Quantifying genomic and pharmacometabolomic differences in antiretroviral exposure in MACS/WIHS Combined Cohort Study

PROJECT SUMMARY/ABSTRACT A key challenge in medicine is identifying individuals who will benefit the most from treatment. Despite the effectiveness of combination antiretroviral therapy (cART), patients experience side effects that challenge future treatment strategies. Since most drugs' therapeutic and toxic effects are directly related to drug

exposure, identifying predictors of exposure can help better predict variability in response to medication. For the proposed project, we are leveraging the unprecedented time-series plasma samples collected during ongoing (AI153007) intensive pharmacokinetic (iPK) studies of dolutegravir (DTG) and tenofovir alafenamide

fumarate (TAF), a prodrug of tenofovir (TFV), in representative and understudied HIV+ men and women in the multi-ethnic cohort MACS/WIHS Combined Cohort Study (MWCCS). Given the recent development in the field of pharmacometabolomic, where endogenous metabolite concentrations in plasma are shown to predict

response to sertraline, escitalopram, and aspirin, we plan to determine the plasma metabolome profile of MWCSS participants treated with DTG and TAF. Our immediate objective is to identify, through correlations of plasma drug concentrations with endogenous metabolite plasma levels. These genes control metabolic

pathways affecting DTG, TFV plasma, and tenofovir-diphosphate (TFV-dp) intracellular concentrations and their associated metabolic adverse effects (i.e., weight gain and insulin resistance). To achieve our immediate objective, we have three specific aims. In aim 1, we plan to identify endogenous metabolites associated with

concentrations of DTG (n=60), TFV, and TFV-dp (n~42) at nine different time points in virally suppressed HIV+ men and women under actual use conditions. Using these correlated metabolites as biomarkers of medication concentration, in aim 2, we will identify, through genome-wide association analyses, novel genetic variants

impacting metabolite concentrations in 16,322 individuals from two independent population-based cohorts from the United Kingdom (UK): The UK National Institute of Health Research and Twins UK. The extensive UK sample size provides ample power to identify gene-metabolite associations reliably, offering a higher-resolution

picture of metabolism and elimination for DTG and TAF. In aim 3, the effect of identified novel genes on DTG, TFV, and TFV-dp concentrations and their associated metabolic adverse effects (i.e., weight gain, insulin resistance) will be further validated in 1157 MWCSS women and men treated with these medications. This

novel approach will help identify new genes impacting DTG and TFV plasma exposure and clinically significant adverse effects. The deliverables from this study will positively impact future studies in the field of PGx of anti- HIV medication and beyond in two ways: First, we will characterize for the first time and with much higher

resolution the primary and secondary metabolic and elimination pathways relevant to DTG and TFV and second, it will provide a novel multi-omic study design that can be implemented to discover genetic factors associated with drug effect.