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Hepatitis B Virus (HBV) and HIV Current Management Strategies Gregory P. Melcher, M.D. Division of Infectious Diseases UC Davis AETC Hepatitis B Virus (HBV) and HIV Current Management Strategies • • • • • Epidemiology Diagnosis Treatment Monitoring Vaccination Disclosures: none 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 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 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 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. 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)61425-1 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 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 HBV Infection Natural History Diagnosis of HBV Infection 44 yo male • Hepatitis B surface antigen (HBsAg) • HBsAb • Hepatitis B core antibody (HBcAb) IgM • HBcAb total + Poll #1 25 yo female • HBsAg + • HBeAg + • HBcAb total + 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 Diagnosis of HBV Infection Phase HBsAg HBcAb total HBeAg HBeAb HBsAb HBV DNA Immune active + + + - - + Inactive carrier + + _ + - - (or low level +) Diagnosis of HBV Infection 32 yo male • HBsAg • HBcAb total + • HBsAb + Poll #2 19 yo female • HBsAg • HBcAb – • HBsAb + Diagnosis of HBV Infection Phase Resolved HBV infection Vaccinated HBsAg HBcAb IgM HBcAb Total HBsAb HBV DNA - - + + - - - - + - 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 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 Clinical Case • • • • HIV Western Blot reactive Viral load 75,150 copies/ml CD4 cell count 750 HBsAg -, HBcAb IgM +, HBcAb total -, HBsAb - Poll #4 Diagnosis of HBV Infection Phase HBsAg HBcAb IgM HBcAb Total HBsAb HBV DNA Acute HBV infection + + - - + Acute HBV “window period” - + - - + or - 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) 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)61425-1 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 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 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 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 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 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 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 Monitoring HBV Treatment • Goal: suppress HBV viral load to undetectable • Monitor HBV DNA level at 3-6 month intervals – Virologic response is > 2 log10 copies/ml decrease from baseline at 6 months – No role for additional anti-HBV agents if not able to reach undetectable 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 Monitoring HBV Treatment • Elevated aminotransferases – Chronic HVB infection – Immune reconstitution inflammatory syndrome (IRIS) – Drug related liver injury – Emergence of HBV drug resistance 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 HBV Drug Resistance • Inferred when > 1 log10 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 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 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? 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 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 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 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 Hepatitis B Virus (HBV) and HIV Current Management Strategies • • • • • Epidemiology Diagnosis Treatment Monitoring Vaccination References • • • • • Hepatits B and HIV Coinfection http://hivinsite.ucsf.edu/InSite?page=kb-0503-04#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)61425-1