Dosing HIV integrase inhibitors with enzyme inducers: Convenience vs . control?

Dolutegravir and bictegravir, both second-generation integrase strand transfer inhibitors (INSTIs), are widely used as key components of antiretroviral therapy (ART) because they combine strong antiviral activity with good tolerability and a low potential for drug-drug interactions (DDIs). 1 However, both agents are vulnerable to pharmacokinetic interactions, notably with strong inducers of their metabolic pathways.Dolutegravir is metabolized predominantly by uridine diphosphate glucuronosyltransferase (UGT) 1A1, with cytochrome (CYP) 3A4 playing a minor role, whereas bictegravir undergoes metabolism through both UGT1A1 and CYP3A4 to a similar extent.Consequently, strong inducers of these enzymes, such as rifamycins, antiepileptic drugs (e.g., carbamazepine, cenobamate, phenobarbital, phenytoin and primidone), cancer drugs (e.g., apatulamide, dabrafenib, enzalutamide, ivosidenib and mitotane), cystic fibrosis transmembrane conductance (CFTR) modulators (e.g., ivacaftor and lumacaftor) or St John's wort, can substantially reduce dolutegravir and bictegravir concentrations, which may lead to treatment failure and resistances.2 Strong inducers require twice-daily dosing of dolutegravir, which may compromise adherence, and currently preclude the use of bictegravir.2 Randomized clinical trials have therefore investigated whether oncedaily dolutegravir retains efficacy when coadministered with rifampicin and whether twice-daily bictegravir can overcome rifampicin induction.3,4 The clinical appropriateness of these alternative dosing strategies remains a matter for debate.This commentary reviews the available evidence and discusses clinical situations in which these alternative dosing strategies should be avoided.