These findings potentially have clinical implications for decisions regarding which patients may experience a greater benefit from starting etravirine after prolonged exposure to NNRTI-based failing regimens. However, our interpretation relies on the predictions of

currently available IS which are known to be imperfect. It is possible that the estimates may have varied if an alternative system (e.g. Stanford-HIVDB) had been used [30]. Two studies performed in the USA showed a rate of NNRTI accumulation very similar to ours (approximately 0.35 new NNRTI mutations/year) [31,32]. Two more recent analyses of patients with HIV clade C showed a high level of NNRTI buy Sotrastaurin resistance at the failure of their first ART regimen [33,34]. In one of these analyses, at the detection of viraemia, five (71%) of seven tested patients had NNRTI resistance mutations; this

number increased to eight (89%) of nine patients by 6 months, 11 (78%) of 14 patients by 12 months, and 15 (94%) of 16 patients by 18 months, perhaps Talazoparib research buy suggesting a higher rate of accumulation in the population mainly infected with C subtype viruses [34]. However, the difference in virus subtype is likely not to be the only difference between this cohort and that of EuroSIDA. Some limitations of this analysis should be discussed. First, in the absence of adherence data, in order to exclude patients who might have been completely nonadherent, we restricted the analysis to those for whom there was evidence of resistance to at least one of the drugs used at t0. Secondly, it is not possible from our data to establish the most likely reason that patients in EuroSIDA were kept on virologically failing regimens (reasons may have included waiting for the results of a genotypic test, a lack of available options, and patients’ Methocarbamol choice) so selection bias cannot be

ruled out. Further, because standard genotyping can only detect mutations that are well represented in major populations, we cannot rule out the possibility that mutations defined in our analysis as ‘newly detected at t1’ could already have been present at t0 but not detectable in the majority virus, resulting in a possible overestimate of the true rate of NNRTI accumulation. Data obtained from ultra-deep sequencing are not yet available for patients in EuroSIDA. Also, not all participants were tested prior to failing the NNRTI regimen and therefore we could have underestimated the proportion of resistance detected at failure which was caused by transmission of resistant variants. Lastly, our results may only apply to patients with little initial resistance to etravirine but with extensive resistance to nevirapine, efavirenz and other drugs.