Fast track — ArticlesRisk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score
Introduction
Chronic hepatitis B is a major cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide, accounting for around 1 million deaths every year.1 The risk of chronic hepatitis B progression to HCC can be reduced by hepatitis B virus (HBV) therapy, as suggested by a meta-analysis.2 The identification and classification of patients who are at high risk of developing HCC is therefore important, and will allow timely intervention in those who will most benefit.3
Known risk factors for disease progression in chronic hepatitis B can be broadly divided into host, viral, and environmental factors.4 Host factors include age, sex, genetic susceptibility, family history, obesity, and immune status. Findings from a Korean study3 showed that age, male sex, and raised alanine aminotransferase (ALT) concentration were prognostic for HCC development. Viral factors can include HBeAg status, HBV DNA level, genotype, mutants, and co-infection. HBsAg seropositivity is an important risk factor for HCC, and HBeAg seropositivity has been associated with an increased risk of developing HCC.4, 5 Increasing HBV DNA levels have been associated with a stepwise increase in HCC risk, with high HBV DNA associated with an increased risk of HCC.6, 7, 8 Findings from several studies have shown that the risk of liver-related mortality is increased with even slight increases in serum ALT.9, 10 Gradual and cumulative liver damage caused by low level viraemia, and indicated by small rises in ALT concentrations, could be the pathway for severe complications and disease progression in Asian patients with chronic hepatitis B.10 HBV genotype is a contentious risk factor for HCC. A previously reported risk between HCC and HBV genotype C11, 12 could be attributable to close associations with genotype C and core promoter mutations,7 which are an independent risk factor.13 Furthermore, a meta-analysis14 has suggested that basal core promoter mutants might be an important risk factor. Environmental factors are the most difficult to quantify clinically, and include alcohol use, cigarette smoking, chemical carcinogens, and aflatoxin exposure.
The primary aim of therapy for chronic hepatitis B is to prevent disease progression to liver cirrhosis, HCC, and death.15 Although there is general consensus in guidelines about when and how to treat this disease and who should be treated, several other areas of management are controversial.16 Definitions for normal ALT, appropriate serum HBV DNA cutoff points, and the suitability of liver biopsy differ between guidelines.15, 17, 18, 19 There is no standardised and accurate guidance about assessment of HCC risk in chronic hepatitis B. Several HBV risk scores have been published; however, most are limited by population size.3, 7, 20, 21 A published nomogram had high potential to be adapted into a simplified clinical instrument, but it has not been externally validated.20
The successful development and use of risk calculators in cardiovascular disease have shown the benefits of such instruments to both patients and physicians.22, 23 All reliable, easily accessible, and accurate clinical factors predicting complications from chronic hepatitis B need to be identified and consolidated. This process could facilitate the timely identification of high-risk patients for whom treatment is still viable. The REACH-B (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B) study aimed to develop and validate a simple, clinically useful long-term prediction score, to identify the risk of progression to HCC in patients with chronic hepatitis B by use of a snapshot risk profile consisting of currently used non-invasive parameters.
Section snippets
Study populations for model derivation
The patient population used to develop the risk score (development cohort) consisted of patients from the population-based prospective REVEAL-HBV database, which has been described previously.8 Briefly, 3584 patients aged 30–65 years who were HBsAg seropositive, were anti-HCV seronegative, did not have cirrhosis, and had serum HBV DNA measured at study entry were used for this study. Patients did not receive antiviral treatment during the median follow-up of 12·0 years (IQR 11·5–12·4), during
Results
Table 1 shows the baseline characteristics of the development and validation cohorts. In both cohorts, most patients were men and HBeAg negative. As per the entry criteria, all patients in the development cohort did not have cirrhosis at baseline, compared with 82% (1228 of 1505) of patients in the hospital-based validation cohort. Patients in the development cohort differed from those in the validation cohort in terms of the distribution of sex, age, viral load, HBeAg status, and ALT and HBV
Discussion
This study was undertaken to develop a clinically useful HCC risk-prediction score in patients with chronic hepatitis B, with use of a community-based natural history cohort from Taiwan. The resulting predictive risk score was validated in a hospital-based composite cohort from several centres in Hong Kong and South Korea. To maximise clinical use, this risk calculator was designed to include simple, non-invasive, and routinely measured factors. Factors predictive of HCC in this study—sex, age,
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