title: Mutations in HIV-1 reverse transcriptase during therapy with abacavir, lamivudine and zidovudine in HIV-1-infected adults with no prior antiretroviral therapy.
abstract: OBJECTIVE
  To evaluate HIV-1 reverse transcriptase (RT) drug resistance in patients receiving abacavir, lamivudine and zidovudine therapy.
  
  
  METHODS
  In a randomized, double-blind study, 173 antiretroviral treatment-naive HIV-1-infected adults received abacavir/lamivudine/zidovudine or lamivudine/zidovudine for up to 48 weeks. After week 16, patients could switch to open-label abacavir/lamivudine/zidovudine, and those with plasma HIV-1 RNA (vRNA) > 400 copies/ml could add other antiretrovirals. From weeks 11 to 48, samples with vRNA > 400 copies/ml were collected for genotyping and phenotyping.
  
  
  RESULTS
  At baseline, 90% of isolates were wild-type (WT). At week 16, vRNA was > 400 copies/ml in seven of 72 (10% patients receiving abacavir/lamivudine/zidovudine and in 41 of 66 (62%) receiving lamivudine/ zidovudine. At week 16, the genotypes in isolates from the abacavir/lamivudine/zidovudine group were M184V alone (n = 3 cases), WT (n = 3) and M184V plus thymidine analogue mutations (TAMs) (n = 1). The genotypes in isolates from the lamivudine/zidovudine group were M184V alone (n = 37), WT ( n= 1) and M184V plus TAMs (n = 3). In the four cases where M184V plus TAMs were detected some mutations were present at baseline. Despite detectable M184V in 74% of patients on lamivudine/zidovudine, addition of abacavir with or without another antiretroviral therapy resulted in a reduction in vRNA, with 42 of 65 (65%) patients having week 48 vRNA < 400 copies/ml (intent-to-treat with missing = failure). At week 48, the most common genotype was M184V alone in the abacavir/ lamivudine/zidovudine group (median vRNA 1-2 log,10 below baseline), and M184V with or without TAMs in patients originally assigned to lamivudine/zidovudine. At week 48, phenotypic results were obtained for 11 isolates for patients from both arms, and all had reduced susceptibility to lamivudine but all remained sensitive to stavudine, all protease inhibitors and all non-nucleoside reverse transcriptase inhibitors. Three, three and two isolates had reduced susceptibility to abacavir, didanosine and zidovudine, respectively.
  
  
  CONCLUSIONS
  Abacavir retained efficacy against isolates with the M184V genotype alone. TAMs did not develop during 48 weeks of abacavir/lamivudine/zidovudine therapy and were uncommon when abacavir was added after 16 weeks of lamivudine/zidovudine therapy. Limited mutations upon rebound on this triple nucleoside combination allows for several subsequent treatment options.
authors: GlaxoSmithKline Research and Development, Stevenage, UK. mak75231@glaxowellcome.co.uk
authors: Mounir
authors: M
authors: Ait-Khaled
authors: Abdelrahim
authors: A
authors: Rakik
authors: Philip
authors: P
authors: Griffin
authors: Amy
authors: A
authors: Cutrell
authors: Margaret A
authors: MA
authors: Fischl
authors: Nathan
authors: N
authors: Clumeck
authors: Stephen B
authors: SB
authors: Greenberg
authors: Rafael
authors: R
authors: Rubio
authors: Barry S
authors: BS
authors: Peters
authors: Federico
authors: F
authors: Pulido
authors: Jayne
authors: J
authors: Gould
authors: Gill
authors: G
authors: Pearce
authors: William
authors: W
authors: Spreen
authors: Margaret
authors: M
authors: Tisdale
authors: Steve
authors: S
authors: Lafon
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D015224:Dideoxynucleosides / Q000008:administration & dosage; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005838:Genotype; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage; D009154:Mutation; D010641:Phenotype; D015215:Zidovudine / Q000008:administration & dosage; D000099227:Abacavir
chemical_list: D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D054303:HIV Reverse Transcriptase; D019259:Lamivudine; D015215:Zidovudine; D000099227:Abacavir