Emergence of Minor Drug-Resistant HIV-1 Variants after Triple Antiretroviral Prophylaxis for Prevention of Vertical HIV-1 Transmission

Abstract

Background WHO-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. Method 1395 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%. Results 50/87 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. Conclusion Complex 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.

Emergence of HIV-1 drug-resistant variants in women following antiretroviral prophylaxis for the prevention of mother to child transmission

“…hauser et al (2012) has compared the utility of population sequencing and the allele-specific PCR for the detection of minor variants up to 1% in women who were given the complex prophylaxis regimen. [8] They showed the emergence of HIV-1 drug resistant variants in 20 out of 50 (40%) women by the allele-specific PCR. Mutation to AZT were found in 11 (22%), NVP-resistant mutation in (18%) and 3TC-resistant mutation in 4 women (8%).…”

“…[3] Irrespective of these regimens used, these women developed drug resistance following ART prophylaxis. [4,8] The emergence of drug resistance is associated with incomplete suppression of HIV-1 viral load in mothers who are taking ART prophylaxis. In our study group, majority [91%] of the women were on a complex prophylaxis based on the WHO PMTCT (prevention of MTCT) guidelines' recommendation of >3%.…”

HIV and Pregnancy

“…However, it can be a complex strategy particularly when combined with a prenatal course of zidovudine monotherapy (WHO Option A, 2010), subject to supply chain disruptions, and still may be associated with substantial acquisition of antiretroviral drug resistance. A small study done between 2008 and 2009 in 50 urban pregnant Tanzanian women treated antenatally with zidovudine from 28 weeks to delivery and single dose nevirapine intrapartum supplemented with combination zidovudine and lamivudine intrapartum and for one week postpartum, showed 40 % acquired antiviral drug resistance when evaluated with both bulk population genotyping and allelespecific single genome sequencing by polymerase chain reaction (ASPCR) [58].…”

HIV Drug Resistance in Mothers and Infants Following Use of Antiretrovirals to Prevent Mother-to-Child Transmission

“…More recently, among Tanzanian women who received antenatal ZDV (median duration 53 days), sdNVP, and ZDV/3TC postpartum for 1 week, at time of delivery, ZDV resistance was detected in 10 % using a sensitive allele-specific PCR (AS-PCR) (Hauser et al 2012). Over a 16-week followup period, however, ZDV resistance was detected in 22 %, suggesting that postpartum ARV tails administered following sdNVP to diminish the emergence of NVP-resistant virus may continue to exert selective pressure for ZDV resistance mutations.…”

“…The observations of resistance in a substantial proportion of US (Frenkel et al 2006) and Tanzanian (Hauser et al 2012) women with >350 CD4 cells/uL after ZDV argue for studies to evaluate the effect of ZDV monotherapy on subsequent maternal ART, as mutations selected by ZDV monotherapy may be archived in long-lived cells, potentially diminishing the efficacy of subsequent maternal ART containing ZDV or other NRTI.…”