Background:  Entecavir (ETV) is a potent and selective hepatitis B virus (HBV) inhibitor with no known intracellular interactions with other nucleoside/nucleotides. Resistance emergence has not been observed in nucleoside-naive patients treated with ETV for 2 years. Virologic rebounds due to ETV resistance (ETVr), observed in 1% of lamivudine (3TC)-refractory patients treated with ETV at 1 year, required the pre-existence of 3TC resistance (3TCr) substitutions (rtM204I/V ± rtL180M) and an additional substitution at HBV RT residues rtT184, rtS202, or rtM250. These additional substitutions are selected by 3TC and were present at low frequencies at study entry. Since 3TC is frequently used for prolonged periods in HIV/HBV-co-infected patients, a double blind comparative trial (AI463038) was conducted to determine the efficacy of 1.0 mg daily ETV in HIV/HBV-co-infected patients experiencing HBV viremia during therapy on 3TC-containing HAART regimens.

Methods:  The HBV RT gene was polymerase chain reaction (PCR) amplified from serum DNA and sequenced at study entry and Week 48. Susceptibility assays on all emerging substitutions were conducted in HepG2 cells transfected with recombinant viruses.

Results:  At study entry, 48 of 50 (96%) of the samples sequenced had 3TCr substitutions in the HBV RT, while none had ETVr substitutions (rtT184, rtS202 or rtM250) detectable by standard sequencing. The median ETV EC₅₀ of these 48 baseline samples was 22.7 nM (range = 3.3 to 64.8 nM), within the EC₅₀ range normally observed for 3TCr HBV. The mean HBV DNA level at baseline was 9.13 log₁₀ copies/ml, which was reduced 4.20 log₁₀ copies/mL for the 43 patients that reached week 48 of treatment. Of treated patients, 9% achieved HBV DNA levels <300 copies/mL and no patients exhibited a virologic rebound. Genotypic detection of ETVr substitutions at residues rtT184S and rtS202C was evident in 2 patients at week 48, and both substitutions were subsequently found at study entry using a highly sensitive single nucleotide polymorphism assay. On ETV treatment, 19 novel substitutions also emerged, but none were correlated with reduced susceptibility to ETV in phenotypic assays.

Conclusions:  HIV/HBV-co-infected patients with 3TC-refractory HBV treated with ETV for 48 weeks experienced significant HBV DNA reductions and no virologic rebounds. Two patients experienced an enrichment of ETVr virus present at very low levels at study entry. ETV is a valuable treatment option for chronic HBV in patients co-infected with HIV.