Successful HCV Treatment with DAAs Linked to Lower Extrahepatic Manifestation Risk

Successful hepatitis C virus (HCV) treatment with direct-acting antivirals (DAAs) is associated with a reduced risk of several extrahepatic manifestations (EHMs), according to findings from a recent study.1

Leveraging data from the BC Hepatitis Testers Cohort, the study found successful DAA treatment leading to sustained virologic response (SVR) was linked to lower risks of chronic kidney disease (CKD), stroke, major adverse cardiac events (MACE), and neurocognitive disorders, but not type 2 diabetes, compared with no treatment.1

According to the World Health Organization, globally, an estimated 50 million people have chronic HCV infection, with about 1 million new infections occurring per year. Although there is no effective vaccine against HCV, DAAs can cure more than 95% of persons with infection.2

“Studies following the advent of DAAs suggested that HCV cure achieved through DAA treatment may be associated with reduction of EHMs,” Naveed Zafar Janjua, MBBS, DrPH, an executive director of data and analytic services at the BC Centre for Disease Control and a clinical associate professor in the School of Population and Public Health at the University of British Columbia, and colleagues wrote, describing inherent limitations to existing research and a lack of data on certain extrahepatic manifestations.1 “To advance our understanding of the protective effects of DAAs against extrahepatic manifestations, it is critical to assess diverse extrahepatic manifestations, particularly within large, population-based cohorts.”

Seeking to address these gaps in research, investigators conducted a population-based retrospective cohort study using data from the BC Hepatitis Testers Cohort, which includes > 1,300,000 people tested for HCV in British Columbia between 1990 and 2015. The study population included individuals diagnosed with chronic HCV by March 2020. Investigators matched people treated with DAAs to those who were never treated by the year of their first HCV RNA diagnosis, within a 12-month time frame, in a 1:1 ratio without replacement using prescription-time distribution matching.1

SVR was determined by a negative HCV RNA test ≥ 10 weeks post treatment. Individuals were classified as treated and SVR, treated and no SVR, or untreated.1

Investigators categorized EHMs into 5 groups:

• CKD and end-stage kidney diseases (ESKD)
• Type 2 diabetes
• Hospitalized stroke, including hemorrhagic, ischemic stroke and transient ischemic attack
• MACE, including acute myocardial infarction, angina, heart failure, peripheral vascular disease, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, and stroke
• Neurocognitive disorders, including dementia, delirium, and Alzheimer disease

Among the 22,576 individuals included in the study, the mean age at HCV diagnosis was 42.0 (Standard deviation, 12.0) years and the majority of the cohort was male (66.2%). In total, 1953 patients received DAA treatment and achieved SVR, 386 received treatment but did not achieve SVR, and 10,237 never received treatment.1

While there were no statistically significant differences in EHM prevalence among those who achieved SVR versus those who did not, incident cases varied. Among the overall study population, individuals in the untreated group and those in the treated and no SVR group had greater incident rates of EHMs compared with those who were in the treated and SVR group, except for type 2 diabetes.1

The incidence rates per 1000 person-years in untreated versus treated with SVR groups were as follows:

• CKD/ESKD: 21.0 (95% CI, 19.0-23.1) vs 14.7 (95% CI, 13.4-16.1)
• Stroke: 8.9 (95% CI, 7.7-10.2) vs 6.3 (95% CI, 5.5-7.2)
• MACE: 26.7 (95% CI, 24.5- 29.1) vs 19.3 (95% CI, 17.8-20.9)
• Neurocognitive disorders: 19.2 (95% CI, 17.3-21.2) vs 10.3 (95% CI, 9.2-11.5)
• Type 2 diabetes: 6.4 (95% CI, 5.4-7.7) vs 9.2 (95% CI, 8.1-10.4)

After adjusting for confounders, investigators found successful HCV treatment with DAA was associated with reduced risks of incident CKD/ESKD (adjusted cause-specific hazard ratio [acsHR], 0.54; 95% CI, 0.47-0.63), stroke (acsHR, 0.66; 95% CI, 0.54-0.81), MACE (acsHR, 0.58; 95% CI, 0.52-0.66), and neurocognitive disorders (acsHR, 0.52; 95% CI, 0.45-0.66) compared with no treatment. Of note, type 2 diabetes risk was not reduced (acsHR, 1.04; 95% CI, 0.84-1.29).1

“The potential extrahepatic benefits of HCV treatment highlighted in this study provide additional rationale for enhanced efforts to identify and overcome barriers to care, including reducing stigma, increasing clinician awareness, addressing socioeconomic challenges, and implementing innovative care models to improve overall health of people affected by HCV,” investigators concluded.1

References

1. Jeong D, Wong S, Karim ME, et al. Direct-Acting Antivirals and Risk of Hepatitis C Extrahepatic Manifestations. JAMA Netw Open. 2025;8(6):e2514631. doi:10.1001/jamanetworkopen.2025.14631

2. World Health Organization. Hepatitis C. Newsroom. April 9, 2024. Accessed June 12, 2025. https://www.who.int/news-room/fact-sheets/detail/hepatitis-c