Coinfection with Hepatitis B and HIV

1. Coinfection with Hepatitis B and HIV Chia C. Wang Assistant Professor of Medicine AIDS Clinical Conference February 20, 2007

2. Outline • Epidemiology and Natural history • Endpoints of therapy • Therapeutic options • Resistance • Hepatocellular carcinoma • Hepatitis B vaccination

3. Areas with high rates of hepatitis B 8% - High 2-7% - Intermediate <2% - Low 1 World Health Organization. Hepatitis B. Available at: http://www.who.int/emc-documents/hepatitis/docs/whocdscsrlyo20022/disease/world_ distribution.html. Accessed June 1, 2004.

4. Worldwide prevalence of hepatitis and HIV

5. 20% Cirrhosis and/or liver cancer Chronic hepatitis Progression to adverse clinical sequelae in HIV-negative individuals

6. Epidemiology of HBV in HIV-infected individuals • Reported prevalence has ranged from 6-13% • ~ 4 million individuals worldwide with HIV/HBV coinfection • Lower prevalence than 20-80% reported for HCV

7. Genotypes in hepatitis B

8. Natural history of HBV in HIV-coinfected patients • Higher levels of HBV DNA1 • Lower rates of spontaneous HBeAg seroconversion1 • Increased rates of liver-related mortality2 • Hadler S, et al. J Infect Dis 1991;163:454-459 • Thio CL, Lancet 2002;360:1921-1926

9. Multicenter AIDS Cohort Study1 • Thio CL, Lancet 2002;360:1921-1926. Longitudinal follow-up study of 5293 MSM in Baltimore, Chicago, Pittsburgh, LA. Men were followed from study entry to death, last time seen, or March 30, 2000 (whichever first: median followup 10.5 years). Total 1648 deaths, with 62 liver-related deaths.

11. Staging of Hepatitis B Infection

12. Staging of Hepatitis B Infection

13. Staging of Hepatitis B Infection

14. Staging of Hepatitis B Infection

15. Staging of Hepatitis B Infection

16. Staging of Hepatitis B Infection

17. Staging of Hepatitis B Infection

18. Endpoints of therapy

19. Rates of HBeAg seroconversion • Occurs at a rate of 8-12% yearly1 • With treatment, rate is increased to 15-27%1 • HBeAg loss has been associated with decreased rates of progression to cirrhosis or hepatocellular carcinoma2 • Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2001;34(6):1225-41. • Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med. 1996;334:1422-1427.

20. Cumulative survival (until liver transplantation or death) among Interferon-treated patients (solid lines) and untreated patients (dashed lines) compared to patients who did not lose HBeAg Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med. 1996;334:1422-1427.

21. HBV DNA suppression as an endpoint of therapy • 3 recent papers have demonstrated that HBV DNA suppression may be an important therapeutic goal, regardless of seroconversion • Conventional Wisdom • Chronic HBV does not need to be treated unless liver enzymes are elevated, liver biopsy is abnormal, or both • The cost/risk of treatment of HBV treatment do not outweigh the potential benefit in patients with low likelihood of HBeAg seroconversion

22. “Therapy should be reserved for patients who need to be treated, those with active liver disease exemplified by raised serum ALT and by clinical or histologic evidence or progressive disease, or both.” Jay Hoofnagle, NEJM, March 9 2006

26. Development of HCC was associated with viral load

28. Rx in HBeAg positive

29. New England Journal of Medicine, June 30, 2005

30. Rx in HBeAg positive

31. Rx in HBeAg positive

32. Rx in HBeAg positive

33. HBV Therapy

34. Recommendations for HBV treatment in HIV patients NOT on HAART • Pegylated interferon alpha 2a • (CD4 count >500) • Entecavir • Adefovir (!) • not Telbivudine (induce M204I mutation)

35. Recommendations for HBV treatment in HIV patients on HAART • Include in the regimen a drug that has activity against HBV • If HBV DNA levels are high, use two drugs • Be cautious when discontinuing or switching HAART • Hepatitis flares may occur with withdrawal of hepatitis B treatment

36. From Lai et al, Gastroenterology 2005;129:528. Monitoring on therapy 24 week viral suppression

37. Monitoring on therapy (some experts) • Based on GLOBE trial data, maximize early viral suppression at 24 weeks • Goal=1 log decrease every 3 months • Undetectable viral load should occur at some point during therapy if no eAg seroconversion

38. Resistance to nucleoside analogues *resistance occurs via two-hit mechanism with initial selection of M204 V/I mutation followed by amino acid substitutions at one of the rt-sites. In vitro studies showed that the mutations at positions 169,184,202, or 250 on their own have minimal effect on susceptibility to entecavir, but susceptibility is decreased by 10 to 250-fold when one of these mutations is present with lamivudine-resistant mutations, and by >500-fold when two or more entecavir-resistant mutations are present with lamivudine resistance mutations. **The N237 T mutation has been shown to be susceptible to lamivudine and entecavir in vitro, but the A181V mutation has reduced susceptibility to both lamivudine and entecavir in vitro, but remains sensitive to tenofovir

39. Manifestations of Antiviral Resistance 8 Antiviral Treatment Virologic rebound 6 ALT Hepatitis flare 4 HBV DNA (log10 IU/ml) Genotypic resistance Biochemical breakthrough 2 viral load 0 0 1 2 3 Years

40. Comparison of antiviral responses at 48 weeks of ADV therapy according to emergence of ADV-resistant mutations in LAM-Resistant patients from Lee et al, Hepatology June, 2006.

41. HBV DNA Levels Over Time 12 On-treatment Follow-up 10 PEGASYS® + placebo HBeAg serocon EOT = 27%; EOF = 32% -1.95 8 -2.61 Mean HBV DNA (log10 cp/mL) -2.39 PEGASYS® 6 + lamivudine -4.48* HBeAg serocon EOT = 24%; EOF = 27% -5.81 4 -7.18 lamivudine HBeAg serocon EOT = 20%; EOF = 19% 2 0 6 12 18 24 30 36 42 48 54 60 66 72 Lau et al AASLD 2004

42. Evidence that combination therapy may slow resistance • 29 HIV/HBV patients with documented lamivudine resistance • All were treated with adefovir 10 mg daily • None developed resistance to adefovir after 144 weeks (2.8 years) • All maintained lamivudine resistance • Only 25% developed HBV DNA below the level of detection (200 copies/ml) from Benhamou et al, Journal of Hepatology 44 (2006) 62-7.

43. Conclusions, hepatitis B treatment in HIV-coinfected patients • Include emtricitabine and tenofovir in HAART regimen if possible • If previously treated with lamivudine & emtricitabine and with high viral load, likely underlying lamivudine resistance, consider including entecavir (particularly if no response in first 6 months of treatment) • Goal of therapy is DNA suppression <10,000 copies/ml, or eAg seroconversion • Telbivudine likely not useful if underlying lamivudine resistance

44. B-yond

45. Future management of hepatitis B • Baseline genotyping on all patients • Resistance monitoring (?every 6 months) in treated patients

46. Two more things . . . • HBV vaccination • Hepatocellular carcinoma screening

47. Hepatitis B vaccination response rates • 87% if CD4 count > 500 • 33% if CD4 between 200-500 from Tenaldi et al, Clin Inf Dis 2004’38:1478-1484.

48. Hepatitis B vaccination • Hepatitis B vaccination should be given when CD4 count > 200 cells/ul • Otherwise HAART should be given first and then HBV vaccination given • If CD4 between 200-500, an intensive schedule is recommended1: • Months 0, 1, 2, and 6-12 • If no response a new cycle with 40 ug (double dose) 1Soriano et al, AIDS 2005, 19:221-240.

49. Liver Cancer

50. Hepatocellular carcinoma in patients with chronic hepatitis B Chronic HBV infection Cirrhosis HCC Decompensated cirrhosis Death