Neonatal hepatitis B vaccination has been implemented worldwide to prevent hepatitis B virus (HBV) infections. Its long-term protective efficacy on primary liver cancer (PLC) and other liver diseases has not been fully examined.The Qidong Hepatitis B Intervention Study, a population-based, cluster randomized, controlled trial between 1985 and 1990 in Qidong, China, included 39,292 newborns who were randomly assigned to the vaccination group in which 38,366 participants completed the HBV vaccination series and 34,441 newborns who were randomly assigned to the control group in which the participants received neither a vaccine nor a placebo. However, 23,368 (67.8%) participants in the control group received catch-up vaccination at age 10-14 years. By December 2013, a total of 3,895 (10.2%) in the vaccination group and 3,898 (11.3%) in the control group were lost to follow-up. Information on PLC incidence and liver disease mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31, 2013. Two cross-sectional surveys on HBV surface antigen (HBsAg) seroprevalence were conducted in 1996-2000 and 2008-2012. The participation rates of the two surveys were 57.5% (21,770) and 50.7% (17,204) in the vaccination group and 36.3% (12,184) and 58.6% (17,395) in the control group, respectively. Using intention-to-treat analysis, we found that the incidence rate of PLC and the mortality rates of severe end-stage liver diseases and infant fulminant hepatitis were significantly lower in the vaccination group than the control group with efficacies of 84% (95% CI 23%-97%), 70% (95% CI 15%-89%), and 69% (95% CI 34%-85%), respectively. The estimated efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was 21% (95% CI 10%-30%), substantially weaker than that of the neonatal vaccination (72%, 95% CI 68%-75%). Receiving a booster at age 10-14 years decreased HBsAg seroprevalence if participants were born to HBsAg-positive mothers (hazard ratio [HR] = 0.68, 95% CI 0.47-0.97). Limitations to consider in interpreting the study results include the small number of individuals with PLC, participants lost to follow-up, and the large proportion of participants who did not provide serum samples at follow-up.Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China. The findings underscore the importance of neonatal HBV vaccination. Our results also suggest that an adolescence booster should be considered in individuals born to HBsAg-positive mothers and who have completed the HBV neonatal vaccination series. Please see later in the article for the Editors' Summary.

Qidong City, China, has had high liver cancer incidence from endemic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin. Based on etiologic studies, we began interventions in 1980 to reduce dietary aflatoxin and initiate neonatal HBV vaccination. We studied trends in liver cancer incidence rates in the 1.1 million inhabitants of Qidong and examined trends in aflatoxin exposure, staple food consumption, HBV infection markers and annual income. Aflatoxin exposure declined greatly in association with economic reform, increased earnings and educational programs to shift staple food consumption in the total population from moldy corn to fresh rice. A controlled neonatal HBV vaccination trial began in 1983 and ended in November, 1990, when vaccination was expanded to all newborns. Liver cancer incidence fell dramatically in young adults. Compared with 1980-83, the age-specific liver cancer incidence rates in 2005-08 significantly decreased 14-fold at ages 20-24, 9-fold at ages 25-29, 4-fold at ages 30-34, 1.5-fold at ages 35-39, 1.2-fold at ages 40-44 and 1.4-fold at ages 45-49, but increased at older ages. The 14-fold reduction at ages 20-24 might reflect the combined effects of reduced aflatoxin exposure and partial neonatal HBV vaccination. Decrease incidence in age groups >25 years could mainly be attributable to rapid aflatoxin reduction. Compared with 1980-83, liver cancer incidence in 1990-93 significantly decreased 3.4-fold at ages 20-24, and 1.9-fold at ages 25-29 when the first vaccinees were <11 years old.

Objective To identify the association strength of the prevalence of HBeAg, cccDNA with the occurrence of HBV related hepatocellular carcinoma (HCC) in high risk male cohort in Qidong area in China. Methods A cohort of 377 middle aged HBV infected men in Qidong was followed from 1989 for 13. 25 years. HCC cases were registered. A matched case-controlled study was conducted on 32 pairs of inherent HCC cases with non-HCC controls. Serum HBeAg was measured by ELISA. cccDNA was detected by semi-nested PCR and verified by DNA sequencing. Standard statistical comparison between the prevalence of each HBV marker in HCC versus control group provided the odds ratio and P-value was used to evaluate its association strength with HCC occurrence. Results Serum HBeAg prevalence was 53. 1% (17/32) in HCC group versus 15. 6% (5/32) in controls, odds ratio (OR) =6. 12, P <0. 01. Prevalence of serum cccDNA was detected in 62. 5% (21/32) of HCC cases and in 21. 8% (8/32) of controls, with OR of 5. 73 and P <0. 01. Sequence of detected cccDNA was, found to be over 90% homologous with HBV. Conclusions A case-controlled study in this cohort showed that serum HBeAg and cccDNA prevalence were highly associated with hepatocellular carcinoma occurrence in HBV infected men. These viral markers may be of predictive value for early HCC diagnosis.

BACKGROUND:Hepatocellular carcinoma (HCC) is the second most common cancer in China. Hepatitis B and C viruses (HBV and HCV) and aflatoxins are known risk factors for HCC, but the etiological status of these factors in HCC development is not clear. This study was undertaken to define the absolute importance of HBV in hepatocarcinogenesis of North China.METHODS:A consecutive series of 119 patients with pathologically proven HCC were collected from North China during January 1998 to December 2000 by the Cancer Hospital of the Chinese Academy of Medical Sciences, Beijing. Serum HBsAg, anti-HBc and anti-HCV were negative HBV sero-markers. The HBV X gene was analyzed for its expression by PCR, DNA sequencing, and immunohistochemistry.RESULTS:In the 119 HCC patients, 82.4% (98/119) were HBsAg seropositive. When a comprehensive set of HBV markers were detected, the HBV infection rate in these HCC patients was 99.2% (118/119). Of the patients, 11.8%(14/119) were found to be anti-HCV positive. But all the anti-HCV positive HCC patients were co-infected with HBV.CONCLUSIONS:HBV infection is virtually ubiquitous in HCC patients in North China. The tight association of HBV with HCC strongly suggests the dominant role of HBV infection in causing hepatocellular carcinoma. About 11.8% of HCC patients being HCV-related are co-infected with HBV.

Objective To define the importance of HBV and HCV infection in pathogenesis of hepatocellular carcinoma (HCC) in North China. Methods A consecutive series of 119 patients with HCC living in North China who were treated in our hospital were included in this study. Serum HBsAg, anti-HBc and anti-HCV were detected by Abbotts AxSym System. For those patients with negative detection of HBV sero-markers, HBV X gene was analyzed with nested PCR, DNA sequencing and immunohistochemistry for its expression. Results Amongst the 119 patients, 98 (82.4%) were HBsAg sero-positive. When a comprehensive set of HBV markers were detected, the rate of HBV infection in these patients reached the level of 99.2% (118/119). Of the 119 cases, 14 (11.8%) were found to be anti-HCV positive. However, all the anti-HCV positive cases had co-infection of HBV. Conclusions In North China, HBV infection is closely related to pathogenesis of HCC. Meanwhile, HBV infection is the major cause for HCC in this region. HCV is an important auxiliary factor for HCC.

A large-scale, controlled study of universal immunization of newborns against HBV infection has been conducted in the high incidence area of hepatocellular carcinoma, Qidong County of China. This area has a stable population, standardized cancer registration system, and an epidemiological base for measurements of liver cancer prevention by vaccine. Randomization was done on the community level. The vaccination and the control group each will consist of 38,000 children by the end of 1990. It is anticipated that the design will provide high statistical power to detect 50% reduction in the prevalence rate of chronic hepatitis among the vaccinees vs. the controls at 6 to 10 years of age, and 50% reduction in the incidence rate of hepatocellular carcinoma at 35 to 40 years of age. The vaccine used is Hep-B Vax, donated by Merck and Co. through WHO. The vaccine was administered at 0, 1, and 6 months after birth, the dosage of 5 or 2.5 micrograms in the pilot study as used before 1985 and of 5 micrograms dose level during the main study starting from January 1, 1985. About 85% of the cohorts have now entered the protocol. The vaccination coverage during 1984 to 1989 was 98.0% (35,064/35,789). Follow-up of the vaccinees and the age-matched controls at 5 years has exceeded 97%. The cumulative mortality in the vaccinated group up to 1988 was 1.29% (354/27,450). No single death nor serious adverse reaction was found that was associated with vaccination. The use of HBV vaccine at a reduced dose was especially important for the developing countries at the present time in order to achieve widespread immunization. Five-year results of the pilot study of this vaccination project showed that significant protection against HBV infection was achieved with the 5 or 2.5 micrograms per dose regimen plus a booster of 5 micrograms given at 3.5 to 4 years of age.(ABSTRACT TRUNCATED AT 250 WORDS)