Warfarin-antiretroviral interactions.
OBJECTIVE
To review the literature for information regarding interactions between warfarin and antiretroviral agents and evaluate the clinical significance of these interactions.


METHODS
Primary literature was identified through a search of MEDLINE (1950-July 2008) and International Pharmaceutical Abstracts (1970-July 2008) using individual antiretroviral drug names and the following key search terms: warfarin, antiretroviral, protease inhibitor, nonnucleoside reverse transcriptase inhibitor, cytochrome P450, 2C9, HIV, and drug interactions. Relevant abstracts from infectious disease and HIV conferences (2005-2008), reference citations from relevant articles, and manufacturers' product information were also reviewed.


METHODS
All English-language articles identified through the data search were examined. Studies and reports addressing warfarin interactions with antiretrovirals, CYP2C9 polymorphism, and antiretroviral CYP2C9 effects were evaluated. A total of 12 case reports were identified that described interactions between warfarin and either protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs).


RESULTS
The drugs used in the case reports were limited to 6 antiretroviral agents (efavirenz, nevirapine, lopinavir/ritonavir, nelfinavir, saquinavir, ritonavir). The mechanism of interaction between antiretroviral agents and warfarin appears to be mediated through alteration in CYP2C9 metabolism. Concurrent use of warfarin with efavirenz or saquinavir was associated with overanticoagulation, identified by increases in international normalized ratio (INR). Use of warfarin with lopinavir/ritonavir, nelfinavir, ritonavir, and nevirapine resulted in subtherapeutic INRs. Interactions with delavirdine, etravirine, and atazanavir are anticipated; however, no published cases have reported these interactions. Interactions between warfarin and nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, and CCR5 antagonists are not anticipated.


CONCLUSIONS
Interactions between warfarin and antiretrovirals are likely, especially when PIs or NNRTIs are used. Induction or inhibition of warfarin metabolism may occur, depending on the specific antiretroviral agent. When warfarin is used concurrently with antiretrovirals, close monitoring of INR response is recommended in lieu of empiric warfarin dosing adjustments, given the limited information available and the quality of evidence.
Liedtke
Michelle D
MD
Department of Pharmacy, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA. michelle-liedtke@ouhsc.edu
Rathbun
R Chris
RC
D044966:Anti-Retroviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000378:metabolism; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9; D004347:Drug Interactions; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D019934:International Normalized Ratio; D011480:Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014859:Warfarin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
D044966:Anti-Retroviral Agents; D011480:Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases