SUMMARY: The American Cancer Society estimates that in 2025, about 67,440 people will be diagnosed with pancreatic cancer and 51,980 people will die of the disease. Pancreatic Ductal AdenoCarcinoma (PDAC) remains one of the most lethal malignancies, with most cases diagnosed at advanced stages and few modifiable risk factors identified to date. Detecting cancer at early stages can significantly increase survival rates and outcomes.
A large population–based cohort study from the US Veterans Health Administration (VA) provides compelling new evidence that chronic hepatitis C virus (HCV) infection independently increases PDAC risk, strengthening the rationale for broad HCV screening and antiviral treatment initiatives.
Study Design
This retrospective cohort study evaluated 6.3 million veterans with documented HCV testing between 2001 and 2020, leveraging two decades of integrated VA electronic health records and linked Medicare data. Veterans were classified into three groups:
- Chronic HCV infection (confirmed via viral load, genotype, or treatment history)
- HCV exposure only (positive antibody or diagnostic code without RNA confirmation)
- No HCV infection
More than 5.6 million individuals comprised the final analytic cohort. Individuals were followed for a median 5.1 years, with adjustment for key PDAC risk factors such as smoking, alcohol use, pancreatitis, diabetes, liver disease, and demographic variables.
Key Findings
- HCV infection significantly increases PDAC risk.
Compared with veterans without HCV, the risk of PDAC was higher among those with:
- Chronic HCV Infection: adjusted HR=1.76 (95% CI, 1.67–1.86)
- HCV exposure: adjusted HR=1.18 (95% CI, 1.11–1.25)
Veterans with chronic HCV infection developed PDAC at markedly younger ages (median 65 years vs 72 years in non-HCV patients), suggesting accelerated carcinogenesis.
- PDAC incidence rates were substantially higher with chronic HCV.
- 107.7 per 100,000 person-years (chronic HCV infection)
- 68.0 per 100,000 person-years (HCV exposure)
- 51.9 per 100,000 person-years (non-HCV)
- HCV genotype influences PDAC risk.
Among individuals with chronic HCV infection, risk varied significantly compared with no HCV infection:
- Genotype 3: adjusted HR=2.02
- Genotype 1: adjusted HR=1.75
- Genotype 2: adjusted HR=1.35
Higher-risk genotypes (1 and 3) parallel patterns previously observed in HCV-associated hepatocellular carcinoma.
Biological Context
The study supports earlier observations linking HCV to pancreatic injury and inflammation. Proposed mechanisms include:
- Chronic inflammation induced by persistent viral infection may create a tumor-promoting microenvironment similar to that seen in HCV-associated hepatocellular carcinoma.
- Viral antigens identified in pancreatic acinar cells suggest the possibility of direct infection, with potential for genomic injury and local inflammation.
- Activation of pancreatic stellate cells, analogous to hepatic stellate cell activation in liver fibrosis and cirrhosis, may facilitate desmoplasia and tumor progression
These pathways align with known inflammatory drivers of PDAC, including tobacco use, alcohol-associated disease, and metabolic dysfunction.
Clinical and Public Health Implications
This analysis, the largest of its kind, suggests that chronic untreated HCV is a modifiable PDAC risk factor, independent of other established contributors. With direct-acting antiviral (DAA) therapies achieving >95% cure rates, improving HCV screening and treatment uptake may hold downstream benefits for PDAC prevention.
Key implications include:
- Risk stratification: Incorporating HCV status into PDAC prediction models may enhance early detection strategies.
- Genotype-specific counseling: Patients with genotype 1 or 3 may represent a higher-risk subgroup requiring closer surveillance.
- Therapeutic impact: Future research is needed to clarify whether DAA-mediated HCV eradication attenuates long-term PDAC risk.
Conclusion
In a nationwide cohort of more than 6 million veterans, chronic HCV infection was associated with a 1.8-fold increase in PDAC risk, with particularly elevated risk among those with HCV genotypes 1 and 3. These findings underscore the importance of early HCV identification and treatment, not only to prevent liver disease, but potentially to reduce the burden of pancreatic cancer.
Pancreatic Ductal Adenocarcinoma After Hepatitis C Infection. Levinson RN, Bushman R, Tate JP, et al. JAMA Netw Open. Published online:November 14, 2025;8;(11):e2543701. doi:10.1001/jamanetworkopen.2025.43701.
