title: Population-based sequencing of the V3-loop can predict the virological response to maraviroc in treatment-naive patients of the MERIT trial.
abstract: BACKGROUND
  MERIT was a randomized trial comparing maraviroc (MVC) + Combivir versus efavirenz (EFV) + Combivir in drug-naive patients screened as having R5 HIV-1 by the original Trofile assay (OTA). We retrospectively evaluated treatment response after rescreening for viral tropism using population-based V3-loop sequencing.
  
  
  METHODS
  HIV env V3-loop was amplified in triplicate using reverse transcriptase-polymerase chain reaction from stored screening plasma and sequenced. Automated base calling was performed using custom software (RECall) and tropism inferred by geno2pheno (5.75% false-positive rate). Tropism results by genotype were compared with those of OTA and Enhanced Sensitivity Trofile assay (ESTA), where all results were available (n = 876).
  
  
  RESULTS
  Approximately 8% of patients screened as having R5 virus by OTA were classified as having non-R5 virus by V3-loop genotyping. These patients were less likely to have early or sustained week-48 treatment response to MVC, but not EFV. When restricted to patients with R5 virus by genotype, reanalysis of the primary study endpoint (plasma viral load <50 copies/mL at week 48) showed noninferiority of MVC twice daily to EFV (67% vs. 68%). Rescreening by genotype and ESTA had 84% concordance; patients receiving MVC twice daily rescreened as having R5 virus had greater than 1 log10 copies per milliliter decrease in viral load over those rescreened as having non-R5 virus. Where genotype and ESTA screening results were discordant outcomes were similar.
  
  
  CONCLUSIONS
  The exclusion of ∼8% of patients with CXCR4-using virus by population-based sequencing would likely have resulted in noninferior responses in the MVC twice-daily and EFV arms. Rescreening by ESTA and population-based sequencing predicted similar virological response.
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, St Paul's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: McGovern
authors.forename: Alexander
authors.initials: A
authors.lastname: Thielen
authors.forename: Simon
authors.initials: S
authors.lastname: Portsmouth
authors.forename: Theresa
authors.initials: T
authors.lastname: Mo
authors.forename: Winnie
authors.initials: W
authors.lastname: Dong
authors.forename: Conan K
authors.initials: CK
authors.lastname: Woods
authors.forename: Xiaoyin
authors.initials: X
authors.lastname: Zhong
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
authors.forename: Douglass
authors.initials: D
authors.lastname: Chapman
authors.forename: Marilyn
authors.initials: M
authors.lastname: Lewis
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.forename: Jayvant
authors.initials: J
authors.lastname: Heera
authors.forename: Hernan
authors.initials: H
authors.lastname: Valdez
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use; D003510:Cyclohexanes / Q000008:administration & dosage / Q000627:therapeutic use*; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D019562:Viral Load / Q000187:drug effects; D056189:Viral Tropism / Q000235:genetics; D055815:Young Adult; D015215:Zidovudine / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D003510:Cyclohexanes; D004338:Drug Combinations; D023581:HIV Fusion Inhibitors; D014230:Triazoles; C109078:lamivudine, zidovudine drug combination; D019259:Lamivudine; D015215:Zidovudine; D000077592:Maraviroc