Evaluation of cardiac function by global longitudinal strain before and after treatment with sofosbuvir-based regimens in HCV infected patients

Extra-hepatic manifestations (such as neoplastic, autoimmune and vascular diseases) occur in about 70% of patients infected by hepatitis C virus (HCV) [1‐3]. Among these manifestations, cardiovascular diseases (CVD) are more prevalent in HCV infected patients, but mechanisms are currently unknown. HCV related inflammation, oxidative stress [4, 5] and direct damage due to HCV infecting cardiac cells [6‐8] might have a impact.

Animal studies reported death for cardiac causes after administration of a sofosbuvir metabolite at blood concentrations much higher than the therapeutic index used in humans [9]. Currently there is a lack data on the effects of sofosbuvir on heart function. Such data are important to confirm safety of sofosbuvir because we are currently treating aging populations with a significant prevalence of heart diseases. On the other way round, it is possible that clearance of HCV with interferon-free regimens would act favourably, as it was previously demonstrated that HCV eradication with interferon based regimens is able to reduce mortality for cardiovascular events [10, 11].

Left ventricular function (LVF) is routinely evaluated through the ejection fraction (EF), calculated by means of the modified Simpson method in current clinical practice, with the use of trans-thoracic echocardiography [12]. Trans-thoracic echocardiography based speckle tracking assessment is more reliable and precise for the assessment of myocardial function than trans-oesophageal ultrasound [13].

More recently, the global longitudinal strain (GLS) was developed as a more reliable index to measure left ventricular function [14]. Indeed, GLS was shown to be a valuable clinical parameter and a independent predictor of all cause mortality in patients with CVD [15]. Moreover, variations of GLS have been found in diverse conditions such as doxorubicin-induced cardiomyopathy, HIV infection in children and young adults, or viral myocarditis [16‐19]. In these conditions, even minor variations of GLS were clinically meaningful, even when EF seemed to be preserved [18, 19]. For instance, data showed that GLS provides incremental diagnostic and prognostic information, that are correlated with histological findings in patients with viral myocarditis for whom conventional 2D echocardiography is unspecific, particularly in those with a preserved EF [18, 19]. This correlation was independent from conventional 2D echocardio-graphic parameters showing that strain rate and strain imaging are more sensitive in the detection of early changes or mild myocardial damage. Moreover, patients with impaired strain rate and strain at the acute phase of the disease showed worse short-time echocardiographic outcomes. For these patients, clinical history, physical examination, ECG, and serology were shown to be unreliable compared with GLS.

The main finding of our study is that cardiac function measured through GLS seemed to worsen in the overall population, while EF did not change significantly. This may indicate that sofosbuvir based treatment could exert a negative impact on cardiac function. Possible toxicity of sofosbuvir may be supported from data showing that development of another NS5B polymerase inhibitor (BMS5986094) was stopped after a safety signal of cardiotoxicity [30]. In this work a young male died for rapidly progressive heart failure and 41.2% (14/34) patients had some evidence of cardiac dysfunction (6/14 with EF < 30% and 8/14 from 30 to 50%). So, as far as cardiotoxicity is concerned, a class effect of NS5B polymerase inhibitors should be studied further. Interestingly, after stopping DAAs, GLS continued to worsen, possibly indicating a prolonged effect. In addition, since EF remained stable, we may hypothesize that, similar to other conditions [14, 15], GLS is a more sensitive method to measure cardiac function.

However, the clinical significance and the long-term effects of the GLS variations in our patients are unknown. Correlations with other biomarkers of heart dysfunction (such as troponin, NT-pro-BNP, and micro-RNAs) [31‐34] and long term studies with “hard” clinical end-points would be helpful. Also, it is difficult to explain why such an effect was demonstrated. In fact, besides a direct effect of sofosbuvir, other explanations may be found, including a random effect due to the small number of patients, an effect of concomitant drugs, or an indirect effect of HCV eradication mediated by inflammatory changes [4, 35]. So, the major difficulty that comes with the dataset studied herein is to dissect whether the effect can be ascribed entirely to sofosbuvir or to other factors. For this reason, more powerful studies should adjust for possible confounders (including concomitant drugs and co-morbidities such as hypertension or cholesterol level and its variations), and using immune parameters to provide more specific and detailed information from the pathogenic point of view. Also, we need studies with a different design to assess whether sofosbuvir or HCV eradication (and possible immune effects related to this eradication) are implicated. For instance, one could compare cardiac function in patients with sustained virological response with respect to those without response, or cardiac function may be evaluated in healthy volunteers. Moreover, a group of control patients with other aetiologies presenting the same risk factors, but not treated with sofosbuvir-based treatments would be helpful. Unfortunately, however, this is difficult (or unethical) to be accepted for the legitimate desires of patients to be treated as soon as possible.

Since we did not find any significant correlations between GLS and ribavirin or anaemia (data not shown), we may hypothesize that these factors were not implicated. However, we have to take into account that the small sample size reduced the power to detect a smaller effect of ribavirin, significantly. Indeed, the evidence of a prolonged worsening of GLS after stopping treatment is more consistent with an effect of ribavirin (whose multiple dose half-life is around 12 days, persisting in non-plasma compartments for as long as 6 months) than with an effect of sofosbuvir (whose half life is only 0.4 h). For the same reason, the trend in GLS is more consistent with an immune-mediated phenomenon occurring after viral eradication, so consideration of immune markers could provide better insights on the phenomenon. With regard to hypertension, we did not find any significant evidences of a possible role at interaction model independently from time, but a complete assessment in a multivariable model would require grater numbers and a time-dependent consideration of hypertension as a variable in future studies.

In patients treated for three months, we noted an initial improvement of GLS, followed by a progressive worsening. The first phase of improvement could be due to a beneficial reduction of HCV RNA [10] while apparent sofosbuvir toxicity or other negative phenomena may have become more evident afterwards. This biphasic trend was not evident in patients treated for 6 months. The fact that patients who received 6 months of treatment were older, more likely to present advanced liver fibrosis or cirrhosis and comorbidities (including cardiac ones) could explain the discordant trends of GLS in the two groups. In fact, healthier individuals could benefit more from HCV RNA clearance in the short-term, while more compromised patients may suffer from a more prompt cardiotoxicity of sofosbuvir. Thus, it is worth considering that extreme elderly patients are receiving DAA treatments, with a high SVR rate, but at the same time they may experience more frequent cardiovascular complications, therefore a close and accurate monitoring of heart function could be required [36‐38].

The associations between worse GLS and smoking or high BMI at baseline was not unexpected, suggesting the importance to quit negative behaviours, such as smoking and unhealthy diet in patients chronically infected by HCV. This is even more relevant if one considers that cardiac function may worsen after treatment, concomitantly with an increase of cholesterol occurring after HCV eradication as demonstrated in our study and confirmed by others [39]. Appropriate time dependent analysis should be conducted to assess whether variations in cholesterol levels may lead to GLS changes during SOF-based regimens.

In conclusions, if confirmed by datasets from independent cohorts to replicate the data, our results are important because demonstrated for the first time the possible cardiotoxicity of DAA treatments. The same study protocol for patients who are eligible for DAAs treatment with sofosbuvir-free regimens should be applied, in order to evaluate whether worsening of GLS is a specific drug-related or a class effect. While these results should be confirmed in more powerful studies and pathogenic hypotheses should be tested in translational studies, in the meantime a cautious approach should include assessment of cardiac function during DAA treatment, particularly for the most fragile patients, who may benefit from interventions to reduce the risk of cardiovascular diseases both before and after treatment.