Certain Patients With Cured Hepatitis C Virus Infection Still Face Risks for Hepatocellular Carcinoma

Carolyn Crist

September 23, 2022

In patients with cured hepatitis C, the risk for hepatocellular carcinoma remains high among those who had cirrhosis before infection, according to a new report.

In those without cirrhosis, diabetes and hypertension also play a role in the risk for hepatocellular carcinoma.

Jennifer Kramer, PhD

"This paper highlights the need for patients with cured hepatitis C virus infection and preexisting cirrhosis to be monitored over time to examine changes in their bloodwork that may signify increased risk for developing liver cancer," Jennifer Kramer, PhD, an associate professor of health services research at the Baylor College of Medicine and a health science specialist at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas, told Medscape Medical News.

"Also, patients with cured hepatitis C virus infection without cirrhosis but with underlying diabetes and hypertension are not yet out of the woods for developing hepatocellular carcinoma, and should also be followed by their physician," she said.

The study was published online in The American Journal of Gastroenterology.

Calculating the Major Risk Factors

Kramer and colleagues conducted a retrospective cohort study of 92,567 patients with hepatitis C virus infection who achieved a sustained virologic response with direct-acting antivirals. They looked at patients who visited one of the 130 Veterans Administration hospitals during 2014-2018 and were followed through 2021.

The research team analyzed the associations between demographic, clinical, and behavioral factors and liver cancer risk, measuring at baseline and at 12 and 24 months after a sustained virologic response.

Among the 92,567 patients, approximately 27% had a cirrhosis diagnosis before hepatitis C virus infection. In addition, 5.5% had a Fibrosis-4 (FIB-4) value greater than 3.25, 36.7% had diabetes, 83.1% had hypertension, 51.2% had dyslipidemia, and 14.1% had an active alcohol use disorder. The average age was 61 years, and 96% were men.

Overall, 3247 hepatocellular carcinoma cases were diagnosed during an average 2.5 years of follow-up. Among those, 2404 cases (74%) were diagnosed in patients with cirrhosis at baseline.

Among the 29,398 patients with cirrhosis, the cumulative incidence of hepatocellular carcinoma was 2.0% at 1 year, 3.8% at 2 years, and 5.4% at 3 years.

The risk was substantially lower in the 63,169 patients without cirrhosis, of whom 843 were diagnosed with hepatocellular carcinoma. The risk was 0.2% at 1 year, 0.5% at 2 years, and 0.8% at 3 years.

In patients with cirrhosis, the risk for liver cancer was higher in men, smokers, those with hepatitis C genotype 3, and those with 5 or more years since cirrhosis diagnosis. The risk was lower in African American patients.

In addition, serum bilirubin, albumin, presence of varices, and higher FIB-4 scores were associated with hepatocellular carcinoma risk. For the latter variable, the risk was 2.5-fold higher in cirrhosis patients who had a FIB-4 score higher than 3.25 vs those with FIB-4 scores less than 1.45.

Over time, most of the associations observed at baseline persisted at the 12- and 24-month points, with a few notable exceptions, the study authors write. For instance, the presence of ascites was associated with an increased risk for hepatocellular carcinoma at both these follow-up times.

There was also a strong association between the risk for liver cancer and changes in serum albumin, bilirubin, and FIB-4 scores. A one-unit increase in serum bilirubin between baseline and 24 months was associated with a 22% increase in cancer risk.

The risk for hepatocellular carcinoma was almost twofold higher in patients who had persistently high FIB-4 scores at the time of virologic cure and 24 months, compared with patients who had persistently low FIB-4 scores. In addition, the risk was 81% higher in patients who had low scores at baseline that increased to high scores at 24 months.

In patients without cirrhosis, those with hypertension and diabetes had a 1.5-fold higher risk for hepatocellular carcinoma than their peers. After diabetes and hypertension were controlled for, there were no differences between patients with a body mass index (BMI) of 30 or higher and those with a BMI of 25-30. In contrast, the risk was higher in patients with a BMI less than 25, with the highest risk in patients with a BMI less than 18.5.

In addition, baseline serum albumin and FIB-4 scores were associated with liver cancer risk. Patients with a baseline FIB-4 score between 1.45 and 3.25 had a 2.3-fold higher risk than those with a low score. Prior failure of hepatitis C treatment, genotype 3, and current smoking were also associated with a higher risk in patients without cirrhosis.

Putting These Results Into Practice

Conducting risk assessments based on repeat measurements at 24 months is "practical and can improve shared decision-making between patients and their physicians," the study authors write.

George Ioannou, MD

"We are all struggling to determine how to best approach hepatocellular carcinoma screening as time accrues after sustained virological response in patients with and without cirrhosis," George Ioannou, MD, professor of medicine at the University of Washington, told Medscape Medical News.

Ioannou, who wasn't involved with this study, also serves as director of hepatology at the Veterans Affairs Puget Sound Health Care System. He and colleagues have found that an increased liver cancer risk persists up to 10 years after hepatitis C eradication, particularly in patients with baseline cirrhosis and high FIB-4 scores.

"This study provides some insights, especially that changes in risk factors over time will need to be carefully considered," he said. "More work will be needed to operationalize an approach for estimating hepatocellular carcinoma risk after sustained virological response in individual patients."

In addition, Kramer suggested measures to address major risk factors before they develop into an underlying condition.

"All adults over the age of 18 should be tested for hepatitis C virus infection, even without the presence of symptoms, as it can be easily cured before cirrhosis develops," she said.

The study was based on work supported by the Department of Defense and was supported by the National Cancer Institute, the Cancer Prevention & Research Institute of Texas, the Veterans Administration Center for Innovations in Quality, Effectiveness and Safety, the Michael E. DeBakey VA Medical Center, and the Center for Gastrointestinal Development, Infection and Injury. The authors reported no competing interests. Ioannou reported no relevant disclosures.

Am J Gastroenterol. Published online August 23, 2022. Abstract

Carolyn Crist is a health and medical journalist who reports on the latest studies for Medscape, MDedge, and WebMD.

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