Patients with chronic hepatitis B who received long-term entecavir or tenofovir remained at risk for hepatocellular carcinoma (HCC) after more than 10 years of therapy, although the incidence rate declined significantly after year 10, according to findings from the PAGE-B cohort published in the Journal of Hepatology.
The findings support continued HCC risk assessment in patients receiving long-term nucleos(t)ide analogue therapy, particularly those with cirrhosis or higher PAGE-B scores. They also suggest that PAGE-B — a risk score based on platelet count, age and sex — may remain useful for identifying patients at higher or lower long-term HCC risk.
The long-term PAGE-B cohort included 1,644 Caucasian adults with chronic hepatitis B who were initially treated with entecavir or tenofovir disoproxil fumarate. Patients were followed at eight European centers in Greece, Italy, Turkey, Spain and the Netherlands. Mean follow-up was 10 ± 3 years overall, and 903 patients were followed beyond year 10 for a mean of 14 ± 2 years.
Before starting entecavir or tenofovir, no patient had HCC, decompensated cirrhosis, prior liver transplantation, or coinfection with hepatitis D, hepatitis C, or HIV. At baseline, the mean age was 53 years, 72% of patients were male and 28% had cirrhosis.
HCC incidence fell after year 10
HCC developed in 175 of 1,644 patients, including 157 cases before year 10 and 18 cases after year 10. The 10-year cumulative incidence of HCC was 10.9%, and the 15-year cumulative incidence was 13.2%.
The incidence rate of HCC declined significantly after year 10, from 1.25 per 100 person-years during the first 10 years of therapy to 0.55 per 100 person-years after year 10 (P < .001). The decline remained significant in sensitivity analyses using inverse probability weighting to account for potential survival bias among patients with longer follow-up.
The decrease was seen in patients with and without cirrhosis at baseline. Among patients with cirrhosis, the HCC incidence rate declined from 3.03 per 100 person-years before year 10 to 1.56 per 100 person-years after year 10. Among those without baseline cirrhosis, the rate declined from 0.58 to 0.18 per 100 person-years.
The authors noted that the remaining absolute risk among patients with baseline cirrhosis supports continued HCC surveillance. In patients without cirrhosis, the reduction to less than 0.2% annually supports further risk stratification to help target surveillance.
PAGE-B score identified long-term risk
In multivariable analysis, HCC risk was independently associated with older age, male sex, undetectable baseline hepatitis B virus (HBV) DNA, lower platelet count and baseline cirrhosis. The type of therapy – tenofovir vs. entecavir – was not associated with HCC risk.
PAGE-B score also remained associated with HCC development. The 15-year cumulative incidence of HCC was 26.7% among patients with high PAGE-B risk and 9.3% among those with intermediate risk. No HCC cases occurred among 356 patients with a low baseline PAGE-B score of less than 10.
According to the authors, that finding may be clinically useful because PAGE-B can be calculated at the start of therapy. In this cohort, baseline PAGE-B score continued to stratify HCC risk beyond 10 years of follow-up.
HCC remained the key driver of mortality
Although HCC incidence declined after year 10, HCC remained the main determinant of liver-related and overall mortality.
The incidence rate of liver-related death or liver transplantation was similar before and after year 10, at 0.74 vs. 0.70 per 100 person-years, respectively. The incidence rate of any death or liver transplantation was numerically higher after year 10, at 1.95 per 100 person-years, compared with 1.50 per 100 person-years before year 10, although the difference did not reach statistical significance.
In multivariable analysis, liver-related death or transplantation was independently associated with lower platelet count and HCC development. Any death or transplantation was independently associated with older age, diabetes, hepatitis B e antigen (HBeAg) positivity, lower platelet count and HCC development.
Hepatitis B surface antigen loss increased but remained uncommon
Among patients who remained on nucleos(t)ide analogue therapy, the 10- and 15-year cumulative hepatitis B surface antigen (HBsAg) loss rates were 8.3% and 14.3%, respectively.
The incidence rate of HBsAg loss increased after year 10, from 0.94 per 100 person-years before year 10 to 1.42 per 100 person-years after year 10 (P = .025), but remained low overall.
HBsAg loss was independently associated with older age, baseline HBeAg positivity, undetectable baseline HBV DNA and nucleos(t)ide analogue discontinuation while HBsAg-positive. The authors cautioned that treatment discontinuation occurred according to treating physicians’ decisions, not a study protocol, so findings related to discontinuation should be interpreted carefully.
Limitations and clinical takeaways
The study had several limitations. It was a real-world cohort study, and some patients were lost during follow-up. Additionally, the cohort included only Caucasian patients, so the findings need confirmation in patients of other backgrounds. Several potentially important predictors, including HBV genotype and serial HBsAg levels, were not available. Treatment adherence and interruptions were not systematically monitored, and comorbidities such as metabolic dysfunction-associated steatotic liver disease and alcohol use were not systematically recorded.
For clinicians, the findings suggest that long-term antiviral therapy substantially lowers but does not eliminate HCC risk in chronic hepatitis B. Patients with cirrhosis and those with high PAGE-B scores remain important candidates for continued surveillance, while low PAGE-B scores may help identify patients at very low long-term risk.
Several authors reported advisory, speaking, consulting and/or research relationships with pharmaceutical companies, including AbbVie, Gilead, GlaxoSmithKline, Roche, and others. Several authors reported no conflicts of interest. The study received no financial or other support.