Investigating the expansion of genotypic HIV drug resistance testing beyond current clinical guidelines
department or school: Medicine, Faculty of
department or school: Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Sudderuddin, Hanwei
issued: 2024-11-20T23:16:22Z
issued: 2024
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: 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…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/89691
note: INVESTIGATING THE EXPANSION OF GENOTYPIC HIV DRUG RESISTANCE TESTING BEYOND CURRENT CLINICAL GUIDELINES by Hanwei Sudderuddin B.Sc.(Hons), Simon Fraser University, 2017 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in The Faculty of Graduate and Postdoctoral Studies (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) November 2024 © Hanwei Sudderuddin, 2024 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the thesis entitled: Investigating the Expansion of Genotypic HIV Drug Resistance Testing Beyond Current Clinical Guidelines submitted by Hanwei Sudderuddin in partial fulfilment of the requirements for the degree of Master of Science in Experimental Medicine Examining Committee: Dr. Chanson Brumme, Assistant Professor, Experimental Medicine, UBC Supervisor Dr. Viviane Dias Lima, Professor, Experimental Medicine, UBC Supervisory Committee Member Dr. Melanie Murray, Clinical Associate Professor, Experimental Medicine, UBC Supervisory Committee Member Dr. Agatha Jassem, Clinical Associate Professor, Pathology and Laboratory Medicine, UBC Additional Examiner iii Abstract 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…
has type: Thesis/Dissertation
spatial: Downtown-Eastside (Vancouver, B.C.)
date issued: 2025-05
is shown at: 10.14288/1.0447299
language: eng
degree discipline: Experimental Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Brumme, Chanson J.
type: Text
identifier URI: http://hdl.handle.net/2429/89691