title: Hepatitis B virus sub-genotype A1 infection is characterized by high replication levels and rapid emergence of drug resistance in HIV-positive adults receiving first-line antiretroviral therapy in Malawi.
abstract: BACKGROUND
  It has been proposed that hepatitis B virus (HBV) sub-genotype A1 infections have mild outcomes and a low risk of drug-resistance among patients infected with human immunodeficiency virus (HIV) receiving lamivudine-containing antiretroviral therapy (ART) without tenofovir in Africa.
  
  
  METHODS
  The virologic expression of HBV sub-genotype A1 coinfection was studied over 12 months in HIV-positive adults starting stavudine/lamivudine/nevirapine in Malawi, using Sanger, deep, clonal, and single full-genome sequencing for the sensitive characterization of HBV resistance-associated mutations (RAMs).
  
  
  RESULTS
  Among 1117 subjects, 133 (12%) tested HBsAg-positive. After starting ART, retention rates were 96/133 (72%) at 6 months and 54/133 (41%) at 12 months. Based upon the last available follow-up, 92/96 (96%) subjects achieved HIV-1 RNA <40 copies/mL, 48/96 (50%) showed HBV DNA <14 IU/mL, and 24/96 (25%) acquired HBV RAMs. At 6 months, M204I was detected in 8/46 (17%) and 16/17 (94%) subjects using Sanger and deep sequencing, respectively. At 12 months, all viremic patients had multiple resistance and compensatory mutations coexisting on the same HBV genomes. Comparing HBeA-positive (67/133, 50%) with HBeAg-negative subjects, 64/67 (96%) vs 35/66 (55%) showed baseline HBV DNA >2000 IU/mL (P = .0006), 39/47 (17%) vs 9/49 (82%) had persistent HBV DNA detection during follow-up (P < .0001), and 23/47 (49%) vs 2/49 (4%) acquired HBV RAMs (P < .0001). Baseline HBV DNA levels were median 8.1 vs 5.3 log10 IU/mL in subjects with vs those without treatment-emergent RAMs (P < .0001).
  
  
  CONCLUSIONS
  HBV sub-genotype A1 infections showed a severe virologic expression in HIV-positive Malawians. The findings strengthen the urgency of interventions to improve ascertainment and management of chronic hepatitis B in the region.
authors.affiliation: Division of Infection & Immunity and London Centre for Nanotechnology.
authors.forename: Samir
authors.initials: S
authors.lastname: Aoudjane
authors.affiliation: Department of Infectious Diseases, University of Liverpool/Malawi Liverpool Wellcome Trust, United Kingdom.
authors.forename: Mas
authors.initials: M
authors.lastname: Chaponda
authors.affiliation: Division of Infection & Immunity and London Centre for Nanotechnology.
authors.forename: Antonio Adrián
authors.initials: AA
authors.lastname: González Del Castillo
authors.affiliation: Department of Infection & Population Health, University College London.
authors.forename: Jemma
authors.initials: J
authors.lastname: O'Connor
authors.affiliation: IrsiCaixa & AIDS Unit, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Noguera
authors.affiliation: Institute of Infection and Global Health.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Beloukas
authors.affiliation: Department of Virology.
authors.forename: Mark
authors.initials: M
authors.lastname: Hopkins
authors.affiliation: Institute of Translational Medicine, University of Liverpool, United Kingdom.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: College of Medicine, University of Malawi, Blantyre Dignitas International, Zomba, Malawi.
authors.forename: Joep J
authors.initials: JJ
authors.lastname: van Oosterhout
authors.affiliation: Institute of Infection and Global Health.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Geretti
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006509:Hepatitis B / Q000188:drug therapy / Q000821:virology*; D006515:Hepatitis B virus / Q000145:classification / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019259:Lamivudine / Q000009:adverse effects / Q000627:therapeutic use; D008295:Malawi; D008297:Male; D019829:Nevirapine / Q000009:adverse effects / Q000627:therapeutic use; D010802:Phylogeny; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D018119:Stavudine / Q000009:adverse effects / Q000627:therapeutic use; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D004279:DNA, Viral; C516355:stavudine, lamivudine, nevirapine drug combination; D019259:Lamivudine; D019829:Nevirapine; D018119:Stavudine
keywords: Africa; lamivudine; resistance; sub-genotype A1; viral load
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