Abstract
BackgroundWHO-guidelines for prevention of mother-to-child transmission of HIV-1 in resource-limited settings recommend complex maternal antiretroviral prophylaxis comprising antenatal zidovudine (AZT), nevirapine single-dose (NVP-SD) at labor onset and AZT/lamivudine (3TC) during labor and one week postpartum. Data on resistance development selected by this regimen is not available. We therefore analyzed the emergence of minor drug-resistant HIV-1 variants in Tanzanian women following complex prophylaxis.Method1395 pregnant women were tested for HIV-1 at Kyela District Hospital, Tanzania. 87/202 HIV-positive women started complex prophylaxis. Blood samples were collected before start of prophylaxis, at birth and 1–2, 4–6 and 12–16 weeks postpartum. Allele-specific real-time PCR assays specific for HIV-1 subtypes A, C and D were developed and applied on samples of mothers and their vertically infected infants to quantify key resistance mutations of AZT (K70R/T215Y/T215F), NVP (K103N/Y181C) and 3TC (M184V) at detection limits of <1%.Results50/87 HIV-infected women having started complex prophylaxis were eligible for the study. All women took AZT with a median duration of 53 days (IQR 39–64); all women ingested NVP-SD, 86% took 3TC. HIV-1 resistance mutations were detected in 20/50 (40%) women, of which 70% displayed minority species. Variants with AZT-resistance mutations were found in 11/50 (22%), NVP-resistant variants in 9/50 (18%) and 3TC-resistant variants in 4/50 women (8%). Three women harbored resistant HIV-1 against more than one drug. 49/50 infants, including the seven vertically HIV-infected were breastfed, 3/7 infants exhibited drug-resistant virus.ConclusionComplex prophylaxis resulted in lower levels of NVP-selected resistance as compared to NVP-SD, but AZT-resistant HIV-1 emerged in a substantial proportion of women. Starting AZT in pregnancy week 14 instead of 28 as recommended by the current WHO-guidelines may further increase the frequency of AZT-resistance mutations. Given its impact on HIV-transmission rate and drug-resistance development, HAART for all HIV-positive pregnant women should be considered.
Highlights
Mother-to-child transmission of HIV-1 in resource-limited settings accounts for almost 16% of all new HIV-1 infections in Sub-Saharan Africa [1]
We developed, evaluated and applied highly sensitive allele-specific PCR (ASPCR) assays enabling the detection and quantification of three key mutations for AZT resistance (K70R, T215Y and T215F), the two most common NVP-associated resistance mutations (K103N and Y181C) and the most frequent 3TC-selected mutation M184V in the pol open reading frame with a detection limit of,1% [25,26]
Since AZT monotherapy and usage of drugs with low genetic barriers like NVP and 3TC might facilitate the formation of drug resistance, we aimed at monitoring the emergence and persistence of key resistance mutations selected by AZT, NVP and 3TC in 50 Tanzanian women from enrolment up to three months postpartum
Summary
Mother-to-child transmission of HIV-1 in resource-limited settings accounts for almost 16% of all new HIV-1 infections in Sub-Saharan Africa [1]. To reduce viral resistance as well as to further lower the vertical transmission risk of HIV-1, the WHO guidelines for the prevention of mother-to-child transmission (PMTCT) of 2006 and 2010 [14,15] recommend complex antiretroviral prophylaxis This is composed of antenatal zivoduvine (AZT) for three (2006) or six months (2010), NVP-SD at labor onset and AZT/lamivudine (3TC) during labor and for one week postnatally. The aim of this study was to evaluate the emergence of HIV-1 variants resistant against AZT, NVP and/or 3TC following complex antiretroviral prophylaxis in a rural district hospital in Kyela, Mbeya Region, Tanzania For this purpose, we developed, evaluated and applied highly sensitive allele-specific PCR (ASPCR) assays enabling the detection and quantification of three key mutations for AZT resistance (K70R, T215Y and T215F), the two most common NVP-associated resistance mutations (K103N and Y181C) and the most frequent 3TC-selected mutation M184V in the pol open reading frame with a detection limit of ,1% [25,26]. We analyzed the emergence of minor drug-resistant HIV-1 variants in Tanzanian women following complex prophylaxis
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