A randomized study of tenofovir containing HAART compared to lamivudine containing HAART in antiretroviral naïve HIV/HBV coinfected patients in Thailand: 48 week findings Matthews GV, Avihingsanon A, Lewin SR, Amin J, Rerknitmitr R, Petcharat P, Marks P, Sasadeusz J, Cooper DA, Bowden S, Locarnini S, Ruxrungtham K, Dore GJ

Background Prevalence of HBV in HIV populations ~ 5 -10% HIV/HBV coinfected individuals have high rates of progression to significant liver disease Lamivudine monotherapy for HBV results in high rates of drug resistance Evidence for optimal therapy of HBV in HIV coinfected individuals is based predominantly on observational data

Study design N=36 Primary objective AZT / LAM / EFV AZT / TDF / EFV To compare the safety and efficacy of tenofovir (TDF) to lamivudine (LAM) and to combination TDF/LAM in treating HBV in ARV- naive patients with HIV/HBV co-infection over 48 weeks AZT / LAM / EFV Gp 1 VK N=36 AZT / TDF / EFV Gp 2 VK LAM / TDF / EFV Gp 3 VK Week 12 Week 48

Study endpoints Primary endpoint HBV DNA time-weighted change over 48 weeks (DAVG) Secondary endpoints HBV DNA suppression HBeAg/HBsAg seroconversion HBV resistance Hepatic flare events ALT normalisation Change in HIV-RNA and CD4+ /CD8+ counts Histological improvement/reduction in ccc-HBV-DNA

Study set-up Australia-Thai collaboration HBV virology Subject recruitment through HIV-NAT, Bangkok, Thailand Study management NCHECR, Australia HBV virology performed at VIDRL, Australia HBV virology Bayer Versant bDNA assay (2,000 – 108 copies/ml) Roche Taqman assay (LLD 200 c/ml)

Study eligibility Inclusion criteria Exclusion criteria HIV positive and ARV naive HBsAg positive for > 6 months HBV DNA > 105 copies/ml No prior exposure to anti-HBV agents (excl IFN) Exclusion criteria HCV-RNA positive or Anti-HAV IgM positive Acute hepatitis (serum ALT > 1000 U/L) Active opportunistic infection Pregnancy or lactation Concurrent malignancy Decompensated or Child’s C cirrhosis AFP > 3X ULN

Baseline characteristics

Baseline characteristics : HBV * Clinical or histological

Median HBV reduction 48 weeks DAVG analysis 4.07 log 4.51 log 4.73 log p=0.700 This graph demonstrates the median HBV reduction over the 48 weeks in the 3 arms and visually you acns ee there is little difference between the groups. This is confirmed by the DAVG analysis which wwasth primary endpoint, demonstarting no significant difference in the values between groups although it was highest in the combination group.

HBV DNA suppression at 48 w On treatment

HBV resistance M204V/L180M HBV DNA reduction (log10 c/ml) No PCR M204I BL wk 4 wk 8 wk 12 wk 24 wk 36 wk 48 -1 M204V/L180M -2 No PCR HBV DNA reduction (log10 c/ml) -3 M204I -4 WT -5 -6

CD4 change P=0.048 P=0.072

HIV RNA suppression ITT

Hepatic flare Incidence 25% sAg loss Anti-HBE Anti-HBE sAg loss Reasons for hepatic flare in patients with HIV HBV who initiate HAART may be multifactoiral, and include drug toxicity, flare in HBV disease and immune reconstitution disease. In our patients hepatic falre was followed by seroconversion to anti-HBE in 2 and to anti-HBe followed by anti-HBs in two.

Serological response Group 1 LAM Group 2 TDF Group 3 LAM/TDF Total HBeAg loss* 3 (33%) 1 (17%) 3 (43%) 7 (32%) Anti-HBe Seroconversion* 1 (11%) 6 (27%) HBsAg loss 1 (8%) 1 (9%) 3 (8%) * Of 22 HBeAg positive at BL p=1.00

Conclusions Combination TDF/LAM not demonstrated as superior to monotherapy in this study Proportion of patients with HBV DNA > 3 log c/ml at week 48 significantly greater in LAM monotherapy arm 2 cases of LAM resistance both in GP 1 Good HIV control was achieved and maintained in the majority Both seroconversion and hepatic flare common after HBV-active HAART in this population

Acknowledgements HIV-NAT Thai Red Cross AIDS Research Centre, Bangkok, Thailand Anchalee Avihingsanon Kiat Ruxrungtham R Rerknitmitr P Petcharat Peeraporn Kaewon National Centre in HIV Epidemiology and Clinical Research Greg Dore David Cooper Pip Marks Janaki Amin Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia Stephen Locarnini Scott Bowden Anna Ayres Peter Revill The Alfred Hospital, Melbourne Sharon Lewin Joe Sasadeusz Jenny Hoy