BHIVA - Patrick Kennedy

BHIVA ANNUAL MEETING 2016
BHIVA Hepatology highlights
Chronic hepatitis B: Role of new agents & future management strategies
Patrick T. F. Kennedy
Senior Lecturer & Honorary Consultant Hepatologist
Blizard Institute, Barts and The London SMD, QMUL, London
Chronic HBV Infection
350 million people worldwide with CHB
>600,000 deaths per year
80% of deaths in those infected at birth/early childhood
25% of those infected in childhood develop cirrhosis or HCC
Chronic HBV Infection
Locarnini & Zoulim, Anitvir Ther 2010
Chronic HBV Infection
NUC target
Locarnini & Zoulim, Anitvir Ther 2010
Chronic HBV Infection
NUC target
Ideal therapy
target
Locarnini & Zoulim, Anitvir Ther 2010
Unmet Challenges in CHB
• Strategies to achieve HBsAg loss and ‘cure’
• Understanding natural history of CHB
• Reducing risk of HCC
How can these be addressed?
HEPATITIS B RESEARCH UK
(HBV RUK)
How can these be addressed?
HEPATITIS B RESEARCH UK
(HBV RUK)
•
•
•
•
Consortium for Hepatitis B Research
UK network
Benefit academia and industry
Serve the best interests of patients, the NHS and science to improve prevention, diagnosis and management of CHB
HBV RUK DOMAINS
• Epidemiology
• Molecular & Diagnostic Virology
• Viral Immunology
• Clinical Hepatology
HBV RUK DOMAINS
• Epidemiology
• Molecular & Diagnostic Virology
• Viral Immunology
• Clinical Hepatology
Natural history & disease phase
Better definitions of disease phase
Gill & Kennedy;; Clin Med 2015 Is our current understanding of natural history & disease phase accurate?
Does this implicate on disease management?
Is our current understanding of natural history & disease phase accurate?
How does this impact disease management?
Evidence of immune activity in the ‘immune tolerant’ disease phase
10
P<0.001
6
4
4
2
0
0
CA<30
HC<30
P<0.001
6
2
IT
P<0.001
8
% P D-­‐1+ CD4 T cells
8
%PD-­‐1+ CD8 T cells
10
P<0.001
IT
CA<30
HC<30
Kennedy et al., Gastroenterology 2012
18
P = .006
14
10
6
4
2
0
0
20
40
Age (Years)
60
80
% CD127low PD1+ CD4 T cells
% CD127low PD1+ CD8 T cells
Evidence of immune activity in the ‘immune tolerant’ disease phase
8
P = .4383
6
4
2
0
0
20
40
60
80
Age (Years)
Kennedy et al., Gastroenterology 2012
Evidence of liver damage in the ‘immune tolerant’ disease phase
SIRIUS RED STAIN (COLLAGEN)
HBeAg Positive;; HBeAb Negative
ALT 39;; HBV DNA 9.71 log IU/ml
HBsAg 145,138 IU/ml (5.16 log IU/ml)
HBeAg Positive;; HBeAb Negative
ALT 159;; HBV DNA 7.98 log IU/ml
HBsAg 1,053 IU/ml (3.02 log IU/ml)
Mason/Kennedy et al., Manuscript in preparation
Evidence of liver damage in the ‘immune tolerant’ disease phase
SIRIUS RED STAIN (COLLAGEN)
HBeAg Positive;; HBeAb Negative
ALT 40;; HBV DNA 8.66 log IU/ml
HBsAg 22,916 IU/ml (4.56 log IU/ml)
HBeAg Positive;; HBeAb Negative
ALT 159;; HBV DNA 7.98 log IU/ml
HBsAg 1,053 IU/ml (3.02 log IU/ml)
Mason/Kennedy et al., Manuscript in preparation
Nuclear core positive hepatocytes differentiate ‘immune tolerant’ disease
HB NUCLEAR CORE STAINING
IMMUNE TOLERANT DISEASE
IMMUNE ACTIVE DISEASE
Mason/Kennedy et al., Manuscript in preparation
Clonal hepatocyte expansion
Mason/Kennedy et al., Manuscript in preparation
Redefining disease phase in CHB
Immune Tolerance
Non-Inflammatory
Immune Clearance
Inflammatory
Bertoletti & Kennedy, Cell & Mol.Immunol 2014
The role of quantitative HBsAg
•Assessment of on-­treatment response
– Peg-­IFN stopping rules
•Inverse correlation with fibrosis stage in HBeAg positive disease
-­ Defining the true ‘immune-­tolerant’ patient
•Defining the ‘low-­risk’ inactive carrier state;;
-­ Reduced risk of disease progression & HCC
Natural History & qHBsAg
•Assessment of on-­treatment response
-­ Peg-­IFN stopping rules
•Inverse correlation with fibrosis stage in HBeAg positive disease
-­Defining the true ‘immune-­tolerant’ patient
•Defining the ‘low-­risk’ inactive carrier state;;
-­Reduced risk of disease progression
-­Reduced risk of HBV related HCC
Natural History & qHBsAg
•Assessment of on-­treatment response
-­ Peg-­IFN stopping rules
•Inverse correlation with fibrosis stage in HBeAg positive disease
-­Defining the true ‘immune-­tolerant’ patient
•Defining the ‘low-­risk’ inactive carrier state;;
-­Reduced risk of disease progression
-­Reduced risk of HBV related HCC
HBsAg in Immune Tolerant Disease
p=0.04
qHBsAg level (IU/ml)
qHBsAg level (IU/ml)
200000
150000
100000
50000
600000
400000
200000
rs =0.06
p=0.04
100000
80000
60000
40000
20000
0
2-­6
0-­1
Ishak fibrosis stage
0
0
1
2
3
4
5
6
Ishak fibrosis stage
Hansi et al., Unpublished
Natural History & qHBsAg
•Assessment of on-­treatment response
-­ Peg-­IFN stopping rules
•Inverse correlation with fibrosis stage in HBeAg positive disease
-­Defining the true ‘immune-­tolerant’ patient
•Defining the ‘low-­risk’ inactive carrier state;;
-­Reduced risk of disease progression
-­Reduced risk of HBV related HCC
Natural History & qHBsAg
HBeAg Negative Disease – Inactive Carrier phase
10000
5000
0
30000
p=0.003
qHBsAg level (IU/ml)
qHBsAg level (IU/ml)
15000
>30
≤30
Patient Age (years)
rs=0.03
p=0.006
20000
15000
10000
5000
0
10
20
30
40
50
60
Patient Age (years)
Hansi et al., Unpublished
Monitoring in CHB (NIHR RfPB grant)
Treatment & management strategies
Treatment sequence in CHB
• PegIFN x 48 weeks (1st line)
• Tenofovir (2nd line treatment)
• Entecavir (alternative 2nd line
for those who cannot tolerate
TDF or contraindicated)
• Application
of
Peg-­IFN
stopping rules to switch to
NUC
Current Treatment Regimes
NUCs
PegIFN-­α
-­ Excellent viral suppression
-­Immunomodulatory agent
-­ Long term therapy
-­HBsAg decline or loss
-­ High barrier to resistance
-­Moderate rate of relapse
-­ Limited HBsAg reduction
-­Finite therapy
-­ ? Treatment endpoints
-­Use of stopping rules
HBV Treatment regimes
Nucleos(t)ide Analogues (NUCs)
TENOFOVIR
ENTECAVIR
Marcellin et al, Lancet 2015;; Chang, et al. Hepatology 2010
Current therapies are non-­curative
• Peg-­IFN sustained immune control, but only in a minority of patients1
• HBeAg-­negative & positive disease: – limited decline in HBsAg during NUC monotherapy2
• Long-­term viral suppression is achieved, but sustained immune control following treatment cessation is limited3
1. EASL guidelines. J Hepatol 2012;;57:167–85;; 2. Z outendijk R, et al. J Infect Dis 2011;;204(3):415–8;; 3. Hadziyannis SJ, et al. Gastroenterology 2012;;143:629–36.
Cytotoxic capacity & effector function of CD56bright NK cells is maintained on sequential NUC therapy ***
***
50
40
30
20
10
70
60
50
40
30
20
10
Pre-­Treatment PEG-­IFNα Sequential NUC
30.2
29.7
CD107
* p=<0.05;; ** p=<0.01;; *** p=<0.001
CD56
CD56
Pre-­Treatment PEG-­IFNα Sequential NUC
13.0
ns
***
ns
IFNγ+ CD56bright NK cells (%)
CD107+ CD56bright NK cells (%)
*
6.3
53.2
69.1
IFNγ
Gill et al., submitted
60
40
20
80
60
40
20
0
0
60
40
50
40
30
20
10
NKp46+ CD56bright NK cells (%)
80
100
IFNγ+ CD56bright NK cells (%)
NKp44+ CD56bright NK cells (%)
100
CD107+ CD56bright NK cells (%)
TRAIL+ CD56bright NK cells (%)
NKp30+ CD56bright NK cells (%)
Phenotypic & functional capacity of CD56bright NK cells is greater on sequential NUCs compared to de novo NUC therapy & PegIFNα only therapy
30
20
10
0
0
Peg-IFNα therapy
(EoT)
100
80
60
40
20
0
40
30
20
10
0
Sequential
NUC
de novo
NUC
9-12m post Peg-IFNα
(no further therapy)
Decline in HBsAg is greater with sequential NUC therapy
n=9
n=12
Sequential NUC
de novo NUC
Gill et al., submitted
* p=<0.05;; ** p=<0.01;; *** p=<0.001
Decline in HBsAg is greater with sequential NUC therapy
n=9
n=30
n=12
Sequential NUC
n=28
de novo NUC
Gill et al., submitted
* p=<0.05;; ** p=<0.01;; *** p=<0.001
Novel Strategies for HBsAg loss
Bertoletti & Rivino, Curr Opin Infect Dis., 2014
Future drug targets for HBV therapies
Tenofovir alafenamide (TAF)
• Non-­inferiority to TDF in treatment naive & experienced HBeAg+ Pts
• Similar rates of HBeAg loss/seroconv
• High levels of ALT normalisation
• No resistance reported
Tenofovir alafenamide (TAF)
• Safe & well tolerated
• Significantly less changes in markers of bone mineral loss
• Improvement in renal tubular function
SUMMARY
• Better understanding of clinical phenotypes & natural
history of CHB is central to better treatment outcomes
• Long term on-­treatment viral suppression is standard of
care – but suboptimal
• Strategies to target cccDNA & achieve global immune
restoration will be critical to delivering cure in CHB
Progression of NAFLD
30% of population has NAFLD
10% of NAFLD develop NASH
25% of NASH develop cirrhosis
10 -­ 25% of cirrhosis develop HCC
Siegel & Zhu 2009
Non-­Alcoholic Fatty Liver Disease
FAT
INFLAMMATION
Management of NAFLD
• Mgt of metabolic syndrome:
– Correct hyperlipidaemia
• Diet & Exercise
• Statins – monitor change from baseline
• Glitazones – not soundly proven – Other CV risk factors
• Hypertension
• Smoking cessation
– Insulin Resistance & optimise diabetes control
ACKNOWLEDGEMENTS
Fox Chase Cancer Centre
Samuel Litwin
William Mason
Rayne Institute, UCL
Dimitra Peppa, Lorenzo Micco, Harsimran D. Singh,
Mala K. Maini
ILS, Kings College
Oltin Pop, Ivana Carey
Alberto Quaglia
Blizard Institute, QMUL
Graham Foster
Jyoti Hansi
Uppy Gill
Duke, NUS/SICS A* Star
Elena Sandalova, Laura Rivino,
Nina Le Bert, Evan Newell
Antonio Bertoletti