1. Choice of CHB treatment and predictors of outcome
George Lau
MBBS (HK), MRCP(UK), FHKCP, FHKAM (GI), MD(HK), FRCP (Edin, Lond), FAASLD (US)
Chair Professor & Co-Director
Liver Disease & Transplant Centre, The Fifth Medical Centre of Chinese PLA General Hospital – Humanity & Health Medical Group, Beijing, China
Chairman
Humanity and Health Medical Group, Hong Kong, HKSAR, China
Consultant in Gastroenterology & Hepatology
Humanity and Health Clinical Trial Centre, Hong Kong, HKSAR, China

2. Goals of HBV Treatment 3.4.1 Global eradication
Vaccination, treatment and prevention of transmisssion. [A1]
3.4.2 Goal of therapy
To improve quality of life and survival
by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end-stage liver disease, HCC and death; and prevention of transmission of HBV to others. [A1]
APASL guidelines on the management of hepatitis B: a 2015 update Hepatology International 2015

3. Current treatment

4. HBV treatment registered by 2019
2001
Discovery
telbivudine
2008
Tenofovir
licensed
1990
Discovery
PMEA
1957
Discovery
interferon
2005
Peginterferon ⍺-2a/b
licensed
1998
Discovery
entecavir
1991
Discovery
Iamivudine (3TC)
1991
Interferon alfa-2b
licensed
2003
Adefovir dipivoxil (PMEA prodrug) licensed
2007
Telbivudine licensed
1999
Lamivudine (3TC) licensed
2006
Entecavir licensed
2015
TAF licensed

5. Endpoints of CHB used for regulatory approval of anti-HBV therapy
Surrogate endpoints
Ultimate endpoints
Undetectable HBV DNA
HBeAg seroconversion
HBsAg reduction/loss or seroconversion
Reduce liver-related morbidity & mortality
HCC
Mainly ACLF
End-staged liver cirrhosis

6. Algorithm showing guideline recommendations for the treatment of patients with HBeAg-positive CHB
Chen GF, Wang C, Lau G. Liver Int. 2017;37;1:59-66

7. Algorithm showing guideline recommendations for the treatment of patients with HBeAg-negative CHB
Chen GF, Wang C, Lau G. Liver Int. 2017;37;1:59-66

8. Risk of HCC after HBsAg seroclearance
Systematic review:
Risk of HCC after HBsAg seroclearance
28 studies, 105,111 pts
7656 HBsAg spontaneous clearance 1248 IFN or NA induced HBsAg clearance
Risk of HCC:
HBsAg positive Vs HBsAg clearance
6.56% Vs 1.86%
Risk factors included:
Cirrhosis, Male, age ≥ 50 year at
HBsAg seroclearance
Kuang XJ, et al. J Viral Hepat. 2018;25(9):

9. Factor associated with HBsAg seroclearance rate
34 studies, 42,588 patients, 303,754 person-years of follow-up
and 3194 HBsAg seroclearance events
The annual HBsAg seroclearance rate was 1.02%(95%CI: )
Lower baseline HBsAg, qHBsAg, HBeAg negative were associated
with significant higher rate of HBsAg seroclearance rate
Yeo YH, at al. Gastroenterology. 2019;156(3):

10. PEG-IFN therapy

11. HBsAg loss to monotherapies and combination therapy in CHB patients.

12. Identify responders
Brunetto, M. R. et al. Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology 49 , 1141–1150 (2009).
Marcellin, P. et al. Hepatitis B surface antigen levels: association with 5-year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients. Hepatol. Int. 7, 88–97 (2013).
Peng, C. Y. et al. Early serum HBsAg level as a strong predictor of sustained response to peginterferon alfa- 2a in HBeAg-negative chronic hepatitis B. Aliment. Pharmacol. Ther. 35, 458–468 (2012).

13. HBsAg kinetic: 3 years long term response to PEG-IFN therapy in HBeAg-Negative CHB
Decline >1 log IU/ml or <10 IU/ml at EOT : HBsAg loss in 3 years: 30% or 52%
Brunetto MR. et al. Hepatology. 2009;49(4):

14. HBsAg kinetic: 5 years long term response to PEG-IFN therapy in HBeAg-Negative CHB
Decline >10% by week 12 or 24:
HBsAg loss in 5 years: 22.6% or 22.4%
Marcellin P. et al. Hepatol Int. 2013;7(1):88-97.

15. Early HBsAg decline: a strong predictor of SVR to Peg-IFN treatment in HBeAg negative CHB
<150 by week 12: Predict response: PPV 86%, NPV 85%
Lee IC, et al. J Infect Dis. 2018;218(7):

16. Early HBsAg drop: Strong predictor of SVR
to peg-IFNin HBeAg-negative patients
The distribution of HBV genotype was: A, 27%; B, 17%; C, 12%; D, 29%; and E,14%.
Moucari R. et al. Hepatology Apr;49(4):

17. Stopping rules

18. Stopping rule at week 12 using HBsAg+HBV DNA in HBeAg-Negative CHB patient receiving PEG-IFN therapy
Early stopping rule: if combined with
HBV DNA level decline <2 log by week 12, NPV 100%
Rijckborst V. et al. J Hepatol May;56(5):

19. Predictive role of serum HBsAg and HBcrAg kinetics
in HBeAg-Negative CHB patient receiving PEG-IFN
Quantitative HBcrAg was significantly associated
with cccDNA in HBeAg negative CHB.
HBcrAg+HBsAg, could identify patients with low
probability of PVR and HBsAg clearance in long-term follow-up.
<0.5 log10 decline by week 12: NPV = 90%
Lee IC, et al. J Infect Dis Aug 24;218(7):

20. NUCs

21. AFP dependent HBsAg decline during ETV therapy in CHB patient with hepatitis flare
Patients with ALT ≥10ULN and AFP ≥20 ng/mL by mon 6 had greater reduction of HBsAg .
Jeng WJ, et al. J Antimicrob Chemother. 2016;71(6):1601-8

22. predicts long term HBsAg loss
Early HBsAg decline
predicts long term HBsAg loss
>75% (0.6 log10) decline in 1 yr
High chance of achieving HBsAg level <100 IU/ml and HBsAg loss in 5 yrs (HR 5.8 and 8.2, respectively) .
Peng CY, et al. Sci Rep ;7:42879.

23. combination therapy

24. Peg-IFN & NUCs combination treatment-
Systematic review with meta-analysis
Single(Switch to) is better than couple(de novo, add-on)
24 studies enrolled
Overall, Peg-IFN containing therapy during the whole treatment period increased HBsAg loss rate to 9%
“NUCs -experienced” “switch to” (14%) had higher HBsAg loss than “add-on” strategy(8%), P=0.012 .
Qiu K, et al. Aliment Pharmacol Ther. 2018;47(10):

25. predict HBsAg loss by wk 96
Greater HBsAg decline by wk12
predict HBsAg loss by wk 96 .
Bourlière M, et al. Lancet Gastroenterol Hepatol. 2017;2(3):

26. A small body of determined spirits fired by an unquenchable faith in their mission can alter the course of history
Mahatma Gandhi

27. Our Team Nanfang Hospital, Guangzhou
Jinlin Hou
Jian Sun
Humanity & Health Medical Group, Hong Kong
George Lau (GI and Liver)
Siu Kum Lam (GI and Liver)
Gregory Cheng (Oncology)
CK Chan (GI and Liver)
Jane Chan (Respiratory)
Richard Choi (General surgery)
Derek Lee (GI and Liver)
Ling Ling Cheung (Cardiology)
Danny Wang (Associate research director)
Cheng Wang (Research assistant)
Rick Cheung (Research associate)
Emory University
Raymond F. Schinazi
Leda Bassit
Hui-Mien Hsiao
Los Alamos National Laboratory
Alan S. Perelson
Rujan Ke
SomaLogic Inc
Larry Gold
Roy Smythe
Stephen A. Williams
PLA fifth Medical Center, Beijing
Fusheng Wang
Ming Shi
Guofeng Chen
Qing Shao
Dong Ji
Zhenwen Liu
Yinjie Gao
Hong Kong Molecular Pathology Diagnostic Centre
Chris L.P. Wong
Stella T.Y. Tsang
Patients