1. Hepatitis B Virus (HBV) and HIV Current Management Strategies Gregory P. Melcher, M.D. Division of Infectious Diseases UC Davis AETC

2. Hepatitis B Virus (HBV) and HIV Current Management Strategies Epidemiology Diagnosis Treatment Monitoring Vaccination Disclosures: none

3. Global HBV Epidemiology Leading cause of chronic liver disease Accounts for 50% of global cases of cirrhosis and hepatocellular carcinoma (HCC) 400 million people infected; highest rates in Asia and Africa –70% of adults current or past infection –8-15% chronic HBV infection

4. HBV/HIV Epidemiology 70-90% of HIV-infected persons in US have evidence of past or active Hepatitis B virus (HBV) infection In US, HBV most often acquired in adolescence or adulthood via intravenous drug use (IVDU) or sexual contact Spontaneous clearance in > 90%, but only in about 45% of HIV-infected persons acutely infected with HBV –20-40% of all HIV/HBV co-infected are chronic

5. HBV/HIV Epidemiology Prevalence of chronic HBV infection among HIV-infected persons –5-10% HBV/HIV co-infection in US and Western Europe Higher in men who have sex with men (MSM) and IVDU –20-30% HBV/HIV co-infection in Asia and parts of sub-Saharan Africa Chronic HBV infection develops in 90% of HBV infected infants in Asia and sub-Saharan Africa

6. Interaction of HBV/HIV Coinfection In era of highly active antiretroviral therapy (ART) –Declining rates of opportunistic infections –Prolonged lifespan for HIV-infected persons –Increase in other diseases causing morbidity and mortality End-stage liver disease (ESLD) from HBV and HCV Most frequent cause of death from non-AIDS defining condition Weber, R et al. Arch Intern Med 2006; 166:1632.

7. Interaction of HBV/HIV Coinfection Co-infected patients have higher levels of HBV DNA, lower rates of clearance of Hepatitis B early antigen (HBeAg) Increased risk of cirrhosis and ESLD Increased risk of hepatocellular carcinoma (HCC) if develop cirrhosis –Worldwide, 50% of all cases of HCC due to HBV; 80% develop in setting of cirrhosis* *Marcellin P, et al. www.thelancet.com http:..dx.doi.org/10.1016/S0140-6736(12)61425-1www.thelancet.com

8. Interaction of HBV/HIV Coinfection More frequent flares of hepatic enzymes –Immune reconstitution syndrome (IRIS) –Interruption of HIV/HBV treatment –Development of resistance to HIV/HBV treatment

9. HBV Infection Natural History Stages can be linear, but reversions also occur –Immune tolerant phase – high level of HBV replication, little or no hepatic inflammation –Immune active phase – elevated liver enzymes and liver inflammation on biopsy –Inactive carrier phase – HBeAg is lost, may convert to early antibody (HBeAb), then undergoes Hepatitis B surface antibody (HBsAb) conversion indicating immune control Small proportion remain DNA positive, “occult” HBV infection

10. HBV Infection Natural History

11. Diagnosis of HBV Infection 44 yo male Hepatitis B surface antigen (HBsAg) - HBsAb - Hepatitis B core antibody (HBcAb) IgM - HBcAb total + 25 yo female HBsAg + HBeAg + HBcAb total + Poll #1

12. Diagnosis of HBV Infection 44 yo male Isolated HBcAb –“Occult” HBV viremia Confirm with HBV DNA –Waned HBsAb response –False positive HBcAb Recommend HBV DNA viral load for all patients with isolated HBcAb total positive 25 yo female Chronic HBV infection Define activity based on liver enzymes and HBV DNA level –Immune tolerant phase vs. immune active phase vs. inactive carrier phase

13. Diagnosis of HBV Infection PhaseHBsAgHBcAb total HBeAgHBeAbHBsAbHBV DNA Immune active +++--+ Inactive carrier ++_+- - (or low level +)

14. Diagnosis of HBV Infection 32 yo male HBsAg - HBcAb total + HBsAb + 19 yo female HBsAg - HBcAb – HBsAb + Poll #2

15. Diagnosis of HBV Infection PhaseHBsAgHBcAb IgM HBcAb Total HBsAbHBV DNA Resolved HBV infection --++- Vaccinated ---+-

16. Clinical Case 22 yo male with multiple unprotected sexual encounters with men malaise, fatigue, anorexia Mild scleral icterus, tender to palpation in RUQ HIV rapid test reactive Poll #3

17. Clinical Case Serum for confirmatory Western Blot, RPR, liver panel –HIV RNA and genotype CBC for absolute lymphocyte count –CD4 cell count Hepatitis panel –HAV IgM, HBsAg, HBcAb IgM, HBcAb total, HBsAb, HCV Ab Urine for GC/Chlamydia NAT, rectal and pharyngeal culture for GC

18. Clinical Case HIV Western Blot reactive Viral load 75,150 copies/ml CD4 cell count 750 HBsAg -, HBcAb IgM +, HBcAb total -, HBsAb - Poll #4

19. Diagnosis of HBV Infection PhaseHBsAgHBcAb IgM HBcAb Total HBsAbHBV DNA Acute HBV infection ++--+ Acute HBV “window period” -+--+ or -

20. HBV/HIV Coinfection Goals of treatment –Suppress HBV replication (HBV DNA level) and minimize resultant hepatic damage –Seroconversion of HBeAg to HBeAb Transition from active liver disease to inactive carrier state –Seroconversion of HBsAg to HBsAb Transition from inactive carrier state to resolution of infection (rare for HIV/HBV coinfected)

21. HBV/HIV Coinfection Goals of treatment –Prevent or reverse fibrosis/cirrhosis* 5 years of treatment with tenofovir – 51% had regression of fibrosis on liver biopsy Virologic breakthrough rare; not due to resistance to tenofovir –Prevent hepatocellular carcinoma Indirectly through decrease in hepatic fibrosis *Marcellin P, et al. www.thelancet.com http:..dx.doi.org/10.1016/S0140-6736(12)61425-1www.thelancet.com

22. HBV/HIV Coinfection Treatment Prior to 2013 DHHS HIV infection treatment guidelines revision –HIV/HBV-coinfected persons with abnormal alanine aminotransferase (ALT) values and HBV DNA levels > 2,000 IU/ml –Corresponds with active HBV infection Current expert opinion is to treat HIV/HBV infection concomitantly with ART active for both viruses if feasible

23. HBV/HIV Coinfection Treatment pitfalls –Some HBV drugs have efficacy against HIV and should not be used alone without full HIV treatment regimen to prevent HIV resistance Lamivudine (3TC) Emtricitabine (FTC) Tenofovir Entecavir* Telbivudine* *denotes HBV treatment only

24. HBV/HIV Coinfection Treatment HBV resistance –Commonly occurs when 3TC or FTC used alone; rare with tenofovir, entecavir –HBV genotype can detect resistance Not indicated pre-treatment for naïve patients Failure to suppress HBV DNA or rebound Flare of hepatitis –Associated with discontinuation of HBV treatment or development of drug resistance

25. HBV Treatment Options Interferon – low HBV viral load Nucleoside/nucleotide analogues –Lamivudine (3TC) and emtricitabine (FTC) –Entecavir – potent –Telbivudine –not indicated if 3TC/FTC failure –Adefovir – less potent, active if 3TC resistance –Tenofovir (TDF) TDF/FTC superior to TDF alone in HIV/HBV coinfected* *Matthews, GV CID (2013) doi:10.1093/cid/cit02

26. Clinical Case HIV infection and “window period” acute HBV infection Treatment options –Treat HIV and wait to see if HBV becomes chronic –Treat HIV and HBV –Repeat serology in 6-8 weeks to see if resolves with HBsAb Poll #5

27. Clinical Case Repeat HBV serology 6 weeks later –HBsAg +, HBcAb total +, HBeAg +, HBV DNA 100, 000 copies/ml –Immune active carrier DHHS HIV treatment guidelines 2013 –All preferred regimens include tenofovir (TDF) and emtricitabine (FTC) plus either efavirenz (EFV) or a boosted protease inhibitor (atazanavir or darunavir) or raltegravir

28. Clinical Case Start patient on TDF/FTC/EFV (Atripla) At 8 weeks, no significant side effects other than vivid dreams HIV RNA level 250 copies/ml Poll #6

29. Monitoring HBV Treatment Goal: suppress HBV viral load to undetectable Monitor HBV DNA level at 3-6 month intervals –Virologic response is > 2 log 10 copies/ml decrease from baseline at 6 months –No role for additional anti-HBV agents if not able to reach undetectable

30. Monitoring HBV Treatment HBeAg+ –Higher levels of HBV DNA –Monitor for seroconversion every 3-6 months –Unclear if able to stop HBV therapy if converts to HBeAb HBsAg –Monitor annually; rare to seroconvert

31. Monitoring HBV Treatment Elevated aminotransferases –Chronic HVB infection –Immune reconstitution inflammatory syndrome (IRIS) –Drug related liver injury –Emergence of HBV drug resistance

32. HBV/HIV Coinfection and IRIS HBV is an immune-mediated disease Enhanced immunity with reconstitution of immune system with ART –Higher levels of HIV RNA and CD4 < 200 –Usual onset within 4-8 weeks of starting ART –Associated with > 50 CD4 cells Symptoms of acute hepatitis Usually resolves spontaneously

33. HBV Drug Resistance Inferred when > 1 log 10 copies/ml increase in HBV DNA viral load from nadir Highest risk for monotherapy with either lamivudine or emtricitabine Rare with entecavir –Overlaps with lamivudine resistance Not reported with tenofovir Identify by requesting HBV resistance genotype

34. HCC Screening HCC can develop even in absence of cirrhosis Screen with serum alpha-feto protein (AFP) and hepatic ultrasound every 6-12 months –Higher risk is for patients with HBV/HIV coinfection; many experts recommend screening every 6 months

35. Clinical Case Two years on TDF/FTC/EFV –HIV RNA viral load < 20 copies/ml –HBV DNA viral load < 40 copies/ml –Develops renal insufficiency due to tenofovir What options are available for continuing to treat both HIV and HBV infections?

36. HBV Treatment Options Interferon – low HBV viral load Nucleoside/nucleotide analogues –Lamivudine and emtricitabine –Entecavir – potent –Telbivudine –not indicated if 3TC/FTC failure –Adefovir – less potent, active if 3TC resistance –Tenofovir

37. Clinical Case HLA B5701 allele negative Change ART to abacavir/lamivudine (Epzicom) + EFV Add entecavir 0.5 mg daily for HBV Repeat monitoring in 6 weeks –HBV DNA < 40 copies/ml –HIV RNA < 20 copies/ml

38. HBV Vaccination Recommended for all HIV infected persons lacking HBsAb and are HBsAg- Response rates 18-71% –Lower seroconversion rates associated with low CD4 cell count, high HIV RNA and HCV –Higher dose (40 mcg – 47%) vs. standard dose (20 mcg – 34%) recommended by experts

39. HBV Vaccination If vaccinated with CD4 cell count < 200, may need to repeat if HBsAb < 10 IU/ml Check HBsAb 1-2 months after series completed; repeat with 40 mcg dose if not immune Some experts recommend annual HBsAb testing; re-dosing if falls < 10 IU/ml

40. Hepatitis B Virus (HBV) and HIV Current Management Strategies Epidemiology Diagnosis Treatment Monitoring Vaccination

41. References Hepatits B and HIV Coinfection http://hivinsite.ucsf.edu/InSite?page=kb-05- 03-04#S1Xhttp://hivinsite.ucsf.edu/InSite?page=kb-05- 03-04#S1X Weber R, Sabin CA, Frils-Møller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006 Aug 14-28;166(15):1632-41. Zoutendijk R, Zaaijer HL, deVries-Sluijs TE, et al. Hepatits B surface antigen decline and clearance during long-term tenofovir therapy in patients coinfected with HBV and HIV. J Infect Dis. 2012 15 Sep; 206:974-980. Peters MG, Koziel MJ. Viral hepatitis in HIV infection. N Engl J Med. 2007 Apr 5; 356:1445-1454. Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. http://dx.doi.org/10.1016/50140-6736(12)61425-1http://dx.doi.org/10.1016/50140-6736(12)61425-1