ALTERNATIVE VIEWPOINT Dolutegravir: A New Integrase Strand Transfer Inhibitor for the Treatment of HIV – An Alternative Viewpoint Michael A. Gillette,* Bhavik M. Shah, Jason J. Schafer, and Joseph A. DeSimone, Jr Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, Texas
KEY WORDS dofetilide, atrial fibrillation, dolutegravir, drug interactions. (Pharmacotherapy 2014;34(9):e173--e174) doi: 10.1002/phar.1478
Dolutegravir, a new addition to the class of integrase strand transfer inhibitors (INSTIs), was recently discussed in an excellent overview by Shah and colleagues.1 I would like to include a key interaction that was not highlighted but should be of particular concern to readers. Dolutegravir has been shown in vivo to inhibit the renal cation transporter OCT2 (IC50 = 1.93 lmol/L), which is involved in the elimination of a notable class III antiarrhythmic, dofetilide (Tikosyn).2 Although not formally evaluated in humans, this combination is listed as a contraindication by the manufacturer due to the theoretical increase in dofetilide concentrations that may occur.2 Dofetilide, when used as maintenance therapy for atrial fibrillation/flutter, can be useful in those with cardiovascular comorbidities such as heart failure but is limited by its propensity to prolong the corrected QT interval, which can subsequently increase the risk for more serious or fatal arrhythmias such as torsades de pointes. Atrial fibrillation is the most common arrhythmia encountered whose incidence has been shown to increase in human immunodeficiency virus–infected persons compared with healthy cohorts and be as high as 15.5 per 1,000 person-years in those aged 65 to Nothing to disclose. The views expressed herein reflect those of the author, and not necessarily those of the Department of Veterans Affairs. *Address for correspondence: Michael A. Gillette, Attn: Pharmacy Service (119), Michael E. DeBakey VA Medical Center, Baylor College of Medicine, 2002 Holcombe Blvd. Houston, TX 77030; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
74 years.3, 4 Thus, there is need for a heightened awareness of this drug interaction and its potential clinical implications. Although dolutegravir by itself has not been shown to affect cardiac repolarization, other alternatives should be used for either of these agents when prescribed together until proven otherwise.5 References 1. Shah BM, Shafer JJ, DeSimone JA. Dolutegravir: a new integrase strand transfer inhibitor for the treatment of HIV. Pharmacotherapy 2014;34:506–20. 2. ViiV Healthcare. Tivicay (dolutegravir) package insert. Research Triangle Park, NC; 2014. 3. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation 2014;129:e28–292. 4. Hsu JC, Li Y, Marcus GM, et al. Atrial fibrillation and atrial flutter in human immunodeficiency virus-infected persons. J Am Coll Cardiol 2013;61:2288–95. 5. Chen S, Min SS, Peppercorn A, et al. Effect of a single supratherapeutic dose of dolutegravir on cardiac repolarization. Pharmacotherapy 2012;32:333–9.
Author’s Reply We thank Dr. Gillette for his correspondence in highlighting the important drug interaction between dolutegravir and dofetilide.1 We briefly covered this potential interaction in our therapeutic review and pointed out the mechanism as dolutegravir’s inhibition of the renal organic cation transporter 2 (OCT-2).2 We agree with Dr. Gillette that given dofetilide’s narrow therapeutic window and potential to cause corrected QT interval prolongation at supratherapeutic concentrations, the concurrent use of the two agents should be avoided. Although the interaction lacks data from formal studies conducted in human
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subjects, the theoretical possibility of this interaction having significant clinical consequences is substantial. The manufacturer lists the combination as a contraindication in the package label.3 As this interaction with dofetilide is not a class effect of integrase inhibitors, some therapeutic options can be suggested for optimizing pharmacotherapy. Raltegravir does not inhibit OCT-2 and can remain an option as part of the antiretroviral regimen for select patients also taking dofetilide. Elvitegravir, available as a single-tablet regimen also containing cobicistat, may theoretically increase the concentration of dofetilide through a different mechanism―cobicistat’s potent inhibition of CYP3A4. However, dofetilide is predominately eliminated unchanged in the urine (80%), and is a weak substrate of CYP3A4.4 As a result, neither the package labels nor the Department of Health and Human Services guidelines list the concurrent use of these agents as an interaction or contraindication.4–6 Therefore, one may also consider
the single-tablet regimen containing elvitegravir an option for select patients who are prescribed dofetilide. When any new pharmacotherapy is introduced into practice, the implications for combining therapies cannot be completely known. References 1. Gillette MA. Dolutegravir: a new integrase strand transfer inhibitor for the treatment of HIV – an alternative viewpoint. Pharmacotherapy 2014;34:e173–e174. 2. Shah BM, Schafer JJ, DeSimone JA Jr. Dolutegravir: a new integrase strand transfer inhibitor for the treatment of HIV. Pharmacotherapy 2014;34:506–520. 3. Viiv Healthcare. Tivicay (dolutegravir) package insert. Research Triangle Park, NC; 2014. 4. Pfizer, Inc. Tikosyn (dofetilide) package insert. New York, NY; 2014. 5. Gilead Sciences, Inc. Stribild (elvitegravir/cobicistat/tenofovir/ emtricitabine) package insert. Foster City, CA; 2013. 6. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, 2014. Available from http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Accessed June 27, 2014.
KEY WORDS dofetilide, atrial fibrillation, dolutegravir, drug interactions. (Pharmacotherapy 2014;34(9):e173--e174) doi: 10.1002/phar.1478
Dolutegravir, a new addition to the class of integrase strand transfer inhibitors (INSTIs), was recently discussed in an excellent overview by Shah and colleagues.1 I would like to include a key interaction that was not highlighted but should be of particular concern to readers. Dolutegravir has been shown in vivo to inhibit the renal cation transporter OCT2 (IC50 = 1.93 lmol/L), which is involved in the elimination of a notable class III antiarrhythmic, dofetilide (Tikosyn).2 Although not formally evaluated in humans, this combination is listed as a contraindication by the manufacturer due to the theoretical increase in dofetilide concentrations that may occur.2 Dofetilide, when used as maintenance therapy for atrial fibrillation/flutter, can be useful in those with cardiovascular comorbidities such as heart failure but is limited by its propensity to prolong the corrected QT interval, which can subsequently increase the risk for more serious or fatal arrhythmias such as torsades de pointes. Atrial fibrillation is the most common arrhythmia encountered whose incidence has been shown to increase in human immunodeficiency virus–infected persons compared with healthy cohorts and be as high as 15.5 per 1,000 person-years in those aged 65 to Nothing to disclose. The views expressed herein reflect those of the author, and not necessarily those of the Department of Veterans Affairs. *Address for correspondence: Michael A. Gillette, Attn: Pharmacy Service (119), Michael E. DeBakey VA Medical Center, Baylor College of Medicine, 2002 Holcombe Blvd. Houston, TX 77030; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
74 years.3, 4 Thus, there is need for a heightened awareness of this drug interaction and its potential clinical implications. Although dolutegravir by itself has not been shown to affect cardiac repolarization, other alternatives should be used for either of these agents when prescribed together until proven otherwise.5 References 1. Shah BM, Shafer JJ, DeSimone JA. Dolutegravir: a new integrase strand transfer inhibitor for the treatment of HIV. Pharmacotherapy 2014;34:506–20. 2. ViiV Healthcare. Tivicay (dolutegravir) package insert. Research Triangle Park, NC; 2014. 3. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation 2014;129:e28–292. 4. Hsu JC, Li Y, Marcus GM, et al. Atrial fibrillation and atrial flutter in human immunodeficiency virus-infected persons. J Am Coll Cardiol 2013;61:2288–95. 5. Chen S, Min SS, Peppercorn A, et al. Effect of a single supratherapeutic dose of dolutegravir on cardiac repolarization. Pharmacotherapy 2012;32:333–9.
Author’s Reply We thank Dr. Gillette for his correspondence in highlighting the important drug interaction between dolutegravir and dofetilide.1 We briefly covered this potential interaction in our therapeutic review and pointed out the mechanism as dolutegravir’s inhibition of the renal organic cation transporter 2 (OCT-2).2 We agree with Dr. Gillette that given dofetilide’s narrow therapeutic window and potential to cause corrected QT interval prolongation at supratherapeutic concentrations, the concurrent use of the two agents should be avoided. Although the interaction lacks data from formal studies conducted in human
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subjects, the theoretical possibility of this interaction having significant clinical consequences is substantial. The manufacturer lists the combination as a contraindication in the package label.3 As this interaction with dofetilide is not a class effect of integrase inhibitors, some therapeutic options can be suggested for optimizing pharmacotherapy. Raltegravir does not inhibit OCT-2 and can remain an option as part of the antiretroviral regimen for select patients also taking dofetilide. Elvitegravir, available as a single-tablet regimen also containing cobicistat, may theoretically increase the concentration of dofetilide through a different mechanism―cobicistat’s potent inhibition of CYP3A4. However, dofetilide is predominately eliminated unchanged in the urine (80%), and is a weak substrate of CYP3A4.4 As a result, neither the package labels nor the Department of Health and Human Services guidelines list the concurrent use of these agents as an interaction or contraindication.4–6 Therefore, one may also consider
the single-tablet regimen containing elvitegravir an option for select patients who are prescribed dofetilide. When any new pharmacotherapy is introduced into practice, the implications for combining therapies cannot be completely known. References 1. Gillette MA. Dolutegravir: a new integrase strand transfer inhibitor for the treatment of HIV – an alternative viewpoint. Pharmacotherapy 2014;34:e173–e174. 2. Shah BM, Schafer JJ, DeSimone JA Jr. Dolutegravir: a new integrase strand transfer inhibitor for the treatment of HIV. Pharmacotherapy 2014;34:506–520. 3. Viiv Healthcare. Tivicay (dolutegravir) package insert. Research Triangle Park, NC; 2014. 4. Pfizer, Inc. Tikosyn (dofetilide) package insert. New York, NY; 2014. 5. Gilead Sciences, Inc. Stribild (elvitegravir/cobicistat/tenofovir/ emtricitabine) package insert. Foster City, CA; 2013. 6. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents, 2014. Available from http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Accessed June 27, 2014.
