Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens

Context Loss of viral suppression in patients infected with human immunodef iciency virus (HIV), who,are receiving potent antiretroviral therapy, has b een attributed to outgrowth of drug-resistant virus; however, resistance pa tterns are not well characterized in patients whose protease inhibitor comb ination therapy fails after achieving viral suppression. Objective To characterize drug susceptibility of virus from HIV-infected pa tients who are failing to sustain suppression while taking an indinavir-con taining antiretroviral regimen. Design and Setting Substudy of the AIDS Clinical Trials Group 343, a multic enter clinical research trial conducted between February 1997 and October 1 998. Patients Twenty-six:subjects who experienced rebound (HIV RNA level greater than or equal to 200 copies/mL) during indinavir monotherapy (n = 9) or tr iple-drug therapy (indinavir, lamivudine, and zidovudine; n = 17) after ini tially achieving suppression while receiving all 3 drugs, and 10 control su bjects 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 du ring triple-drug therapy, despite plasma HIV RNA levels ranging from 10(2) to 10(5) copies/mL. In contrast, lamivudine resistance was detected by phen otypic assay in rebound isolates from 14 of 17 subjects receiving triple-dr ug therapy, and genotypic analyses sh owed chan ges at codon 184 of reverse transcriptase in these 14 isolates. Mean random plasma indinavir concentra tions 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 po tency, and selection of a predominantly indinavir-resistant virus populatio n may be delayed for months even in the presence of ongoing indinavir thera py. The results suggest possible value in assessing strategies using drug c omponents of failing regimens evaluated with resistance testing.