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Optimizing Hepatitis B Virus Treatment in HIV-Infected Individuals

Optimizing Hepatitis B Virus Treatment in HIV-Infected Individuals. Chloe L. Thio, MD Associate Professor of Medicine The Johns Hopkins University. The International AIDS Society–USA. Natural History. HBsAg HBV DNA HBeAg/anti-HBe ALT/hepatitis Immune state Clinical. HBsAg+. HBsAg-.

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Optimizing Hepatitis B Virus Treatment in HIV-Infected Individuals

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  1. Optimizing Hepatitis B Virus Treatment in HIV-Infected Individuals Chloe L. Thio, MD Associate Professor of Medicine The Johns Hopkins University The International AIDS Society–USA

  2. Natural History HBsAg HBV DNA HBeAg/anti-HBe ALT/hepatitis Immune state Clinical HBsAg+ HBsAg- HBeAg+ Anti-HBe+ Reactivation Tolerance Active Non-replicative Incubation (wks-years) Symptoms (wks:self-limited or years:chronic) Inactive carrier (may last lifetime-risk of reactivation) Minimal Exposure

  3. Hepatitis B Virus – Replication Viral accessory proteins: HBeAg and HBX Export Viral entry Uncoating Assembly & budding ER Positive strand synthesis Nuclear import HBsAg Removal of pregenome cccDNA Repair Transcription Negative strand synthesis 5’ 3’ 2.4/2.1 kb RNA 5’ 3’ Translation 3.5 kb RNA Encapsidation CL Thio, MD.Presented at RWCA Clinical Update, August 2006.

  4. Classification of Hepatitis B Chronic HBsAg > 6 months Acute IgM anti-HBc Vaccine recipient Anti-HBs only Past infection Anti-HBs and anti-HBc

  5. Classification of Chronic Hepatitis B Chronic (HBsAg > 6 mo) HBeAg pos with active hepatitis ALT > 2x HBV DNA >105 Liver histology HBeAg neg with active hepatitis ALT > 2x HBV DNA >104 Liver histology HBeAg neg healthy carrier ALT <2x No HBV DNA No liver lesions

  6. Why treat HBV in HIV-infected persons • Co-infection is common-10% of HIV-infected • More rapid progression of liver disease • Increased risk of liver-related mortality • Increased risk of HAART-related hepatotoxicity • ?Immune reconstitution syndrome

  7. Increased Liver Mortality in HIV-HBV co-infected men: MACS • 5293 men (326 HBsAg+ baseline) followed 10.5 years • RR of liver death 18.7 in coinfected vs. only HBsAg+ 14.2 1.7 0.8 0.0 Thio et al, Lancet2002

  8. Available therapies for HBV FDA approved • Lamivudine* • Adefovir dipivoxil • Pegylated-interferon*-not tested in HIV+ • Entecavir Available but not FDA approved • Emtricitabine* • Tenofovir disoproxil fumarate* *active against HIV

  9. Adefovir dipivoxil for treatment of LMV-R HBV in HIV infected persons Observational cohort (n=35) receiving 10 mg ADV. 31 persons at 48 weeks and 29 at 144 weeks. Benhamou et al, J Hepatol 2006

  10. Double-blind, placebo-controlled study of ADF (10 mg) vs TDF (300 mg) Patients on stable HAART; n=52 HBV DNA >100,000 c/mL HIV RNA <10,000 c/mL Early termination when endpoints met ACTG A5127:TDFvs adefovir for HBV in HIV coinfection Serum HBV DNA DAVG48 (log10 c/mL) Mean change in HBV DNA from BL Peters M, et al. 12th CROI, Boston 2005, #124 DAVG: time-weighted average change from baseline

  11. Entecavir • Double-blind placebo controlled study of ETV vs. continuing LMV in LMV-R CHB for 24 wks • 68 HIV-HBV patients • Mean HBV DNA 9.13 log copies/ml • Mean HIV RNA 2 log copies/ml

  12. Development of LMV and ADV Resistant HBV • Emergence of resistance is clinically evident with elevation in ALT/AST • In US, 90% of coinfected persons with h/o LMV use Drug resistant HBV (%) Years on therapy

  13. Cross-resistance of Drug-Resistant HBV 1. Chin et al. AAC 2001; 45:2495. 4.Levine et al. AAC 2002; 46:2525. 2. Angus et al. Gastroenterology 2004; 125:297. 5. Tenny et al. AAC 2004 (in press). 3. Ono-Nita et al. AAC 2002; 46:2602.

  14. Strategies to treat HBV and not HIV Use agents that are not active against HIV to prevent development of drug-resistant HIV • Pegylated-interferon-alfa • HBeAg+, genotype A, elevated ALT • Entecavir • Adefovir • ?combination entecavir+ adefovir

  15. Strategies to treat HBV and HIV • All of the following should be used with HAART • LMV naive • First line: TDF plus LMV/FTC (emtricitabine) • Other considerations • Entecavir +/- TDF • PEG-IFN • LMV experienced • First line: Add TDF to LMV • Other considerations • Entecavir 1.0 mg- resistance with LMV-R HBV • Add ADV

  16. Summary • Treatment of HBV should be considered in HIV-infected persons. • Resistance occurs but rates vary. • Cross-resistance also occurs • Treatment plan is individualized based on need for HIV treatment and prior LMV therapy. • Prevent emergence of drug-resistant HBV and HIV. • More potent agents are needed. • Combination therapy needs further investigation.

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