Intrapartum tenofovir and emtricitabine reduces low-concentration drug resistance selected by single-dose nevirapine for perinatal HIV prevention

Abstract

A single dose of tenofovir/emtricitabine (TDF/FTC) during labor significantly reduces peripartum nevirapine-associated viral drug resistance when measured by consensus HIV sequencing. It is unknown whether this effect extends to HIV subpopulations of <25-50%. We conducted a randomized trial of single-dose TDF/FTC added to peripartum nevirapine to reduce drug resistance associated with nonnucleoside reverse transcriptase inhibitors (NNRTIs). To detect mutations for NNRTIs comprising > or = 2% of the viral population, we used an oligonucleotide ligation assay (OLA) at codons 103, 106, 181, and 190 of HIV reverse transcriptase. To assess development of drug resistance mutations to our study intervention, OLA was also performed at codons 65 and 184. Among the 328 women included in the 2-week analysis, those receiving TDF/FTC were less likely to have NNRTI resistance by OLA (RR = 0.40, 95% CI = 0.21-0.77). A similar trend was observed among the 315 women included in the 6-week analysis (RR = 0.45, 95% CI = 0.31-0.66). Only two (1%) specimens had detectable K65R by OLA. Both were at 6 weeks postpartum; one was detected in the intervention arm and one in the control arm (p = 0.96). M184V was not detected. The ability of single-dose TDF/FTC to protect against peripartum NVP-induced NNRTI resistance extends to minority populations. This efficacy is achieved without significant selection of TDF- or FTC-resistant viruses.

Trial registration: ClinicalTrials.gov NCT00204308.

FIG. 1.

Proportion of participants with HIV-1 drug resistance to nonnucleotide reverse transcriptase inhibitors as assessed by oligonucleotide ligation assay at 2 (a) and 6 (b) weeks postpartum. Results from codons 103, 106, 181, and 190 are shown; the specific nucleotide sequences detected are included in parentheses. Black columns represent the control arm. White columns represent the intervention arm.

FIG. 2.

Relative concentrations of HIV-1 variants resistant to nonnucleotide reverse transcriptase inhibitors by the oligonucleotide ligation assay (OLA). The following mutations were tested: (a) K103N, sequence AAC, (b) K103N, AAT, (c) V106M, ATG, (d) Y181C, TGY, and (e) G190A, GCA. Thresholds for 0%, 2%, 5%, and 20% of circulating mutant concentrations are based on optical density readings from OLA and logistic regression (see Materials and Methods section). Results are categorized by study arm and are cumulative across 2- and 6-week visits. Black triangles indicate specimens with no resistance mutations detected by consensus sequencing. Open circles represent specimens with resistance mutations detected by consensus sequencing. “X” indicates that the specimens were missing a consensus sequence or the OLA was indeterminate.

FIG. 2.

Relative concentrations of HIV-1 variants resistant to nonnucleotide reverse transcriptase inhibitors by the oligonucleotide ligation assay (OLA). The following mutations were tested: (a) K103N, sequence AAC, (b) K103N, AAT, (c) V106M, ATG, (d) Y181C, TGY, and (e) G190A, GCA. Thresholds for 0%, 2%, 5%, and 20% of circulating mutant concentrations are based on optical density readings from OLA and logistic regression (see Materials and Methods section). Results are categorized by study arm and are cumulative across 2- and 6-week visits. Black triangles indicate specimens with no resistance mutations detected by consensus sequencing. Open circles represent specimens with resistance mutations detected by consensus sequencing. “X” indicates that the specimens were missing a consensus sequence or the OLA was indeterminate.

FIG. 3.

Relative concentrations of variants resistant to tenofovir and emtricitabine by the oligonucleotide ligation assay. We tested for mutations (a) K65R, AGR sequence and (b) M184V, GTG. Thresholds for 0%, 2%, 5%, and 20% of circulating mutant concentrations are based on optical density readings from OLA and logistic regression (see Materials and Methods section). Results are categorized by study arm and are cumulative across 2- and 6-week visits. Black triangles indicate specimens with no resistance mutations detected by consensus sequencing. Open circles represent specimens with resistance mutations detected by consensus sequencing. “X” indicates that the specimens were missing a consensus sequence or the OLA was indeterminate.