Management of Chronic Hepatitis

1. Management of Chronic Hepatitis

2. All cirrhotic patients • periodic screening for HCC with ultrasound and alfa-feto protein level every 6 month is recommended in CHB and CHC. • CLD patients should be considered for HAV vaccination.

4. Diagnosis • Serology HBSAg-HBSAb,HBeAg-HBeAb, HBcAb. • DNA detection methods BDNA,hybridization assay,single amplification assay 105-106, PCR based assays detect 10-100 copies/ml. • Liver BX.

5. Antiviral therapy is not indicated in patients with acute hepatitis. • Patients with FHF should be considered for liver transplantation. • The main efficacy of antiviral therapy in chronic hepatitis B is to increase the seroconversion rate.

6. Chronic HBV Infection: Target Population for Treatment • Treatment indicated in those with “active” CHB • Greatest benefit (at highest risk for disease progression) • Most likely to respond to currently available agents • “Activity” defined by • Elevated ALT/AST • Necroinflammation on liver biopsy • Elevated HBV DNA levels

7. HBV Treatment Guidelines Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.

8. Goals of Therapy in Patients With Chronic HBV Infection • Eradication of infection • HBsAg seroconversion • Undetectable HBV DNA • Prevent complications of liver disease • Histologic progression to cirrhosis • Decompensated liver disease • Liver cancer

9. Therapeutic Endpoints • HBeAg-positive patients (wild type) • HBeAg seroconversion is KEY • Sustained suppression of HBV DNA to low or undetectable levels • ALT normalization • Reduced necroinflammation on biopsy • HBeAg-negative patients (precore and core promoter mutants) • HBeAg seroconversion not an endpoint • Sustained suppression of HBV DNA to low or undetectable levels • ALT normalization • Reduced necroinflammation on biopsy

10. Approved HBV Therapies • Interferon • Peginterferon • Lamivudine • Adefovir dipivoxil • Wild-type HBV, lamivudine-resistant HBV • Entecavir • Wild-type HBV, lamivudine-resistant HBV

11. Interferon

12. Peginterferon Summary Advantages • Less frequent injections than IFN • Defined treatment interval • High rate of HBeAg seroconversion in wild-type infection • High rate of HBV DNA suppression in precore mutant variant • High rate of HBsAg seroconversion • No reports of resistance mutations Disadvantages • Requires injection • Frequent side effects • Not recommended for some patient groups • Decompensated cirrhotics • Liver transplant recipients • Higher cost

13. Lamivudine

14. Lamivudine Treatment in HBeAg-Positive Patients for 1 Year 100 mg/day for 52 Weeks 60 Lai[1] Dienstag[2] Schalm[3] Schiff[4] 40 33% 32% Percentage of Patients 22% 18% 18% 20 17% 17% 16% 0 HBeAg Seroconversion HBeAg Loss 1. Lai CL, et al. N Engl J Med. 1998;339:61-68. 2. Dienstag JL, et al. N Engl J Med. 1999;341:1256-1263. 3. Schalm SW, et al. Gut. 2000;46:562-568. 4. Schiff ER, et al. J Hepatol. 2003;38:818-826.

15. Lamivudine in HBeAg-Negative Cirrhosis: Long-term Outcomes *5-year probability Lampertico P, et al. Hepatology. 2004;40:674A.

16. Incidence of YMDD Mutations by Duration of Lamivudine Therapy 80 Asia[1,2] 69% 66% International[3] 60 55% USA[4] Patients With Resistance (%) 40 40% 32% 27% 20 15% 0 1 2 3 4 5 Duration of Treatment, Years 1. Guan R. APDW. 2001. 2. Leung NW, et al. Hepatology. 2001;33:1527-1532. 3. Tassopoulos NC, et al. Hepatology. 1999;29:889-896. 4. Dienstag JL, et al. N Engl J Med. 1999;30:1082-1087.

17. Consequences of Drug Resistance • Relapse of HBV DNA • Elevated ALT • Decreased rate of HBeAg seroconversion • Loss of histologic improvement • Possible clinical decompensation • Poorer outcomes if underlying cirrhosis Perrillo RP, et al. Hepatology. 2002;36:186-194. Leung NW, et al. Hepatology. 2001;33:1527-1532.

18. Adefovir Dipivoxil

19. HBeAg-Positive PatientsAdefovir Efficacy at 48 and 72 Weeks 78% 80 Week 48 63% Week 72 60 46% 44% Percentage of Patients* 40 26% 23% 23% 20 14% 0 HBV DNA < 400 copies/mL ALT Normalization HBeAg Loss HBeAg Seroconversion *Kaplan-Meier estimates Marcellin P, et al. N Engl J Med. 2003;348:808-816.

20. Adefovir in HBeAg-Negative PatientsVirologic and Biochemical Response ALT Normalization Serum HBV DNA < 1000 copies/mL 100 78% 80 77% 75% 75% 72% 71% 69% 68% 67% 67% 60 Percentage of Patients 40 20 0 48 96 144 192 48 96 144 192 240 240 Treatment Duration (Weeks) n = 69 58 69 65 55 64 53 64 59 55 Hadziyannis S, et al. EASL. 2005. Abstract 492. Hadziyannis S, et al. AASLD 2005. Abstract LB14.

21. Entecavir

22. Entecavir vs Lamivudine in Nucleoside-Naive HBeAg+ CHB Results at 48 Weeks Entecavir 0.5 mg/day (n = 354) Lamivudine 100 mg/day (n = 355) P < .05 P = NS P < .05 100 25 21% 80 80 72% 68% 18% 62% 20 60% 60 60 15 Percentage of Patients Percentage of Patients 40 Percentage of Patients 40 10 20 20 5 0 0 0 Histological Improvement(n = 314 with evaluable histology in each group) HBeAg Seroconversion ALT Normalization(≤ 1.00 x ULN) Chang TT, et al. Hepatology. 2004;40:193A.

23. HBeAg-Positive Patients Treated up to 96 Weeks With Entecavir Cumulative Outcome by Week 96 Sustained Responses 24 Weeks Off Therapy 100 100 P < .0001 80 80 80 71 69 60 60 Percentage of Patients Percentage of Patients 39 40 40 31 31 29 26 20 20 0 0 Undetectable HBV DNA* HBeAg Seroconversion Undetectable HBV DNA* HBeAg Seroconversion Entecavir (n = 354) Entecavir (n = 111) Lamivudine (n = 355) Lamivudine (n = 93) *Undetectable HBV DNA, < 300 copies/mL Gish R, et al. AASLD 2005. Abstract 181.

24. ETV vs LAM in Nucleoside-Naive HBeAg-Negative Patients Results at 48 Weeks Entecavir 0.5 mg/day (n = 325) Lamivudine 100 mg/day (n = 313) 90 P < .05 78% 100 80 90% P < .05 71% 70 80 72% 60 Patients Achieving Response (%) 50 Patients Achieving Response (%) 60 40 40 30 20 20 10 0 0 ALT Normalization(≤ 1.00 x ULN) HBV DNA < 300 copies/mL (PCR) Shouval D, et al. Hepatology. 2004;40:728A.

25. Incidence of Resistance in Patients Treated With Antivirals • Viral mutations conferring resistance are less frequent and delayed in onset with ADV and ETV vs LAM 80 70% 60 ADV (N236T + A181V)[1] 53% 42% LAM[2] (YMDD) Incidence of Resistance (%) 40 ETV- Lam-R[3] (L180M + M204V) 24% 20 18% ETV- Rx naive[3] 11% 9% 6% 2% 0 Year 1 Year 2 Year 3 Year 4 1. Westland CE, et al. Hepatology. 2003;38:96-103. 2. Lai CL, et al. Clin Infect Dis. 2003; 36:687-696. 3. Colonno R, et al. AASLD 2005. Abstract 962.

27. Hepatitis C Virus Infection:Magnitude of the Problem • Nearly 4 million persons in United States infected • Approximately 35,000 new cases yearly • 85% of new cases become chronic • 10,000-20,000 HCV-related deaths per year • Number expected to triple in next 10-20 years • Leading cause of • Chronic liver disease • Cirrhosis • Liver cancer • Liver transplantation

28. Goals of HCV Therapy • Primary goal of treatment is to eradicate the virus • Additional goals • Slow disease progression • Minimize risk of hepatocellular carcinoma • Improve liver histology • Enhance quality of life • Prevent transmission of virus • Reduce extrahepatic manifestations

29. Overview of Current FDA-Approved Treatments for HCV

30. SVR Rates: Progress in the Treatment of Chronic Hepatitis C SVR Rates With Standard Interferon 100 80 60 Patients (%) 43 40 19 20 6 0 IFN 24 Weeks IFN 48 Weeks IFN/RBV 48 Weeks McHutchison J, et al. N Engl J Med. 1998;339:1485-1492. Poynard T, et al. Lancet. 1998;352: 1426-1432.

31. Peginterferon alfa-2b 1.5 µg/kg/wk + ribavirin 800 mg/d for 48 weeks Peginterferon alfa-2a 180 µg/wk + weight-based ribavirin (1000 or 1200 mg/d) for 48 weeks SVR Rates: Progress in the Treatment of Chronic Hepatitis C 100 82 76 80 56 60 Sustained Virologic Response (%) 54 46 42 40 20 n = 453 n = 298 n = 140 n = 511 n = 348 n = 163 0 Overall Genotype 1 Genotype 2/3 Overall Genotype 1 Genotype 2/3

32. Factors That May Influence the Outcome of Hepatitis C Host Sex Age Race Genetics Immune response Duration of Infection Virus Viral load HCV genotype Quasispecies Environment Alcohol or drugs HBV coinfection HIV coinfection Steatosis Iron NASH Alberti A, et al. J Hepatol. 1999;31(suppl 1):17-24.

33. Predictors of Sustained Virologic Response: Fixed Factors

34. Virologic Monitoring Markers and Definitions of Response to Treatment

35. Week 12 Stopping Rule: Patients Without EVR Unlikely to Achieve SVR • Week 12 viral kinetics predictor of SVR • Only 1.6% of patients who fail to meet EVR criteria achieve SVR (NPV: 98.4%) • 2 log cutoff at Week 12 optimal for predicting response • Poor PPV of Week 12 EVR (68%) • Week 12 HCV RNA predictor of treatment failure but not predictor of success in achieving SVR • Week 12 stopping rule included in current guidelines • ~ 20% of patients can stop early, lowering total treatment costs by 16% and decreasing unnecessary side effects

36. Time to Undetectable HCV RNA Identified as Best Predictor of SVR • Pooled data from PegIFN alfa-2b/RBV and PegIFN alfa-2a/RBV phase III trials PPV of HCV RNA Undetectability Determining SVR 100 86 80 76 80 PPV for SVR (%) 60 40 20 0 Week 4 Week 12 Week 24 Time to Undetectable HCV RNA

37. Relationship Between SVR and Time to HCV RNA Undetectability • Retrospective analysis of genotype 1 patients receiving 48 weeks of PegIFN alfa-2a + RBV End-of-treatment response 100 91 91 90 90 SVR 80 60 60 48 Patients (%) 40 13 20 2 0 Week 4 Week 12 Week 24 Negative Negative Negative < 2 log drop Negative Negative < 2 log drop > 2 log drop Negative Any drop Any drop Positive

38. Week 4 Response as a Predictor of SVR • Patients with undetectable HCV RNA by Week 4 on PegIFN alfa-2a + RBV treated for total of 24 weeks • SVR rate for Week 4 responders (per-protocol analysis) • Overall: 87% –Genotype 1: 84% –Genotype 4: 100% • Higher baseline, Week 4 viral load predictive of relapse Relapse Rate Based on Week 4 Viral Load (ITT Analysis) 100 80 Week 4 HCV RNA 60 Patients (%) 38 < 10 IU/mL 40 22 10-49 IU/mL 15 10 20 7 5 0 All Patients < 600,000 ≥ 600,000 Baseline Viral Load (IU/mL)

39. Anti-HCV Treatment Paradigmis Changing • New interferons • Oral interferon inducers • Ribavirin alternatives • Immune therapies • Telapovir. • VIRAL ENZYME INHIBITORS

41. AI liver disease • PBC • clinical evidence women =95% age 30-65 • Biochemical cholestasis • IgM • AMA 2 >1/40 • BX middle size duct destruction ,granuloma in 32% staging 1-4 • 2,4,5 definite PBC one criteria probable PBC • +ve AMA alone is predictive of developing PBC later

42. Treatment of PBC • Treat complications • progression of the disease • Ursodeoxycholic acid • Methotrexate • Combination

43. Recommendation for Rx PBC • UDCA 13 -15mg/kg day divided LFT 2 -3 month if normal LB at 18 -24 month if stable cont if not or no response add colchicine 0.6mg Bid follow up LB at 1-2 years then Q 3 years

44. PSC • clinical associated with IBD in 70-90% male predominance • PANCA in 85% • -ve AAb • ERCP intra +extra hepatic ducts involvement • LB fibrosing oblitrative cholangitis mostly involving medium size ducts and ductopenia of small ducts.

45. Treatment of PSC • Medication tried • - D penicillamine • - steroid • - cyclosporine • - azathioprine • - UDCA • - Tacrolimus • Non shown to delay disease progression

46. Treatment of PSC • Endoscopic therapy • surgical management • Liver transplantation

47. AIH • AIH scoring system .Is this highly accurate? • LB characterized by interface hepatitis

49. Treatment of AIH • Corticosteroid are the main stay +azathioprine • Response rate up to 90% • Effective even in advanced disease • reduction ,maintenance (daily) • Failure rate 20% • Alternatives (cyclosporine,Fk506) • Future therapy Tcell vaccine,lymphokines, MAb