Bictegravir-emtrictabine-tenofovir alafenamide in combination with oxcarbazepine in a person living with HIV and viral load suppression

Introduction

Integrase strand transfer inhibitors (INSTIs) (either bictegravir or dolutegravir) based therapy are recommended first line treatment options for most persons living with human immunodeficiency virus (PWH, HIV). ¹ Bictegravir and dolutegravir have similar once-daily pharmacokinetic profiles, but bictegravir is metabolized by both cytochrome P450 (CYP) 3A4 and uridine diphosphate (UDP) glucuronidation (UDG) (50:50) with dolutegravir primarily eliminated via UDG. ² Antiepileptic drugs (AED) (carbamazepine) demonstrate significant reductions in antiretrovirals (ARVs) via strong CYP and UDG induction and are contraindicated based on drug-drug interaction (DDI) references.^2,3 Oxcarbazepine is similar to carbamazepine with a concern for many DDIS. Oxcarbazepine’s metabolic profile is different compared to carbamazepine as it does not demonstrate auto-induction and is primarily converted to its active monohydroxy metabolite (MHM) which is responsible for the pharmacologic effect.^4,5 Oxcarbazepine induces both CYP 3A4 and UDG with significant reduction in CYP substrates (felodipine). ⁵ The glucuronidation induction effects of MHM are decreased (only 22%) compared to the parent oxcarbazepine (47%) with the Federal Food and Drug Administration labeling noting UDG induction to be clinically insignificant for UDP substrates. ⁵

To our knowledge, no case reports with oxcarbazepine with bictegravir are published. We report the therapeutic drug monitoring (TDM) and virologic response of a PWH on fixed dose combination bictegravir and concurrent oxcarbazepine.

Case

A 54 year old PWH [diagnosis in 2020; baseline viral load (VL) 3600 copies/mL and wild-type genotype] with ARV initiation with bictegravir fixed dose combination tablet remained virologically suppressed since treatment initiation. The past medical history included bilateral lower extremity neuropathy with prior failed treatments (amitriptyline, gabapentin, pregabalin and topical agents). Without knowledge of the infectious diseases (ID) providers, oxcarbazepine 300 mg twice daily (BID) was initiated 17 months previously. A refill request for the ARV regimen with a medication review alerted the provider of a possible DDI. Upon electronic medical record review, no formal DDI notification notified either the neurologist or the ID provider. A discussion with the information technology team revealed the electronic DDI designation as only a possible non-major DDI and deactivated to prevent prescriber alert fatigue. The patient reported oxcarbazepine downward titration on her own volition with a daily dose between 150 mg BID or thrice daily. An additional variable included a new ID provider 4 months prior to the reviewed possible DDI. Upon review of the prior three HIV VLs over the last 12 months, the patient-maintained suppression (<50 copies/mL) with no blips. A therapeutic bictegravir trough concentration (Table 1) resulted with the patient confirming no oxcarbazepine dose adjustment. ⁶ Oxcarbazepine TDM was never obtained by the neurology provider. Based on the bictegravir TDM result, continuation of oxcarbazepine was cautiously continued. Three months later, the bictegravir concentration remained therapeutic with viral suppression and an oxycarbazepine dose of 150 mg daily-BID (due to intolerable somnolence). No further dose adjustments and continuation of the prescribed ARV and AED combination continued.

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Table 1.

Oxcarbazepine dose, bictegravir concentrations and concurrent viral loads.

Oxcarbazepine dose	Bictegravir concentration	HIV viral load
150 mg 2–3 times daily	2650 ng/mL*	<50 copies/mL
150 mg 1–2 times daily	3900 ng/mL**	<50 copies/mL

Discussion

This report describes INSTI TDM to assist in determining the significance of the DDI between concurrent oxcarbazepine and bictegravir. Oxcarbazepine and carbamazepine both induce CYP and UDG, but clinical data demonstrate differences with carbamazepine being a stronger perpetrator. In a pharmacokinetic analysis, the glucuronidation induction effects of carbamazepine and oxcarbazepine with the UDP substrate, lamotrigine, were evaluated. ⁷ Subjects were administered carbamazepine (N = 131) or oxcarbazepine (N = 14) with lamotrigine. The lamotrigine concentrations were approximately reduced by 54% and 29% when co-administered with carbamazepine and oxcarbazepine, respectively.

In a small analysis of eight healthy subjects, oxcarbazepine 300 mg BID administered for 2 weeks with antipyrine (CYP 3A4 substrate) did not demonstrate reduced concentrations. ⁴ The authors concluded oxcarbazepine demonstrates a dose-dependent inductive effects with lower doses (≤600 mg) not possessing significant perpetrator effects.

In comparison to the above DDI study in healthy volunteers, a small case series of eight PWH on concomitant dolutegravir and oxcarbazepine, demonstrated either achieving or maintaining HIV VL suppression with concurrent use. ⁸ This report summarizes five males and three females prescribed oxcarbazepine (median dose = 600 mg) without knowledge of the HIV provider for 3–26 months on dolutegravir 50 mg with 2–3 nucleoside/tide reverse transcriptase inhibitors (NRTIs). Although VL suppression maintained with concurrent use, dolutegravir TDM was not performed.

The oxcarbazepine dose-dependency induction effects are further elucidated in an evaluation including raltegravir and dolutegravir which are primarily metabolized by UDG. ⁹ This small analysis included PWH on concomitant carbamazepine (N = 7; dose ranged of 200–900 mg) or oxcarbazepine (N = 4; dose range 600–4000 mg) and several ARV agents (atazanavir, darunavir and INSTIs). Raltegravir concentrations demonstrated variability with some values remaining therapeutic. In one PWH, the raltegravir trough concentration decreased to below the limit of detection resulting in new INSTI resistant mutations (G140S and Q148H—concomitant oxcarbazepine). In seven dolutegravir concentrations assessed, the values clinically significantly declined by 83% (191 ng/mL) compared to a control group not receiving either of the AEDs. Carbamazepine and oxcarbazepine were discontinued in 8/11 PWH, but the dolutegravir concentrations remained above 100 ng/mL for a minimum effective concentration. This small report utilized higher oxcarbazepine doses and does not provide which of the seven dolutegravir trough concentrations included carbamazepine only.

An additional concern with oxcarbazepine is the perpetrator effects on tenofovir alafenamide (TAF) concentrations in the fixed dose bictegravir tablet. ³ Emtricitabine is eliminated renally and thus, no DDI is expected. ² TAF is a p-glycoprotein (p-gp) substrate and may be affected by strong inducers. ² TDM with NRTIs is generally not recommended as these agents are pro-drugs [converted intracellularly to either di- (tenofovir) or tri-phosphorylated (e.g., zidovudine) active agents] and plasma concentrations are not well-correlated with safety or efficacy. ¹⁰ In a small analysis of 18 PWH on concurrent treatment with rifampin (strong CYP and p-gp perpetrator) and TAF 25 mg, tenofovir diphosphate concentrations increased by 5-fold compared to tenofovir disoproxil fumarate administered alone. ¹¹ No serious adverse effects resulted and TAF is now recommended for cautious use with rifamyicins with VL monitoring.^1,2,11 Similar to rifampin, oxcarbazepine and TAF would not be contraindicated.

Based on an evaluation of the published clinical data and the dose-dependency inductive oxcarbazepine effects, it may be safe to consider concomitant administration of bictegravir or dolutegravir with lower doses (<600 mg). If oxcarbazepine >600 mg is prescribed, then an adjusted dose may be considered based on a small analysis in PWH (N = 80) treated with fixed dose combination bictegravir or dolutegravir twice daily with concurrent rifampin for 24 weeks with no safety events and maintained VL suppression.^12,13 Although this is a single case and VL suppression preceded oxcarbazepine prescription, this report demonstrates no rebound HIV viremia and therapeutic bictegravir concentrations with concurrent low dose oxcarbazepine. Additional TDM bictegravir monitoring may be warranted with baseline poor VL suppression or if oxcarbazepine precedes ARV initiation. Based on this case, bictegravir and low dose oxcarbazepine may be a safe consideration for providers with a similar DDI query.