Impact of Comorbidity and Drug Use Patterns on Recurrence and Mortality Risks in Primary Hepatocellular Carcinoma: A Chinese Cohort Network Analysis Study

Background & Aims: Comorbidities in hepatocellular carcinoma (HCC) impair liver function, limit treatment choices, disrupt drug metabolism, and adversely impact survival. This study identifies comorbidity and multidrug combination patterns to evaluate their relationships with HCC outcomes. Methods: This cohort study comprised 15,998 patients (62.7% male, age at HCC diagnosis: 69.2 [IQR: 58.7-78.7] years old) from the Hong Kong Hospital Authority, enrolled between January 2008 and December 2019 with follow-up until May 2024. Primary endpoints were HCC recurrence and liver cancer-related mortality, while secondary endpoints included cancer-related mortality, non-cancer-related mortality, and all-cause mortality. We identified the most frequent double, triple, quadruple, quintuple patterns of both comorbidities and multidrug combinations using UpSet plots, then examined their associations with clinical outcomes using network analyses. Risk factors were evaluated through Cox proportional hazards regression models, with robustness confirmed via sensitivity analyses and subgroup assessments. Results In this cohort, 93.0% of patients had at least one pre-existing comorbidity (mean 3.0 per patient), of whom 87.8% (N=13,084) had 1-5 comorbidities. Diabetes mellitus, hypertension, and existing chronic liver diseases were the predominant comorbidities across all combinations, followed by colorectal cancer and renal diseases. Males demonstrated greater comorbidity burden, particularly involving metabolic disorders and advanced liver diseases. Notably, males with moderate-to-severe liver diseases had elevated HCC recurrence risk compared to females. Multidrug use rate among those with HCC recurrence was 79.5% (N=9999), of whom 25.7% with double-drug exposure, 13.8% with triple-drug exposure. Anti-diabetic drugs, ACEI/ARB, and diuretics for heart failure, anti-cancer drugs, and NSAIDs were the most common combination use. Both adjusted Cox regression models and subgroup analyses confirmed multi-comorbidity as a robust predictor of clinical outcomes. Conclusion: Our gender and age-specific characterization of comorbidity and multidrug patterns in HCC provides clinicians and patients with actionable insights to guide proactive management and patient-centered care, enabling earlier comorbidity detection and prevention strategies.