The drug-drug interactions between antiretrovirals and carbamazepine or oxcarbazepine were evaluated in a clinical setting using therapeutic drug monitoring (TDM) trough concentrations collected from HIV+ patients treated concomitantly with carbamazepine or oxcarbazepine and antiretrovirals for at least 3 months. HIV-infected patients not concomitantly treated with antiepileptic drugs and who underwent TDM for antiretrovirals in the previous 2 years were considered as controls. Eleven HIV-positive patients prescribed carbamazepine (n=7) or oxcarbazepine (n=4) were identified. All the TDM evaluations for carbamazepine and oxcarbazepine were within the therapeutic ranges. Trough concentrations for dolutegravir were ~83% lower when compared with HIV-infected patients not treated with antiepileptic drugs (191 ± 78 versus 1096 ± 510 ng/mL). Co-administration of carbamazepine or oxcarbazepine with dolutegravir should be avoided owing to the potential risk of virological failure; the adoption of TDM is strongly advisable, eventually combining with increased antiretroviral doses.

A 41-year-old Ukrainian refugee with a medical history including a HIV infection diagnosed in 2011 and a cerebral toxoplasmosis with neurological sequelae which occurred following antiretroviral treatment discontinuation leading to AIDS in 2019 (CD4 cell count: 17 cells/mm3) presented a seizure at the end of 2021 and another one in spring 2022 which prompted carbamazepine treatment at a dose of 400 mg once daily. At the time, HIV infection was well controlled with dolutegravir/lamivudine/tenofovir-DF (50/300/300 mg once daily). Remarkably the patient has remained virologically suppressed since initiating carbamazepine even though dolutegravir was dosed at 50 mg once daily. The magnitude of the drug interaction was documented by measuring the plasma concentrations of dolutegravir and carbamazepine. Dolutegravir was found to be 893 ng/mL 21 h post-dose, whereas carbamazepine concentration was 5.2 mg/L 8 h post-dose and within the therapeutic range. The dolutegravir level measured in this patient was reduced by 40% relative to the reference dolutegravir plasma profile when administered alone at a dose of 50 mg once daily. The extrapolated dolutegravir concentration 24 h post-dose (using an elimination half-life of 7.3 h to factor in the inducing effect of carbamazepine) was estimated to be 670 ng/mL and therefore well above the clinical target concentration threshold of 300 ng/mL. The sustained long-term virological suppression and the therapeutic dolutegravir concentration in our patient suggest that dolutegravir 50 mg once daily may be acceptable when using lower doses of carbamazepine. The magnitude of the interaction with carbamazepine measured in this patient was less pronounced compared to a published drug interaction study, an observation that relates likely to the lower dose of carbamazepine in this patient (400 mg) compared to the daily dose used in the previously published drug interaction study (600 mg), knowing that carbamazepine induction is dose/concentration dependent. It should also be emphasized that dolutegravir twice daily dosing has been challenged following the publication of studies showing similar rates of viral suppression with once daily compared to twice daily dolutegravir dosing in presence of the strong inducer rifampicin. These studies suggest that the 300 ng/mL clinical threshold could be too conservative. Therapeutic drug monitoring can guide the need for twice daily dosing dolutegravir in presence of strong inducers.