Pharmacogenomics of current antiretroviral drugs

Advances in antiretroviral drug development have led to safer drugs with improved tolerability, enhanced activity against drug-resistant HIV, higher genetic barrier to resistance, and fewer drug-drug interactions. Genetic polymorphisms in drug-metabolizing enzymes, transporters, and immune pathways contribute to interindividual variability in antiretroviral pharmacokinetics and toxicity. HLA-B *57:01 screening prior to abacavir initiation is an example of clinically implemented pharmacogenetics in high-income settings. Conversely, despite robust evidence linking UGT1A1 variants to atazanavir-associated hyperbilirubinaemia, routine UGT1A1 testing has not been widely adopted. We conducted a narrative review of genetic polymorphisms associated with the toxicity and pharmacokinetics of current antiretroviral therapy. We searched Pharmacogenomics Knowledgebase (PharmGKB®) for abacavir, tenofovir disoproxil fumarate, tenofovir alafenamide, lamivudine, emtricitabine, dolutegravir, elvitegravir, raltegravir, bictegravir, cabotegravir, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, lenacapavir, rilpivirine and doravirine. We supplemented our review with targeted searches in PubMed®. We found that most pharmacogenetic associations for current antiretroviral drugs come from single studies and lack replication. Although UGT1A1 loss-of-function alleles increase dolutegravir and cabotegravir exposure, no association with toxicity has been shown. No relevant studies were identified for doravirine, lenacapavir or bictegravir. Actionable pharmacogenetic associations with antiretroviral drugs remain limited to abacavir. Future research should prioritize replicating pharmacogenetic associations across diverse populations and establishing clinical relevance.