Ritonavir and saquinavir combination therapy for the treatment of HIV infection.

Objective: To evaluate the safety and antiretroviral activity of ritonavir (NorvirTM) and saquinavir (InviraseTM) combination therapy in patients with HIV infection. Design: A multicenter, randomized, open-label clinical trial. Setting: Seven HIV research units in the USA and Canada. Patients: A group of 141 adults with HIV infection, CD4 T lymphocyte counts of 100-500×106 cells/l, whether treated previously or not with reverse transcriptase inhibitor therapy, but without previous HIV protease inhibitor drug therapy. Interventions: After discontinuation of prior therapy for 2 weeks, group I patients were randomized to receive either combination (A) ritonavir 400mg and saquinavir 400mg twice daily or (B) ritonavir 600mg and saquinavir 400mg twice daily. After an initial safety assessment of group I patients, group II patients were randomized to receive either (C) ritonavir 400mg and saquinavir 400mg three times daily or (D) ritonavir 600mg and saquinavir 600mg twice daily. Investigators were allowed to add up to two reverse transcriptase inhibitors (including at least one with which the patient had not been previously treated) to a patient‚s regimen after week 12 for failure to achieve or maintain an HIV RNA level ≤ 200 copies/ml documented on two consecutive occasions. Measurements: Plasma HIV RNA levels and CD4+ T-lymphocyte counts were measured at baseline, every 2 weeks for 2 months, and monthly thereafter. Safety was assessed through the reporting of adverse events, physical examinations, and the monitoring of routine laboratory tests. Results: The 48 weeks of study treatment was completed by 75% (106/141) of the patients. Over 80% of the patients on treatment at week 48 had an HIV RNA level ≤200 copies/ml. In addition, intent-to-treat and on-treatment analyses revealed comparable results. Suppression of plasma HIV RNA levels was similar for all treatment arms (mean areas under the curve minus baseline through 48 weeks were -1.9, -2.0, -1.6, -1.8 log10 copies/ml in ritonavir-saquinavir 400-400mg twice daily, 600-400mg twice daily, 400-400mg three times daily, and 600-600mg twice daily, respectively). Median CD4 T-lymphocyte count rose by 128×106 cells/l from baseline, with an interquartile range (IQR) of 82-221×106 cells/l. The most common adverse events were diarrhea, circumoral paresthesia, asthenia, and nausea. Reversible elevation of serum transaminases (>5×upper limit of normal) occurred in 10% (14/141) of the patients enrolled in this study and was associated with baseline abnormalities in liver function tests, baseline hepatitis B surface antigen positivity, or hepatitis C antibody positivity (relative risk, 5.0; 95% confidence interval 1.5-16.9). Most moderate or severe elevations in liver function tests occurred in patients treated with ritonavir-saquinavir 600-600mg twice daily. Conclusions: Ritonavir 400mg combined with saquinavir 400mg twice daily with the selective addition of reverse transcriptase inhibitors was the best-tolerated regimen of four dose-ranging regimens and was equally as active as the higher dose combinations in HIV-positive patients without previous protease inhibitor treatment.