Impact of drugs for hepatocellular carcinoma development in chronic hepatitis B patients who treated with entecavir and tenofovir disoproxil as initial therapy: population-based study

초록

Background and aims: Entecavir (ETV) and Tenofovir disoproxil fumarate (TDF) have been used as the first-line antiviral agents for patients with treatment-naive chronic hepatitis B (CHB), resulting in successful decline of hepatocellular carcinoma (HCC) development and mortality. However, there has been controversy about the equivalence of long-term efficacies between ETV and TDF. In addition to antiviral agents, other drugs including aspirin, statin, and H1- antihistamines had protective effects on HCC development in several studies. Thus, we aimed to compare these effects of diverse drugs in a unified population-based cohort. Method: Using the Korean National Health Insurance Service database, we extracted a nationwide population cohort of patients with CHB who initiated ETV or TDF between January 2012 and December 2020. Then, a 15,569 pair propensity score-matched cohort was constructed. We compared cumulative incidence rates of HCC and mortality one year after starting treatment according to the drug prescription and dosage, using competing risk analyses. Results: The incidence of HCC was 51.0 and 41.5 per 1000 personyears in the ETV and TDF groups of a total cohort. In the matched cohort, HCC development was significantly lower in the TDF group than ETV group (subdistribution hazard ratio [SHR], 0.91). In addition, the use of statin and H1-antihistamines was significantly associated with a low risk of HCC development (SHR, 0.57 and 0.69, respectively). Even after applying antiviral groups, the low risks of statin and H1-antihistamines independently remained (SHR, 0.58 and 0.69, respectively). Furthermore, H1-antihistamines use had a dose-response relationship with the risk of HCC. The SHR of the H1- antihistamines use of 28–90, 90–180, and > 180 cumulative defined daily doses were 0.48, 0.31, and 0.29, respectively, relative to no H1- antihistamines use. Conclusion: In this study, TDF showed a more protective effect on HCC development compared to ETV. In addition, the use of statin and H1-antihistamines was independently associated with a lower risk of HCC development relative to no use of each drug. The effects of various drugs on the development of HCC were confirmed, and further research is needed on these mechanisms.