Pharmacogenomics of dolutegravir: A scoping review of evidence, gaps and clinical implications

Dolutegravir underpins modern first- and second-line HIV treatment regimens; however, interindividual variability in its disposition and tolerability presents challenges for optimal use. This scoping review mapped current evidence on the pharmacogenomics of dolutegravir, focusing on pharmacokinetics and pharmacodynamics, and methodological limitations of existing studies. Reduced-function UGT1A1 alleles (*6, *28, *37) emerged as the most consistent determinants of increased dolutegravir exposure across African, European and Asian populations, reinforcing UGT1A1 as the predominant genetic pathway for dolutegravir clearance. Transporter polymorphisms, particularly in ABCG2, showed variable associations with dolutegravir concentrations, with differing results in children compared with adults. Genome-wide association studies in African populations have identified novel candidate loci (e.g., CAMKMT and MIR99AHG) requiring replication. Evidence linking genetic variation to clinical outcomes remains weak: Associations with neuropsychiatric adverse events (notably in UGT1A1 and SLC22A2), weight gain (ABCG2, MC4R and TMEM163) and viral suppression were inconsistent and underpowered. Suggestive gene-gene and gene-drug interactions merit further investigation. The current evidence base is constrained by small sample sizes, heterogeneous study designs, overlapping datasets, non-adjustment for multiple testing, limited ancestral diversity and inconsistent phenotyping. Overall, UGT1A1 variation is the only reproducible pharmacogenomic signal of clinical relevance; however, its effect size does not currently justify routine genotype-guided dosing. In the future, priority should be given to well-powered, multi-ancestry, harmonised studies with functional validation to clarify the role of pharmacogenomics in tailoring dolutegravir-based therapy

• Population(s)
  • General HIV+ population
  • Other
• Prevention, Engagement and Care Cascade
  • Engagement and Care Cascade
• Engagement and Care Cascade
  • Treatment