Concentration-controlled compared with conventional antiretroviral therapy for HIV infection.
OBJECTIVE
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.


METHODS
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.


METHODS
Forty antiretroviral-naive individuals with plasma HIV-RNA levels > 5000 copies/ml.


METHODS
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.


METHODS
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.


CONCLUSIONS
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.
Fletcher
Courtney V
CV
Department of Experimental and Clinical Pharmacology, University of Minnesota Academic Health Sciences Center, Minneapolis, MN, USA. courtney.fletcher@uchsc.edu
Anderson
Peter L
PL
Kakuda
Thomas N
TN
Schacker
Timothy W
TW
Henry
Keith
K
Gross
Cynthia R
CR
Brundage
Richard C
RC
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D019259:Lamivudine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D015215:Zidovudine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D019469:Indinavir