Efavirenz, nelfinavir, and stavudine rescue combination therapy in HIV-1-positive patients heavily pretreated with nucleoside analogues and protease inhibitors

Tolerability, activity, and pharmacokinetic parameters of a combination the rapy with efavirenz (EFV), nelfinavir (NFV), and stavudine (d4T) were evalu ated in this study. Forty-seven HIV-l-infected study subjects, naive to NFV and non-nucleoside reverse transcriptase inhibitors (NNRTIs), who had expe rienced virologic failure while being treated with combination antiretrovir al therapies including protease inhibitors (PIs), were enrolled. At baselin e, HIV-I viral load in plasma was 4.8 log(10), CD4(+) count was 204 cells/m u l (both mean values); patients had received a mean of 3.1 different treat ments (range, 2-5 treatments). Study medications were generally well tolera ted; 7 of 47 patients (14.8%) were dropped from the study because of relate d drug toxicity. At week 24, mean plasma viral load (pVL) was reduced by 1. 9 log(10), with mean CD4(+) count increased to 324 cells/mu l (+/-59% from baseline); pVL was below the limit of detection (500 copies/ml) in 46.1% of patients. An extended follow-up study was performed at 12 months. Results showed a reduction of 1.7 log(10) in pVL from basal values that was consist ent with values observed at months 3 and 6. A history of previous use of PI s represented a negative prognostic marker, Sequencing analysis, performed in a subset of patients, showed the presence of multiple point mutations as sociated with PI resistance. Pharmacokinetic analysis demonstrated a marked interindividual variability in NFV plasma concentrations, producing in 4 o f 18 patients (22%) trough concentrations lower than minimum effective conc entration. In pretreated patients, further studies are needed to characteri ze the pharmacokinetic factors that affect response to therapy and the asso ciation of these results with the 95% inhibitory concentration (IC95) deter mined by phenotyping.