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N Engl J Med 2015; 373:1886-1888November 5, 2015DOI: 10.1056/NEJMc1505967
To the Editor:
Treatment with sofosbuvir-based regimens is associated with a sustained virologic response in more than 90% of patients with chronic hepatitis C virus (HCV) infection, with a rate of serious adverse events of less than 5%.1 Here, we report three cases of severe bradyarrhythmia that occurred during treatment with sofosbuvir plus daclatasvir, simeprevir, or ribavirin among 415 patients treated in our unit from January 2 to December 31, 2014.
The characteristics of the patients at baseline are provided in Table 1, and electrocardiograms for Patients 1 and 3 are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org. Symptomatic bradycardia, with syncope in two cases (Patients 2 and 3), occurred within the first 10 days of treatment with sofosbuvir. The bradycardia was due to sinus-node dysfunction in Patients 1 and 2 and to intermittent third-degree atrioventricular block in Patient 3. In Patient 1, sinus-node dysfunction persisted after treatment with propranolol was discontinued. In Patient 2, sinus-node dysfunction resolved after discontinuation of treatment with sofosbuvir, simeprevir, and amiodarone. However, the reintroduction of sofosbuvir (with ribavirin), 46 days later, was followed by recurrence of the conduction abnormality at day 6. Pacemakers were implanted in all three patients. In Patient 1, interrogation of the pacemaker (performed by a cardiologist who was unaware of the patient’s identity) during sofosbuvir treatment revealed atrial pacing during 26% of the exposure time. Three months after the discontinuation of sofosbuvir treatment, atrial pacing was observed for 4% of the exposure time.
Common causes of bradyarrhythmia (electrolyte disorders, renal insufficiency, thyroid dysfunction, and cardiac ischemia) were ruled out. In Patient 2, a known drug interaction between amiodarone and simeprevir could have been a factor in the initial occurrence of bradyarrhythmia. Simeprevir could not have contributed to the recurrence 46 days later. Given the long half-life of amiodarone, we cannot exclude the possibility that residual levels of this agent contributed to the recurrence when sofosbuvir treatment was reintroduced.
In January 2015, after four arrhythmias in 1337 patients were found in a safety investigation of the compassionate use of daclatasvir given with sofosbuvir in France, the French National Agency for Medicines and Health Products Safety published an online warning.2 In March 2015, the Food and Drug Administration warned that serious slowing of the heart rate can occur when HCV treatments, including sofosbuvir plus another antiviral drug, are taken together with amiodarone.3
The pathophysiological mechanism underlying this potential adverse event is not clear. However, the potential cardiac toxicity of sofosbuvir-containing regimens suggests the need for caution with the use of such regimens, including review of other medications, consideration of risk factors for bradyarrhythmias, and possibly monitoring of cardiac rhythm during the initiation of therapy.
Read complete letter to the editor here: http://www.nejm.org/doi/full/10.1056/NEJMc1505967