Chronic hepatitis B virus (HBV) infection is a serious public health problem because of its worldwide prevalence and potential to cause adverse consequences. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer‐Hepatitis B Virus (REVEAL‐HBV) study carried out in Taiwan was used to investigate the natural history of chronic hepatitis B. The REVEAL‐HBV study has established an HBV viral load paradigm in the natural history of chronic hepatitis B (CHB). Serum HBV DNA level has been shown to be significantly and independently associated with incidence of hepatocellular carcinoma (HCC) and cirrhosis and liver‐related mortality across a biological gradient. It is also a major predictor of HBsAg seroclearance. Genetic features including HBV genotype and basal core promoter A1762T/G1764A mutant, and precore G1896A mutant were documented as predictors of HCC risk. Inactive HBV carriers still had an increased risk on HCC development and liver‐related mortality compared with HBsAg ‐seronegatives. Nomograms focusing on facilitating risk communication between patients and clinicians were developed incorporating non‐invasive clinical parameters to predict long‐term HCC risk. These will hopefully contribute to evidence‐based decisions in the clinical management of CHB patients. A somewhat provocative and novel finding from the REVEAL‐HBV study is the association of chronic HBV infection in active replication with an increased pancreatic cancer risk especially in women less than 50 years old. This finding will hopefully spur further research in this area seeking confirmatory evidence. Finally, we hope that the REVEAL‐HBV study will continue to be a source of data to answer other important questions in chronic hepatitis B research going forward.

Summary: Background: Anti‐viral therapy in chronic hepatitis B (CHB) is associated with a reduced risk of hepatocellular carcinoma (HCC) primary described in patients with cirrhosis.Aim: To examine the effects of treatment on HCC incidence in CHB with and without cirrhosis, after adjustment for background risks.Methods: A total of 2255 CHB patients from a US cohort (973 received anti‐viral therapy) and 3653 patients from the community‐based Taiwanese REVEAL‐HBV study, none of whom received treatment. We used Cox proportional hazard models to calculate the risk of developing HCC after adjustment with the previously validated REACH‐B risk score.Results: We found 273 incident cases of HCC. After adjustment, therapy lowered the risk of HCC development in the US treated cohort when compared to the US untreated cohort (HR 0.31; 95% CI: 0.15–0.66; P = 0.002). HCC risk reduction was also confirmed when compared to the REVEAL cohort (HR 0.22; 95% CI: 0.12–0.40; P < 0.001). Each REACH‐B point was associated with a 53% increased risk of HCC (HR 1.53; 95% CI 1.46–1.59; P < 0.001). We found a significant statistical reduction in HCC incidence with therapy regardless of gender, age, cirrhosis status, HBeAg serology, alanine aminotransferase level, REACH‐B score or treatment medication. Therapy was beneficial to those with mildly‐ to moderately elevated HBV DNA levels (>2000 IU/mL) and of even greater benefit to those with levels >200 000 IU/mL.Conclusion: After adjustment for background risk, anti‐viral therapy was associated with a significant reduction in HCC incidence in both community and real‐life clinical cohorts, including in those patients previously thought to be at low risk.