A pilot trial of indinavir, ritonavir, didanosine, and lamivudine in a once-daily four-drug regimen for HIV infection

Objective: To evaluate the tolerance, pharmacokinetics, and virologic and i mmunologic outcomes of once-daily indinavir, ritonavir, didanosine, and lam ivudine in HIV-seropositive individuals. Design: Open-label 24-week pilot study. Patients: Ten HIV-seropositive subjects who were either antiretroviral-naiv e or minimally experienced with short-term single- or dual-nucleoside thera py provided informed consent and were enrolled. All subjects received didan osine (400 mg) 30 to 60 minutes before a meal followed by indinavir (1200 m g), ritonavir (400 mg), and lamivudine (300 mg) concurrent with the aforeme ntioned meal. Methods: Safety laboratory tests, including a complete blood cell count and amylase, lipase, liver transaminase, and nonfasting lipid monitoring os we ll as plasma HIV viral load and CD4(+) lymphocyte count, were carried out a t monthly intervals. Genotyping was performed at baseline. Pharmacokinetic studies for indinavir and ritonavir were performed at week 8. Results: Nine of 10 subjects completed 24 weeks of therapy. No subject demo nstrated primary protease inhibitor mutations at baseline. Toxicities exper ienced by subjects were typically mild and consistent with those commonly r eported for each of the medications, including two cases of hematuria. By w eek 24, median nonfasting cholesterol and triglyceride levels increased by 49% and 108%, respectively. Median baseline plasma HIV viral load and CD4() lymphocyte count were 29,292 (4.37 log(10)) copies/ml and 224 cells/mm(3) , respectively. Eight of 10 subjects had a plasma HIV viral load of < 50 co pies/ml by week 12. The 2 subjects with a detectable HIV viral load reached < 50 copies/ml by week 28. Median CD4(+) lymphocyte counts increased by 19 3 cells/mm(3) at week 24. Indinavir and ritonavir plasma concentrations rem ained above respective inhibitory and effective concentrations (IC95 and EC 50) (uncorrected for protein binding) throughout the 24-hour dosing interva l for 6 of 10 and 8 of 10 subjects, respectively. Conclusions: Our pilot study demonstrates excellent virologic suppression d espite low minimum protease inhibitor concentrations during a dosing interv al in some patients and is supportive of further study.