Clonal amplification and maternal-infant transmission of nevirapine-resistant HIV-1 variants in breast milk following single-dose nevirapine prophylaxis

Sallie R Permar,Jesus F Salazar-Gonzalez,George M Shaw,Maria G Salazar,Beatrice H Hahn,Feng Gao,Gerald H Learn,Fangping Cai,Linda Kalilani

doi:10.1186/1742-4690-10-88

Abstract

BackgroundIntrapartum administration of single-dose nevirapine (sdNVP) reduces perinatal HIV-1 transmission in resource-limiting settings by half. Yet this strategy has limited effect on subsequent breast milk transmission, making the case for new treatment approaches to extend maternal/infant antiretroviral prophylaxis through the period of lactation. Maternal and transmitted infant HIV-1 variants frequently develop NVP resistance mutations following sdNVP, complicating subsequent treatment/prophylaxis regimens. However, it is not clear whether NVP-resistant viruses are transmitted via breastfeeding or arise de novo in the infant.FindingsWe performed a detailed HIV genetic analysis using single genome sequencing to identify the origin of drug-resistant variants in an sdNVP-treated postnatally-transmitting mother-infant pair. Phylogenetic analysis of HIV sequences from the child revealed low-diversity variants indicating infection by a subtype C single transmitted/founder virus that shared full-length sequence identity with a clonally-amplified maternal breast milk virus variant harboring the K103N NVP resistance mutation.ConclusionIn this mother/child pair, clonal amplification of maternal NVP-resistant HIV variants present in systemic and mammary gland compartments following intrapartum sdNVP represents one source of transmitted NVP-resistant variants that is responsible for the acquisition of drug resistant virus by the breastfeeding infant. This finding emphasizes the need for combination antiretroviral prophylaxis to prevent mother-to-child HIV transmission.

Highlights

In 2011, 330,000 infants acquired HIV infection from their mothers [1]
In this mother/child pair, clonal amplification of maternal NVP-resistant HIV variants present in systemic and mammary gland compartments following intrapartum single-dose nevirapine (sdNVP) represents one source of transmitted NVP-resistant variants that is responsible for the acquisition of drug resistant virus by the breastfeeding infant
Env sequences conformed to predictions of a mathematical model of random evolution by a single virus [18]; as sequences exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to an inferred consensus sequence that identifies the virus present at or near the estimated time of transmission (Table 2)

Summary

Introduction

In 2011, 330,000 infants acquired HIV infection from their mothers [1]. Most of mother-to-child transmissions (MTCT) occur in low- and middle-income countries, where HIV transmission through breastfeeding accounts for 30–50% of infant infections in the absence of antiretroviral (ARV) prophylaxis [2]. To test this hypothesis, we conducted a longitudinal genetic and drugresistant mutation analysis of HIV variants in plasma and milk of a postnatal-transmitting mother-infant pair following sdNVP administration. Intrapartum administration of single-dose nevirapine (sdNVP) reduces perinatal HIV-1 transmission in resource-limiting settings by half This strategy has limited effect on subsequent breast milk transmission, making the case for new treatment approaches to extend maternal/infant antiretroviral prophylaxis through the period of lactation. Maternal and transmitted infant HIV-1 variants frequently develop NVP resistance mutations following sdNVP, complicating subsequent treatment/prophylaxis regimens It is not clear whether NVP-resistant viruses are transmitted via breastfeeding or arise de novo in the infant

Results

Discussion

Conclusion