Increase in international normalized ratio after switching from atazanavir/ritonavir to darunavir/cobicistat in a patient on warfarin

The oral anticoagulant warfarin is a racemic mixture comprised of the R-isomer, which is a substrate of CYP1A2 and 3A4, and the S-isomer, which is metabolized by CYP2C9. Other CYP450 isoenzymes which may be involved in warfarin metabolism include CYP2C19, 2C8, and 2C18. The S-enantiomer of warfarin exhibits two to five times more anticoagulant activity than the R-enantiomer in humans, but has a more rapid clearance [1]. Warfarin is susceptible to interactions with many drugs including antiretrovirals [2]. Coadministration with ritonavir-boosted protease inhibitors generally results in decreased warfarin exposures secondary to CYP2C9 induction by ritonavir, and warfarin dose increases of 45–100% are often necessary [3]. Cobicistat is a pharmacokinetic enhancer which is coformulated with various antiretrovirals to permit once daily dosing. Similar to ritonavir, cobicistat inhibits cytochrome P450 3A4 isozyme (CYP3A4), P-glycoprotein, breast cancer resistance protein, organic anion transporter polypeptide (OATP)1B1 and OATP1B3. However, in contrast to ritonavir, cobicistat does not possess notable enzyme or transporter-inducing activity [4]. We report a case of an HIV-infected individual on stable warfarin therapy who experienced significant changes in international normalized ratio (INR) after switching from ritonavir-boosted atazanavir to cobicistat-boosted darunavir treatment. A 72-year-old HIV-positive Caucasian male had been on atazanavir 300 mg and ritonavir 100 mg once daily and tenofovir disoproxil/emtricitabine since 2009 with an HIV RNA less than 50/ml and a CD4+ cell count of 437 cells/mm3. His medical history was also significant for myocardial infarction, coronary artery bypass graft, atrial flutter, diffuse large B-cell lymphoma (successfully treated in 2007), chronic obstructive pulmonary disease/emphysema, and neuropathy. His concomitant medications included acyclovir, pravastatin, ASA, metoprolol, warfarin, pregabalin, fluticasone/salmeterol, and salbutamol. In September 2015, the patient was switched to a single-tablet formulation of darunavir 800 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg as part of a study. At that time, his INR was 2.5 and his warfarin dose of 10 mg daily had been stable for over the past year. One month later, his INR had increased to 3.4 and his warfarin dose was decreased to 8.75 mg daily. In January 2016, his INR was 3.6 and his warfarin was further reduced to 7.5 mg daily. At this time, the patient also reported onset of recurrent nosebleeds. His warfarin dose was decreased to 4 mg daily and his INR returned to baseline. The patient has remained stable on this dose for 4 months with no further reported issues (Fig. 1).Fig. 1: Daily warfarin dose and INR values on atazanavir/ritonavir therapy and after switching to darunavir/cobicistat therapy.ATV/r, atazanavir/ritonavir; DRV/cobi, darunavir/cobicistat; FTC, emtricitabine; INR, international normalized ratio; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil.Although ritonavir has both inhibiting and inducing effects, the net clinical effect with warfarin coadministration is reduction in warfarin exposure and activity, via predominance of 2C9 induction. This pattern has been observed with various ritonavir-boosted protease inhibitors [3]. A 56-year-old HIV-positive male required a 38% increase of his acenocoumarol dose to maintain therapeutic INR when he was switched from efavirenz to atazanavir 300/100 mg daily. When atazanavir/ritonavir was replaced with raltegravir, the acenocoumarol dose was reduced and therapeutic INR was maintained [5]. Similarly, a 50-year-old HIV-positive patient stabilized on warfarin and emtricitabine monotherapy required a 45% increase in mean warfarin dose upon initiation of etravirine, darunavir/ritonavir, and raltegravir [6]. In healthy volunteers, administration of single-dose warfarin with darunavir 600 mg/ritonavir 100 mg twice daily resulted in a 21% decrease in S-warfarin exposures [7]. As previously mentioned, cobicistat lacks significant enzyme induction activity. However, elvitegravir is an inducer of CYP2C9 [8]. A 42-year-old, HIV-positive male with recurrent lower deep vein thromboembolism on efavirenz/tenofovir/emtricitabine and stable warfarin experienced subtherapeutic INR and required a 60% increase in warfarin dose after switching to elvitegravir/cobicistat/tenofovir/emtricitabine. This observation suggests that CYP2C9 induction by elvitegravir outweighed the CYP3A4 inhibition by cobicistat on warfarin metabolism [9]. In contrast, our patient received cobicistat paired with darunavir which does not induce 2C9. Removal of ritonavir led to a loss of 2C9 induction and a subsequent increase in warfarin effect, manifested by increased INR and recurrent nosebleeds, which necessitated a 60% reduction in warfarin dose. According to the Drug Interaction Probability Scale [10], this represented a possible interaction between darunavir/cobicistat and warfarin. When switching from a ritonavir to a cobicistat-boosted protease inhibitor regimen, clinicians should be aware of the potential for increased warfarin exposures and need for INR monitoring and dose adjustment. This also applies to drugs which are substrates of other isozymes induced by ritonavir but not cobicistat, including CYP1A2, 2B6, 2C8, 2C19, or glucuronyl transferase [4]. Finally, clinicians are reminded to be cognizant of the pharmacokinetic properties of drugs coformulated with cobicistat; if our patient had been switched from atazanavir/ritonavir to elvitegravir/cobicistat, it is possible that a significant change in INR may not have been observed as elvitegravir is also an inducer of CYP2C9. Acknowledgements Conflicts of interest There are no conflicts of interest.

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