Revealing New Trends in the Global Burden of Hepatocellular Cancer Related to Hepatitis C Virus by Region, Sociodemographic Index, and Sex

<b>Background/Objectives</b>: Hepatocellular carcinoma (HCC) remains a leading cause of global cancer mortality, with increasing incidence and persistently poor survival. Hepatitis C virus (HCV) is a major risk factor for HCC, and while the advent of direct-acting antivirals (DAAs) has significantly altered HCV-related hepatocellular cancer (HCC-HCV) risk, the global burden remains substantial. With the World Health Organization (WHO) aiming to reduce hepatitis-related deaths by 2030, we set out to evaluate global HCC-HCV trends from 1990 to 2021, stratified by sex, WHO region, and sociodemographic index (SDI), using data from the Global Burden of Disease (GBD) 2021 study. <b>Methods</b>: We analyzed age-standardized incidence (ASI), deaths, and disability-adjusted life years (DALYs) due to HCV-HCC from 1990 to 2021 using GBD 2021 data. Trends were stratified by WHO region, sociodemographic index (SDI), and sex. Joinpoint regression modeling was used to identify statistically significant temporal inflection points and calculate the annual percent change (APC) in unique time segments and average annual percent change (AAPC) over the entire study period (1990 to 2021). <b>Results</b>: Globally, deaths and DALYs attributable to HCV-HCC increased over the study period while ASI declined modestly. The region of the Americas exhibited the highest AAPC in all three metrics, potentially driven by an aging HCV-infected population, rising comorbidities (e.g., obesity, diabetes), and improved case detection. Nevertheless, on a global level, high-SDI regions showed the most favorable trends, particularly after 2016, likely reflecting the earlier adoption of DAAs and a differential success of WHO goals. Lower-SDI regions continued to exhibit increasing burden. Notably, ASI began to rise again between 2019 and 2021, suggesting an ongoing need to critically evaluate and restructure our approach to reducing HCV and HCV-HCC. <b>Conclusions</b>: Our findings underscore the urgent need for equity-driven, region-specific strategies to achieve better control of this highly morbid disease.