Resistance profile of darunavir: combined 24-week results from the POWER trials.
The resistance profile of darunavir (TMC114) in treatment-experienced patients was explored using pooled week 24 data from POWER 1, 2, and 3 at the recommended dose of darunavir with low-dose ritonavir (darunavir/r, 600/100 mg bid, N = 458). Baseline darunavir fold change in EC(50) was a strong predictor of virological response at week 24. Preliminary phenotypic clinical cut-offs of 10 and 40 were established. Virological response to darunavir/r was maintained in the presence at baseline of a high number of IAS-USA PI resistance-associated mutations (IAS-USA PI RAMS); a diminished response occurred with >or=14. Eleven protease mutations associated with diminished darunavir/r virological response were identified (V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V). These darunavir resistance-associated mutations (DRV RAMS) occurred in the presence of a high number of IAS-USA PI RAMS. Virological response was diminished with three or more DRV RAMS in the background of a high number of IAS-USA PI RAMS. Incremental numbers of DRV RAMS were more predictive of outcome than were IAS-USA PI RAMS. Mutations developing during darunavir/r virological failure (V32I, L33F, I47V, I54L, and L89V) were also featured in the DRV RAMS list. Site-directed mutants carrying these five mutations, or any one of these mutations either alone or together with one or two IAS-USA PI RAMS, showed no reduced darunavir susceptibility, suggesting that a high number of additional background mutations is required for darunavir resistance. In this population of treatment-experienced patients, darunavir/r demonstrated significantly greater efficacy than investigator-selected control PIs of trials POWER 1 and 2, regardless of baseline viral genotype or phenotype, while exhibiting a high genetic barrier to the development of resistance.
de Meyer
Sandra
S
Tibotec BVBA, Gen De Wittelaan L 11B 3, B2800 Mechelen, Belgium.
Vangeneugden
Tony
T
van Baelen
Ben
B
de Paepe
Els
E
van Marck
Herwig
H
Picchio
Gaston
G
Lefebvre
Eric
E
de Béthune
Marie-Pierre
MP
D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D000069454:Darunavir; D024882:Drug Resistance, Viral / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
D017320:HIV Protease Inhibitors; D013449:Sulfonamides; D000069454:Darunavir