New Model Predicts the Hepatocellular Carcinoma Risk in Chronic Hepatitis B

Gi-Ae Kim, MD, PhD

Credit: Kyung Hee University

A new predictive model, the Revised REACH-B, outperformed a previous model in predicting the risk of hepatocellular carcinoma in noncirrhotic patients with chronic hepatitis B.¹

“The reREACH-B model showed improved discrimination and overall performance, maintained reasonable calibration, and offered higher clinical utility compared with the REACH-B model,” wrote investigators, led by Gi-Ae Kim, MD, PhD, from Kyung Hee University Hospital in Seoul, Republic of Korea.

Reports have shown 75% of all liver cancer occurs in Asia, predominantly hepatitis B virus (HBV) or hepatitis C virus infection.² People with HBV are at an increased risk of hepatocellular carcinoma by 5 – 100-fold.

Most (80%) of HBV infections spread from mother to child, and vaccination is the best tool to prevent an infection. For those who are already infected, antiviral therapy and surveillance are effective options. However, with HBV estimated to infect approximately 400 million people worldwide, universal surveillance for hepatocellular carcinoma is not feasible, and risk scores are needed to identify the populations most at risk.

Research has indicated a nonlinear association exists between serum hepatitis B virus (HBV) DNA levels and hepatocellular carcinoma in patients with chronic hepatitis B.1 The prognostic model REACH-B used data from REVEAL-HBV, a Taiwanese community-based prospective cohort, along with additional cohorts from Korea, Hong Kong, and Chinese University, and together the research showed the risk for hepatocellular carcinoma increases 10-fold with increasing levels of baseline HBV DNA ≥ 106 copies/ mL.

Investigators sought to revise the REACH-B model to include predictors of age, sex, platelet count, ALT levels, and positive hepatitis B antigen result. To do so, investigators developed and externally validated a predictive model, Revised REACH-B, for the hepatocellular carcinoma risk in noncirrhotic adult patients with chronic hepatitis B. The model was intended to predict the risk of incident hepatocellular carcinoma in noncirrhotic adult patients with chronic hepatitis.

“Our reREACH-B model improves on [the REACH-B model] framework by incorporating the novel finding of a nonlinear parabolic association between a wider range of HBV viral load (up to 9 log₁₀ IU/mL) and [hepatocellular carcinoma] risk,” investigators wrote. “In addition, it introduces platelet counts as a predictor, both of which were identified as robust predictors of [hepatocellular carcinoma].”

The multinational cohort study included 6949 patients with chronic hepatitis B from Korea for the model development and 7429 patients from Taiwan, Hong Kong, and the Chinese University for external validation. Participants did not have elevated levels of alanine aminotransferase (ALT), and thus they were not recommended for antiviral treatment

“This stance is rooted in the notion that patients in the immune-tolerant phase are at very low risk for developing [hepatocellular carcinoma],” investigators wrote. “However, the immune-tolerant phase, as defined by current guidelines, includes patients with HBV DNA levels around 6 log₁₀ IU/mL who face the highest risk for [hepatocellular carcinoma].”

Investigators added how patients with moderate HBV viremia, around 6 log₁₀ IU/mL, tend to fall into an undefined gray zone and are not recommended for treatment.

“Although these guidelines may help prevent liver failure, they may not be adequately protective against [hepatocellular carcinoma],” investigators continued.

Over a median follow-up of 10 or 12.2 years, the model development cohort and validation cohorts had 435 and 467 incident hepatocellular carcinoma cases, respectively. The study revealed baseline HBV DNA level was 1 of the strongest predictors of hepatocellular carcinoma.

Both cohorts reflected a nonlinear parabolic association between HBV DNA levels and hepatocellular carcinoma. Moderate viral loads, around 6 log₁₀ IU/mL, had the greatest hepatocellular carcinoma risk. Ultimately, this model demonstrated satisfactory discrimination and calibration; the c-statistics were 0.844 for the derivation cohort and 0.813 for the validation cohorts with multiple imputations.

“The Revised REACH-B model is easy to use, with readily available variables and high accuracy in [hepatocellular carcinoma] risk prediction, with outstanding discrimination and calibration,” wrote Ju Dong Yang, MD, MS, from Cedars-Sinai Medical Center and Patrick S. Kamath, from Mayo Clinic College of Medicine and Science in a commentary paper.² “Thus, this tool will be useful for patient counseling, monitoring, treatment planning, and prognostication.”

Yang and Kamath added how the model is only being developed and validated in East Asian countries where HBV infection is often acquired via vertical transmission, the generalizability of other countries is unknown. This is particularly because the route of transmission, duration of infection, host genetic susceptibility, and virus characteristics vary globally.

Kim and colleagues also acknowledge the findings were limited by the lack of validation in other races, as well as a lack of validation in those receiving antiviral treatment.¹

“By providing more comprehensive risk stratification, this model has the potential to inform optimal medical management strategies for patients with CHB who do not meet the current criteria for antiviral treatment,” investigators wrote.

References

1. ^{Kim GA, Lim YS, Han S, et al. Viral Load-Based Prediction of Hepatocellular Carcinoma Risk in Noncirrhotic Patients With Chronic Hepatitis B : A Multinational Study for the Development and External Validation of a New Prognostic Model. Ann Intern Med. Published online September 17, 2024. doi:10.7326/M24-0384}
2. ^{Yang JD, Kamath PS. Revised REACH-B Model for Hepatocellular Carcinoma Risk Prediction in Patients With Chronic Hepatitis B. Ann Intern Med. Published online September 17, 2024. doi:10.7326/M24-0894}