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

Reduced-function UGT1A1 star alleles (6, 28 and 37) increase dolutegravir exposure, confirming UGT1A1 as the predominant genetic pathway of its clearance, while ABCG2 transporter polymorphisms show variable associations.

Dolutegravir underpins first- and second-line antiretroviral regimens, with interindividual variability in disposition and tolerability that complicates optimal use. This scoping review mapped the available pharmacogenomic evidence, both pharmacokinetic and pharmacodynamic, along with the methodological limitations of existing studies. Reduced-function UGT1A1 star alleles (6, 28 and 37) emerged as the most consistent determinants of increased dolutegravir exposure across African, European and Asian populations; ABCG2 transporter polymorphisms showed variable associations, differing between children and adults, and genome-wide association studies in African populations identified candidate loci, CAMKMT and MIR99AHG, still requiring replication. Links to clinical outcomes remain weak, with associations for neuropsychiatric adverse events (UGT1A1, SLC22A2), weight gain (ABCG2, MC4R, TMEM163) and viral suppression inconsistent and underpowered. The authors conclude that UGT1A1 variation is the only reproducible pharmacogenomic signal of clinical relevance, but that its effect size does not currently justify routine genotype-guided dosing.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The negative conclusion is the useful part: a reproducible pharmacokinetic signal does not make a clinically useful test, and the authors hold that distinction to the end rather than advocating for their subject. The catalogue of methodological weaknesses they list — small samples, overlapping datasets, no correction for multiple testing, limited ancestral diversity — serves as a warning for antiretroviral pharmacogenetics as a whole. This is the exact mirror of the NAT2 work published the same week: on one side a typing method being refined, on the other a determinant being documented, and in both cases a clinical demonstration still missing.

Analysis by Dr Thibaut Benquey