1. 1 Hepatitis B Treatment Dr R.V.S.N.Sarma., M.D., Consultant Physician & Chest Specialist

2. 2 TREATMENT OF CHRONIC HEPATITIS B Review of trials and meta-analysis of RCT of Interferon (IFN) and Lamivudine (LAM) Clinical Practice Guidelines Issues for future clinical trials

3. 3 Goals of Antiviral Treatment of Chronic Hepatitis B 1. Sustained suppression of HBV replication Decrease in serum HBV DNA to <10 5 copies/ml HBeAg to anti-HBe seroconversion HBsAg to anti-HBs seroconversion 2. Remission of liver disease Normalization of serum ALT levels Decreased necroinflammation in liver 3. Improvement in clinical outcome Decreased risks of developing cirrhosis, liver failure and HCC Increased survival

4. 4 Lamivudine R x of HBeAg+ CHB Placebo Lam x 52 wk IFN x 16 wk Lam x 24 wk +IFN x 16 wk HBeAg seroconversion at week 52 Lai et al., NEJM 1998 Dienstag et al., NEJM 1999 Schalm et al., Gut 2000 13

5. 5 Lamivudine R x of HBeAg+ CHB Histologic response at week 52 Placebo Lam x 52 wk IFN x 16 wk Lam x 24 wk. +IFN x 16 wk Dienstag et al., NEJM 1999 Schalm et al., Gut 2000 Lai et al., NEJM 1998 14

6. 6 Lamivudine Rx of HBeAg+ CHB Normal ALT at Week 52 LAM PLA LAM & IFN IFN

7. 7 Lamivudine Treatment (0-52 Weeks) Lamivudine R x of HBeAg- CHB HBV DNA (pg/mL) ALT (xULN) Normal ALT Tassopoulos et al., Hepatology 1999; 29:889

8. 8 Treatment of HBeAg - CHB Treatment On-Therapy Response Sustained Response IFN (3-6 MU tiw) 6 months60 – 90%10 – 15% > 12 months50 – 75%20 – 25% Lamivudine (100-150mg) 12 months65 – 80%~10% 24 months50 – 60%? > 36 months30 – 40%? Adefovir 12 months70%?

9. 9 Treatment of Decompensated Cirrhosis Measurements of Response –Viral suppression –Biochemical improvement –Decrease in CTP score (Alb, bil, PT, ascites, encephalopathy) –Decrease clinical complications + –Decrease need for transplant + –Decrease HCC ? –Improve survival +

10. 10 Clinical Practice Guidelines Who to treat What treatment When to stop treatment

11. 11 AASLD Practice Guidelines Current therapy has limited long-term efficacy Careful balance of benefits and risks before treatment is initiated –patients’ age –severity of liver disease –likelihood of response –potential adverse events Lok and McMahon, Hepatology 2001;34:1225

12. 12 + +<2x ULNBoth IFN and Lam low efficacy Observe + +>2x ULNIFN or Lam IFN NR or contraindications  Lam – +>2x ULNIFN or Lam Long-term R x required – –normalNo Rx required +/ – +cirrhosisCompensated: IFN low dose or Lam Decompensated: Lam, optimal timing unknown - Transplant +/ – –cirrhosisCompensated: observe Decompensated: Transplant *HBV DNA in serum >10 5 copies/ml AASLD Practice Guidelines: Rx Strategies HBeAgHBV DNA* ALTTreatment Lok and McMahon, Hepatology 2001;34:1225

13. 13 Finite duration of R x More durable response Resistant mutants not reported Expensive Frequent side effects Long/indefinite duration of R x Resistant mutants Oral administration Negligible side effects Lower costs? Interferon Lamivudine Pros Cons Treatment of Chronic Hepatitis B

14. 14 AASLD Practice Guidelines Treatment Regimen - IFN Dose 5 MU QD or 10 MU tiw SC Duration e + CHB - 16 wk e – CHB - 12 months Lok and McMahon, Hepatology 2001;34:1225

15. 15 AASLD Practice Guidelines Treatment Regimen - Lamivudine Dose 100mg daily po (Lamivir HBV – 100 mg Cipla) HIV Coinfection – 150mg bid + other HIV R x Duration e+ CHB – 1yr... HBeAg seroconversion – Stop R x ? DNA suppression, HBeAg+ - Continue R x ? Breakthrough infection – continue R x if clinically stable? Stop R x if clinical deterioration e- CHB > 1yr, optimal duration? Lok and McMahon, Hepatology 2001;34:1225

16. 16 Impact of HBeAg Clearance on Long-Term Clinical Outcome 0 12 24 36 48 60 72 84 96 1.0 0.8 0.6 0.4 0.2 0.0 Month Proportion with complication free survival Niederau et al., NEJM 1996;334:1422-7 IFN No R x Clearance of HBeAg No Clearance of HBeAg

17. 17 IFN Treatment of HBeAg- Patients Hadziyannis S, et al., J Hepatology 1990; 11(Suppl 1):513 Fattovich G, Hepatology 1992; 15:584 Pastore G, J Hepatology 1992; 14;221 Lampertico p, Hepatology 1997; 26:1621