The impact of COVID-19 on the diagnosis and treatment of HCC: analysis of a nationwide registry for advanced liver diseases (REAL)

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Study design and participants

In this study, we retrieved data of patients initially diagnosed with HCC between January 2018 and December 2021 from the REAL database12. The collected data included anthropometric parameters, viral hepatitis parameters, antiviral treatment history before each admission, hepatic encephalopathy status, ascites, esophageal and gastric varices, tumor characteristics, treatment modalities for PLC and DC, and laboratory data (total bilirubin, serum albumin, serum creatinine, platelet count, and prothrombin time)12. We intended to enroll as many patients as possible; only those with missing information on the initial treatment were excluded.

The study was conducted in accordance with the principles of the Declaration of Helsinki. This study complied with the ethical guidelines for medical and health research involving human subjects established by the Japanese Ministry of Education, Culture, Sports, Science, and Technology and the Ministry of Health, Labour, and Welfare. The study protocol was approved by the Research Ethics Committee of the Faculty of Medicine at the University of Tokyo (approval number: 2018053NI). The requirement for individual informed consent was waived by the Research Ethics Committee of the Faculty of Medicine at the University of Tokyo due to the retrospective design of the study. All personal information was anonymized at data entry and an individual identifier was created with a hash function using the patients’ names and birth dates. The study was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN000035000). All authors had access to the study data and reviewed and approved the final manuscript.

Classification of etiology

We classified the patients into four etiologies: hepatitis B virus (HBV), hepatitis C virus (HCV), coinfection with HBV and HCV, and non-B, non-C12. Patients were classified as HBV-positive if they were positive for HBs antigen at least once at initial diagnosis or at any admission. Furthermore, patients were classified as having HBV infection if they had a history of receiving antiviral therapy for HBV. Patients were classified as having HCV if they had a positive HCV antibody result at initial diagnosis or at any admission. Furthermore, patients were classified as having HCV infection if they had a history of receiving antiviral therapy. Patients coinfected with HBV and HCV met the criteria for both HBV and HCV infections. The remaining patients were classified as non-B, non-C12.

Diagnosis of primary liver cancer and decompensated cirrhosis

PLC were classified based on the World Health Organization (WHO) classification of Tumours of the Digestive System13. HCC was diagnosed pathologically or using imaging criteria based on the Japanese Clinical Practice Guidelines14. Hyperattenuation during the arterial phase with washout during the late phase on dynamic computed tomography or dynamic magnetic resonance imaging images was considered a specific finding.

Definition of before and during the COVID-19 era

COVID-19 was first documented in December 201915 and the WHO declared the COVID-19 outbreak as a global pandemic on March 11, 2020. The study period was divided into the pre-COVID-19 era (January 2018 to December 2019) and the COVID-19 era (January 2020 to December 2021).

Study outcomes and variables

Among the various indicators of tumor characteristics, we selected tumor size, the most robust and reliable indicator of tumor growth, as the primary outcome measure. We compared the diameter of the maximal intrahepatic lesion at initial diagnosis before and during the COVID-19 era. The following variables were also assessed: number of intrahepatic tumors, vascular invasion, extrahepatic spread, tumor rupture, Barcelona Clinic Liver Cancer (BCLC) stage16, duration from diagnosis to initial treatment for HCC, etiology, Child–Pugh score17, status of hepatic encephalopathy, ascites, esophageal and gastric varices, tumor characteristics, treatment modalities for HCC, anthropometric parameters, and laboratory data (total bilirubin, serum albumin, serum creatinine, platelet count, and prothrombin time). We further conducted a subgroup analysis stratified by etiology, including HBV, HCV, and non-B, non-C.

Statistical analysis

Data are presented as means and standard deviations (SD) or medians and interquartile ranges (IQR) for quantitative variables and as numbers and percentages for qualitative variables. The body mass index (BMI), Child–Pugh score, and BCLC stage were calculated using the obtained data (Supplementary Fig. S1). The following unrealistic outliers were treated as missing. Height less than 100 cm, weight less than 10 kg, prothrombin activity less than 10%, and diameter of the maximal intrahepatic lesion greater than 30 cm. BMI, Child–Pugh score, and BCLC stage calculated from these values were also treated as missing.

For comparisons between before and during the COVID-19 era, for continuous variables, Welch’s t-test was used to assess the statistical significance. The Cochran–Armitage trend test was used for statistical analyses of the change in Child–Pugh class, number of intrahepatic tumors, BCLC stage, and tumor markers, and The Chi-squared test was used for other categorical variables. In this study, p < 0.05 was considered statistically significant, and all tests were two-tailed. All statistical analyses were performed using the R software version 4.1 and later (R Foundation, Vienna, Austria,

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