High Incidence of Lamivudine-Resistance-Associated Vaccine-Escape HBV Mutants among HIV-Coinfected Patients on Prolonged Antiretroviral Therapy

Abstract

Background

Worldwide, frequent emergence of lamivudine (3TC)-resistant HBV mutants has been reported in HIV–HBV-coinfected patients during long-term antiretroviral therapy (ART) that contains 3TC as the sole anti-HBV drug. Three major patterns of mutations in HBV polymerase gene, namely single (rtM204V), double (rtL180M+rtM204V) and triple (rtV173L+rtL180M+rtM204V) mutations, are associated with 3TC-resistance; additionally, the triple mutation has vaccine-escape potential due to a corresponding change in overlapping surface gene. Data from India, a major reservoir for HIV and HBV infection, is lacking. Here we investigated the effect of long-term 3TC treatment on virological response for HBV and characterized the 3TC-resistant HBV mutations in a cohort of HIV–HBV-coinfected patients from eastern India.

Methods

A cross-sectional study was performed in HIV-infected patients (n=563) receiving 3TC-containing ART for ≥6 months from the major ART centre of eastern India during 2011–2012. The hepatitis B surface antigen-positive HIV-infected patients (n=62) were categorized into four groups with comparable sample size according to the 3TC exposure for ≥6–<12 months (group I; n=15), ≥12–<24 months (group II; n=20), ≥24–<48 months (group III; n=13) and ≥48 months (group IV; n=14). Patients’ plasma samples were examined for hepatitis B e antigen (HBeAg), HBV DNA, viral load and covalently closed circular DNA (cccDNA). HBV reverse transcriptase region was sequenced.

Results

With a longer period of 3TC exposure, the frequency of HIV–HBV-coinfected patients having HBV DNA suppression decreased. The prevalence of HBeAg-positivity, serum HBV DNA load >2,000 IU/ml and 3TC-resistant mutations simultaneously increased. Remarkably, the 3TC-resistant triple mutation predominated over the double mutation in this cohort (32.26% versus 19.34%) and prevailed in significantly higher frequency among HBV viraemic patients experiencing 3TC for ≥48 months (60% versus 10%; P=0.03). Patients with 3TC-resistant triple mutants had HBV genotype-D, high serum HBV DNA load and elevated alanine aminotransferase level, and presence of cccDNA in their serum.

Conclusions

Considering this alarmingly high incidence of 3TC-resistant triple mutation and its possible clinical/ public health implications, proper management of 3TC-resistance among HIV–HBV-coinfected patients is an urgent necessity in India.