Prevalence and Impact of Minority Variant Drug Resistance Mutations in Primary HIV-1 Infection

Joanne D Stekler,Janine Maenza,Lisa M Frenkel,Claire E Stevens,Jacquelyn Carlsson,Giovanina M Ellis,Sarah Holte,Braiden Eilers,Ann C Collier,Cheryl A Stoddart

doi:10.1371/journal.pone.0028952

Abstract

ObjectiveTo evaluate minority variant drug resistance mutations detected by the oligonucleotide ligation assay (OLA) but not consensus sequencing among subjects with primary HIV-1 infection.Design/MethodsObservational, 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.ResultsConsensus 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.ConclusionsConsensus 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.

Highlights

Transmission of drug resistant HIV-1 has been well-documented following the widespread availability of antiretroviral (ARV) therapy [1,2,3,4,5,6,7,8,9,10,11]
Compared to subjects without mutations, time to virologic suppression was similar for subjects with minority variant mutations treated with $3 active ARVs and subjects with minority variant mutations treated with,3 active ARVs
Consensus sequencing significantly underestimated the prevalence of drug resistance mutations in ARV-naıve subjects with primary HIV-1 infection

Summary

Results

The second subject with virologic failure (ID #26973) had no major mutations identified by consensus sequencing His HIV-1 RNA level decreased to 2.0 log copies/mL before it quickly rebounded; T215Y was detected by only OLA in his PBMCs from baseline. The median follow-up time in our study was longer than other studies that observed higher rates of virologic failure, it is possible we would have seen differences in rates of virologic failure if subjects had remained on treatment and in follow-up or if we had studied more subjects Another likely explanation for our failure to identify negative consequences from minority variant mutations was the lack of uniformity of the impact of HIV-1 drug resistance mutations across regimens and the use of ARV therapy with a high genetic barrier to resistance to the mutations we observed. Given the uncertainty regarding the clinical impact of minority variant mutations and the fact that many people with these mutations still have excellent responses to therapy, prospective randomized trials that include cost-effectiveness analyses should be completed prior to the adoption of more-sensitive assays for clinical care

Conclusions

Introduction

Materials and Methods