title: Phenotypic and genotypic analyses to guide selection of reverse transcriptase inhibitors in second-line HIV therapy following extended virological failure in Uganda.
abstract: OBJECTIVE
  We investigated phenotypic and genotypic resistance after 2 years of first-line therapy with two HIV treatment regimens in the absence of virological monitoring.
  
  
  METHODS
  NORA [Nevirapine OR Abacavir study, a sub-study of the Development of AntiRetroviral Therapy in Africa (DART) trial] randomized 600 symptomatic HIV-infected Ugandan adults (CD4 cell count <200 cells/mm(3)) to receive zidovudine/lamivudine plus abacavir (cABC arm) or nevirapine (cNVP arm). All virological tests were performed retrospectively, including resistance tests on week 96 plasma samples with HIV RNA levels ≥1000 copies/mL. Phenotypic resistance was expressed as fold-change in IC(50) (FC) relative to wild-type virus.
  
  
  RESULTS
  HIV-1 RNA viral load ≥1000 copies/mL at week 96 was seen in 58/204 (28.4%) cABC participants and 21/159 (13.2%) cNVP participants. Resistance results were available in 35 cABC and 17 cNVP participants; 31 (89%) cABC and 16 (94%) cNVP isolates had a week 96 FC below the biological cut-off for tenofovir (2.2). In the cNVP arm, 16/17 participants had resistance mutations synonymous with high-level resistance to nevirapine and efavirenz; FC values for etravirine were above the biological cut-off in 9 (53%) isolates. In multivariate regression models, K65R, Y115F and the presence of thymidine analogue-associated mutations were associated with increased susceptibility to etravirine in the cABC arm.
  
  
  CONCLUSIONS
  Our data support the use of tenofovir following failure of a first-line zidovudine-containing regimen and shed further light on non-nucleoside reverse transcriptase inhibitor hypersusceptibility.
authors.affiliation: MRC Clinical Trials Unit, London, UK r.goodall@ctu.mrc.ac.uk.
authors.forename: R L
authors.initials: RL
authors.lastname: Goodall
authors.affiliation: MRC Clinical Trials Unit, London, UK.
authors.forename: D T
authors.initials: DT
authors.lastname: Dunn
authors.affiliation: Virco BVBA, Beerse, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Pattery
authors.affiliation: Virco BVBA, Beerse, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: van Cauwenberge
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
authors.forename: P
authors.initials: P
authors.lastname: Nkurunziza
authors.affiliation: Joint Clinical Research Centre, Kampala, Uganda.
authors.forename: P
authors.initials: P
authors.lastname: Awio
authors.affiliation: Institute of Human Virology, Abuja, Nigeria.
authors.forename: N
authors.initials: N
authors.lastname: Ndembi
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
authors.forename: P
authors.initials: P
authors.lastname: Munderi
authors.affiliation: Joint Clinical Research Centre, Kampala, Uganda.
authors.forename: C
authors.initials: C
authors.lastname: Kityo
authors.affiliation: School of Population Health, University of Queensland, Brisbane, Australia.
authors.forename: C F
authors.initials: CF
authors.lastname: Gilks
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
authors.forename: P
authors.initials: P
authors.lastname: Kaleebu
authors.affiliation: Department of Infection, University College London, London, UK Centres for Infection, Public Health England, Colindale, UK.
authors.forename: D
authors.initials: D
authors.lastname: Pillay
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use; D000068698:Tenofovir; D014454:Uganda; D015215:Zidovudine / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D015215:Zidovudine; D000068698:Tenofovir; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000225:Adenine
keywords: Africa; hypersusceptibility; resistance