title: The rate of accumulation of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in patients kept on a virologically failing regimen containing an NNRTI*.
abstract: BACKGROUND
  Virological failure of first-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs) can compromise the efficacy of etravirine as a result of the accumulation of NNRTI resistance mutations. How quickly NNRTI resistance accumulates in patients with a delayed switch from nevirapine or efavirenz despite virological failure, when these drugs are used as a component of combination antiretroviral therapy (cART), remains unclear.
  
  
  METHODS
  The rate of NNRTI resistance accumulation was estimated in patients in EuroSIDA with at least two available genotypic resistance tests (GRTs), provided that (1) the date of the first GRT (t0) was after the date of the first virological failure (VF) of an NNRTI, and (2) patients were receiving an NNRTI and HIV RNA was >500 HIV-1 RNA copies/mL in all measurements between GRTs.
  
  
  RESULTS
  A total of 227 patients were included in the study, contributing 467 GRT pairs. At baseline-t0, a median of 3 months after VF, 66% of patients had at least one NNRTI mutation: 103N (34%), 181C (22%) and 190A (20%) were the most common mutations. Overall, 180 additional NNRTI mutations were found to have accumulated over 295 years [1 new/1.6 years; 95% confidence interval (CI) 1.5-1.8]. The rate of accumulation was faster in the first 6 months from VF (1 new/1.1 years), and slower in patients exposed to nevirapine vs. those receiving efavirenz [relative risk (RR) 0.66; 95% CI 0.46-0.95; P=0.03].
  
  
  CONCLUSIONS
  There is an initial phase of rapid accumulation of NNRTI mutations close to the time of VF followed by a phase of slower accumulation. We predict that it should take approximately one year of exposure to a virologically failing first-generation NNRTI-based cART regimen to reduce etravirine activity from fully susceptible to intermediate resistant, and possibly longer in patients kept on a failing nevirapine-containing regimen.
authors.affiliation: Department of Infection & Population Health, Division of Population Health, University College London, London, UK. a.cozzi-lepri@ucl.ac.uk
authors.forename: A
authors.initials: A
authors.lastname: Cozzi-Lepri
authors.lastname: Paredes
authors.forename: A N
authors.initials: AN
authors.lastname: Phillips
authors.forename: B
authors.initials: B
authors.lastname: Clotet
authors.forename: J
authors.initials: J
authors.lastname: Kjaer
authors.forename: V
authors.initials: V
authors.lastname: Von Wyl
authors.forename: G
authors.initials: G
authors.lastname: Kronborg
authors.forename: A
authors.initials: A
authors.lastname: Castagna
authors.forename: J R
authors.initials: JR
authors.lastname: Bogner
authors.forename: J D
authors.initials: JD
authors.lastname: Lundgren
mesh_terms: D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D048588:Benzoxazines / Q000627:therapeutic use*; D003521:Cyclopropanes; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019829:Nevirapine / Q000627:therapeutic use*; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D019562:Viral Load; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C098320:efavirenz