This retrospective cohort study used data from a single tertiary hospital recorded between January 2005 and December 2020. Patients who were anti-HCV positive and visited a single tertiary academic institution (Gangnam Severance Hospital) during the study period were included. HCV genotyping and serum HCV RNA quantification were performed.
The exclusion criteria were as follows: (1) previous history of HCC or HCC diagnosis within 6 months after HCV treatment, (2) previous history of hepatic decompensation or decompensation development within 6 months after HCV treatment, (3) liver transplant status or transplantation within 6 months after HCV treatment, (4) heavy alcohol consumption, (5) toxic hepatitis, and (6) follow-up period less than 6 months.
The study protocol was performed in accordance with the principles of the 1975 Declaration of Helsinki, and approved by the Yonsei University Gangnam Severance Hospital, Institutional Review Board (3-2021-0255). The need for informed consent was waived by the ethics committee/Institutional Review Board of Yonsei University Gangnam Severance Hospital, because of the retrospective nature of the study.
Baseline workup and treatment plan
HCV antibody examination was performed at baseline visits as part of the study enrollment process. Next, those who were anti-HCV positive underwent HCV RNA quantification to confirm HCV infection and HCV genotyping. In patients who were HCV RNA negative, past HCV infection and false-positive results for anti-HCV were distinguished using the recombinant immunoblot assay (RIBA) test.
Patients who were confirmed to be HCV RNA positive were started on hepatitis C treatment. HCV treatment is largely divided into interferon-based treatment that stimulates the immune response to HCV and DAA therapy, which directly inhibits the protein components of the HCV. For DAAs, daclatasvir/asunaprevir (DCV/ASV), ledipasvir/sofosbuvir (LED/SOF), sofosbuvir (SOF) and ribavirin, elbasvir/grazoprevir (EBR/GZR), ombitasvir/paritaprevir/ritonavir (OBV/PTV/r), and more recently, the pangenotype agent glecaprevir/pibrentasvir (G/P) were used. The treatment period varied from 8 to 12 weeks, depending on the genotype and presence of cirrhosis. Patients’ HCV RNA was analyzed 4 weeks after the initiation of treatment to confirm patient compliance and evaluate drug according to treatment response, as well as at the end of treatment to evaluate the response at the end of treatment. Moreover, the overall rate of SVR 12 or 24 weeks after completion of therapy (SVR12 or SVR24) was investigated for all types of HCV treatment. After completion of treatment, each patient underwent abdominal ultrasonography for the surveillance of HCC and fibrosis progression, and the cumulative incidence of HCC and liver cirrhosis was investigated according to SVR12 or SVR24, baseline liver cirrhosis.
HCV genotyping was performed using the restriction fragment mass polymorphism method.
Serum HCV RNA quantification (lower limit of quantification, 15 IU/mL) was performed with a Cobas 4800 system (Roche Diagnostics GmbH, Mannheim, Germany), which consists of a Cobas x480 instrument and a Cobas z480 analyzer, to confirm the sustained virological response before and after treatment. In addition, the RIBA test was performed with samples that were HCV RNA negative using MP Diagnostics HCV Blot 3.0 (MP Biomedicals, Singapore).
Diagnosis of hepatocellular carcinoma and liver cirrhosis
HCC diagnosis was based on the guidelines of the Korean Liver Cancer Association-National Cancer Center.5 HCC was diagnosed when typical radiologic features such as hypervascularity on arterial phase and washout on portal venous or delayed phase were detected by four-phase multi-detector computed tomography or dynamic contrast-enhanced magnetic resonance imaging. When the diagnosis of HCC was uncertain, it was finally confirmed using two imaging modalities or a liver biopsy.6
Liver cirrhosis was defined by ultrasonography (US) features such as a blunted, nodular liver surface accompanied by splenomegaly (>12 cm), in accordance with previous studies.7, 8
Patients’ baseline characteristics were expressed as mean with standard deviation in the case of continuous variables and numbers with percentages in the case of categorical variables. Student’s t-test was used to compare continuous variables, while Fisher’s exact tests or chi-squared test were used to compare categorical variables. The cumulative incidence rates of HCC and liver cirrhosis were investigated using the Kaplan–Meier method and compared by the log-rank test. Data of patients with HCC or liver cirrhosis at the last follow-up were censored. Multivariate Cox proportional hazard analysis was used to identify independent predictors of HCC or liver cirrhosis development. All statistical analyses were performed using SPSS version 25.0 (IBM Co., Armonk, NY, USA). Statistical significance was set at P <0.05.