A SHORT-TERM STUDY OF THE SAFETY, PHARMACOKINETICS, AND EFFICACY OF RITONAVIR, AN INHIBITOR OF HIV-1 PROTEASE

Background. Reverse-transcriptase inhibitors have only moderate clinic al efficacy against the human immunodeficiency virus type 1 (HIV-1). R itonavir is an inhibitor of HIV-1 pretease with potent in vitro anti-H IV properties and good oral bioavailability. Methods. We evaluated the antiviral activity and safety of ritonavir in a double-blind, randomi zed, placebo-controlled phase 1 and 2 study of 84 HIV-positive patient s with 50 or more CD4+ lymphocytes per cubic millimeter. The patients were randomly assigned to one of four regimens of ritonavir therapy, o r to placebo for four weeks and then (by random assignment) to one of the ritonavir regimens. Results. During the first 4 weeks, increases i n CD4+ lymphocyte counts and reductions in the log number of copies of HIV-1 RNA per milliliter of plasma were similar among the four dosage groups, but in the three lower-dosage groups there was a return to ba se-line levels by 16 weeks. After 32 weeks, in the seven patients in t he highest-dosage group (600 mg of ritonavir every 12 hours), the medi an increase from base line in the CD4+ lymphocyte count was 230 cells per cubic millimeter, and the mean decrease in the plasma concentratio n of HIV-1 RNA (as measured by a branched-chain DNA assay) was 0.81 lo g (95 percent confidence interval, 0.40 to 1.22). In a subgroup of 17 patients in the two higher-dosage groups, RNA was also measured with a n assay based on the polymerase chain reaction, and after eight weeks of treatment there was a mean maximal decrease in viral RNA of 1.94 lo g (95 percent confidence interval, 1.37 to 2.51). Adverse events inclu ded nausea, circumoral paresthesia, elevated hepatic aminotransferase levels, and elevated triglyceride levels. Ten withdrawals from the stu dy were judged to be related to ritonavir treatment. Conclusions. In t his short-term study, ritonavir was well tolerated and had potent acti vity against HIV-1, but its clinical benefits remain to be established .