Tenofovir is non-inferior to adefovir for the treatment of hepatitis B in HBV-HIV co-infected patients

Marion Peters and colleagues presented 48-week results from a randomised, double blind, placebo controlled trial study comparing tenofovir disoproxil fumarate (TDF) to adefovir dipivoxil (ADV) in coinfected patients. The non-inferiority design indeed showed that TDF was not inferior to ADV for the treatment of hepatitis B virus (HBV).

ADV 10mg is active against both wild type and lamivudine-resistant HBV and is licensed to treat HBV. TDF 300mg is licensed to treat HIV and has in vitro activity against both wild type and lamivudine-resistant HBV but this has not been studied in randomised, controlled trials. The aim of ACTG A5127 was to assess TDF 300mg daily compared to ADV 10mg daily using time weighted average change from baseline in serum HBV DNA up to week 48. Non-inferiority was defined as a tolerance of –1log10 copies/mL. The research was also designed to compare the clinical responses of the two drugs, and to evaluate safety and tolerability.

The subjects were coinfected patients on stable HAART with serum HBV DNA >100,000 copies/mL and plasma HIV-1 RNA < 10,000 copies/mL within 12 weeks prior to study entry.

52 subjects received either ADV with TDF placebo, or TDF with ADV placebo, for up to 96 weeks. The study closed early based on the results of a prespecified interim review.

At baseline, 75% of subjects had HIV RNA <50 copies/mL and 98% had compensated liver disease; median serum HBV DNA was 8.71 and 9.36 log10 copies/mL in the ADV and TDF arms respectively. Median duration of follow-up was 75 weeks. Mean log10 time-weighted average change from baseline to week 48 was–3.21 and –4.44 log in the adefovir and tenofovir arms respectively. The 99.9% lower bound on this reduction was –0.05 logs, which confirmed the non-inferiority of TDF.

However these results certainly appeared to show a trend for greater potency with tenofovir, and this point was raised by several questions from the audience. Gilead Sciences are the manufacturer of both these drugs.

In multi-covariate analysis, treatment arm (p = 0.017), baseline serum HBV DNA (p = 0.0001), and alkaline phosphatase (p = 0.033) were associated with time-weighted average change from baseline to week 48.

Laboratory abnormalities were noted in 18 subjects in each arm; 11 subjects (5 ADV, 6 TDF) experienced serum ALT flares between 3.0 and 15.9 times baseline. ALT flares did not lead to decompensation in these compensated subjects. Four subjects on each arm prematurely discontinued drug including 2 deaths.

Peters M, Anderson J, Lynch P et al. Tenofovir disoproxil fumarate is not inferior to adefovir dipivoxil for the treatment of hepatitis B virus in subjects who are co-infected with HIV: Results of ACTG A5127. 12th CROI, Boston, 2005.
Abstract 124.