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BACKGROUND: South Africa (SA) has expanded efforts to reduce mother-to-child transmission of HIV (MTCT) to less than 2% at six weeks after birth and to less than 5% at 18 months postpartum by 2016. Despite improved antiretroviral regimens and coverage between 2001 and 2016, there is little data on infant HIV drug resistance. This paper tracks the prevalence of HIV drug resistance patterns amongst HIV infected infants from three nationally representative studies that assessed the effectiveness of national programs to prevent MTCT (PMTCT). The first study was conducted in 2010 (under the dual therapy PMTCT policy), the second from 2011 to 12 (PMTCT Option A policy) and the third from 2012 to 13 (PMTCT Option A policy). From 2010 to 2013, infant non-nucleoside reverse transcriptase inhibitor (NNRTI) exposure increased from single dose to daily throughout breastfeeding; maternal nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI exposure increased with initiation of NNRTI-and NRTI- containing triple antiretroviral therapy (ART) earlier in gestation and at higher CD4 cell counts. METHODS: Three nationally representative surveys were conducted in 2010, 2011-12 and 2012-13. During the surveys, mothers with known, unknown, or no exposure to antiretrovirals for PMTCT and their infants were included, and MTCT was measured. For this paper, infant dried blood spots (iDBS) from HIV PCR positive infants aged 4-8 weeks, with consent for additional iDBS testing, were analysed for HIV drug resistance at the National Institute of Communicable Diseases (NICD), SA, using an in-house assay validated by the Centers for Disease Control and Prevention (CDC). Total viral nucleic acid was extracted from 2 spots and amplified by nested PCR to generate a ~ 1 kb amplicon that was sequenced using Sanger sequencing technologies. Sequence assembly and editing was performed using RECall v3. RESULTS: Overall, HIV-1 drug resistance was detected in 51% (95% Confidence interval (CI) [45-58%]) of HIV PCR positive infants, 37% (95% CI [28-47%]) in 2010, 64% (95% CI [53-74%]) in 2011 and 63% (95% CI [47-77%]) in 2012 (p < 0.0001), particularly to the NNRTI drug class. Pooled analyses across all three surveys demonstrated that infants whose mothers received ART showed the highest prevalence of resistance (74%); 26% (21/82) of HIV PCR positive infants with no or undocumented antiretroviral drug (ARV) exposure harboured NNRTI resistance. CONCLUSIONS: These data demonstrate increasing NNRTI resistance amongst newly-diagnosed infants in a high HIV prevalence setting where maternal ART coverage increased across the years, starting earlier in gestation and at higher CD4 cell counts. This is worrying as lifelong maternal ART coverage for HIV positive pregnant and lactating women is increasing. Also of concern is that resistant virus was detected in HIV positive infants whose mothers were not exposed to ARVs, raising questions about circulating resistant virus. Numbers in this group were too small to assess trends over the three years.
Data for this resistance sub-study were drawn from the three nationally representative, cross-sectional SAPMTCTE, conducted amongst infants aged 4–8 weeks receiving their first immunisation. Data were collected at 580 public primary health care clinics and community health centres in all nine South African provinces between June – December 2010 (2010 survey), August 2011 – March 2012 (2011 survey), and October 2012 – May 2013 (2012 survey), respectively [13]. Caregiver/infant pairs of known or unknown HIV and PMTCT status were consecutively or systematically selected depending on facility size. Data were gathered from patient-held charts (“Road to Health Charts/Booklets”) and during interviews (self-reported maternal HIV testing and HIV status, infant feeding practices and ARV regimen). Infant dried blood spots (iDBS) were collected by heel-prick from all consented infants and assessed for HIV-exposure using a biomedical marker HIV Enzyme immunoassay (EIA). The iDBS with positive EIA or discordant EIA results were compared with self-reported results or were tested using a qualitative total nucleic acid (TNA) PCR to determine infant’s HIV infection. All DBS cards were stored at -20 °C before analysis. HIVDR genotyping was performed on all adequate HIV PCR positive iDBS specimens from participants that had consented for further testing. Specimens from participants from whom consent for further testing was not received, or iDBS cards with insufficient or unusable blood spots were excluded. Genotyping for resistance mutations to the NRTI, NNRTI and protease inhibitor (PI) drug classes was performed using a validated in-house sequencing method recommended by the CDC [14] as previously described [15]. Briefly, total viral nucleic acid was extracted from two spots and amplified by nested PCR to generate a ~ 1 kb amplicon that was sequenced using Sanger sequencing technologies. Sequence assembly and editing was performed using RECall v3 [16]. Resistance was defined as the presence of mutations associated with impaired drug susceptibility using the Stanford algorithm (https://hivdb.stanford.edu/) and the 2015 IAS-USA drug resistance mutation list [17]. Group comparisons for categorical data were performed using chi-square tests. Binomial regression models were applied to estimate absolute differences in resistance prevalence over the different years and exposure categories. The analyses performed are unweighted and did not take the survey design into account due to the small number of HIV positive participants involved. Summary statistics were calculated using STATA v14 (StataCorp. 2015 Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). For the purpose of this analysis we categorised maternal and infant antiretroviral access into five main groups: maternal ART with infant prophylaxis (NVP or AZT); maternal ARV prophylaxis with infant prophylaxis (NVP or AZT); infant prophylaxis only (mother reported not receiving any antiretroviral drug), any other antiretroviral combination including maternal ART only or maternal ARV only (no infant prophylaxis) or maternal ART and ARV (not one or the other) for some duration of pregnancy, and no known maternal antiretroviral exposure. The SAPMTCTE was approved by the institutional review board of the SA Medical Research Council (MRC), study number EC09–002. The project was reviewed according to the CDC human research procedures and was determined to be research, but CDC was not engaged. The resistance sub-analysis study was approved by the Institutional Review Board of the University of the Witwatersrand (M110737).
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