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 nevirapineassociated 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 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 ¼ 0.40, 95% CI ¼ 0.21-0.77). A similar trend was observed among the 315 women included in the 6-week analysis (RR ¼ 0.45, 95% CI ¼ 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 ¼ 0.96). M184V was not detected. The ability of single-dose TDF=FTC to protect against peripartum NVPinduced NNRTI resistance extends to minority populations. This efficacy is achieved without significant selection of TDF-or FTC-resistant viruses.

Efficacy and Safety of 1‐Month Postpartum Zidovudine‐Didanosine to Prevent HIV‐Resistance Mutations after Intrapartum Single‐Dose Nevirapine

“…Although no direct comparison can be made with subtypes prevalent in Thailand, the incidence of resistance with subtype-C appears to be higher than with subtypes E/B. For example, in Zambia where subtype-C predominates, the prevalence of NNRTI resistance mutations at 6-week postpartum in a similar population (women not eligible for HAART who received antepartum ZDV) was 25% using population sequencing (44% with OLA) [23], compared with 6.4% (13.2% with OLA) in PHPT-2 participants.…”

“…In Zambia, women not eligible for HAART who received short course zidovudine plus intrapartum nevirapine, received either single-dose tenofovir-plus-emtricitabine (Truvada ® ) during labor or no intervention [26]. At 6 weeks postpartum, Truvada ® reduced NNRTI resistance mutations detected by population sequencing from 25% to 12%, and by OLA from 45% to 20%[23]. Finally, in the TEmAA ANRS12109 study [27], no resistance mutations were detected by population sequencing at 4 weeks postpartum in 37 women with over 200 CD4 cells/mm 3 who received antepartum zidovudine, intrapartum single-dose nevirapine together with double-dose Truvada ® , continued for one week once daily.…”

Simultaneous and sensitive detection of human immunodeficiency virus type 1 (HIV) drug resistant genotypes by multiplex oligonucleotide ligation assay

“…Additionally, the probes often need to be adapted to regional HIV variants to limit indeterminate reactions by OLA. Previous studies have reported rates of indeterminate reactions between 5.5% and 7% (Chi, Ellis, Chintu, Cantrell, Sinkala, Aldrovandi, Warrier, Mbewe, Nakamura, Stringer, Frenkel, Stringer, 2009; Ellis, Page, Burman, Buskin, Frenkel, 2009). Importantly, when the MPX-OLA queries codons conferring resistance to the same ARV, such as the 103/181 pair, detection of a mutant at either codon provides clinically relevant drug-resistance information.…”

HIV-1 Drug Resistance by Ultra-Deep Sequencing Following Short Course Zidovudine, Single-Dose Nevirapine, and Single-Dose Tenofovir with Emtricitabine for Prevention of Mother-to-Child Transmission

“…18 The addition of peripartum AZT 19 and postpartum TDF/FTC 20 was shown to reduce the rate of resistance conferred by sd NVP. An open-labeled randomized control trial in Zambia found that the addition of sd TDF/FTC reduced NNRTI resistance by half at 6 weeks post-delivery.…”