title: Prevalence of etravirine-associated mutations in clinical samples with resistance to nevirapine and efavirenz.
abstract: OBJECTIVE
  To evaluate the expected activity of etravirine in clinical samples, according to mutational patterns associated with decreased virological response (VR).
  
  
  METHODS
  We identified 1586 routine clinical samples with resistance-associated mutations (RAMs) to nevirapine and efavirenz (K103N 60%, Y181C 37%, G190A 27%, V108I 13%). Concerning in vitro identified etravirine mutations, samples with F227C, Y181I, M230L or L100I plus K103N plus Y181C were considered highly resistant. Samples with two RAMs plus Y181C or V179D or K101E or Y188L were considered intermediate. The prevalence of 13 RAMs recently associated with decreased VR to etravirine in the DUET clinical trials was also investigated.
  
  
  RESULTS
  Most samples (69%) harboured more than one IAS-USA RAM to first-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs): 42% harboured two RAMs, 21% three RAMs and 6% four or more RAMs. The prevalence of 13 specific etravirine RAMs was V179F 0.12%, G190S 3.9%, Y181V 0.1%, V106I 2.6%, V179D 1.6%, K101P 2.0%, K101E 10.1%, Y181C 36.9%, A98G 5.9%, V90I 6.9%, Y181I 3.6%, G190A 27% and L100I 9.1%. The five RAMs with the most impact on VR (V179F/D, G190S, Y181V and V106I) occurred less often. Overall, 8.2% of the samples had three or more etravirine RAMs and only 1.1% had four or more. In addition, patterns of RAMs previously associated with intermediate etravirine resistance were present in 26.2% of the samples, whereas 4.85% displayed patterns of high-degree resistance.
  
  
  CONCLUSIONS
  For RAMs associated with decreased VR, etravirine resistance in routine clinical samples was lower than previously reported. High-degree resistance was uncommon, even in patients with resistance to first-generation NNRTIs, whereas low-to-intermediate etravirine resistance was more common.
authors.affiliation: Lluita contra la SIDA Foundation, Germans Trias i Pujol University Hospital, Ctra de Canyet s/n, 08916 Badalona, Barcelona, Spain. jmllibre@flsida.org
authors.forename: J M
authors.initials: JM
authors.lastname: Llibre
authors.forename: J R
authors.initials: JR
authors.lastname: Santos
authors.forename: T
authors.initials: T
authors.lastname: Puig
authors.forename: J
authors.initials: J
authors.lastname: Moltó
authors.forename: L
authors.initials: L
authors.lastname: Ruiz
authors.forename: R
authors.initials: R
authors.lastname: Paredes
authors.forename: B
authors.initials: B
authors.lastname: Clotet
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology*; D003521:Cyclopropanes; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense; D019829:Nevirapine / Q000494:pharmacology*; D009570:Nitriles; D011724:Pyridazines / Q000494:pharmacology*; D011743:Pyrimidines
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine; D019829:Nevirapine; C098320:efavirenz