0.0001) variants, were associated
with F2-F4. HBsAg >4.3 log10IU/ml was associated with F0-F1 (p=0.04). No association
between fibrosis, ethnicity, genotypes, IFNL3. In multivariate analysis, 1762T/1764A
(p<0.0001), 1762T/1764A/1896A (p=0.0001) variants (strongest predictors), HBV-DNA
>4.3 log10IU/ml (p<0.0001), ALT >2xN (p=0.001), age (p=0.0002), were independently
associated with F2-F4. The high good discrimination to correctly identify F2-F4 versus F0F1 obtained with multivariate model: age, HBV-DNA, ALT, HBV variants was evidenced
by a c-statistic of 0.77 (95% CI, 0.72-0.82). The Hosmer-Lemeshow test p-value of 0.7
showed no model misspecification
Conclusions: The main factors of moderate to advanced fibrosis development are:
advanced age, ALT (>2xN), high HBV-DNA (>4.3 log10IU/ml) and HBV variants. The
ability to correctly identify F2-F4 versus F0-F1 obtained with this multivariate model (age
+ HBV-DNA + ALT + HBV variants), suggests that it may be a useful marker in facilitating
patients monitoring.
209
POSTER ABSTRACTS
Methodology: 406 patients with available liver biopsy were included, ethnicity, clinical
and host characteristics, complete HBV virology (HBsAg and HBV-DNA levels, genotype,
IFNL3 polymorphism, BCP/PC variants) were determined the day of the biopsy. Histological
lesions were assessed using METAVIR score. Predictors of moderate to advance fibrosis
(F2-F4) were evaluated.
P67
CONSOLIDATING DIVERSE CLINIC DATA ON HEPATITIS B
PATIENTS TO CREATE UNIFIED RECORDS FOR REAL-TIME
PATIENT AND CLINIC MANAGEMENT AND OUTCOMES
REPORTING USING EXISTING SYSTEMS, OPEN SOURCE
SOFTWARE AND HEP-PRO PROPRIETARY SOFTWARE
Dominic Morgan1, Edward Evans1, Ian Hamer1, Michael Leenane2, Ankur Srivastava3,
Geoffrey Dusheiko3,William Rosenberg3
1
Integrated Pharma solutions, Sciensus, Brighton, 2IM&T Directorate, 3Department of
Hepatology, Royal Free London NHS Foundation Trust, London, United Kingdom
Introduction: Hospital systems often contain unconnected data in disparate systems.
Compiled into a single, disease specific unified patient record, this data could be of
significant value to Clinicians.
Hep-Pro is designed to use existing systems, along with open-source software, to produce
a medical record specifically designed for the management and reporting of Hepatitis B
(HBV) patients.
POSTER ABSTRACTS
Aims: Hep-Pro will enable the automatic combination, cleaning and mapping of multiple
data sources into a unified HBV specific database using existing resources and clinic data
sources. The database would be available for complex web-based data queries and patient
and clinic level reporting on actions and outcomes.
Methodology: Patients tested HBsAg + from 2011 were included in the database, and their
demographic, pathology and pharmacy records were extracted by the Clinic IT staff from
hospital systems.
The data was sent in HL7 format to Sciensus via an encrypted connection, and was
processed, cleaned and mapped using an open-source Mirth integration engine. The output
fed into the Hep-Pro database. Subsequent data were processed and transmitted daily using
the same methodology.
HCPs accessed the system using a secure web interface, and could undertake complex data
queries using client-side proprietary database query algorithms, and data was returned from
the database on demand.
210
Results: 1,948 HBsAg + patients were identified, 329,062 pathology and 4,302 pharmacy
results were processed. Invalid data was included in the database, but was excluded from
data queries. 4.37% (14,400) results were mapped according to the clinically agreed rules.
2,338 Fib4 scores were calculated from the source data.
A web-based database query to find patients with HBV DNA levels >2000 and ALT levels
> 40 within 90 days was completed in 7.62 seconds. Retrieving a single patient record, of
around 2000 results from 50 fields took 2.0 seconds.
Conclusions: HBV disease specific data can be extracted from existing hospital systems
without the need to install additional hardware or software at the clinic. Open-source
software, internationally accepted health data formats, and industry standard software
encryption techniques can be used to apply rules to clean and map the data originating from
the clinic, and transmit it securely, in a manner which meets local and national governance
and security requirements. The cleaned, consolidated, data can be queried rapidly in realtime using a simple web interface available to clinicians.
POSTER ABSTRACTS
Figure:
211
P68
IS ANTIVIRAL PROPHYLACTIC TREATMENT NECESSARY
IN HBSAG (-), ANTIHBC (+) AND ANTIHBS (+) ONCOHEMATOLOGIC PATIENTS WITH HIGH OR MODERATE
RISK FOR HBV REACTIVATION?
Nikolaos Papadopoulos1, Melanie Deutsch2, Spilios Manolakopoulos 2,
Eftichia Tsironi3, Adonia Solomou3, Maria Skondra2, George V Papatheodoridis4,
John Koskinas2, Dimitrios Pectasides 2
1
1st Department of Internal Medicine, 401 General Army Hospital , 22nd Department of
Internal Medicine, Athens University Medical School, Hippokration Hospital , 3Gastroenterology
Department, “Metaxa” General Hospital , 4Gastroenterology Department, Athens University
Medical School, “Laiko” General Hospital , Athens, Greece
Introduction: According to Clinical Practice Guidelines of different International Medical
Associations (hepatology, oncology, hematology) it is still debatable if patients who receive
chemotherapy should be universally tested for the presence of past HBV infection. Moreover
there are no clear recommendations for prophylactic antiviral therapy especially in patients
with HBsAg-/HBcAb+/HBsAb+.
Aims: The aim of this retrospective observational study was to determine the role of antiviral
prophylaxis or therapy in HBsAg(-)/HBcAb(+) patients with hematological malignancies or
solid tumors who received chemotherapy.
POSTER ABSTRACTS
Methodology: Forty patients (26 males/14 females, mean age 65.2±13.2 years) with
HBsAg-/HBcAb+ (with or without HBsAb) receiving chemotherapy who were followed or
presented at our departments between 2010-2013 were included in this retrospective study.
Of them, 70% were taking anti-CD20 or antiCD52 agents, while 14 (35%) were HBsAband 26 (65%) HBsAb+.
Results: In total 33 patients received antiviral prophylaxis before the onset of chemotherapy
[ lamivudine (LAM) 19 and entecavir( ENT) or tenofovir (TDF): 14]. HBV reactivation
occurred in none of the 14 patients who received prophylaxis with ENT or TDF and in one
(5%) of the 19 patients who received LAM prophylaxis. The patient with HBV reactivation
under LAM died despite switching LAM to ENT.
212
During the same period, 7 patients with HBsAg(-)/HBcAb(+) receiving chemotherapy
including monoclonal antibodies for hematologic malignancies presented with HBV
reactivation. All patients were HBsAb (+) before chemotherapy and presented with
HBsAg(+)/HBeAg(+) seroreversion, a mean HBV DNA level of 780207±624378 IU/ml
and mean ALT of 292±303 IU/l at the diagnosis of reactivation. One of these 7 patients
died due to acute liver failure, while all the others recovered under ENT or TDF therapy.
POSTER ABSTRACTS
Conclusions: Patients with serological markers of past HBV infection are at risk for HBV
reactivation especially when they receive chemotherapy including specific monoclonal
agents and therefore screening is mandatory. In this setting, prophylactic antiviral therapy
should be initiated even in cases with HBsAb(+). Although LAM seems to be effective
in preventing reactivation in the majority of the patients it may not be the first choice of
antiviral prophylaxis, since fatal LAM failure can occur. On the other hand, the choice of
ENT or TDF prophylaxis is effective and safe.
213
P69
LACK OF USEFULNESS OF SERUM MAKERS FOR
ASSESSMENT OF SIGNIFICANT LIVER FIBROSIS IN
INACTIVE CARRIERS OF HEPATITIS B INFECTION
Mar Riveiro-Barciela1, Francisco Rodríguez-Frías2,3, María Homs2,3, David Tabernero2,3,
Leonardo Nieto2, María Buti1,3, Rafael Esteban1,3
1
Liver Unit, Internal Medicine Department, 2Liver Pathology Unit /Virology Unit Biochemistry
& Microbiology Departments, Hospital Universitario Vall d’Hebron, Barcelona, 3Centro de
Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) , Instutito
de salud Carlos III, Madrid, Spain
Introduction: The usefulness of biomarkers has been widely described in hepatitis C as a
reliable estimation of liver fibrosis. However, concerning hepatitis B virus (HBV), its role
remains unclear, mainly for the inactive carriers of the infection. Recently, the cut-off of
liver stiffness measurement (LSM) of 6.5 kPa has shown excellent accuracy for fibrosis
severity in HBeAg negative patients [Papatheodoris GV et al. J Viral Hepat 2013].
Aims: The aim of the study was to analyse the role of biomarkers of fibrosis in a cohort of
95 hepatitis B inactive carriers in comparison to TE.
POSTER ABSTRACTS
Methodology: Well characterized chronic inactive carriers defined by normal ALT and
HBV DNA <20.000 IU/mL levels in three consecutive determinations were included. Noninvasive estimation of hepatic fibrosis was performed by transient elastography (TE). Serum
markers (APRI, FIB-4, Forns´Index and FibroIndex) were calculated and compared with
TE. Predictive value and efficiency rates were calculated.
Results: 66 (69.5%) patients presented a TE value < 6.5 kPa and 29 (30.5%) > 6.5 kPa.
Subjects with a TE > 6.5 kPa had a higher body mass index (BMI) and insulin resistance
measured by HOMA-IR than patients with TE < 6.5 kPa (25.4 vs 27.2, p= 0.05; 2.8 vs 4.5,
p= 0.05, respectively). The efficiency rates, sensitivity, specificity and positive and negative
predictive values (PPV and NPV) of the main serum markers are showed in table 1 (the
cut-off applied for significant fibrosis were as follow: APRI ≤ 0.5; FIB-4≤ 0.6; Forns’ Index<
4.21; FibroIndex <1.25).
214
The area under curve of APRI, FIB-4, Forns and FibroIndex scores were 0.5 [95% IC: 0.40.6], 0.54 [95% IC: 0.42- 0.63], 0.43 [95% IC: 0.33- 0.54] and 0.49 [95% IC: 0.39- 0.6],
respectively. Assuming that approximately 20% of inactive carriers with a LSM below 6.5
kPa could present some degree of fibrosis, the optimal cut-off in our cohort, in order to rule
out significant fibrosis, would be:
•
•
•
•
APRI: 0.65 (PPV 43.5% and NPV 81.2%)
FIB-4: 0.84 (PPV 100% and NPV 81%)
Forns’ Index: 6.1 (PPV 100% and NPV 80.7%)
FibroIndex: 1.67 (PPV 100% and NPV 80.2%)
POSTER ABSTRACTS
Conclusions: Serum non-invasive markers are unable to properly diagnose significant
fibrosis in HBV inactive carriers. Cut-off values, derived from HCV, are too low and should
be further refined for hepatitis B inactive carriers in order to improve efficiency rates.
215
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INSULIN RESISTANCE IS ASSOCIATED WITH HIGHER
LIVER STIFFNESS AND INCREASED IMMUNE RESPONSE
IN INACTIVE CARRIERS OF HEPATITIS B
Mar Riveiro-Barciela1, Francisco Rodríguez-Frías2,3, María Homs2,3, David Tabernero2,3,
Leonardo Nieto2, Rafael Esteban1,3, María Buti1,3
1
Liver Unit, Internal Medicine Department, 2Liver Pathology Unit /Virology Unit Biochemistry
& Microbiology Departments, Hospital Universitario Vall d’Hebron, Barcelona, 3Centro de
Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instutito
de salud Carlos III, Madrid, Spain
Introduction: There is scarce data regarding the relationship between hepatitis B virus
(HBV) infection, insulin resistance and predisposition to hepatic fibrosis, especially in
chronic inactive carriers.
Aims: Analysis of the role of insulin resistance in hepatitis B inactive carriers.
POSTER ABSTRACTS
Methodology: Prospective analysis of the epidemiological, biochemical, anthropometric
and metabolic characteristics of a cohort of 100 HBeAg negative patients with normal ALT
levels and HBV DNA below 20.000 IU/mL and comparison based on the Homeostasis
Model of Assessment-Insulin Resistance (HOMA-IR).
Results: 54 out of 100 patients were male, with a median age of 47.8 years [IQR 3457]. 76% of patients were Caucasian. 25% of patients presented central obesity (waist
circumference >102 cm for men/88 cm for women) and the median body mass index (BMI)
was 26.2 [IQR 22.8-28.7]. 21% of patients suffered from arterial hypertension, 26% from
dyslipidemia and 4% from diabetes. The median insulin resistance measured by the HOMAIR was 2.44 [IQR 1.9-4], HBV DNA titters 390 IU/mL [IQR 71.5-1300] and HBsAg
level 1086 IU/mL [IQR 137-5075]. The median liver stiffness measurement (LSM) was 5.3
kPa [IQR 4-6.8]. Taking the median of the HOMA-IR index as reference, the differences
between the two groups were contrasted. Those differences reaching statistical significance
are summarized in table 1. Although the HBV DNA was higher in those patients with a
lower HOMA-IR (2482.8 vs 880.5, p =0.02), the degree of fibrosis measured by transient
elastography was statistically lower.
216
Other parameters as AST, cholesterol and HBsAg levels, and NK lymphocytes count did not
reach significance. Those patients with a higher HOMA-IR also presented a higher rate of
metabolic Syndrome (MS). However, when the LSM was contrasted based on the presence
of any parameter of the metabolic syndrome, the median BMI or waist circumference, there
were not significant differences (5.7 vs 6, p = 0.69; 5.74 vs 5.93, p = 0.8; 5.4 vs 6.5, p =
0.06, respectively).
POSTER ABSTRACTS
Conclusions: Insulin resistance in chronic HBV inactive carriers is associated with
increased liver stiffness and immune response. This subgroup of patients present higher
ALT and GGT levels, but within the normal range, and lower levels of HBV DNA.
217
P71
SAFETY AND EFFICACY OF TENOFOVIR IN TREATMENT
HEPATITIS B PATIENTS IN CLINICAL PRACTICE
Ângela Rodrigues1, Teresa Moreira1, José Ferreira1, Isabel Pedroto1
1
Gastroenterology, Centro Hospitalar do Porto - Hospital Santo António, Porto, Portugal
Introduction: Tenofovir is a potent nucleotide analogue recommended as first-line therapy
for chronic hepatitis B virus (HBV) infection.
Aims: To determine the efficacy and safety of tenofovir in patients with HBV infection.
Methodology: A retrospective evaluation of biochemical, virological and serological
response and side effects of tenofovir in patients with HBV infection treated in our
Gastroenterology Department.
POSTER ABSTRACTS
Results: Were included a total of 117 patients treated with tenofovir, 65% were male, with
a mean age of 45 years. Patients were followed for a median of 21 months and 89% had a
follow-up of more than 12 months; 26% with vertical transmission, 70% HBeAg negative,
76% genotype D and 28% treatment naïve. High levels of alanine aminotransferase (ALT)
found in 53% of patients, 28% with a viral load > 6 log10UI/ml and 10% had cirrhosis.
About 79% of patients had ALT normalization; 86% achieved DNA < 20 IU/ml after a
median of 5 months of treatment (1-50), this response reached 95% in HBeAg negative
patients and 66% of HBeAg positive patients. Patients with higher viral load (> 6 log10IU/
ml) had a lower likelihood of virological response (54.5 % versus 98.7 %, p< 0.001).
One patient had HBeAg seroconversion (2.8%) and one other HBsAg loss (0.8%). One
patient had a significant alteration in renal function (>0.5 mg/dl) due to progression of
chronic kidney disease; therapy was discontinued in two patients, in one because of tubular
dysfunction and in another due to significant nausea.
Conclusions: The “real life” studies are important and necessary because they reflect more
adequately the reality of clinical practice than the clinical trials. Our study, like others,
demonstrates high efficacy and safety of tenofovir, confirming the results obtained in
clinical trials.
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INVOLVEMENT OF TNF-ALPHA IN IMMUNE REACTION
ASSOCIATED WITH VIRAL HEPATITIS B
Alexandra Floriana Rosu1, Tudorel Ciurea1,2, Dan Ionut Gheonea1,2, Maria Konstantellou3,
Lucica Rosu4,5, Michael Chrisofos6, Daniela Calina7,8, Ovidiu Zlatian4,5
1
Gastroenterology department, County Clinical Emergency Hospital, 2Internal Medicine
department, University of Medicine and Pharmacy, Craiova, Romania, 3Internal Medicine
department, Private clinic, Athens, Greece, 4Microbiology department, University of Medicine
and Pharmacy, 5Medical analysis laboratory, County Clinical Emergency Hospital, Craiova,
Romania, 6Urology department, National & Kapodistrian University - Athens Medical School,
Athens, Greece, 7Clinical Pharmacy department, University of Medicine and Pharmacy, 8Hospital
Pharmacy, County Clinical Emergency Hospital, Craiova, Romania
Introduction: Recent data suggest that the TNF-alpha can induce secretion of cytokines
by other immune cells, which contribute to the immune-mediated liver damage in viral
hepatitis.
Aims: Our study proposed to investigate in patients with viral hepatitis B the link between
hepatopathy evolution and serum levels of TNF-alpha and other biochemical markers, in
order to perform an evolution prognosis and conducting the therapy.
Results: TNF alpha levels differed significantly with the stage of the hepatic viral disease.
In patients with active viral chronic hepatitis TNF-alpha has high levels (22.2±2.17 pg/ml)
and in cirrhosis patients has moderate levels (15.1±1.75 pg/ml), compared with control lot
(7±1.01 pg/ml). Regarding the clinical stage, the TNF-alpha levels were significantly higher
in patients with active chronic hepatitis and in those with associated autoimmune diseases
(tiroiditis), compared with patients diagnosed with cirrhosis.
Conclusions: Our study shows the importance of assessing the serum TNF-alpha levels
in hepatopathies. This cytokine is a marker of unfavorable evolution of active viral hepatitis
towards cirrhosis.
219
POSTER ABSTRACTS
Methodology: We studied 2 lots of patients: a) control lot composed of 15 persons,
regular blood donors and b) test lot formed of 60 patients with hepatitis B viral infection
(20 with cirrhosis and 40 with chronic active hepatitis), hospitalized in medical clinics of
Clinical Emergency Hospital, Craiova, Romania. The viral infections was confirmed by
ELISA method: HBs antigen, HBe antigen and anti-HBc antibodies. All patients were
clinically evaluated and the usual biochemical tests for hepatitis were performed. We used
an immunoenzymatic assay (DRG Instruments GmbH, Germany) to quantify the serum
levels of TNF-alpha.
P73
INFLUENCE OF PREDICTOR VARIABLES ON DEGREE OF
FIBROSIS IN CHRONIC HBV-INFECTION MEASURED BY
FIBROTEST
Narina Sargsyants1, Arthur Melkonyan2,Yelena Kazanchyan2
1
Infectious Diseases, Armenicum Clinical Center, 2“Promtest” Diagnostic Laboratory,
Yerevan, Armenia
Introduction: Armenia characterized with predominantly HBeAg-negative chronic HBVinfection and genotype D of HBV. In HBeAg-negative genotype D CHB, the combination
of an HBsAg level <1000 IU/ml and HBV DNA level <2000 IU/ml at a single time point
accurately identifies true inactive carriers. According to the recent EASL guidelines, patients
should be considered for treatment when they have HBV DNA above 2000 IU/ml, elevated
serum ALT and moderate/severe necroinflammation and/or at least moderate fibrosis
assessed by liver biopsy or non-invasive markers once validated in HBV-infected patients.
Aims: The aim of the study is evaluation of gender, HBV DNA and HBsAg level influence
of Fibrotest degree of fibrosis in patients with chronic HBV-infection.
POSTER ABSTRACTS
Methodology: 161 patients with chronic HBV-infection (64% male) from 15 to 69 years
old (35.8±11.9) were involved in the study. Viral load (VL) was checked by Abbott RealTime™ HBV. HBsAg level was measured by ARCHITECT assay, Abbott Laboratories. Stage
of liver fibrosis was checked by Fibrotest, BioPredictive. Statistic analysis was done by
SPSS 11.0. Binary logistic regression was used for estimation of independent or predictor
variables (gender, VL and HBsAg level) influence on degree of fibrosis. Gender and fibrosis
degree (F >= 2 or <2) are considered as dichotomous.
Results: Range of VL was from 13 to 20771300 IU/ml. In 30% of patients with chronic
HBV-infection HBV DNA was > 2000 UI/ml. Low level (<200 IU/ml) HBV DNA in blood
enrolled in 36% of patients. Results of HBsAg quantification are 26.7–125000 IU/mL with
HBsAg level less than 1000 IU/mL in 20% of cases. Among checked=”checked” chronically
HBV-infected patients 18% had HBsAg level <1000 IU/ml and an HBV DNA level <2000
IU/ml. Assessment of liver fibrosis by FibroTest revealed >= 2 in 18.2% patients. Significant/
severe inflammation activity by ActiTest enrolled in 13.6% patients. In patients with VL
more than 2000 UI/ml F >= 2 estimated in 36.9% and A >= 2 in 21.1%.
220
Logistic regression has shown HBsAg level are significant predictor when all three variables
are considered together (p=0.05). Only HBV DNA separately significantly related to
fibrosis degree (p=0.025). Percentage of correct predictions is 81.5%, model was significant
(x2 =16.9, df=3, p=0.001).
Conclusions: HBsAg level in case then gender, HBsAg and HBsAg level are considered
together and HBV DNA level separately influence on severity of fibrosis measured by
Fibrotest in chronic HBV-infection.
POSTER ABSTRACTS
Table:
221
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SINGLE CENTER EXPERIENCE: EFFICACY AND SAFETY OF
LONG TERM THERAPY WITH NUCLEOS(T)IDE ANALOGS
IN CHRONIC HEPATITIS B (CHB) PATIENTS
Elisaveta Sidorova1, Djamal Abdourakhmanov1
1
gastroenterology and hepatology, E.M. Tareev clinic of nephrology, internal and occupational
diseases, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
Introduction: Potential therapy of chronic hepatitis B
Aims: Registration studies showed Entecavir (ETV) and Telbivudin (TLB) to be an
effective and safety therapy for naive patients with chronic hepatitis B up to 4 years, but few
real clinical practice data is reported nowadays.
POSTER ABSTRACTS
Methodology: 52 patients: 41,6 (20 – 75) years, 40 (77%) males, HBV DNA 1,2x108
(1,7x103 – 1x109) IU/ml (8,1 log), 35 (67%) HBeAg negative, 6 (11%) with F4 fibrosis
(METAVIR), 52 % with BMI > 27. Naive patients 43 (83%) on therapy with ETV or TLB
monotherapy for CHB and 9 (17%) commenced lamivudine (LAM-refractory) therapy
were enrolled in a retrospective/prospective cohort study from single clinic. Median followup was 30 months (range 0–60). Virological response was undetectable HBV DNA by
sensitive assays; AST/ALT elevations; safety analysis focused on creatinine and creatine
kinase (CK) levels - renal function and myopathy.
Results: Virological response rates on ETV increased over time: 60% at 6 months (21 from
35) and 2 from 7 LAM-refractory patients, 83% at 12 (29 from 35) and 3 from 6 LAMrefractory, 86% at 18 (30 from 35) 3 from 6 LAM-refractory, 88% at 24 (31 from 35) and
5 from 6 LAM-refractory, 94% at 30 (32 from 34) and 5 from 6 LAM-refractory, 94% at
36 (31 from 33), 91% at 42 (30 from 33), 91% at 48 (29 from 32) with time to HBV DNA
undetectabllity significantly affected by baseline viremia (p < 0.001). The different way with
TLB: 55%, 76%, 76%, 76%? 62%, 50%, 50% and 50% at 6, 12, 18, 24, 30, 36, 42 and
48 months (17 patients). With ETV 87% of HBeAg “+” and 13% of HBeAg “-” patients
had undetectable viral load at month 48. Primary non response occurred in 9% of the
patients, partial virological response at month 30 in 8%, virological breakthroughs in 6%
and virological blips in 7%. Approximately 41% of all the patients (42) showed >0.5 mg/dl
increase of serum creatinine.
222
There were no patients with eGFR <50 ml/min by CKD-EPI at baseline and remained
unchanged during the study. ENT and TLB were not ever discontinued or downdosed
during the follow-up. No decline of renal function was mentioned. 1 patient on TLB therapy
was excluded (24 month) because of the collateral reactions: increase of the CK level in
blood, a mialgiya, increased fatigue.
Conclusions: ENT monotherapy provided high rates of HBV suppression and increasing
rates of HBeAg seroconversion with a favourable safety profile in contrast to TLB. Such
outcomes offer the potential of a cure to more patients than has been previously possible.
POSTER ABSTRACTS
Figure:
223
P75
NONINVASIVE PREDICTION OF HEPATOCELLULAR
CARCINOMA DEVELOPMENT: FIB-4 INDEX IN PATIENTS
WITH CHRONIC HEPATITIS B Goktug Sirin1, Omer Senturk2, Altay Celebi2, Sadettin Hülagu2
1
Gastroenterology, Derince Education and Research Hospital, 2Gastroenterology, Kocaeli
University, Kocaeli, Turkey
Introduction: The FIB-4 index is a simple formula to predict liver fibrosis.
Aims: This study aimed to evaluate the utility of the FIB-4 index and associated timecourse changes as a predictor of hepatocellular carcinoma (HCC) development in patients
with chronic hepatitis B.
POSTER ABSTRACTS
Methodology: A total of 285 chronic hepatitis B patients that received a liver biopsy in
Kocaeli University Medical School Hospital were investigated. 98 patients had received
antiviral therapy (0ral and/or interferon) after the biopsy and 7 of them not achieved sustain
virological response. We examined a relation between the time-course changes of the FIB-4
index and HCC development.
Results: Mean follow up periods were 8.2 years and HCC developed in 16 patients during
follow up periods. Univariate analysis demonstrated that the FIB-4 index >3.25 and cFIB4/year ≥0.3 were predictive factors for HCC development. Multivariate analysis revealed
that these two factors were independent. Patients with a FIB-4 index >3.25 and a cFIB- 4/
year ≥0.3 were defined as high risk, those with a FIB4 index ≤3.25 and a cFIB-4/year <0.3
were defined as low risk, and other patients were defined as intermediate risk. The 5-, 8-year
cumulative number of HCC in patients with high risk group was 6 and 8, respectively,
whereas it was 0 and 2 in patients with intermediate risk group. There was never HCC in
patients with low risk group (p<0.001).
Conclusions: Measurement of the FIB-4 index and cFIB-4 seems to be a useful noninvasive tool(s) for real-time monitoring of HCC development in patients with chronic
hepatitis B.
224
P76
REAL-LIFE DATA ON LONG-TERM VIROLOGICAL
RESPONSE TO ORAL ANTIVIRAL THERAPY FOR
TREATMENT-NAÏVE PATIENTS WITH CHRONIC HEPATITIS
B: A KOREAN MULTICENTER, RETROSPECTIVE COHORT
STUDY
Joo Hyun Sohn1, Tae Yeob Kim1,Won Young Tak2, Byung Hoon Han3,Woo Jin Chung4,
Hyun Ju Min5, Hyun Phil Shin6, Soon Woo Nam7, In Hee Kim8
1
Gastroenterology, Hanyang University Guri Hospital, Guri, 2Gastroenterology, Kyungpook
National University Hospital, Daegu, 3Gastroenterology, Kosin University College of Medicine,
Busan, 4Gastroenterology, Keimyung University School of Medicine, Daegu, 5Gastroenterology,
Gyeongsang National University College of Medicine, Jinju, 6Gastroenterology, Kyung Hee
University Hospital at Gandong, Seoul, 7Gastroenterology, The Catholic University of Korea
Daejeon St. Mary’s Hospital, Daejeon, 8Gastroenterology, Chonbuk National University Medical
School and Hospital , Jeonju, Korea, South
Introduction: Although real-life studies have more diverse patient populations and real-life
compliance, real-life data on the long-term antiviral treatment of chronic hepatitis B (CHB)
were insufficient.
Methodology: Data were initially collected retrospectively but consecutively from 1,028
naïve CHB patients who started with oral antiviral treatment at nation-wide 8 academic
hospitals from January 2007 to December 2009. After exclusion of 305 patients due to
incomplete data or cancer, a total of 723 (entecavir, n=368; lamivudin or clevudine, n=355)
were analysed. Study subjects were divided into 6-month virological responder (VR, n=402)
and no VR (n=321) groups according to the achievement of undetectable HBV DNA (<
300 copies/ml) at 6 months of treatment. Cumulative incidence for virological response
variables was analyzed by Kaplan-Meier curve.
225
POSTER ABSTRACTS
Aims: The aims are to investigate long-term virological response to oral antiviral therapy
for treatment-naïve patients with CHB in real-life clinical practice setting.
Results: A mean age of study subjects was 47.1+/-11.9 years old with 64.2% male.
Among them, 42.5% had cirrhosis, 64.3% was HBeAg positive and mean baseline HBV
DNA level was 7.1 log10copies/mL. During a median follow-up of 2.5 (range 0.5-5.0)
years, viral mutation occurred in 18.9% (137/723) including 4 cases in entecavir-treated
patients. Among 434 HBeAg (+) patients HBV DNA negativity, HBeAg seroclearance and
seroconversion was achieved in 82.0%, 37.6% and 29.1% respectively, whereas among 241
HBeAg (-) patients HBV DNA negativity was achieved in 94.2%. In VR vs. no VR groups,
the cumulative rates of HBeAg seroclearance (seroconversion) at 1-, 2-, 3-, and 4-year were
35.8% (28.3%), 52.1% (37.6%), 66.7% (52.9%), and 75.9% (65.0%) vs. 6.9% (4.7%),
19.0% (13.6%), 27.3% (21.8%), and 37.9% (40.2%), respectively (all, P < 0.001 ). The
cumulative rates of viral resistance at 1-,2-,3-, and 4-year in VR vs. no VR were 0.3%, 5.0%,
10.3%, and 13.0% vs. 3.8%, 19.9%, 30.3%, and 37.7%, respectively (P < 0.001). In no VR
group at 6-month, the cumulative rates of HBV DNA negativity at 1-, 2-, 3-, and 4-year
were 14.9%, 23.7%, 34.4% and 40.8%.
POSTER ABSTRACTS
Conclusions: This study showed a real-life data and confirmed again that undetectable
serum HBV DNA at 6 months of antiviral treatment is helpful to predict future viral
responses.
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P77 - YI
DESIGNING ENHANCED PATHWAYS OF CARE FOR
PATIENTS WITH CHRONIC HEPATITIS B USING HEPBASE,
A PROPRIETARY DATABASE USED TO STRATIFY
PATIENTS
Ankur Srivastava1, Paul Trembling1, Sudeep Tanwar1, Janet Catt1, Zareen Mehboob2,
Dominic Morgan2, Geoffrey Dusheiko1,William Rosenberg1
1
Department of Hepatology, Royal Free London NHS Foundation Trust, London, 2of Health
Informatics, Sciensus Health Informatics, Brighton, United Kingdom
Introduction: Greater awareness of chronic hepatitis B (CHB), improved therapy and
clinical guidelines have all increased patient referrals to liver clinics. Improved understanding
of disease progression and fibrosis biomarkers has created the opportunity to redesign
pathways of care.
Methodology: HepBase, (Sciensus Health Informatics, Brighton) is a real-time clinical
and research database, which uses ODBC, SPSS and MATLAB computing programmes
to analyse hospital electronic medical record system and pharmacy data to generate patient
cohorts. Patient care pathways were designed in consultation with clinical colleagues based
upon EASL clinical care guidelines to identify inactive or pharmacologically controlled
CHB who have either a) mild fibrosis or b) advanced fibrosis/cirrhosis.
Inclusion criteria included: e-antigen positive or negative, ALT<ULN, HBV DNA <2000
IU/ml, FIB4 < 1.45 or >3.25. Patients discharged, transferred, lost to follow up or died
were excluded.
Results: Between January 2011 and October 2013 the records of 1796 patients were
entered in the RFL HepBase. Of these 867 (48%) satisfied the study’s inclusion criteria
(table 1)
227
POSTER ABSTRACTS
Aims: Using proprietary database software and non-invasive tests to stratify patients
attending the Royal Free London (RFL) Hospital for CHB allows identification of patients
who are at low risk of disease progression allowing exploration of alternative follow-up
arrangements.
Groups 1 and 2 (36%) are considered low risk for disease progression and will be reviewed
for allocation to a nurse-led, consultant monitored follow up clinic.
27 patients (FIB4>3.25) are at risk of advanced fibrosis/cirrhosis. 70% were already
diagnosed as cirrhotic. An additional 22% were under close monitoring for advanced
liver disease. 9 patients with FIB4>3.25 were not on treatment with an active decision to
withhold treatment documented in five cases.
Conclusions: Using an integrated database, 36% of CHB clinic attenders have been
identified as inactive or pharmacologically controlled CHB who might be eligible for
alternative pathways of care.
Use of HepBase has facilitated redesign of pathways of care for patients with CHB,
identifying those who might benefit from less intensive hospital management and those who
might benefit from closer monitoring for complications of advanced CHB and consideration
of treatment. This approach may also reduce pressure on hospital clinics. We will go on to
determine the effectiveness, cost-effectiveness and acceptability of these strategies.
POSTER ABSTRACTS
Table 1:
228
P78 - YI
A NEW CLINICAL DATABASE TOOL TO IMPROVE
IDENTIFICATION OF HEPATITIS B AND C VIRUSES IN THE
PRIMARY CARE SETTING
Ankur Srivastava1, Grainne Nixon2, Satya Bobba3, Alex Warner4, Karen Sennett5,
Douglas Thorburn1,William Rosenberg1, Sarah Morgan4
1
Department of Hepatology, Royal Free London NHS Foundation Trust, 2North East & Central
London Health Protection Team, Public Health England, 3IT & Systems Team, 4Primary
Care, NHS Camden Clinical Commissioning Group, 5Primary Care, NHS Islington Clinical
Commissioning Group, London, United Kingdom
Introduction: Advances in our understanding of Chronic Viral Hepatitis B & C (CHB,
CHC) coupled with improved treatment options have enabled clearer management
guidelines. However, identifying patients at risk of these largely asymptomatic diseases
requires urgent attention to ensure maximal benefit. We describe an innovative primary care
database tool, which identifies those at high risk of HBV & HCV allowing screening with
standard blood tests.
Methodology: All new registrants to general practices (GP) in Camden and Islington will
complete a health questionnaire which will be entered electronically onto the GP clinical
patient record system (Egton Medical Information System, EMIS). All current patients
will have their EMIS computerized case records scrutinised by the application. The tool
searches specific ‘read codes’ aimed at identifying patients with risk factors for HBV & HCV
defined as:
• Country of origin with a CHB prevalence of >8%
• Record of a family member with Hep B
• Men who have sex with men
• Commercial sex workers
• History of sexually transmitted infection
• People who inject drugs
• On methadone medication
• Transfusion overseas or before Sept 1991
• Hepatitis B diagnosis
• Hepatitis C diagnosis
• HIV diagnosis
229
POSTER ABSTRACTS
Aims: To develop a clinical primary care tool to identify patients at high risk of HBV &
HCV to allow chronic viral hepatitis and HIV testing.
Patients identified as being at risk will be flagged as ‘high risk’ allowing GP’s to offer
testing for HBV, HCV and HIV (figure 1). All positive cases will be referred for appropriate
management.
Results: The screening tool was implemented in all GP practices in Camden and Islington
(total 73) in March 2014. A formal evaluation aimed at assessing the impact of HBsAG
and HCV antibody testing and subsequent positive results detected will be performed at 6
months and beyond.
Conclusions: Improvements in understanding of disease progression and treatments in
chronic viral hepatitis will have a limited impact until screening and detection of disease is
enhanced.
We describe in this abstract a primary care clinical patient record based tool that will allow
screening of HBV & HCV based on commonly accepted risk factors. A formal evaluation
to assess the clinical effectiveness of the tool is underway and will be shared in the future.
POSTER ABSTRACTS
Figure:
230
P79
IFNL3 (IL28B) AND IFNL4 POLYMORPHISMS ARE
NOT ASSOCIATED WITH TREATMENT RESPONSE TO
PEGYLATED INTERFERON-BASED THERAPY IN THAI
PATIENTS WITH HBEAG-NEGATIVE CHRONIC HEPATITIS B
Umaporn Limothai1, Srunthron Akkarathamrongsin1,Yong Poovorawan1, Pisit Tangkijvanich2
1
Center of Excellence in Clinical Virology, Department of Pediatrics, 2Research Unit of Hepatitis
and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University,
Bangkok, Thailand
Introduction: Recent studies have shown an association between single nucleotide
polymorphisms (SNPs) in the interferon lambda-3 (IFNL3 or IL-28B) and IFNL4 genes
and treatment response to chronic hepatitis C. However, the importance of these SNPs in
chronic hepatitis B is unclear.
Aims: The aim of this study was to investigate whether these SNPs could predict treatment
response to pegylated interferon (PEG-IFN)-based therapy in patients with HBeAgnegative chronic hepatitis B.
Results: A total 126 patients (63 patients in each group) were enrolled in the study. There
was no significant difference in rate of virological response between group 1 and group 2
(41.3% vs. 36.5%, respectively). HBsAg clearance was detected in 6 (9.5%) and 3 (4.8%)
in groups 1 and 2, respectively (p=0.299). Overall, the distribution of CC, CT and TT
genotypes of rs12979860 was 109 (86.5%), 17 (13.5%) and 0 (0%), respectively, while the
distribution of TT/TT, ∆G/TT and ∆G /∆G genotypes of ss469415590 was identical. There
was no association between rs12979860 or ss469415590 genotypes and virological response
at the end of follow-up. Similarly, there was no association between these genotypes and
HBsAg clearance. In addition, there was no difference in baseline HBV DNA, HBsAg and
ALT levels according to the SNP genotypes.
Conclusions: These SNPs were not associated with treatment response to PEG-IFNbased therapy in Thai patients with HBeAg-negative chronic hepatitis B.
231
POSTER ABSTRACTS
Methodology: We analyzed data from a randomized study comparing efficacy of PEG-IFN
monotherapy (group 1) versus simultaneous combination with entecavir (group 2) in Thai
patients with HBeAg-negative chronic hepatitis B. All patients were treated for 48 weeks
and followed-up for additional 48 weeks to assess virological response, which was defined as
HBV DNA level <2,000 IU/mL. DNA extracted from blood samples was analyzed for the
SNPs rs12979860 and ss469415590.
P80
THE DRAGON PROJECT – A COMMUNITY APPROACH TO
DELIVERING HEPATITIS B SCREENING FOR THE CHINESE
COMMUNITY IN MANCHESTER, UK
Alison Uriel1, Shirley He2, Emily Lam3, Charlotte Bowen4, Siobhan Fahey5, Javier Vilar1
1
Infectious Diseases and Tropical Medicine, Monsall Unit, North Manchester General Hospital,
2
Chinese Health Information Centre, 3National Institute for Clinical Excellence, 4British Liver
Trust, 5Greater Manchester Public Health Network, Manchester, United Kingdom
Introduction: UK guidelines advise screening for Hepatitis B surface antigen (HBsAg)
in high-risk groups, including immigrants from high prevalence areas such as China.
Manchester has the 3rd largest Chinese community (CC) in the UK, a significant proportion
of whom cannot speak English, a potential barrier to accessing healthcare.
Aims: To set up a readily accessible and bilingual Hepatitis B (HB) screening clinic in
Manchester.
Methodology: Testing for HBsAg and HB core antibody (anti-HBc) was carried out by
a bilingual nurse, in a community based clinic, over a 6-month period (September 2012
– February 2013) using dried blood spot kits (funded through a Gilead UK and Ireland
Fellowship programme). Participants found to be HBsAg positive were offered secondary
care following a locally agreed HB care pathway, or vaccination by their GPs if HBsAg and
anti-HBc negative. A proportion of the cohort completed a user survey to gauge satisfaction
with previous and ongoing interactions regarding HB with healthcare professionals.
POSTER ABSTRACTS
Results: Tests were carried out on 150 individuals and100% returned for results. Twothirds were aged 45 to 70 years (49% male, and 73% from Central Manchester); 87% spoke
Cantonese, 9% Mandarin and 4% Hakka. Thirty (20%) were HBsAg negative, anti-HBc
positive, and 111 (74%) were HBsAg and anti-HBc negative.
Significantly, 9 (6%) were HBsAg positive (median age 55 years; range 31-65), of these, 5
were male, and 7 had a family member with Chronic HB. All were HB e Antigen negative.
Median HBV DNA level was 790 IU/ml (range 40 – 38,275) and median ALT level 23 U/L
(range 16 -148).
From the user surveys it was clear that, despite being registered with a GP and having disease
awareness, a large proportion had had no prior HB related discussions with healthcare
professionals. Nearly all found the testing process ‘easy’, and ‘painless’; 100% found the
information helpful, and well explained and 60% felt that they received new information.
Conclusions: Our pilot project confirms the feasibility of HBsAg screening in an accessible
community based ‘bilingual’ healthcare setting and was popular with the CC. The high rate
of tested individuals returning for results, and attendance of HBsAg positive individuals for
secondary care appointments attests to the acceptability of our approach.
232
P81 - YI
DETERMINANTS OF HBSAG RESPONSE INDUCED BY
ADDITION OF PEGINTERFERON TO ENTECAVIR IN
HBEAG-POSITIVE CHRONIC HEPATITIS B
Margo J.H. van Campenhout1,Willem P. Brouwer1, Qing Xie2, Ningping Zhang3,
Qing Zhang4, Fehmi Tabak5, Anca Streinu6, Ji-Yao Wang3, Ramazan Idilman7,
Hendrik W. Reesink8, Mircea Diculescu9, Krzysztof Simon10, Mihai Voiculescu11, Meral Akdogan12,
Wlodzimierz Mazur13, Robert J. de Knegt1, Heng Chi14, Milan J. Sonneveld1,
Bettina E Hansen15, Harry L.A. Janssen16
1
Department of Gastroenterology & Hepatology, Erasmus MC, University Medical Hospital
Rotterdam, Rotterdam, Netherlands, 2Infectious diseases, Ruijin Hospital, Jiaotong University,
3
Gastroenterology & Hepatology, Zhong Shan Hospital, Fu Dan University, 4Gastroenterology &
Hepatology, Shanghai Public Health Center, Fu Dan University, Shanghai, China, 5Cerrahpasa
Medical Faculty, Istanbul, Turkey, 6National Institute of Infectious Disease, Bucharest, Romania,
7
University of Ankara, Medical School, Ankara, Turkey, 8Gastroenterology & Hepatology,
Academic Medical Centre Amsterdam, Amsterdam, Netherlands, 9Fundeni Cinical Institute,
Bucharest, Romania, 10Division of Infectious Diseases and Hepatology,Wroclaw Medical
University,Wroclaw, Poland, 11Department of Internal Medicine, Fundeni Cinical Institute,
Bucharest, Romania, 12Department of Gastroenterology,Yuksek Ihsitas Hospital, Ankara,
Turkey, 13Department of Infectious Diseases, Silesian Medical University, Katowice, Poland,
14
Gastroenterology & Hepatology, 15Department of Public Health, Erasmus MC, University
Medical Hospital Rotterdam, Rotterdam, Netherlands, 16Toronto Center for Liver Disease, Toronto
Western and General Hospital, University Health Network, Toronto, Canada
Aims: We aimed to identify factors that predict immune control induced by ETV
monotherapy, or by addition PEG-IFN to entecavir (ETV) in HBeAg-positive CHB.
233
POSTER ABSTRACTS
Introduction: Serum HBsAg levels reflect the interaction between the hepatitis B virus and
the immune system in chronic hepatitis B (CHB) infection. HBsAg decline of ≥1 log IU/mL
and post-treatment levels <1000 IU/mL are both associated with enhanced immune control
and sustained remission of disease.
Methodology: In a randomised clinical trial comparing 48 weeks of ETV monotherapy to
24 weeks of ETV followed by 24 weeks of ETV and PEG-IFN combination therapy, 182
patients participated, and 175 patients were included in the modified intention to treat
analysis. We assessed the rate of patients achieving either HBsAg decline ≥1 log IU/mL or
HBsAg <1000 IU/mL at week 96 (HBsAg response).
Results: HBsAg response at week 96 was achieved in 39 of 85 (46%) of patients who
received PEG-IFN add-on treatment compared to 24 of 90 (27%) who received ETV
monotherapy (p=0.011). Response was achieved in 3 of 13 patients (23%) in genotype
A, 21 of 33 (64%) in genotype B, 32 of 74 (43%) in genotype C, and 7 of 55 (13%) in
genotype D (overall p<0.001). Patients with any precore (PC) and/or basal core promoter
(BCP) mutation showed higher rate of HBsAg response compared to patients without
mutations (3/16 patients, 38% vs 55/145 patients,19%; p=0.173). HBsAg responders had
higher baseline ALT levels (3.8x ULN vs. 2.4x ULN, p=0.001). Log HBsAg levels and
log HBV DNA at baseline did not differ (4.1 IU/mL vs. 4.2 log IU/mL, p=0.551, and 1.2
IU/mL vs. 1.2 IU/mL, p=0.464, respectively). In multivariable analysis, PEG-IFN addon was associated with a higher chance of HBsAg response (OR 2.42, CI-95% 1.18-4.9,
p=0.014), as well as both genotype B and C (genotype A vs. B: OR 0.16, CI-95% 0.03 –
0.75, p= 0.020; genotype C vs. B: OR 0.49, CI-95% 0.2-1.2, p=0.118, genotype D vs. B:
OR 0.08, CI-95% 0.03-0.26, p<0.001) and higher baseline ALT (OR 1.27, 95% CI 1.051.53, p=0.014). Predicted probabilities of achieving HBsAg response to PEG-IFN add-on
therapy for a patient with ALT of 2xULN were 25%, 68 %, 51% and 15% for genotype A,
B, C and D, respectively.
POSTER ABSTRACTS
Conclusions: The addition of PEG-IFN to ETV in HBeAg-positive CHB enhanced
immune control compared to ETV monotherapy. Higher baseline ALT was associated with
HBsAg response. Genotype D was associated with lower probability of achieving HBsAg
response compared to genotype B and C.
234
P82
ANTIBODY TO HEPATITIS CORE ANTIGEN LEVELS IN THE
NATURAL HISTORY OF CHRONIC HEPATITIS B
Gui-Qiang Wang1 and Wei Jia, Liu-Wei Song,Yu-Qing Fang, Xiao-Feng Wu, Dan-Yang Liu,
Chun Xu, Xiao-Mei Wang,Wen Wang, Dong-Xia Lv, Jun Li,Yong-Qiong Deng,Yan Wang,
Na Huo, Min Yu, Hong-Li Xi, Dan Liu,YiXing Zhou, Ming-Xiang Zhang, Ning-Shao Xia
1
Infectious Diseases and Center for Liver Diseases, Peking University First Hospital,
Beijing, China
Introduction: Previous studies have revealed anti-HBc levels as predictors of treatment
response in HBeAg positive chronic hepatitis B (CHB) patients in both interferon-α and
nucleos(t)ide analogue therapy cohorts. However, there is limited information about antiHBc levels in the natural history of CHB.
Aims: This study aimed to define anti-HBc levels of different phases in the natural history
of CHB.
Results: Serum anti-HBc levels were statistically significant between patients in different
phases of CHB (p < 0.001). The median anti-HBc levels were: IT (3.28 log10 IU/ml),
IC (4.35 log10 IU/ml), LR (3.29 log10 IU/ml), ENH (4.12 log10 IU/ml) and PBI (0.61
log10 IU/ml). There existed a strong correlation in IC (r = 0.519, p < 0.001) and a poor
correlation in ENH (r = 0.275, p = 0.042). Anti-HBc levels with HBeAg serostatus could
be used to distinguish different phases of CHB.
Conclusions: Anti-HBc levels show significant differences during the natural course
of CHB. These results may provide some potentially useful insights into hepatitis B
pathogenesis and immune status.
235
POSTER ABSTRACTS
Methodology: 211 treatment naive CHB patients were included in the study. They were
classified into four phases: immune tolerance phase (IT, n=39), immune clearance phase
(IC, n=48), non/low-replicative phase (LR, n=55) and HBeAg negative hepatitis (ENH,
n=69). 50 patients who were HBsAg negative and anti-HBc positive were also recruited
as past HBV infection (PBI) control group. Anti-HBc levels were measured by a newdeveloped double-sandwich immunoassay. Correlation of anti-HBc levels with ALT and
other HBV-related markers within each phase was performed.
P83
QUANTITATIVE HEPATITIS B CORE ANTIBODY LEVEL IS A
NEW BASELINE PREDICTOR FOR TREATMENT RESPONSE
IN HBEAG-POSITIVE CHRONIC HEPATITIS B PATIENTS
RECEIVING PEGINTERFERON THERAPY
Gui-Qiang Wang1 and Feng-Qin Hou1#, Liu-Wei Song2#, Quan Yuan2, Lin-Lin Fang2,
Sheng-Xiang Ge2, Jun Zhang2# Ji-Fang Sheng3, Dong-Ying Xie4, Jia Shang5,
Shu-Huan Wu6,Yong-Tao Sun7, Shao-Feng Wei8, Mao-Rong Wang9, Mo-Bin Wan10,
Ji-Dong Jia11, Hao Wang12,Ning-Shao Xia
1
Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, Beijing, China
Introduction: Recent study revealed that quantitative hepatitis B core antibody (qAntiHBc) level could be served as a novel marker for predicting treatment response.
Aims: In this study, we further investigated the predictive value of qAnti-HBc level in
HBeAg positive patients with PEG-IFN therapy.
POSTER ABSTRACTS
Methodology: 140 patients HBeAg positive patients received PEG-IFN therapy for 48
weeks and followed up for 24 weeks were enrolled in this study. Serum samples were
taken every 12 weeks post-treatment. The predictive value of baseline qAnti-HBc level for
treatment response was assessed. Patients were further divided into two groups according
to baseline qAnti-HBc level and the response rate was compared, in addition, the kinetics of
virological and biochemical parameters was analyzed.
Results: Patients achieved response had a significantly higher baseline qAnti-HBc level
[Serological response (SR): 4.52±0.36 v.s 4.19±0.58, p=0.0014; Virological response
(VR): 4.53±0.35 v.s 4.22±0.57, p=0.0053]. Baseline qAnti-HBc is the only parameter
independently correlated with either SR (p=0.008) or VR (p=0.010). Patients with baseline
qAnti-HBc level ≥30000 IU/mL had significantly higher response rate, more HBV DNA
suppression and better hepatitis control in PEG-IFN treatment.
236
Conclusions: Quantitative Anti-HBc level may be a novel biomarker to predict treatment
response in HBeAg positive patients with PEG-IFN therapy.
POSTER ABSTRACTS
Figure:
237
P84
SERUM GAMMA-GLUTAMYLTRANSFERASE IS USEFUL
FOR MONITORING NATURAL COURSE AND PREDICTING
TREATMENT OUTCOME OF CHRONIC HEPATITIS B VIRUS
INFECTION
Chao Wu1, Rui Huang2, Chenchen Yang1,Yong Liu3, Xiaomin Yan1,Yali Xiong1, Ran Su1
1
Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical
School, 2Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of
Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 3Department
of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School,
Nanjing, China
Introduction: Serum gamma-glutamyltransferase (GGT) has been demonstrated to be
associated with treatment response and clinical outcomes of chronic hepatitis C. However,
less is known about its association with chronic hepatitis B (CHB).
Aims: We aimed to compare serum GGT levels during the natural course of chronic
hepatitis B virus (HBV) infection and investigate the relationship between GGT and clinical
outcomes during nucleos(t)ide analogues (NA) therapy in patients with HBeAg-positive
CHB.
POSTER ABSTRACTS
Methodology: Two hundred and fifteen patients with chronic HBV infection and 83
healthy individuals were retrospectively enrolled and classified according to definitions of
the natural phases of chronic HBV infection. The patients were categorized into immune
tolerance (IT, n=47), HBeAg-positive hepatitis (EPH, n=93), HBeAg-negative hepatitis
(ENH, n=20) and inactive carrier (IC, n=55). Thirty-three EPH patients who received
NA therapy including lamivudine plus adefovir combination therapy (n=20) or entecavir
monotherapy (n=13) were followed for 48 weeks.
Results: The serum GGT levels were significantly higher in patients with EPH and ENH
as compared with IT, IC and healthy control groups (P<0.01). However, no significant
difference was found between EPH and ENH groups (P>0.05). Seven of the 33 (21.2%)
patients achieved complete response (CR) (defined as serum HBV DNA level less than 500
copies/ml and undergone HBeAg seroconversion) after NA therapy for 48 weeks. Baseline
GGT levels were significantly higher in patients who did achieve vs. patients who did not
achieve CR (1.83±0.39 vs. 0.93±0.10 upper limit of normal (ULN) , P=0.018).
238
The decline of GGT levels was significantly more rapidly in the CR group after 12, 24
and 48 weeks of treatment compared with non-complete response (NCR) group (P<0.05,
P<0.01 and P<0.01, respectively). Based on the receiver operating characteristic (ROC)
curve, a cut-off of 0.89 × ULN of the baseline GGT had a sensitivity of 85.71% and a
specificity of 61.54% to predict the CR after 48 weeks of treatment.
Conclusions: The GGT levels varied significantly in different phases of chronic HBV
infection and elevated in EPH and ENH patients. GGT may be a biomarker for prediction
of subsequent HBeAg seroconversion in HBeAg-positive CHB with NA treatment. GGT
will provide additional information for monitoring and treating CHB patients in actual
clinical practice.
POSTER ABSTRACTS
Figure:
239
P85 - YI
ACCUMULATION OF PLATELETS IN THE LIVER MAY
BE AN IMPORTANT CONTRIBUTORY FACTOR TO LIVER
INJURY IN CHRONIC HEPATITIS B VIRUS INFECTION
Rui Huang1, Hongyan Wu2, Chenchen Yang3, Xiaomin Yan3,Yong Liu4,Yali Xiong3,
Ran Su3, Chao Wu3
1
Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional
Chinese and Western Medicine, Nanjing University of Chinese Medicine, 2Department of
Pathology, 3Department of Infectious Diseases, 4Department of Laboratory Medicine, Nanjing
Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
Introduction: Besides hemostatic properties, platelets have the features of inflammatory
cells. Platelets have been shown to be contributed to the pathogenesis of acute liver damage
of self-limited viral hepatitis and hepatitis B virus (HBV)-associated liver cancer in mouse
models. However, the association between the platelets and chronic HBV infection remains
largely unknown.
Aims: We tried to clarify whether an accumulation of platelets in the liver contributes to
liver injury and fibrosis in chronic HBV infection.
POSTER ABSTRACTS
Methodology: Fifty patients with chronic HBV infection who underwent liver biopsy were
included. Seventeen healthy liver tissue samples were obtained from donors whose livers were
used for transplantation. The platelets (marked by CD61) in the liver tissues were identified
by immunohistochemistry. Nonspecific inflammatory cells such as CD68+ macrophages
and monocytes in the liver of patients were also measured by immunohistochemical staining.
According to the modified histology activity index described by Scheuer, the degree of
hepatic inflammation and fibrosis of liver fibrosis in patients with chronic HBV infection
was graded.
Results: Patients with chronic HBV infection had a significantly more extensive CD61+
platelets in the liver tissues compared to healthy controls (74.68±7.38 vs. 18.69±2.59 /
HPF, P<0.001). Patients with chronic HBV infection with higher inflammatory grading
(G) scores had more CD61+ platelets in their livers compared to those with lower scores
(P<0.05). However, no association between liver platelets and fibrotic staging (S) scores was
found in the patients (P>0.05).
240
The platelets in the liver tissues were strongly positively correlated with the nonspecific
inflammatory cells such as CD68+ macrophages (r=0.625, P<0.0001) and MAC387+
monocytes (r=0.780, P<0.0001). The platelets in the liver tissues of patients with chronic
HBV infection were also positively correlated with alanine transaminase (r=0.325, P=0.023)
and total bilirubin levels (r=0.292, P=0.042).
Conclusions: The accumulation of platelets in the liver may be involved in hepatic injury
of patients with chronic HBV infection. Platelets may accumulate in the liver and take part
in the pathogenesis of the liver injury in chronic HBV infection through the mechanism
involving the nonspecific inflammatory cells such as macrophages and monocytes.
POSTER ABSTRACTS
Figure:
241
P86
EFFICACY OF PROPHYLACTIC ANTIVIRAL THERAPY IN
PREVENTING HEPATITIS DURING RITUXIMAB-BASED
CHEMOTHERAPY IN PATIENTS WITH LYMPHOMA AND
PRIOR RESOLVED HEPATITIS B
Winnie Yeo1, Elizabeth Pang2, Leung Li2, Hei WC Yip2,Wa Li2, Kenny IK Li2, Paul KS Chan3
1
Clinical Oncology, Chinese University of Hong Kong, Hong Kong, 2Clinical Oncology,
3
Microbiology, Chinese University of Hong Kong, Hong Kong, Hong Kong, China
Introduction: Hepatic impairment and hepatitis B virus (HBV) reactivation commonly
occurs in patients who are hepatitis B surface antigen (HBsAg) positive and undergoing
cytotoxic chemotherapy. For patient who have prior resolved HBV infection, as evident
by HBsAg negative/anti-HBc positive, the use of rituximab, an anti-CD20+ antibody, has
increased the risk of hepatitis and HBV reactivation.
Aims: To determine the efficacy of antiviral prophylaxis in preventing hepatitis and HBV
reactivation during rituximab-based chemotherapy in patients with lymphoma and resolved
hepatitis B.
POSTER ABSTRACTS
Methodology: In this retrospective study, consecutive patients who were diagnosed with
CD20+ non-Hodgkin’s lymphoma (NHL) in the year 2013 and who had resolved HBV
infection were reviewed. They were all commenced on R-CHOP combination chemotherapy
(consisting of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone)
and were started on antiviral agents (either lamivudine or entecavir) within the first 2 cycles
of R-CHOP. They were followed up for the incidence of hepatitis, upon which HBsAg and
HBV DNA was assessed to determine the incidence ofHBV reactivation. Hepatitis was
defined as an increase in alanine transaminase above the upper normal limit of institutional
normal (i.e. 58 iu/l).
Results: Twenty patients diagnosed with CD20+ NHL were found to be HBsAg negative/
anti-HBc positive; 16 had diffuse large B-cell lymphomas, 3 had follicular lymphomas
and 1 had MALT NHL. 18 patients received 6 cycles of R-CHOP, 1 received 7 cycles
and 1 had the omission of doxorubicin after 2 cycles (due to cardiotoxicity); 4 of the 20
patients received rituximab maintenance therapy after R-CHOP. Thirteen patients received
entecavir and 7 received lamivudine.
242
The antiviral therapy was continued throughout R-CHOP therapy. One patient had antiviral
agent discontinued 3 months after R-CHOP, the others were planned for and received a
minimum of 6 months of antiviral therapy, 11 patients are still currently on antiviral therapy.
At a median follow-up of 15.5 months, there was no incidence of hepatitis.
POSTER ABSTRACTS
Conclusions: Prophylactic antiviral can potentially prevent hepatitis during rituximabbased chemotherapy in patients who have NHL and evidence of resolved hepatitis B.
Further study is warranted to determine the optimal agent and the duration of antiviral
therapy. In particular, follow-up after discontinuation of the antivirals to further detect
HBV-related hepatitis is required.
243
P87
SEROPREVALENCE AND RISK FACTORS OF HEPATITIS
B VIRUS INFECTION IN BIRJAND, IRAN: A POPULATIONBASED STUDY
Masood Ziaee1, Gholam Reza Sharifzadeh1, Ghodsyeh azarkar1, Azadeh Ebrahimzadeh1,
Zohreh azarkar1, Mohammad Hasan NAMAEE1
1
Hepatitis Research Center, Birjand University of Medical Sciences, birjand, Iran
Introduction: Hepatitis B is a major global health problem and a potentially life-threatening
liver infection caused by hepatitis B virus.
Aims: Since information on its prevalence in general population is mandatory for formulating
effective policies, the current population-based serological survey was conducted in Birjand,
where no epidemiological data is available for determining the prevalence and risk factors
of HBV infection.
POSTER ABSTRACTS
Methodology: Using the cluster-sampling method, 4010 individuals living in Birjand were
studied. Data were collected by trained interviewers through validated questionnaires. The
age of participants ranged from 15 to 70 years. Serum samples were tested for HBcAb and
HBsAg through third generation ELISA screening tests. Various risk factors were recorded
and multivariate analysis was performed.
Results: Out of 4010 subjects, 2117 (52.8%) were female and 1893 (47.2%) were male,
with the mean age of 39.8 ±14.5 years. The prevalence of HBcAb and HBV markers were
14.7% and 1.3%, respectively. The prevalence of HBsAg was significantly higher in men
(1.6%), compared to female participants (1%) (OR: 1.68). The age groups had different
frequencies of HBcAb and HBV markers. The lowest and the highest positivity rates of
HBsAg (0.24%; 2.5%) and HBcAb (4%; 33.6%) were found in the age groups of <25
and > 65 years, respectively (P value =.03).The risk of infection in married individuals
was significantly higher than singles in cases, (OR:2.8).There was a significant relationship
between HBV infection and the history of major surgeries, blood transfusion, and war
injuries (P value =.01), while such relationships were not found between HBV infection
and the history of tattooing, imprisonment, injection drug use, and needle stick.
Conclusions: The study demonstrated a prevalence rate of 1% for HBsAg seropositivity in
Birjand. It was found that variables including gender and age were significantly associated with
HBsAg positivity. The lower prevalence of HBsAg positivity in the lower age groups is probably
due to success of the HBV infant vaccination program in Iran, which initiated in 1993.
244
P88 - YI
HBV GENOTYPES IN CHILDREN WITH CHRONIC
HEPATITIS B IN BELARUS
Yana Zinovich1, Elena Gasich2,Vladimir Eremin2, Anna Klyuchareva1, Mikalai Halabarodzka1
1
Pediatric Infectious Diseases Department, Belarusian Medical Academy of Post-Graduate
Education, 2Republican Center for Epidemiology and Microbiology, Minsk, Belarus
Introduction: Pediatric HBV-infection is getting uncommon in Belarus since routine
vaccination and mother-to-child transmission (MTCT) prophylaxis program were started
in 2000. But some children with chronic hepatitis B (CHB) are still observed in Republican
pediatric hepatology center.
Methodology: 36 children with CHB (16 females, 20 males, from 7 months to 15 years,
median age 4 years) were observed in Republican pediatric hepatology center, Belarus, in
2011-2013. 27 had vertically (MTCT) acquired HBV (no one received specific immune
globulin, 19 were not vaccinated at birth), 9 had horizontally acquired HBV. HBeAgpositive CHB had 30 children (11 in immune tolerant phase, 19 – in immune reactive
phase), HBeAg-negative CHB – 2, HBV carriage – 4. Plasma samples were tested for HBV
DNA concentration by real-time PCR (Rotor-Gene 3000, Amplisens HBV tests) and HBV
genotypes using sequencing analysis (ABI PRISM 3100-Avant Genetic Analyzer).
Results: Majority of children had HBV genotype D (83.3%): D1 genotype was detected
in 7 children (including 1 child with MTCT CHB), D2 – in 8 (4 with MTCT CHB), D3
– in 14 (1 with MTCT CHB), and D4 – in 1. Other genotypes were revealed: A2 – in 4
children (2 with MTCT CHB), and C2 – in 2 emigrants from Asia. No differences were
revealed in genotypes distribution by sex: D1 (2 females, 5 males), D2 (3 females, 5 males),
D3 (6 females, 8 males), D4 (1 female), A2 (2 females, 2 males), C2 (2 females). Low HBV
DNA concentration (<10,000 copies/ml) had only 1 child, with genotype D1. HBV DNA
concentration 10^9 copies/ml and more had 4 children with D3 genotype, 1 child with D1
genotype, and 1 child with D2 genotype.
Conclusions: HBV genotypes D, A and C were found in children with CHB in Belarus, the most
common genotype was D (83.3%). We have not found significant differences between different
genotype groups in sex, mode of transmission, HBV DNA concentration and phase of CHB.
245
POSTER ABSTRACTS
Aims: to describe genotypes of HBV in children with CHB in Belarus, and to compare
genotypes with patients’ demographic data and clinical picture of the disease.
P89
DEFINING NORMAL VALUES OF LIVER AND SPLEEN
STIFFNESS USING SHEAR WAVE ELASTOGRAPHY (SWE)
Pavlos Zoumpoulis1, Emanouil Manessis2, Maria Shina3, Irene Vafiadis4,
Eleni Panteleakou1, Irene Mastorakou5, Ioannis Theotokas1, Olga Karapanagiotou5,
Elias Gatos1, Ioannis Mathioudakis1, Georgios Mousoulis3
1
Diagnostic Echotomography SA, 2Euroclinic Athens, 3Evagelismos Hospital,
4
Laiko General Athens Hospital, 5Onassis Cardiac Surgery Center, Athens, Greece
Introduction: Defining normal values of liver and spleen stiffness using Shear Wave
Elastography (SWE)
Aims: To determine the normal range of Liver Stiffness (LS) and Spleen Stiffness (SS)
measured by Shear Wave Elastography (SWE) and the cutoff level between normal liver
and CLD.
POSTER ABSTRACTS
Methodology: 112 patients with CLD underwent US and Color Doppler of the liver, the
portal vein, the spleen and SWE of the liver and spleen. Normal group (n=65) was defined
as men and women 21 to 50 years old with body mass index < 25 and without any clinical
evidence of liver disease and normal laboratory and ultrasonographic findings.
Comparative groups were non-cirrhotic chronic liver disease (NCCLD; n=52) and liver
cirrhosis (LC; n=60) groups with various CLD, including viral hepatitis and alcoholic LD.
Results: In the normal group, mean value of LS was 4.4 ± 1.6 kPa (95% CI, 4.2-6.6 kPa)
and mean SD was 1.7 ± 0.5 kPa (95% CI, 1.5-1.7 kPa).
In the normal group the mean spleen stiffness (SS) was 9.6 ± 3.2 kPa (95% CI, 9,1-10,4 kPa).
In the NCCLD group mean LS were 9.4 ± 3.94 kPa (95% CI, 7.8-9.9 kPa).
In the LC group the LS were 18.7 ± 8.9 kPa (95% CI, 15.9-21.7 kPa).
SD were 2.35 ± 1.49 kPa (95% CI, 1.96-2.74 kPa) in NCCLD and 7.37 ± 2.06 kPa (95%
CI, 4.74-10.01 kPa) in LC.
Conclusions: The range of Liver Stiffness in the normal group was 4.2 to 6.6 kPa and for
Spleen Stiffness was 9,1 to 10,4 kPa.
246
P90
FIBROSIS QUANTIFICATION IN CHRONIC LIVER DISEASE
(CLD): A PROSPECTIVE STUDY COMPARING TWO
ELASTOGRAPHIC METHODS: VIBRATION CONTROLLED
TRANSIENT ELASTOGRAPHY (VCTE-FIBROSCAN) AND
SHEARWAVE ELASTOGRAPHY (SWE)
Pavlos Zoumpoulis1, Irene Vafiadis2, Irene Mastorakou3, Ioannis Theotokas1,
Olga Karapanagiotou3, Elias Gatos1, Ioannis Mathioudakis1, Dimitrios Karagiannakis4
1
Diagnostic Echotomography SA, 2Laiko General Athens Hospital, 3Onassis Cardiac Surgery
Center, 4Iaso General Hospital, Athens, Greece
Introduction: Fibrosis quantification in Chronic Liver Disease (CLD): A prospective
study comparing two elastographic methods: Vibration Controlled Transient Elastography
(VCTE-Fibroscan) and ShearWave Elastography (SWE)
Aims: To assess two different methods of liver elastography in the study of tissue stiffness
in CLD.
Results: A statistically significant difference (p<0,01) between the elastography values of
normal and subjects with CLD, both with VCTE and SWE, were observed. There was a
good correlation between the two methods and each one with LB. Intra- and inter-observer
variability was low with both methods.
VCTE showed 82.3% sensitivity and 68.2% specificity in diagnosing liver cirrhosis (LC) at
a cut-off value of 11.9 kPa.
SWE showed 88.5% sensitivity and 74.2% specificity in diagnosing LC at a cut-off value
of 12.8 kPa.
Conclusions: VCTE and SWE succeed to differentiate normal liver from LF. SWE can
differentiate between F1-F2 stages of LF and F3-F4 stages better than VCTE. Further
work is needed to investigate whether VCTE and SWE could discriminate various stages
(F1,2,3,4) of LF.
247
POSTER ABSTRACTS
Methodology: Normal (N1=52) and a population in different stages of CLD (N2=112),
verified by blood tests for liver fibrosis (LF), US examination and liver biopsy (LB)(72
patients) were included.
Assessment of LF with VCTE and SWE was carried out.
Four measurements were made by two examiners with each method. The findings were
compared for LF staging using LB.
FEB. 5-7, 2015, LAUSANNE, SWITZERLAND
COURSE 10:
Molecular biology
and pathogenesis of
hepatitis viruses
Course Directors
Darius Moradpour, Switzerland
Fabien Zoulim, France
For the scientific programme, online applications,
and further information please visit:
www.easl.eu/_events
AP
www.easl.eu
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11, D
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OPTIMAL MANAGEMENT OF HEPATITIS B VIRUS INFECTION

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