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HIV genomics : trends in antiretroviral resistance and future directions for pharmacogenetic testing

University of British Columbia

Antiretroviral drugs are fundamental to the treatment of Human Immunodeficiency Virus (HIV), effectively inhibiting viral replication, the emergence of Acquired Immune Deficiency Syndrome (AIDS), and subsequent mortality. Combined antiretroviral therapy (cART) is the cornerstone of HIV treatment, and has been adopted by agencies around the world. An estimated 18.2 million individuals accessed cART worldwide in 2016. However, HIV drug resistance to cART leads to ineffective HIV treatment, is associated with AIDS-related morbidity and mortality, and the potential onward transmission of drug resistant HIV strains. Since cART became available in BC in the mid-1990s, antiretroviral drugs and clinical guidelines for HIV management have evolved to reflect best practices. Over the past two decades, genetic testing for HIV drug resistance has become an important tool for HIV care. Next generation massively parallel sequencing has proven to be a powerful sequencing tool rivaling the gold standard Sanger sequencing method, however it is not yet widely adopted for HIV-related genetic testing in BC. There are three primary objectives discussed in this thesis: 1) identification of long-term trends in transmitted and acquired HIV drug resistance in BC, Canada; 2) determination of sociodemographic covariates of drug resistance development and testing uptake; and 3) validation and application of an HIV-related next generation sequencing (NGS) assay for abacavir hypersensitivity screening. Prevalence data of acquired and transmitted drug resistance over the past two decades are presented. Acquired resistance was examined in further detail in order to assess the effect of therapy duration on drug resistance, as well as temporal effects and other factors. Covariates of acquired drug resistance were also examined over calendar time, with a particular focus on adherence to treatment regimens, including sociodemographic predictive factors, as well as sociodemographic covariates of resistance testing uptake. After characterizing historical trends of drug resistance, a glimpse at the future of HIV-related genetic testing is presented: an NGS assay for abacavir hypersensitivity screening was validated and applied as a proof of principle on the Illumina MiSeq platform. This assay was shown to be highly accurate and reliable, providing higher resolution sequencing compared to currently used methods, and expediting testing.

Text

2017-11-10

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/63579

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/