Iwuji, CC; (2017) Will earlier treatment lead to drug resistance of the form and prevalence likely to compromise future elimination of HIV? Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

South Africa has the biggest HIV epidemic in the world. Early antiretroviral therapy (ART) is recognised as an effective HIV prevention approach and was introduced to control transmission as well as to delay HIV progression. However, it is unknown whether early treatment will result in suboptimal adherence, poor virological outcomes and emergence of drug resistance, which would hinder HIV elimination. To address this knowledge gap, I undertook a cohort analysis nested within the ANRS-sponsored TasP trial, in which ART was initiated early, to examine adherence in individuals initiating ART at high CD4 counts and quantify virological suppression in those who were ART-naïve at trial entry. I also estimated virological suppression at trial entry amongst individuals already ART-experienced at their first trial clinic visit. I examined acquired resistance mutations in individuals with virological failure and estimated prevalence of pre-treatment drug resistance (PDR) in ART-naïve individuals and investigated impact of PDR on virological suppression. I found no evidence of a relationship between CD4 count at ART initiation and adherence, but virological suppression was significantly better in individuals who initiated ART at higher CD4 counts, even at the same level of adherence. Most individuals with virological failure had emergent drug resistance, predominantly the M184V mutation associated with lamivudine or emtricitabine resistance. Prevalence of PDR was moderate at nearly 10%, but doubled when low frequency variants were accounted for. This was predominantly the K103N/S mutation which causes high-level resistance to efavirenz and nevirapine. However, PDR was not significantly associated with decreased virological suppression. My results are encouraging over the 12 months’ duration of ART investigated in this study with positive effects amongst patients who started ART at high CD4 counts. However, long-term follow up is required to evaluate the impact of HIV drug resistance on HIV prevention efforts.

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