title: Factors associated with the emergence of K65R in patients with HIV-1 infection treated with combination antiretroviral therapy containing tenofovir.
abstract: BACKGROUND
  The human immunodeficiency virus type 1 reverse-transcriptase mutation K65R is a single-point mutation that has become more frequent after increased use of tenofovir disoproxil fumarate (TDF). We aimed to identify predictors for the emergence of K65R, using clinical data and genotypic resistance tests from the Swiss HIV Cohort Study.
  
  
  METHODS
  A total of 222 patients with genotypic resistance tests performed while receiving treatment with TDF-containing regimens were stratified by detectability of K65R (K65R group, 42 patients; undetected K65R group, 180 patients). Patient characteristics at start of that treatment were analyzed.
  
  
  RESULTS
  In an adjusted logistic regression, TDF treatment with nonnucleoside reverse-transcriptase inhibitors and/or didanosine was associated with the emergence of K65R, whereas the presence of any of the thymidine analogue mutations D67N, K70R, T215F, or K219E/Q was protective. The previously undescribed mutational pattern K65R/G190S/Y181C was observed in 6 of 21 patients treated with efavirenz and TDF. Salvage therapy after TDF treatment was started for 36 patients with K65R and for 118 patients from the wild-type group. Proportions of patients attaining human immunodeficiency virus type 1 loads <50 copies/mL after 24 weeks of continuous treatment were similar for the K65R group (44.1%; 95% confidence interval, 27.2%-62.1%) and the wild-type group (51.9%; 95% confidence interval, 42.0%-61.6%).
  
  
  CONCLUSIONS
  In settings where thymidine analogue mutations are less likely to be present, such as at start of first-line therapy or after extended treatment interruptions, combinations of TDF with other K65R-inducing components or with efavirenz or nevirapine may carry an enhanced risk of the emergence of K65R. The finding of a distinct mutational pattern selected by treatment with TDF and efavirenz suggests a potential fitness interaction between K65R and nonnucleoside reverse-transcriptase inhibitor-induced mutations.
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: Sabine
authors.initials: S
authors.lastname: Yerly
authors.forename: Jürg
authors.initials: J
authors.lastname: Böni
authors.forename: Philippe
authors.initials: P
authors.lastname: Bürgisser
authors.forename: Thomas
authors.initials: T
authors.lastname: Klimkait
authors.forename: Manuel
authors.initials: M
authors.lastname: Battegay
authors.forename: Enos
authors.initials: E
authors.lastname: Bernasconi
authors.forename: Matthias
authors.initials: M
authors.lastname: Cavassini
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Furrer
authors.forename: Bernard
authors.initials: B
authors.lastname: Hirschel
authors.forename: Pietro L
authors.initials: PL
authors.lastname: Vernazza
authors.forename: Martin
authors.initials: M
authors.lastname: Rickenbach
authors.forename: Bruno
authors.initials: B
authors.lastname: Ledergerber
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000009:adverse effects / Q000627:therapeutic use*; D017354:Point Mutation / Q000187:drug effects*; D000068698:Tenofovir
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000225:Adenine