title: A randomized trial to evaluate continuation versus discontinuation of lamivudine in individuals failing a lamivudine-containing regimen: the COLATE trial.
abstract: BACKGROUND
  Lamivudine (3TC) therapy can cause the emergence of M1841/V. Previous studies suggest a higher fidelity of the mutant reverse transcriptase and lower replication capacity of the mutant virus. No data exist from clinical comparative studies evaluating the benefit of M1841/V in patients receiving combination antiretroviral therapy (cART).
  
  
  METHODS
  HIV-1-infected adults failing a 3TC-containing regimen were randomized to continue (On-3TC) or discontinue 3TC (Off-3TC) whilst receiving cART. The primary efficacy measure was the log10 average-area-under-the-curve-minus-baseline reduction in HIV RNA over 48 weeks. Cryopreserved plasma samples from patients with baseline and > or =1 follow-up sample with HIV RNA >500 copies/ml were sequenced for a nucleotide distances substudy. Evolutionary distances were compared between treatment arms and between viruses with and without M1841/V.
  
  
  RESULTS
  The overall 48-week log10 HIV RNA change was -1.4 (95% CI: -1.6, -1.1) for On-3TC (n=65) and -1.5 (95% CI: -1.7, -1.2) for Off-3TC (n=66; P=0.51). No difference was seen in the magnitude of the CD4+ T-cell count increases (median increase: 87 vs 76 cells/ml for 3TC vs Off-3TC, respectively). Thirty-seven patients had baseline and follow-up sequencing. Overall, there were 1.2 (95% CI: -2.2, 4.6) more nucleotide substitutions from baseline for Off-3TC patients (P=0.50), and 10.7 (95% CI: 7.5, 14.0) fewer nucleotide changes in viruses containing M18411V (P<0.0001).
  
  
  CONCLUSIONS
  This study found no added virological or immunological benefit of continuing 3TC in patients on cART harbouring M1841/V. Evolutionary distances from baseline were larger in viruses that did not contain M1841/V. More discernable benefits may be seen in patients with fewer drug options as potent cART may eclipse a benefit of M1841/V in COLATE.
authors.affiliation: Copenhagen HIV Programme (CHIP), Hvidovre University Hospital, Copenhagen, Denmark.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Fox
authors.forename: Ulrik B
authors.initials: UB
authors.lastname: Dragsted
authors.forename: Jan
authors.initials: J
authors.lastname: Gerstoft
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Phillips
authors.forename: Jesper
authors.initials: J
authors.lastname: Kjaer
authors.forename: Lars
authors.initials: L
authors.lastname: Mathiesen
authors.forename: Mike
authors.initials: M
authors.lastname: Youle
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.forename: Andrew
authors.initials: A
authors.lastname: Hill
authors.forename: Johan N
authors.initials: JN
authors.lastname: Bruun
authors.forename: Nathan
authors.initials: N
authors.lastname: Clumeck
authors.forename: Pierre
authors.initials: P
authors.lastname: Dellamonica
authors.forename: Jens D
authors.initials: JD
authors.lastname: Lundgren
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D054303:HIV Reverse Transcriptase