Integrating host and HBV characteristics, this study aimed to develop models for predicting long‐term cirrhosis and hepatocellular carcinoma (HCC) risk in chronic hepatitis B virus (HBV) patients. ...This analysis included hepatitis B surface antigen (HBsAg)‐seropositive and anti‐HCV‐seronegative participants from the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer in HBV (R.E.V.E.A.L.‐HBV) cohort. Newly developed cirrhosis and HCC were ascertained through regular follow‐up ultrasonography, computerized linkage with national health databases, and medical chart reviews. Two‐thirds of the participants were allocated for risk model derivation and another one‐third for model validation. The risk prediction model included age, gender, HBV e antigen (HBeAg) serostatus, serum levels of HBV DNA, and alanine aminotransferase (ALT), quantitative serum HBsAg levels, and HBV genotypes. Additionally, the family history was included in the prediction model for HCC. Cox's proportional hazards regression coefficients for cirrhosis and HCC predictors were converted into risk scores. The areas under receiver operating curve (AUROCs) were used to evaluate the performance of risk models. Elder age, male, HBeAg, genotype C, and increasing levels of ALT, HBV DNA, and HBsAg were all significantly associated with an increased risk of cirrhosis and HCC. The risk scores estimated from the derivation set could accurately categorize participants with low, medium, and high cirrhosis and HCC risk in the validation set (P < 0.001). The AUROCs for predicting 3‐year, 5‐year, and 10‐year cirrhosis risk ranged 0.83‐0.86 and 0.79‐0.82 for the derivation and validation sets, respectively. The AUROC for predicting 5‐year, 10‐year, 15‐year risk of HCC ranged 0.86‐0.89 and 0.84‐0.87 in the derivation and validation sets, respectively. Conclusion: The risk prediction models of cirrhosis and HCC by integrating host and HBV profiles have excellent prediction accuracy and discriminatory ability. They may be used for clinical management of chronic hepatitis B patients. (Hepatology 2013;58:546‐554)
Chronic hepatitis B is a worldwide public health challenge. Knowledge of natural history of chronic hepatitis B is important for the management of the disease. A community‐based prospective cohort ...study was carried out to evaluate the risk predictors of progression of chronic hepatitis B in Taiwan. A total of 23 820 participants were enrolled in 1991–1992 from seven townships in Taiwan. Their serum samples were collected at study entry and tested for hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), antibodies against hepatitis C virus (anti‐HCV), alanine aminotransferase (ALT), and α‐fetoprotein (AFP). A subcohort of 3653 male and female participants who were seropositive for HBsAg and seronegative for anti‐HCV was included in the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer‐Hepatitis B Virus (REVEAL‐HBV) study. Newly developed cases of cirrhosis and hepatocellular carcinoma (HCC) were ascertained through follow‐up examination and data linkage with profiles of the National Cancer Registry, National Health Insurance Database and Death Certification System. The incidence of both HCC and cirrhosis were significantly associated with serum HBV DNA levels in a dose‐response relationship from < 300 (undetectable) to ≥ 1 000 000 copies/mL. The biological gradients remained significant (P < 0.001) after adjustment for age, sex, habits of cigarette smoking and alcohol drinking, HBeAg serostatus, and serum ALT level at cohort entry. A significant association with risk of cirrhosis and HCC was also observed for HBV genotype, precore G1896A mutant and basal core promoter A1762T/G1764A double mutant. Nomograms have been developed for the long‐term risk prediction of cirrhosis and HCC for patients with chronic hepatitis B. Inactive carriers of HBV have an increased HCC incidence and liver‐related mortality than HBsAg‐seronegative controls. Serum HBV DNA level at study entry is a major predictor of spontaneous seroclearance of HBeAg, HBV DNA and HBsAg. These findings may inform the effective and efficient management of chronic hepatitis B.
LINKED CONTENT
This article is linked to Lin et al papers. To view these articles, visit https://doi.org/10.1111/apt.17915 and https://doi.org/10.1111/apt.17971
LINKED CONTENT
This article is linked to Lin et al papers. To view these articles, visit https://doi.org/10.1111/apt.17915 and https://doi.org/10.1111/apt.17965.
Background & Aims The risk and the predictors of liver disease progression in carriers of inactive hepatitis B virus (HBV) are unclear. Methods Participants in the Risk Evaluation of Viral Load ...Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study who were seronegative for hepatitis B e antigen; had serum levels of HBV DNA <10,000 copies/mL; and did not have cirrhosis, hepatocellular carcinoma, or increased serum levels of alanine aminotransferase were classified as carriers of inactive HBV (n = 1932). Study participants who were seronegative for HB surface antigen and antibodies against hepatitis C virus, yet had similar clinical liver features, were the controls (n = 18,137). Liver-related death and new cases of hepatocellular carcinoma were ascertained through computerized data linkage with National Cancer Registry and Death Certification profiles. The disease progression rates were estimated. The multivariate-adjusted hazard ratios for risk predictors were derived from Cox regression models. Results There were 20,069 participants, contributing a total of 262,122 person-years, with a mean follow-up of 13.1 years. Annual incidence rates of hepatocellular carcinoma and liver-related death were 0.06% and 0.04%, respectively, for inactive HBV carriers; rates were 0.02%, and 0.02% for controls, respectively. The multivariate-adjusted hazard ratios for carriers of inactive HBV, compared to controls, were 4.6 (95% confidence interval: 2.5–8.3) for hepatocellular carcinoma and 2.1 (95% confidence interval: 1.1–4.1) for liver-related death. Older age and alcohol drinking habits were independent predictors of risk for carriers of inactive HBV to develop hepatocellular carcinoma. Conclusions Carriers of inactive HBV have a substantial risk of hepatocellular carcinoma and liver-related death compared with individuals not infected with HBV.
Background & Aims: This study investigated whether obesity, diabetes, and other metabolic factors are independently associated with hepatocellular carcinoma (HCC), stratified by hepatitis B virus ...(HBV) and hepatitis C virus (HCV) serostatus, and explored the possible joint influence of obesity/diabetes and HBV/HCV infections on the risk of HCC. Methods: A total of 23,820 residents in Taiwan were recruited and followed up for 14 years. All analyses were stratified by hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) at enrollment, and 218 subjects positive for both seromarkers were excluded. Incident HCC cases were identified via linkage to the national cancer registry. Multivariate-adjusted relative risk (RRa ) and 95% confidence interval (95% CI) were estimated using Cox proportional hazards models. Results: Extreme obesity (body mass index ≥30 kg/m2 ) was independently associated with a 4-fold risk of HCC (RRa , 4.13; 95% CI, 1.38–12.4) among anti-HCV–seropositive subjects and a 2-fold risk (RRa , 2.36; 95% CI, 0.91–6.17) in persons without HBV and HCV infections, after controlling for other metabolic components, but not in HBsAg-seropositive subjects (RRa , 1.36; 95% CI, 0.64–2.89). Diabetes was associated with HCC in all 3 groups, with the highest risk in those with HCV infection (RRa , 3.52; 95% CI, 1.29–9.24) and lowest in HBV carriers (RRa , 2.27; 95% CI, 1.10–4.66). We found more than 100-fold increased risk in HBV or HCV carriers with both obesity and diabetes, indicating synergistic effects of metabolic factors and hepatitis. Conclusions: The finding that both obesity and diabetes are predictors of HCC risk, possibly differently depending on HBV and HCV infection status, may shed some light in preventing HCC.
Background & Aims Little is known about the effects of family history of hepatocellular carcinoma (HCC) on hepatitis B progression or risk of HCC. We examined how family HCC history and presence or ...stage of hepatitis B virus (HBV) infection affect risk for HCC. Methods We performed a population-based cohort study of 22,472 participants from 7 townships in Taiwan who underwent evaluation for liver disease from 1991 through 1992. Those who received a first diagnosis of HCC from January 1, 1991, to December 31, 2008, were identified from the Taiwanese cancer registry. Results There were 374 cases of incident HCC over 362,268 person-years of follow-up evaluation. The cumulative risk of HCC in hepatitis B surface antigen (HBsAg)-seronegative patients without a family history of HCC was 0.62%, in those with a family history of HCC the cumulative risk was 0.65%, in HBsAg-seropositive patients without a family history of HCC the cumulative risk was 7.5%, and in HBsAg-seropositive patients with a family history of HCC the cumulative risk was 15.8% ( P < .001). The multivariate-adjusted hazard ratio for HBsAg-seropositive individuals with family history, compared with HBsAg-seronegative individuals without a family history of HCC, was 32.33 (95% confidence interval, 20.8–50.3; P < .001). The relative excess risk owing to interaction was 19, the attributable proportion was 0.59, and the synergy index value was 2.54. These findings indicate synergy between family HCC history and HBsAg serostatus. The synergy between these factors remained significant in stratification analyses by HBeAg serostatus and serum level of HBV DNA. Conclusions Family history of HCC multiplies the risk of HCC at each stage of HBV infection. Patients with a family history of HCC require more intensive management of HBV infection and surveillance for liver cancer.
Summary
Background
High hepatitis B surface antigen (HBsAg) level predicts hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with low viral load. The role of longitudinal HBsAg ...levels in predicting HCC in HBeAg‐positive CHB patients remains unknown.
Method
HBeAg‐positive CHB participants from the REVEAL‐HBV cohort with ≥2 HBsAg measurements before HBeAg seroclearance were enrolled. Group‐based trajectory modelling identified distinct HBsAg trajectory groups during a median of 11 years of HBeAg‐positive status. Cox regression models were applied for investigating independent predictors of HCC and estimating adjusted hazard ratio (HRadj) with a 95% confidence interval (CI). A p‐value less than 0.05 was considered statistically significant.
Results
A total of 319 patients were enrolled and classified by HBsAg trajectory patterns as (A) persistently high group (n = 72): HBsAg persistently ≥104 IU/mL, and (B) non‐stationary group (n = 233): low HBsAg at baseline or declining to <104 IU/mL during the follow‐up. Group B had higher proportions of abnormal ALT levels, HBV genotype C and basal core mutation than group A (p < 0.05); age at entry and gender were comparable. The annual incidence of HCC in group A and group B were 0.37% and 1.16%, respectively (p = 0.03). In multivariate analysis, age >40 years (HRadj 95% CI = 4.11 2.26–7.48), genotype C (HRadj 95% CI = 4.39 1.96–9.81) and the non‐stationary group (HRadj 95% CI = 3.50 1.49–8.21) were independent predictors of HCC. Basal core promoter mutation was the only risk factor of HCC in the persistently high HBsAg group (HRadj 95% CI = 32.75 5.41–198.42).
Conclusion
Patients with persistently high HBsAg levels during HBeAg‐seropositive stage represent a unique population with low risk of HCC development.
Persistent high HBsAg levels during HBeAg‐seropositive stage predicts lower risk of hepatocellular carcinoma in chronic hepatitis B patients
Background & Aims Seroclearance of hepatitis B surface antigen (HBsAg) is one of the most important clinical outcomes for chronic hepatitis B treatment trials. Few studies have explored the incidence ...and determinants of spontaneous seroclearance using a long-term follow-up study. This study aimed to examine the natural history and predictors of HBsAg seroclearance. Methods A total of 3087 individuals with chronic hepatitis B virus infection were enrolled between 1991 and 1992 in this community-based study. Serum samples collected at baseline and follow-up examinations were tested for HBsAg, hepatitis B e antigen (HBeAg), serum hepatitis B virus (HBV)-DNA levels, and anti–hepatitis C virus serostatus. Cox proportional hazards models were used to estimate HBsAg seroclearance rate ratios associated with various determinants. Results HBsAg seroclearance occurred in 562 participants during 24,829 person-years of follow-up evaluation, giving a 2.26% annual seroclearance rate. HBV-DNA levels at baseline and follow-up evaluation were the most significant predictor of seroclearance. Higher HBV viral loads conferred lower HBsAg seroclearance rates ( P < .001). A spontaneous decrease in follow-up HBV-DNA level (≥3 log) was associated significantly with seroclearance, showing an adjusted odds ratio of 4.17 (95% confidence interval, 2.55–6.82). Among those with seroclearance, 95.8% had undetectable HBV-DNA levels before seroclearance. Cumulative incidence of HBsAg seroclearance at 60 and 100 months after serum HBV-DNA level decreased to undetectable was 25.8% and 51.3%, respectively. Conclusions This study reveals determinants of HBsAg seroclearance, and suggests that a low viral load is an important factor affecting the natural seroclearance of HBsAg, indicating significant clinical implications for the treatment of chronic HBV.
Summary Background Therapy for chronic hepatitis B reduces the risk of progressing to hepatocellular carcinoma (HCC); however, there is no suitable and accurate means to assess risk. This study aimed ...to develop and validate a simple scoring system to predict HCC risk in patients with chronic hepatitis B. Methods The development cohort consisted of 3584 patients without cirrhosis from the community-based Taiwanese REVEAL-HBV study (of whom 131 developed HCC during follow-up), and a validation cohort of 1505 patients from three hospitals in Hong Kong and South Korea (of whom 111 developed HCC during follow-up). We used Cox multivariate proportional hazards model to predict risk of HCC at 3, 5, and 10 years. Variables included in the risk score were sex, age, serum alanine aminotransferase concentration, HBeAg status, and serum HBV DNA level. We calculated the area under receiver operating curve (AUROC) and calibration of predicted and observed HCC risk. Findings A 17-point risk score was developed, with HCC risk ranging from 0·0% to 23·6% at 3 years, 0·0% to 47·4% at 5 years, and 0·0% to 81·6% at 10 years for patients with the lowest and highest HCC risk, respectively. AUROCs to predict risk were 0·811 (95% CI 0·790–0·831) at 3 years, 0·796 (0·775–0·816) at 5 years, and 0·769 (0·747–0·790) at 10 years in the validation cohort, and 0·902 (0·884–0·918), 0·783 (0·759–0·806), and 0·806 (0·783–0·828), respectively, after exclusion of 277 patients in the validation cohort with cirrhosis. Predicted risk was well calibrated with Kaplan-Meier observed HCC risk. Interpretation A simple-to-use risk score that uses baseline clinical variables was developed and validated. The score accurately estimates the risk of developing HCC at 3, 5, and 10 years in patients with chronic hepatitis B. Clinicians can use this score to assess risk of HCC in patients with chronic hepatitis B and subsequently make evidence-based decisions about their clinical management. Funding The Academia Sinica; the National Health Research Institute, Taiwan; and Bristol-Myers Squibb.
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