Background:  Chronic hepatitis B virus (HBV) infection is an important worldwide cause of morbidity and mortality, in subjects co-infected with HIV. Teonfovir disoproxil fumarate (TDF) is a frequent component of HAART. Although not studied in randomized controlled trials, it has been shown to have HBV activity. Our aims were to assess the non-inferiority of TDF compared with adefovir dipivoxil (ADV) with respect to HBV DNA (time-weighted average change from baseline to week 48); to assess the clinical response to ADV versus TDF; and to evaluate the safety and tolerability of ADV and TDF.

Methods:  A5127 was a randomized, double-blind, placebo-controlled trial of ADV vs TDF in HIV- and HBV-co-infected subjects on stable HAART with serum HBV DNA  ≥ 100,000 copies/mL and plasma HIV-1 RNA ≤1 0,000 copies/mL within 12 weeks prior to study entry. Subjects received daily either ADV 10 mg plus TDF placebo or TDF 300 mg with ADV placebo for up to 96 weeks. Subjects were seen every 4 weeks with laboratory evaluations. Non-inferiority was defined with a tolerance of –1 log. This study closed early based on the results of prespecified interim review. Results utilized the Haybitle-Peto boundary of 0.001 for the non-inferiority analysis.

Results:  As of August 2004, 52 subjects had been randomized:  92% male; median age 41 years; 56% Caucasian; 33% African American; median CD4 count 467 /mm³. At baseline, 75% of subjects had HIV RNA < 50 copies/mL and 98% had compensated liver disease; median serum HBV DNA was 8.71 log₁₀ copies/mL and 9.36 log₁₀ copies/mL in the ADV and TDF arms, respectively. Median duration of follow-up is 75 weeks. Mean log₁₀ time-weighted average change from baseline to week 48 was –4.44 on TDF and –3.21 on ADV, and the 99.9% lower bound on it was –0.05 logs, which confirms the non-inferiority of TDF. 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 elevations of serum ALT (flares) between 3.0 and 15.9 times baseline during therapy. Four subjects on each arm prematurely discontinued drug including 2 deaths (HCC at week 49 on ADV; unknown cause week 57 on TDF).

Conclusions:  Both ADV and TDF successfully lower HBV DNA and are safe and efficacious in HIV/HBV co-infected subjects over 48 weeks. ALT flares occur but did not lead to decompensation in these compensated subjects.

Keywords: Hepatitis B; Adefovir; Tenofovir