Impact of Nucleos(t)ide Analogues on the Risk of Hepatocellular Carcinoma in Chronic Hepatitis B Patients: A Time-Dependent Cox Regression Analysis

Background and Aims The preventive effect of nucleos(t)ide analog (NA) use on HCC development in patients with chronic hepatitis B (CHB) is controversial due to the difficulty of conducting randomized controlled trials. Approach and Results In this single-center, retrospective study, NA-naïve CHB patients without a history of HCC were enrolled and followed-up from the first visit on or after January 2000 to December 2020. Patients were categorized into the NA group, including those who started NA after study enrollment, and the non-NA group, including patients to whom NA was never administered during the follow-up period. After propensity score matching (PSM) to balance the confounding factors, we applied a multivariable time-dependent Cox proportional regression analysis with the initiation of NA as a time-dependent covariate. We further performed a subgroup analysis according to the presence or absence of cirrhosis. The baseline characteristics of 212 pairs of patients retrieved by PSM were comparable. During the mean follow-up of 12.9 and 6.8 years in the NA and non-NA groups, respectively, 25 and 28 patients developed HCC, respectively. Multivariable analysis with time-dependent covariates showed that NA did not affect HCC risk (HR, 0.68; 95% CI, 0.36–1.31; p = 0.25) after adjusting for other risk factors, including age, sex, and HBV viral load. Subgroup analysis showed that NA use significantly reduced the risk of HCC in cirrhotic patients (HR, 0.26; 95% CI, 0.08–0.85; p = 0.03). Conclusions The preventive effect of NA on hepatocarcinogenesis may be limited to cirrhotic patients. ### Competing Interest Statement Kazuhiko Koike has received research funding from Bristol-Meyers Squibb, Gilead Sciences. Ryosuke Tateishi has received lecture fee from Bristol-Meyers Squibb, Gilead Sciences. Tatsuya Minami has received lecture fee from Gilead Sciences. ### Funding Statement Japan Agency for Medical Research and Development (AMED): JP22fk0210066 and JP22fk0210090 The Health, Labour, and Welfare Policy Research Grants from the Ministry of Health, Labour, and Welfare of Japan: H30-Kansei- Shitei-003. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This retrospective study was conducted according to the ethical guidelines for epidemiological research established by the Japanese Ministry of Education, Culture, Sports, Science and Technology and Ministry of Health, Labour, and Welfare. The study design was included in a comprehensive protocol of retrospective studies at the Department of Gastroenterology, the University of Tokyo Hospital, and approved by the University of Tokyo Medical Research Center Ethics Committee (approval no. 2058). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All relevant data are within the paper and its Supporting information files.