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Diane V. Havlir, MD; Nick S. Hellmann, MD; Christos J. Petropoulos, PhD; Jeannette M. Whitcomb, PhD; Ann C. Collier, MD; Martin S. Hirsch, MD; Pablo Tebas, MD; Jean-Pierre Sommadossi, PhD; Douglas D. Richman, MD

JAMA. 2000;283:229-234.

Context  Loss of viral suppression in patients infected with human immunodeficiency virus (HIV), who are receiving potent antiretroviral therapy, has been attributed to outgrowth of drug-resistant virus; however, resistance patterns are not well characterized in patients whose protease inhibitor combination therapy fails after achieving viral suppression.

Objective  To characterize drug susceptibility of virus from HIV-infected patients who are failing to sustain suppression while taking an indinavir-containing antiretroviral regimen.

Design and Setting  Substudy of the AIDS Clinical Trials Group 343, a multicenter clinical research trial conducted between February 1997 and October 1998.

Patients  Twenty-six subjects who experienced rebound (HIV RNA level 200 copies/mL) during indinavir monotherapy (n = 9) or triple-drug therapy (indinavir, lamivudine, and zidovudine; n = 17) after initially achieving suppression while receiving all 3 drugs, and 10 control subjects who had viral suppression while receiving triple-drug therapy.

Main Outcome Measure  Drug susceptibility, determined by a phenotypic assay and genotypic evidence of resistance assessed by nucleotide sequencing of protease and reverse transcriptase, compared among the 3 patient groups.

Results  Indinavir resistance was not detected in the 9 subjects with viral rebound during indinavir monotherapy or in the 17 subjects with rebound during triple-drug therapy, despite plasma HIV RNA levels ranging from 10² to 10⁵ copies/mL. In contrast, lamivudine resistance was detected by phenotypic assay in rebound isolates from 14 of 17 subjects receiving triple-drug therapy, and genotypic analyses showed changes at codon 184 of reverse transcriptase in these 14 isolates. Mean random plasma indinavir concentrations in the 2 groups with rebound were similar to those of a control group with sustained viral suppression, although levels below 50 ng/mL were more frequent in the triple-drug group than in the control group (P = .03).

Conclusions  Loss of viral suppression may be due to suboptimal antiviral potency, and selection of a predominantly indinavir-resistant virus population may be delayed for months even in the presence of ongoing indinavir therapy. The results suggest possible value in assessing strategies using drug components of failing regimens evaluated with resistance testing.

Author Affiliations: University of California, San Diego (Drs Havlir and Richman), San Diego Veterans Affairs Medical Center (Dr Richman); ViroLogic Inc, San Francisco, Calif (Drs Hellmann, Petropoulos, and Whitcomb); Harvard Medical School, Boston, Mass (Dr Hirsch); University of Washington School of Medicine, Seattle (Dr Collier); Washington University, St Louis, Mo (Dr Tebas); and the University of Alabama, Birmingham (Dr Sommadossi).

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