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EFFICACY OF NEONATAL HBV VACCINATION ON LIVER CANCER AND OTHER LIVER DISEASES OVER 30-YEAR FOLLOW-UP OF THE QIDONG HEPATITIS B INTERVENTION STUDY: A CLUSTER RANDOMIZED CONTROLLED TRIAL

Monday, 5th of January 2015

“. . . These findings therefore support the importance of neonatal HBV vaccination. In addition, they suggest that booster vaccination during adolescence might consolidate the efficacy of neonatal vaccination among individuals who were born to HBsAg-positive mothers, a suggestion that needs to be confirmed in randomized controlled trials before booster vaccines are introduced into vaccination programs.”

EFFICACY OF NEONATAL HBV VACCINATION ON LIVER CANCER AND OTHER LIVER DISEASES OVER 30-YEAR FOLLOW-UP OF THE QIDONG HEPATITIS B INTERVENTION STUDY: A CLUSTER RANDOMIZED CONTROLLED TRIAL

• Chunfeng Qu equal contributor mail,
• Taoyang Chen equal contributor,
• Chunsun Fan,
• Qimin Zhan,
• Yuting Wang,
• Jianhua Lu,
• Ling-ling Lu,
• Zhengping Ni,
• Fei Huang,
• Hongyu Yao,
• Jian Zhu,
• Jian Fan,
• Yuanrong Zhu,
•  [ ... ],
• Zongtang Sun mail
• , [ view all ]

• Published: December 30, 2014
• DOI: 10.1371/journal.pmed.1001774

Abstract and summary below; full text, with figures, is at http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001774

Background

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.

Methods and Findings

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.

Conclusions

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

Editors Summary

Background

Hepatitis B is a life-threatening liver infection caused by the hepatitis B virus (HBV). HBV, which is transmitted through contact with the blood or other bodily fluids of an infected person, can cause both acute (short-term) and chronic (long-term) liver infections. Acute infections rarely cause any symptoms and more than 90% of adults who become infected with HBV (usually through sexual intercourse with an infected partner or through the use of contaminated needles) are virus-free within 6 months. However, in sub-Saharan Africa, East Asia, and other regions where HBV infection is common, HBV is usually transmitted from mother to child at birth or between individuals during early childhood and, unfortunately, most infants who are infected with HBV during the first year of life and many children who are infected before the age of 6 years develop a chronic HBV infection. Such infections can cause liver cancer, liver cirrhosis (scarring of the liver), and other fatal liver diseases. In addition, HBV infection around the time of birth can cause infant fulminant hepatitis, a rare but frequently fatal condition.

Why Was This Study Done?

HBV infections kill about 780,000 people worldwide annually but can be prevented by neonatal vaccination—immunization against HBV at birth. A vaccine against HBV became available in 1982 and many countries now include HBV vaccination at birth followed by additional vaccine doses during early childhood in their national vaccination programs. But, although HBV vaccination has greatly reduced the rate of chronic HBV infection, the protective efficacy of neonatal HBV vaccination against liver diseases has not been fully examined. Here, the researchers investigate how well neonatal HBV vaccination protects against primary liver cancer and other liver diseases by undertaking a 30-year follow-up of the Qidong Hepatitis B intervention Study (QHBIS). This cluster randomized controlled trial of neonatal HBV vaccination was conducted between 1983 and 1990 in Qidong County, a rural area in China with a high incidence of HBV-related primary liver cancer and other liver diseases. A cluster randomized controlled trial compares outcomes in groups of people (towns in this study) chosen at random to receive an intervention or a control treatment (here, vaccination or no vaccination; this study design was ethically acceptable during the 1980s when HBV vaccination was unavailable in rural China but would be unethical nowadays).

What Did the Researchers Do and Find?

The QHBIS assigned nearly 80,000 newborns to receive either a full course of HBV vaccinations (the vaccination group) or no vaccination (the control group); two-thirds of the control group participants received a catch-up vaccination at age 10–14 years. The researchers obtained data on how many trial participants developed primary liver cancer or died from a liver disease during the follow-up period from a population-based tumor registry. They also obtained information on HBsAg seroprevalence—the presence of HBsAg (an HBV surface protein) in the blood of the participants, an indicator of current HBV infection—from surveys undertaken in1996–2000 and 2008–2012. The researchers estimate that the protective efficacy of vaccination was 84% for primary liver cancer (vaccination reduced the incidence of liver cancer by 84%), 70% for death from liver diseases, and 69% for the incidence of infant fulminant hepatitis. Overall, the efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was weak compared with neonatal vaccination (21% versus 72%). Notably, receiving a booster vaccination at age 10–14 years decreased HBsAg seroprevalence among participants who were born to HBsAg-positive mothers.

What Do These Findings Mean?

The small number of cases of primary liver cancer and other liver diseases observed during the 30-year follow-up, the length of follow-up, and the availability of incomplete data on seroprevalence all limit the accuracy of these findings. Nevertheless, these findings indicate that neonatal HBV vaccination greatly reduced HBsAg seroprevalence (an indicator of current HBV infection) in childhood and young adulthood and subsequently reduced the risk of liver cancer and other liver diseases in young adults. These findings therefore support the importance of neonatal HBV vaccination. In addition, they suggest that booster vaccination during adolescence might consolidate the efficacy of neonatal vaccination among individuals who were born to HBsAg-positive mothers, a suggestion that needs to be confirmed in randomized controlled trials before booster vaccines are introduced into vaccination programs.

Additional Information

Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1​001774.

• The World Health Organization provides a fact sheet about hepatitis B (available in several languages) and information about hepatitis B vaccination
• The World Hepatitis Alliance (an international not-for-profit, non-governmental organization) provides information about viral hepatitis, including some personal stories about hepatitis B from Bangladesh, Pakistan, the Philippines, and Malawi
• The UK National Health Service Choices website provides information about hepatitis B
• The not-for-profit British Liver Trust provides information about hepatitis B, including Hepatitis B: PATH B, an interactive educational resource designed to improve the lives of people living with chronic hepatitis B
• MedlinePlus provides links to other resources about hepatitis B (in English and Spanish)
• Information about the Qidong Hepatitis B intervention Study is available
• Chinese Center for Disease Control and Prevention provides links about hepatitis B prevention in Chinese