Hepatitis C Virus (HCV) infection affects approximately 71 million people, accounting for 400,000 deaths per year worldwide.¹ More than 70% of these patients develop Chronic Hepatitis C (CHC), progressing with different degrees of liver impairment.² CHC has been reported as a cause of atherosclerotic heart disease and cardiomyopathies.^{3 , 4} Advanced liver fibrosis may also contribute to the development of structural, hemodynamic, and electrophysiological cardiac changes, which characterize cirrhotic heart disease.⁵ Furthermore, antiviral treatment of HCV with interferon or antivirals may be associated with cardiac arrhythmias.⁶

The introduction of direct acting antivirals (DAAs), including sofosbuvir, allowed for patients to be treated with CHC exclusively via the oral route, without interferon (IFN-free). These medications have an excellent efficacy and safety profile.⁷ However, after the beginning of the use of DAA regimens in 2012,⁸ the FDA reported nine cases of severe bradyarrhythmia occurring on the first days of therapy.⁹ Another study reported the occurrence of three similar cases in a French reference center, among more than 400 patients treated with DAAs.¹⁰ The nine patients from the FDA report who developed bradyarrhythmia were undergoing amiodarone therapy. In the French report, only one patient was treated with this drug, one patient used a beta-blocker, and the third patient did not use antiarrhythmic drugs. These facts have raised questions about the possible effect of sofosbuvir on patient heart rates (HR).

The objective of this study was to evaluate the HR changes and other clinical and electrocardiographic parameters in patients with CHC during DAA treatment, including sofosbuvir, analyzed by a 12-lead electrocardiography (ECG) and a 24-h ambulatory electrocardiographic monitoring (Holter system),

From December 2015 to August 2017, 53 patients were evaluated. Two patients were excluded from the study because of the presence of chronic arrhythmias (atrial fibrillation and flutter, respectively) and three patients were excluded because they failed to attend the subsequent evaluations. Of the three patients who did not undergo reevaluation, two finished the therapy without complications. The third patient discontinued antiviral therapy without medical advice; however, no complications were found to justify the discontinuation of the treatment. Therefore, 48 patients comprised the final study sample and underwent cardiovascular monitoring.

The following drug combinations were used: sofosbuvir, daclatasvir, plus ribavirin - 21 patients (43.8%); sofosbuvir plus simeprevir - 15 patients (31.2%); sofosbuvir plus daclatasvir - 11 patients (22.9%); and sofosbuvir, simeprevir plus ribavirin - 1 patient (2.1%).

The mean age of the patients was 61 ± 9.8 years (range 37–81), and most patients (56.3%) were males. Two patients (4.3%) had a positive serology for HIV. The evaluation of liver fibrosis stages was obtained by liver biopsy in 34 patients, by hepatic elastography in one patient, and by APRI and FIB 4 scores in 13 patients. Thirty-three patients (68.8%) presented advanced liver fibrosis, while 21 patients (43.8%) had a clinical diagnosis of liver cirrhosis. The HCV genotype 1 was present in 73% of the sample. Eleven patients (22.9%) were using beta-blockers. Clinical and laboratory data on liver disease are summarized in Table 1.

Specific symptoms were present in 25% of the patients in the initial cardiovascular evaluation. Dyspnea was the most common symptom, alone or combined with other complaints, and was reported by nine patients (18.8%), although none of these cases included cardiac or respiratory changes. With respect to the history of cardiovascular problems, SAH and DM were observed in 56.3% and 39.6% of the sample, respectively. Only one patient had a diagnosis of CAD with previous myocardial revascularization surgery.

Four patients (8.3%) reported symptoms in the reassessment performed after an average of 18.7 ± 9.4 days of treatment initiation. Three (6.2%) of these patients reported palpitations, and one reported dyspnea, which had no association with diagnosed cardiac changes. The systolic blood pressure (131.6 ± 20.8 vs. 128.2 ± 15.8, p = 0.3) and diastolic blood pressure (76.8 ± 10.3 vs. 78 ± 10.5, p = 0.4) before and during treatment were not significantly different.

The baseline ECG data showed changes in 14 patients (29.2%). Sinus bradycardia was the most common finding, found in six patients (12.5%), with HR values ranging from 50 to 60 bpm. First-degree AV block was observed in two patients (4.2%), intraventricular conduction delays in six (12.5%) patients, and increased QTc interval in four patients; however, none of these patients had QTc values > 480 ms. The second ECG recording performed during therapy was considered abnormal in 14 patients (29.2%), particularly in four patients (8.3%) with a long QTc interval, two of whom did not present this alteration at baseline. However, the increase in the QT interval was considered mild in three of the four patients (from 461 to 471 ms) and significant in only one patient (464 ms in the first examination and 494 ms in the second examination). Furthermore, this increase was not correlated with significant changes in the T-wave morphology or the presence of polymorphic ventricular arrhythmias analyzed by 24-h Holter monitoring, and treatment interruption was not necessary. This patient finished therapy without suffering cardiac complications.

The 24-h Holter monitoring did not indicate a significant difference in the minimum, medium, and maximum HR values and the presence of recurrent supraventricular or ventricular arrhythmias when comparing the periods before and during treatment (Table 2). Two patients without ventricular arrhythmias at baseline had a high frequency of ventricular extrasystoles during therapy, corresponding to 13.3% and 3.4% of the total heart beats, respectively. The increase in the number of ventricular ectopic beats in these patients was not associated with the presence of symptoms or other cardiovascular alterations, and interruption of treatment was not indicated. No cases of supra-ventricular or ventricular tachycardia or significant bradycardia with pauses exceeding 3 s were observed. None of the patients using DAAs had cardiovascular complications that required the discontinuation of treatment.

Subgroup analysis was performed to assess the effect of beta-blockers or advanced liver disease on ECG and 24-h Holter monitoring parameters. Eleven patients were on beta-blockers, with propranolol being used by six of them. The use of beta-blockers did not affect the ECG and HR parameters evaluated by 24-h Holter monitoring before and after therapy (Table 3). Moreover, the use of ribavirin by 22 patients did not affect the ECG and HR parameters evaluated by 24-h Holter monitoring before and after therapy. No differences were found before and during treatment: minimum HR (52.48 ± 7.34 vs 54.76 ± 9.15 bpm, p = 0.06), median HR (73.67 ± 10.48 vs 74.48 ± 10.13 bpm, p = 0.58), and maximum HR (114.71 ± 14.24 vs 112.33 ± 16.45 bpm, p = 0.36), respectively. Similarly, there were no significant differences in these parameters when comparing the periods before and during antiviral therapy in the 21 patients with cirrhosis.

However, during the treatment with DAAs, the 21 patients with cirrhosis presented significantly lower median HR and maximum HR values analyzed by 24-h Holter monitoring than did the patients without cirrhosis (Table 4). This difference was possibly due to a slight decrease in maximum HR during treatment in cirrhotic patients and the slight increase in median HR and maximum HR in non-cirrhotic patients (Table 4).

Our findings did not demonstrate the presence of significant changes in the ECG parameters and HR evaluated by dynamic ECG (24-h Holter monitoring) during treatment with DAAs. To date, no studies have been found in the literature that evaluate 24-h Holter monitoring during treatment with DAAs for CHC patients.

At the beginning of the CHC treatment with these new antivirals, some reported cases of severe bradyarrhythmia that were associated with prior use of amiodarone, and the clinical complication was explained by the interaction between this drug and DAAs, particularly sofosbuvir.¹⁵ Therefore, some studies have investigated the cardio-vascular safety profile of DAAs. In effect, Caldeira et al. performed a meta-analysis that included six large studies and 1,625 patients with CHC on antiviral therapy and found no significant differences in the rate of occurrence of cardiac arrhythmias between patients receiving sofosbuvir and those receiving other treatment regimens without this drug. The presence of arrhythmias was defined by the ECG records or compatible symptoms, including palpitations, pre-syncope, or syncope, and was reported in only three of these studies, with an overall risk of approximately 2% in patients using sofosbuvir.¹⁶

In effect, Durante-Mangoni et al. found that 26 patients on sofosbuvir regimens did not present changes in HR on serial ECG, including patients using beta-blockers, which suggested that this drug does not increase the risk of developing bradyarrhythmia during treatment with DAAs. These authors reported that the QTc interval increased in the first week after beginning therapy and returned to baseline levels during treatment.¹⁷ Nonetheless, changes in HR were not found in the 11 patients from our study who were using beta-blockers, analyzed by 24-h Holter monitoring.

Additionally, there were four cases of increased QTc interval during treatment among our patients, although the interruption of antiviral therapy was not necessary, since this increase was either mild or moderate (QTc below 480 ms) in three patients and significant in only one case, which was not associated with ventricular arrhythmias or changes in T-wave morphology analyzed by 24-h Holter monitoring. Hagiwara et al.,¹⁸ found cardio-vascular changes related to antiviral therapy in three cases (3.3%) among 91 patients using sofosbuvir plus ledipasvir. According to these authors, one of the patients presented bradycardia and increased QT interval, another patient developed atrial fibrillation, and the third patient presented a prolonged QT interval associated with previous heart failure. The three patients presented clinical improvement after discontinuing the treatment.¹⁸ In contrast, Biomy et al.¹⁹ evaluated patients using sofosbuvir plus simeprevir and found no cardiovascular events or changes in clinical, electrocardiographic, and echocardiographic parameters within 6 months after treatment.¹⁹

In the present study, two of the non-cirrhotic patients who did not present ventricular arrhythmia before therapy did show a high rate of monomorphic ventricular arrhythmia when analyzed by 24-h Holter monitoring during treatment. The occurrence of ventricular arrhythmia was also reported by Nirei et al. in two cirrhotic patients with spontaneous resolution.²⁰ The asymptomatic monomorphic ventricular tachycardia occurred at the beginning of therapy with sofosbuvir plus ledipasvir, leading to the interruption of treatment. These authors did not investigate the mechanisms involved in the onset of the arrhythmias but recommended caution in the use of these drugs in patients with advanced liver disease.²⁰

In the present study, HR was evaluated in patients with cirrhosis, and in this subgroup, the use of DAAs did not induce the development of significant bradyarrhythmia. The median and maximum HR values evaluated by 24-h Holter monitoring were lower in patients with liver cirrhosis than in non-cirrhotic patients, particularly during treatment, with a decrease in HR values compared with baseline values. Moreover, the use of DAAs appears to increase the median and maximum HR in non-cirrhotic patients. It is noteworthy that these findings were not associated with the use of beta-blockers, which is prescribed for portal hypertension in cirrhotic patients. Likewise, no differences were found in HR during ribavirin use, although this drug may induce hemolytic anemia, which can increase the HR.²¹

The degree of hepatic dysfunction may affect cardiac and autonomic function, causing chronotropic incompetence and an increase in the QT interval.²² Other authors have reported a lower HR in response to physical or pharmacological stress in cirrhotic patients, as evidenced by maximum HR values in provocation tests, such as physical effort in cycle ergometry²³ or the use of dobutamine.²⁴ Two mechanisms that lead to this alteration are decreased sensitivity of cardiac beta-adrenergic receptors as a consequence of the chronic hyperadrenergic state observed in cirrhotic cardiomyopathy (down-regulation) and the impairment of other factors involved in sympathetic signal transduction, including the receptor and the activity of G protein and adenyl cyclase, resulting in a decrease in cAMP levels.²⁵ These changes in HR have not yet been described when using 24-h Holter monitoring in patients with CHC during treatment with DAAs. The mechanism by which DAAs sensitize chronotropic incompetence in patients with cirrhosis or even increase the HR in non-cirrhotic individuals remains unclear.

The results of this study reinforce the cardiovascular safety profile of the treatment of CHC with DAAs. The widespread use of this therapy in several countries and the low number of complications in the medical literature strongly suggest that the reported complications are due to other factors, including the concomitant use of antiarrhythmics, as well as existing cardiac problems or other cardiovascular risk factors. The strength of this study was the use of 24-h Holter monitoring to evaluate the dynamic characteristics of HR, which allowed for the detection of cardiac arrhythmias, even in the absence of symptoms. In addition, strict parameters were used to define ECG changes, including abnormal QTc intervals > 450 ms instead of values starting from 440 ms, which is the cut-off used in most studies.

One limitation of this study was the low number of patients in the sample due to the high cost of treatment with DAAs, which restricted the access to therapy offered by the Brazilian public health system to patients with more advanced liver disease or comorbidities. This public policy has been reviewed in recent years when treatment became available to all CHC patients.

Another limitation of this study may have been the completion of the evaluation by ECG and 24-h Holter parameters between 10 and 14 days after the start of antiviral therapy, which may have caused some changes in HR that have not been diagnosed. For that reason, long-term continuous ECG monitoring, immediately after beginning treatment, could be more effective in detecting cardiac arrhythmias.

Our results demonstrate that HCV treatment with DAAs, including sofosbuvir, was not associated with significant clinical and ECG changes, and did not affect the main ECG or 24-h Holter parameters, even in patients using beta-blockers and ribavirin. Long QT interval and ventricular arrhythmia occurred in isolation and did not require the discontinuation of therapy. However, the use of DAAs appears to decrease the median and maximum HR in patients with cirrhosis analyzed by 24-h Holter monitoring. Further studies with larger sample sizes are necessary to confirm our findings.