Low-frequency nevirapine (NVP)-resistant HIV-1 variants are not associated with failure of antiretroviral therapy in women without prior exposure to single-dose NVP

Abstract

Background: Low-frequency nevirapine (NVP)-resistant variants have been associated with virologic failure (VF) of initial NVP-based combination antiretroviral therapy (cART) in women with prior exposure to single-dose NVP (sdNVP). We investigated whether a similar association exists in women without prior sdNVP exposure.

Methods: Pre-cART plasma was analyzed by allele-specific polymerase chain reaction to quantify NVP-resistant mutants in human immunodeficiency virus-infected African women without prior sdNVP who were starting first-line NVP-based cART in the OCTANE/A5208 trial 2. Associations between NVP-resistant mutants and VF or death were determined and compared with published results from women participating in the OCTANE/A5208 trial 1 who had taken sdNVP and initiated NVP-based cART.

Results: Pre-cART NVP-resistant variants were detected in 18% (39/219) of women without prior sdNVP exposure, compared to 45% (51/114) with prior sdNVP exposure (P < .001). Among women without prior sdNVP exposure, 8 of 39 (21%) with NVP-resistant variants experienced VF or death vs 31 of 180 (17%) without such variants (P = .65); this compares with 21 of 51 (41%) vs 9 of 63 (14%) among women with prior exposure (P = .001).

Conclusions: The risk of VF on NVP-based cART from NVP-resistant variants differs between sdNVP-exposed and -unexposed women. This difference may be driven by drug-resistance mutations emerging after sdNVP exposure that are linked on the same viral genome.

Clinical trials registration: NCT00089505.

Keywords: antiretroviral therapy failure; minor drug-resistant variants; single-dose nevirapine.

Figure 1.

Proportion of women in trial 1, women with single-dose nevirapine (sdNVP) exposure; and trial 2, women without sdNVP exposure reaching a study endpoint of virologic failure or death in each of 3 mutant frequency categories detected at entry compared to women with no mutation in each trial. Trial 1: trend P < .001; trial 2: trend P = .93; comparison of trends between trials: interaction P = .025; comparison of the rates of “no mutations” between trial 1 and trial 2: P = .69, P values from exact logistic regression.

Figure 2.

Kaplan-Meier plots showing the proportion of women in trial 2 (A, women without single-dose nevirapine [sdNVP] exposure) and trial 1 (B, women with sdNVP exposure) alive and without virologic failure (VF) in each of 3 categories of mutant copy number detected at entry compared to women with no mutations detected. P values from proportional hazards models.

Figure 3.

Kaplan-Meier plot showing the proportion of women identified with 181C at entry in trial 2 (A, women without single-dose nevirapine [sdNVP] exposure) and trial 1 (B, women with sdNVP exposure) reaching a study endpoint of virologic failure (VF) or death and compared to women with no mutation. The median mutant frequency for trial 1 was 0.6% and for trial 2 was 0.7% (P = .59); the median mutant copy number was 1297/mL and 1007/mL (P = .25) and the number of women in each trial identified with 181C was 14 and 13, respectively. P values from proportional hazards models.

Figure 4.

Model proposed to explain differing impact of preexisting nevirapine (NVP)–resistant mutations in trial 1 (women with single-dose NVP [sdNVP] exposure) and trial 2 (women without sdNVP exposure). The greater area under the curve shaded in gray represents the greater expansion of mutant populations under drug selective pressure in women with sdNVP exposure providing more opportunity for linkage of other resistance mutations during ongoing cycles of replication. The smaller area under the curve shown in dark gray represents the smaller proportions of mutations occurring stochastically in women without sdNVP exposure, providing fewer opportunities for linkage to other resistance mutations on the same genome. Abbreviations: cART, combination antiretroviral therapy; NRTI, nucleoside reverse transcriptase inhibitor.