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Populational studies of HIV-1 drug resistance in British Columbia

University of British Columbia

Objective: Highly active antiretroviral therapy (HAART) has led to a dramatic decrease in AIDS-related morbidity and mortality, but can be compromised by the development of HIV drug resistance. The objective of this thesis is to explore issues important to the understanding of HIV drug resistance at the populational level in British Columbia, Canada. Methods: HIV drug resistance was analyzed via retrospective, observational analyses of the population of HIV-infected individuals receiving treatment through the HIV/AIDS Drug Treatment Program in British Columbia, Canada. Analyses were largely based upon viral protease and reverse transcriptase genotypic sequences obtained from archived plasma samples as well as information in the BC Centre for Excellence in HIV/AIDS’ monitoring and evaluation system. Results: One analysis demonstrated a drastic, exponential decrease in the incidence of new cases of HIV-1 drug resistance over time in individuals followed from 1996-2008 that has been concomitant with linear increases in the proportion of individuals with undetectable plasma viral loads. An analysis of the probability of developing resistance, adjusted for several factors, between different initial antiretroviral regimens showed 2.4-fold lower odds of developing HIV drug resistance among individuals initiating HAART with a boosted protease-inhibitor-based regimen versus other common regimens, as well as a decreased likelihood of developing resistance based upon initiating more modern HAART regimens. Finally, a third analysis focussed on specific K65K and K66K silent mutations in HIV reverse transcriptase, which are strongly co-selected with known thymidine analogue mutations, in particular D67N. In steady-state kinetic assays, the presence of these mutations was shown to alleviate replicative pausing and/or dissociation events of HIV-1 reverse transcriptase on RNA reverse transcriptase templates that contained the D67N and K70R mutations. Conclusion: Changes in HIV drug resistance have occurred at the populational level in BC over the period of 1996-2008. The superiority of modern HAART regimens in regard to the development of resistance, and overall drastic exponential decreases in the levels of incident drug resistance over time, provide new benchmarks for the analysis of the efficacy of current and future antiretroviral regimens. Furthermore, the identification of novel silent mutations co-selected with therapy exposure may have clinical implications.

Text

2010-03-09

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/21698

Experimental Medicine

University of British Columbia

UBCV

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