title: Prevalence and impact of minority variant drug resistance mutations in primary HIV-1 infection.
abstract: OBJECTIVE
  To evaluate minority variant drug resistance mutations detected by the oligonucleotide ligation assay (OLA) but not consensus sequencing among subjects with primary HIV-1 infection.
  
  
  METHODS
  Observational, longitudinal cohort study. Consensus sequencing and OLA were performed on the first available specimens from 99 subjects enrolled after 1996. Survival analyses, adjusted for HIV-1 RNA levels at the start of antiretroviral (ARV) therapy, evaluated the time to virologic suppression (HIV-1 RNA<50 copies/mL) among subjects with minority variants conferring intermediate or high-level resistance.
  
  
  RESULTS
  Consensus sequencing and OLA detected resistance mutations in 5% and 27% of subjects, respectively, in specimens obtained a median of 30 days after infection. Median time to virologic suppression was 110 (IQR 62-147) days for 63 treated subjects without detectable mutations, 84 (IQR 56-109) days for ten subjects with minority variant mutations treated with ≥3 active ARVs, and 104 (IQR 60-162) days for nine subjects with minority variant mutations treated with <3 active ARVs (p = .9). Compared to subjects without mutations, time to virologic suppression was similar for subjects with minority variant mutations treated with ≥3 active ARVs (aHR 1.2, 95% CI 0.6-2.4, p = .6) and subjects with minority variant mutations treated with <3 active ARVs (aHR 1.0, 95% CI 0.4-2.4, p = .9). Two subjects with drug resistance and two subjects without detectable resistance experienced virologic failure.
  
  
  CONCLUSIONS
  Consensus sequencing significantly underestimated the prevalence of drug resistance mutations in ARV-naïve subjects with primary HIV-1 infection. Minority variants were not associated with impaired ARV response, possibly due to the small sample size. It is also possible that, with highly-potent ARVs, minority variant mutations may be relevant only at certain critical codons.
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America. jstekler@uw.edu
authors.forename: Joanne D
authors.initials: JD
authors.lastname: Stekler
authors.forename: Giovanina M
authors.initials: GM
authors.lastname: Ellis
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Carlsson
authors.forename: Braiden
authors.initials: B
authors.lastname: Eilers
authors.forename: Sarah
authors.initials: S
authors.lastname: Holte
authors.forename: Janine
authors.initials: J
authors.lastname: Maenza
authors.forename: Claire E
authors.initials: CE
authors.lastname: Stevens
authors.forename: Ann C
authors.initials: AC
authors.lastname: Collier
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Frenkel
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D003710:Demography; D024882:Drug Resistance, Viral / Q000235:genetics*; D015658:HIV Infections / Q000097:blood / Q000235:genetics* / Q000628:therapy / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009841:Oligonucleotides / Q000378:metabolism; D015995:Prevalence; D012367:RNA, Viral / Q000097:blood; D017422:Sequence Analysis, DNA; D013997:Time Factors
chemical_list: D009841:Oligonucleotides; D012367:RNA, Viral