Accepted Manuscript Letter to the Editor Myo-pericarditis Secondary to Ledipasvir-Sofosbuvir Therapy Allison Padegimas, Kimberly A. Forde, Lee R. Goldberg, Edo Y. Birati PII: DOI: Reference:
S0168-8278(16)00021-0 http://dx.doi.org/10.1016/j.jhep.2016.01.015 JHEPAT 5964
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
29 September 2015 13 January 2016 14 January 2016
Please cite this article as: Padegimas, A., Forde, K.A., Goldberg, L.R., Birati, E.Y., Myo-pericarditis Secondary to Ledipasvir-Sofosbuvir Therapy, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.01.015
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Myo-pericarditis Secondary to Ledipasvir-Sofosbuvir Therapy Allison Padegimas1, Kimberly A. Forde1,3, Lee R. Goldberg1,2* and Edo Y. Birati1,2*
Department of Medicine1, Division of Cardiovascular Medicine2 and Division of Gastroenterology3, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, USA
*Dr. Birati and Dr. Goldberg contributed equally to this paper. Financial disclosure and Conflict of Interest: Allison Padegimas, MD: none Kimberly A. Forde, MD, MHS: none Lee R. Goldberg, MD, MPH: none Edo Birati, MD: research and fellowship support - HeartWare, Ltd. Correspondence: Edo Y. Birati, M.D. Hospital of the University of Pennsylvania 2 East Perelman Center 3400 Civic Center Blvd. Philadelphia, PA 19104 Office (215) 662-2683 Fax (215) 615-0828 Email: [email protected]
Keywords: HCV; myocarditis; cardiomyopathy; sofosbuvir-ledipasvir Word Count: 800 Abbreviations: LDV/SOF: Ledipasvir-Sofosbuvir; HCV: hepatitis C virus; DAAT: Direct-acting anti-viral treatment; LVAD: left ventricular assist device; LV: left ventricle; EF: ejection fraction; RV: right ventricle
To the editor: Our case of myo-pericarditis in a patient on ledipasvir/ sofosbuvir (LDV/SOF) on the background of known cardiotoxicity of multiple classes of anti-hepatitis C virus (HCV) directacting antivirals (DAATs) raises the concern of previously-unrecognized adverse effect of LDV/SOF. Our patient, a 55 year-old male with non-ischemic cardiomyopathy on HeartWare left ventricular assist device (LVAD) and HCV (genotype 1a) pursued DAAT for consideration for heart transplant candidacy. Prior to starting LDV/SOF amiodarone was stopped for 3 months, and blood pressure and renal function demonstrated stability (creatinine 1.3-1.6 mg/dl, eGFR 50-70 mL/min/1.73m2). His initial HCV viral load was 4.2 million copies. Three days after initiating treatment, the patient developed intermittent left-sided sharp chest pain unrelated to exertion, inspiration, infection, or changes in LVAD parameters. ECGs showed no ischemic changes. Cardiac enzymes were mildly elevated with peak troponin-T 0.186 ng/mL and CPK 5849 U/L. Renal function stayed stable during therapy (creatinine level and eGFR at baseline, 1.38 mg/dL and 65 mL/min/1.73m2, respectively), HCV was detectable below the lower limit of quantification. Transthoracic echocardiogram revealed stable reduced left ventricular (LV) ejection fraction (EF) with worsening right ventricular (RV) systolic function. Chest CT was negative for pulmonary embolism. Anti-nuclear antibody was weakly positive 1:160 but anti-histone antibody was negative making drug-induced lupus unlikely; however, hydralazine was discontinued. The patient was counseled and continued LDV/SOF; his cardiology team accepted this decision given his LVAD support. The patient remained asymptomatic for one week and then had substernal chest pain. ECGs showed no evidence of ischemia. Cardiac enzymes were positive with peak troponin-T 4.96
ng/mL, CPK 17889U/L, and CPK-MB 132.4 ng/mL. Creatinine remained stable compared to baseline values (1.57 mg/dL, eGFR 56 mL/min/1.73m2), HCV was detectable below the lower limit of quantification. Transthoracic echocardiogram was stable. Coronary angiography revealed no coronary artery disease. Endomyocardial biopsy was deferred given procedural risks versus exhaustive clinical workup already consistent with myo-pericarditis. Overall, the patient’s recurrent chest pain with elevated cardiac enzymes and with ECGs, echocardiograms, and cardiac catheterization, all refuting ischemic disease is consistent with myo-pericarditis. The only medication change was initiating LDV/SOF three days prior to symptom onset. There were no infectious symptoms supporting viral myocarditis which would rarely recur. Amiodarone was discontinued >3 months before administration of LDV/SOF, making it unlikely that amiodarone had a contributory role. Therefore, it is reasonable to conclude that this is the first noted case of LDV/SOF-associated myo-pericarditis. The mechanism of LDV/SOF cardiotoxicity is unclear but may be related to HCV DAATs already discontinued secondary to cardiotoxicity. BMS-986094, the same nucleotide polymerase inhibitor class as sofosbuvir, was terminated in August 2012[1]. BILN 2061, an NS3 inhibitor, was terminated in 2011[2]; this class is weakly linked to NS5A protein activity which is the target of ledipasvir[3]. The cardiotoxicity of BMS-986094 was identified after the death of a 25 year-old from systolic congestive heart failure. Ensuing echocardiograms of all participants identified heart failure with reduced EF in 14 of 34 subjects, all asymptomatic with nonspecific ECGs (n=6 EF
S0168-8278(16)00021-0 http://dx.doi.org/10.1016/j.jhep.2016.01.015 JHEPAT 5964
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
29 September 2015 13 January 2016 14 January 2016
Please cite this article as: Padegimas, A., Forde, K.A., Goldberg, L.R., Birati, E.Y., Myo-pericarditis Secondary to Ledipasvir-Sofosbuvir Therapy, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep.2016.01.015
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Myo-pericarditis Secondary to Ledipasvir-Sofosbuvir Therapy Allison Padegimas1, Kimberly A. Forde1,3, Lee R. Goldberg1,2* and Edo Y. Birati1,2*
Department of Medicine1, Division of Cardiovascular Medicine2 and Division of Gastroenterology3, Perelman School of Medicine, University of Pennsylvania Philadelphia, Pennsylvania, USA
*Dr. Birati and Dr. Goldberg contributed equally to this paper. Financial disclosure and Conflict of Interest: Allison Padegimas, MD: none Kimberly A. Forde, MD, MHS: none Lee R. Goldberg, MD, MPH: none Edo Birati, MD: research and fellowship support - HeartWare, Ltd. Correspondence: Edo Y. Birati, M.D. Hospital of the University of Pennsylvania 2 East Perelman Center 3400 Civic Center Blvd. Philadelphia, PA 19104 Office (215) 662-2683 Fax (215) 615-0828 Email: [email protected]
Keywords: HCV; myocarditis; cardiomyopathy; sofosbuvir-ledipasvir Word Count: 800 Abbreviations: LDV/SOF: Ledipasvir-Sofosbuvir; HCV: hepatitis C virus; DAAT: Direct-acting anti-viral treatment; LVAD: left ventricular assist device; LV: left ventricle; EF: ejection fraction; RV: right ventricle
To the editor: Our case of myo-pericarditis in a patient on ledipasvir/ sofosbuvir (LDV/SOF) on the background of known cardiotoxicity of multiple classes of anti-hepatitis C virus (HCV) directacting antivirals (DAATs) raises the concern of previously-unrecognized adverse effect of LDV/SOF. Our patient, a 55 year-old male with non-ischemic cardiomyopathy on HeartWare left ventricular assist device (LVAD) and HCV (genotype 1a) pursued DAAT for consideration for heart transplant candidacy. Prior to starting LDV/SOF amiodarone was stopped for 3 months, and blood pressure and renal function demonstrated stability (creatinine 1.3-1.6 mg/dl, eGFR 50-70 mL/min/1.73m2). His initial HCV viral load was 4.2 million copies. Three days after initiating treatment, the patient developed intermittent left-sided sharp chest pain unrelated to exertion, inspiration, infection, or changes in LVAD parameters. ECGs showed no ischemic changes. Cardiac enzymes were mildly elevated with peak troponin-T 0.186 ng/mL and CPK 5849 U/L. Renal function stayed stable during therapy (creatinine level and eGFR at baseline, 1.38 mg/dL and 65 mL/min/1.73m2, respectively), HCV was detectable below the lower limit of quantification. Transthoracic echocardiogram revealed stable reduced left ventricular (LV) ejection fraction (EF) with worsening right ventricular (RV) systolic function. Chest CT was negative for pulmonary embolism. Anti-nuclear antibody was weakly positive 1:160 but anti-histone antibody was negative making drug-induced lupus unlikely; however, hydralazine was discontinued. The patient was counseled and continued LDV/SOF; his cardiology team accepted this decision given his LVAD support. The patient remained asymptomatic for one week and then had substernal chest pain. ECGs showed no evidence of ischemia. Cardiac enzymes were positive with peak troponin-T 4.96
ng/mL, CPK 17889U/L, and CPK-MB 132.4 ng/mL. Creatinine remained stable compared to baseline values (1.57 mg/dL, eGFR 56 mL/min/1.73m2), HCV was detectable below the lower limit of quantification. Transthoracic echocardiogram was stable. Coronary angiography revealed no coronary artery disease. Endomyocardial biopsy was deferred given procedural risks versus exhaustive clinical workup already consistent with myo-pericarditis. Overall, the patient’s recurrent chest pain with elevated cardiac enzymes and with ECGs, echocardiograms, and cardiac catheterization, all refuting ischemic disease is consistent with myo-pericarditis. The only medication change was initiating LDV/SOF three days prior to symptom onset. There were no infectious symptoms supporting viral myocarditis which would rarely recur. Amiodarone was discontinued >3 months before administration of LDV/SOF, making it unlikely that amiodarone had a contributory role. Therefore, it is reasonable to conclude that this is the first noted case of LDV/SOF-associated myo-pericarditis. The mechanism of LDV/SOF cardiotoxicity is unclear but may be related to HCV DAATs already discontinued secondary to cardiotoxicity. BMS-986094, the same nucleotide polymerase inhibitor class as sofosbuvir, was terminated in August 2012[1]. BILN 2061, an NS3 inhibitor, was terminated in 2011[2]; this class is weakly linked to NS5A protein activity which is the target of ledipasvir[3]. The cardiotoxicity of BMS-986094 was identified after the death of a 25 year-old from systolic congestive heart failure. Ensuing echocardiograms of all participants identified heart failure with reduced EF in 14 of 34 subjects, all asymptomatic with nonspecific ECGs (n=6 EF
