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Qu et al. Etiological prevention of liver cancer

rate of 10.13% (95% CI: 9.81-10.45%) in 1992. Further abuse leading to liver cirrhosis . In addition, cohort
[2]
analysis found that HBsAg prevalence was only 0.64% studies showed that the intakes of vitamin C and
[41]
(95% CI: 0.54-0.75%) in 2014 among those (1-12 years vitamin E [42] , from both diet and supplements could
of age) who were born between 2002-2013 after HBV potentially reduce the risk of liver cancer. Reducing
vaccination was integrated into national EPI program [28] . the dietary aflatoxin exposure to non-detectable levels
China has already reached the national goal of reducing could also reduce HCC cases in high risk areas by about
HBsAg prevalence to less than 1% among children under 23% [43] . An observational study in a rural population
5 years, and an estimated 16-20 million HBV carriers indicated that decline of liver cancer incidence in the
were prevented through the HBV vaccination program [27] . younger generation was not fully attributed to controlling
chronic HBV infection alone. Changes in their staple
Reduced liver cancer incidence in general food and drinking water were also important in reducing
population by historical comparison cannot liver cancer risk [44] . A study conducted in an urban
be entirely attributed to HBV vaccination area of China reported the positive roles of vegetable-
Some perinatal infection from maternal HBV based dietary pattern in decreasing liver cancer risk [45] .
transmission may cause fulminant hepatitis in infancy , All studies based on cancer registry data historically
[11]
a very rare condition that develops in about 0.5-1% of comparing the immunized and unimmunized cohorts
cases [29] . Mortality rate of fulminant hepatitis can be as at either the national or community level, support the
high as 67% [30] . Reports from several countries and hypothesis that HB vaccination is associated with a
areas have documented the dramatic decrease of the reduced risk of liver cancer. Nevertheless, because of
incidence of fulminant hepatitis after HBV immunization potential differences in baseline characteristics and in
to newborns was implemented [31-34] . However, the exposures to other risk factors between the immunized
[2]
infection in the perinatal period and early life mainly and historical comparison (unimmunized) birth cohorts,
resulted in chronic HBV infection, which could be as it is difficult to make the inference that the observed
high as 90% [12,14] . reduced liver cancer risk was entirely attributed to HBV
vaccination [35,44,46] . The Qidong Hepatitis B Intervention
Long-term major adverse outcomes of chronic HBV Study (QHBIS) addressed the causal link between HBV
infection are liver cancer and cirrhosis. Studies from vaccination and the observed benefits [33,47,48] .
Taiwan, which analyzed data based on cancer registry
in birth cohorts born after the universal vaccination Efficacies of HBV vaccination in preventing
program as compared to the birth cohorts born before liver cancer and other liver diseases in rural
the program, documented that HBV vaccination was China: experience from Qidong Hepatitis B
effective in reducing the incidence and mortality of liver Intervention Study
cancer [35] . A study among the Alaskan Native of the Qidong County, China, is a rural area with high liver cancer
United States reported the elimination of HCC and acute incidence and mortality compared to China as a whole.
hepatitis B in children 25 years after a HBV immunization The incidence of PLC in Qidong was 79.6/10 for man
5
program [36] . Studies based on the cancer registry data and 23.1/10 for woman during 1978-2002 [49] , and it was
5
of Korea [37] and Japan [38] also reported a decreased 28.15/10 for man, 9.31/10 for woman in China cancer
5
5
incidence of liver cancer after the implementation of HBV registry which covered 11 cities and counties during 1988-
vaccination programs. In China, the time trend analysis 2005 [39] . Two major risk factors identified in Qidong were
of liver cancer incidence during 1988-2005 also showed high prevalence of chronic HBV infection and appreciable
a gradual decrease based on the cancer registry data dietary aflatoxin exposure, with the HBV infection greatly
in 11 cities and counties that covered a population of sensitizing hepatocytes to the mutagenic effects of
401,506,812 (male patients 204,475,147; female patients aflatoxin [50-52] . Therefore, the neonatal HB vaccination
197,031,665, sex ratio 1.04). The annual percent change began in a large controlled clinical trial on 1 September
was -1.44% [39] . Recent analysis showed that the age- 1983 in Qidong (World Health Organization, Prevention
standardized liver cancer incidence rate during 2000- of liver cancer. Technical Report Series 691, World Health
2011 was further decreased with an average annual Organization, Geneva.1983). It was later registered with
percentage change of -1.8% [40] , reflecting the effect of Clinical Trials.gov number NCT00222664 [33] .
HBV vaccination in reducing liver cancer risk.
QHBIS is a population-based, cluster randomized,
Chronic HBV infection is the most important risk factor controlled trial of HBV vaccination conducted between
for liver cancer in humans, which is endemic in the 1983-1990 in Qidong. During that time, Qidong had
regions of Africa and Asia, especially in China. The a population of 1.1 million and approximately 13,000
other established etiological factors also include heavy births each year. Approximately 80,000 newborns
exposure to aflatoxin, algal hepatotoxins in contaminated were randomly assigned into the vaccination or control
water, betel nut chewing, diabetes mellitus, and alcohol groups [18,33,53] . The study was conducted during a time

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