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Standard and enhanced genotypic assessment of HIV drug resistance and tropism in subtype-B and non-subtype-B HIV-1 infections

University of British Columbia

Sequencing human immunodeficiency virus type 1 (HIV-1) for drug resistance mutations and viral tropism is crucial to the current HIV/AIDS personalized treatment approach. This thesis addresses particular areas where clinical utility data is lacking: First, current methods were validated as clinically useful with plasma viral RNA primarily from patients infected with subtype B HIV-1, the dominant strain in developed countries; however, globally most patients are infected with non-subtype B variants. Secondly, there is insufficient data available with respect to the newest classes of antiretroviral drugs (i.e. CCR5-antagonist and integrase inhibitors). Finally, modern antiretroviral therapies often lead to “undetectable plasma viremia” (i.e. successful ongoing treatment) which make plasma-based genotypic testing impossible; the utility of examining alternative sample types is being actively explored. The overall objective of this thesis is to evaluate genotypic assessment of HIV-1 using standard and “second generation” DNA sequencing methods for guiding clinical decisions in nonconventional sample types. Specifically, it is hypothesized that genotypic assessment of subtype A, C and D HIV-1, plasma viral RNA collected pre-therapy, and viral DNA archived in blood cells are useful predictors of in vitro phenotype and/or clinical outcomes. Chapter 1 and 2 examine the clinical utility of current genotyping approaches when applied to non-subtype-B HIV-1. Results suggest that (1) transmitted genotypic drug resistance predicted small but negative treatment outcomes in non-B infections, and (2) current genotypic tools for predicting viral tropism had poor sensitivities and/or specificities in subtypes A and D, but not C HIV-1. Chapter 3 and 4 examine the clinical utility of current genotypic approaches coupled with alternative sample types. Results suggest that (3) pre-therapy plasma sample tropism results predicted post-therapy post-suppression tropism in 90% of subjects, and (4) viral DNA archived in blood and plasma RNA had similar integrase inhibitor-associated mutations, but mutations in DNA were detected substantially later and were substantially less prevalent. In conclusion, genotypic assessment of HIV-1 using nonconventional sample types is clinically relevant, but has specific limitations. Further methodological research and clinical validation studies are needed to ensure proper interpretation of results.

Text

2015-01-06

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/51771

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/