Pharmacokinetics and resistance mutations affect virologic response to ritonavir/saquinavir-containing regimens

The authors assessed the impact of protease and reverse transcription (RT) mutations and individual pharmacokinetic parameters on virologic response t o a four-drug regimen including ritonavir/saquinavir. Treatment was given a t the start of the study (M0) to 22 HIV-1 protease inhibitor-naive or pretr eated patients. Protease and RT genes were sequenced at M0, at the time of virologic failure, or at the end of the follow-up. Plasma ritonavir and saq uinavir peak C-max, C-min, and area under the curve (AUC) were determined b ased on samples taken 0, 1, 2, 3, 4, 6, 8, and 12 hours after administratio n. HIV-1 RNA decreased to less than 50 copies/mL in 11 patients (group 1). At M0, five of them had no RT mutation and 10 had three or fewer secondary protease mutations with no new mutation during follow-up. Ritonavir and saq uinavir pharmacokinetics showed wide interindividual variability. Treatment failed in 11 patients (group 2): 9 had three to eight protease mutations a nd a mean of 5.8 RT mutations at M0, with emergence of new mutations during follow-up. Pharmacokinetics was similar to those of group 1. The other two patients with virologic failure showed no baseline primary mutation but we re the only patients with insufficient saquinavir and ritonavir AUC. The au thors showed the complementarity between drug-resistance genotype and indiv idual pharmacokinetics and the potential utility of AUC and C-max to manage treatment.