Pre-existing Minority Drug-Resistant HIV-1 Variants, Adherence, and Risk of Antiretroviral Treatment Failure

• Published in: The Journal of infectious diseases Vol. 201; no. 5; pp. 662 - 671
• Main Authors: Paredes, Roger, Lalama, Christina M., Ribaudo, Heather J., Schackman, Bruce R., Shikuma, Cecilia, Giguel, Francoise, Meyer, William A., Johnson, Victoria A., Fiscus, Susan A., D'Aquila, Richard T., Gulick, Roy M., Kuritzkes, Daniel R.
• Format: Journal Article
• Language: English
• Published: Oxford The University of Chicago Press 01-03-2010; University of Chicago Press; Oxford University Press
• Subjects: Adult; AIDS; Amino Acid Substitution - genetics; Anti-HIV Agents - therapeutic use; Antiretrovirals; Benzoxazines - therapeutic use; Biological and medical sciences; Case-Control Studies; Clinical trials; Cohort Studies; Drug Resistance, Viral; Female; Fundamental and applied biological sciences. Psychology; Genetic mutation; HIV 1; HIV Infections - drug therapy; HIV Infections - virology; HIV Reverse Transcriptase - genetics; HIV-1 - classification; HIV-1 - genetics; HIV-1 - growth & development; HIV-1 - isolation & purification; HIV/AIDS; Human immunodeficiency virus 1; Humans; Infectious diseases; Male; Medical sciences; Medication Adherence; Microbiology; Middle Aged; Miscellaneous; Mutation, Missense; Polymerase chain reaction; Polymerase Chain Reaction - methods; Randomized Controlled Trials as Topic; RNA; Sequencing; Treatment Failure; Virology; Viruses; Virus; Infection; Resistance; Antiretroviral agent; Treatment; HIV-1 virus; Retroviridae; Antiviral; Human immunodeficiency virus; Lentivirus; Adhesion; Failure
• ISSN: 0022-1899; 1573-6613; 1537-6613
• DOI: 10.1086/650543

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.