Hepatic Steatosis Risk Persists After HCV Clearance Despite Fibrosis Marker Improvement

New research is shedding light on a significant increase in the prevalence of hepatic steatosis after achieving sustained virologic response (SVR) with direct acting antiviral (DAA) therapy.1

Although study findings reaffirm that hepatitis C virus (HCV) clearance is associated with substantial improvements in non-invasive markers of liver fibrosis, they also point to a significant increase in steatosis prevalence, driven both by the persistence of steatosis in those with baseline involvement and the emergence of new-onset steatosis in individuals without prior steatosis.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. Because DAAs can cure more than 95% of people with hepatitis C infection and prevent long-term liver damage, the World Health Organization recommends therapy with pan-genotypic DAAs for all adults, adolescents and children ≥ 3 years of age with chronic hepatitis C infection.2

“Despite successful viral eradication [with DAAs], growing evidence suggests that people with HCV may continue to experience long-term hepatic and metabolic complications,” Giada Sebastiani, MD, an associate professor of medicine at McGill University and a clinician scientist at the Research Institute of McGill University Health Centre, and colleagues wrote.1 “Among these, hepatic steatosis is particularly prevalent and clinically relevant, which may persist or even newly develop post-SVR.”

Acknowledging gaps in research about the evolution of steatosis following SVR, investigators sought to assess early changes in non-invasive markers of steatosis and fibrosis post-SVR following DAA therapy through a retrospective, bicenter cohort study of patients from McGill University Health Centre in Canada, and the University of Milan in Italy, between 2016 and 2019. For inclusion, patients were required to be ≥ 18 years of age, receive DAA therapy, and achieve SVR, defined as undetectable HCV RNA 12 weeks after treatment completion.1

At baseline, participants were stratified according to the presence or absence of steatosis, which investigators defined as a CAP value ≥248 dB/m, and further assessed for cardiometabolic risk factors—including elevated body mass index (BMI) ≥25 kg/m², fasting plasma glucose ≥100 mg/dL or a diagnosis of type 2 diabetes, high blood pressure (≥130/85 mmHg), plasma triglycerides ≥150 mg/dL, and high-density lipoprotein cholesterol ≤40 mg/dL in males or ≤50 mg/dL in females—to determine whether they met the criteria for metabolic dysfunction-associated steatotic liver disease (MASLD).1

Liver stiffness measurement (LSM) was used to assess liver fibrosis via transient elastography. Significant liver fibrosis and cirrhosis were defined as LSM ≥8 kPa and ≥13 kPa, respectively.1

The primary outcome was the change in steatosis status over time, categorized as resolution, persistence, or new onset. Secondary outcomes included change in MASLD status and change in the degree of liver fibrosis.1

A total of 108 participants were included. Among the cohort, the overall median age was 62 years (interquartile range, 56-73), 50% were female, 47% had steatosis, and 49% had significant liver fibrosis or cirrhosis at baseline.1

At 24 weeks post-SVR, investigators noted the prevalence of steatosis increased from 47% to 61%, while MASLD remained highly prevalent, from 94% to 92%. In contrast, the proportion of participants with significant liver fibrosis and cirrhosis decreased from 49% to 17%, and from 16% to 5%, respectively.1

When stratified by baseline steatosis status, 88% of participants with baseline steatosis had persistent steatosis at follow-up, whereas 12% showed resolution. In contrast, among those without steatosis at baseline, 37% developed new-onset steatosis and 63% remained steatosis-free. Paired comparisons from baseline to the end of follow-up revealed modest worsening in CAP values, rising from 245 to 260 dB/m (P = .0007) and indicating a trend toward increased hepatic fat content despite viral eradication.1

In contrast, investigators observed significant improvements in liver fibrosis markers, with a notable reduction in median LSM from 7.9 to 5.6 kPa (P <.0001), and FIB-4 score from 2.13 to 1.58 (P <.0001). They also pointed out substantial improvements in liver enzymes, including ALT, AST, and GGT (all P <.0001).1

In patients without baseline steatosis, total cholesterol and triglycerides increased (P = .0084 and P <.0001, respectively), whereas in those with baseline steatosis, only total cholesterol rose (P = .0296).1

Further analysis revealed elevated BMI at 24 weeks was the only independent predictor of steatosis at the end of follow-up, with each unit increase in BMI associated with a nearly 2-fold increase in the odds of steatosis (adjusted odds ratio, 1.92; 95% CI, 1.22–3.03; P = .0049).1

“These findings underscore the growing importance of metabolic liver disease in the post-SVR era, suggesting that clearance of HCV does not fully eliminate the risk of progressive liver injury, particularly when metabolic risk factors are present,” investigators concluded.1

References

1. Shengir M, Elgretli W, Cinque F, et al. Metabolic Factors Drive Early Increase in Hepatic Steatosis Despite Improvement in Non-Invasive Fibrosis Markers after Hepatitis C Eradication with Direct-Acting Antivirals. Clin Res Hepatol Gastroenterol. doi:10.1016/j.clinre.2025.102639

2. World Health Organization. Hepatitis C. April 9, 2024. Accessed June 23, 2025. https://www.who.int/news-room/fact-sheets/detail/hepatitis-c