Mei-Hwei Chang, Department of Pediatrics, National Taiwan University Hospital, No. 7, Chung-Shan S. Road, Taipei, Taiwan. Tel: (886-2)-23123456, ext. 7120. Fax: (886-2)-23938871. e-mail: firstname.lastname@example.org
Abstract: Hepatocellular carcinoma (HCC) is one of the 10 most common malignant tumors worldwide. Chronic infection with hepatitis B or C virus is closely related to hepatocarcinogenesis. The outcome of current therapies for HCC is not satisfactory. Prevention is the best way to control HCC. Among the various strategies of HCC prevention, immunization against hepatitis B virus infection is the most effective. Universal hepatitis B immunization has proved to be effective in reducing the incidence of HCC to 1/4–1/3 of that in children born before the hepatitis B vaccination era in Taiwan. The problems we face in achieving global control of hepatitis-related HCC include: (1) no effective vaccine for the prevention of hepatitis C and its related HCC; (2) no immunization program for hepatitis B in areas with inadequate resources; (3) poor compliance to the immunization program as a result of ignorance, anxiety, or poverty; and (4) vaccine failure. Integration of the hepatitis B vaccination program into the expanded program of immunization for all infants throughout the world will be most urgent and important for HCC control. The reduction of the incidence of HCC will be seen in adults 30–40 years of age after the launch of the universal hepatitis B vaccination program. This concept of cancer vaccine can be applied to other infectious agents and their related cancers.
Primary liver cancer is one of the 10 most common malignancies in humans. Approximately 75–80% of hepatocellular carcinoma (HCC) worldwide is related to chronic infection with hepatitis viruses. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the two most important etiologic agents responsible for human HCC. HBV accounts for 50–55%, while HCV accounts for 25–30% of HCC worldwide (1).
HBV has been closely related to HCC, particularly in areas endemic for chronic HBV infection. Evidence from epidemiologic studies, serum HBV markers in HCC patients, histologic studies of HBV markers in HCC tissues, molecular biological studies, case–control studies, and animal models all support the close relationship between HBV and hepatocarcinogenesis (2). The seroprevalence rates of hepatitis B surface antigen (HBsAg) in adult HCC patients vary in different countries. In Asian adults, it ranges from as low as 19% in Japan, where HCV infection is more prevalent than HBV infection, to as high as 79% in Taiwan (3).
Chronic HBV infection can cause chronic hepatitis, cirrhosis, and HCC. The peak age of HCC in adults is 40–60 years in most regions, while in endemic areas for HCC, as demonstrated in Asia and Africa, it can develop as early as in childhood. Perinatal transmission is the most important route of HBV transmission in Asia, while it occurs mainly during early childhood through horizontal transmission in Africa (4). Hepatitis virus-associated HCC in children is mainly HBV related, and most children with HCC are HBsAg seropositive. They are mostly (around 80%) anti-HBe seropositive (5). The integration of HBV DNA has been detected in the HCC tissues of both children and adults (6). Maternal transmission of HBV to their infants is the main route of transmission in both children and adults with HCC. The HBsAg seropositive rate is 94% in the mothers of HCC children (5), and 74% in the mothers of HCC adults (7). Although the role of HCV in HCC is increasing in many countries, the proportion and importance of HBV in childhood HCC has not changed. Up to now, no HCV-related HCC has been reported in children in the world literature.
Current therapies for chronic hepatitis B, cirrhosis, and HCC are not satisfactory. They cannot effectively prevent HBV-related complications. Furthermore, many HCC patients are diagnosed late, inoperable, and not responsive to non-surgical therapies. Recurrence after therapy is another common problem. Immunoprophylaxis is thus the best way to get rid of the threat of HBV infection and its related HCC. The successful experience of HBV immunoprophylaxis in preventing its related HCC in children will be used as a model to illustrate the important role of hepatitis vaccine in future HCC control in adults.
Strategies to prevent viral hepatitis-associated HCC (Fig. 1)
1Immunoprophylaxis against viral hepatitis and its related HCC: This is the most cost-effective way to prevent HCC. The best timing for hepatitis B immunization is in infancy.
2Treatment of viral hepatitis/cirrhosis: Although the effect of interferon therapy in preventing hepatitis C-related HCC seems slightly favorable, more evidence from a larger study population and a longer duration of follow-up is needed (8). The effect of HCC prevention by interferon therapy has been controversial in hepatitis B-related HCC (9).
3Chemoprevention: Trials in animals and one trial in humans were conducted using oltipraz or chlorophyllin to produce alteration in metabolites or to form tight complexes with aflatoxin B1 (10, 11). Curcumin is also found to possess a chemopreventive effect on murine hepatocarcinogenesis (12). However, the direct evidence of HCC reduction is still awaiting further study.
4Liver transplantation for cirrhosis: The cost–benefit of HCC prevention needs further evaluation.
Hepatitis B immunoprophylaxis
Prevention of HBV infection can be achieved by passive and active immunization. Passive immunization using hepatitis B immunoglobulin (HBIG) provides temporary immunity. For infants of hepatitis B e antigen (HBeAg) seropositive mothers born before the era of HBV immunization, approximately 90% became HBsAg carriers. In infants of HBeAg seropositive mothers, three doses of HBV vaccine decreased the carrier rate to 24%. Injection of HBIG within 24 h after birth followed by three doses of HBV vaccine further reduced the carrier rate to 3% in pilot studies (13), and to 14% in the study of the general population (14). The protective efficacy in infants of high-risk mothers was found to be 86% with the HBIG plus HBV vaccine, and 78% with three doses of the HBV vaccine (14). Active immunization with three or four doses of HBV vaccines without HBIG has proved to be immunogenic in more than 90% of neonates of non-carrier mothers or HBeAg-negative carrier mothers.
Different strategies are used in different countries, depending on the basic epidemiologic features of HBV infection and supporting resources. The first population-based hepatitis B vaccination program in the world was launched in Taiwan in July 1984 (15). Pregnant women are screened for both serum HBsAg and HBeAg. Infants of mothers with HBeAg-negative serum, or with HBsAg-negative serum, received plasma-derived hepatitis B vaccine at 0, 1, 2, and 12 month(s) or recombinant hepatitis B vaccines at 0, 1, and 6 month(s) schedule. Infants of mothers with positive serum HBeAg and HBsAg receive HBIG within 24 h after birth in addition to three or four doses of hepatitis B vaccines. The coverage rate of hepatitis B vaccine for neonates was around 84–94%. It was extended gradually to all the preschool, school, middle- and high-school children, and finally to all the adults.
In many hyperendemic countries, HBV vaccination of all infants is performed, using three doses of hepatitis B vaccine without HBIG. This same scheme is used for infants of HBsAg carrier mothers (16). This proved to be satisfactory for prevention in Thailand, and was only 5–10% less efficacious in infants of HBeAg-positive mothers in Thailand, in comparison to the combination of HBIG plus HBV vaccines. Using this HBV immunization program, the cost of maternal screening and HBIG can be reduced.
Impact of universal hepatitis B immunization on chronic HBV infection
Hepatitis B immunization has proved to be effective in preventing both the total infection rate and the chronicity rate of HBV infection. The seroprevalence rates of HBsAg (representing chronic infection rate) and the hepatitis B core antibody (anti-HBc, representing total infection rate) have decreased in children in many parts of the world after the introduction of HBV vaccination programs. We used the data of Taiwanese, Gambian, and Italian children to demonstrate the remarkable reduction of the chronic infection rate 14–15 years after the HBV vaccination program (Table 1) (17–20). The HBsAg carrier rate and the total infection rate (reflected by the seropositive rate of anti-HBc) decreased in all the children, even in those above 15 years of age who were not vaccinated during infancy. The latter is due to the decrease of horizontal infection contributed by both the decline of the infection source and the vaccination of the older children. These results prove that the HBV vaccination program has indeed reduced both the perinatal and horizontal transmission of HBV (18).
Table 1. Hepatitis B s antigen seropositive rates before and after the universal hepatitis B vaccination program in Taiwan, Gambia, and Afragola (Italy)
Universal hepatitis B vaccination was implemented in Taiwan in July 1984.
** All children in Keneba and Manduar, Gambia <5 years of age were vaccinated in November 1984.
# A pilot project of universal vaccination was launched locally for infants in Afragola (Italy) in 1983.
Comparing the strategies for HBV vaccination, a universal immunization program for infants is better than immunization of high-risk groups (20). Integration of HBV into the routine vaccination program of infancy is most plausible and has the highest compliance. The efficacy in preventing HBV infection is highest and the amount of HBV vaccine needed is the lowest.
Decreasing the incidence of HCC in children born after the HBV immunization era
If HBV infection is indeed an important cause of HCC, a decline in HCC incidence should occur after a successful HBV immunization program. Because the peak age of HCC in adults is 40–60 years, it may take at least 40 years to observe an effect of HBV immunization on the incidence of HCC in adults. Changes in the incidence of HCC in children before and after the HBV vaccination era in endemic areas for HBV and HCC may help to understand the effect of HBV immunization on HCC prevention.
After the implementation of the universal vaccination program of HBV in Taiwan, we have successfully demonstrated the decline of the incidence of HCC in children. When we analyze the incidence of HCC according to the birth cohort, the reduction effect is even clearer. The incidence of HCC in children declined from 0.52 per 100 000 children for those born between 1974 and 1984, to 0.13 per 100 000 children for those born between 1984 and 1986 (21). In contrast, the incidence of hepatoblastoma in children and the incidence of HCC in adults during the same study period are not reduced. This trend remains similar with the passage of time.
The decline of HCC incidence was more prominent in boys than in girls (22). The boy to girl incidence ratio of HCC decreased steadily from 4.5 in 1981–1984 (before the launch of the universal HBV vaccination program) to 1.9 in 1990–1996 (6–12 years after the launch of the universal HBV vaccination program). The incidence of HCC in boys born after 1984 was significantly reduced in comparison with those born before 1978 with a relative risk of 0.72 (P=0.002). In contrast, no significant reduction in HCC was observed in girls born in the same periods.
Problems to be solved in hepatitis and HCC control
To eradicate hepatitis virus infection and its related liver cancer, we have to overcome the following main problems (Fig. 2):
1No vaccine available for HCV infection and its related HCC.
2Inadequate resources of HBV immunization for poor people in developing countries. How to reduce the cost of vaccine and to increase the funds for HBV vaccination of children in hyperendemic areas with poor economic conditions are important issues that we have to solve before eradication of HBV infection and its related liver complications can be addressed.
3Poor compliance to follow the universal hepatitis B vaccination program. The HBV vaccine coverage rate was high in most areas worldwide with the universal vaccination program, but only if the HBV vaccine was free of charge for all neonates. Even then, 5–15% of the infants at risk did not receive HBV vaccine or hepatitis B immunoglobulin. In particular, in rural areas the compliance was not so good in the case where the expense of the HBV vaccine was not covered by the government.
Anxiety over the side effects of HBV vaccination should be reduced. For instance, a relation between central nervous system demyelinating diseases and hepatitis B vaccine has been suggested, but this has not been proven (23). Education and propagation of the benefits of the HBV vaccination will enhance the motivation of the public and the governments to receive HBV vaccination. The anxiety over the mercury content in HBV and other vaccines is another example. Thiomersal is a preservative containing small amounts of ethyl mercury that is used in routine vaccines for infants and children. The mercury content is very low and within a safe range. The removal of mercury from HBV vaccine has solved the anxiety problem (24).
4Vaccine failure or non-responders. Although immunoprophylaxis for HBV infection is very successful, yet around 2.4% of infants of HBeAg-positive HBsAg carrier mothers had HBsAg in the serum at or shortly after birth in Taiwan (25). They become HBsAg carriers in spite of complete immunoprophylaxis with HBIG within 24 h after birth and HBV vaccines. Intrauterine HBV infection, although infrequent, is possible. Risk factors of immunoprophylaxis failure include high levels of maternal HBV DNA, low levels of maternal anti-HBc, uterine contraction, and placental leakage during the process of delivery, etc. (26, 27). Further investigations into the mechanism of HBV vaccine failure will help solve this problem.
Interventions to prevent intrauterine infection, development of the HBV vaccine covering surface gene mutants, and better vaccines for immunocompromised patients are possible ways of reducing the rate of vaccine failure or non-responders.
Conclusions and future prospects on HCC control
HBV is an important etiologic agent of HCC, and prevention of HBV infection can prevent HCC. The universal hepatitis B vaccination program should be integrated into the expanded program of immunization (EPI) in infancy. It is particularly urgent in areas where HBV infection and HCC are hyperendemic. The World Health Organization (WHO) has recommended that universal hepatitis B immunization should be introduced in all countries at the end of 1997 (28). More than 120 countries have followed this recommendation up to now. WHO has established the objective of reducing the incidence of new HBV carriers among children by 80% by 2001, and eventually to eliminate the more than a million deaths that occur annually from HBV-associated cirrhosis and HCC (29).
Universal vaccination is better than immunization of high-risk groups. Universal immunization for HBV has been proved to be effective in reducing the hepatitis B carrier rate to one-tenth of the prevalence before the vaccination program in highly endemic areas, and the incidence of HCC in children has also been reduced significantly. Continued efforts to implement universal vaccination programs in the world will hopefully reduce HBV-related diseases, particularly cirrhosis and HCC.
Hepatitis B vaccine adoption was limited in the poorest countries. The contributions of international organizations, such as the Global Alliance for Vaccines and Immunizations that began in 1999, are needed for people in poor countries. It is expected that within 5 years, the hepatitis B vaccine will be almost universally available to the world's children, saving an estimated one million lives per year (30).
Continuous monitoring of the incidence of HCC is mandatory. Since the peak age of HCC in adults is around 40–60 years, theoretically we may expect a reduction of HCC in adults 30–40 years after universal vaccination. However, based on the data in children, which demonstrated a herd immunity in older children born before the implementation of the universal vaccination program, we predict that the reduction of HCC in adults may come earlier. Furthermore, we hope that the impact of HBV vaccination on the control of hepatitis B and its related complication can be extended to other infectious agents and their related diseases and cancers.