Impact of pre-existing drug resistance on risk of virological failure in South Africa

Abstract

Objectives: There is conflicting evidence on the impact of pre-existing HIV drug resistance mutations (DRMs) in patients infected with non-B subtype virus.

Methods: We performed a case-cohort substudy of the AIDS Drug Resistance Surveillance Study, which enrolled South African patients initiating first-line efavirenz/emtricitabine/tenofovir. Pre-ART DRMs were detected by Illumina sequencing of HIV pol and DRMs present at <20% of the viral population were labelled as minority variants (MVs). Weighted Cox proportional hazards models estimated the association between pre-ART DRMs and risk of virological failure (VF), defined as confirmed HIV-1 RNA ≥1000 copies/mL after ≥5 months of ART.

Results: The evaluable population included 178 participants from a randomly selected subcohort (16 with VF, 162 without VF) and 83 additional participants with VF. In the subcohort, 16% of participants harboured ≥1 majority DRM. The presence of any majority DRM was associated with a 3-fold greater risk of VF (P = 0.002), which increased to 9.2-fold (P < 0.001) in those with <2 active drugs. Thirteen percent of participants harboured MV DRMs in the absence of majority DRMs. Presence of MVs alone had no significant impact on the risk of VF. Inclusion of pre-ART MVs with majority DRMs improved the sensitivity but reduced the specificity of predicting VF.

Conclusions: In a South African cohort, the presence of majority DRMs increased the risk of VF, especially for participants receiving <2 active drugs. The detection of drug-resistant MVs alone did not predict an increased risk of VF, but their inclusion with majority DRMs affected the sensitivity/specificity of predicting VF.

Figure 1.

Prevalence of HIV DRMs by ARV class and frequency. Prevalence calculations performed amongst the subcohort population. Percentage of individuals harbouring minority resistance mutations excludes those with majority resistance. Majority resistance mutations refer to mutations conferring intermediate or greater resistance to the participant’s ARV regimen and present at ≥20% of the viral population. Minority resistance mutations refer to mutations present at ≥0.5% and <20% of the viral population.

Figure 2.

Proportion of subcohort participants at each GSS level calculated with majority DRMs alone (Maj only) or in the presence of varying frequencies of minority DRMs. Maj, majority DRMs; MV, minority DRMs present at the specified frequency.

Figure 3.

Sensitivity and specificity of predicting VF based on the presence of at least one majority and/or minority DRMs. Maj, majority DRMs; MV, minority DRMs present at the specified frequency.