Hepatitis B Update. Jorge L. Herrera, M.D. University of South Alabama Mobile, AL. Gastroenterology

Transcription

1 Hepatitis B Update Jorge L. Herrera, M.D. University of South Alabama Mobile, AL

2 Deciding Who to Treat Is hepatitis B a viral disease or a liver disease?

3 Importance of HBV-DNA Levels in the Natural History of HBV The REVEAL Study 3653 patients, HBV (+) 13 year follow up HBV-DNA level determined at entry and correlated with incidence of HCC and cirrhosis at 13 years Cirrhosis was determined by high resolution ultrasound exam Chen CJ, et al. JAMA 2006;295:65-73 Iloeje UH, et al. 2006;130:

4 HBV DNA Levels and Risk of HCC and Cirrhosis - REVEAL Chen CJ, et al. JAMA 2006;295:65-73 Iloeje UH, et al. 2006;130:

5 The Reveal Study Does it apply to all patients with HBV? Reveal: Study population 1,2 Male 62% Age >40 years 67% No patient <30 y/o enrolled! HBeAg negative 85% The Melbourne study 3 Increasing viral load is associated with significant liver disease only in HBeAg (-) disease Odds ratio of Fibrosis 2/3/4 HBeAg (-): 1.42 for every 1 log increase in DNA HBeAg (+): 0.71 for every 1 log increase in DNA 1. Chen CJ, et al. JAMA 2006;295: Iloeje UH, et al. 2006;130: Croagh MN, et al. Liv Int 2010;30:

6 Four Phases of HBV Infection TREAT 2 TREAT 4 1 TREAT? 3 Yim JY and Lok AS-F. Hepatology 2006;43:S173-S181.

7 The Immune Tolerant Patient Profile Perinatal acquisition of infection Young (<40 years) HBeAg (+), very high viral load Normal ALT (<30 males, <19 females) Normal liver biopsy Natural history No liver damage while immune tolerant Eventually most will develop active disease Mean age 30.7 years 1 1. Andreani T, et al. Clin Gastroenterol Hepatol 2007;5: Hui CK, et al. Hepatology 2007;46:

8 Why not treat them all???? Efficacy of therapy in immune tolerant patients not known Increased risk of resistance? Cost Compliance Toxicity Teratogenicity Is it helping the patient?

9 DNA Levels Cannot be Interpreted in Isolation More Likely to Treat HBV-DNA Elevated Inflammation, fibrosis, cirrhosis e-antigen (-) Age over 40 Positive history Co-infection

10 Approach to the HBV Patient The question is not WHO to treat, but rather WHEN to treat

11 Deciding When to Treat 2 Elements Liver inflammation Elevated viral load Elevated ALT Liver Biopsy eag (+): > 20,000 IU eag (-):( > 2,000 IU Modifiers that increase risk of progression * Supported by strong evidence. Further studies needed Yim JY, Lok AS. Hepatology 2006;43:S173-S181

12 Deciding When to Treat 2 Elements Liver inflammation Elevated viral load Modifiers that increase risk of progression * Supported by strong evidence. Further studies needed Yim JY, Lok AS. Hepatology 2006;43:S173-S181

13 Deciding When to Treat 2 Elements Liver inflammation Elevated viral load Modifiers that increase risk of progression * Supported by strong evidence. Further studies needed Yim JY, Lok AS. Hepatology 2006;43:S173-S181

14 Treatment Algorithm HBeAg Positive HBV DNA >20,000 IU/mL HBeAg Negative HBV DNA >2,000 IU/mL ALT Evaluation Elevated ALT Normal ALT Monitor Liver Biopsy Abnormal Histology Treat Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:

15 Approach to Patients with Cirrhosis Compensated Decompensated HBV DNA <2000 IU/mL HBV DNA >2000 IU/mL Any HBV DNA Level Observe or Treat Treat Treat Wait List for Transplant Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:

16 Recommendations for First-Line Therapy HBeAg Positive or Negative Chronic HBV Keeffe EB, et al. Clin Gastroenterol Hepatol 2008;6:

17 HBeAg(+) Disease Results After 1 year of Therapy Entecavir Tenofovir 100% 80% 60% 40% 20% 0% Normal ALT 100% 80% 60% 40% 20% 0% HBe seroconversion Results from individual randomized clinical trials, NOT head-head comparisons, different HBV-DNA assays used numbers are illustrative EASL Clinical Practice Guidelines. J Hepatol 2009;50:

18 HBeAg(-) ) Disease Results After 1 year of Therapy 100% 80% 60% 40% 20% Entecavir Tenofovir 100% 80% 60% 40% 20% 0% HBV-DNA (-) 0% Normal ALT Results from individual randomized clinical trials, NOT head-head comparisons, different HBV-DNA assays used numbers are illustrative EASL Clinical Practice Guidelines. J Hepatol 2009;50:

19 Antiviral Therapy Selection Entecavir ~1% resistance at 5 years Not ideal in lamivudine experienced patients, effective in adefovir resistance Take on empty stomach Pregnancy class C No concern for renal toxicity Tenofovir No resistance at 3 years Effective in lamivudine resistance, less effective in adefovir genotypic resistance No food effect Pregnancy class B Renal toxicity noted in HIV patients Bone mineral loss concern

20 When to Stop Therapy Interferon therapy 4 to 12 months HBeAg (-) disease Treat indefinitely or until HBsAG (-) / HBsAb (+) Cirrhosis Treat indefinitely HBeAg (+) disease Treat for 6-12 months after HBeAg seroconversion and HBV-DNA not detectable Controversy: Treat all until HBsAg (-) / HBsAb (+)????

21 Special Circumstances Immunosuppression Pregnancy

22 HBV is Always Hiding Somewhere Even after acute, self-limited HBV infection, the virus may remain inactive Immunosuppression allows viral reactivation Chemotherapy, anti-tnf therapy, immunomodulators, corticosteroids 2008 CDC recommendation: Screen all persons needing immunosuppressive therapy including chemotherapy, and immunosuppression for rheumatologic or GI disorders CDC. MMWR 2008;57(No. RR-8):9-10

23 Immunosuppression and HBV Reactivation At risk HBsAG (+), any HBV- DNA level HBsAG (+), negative HBV-DNA HBsAG (-), HBcAB (+), neg HBV-DNA Prior HBV Infection Risk present even if HBsAb (+) as well RISK cccdna remains in the nucleus Mindikoglu AL, et al. Clin Gastroenterol Hepatol 2006;4: Ganem D. NEJM 2004;350:

24 Immunosupression-Induced Reactivation Time Line HBsAG (+) DNA (-)( HBsAG (+) DNA (+) ALT NL HBsAG (+) DNA (+) ALT Fulminant Hepatitis CHEMOTHERAPY Jaundice Asymptomatic Liver Failure

25 Prevention vs. Treatment Lamivudine after increase in ALT did not reduce severity or clinical course of HBV hepatitis Hsu C, et al. Hepatology 2008;47:

26 Recommendations 1. Screen all patients about to undergo immune suppression HBsAg, HBcAb (total) If positive for either, measure HBV-DNA 2. Start antiviral therapy if HBsAg or HBV-DNA positive 2 weeks before and at least for 6-12 months after 3. If HBsAg (-), HBcAb (+), HBV-DNA (-) Treat with antiviral therapy 1 OR Monitor HBV-DNA periodically during immune suppression 2 1 Meeting Report. J Clin Virol 2008;41: Vassiliadis T, et al. Am J Hematol 2005;80:

27 Do we need to treat? Is it safe to treat?

28 Risk of Transmission Maternal Status HBsAg (+) HBsAg (+), HBeAg (+) HBsAg (+) HBsAG (+), HBeAg (+) Risk to Child 10% to 20% 90% HBIG 23%, HBIG + vaccine 3%-7% HBIG + vaccine ~10% Assumes properly vaccinated infants Gambarin-Gelwan M. Clin Liver Dis 2007;11:

29 Risks for Intrauterine Infection Mother HBeAg (+) High titer HBsAg in mother Maternal HBV-DNA titer (>~10 6 to 10 8 copies/ml) History of prior perinatal transmission Monitoring maternal HBV-DNA level may help predict failure of passive- active immunization Xu D, et al. J Med Virol 2002;67:20-26

30 Can We Further Reduce The Risk of Maternal Transmission? 120 HBV mothers, viral load >1000 Meq/mL (~10 9 copies) 68 lamivudine week 34 until 4 weeks postpartum 52 placebo All infants received passive-active immunization p = Xu WM et al. J Viral Hep 2009;16: Lost to follow-up counted as failures

31 Is it Safe? Lamivudine Pregnancy Class C >3,000 pregnant patient treated, no increased risk of birth defects 1 Tenofovir Class B ~1,000 pregnant patients treated, no increased risk of birth defects 2 Telbivudine (B), Entecavir (C), Adefovir (C) no experience 1. Accessed January, Brown RS, et al. Hepatology 2009;50:497A (abstract #407)

32 Recommendations 1. Consider intervention at 32 weeks if viral load > copies/ml No consensus on this issue has been reached 2. Careful discussion with patient and OB 3. Ensure prompt and complete passive-active immunization of neonates Assess for immunity after vaccination 4. No benefit of C-section over vaginal delivery 5. No contraindication to breast feeding unless mother on antiviral therapy Buchanan C, Tran TT. Clin Liv Dis 2010;14:

33 Take Home Points Approach to the patient with chronic HBV 1. All patients are candidates for therapy the question is WHEN to treat a. viremia, b. inflammation, c. prognostic factors 2. Preferred therapeutic options: Tenofovir, entecavir or pegylated interferon 2a 3. Duration of therapy Determined by choice of therapy, e-antigen status, and severity of disease 4. Before initiating immunosuppression, patients should be tested for HBsAg, HBcAb (total), + HBV-DNA 5. High level viremia during pregnancy increases risk of transmission to newborn