Sustained viral suppression with once daily dolutegravir-containing regimen in presence of the strong inducer carbamazepine

Abstract

Dolutegravir 50 mg twice daily (BID) dosing is currently recommended in presence of strong inducers of drug metabolism. However, this dosing has been challenged by studies showing similar rates of viral suppression with dolutegravir once daily (QD) compared to BID dosing in presence of the strong inducer rifampicin. We report the case of a 41-year-old man with sustained virological suppression and documented therapeutic dolutegravir concentration on once daily dosing while treated with the strong inducer carbamazepine. Therapeutic drug monitoring can guide the need for twice daily dosing dolutegravir in presence of strong inducers.

Introduction

Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI) licensed at a dose of 50 mg once daily (QD) in combination with other antiretrovirals for the treatment of HIV infection. Dolutegravir undergoes metabolism by uridine diphosphate glucuronosyltransferase (UGT1A1) and to a lesser extent (10%) by cytochrome P450 3A4 (CYP3A4) ¹ and therefore can be subject to drug–drug interactions, particularly with strong inducers. Carbamazepine, a broad-spectrum antiepileptic drug, ² is a potent inducer of UGT1A1 and CYP3A4 ³ and was shown to reduce dolutegravir (50 mg QD) area under the curve (AUC) by 49% and minimal concentration (C_trough) by 73%, ⁴ an inducing effect which is comparable to rifampicin. ⁵ Thus, the product label recommends a dose adjustment of dolutegravir to 50 mg twice daily (BID) with concurrent administration of carbamazepine or other strong inducers. ⁵ Here, we present a case suggesting that dolutegravir BID dosing may not always be necessary with carbamazepine.

Case report

A 41-year-old Ukrainian refugee came in our clinic (Lausanne, Switzerland) for HIV care in July 2024. His medical history included a HIV infection diagnosed in 2011 and a cerebral toxoplasmosis with neurological sequelae which occurred following antiretroviral treatment discontinuation leading to AIDS (CD4 cell count: 17 cells/mm³) in 2019. The patient presented a seizure end of 2021 and another one in spring 2022 which prompted carbamazepine treatment at a dose of 400 mg QD. At that time, HIV infection was successfully controlled with the fixed-dose combination treatment comprising dolutegravir/lamivudine/tenofovir disoproxil fumarate (50/300/300 mg QD). Remarkably, the patient has remained virologically suppressed (HIV-RNA <20 copies/mL) since initiating carbamazepine even though dolutegravir was dosed at 50 mg QD.

To document the magnitude of the drug interaction, we measured the plasma concentrations of dolutegravir and carbamazepine using fully validated liquid chromatography coupled to tandem mass spectrometry methods. ⁶ Dolutegravir concentration 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 (i.e., 4-12 mg/L). ⁷ Dolutegravir level measured in our patient was reduced by 40% relative to the reference dolutegravir plasma profile when administered alone at a dose of 50 mg QD (Figure 1). ⁴ 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 ⁴ ) was estimated to be 670 ng/mL and therefore well above the clinical target concentration threshold of 300 ng/mL. ⁸

Figure 1.

Dolutegravir (DTG) 50 mg once daily (QD) plasma concentration (filled square) measured in the patient on long-term concurrent treatment with carbamazepine (CBZ) at 400 mg QD. The simultaneously measured CBZ plasma concentration was 5.2 mg/L (target concentration range: 4–12 mg/L). DTG 50 mg QD plasma profiles reported in a previous study evaluating the interaction with CBZ at 300 mg twice daily (BID) ⁴ with (dashed line) and without (continuous line) concurrent CBZ administration. The bottom line represents the clinical minimal concentration threshold of 300 ng/mL issued from a phase 2a study that determined the viral load reduction with DTG monotherapy. ⁸

Discussion

Dolutegravir is recommended at a dose of 50 mg BID in presence of strong inducers. However, the sustained long-term virological suppression and the therapeutic dolutegravir concentration observed in our patient suggest that dolutegravir 50 mg QD may be acceptable when using lower doses of carbamazepine. As depicted in Figure 1, the magnitude of the interaction with carbamazepine was less pronounced in our patient compared to a published drug interaction study. ⁴ This observation likely relates to the lower dose of carbamazepine in our patient (400 mg) compared to the daily dose used in the study (600 mg), knowing that carbamazepine induction is dose/concentration dependent. An inverse association has indeed been reported between carbamazepine dose/concentration and darunavir concentration. ⁹ A daily carbamazepine dose >550 mg and concentration >12.5 mg/L was found to be associated with darunavir C_trough below the minimal effective concentration. ⁹ Thus, the lower dose of carbamazepine may explain the favourable virological outcome in this patient despite dolutegravir QD dosing. Nonetheless, it should be emphasized that dolutegravir BID dosing has been challenged following the publication of studies showing similar rates of viral suppression with QD compared to BID dolutegravir dosing in presence of the strong inducer rifampicin.^10,11 These studies suggest that the 300 ng/mL clinical threshold could be too conservative. Of note, this threshold was issued from a phase 2a study aiming at determining the reduction in viral load for dolutegravir monotherapy. ⁸ However, the minimum concentration for an effect on viral load could not be determined in the phase 2b SPRING-1 study in which various dolutegravir doses (in combination with a NRTI backbone) achieved similar rates of virological suppression. ¹² Additionally, dolutegravir has been shown to have a long dissociation half-life (71 h) from the HIV integrase enzyme which could mitigate breakthrough viraemia in case of transient low dolutegravir C_trough. ¹³

Therapeutic drug monitoring can guide the need for twice daily dosing dolutegravir in presence of strong inducers. Further studies are needed to define dolutegravir minimal plasma concentration for an effect on viral load and to determine whether dolutegravir 50 mg QD dosing would be feasible with strong inducers for individuals without INSTI resistance.