Impact of Clonorchis sinensis infection on long-term survival after curative resection for hepatocellular carcinoma: A multicenter cohort study.

BACKGROUND

Hepatocellular carcinoma (HCC) prognosis is poor in East Asia. The impact of Clonorchis sinensis (C.sinensis) infection, a known carcinogen for cholangiocarcinoma, on HCC prognosis after curative resection in co-endemic regions is unclear. This study aimed to evaluate the independent association of C.sinensis infection with overall survival (OS) and recurrence-free survival (RFS) after curative HCC resection.

METHODS

This retrospective, multicenter cohort study included 1386 patients undergoing R0 hepatectomy for HCC (2011-2021) in Guangxi, China (312 C.sinensis-positive, 1074 C.sinensis-negative). Associations were assessed using multivariable Cox regression and propensity score methods (1:1 PSM [primary], 1:3 PSM, IPTW) for multivariable adjustment for confounding. To assess robustness, additional sensitivity analyses including doubly robust estimation and E-value analysis were performed. Causal mediation analysis evaluated the role of microvascular invasion (MVI) on OS.

RESULTS

C.sinensis prevalence was 22.5%; median follow-up was 88 months. Significant baseline imbalances were observed. After the primary 1:1 PSM adjustment (N = 530), which achieved generally good balance (19/21 covariates SMD < 0.1), C.sinensis infection was significantly associated with poorer OS (adjusted Hazard Ratio [aHR], 1.55; 95% CI, 1.20-2.01; P < 0.001) and RFS (aHR, 1.63; 95% CI, 1.30-2.04; P < 0.001). The adverse OS association was robust across multivariable Cox and other propensity score sensitivity analyses (all P < 0.05). However, the RFS association was inconsistent across methods: while PSM analyses showed a significant association, this was not confirmed in multivariable Cox (P = 0.36), IPTW (P = 0.20), or doubly robust estimation (P = 0.27) analyses. After comprehensive covariate adjustment, MVI was found to significantly mediate the C.sinensis-OS association (Natural Indirect Effect P = 0.006), explaining approximately 12.7% (P = 0.020) of the total effect.

CONCLUSION

Concurrent C.sinensis infection is an independent risk factor for reduced OS after curative HCC resection in this endemic cohort. We recommend routine preoperative screening for C.sinensis to improve risk stratification and guide postoperative management.