Abstract
Drug co-administration often affects the patient response to warfarin through various mechanisms. We describe here five HIV-1-infected patients on treatment with warfarin in whom the use of raltegravir was associated with a favourable outcome.
Drug co-administration often affects the patient response to warfarin through various mechanisms. For example, some drugs induce or inhibit liver enzymes, such as cytochrome P450 (CYP) isozymes responsible for warfarin metabolism;1,2 others alter warfarin sensitivity by changing vitamin K synthesis or absorption, alter warfarin distribution or metabolism by increasing its affinity for receptor sites, or change the synthesis of functional coagulation factors. As the life expectancy of HIV-infected individuals is becoming longer, co-administration of warfarin with antiretrovirals needs to be assessed carefully. Nevirapine and lopinavir-ritonavir reduce serum concentrations of warfarin,3,4 while efavirenz increases the concentration, 4 probably by the induction and inhibition of CYP2C9,1,2 the main enzyme in warfarin metabolism. We reported previously the favourable effects of non-boosted fosamprenavir in patients treated with warfarin. 5 The clinical use of warfarin co-administered with raltegravir has not been described so far, though raltegravir seems to be a safe choice because it does not inhibit or induce CYP isoenzymes. 6 We describe here five HIV-1-infected patients on treatment with warfarin in whom the use of raltegravir was associated with a favourable outcome (Table 1). Cases 1-3 were Japanese men who had been treated with a stable dose of warfarin (mean daily dose, 3-4 mg) for underlying diseases, and their international normalized ratios (INR) were maintained within the optimal ranges (1.5-2.5 or 2.0-3.0) before the introduction of antiretroviral therapy (ART). Dose modification of warfarin was not necessary after starting ART containing raltegravir, as INRs remained within the optimal ranges. Case 4 was a 62-year-old Japanese man who had been treated with abacavir, lamivudine and non-boosted fosamprenavir (1400 mg twice daily). Based on his request, ART was switched to abacavir, lamivudine and raltegravir, and INR was maintained within the optimal range (1.5-2.5). Therefore, warfarin dose modification was not necessary. Case 5 was a 57-year-old Japanese man who had been treated with abacavir, lamivudine and lopinavir/ritonavir. He developed chronic atrial flutter. The initial dose of warfarin was 1 mg/day to maintain INR within the optimal range (1.5-2.5). Three months later, INR control became difficult at 4 mg/day of warfarin (INR; 0.70-0.91) and warfarin was terminated because it seemed ineffective. Non-boosted fosamprenavir could not be used because genotypic analysis showed resistance of HIV-1 to fosamprenavir. When raltegravir became available in Japan (9 months after discontinuation of warfarin), treatment was switched to ART comprising abacavir, lamivudine, raltegravir and etravirine, as well as warfarin (at initial dose of 1 mg/day). Three months later, INR was controlled within 1.46-2.49 at 3.5 mg of warfarin. The new regimen allowed maintenance of INR within the optimal range.
HIV-1 infected patients with favourable outcome following treatment with raltegravir and warfarin
RAL = raltegravir 800 mg/day; ETV = etravirine 400 mg/day; TDF = tenofovir 300 mg/day; FTC = emtricitabine 200 mg/day; ABC = abacavir 600 mg/day; 3TC = lamivudine 300 mg/day; FPV = fosamprenavir 2800 mg/day; LPV/RTV = lopinavir 800 mg/day and ritonavir 200 mg/day
Cardiovascular events are increasing with the long-term use of ART. For patients treated with warfarin, raltegravir is a safe and clinically effective ART agent. Etravirine can potentially interact with warfarin by inducing CYP3A and mild inhibition of CYP2C9 and CYP2C19. 7 However, in Case 5, it was used successfully in combination with raltegravir. Such combinations may be helpful for the control of drug-resistant HIV-1 in warfarin-treated patients. Genetic polymorphisms in CYP2C9 may affect the response to warfarin, 8 though such data were not available in our five patients. The clinical introduction of raltegravir has expanded the ART options, though further clinical evidence is necessary in warfarin-treated patients.