An unexpected interaction between warfarin and cobicistat-boosted elvitegravir

Field: Medicine (Health Sciences)

Elvitegravir, cobicistat, emtricitabine, and tenofovir (Stribild) is a co-formulated once-daily tablet approved for the treatment of HIV type 1 (HIV-1) antiretroviral therapy (ART)-naïve adult patients [1]. Elvitegravir is also available as a single entity, but requires co-administration with cobicistat, a pharmacokinetic booster, or the protease inhibitor, ritonavir, for adequate antiretroviral plasma concentrations [2]. Cobicistat is a potent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4) and P-glycoprotein, and increases the concentration of concurrently administered medications, leading to a number of drug interactions and contraindicated medications [1,3,4]. Unlike other integrase inhibitors, elvitegravir induces CYP2C9 and may lead to decreased concentrations of concurrently administered medications cleared via this isoenzyme [1,2]. Little is known regarding elvitegravir's clinical effects on co-administered CYP2C9 substrates. Warfarin is a racemic mixture consisting of two enantiomers. The S-enantiomer is approximately three to four times more potent and undergoes metabolism primarily by CYP2C9 [5]. The R-enantiomer is less potent and is primarily metabolized by CYP1A2, CYP3A4, and CYP2C19 [5]. It is not known whether warfarin induction or inhibition will occur when administered concurrently with elvitegravir and/or cobicistat, respectively. HIV-1 infection is associated with an increased risk of venous thromboembolism, making concomitant anticoagulation common with ART [6]. Due to many drug interactions between antiretrovirals and the novel anticoagulants, warfarin is most commonly used in HIV-positive patients requiring indefinite anticoagulation [7]. We report a possible interaction between elvitegravir and warfarin in a patient receiving a stable warfarin dose for the preceding 2 years [8]. A 42-year-old Caucasian man with a medical history significant for HIV-1 infection and recurrent bilateral lower extremity deep venous thromboembolism requiring indefinite anticoagulation [goal international normalized ratio (INR) 2.0–3.0] was followed in the infectious diseases clinic. ART consisted of once-daily co-formulated efavirenz 600 mg, emtricitabine 200 mg, and tenofovir 300 mg. During this time, his weekly warfarin dose was stable at 50 mg for approximately 2 years (Fig. 1). The patient maintained an excellent virologic and immunologic response [HIV PCR <20 copies/ml; CD4+ = 714 (34%)], but requested an alternative ART regimen as he continued to experience efavirenz-induced central nervous system dysphoria. The ART regimen was changed to once-daily co-formulated elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir 300 mg. The patient's warfarin regimen was not preemptively altered due to uncertainty in quantitative INR effects. After 14 days on elvitegravir/cobicistat, the warfarin dose remained stable. One week later (on day 20 after elvitegravir/cobicistat initiation), the patient's INR became subtherapeutic (Fig. 1). The patient's warfarin dose was gradually increased to 80 mg per week in order to maintain a therapeutic INR. No other medication changes occurred during this transition. The patient's warfarin weekly dose has remained stable for the subsequent 10 months with concurrent elvitegravir/cobicistat.Fig. 1: Warfarin dose.Change in weekly warfarin dose and resulting INR values over time before and after elvitegravir/cobicistat was initiated.Drug interactions between ART and warfarin are well known [9]. A small retrospective case-control study compared 18 patients receiving concurrent ART with warfarin [efavirenz (N = 7), ritonavir-boosted protease inhibitor (N = 8), and concomitant non-nucleoside reverse transcriptase inhibitor with a protease inhibitor (N = 2)] to 36 control (warfarin only) patients [10]. The mean daily warfarin dose was 3.5 mg higher in case patients. No difference in the daily warfarin dose was seen in case patients for the various ART regimens. In the present case, the patient historically maintained a therapeutic INR on an average warfarin daily dose of 7.1 mg with an efavirenz-based ART regimen. The warfarin daily dose increased to 11.4 mg with elvitegravir-based ART. The patient's warfarin requirement and INR values did not change initially, which may have been confounded by efavirenz's long elimination half-life when elvitegravir was initiated. Additionally, hepatic CYP induction is usually delayed and primarily has its maximum effects within 1–2 weeks after an inducer is added [11]. These effects were demonstrated in the present case as warfarin titration began on day 20. In this case, elvitegravir CYP2C9 induction appears to have the stronger effect on warfarin metabolism as compared to CYP3A4 inhibition by cobicistat. This patient required a 60% warfarin dosage increase, which is similar to previous studies [10,12]. This interaction is unique to elvitegravir as raltegravir and dolutegravir do not have any known CYP induction or inhibition effects [13,14]. On the basis of this case, patients receiving concomitant warfarin and elvitegravir therapy should have close INR monitoring with an expected need for dose titration. Acknowledgements B.L.G. is the first author and was responsible for editing and reviewing the manuscript. D.C.G. is the primary HIV provider of the patient described and was responsible for reviewing the manuscript. P.P.F. provides anticoagulation management for the patient described and was responsible for editing and reviewing the manuscript. Conflicts of interest Denese Gomes, NP, has been a consultant for Gilead Sciences, Inc.