title: 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.
authors: ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, India.
authors: Ananya
authors: A
authors: Pal
authors: Neelakshi
authors: N
authors: Sarkar
authors: Debraj
authors: D
authors: Saha
authors: Subhashish K
authors: SK
authors: Guha
authors: Bibhuti
authors: B
authors: Saha
authors: Sekhar
authors: S
authors: Chakrabarti
authors: Runu
authors: R
authors: Chakravarty
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D060085:Coinfection; D003430:Cross-Sectional Studies; D004279:DNA, Viral / Q000097:blood; D024882:Drug Resistance, Viral / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007194:India; D019259:Lamivudine / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000821:virology; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D019562:Viral Load / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine