HBV Vaccination Program Reduces Liver Cancer in Taiwan

Although liver cancer has a relatively low incidence in the United States, compared with other cancers, it is 10 times more common in many developing countries than in this country.[1] The incidence of liver cancer is highest in sub-Saharan Africa, China, southern Asia, and Japan.[2]

One of the most common forms of liver cancer, hepatocellular carcinoma, has been closely linked to the hepatitis B virus (HBV). The association between seropositivity for hepatitis B and the presence of hepatocellular carcinoma is strongest for children; almost 100% of children who have hepatocellular carcinoma test positive for the hepatitis B surface antigen (HBsAg).[3] In contrast, 70% to 80% of adults with hepatocellular carcinoma are seropositive for hepatitis B.

The incidence of liver cancer is particularly high in Taiwan. Hepatocellular cancer ranks among the leading causes of morbidity and mortality: 1,000 people die of liver cancer and cirrhosis in Taiwan each year. Three million, or 15% of the population, are afflicted with cirrhosis and liver cancer.[4]

There is also a high incidence of hepatitis B in Taiwan. Twenty years ago, the carrier rate of hepatitis B reached an estimated 15% to 20% of the general population of 21 million—one of the highest rates of hepatitis B in Asia.[5]

Although the causal relationship between hepatitis B and hepatocellular cancer has never been established,[3] public health officials in Taiwan and China instituted a nationwide hepatitis B vaccination program to decrease the incidence and carrier rate of hepatitis B, and, hopefully, simultaneously decrease the incidence of hepatocellular cancer.

Seventeen years after the initiation of the program, the prevalence of hepatitis B and the incidence of hepatocellular carcinoma in children age 6 to 14 years have decreased considerably.

Hepatitis B is transmitted from one person to another by blood transfusion, contaminated needle, sexual contact, and childbirth. More than 40% of infants born to HBsAg carrier mothers become HBsAg carriers themselves, indicating the frequent occurrence of mother-to-newborn transmission.[6]

Even if the infants do not become infected with hepatitis B at birth, unvaccinated children of infected mothers run a 60% risk of developing hepatitis B before age 5. Children are also more likely than adults to become chronic carriers.

Hepatitis B progresses over several years in two distinct phases.[7] In the first stage, the virus replicates and accumulates in the liver. During this phase, the host does not develop a striking immune response. The second phase often takes place 20 to 30 years after the initial infection, when a cell-mediated immune response destroys hepatitis B-infected liver cells.[7]

Serious consequences of hepatitis B include chronic liver disease, cirrhosis, and hepatocellular carcinoma.[8-11] In fact, results from one study indicate that the hepatitis B genome is integrated into the host genome of hepatocellular carcinoma.[3]

Successful implementation of mass immunoprophylaxis of the magnitude of the Taiwan program required the combined efforts of several councils.[12]

• The National Science Council conducted comprehensive basic science research.

• The Department of Health concentrated on epidemiology, education, and control aspects of the program.

• The Department of Health’s Hepatitis Patient Information Center developed and maintained a databank of hepatitis B carriers and patients. The creation of the databank facilitated the development of early detection programs for liver disease and hepatocellular carcinomas.

• The Government Ministries and Information Office promoted mass media education, mandated health education in schools, and oversaw school cafeteria hygiene.

Initially, in 1984, the vaccination program in Taiwan focused on mother-to-newborn transmission; hence, only newborns of HBsAg-carrier mothers were vaccinated. In 1987, the program extended vaccination to all newborn infants and children of preschool age.[3] Then, between 1988 and 1990, the vaccination program was expanded to include all school children, teenagers, and adults.

Midway through the study, the vaccination protocol was modified. Prior to 1992, one dose of plasma-derived vaccine was given to children at 1 week of age, followed by one dose given at 1, 2, and 12 months of age. After 1992, the protocol was revised to include only three doses of recombinant (yeast-derived) vaccine. The first dose was administered prior to 1 week of age, followed by the second and third dose at 1 month and 6 months of age.[3]

Hepatitis B Rates Fall

A seroepidemiologic survey conducted in 1999 indicated that the vaccination effort had been successful in decreasing the rates of hepatitis B infection in children. The incidence in Chung-Cheng District in Taipei City was only 0.7%, a 93% reduction from the 10% prevalence rate in 1984.[13] Meanwhile, the rates for those born prior to the nationwide vaccination program remained considerably higher (7%).[12]

If the national immunization program continues with the same aggressive proliferation, the HBsAg-carrier rates of the next generation of Taiwanese children may be reduced to 0.1%.[13]

Similar reductions in rates of hepatocellular cancer among children age 6 to 14 years were also noted. The rates of hepatocellular cancer fell from 0.70 per 100,000 children in 1981-1986, to 0.57 in 1986-1990, and to 0.36 in 1990-1994.[3]

Analysis of the incidence of hepatocellular cancer among children also showed a slower decline for children born prior to the initiation of the program than for those born afterward. Moreover, the hepatocellular cancer mortality rate in children showed a similar decline following the introduction of the national immunization program.

Although the institution of a nationwide vaccination program of this scale is certainly costly, the cost-effectiveness of such a program is evident. The cost of hepatitis-B-related medical care and lost wages in Taiwan reached an estimated $318.3 million (US) for the 10-year period 1984 to 1994. The cost of hepatitis B immunizations during that same period amounted to only one third of that cost (US $100 million).[14]

The largest financial impact related to hepatitis B infection will be felt when the children who participated in the vaccination program reach the age of 50 to 60 when the incidence of hepatocellular carcinoma would be expected to peak.[3] Thus, the greatest effects of the national hepatitis B vaccination program are expected to begin in 2034.

The significant decrease in hepatitis B virus infection indicates that a nationwide vaccination program can be successful. Taiwan’s experience should serve as an example for other countries facing similarly high levels of hepatitis B virus infection.

In addition to decreasing the incidence of hepatitis B, the vaccination program significantly decreased the incidence of hepatocellular carcinoma, providing further evidence that hepatitis B is a cause of hepatocellular carcinoma.[3] These results suggest that the prevention of a virus can result in a reduction in the incidence of a related cancer.[3]

References:

1. American Cancer Society: Cancer Facts and Figures 2002. Atlanta, ACS, 2002.

2. www.mamashealth.com/cancer/livercancer.asp. March 08, 2002.

3. Chang M-H, Chen C-J, Lai M-S, et al: Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 336:1855-1859, 1997.

4. Nystedt D: Researchers test drug for liver cancer. Taipei Times, Oct 14, 2000.

5. Department of Health: The population, in Hsu TC ed: Health and Medicine in Taiwan Area, Republic of China. Taipei, Taiwan, Department of Health, Executive Yuan, pp 3-4, 1985.

6. Stevens CE, Beasley RP, Tsui J: Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med 292:771-774, 1975.

7. Chen DS: From hepatitis to hepatoma: Lessons from type B viral hepatitis. Science 262:369-370, 1993.

8. Hsu HM, Chen DS, Chuan CH: Efficacy of a mass hepatitis B vaccination program in Taiwan. JAMA 260:2231-2235, 1989.

9. Chen DS, Sung JL: Hepatitis B virus infection and chronic liver diseases in Taiwan. Acta Hepatol-Gastroenterol 25:423-430, 1978.

10. Sung JL, Chen DS, Lai M, et al: Epidemiological study on hepatitis B virus infection in Taiwan. Chin J Gastroenterol 1:1-19, 1984.

11. Beasley RP, Hwang LY, Lin CC: Hepatocellular carcinoma and hepatitis B virus: A prospective study of 22,707 men in Taiwan. Lancet 2:1129-1133, 1981.

12. Ni YH, Chang MH, Huang LM, et al: Hepatitis B virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis B vaccination. Ann Intern Med 135:796-800, 2001.

13. Alter MJ: Protecting future generations through immunization against hepatitis B. Ann Intern Medicine 135:835-836, 2001.

14. Chen DS, Hsu HM, Bennett CL, et al: A program for eradication of hepatitis B from Taiwan by a 10-year, four-dose vaccination program. Cancer Causes and Control 7:305-311, 1996.

Ms. Gibbons, Ms. Newlin, and Ms. Phan are project managers, NorthwesternUniversity Medical School. Dr. Bennett is professor of medicine, NorthwesternUniversity Medical School, Robert H. Lurie Comprehensive Cancer Center, anddirector of HSR&D, VA Chicago Health Care System—Lakeside Division.