Population dynamics in HIV-1 transmitted antiretroviral drug resistance

Harris, Dean Mark
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It is well known that antiretroviral (ARV) drug resistant variants of HIV-1 can be sexually transmitted. Several studies have shown that in resource-rich geographical locations as many as 15-20% of individuals are newly infected with HIV-1 containing at least one drug resistant mutation. In contract, resource limited geographical locations, such as Sub-Saharan Africa, have shown prevalences in the range of 5 to 10%. Since the ART rollout in these resource-limited locations are generally not well monitored with virological genotyping, the transmission of drug resistant HIV-1 is likely to increase, with significant clinical and public health consequences. HIV-1 transmission is characterised by the transmission of a single founder virus, or narrow spectrum of founder viruses, that develop into the viral quasispecie. It is unlikely that drug resistant virus will coexist with wild type (wt) virus, in the case of non-drug resistance transmission. However, initiating in ARV treatment, drug non-adherence may select of ARV drug resistance mutations and may subsequent lead to treatment failure. Drug resistant virus may be transmitted to a new host, as drug resistant mutations do not appear to hamper transmission efficiency of the mutated virus. Several studies have shown that transmitted drug resistance mutations (TDRMs) persist either as the dominant species or as minority variants, or revert to wild type over time, in the absence of drug pressure. It is generally acknowledged that many drug resistance mutations decrease the replicative capacity of HIV-1, and thus reversion confers a potential survival advantage. Because of the emergence of wild type variants from TDRM quasispecies requires evolution and back-mutation, the rate at which individual TDRMs become undetectable may vary substantially. Contradictory findings of persistence versus reversion of TDRMs have been reported, and may be attributed to the fact that minority variants are difficult to detect by conventional population based Sanger sequencing, and patient numbers studied are small. Consequently, individuals infected with HIV-1 harbouring TDRM have a higher chance of failing their first-line therapy. Understanding the population dynamics of transmitted drug resistant HIV-1 in the absence of drug pressure is essential for clinical management and public health strategies. The individuals identified with TDRMs from the IAVI-Early Infections Cohort (Protocol C) provides a unique research opportunity to address the aforementioned issue. This study describes III the evolutionary mechanisms of ARV drug resistant HIV-1 after transmission to a new host to provide insight into persistence and/or rates of reversion to wild type. TDRMs initially identified by Price et al. (2011) in the IAVI-Early Infections Cohort (Protocol C) using population-based Sanger sequencing (the current diagnostic gold standard), were confirmed in this study by newer ultra-deep next generation sequencing (NGS) technology on the Illumina Miseq platform. Longitudinal samples were made available for individuals in which transmitted drug resistance were identified, and we also sequenced using NGS on the Illumina Miseq platform. Additional minority variants (present at <20% of the sequenced viral population) were identified by NGS. This study found a large percentage of TDRMs to persist for a significant amount of time after transmission to a new, drug naïve host, in the longitudinal samples. The level of persistence, or rate of reversion of TDRMs, appear to be subject to the type of resistance (NRTI, NNRTI or PI), level of resistance the mutation confers, as well as the combination of mutations that are cotransmitted. Findings of this study highlight the importance of drug resistance screening prior to ART initiation, as well as the importance of the drug resistance screening assay sensitivity. As rates of transmitted drug resistance are increasing in developing countries of which the IAVI-Early Infections Cohort (Protocol C) are composed of, understanding the population dynamics of transmitted drug resistant HIV-1 in the absence of drug pressure is essential for clinical management, public health strategies and informing future vaccine design.
A dissertation submitted to Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Master of Science in Medicine, Johannesburg, June 2018