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

Figure 1. Case-cohort design and subject disposition

Subjects were excluded if they had no result for both minority variants. Subjects were considered to have incomplete data if they had a result for only one minority variant.

Figure 2. Levels of minority Y181C mutants in the virus population

The horizontal line represents the sensitivity threshold of the allele-specific PCR assay for detecting Y181C mutants (0.03%). Circles represent the levels at which Y181C were found among each plasma sample. Each circle corresponds to one subject.

Figure 3. Prevalence of baseline minority K103N and Y181C mutants according to virologic outcome

Figures show the proportion of subjects with and without virologic failure in whom low-abundance K103N (upper figure) and Y181C (lower figure) mutations were detected at baseline among those without NNRTI resistance by population sequencing in the random subcohort. The upper figure includes 2 subjects with a K103N result only and the lower figure includes 2 subjects with an Y181C result only; these subjects are excluded from all other analyses. Analyses were done overall; for subjects with the Y181C mutation detected by ASPCR (Y181C+) or not (No Y181C); for subjects with the K103N mutation detected by ASPCR (K103N+) or not (No K103N); for those receiving abacavir (ABC), zidovudine (ZDV), lamivudine (3TC) and efavirenz (EFV) or those receiving zidovudine (ZDV), lamivudine (3TC) and efavirenz (EFV); and for subjects with screening HIV-1 RNA levels (VL) greater than or equal to, or lower than 100,000 copies/mL. The prevalence of low-abundant K103N mutants among failures and non-failures was not significantly different overall (p-value not shown). P-value for difference in prevalence of low-abundant Y181C mutants among failures and non-failures overall is shown. P_interaction values are based on exact test for homogeneity of odds ratios across subgroups. P-values are nominal and unadjusted for multiple comparisons. * P interaction = 1.0; ** P interaction = 0.27; *** P Interaction = 0.71

Figure 4. Effect of Y181C in the presence of recent adherence (adjusted for presence of minority of K103N by ASPCR)

As-treated weighted Cox proportional hazards model of time to virologic failure; Adherent, adequate recent self-reported adherence to therapy; Sensitive, no evidence of non-nucleoside reverse transcriptase inhibitors (NNRTI) resistance mutations by population sequencing and by allele-specific PCR (ASPCR); 95% CI, 95% confidence interval.