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The global burden of hepatocellular carcinoma (HCC; primary liver cancer) is increasing. HCC is often unaccompanied by clear symptomatology, causing patients to be unaware of their disease. Moreover, effective treatment for those with advanced disease is lacking. As such, effective surveillance and early detection of HCC are essential. However, current screening and surveillance guidelines are not being fully implemented. Some at-risk populations fall outside of the guidelines, and patients who are screened are often not diagnosed at an early enough stage for treatment to be effective. From March 17 to 19, 2015, the Hepatitis B Foundation sponsored a workshop to identify gaps and limitations in current approaches to the detection and treatment of HCC and to define research priorities and opportunities for advocacy. In this Commentary, we summarize areas for further research and action that were discussed throughout the workshop to improve the recognition of liver disease generally, improve the recognition of liver cancer risk, and improve the recognition that screening for HCC makes a life-saving difference. Participants agreed that primary prevention of HCC relies on prevention and treatment of viral hepatitis and other underlying etiologies. Earlier diagnosis (secondary prevention) needs to be substantially improved. Areas for attention include increasing practitioner awareness, better definition of at-risk populations, and improved performance of screening approaches (ultrasound, biomarkers for detection, risk stratification, targeted therapies). The heterogeneous nature of HCC makes it unlikely that a single therapeutic agent will be universally effective. Medical management will benefit from the development of new, targeted treatment approaches., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Studies of chronic hepatitis B virus (HBV) infection in endemic populations have rarely documented causes of mortality other than liver disease and hepatocellular carcinoma (HCC)., Methods: We analysed all-cause mortality related to HBV infection, focusing on the deaths not related to liver disease in a prospective cohort of adults living in Haimen City, China, who were followed from 1992 to 2002. Death certificate data from 4590 deaths among 83 794 individuals were analysed. At cohort entry, 15.0% of the 58 454 male subjects and 10.7% of 25 340 female subjects were hepatitis B surface antigen positive [HbsAg(+)]. HCC and chronic liver disease were the major causes of death in both men and women in this population. The analysis focused on non-liver causes of death., Results: When liver-related causes of death were excluded, there was still a significantly higher age-adjusted death rate among HBsAg(+) individuals. The relative risks (RRs) and 95% confidence intervals (CIs) for all non-liver deaths among HBsAg(+) subjects were 1.2 (1.1-1.3) in men and 1.4 (1.1-1.7) in women. Non-liver causes were further subdivided into cancer and non-cancer groups. For all non-liver cancers, the RR was 1.2 (1.0-1.4) for males and 1.7 (1.2-2.3) for females. Non-liver, non-cancer deaths had RRs of 1.2 (1.1-1.4) and 1.2 (0.9-1.6) in males and females, respectively., Conclusions: HBV-infected individuals may be at increased mortality risk from non-liver causes. Possible reasons include a direct effect of HBV infection, changes in the host immune system as a cause or effect of chronic infection, and behavioural factors associated with HBV infection. Further studies are needed to confirm this finding.

This study compared rates of spontaneous hepatitis B e antigen (HBeAg)-positive to -negative seroconversion in chronic carriers of hepatitis B virus (HBV) with rates reported during interferon-alpha therapy. Four hundred fifty-four Asian-American HBeAg-positive HBV carriers, followed for 1-10 years, were tested approximately every 6 months for HBeAg. Patients with alanine aminotransferase levels > or = 50 IU/mL at entry had 1067.3 seroconversions/10(5) person-months in the 5- to 19-year age group, 1753.3 in the 20- to 34-year group, and 1257.2 in the 35- to 50-year group. Published data indicate that 30% of children and 33% of adults seroconvert during interferon-alpha treatment and follow-up. In our study population, spontaneous seroconversion occurred in 15% of children (95% confidence interval [CI], 8%-27%), 23% of adults 20-34 years (95% CI, 15%-34%), and 17% of adults 35-50 years (95% CI, 10%-28%) during the same interval. The high rate of spontaneous seroconversion should be weighed in decisions to treat HBV carriers with interferon-alpha.

When risk factors for an infectious disease are unknown, a method commonly employed is to investigate parallels with known infections (covariate infections). Data sets of value here are those for specified populations in which the seroprevalence of antibodies for multiple infections has been ascertained. The use of markers of covariate infections in multivariable analyses is problematic when the covariate infection is not itself an independent risk factor for the outcome of interest. In the performance of these analyses, the authors recommend the following strategy: 1) For estimates of the effects of measured risk factors on the outcome, adjustment for the covariate infection should not be done; this will avoid problems of overadjustment. 2) After control for the measured risk factors, an estimate of the "effect" of the covariate infection may be used as an indicator of the presence of unmeasured shared risk factors. 3) When shared, measured risk factors exist, the authors propose the use of methods developed for analysis of repeated measures of categorical variables to assist in inference about shared mechanisms of action of these risk factors. This analytic strategy takes advantage of the method of analogy for building understanding of transmission of new agents through their parallels with better known ones and is useful in the development of hypotheses.