title: Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes.
abstract: BACKGROUND
  Minor (i.e., <20% prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important.
  
  
  OBJECTIVE
  To compare the prevalence of drug-resistant variants detected with standard and ultra-deep sequencing (detection down to 1% prevalence) and to determine the impact of minor resistant variants on virologic failure (VF).
  
  
  METHODS
  The Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study (N = 1397) compared 3 initial antiretroviral therapy (ART) strategies. A random subset (n = 491) had baseline testing for drug-resistance mutations performed by use of standard sequencing methods. Ultra-deep sequencing was performed on samples that had sufficient viral content (N = 264). Proportional hazards models were used to compare rates of VF for those who did and did not have mutations identified.
  
  
  RESULTS
  Mutations were detected by standard and ultra-deep sequencing (in 14% and 28% of participants, respectively; P < .001). Among individuals who initiated treatment with an ART regimen that combined nucleoside and nonnucleoside reverse-transcriptase inhibitors (hereafter, "NNRTI strategy"), all individuals who had an NNRTI-resistance mutation identified by ultra-deep sequencing experienced VF. When these individuals were compared with individuals who initiated treatment with the NNRTI strategy but who had no NNRTI-resistance mutations, the risk of VF was higher for those who had an NNRTI-resistance mutation detected by both methods (hazard ratio [HR], 12.40 [95% confidence interval {CI}, 3.41-45.10]) and those who had mutation(s) detected only with ultra-deep sequencing (HR, 2.50 [95% CI, 1.17-5.36]).
  
  
  CONCLUSIONS
  Ultra-deep sequencing identified a significantly larger proportion of HIV-infected, treatment-naive persons as harboring drug-resistant viral variants. Among participants who initiated treatment with the NNRTI strategy, the risk of VF was significantly greater for participants who had low- and high-prevalence NNRTI-resistant variants.
authors.affiliation: 454 Life Sciences, a Roche Company, Branford, Connecticut, USA.
authors.forename: Birgitte B
authors.initials: BB
authors.lastname: Simen
authors.forename: Jan Fredrik
authors.initials: JF
authors.lastname: Simons
authors.forename: Katherine Huppler
authors.initials: KH
authors.lastname: Hullsiek
authors.forename: Richard M
authors.initials: RM
authors.lastname: Novak
authors.forename: Rodger D
authors.initials: RD
authors.lastname: Macarthur
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
authors.forename: Chunli
authors.initials: C
authors.lastname: Huang
authors.forename: Christine
authors.initials: C
authors.lastname: Lubeski
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Turenchalk
authors.forename: Michael S
authors.initials: MS
authors.lastname: Braverman
authors.forename: Brian
authors.initials: B
authors.lastname: Desany
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Rothberg
authors.forename: Michael
authors.initials: M
authors.lastname: Egholm
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kozal
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D002908:Chronic Disease; D018076:DNA, Complementary / Q000737:chemistry; D018450:Disease Progression; D024882:Drug Resistance, Viral; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D012367:RNA, Viral / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D018076:DNA, Complementary; D012367:RNA, Viral