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Director, Medical Data Analytics Centre (MDAC)
Deputy Director, Center for Liver Health
Assistant Dean (Learning Experience), Faculty of Medicine
The Chinese University of Hong Kong
Division of Gastroenterology and Hepatology
Department of Medicine and Therapeutics
Prince of Wales Hospital
Grace L. H. Wong, MD, has disclosed that she has received consulting fees from Gilead Sciences and Janssen; funds for research support from AbbVie and Gilead Sciences; and fees for non-CME/CE services from Abbott, AbbVie, Bristol-Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen, and Roche.
The World Health Organization (WHO) has set the goal of eliminating hepatitis B virus (HBV) infection as a public health threat by 2030, including reductions in incidence and mortality of 90% and 65%, respectively. A significant proportion of deaths in patients with HBV is due to hepatocellular carcinoma (HCC). The majority of HCC disease burden (85%) is in low- and middle-income countries with high HBV prevalence, such as the Asia-Pacific region. Resources for antiviral therapy, HCC surveillance, diagnosis, and treatment are often limited in this region. Even though the proportion of patients with HBV infection who receive treatment has been trending upwards, it was still below 70% in Hong Kong from 2014-2017 (a place where healthcare is highly subsidized by the government). Treatment uptake may be even lower in Asia-Pacific regions where the reimbursement criteria are more stringent. Compounding the problem, attending physicians’ prescribing behavior is influenced by reimbursement criteria, and some patients decline treatment when offered due to the costs and long duration of HBV treatment. Hence, there is an urgent need to offer effective, easy-to-use HCC risk assessment to guide patient selection for antiviral therapy and HCC surveillance in the region.
HCC Prediction Models: Helpful Clinical Tools for HCC Risk Stratification in Patients With Treatment-Naive HBV
The first few HCC prediction models were developed and validated in mostly untreated, Asian patients with HBV. The REACH-B risk score came from a cohort of 3584 treatment-naive, patients without cirrhosis but with HBV, from the landmark, community-based Taiwanese REVEAL-HBV study. The REACH-B risk calculation produces scores from 0-17 and uses risk factors that are readily available in the clinic setting: sex, age, alanine aminotransferase, hepatitis B e-antigen status, and HBV DNA level. Another cohort of 1505 treatment-naive patients from Hong Kong and South Korea constituted the validation cohort. In this cohort, the REACH-B areas under the receiver operating characteristic curve (AUROC) were 0.811 at 3 years, 0.796 at 5 years, and 0.769 at 10 years, which is considered good discriminatory capability. As this risk score was derived from a cohort without cirrhosis, its performance was indeed better in the validation cohort patients without cirrhosis, yielding AUROC of 0.902 at 3 years, 0.783 at 5 years, and 0.806 at 10 years.
The Chinese University HCC (CU-HCC) score was established in a cohort of 1005 patients with chronic HBV infection in Hong Kong. The CU-HCC risk score ranges from 0-44.5 and is calculated using age, serum albumin, total bilirubin, HBV DNA, and degree of cirrhosis. Using CU-HCC risk score cutoff values of 5 and 20, patients were stratified into low-risk, intermediate-risk, and high-risk groups. The corresponding sensitivity and negative predictive value (NPV) were 88.6% and 97.8%, respectively, and remained similarly high in an independent cohort of 424 patients with chronic HBV infection (82.2% and 97.3%, respectively). The CU-HCC score was subsequently optimized by the same group of investigators by using a liver stiffness measurement (LSM) rather than ultrasonography, to diagnose cirrhosis. The LSM-HCC score was derived from LSM, age, serum albumin, and HBV DNA level (eliminates total bilirubin) and ranges in value from 0-30. By using 11 as a cutoff value, the corresponding sensitivity and NPV at 5 years of the LSM-HCC score were 87.9% and 99.4%, respectively.
HCC Prediction Models in Patients With HBV Receiving Antiviral Treatment
The value of risk scores derived from treatment-naive cohorts, such as REACH-B and CU-HCC, is limited in patients treated with nucleos(t)ide analogues. The PAGE-B score was developed using age, sex, and platelet counts and has been used to predict HCC risk for up to 5 years among White patients undergoing treatment with entecavir or tenofovir. Subsequently, Korean investigators modified the weighting system for age, sex, and platelet count and added serum albumin as a risk factor to generate the modified PAGE-B (mPAGE-B) score for Asian patients with chronic HBV infection receiving entecavir or tenofovir treatment. Both PAGE-B and mPAGE-B scores show a good predictive ability (AUROC of >0.8) on HCC development in treated patients; both scores have also been well validated in independent treated cohorts.
HCC Risk Assessment and Surveillance
As outlined above, a handful of HCC risk scores have been developed for patients with treated and untreated chronic HBV infection, yet no formal recommendation has been made, including by the Asian Pacific Association for the Study of the Liver, on the optimal use of HCC risk scores in clinical practice. Most of the lower cutoff values of HCC risk scores have high NPVs; in the Asia-Pacific region with its very high HBV disease burden, patients with chronic HBV infection and low HCC risk scores may be offered less extensive HCC screening and surveillance. In my own clinical practice, CU-HCC score is calculated for all of my patients with HBV infection, as it is mandatory information we have to provide to arrange a surveillance ultrasound, and to establish the interval of surveillance. We recalculate CU-HCC score every 2 years.
Interdisciplinary Management of HCC
The coexistence of 2 diseases (HCC and cirrhosis) requires the expertise of many specialists to provide optimal care, as both the tumor and the cirrhotic liver may be drivers of mortality. Interdisciplinary management of HCC has become the preferred approach to address the increasing complexity of cancer treatment. Expert input from hepatologists alongside hepatobiliary and transplant surgeons, clinical and radiation oncologists, and interventional radiologists has become increasingly important to optimize HCC treatment outcomes. Treatment options should be discussed in interdisciplinary meetings, as no single treatment strategy can be applied to all patients, and treatment must be individualized to improve overall survival of patients with HCC. The team needs very good coordination, which takes at least 1 support staff to coordinate care, make agendas, and guide patients through the healthcare workflow. Of particular concern in Asia-Pacific region is the lack of certain specialists in some small, rural hospitals. More research is needed to define the cost-effectiveness of this interdisciplinary management team in the Asia-Pacific region.
Which HCC prediction model or risk score do you use to assess HCC risk in your patients with chronic HBV infection? How frequently do you reassess the HCC risk scores? Who should take the lead role on the interdisciplinary team for HCC treatment? Please share your thoughts and elaborate in the comments section.