Possible Antiretroviral Therapy‐Warfarin Drug Interaction

Abstract

Highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) has resulted in significant morbidity and mortality reductions. Lifelong antiretroviral therapy must be incorporated into each patient's medical regimen. Patients with HIV may also have simultaneous chronic medical conditions, resulting in the possibility of complex drug-drug interactions. We report a possible drug-drug interaction between HAART and warfarin in two patients, as assessed by the Naranjo adverse drug reaction probability scale and the Drug Interaction probability scale. Both patients' pharmacotherapy regimens included a nonnucleoside reverse transcriptase inhibitor (NNRTI), nevirapine, or a protease inhibitor, nelfinavir or lopinavir-ritonavir, and two nucleoside analogs. In both patients, high warfarin doses were required to maintain therapeutic international normalized ratios (INRs). Warfarin has two enantiomers, R-and S-warfarin, which are substrates primarily of cytochrome P450 (CYP) 3A4 (R-warfarin), CYP1A2 (R-warfarin), and CYP2C9 (S-warfarin). Protease inhibitors and NNRTIs have variable effects on CYP: induction, inhibition, or mixed. The increased warfarin doses required in these two patients may have been caused by induction of CYP3A4 by nevirapine, CYP2C9 by nelfinavir, or CYP2C9 by lopinavir-ritonavir. Thus, practitioners should prudently monitor INRs in patients receiving warfarin with concomitant HAART that includes either a protease inhibitor or an NNRTI.

Managing drug interactions in HIV-infected adults with comorbid illness

“…68 Numerous case reports have shown the need to monitor international normalized ratio closely when initiating protease inhibitor therapy, with substantial increases in the warfarin dose often being needed. [69][70][71][72][73] The effects of NNRTIs, including efavirenz, are less clear. One case described the need for an increase in warfarin dose with efavirenz, 69 but another reported a decrease in warfarin dose after initiation of the same NNRTI.…”

Human Immune-Deficiency Virus Associated Deep Vein Thrombosis Coexisting with Venous Ulcer

“…Interactions between warfarin and antiretrovirals is possible, given the influence of many antiretrovirals on CYP2C9 the enzyme responsible for the metabolism of the more active Senantiomer of warfarin therefore the need for meticulous monitoring of therapy using the international normalised ratio (INR). [12,13] It therefore behove the physician to be more meticulous with the monitoring of such patients while on anticoagulant therapy. Because of this weekly INR was used to monitor anticoagulation in this reported patient where equivalent dose of warfarin was appropriate for maintenance of optimal anticoagulation of INR of 2-3 times normal.…”

Drug and dietary interactions of warfarin and novel oral anticoagulants: an update

“…Therefore, safe pharmacological treatment of this complication requires consideration of drug-drug interactions between warfarin any antiretroviral medications. Of the many classes of antiretrovirals, the majority of the interactions are seen with the non-nucleotide reverse-transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) [56][57][58], as both are metabolized by multiple CYP450 enzymes. The NNRTI, nevirapine is a substrate and a selective inducer of CYP3A4 and CYP2B6 [59,60].…”

“…The NNRTI, nevirapine is a substrate and a selective inducer of CYP3A4 and CYP2B6 [59,60]. Four case reports have documented an induction interaction in which the patient required an increased dose of warfarin to maintain a therapeutic INR [57,59]. Efavirenz has both inhibition and induction effects on CYP3A4.…”