Ritonavir- or cobicistat-boosted antiretroviral therapy and direct oral anticoagulants: A case for apixaban

Abstract

Summary

The potential for drug–drug interactions (DDIs) between direct oral anticoagulants and antiretroviral therapy (ART) is vast. Ritonavir and cobicistat are used as pharmacokinetic enhancers with either concurrent protease inhibitors or the integrase strand transfer inhibitor, elvitegravir, to optimize therapeutic concentrations by cytochrome P450 (CYP) inhibition. To date, only rivaroxaban and dabigatran have reported cases of use with ritonavir-boosted ART. Apixaban is metabolized similarly to rivaroxaban, but offers a dose reduction in the case of major DDIs. We report the successful use of reduced-dose apixaban to treat and prevent thromboembolic complications in six persons living with human immunodeficiency virus (HIV) on ritonavir- or cobicistat-boosted ART. This case series and available literature support the use of apixaban or dabigatran, depending on the boosted ART regimen.

Keywords

Antiretroviral therapy direct oral anticoagulant human immunodeficiency virus interaction

Get full access to this article

View all access options for this article.

References

Xarelto® [package insert]. Titusville: Janssen Pharmaceuticals, Inc., 2017.

Eliquis® [package insert]. Princeton: Bristol-Myers Squibb Company, 2018.

Pradaxa® [package insert]. Ridgefield: Boehringer Ingelheim Pharmaceuticals, Inc., 2017.

Savaysa® [package insert]. Basking Ridge: Daiichi Sankyo, Inc., 2017.

Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV, http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf (2018, accessed 3 January 2019).

Mavrakanas

Samer

Nessim

et al . Apixaban pharmacokinetics at steady state in hemodialysis patients. JASN 2017; 28: 2241–2248.

Lakatos

Stoeckle

Elzi

et al . Gastrointestinal bleeding associated with rivaroxaban administration in a treated patient infected with human immunodeficiency virus. Swiss Med Wkly 2014; 144: w13906.

Corallo

Grannell

Tran

Postoperative bleeding after administration of a single dose of rivaroxaban to a patient receiving antiretroviral therapy. Drug Saf Case Rep 2015; 2: 11.

Mueck

Kubitza

Becka

Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 2013; 76: 455–466.

10.

Egan

Hughes

Ackman

ML.

Drug interactions between antiplatelet or novel oral anticoagulant medications and antiretroviral medications. Ann Pharmacother 2014; 48: 734–740.

11.

Frost

Byon

Song

et al . Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Br J Clin Pharmacol 2014; 79: 838–846.

12.

Bates

Dalton

Gilmour

et al . Venous thromboembolism due to suspected interaction between rivaroxaban and nevirapine. CJHP 2013; 66: 125–129.

13.

Perram

Joseph

Holloway

Novel oral anticoagulants and HIV: dabigatran use with antiretrovirals. BMJ Case Rep 2015; pii: bcr2015211651.

14.

Barco

Coppens

van den Dool

et al . Successful co-administration of dabigatran etexilate and protease inhibitors ritonavir/lopinavir in a patient with atrial fibrillation. Thromb Haemost 2014; 112: 836–838.

15.

Kakadiya

Higginson

Fulco

Ritonavir boosted protease inhibitors but not cobicistat appear safe in HIV positive patients ingesting dabigatran. Antimicrob Agents Chemother 2018; 62: e02275–e02217.

16.

Stanger

Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285–295.

17.

Horn

Hansten

Dabigatran: a new oral anticoagulant. Pharm Times 2010; 10: 59.

18.

Kumar

Gordon

Brooks

et al . Differential influence of the antiretroviral pharmacokinetic enhancers ritonavir and cobicistat on intestinal P-glycoprotein transport and the pharmacokinetic/pharmacodynamic disposition of dabigatran. Antimicrob Agents Chemother 2017; 61: e01201–e01217.

19.

Gordon

Kumar

Brooks

et al . Antiretroviral boosting agent cobicistat increases the pharmacokinetic exposure and anticoagulant effect of dabigatran in HIV-negative healthy volunteers. Circulation 2016; 134: 1909–1911.