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HBcrAg: A Novel Serum Biomarker With Potential for HCC Risk Prediction

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Yasuhito Tanaka, MD, PhD

Chief Professor
Department of Gastroenterology and Hepatology
Faculty of Life Sciences
Kumamoto University
Kumamoto, Japan

Yasuhito Tanaka, MD, PhD, has disclosed that he has received funds for research support from Fujirebio, and fees for non-CME/CE services from Fujirebio and Gilead Sciences.

View ClinicalThoughts from this Author

Released: May 6, 2021

Chronic hepatitis B (CHB) affects approximately 260 million persons worldwide. A significant percentage (15% to 40%) of people with CHB develop cirrhosis and/or hepatocellular carcinoma (HCC), making it a health problem associated with a high risk of death.

Most new hepatitis B virus (HBV) infections occur in HBV-endemic regions, such as China, southeast Asia, and sub-Saharan Africa. Although the overall prevalence of CHB in Japan is relatively low (the hepatitis B surface antigen [HBsAg] prevalence was approximately 1.2 million in 2011), HCC was the fourth most frequent cause of cancer death in Japanese men and the sixth most common cause of cancer death in Japanese women in 2016. (There were 28,528 deaths from HCC reported in Japan in 2016.) But with the development of effective anti-HBV treatments and the availability of guidance on routine HCC surveillance from clinical societies in Japan, the United States, Europe, and the Asia-Pacific region, a decrease in HCC risk in patients with CHB is achievable.

In Japan, patients are considered to be at high risk for HCC if they have cirrhosis, CHB, or chronic hepatitis C and at extremely high risk if they have CHB and/or chronic hepatitis C plus the presence of cirrhosis. The Japan Society of Hepatology recommends that high-risk patients undergo surveillance with ultrasound and 1 or more serum biomarkers every 6 months (α-fetoprotein [AFP], des-γ-carboxy-prothrombin [DCP], AFP-lens culinaris agglutinin-binding fraction [AFP-L3]). Extremely high–risk patients should be screened with ultrasound and concomitant biomarkers every 3-4 months, with optional dynamic CT/MRI every 6-12 months. If small nodules are detected, dynamic CT/MRI or EOB-MRI should be applied as well as combined serum biomarkers (AFP, DCP, and AFP-L3).

In terms of HBV control, the current goal is to achieve virologic suppression, preferably with seroclearance of HBsAg, and concomitant histologic improvement and decreased risk of complications. However, some patients may develop HCC even after treatment with nucleos(t)ide analogues (NAs), and it is difficult to predict which patients will have progression of liver disease. Several HBV markers have been identified as factors correlated with the development of HCC in patients with CHB.

HBcrAg: A Novel Serum Biomarker to Predict CHB Progression
Baseline HBV DNA level is a known independent predictor of HCC risk, but treatment with NAs only suppresses HBV replication and does not directly target covalently closed circular DNA (cccDNA). cccDNA is the key molecule responsible for viral persistence in the liver, and the quantity and transcriptional activity of cccDNA in liver cells correlates with CHB progression. Hepatitis B core-related antigen (HBcrAg) is a novel serum biomarker that correlates with levels of cccDNA in the liver, and it has been used to support CHB monitoring in Japan. Recent studies have demonstrated the association between serum HBcrAg level and the development of HCC in patients with CHB. Since the HBcrAg assay is simple to perform and low-cost (less than $15 USD/assay) compared with reverse transcriptase polymerase chain reaction (RT-PCR) ($60-200 USD/assay), it represents a potential alternative for monitoring CHB progression in resource-limited regions. More than 95% of people with CHB live in low-income to middle-income countries, so limited access and the expense of RT-PCR represents a major barrier to monitoring CHB progression and achieving global hepatitis elimination. The World Health Organization has recognized the urgent need for a low-cost assay to measure active HBV replication.

HBcrAg for HCC Risk Prediction in Treatment-Naive Patients With CHB
Chen and colleagues found that HBcrAg correlated positively with HBV DNA levels, regardless of detectable hepatitis B e antigen. HCC recurrence–free survival in 56 treatment-naive patients with CHB-related HCC was significantly reduced in patients with high HBcrAg vs low HBcrAg (>5.2 ≤5.2 log U/mL, respectively; P = .003). In another large, retrospective cohort study, Tada and colleagues demonstrated that HBcrAg was superior to HBV DNA at predicting HCC development in treatment-naive patients with CHB. During the mean follow-up period of 10.7 years, 78/1031 (76%) of participants developed HCC; an HBcrAg level >2.9 log IU/mL was associated with the incidence of HCC, with an HR of 5.05 (95% CI: 2.40-10.63).

HBcrAg for HCC Risk Prediction in Treatment-Experienced Patients With CHB
Studies have shown that in treatment-experienced patients, NA treatment reduced serum HBV DNA levels but did not eliminate the risk of HCC. In a study of 109 Japanese patients with CHB treated with NAs for at least 2 years, Honda and colleagues showed that HBcrAg positivity was an independent risk factor for HCC. In another study of 76 patients with CHB treated with NAs with undetectable serum HBV DNA, Cheung and colleagues found that median pretreatment and posttreatment HBcrAg levels were significantly higher in the group with HCC compared with the matched control group without HCC. Recently, Hosaka and colleagues investigated whether baseline and on-treatment serum HBcrAg levels could predict HCC incidence in 1268 NA-treated patients with CHB on therapy for more than 1 year. During the median follow-up of approximately 9 years, 113 patients (8.9%) developed HCC, and patients with high on-treatment HBcrAg levels had a higher risk of HCC compared with patients with low on-treatment HBcrAg levels.

HBcrAg for Prediction of HCC Recurrence After Resection or Radiofrequency Ablation
Postsurgical HCC recurrence rates remain high regardless of NA treatment status, with reported recurrence rates of more than 40% in 2 years. Hosaka and colleagues demonstrated the predictive value of HBcrAg for HCC recurrence after curative resection or percutaneous ablation. They found that a serum HBcrAg level >4.8 log U/mL at the time of first HCC diagnosis was associated with an HR of 8.96 for subsequent HCC recurrence. And remember the aforementioned study by Chen and colleagues demonstrating that recurrence-free survival rates were significantly lower in patients with CHB-related HCC who had high serum HBcrAg. Therefore, presurgery HBcrAg level could potentially be a biomarker to stratify postsurgical surveillance approaches and to identify patients with a high risk of HCC recurrence.

Take-home Points
Even in patients with CHB who achieve a functional cure (as defined by undetectable serum HBV DNA and HBsAg), HBV reactivation and HCC may develop. Because serum HBcrAg correlates with cccDNA, and HBcrAg may remain detectable in the absence of detectable HBV DNA, prospective studies comparing the long-term outcome between HBcrAg-positive and HBcrAg-negative patients are warranted. Recently, interest in HBcrAg as a predictive biomarker has been increasing, but most reports have been published from Asian countries. More large cohort studies including patients with and without HCC should be performed in other regions as well.

Your Thoughts?
Do you use serum biomarkers to assess HCC risk in patients with CHB? How do you predict risk of HCC recurrence after resection for CHB-related HCC? Please share your thoughts and elaborate in the comments section.

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