Pre-existing minority drug-resistant HIV-1 variants, adherence, and risk of antiretroviral treatment failure.

TitlePre-existing minority drug-resistant HIV-1 variants, adherence, and risk of antiretroviral treatment failure.
Publication TypeJournal Article
Year of Publication2010
AuthorsParedes R, Lalama CM, Ribaudo HJ, Schackman BR, Shikuma C, Giguel F, Meyer WA, Johnson VA, Fiscus SA, D'Aquila RT, Gulick RM, Kuritzkes DR
Corporate AuthorsAIDS Clinical Trials Group(ACTG) A5095 Study Team
JournalJ Infect Dis
Volume201
Issue5
Pagination662-71
Date Published2010 Mar
ISSN1537-6613
KeywordsAdult, Amino Acid Substitution, Anti-HIV Agents, Benzoxazines, Case-Control Studies, Cohort Studies, Drug Resistance, Viral, Female, HIV Infections, HIV Reverse Transcriptase, HIV-1, Humans, Male, Medication Adherence, Middle Aged, Mutation, Missense, Polymerase Chain Reaction, Randomized Controlled Trials as Topic, Treatment Failure
Abstract

BACKGROUND: The clinical relevance of detecting minority drug-resistant human immunodeficiency virus type 1 (HIV-1) variants is uncertain.

METHODS: To determine the effect of pre-existing minority nonnucleoside reverse-transcriptase inhibitor (NNRTI)-resistant variants on the risk of virologic failure, we reanalyzed a case-cohort substudy of efavirenz recipients in AIDS Clinical Trials Group protocol A5095. Minority K103N or Y181C populations were determined by allele-specific polymerase chain reaction in subjects without NNRTI resistance by population sequencing. Weighted Cox proportional hazards models adjusted for recent treatment adherence estimated the relative risk of virologic failure in the presence of NNRTI-resistant minority variants.

RESULTS: The evaluable case-cohort sample included 195 subjects from the randomly selected subcohort (51 with virologic failure, 144 without virologic failure), plus 127 of the remaining subjects who experienced virologic failure. Presence of minority K103N or Y181C mutations, or both, was detected in 8 (4.4%), 54 (29.5%), and 11 (6%), respectively, of 183 evaluable subjects in the random subcohort. Detection of minority Y181C mutants was associated with an increased risk of virologic failure in the setting of recent treatment adherence (hazard ratio, 3.45 [95% confidence interval, 1.90-6.26]) but not in nonadherent subjects (hazard ratio, 1.39 [95% confidence interval, 0.58-3.29]). Of note, 70% of subjects with minority Y181C variants achieved long-term viral suppression.

CONCLUSIONS: In adherent patients, pre-existing minority Y181C mutants more than tripled the risk of virologic failure of first-line efavirenz-based antiretroviral therapy.

CLINICAL TRIALS REGISTRATION: NCT00013520.

DOI10.1086/650543
Alternate JournalJ. Infect. Dis.
PubMed ID20102271
PubMed Central IDPMC2825289
Grant ListAI027767 / AI / NIAID NIH HHS / United States
AI051966 / AI / NIAID NIH HHS / United States
AI060354 / AI / NIAID NIH HHS / United States
AI06836 / AI / NIAID NIH HHS / United States
AI068636 / AI / NIAID NIH HHS / United States
AI069419 / AI / NIAID NIH HHS / United States
AI069452 / AI / NIAID NIH HHS / United States
AI069472 / AI / NIAID NIH HHS / United States
AI38858 / AI / NIAID NIH HHS / United States
AI50410 / AI / NIAID NIH HHS / United States
K24 AI051966 / AI / NIAID NIH HHS / United States
K24 AI051966-07 / AI / NIAID NIH HHS / United States
P30 AI027767 / AI / NIAID NIH HHS / United States
P30 AI027767-099003 / AI / NIAID NIH HHS / United States
P30 AI050410-099003 / AI / NIAID NIH HHS / United States
P30 AI060354 / AI / NIAID NIH HHS / United States
P30 AI060354-019003 / AI / NIAID NIH HHS / United States
RR024996 / RR / NCRR NIH HHS / United States
U01 AI038858 / AI / NIAID NIH HHS / United States
U01 AI038858-05 / AI / NIAID NIH HHS / United States
U01 AI068636 / AI / NIAID NIH HHS / United States
U01 AI068636-04S1 / AI / NIAID NIH HHS / United States
U01 AI069419 / AI / NIAID NIH HHS / United States
U01 AI069419-03 / AI / NIAID NIH HHS / United States
U01 AI069452 / AI / NIAID NIH HHS / United States
U01 AI069452-01 / AI / NIAID NIH HHS / United States
U01 AI069472 / AI / NIAID NIH HHS / United States
U01 AI069472-01 / AI / NIAID NIH HHS / United States
UL1 RR024996 / RR / NCRR NIH HHS / United States
UL1 RR024996-01 / RR / NCRR NIH HHS / United States