IJCS | Volume 32, Nº2, May/June 2019

287 Rezende et al. Cardiac disorders in chronic hepatitis C Int J Cardiovasc Sci. 2019;32(3)283-289 Review Article greater efficacy to the treatment of hepatitis C compared to conventional IFN, with sustained virologic response rates (absence of viral RNA detection after treatment) in about 50% of the cases. However, many patients discontinued treatment because of adverse drug-related effects. The cardiovascular effects of this treatment are rare and arise as reports of cases in the literature involving supraventricular and ventricular arrhythmias, atrioventricular and intraventricular conduction disorders, cardiomyopathies and pericarditis. 27 On the other hand, Almawardy et al., 28 studied 120 patients with heart disease that underwent antiviral therapy of hepatitis C with peginterferon and ribavirin and did not find any significant disorders in the incidence of complications or worsening of heart disease in this group of patients. 28 Direct action antivirals At the beginning of the current decade, direct-acting antivirals (DAAs) were incorporated into the treatment of hepatitis C in combination with peginterferon for patients with HCV genotype 1. 29 More recently, the introduction of new agents, including sofosbuvir, has led to sustained virologic response rates inmore than 90% of the cases. Sofosbuvir is a nucleotide analogue (SN5b) that inhibits HCV polymerase and prevents viral replication. It presents a high genetic barrier to the development of resistance, but should be always associated with another second-generation antiviral such as daclatasvir, simeprevir or ledispavir and possibly ribavirin. The treatment of hepatitis C could be then done with drugs of oral administration only. 30 In March 2015, an alert was issued by the FDA (Food and Drug Administration), reporting nine cases of bradycardia with severe clinical repercussion in patients using sofosbuvir associated with the concomitant use of amiodarone in the United States. Six of these cases were observed in the first 24 hours of treatment and the others before the end of the second week. Three patients required pacemaker implantation and another case resulted in death. 31 The mechanism by which this association would provoke such disorder has not been elucidated. Such information generated a warning that the use of sofosbuvir in patients using amiodarone should not be recommended or, if the latter were essential for the treatment of potentially serious arrhythmias, the patient should bemonitoredwithin the first 48 hours of treatment with sofosbuvir in a hospital environment. Subsequently, in November 2015, a communication published in the New England Journal of Medicine reported three cases of severe bradyarrhythmia among more than 400 patients treated with AADs, including sofosbuvir, in a French reference center. Of these, two presented severe bradycardia due to sinus dysfunction and there was one case of atrioventricular block with syncope, requiring definitive pacemaker implantation in the three patients. Only one patient was on amiodarone, one was on low-dose propranolol, and the third one did not use drugs known to be heart rate depressants. 32 Although the safety and efficacy profile of these regimens has been tested in controlled studies, the actual influence of the new antiviral agents on heart rhythm still remains unanswered. The occurrence of drug interactions between AADs and antiarrhythmic drugs or other hepatic metabolizing drugs and bradyarrhythmia prior to treatment are possible mechanisms that justify the complications described. Most reported cases of severe bradyarrhythmia associated with the new antivirals were associated with previous use of the antiarrhythmic drug amiodarone. Amiodarone has extensive hepatic metabolism inhibiting CYP3A4, CYP2D6 and CYP2C9, CYP450 isoenzymes (Cytochrome P 450). In addition, it has a P-glycoprotein inhibitory effect (Gp-P), which is also present in cardiomyocytes. As sofosbuvir is a substrate of Gp-P, lower transport of this substance would lead to its increased intracellular concentration and consequent cardiotoxicity, leading to bradyarrhythmia. One criticism to this model is the fact that bradycardia has not been described as an adverse reaction in previous studies using high doses of sofosbuvir. On the other hand, other substrates of Gp-P, such as ritonavir (antiretroviral drug), have been related to bradyarrhythmia, raising the hypothesis that drugs with this potential could interact with sofosbuvir. 33 Simeprevir, one of the antivirals that may be associated with sofosbuvir in the treatment of hepatitis C, is a moderate inhibitor of CYP3A4, which has the potential to increase the effect of amiodarone. Another mechanism that could explain the events of bradycardia with the association between the antivirals and amiodarone would be the high plasma binding of this antiarrhythmic drug and the antivirals simeprevir and daclatasvir, promoting a higher plasma concentration of free amiodarone, increasing its effects on the cardiac tissue. 34 Recently, Millard et al. published an experimental study demonstrating in vitro that the electrophysiological