Objectives: To demonstrate the feasibility of a concentration-controlled approach to combination antiretroviral therapy, and to compare the virological responses and safety of this strategy versus conventional fixed-dose therapy.
Design: A prospective, randomized, 52 week, open-label trial of concentration-controlled compared with conventional dose zidovudine, lamivudine, and indinavir therapy conduced in a university-based general clinical research center in the United States.
Patients: Forty antiretroviral-naive individuals with plasma HIV-RNA levels > 5000 copies/ml.
Interventions: Zidovudine, lamivudine, and indinavir plasma concentrations were measured in all participants. Doses were adjusted in those assigned to concentration-controlled therapy to achieve levels equal to or greater than target values.
Main outcome measures: The proportion of patients who achieved the desired drug concentrations, the proportion of patients with HIV-RNA levels < 50 copies/ml at week 52, and safety and tolerance in the concentration-controlled versus conventional therapy arms.
Results: Significantly more concentration-controlled recipients achieved the desired concentration targets for all three drugs: 15 of 16 concentration-controlled recipients compared with nine of 17 conventional recipients (P = 0.017) had HIV-RNA levels < 50 copies/ml at week 52. No difference was observed in the occurrence of drug-related clinical events or laboratory abnormalities between the two treatment arms.
Conclusion: Concentration-controlled therapy implemented simultaneously for three antiretroviral agents was feasible, as well tolerated as conventional therapy, and resulted in a greater proportion of recipients with HIV-RNA levels < 50 copies/ml after 52 weeks. These findings provide a scientific basis to challenge the accepted practice of administering the same dose of antiretroviral agents to all adults, ignoring the concentrations actually achieved.
From the Departments of aExperimental and Clinical Pharmacology, and bInfectious Diseases, University of Minnesota Academic Health Sciences Center, Minneapolis, MN, USA; and c HIV Program, Hennepin County Medical Center, Minneapolis, MN, USA.
Correspondence and reprint requests to: Courtney V. Fletcher, PharmD, University of Colorado Health Science Center, School of Pharmacy, C-238, 4200 East Ninth Avenue, Denver, Colorado 80262, USA. Tel: +1 303 315 5229; fax: +1 303 315 4630; e-mail: email@example.com
Received: 17 August 2001;
revised: 16 October 2001; accepted: 24 October 2001.
Sponsorship: This work was supported by grant nos. RO1 AI33835-08 (to C.V.F.) from the National Institute of Allergy and Infectious Diseases, and MO1 RR00400 from the National Institutes of Health, Center for Research Resources General Clinical Research Centers Program.