title: HIV-1 reverse transcriptase connection domain mutations: dynamics of emergence and implications for success of combination antiretroviral therapy.
abstract: BACKGROUND
  Factors promoting the emergence of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) connection domain mutations and their effect on antiretroviral therapy (ART) are still largely undetermined. We investigated this matter by analyzing genotypic resistance tests covering 400 amino acid positions in the RT of HIV-1 subtype B viruses and corresponding treatment histories and laboratory measurements.
  
  
  METHODS
  The emergence of connection domain mutations was studied in 334 patients receiving monotherapy or dual therapy with thymidine analogues at the time of the genotypic resistance test. Response to subsequent combination ART (cART) was analyzed using Cox regression for 291 patients receiving unboosted protease inhibitors. Response was defined by ever reaching an HIV RNA level <50 copies/mL during the first cART.
  
  
  RESULTS
  The connection domain mutations N348I, R356K, R358K, A360V, and A371V were more frequently observed in ART-exposed than ART-naive patients, of which only N348I and A360V were nonpolymorphic (with a prevalence of <1.5% in untreated patients). N348I correlated with M184V and predominantly occurred in patients receiving lamivudine and zidovudine concomitantly. A360V was not associated with specific drug combinations and was found to emerge later than M184V or thymidine analogue mutations. Nonpolymorphic connection domain mutations were rarely detected in the absence of established drug resistance mutations in ART-exposed individuals (prevalence, <1%). None of the 5 connection domain mutations associated with treatment showed a statistically significant effect on response to cART.
  
  
  CONCLUSIONS
  Despite their frequent emergence, connection domain mutations did not show large detrimental effects on response to cART. Currently, routine implementation of connection domain sequencing seems unnecessary for developed health care settings.
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland. vowv@usz.uzh.ch
authors.forename: Viktor
authors.initials: V
authors.lastname: von Wyl
authors.forename: Maryam
authors.initials: M
authors.lastname: Ehteshami
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Demeter
authors.forename: Philippe
authors.initials: P
authors.lastname: Bürgisser
authors.forename: Monique
authors.initials: M
authors.lastname: Nijhuis
authors.forename: Jori
authors.initials: J
authors.lastname: Symons
authors.forename: Sabine
authors.initials: S
authors.lastname: Yerly
authors.forename: Jürg
authors.initials: J
authors.lastname: Böni
authors.forename: Thomas
authors.initials: T
authors.lastname: Klimkait
authors.forename: Rob
authors.initials: R
authors.lastname: Schuurman
authors.forename: Bruno
authors.initials: B
authors.lastname: Ledergerber
authors.forename: Matthias
authors.initials: M
authors.lastname: Götte
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001483:Base Sequence; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005838:Genotype; D054303:HIV Reverse Transcriptase / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D009154:Mutation; D012189:Retrospective Studies
chemical_list: D019380:Anti-HIV Agents; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase