The Impact of Cirrhosis and History of Hepatocellular Carcinoma on All-Cause Mortality After Eradication of Hepatitis C Virus in Patients With Chronic Hepatitis C (2024)

Patients

A total of 6201 patients underwent interferon-free DAA-based anti-HCV therapy between October 2012 and December 2018 at one of the following 16 institutions across Japan: Asai General Hospital, Ehime Prefectural Central Hospital, Jikei University Katsushika Hospital, Kagawa Prefectural Central Hospital, Kikkoman General Hospital, Kitasato University Hospital, Nagoya City University Hospital, Nippon Medical School Hospital, Nippon Medical School Chiba Hokusoh Hospital, Ogaki Municipal Hospital, Otakanomori Hospital, Saiseikai Niigata Hospital, Shinmatsudo Central General Hospital, St. Marianna University Hospital, Teine Keijinkai Hospital, and Yokohama City University Medical Center. Some patients underwent DAA therapy in the context of clinical trials. SVR was confirmed by the absence of serum HCV RNA at 12 weeks after the end of DAA therapy (ie, SVR12) in 5794 patients, and 5458 patients were continuously followed up for more than 1 year. We excluded 336 patients whose follow-up period after SVR was <1 year because post-SVR HCC within 1 year after SVR might have existed before SVR. We enrolled these 5458 patients in this study (FigureA1). The presence of compensated cirrhosis was clinically determined by attending hepatologists based on the results of imaging and endoscopic studies, including the presence of esophageal/gastric varices, collateral veins due to portal hypertension, and splenomegaly. Laboratory liver fibrosis markers such as the FIB-4 index6 or aspartate aminotransferase platelet ratio index7 and liver stiffness determined by ultrasonographic or magnetic resonance elastography were also taken into consideration. Patients with decompensated cirrhosis were not included in this study because the use of DAAs was not allowed in this population in Japan during the study period. Curatively treated HCC was defined as HCC treated by resection or locoregional ablation, and patients were confirmed to have no residual intrahepatic or extrahepatic liver tumors on computed tomography or magnetic resonance imaging scans before the start of DAA therapy. Patients with active HCC were not included in this study because the use of DAAs is not permitted in this population in Japan.

The study protocol was approved by the institutional review board of each participating hospital. Written informed consent was waived for this descriptive, observational study.

Post-SVR Follow-Up and Outcomes

All patients were followed up after SVR; they regularly underwent ultrasonography and laboratory testing, including measurements of tumor markers, and computed tomography or magnetic resonance imaging was planned if necessary. Principally, patients with a history of curatively treated HCC were followed up every 3 months with laboratory tests and every 6 months with imaging studies for the first 5 years after treatment of HCC and every 6 months thereafter. Patients with no history of HCC were followed up every 6 months with laboratory tests and imaging studies. When a liver nodule was detected, further imaging and laboratory examinations for the diagnosis of HCC were conducted. Diagnosis and treatment of HCC were based on Japanese guidelines.8

Patients were followed up from the time of SVR confirmation by negative serum HCV RNA at SVR12 until the last visit before the end of October 2020, and their outcomes were measured. Causes of death during the study were categorized as liver related or nonliver related.

Statistical Analysis

For comparisons of baseline characteristics between patient groups, differences in distribution were analyzed using the chi-square test, and differences in quantitative values were analyzed using the Mann–Whitney U test. Multivariate analyses with the Cox proportional hazard model were performed for factors associated with the development of HCC or death after SVR. Factors potentially associated with the post-SVR HCC development or mortality, including patient age, gender, hepatitis B virus (HBV) coinfection, regular alcohol intake, presence of diabetes, presence of hypertension, compensated cirrhosis, and history of curatively treated HCC, were included in the multivariate analysis. To compare the incidences of HCC development and mortality after SVR, the Kaplan–Meier method and log-rank test were used. Actuarial analysis of cumulative mortality from cause of death category (liver-related mortality and nonliver-related mortality) was performed using cumulative incidence with the competing risks method, and differences across groups were tested using the Gray test. The date of the definition of SVR (SVR12, 12 weeks after the end of DAA therapy) was defined as time 0 for calculations of the incidence of HCC development or mortality. In the analysis of the incidence of HCC after SVR, patients who developed HCC after SVR were not censored, whereas those with no HCC development were censored. The observation period ended on the date of HCC development in noncensored cases and the date of the last visit in censored cases. In the analysis of mortality incidence, patients who died after SVR were not censored, whereas those who survived were censored. The observation period ended on the date of death in noncensored cases and the date of the last visit in censored cases. Propensity score matching (PSM) involving one-to-one pairing of patients was performed with propensity scores matched at 2 decimal places. PSM was conducted based on age, gender, HBV coinfection, regular alcohol intake, presence of diabetes, and presence of hypertension with calibration of 0.2. Statistical analysis was performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). All P values were derived from 2-tailed tests, with P < .05 accepted as statistically significant.

Background Characteristics of Study Patients

Table1 lists the background characteristics of study patients at the start of DAA therapy. Patients consisted of 2603 (47.7%) males and 2855 (52.3%) females, with a median age of 68 years (interquartile range [IQR], 59–75) years. Among the 5458 total patients, 1513 (27.7%) had compensated cirrhosis and 604 (11.1%) had a history of curative treatment of HCC (441 patients had both compensated cirrhosis and a history of curatively treated HCC). Patients were followed up after SVR for a median of 2.9 years (IQR, 2.0–3.4 years). During follow-up, 481 patients (8.8%) were lost to follow-up, with median 1.9 years (IQR, 1.4–2.6 years) after SVR. There were no differences in patient background characteristics between patients who continued follow-up and those who dropped out (data not shown). HCC was developed in 525 patients (344 recurrences in patients with a history of curatively treated HCC and 181 cases of de novo HCC after SVR), and 189 patients died during the study period. The causes of death in the overall population were HCC in 53 patients, liver-related causes excluding HCC in 17 patients, and nonliver-related causes in 119 patients. In patients who died due to nonliver-related causes, 29 (24.4%) died of non-HCC gastroenterological cancer, 2 (1.7%) died of benign gastroenterological diseases, 10 (8.4%) died of lung malignancy, 12 (10.1%) died of benign lung diseases, 8 (6.7%) died of hematological malignancy, 14 (11.8%) died of cardiovascular diseases, 8 (6.7%) died of cerebrovascular diseases, 5 died (4.2%) of renal diseases, 11 (9.2%) died of other diseases, and 20 (16.8%) died of unknown causes (TableA1).

Impact of a History of Curatively Treated HCC and Compensated Cirrhosis on Mortality After SVR

Mortality after SVR was significantly higher in patients with a history of curatively treated HCC (hazard ratio [HR] 6.30, 95% confidence interval [CI], 4.51–8.03; Figure1A) and in those with compensated cirrhosis (HR 2.57, 95% CI 1.93–3.43) before SVR than in patients without these complications. Multivariate analysis identified higher age, male gender, and a history of curative treatment of HCC (adjusted HR 3.76, 95% CI 2.71–5.21) as independent factors correlated with higher likelihood of mortality (Table2). Cirrhosis was not significantly associated with high mortality in multivariate analysis (adjusted HR 1.27, 95% CI 0.93–1.75).

Among 4854 patients with no history of HCC, mortality after SVR remained significantly higher in patients with compensated cirrhosis before SVR than in those without cirrhosis (HR 1.95, 95% CI 1.30–2.88; Figure 1B). In multivariate analysis, cirrhosis before SVR was significantly associated with high mortality (adjusted HR 1.53, 95% CI 1.02-2.26) as were older age, male gender, and alcohol intake (Table3).

Impact of a History of Curatively Treated HCC and Compensated Cirrhosis on Liver-Related and Nonliver-Related Mortality After SVR

Competing risks analysis was performed to compare liver-related and nonliver-related mortality based on a history of curatively treated HCC and the presence of compensated cirrhosis. Liver-related mortality was significantly higher in patients with a history of HCC before SVR than in those without it (HR 32.27, 95% CI 17.22–60.50). A history of HCC had a similar impact on nonliver-related mortality (HR 2.58, 95% CI 1.72–3.87) but to a lesser degree (Figure2A). When patient backgrounds were adjusted using PSM by patient age, gender, HBV coinfection, alcohol intake, and comorbidities (diabetes and hypertension), liver-related mortality in patients with a history of HCC remained higher than in those with no history of HCC (HR 49.39, 95% CI 6.83–357.2). By contrast, nonliver-related mortality did not differ between the 2 groups (P= .3430, HR 1.34, 95% CI 0.77–2.33; FigureA2A).

In patients without a history of HCC, both liver-related and nonliver-related mortality rates were significantly higher in patients with compensated cirrhosis before SVR than in those without it, but the difference was less significant for nonliver-related mortality (liver-related mortality, HR 10.24, 95% CI 2.70–38.83; nonliver-related mortality, HR 1.80, 95% CI 1.16–2.79; Figure2B). When patient backgrounds were adjusted using PSM, there was no significant difference in liver-related and nonliver-related mortality rates based on the presence of cirrhosis before SVR (liver-related mortality, HR 2.03, 95% CI 0.82–4.63, nonliver-related mortality, HR 1.50, 95% CI 0.85–2.64; FigureA2B).

Impact of a History of Curatively Treated HCC and Compensated Cirrhosis on the Development of HCC After SVR

The incidence of post-SVR HCC was significantly higher in patients with a history of curatively treated HCC (HR 22.20, 95% CI 18.51–26.71; Figure3A) and in those with pre-SVR compensated cirrhosis than in those without these complications (HR 7.31, 95% CI 6.05–8.89). Multivariate analysis identified higher age, male gender, hypertension, presence of compensated cirrhosis (adjusted HR 2.70, 95% CI 2.19–3.35), and a history of curatively treated HCC (adjusted HR 11.62, 95% CI 9.46–14.33) as factors independently associated with a higher likelihood of HCC development after SVR (TableA2).

When patients with a history of curatively treated HCC before SVR were excluded, the incidence of HCC remained higher in patients with compensated cirrhosis than those without cirrhosis (HR 6.09, 95% CI 4.40–8.50; Figure3B), and cirrhosis was associated with HCC development after SVR in multivariate analysis (adjusted HR 5.20, 95% CI 3.74–7.29; TableA3).

Effects of de Novo and Recurrent HCC After SVR on Post-SVR Mortality

Among patients with a history of curatively treated HCC before SVR, the mortality in patients in whom HCC developed (ie, recurred) after SVR was significantly higher than that in patients with no post-SVR HCC (HR 2.25, 95% CI 1.38–3.86; FigureA3A). By contrast, among patients with no history of HCC before SVR, there was no difference in post-SVR mortality between patients who experienced HCC after SVR (ie, de novo HCC) and in those who did not (HR 1.83, 95% CI 0.86–3.42; FigureA3B).

Conflicts of Interest: These authors disclose the following: H.T. reports speaker honoraria from AbbVie and Bayer. M.A. reports a speaker honorarium from AbbVie. Ko.T. reports speaker honoraria from MSD, Bristol-Meyers Squibb, AbbVie, and Astra Zeneca. T.K. reports speaker honoraria from AbbVie, Gilead Sciences, and Bristol-Meyers Squibb. Y.T. reports speaker honoraria from Jansen Pharmaceuticals and Gilead Sciences. The remaining authors disclose no conflicts.

Funding: This work was supported by the Japanese Ministry of Labor, Health, and Welfare Policy Research for Hepatitis Measures Program Grant Number JPMH19HC1001.

Ethical Statement: The corresponding author, on behalf of all authors, jointly and severally, certifies that their institution has approved the protocol for any investigation involving humans or animals and that all experimentation was conducted in conformity with ethical and humane principles of research.

Data Transparency Statement: Data, analytic methods, and study materials will be available to other researchers on request to corresponding author.

Material associated with this article can be found in the online version at https://doi.org/10.1016/j.gastha.2022.02.018.

TablesA1–A3:

FiguresA1–A3:

FiguresA1–A3 captions:

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