title: Low-frequency HIV-1 drug resistance mutations and risk of NNRTI-based antiretroviral treatment failure: a systematic review and pooled analysis.
abstract: BACKGROUND
  Presence of low-frequency, or minority, human immunodeficiency virus type 1 (HIV-1) drug resistance mutations may adversely affect response to antiretroviral treatment (ART), but evidence regarding the effects of such mutations on the effectiveness of first-line ART is conflicting.
  
  
  OBJECTIVE
  To evaluate the association of preexisting drug-resistant HIV-1 minority variants with risk of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral virologic failure.
  
  
  METHODS
  Systematic review of published and unpublished studies in PubMed (1966 through December 2010), EMBASE (1974 through December 2010), conference abstracts, and article references. Authors of all studies were contacted for detailed laboratory, ART, and adherence data.
  
  
  METHODS
  Studies involving ART-naive participants initiating NNRTI-based regimens were included. Participants were included if all drugs in their ART regimen were fully active by standard HIV drug resistance testing. Cox proportional hazard models using pooled patient-level data were used to estimate the risk of virologic failure based on a Prentice weighted case-cohort analysis stratified by study.
  
  
  RESULTS
  Individual data from 10 studies and 985 participants were available for the primary analysis. Low-frequency drug resistance mutations were detected in 187 participants, including 117 of 808 patients in the cohort studies. Low-frequency HIV-1 drug resistance mutations were associated with an increased risk of virologic failure (hazard ratio (HR], 2.3 [95% confidence interval {CI}, 1.7-3.3]; P < .001) after controlling for medication adherence, race/ethnicity, baseline CD4 cell count, and plasma HIV-1 RNA levels. Increased risk of virologic failure was most strongly associated with minority variants resistant to NNRTIs (HR, 2.6 [95% CI, 1.9-3.5]; P < .001). Among participants from the cohort studies, 35% of those with detectable minority variants experienced virologic failure compared with 15% of those without minority variants. The presence of minority variants was associated with 2.5 to 3 times the risk of virologic failure at either 95% or greater or less than 95% overall medication adherence. A dose-dependent increased risk of virologic failure was found in participants with a higher proportion or quantity of drug-resistant variants.
  
  
  CONCLUSIONS
  In a pooled analysis, low-frequency HIV-1 drug resistance mutations, particularly involving NNRTI resistance, were significantly associated with a dose-dependent increased risk of virologic failure with first-line ART.
authors.affiliation: Section of Retroviral Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Harvard University, Boston, Massachusetts 02139, USA. jli22@partners.org
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Li
authors.forename: Roger
authors.initials: R
authors.lastname: Paredes
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Ribaudo
authors.forename: Evguenia S
authors.initials: ES
authors.lastname: Svarovskaia
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Metzner
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kozal
authors.forename: Kathy Huppler
authors.initials: KH
authors.lastname: Hullsiek
authors.forename: Melanie
authors.initials: M
authors.lastname: Balduin
authors.forename: Martin R
authors.initials: MR
authors.lastname: Jakobsen
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Geretti
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Thiebaut
authors.forename: Lars
authors.initials: L
authors.lastname: Ostergaard
authors.forename: Bernard
authors.initials: B
authors.lastname: Masquelier
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Kuritzkes
mesh_terms: D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D016022:Case-Control Studies; D015331:Cohort Studies; D024882:Drug Resistance, Viral / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D009154:Mutation; D012306:Risk; D017211:Treatment Failure
chemical_list: D044966:Anti-Retroviral Agents