Need for increased dose of warfarin in HIV patients taking nevirapine

Abstract

Nevirapine, a non-nucleoside inhibitor of the HIV-1 reverse transcriptase enzyme, is concomitantly administered to patients with a variety of medications. Nevirapine induces its own metabolism by the liver cytochrome P450 enzyme complex (CYP3A4 and CYP2B6) [1–3]. Current data indicate that nevirapine has little potential to be involved in inhibitory drug interactions, although it also induces the metabolism of other drugs that are metabolized by cytochrome P450, including oral contraceptives, rifampin, rifabutin, and protease inhibitors [1,2,4]. The clinical significance of these observations is unclear [1]. There are no reports of interactions between nevirapine and warfarin, an oral anticoagulant that also undergoes liver metabolism by cytochrome P450 (CYP2C9) [5,6]. We describe three cases in HIV-infected Italian patients, in whom the need for an increased dose of warfarin was linked with concomitantly administered nevirapine. Case 1 A 38-year-old man with severe primary pulmonary hypertension was given a 2 year treatment with warfarin 2.5 mg a day while he was under combination therapy with zidovudine and didanosine (CD4 T cell count 742 cells/mm3). During this period the Quick time stably ranged between 35 and 38%, with an international normalization ratio (INR) of 2.1–2.4. Subsequently, because of virological failure, antiretroviral agents were changed to a combination of stavudine, lamivudine and nevirapine, and the INR promptly dropped to 1.3 with a Quick time of 55%. An increase of warfarin to 5 mg a day restored anticoagulant activity (Quick time 37%, INR 2.0) until all drugs were stopped as a result of urticarioid eruption. A few days later, a new treatment with stavudine, lamivudine, and saquinavir was administered, and warfarin 2.5 mg a day was able to optimize stably the Quick time and INR. Case 2 A 28-year-old man developed a proximal deep-vein thrombosis in his left leg while he was undergoing combination treatment with zidovudine, lamivudine and nevirapine (CD4 T cell count 420 cells/mm3). After continuous intravenous heparin, warfarin was administered, but in spite of the dose increasing up to 17 mg a day, the Quick time did not drop below 65%. Only after stopping nevirapine, was a 5 mg a day warfarin dose sufficient to stabilize the Quick time and INR within the therapeutic range. Subsequently, nevirapine was added again to zidovudine and lamivudine, and warfarin up to 12 mg a day was required to maintain coagulation within the therapeutic range. Case 3 A 39-year-old man was given warfarin because of a deep-vein thrombosis developing in his left leg. At the time he was under combination treatment with zidovudine, lamivudine, and nevirapine (CD4 T cell count 28 cells/mm3), together with antituberculous therapy including rifampin. In spite of stopping rifampin and increasing warfarin up to 12.5 mg a day, the Quick time did not drop below 83% (INR 1.18). Only after stopping nevirapine, was a 7.5 mg a day warfarin dose sufficient to achieve the therapeutic range stably (Quick time 26%, INR 3.47). Little is known about the potential inhibitory effects of nevirapine on concomitantly administered drugs that also undergo metabolism by cytochrome P450. The findings reported here may expand information in this setting. Indeed, they document a clinically relevant inhibitory effect of nevirapine on the anticoagulant activity of warfarin. The required dose of warfarin exceeded the maximum recommended by standard guidelines in two patients, and doubled the minimum for a long time proved to be effective in the other patient [5]. A decrease in warfarin plasmatic levels because of the induction of cytochrome P450 by nevirapine might be considered in these cases. This hypothesis agrees with conceivable interactions based on either drug metabolism [1–5] and with adherence to treatment, and no evidence of malabsorption (as judged by the absence of weight loss, diarrhoea or vomiting) in all patients. Studies that include the measurement of both drug plasmatic concentrations are required to investigate the exact mechanisms involved in such an inhibitory effect of nevirapine. Daniele Dionisioa Simone Mininnib Dario Bartolozzic Francesco Espertia Angela Vivarellia Francesco Leoncinic