pulmonary arterial hypertension ( pah ) is an infrequent but nevertheless serious life - threatening severe complication of hiv infection . it is associated with an increase of pulmonary vascular resistance , pulmonary artery pressure , right - ventricular failure and death . bosentan , a dual endothelin-1 receptor antagonist , is indicated in the treatment of pah . it also improves exercise capacity , new york heart association ( nyha ) functional class , quality of life as well as cardiopulmonary hemodynamics , cardiac geometry , and cardiac function in these patients . the combination of bosentan with antiretroviral therapy appears to be safe and to have no adverse impact on the control of hiv infection . nowadays , hiv patients have a greater life expectancy compared to a few years ago . bosentan could induce both cytochrome p450 ( cyp ) 3a4 and cyp2c9 enzymes , which are also involved in acenocoumarol metabolism , and it is eliminated by biliary excretion . until now , the clinical data regarding the interaction between bosentan or ritonavir with oral anticoagulants ( either warfarin or acenocoumarol ) are limited . so , we present a case of interaction between bosentan and oral anticoagulants in an hiv patient and we made a systematic review in medline to identify published papers in english to identify cases of interaction between bosentan and oral anticoagulants in hiv patients . the keywords used in the search were acenocoumarol , warfarin , bosentan , drug interactions , protease inhibitors , international normalized ratio and pulmonary arterial hypertension . the search covered the period from 1966 to 2011 , the last search made was on 29 jul 2011 . the cases selected were those where there was interaction between the three drugs : bosentan , oral anticoagulants and protease inhibitors . in august 2009 , a 48-year - old caucasian male was diagnosed with pah , associated with hiv infection . he also had a double aortic lesion with dilatation of the right cavities and he was being treated with acenocoumarol . the patient was an ex - smoker , ex - parenteral drug addict and had previously been diagnosed with chronic but stable hepatitis c ( child - pugh class a ) . on 24 october 2009 , he came to our haematology department for anticoagulation control . over the previous year , his medication regimen had included lopinavir 200 mg / ritonavir 50 mg 2 capsules twice daily and emtricitabine 200 mg / tenofovir 300 mg once daily . over the previous month , he had taken acenocoumarol 56 mg / week ( achieving an inr values in the therapeutic range , 2.03.0 ) . in the last week of september one month later , the bosentan dose was increased from 62.5 mg to 125 mg and two weeks after that , he presented an international normalized ratio ( inr ) of less than 2 . the acenocoumarol dose was progressively increased up to 56 mg / week to obtain an adequate inr level . in the last week of march 2010 , the patient again presented with an inr of less than 2 ( bosentan 125 mg twice daily initiated on 8 march 2010 ) . the acenocoumarol dose was raised to 70 mg / week ( + 33% ) but failed to produce an adequate inr level . on 21 april 2010 , in an attempt to avoid an interaction between bosentan and acenocoumarol , this was stopped . forty - nine days later , we achieved a therapeutic inr with 90 mg / week ( + 157% ) of warfarin ( table 1 ) . he denied using alcohol or tobacco , having changed his dietary intake , or either missing or taking extra doses of oral anticoagulants . viral load remained undetectable ( < 50 hiv rna copies / ml ) and lymphocytes cd4 + > 300 cells / mm during this period . the horn drug interaction probability scale indicated a probable interaction between bosentan , acenocoumarol and lopinavir / ritonavir.6 
 
 table 1anticoagulant history.dateinr*anticoagulant dose , mg / wknotes10/24/092.252.5 ( ac)bosentan dose  from 62.5125mg11/10/091.552.5ac dose  to 53.5 mg / wk11/19/091.453.5ac dose  to 56 mg / wk11/26/091.856 - 12/04/092.856 - 2/15/102.656 - 3/23/101.656bosentan 125 mg bid initiated on 3/08/10 ; ac dose  to 63 mg / wk4/14/101.763ac dose  to 70 mg / wk4/21/101.770ac was stopped . warfarin 35 mg / wk and subcutaneous bemiparin 7500 iu / day was initiated4/26/101.235warfarin dose  to 42.5 mg / wk5/06/101.342.5warfarin dose  to 50 mg / wk5/13/101.350warfarin dose  to 57.5 mg / wk.5/20/101.457.5warfarin dose  to 62.5 mg / wk5/27/101.462.5warfarin dose  to 70 mg / wk6/03/101.570warfarin dose  to 90 mg / wk6/09/10390bemiparin was stopped6/292.590 - 7/14290 - 8/05/102.390-ac , acenocoumarol ; bid , twice daily;*inr , international normalized ratio ( therapeutic range , 2.03.0);bosentan initiated at 62.5 mg bid on 9/24/09 . ac , acenocoumarol ; bid , twice daily ; inr , international normalized ratio ( therapeutic range , 2.03.0 ) ; bosentan initiated at 62.5 mg bid on 9/24/09 . bosentan could increase the metabolization of both oral anticoagulants and develop a clinically - relevant decrease of oral anticoagulant concentrations . in our patient , it was necessary to significantly increase the dose of acenocoumarol and warfarin to try achieving a therapeutic inr . spangler and saxena reported that a patient treated with bosentan and warfarin needed a warfarin dose increase of 43% ( 75 mg / wk ) to maintain the therapeutic inr . in addition , murphey and hood reported a warfarin dose increase of 64% ( 45 mg / wk ) . in both cases , the interaction occurred in the first 10 days of treatment with bosentan while in our case it occurred on the 40 day and he needed a higher dose ( 2050% ) of warfarin to reach a therapeutic inr . in other reported cases , after increasing the bosentan dose our patient presented a delay in the response of more than 1 month . in other case , llibre et al . reported a dramatic drop of inr after concomitant treatment with ritonavir and acenocoumarol . in our patient , this interaction was not shown . after a month of treatment with lopinavir / ritonavir and acenocoumarol , our patient presented a stable value of inr , viral load and cd4 + lymphocytes . the inr values only dropped drastically after receiving two months treatment of bosentan and acenocoumarol . he required very high doses of warfarin in order to achieve an inr within the therapeutic range . dingemanse and van giersbergen observed an increase in bosentan concentration up to 48-fold during the first 4 days of coadministration with lopinavir / ritonavir . in our case , firstly , in patients with mild hepatic impairment ( child - pugh class a ) , such as the case in our patient , an increase of the bosentan dose along with its active metabolite , ro 48 - 5033 , has been reported . in addition , dingemanse and van giersbergen reported that the exposure to bosentan in patients with pah could present with low hepatic clearance . an increase in the bosentan dose could reduce the bile salt export pump level by up to 78% , increasing its half - life . in our patient , the delay in the onset of symptoms could be related to a reduction in the hepatic uptake of bosentan and a reduction of the induction effect on cyp2c9 . secondly , bosentan might induce cyp3a4 and cyp2c9 activity - acenocoumarol and warfarin mainly being metabolized by cyp2c9 . this might be related to an increase in the elimination of the oral anticoagulant and the dramatic drop in the inr values . however , it did not seem to affect the effectiveness of lopinavir / ritonavir and dose adjustment of this might not be required . other factors , such as genetic polymorphism in cyp2c9 ( or in cyp2c29 , a murine homologue of human cyp2c9 ) , could represent another potential complicating factor in this interaction and should be studied in these patients . so , the genetic contribution to variation in dose requirements seems to be more pronounced for warfarin than acenocoumarol . patients treated with bosentan , oral anticoagulants may need a significant increase in the anticoagulant dose to achieve an inr in the therapeutic range . however , randomised controlled trials comparing the dosage and safety of bosentan and oral anticoagulants in hiv patients are needed . until then , the use of bosentan and oral anticoagulants in these patients not only seems to require closer monitoring during the first weeks of treatment with bosentan , or after an increase in its dose , but for even longer periods of time .