A preliminary analysis of the impact of pharmacogenetic variation on bictegravir and dolutegravir concentrations in individuals with HIV and tuberculosis

11 Background: Bictegravir and dolutegravir are potent antiretrovirals recommended for first-line treatment of HIV. We evaluated the effect of pharmacogenetic variation in drug metabolizing and transporter enzymes using the Axiom Precision Medicine Diversity Research Array (>850 000 single-nucleotide polymorphisms [SNP] across the human genome) on drug concentrations of bictegravir and dolutegravir in individuals with HIV and tuberculosis. Methods: We conducted a pharmacogenetic analysis African participants (black race, mainly isiZulu speaking) randomized to receive bictegravir, emtricitabine, tenofovir alafenamide (BIC arm) or dolutegravir, lamivudine, tenofovir (DTG arm) in the INSIGHT trial (NCT04734652) conducted in Durban, South Africa. The bictegravir regimen or dolutegravir was dosed twice daily during rifampicin-based first-line tuberculosis treatment and once daily thereafter. Trough concentrations of bictegravir and dolutegravir were measured both during and after tuberculosis treatment using validated assays at the Division of Clinical Pharmacology, University of Cape Town. DNA was extracted from buffy coat samples, and quality was assessed using the QIAxcel Connect System. Samples were processed on the Applied Biosystems GeneTitan Multi-Channel (MC) Fast Scan Instrument. We performed genome-wide association studies (GWAS) using a pharmacogenomics-focused genotyping panel, which includes variants in genes associated with drug metabolism and transport. In this preliminary analysis, we focused on identifying associations between genetic variants in key enzymes and drug transporters known to be involved in bictegravir and dolutegravir metabolism and transport. All statistical analyses were conducted using R Studio (Version 2025.05.0 + 496). An R script was developed for analysis, data cleaning, extraction and matching polymorphisms with genes, linking genetic variations to drug concentrations. T-tests were performed to compare average changes in drug concentrations (trough concentrations) among different genotypes. Significance was assessed using p-values with a threshold of 0.05. Results: We enrolled 80 participants in the BIC arm and 42 in the DTG arm. Pharmacokinetic (PK) data for 77 participants in the BIC and 42 participants in the DTG arm during and after TB treatment were included in the analysis. Bictegravir is primarily metabolized by CYP3A4 and UGT1A1. Since CYP3A5 and CYP3A4 share some substrate overlap (and both are part of the CYP3A subfamily), there has been some interest in whether CYP3A5 expressor status could affect bictegravir clearance. Our results show that a specific SNP (rs4646457) within the CYP3A5 gene was associated with higher bictegravir concentrations (p = 0.02, effect = 4.8 for the CC Genotype vs. AA/CC) during and after TB treatment. In addition, we identified rs887829 (located with the UGT1A1 gene), a known genetic marker linked with metabolism of bictegravir, which in the CC genotype (vs. CT/TT) was associated with lower bictegravir levels (p = 0.008, effect = 0.64) during and after TB treatment. This UGT1A1 mutation (rs887829) CC genotype vs. CT/TT was also linked with lower dolutegravir levels in our study (p = 0.01, effect = 0.9) during TB treatment. Conclusion: We observed significant associations between SNPs in the CYP3A5 and UGT1A1 genes and bictegravir and dolutegravir plasma concentrations. The clinical relevance of these findings requires further evaluation and should also be explored in population PK models to account for other sources of variability in drug concentrations.