Reply to Letter: Influence of Liver and Kidney Disease on Sofosbuvir Electrophysiological Effects.

We thank Drs Rossotti, Puoti, and colleagues for further reasoning on the electrophysiological effects of sofosbuvir for hepatitis C. Indeed, they analyze 2 important variables that we did not assess in our study,1 namely antiretroviral therapy for HIV coinfection and liver cirrhosis. None of our patients had HIV coinfection, but many had cirrhosis, a condition that can affect both cardiac electrical parameters and drug metabolism. A high frequency of mostly nonsignificant electrophysiological abnormalities occurs in patients with cirrhosis, including chronotropic incompetence, electromechanical uncoupling, and QT interval prolongation progressing from Child-Pugh-Turcotte (CPT) stage A to C.2 We therefore analyzed QTc duration in 18 cirrhotic and 8 noncirrhotic advanced fibrosis (F3) patients, all treated with sofosbuvir-based regimens. At week 1 of therapy, cirrhotic patients had no significant variation of QTc values compared with baseline (431.2 milliseconds vs 424.3 milliseconds, P = .480). Similar results were observed comparing QTc changes at week 4 (422.7 milliseconds vs 424.3 milliseconds at baseline, P = .554). When the same analysis was performed in CPT A patients (n = 15), the results were similar: 423.3 milliseconds at baseline, 429.9 milliseconds at week 1 and 421.5 milliseconds at week 4 (T0 to TW1 P = .575; T0 to TW4 P = .826). F3 patients similarly showed stable QTc values (424.4, 430.8, and 423.5 milliseconds at baseline, week 1, and week 4, respectively; T0 to TW1 P = .463; T0 to TW4 P = .161). Results confirm the overall conclusions of our study. We did not perform the same analysis in the CPT B group, due to the small number of patients (N = 3). The area under the concentration-time curve (AUC) of sofosbuvir given at 400 mg/day increased after 7 days of dosing by 126% and 143% in CPT B and CPT C patients, respectively, consistent with a potentially stronger electrophysiological effect. However, there are other conditions that can influence AUC. In patients with mild or moderate renal insufficiency, sofosbuvir AUC values were elevated by 61% and 107%, respectively, compared to controls.3 In this setting, sofosbuvir has demonstrated a favorable safety profile that did not appear to contribute any additional significant toxicity. Furthermore, no clinically significant electrocardiogram abnormalities and no meaningful changes in Fridericia-corrected QT intervals were observed in patients with a glomerular filtration rate <30 mL/min, although AUC increased by 171%.4 In light of the common occurrence of renal functional impairment in HIV infection, results of Rossotti et al in this specific clinical setting could be explained by the double effect of liver and kidney impairment. Accordingly, we further assessed the influence of renal function on QTc duration. We divided sofosbuvirtreated patients in 2 groups according to the median value of the estimated glomerular filtration rate. Comparing patients with higher estimated glomerular filtration rate values with those showing lower estimated glomerular filtration rate levels, we found no significant differences in QTc duration in either of the 2 groups from baseline to week 1 or week 4 (Figure 1). In conclusion, with the given number of subjects studied, we could not find any association between the stage of liver disease or the degree of renal functional impairment and QTc changes in hepatitis C virus patients treated with sofosbuvir. These findings further support the cardiovascular safety of this drug in the absence of amiodarone coadministration.