[Resistance to darunavir].
The resistance profile of darunavir (DRV) was initially explored using pooled week 24 data from POWER 1, 2, and 3 at the recommended dose of DRV (n=467) with the subsequent addition of data from the placebo arm without etravirine (ETR) of DUET 1 and 2 (n=604). The two strongest predictors of virological response were firstly baseline phenotype expressed as the darunavir fold change in 50% effective concentration (EC(50)), with phenotypic clinical cut-offs of 10 and 40 being established for diminished response and loss of response, respectively, and secondly, the DRV score 2006 of 11 mutations in 10 positions: V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V and L89V, recently revised (DRV score 2007) with removal of G73S and addition of T74P. The presence of three or more mutations was associated with a diminished virological response in both the 2006 and 2007 lists but slightly better prediction was observed with the 2007 list. Each of the above-mentioned mutations was associated with a mean of at least 10 mutations of the International AIDS Society's (IAS) list. Moreover, good genophenotypic correlation was found, corroborating a progressive reduction in fold change with the progressive accumulation of mutations from both lists. In multiresistant patients in the POWER and DUET studies, the most commonly selected mutations upon DRV failure were those in the DRV score, especially V32I and I54L. Similar mutations were selected by patients from TITAN, who showed a much lower level of resistance; however, these mutations were selected much less frequently in the few virological failures described. Furthermore, virological failure and mutations were much less frequent in the DRV arm than in the lopinavir arm. Lastly, no protease mutations were found upon DRV failure in treatment-naive patients in the ARTEMIS study, an effect already known in enhanced proteases.
García Deltoro
Miguel
M
Unidad de Enfermedades Infecciosas. Consorcio Hospital General Universitario. Valencia. España. med001007@saludalia.com.
D000328:Adult; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D000069454:Darunavir; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D006678:HIV / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D061466:Lopinavir; D008297:Male; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009570:Nitriles; D010641:Phenotype; D017354:Point Mutation; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D017320:HIV Protease Inhibitors; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D011744:Pyrimidinones; D013449:Sulfonamides; C451734:etravirine; D061466:Lopinavir; D016333:HIV Protease; D000069454:Darunavir