Cause-Specific Mortality Following Sustained Virologic Response in hepatitis C patients Treated with Direct-Acting Antivirals: A Standardized Mortality Ratio Analysis

Cause-Specific Mortality Following Sustained Virologic Response in hepatitis C patients Treated with Direct-Acting Antivirals: A Standardized Mortality Ratio Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Cause-Specific Mortality Following Sustained Virologic Response in hepatitis C patients Treated with Direct-Acting Antivirals: A Standardized Mortality Ratio Analysis Seiichi Mawatari, Shiroh Tanoue, Kotaro Kumagai, Kohei Oda, Ai Toyodome, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7721910/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Nov, 2025 Read the published version in Scientific Reports → Version 1 posted 7 You are reading this latest preprint version Abstract Background Direct-acting antivirals (DAAs) achieve high sustained virologic response (SVR) rates in patients with hepatitis C virus (HCV) infection. However, the long-term prognosis and cause-specific mortality following SVR remain incompletely defined. Methods This study analyzed 1,753 HCV-infected patients without a history of hepatocellular carcinoma (HCC) treatment who achieved SVR with DAAs. Liver disease-related (LDR) and non-LDR mortality were assessed using age- and sex-adjusted standardized mortality ratios (SMR) compared with the general population. Results During a mean follow-up of 59.2 months, 122 patients died. The SMR for all-cause mortality was 1.050 ( p = 0.588). The SMR for LDR and non-LDR mortality were 7.819 (p < 0.001) and 0.566 (p < 0.001), respectively. The SMR for extrahepatic malignancy-related mortality was significantly lower at 0.593 (p = 0.013), whereas cardiovascular disease (CVD)–related mortality did not differ significantly at 0.884 (p = 0.554). These findings were consistent regardless of age, sex, presence of LC, diabetes, or chronic kidney disease. Conclusions Overall mortality after SVR in patients with HCV was comparable with that of the general population. Nevertheless, LDR mortality remained significantly elevated, whereas non-LDR and extrahepatic malignancy-related mortality were significantly reduced. These results underscore the importance of continued liver disease surveillance post-SVR, while CVD management should parallel that of the general population. Biological sciences/Cancer Health sciences/Diseases Health sciences/Gastroenterology Health sciences/Oncology HCV DAAs SVR SMR mortality cardiovascular disease Figures Figure 1 Figure 2 Introduction Infection with hepatitis C virus (HCV) causes chronic hepatitis and may progress to cirrhosis and hepatocellular carcinoma (HCC). HCV infection is a major public health concern and a leading cause of chronic liver disease, resulting in approximately 399,000 deaths annually 1 . The World Health Organization estimates that 58 million individuals are chronically infected and that 1.5 million new HCV infections occur annually (Updated recommendations on treatment of adolescents and children with chronic HCV infection, and HCV simplified service delivery and diagnostics) 1 . In recent years, direct-acting antivirals (DAAs) have achieved sustained virologic response (SVR) rates exceeding 95% 2,3 , although treatment failure still occurs in some patients 4 5 . Several studies have demonstrated that patients who achieve SVR experience a significantly reduced incidence of new HCC compared with those who do not 6 . However, males and patients with advanced fibrosis remain at higher risk of developing HCC 7 – 9 .Conversely, DAA therapy has shown high efficacy even among older adults and patients with liver cirrhosis (LC) 10 . Viral eradication through DAA treatment has also been associated with reduced all-cause mortality 11 – 13 . Despite these advances, limited evidence exists regarding long-term prognosis and cause-specific mortality following viral eradication, particularly in comparison with the general population. Therefore, this study aimed to clarify life expectancy and specific causes of death after achieving SVR with DAAs. Results Patients characteristics Baseline characteristics before DAA administration and at the end of treatment (EOT) are summarized in Table 1 . The mean age was 67.0 years; 712 patients (40.6%) were male, 370 patients (21.1%) had LC, and 294 patients (16.8%) had diabetes mellitus (DM). The mean follow-up period was 59.2 months. Table 1 Baseline characteristics Age, years 67.0 ± 11.1 Male, n (%) 712 (40.6) BMI, kg/m2 (n = 1409) 22.9 ± 3.5 Liver cirrhosis, (%) 370 (21.1) Prior DAA therapy, none/ experience 1,684/ 69 Genotype 1/ 2/ 1 + 2/ 3 1,350/ 401/ 1/ 1 Diabetes Mellitus, n (%) 294 (16.8) ・DCV + ASV/・SOF/LDV/・OBV/PTV/r/・SOF + RBV 361/ 506/ 110/ 200 ・GZR + EBR/・DCV/ASV/BCV/・GLE/PIB/・SOF/VEL 110/ 12/ 422/ 32 HCV-RNA, logIU/mL 6.0 ± 0.9 Observation period, months 59.2 ± 32.0 Platelet counts, ×104/µL 16.1 ± 6.2 Total bilirubin, mg/dL (n = 1750) 0.9 ± 0.5 AST, U/L 50 ± 35 ALT, U/L 50 ± 46 GGT, U/L (n = 1,753) 47 ± 58 Creatinine, mg/dL (n = 1,604) 1.0 ± 1.3 Albumin, g/dL (n = 1,712) 4.0 ± 0.4 Fib-4 index 3.78 ± 2.99 Hyaluronic acid, ng/mL (n = 1,614) 169.1 ± 288.0 AFP (Before), ng/mL (n = 1,731) 9.3 ± 29.9 ALT (EOT), non WNL 175 (10.0) Albumin (EOT), g/dL (n = 1,659) 4.1 ± 0.4 AFP (EOT), ng/mL (n = 1,612) 4.8 ± 11.2 Mean ± Standard deviation BMI, body mass index; DAA, direct-acting antivirals; DCV, daclatasvir; ASV, asunaprevir; SOF, sofosbuvir; LDV, ledipasvir; OBV, ombitasvir; PTV, paritaprevir; r, ritonavir; RBV, ribavirin; GZR, grazoprevir; EBR, elbasvir; BCV, beclabuvir; GLE, glecaprevir; PIB, pibrentasvir; VEL, velpatasvir, AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, γ-glutamyltransferase; AFP, alpha-fetoprotein; EOT, end of treatment Development of HCC and cause of death During the course of the study, 108 patients developed HCC, and 122 patients died. A detailed breakdown of causes of death is shown in Table 2 . Among 34 LDR deaths, 21 were due to HCC, four to intrahepatic cholangiocarcinoma, four to liver failure, two to variceal bleeding, one to cystadenocarcinoma, and one to an unknown cause. Other causes of death included CVD in 23 patients (13 cardiovascular, 10 cerebrovascular), gastrointestinal disease in 13, and respiratory disease in nine. Malignancy accounted for 48 deaths, of which 22 were due to extrahepatic cancers. Table 2 Causes of death Organs diseases Number of death Liver Hepatocellular carcinoma 21 n = 34 Intrahepatic cholangiocarcinoma 4 Liver failure 4 Varix 2 Cystadenocarcinoma 1 Unknown 1 Cardiovascular Cerebral hemorrhage 8 n = 23 Heart failure 7 Cardiac infarction 4 Cerebral infarction 2 Pulmonary hypertension 1 Pulmonary embolism 1 Digestive Pancreas carcinoma (IPMN) 5 (1) n = 13 Intra-abdominal hemorrhage 3 Colo-rectal cancer 2 Perforated digestive tract 1 Cholangiocarcinoma 1 Gastric cancer 1 Respiratory Infectious Pneumonia 3 N = 9 Lung Cancer 3 Interstitial pneumonia 2 Respiratory failure 1 Oral cavity Carcinoma of tongue 1 (n = 2) Gingival carcinoma 1 Blood Myelodysplastic syndrome 1 (n = 2) Leukemia 1 Renal, urinary tract Renal failure 2 (n = 3) Bladder cancer 1 Infection Sepsis 1 (n = 2) Infection 1 Mammary gland Breast cancer 1 (n = 2) Extramammary Paget's disease 1 Uterus (n = 1) Cancer of the uterine body 1 Primary undetermined Cancer of unknown primary origin 2 Multiple organ failure 1 Heatstroke 1 Accident 2 Unknown 25 IPMN, intraductal papillary mucinous neoplasm Mortality rate and factors associated with mortality Overall mortality rates were 3.3%, 6.2%, and 10.1% at 3, 5, and 7 years, respectively (Fig. 2a). LDR and non-LDR mortality rates were 0.4% and 1.9% at 3 years, 1.5% and 3.5% at 5 years, and 3.3% and 5.1% at 7 years, respectively (Fig. 2b, 2c). Multivariate analysis identified age, male sex, cirrhosis, creatinine, and albumin level at the EOT as factors associated with overall mortality (Table 3 ). LDR mortality was associated with age, male sex, albumin level, total bilirubin, and alpha-fetoprotein (AFP) level at EOT (Table 3 ). Non-LDR mortality was associated with age, male sex, creatinine, and baseline albumin level (Table 3 ). Table 3 Factors associated with cause of death All (n = 1,419) Hazard Ratio 95%CI P value Age 1.084 1.057–1.112 < 0.001 Male 2.314 1.538–3.481 < 0.001 Presence of liver cirrhosis 2.150 1.384–3.338 0.001 Creatinine 1.131 1.013–1.263 0.029 EOT-Albumin 0.515 0.311–0.852 0.010 ALT 0.993 0.985–1.000 0.062 Liver disease-related death (n = 1297) Age 1.086 1.031–1.144 0.002 Male 2.121 0.942–4.776 0.069 EOT-albumin 0.122 0.050–0.300 < 0.001 Total-bilirubin 2.371 1.518–3.702 < 0.001 EOT-AFP 1.018 1.004–1.031 0.01 Non-liver disease-related death (n = 1397) Age 1.091 1.055–1.128 < 0.001 Male 2.157 1.228–3.788 0.007 Creatinine 1.207 1.066–1.367 0.003 Albumin before therapy 0.412 0.222–0.763 0.005 Presence of diabetes mellitus 1.668 0.915–3.039 0.095 CI: confidence interval; EOT: end of treatment SMR for all-cause and each cause of death Standardized mortality ratios (SMRs) for this cohort are shown in Table 4 . The SMR for all-cause mortality was 1.050 (95% confidence interval (CI): 0.872–1.254), not significantly different from that of the general population (p = 0.588). Stratification by age, sex, and presence of cirrhosis demonstrated no significant differences for age or sex (Supplementary Table 1). However, the SMR was significantly lower in patients without LC at 0.762 (95% CI: 0.594–0.963, p = 0.023), and significantly higher in patients with LC at 2.139 (95% CI: 1.598–2.805, p < 0.001) and in those with DM at 1.451 (95% CI: 0.993–2.049, p = 0.034) (Supplementary Table 1). Table 4 Standardized mortality ratio for all-cause mortality and each cause of death The sum of observation periods (person years) Observed deaths (n) Expected deaths (n) SMR 95%CI P value All-cause mortality 8,683.3 122 116.2 1.050 0.872–1.254 0.588 LDR death 8,592.7 34 4.3 7.819 5.415–10.926 < 0.001 Non-LDR death 8,592.7 62 109.6 0.566 0.434–0.725 < 0.001 Malignancy death 8,592.7 48 39.4 1.219 0.899–1.616 0.169 Hepatic malignancy death 8,592.7 26 2.2 11.612 7.586–17.015 < 0.001 Extrahepatic malignancy death 8,592.7 22 37.1 0.593 0.371–0.897 0.013 Cardiovascular death 8,592.7 23 26.0 0.884 0.560–1.326 0.554 CI, confidence interval; LDR, liver disease-related; SMR, standardized mortality ratio Further comparisons of SMRs stratified by age and sex revealed that in patients without LC, the SMR was significantly lower among those without DM at 0.692 (95% CI: 0.517–0.908, p = 0.008) (Supplementary Table 1). No significant differences in SMR were observed by age, sex, presence of DM, or chronic kidney disease (CKD) stage. In contrast, in patients with LC, SMRs were significantly elevated regardless of age, sex, DM status, or CKD stage (Supplementary Table 1). SMR for cause-specific mortality Cause-specific SMRs were calculated among individuals with confirmed causes of death (Table 4 ). The SMR for LDR-related mortality was markedly elevated at 7.819 (95% CI 5.415–10.926, p < 0.001). Stratified analyses by age, sex, liver cirrhosis, DM, and CKD stage demonstrated consistently high SMRs across all subgroups (Supplementary Table 2). In contrast, the SMR for non-LDR-related deaths was significantly lower at 0.566 (95% CI 0.434–0.725, p < 0.001) (Supplementary Table 2). Stratified analyses by age, sex, and non-cirrhotic status also showed significantly lower SMRs, whereas among individuals with cirrhosis, DM, or CKD stage ≥ 3, no significant differences were observed (Supplementary Table 2). The SMR for malignancy-related deaths was 1.219, revealing no significant difference overall (95% CI 0.899–1.616, p = 0.169) (Table 4 ). Stratified analyses based on presence of cirrhosis and DM yielded significantly higher SMRs at 2.476 (95% CI 1.512–3.823, p < 0.001) and 1.733 (95% CI 0.923–2.984, p = 0.045), respectively (Supplementary Table 2). However, stratified analyses based on age, sex, absence of cirrhosis, absence of DM, and CKD stage status revealed no significant differences (Supplementary Table 2). The SMR for deaths due to hepatic malignancies was strikingly elevated at 11.612 (95% CI 7.586–17.015, p < 0.001) (Table 4 ), remaining significantly higher across all strata of age, sex, cirrhosis, DM, and CKD status (Supplementary Table 2). Conversely, the SMR for deaths due to extrahepatic malignancies was significantly reduced at 0.593 (95% CI 0.371–0.897, p = 0.013) (Table 4 ). This reduction was particularly evident among individuals aged ≥ 75 years (0.529, 95% CI 0.254–0.972, p = 0.040), males (0.520, 95% CI 0.250–0.957, p = 0.036), those without cirrhosis (0.508, 95% CI 0.285–0.839, p = 0.008), those without DM (0.465, 95% CI 0.254–0.781, p = 0.003), and those with CKD stage < 3 (0.536, 95% CI 0.286–0.917, p = 0.022) (Supplementary Table 2). The SMR for cardiovascular disease (CVD) mortality was 0.884 (95% CI 0.560–1.326, p = 0.554) (Table 4 ). Stratified analyses by age, sex, cirrhosis, DM, and CKD stage revealed no significant differences (Supplementary Table 2). Discussion Regarding prognosis after achieving SVR for HCV, several studies have reported reductions in all-cause, LDR, and non-LDR mortality compared with non-SVR patients 14 , 15 . In the present cohort, however, liver disease remained the leading cause of death, accounting for 34 cases (31.5%), with HCC comprising 21 cases. Multivariate analysis demonstrated that LDR mortality was associated with age, male sex, albumin, bilirubin, and EOT-AFP, consistent with previously reported HCC risk factors 7 , 16 , 17 . Elevated SMRs for LDR deaths were observed even among patients without LC, DM, or CKD (Table 4 ). These findings underscore the importance of ongoing surveillance for liver disease, as recommended by current clinical guidelines 18 . Most deaths in this cohort were due to non-LDR causes. Multivariate analysis identified creatinine as a predictor of non-LDR mortality, suggesting an association with lifestyle-related conditions. Few studies have evaluated cause-specific mortality due to extrahepatic malignancies or CVD in patients with SVR compared with the general population. Notably, the SMR for non-LDR deaths, particularly extrahepatic malignancies, was significantly lower. This reduction may reflect early detection through routine medical follow-up. In contrast, the SMR for CVD mortality did not differ from that of the general population, regardless of age, sex, cirrhosis, or DM status, suggesting that CVD should be monitored in the same manner as in the general population. In Japan, Miuma et al. reported that in patients with DAA-induced SVR, malignant neoplasms excluding HCC were the predominant cause of death, accounting for 36.3% of deaths in cohort A and 44.4% in cohort B. However, the SMR was 0.96 for those without advanced fibrosis or cirrhosis and 0.92 for those with advanced fibrosis or LC 19 . The differences compared with the present study may reflect higher mortality, differing patient backgrounds, and a longer observation period. In our cohort, LDR deaths were more frequent among individuals with cirrhosis, while deaths unrelated to liver disease occurred at similar rates. Obi et al. analyzed 651 patients who achieved SVR across Japan (median follow-up, 5.44 years) and reported survival rates of 99.3% at 1 year, 96.5% at 3 years, and 94.4% at 5 years, with age- and sex-adjusted SMRs comparable to those of the general Japanese population 20 .They also noted that malignancies of other organs occurred as frequently as HCC 20 , although comparisons with the general population were not reported. Calvaruso et al. assessed cardiovascular outcomes after SVR in 4,307 patients and found improved hepatic and cardiovascular survival among those treated with DAAs 21 . In that study, SVR, CKD stage ≥ 3, and DM were significantly associated with CVD mortality 21 . Several prior investigations and meta-analyses suggest that HCV infection increases CVD risk, particularly among individuals with pre-existing conditions such as DM and hypertension 22 . In contrast, the present study compared SVR patients with the general population and found no excess CVD mortality, even among those with cirrhosis or CKD. These findings indicate that achieving SVR reduces CVD risk to levels similar to the general population, supporting the need for routine CVD follow-up consistent with standard practice. This study has several limitations. First, the cause of death was unknown for some non-LDR patients. Second, the number of patients and the follow-up period remain insufficient to fully evaluate long-term mortality. Larger cohorts with extended follow-up are necessary for more definitive analysis. Third, data on lifestyle-related diseases other than DM, such as hypertension and dyslipidemia, were not collected. Nonetheless, because CVD SMRs were comparable to the general population, careful monitoring of CVD remains warranted after HCV-SVR. In conclusion, compared with the general population, all-cause mortality in patients with HCV-SVR was similar, whereas LDR mortality was significantly elevated. Conversely, non-LDR mortality and deaths due to extrahepatic malignancies were reduced, while CVD mortality was comparable. These results highlight the continued importance of liver disease management after SVR, along with standard CVD monitoring. Material and Methods Data collection This observational study was conducted at 21 facilities of the Kagoshima Liver Study Group in Japan. The enrollment of the study population is presented in Fig. 1. Of 1,790 patients without a history of HCC who achieved SVR following DAA therapy between October 2014 and May 2024, 1,753 patients were included. Patients with hepatitis B virus (HBV) co-infection or who developed cancer before completion of DAA therapy were excluded. Patients with hypovascular tumors were also excluded because such lesions frequently progress to HCC despite HCV eradication with DAA therapy 23 , 24 . Written informed consent was obtained from all enrolled patients. Data regarding survival status, cause of death, and mortality were collected from medical records. The study protocol adhered to the ethical principles of the Declaration of Helsinki and was approved by the Kagoshima University Hospital Clinical Research Ethics Committee and the ethics committees of all participating institutions (approval numbers: 150138, 170199, 190297). HCV RNA levels were measured by TaqMan polymerase chain reaction (PCR), which has a lower quantitation limit of 1.2 log IU/mL. Liver cirrhosis (LC) was diagnosed by hepatologists at each facility based on platelet count, imaging, fibrosis markers, transient elastography, or the presence of varices. DM was defined as treatment with antidiabetic medications, fasting blood glucose level ≥ 126 mg/dL, and/or hemoglobin A1c concentration ≥ 6.5%. Non–liver disease–related (LDR) deaths were defined as deaths from causes other than liver disease when the cause was confirmed; accidental deaths were excluded. Cardiovascular disease (CVD) deaths were classified according to Japanese guidelines and included coronary heart disease, aortic disease, and cerebrovascular disease. Chronic kidney disease (CKD) stage was determined based on glomerular filtration rate (GFR). Treatment protocol The treatment regimens included daclatasvir (DCV) plus asunaprevir (ASV) for 24 weeks; sofosbuvir (SOF) plus ledipasvir (LDV) for 12 weeks; ombitasvir (OBV), paritaprevir (PTV), and ritonavir (r) for 12 weeks; SOF plus ribavirin (RBV) for 12 weeks; elbasvir (EBR) plus grazoprevir (GZR) for 12 weeks; DCV, ASV, and beclabuvir (BCV) for 12 weeks; glecaprevir (GLE) plus pibrentasvir (PIB) for 8 or 12 weeks; and SOF plus velpatasvir (VEL) for 12 weeks. All treatments were administered according to the Japanese guidelines for chronic HCV infection 25 . The observation period commenced at the EOT. Statistical analyses Analyses were conducted using IBM SPSS Statistics software (version 22; IBM, Armonk, NY, USA). Categorical variables were compared using the chi-squared test or Fisher’s exact test, as appropriate. Continuous variables were analyzed with the Mann–Whitney U test or the Kruskal–Wallis test. Mortality was assessed using the Kaplan–Meier method and compared using the log-rank test. Factors associated with mortality were examined with a Cox proportional hazards model using forward selection with p < 0.10 as the inclusion threshold. Covariates included age, sex, presence of LC, presence of DM, history of DAA therapy, pre-treatment laboratory values (platelet count, total bilirubin, alanine aminotransferase [ALT], γ-glutamyl transpeptidase [γ-GTP], creatinine, albumin, AFP, hyaluronic acid, and FIB-4 index), and albumin, AFP, and ALT levels at EOT. Mortality rates adjusted for sex and age, were compared with those of the general Japanese population using SMRs. The SMR was calculated as the ratio of observed to expected deaths, where expected deaths were obtained by multiplying person-years at risk in each stratum by the corresponding mortality rate of the reference population and summing across all strata. Population data on age group, sex, mortality, and cause of death were derived from the 2023 Population Survey Report of the Ministry of Health, Labour, and Welfare (eSTAT; Supplementary Table) 26 . The 95% confidence intervals (CIs) were calculated based on observed and expected deaths. Declarations Author Contribution SM and ST contributed to the study conceptualization and design. Data collection was performed by all authors, and analysis was performed by SM and ST. The first draft of the manuscript was written by SM. All authors commented on previous versions of the manuscript and approved the final manuscript. Acknowledgement The present study was carried out in the following 21 facilities (Kagoshima liver study group): Kagoshima University Hospital, Kirishima Medical Center, Miyazaki Medical Center Hospital, Kagoshima Kouseiren Hospital, Kagoshima City Hospital, Saiseikai Sendai Hospital, Kohshinkai Ogura Hospital, Ikeda Hospital, Izumi General Medical Center, Oshima Hospital, Ibusuki Medical Center, Southern Region Hospital, Tanegashima Medical Center, Fujimoto General Hospital, Hirono Clinic, Kagoshima Teishin Hospital, Satsunan Hospital, Nagaki Clinic, Hayatonomori clinic, Nakayama clinic, and Dr. NAKANISHI’s office. We thank the following investigators: Ms. Yuko Morinaga, Ms. Hiromi Eguchi, and Ms. Eriko Koreeda for their technical assistance and data management. This work was partially supported by a Japan Agency for Medical Research and Development (JP25fk0210174).We would like to thank Editage (www.editage.jp) for English language editing Data Availability The data supporting the findings of this study are available from the corresponding author upon reasonable request. References World Health Organization. Hepatitis C fact Sheet World Health Organization 2025 , < https://www.who.int/en/news-room/fact-sheets/detail/hepatitis-c (. Bhattacharya, D., Aronsohn, A., Price, J., Lo Re, V. & Hepatitis, C. Guidance 2023 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Clin Infect. Dis , (2023). EASL recommendations on treatment of hepatitis C. Final update of the series(☆). J. Hepatol. 73 , 1170–1218 (2020). Mawatari, S. et al. Viral and host factors are associated with retreatment failure in hepatitis C patients receiving all-oral direct antiviral therapy. Hepatol. Res. 50 , 453–465 (2020). Toyodome, A. et al. Analysis of the susceptibility of refractory hepatitis C virus resistant to nonstructural 5A inhibitors. Sci. Rep. 14 , 16363 (2024). Ioannou, G. N., Green, P. K. & Berry, K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. J. Hepatol. 68 , 25–32 (2018). Nahon, P. et al. Incidence of Hepatocellular Carcinoma After Direct Antiviral Therapy for HCV in Patients With Cirrhosis Included in Surveillance Programs. Gastroenterology 155 (.e1436), 1436–1450 (2018). Hiramatsu, N., Oze, T. & Takehara, T. Suppression of hepatocellular carcinoma development in hepatitis C patients given interferon-based antiviral therapy. Hepatol. Res. 45 , 152–161 (2015). Mawatari, S. et al. Features of patients who developed hepatocellular carcinoma after direct-acting antiviral treatment for hepatitis C Virus. PLoS One . 17 , e0262267 (2022). Toyoda, H. et al. Trends and Efficacy of Interferon-Free Anti-hepatitis C Virus Therapy in the Region of High Prevalence of Elderly Patients, Cirrhosis, and Hepatocellular Carcinoma: A Real-World, Nationwide, Multicenter Study of 10 688 Patients in Japan. Open. Forum Infect. Dis. 6 , ofz185 (2019). Backus, L. I., Belperio, P. S., Shahoumian, T. A. & Mole, L. A. Impact of sustained virologic response with direct-acting antiviral treatment on mortality in patients with advanced liver disease. Hepatology , (2017). Backus, L. I., Belperio, P. S., Shahoumian, T. A. & Mole, L. A. Direct-acting antiviral sustained virologic response: Impact on mortality in patients without advanced liver disease. Hepatology 68 , 827–838 (2018). Tada, T. et al. Viral eradication reduces all-cause mortality in patients with chronic hepatitis C virus infection who had received direct-acting antiviral therapy. Liver international: official J. Int. Association Study Liver . 44 , 3060–3071 (2024). Simmons, B., Saleem, J., Heath, K., Cooke, G. S. & Hill, A. Long-Term Treatment Outcomes of Patients Infected With Hepatitis C Virus: A Systematic Review and Meta-analysis of the Survival Benefit of Achieving a Sustained Virological Response. Clin. Infect. Dis. 61 , 730–740 (2015). Nahon, P. et al. Eradication of Hepatitis C Virus Infection in Patients With Cirrhosis Reduces Risk of Liver and Non-Liver Complications. Gastroenterology 152 (.e142), 142–156 (2017). Ioannou, G. N. et al. Development of models estimating the risk of hepatocellular carcinoma after antiviral treatment for hepatitis C. J. Hepatol. 69 , 1088–1098 (2018). Yamada, R. et al. Incidence and risk factors of hepatocellular carcinoma change over time in patients with hepatitis C virus infection who achieved sustained virologic response. Hepatol. Res. 49 , 570–578 (2019). Reiberger, T. et al. EASL position paper on clinical follow-up after HCV cure. J. Hepatol. 81 , 326–344 (2024). Miuma, S. et al. Non-liver-related mortality in the DAA era: Insights from post-SVR patients with and without previous HCC history. J. Med. Virol. 96 , e29432 (2024). Obi, S. et al. The incidence of all organ malignancies and overall survival of patient with sustained virological response of HCV-comparable to SMR (standardized mortality ratio) of Japan general population. Hep. Intl. 17 , 562–572 (2023). Calvaruso, V. et al. Liver and cardiovascular mortality after hepatitis C virus eradication by DAA: Data from RESIST-HCV cohort. J. Viral Hepatitis . 28 , 1190–1199 (2021). Petta, S. et al. Hepatitis C Virus Infection Is Associated With Increased Cardiovascular Mortality: A Meta-Analysis of Observational Studies. Gastroenterology 150 , 145–155 (2016). e144; quiz e115-146. Toyoda, H. et al. The impact of HCV eradication by direct-acting antivirals on the transition of precancerous hepatic nodules to HCC: A prospective observational study. Liver international: official J. Int. Association Study Liver . 39 , 448–454 (2019). Tabu, K. et al. Hypovascular tumors developed into hepatocellular carcinoma at a high rate despite the elimination of hepatitis C virus by direct-acting antivirals. PLoS One . 15 , e0237475 (2020). Guidelines for the Management of Hepatitis C Virus Infection , < http://www.jsh.or.jp/medical/guidelines/jsh_guidlines/hepatitis_c. (. Statistics of Japan, e-Stat is a portal site for Japanese Government Statistics. , https://www.e-stat.go.jp/en (. Additional Declarations No competing interests reported. Supplementary Files suppletable.docx suppletable3.xlsx Cite Share Download PDF Status: Published Journal Publication published 27 Nov, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 24 Oct, 2025 Reviews received at journal 17 Oct, 2025 Reviewers agreed at journal 16 Oct, 2025 Reviewers invited by journal 14 Oct, 2025 Editor assigned by journal 30 Sep, 2025 Submission checks completed at journal 30 Sep, 2025 First submitted to journal 26 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7721910","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":534499955,"identity":"58201b80-49cf-4f18-bbe8-e58c9940e2db","order_by":0,"name":"Seiichi Mawatari","email":"data:image/png;base64,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","orcid":"","institution":"Kagoshima University Graduate School of Medical and Dental Sciences","correspondingAuthor":true,"prefix":"","firstName":"Seiichi","middleName":"","lastName":"Mawatari","suffix":""},{"id":534499956,"identity":"3e7ed430-15e1-438c-8296-9716c629eeef","order_by":1,"name":"Shiroh Tanoue","email":"","orcid":"","institution":"Kagoshima University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Shiroh","middleName":"","lastName":"Tanoue","suffix":""},{"id":534499957,"identity":"7b60eb6c-2b71-46ac-8d5d-0b794914af28","order_by":2,"name":"Kotaro Kumagai","email":"","orcid":"","institution":"Kagoshima University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Kotaro","middleName":"","lastName":"Kumagai","suffix":""},{"id":534499958,"identity":"d5d3a51c-cf40-43c4-9b7a-81950726b2d4","order_by":3,"name":"Kohei Oda","email":"","orcid":"","institution":"Kagoshima University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Kohei","middleName":"","lastName":"Oda","suffix":""},{"id":534499959,"identity":"0e59eeec-bf5b-48f7-85fd-83f5e059111a","order_by":4,"name":"Ai Toyodome","email":"","orcid":"","institution":"Kagoshima University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ai","middleName":"","lastName":"Toyodome","suffix":""},{"id":534499960,"identity":"2308a3c6-a81e-4110-b009-d51b34aca947","order_by":5,"name":"Haruka Sakae","email":"","orcid":"","institution":"Kagoshima University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Haruka","middleName":"","lastName":"Sakae","suffix":""},{"id":534499961,"identity":"b3a854c3-36ce-43f6-855a-ae1d3f60efe9","order_by":6,"name":"Kunio Fujisaki","email":"","orcid":"","institution":"Kirishima Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kunio","middleName":"","lastName":"Fujisaki","suffix":""},{"id":534499962,"identity":"b913d8a1-57a3-40fa-bb8e-012736e6d62c","order_by":7,"name":"Yukiko Inada","email":"","orcid":"","institution":"Miyazaki Medical Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yukiko","middleName":"","lastName":"Inada","suffix":""},{"id":534499963,"identity":"91aa10e7-e35e-4706-ab31-85f71e695fa0","order_by":8,"name":"Hirofumi Uto","email":"","orcid":"","institution":"Miyazaki Medical Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hirofumi","middleName":"","lastName":"Uto","suffix":""},{"id":534499964,"identity":"72699155-917c-4d5e-b6cf-ca16dfa624a0","order_by":9,"name":"Akiko Saisyoji","email":"","orcid":"","institution":"Kagoshima University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Akiko","middleName":"","lastName":"Saisyoji","suffix":""},{"id":534499965,"identity":"3266796b-d31f-462e-bf48-c9d6283ad41b","order_by":10,"name":"Yasunari Hiramine","email":"","orcid":"","institution":"Kagoshima Kouseiren Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yasunari","middleName":"","lastName":"Hiramine","suffix":""},{"id":534499966,"identity":"349307cc-888a-4a4d-8df6-cd9b19178fff","order_by":11,"name":"Kazuaki Tabu","email":"","orcid":"","institution":"Kagoshima University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Kazuaki","middleName":"","lastName":"Tabu","suffix":""},{"id":534499967,"identity":"db699383-938d-40af-b9c8-513a1fab5e95","order_by":12,"name":"Sho Ijuin","email":"","orcid":"","institution":"Kagoshima University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Sho","middleName":"","lastName":"Ijuin","suffix":""},{"id":534499968,"identity":"cbbbc111-74a3-4164-a60d-a1e7396ac9f6","order_by":13,"name":"Takeshi Hori","email":"","orcid":"","institution":"Kagoshima City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Hori","suffix":""},{"id":534499969,"identity":"d8000be9-6ed6-46a3-9d55-0f94600bcbf4","order_by":14,"name":"Tsutomu Tamai","email":"","orcid":"","institution":"Kagoshima University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Tsutomu","middleName":"","lastName":"Tamai","suffix":""},{"id":534499970,"identity":"460f2cf5-b0e7-4a04-bcbb-1b9ea2112fd2","order_by":15,"name":"Akihiro Moriuchi","email":"","orcid":"","institution":"Kagoshima University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Akihiro","middleName":"","lastName":"Moriuchi","suffix":""},{"id":534499971,"identity":"3e83c2e4-f9bc-4718-a66b-768d33a64eb4","order_by":16,"name":"Shuji Kanmura","email":"","orcid":"","institution":"Kagoshima University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Shuji","middleName":"","lastName":"Kanmura","suffix":""},{"id":534499972,"identity":"b40f1d56-2cd0-48b1-95f9-ffda3121ec50","order_by":17,"name":"Akio Ido","email":"","orcid":"","institution":"Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Akio","middleName":"","lastName":"Ido","suffix":""}],"badges":[],"createdAt":"2025-09-26 12:38:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7721910/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7721910/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-29972-6","type":"published","date":"2025-11-27T15:58:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":94623427,"identity":"02a2ab4f-f8f7-4f9f-9dbf-df7484b5bdcf","added_by":"auto","created_at":"2025-10-29 04:19:08","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":101438,"visible":true,"origin":"","legend":"","description":"","filename":"maintexttable20250930.docx","url":"https://assets-eu.researchsquare.com/files/rs-7721910/v1/9bcb9782d5dddf17d0653857.docx"},{"id":94623156,"identity":"1d178422-9300-4242-b6f8-d73064c2d6ba","added_by":"auto","created_at":"2025-10-29 04:18:55","extension":"json","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":17321,"visible":true,"origin":"","legend":"","description":"","filename":"3feaaf05fcd74111a089d01fbf897270.json","url":"https://assets-eu.researchsquare.com/files/rs-7721910/v1/ffa759c5754e030b8c3f4cfe.json"},{"id":94623195,"identity":"1002fe55-2cdb-4c17-b38f-8f9770da015d","added_by":"auto","created_at":"2025-10-29 04:19:00","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":17763,"visible":true,"origin":"","legend":"","description":"","filename":"suppletable3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7721910/v1/34df8fb65ab4eb4a7fee23ca.xlsx"},{"id":94623423,"identity":"0ee1a545-9429-4a2b-9764-2805798d37f0","added_by":"auto","created_at":"2025-10-29 04:19:08","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":42423,"visible":true,"origin":"","legend":"","description":"","filename":"suppletable.docx","url":"https://assets-eu.researchsquare.com/files/rs-7721910/v1/e56c94d9e693e4a1648516d0.docx"},{"id":94623287,"identity":"b3b65bd0-5c14-4912-8516-7a6e68498610","added_by":"auto","created_at":"2025-10-29 04:19:03","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97170,"visible":true,"origin":"","legend":"","description":"","filename":"3feaaf05fcd74111a089d01fbf8972701enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7721910/v1/38525a3a1f1e2862cd4781b6.xml"},{"id":94623136,"identity":"dff654ec-3bb8-4627-b3ce-bb361c6c17c2","added_by":"auto","created_at":"2025-10-29 04:18:53","extension":"pptx","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":103673,"visible":true,"origin":"","legend":"","description":"","filename":"figure12.pptx","url":"https://assets-eu.researchsquare.com/files/rs-7721910/v1/cf44f55a0cffc66aa7c3c65c.pptx"},{"id":94640557,"identity":"304f0bcf-ea8b-4955-9a5d-2190d55b27eb","added_by":"auto","created_at":"2025-10-29 07:49:50","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97174,"visible":true,"origin":"","legend":"","description":"","filename":"3feaaf05fcd74111a089d01fbf8972701structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7721910/v1/72a08b141ee7e8f29f62a948.xml"},{"id":94623150,"identity":"f430674f-4fb9-4221-8d7b-5974497c435d","added_by":"auto","created_at":"2025-10-29 04:18:55","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":107796,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7721910/v1/766c92faa9e52dd0b29073f1.html"},{"id":94623340,"identity":"7a0e9d48-35af-4f80-81e3-831a16747c22","added_by":"auto","created_at":"2025-10-29 04:19:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":29502,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-7721910/v1/2159de679dd0682bfb9aa590.png"},{"id":94623284,"identity":"53050c15-b919-4e16-a6c0-d33ef215c926","added_by":"auto","created_at":"2025-10-29 04:19:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":35046,"visible":true,"origin":"","legend":"\u003cp\u003eMortality rate. (a) overall mortality rate, (b) LDR mortality rate, (c) non-LDR mortality rate. LDR, liver-diseases related.\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-7721910/v1/765fe3848457a34c95cc4d9a.png"},{"id":97178457,"identity":"ed25bc9e-eae2-406c-9a42-2cdda053bdb5","added_by":"auto","created_at":"2025-12-01 16:10:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":970658,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7721910/v1/115317d1-d81c-4ef1-a789-583d9017c431.pdf"},{"id":94623221,"identity":"4c23da6c-38af-453b-ad3b-42897ebc24ff","added_by":"auto","created_at":"2025-10-29 04:19:01","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":42423,"visible":true,"origin":"","legend":"","description":"","filename":"suppletable.docx","url":"https://assets-eu.researchsquare.com/files/rs-7721910/v1/158c906058a8f06bf2073004.docx"},{"id":94623020,"identity":"66edbffa-225f-43b8-805a-77bcca3c8f18","added_by":"auto","created_at":"2025-10-29 04:18:44","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17763,"visible":true,"origin":"","legend":"","description":"","filename":"suppletable3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7721910/v1/875ff7afab71b792cbc0116a.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cause-Specific Mortality Following Sustained Virologic Response in hepatitis C patients Treated with Direct-Acting Antivirals: A Standardized Mortality Ratio Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInfection with hepatitis C virus (HCV) causes chronic hepatitis and may progress to cirrhosis and hepatocellular carcinoma (HCC). HCV infection is a major public health concern and a leading cause of chronic liver disease, resulting in approximately 399,000 deaths annually\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The World Health Organization estimates that 58\u0026nbsp;million individuals are chronically infected and that 1.5\u0026nbsp;million new HCV infections occur annually (Updated recommendations on treatment of adolescents and children with chronic HCV infection, and HCV simplified service delivery and diagnostics)\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. In recent years, direct-acting antivirals (DAAs) have achieved sustained virologic response (SVR) rates exceeding 95%\u003csup\u003e2,3\u003c/sup\u003e, although treatment failure still occurs in some patients\u003csup\u003e4 5\u003c/sup\u003e. Several studies have demonstrated that patients who achieve SVR experience a significantly reduced incidence of new HCC compared with those who do not\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. However, males and patients with advanced fibrosis remain at higher risk of developing HCC\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.Conversely, DAA therapy has shown high efficacy even among older adults and patients with liver cirrhosis (LC)\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Viral eradication through DAA treatment has also been associated with reduced all-cause mortality\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Despite these advances, limited evidence exists regarding long-term prognosis and cause-specific mortality following viral eradication, particularly in comparison with the general population. Therefore, this study aimed to clarify life expectancy and specific causes of death after achieving SVR with DAAs.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients characteristics\u003c/h2\u003e\u003cp\u003eBaseline characteristics before DAA administration and at the end of treatment (EOT) are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean age was 67.0 years; 712 patients (40.6%) were male, 370 patients (21.1%) had LC, and 294 patients (16.8%) had diabetes mellitus (DM). The mean follow-up period was 59.2 months.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e67.0\u0026thinsp;\u0026plusmn;\u0026thinsp;11.1\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e712 (40.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI, kg/m2 (n\u0026thinsp;=\u0026thinsp;1409)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiver cirrhosis, (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e370 (21.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrior DAA therapy, none/ experience\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,684/ 69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGenotype 1/ 2/ 1\u0026thinsp;+\u0026thinsp;2/ 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,350/ 401/ 1/ 1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes Mellitus, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e294 (16.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e・DCV\u0026thinsp;+\u0026thinsp;ASV/・SOF/LDV/・OBV/PTV/r/・SOF\u0026thinsp;+\u0026thinsp;RBV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e361/ 506/ 110/ 200\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e・GZR\u0026thinsp;+\u0026thinsp;EBR/・DCV/ASV/BCV/・GLE/PIB/・SOF/VEL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e110/ 12/ 422/ 32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHCV-RNA, logIU/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eObservation period, months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e59.2\u0026thinsp;\u0026plusmn;\u0026thinsp;32.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlatelet counts, \u0026times;104/\u0026micro;L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal bilirubin, mg/dL (n\u0026thinsp;=\u0026thinsp;1750)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.9\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAST, U/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50\u0026thinsp;\u0026plusmn;\u0026thinsp;35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eALT, U/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50\u0026thinsp;\u0026plusmn;\u0026thinsp;46\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGGT, U/L (n\u0026thinsp;=\u0026thinsp;1,753)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e47\u0026thinsp;\u0026plusmn;\u0026thinsp;58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCreatinine, mg/dL (n\u0026thinsp;=\u0026thinsp;1,604)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlbumin, g/dL (n\u0026thinsp;=\u0026thinsp;1,712)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFib-4 index\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.78\u0026thinsp;\u0026plusmn;\u0026thinsp;2.99\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHyaluronic acid, ng/mL (n\u0026thinsp;=\u0026thinsp;1,614)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e169.1\u0026thinsp;\u0026plusmn;\u0026thinsp;288.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAFP (Before), ng/mL (n\u0026thinsp;=\u0026thinsp;1,731)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.3\u0026thinsp;\u0026plusmn;\u0026thinsp;29.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eALT (EOT), non WNL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e175 (10.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlbumin (EOT), g/dL (n\u0026thinsp;=\u0026thinsp;1,659)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAFP (EOT), ng/mL (n\u0026thinsp;=\u0026thinsp;1,612)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.8\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;Standard deviation\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eBMI, body mass index; DAA, direct-acting antivirals; DCV, daclatasvir; ASV, asunaprevir; SOF, sofosbuvir; LDV, ledipasvir; OBV, ombitasvir; PTV, paritaprevir; r, ritonavir; RBV, ribavirin; GZR, grazoprevir; EBR, elbasvir; BCV, beclabuvir; GLE, glecaprevir; PIB, pibrentasvir; VEL, velpatasvir, AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, γ-glutamyltransferase; AFP, alpha-fetoprotein; EOT, end of treatment\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDevelopment of HCC and cause of death\u003c/h3\u003e\n\u003cp\u003eDuring the course of the study, 108 patients developed HCC, and 122 patients died. A detailed breakdown of causes of death is shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Among 34 LDR deaths, 21 were due to HCC, four to intrahepatic cholangiocarcinoma, four to liver failure, two to variceal bleeding, one to cystadenocarcinoma, and one to an unknown cause. Other causes of death included CVD in 23 patients (13 cardiovascular, 10 cerebrovascular), gastrointestinal disease in 13, and respiratory disease in nine. Malignancy accounted for 48 deaths, of which 22 were due to extrahepatic cancers.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCauses of death\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrgans\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ediseases\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNumber of death\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiver\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHepatocellular carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIntrahepatic cholangiocarcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLiver failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVarix\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCystadenocarcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiovascular\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCerebral hemorrhage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHeart failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCardiac infarction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCerebral infarction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePulmonary hypertension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePulmonary embolism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDigestive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePancreas carcinoma (IPMN)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIntra-abdominal hemorrhage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eColo-rectal cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePerforated digestive tract\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCholangiocarcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGastric cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInfectious Pneumonia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLung Cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInterstitial pneumonia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRespiratory failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOral cavity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCarcinoma of tongue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGingival carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMyelodysplastic syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLeukemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal, urinary tract\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRenal failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBladder cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInfection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSepsis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInfection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMammary gland\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBreast cancer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExtramammary Paget's disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUterus (n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCancer of the uterine body\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrimary undetermined\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCancer of unknown primary origin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMultiple organ failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHeatstroke\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAccident\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"3\"\u003eIPMN, intraductal papillary mucinous neoplasm\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eMortality rate and factors associated with mortality\u003c/h3\u003e\n\u003cp\u003eOverall mortality rates were 3.3%, 6.2%, and 10.1% at 3, 5, and 7 years, respectively (Fig.\u0026nbsp;2a). LDR and non-LDR mortality rates were 0.4% and 1.9% at 3 years, 1.5% and 3.5% at 5 years, and 3.3% and 5.1% at 7 years, respectively (Fig.\u0026nbsp;2b, 2c). Multivariate analysis identified age, male sex, cirrhosis, creatinine, and albumin level at the EOT as factors associated with overall mortality (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). LDR mortality was associated with age, male sex, albumin level, total bilirubin, and alpha-fetoprotein (AFP) level at EOT (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Non-LDR mortality was associated with age, male sex, creatinine, and baseline albumin level (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eFactors associated with cause of death\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAll (n\u0026thinsp;=\u0026thinsp;1,419)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHazard Ratio\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95%CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.084\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.057\u0026ndash;1.112\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.314\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.538\u0026ndash;3.481\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePresence of liver cirrhosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.384\u0026ndash;3.338\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCreatinine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.131\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.013\u0026ndash;1.263\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.029\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEOT-Albumin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.515\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.311\u0026ndash;0.852\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.010\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eALT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.993\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.985\u0026ndash;1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.062\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eLiver disease-related death (n\u0026thinsp;=\u0026thinsp;1297)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.086\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.031\u0026ndash;1.144\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.121\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.942\u0026ndash;4.776\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.069\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEOT-albumin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.122\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.050\u0026ndash;0.300\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal-bilirubin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.371\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.518\u0026ndash;3.702\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEOT-AFP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.004\u0026ndash;1.031\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eNon-liver disease-related death (n\u0026thinsp;=\u0026thinsp;1397)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.091\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.055\u0026ndash;1.128\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.157\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.228\u0026ndash;3.788\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.007\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCreatinine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.207\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.066\u0026ndash;1.367\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlbumin before therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.412\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.222\u0026ndash;0.763\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePresence of diabetes mellitus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.668\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.915\u0026ndash;3.039\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.095\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eCI: confidence interval; EOT: end of treatment\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eSMR for all-cause and each cause of death\u003c/h3\u003e\n\u003cp\u003eStandardized mortality ratios (SMRs) for this cohort are shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The SMR for all-cause mortality was 1.050 (95% confidence interval (CI): 0.872\u0026ndash;1.254), not significantly different from that of the general population (p\u0026thinsp;=\u0026thinsp;0.588). Stratification by age, sex, and presence of cirrhosis demonstrated no significant differences for age or sex (Supplementary Table\u0026nbsp;1). However, the SMR was significantly lower in patients without LC at 0.762 (95% CI: 0.594\u0026ndash;0.963, p\u0026thinsp;=\u0026thinsp;0.023), and significantly higher in patients with LC at 2.139 (95% CI: 1.598\u0026ndash;2.805, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and in those with DM at 1.451 (95% CI: 0.993\u0026ndash;2.049, p\u0026thinsp;=\u0026thinsp;0.034) (Supplementary Table\u0026nbsp;1).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eStandardized mortality ratio for all-cause mortality and each cause of death\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eThe sum of observation periods (person years)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eObserved deaths\u003c/p\u003e\u003cp\u003e(n)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eExpected deaths (n)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSMR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e95%CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAll-cause mortality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8,683.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e122\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e116.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.050\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.872\u0026ndash;1.254\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.588\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLDR death\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8,592.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7.819\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e5.415\u0026ndash;10.926\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNon-LDR death\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8,592.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e109.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.566\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.434\u0026ndash;0.725\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMalignancy death\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8,592.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e39.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.219\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.899\u0026ndash;1.616\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.169\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatic malignancy death\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8,592.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e11.612\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e7.586\u0026ndash;17.015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExtrahepatic malignancy death\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8,592.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e37.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.593\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.371\u0026ndash;0.897\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.013\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiovascular death\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8,592.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e26.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.884\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.560\u0026ndash;1.326\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.554\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eCI, confidence interval; LDR, liver disease-related; SMR, standardized mortality ratio\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFurther comparisons of SMRs stratified by age and sex revealed that in patients without LC, the SMR was significantly lower among those without DM at 0.692 (95% CI: 0.517\u0026ndash;0.908, p\u0026thinsp;=\u0026thinsp;0.008) (Supplementary Table\u0026nbsp;1). No significant differences in SMR were observed by age, sex, presence of DM, or chronic kidney disease (CKD) stage. In contrast, in patients with LC, SMRs were significantly elevated regardless of age, sex, DM status, or CKD stage (Supplementary Table\u0026nbsp;1).\u003c/p\u003e\n\u003ch3\u003eSMR for cause-specific mortality\u003c/h3\u003e\n\u003cp\u003eCause-specific SMRs were calculated among individuals with confirmed causes of death (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The SMR for LDR-related mortality was markedly elevated at 7.819 (95% CI 5.415\u0026ndash;10.926, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Stratified analyses by age, sex, liver cirrhosis, DM, and CKD stage demonstrated consistently high SMRs across all subgroups (Supplementary Table\u0026nbsp;2). In contrast, the SMR for non-LDR-related deaths was significantly lower at 0.566 (95% CI 0.434\u0026ndash;0.725, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Supplementary Table\u0026nbsp;2). Stratified analyses by age, sex, and non-cirrhotic status also showed significantly lower SMRs, whereas among individuals with cirrhosis, DM, or CKD stage\u0026thinsp;\u0026ge;\u0026thinsp;3, no significant differences were observed (Supplementary Table\u0026nbsp;2).\u003c/p\u003e\u003cp\u003eThe SMR for malignancy-related deaths was 1.219, revealing no significant difference overall (95% CI 0.899\u0026ndash;1.616, p\u0026thinsp;=\u0026thinsp;0.169) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Stratified analyses based on presence of cirrhosis and DM yielded significantly higher SMRs at 2.476 (95% CI 1.512\u0026ndash;3.823, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 1.733 (95% CI 0.923\u0026ndash;2.984, p\u0026thinsp;=\u0026thinsp;0.045), respectively (Supplementary Table\u0026nbsp;2). However, stratified analyses based on age, sex, absence of cirrhosis, absence of DM, and CKD stage status revealed no significant differences (Supplementary Table\u0026nbsp;2).\u003c/p\u003e\u003cp\u003eThe SMR for deaths due to hepatic malignancies was strikingly elevated at 11.612 (95% CI 7.586\u0026ndash;17.015, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), remaining significantly higher across all strata of age, sex, cirrhosis, DM, and CKD status (Supplementary Table\u0026nbsp;2). Conversely, the SMR for deaths due to extrahepatic malignancies was significantly reduced at 0.593 (95% CI 0.371\u0026ndash;0.897, p\u0026thinsp;=\u0026thinsp;0.013) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). This reduction was particularly evident among individuals aged\u0026thinsp;\u0026ge;\u0026thinsp;75 years (0.529, 95% CI 0.254\u0026ndash;0.972, p\u0026thinsp;=\u0026thinsp;0.040), males (0.520, 95% CI 0.250\u0026ndash;0.957, p\u0026thinsp;=\u0026thinsp;0.036), those without cirrhosis (0.508, 95% CI 0.285\u0026ndash;0.839, p\u0026thinsp;=\u0026thinsp;0.008), those without DM (0.465, 95% CI 0.254\u0026ndash;0.781, p\u0026thinsp;=\u0026thinsp;0.003), and those with CKD stage\u0026thinsp;\u0026lt;\u0026thinsp;3 (0.536, 95% CI 0.286\u0026ndash;0.917, p\u0026thinsp;=\u0026thinsp;0.022) (Supplementary Table\u0026nbsp;2).\u003c/p\u003e\u003cp\u003eThe SMR for cardiovascular disease (CVD) mortality was 0.884 (95% CI 0.560\u0026ndash;1.326, p\u0026thinsp;=\u0026thinsp;0.554) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Stratified analyses by age, sex, cirrhosis, DM, and CKD stage revealed no significant differences (Supplementary Table\u0026nbsp;2).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRegarding prognosis after achieving SVR for HCV, several studies have reported reductions in all-cause, LDR, and non-LDR mortality compared with non-SVR patients \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. In the present cohort, however, liver disease remained the leading cause of death, accounting for 34 cases (31.5%), with HCC comprising 21 cases. Multivariate analysis demonstrated that LDR mortality was associated with age, male sex, albumin, bilirubin, and EOT-AFP, consistent with previously reported HCC risk factors \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Elevated SMRs for LDR deaths were observed even among patients without LC, DM, or CKD (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). These findings underscore the importance of ongoing surveillance for liver disease, as recommended by current clinical guidelines \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eMost deaths in this cohort were due to non-LDR causes. Multivariate analysis identified creatinine as a predictor of non-LDR mortality, suggesting an association with lifestyle-related conditions. Few studies have evaluated cause-specific mortality due to extrahepatic malignancies or CVD in patients with SVR compared with the general population. Notably, the SMR for non-LDR deaths, particularly extrahepatic malignancies, was significantly lower. This reduction may reflect early detection through routine medical follow-up. In contrast, the SMR for CVD mortality did not differ from that of the general population, regardless of age, sex, cirrhosis, or DM status, suggesting that CVD should be monitored in the same manner as in the general population.\u003c/p\u003e\u003cp\u003eIn Japan, Miuma et al. reported that in patients with DAA-induced SVR, malignant neoplasms excluding HCC were the predominant cause of death, accounting for 36.3% of deaths in cohort A and 44.4% in cohort B. However, the SMR was 0.96 for those without advanced fibrosis or cirrhosis and 0.92 for those with advanced fibrosis or LC \u003csup\u003e19\u003c/sup\u003e. The differences compared with the present study may reflect higher mortality, differing patient backgrounds, and a longer observation period. In our cohort, LDR deaths were more frequent among individuals with cirrhosis, while deaths unrelated to liver disease occurred at similar rates.\u003c/p\u003e\u003cp\u003eObi et al. analyzed 651 patients who achieved SVR across Japan (median follow-up, 5.44 years) and reported survival rates of 99.3% at 1 year, 96.5% at 3 years, and 94.4% at 5 years, with age- and sex-adjusted SMRs comparable to those of the general Japanese population \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e.They also noted that malignancies of other organs occurred as frequently as HCC\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, although comparisons with the general population were not reported.\u003c/p\u003e\u003cp\u003eCalvaruso et al. assessed cardiovascular outcomes after SVR in 4,307 patients and found improved hepatic and cardiovascular survival among those treated with DAAs \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. In that study, SVR, CKD stage\u0026thinsp;\u0026ge;\u0026thinsp;3, and DM were significantly associated with CVD mortality \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Several prior investigations and meta-analyses suggest that HCV infection increases CVD risk, particularly among individuals with pre-existing conditions such as DM and hypertension \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. In contrast, the present study compared SVR patients with the general population and found no excess CVD mortality, even among those with cirrhosis or CKD. These findings indicate that achieving SVR reduces CVD risk to levels similar to the general population, supporting the need for routine CVD follow-up consistent with standard practice.\u003c/p\u003e\u003cp\u003eThis study has several limitations. First, the cause of death was unknown for some non-LDR patients. Second, the number of patients and the follow-up period remain insufficient to fully evaluate long-term mortality. Larger cohorts with extended follow-up are necessary for more definitive analysis. Third, data on lifestyle-related diseases other than DM, such as hypertension and dyslipidemia, were not collected. Nonetheless, because CVD SMRs were comparable to the general population, careful monitoring of CVD remains warranted after HCV-SVR.\u003c/p\u003e\u003cp\u003eIn conclusion, compared with the general population, all-cause mortality in patients with HCV-SVR was similar, whereas LDR mortality was significantly elevated. Conversely, non-LDR mortality and deaths due to extrahepatic malignancies were reduced, while CVD mortality was comparable. These results highlight the continued importance of liver disease management after SVR, along with standard CVD monitoring.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eData collection\u003c/h2\u003e\u003cp\u003eThis observational study was conducted at 21 facilities of the Kagoshima Liver Study Group in Japan. The enrollment of the study population is presented in Fig.\u0026nbsp;1. Of 1,790 patients without a history of HCC who achieved SVR following DAA therapy between October 2014 and May 2024, 1,753 patients were included. Patients with hepatitis B virus (HBV) co-infection or who developed cancer before completion of DAA therapy were excluded. Patients with hypovascular tumors were also excluded because such lesions frequently progress to HCC despite HCV eradication with DAA therapy \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Written informed consent was obtained from all enrolled patients. Data regarding survival status, cause of death, and mortality were collected from medical records. The study protocol adhered to the ethical principles of the Declaration of Helsinki and was approved by the Kagoshima University Hospital Clinical Research Ethics Committee and the ethics committees of all participating institutions (approval numbers: 150138, 170199, 190297).\u003c/p\u003e\u003cp\u003eHCV RNA levels were measured by TaqMan polymerase chain reaction (PCR), which has a lower quantitation limit of 1.2 log IU/mL. Liver cirrhosis (LC) was diagnosed by hepatologists at each facility based on platelet count, imaging, fibrosis markers, transient elastography, or the presence of varices. DM was defined as treatment with antidiabetic medications, fasting blood glucose level\u0026thinsp;\u0026ge;\u0026thinsp;126 mg/dL, and/or hemoglobin A1c concentration\u0026thinsp;\u0026ge;\u0026thinsp;6.5%. Non\u0026ndash;liver disease\u0026ndash;related (LDR) deaths were defined as deaths from causes other than liver disease when the cause was confirmed; accidental deaths were excluded. Cardiovascular disease (CVD) deaths were classified according to Japanese guidelines and included coronary heart disease, aortic disease, and cerebrovascular disease. Chronic kidney disease (CKD) stage was determined based on glomerular filtration rate (GFR).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eTreatment protocol\u003c/h2\u003e\u003cp\u003eThe treatment regimens included daclatasvir (DCV) plus asunaprevir (ASV) for 24 weeks; sofosbuvir (SOF) plus ledipasvir (LDV) for 12 weeks; ombitasvir (OBV), paritaprevir (PTV), and ritonavir (r) for 12 weeks; SOF plus ribavirin (RBV) for 12 weeks; elbasvir (EBR) plus grazoprevir (GZR) for 12 weeks; DCV, ASV, and beclabuvir (BCV) for 12 weeks; glecaprevir (GLE) plus pibrentasvir (PIB) for 8 or 12 weeks; and SOF plus velpatasvir (VEL) for 12 weeks. All treatments were administered according to the Japanese guidelines for chronic HCV infection \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. The observation period commenced at the EOT.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analyses\u003c/h2\u003e\u003cp\u003eAnalyses were conducted using IBM SPSS Statistics software (version 22; IBM, Armonk, NY, USA). Categorical variables were compared using the chi-squared test or Fisher\u0026rsquo;s exact test, as appropriate. Continuous variables were analyzed with the Mann\u0026ndash;Whitney U test or the Kruskal\u0026ndash;Wallis test. Mortality was assessed using the Kaplan\u0026ndash;Meier method and compared using the log-rank test. Factors associated with mortality were examined with a Cox proportional hazards model using forward selection with p\u0026thinsp;\u0026lt;\u0026thinsp;0.10 as the inclusion threshold. Covariates included age, sex, presence of LC, presence of DM, history of DAA therapy, pre-treatment laboratory values (platelet count, total bilirubin, alanine aminotransferase [ALT], γ-glutamyl transpeptidase [γ-GTP], creatinine, albumin, AFP, hyaluronic acid, and FIB-4 index), and albumin, AFP, and ALT levels at EOT. Mortality rates adjusted for sex and age, were compared with those of the general Japanese population using SMRs. The SMR was calculated as the ratio of observed to expected deaths, where expected deaths were obtained by multiplying person-years at risk in each stratum by the corresponding mortality rate of the reference population and summing across all strata. Population data on age group, sex, mortality, and cause of death were derived from the 2023 Population Survey Report of the Ministry of Health, Labour, and Welfare (eSTAT; Supplementary Table) \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. The 95% confidence intervals (CIs) were calculated based on observed and expected deaths.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eSM and ST contributed to the study conceptualization and design. Data collection was performed by all authors, and analysis was performed by SM and ST. The first draft of the manuscript was written by SM. All authors commented on previous versions of the manuscript and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe present study was carried out in the following 21 facilities (Kagoshima liver study group): Kagoshima University Hospital, Kirishima Medical Center, Miyazaki Medical Center Hospital, Kagoshima Kouseiren Hospital, Kagoshima City Hospital, Saiseikai Sendai Hospital, Kohshinkai Ogura Hospital, Ikeda Hospital, Izumi General Medical Center, Oshima Hospital, Ibusuki Medical Center, Southern Region Hospital, Tanegashima Medical Center, Fujimoto General Hospital, Hirono Clinic, Kagoshima Teishin Hospital, Satsunan Hospital, Nagaki Clinic, Hayatonomori clinic, Nakayama clinic, and Dr. NAKANISHI\u0026rsquo;s office. We thank the following investigators: Ms. Yuko Morinaga, Ms. Hiromi Eguchi, and Ms. Eriko Koreeda for their technical assistance and data management. This work was partially supported by a Japan Agency for Medical Research and Development (JP25fk0210174).We would like to thank Editage (www.editage.jp) for English language editing\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e\u003cem\u003eWorld Health Organization. Hepatitis C fact Sheet World Health Organization 2025\u003c/em\u003e, \u0026lt;\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.who.int/en/news-room/fact-sheets/detail/hepatitis-c\u003c/span\u003e\u003cspan address=\"https://www.who.int/en/news-room/fact-sheets/detail/hepatitis-c\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBhattacharya, D., Aronsohn, A., Price, J., Lo Re, V. \u0026amp; Hepatitis, C. Guidance 2023 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. \u003cem\u003eClin Infect. Dis\u003c/em\u003e, (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEASL recommendations on treatment of hepatitis C. Final update of the series(☆). \u003cem\u003eJ. Hepatol.\u003c/em\u003e \u003cb\u003e73\u003c/b\u003e, 1170\u0026ndash;1218 (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMawatari, S. et al. Viral and host factors are associated with retreatment failure in hepatitis C patients receiving all-oral direct antiviral therapy. \u003cem\u003eHepatol. Res.\u003c/em\u003e \u003cb\u003e50\u003c/b\u003e, 453\u0026ndash;465 (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eToyodome, A. et al. Analysis of the susceptibility of refractory hepatitis C virus resistant to nonstructural 5A inhibitors. \u003cem\u003eSci. Rep.\u003c/em\u003e \u003cb\u003e14\u003c/b\u003e, 16363 (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIoannou, G. N., Green, P. K. \u0026amp; Berry, K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. \u003cem\u003eJ. Hepatol.\u003c/em\u003e \u003cb\u003e68\u003c/b\u003e, 25\u0026ndash;32 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNahon, P. et al. Incidence of Hepatocellular Carcinoma After Direct Antiviral Therapy for HCV in Patients With Cirrhosis Included in Surveillance Programs. \u003cem\u003eGastroenterology\u003c/em\u003e \u003cb\u003e155\u003c/b\u003e (.e1436), 1436\u0026ndash;1450 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHiramatsu, N., Oze, T. \u0026amp; Takehara, T. Suppression of hepatocellular carcinoma development in hepatitis C patients given interferon-based antiviral therapy. \u003cem\u003eHepatol. Res.\u003c/em\u003e \u003cb\u003e45\u003c/b\u003e, 152\u0026ndash;161 (2015).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMawatari, S. et al. Features of patients who developed hepatocellular carcinoma after direct-acting antiviral treatment for hepatitis C Virus. \u003cem\u003ePLoS One\u003c/em\u003e. \u003cb\u003e17\u003c/b\u003e, e0262267 (2022).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eToyoda, H. et al. Trends and Efficacy of Interferon-Free Anti-hepatitis C Virus Therapy in the Region of High Prevalence of Elderly Patients, Cirrhosis, and Hepatocellular Carcinoma: A Real-World, Nationwide, Multicenter Study of 10 688 Patients in Japan. \u003cem\u003eOpen. Forum Infect. Dis.\u003c/em\u003e \u003cb\u003e6\u003c/b\u003e, ofz185 (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBackus, L. I., Belperio, P. S., Shahoumian, T. A. \u0026amp; Mole, L. A. Impact of sustained virologic response with direct-acting antiviral treatment on mortality in patients with advanced liver disease. \u003cem\u003eHepatology\u003c/em\u003e, (2017).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBackus, L. I., Belperio, P. S., Shahoumian, T. A. \u0026amp; Mole, L. A. Direct-acting antiviral sustained virologic response: Impact on mortality in patients without advanced liver disease. \u003cem\u003eHepatology\u003c/em\u003e \u003cb\u003e68\u003c/b\u003e, 827\u0026ndash;838 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTada, T. et al. Viral eradication reduces all-cause mortality in patients with chronic hepatitis C virus infection who had received direct-acting antiviral therapy. \u003cem\u003eLiver international: official J. Int. Association Study Liver\u003c/em\u003e. \u003cb\u003e44\u003c/b\u003e, 3060\u0026ndash;3071 (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSimmons, B., Saleem, J., Heath, K., Cooke, G. S. \u0026amp; Hill, A. Long-Term Treatment Outcomes of Patients Infected With Hepatitis C Virus: A Systematic Review and Meta-analysis of the Survival Benefit of Achieving a Sustained Virological Response. \u003cem\u003eClin. Infect. Dis.\u003c/em\u003e \u003cb\u003e61\u003c/b\u003e, 730\u0026ndash;740 (2015).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNahon, P. et al. Eradication of Hepatitis C Virus Infection in Patients With Cirrhosis Reduces Risk of Liver and Non-Liver Complications. \u003cem\u003eGastroenterology\u003c/em\u003e \u003cb\u003e152\u003c/b\u003e (.e142), 142\u0026ndash;156 (2017).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIoannou, G. N. et al. Development of models estimating the risk of hepatocellular carcinoma after antiviral treatment for hepatitis C. \u003cem\u003eJ. Hepatol.\u003c/em\u003e \u003cb\u003e69\u003c/b\u003e, 1088\u0026ndash;1098 (2018).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYamada, R. et al. Incidence and risk factors of hepatocellular carcinoma change over time in patients with hepatitis C virus infection who achieved sustained virologic response. \u003cem\u003eHepatol. Res.\u003c/em\u003e \u003cb\u003e49\u003c/b\u003e, 570\u0026ndash;578 (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eReiberger, T. et al. EASL position paper on clinical follow-up after HCV cure. \u003cem\u003eJ. Hepatol.\u003c/em\u003e \u003cb\u003e81\u003c/b\u003e, 326\u0026ndash;344 (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMiuma, S. et al. Non-liver-related mortality in the DAA era: Insights from post-SVR patients with and without previous HCC history. \u003cem\u003eJ. Med. Virol.\u003c/em\u003e \u003cb\u003e96\u003c/b\u003e, e29432 (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eObi, S. et al. The incidence of all organ malignancies and overall survival of patient with sustained virological response of HCV-comparable to SMR (standardized mortality ratio) of Japan general population. \u003cem\u003eHep. Intl.\u003c/em\u003e \u003cb\u003e17\u003c/b\u003e, 562\u0026ndash;572 (2023).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCalvaruso, V. et al. Liver and cardiovascular mortality after hepatitis C virus eradication by DAA: Data from RESIST-HCV cohort. \u003cem\u003eJ. Viral Hepatitis\u003c/em\u003e. \u003cb\u003e28\u003c/b\u003e, 1190\u0026ndash;1199 (2021).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePetta, S. et al. Hepatitis C Virus Infection Is Associated With Increased Cardiovascular Mortality: A Meta-Analysis of Observational Studies. \u003cem\u003eGastroenterology\u003c/em\u003e \u003cb\u003e150\u003c/b\u003e, 145\u0026ndash;155 (2016). e144; quiz e115-146.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eToyoda, H. et al. The impact of HCV eradication by direct-acting antivirals on the transition of precancerous hepatic nodules to HCC: A prospective observational study. \u003cem\u003eLiver international: official J. Int. Association Study Liver\u003c/em\u003e. \u003cb\u003e39\u003c/b\u003e, 448\u0026ndash;454 (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTabu, K. et al. Hypovascular tumors developed into hepatocellular carcinoma at a high rate despite the elimination of hepatitis C virus by direct-acting antivirals. \u003cem\u003ePLoS One\u003c/em\u003e. \u003cb\u003e15\u003c/b\u003e, e0237475 (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e\u003cem\u003eGuidelines for the Management of Hepatitis C Virus Infection\u003c/em\u003e, \u0026lt;\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.jsh.or.jp/medical/guidelines/jsh_guidlines/hepatitis_c.\u003c/span\u003e\u003cspan address=\"http://www.jsh.or.jp/medical/guidelines/jsh_guidlines/hepatitis_c.\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e\u003cem\u003eStatistics of Japan, e-Stat is a portal site for Japanese Government Statistics.\u003c/em\u003e, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.e-stat.go.jp/en\u003c/span\u003e\u003cspan address=\"https://www.e-stat.go.jp/en\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"HCV, DAAs, SVR, SMR, mortality, cardiovascular disease","lastPublishedDoi":"10.21203/rs.3.rs-7721910/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7721910/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eDirect-acting antivirals (DAAs) achieve high sustained virologic response (SVR) rates in patients with hepatitis C virus (HCV) infection. However, the long-term prognosis and cause-specific mortality following SVR remain incompletely defined.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis study analyzed 1,753 HCV-infected patients without a history of hepatocellular carcinoma (HCC) treatment who achieved SVR with DAAs. Liver disease-related (LDR) and non-LDR mortality were assessed using age- and sex-adjusted standardized mortality ratios (SMR) compared with the general population.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eDuring a mean follow-up of 59.2 months, 122 patients died. The SMR for all-cause mortality was 1.050 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.588). The SMR for LDR and non-LDR mortality were 7.819 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 0.566 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), respectively. The SMR for extrahepatic malignancy-related mortality was significantly lower at 0.593 (p\u0026thinsp;=\u0026thinsp;0.013), whereas cardiovascular disease (CVD)\u0026ndash;related mortality did not differ significantly at 0.884 (p\u0026thinsp;=\u0026thinsp;0.554). These findings were consistent regardless of age, sex, presence of LC, diabetes, or chronic kidney disease.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eOverall mortality after SVR in patients with HCV was comparable with that of the general population. Nevertheless, LDR mortality remained significantly elevated, whereas non-LDR and extrahepatic malignancy-related mortality were significantly reduced. These results underscore the importance of continued liver disease surveillance post-SVR, while CVD management should parallel that of the general population.\u003c/p\u003e","manuscriptTitle":"Cause-Specific Mortality Following Sustained Virologic Response in hepatitis C patients Treated with Direct-Acting Antivirals: A Standardized Mortality Ratio Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-29 04:10:12","doi":"10.21203/rs.3.rs-7721910/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-24T12:27:11+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-17T06:35:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"58855240863482197892179273212435393171","date":"2025-10-16T10:26:25+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-14T09:57:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-30T07:58:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-30T05:05:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-09-26T12:27:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"594df3f2-8325-4c99-bbe0-d676eb0ea98a","owner":[],"postedDate":"October 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":56834281,"name":"Biological sciences/Cancer"},{"id":56834282,"name":"Health sciences/Diseases"},{"id":56834283,"name":"Health sciences/Gastroenterology"},{"id":56834284,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2025-12-01T16:03:53+00:00","versionOfRecord":{"articleIdentity":"rs-7721910","link":"https://doi.org/10.1038/s41598-025-29972-6","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-11-27 15:58:21","publishedOnDateReadable":"November 27th, 2025"},"versionCreatedAt":"2025-10-29 04:10:12","video":"","vorDoi":"10.1038/s41598-025-29972-6","vorDoiUrl":"https://doi.org/10.1038/s41598-025-29972-6","workflowStages":[]},"version":"v1","identity":"rs-7721910","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7721910","identity":"rs-7721910","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}