Viral Hepatitis The Preventive Potential of Antiviral Therapy. Thomas Berg

Transcription

1 Viral Hepatitis The Preventive Potential of Antiviral Therapy Thomas Berg

2 Therapeutic and preventive strategies in patients with hepatitis virus infection Treatment of acute infection Treatment of chronic infection Treatment of cirrhosis Prevention of Reactivation

3 350 Mio. chronic hepatitis B virus (HBV) carriers worldwide HBV carriers 8% 2% - 7% < 2% Over 1 million people die each year from HBV-related chronic liver disease

4 HBV - Major Cause of Liver Cancer Lavanchy J Viral Hepatitis 2004; 11: Yearly deaths estimated from HBV in Europe Liver Cancer due to HBV (%) Southeast Asia Greece Turkey Italy Europe overall

5 REVEAL: Natural history of HBV infection and Liver Disease Progression REVEAL: prospective, multicenter, observational cohort study : Recruitment 7 Taiwanese townships Individuals aged years eligible (N = 89,293) HCC-free individuals enrolled (n = 23,820) June 2004: 43,993 PYs follow-up HCC Analysis HBsAg+ with baseline HBV DNA (n = 3851) Cirrhosis Analysis (n = 3774) Those cirrhotic within 6 months excluded Chen, et al. EASL Abstract 35. Chen, et al. EASL Abstract 476.

6 REVEAL: Relationship Between HBV DNA Levels and Cirrhosis Baseline HBV DNA predicted progression to cirrhosis Relationship independent of HBeAg status Adjusted for gender, age, anti-hcv levels, smoking, and alcohol use. Chen, et al. EASL Abstract 476. % patients with cirrhosis 30 HBeAg negative (N=3,214) HBeAg positive (N=560) HBV DNA < 10 4 copies/ml HBV DNA copies/ml HBV DNA > 10 5 copies/ml

7 HBV DNA replication and HCC risk Cumulative incidence of hepatocellular carcinoma by baseline HBV DNA (n=3.851) Chen CJ et al. EASL 2005 Abstract No.35 HCC Incidence Rate x 10 3 Per 100,000 P<0.01 Adjusted for gender, age, anti-hcv, habits of cigarette smoking and alcohol consumption.

8 Treatment Landscape Treatment has advanced dramatically due to the introduction of new agents with different safety, efficacy, and resistance profiles Cytokines Nucleoside Analogue Nucleotide Analogue Interferon (1992) Peg-Interferon α-2a (2005) Lamivudine (1999) Adefovir dipivoxil (2003) Entecavir (2005 US) Tenofovir (HIV approved) Telbivudine Clevudine Emtricitabine...

9 Concepts of HBV Therapy (Peg)-Interferon Nukleos(t)idanalogues Combination + Induction of sustained remission in a limited period of time Long-term suppression of HBV replication Stopping disease progression (histological improvement) Problem of resistance Viral elimination? HBV-DNA Suppression Resistance development Effect on clinical endpoints? Treatment regimen?

10 HBeAg loss associated with better outcome 1,0 HBeAg Clearance Cumulative survival 0,8 0,6 0,4 0,2 IFNa-treated patients Untreated patients No HBeAg Clearance Months Niederau et al. N Engl J Med 1996;334:1422-7

11 Correlation between change in viral load during treatment and histological outcome (Mommeja-Marin H et al. Hepatology 2003; 37: 1309) Median Histologic Activity Index Improvement from Baseline Median log 10 HBV DNA Level Decrease from Baseline N=3,428

12 Histologic response during antiviral therapy (reversion of fibrosis of cirrhosis) (Dienstag JL et al. Gastroenterology 2003; 124: 105) before lamivudine after lamivudine (3 y)

13 Time to disease progression in patients with advanced fibrosis or cirrhosis (Ishak score 4) Lamivudin vs. Placebo (Liaw YF et al. N Engl J Med 2004;351:1521) Disease progression HCC-Development Definition of disease progression Increase in Child Score 2, SBP, HRS, Variceal bleeding, HCC or death

14 Cumulative Incidence HBV Antiviral Resistance Incidence of Resistance (%) Entecavir (ETV) 0% / 6% Lamivudine (LAM) 3.9% Adefovir (ADV) Year 1 Year 2 Year 3 Year 4 70% 18% ADV (N236T/A181V) [1] LAM (M204V/I) [2] ETV (WT / LAM refractory) [3] 1. Qi, et al. EASL 2004, Abstract Lai, et al. Clin Infect Dis. 2003;36: Tenney DJ, et al. AASLD 2004 Abstract 184.

15 Clinical relevance of lamivudine-resistance: progression-free survival *Child Score 2 or clinical decompensation Progression-free* survival in patients with HBeAg-negative cirrhosis 1,0 0,8 0,6 0,4 0,2 0 (Di Marco V et al. Hepatology 2004; 40: 883) maintained virologic response (MVR; no resistance) virologic breakthrough (VBT, lamivudine resistance) Monate MVR VBT

16 Patient survival after liver transplantation according to prophylactic strategy Survival (%) p< [Anselmo et al. (UCLA). Ann Surg 2002;235:611] HBIG + Lamivudine (n=89) only Lamivudine (n=20) only HBIG (n=28) no treatment (n=29) Months

17 Transplantation-free survival in patients with decompensated HBV cirrhosis (Child score >10) 100 (Yao FY et al. Hepatology 2001; 34: 411) cumulative survival (%) Control (n=23) Lamivudine therapy (n=23) Months

18 Preemptive lamivudine treatment prevents HBV reactivation during chemotherapy (Lau GKK et al. Gastroenterology 2003; 125: 1742) Survival free from hepatitis B virologic reactivation (%) preemptive prophylactic lamivudine treatment (n=15) no prophylaxis (deferred lamivudine treatment) (n=15) P=0.001 log rank test Wochen

19 Natural course of chronic hepatitis C (different situations) retrospective Post-transfusion Hepatitis C (n=895) follow-up years 23% Cirrhosis 1% HCC 3% Death (1-6%) prospectiv Acute hepatitis C after anti-d Prophylaxis (n=376) (Alberti. J Hepatol 1999;31(Suppl 1):17; Kenny-Walsh.NEJM 1999;340:1228) 17 years 2% Cirrhosis 98% chronic hepatitis 49% no fibrosis 34% portal fibrosis 15% advanced fibrosis

20 6 6 5 Grading 4 Cirrhosis: 9% HCV-associated mortality: 5% No fibrosis: 20% y = 0,011x + 2,63 Staging y = 0,0674x - 0, Years of Hepatitis C Biopsy n = (Wiese et al. 2005) Grading Staging Linear Regression (Grading) Linear Regression (Staging)

21 Acute Hepatitis C: Interferon therapy Nomura H et al. Hepatology 2004; 39: patients with acute hepatitis C n=15 Therapy (Week 8) n=15 Observation (52 weeks) 6 MioE IFNa every second day for 4 weeks SVR 13/15 (87%) SVR 6/15 (40%) Rescue therapy (3 x 3 MioE IFNa for 20 weeks SVR 15/15 (100%) SVR 8/15 (53%)

22 Treatment evolution in chronic hepatitis C: sustained virologic response rates Peg-Interferon + Ribavirin? Interferon + Ribavirin 52-56% *62-64% 41-47% Interferon mono Weeks 8-12% 15-22% Future *80% treatment duration and dosage

23 Survival of non-cirrhotic HCV patients according to number of IFNa courses and treatment response (Akuta N et al. Scand J Gastroenterol 2005; 40: 688) (SVR, n=152) (non-svr; n=130) (multiple IFNa courses) (non-svr; n=172) (single IFNa course) 454 non-cirrhotic HCV-infected patients SVR

24 Sustained virologic response rates (SVR) in relation to HCV genotype % SVR HCV Type 1 Type 4 Type 3 Type 2

25 Sustained virologic response (SVR) rate in HCV type 1: impact of patient s age (N=697) SVR in % Age (years) % Patients < > 60 (11%) (24%) (33%) (22%) (10%)

26 Increase in the number of nonresponder patients in the future Non-Responder (000s) Normal ALT levels HIV-HCV Co-Infection All other patients Source: EQUINOX / Alignment with affiliates. Approved by James Creeden, PBSE (June 2005). *CAGR

27 Mechanisms of action Anti-viral Enhanced immune response Anti-fibrotic IFN Anti-proliferative Anti-carcinogenic Regulation of TGF-β Inhibition of Angiogenesis

28 HCC Prophylaxis with IFNa in HCV-Cirrhosis (Papatheodoridis GV et al., Aliment Pharmacol Ther 2001; 15: 689)

29 COPILOT Study: Long-term Peg-IFNa monotherapy in nonresponder patients with advanced fibrosis (Afdhal N et al. Hepatology 2004; 40: 239A) Event free survival p = % CI PEG-IFN-α2b Colchicine Days Events: variceal bleeding, decompensation, HCC, transplantation, and death

30 Conclusion Long-term suppression of viral replication prevents the long-term consequences of chronic hepatitis ( treat the infection and cure the disease ) The preventive potential of IFNa regarding disease progression and HCC development irrespective of its antiviral effects should be further studied

31 Phase IB Study: VX-950 in chronic hepatitis C (protease inhibitor) (Reesink et al DDW 2005; Abstract 527) mean HCV RNA log decline (IU/mL) out of 8 pts. HCV RNA negative (< 30 IU/mL) n=10 n=10 n=8 3 x 450 mg 2 x 1250 mg 3 x 750 mg VX-950 dosages given for 14 days

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33 Natural course in patients with compensated HCV-induced cirrhosis (5 years) 18-20% Cirrhosis Child A 7-15% Decompensation HCC 9-15% Liver-related mortality (Alberti. J Hepatol 1999;31(Suppl 1):17; Fattovich et al. Gastroenterology 1997; Degos et al. Gut 2000)

34 Increase in Future Disease Burden: 1998 vs 2008 Need for Liver Transplantation 528% Decompensation 279% Liver-Related Deaths 223% HCC 68% Cirrhosis 61% Estimated Increase From 1998 to 2008 (%) Davis et al. Hepatology

35 Calculated Effect of combination therapy on HCV-related morbidity (hepatic decompensation) Patients with decompensated diesease (x1000) (Davis GL et al. Liver Transpl 2003; 9: 331) all untreated 10% treated 50% treated 75% treated all treated Jahr

36 REVEAL: Relationship Between HBV DNA Levels and Cirrhosis Baseline HBV DNA predicted progression to cirrhosis Relationship independent of HBeAg status * Adjusted for gender, age, anti-hcv levels, smoking, and alcohol use. NS, not significant Serum HBV DNA (copies/ml) Total Patients Cases of Cirrhosis Adjusted RR* (95% CI) P Value HBeAg-Negative Patients < (reference) to < < <.001 HBeAg-Positive Patients < NS 10 4 to < < <.001 Chen, et al. EASL Abstract 476.

37 Nucleos(t)id-Analogues: Therapeutic efficacy in special situations decompensated cirrhosis co-infections fulminant hepatitis B reinfection prophylaxis extrahepatic manifestations medical personal prophylaxis of reactivation