PHARMACOKINETICS AND PHARMACOGENOMICS OF DOLUTEGRAVIR-BASED ANTIRETROVIRAL THERAPY IN YOUNG PEOPLE LIVING WITH HIV IN GHANA (PHARMA-YOUNG-HIV)

PROJECT SUMMARY The World Health Organization (WHO) in 2019 recommended dolutegravir (DTG)-based antiretroviral therapy (ART) as the preferred treatment regimen for all persons living with human immunodeficiency virus (HIV) in sub-Saharan Africa (SSA),

including children, adolescents, and young adults. Since then, most countries, including Ghana, have transitioned patients

from non-nucleoside reverse transcriptase-based antiretrovirals to DTG-based regimens. Despite the wide acceptability and

effectiveness of DTG, important side effects such as neural tube defects, hyperglycemia, obesity, and mood disorders are now coming to the fore in several reports from SSA. In young people living with HIV (YPLWH) in Africa, the DTG switch was

done without a lot of studies. After the switch, the effectiveness (viral suppression) and adverse events have not been studied

in this population. According to the WHO, young people, defined as aged 10-24-years, are in a transition that poses risks to their health and well-being. This population, even when fully adherent to medications, may be prone to suboptimal or

supratherapeutic drug concentrations, resulting in off-target effects, virologic failure, adverse drug events, drug-drug

interactions, and poor adherence. Therefore, there is an urgent need to study how this population metabolizes new drugs like DTG that have been introduced into the ART regimen on a large scale. We hypothesize that reduced or non-response to DTG-based ART is due to pharmacokinetic differences emanating from

pharmacogenetic variations, which cause adverse events without the benefits of viral control. We will test this hypothesis with the following specific aims: Aim 1: Determine rates of DTG-based ART resistance in young people living with HIV. We will determine which drug(s) are responsible for virologic failure in YPLWH on DTG-based regimens. We will compare participants who are ART

experienced and naïve focusing on those with virologic failure on a DTG-based regimen and sequence protease, reverse transcriptase and INSTI regions and identify mutations associated with drug resistance. Aim 2: Determine the pharmacokinetic and pharmacogenomics variability of DTG-based ART and its influence on off-target

effects. First, we will use blood samples collected from ART-experienced and naïve young people at specific but different time points following DTG-based ART administration to establish pharmacokinetic characteristics of patients using LC-

MS/MS to capture inter- and intra-individual variability. Second, we will use high throughput genotyping techniques, iPLEX, PCR-RFLP, and TaqMan assays to analyze pharmacogenetic variations associated with phase I and II drug metabolism (cytochrome P450 enzymes, UGTs), transporters, and target interactions.

Our study may help understand why some YPLWH develop resistance while on DTG or have off target effects on the drug spurring further larger studies which may eventually help revise the one size fits all approach adopted for DTG- based regimens in sub-Saharan Africa.