Pharmacogenomics and pharmacokinetics of dolutegravir and tenofovir in Southern Africans living with HIV

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Background The World Health Organization (WHO) recommends dolutegravir in combination with a nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone as the preferred first-line regimen for people living with HIV (PLWHIV) initiating antiretroviral therapy (ART). Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are both prodrugs of tenofovir. However, plasma tenofovir exposure is higher when given as TDF, and TAF yields lower plasma but higher intracellular tenofovir concentrations. Although generally well tolerated, excessive weight gain has been associated with dolutegravir and (TAF) in PLWHIV initiating ART or those switching from efavirenz- or TDF-containing ART. Interindividual variability in dolutegravir and tenofovir pharmacokinetics or the interindividual differences in host response may, in part, be explained by host genetics. We characterized associations between genetic polymorphisms and dolutegravir exposure, tenofovir clearance and magnitude of weight gain in Southern Africans initiating ART. Methods We collected clinical and laboratory data in adults randomized to initiate TAF or TDF in dolutegravir-containing arms of the ADVANCE trial (NCT03122262). We measured dolutegravir and tenofovir concentrations and developed population pharmacokinetic models for dolutegravir and tenofovir using non-linear mixed-effects modelling. Genome-wide genotyping followed by imputation was performed. Linear regression models examined associations between genetic polymorphisms and unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR), unexplained variability in tenofovir clearance, and percentage weight gain from baseline to week 48. Results Considering genetic associations with unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR), the lowest P-value with AUCVAR was UGT1A1 rs887829 (P = 1.8 x 10-4 ), which was also associated with log10 bilirubin (P = 8.6 x 10-13). After adjusting for rs887829, AUCVAR was independently associated with rs28899168 in the UGT1A locus (P = 0.02), as were bilirubin concentrations (P = 7.7 x 10-8 ). In the population pharmacokinetic model, compared to C/C, rs887829 T/T and C/T were associated with 25.9% and 10.8% decreases in dolutegravir clearance, respectively. There were no significant genome-wide associations. Considering genetic associations with unexplained variability in tenofovir clearance, we found no significant associations with tenofovir clearance for either TAF or TDF among 5 polymorphisms previously associated with tenofovir pharmacokinetics (lowest P-value > 0.3 for each drug). Among 11 polymorphisms selected based on both prior strong association with any drug phenotype in PharmGKB and any genome-wide association with any trait in the GWAS catalog, IFNL4 rs12979860 T>C was significantly associated with increased tenofovir clearance (TAF: P = 0.003; TDF: P = 0.003). In genome-wide analyses, the lowest P-values for tenofovir clearance in the TAF and TDF arms were with LINC01684 rs9305223 (P = 3.0 x 10-8 ) and intergenic rs142693425 (P = 1.4 x 10-8 ), respectively. Four additional polymorphisms were genome-wide significant. In genome-wide multivariate linear regression analyses adjusting for baseline age, sex, concomitant NRTI, and population stratification, there were no significant associations between 59 polymorphisms relevant to dolutegravir and tenofovir disposition and the percentage weight gain. We found a genome-wide significant association between TMEM163 rs7590091 and percentage weight gain from baseline to week 48 (P = 3.7 x 10-8 ). Conclusion Among Southern African people living with HIV randomized to TAF or TDF, we identified several potential genetic associations with dolutegravir exposure, tenofovir clearance and weight gain. The novel associations between dolutegravir AUCVAR and rs28899168, tenofovir clearance and IFNL4 rs12979860, and weight gain and TMEM163 rs7590091 require independent replication. These findings enhance our understanding of dolutegravir and tenofovir pharmacogenetics among Southern Africans living with HIV.