Fox, Z.V.; (2008) Analyses of observational studies and randomised trials to increase understanding of the occurrence and role of drug resistance in HIV infection. Doctoral thesis , University of London.

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Abstract

This thesis explores the relationship between the use of antiretroviral therapy (ARVs) and drug resistance emergence in HIV-1 infected individuals. It also describes the combined impact of treatment use and resistance mutations on virological and immunological response in individuals who are under follow-up in one of four trials: MaxCminl, MaxCmin2, COLATE or SMART and three observational studies: EuroSIDA, the UK CHIC study and the UK drug resistance database. The emergence of resistance to an ARV that an individual is receiving may influence viral replication rates, which could increase the risk of CD4+T cell count deterioration, clinical progression and death, unless changes are made to the treatment regimen. Individuals may exhaust all treatment options if large amounts of resistance mutations are detected in their viral sub-populations. In the current era, new ARVs are still arriving on the market, but resistance to these ARVs is only partially understood. Understanding what mutations emerge in individuals who are failing treatment and the impact of specific mutations and combinations of mutations on the likelihood of responding to future regimens is still essential for being able to administer long-term therapy successfully. Research for this thesis started just after the introduction of ritonavir boosted protease inhibitors (Pl/rs). Drug resistance emergence among individuals who experienced virological failure on a Pl/r containing regimen is described in detail, and the relationship between resistance at baseline and virological response is also quantified. Other aspects of drug resistance are investigated, including: the potential benefit of harbouring the M184IA/ mutation, the impact of resistance on immunological response and the relationship between resistance and viral re-suppression rates amongst patients who interrupt an NNRTI containing regimen. This thesis outlines the benefits of resistance testing and highlights some of the key issues with interpreting resistance data. Resistance tests are generally performed on a selective group of individuals so caution needs to be used when extending the results to all HIV-1 infected individuals. Further, consensus sequences are useful for indicating resistance that is present in the predominant virus however, more minor, archived, species are not usually identified through this method and these may also be an important determinant of therapy response.

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