Objective: To evaluate the safety and antiviral activity of different dose levels of the HIV protease inhibitor ABT-378 combined with low-dose ritonavir, plus stavudine and lamivudine in antiretroviral-naive individuals.
Design: Prospective, randomized, double-blind, multicenter.
Methods: Eligible patients with plasma HIV-1 RNA > 5000 copies/ml received ABT-378 200 or 400 mg with ritonavir 100 mg every 12 h; after 3 weeks stavudine 40 mg and lamivudine 150 mg every 12 h were added (group I, n = 32). A second group initiated treatment with ABT-378 400 mg and ritonavir 100 or 200 mg plus stavudine and lamivudine every 12 h (group II, n = 68).
Results: Mean baseline HIV-1 RNA was 4.9 log10 copies/ml in both groups and CD4 cell count was 398 × 106/l and 310 × 106/l in Groups I and II respectively. In the intent-to-treat (ITT; missing value = failure) analysis at 48 weeks, HIV-1 RNA was < 400 copies/ml for 91% (< 50 copies/ml, 75%) and 82% (< 50 copies/ml, 79%) of patients in groups I and II respectively. Mean steady-state ABT-378 trough concentrations exceeded the wild-type HIV-1 EC50 (effective concentration to inhibit 50%) by 50–100-fold. The most common adverse events were abnormal stools, diarrhea and nausea. No patient discontinued before 48 weeks because of treatment-related toxicity or virologic rebound.
Conclusions: ABT-378 is a potent, well-tolerated protease inhibitor. The activity and durable suppression of HIV-1 observed in this study is probably attributable to the observed tolerability profile and the achievement of high ABT-378 plasma concentrations.
From the Department of Medicine, Northwestern University, Chicago, aAbbott Laboratories, Abbott Park, Illinois, bDuke University Medical Center, Durham, the cDepartment of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, the dDepartment of Medicine, Cornell University, New York, eThomas Street Clinic/Baylor College of Medicine, Houston, Texas, the fDepartment of Medicine, University of Colorado, Denver, Colorado, the gAIDS Research Consortium of Atlanta, Atlanta, Georgia, the hDepartments of Medicine and Immunology/Microbiology, Rush Medical College, Chicago, Illinois and the iDepartment of Medicine, Columbia University, New York, USA.
Received: 24 July 2000;
revised: 12 October 2000; accepted: 26 October 2000.
Sponsorship: Supported by Abbott Laboratories, Abbott Park, Illinois, USA.
Requests for reprints to: R. L. Murphy, Department of Medicine, Division of Infectious Diseases, Northwestern University, 676 North St. Clair Street, Suite 1920, Chicago, IL 60611, USA.
Note: James Thommes, Pacific Oaks Research, Los Angeles, California, Mary Albrecht, Department of Medicine, Harvard University, Boston, Massachusetts and Kathryn Real, Abbott Laboratories, Abbott Park, Illinois, USA also contributed to this work.