| Summary: | The WHO currently recommends tenofovir (TFV) disoproxil fumarate (TDF) or TFV alafenamide (TAF) as a preferred first-line antiretroviral therapy (ART) for the treatment and prevention of HIV. However, mild to moderate TFV-related renal toxicity is an uncommon but significant complication for TDF therapy. Efavirenz (EFV) is also approved for first line treatment, with the approval of a lower dose treatment, 600mg to 400mg, offering an opportunity for a greater number of patients to receive ART for the same amount of current public health expenditure, whilst enabling the maintenance of viral load suppression and partial mitigation of adverse events. However, EFV displays broad inter-patient and inter-population variability in its pharmacokinetics and displays a range of dose dependent adverse effects. In order to gain further understanding of the impact patient genetics has on response to ART, studies investigating the effect of single nucleotide polymorphisms (SNPs) within multi ethnic populations receiving either TFV or EFV were completed. Additional work was conducted to investigate potential drug-substrate interactions at the transporter level within proximal tubule cells (PTCs), and the ramifications this may have for diagnosis of renal impairment. This work was conducted through assessing the relationship between SNPs found within genes encoding transporters on the apical membrane of PTCs and a diagnosis of renal dysfunction, defined as kidney tubular dysfunction or chronic kidney disease within a Ghanaian population (Chapter 2). Additionally the association between pharmacogenetic variants linked to TDF metabolism or TFV excretion and TFV plasma and urine concentrations, in a majority Caucasian patient population, receiving TFV as part of their ART was investigated (Chapter 3). This thesis sought to assess whether SNPs in genes involved in EFV and nevirapine metabolism were linked to previously observed changes in the contraceptive subdermal implant levonorgestrels (LNG) pharmacokinetics, when prescribed alongside EFV, 19 within a Ugandan population (Chapter 6). In order to study the effect of transporter interactions at the site of TFV toxicity, the proximal tubule, a transiently transfected Human Embryonic Kidney 293 cell line overexpressing either multidrug and toxin extrusion protein (MATE) 1 or MATE2K was developed and assessed for correct functionality (Chapter 4). This cell line was then utilised for drug-substrate interaction studies between TAF and TFV and either the endogenous biomarker creatinine or the type 2 diabetes drug metformin (Chapter 5). These studies provided a greater understanding of the contribution pharmacogenetics provides to the interaction observed between EFV and LNG, and outlined a genetic association between TFV transporter SNPs and TFV plasma and urine concentrations. Utilisation of these findings in future pharmacogenetics studies would aid in the understanding of the impact of genetic variants in different populations, and the consequences this has for achieving sustained virological response to ART. The study of the effect of TAF and TFV on MATE1 and MATE2K transport of metformin and creatinine produced novel data on these interactions. Overall, the studies included within this thesis have clinical impact through further elucidating the potential mechanisms of toxicity or treatment failure within patients receiving ART.
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