Dolling, DI;
(2017)
HIV-1 viral load outcomes and the evolution of drug-resistance in low-income settings without virological monitoring.
Doctoral thesis , UCL (University College London).
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Abstract
WHO guidelines recommend viral load monitoring for all HIV-1 positive patients on antiretroviral therapy (ART). However, few low-income countries have virological monitoring widely available, and patients may remain on virologically failing regimens. This could compromise future ART through the accumulation of drug resistance mutations and result in worse long-term clinical outcomes. The DART trial was conducted in Uganda and Zimbabwe and compared clinically driven monitoring with or without routine CD4 measurement in ART-naïve adult patients. Annual plasma viral load was retrospectively measured for 1,762 patients. This thesis investigates how no laboratory monitoring impacts virological failure and the development of drug resistance. Time to persistent virological failure was analysed, and analytical weights were calculated to correct for non-random sampling. The long-term durability of first-line ART was remarkable; 21% of patients on an NRTI-NNRTI regimen and 40% on a triple-NRTI regimen experienced persistent virological failure by 240 weeks. Routine CD4 monitoring did not reduce virological failure. Deaths after 48 weeks of ART are widely assumed to be due to virological failure or non-adherence. Analyses revealed that a surprisingly high number of these deaths (40%) occurred without virological criteria for treatment switch being met. Routine CD4 monitoring reduced the rate of death with virological failure but did not impact deaths with virological suppression. Cross-sectional analyses quantified HIV-1 drug resistance at the end of first-line ART. On NRTI-NNRTI regimens, 88% had NRTI resistance, and 66% had NNRTI resistance. Routine CD4 monitoring did not reduce the prevalence or extent of drug resistance. The order and rate of HIV-1 drug resistance mutations were explored using repeated genotypes within patients. On NRTI-NNRTI regimens, NRTI and NNRTI mutations developed at a rate of 0.96 and 0.21 per year respectively. Mutagenic tree models demonstrated that ART regimen influenced the order and rate in which mutations occurred.
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