==== Front Hepatol CommunHepatol Commun10.1002/(ISSN)2471-254XHEP4Hepatology Communications2471-254XJohn Wiley and Sons Inc. Hoboken 10.1002/hep4.1206HEP41206Original ArticleOriginal ArticlesLiver Fibrosis Is Associated With Corrected QT Prolongation During Ledipasvir/Sofosbuvir Treatment for Patients With Chronic Hepatitis C Tahata etal.Tahata Yuki 1 Sakamori Ryotaro 1 Urabe Ayako 1 Morishita Naoki 1 Yamada Ryoko 1 Yakushijin Takayuki 1 Hiramatsu Naoki 1 Doi Yoshinori 2 Kaneko Akira 3 Hagiwara Hideki 4 Yamada Yukinori 5 Hijioka Taizo 6 Inada Masami 7 Tamura Shinji 8 Imai Yasuharu 9 Furuta Kunimaro 1 Kodama Takahiro 1 Hikita Hayato http://orcid.org/0000-0003-2488-7315 1 Tatsumi Tomohide 1 Takehara Tetsuo takehara@gh.med.osaka-u.ac.jp 1 1 Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan 2 Otemae Hospital Osaka Japan 3 NTT West Osaka Hospital Osaka Japan 4 Kansai Rosai Hospital Amagasaki Japan 5 Kaizuka City Hospital Kaizuka Japan 6 National Hospital Organization Osaka Minami Medical Center Kawachinagano Japan 7 Toyonaka Municipal Hospital Toyonaka Japan 8 Minoh City Hospital Minoh Japan 9 Ikeda Municipal Hospital Ikeda Japan * ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: Tetsuo Takehara, M.D., Ph.D. Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine 2‐2 Yamadaoka Suita, Osaka 565‐0871, Japan E‐mail: takehara@gh.med.osaka-u.ac.jp Tel: +81‐6‐6879‐3621 06 8 2018 8 2018 2 8 10.1002/hep4.v2.8884 892 26 2 2018 14 5 2018 15 5 2018 © 2018 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Combination treatment of ledipasvir and sofosbuvir (LDV/SOF) is first‐line treatment for patients with chronic hepatitis C genotype 1 in the United States, Europe, and Japan. However, the influence of LDV/SOF on the cardiovascular system is poorly characterized. A total of 470 chronic hepatitis C patients who started LDV/SOF treatment between September 2015 and February 2016 at nine hospitals in Japan were prospectively enrolled in this study. Corrected QT (QTc) prolongation was defined as a QTc interval ≥450 milliseconds. The sustained virologic response rate was 96.0% (451/470), and the discontinuance rate due to adverse effects was 0.9% (4/470). Among 395 patients whose electrocardiogram was evaluated over time and compared with baseline, the QTc interval was significantly prolonged during treatment and returned to baseline levels 12 weeks after the end of treatment. Twenty‐four of 376 patients with baseline QTc intervals <450 milliseconds experienced on‐treatment QTc prolongation. Higher aspartate aminotransferase‐to‐platelet ratio index scores (≥0.76; odds ratio, 4.375; P = 0.005) and longer QTc intervals (≥416 milliseconds; odds ratio, 4.823; P = 0.003) at baseline were significantly associated with on‐treatment QTc prolongation on multivariate analysis. Patients with cirrhosis showed significantly longer QTc intervals than those without cirrhosis during treatment but not at baseline, and they developed on‐treatment QTc prolongation at a higher rate than patients without cirrhosis. No cardiovascular events occurred, except for 1 patient who developed paroxysmal supraventricular tachycardia. Conclusion: Newly developed QTc prolongation was observed in 6.4% of Japanese patients during treatment and was associated with more advanced fibrosis. (Hepatology Communications 2018; 00:000‐000) Ministry of Health, Labor, and Welfare of JapanJapan Agency for Medical Research and DevelopmentJP18fk021002118fk0210002h000318fk0210025h0002 source-schema-version-number2.0component-idhep41206cover-dateAugust 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:06.08.2018Potential conflict of interest: Dr. Takehara is on the speakers' bureau and received grants from Gilead. Dr. Kodama received grants from Gilead. The other authors have nothing to report. Supported by a Grant‐in‐Aid for Research on Hepatitis from the Ministry of Health, Labor, and Welfare of Japan and the Japan Agency for Medical Research and Development (JP18fk0210021, 18fk0210002h0003, 18fk0210025h0002). ==== Body Antiviral treatments for patients with chronic hepatitis C virus (HCV) infection have changed from interferon‐based treatment to interferon‐free treatment using multiple direct‐acting antivirals. Ledipasvir (LDV; an HCV nonstructural protein 5A protease inhibitor) plus sofosbuvir (SOF; an HCV nonstructural protein 5B polymerase inhibitor) treatment is a once daily medical compound for oral use and shows high sustained virologic response (SVR) rates and low discontinuous rates for patients with chronic HCV genotype 1 infection in clinical trials.2014, 2014, 2014, 2015 LDV/SOF treatment is one of the first‐line choices for patients with chronic HCV genotype 1 infections in the United States, Europe, and Japan.2016, 2016, 2015 SOF was approved in December 2013 for patients with HCV infections by the U.S. Food and Drug Administration, and an SOF‐based regimen has been shown to be relatively safe. However, in the combination treatment of SOF and another direct‐acting antiviral for patients with chronic HCV infection, 9 patients experienced extreme bradycardia in postmarketing reports.2015 All 9 patients took amiodarone by mouth; 1 patient died and 3 patients needed a pacemaker insertion. European guidelines for hepatitis C recommend that amiodarone and SOF should not be co‐administered.2016 Regarding the adverse cardiac events in phase 3 trials, 1 patient experienced unstable angina during LDV/SOF treatment.2014, 2014, 2014 In a Japanese phase 3 trial, 2 patients receiving LDV/SOF plus ribavirin treatment among 341 patients receiving LDV/SOF with or without ribavirin treatment experienced severe adverse cardiac events (including cardiac arrest and acute myocardial infarction).2015 Regarding electrocardiography, Hagiwara etal.2017 reported that corrected QT (QTc) prolongation during LDV/SOF treatment was observed in 2 out of 17 patients who were able to be evaluated by electrocardiography over time. However, the patient sample size was small, the factors associated with QTc prolongation were not investigated, and data on the QTc interval during LDV/SOF treatment were not examined in phase 3 trials. In the present study, we investigated the effect of antiviral treatments on the QTc interval as well as the overall efficacy and safety of treatment in a prospective cohort of patients with chronic HCV genotype 1 infection who were treated in general practice. Patients and Methods STUDY PATIENTS This study is a multicenter prospective study conducted by Osaka University Hospital and other hospitals affiliated with the Osaka Liver Forum. A total of 470 consecutive patients with chronic HCV genotype 1 infection who started the fixed‐dose LDV/SOF combination treatment between September 2015 and February 2016 at 9 institutions were enrolled in this study. Inclusion criteria were patients aged 20 years old or more and infected with HCV genotype 1. Patients with decompensated cirrhosis (Child‐Pugh grade B or C), signs of liver failure, hepatocellular carcinoma (HCC), hepatitis B virus or human immunodeficiency virus co‐infection, other causes of liver disease (e.g., primary biliary cholangitis or autoimmune hepatitis), and comorbidities, such as immunodeficiency or severe chronic renal failure (estimated glomerular filtration rate under 30 mL/minute/1.73 m2), were excluded. This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki, and the Ethics Committee of Osaka University Hospital and institutional review boards of all hospitals affiliated with the Osaka Liver Forum approved this study (UMIN000018561). Written informed consent was obtained from all study patients. TREATMENT PROTOCOL AND DATA COLLECTION Patients received a fixed dose, once daily, oral tablet of LDV (90 mg/day) plus SOF (400 mg/day) (HARVONI; Gilead Science, Foster City, CA) for 12 weeks. For safety evaluation, physical examinations and blood tests were performed at 1 week, 2 weeks, and every 2 weeks until the end of treatment (EOT). A liver biopsy was performed prior to initiating LDV/SOF treatment. Trained liver pathologists confirmed diagnoses and scored the grade of activity and fibrosis of liver tissues based on the meta‐analysis of histological data in viral hepatitis (METAVIR) histological score.1996 Liver cirrhosis was diagnosed according to a METAVIR score of F4 in cases when liver biopsy was performed and according to clinical findings in cases without liver biopsy. Clinical findings included characteristics of liver cirrhosis on a liver imaging test or blood test or physical findings and gastroesophageal varix by gastroendoscopy. We evaluated serum levels of creatinine, alanine aminotransferase, total bilirubin, neutrophil, and hemoglobin and platelet counts as laboratory adverse events according to the Common Terminology Criteria for Adverse Events version 4.0. ELECTROCARDIOGRAM EXAMINATION Electrocardiography was performed at baseline, 4 weeks, 8 weeks, 12 weeks, and 12 weeks after the EOT. QTc interval measurements were automatically calculated according to Bazett's formula (QTc = QT/√RR) or ECAPS, which is a correction formula based on a linear regression technique, (QTc = QT + (1−RR)/7) by the electrocardiogram machine. The maximal value of QTc intervals ≥450 milliseconds was defined as QTc prolongation because QTc intervals ≥450 milliseconds were considered grade 1 adverse events in the Common Terminology Criteria for Adverse Events version 4.0. Patients with a history of atrial fibrillation were excluded from the analysis by electrocardiogram. ASSESSMENT OF THE VIROLOGIC RESPONSE Serum HCV‐RNA levels were routinely monitored during and after the treatment by using real‐time polymerase chain reaction (COBAS TaqMan HCV version 2.0; quantitative range 1.2 to 8.0 log10 IU/mL; Roche Diagnostics K.K., Tokyo, Japan). Serum HCV‐RNA negativity at 24 weeks after the EOT was classified as SVR24. STATISTICAL ANALYSIS The continuous baseline variables were described as the median value and range, and categorical baseline variables were described as absolute frequencies. The Wilcoxon signed‐rank test was used to analyze the differences in the QTc interval during and after treatment, and the Mann‐Whitney test was used to analyze the differences in the QTc interval and delta QTc interval for patients with chronic hepatitis and liver cirrhosis at each time point. Fisher's exact test or the chi‐square test was used to analyze categorical data. Univariate and multivariate logistic regression analyses were used, and all continuous variables were divided according to the median value in the analyses of factors associated with QTc prolongation (QTc interval ≥450 milliseconds). All statistical analyses were conducted using SPSS version 22.0 (IBM, Armonk, NY), and a two‐tailed P value of <0.05 was considered statistically significant. Results BASELINE CHARACTERISTICS OF STUDY PATIENTS The median age was 70 years, and 22.1% (104/470) of patients were diagnosed with liver cirrhosis (Table 1). Among the 104 patients with liver cirrhosis, 33 were diagnosed by liver histology (F4) and 71 were diagnosed clinically. Fifty‐three patients (11.3%) had a history of HCC treatment. These 53 patients received curative treatment for HCC before LDV/SOF treatment, and signs of HCC recurrence were not observed on liver imaging. Additionally, 51.1% (240/470) of patients had never received antiviral therapy. Table 1 Baseline Characteristics of Patients Factor All (N = 470) CH (n = 366) LC (n = 104) Age (years) 70 (26‐92) 68 (26‐92) 72 (43‐85) Sex, male/female 211/259 175/191 36/68 BMI (kg/m2)* 22 (15‐34) 22 (16‐34) 23 (15‐31) Diabetes mellitus, no/yes 386/84 312/54 74/30 Hypertension,† no/yes 285/167 227/123 58/44 Previous antiviral treatment,‡ naive/IFN/IFN and RBV/Peg‐IFN and RBV/PI, Peg‐IFN, and RBV 240/33/14/124/54 193/25/8/95/42 47/8/6/29/12 Cirrhosis, no/yes 366/104 366/0 0/104 Child‐Pugh score, 5/6 59/45 ‐ 59/45 History of HCC treatment, no/yes 417/53 342/24 75/29 HCV‐RNA (median, log10 IU/mL) 6.1 (2.0‐8.0) 6.1 (2.0‐8.0) 6.0 (3.0‐7.0) Liver histology: activity, A0/1/2/3 10/156/43/0 10/133/30/0 0/23/13/0 fibrosis, F0/1/2/3/4 9/104/41/19/33 9/104/41/19/0 0/0/0/0/33 White blood cell (/μL) 4,395 (1,730‐9,400) 4,505 (1,730‐9,400) 3,800 (1,930‐7,800) Hemoglobin (g/dL) 13.5 (8.2‐17.8) 13.6 (8.2‐17.8) 13.1 (9.0‐16.9) Platelets (×104/μL) 14.5 (2.5‐47.6) 16.1 (5.9‐47.6) 10.4 (2.5‐21.7) Total bilirubin (mg/dL) 0.7 (0.2‐2.7) 0.7 (0.2‐2.7) 0.9 (0.3‐1.8) AST (U/L) 42 (13‐230) 39 (13‐230) 50 (18‐164) ALT (U/L) 38 (9‐338) 37 (9‐338) 41 (9‐148) Creatinine (mg/dL) 0.7 (0.4‐1.4) 0.7 (0.4‐1.4) 0.7 (0.4‐1.4) Albumin (g/dL) 3.9 (2.9‐5.0) 4.0 (2.9‐4.9) 3.7 (2.9‐5.0) APRI score 0.76 (0.13‐7.70) 0.62 (0.13‐6.18) 1.29 (0.48‐7.70) FIB‐4 index 3.18 (0.55‐22.72) 2.79 (0.55‐13.31) 5.52 (2.30‐22.72) BNP (ng/mL)§ 27.4 (3.3‐483.5) 24.5 (3.9‐483.5) 35.7 (3.3‐286.6) QTc interval (milliseconds)‖ 416 (334‐492) 417 (334‐474) 416 (338‐492) *BMI data were missing in 22 patients; †hypertension data were missing in 18 patients; ‡previous antiviral treatment data were missing in 5 patients; §BNP data were missing in 39 patients; ‖QTc interval data were missing in 16 patients. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BNP, brain natriuretic peptide; CH, chronic hepatitis; FIB‐4, fibrosis 4; IFN, interferon; LC, liver cirrhosis; Peg‐IFN, pegylated interferon; PI, protease inhibitor; RBV, ribavirin. TREATMENT EFFECT Virologic responses were assessed using intention‐to‐treat analysis. HCV‐RNA negativity rates at the EOT and 12 and 24 weeks after the EOT were 98.1% (461/470), 97.9% (460/470), and 96.0% (451/470), respectively (Supporting Fig. S1). Two patients died before being classified as SVR12, and 4 patients relapsed after the EOT. Thirteen patients were lost to follow‐up on classification as SVR24 and were counted as non‐SVR. SAFETY AND CHARACTERISTICS OF PATIENTS LEADING TO DISCONTINUATION Nine patients experienced an increase in creatinine levels (1.5‐3 times baseline values) (Table 2). One patient discontinued treatment after 4 weeks because of renal impairment. One patient experienced an increase in alanine aminotransferase (3‐5 times upper limit of normal), and 10 other patients experienced an increase in bilirubin (1.5‐3 times upper limit of normal); however, none of these patients discontinued treatment or experienced signs of liver failure. Regarding cardiovascular events, 1 patient developed a paroxysmal supraventricular tachycardia at week 1 and was treated with verapamil hydrochloride but safely completed LDV/SOF treatment. The patient who developed a paroxysmal supraventricular tachycardia was a 56‐year‐old woman who was clinically diagnosed with liver cirrhosis (liver biopsy was not examined). She had a history of cancer of the ovary; however, she had no history of cardiovascular disease and was not receiving any medication at the time she started LDV/SOF treatment. Other patients did not develop cardiac events needing medical treatment, such as severe heart failure or arrhythmia. None of the study patients took amiodarone by mouth. Table 2 Safety During Treatment N = 470 Adverse events leading to discontinuation 4 (0.9%) Reasons Sudden death 1 (0.2%) Renal impairment 1 (0.2%) Hyperkalemia 1 (0.2%) Pneumonia 1 (0.2%) Laboratory abnormalities Increased creatinine 1.5‐3 times BL 9 (1.9%) Increased ALT 3‐5 times ULN 1 (0.2%) Increased bilirubin 1.5‐3 times ULN 10 (2.1%) Decreased neutrophil count 500‐1,000/μL 10 (2.1%) Decreased hemoglobin 8.0‐10.0 g/dL 13 (2.8%) <8.0 g/dL 1 (0.2%) Decreased platelet count 2.5‐5.0 × 104/μL 7 (1.5%) Abbreviations: ALT, alanine aminotransferase; BL, baseline; ULN, upper limit of normal. Four patients discontinued LDV/SOF treatment due to adverse events, and the discontinuous rate was 0.9%. In the 4 patients who discontinued LDV/SOF treatment, 3 patients were aged 80 years or more, 3 patients had liver cirrhosis, and all 4 patients were treatment naive (Table 3). Reasons leading to discontinuation were hyperkalemia, pneumonia, sudden death, and renal impairment. Two out of 4 patients died (cases 2 and 3). One patient was an 84‐year‐old man with underlying chronic obstructive pulmonary disease and liver cirrhosis who died because of pneumonia 10 weeks after a 1‐week administration of LDV/SOF (case 2). The other patient was a 72‐year‐old woman with underlying liver cirrhosis; she died at week 2 from a sudden unexplained death (case 3). Table 3 Characteristics of Patients Leading to Discontinuation Age (Years) Sex Cirrhosis Previous Antiviral Treatment Comorbidity Past Medical History Reasons Leading To Discontinuation Administration Period (Weeks) Case 1 81 female no naive hypertension sepsis hyperkalemia 6 Case 2 84 male yes naive COPD ‐ pneumonia 1 Case 3 72 female yes naive ‐ ‐ sudden death 2 Case 4 81 female yes naive COPD ‐ renal impairment 4 Abbreviations: CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; IFN, interferon. EFFECT OF LDV/SOF TREATMENT ON QTc PROLONGATION Electrocardiography could be evaluated in 395 patients at baseline, 4 weeks, 8 weeks, 12 weeks, and 12 weeks after the EOT (Supporting Fig. S2). The QTc interval during treatment was significantly longer than baseline during treatment and returned to the same level as baseline 12 weeks after the EOT (Fig. 1A). The QTc interval was prolonged to 481‐500 milliseconds during treatment (grade 2 adverse event) in 2 patients and to 501 milliseconds or more (grade 3 adverse event) in 1 patient; however, all 3 patients completed LDV/SOF treatment without cardiovascular events. No patient experienced grade 4 QTc prolongation. Figure 1 Changes in QTc interval during treatment and 12 weeks after the EOT. (A) All patients; (B) patients with chronic hepatitis and liver cirrhosis. White box, patients with chronic hepatitis; gray box, patients with liver cirrhosis. Boxes represent twenty‐fifth to seventy‐fifth percentiles; lines within the boxes represent median values. * P < 0.05, chronic hepatitis versus liver cirrhosis at each time point; ** P < 0.01, 0 week versus each value at each time point. Twenty‐four (6.4%) out of 376 patients with QTc intervals <450 milliseconds at baseline experienced on‐treatment QTc prolongation (QTc interval ≥450 milliseconds) during treatment (Table 4). We collected data on co‐administered drugs on the 24 patients who experienced on‐treatment QTc prolongation. With the exception of 1 patient who was treated for a paroxysmal supraventricular tachycardia, there were no changes in other drugs for these patients after starting administration of LDV/SOF. Table 4 Factors Associated With QTc Prolongation (QTc Interval ≥450 Milliseconds) During Treatment Among Patients Whose QTc Interval Was <450 Milliseconds at Baseline Univariate Analysis Multivariate Analysis Factor Category OR 95% CI P Value OR 95% CI P Value Age (years) <70/≥70 0.966 0.423‐2.210 0.936 Sex Male/Female 1.610 0.672‐3.860 0.286 BMI (kg/m2) <22/≥22 0.862 0.364‐2.042 0.736 Fibrosis F0‐2/F3,4 2.723 0.811‐9.149 0.105 Total bilirubin (mg/dL)′ <0.7/≥0.7 2.789 1.018‐7.639 0.046 2.336 0.831‐6.569 0.108 ALT (U/L) <38/≥38 1.223 0.533‐2.803 0.635 Creatinine (mg/dL) <0.7/≥0.7 0.457 0.190‐1.094 0.079 Albumin (g/dL) <3.9/≥3.9 0.692 0.303‐1.584 0.384 APRI score <0.76/≥0.76 4.258 1.555‐11.657 0.005 4.375 1.566‐12.226 0.005 FIB‐4 index <3.18/≥3.18 2.093 0.873‐5.016 0.098 BNP (ng/mL) <27.4/≥27.4 1.025 0.432‐2.430 0.956 QTc interval (milliseconds) <416/≥416 4.356 1.591‐11.926 0.004 4.823 1.734‐13.413 0.003 Abbreviations: ALT, alanine aminotransferase; BMI, body mass index; BNP, brain natriuretic peptide; FIB‐4, fibrosis 4. In univariate analysis, total bilirubin levels (P = 0.046), aspartate aminotransferase‐to‐platelet ratio index (APRI) scores (P = 0.005), and QTc intervals at baseline (P = 0.004) correlated with on‐treatment QTc prolongation. Multivariate analysis using these three factors revealed that higher APRI scores (≥0.76; odds ratio, 4.375; P = 0.005) and longer QTc intervals at baseline (≥416; odds ratio, 4.823; P = 0.003) were significant independent factors associated with on‐treatment QTc prolongation. No patient met a diagnostic criterion for long QT syndrome. Because the noninvasive indicator of liver fibrosis, the APRI score, independently correlated with QTc prolongation during treatment, we compared the rate of QTc prolongation during treatment in patients with or without cirrhosis. The QTc prolongation rate during treatment was much higher in patients with cirrhosis than in patients without cirrhosis (Fig. 2). The QTc interval was significantly longer in patients with cirrhosis than in patients without cirrhosis during treatment, but this difference was not observed before treatment and disappeared after treatment (Fig. 1B). In addition, we investigated the delta QTc interval (changes in the QTc interval between baseline and each time point). At 8 weeks, the delta QTc interval was longer in patients with cirrhosis than in patients without cirrhosis (Supporting Fig. S3). Figure 2 Incidence of on‐treatment QTc prolongation (QTc interval ≥450 milliseconds) during treatment in patients with chronic hepatitis and liver cirrhosis. Discussion The present study revealed a high SVR24 rate of 96.0% and demonstrated that the discontinuous rate was only 0.9% for Japanese patients with chronic HCV genotype 1 infection in clinical practice. Although the age of this cohort was older than that of previous clinical trials (mean age in previous trials, 51‐60 years old), the effect and safety of LDV/SOF treatment in clinical practice were very high and of similar magnitude to clinical trials that implemented LDV/SOF treatment with or without ribavirin.2014, 2014, 2014, 2015 The present study demonstrated for the first time that the QTc interval was significantly prolonged during LDV/SOF treatment and then returned to a baseline level after treatment. In addition, this study revealed that newly developed QTc prolongation (QTc ≥450 milliseconds) was observed in 6.4% of patients and was associated with liver fibrosis. According to a safety test on healthy subjects, the administration of SOF for a single therapeutic (400 mg) or supratherapeutic (1,200 mg) dose or supratherapeutic doses of LDV (120 mg twice daily) for 10 days alone did not prolong the QTc interval.2016 The difference in the duration of administration, the administration of multiple direct‐acting antivirals, and lack of any liver disease may be possible reasons for the difference between the present study and the previous safety test. QTc prolongation is an important electrocardiogram finding.1991, 1978, 1991 According to reports of patients with or without cardiac disease, patients with QTc prolongation had a 2‐fold to 3‐fold effect on sudden death compared with patients without QTc prolongation.1978, 1991 A QTc interval >450 milliseconds has been reported as a risk factor for all‐cause and cardiovascular mortality in several populations.2014, 2003 QTc prolongation was divided into congenital or acquired factors, such as an electrolyte abnormality, or taking certain types of drugs.1985, 1986, 2004, 2000 A variety of drugs, including anti‐arrhythmic drugs, histamine H2 receptor antagonists, hypocholesterolemic agents, and psychotropic drugs, were reported to prolong the QTc interval.1985, 2015, 1996 Morganroth etal.1985 reported that 1.1% (4/360) of patients experienced QT prolongation (QT interval >550 milliseconds) after the administration of quinidine. Yun etal.2015 reported that 15.5% (56/362) of patients experienced QTc prolongation (QTc interval >450 milliseconds) after the administration of famotidine. Reinoehl etal.1996 reported that 16% (58/359) of patients experienced QTc prolongation (QTc interval ≥450 milliseconds) after the administration of probucol, and predrug QTc interval and female sex were significantly associated with QTc prolongation. In the present study, QTc prolongation (QTc interval ≥450 milliseconds) was observed during SOF/LDV treatment in 6.4% (24/376) of patients whose baseline QTc interval was <450 milliseconds. In this study, baseline APRI scores and QTc intervals were significantly associated with QTc prolongation during LDV/SOF treatment (Table 4). The APRI score is a noninvasive fibrosis diagnostic tool that can be calculated using routine laboratory data (aspartate aminotransferase level and platelet count) and was widely recognized as correlating with liver fibrosis in patients with chronic hepatitis C.2015, 2003 Therefore, we examined the association between QTc prolongation and liver fibrosis. The QTc interval and delta QTc interval from baseline were significantly longer in patients with cirrhosis than in patients without cirrhosis during treatment (Fig. 1B; Supporting Fig. S3), and the QTc prolongation rate during treatment was much higher in patients with cirrhosis than in patients without cirrhosis (Fig. 2). In patients with liver cirrhosis, the QTc interval was reported to be longer than in patients without cirrhosis.1998, 2005 The underlying mechanism was not fully investigated, but activation of sympathetic nerves was reported as a possible mechanism.1998, 2006 For the metabolism of LDV/SOF, the plasma exposure of LDV or SOF in subjects with severe liver impairment was similar to or modestly higher than that in patients with normal liver function.2016 These factors might be part of the cause of QTc prolongation during LDV/SOF treatment in patients with liver cirrhosis, but the specific mechanism is unclear. On the other hand, baseline QTc intervals were similar among patients with cirrhosis and patients without cirrhosis in the present study. Bernardi etal.1998 reported that the QTc interval was prolonged along with an increased Child‐Pugh score. In the present study, patients with cirrhosis with only a Child‐Pugh grade A score were enrolled, and this may be a possible reason why the baseline QTc interval did not change between patients with cirrhosis and patients without cirrhosis at baseline. There are several limitations of the present study. First, this is an observational study and includes some missing values. Among 470 patients, electrocardiography was not evaluated in 75 patients (16%) over time. However, electrocardiography could be evaluated in about 400 patients over time, and the present study is the first report to describe changes in the QTc interval during LDV/SOF treatment. Second, several conditions with electrolyte abnormalities and co‐administered drugs may affect the QTc interval. However, serum electrolyte levels were not studied in the present study and co‐administered drugs were examined only in patients with on‐treatment QTc prolongation. Third, the present study was conducted only in Japanese patients and the influence of race could therefore not be examined. Fourth, our cohort was older than those typically studied in clinical trials and the proportion of younger patients was relatively small. In conclusion, the QTc interval is slightly but significantly prolonged during LDV/SOF treatment. In our cohort, the incidence of QTc prolongation during treatment was 6.4% and no cardiovascular events occurred, except for one case of arrhythmia. During treatment, the QTc interval and the delta QTc interval from baseline were longer and the incidence of on‐treatment QTc prolongation was higher in patients with cirrhosis than in those without cirrhosis. Clinicians need to be aware of the potential for QTc prolongation with LDV/SOF, especially in those with cirrhosis, and should consider monitoring on a case‐by‐case basis. Author names in bold designate shared co‐first authorship. Abbreviations APRIaspartate aminotransferase‐to‐platelet ratio index EOTend of treatment HCVhepatitis C virus LDVledipasvir QTccorrected QT SOFsofosbuvir SVRsustained virologic response Supporting information Additional Supporting Information may be found at http://onlinelibrary.wiley.com/doi/10.1002/hep41206/full. Supporting Information Click here for additional data file.   Click here for additional data file.   Click here for additional data file. Acknowledgment Other institutions that enrolled patients in this study were as follows: Osaka International Cancer Institute, K. Katayama; National Hospital Organization Osaka National Hospital, E. Mita; Osaka Rosai Hospital, A. Hosui; National Hospital Organization Minami Wakayama Medical Center, I. Yabuuchi; Osaka Police Hospital, M. Oshita; Japan Community Healthcare Organization Osaka Hospital, T. Ito; Osaka General Medical Center, A. Inoue; Yao Municipal Hospital, H. Fukui; Nishinomiya Municipal Central Hospital, H. Ogawa; Suita Municipal Hospital, Y. Yoshida; Kinki Central Hospital of Mutual Aid Association of Public School Teachers, M. Yamamoto; Sumitomo Hospital, A. Yamada; Itami City Hospital, S. Tsutsui; Hyogo Prefectural Nishinomiya Hospital, S. Iio; and Saso Hospital, M. Nishiuchi. ==== Refs References Afdhal N , Zeuzem S , Kwo P , Chojkier M , Gitlin N , Puoti M , etal.; ION‐1 Investigators . Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection . N Engl J Med 2014 ;370 :1889 ‐1898 . 24725239 Afdhal N , Reddy KR , Nelson DR , Lawitz E , Gordon SC , Schiff E , etal.; ION‐2 Investigators . Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection . N Engl J Med 2014 ;370 :1483 ‐1493 . 24725238 Kowdley KV , Gordon SC , Reddy KR , Rossaro L , Bernstein DE , Lawitz E , etal.; ION‐3 Investigators . Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis . N Engl J Med 2014 ;370 :1879 ‐1888 . 24720702 Mizokami M , Yokosuka O , Takehara T , Sakamoto N , Korenaga M , Mochizuki H , etal. Ledipasvir and sofosbuvir fixed‐dose combination with and without ribavirin for 12 weeks in treatment‐naive and previously treated Japanese patients with genotype 1 hepatitis C: an open‐label, randomised, phase 3 trial . Lancet Infect Dis 2015 ;15 :645 ‐653 . 25863559 Asahina Y , Izumi N , Hiromitsu K , Kurosaki M , Koike K , Suzuki F , etal. JSH Guidelines for the management of hepatitis C virus infection: a 2016 update for genotype 1 and 2 . Hepatol Res 2016 ;46 :129 ‐165 . 26876581 European Association for the Study of the Liver (EASL) . EASL recommendations on treatment of hepatitis C 2016 . JHepatol 2016 ;65 :146 ‐181 . 27085810 AASLD/IDSA HCV Guidance Panel . Hepatitis C guidance: AASLD‐IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus . Hepatology 2015 ;62 :932 ‐954 . 26111063 Dear Healthcare Provider letter: serious and life‐threating cases of symptomatic bradycardia as well as one case of fatal cardiac arrest reported with coadministration of amiodarone with either Harvoni® (ledipasvir and sofosbuvir fixed‐dose combination) or with Sovaldi® (sofosbuvir) in combination with another direct acting antivilar . Foster City, CA : Gilead Sciences, Inc. ; March 20, 2015 . Hagiwara S , Nishida N , Watanabe T , Sakurai T , Ida H , Minami Y , etal. Outcome of combination therapy with sofosbuvir and ledipasvir for chronic type C liver disease . Oncology 2017 ;92 (Suppl. 1 ):3 ‐9 . Bedossa P , Poynard T . An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group . Hepatology 1996 ;24 :289 ‐293 . 8690394 German P , Mathias A , Brainard D , Kearney BP . Clinical pharmacokinetics and pharmacodynamics of ledipasvir/sofosbuvir, a fixed‐dose combination tablet for the treatment of hepatitis C . Clin Pharmacokinet 2016 ;55 :1337 ‐1351 . 27193156 Moss AJ , Schwartz PJ , Crampton RS , Tzivoni D , Locati EH , MacCluer J , etal. The long QT syndrome. Prospective longitudinal study of 328 families . Circulation 1991 ;84 :1136 ‐1144 . 1884444 Schwartz PJ , Wolf S . QT interval prolongation as predictor of sudden death in patients with myocardial infarction . Circulation 1978 ;57 :1074 ‐1077 . 639227 Algra A , Tijssen JG , Roelandt JR , Pool J , Lubsen J . QTc prolongation measured by standard 12‐lead electrocardiography is an independent risk factor for sudden death due to cardiac arrest . Circulation 1991 ;83 :1888 ‐1894 . 2040041 Cox AJ , Azeem A , Yeboah J , Soliman EZ , Aggarwal SR , Bertoni AG , etal. Heart rate‐corrected QT interval is an independent predictor of all‐cause and cardiovascular mortality in individuals with type 2 diabetes: the Diabetes Heart Study . Diabetes Care 2014 ;37 :1454 ‐1461 . 24574343 Robbins J , Nelson JC , Rautaharju PM , Gottdiener JS . The association between the length of the QT interval and mortality in the Cardiovascular Health Study . Am J Med 2003 ;115 :689 ‐694 . 14693320 Schwartz PJ . Idiopathic long QT syndrome: progress and questions . Am Heart J 1985 ;109 :399 ‐411 . 3966369 Moss AJ . Prolonged QT‐interval syndromes . JAMA 1986 ;256 :2985 ‐2987 . 3773216 Roden DM . Drug‐induced prolongation of the QT interval . N Engl J Med 2004 ;350 :1013 ‐1022 . 14999113 Haverkamp W , Breithardt G , Camm AJ , Janse MJ , Rosen MR , Antzelevitch C , etal. The potential for QT prolongation and proarrhythmia by non‐antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology . Eur Heart J 2000 ;21 :1216 ‐1231 . 10924311 Morganroth J , Horowitz LN . Incidence of proarrhythmic effects from quinidine in the outpatient treatment of benign or potentially lethal ventricular arrhythmias . Am J Cardiol 1985 ;56 :585 ‐587 . 3901720 Yun J , Hwangbo E , Lee J , Chon CR , Kim PA , Jeong IH , etal. Analysis of an ECG record database reveals QT interval prolongation potential of famotidine in a large Korean population . Cardiovasc Toxicol 2015 ;15 :197 ‐202 . 25253561 Reinoehl J , Frankovich D , Machado C , Kawasaki R , Baga JJ , Pires LA , etal. Probucol‐associated tachyarrhythmic events and QT prolongation: importance of gender . Am Heart J 1996 ;131 :1184 ‐1191 . 8644599 European Association for Study of Liver; Asociacion Latinoamericana para el Estudio del Higado . EASL‐ALEH clinical practice guidelines: non‐invasive tests for evaluation of liver disease severity and prognosis . JHepatol 2015 ;63 :237 ‐264 . 25911335 Wai CT , Greenson JK , Fontana RJ , Kalbfleisch JD , Marrero JA , Conjeevaram HS , etal. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C . Hepatology 2003 ;38 :518 ‐526 . 12883497 Bernardi M , Calandra S , Colantoni A , Trevisani F , Raimondo ML , Sica G , etal. Q‐T interval prolongation in cirrhosis: prevalence, relationship with severity, and etiology of the disease and possible pathogenetic factors . Hepatology 1998 ;27 :28 ‐34 . 9425913 Ytting H , Henriksen JH , Fuglsang S , Bendtsen F , Moller S . Prolonged Q‐T(c) interval in mild portal hypertensive cirrhosis . JHepatol 2005 ;43 :637 ‐644 . 16083986 Zambruni A , Trevisani F , Caraceni P , Bernardi M . Cardiac electrophysiological abnormalities in patients with cirrhosis . JHepatol 2006 ;44 :994 ‐1002 . 16510203