Yves BENHAMOU Management of Patients with HIVHBV Coinfection

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 HBs. Ag positive patients (compared to HBV monoinfected): – 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 ; Mc. Donald, J Hepatol 1987 ; Colin, Hepatology 1999 ; Gilson, AIDS 1997

HIV/CHB Coinfection Influence of HAART • Increases duration of CHB by improving survival • Increases the risk of ALT flares related to – Immune restoration – Hepatotoxicity • (Severe) reactivation – Low CD 4 – ARV discontinuation – LAM resistance ? • Inhibition of HBV replication associated with histological improvement (LAM, FTC, TDF) • LAM reduces liver decompensation 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

HBs. Ag+ vs HBs. Ag+/HIV GHPS cohort HIV negative N=504 HIV positive N=164 P Median ALT< 2 x. ULN (%) 50 (45 -56) 26. 7 57 (47 -74) 29. 1 NS HBe. Ag + (%) 49. 9 78. 8% <. 0001 LAM-R HBV (%) 17. 1 34. 8% <. 0001 HBVDNA> 6 log (%) 37. 8 62. 1% <. 0001 Liver biopsy* N=469 N=54 <. 0001 Fibrosis (median) - Cirrhosis (%) 1 (1 -2) 16 2 (2 -2) 29. 6% <. 0001 Inflammation (median) - A 2/3 (%) 1 30. 1 1 34. 7 Assessed by the METAVIR scoring system. Benhamou et al CROI 2005

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

Liver decompensation in HBs. Ag+ Proportion of patients free Of liver decompensation 1 HIV – (n=504) P=0. 004 0. 75 HIV + (n=164) 0. 50 0. 25 0 0 75 150 225 300 Follow up (months) Benhamou et al. CROI 2005

Anti-HBV therapy • Objective: Decrease liver inflammation and fibrosis progression • Criteria for anti-HBV initiation: – HBV DNA • Ag. HBe+ > 20 000 UI/ml • Ag. HBe- > 2000 UI/ml HBe. Ag+/- > 2000 UI/m. L 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

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

IFN- in HBV /HIV co-infection 16 RCT IFN- vs placebo 837 HBs. Ag+ - 107 HIV+ included in 5 studies Author(Yr. ) Hoofnagle(88) Brook (89) Pol (92) Wong (95) n. Tx 10 16 6 16 13 n. Controls 4 6 9 14 13 All 61 46 Placebo IFN 8, 9 100 10 0 0, 1 0, 01 HBe seroconversion/negativation : HIV+ vs HIV: – 0. 38 (CI 0. 06 -0. 7 P =. 02) Puoti et al. personnal comm.

HIV/HBV Lamivudine Serum HBV DNA -2. 7 log 10 copies/m. L Dore GJ, et al. J Infect Dis. 1999; 180: 607 -613.

HIV/HBV Lamivudine Changes in ALT (UI/m. L) during lamivudine therapy 300 HBV DNA >5 x 105 copies/m. L at baseline 250 HBV DNA <5 x 105 copies/m. L at baseline ALT (UI/L) 200 P<0. 05 150 100 50 0 Baseline 2 4 6 8 10 12 Lamivudine therapy duration (months) Y Benhamou et al. Ann Intern Med. 125: 705 -712. ; 1996

Log 10 HBV DNA HIV/HBV FTC HBV+HIV FTC HBV d 4 T HBV+HIV 24 33 10 22 33 10 20 33 7 17 33 7 FTC HBV+HIV FTC is not licensed for the treatment of HBV. Raffi F. IAS Conference, July 13 -16, 2003, Abstract # 215. d 4 T HBV+HIV FTC in Chronic HBV (FTCB-102)

HIV/HBV LAM-R: ETV RDZ double blinded phase All the patients: ETV 1. 0 mg HBV DNA (log 10 copies/ml) 9. 19 ETV 5. 56 PBO 5. 63 4. 79 Weeks Pessoa et al. ICAAC 2005

HIV/HBV LAM-R: ETV ALT/AST flares (>3 x ULN) during ETV therapy Number of patients (%) ETV W 24 ETV W 48 PBO W 24 PBO ETV W 48 ALT 5 (10) 2 (4) 0 (0) 2 (12) AST 5 (10) 0 0 (0) 2(12) Pessoa et al. ICAAC 2005

HBV DNA (log 10 copies/ml) HIV/HBV LAM-R ADV n= HBV DNA (< 2. 6 log 10 copies/ml) 8/35 HBe. Ag negativation 3/33* HBe seroconversion 2/33* - 4. 7 log 10 c/ml P<0. 001* 35 31 31 * p<0. 001 Wilcoxon Sign Rank Test † 27 patients remain on study - 5. 5 log 10 c/ml p<0. 001* 31 30 - 6. 2 log 10 c/ml p<0. 001* - 5. 9 log 10 c/ml p<0. 001* 29 29 27 27† ADV (weeks) Benhamou et al. Lancet. 2001; 358: 718 -23. & J Hepatol. 2006; 44: 62 -7.

HIV/HBV LAM-R ADV Serum ALT (IU/m. L) 180 Mean change from baseline (102. 5 11. 5 IU/L*) in serum ALT levels during ADV 145 110 P<0. 001 75 40 Bas. 12 24 36 48 60 72 84 88 92 Weeks of ADV Benhamou et al. Lancet. 2001; 358: 718 -23. & J Hepatol. 2006; 44: 62 -7.

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

HIV/HBV TDF Median (Q 1 -Q 3) HBV DNA in HBe. Ag+ (n=72) Months of TDF *Roche Cobas Amplicor, LLQ 200 copies/m. L Benhamou Y, et al. Hepatology. 2006; 43: 548 -55.

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

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

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

HIV/HBV ADV vs TDF HBV DNA (log 10 c/m. L)* ADV TDF ADV 25 24 23 20 18 17 TDF 27 26 23 18 17 18 *Roche Cobas Amplicor, LLQ 200 copies/m. L Peters M et al. CROI 2005.

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

HBV resistance HIV/HBV Patients (%) 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-02 B-003. Idenix.

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

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

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

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