La terapia dell`epatite B

Paulilatino 13 marzo 2015
STOPPING RULE BASATO SUL
MONITORAGGIO QUANTITATIVO
DELL’HBsAg
Luchino Chessa
Centro per lo Studio delle Malattie del Fegato
Dipartimento di Scienze Mediche M.Aresu Università di Cagliari
Azienda Ospedaliero-Universitaria di Cagliari
1
Hepatitis B
In the world
2000 milion infected
400 milion with chronic infection
4 milion of new infection
Cause of 35% of liver cirrhosis and 53% of HCC
Over 500000 deaths per year
8 genotypes
with different
outcome and
response to
therapy
In Italy
500000 carriers
(low andemiticy)
Shepard CW et al. Epidemiol Rev, 2006; Custer B et al, J Clin Gastroenterol, 2004; Lavanchy D, J Viral Hepat, 2004; Perz
JF, J Hepatol, 2006, Lock AS et al, Hepatology, 2007; Hoofnagle JH, Hepatology, 2007; Lock AS et al, Hepatology2009 2
Not all patients
have progressive
disease
No further
progression
Normal liver
HCC
Chronic
hepatitis B
Cirrhosis
HBV-related ESLD or HCC are responsible for
> 0.5-1 million deaths per yr and currently represent
5% to 10% of cases of liver transplantation
EASL. J Hepatol. 2012;57:167-185.
ESLD
In
the natural history of HBV
In
PEG-IFN and NUC therapy
In
new therapeutic approaches
4
Evidence of association between HBsAg levels and
cccDNA present in the nuclei of hepatocytes
Werle-Lapostolle B et al, Gastroenterology, 2004
5
HBsAg levels may reflect the expression of HBV in
the liver and predict the response to antiviral
therapy
 Serum HBsAg levels correlate well with the cccDNA and
intrahepatic HBV DNA
 Low pretreatment HBsAg is better than HBV DNA to
predict good response to peginterferon and lamivudine
treatment
Chan HL et al Clin Gastroenterol Hepatol, 2007
6
IU/ml (1 unit = 1-10 ng/ml)
Burdino E et al, J Clin Virol, 2014
7
Chan HL-Y et al, J Hepatol, 2011
8
To monitor the natural history of
HBV
As a predictor factor at the
baseline and during antiviral
therapy
Chan HL-Y et al, J Hepatol, 2011
9
Low HBsAg and HBV DNA levels are an indicator of immune control
Chan et al. Hepatology 2010; Nguyen et al. J Hepatol 2010; Jaroszewicz et al. J Hepatol 2010
10
Higher HBsAg levels during the immune tolerance
phase than during the immune clearance phase
cohort
Immune tolerance
phase
Immune clearance
phase
European (1)
4.96 log IU/ml
4.37 log IU/ml
Asiatic (2)
4.53 log IU/ml
4.03 log IU/ml
1) Jaroszewicz J et al, J Hepatol, 2010 ; 2) Niguyen T et al, J Hepatol, 2010; Moucari R et al, Antivir Ther, 2009
11
HBsAg levels
HBV DNA levels
<1000 IU/mL plus
<2000 IU/mL
Population
209
Sensitivity (%)
91.1
Specificity (%)
95.4
PPV (%)
87.9
NPV (%)
96.7
Diagnostic accuracy (%)
94.5
This provides comparable information to 1-year of
monthly monitoring
Brunetto MR et al, Gastroenterology, 2010
12
 In the follow-up of acute hepatitis
 In the evaluation of HCC risk in untreated patients
 In the monitoring of Delta infection
13
In
the natural history of HBV
In
PEG-IFN and NUC therapy
In
new therapeutic approaches
14
15
PEG-IFN alfa2a
Immunological control
Finite treatment
NUC
Viral inibition
Long term treatment
16
PEG-IFN alfa
 If the criteria for the use of PEG-INF
are not satisfied
 In the case of controindications
 In the case of tolerance
NUC
17
NUC
At baseline
During therapy
PEG-IFN
HBV DNA ≤ 107 UI/ml, ALT > 3ULN, necroinflammation activity
≥ A2 by Metavir
Genotypes A e D
More HBsAg clearances
Genotypes A e B are better than
CeD
HBV DNA NR at week 24 e 48
More anti-Hbe seroconvertson
HBV DNA < 20000 UI/ml at
week 12:
50% anti-Hbe seroconversion
50% sustained response in
HBeAg negative patients
HBeAg decline at week 24 is
predictive of anti-Hbe
seroconversion
Perrillo RP et al, NEJM, 1990; Wong DK, et al, Ann Inter Med, 1993; Perrillo RP et al, Hepatology, 2002; Flink
HJ et al, Am J Gastroenterol, 2006, Hadziyannis SJ, et al, Gastroenterology, 2006, Lai CL, et al, NEJM, 2007,
Yuen MF et al, Hepatology, 2007; Zoulim F et al, Hepatology, 2008; EASL Clinical Practice Guideliness:
managment of chronic hepatitis B viurs. Hepatology, 2012
18
 PEG-IFN therapy or NUC therapy
 HBeAg status
Which is the purpose?
To identify
Good responders
Stopping rules
19
PEG-IFN therapy
Which is the purpose?
To identify
Good responders
Stopping rules
20
PEG-IFN therapy
Which is the purpose?
At the baseline
21
A retrospective analysis used data from
263 HBeAg-negative CHB patients who
received PegIFN alfa-2a 180 mg/week ±
lamivudine for 48 weeks in 2 large studies
http:/www.hbvpredictor.it
Lampertico P et al. A baseline preditive tool for
selecting HNeAg-negative chronic hepatitis B
patients who have high probability of achieving
sustained immune controll with peginterferon
alfa2a. Hepatolgy 2014;60:1107A
22
Sex
Genotipo A
HBsAg (IU/ml)
Female
Male
Yes
No
≥ 20000
< 20000
ALT ULN
< 1.5
≥ 1.5 < 4
≥ 4
HBV DNA (LogIU/ml)
≥ 10
≥ 8< 10
<8
http:/www.hbvpredictor.it
23
Sex
Genotipo A
HBsAg (IU/ml)
Female
Male
Yes
No
≥ 20000
< 20000
ALT ULN
< 1.5
≥ 1.5 < 4
≥ 4
HBV DNA (LogIU/ml)
≥ 10
≥ 8< 10
<8
No good responder!!
HBV DNA < 2000 IU/ml:
HBeAg seroconversion:
Combined response:
7%
7%
4.7%
http:/www.hbvpredictor.it
24
Sex
Genotipo A
HBsAg (IU/ml)
Female
Male
Yes
No
≥ 20000
< 20000
ALT ULN
< 1.5
≥ 1.5 < 4
≥ 4
HBV DNA (LogIU/ml)
≥ 10
≥ 8< 10
<8
Good responder!!
HBV DNA < 2000 IU/ml:
HBeAg seroconversion:
Combined response:
72.7%
81.8%
63.6%
http:/www.hbvpredictor.it
25
Genotipo C
Yes
Age (years)
>45
≥ 45≤ 30
< 30
HBsAg (IU/ml)
≥ 3500
< 3500 ≥ 1000
< 1000
ALT (IU/L)
≥5
HBV DNA (IU/ml)
< 250000
http:/www.hbvpredictor.it
No
<5
≥ 250000
Lampertico P et al. Hepatolgy 2014;60:1107A
26
Genotipo C
Yes
Age (years)
>45
≥ 45≤ 30
< 30
HBsAg (IU/ml)
≥ 3500
< 3500 ≥ 1000
< 1000
ALT (IU/L)
≥5
HBV DNA (IU/ml)
No
<5
< 250000
≥ 250000
No good responder!!
HBV DNA < 2000 IU/ml:
HBV DNA < 2000 IU/ml and normal ALT:
http:/www.hbvpredictor.it
10.8%
8.4%
Lampertico P et al. Hepatolgy 2014;60:1107A
27
Genotipo C
Yes
Age (years)
>45
≥ 45≤ 30
< 30
HBsAg (IU/ml)
≥ 3500
< 3500 ≥ 1000
< 1000
ALT (IU/L
≥5
HBV DNA (IU/ml)
No
<5
< 250000
≥ 250000
Good responder!!
HBV DNA < 2000 IU/ml:
HBV DNA < 2000 IU/ml and normal ALT:
http:/www.hbvpredictor.it
60.8%
45.1%
Lampertico P et al. Hepatolgy 2014;60:1107A
28
PEG-IFN therapy
Which is the purpose?
During therapy
29
Who is the good responder?
HBeAg positive
HBeAg negative
•At week 12 and 24
•HBsAg <1500 IU/ml
•At week 12 and 24 (g D)
•A decline of HBsAg≥10%
47-57% Positive Predictive Values
Piratvisuth T, et al. APASL 2010; Piratvisuth T et al. Hepatol Int 2011; Liaw et al. Hepatology 2011; Gane
E et al. J Hepatol 2011; Marcellin et al, APASL 2010; Lampertico et al. EASL 2012 ; EASL Clinical
Practice Guideliness: managment of chronic hepatitis B viurs. Hepatology, 2012
30
Stopping rule
HBeAg positive
•
•
At Week 12
• No decline of HBsAg (g A,D)
• HBV DNA> 20000 IU/ml (g B,C)
At week 24
• HBsAg > 20000 IU/ml (g AB,C,D)
HBeAg negative
•
At Week 12 (g D)
• No decline of HBsAg and
HBV DNA decline < 2 log
97-100% Negative Predictive Values
Sonneveld et al. Hepatology 2010; Piratvisuth et al. APASL 2010; Liaw et al. Hepatology 2011;
Gane E et al. J Hepatol 2011; Sonneveld et al., AASLD 2012 ; Brunetto MR et al, Hepatology, 2009,
Maucari R et al , Hepatology, 2009; Masucari R et al, Antiviral Ther, 2009; Rijckborst et al.
Hepatology 2010 ;Rijckborst et al. J Hepatol 2012; Lampertico et al. J Hepatol 2012; EASL Clinical
31
Practice Guideliness: managment of chronic hepatitis B viurs. Hepatology, 2012
NUC therapy
Which is the purpose?
To identify
Good responders
Stopping rules
32
 There are few studies, mostly retrospective, and with
heterogeneous cohorts
 HBsAg decline is less evident and does not correlate with
HBV DNA levels
 HBsAg decline may identify patients who will have antiHbe seroconversion and HBsAg loss
Lee JM et al, Hepatology, 2011; Marcellin P et al, J Hepatol, 2011; Fasaro M et al, J Hepatol, 2012; Chevaliez S et al,
Clin Res Hepatol Gastroenterol, 2013; Chavaliez S et al, J Hepatol, 2013
33
In our study, HBsAg kinetics during the first 6 months of therapy was not investigated, however,
a decline of serum HBsAg levels in patients maintaining virological response was noted, which
would appear to indicate that HBsAg measurement could be a tool to identify patients likely to
profit from continuing therapy, although no positive predictors of HBsAg clearance could be
identified.
Fasaro M et al, J Hepatol, 2012
34
Lee JM et al, Hepatology, 2011
35
VR: HBV DNA < 50 U/ml a 24 mes
Lee JM et al, Hepatology, 2011
36
1. The basal levels of HBsAg and HBeAg decline during
treatment in HBeAg positive patients are useful for
predicting the virologic response and to the sustained
response.
2. Further studies are necessary to explore the association
between HBsAg, HBeAg, and HBV DNA in patients
receiving antiviral therapy
Lee JM et al, Hepatology, 2011
37
Heathcot EJ et al, Gatstroenterology, 2011
38
Studio 102
HBeAg-
Studio 103
HBeAg+
HBeAg positive patients treated with tenofovir who had the
clearance of HBsAg showed a decline of HBsAg at week 24
higher than patients who did not have clearance (2:41 log10
IU / mL vs 0:20 log10 IU / mL)
Heathcot EJ et al, Gatstroenterology, 2011
39
Patients with chronic hepatitis B receiving different schedules of
nucleoside/nucleotide analogues were followed for a median
duration of 102 months, i.e., 8.5 years (interquartile range: 88–119
months).
Long-term HBV DNA and HBsAg level kinetics were modeled in
order to estimate time to clear HBsAg during therapy in patients
with undetectable HBV DNA.
Chavaliez S et al, J Hepatol, 2013
40
Our results showed a progressive reduction of HBsAg levels
in the majority of patients who achieved undetectable HBV
DNA during therapy
We projected the median number of years required to clear
HBsAg (excluding patients without an HBsAg level decline)
at 52.2 years
Conclusions: This study, based on the very long-term follow-up
of patients with chronic hepatitis B treated with potent
nucleoside/nucleotide analogues, shows that HBsAg clearance
is unlikely to occur during the patient’s lifetime, even if HBV
replication is well controlled. Thus, lifetime therapy is required
in the vast majority of HBV-infected patients.
Chavaliez S et al, J Hepatol, 2013
41





29 patients with HBeAg chronic hepatitis B
20 males and 9 females
Mean age 50 years (SD±9)
Duration of disease 45 years (SD±9)
All patients were treated with PEG-IFN alfa 2a 180
mcrg/week for 48 weeks
 9 patients (31%) were responders (normal ALT and HBV
DNA < 2000 IU/ml) after a follow-up of 24 months
 5 patients (17,2%) loss HBsAg with anti-HBs seroconversion
42
Totals
(29)
Non Responders
(20)
Responders
(9)
Clearance
(5)
HBsAg decline ≥ 10 at
week 12 n.a.(%)
3 (10.3)
2 (10)
1 (11,1)
0
HBsAg decline ≥ 10 at
week 24 n.a. (%)
10 (34.5)
6 (30)
4 (44,4)
2 (40)
43
No decline in HBsAg + decline
in HBV DNA <2 log n.a. (%)
Totals
(29)
Non
Responders
(20)
Responders
(9)
Clearance
(5)
13 (44,8)
9 (45)
4 (44,4)
3 (60)
44
HBsAg (Abbot Architect)
HBV DNA (Cobas AmpliPrep/Cobas TaqMan 48 Roche < 12 UI/ml)
45
HBsAg (Abbot Architect)
HBV DNA (Cobas AmpliPrep/Cobas TaqMan 48 Roche < 12 UI/ml)
46
HBsAg (Abbot Architect)
HBV DNA (Cobas AmpliPrep/Cobas TaqMan 48 Roche < 12 UI/ml)
47
Is qHBsAg useful?
 qHBsAg is useful to discriminate between active and
inactive carriers of HBV infection
 qHBsAg may be useful in HBeAg positive patients
treated with PEG-IFN alfa at week 12
 Decline below 1500 IU/ml as positive predictive factor
 HBV DNA over 20000 IU/ml as negative predictive
factor
 qHBsAg may be useful in HBeAg positive patients
treated with NUC
 Decline as positive predictive factor
48
Is qHBsAg useful?
 qHBsAg may be useful in HBeAg negative patients
treated with PEG IFN alfa is useful to discriminate
 Decline at 12 and 24 week below 10% as a positive
predictor factor
 No decline combined with HBVDNA < 2 log at 12
week as negative predictor factor and as the main
stoppig rule
 There are a few recommendations about the use of
qHBsAg in HBeAg negative patients treated with NUC
49
 qHBsAg is a cheap marker of cccDNA activity
 qHBsAg may be useful in some clinical applications:
from natural history to antiviral therapy with PEG IFN
or NUC
 Very interesting the use of qHBsAg in the HBV predictor
score (www.hbvpredictor.it)
 In the future qHBsAg could be useful in new approaches
such as PEG IFN and NUC combo or new antiviral
molecules
sodium taurocholate
cotransporting polypeptide
(NTCP)
50
Centro per lo Studio delle Malattie del Fegato
Dipartimento di Scienze Mediche M.Aresu Università di Cagliari
Azienda Ospedaliero-Universitaria di Cagliari
Medici strutturati
Cinzia Balestrieri
Luchino Chessa
Maria Conti
Giancarlo Serra
Tecnici di Laboratorio
Lucia Barca
Carmen Delrio
Giuseppina Palmieri
Rosetta Scioscia
Medici specializzandi
Michele Casale
Stefania Casu
Francesco Figorilli
Simona Onali
M.Cristina Pasetto
Laura Matta
Infermieri
Antonio Saba
Adelaide Tolu
51