Low-frequency HIV-1 drug resistance mutations and risk of NNRTI-based antiretroviral treatment failure: a systematic review and pooled analysis

Abstract

Context: Presence of low-frequency, or minority, human immunodeficiency virus type 1 (HIV-1) drug resistance mutations may adversely affect response to antiretroviral treatment (ART), but evidence regarding the effects of such mutations on the effectiveness of first-line ART is conflicting.

Objective: To evaluate the association of preexisting drug-resistant HIV-1 minority variants with risk of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral virologic failure.

Data sources: Systematic review of published and unpublished studies in PubMed (1966 through December 2010), EMBASE (1974 through December 2010), conference abstracts, and article references. Authors of all studies were contacted for detailed laboratory, ART, and adherence data.

Study selection and data abstraction: Studies involving ART-naive participants initiating NNRTI-based regimens were included. Participants were included if all drugs in their ART regimen were fully active by standard HIV drug resistance testing. Cox proportional hazard models using pooled patient-level data were used to estimate the risk of virologic failure based on a Prentice weighted case-cohort analysis stratified by study.

Data synthesis: Individual data from 10 studies and 985 participants were available for the primary analysis. Low-frequency drug resistance mutations were detected in 187 participants, including 117 of 808 patients in the cohort studies. Low-frequency HIV-1 drug resistance mutations were associated with an increased risk of virologic failure (hazard ratio (HR], 2.3 [95% confidence interval {CI}, 1.7-3.3]; P < .001) after controlling for medication adherence, race/ethnicity, baseline CD4 cell count, and plasma HIV-1 RNA levels. Increased risk of virologic failure was most strongly associated with minority variants resistant to NNRTIs (HR, 2.6 [95% CI, 1.9-3.5]; P < .001). Among participants from the cohort studies, 35% of those with detectable minority variants experienced virologic failure compared with 15% of those without minority variants. The presence of minority variants was associated with 2.5 to 3 times the risk of virologic failure at either 95% or greater or less than 95% overall medication adherence. A dose-dependent increased risk of virologic failure was found in participants with a higher proportion or quantity of drug-resistant variants.

Conclusion: In a pooled analysis, low-frequency HIV-1 drug resistance mutations, particularly involving NNRTI resistance, were significantly associated with a dose-dependent increased risk of virologic failure with first-line ART.

Figure 1

Study Selection Flow Diagram ^aCommon reasons for exclusion include: does not involve low-frequency resistance variants, review article, epidemiological study, and treatment experienced patient population only.

Figure 2

Kaplan-Meier Curves for the Proportion of Patients without Virologic Failure by the Presence of Minority HIV-1 Drug-Resistant Variants Abbreviations: MV, minority variants Both NNRTI- and NRTI-resistant minority variants are included in this analysis. To avoid bias induced by targeted sampling in case-control studies, Kaplan-Meier failure time distributions were estimated using only date from cohort studies^–. Kaplan-Meier curves only shown up to 1,250 days due to the small sample sizes thereafter. P-value comparison by Cox proportional hazard analysis. Median follow-up time is 31 months [IQR 12–34 months].

Figure 3

Effect of Minority Variants and Antiretroviral Therapy Adherence on Virologic Failure Abbreviations: MV, Minority Variants; VF, Virologic Failure ^aMultivariate Cox regression analysis included adherence, ethnicity, baseline CD4 cell count, and HIV-1 RNA levels. ^bNumber of participants with virologic failure / total participants categorized by those with and without detectable minority variants. Participant numbers include additional virologic failure cases from the case-control and case cohort studies^–. Cox proportional hazard rations shown are in comparison to those without minority variants unless otherwise noted. Three studies contributed to the adherence analysis^{, ,} . Analysis of MV copy numbers excluded three studies using assays that could not provide a percentage^{, ,} . For the MV 1% threshold analysis, one study was excluded due to a limit of detection of 2% for the assay and only NNRT1 MVs were evaluated for two studies due to incompatible limits of detection fon the NRTI MVs^, . Four studies were excluded from the 0.5% threshold analysis due to higher limits of MV detection^{, , ,} .

Figure 4

Time to HIV-1 RNA <200 copies/ml in Patients Achieving Virologic Suppression Abbreviations: MV, minority variants Two studies with frequent HIV-1 RNA monitoring^, were used to determine flie time to HIV-1 RNA <200 copies/ml among individuals who became virologically suppressed. P-value comparison by Cox proportional hazard analysis. Median time to virologic suppression was 57 days [IQR 28–112 days] for those with minority variants and 57 days [IQR 27–111 days] for those without.