title: Patterns of HIV-1 drug resistance after first-line antiretroviral therapy (ART) failure in 6 sub-Saharan African countries: implications for second-line ART strategies.
abstract: BACKGROUND
  Human immunodeficiency virus type 1 (HIV-1) drug resistance may limit the benefits of antiretroviral therapy (ART). This cohort study examined patterns of drug-resistance mutations (DRMs) in individuals with virological failure on first-line ART at 13 clinical sites in 6 African countries and predicted their impact on second-line drug susceptibility.
  
  
  METHODS
  A total of 2588 antiretroviral-naive individuals initiated ART consisting of different nucleoside reverse transcriptase inhibitor (NRTI) backbones (zidovudine, stavudine, tenofovir, or abacavir, plus lamivudine or emtricitabine) with either efavirenz or nevirapine. Population sequencing after 12 months of ART was retrospectively performed if HIV RNA was >1000 copies/mL. The 2010 International Antiviral Society-USA list was used to score major DRMs. The Stanford algorithm was used to predict drug susceptibility.
  
  
  RESULTS
  HIV-1 sequences were generated for 142 participants who virologically failed ART, of whom 70% carried ≥1 DRM and 49% had dual-class resistance, with an average of 2.4 DRMs per sequence (range, 1-8). The most common DRMs were M184V (53.5%), K103N (28.9%), Y181C (15.5%), and G190A (14.1%). Thymidine analogue mutations were present in 8.5%. K65R was frequently selected by stavudine (15.0%) or tenofovir (27.7%). Among participants with ≥1 DRM, HIV-1 susceptibility was reduced in 93% for efavirenz/nevirapine, in 81% for lamivudine/emtricitabine, in 59% for etravirine/rilpivirine, in 27% for tenofovir, in 18% for stavudine, and in 10% for zidovudine.
  
  
  CONCLUSIONS
  Early failure detection limited the accumulation of resistance. After stavudine failure in African populations, zidovudine rather than tenofovir may be preferred in second-line ART. Strategies to prevent HIV-1 resistance are a global priority.
authors.affiliation: PharmAccess Foundation, Academic Medical Center of the University of Amsterdam, The Netherlands. r.hamers@aighd.org
authors.forename: Raph L
authors.initials: RL
authors.lastname: Hamers
authors.forename: Kim C E
authors.initials: KC
authors.lastname: Sigaloff
authors.forename: Annemarie M
authors.initials: AM
authors.lastname: Wensing
authors.forename: Carole L
authors.initials: CL
authors.lastname: Wallis
authors.forename: Cissy
authors.initials: C
authors.lastname: Kityo
authors.forename: Margaret
authors.initials: M
authors.lastname: Siwale
authors.forename: Kishor
authors.initials: K
authors.lastname: Mandaliya
authors.forename: Prudence
authors.initials: P
authors.lastname: Ive
authors.forename: Mariette E
authors.initials: ME
authors.lastname: Botes
authors.forename: Maureen
authors.initials: M
authors.lastname: Wellington
authors.forename: Akin
authors.initials: A
authors.lastname: Osibogun
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Stevens
authors.forename: Tobias F
authors.initials: TF
authors.lastname: Rinke de Wit
authors.forename: Rob
authors.initials: R
authors.lastname: Schuurman
mesh_terms: D000328:Adult; D017954:Africa South of the Sahara; D044966:Anti-Retroviral Agents / Q000008:administration & dosage* / Q000494:pharmacology; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D015331:Cohort Studies; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D017211:Treatment Failure
chemical_list: D044966:Anti-Retroviral Agents