Ritonavir and saquinavir combination therapy for the treatment of HIV infection

Objective: To evaluate the safety and antiretroviral activity of ritonavir (Norvir(TM)) and saquinavir (Invirase(TM)) 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 x 10(6) cells/l, whether treated previously ol not with reverse transcriptase inhibitor therapy, but without previous HIV protease inhibit or drug therapy. Interventions: After discontinuation of prior therapy for 2 weeks, group pa tients were randomized to receive either combination (A) ritonavir 400 mg a nd saquinavir 400 mg twice daily or (B) ritonavir 600 mg and saquinavir 400 mg twice daily. After an initial safety assessment of group I patients, gr oup II patients were randomized to receive either (C) ritonavir 400 mg and saquinavir 400 mg three times daily or (D) ritonavir 600 mg and saquinavir 600 mg twice daily. Investigators were allowed to add up to two reverse tra nscriptase inhibitors (including at least one with which the patient had no t been previously treated) to a patient's regimen after week 12 for failure to achieve or maintain an HIV RNA level less than or equal to 200 copies/m l documented on two consecutive occasions. Measurements: Plasma HIV RNA levels and CD4+ T-lymphocyte counts were measu red at baseline, every 2 weeks for 2 months, and monthly thereafter. Safety was assessed through the reporting of adverse events, physical examination s, 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 R NA level less than or equal to 200 copies/ml. In addition, intent-to-treat and on-treatment analyses revealed comparable results. Suppression of plasm a HIV RNA levels was similar for all treatment arms (mean areas under the c urve minus baseline through 48 weeks were -1.9, -2.0, -1.6, -1.8 log(10) co pies/ml in ritonavir-saquinavir 400-400 mg twice daily, 600-400 mg twice da ily, 400-400 mg three times daily, and 600-600 mg twice daily, respectively ). Median CD4 T-lymphocyte count rose by 128 x 10(6) cells/l from baseline, with an interquartile range (IQR) of 82-221 x 10(6) cells/l. The mast comm on adverse events were diarrhea, circumoral paresthesia, asthenia, and naus ea. Reversible elevation of serum transaminases (> 5 x upper limit of norma l) occurred in 10% (14/141) of the patients enrolled in this study and was associated with baseline abnormalities in liver function tests, baseline he patitis B surface antigen positivity, or hepatitis C antibody positivity (r elative risk, 5.0; 95% confidence interval 1.5-16.9). Most moderate or seve re elevations in liver function tests occurred in patients treated with rit onavir-saquinavir 600-600 mg twice daily. Conclusions: Ritonavir 400 mg combined with saquinavir 400 mg twice daily w ith 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 p rotease inhibitor treatment. (C) 1999 Lippincott Williams & Wilkins.