Medical Virology

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Browsing Medical Virology by browse.metadata.advisor "Gaseitsiwe, Simani"

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    Pediatric hiv-1 drug resistance in Botswana
    (Stellenbosch : Stellenbosch University, 2021-12) Moraka, Natasha Onalenna; Van Zyl, Gert U.; Moyo, Sikhulile; Gaseitsiwe, Simani; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology. Medical Virology.
    ENGLISH ABSTRACT: Antiretroviral therapy (ART) treatment in pregnant women and new-borns for prevention of mother-to-child transmission (PMTCT) can result in Human Immunodeficiency Virus drug resistance (HIVDR) in paediatrics; either transmitted or arising de novo after transmission. To our knowledge, there is paucity of data describing patterns of HIVDR in infants in Botswana. The aims of this dissertation were to describe HIVDR patterns in newly diagnosed infants in Botswana and determine the prevalence and role of HIVDR mutations in HIV-1 cell associated DNA (HIV-1 CAD) of early treated <18-month-old infants. Seventy-eight residual dried blood spots (DBS) from <18-month-old HIV positive children from the Botswana HIV early infant diagnosis (EID) program (2016 - 2019) were available for HIVDR surveillance. Protease and reverse transcriptase regions were amplified and sequenced using ATCC HIV-1 Drug Resistance Genotyping kits and big dye chemistry. Surveillance drug-resistance mutations (SDRMs) were assessed using the Calculated Population Resistance program. We analysed 257 proviral near full-length sequences (nFLS) obtained from peripheral blood mononuclear cells (PBMCs) of 27 infants in the Botswana early infant treatment (EIT) Study. Sanger sequencing of HIV pol was also performed for 22 maternal samples at delivery and at clinical failure in children. All nFLS and HIV pol sequences were analysed for the presence of HIVDR mutations using the Stanford HIV Drug Resistance database. Of the 78 DBS samples, 32 (41%) were successfully amplified and sequenced. The median age was 2 months (IQR: 2-4). Three (9.7%) newly diagnosed infants had detectable SDRMs. Among these infants, one (33%) had a non-nucleoside reverse transcriptase inhibitor (NNRTI) HIV SDRM (K103N) detected and two (67%) had a detectable protease inhibitor (PI) SDRMs (M46L and L23I). A total of 27 (56.2%) EIT infants had nFLS within one month of life. The median age at enrolment for infants was 2 days [Range: 2-3], with a median digital droplet PCR (ddPCR) HIV-1 CAD load value of 492 units [IQR: 78-1246]. Cell-associated HIVDR mutations were detected in 3/27 (11.1%) infants with intact HIV-1 CAD. A total of 106 (41.3%) intact sequences had at least 1 DRM; 29.2% had NNRTI, 7.5% NRTI, 0.9% PI and none with INSTI associated mutations. A total of 151 (58.7%) defective sequences had at least 1 DRM; 31.8% NNRTI, 15.2% NRTI, 5.3% PI and 15.5% INSTI associated mutations. Higher frequency of DRM was detected in defective HIV-1 CAD compared to intact infant HIV-1 CAD, although not statistically significant (p=0.14). Three infants had the same HIVDR mutations detected in their intact HIV-1 CAD and corresponding maternal plasma at delivery. Archived HIV-1 CAD HIVDR mutations were detectable at later clinical rebound on only one occasion. In conclusion, we report relatively high rates of HIVDR mutations among newly diagnosed and early treated infants with known and unknown PMTCT exposure in Botswana. Our results suggest that exclusion of sequences with defects when interpreting HIVDR mutations from HIV-1 CAD is crucial as these may overestimate true mutations which may impact future clinical outcomes in children.