Hepatitis B: predictors and endpoints revisited?

1. Hepatitis B: predictors and endpoints revisited? Rami MOUCARI, MD Hôpital Beaujon, France

2. Rational • Durable virological remission • Finite period of treatment • HBsAg clearance (closest to cure)

3. History • A 52-year-old white female • HBsAg positive test ordered by her internist • Multiple risk factors including: multiple sexual partners and multiple tattoos and piercings. • She has no history of injection drug use, or of excessive alcohol intake.

4. Current Presentation She is referred to you for workup and management of her hepatitis B. You order laboratory testing that reveals: • Hepatitis B antigen HBeAg–negative disease • HBV DNA: 107 IU/mL • Alanine aminotransferase (ALT): 95 IU/L • Aspartate aminotransferase (AST): 75 IU/L • Alpha-fetoprotein (AFP): 22 µg/L • Platelet count: 152,000/mm3 • Albumin: 3.8 g/dL • Bilirubin: 1.0 mg/dL • International normalized ratio (INR): 1.1

5. How would you manage the patient at this time? • A. HBV Genotype • B. Abdominal Ultrasound • C. Perform a Liver Biospy • D. Start Antiviral Therapy

6. Investigations • HBV Genotype : D • Abdominal Ultrasound: no evidence of cancer or liver mass. • Liver Biopsy: A2F2 (METAVIR). No steatosis

7. Which of the following agents would be preferable for this patient? • A. Pegylated Interferon Alfa-2a • B. Telbivudine • C. Tenofovir • D. Entecavir

8. Pegylated Interferon Therapy HBsAg: Positive HBV DNA (Log IU/Ml)

9. What is Your Preferred Strategy • A. Add Entecavir • B. Add Telbivudine • C. Add Tenofovir • D. Prolong Treatment Duration with Pegylated Interferon Alfa-2a

10. HBsAg Quantification HBsAg Log IU/mL

11. Prolongation of Pegylated Interferon Therapy HBsAg Log IU/mL

12. IFN-Long-Term Results HBsAg Moucari et al. J Hepatol 2009

13. IFN-Long-Term Results HBsAg Moucari et al. J Hepatol 2009

14. IFN-Long-Term Results HBsAg Moucari et al. J Hepatol 2009

15. HBsAg – Peginterferon Alfa 2a 38 % 23 19 17 11 3 HBV DNA < 10 000 copies/mL HBV DNA < 400 copies/mL HBsAg Loss Marcellin et al. NEJM 2004; Marcellin et al. EASL 2008

16. Baseline Predictors Of ResponseMultivariate Analysis • Significant predictors of sustained response: • Age & Gender • High baseline ALT • Low baseline HBV DNA • HBV Genotype Bonino et al. GUT 2007

17. Early Serum HBsAg Drop: A Strong Predictor of Sustained Virological Response to Pegylated Interferon Alfa-2a in HBeAg-Negative Patients Moucari et al. Hepatology 2009

18. Patients • 48 consecutive HBeAg-negative patients • Pegylated Interferon alfa-2a /180 micrograms per week / 48 weeks. • End of treatment (EOT) response: undetectable serum HBV DNA at the EOT • SVR: undetectable serum HBV DNA 24 weeks after treatment cessation • Follow-up: 48 weeks after treatment cessation Moucari et al. Hepatology 2009

19. Methods • HBV genotype: TRUGENE HBV genotyping kit Baseline, Treatment weeks 12, 24 and 48 and Follow-up weeks 72 and 96: • Serum HBV DNA: TaqMan polymerase chain reaction assay (COBAS TaqMan, Roche Molecular System – lower limit of detection =70 copies/mL) • Serum HBsAg: Abbott Architect HBsAg QT assay (limits of detection: 0.05 – 125 000 IU/mL) Moucari et al. Hepatology 2009

20. Baseline Characteristics Moucari et al. Hepatology 2009

21. Virological Response 62 25 30/48 12/48 Moucari et al. Hepatology 2009

22. HBV DNA LevelSVRs vs. Non Responders NRs (n=18) Log copies/mL SVRs (n=12) Treatment FUP Moucari et al. Hepatology 2009

23. HBV DNA Level SVRs vs. Relapsers Relapsers (n=18) Log copies/mL SVRs (n=12) Treatment FUP Moucari et al. Hepatology 2009

24. HBsAg LevelSVRs vs. Non Responders NRs (n=18) Log IU/mL SVRs (n=12) Treatment FUP Moucari et al. Hepatology 2009

25. HBsAg Level SVRs vs. Relapsers Relapsers (n=18) Log copies/mL SVRs (n=12) Treatment FUP Moucari et al. Hepatology 2009

26. HBsAg: Predictive Value of Week 12 Drop (0.5 log IU/mL) SVR (+) Week 12 ↓ HBsAg ≥ 0.5 LogIU/mL N = 8 PPV = 89 % N = 9 N=1 SVR (-) 48 Patients SVR (+) N = 4 N=39 Week 12 ↓ HBsAg < 0.5 LogIU/mL N = 35 NPV = 90 % SVR (-) Moucari et al. Hepatology 2009

27. HBsAg: Predictive Value of Week 24 Drop (1 log IU/mL) SVR (+) Week 24 ↓ HBsAg ≥ 1 LogIU/mL N = 11 PPV = 92 % N = 12 N = 1 SVR (-) 48 Patients SVR (+) N = 1 N = 36 Week 24 ↓ HBsAg < 1 LogIU/mL N = 35 NPV = 97 % SVR (-) Moucari et al. Hepatology 2009

28. HBsAg Level in SVRsHBsAg (-) vs. HBsAg (+) Log IU/mL HBsAg (+) (n=9) HBsAg (-) (n=3) Moucari et al. Hepatology 2009 Treatment FUP

29. Conclusion (1) • HBsAg clearance = closest to cure in chronic HBV infection • Reduced rate of cirrhosis and HCC • Improved survival • HBsAg clearance is achievable in a high steady rate in CHB patients responding to IFN therapy

30. Conclusion (2) Serum quantitative HBsAg seems to be an excellent on-treatment marker predicting sustained off-treatment response, and identifying in the early phase of PEG-IFN therapy the patients who are most likely to benefit from this treatment.

31. Virologic Response in HBeAg- Patients (Undetectable HBV DNA at Year 1) Not head-to-head trials; different patient populations and trial designs 100 93 90 87 88 80 ~ 70 63 60 51 Patients With Undetectable HBV DNA (%) 40 20 0 LAM ADV ETV LdT TDF Peg-IFN Peg-IFN +LAM HBsAg loss 0%

32. Early viral kinetic (day 10) is predictive of long term virological response 69 HBe+ patients Predictive value of early kinetic (D10) on virological response (<300 cp/ml) at W24 et W48: - HBV DNA < 6log: 76 and 82% - 7log < HBV DNA < 8log: 14 and 29% Leung N, Hepatology 2009

33. HBsAg Loss in HBeAg-Negative Patients Following Long-term Adefovir Treatment • 33 HBeAg-negative CHB patients • Adefovir for 4-5 years with undetectable HBV DNA • 4 years of follow-up after Adefovir discontinuation • 18 of 33 patients (55%): SVR • 9/18 (50%): HBsAg Clearance Hadziyannis SJ et al. AASLD 2008 (Abstract 874)