Hepatitis C virus (HCV) is a hepatotropic RNA virus that causes both acute and chronic hepatitis, with approximately 58 million people worldwide infected with HCV and 1.5 million new infections occurring each year. HCV infection remains an ongoing public health threat (1). Acute hepatitis C (AHC) is defined as the 6-month period following infection with HCV, a critical phase during which 15–45% of immunocompetent individuals achieve spontaneous viral clearance, while the majority develop chronic infection leading to cirrhosis and hepatocellular carcinoma (2). Although an increasing incidence of acute hepatitis C has been reported in certain high-risk populations, this trend varies considerably across geographic regions. In some high-income countries, rising incidences have primarily been driven by people who inject drugs, whereas in other regions, healthcare-related or vertical transmission remains more prominent (3). This underscores the necessity of expanding screening and prevention efforts beyond clinical settings to actively reach these key populations. Accordingly, hepatitis C screening and prevention strategies differ substantially across regions and countries, reflecting local epidemiological characteristics and healthcare systems. The advent of therapies with direct antiviral agents (DAAs) has revolutionized the treatment of HCV, achieving sustained virological response (SVR) rates of >95% in patients with chronic infections (4). Therefore, optimising strategies for the early identification and treatment of acute HCV is essential to achieve the World Health Organization’s (WHO) goal of eliminating viral hepatitis by 2030. The Global Burden of Disease Study 2021 (5) has significantly contributed to outlining the epidemiological landscape of HCV through systematic data integration. However, the trends in the disease burden of AHC and its underlying causes remain underexplored. Specifically, the lack of studies that analyse the heterogeneity in AHC incidence across regions with different SDI from an APC perspective impedes a comprehensive understanding of how health system performance, historical exposure events, and birth cohort risks collectively shape the epidemic dynamics of AHC.

In this study, we used data from the GBD 2021 database to analyse the trends and temporal distribution of the burden of hepatitis C globally, in China, and in countries with five SDI levels from 1990 to 2021. The aim is to propose precise screening and prevention efforts and provide a comprehensive perspective for developing targeted hepatitis C prevention strategies that address the specific needs of different countries.

Based on the data of GBD 2021, this study systematically analysed the long-term trend of acute hepatitis C incidence in the world and China from 1990 to 2021 and revealed the effects of socio-economic development, age structure, time period change, and birth cohort on the incidence risk through the APC model. The results showed substantial differences in incidence rates across SDI categories, with low-SDI countries exhibiting the highest standardized incidence rates of acute hepatitis C, far exceeding the global average. Globally, the standardized incidence of acute hepatitis C shows an overall downward trend. Notably, a particularly rapid decline was observed in China. Women face a higher risk of infection than men within the same age group, and low-SDI countries continue to have the highest death rates. The global risk of acute hepatitis C was “bimodal” with increasing age, with the highest incidence risk in the age group of 0–4 years, followed by the age group of 95 years and above, and the fastest decline in incidence rate in China. The global risk of acute hepatitis C began to rise between 2015 and 2019, peaking in 2020–2021.

In this study, we found that the standardized incidence of acute hepatitis C was significantly higher in low-SDI countries than in high-SDI countries, which is consistent with previous studies (7). The high incidence in low-SDI regions can be attributed to multiple factors: risky healthcare practices, unsafe injections, insufficient screening of blood products, and the reuse of medical devices are the main routes of HCV transmission. The rate of HCV infection due to transfusion safety breaches is as high as 20% in some parts of Africa (8). Low coverage of screening and intervention programmes targeting high-risk groups results in the persistence of hidden chains of transmission (9). The risk of transmission is further exacerbated by poor sterilisation in traditional medical practice (10). In contrast, high-SDI countries have significantly reduced incidence through systematic prevention and control measures. Since the 1990s, Europe and the United States have implemented rigorous blood donor screening and viral inactivation techniques, which have reduced the rate of transfusion-associated HCV infection to <0.001% (11). Since 2014, the widespread use of direct-acting antiviral agents (DAAs), primarily for chronic HCV infection, has achieved cure rates of >95%. By rapidly curing existing chronic infections, DAAs reduce the reservoir of transmissible viruses in the community. This “treatment-as-prevention” effect consequently lowers the incidence of new acute infections and, thereby, the future risk of chronicity at the population level (12). Since 2008, China’s ASIR has remained at a level comparable to or below that of high-SDI countries. It is important to note that the Joinpoint acceleration around 2008 occurred before the widespread availability and reimbursement of DAAs in China, which began primarily after 2017. This initial decline in incidence is likely related to early public health interventions, including enhanced blood safety regulations and stricter screening of blood donors implemented in the early 2000s. However, further evidence is needed to confirm the specific impact of these interventions on HCV incidence trends. The increased accessibility of DAAs in later years further consolidated this declining trend (13). The comprehensive prevention benefits of DAAs are constrained by unequal access, with costs and health system barriers disproportionately affecting high-risk populations and low socioeconomic areas, thereby perpetuating transmission reservoirs. However, uneven regional development has resulted in a higher risk in rural areas of central and western China, suggesting the need to strengthen the capacity of primary care (14). It is important to note that significant regional disparities persist within China, mirroring the health inequities observed across SDI groups globally and underscoring the ongoing challenge of ensuring equitable access to interventions. The APC model revealed a persistent ‘bimodal’ age-specific risk pattern for acute hepatitis C globally, characterised by peaks in early childhood (0–4 years) and very old age (≥95 years), with a pronounced trough during working ages (15–64 years). This pattern is likely driven by distinct aetiologies. The early-childhood peak is predominantly attributable to vertical (mother-to-child) transmission, sustained by uneven implementation of prenatal HCV screening, particularly in low-SDI settings (15, 16). In China, the higher relative risk in younger age groups compared to the global average may signal gaps in universal perinatal screening (17). Conversely, the peak in the older adults reflects cumulative historical exposures from periods of less stringent infection control (e.g., unscreened blood transfusions, unsafe injections) during the mid-to-late twentieth century (18), with age-related immunosenescence potentially increasing the severity of acute episodes (19). The consistency of this bimodal pattern underscores it as a robust epidemiological feature stemming from biological vulnerability and cohort-specific historical risks. The higher prevalence in women than in men in the same age group may be related to differences in the frequency of healthcare contacts and hormone-regulated immune responses (20), which need to be targeted to optimize women’s health services. The age-related double-peak structure identified in this study has been reported in HCV burden studies across multiple countries worldwide, indicating that it is not an isolated data phenomenon. The renewed increase in risk during advanced age more likely reflects historical cohort effects: older adults populations experienced unscreened blood products, repeated injections, or iatrogenic exposures during their youth, with long-term latent effects manifesting predominantly in later life (21). Although GBD estimates for the older adults cohort may exhibit some variability due to smaller case numbers, higher mortality rates, and increased data uncertainty, the consistent emergence of an older adults peak across multinational studies suggests that this phenomenon is unlikely to be primarily driven by model instability. The older adults peak is more likely to be driven by cumulative historical exposure, with model variability playing only a secondary role.

The resurgence in the global ASIR beginning around 2015 likely results from a confluence of factors that vary across the SDI spectrum. In many low- and middle-SDI countries, the observed increase may be partially artefactual, reflecting significant improvements in diagnostic capacity and surveillance systems since the early 2010s, which are uncovering a reservoir of previously undiagnosed prevalent and incident cases (21). Additionally, persistent health system gaps in some settings may contribute to ongoing iatrogenic transmission. In contrast, in high-SDI countries, the increase is largely driven by well-documented shifts in risk factors, most notably the opioid crisis, supported by international evidence from North America and parts of Europe, which has increased injection drug use and sustained person-to-person transmission among younger populations (22). The period effect showing the highest risk in 2020–2021 also necessitates consideration of the impact of the COVID-19 pandemic, which disrupted routine hepatitis prevention and treatment services in many settings, potentially causing delayed diagnoses and a backlog of cases being identified as services resumed (23). Therefore, the post-2015 trend represents a composite picture: improved case ascertainment in some areas, genuine epidemic dynamics driven by behavioural risks in others, and the transient disruptive effect of the pandemic. The cohort effect showed a significant reduction in the risk of morbidity in the late-born cohort, corroborating the protective effect of universal access to DAAs and preventive education for the younger generation (24). However, the persistent decline in the risk of morbidity in high-SDI countries and the increase in the risk in low-SDI countries highlight the long-term challenge of unequal distribution of global health resources. Addressing this requires policies that couple targeted screening for high-risk groups with concerted efforts to ensure equitable access to DAAs across all SDI strata.

Despite a long-term decline, the global increase in acute hepatitis C incidence underscores an ongoing public health challenge. Our findings highlight the urgent need to strengthen prevention and screening strategies, particularly in low-SDI regions, among vulnerable age groups, and to implement targeted screening and prevention programmes for key populations. This includes expanding point-of-care testing and harm-reduction services for people who inject drugs in high-incidence areas and ensuring universal prenatal HCV screening to interrupt vertical transmission. There is an urgent need to accelerate equitable access to DAA treatment. Policies should aim to remove financial and systemic barriers to DAAs, particularly in low- and middle-SDI countries, to rapidly reduce the community viral reservoir and achieve the “treatment as prevention” effect, and for high-risk populations, to achieve the goal of hepatitis C elimination.

First, all data used in this study are sourced from the GBD 2021 database. This database generates temporally and spatially comparable disease burden estimates through complex statistical modelling, bias correction, and smoothing algorithms based on multiple data sources, rather than relying solely on raw national surveillance data. While such modelled estimates help address data gaps and enhance comparability across countries, their inherent smoothing mechanisms may reduce sensitivity to short-term fluctuations or localised anomalies in incidence rates. Second, the modelling nature of GBD estimates may affect the precision of this study’s APC decomposition results, particularly when identifying smaller cohort effects. Due to the model’s inherent smoothing mechanism, subtle cohort fluctuations may be absorbed and merged into broader age or period effects, making them difficult to identify as statistically significant independent cohort variations. Finally, due to limited AHC surveillance and screening capabilities in some countries and regions—particularly in low-SDI countries—actual incidence rates may be underestimated. This limitation may further compromise the accuracy of the GBD model estimates in these areas.