title: Prevalence of etravirine mutations and impact on response to treatment in routine clinical care: the Swiss HIV Cohort Study (SHCS).
abstract: OBJECTIVE
  Etravirine (ETV) is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) with reduced cross-resistance to first-generation NNRTIs, which has been primarily studied in randomized clinical trials and not in routine clinical settings.
  
  
  METHODS
  ETV resistance-associated mutations (RAMs) were investigated by analysing 6072 genotypic tests. The antiviral activity of ETV was predicted using different interpretation systems: International AIDS Society-USA (IAS-USA), Stanford, Rega and Agence Nationale de Recherches sur le Sida et les hépatites virales (ANRS).
  
  
  RESULTS
  The prevalence of ETV RAMs was higher in NNRTI-exposed patients [44.9%, 95% confidence interval (CI) 41.0-48.9%] than in treatment-naïve patients (9.6%, 95% CI 8.5-10.7%). ETV RAMs in treatment-naïve patients mainly represent polymorphism, as prevalence estimates in genotypic tests for treatment-naïve patients with documented recent (<1 year) infection, who had acquired HIV before the introduction of NNRTIs, were almost identical (9.8%, 95% CI 3.3-21.4). Discontinuation of NNRTI treatment led to a marked drop in the detection of ETV RAMs, from 51.7% (95% CI 40.8-62.6%) to 34.5% (95% CI 24.6-45.4%, P=0.032). Differences in prevalence among subtypes were found for V90I and V179T (P<0.001). Estimates of restricted virological response to ETV varied among algorithms in patients with exposure to efavirenz (EFV)/nevirapine (NVP), ranging from 3.8% (95% CI 2.5-5.6%) for ANRS to 56.2% (95% CI 52.2-60.1%) for Stanford. The predicted activity of ETV decreased as the sensitivity of potential optimized background regimens decreased. The presence of major IAS-USA mutations (L100I, K101E/H/P and Y181C/I/V) reduced the treatment response at week 24.
  
  
  CONCLUSIONS
  Most ETV RAMs in drug-naïve patients are polymorphisms rather than transmitted RAMs. Uncertainty regarding predictions of antiviral activity for ETV in NNRTI-treated patients remains high. The lowest activity was predicted for patients harbouring extensive multidrug-resistant viruses, thus limiting ETV use in those who are most in need.
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: A U
authors.initials: AU
authors.lastname: Scherrer
authors.forename: B
authors.initials: B
authors.lastname: Hasse
authors.forename: V
authors.initials: V
authors.lastname: von Wyl
authors.forename: S
authors.initials: S
authors.lastname: Yerly
authors.forename: J
authors.initials: J
authors.lastname: Böni
authors.forename: P
authors.initials: P
authors.lastname: Bürgisser
authors.forename: T
authors.initials: T
authors.lastname: Klimkait
authors.forename: H C
authors.initials: HC
authors.lastname: Bucher
authors.forename: B
authors.initials: B
authors.lastname: Ledergerber
authors.forename: H F
authors.initials: HF
authors.lastname: Günthard
mesh_terms: D000465:Algorithms; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D009154:Mutation / Q000235:genetics; D009570:Nitriles; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011724:Pyridazines / Q000627:therapeutic use*; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D013557:Switzerland; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine