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.