Prevalence and impact of minority variant drug resistance mutations in primary HIV-1 infection

• Published in: PloS one Vol. 6; no. 12; p. e28952
• Main Authors: Stekler, Joanne D, Ellis, Giovanina M, Carlsson, Jacquelyn, Eilers, Braiden, Holte, Sarah, Maenza, Janine, Stevens, Claire E, Collier, Ann C, Frenkel, Lisa M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16-12-2011; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; Adult; AIDS; Antiretroviral agents; Antiretroviral drugs; Antiretroviral Therapy, Highly Active; Biological products industry; Biology; Codons; Demography; Drug resistance; Drug Resistance, Viral - genetics; Drug therapy; Health aspects; HIV; HIV Infections - blood; HIV Infections - genetics; HIV Infections - therapy; HIV Infections - virology; HIV-1 - genetics; Human immunodeficiency virus; Humans; Infections; Male; Medicine; Mutation; Mutation - genetics; Oligonucleotides; Oligonucleotides - metabolism; Patient compliance; Prevalence; Ribonucleic acid; RNA; RNA, Viral - blood; Sequence Analysis, DNA; Time Factors; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0028952

To evaluate minority variant drug resistance mutations detected by the oligonucleotide ligation assay (OLA) but not consensus sequencing among subjects with primary HIV-1 infection.
Observational, longitudinal cohort study. Consensus sequencing and OLA were performed on the first available specimens from 99 subjects enrolled after 1996. Survival analyses, adjusted for HIV-1 RNA levels at the start of antiretroviral (ARV) therapy, evaluated the time to virologic suppression (HIV-1 RNA<50 copies/mL) among subjects with minority variants conferring intermediate or high-level resistance.
Consensus sequencing and OLA detected resistance mutations in 5% and 27% of subjects, respectively, in specimens obtained a median of 30 days after infection. Median time to virologic suppression was 110 (IQR 62-147) days for 63 treated subjects without detectable mutations, 84 (IQR 56-109) days for ten subjects with minority variant mutations treated with ≥3 active ARVs, and 104 (IQR 60-162) days for nine subjects with minority variant mutations treated with <3 active ARVs (p = .9). Compared to subjects without mutations, time to virologic suppression was similar for subjects with minority variant mutations treated with ≥3 active ARVs (aHR 1.2, 95% CI 0.6-2.4, p = .6) and subjects with minority variant mutations treated with <3 active ARVs (aHR 1.0, 95% CI 0.4-2.4, p = .9). Two subjects with drug resistance and two subjects without detectable resistance experienced virologic failure.
Consensus sequencing significantly underestimated the prevalence of drug resistance mutations in ARV-naïve subjects with primary HIV-1 infection. Minority variants were not associated with impaired ARV response, possibly due to the small sample size. It is also possible that, with highly-potent ARVs, minority variant mutations may be relevant only at certain critical codons.