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Sudderuddin, Hanwei

University of British Columbia

Antiretroviral therapy (ART) has significantly improved morbidity and mortality for Persons Living with HIV (PLWH); however, the effectiveness of ART can be compromised by HIV drug resistance. Hence, clinical guidelines recommend performing genotypic HIV drug resistance testing (DRT) on drug-target genes at ART initiation and at virological failure. The utility of performing HIV DRT beyond these scenarios remains unclear. This thesis examined two such clinical scenarios. First, given in vitro evidence that mutations conferring resistance to HIV Integrase Strand Transfer Inhibitors (INSTI) can occur outside integrase, including in env gp41, this thesis investigated how frequently such “off-target” substitutions are observed in clinical samples. Using a large clinical database of HIV sequences linked to ART histories, we identified 52 PLWH with subtype B HIV and detectable INSTI levels, for whom genotypic INSTI resistance testing ≥3 months after INSTI exposure revealed susceptibility to INSTIs. Comparing gp41 sequences from these PLWH to 1221 sequences from INSTI-naïve PLWH identified the V182I substitution as over-represented among INSTI-treated PLWH (Odds Ratio=3.75, p=2.2x10⁻⁴). When comparing longitudinally-collected gp41 sequences from INTSI-treated PLWH, no evidence of INSTI-driven selection was observed at this position. While off-target INSTI substitutions may arise in vivo, there is currently insufficient evidence to expand INSTI DRT beyond integrase. Second, HIV DRT can be performed on low viral load (LVL) samples (plasma viral load [pVL] below typical level of virological failure), but such testing is resource-intensive, and its clinical benefit is unclear. This thesis investigated the frequency and factors associated with emergent resistance in LVL samples using a provincial database of HIV Protease-Reverse Transcriptase sequences. A total of 43,979 Protease-Reverse Transcriptase DRTs were performed in British Columbia between 1999–2022, of which 2970 (6.7%) were on LVL samples. Compared to prior genotypes from non-LVL samples, a total of 104 (7.3%) cases of emergent drug resistance were identified. Multivariable analyses identified increased time elapsed between DRTs and prior resistance to be significantly associated with emergent resistance. Given its resource-intensive nature, resistance testing of LVL samples may only be warranted when these risk factors are present. Both studies demonstrate HIV drug resistance testing strategies can be further optimized.

Thesis/Dissertation

eng

Vancouver : University of British Columbia Library

10.14288/1.0447299

Master of Science - MSc

Medicine, Faculty of; Medicine, Department of

2025-05

Graduate

DSpace