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Yves BENHAMOU

Yves BENHAMOU. Management of Patients with HIV/HBV Co-infection. Yves Benhamou Hepatology Department Groupe Hospitalier Pitié Salpétrière Paris, France. Influence of HIV on HBV. HIV in HBsAg positive patients (compared to HBV mono-infected):

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Yves BENHAMOU

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  1. Yves BENHAMOU

  2. Management of Patients with HIV/HBV Co-infection Yves Benhamou Hepatology Department Groupe Hospitalier Pitié Salpétrière Paris, France

  3. Influence of HIV on HBV HIV in HBsAg positive patients (compared to HBV mono-infected): • Increases the risk of chronicity after HBV contamination • Reduces the seroconversion rate to anti-HBe • Increases reactivation rate • Increases HBV replication • Accelerates fibrosis progression • Increases the risk of liver decompensation, HCC and liver death Bodsworth, JID 1989 ; Hadler, JID 1991 ; Krogsgaard, Hepatology 1987 ; Bodsworth, JID 1989 ; Gilson, AIDS 1997. Piroth, J Hepatol 2002 Vogel Cancer Res 1991; Corallini Cncer Res 1993 ; Altavilla Am J Pathol 2000 ; Bodsworth, JID 1989 ; Mills, Gastroenterol 1990 ; Goldin, J Clin Pathol 1990 ; Gilson, AIDS 1997 ; Thio, Lancet 2002. RR 8.3 (4.8-14.3) ; Di Martino, Gastroenterol 2002 ; Colin : Hepatol 1999 ; Di Martino, Gastroenterol ; Perillo, Ann Int Med 1986 ; McDonald, J Hepatol 1987 ; Colin, Hepatology 1999 ; Gilson, AIDS 1997

  4. HIV/CHB CoinfectionInfluence of HAART • Inhibition of HBV replication associated with histological improvement (LAM, FTC, TDF) • LAM reduces liver decompensation • Increases duration of CHB by improving survival • Increases the risk of ALT flares related to • Immune restoration • Hepatotoxicity • (Severe) reactivation • Low CD4 • ARV discontinuation • LAM resistance ? Proia et al. Am J Med 2000. Wit et al. JID 2002. Benhamou et al. J Hepatol 2005. Bruno et al. Gastroenerol 2002. Bonacini et al. Gastroenterol 2002. Puoti et al. Antiviral Ther 2004. Gouskos AIDS 2004

  5. HBsAg+ vs HBsAg+/HIV GHPS cohort Assessed by the METAVIR scoring system. Benhamou et al CROI 2005

  6. Liver Mortality Rate (per 1000 PY)MACS Thio et al. Lancet 2004

  7. Liver decompensation in HBsAg+ 1 HIV – (n=504) P=0.004 0.75 HIV + (n=164) Proportion of patients free Of liver decompensation 0.50 0.25 0 0 75 150 225 300 Follow up (months) Benhamou et al. CROI 2005

  8. Anti-HBV therapy • Objective: Decrease liver inflammation and fibrosis progression • Criteria for anti-HBV initiation: • HBV DNA • AgHBe+ > 20 000 UI/ml HBeAg+/- > 2000 UI/mL • AgHBe- > 2000 UI/ml Alberti A et al. J Hepatol. 2005 • Histology • METAVIR A≥2 or F≥2 Thresholds based on HBV mono-infected knowledge May be used in HIV/HBV co-infected patients Alberti A et al. J Hepatol. 2005

  9. Licensed for Treatment of CHB Lamivudine Adefovir dipivoxil Entecavir IFN/Pegylated IFN Licensed for Treatment of HIV Only with Demonstrated Anti-HBV Activity Tenofovir DF Emtricitabine HIV/HBV: Treatment

  10. IFN- in HBV /HIV co-infection 16 RCT IFN-vs placebo 837 HBsAg+ - 107 HIV+ included in 5 studies Placebo IFN Author(Yr.) n. Tx n. Controls Hoofnagle(88) 10 4 Brook (89) 16 6 Brook (89) 6 9 Pol (92) 16 14 Wong (95) 13 13 All 61 46 8,9 10 0 0,1 0,01 100 HBe seroconversion/negativation : HIV+ vs HIV: – 0.38 (CI 0.06-0.7 P =.02) Puoti et al. personnal comm.

  11. HIV/HBVLamivudine Serum HBV DNA • 2.7 log10 copies/mL Dore GJ, et al. J Infect Dis. 1999;180:607-613.

  12. HIV/HBVLamivudine Changes in ALT (UI/mL) during lamivudine therapy 300 HBV DNA >5x105 copies/mL at baseline 250 HBV DNA <5x105 copies/mL at baseline 200 P<0.05 150 ALT (UI/L) 100 50 0 Baseline 2 4 6 8 10 12 Lamivudine therapy duration (months) Y Benhamou et al. Ann Intern Med. 1996;125:705-712.

  13. FTC HBV+HIV d4T HBV+HIV FTC in Chronic HBV (FTCB-102) HIV/HBVFTC Log10 HBV DNA 24 22 20 20 17 33 33 33 33 33 10 10 10 7 7 FTC HBV+HIV FTC HBV d4T HBV+HIV FTC is not licensed for the treatment of HBV. Raffi F. IAS Conference, July 13-16, 2003, Abstract # 215.

  14. HIV/HBV LAM-R: ETV RDZ double blinded phase All the patients: ETV 1.0 mg 9.19 ETV PBO HBV DNA (log10 copies/ml) 5.56 5.63 4.79 Weeks Pessoa et al. ICAAC 2005

  15. HIV/HBV LAM-R: ETV ALT/AST flares (>3 x ULN) during ETV therapy Pessoa et al. ICAAC 2005

  16. - 4.7 log10 c/ml P<0.001* - 5.5 log10 c/ml p<0.001* - 5.9 log10 c/ml p<0.001* ADV (weeks) n = 35 31 31 31 30 29 29 27 27† HIV/HBV LAM-RADV HBV DNA (log10 copies/ml) HBV DNA (< 2.6 log10 copies/ml) 8/35 HBeAg negativation 3/33* HBe seroconversion 2/33* - 6.2 log10 c/ml p<0.001* * p<0.001 Wilcoxon Sign Rank Test †27 patients remain on study Benhamou et al. Lancet. 2001;358: 718-23. & J Hepatol. 2006;44:62-7.

  17. 180 145 110 Serum ALT (IU/mL) P<0.001 75 40 Bas. 12 24 36 48 60 72 84 88 92 Weeks of ADV HIV/HBV LAM-RADV Mean change from baseline (102.511.5 IU/L*) in serum ALT levels during ADV Benhamou et al. Lancet. 2001;358: 718-23. & J Hepatol. 2006;44:62-7.

  18. Week 48 Week 192 70% 50% Improved * 30% 50% 33% 10% 8% -10% 20% Worsened ** N = 15 12 -30% Improvement in Fibrosis - METAVIR Score* Median METAVIR Fibrosis Score at Baseline = 2 * Improvement defined as ≥1 point reduction ; ** Worsening defined as ≥ 1 point increase Benhamou Y et al. J Hepatol. 2006;44:62-7.

  19. Median (Q1-Q3) HBV DNA in HBeAg+ (n=72) HIV/HBVTDF Months of TDF *Roche Cobas Amplicor, LLQ 200 copies/mL Benhamou Y, et al. Hepatology. 2006;43:548-55.

  20. HIV/HBV: TDF Retrospective Analysis TDF added to 3TC HBV LAM-R vs TDF+ 3TC first line Mauss S. et al. EASL 2006

  21. Coinfection HBV: TDF TDF added to 3TC HBV LAM-R vs TDF+ 3TC first line Mauss S. et al. EASL 2006

  22. Coinfection HBV: TDF TDF added to 3TC HBV LAM-R vs TDF+ 3TC first line Mauss S. et al. EASL 2006

  23. TDF ADV HBV DNA (log10 c/mL)* ADV 25 24 23 20 18 17 TDF 27 26 23 18 17 18 HIV/HBVADV vs TDF *Roche Cobas Amplicor, LLQ 200 copies/mL Peters M et al. CROI 2005.

  24. PEG 2a + ADV in HIV/HBV LAM-R HBV DNA ALT PEGASYS + ADV PEGASYS + ADV Benhamou Y et al. ADPEG Study Preliminary report

  25. Patients (%) HBV resistance HIV/HBV HBV Lai C et al. N Engl J Med 1998. Leung N et al. J Hepatol 1999. Chang T et al. Antiv Ther 2000. Benhamou Y et al. Hepatology 1999. Benhamou Y et al. Lancet 2001 and AADSL 2003. Data on file. NV-02B-003. Idenix.

  26. HIV/HBV: TDF Resistance ? Sheldon J et al. Antiviral Ther. 2005

  27. Patients with no indication for anti-HIV therapy HBeAg, HBV DNA ALT Normal ALT Low HBV DNA* Elevated ALT High HBV DNA* MONITOR Evaluation of liver lesions METAVIR A≤1 F≤1 METAVIR A≥2 F≥2 Treat HBV only MONITOR HBeAg + ADV + ETV or + LdT PEG IFN ? HBeAg – Treat HBV only ADV + ETV or + LdT Management and therapeutic options in HBV/HIV • * HBV DNA • HBeAg+ : >20,000 IU/mL • HBeAg-: >2000 IU/mL Alberti A et al. J Hepatol. 2005 • HBeAg+/- > 2000 UI/mL Adapted from Alberti A et al. J Hepatol. 2005

  28. Management and therapeutic options in HBV/HIV Immediate indication for anti-HIV therapy Cirrhosis Low HBV DNA* High HBVDNA* Any ARV Lamivudine-naive ARV with Lamivudine resistant HBV Monitor HBV DNA ARV with TDF + tenofovir + Monitor liver function FTC/lamivudine FTC/lamivudine Substitute 1 NRTI with tenofovir or add tenofovir • * HBV DNA • HBeAg+ : >20,000 IU/mL • HBeAg-: >2000 IU/mL • HBeAg +/- > 2000 IU/mL Adapted from Alberti A et al. J Hepatol. 2005

  29. HBV/HIV Co-infected Patient CHB Hepatotoxicity 3TC, TDF, FTC activity Successful immune reaction Non compliance HBV Resistance Unsuccessful immune reaction Others Drug Alcohol HDV superinfection Concurrent medications Metabolic disorders … Control of HBV replication HBV «reactivation» Improvement of liver lesions Liver disease progression Cirrhosis

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