Global control of primary hepatocellular carcinoma with hepatitis B vaccine: the contributions of research in Taiwan.

Health workers and epidemiologists concerned with the prevention of cancer are largely unaware of one of the most significant recent developments in global cancer control, the integration of HB vaccine into the national immunization programs in developing countries, including the poorest. PHC caused by chronic HB infection is the number one or two cause of cancer death in men in most Asian and sub-Saharan African countries and an important cause of cancer death in women. Chronic HB infection is approximately 90% preventable with proper use of HB vaccine but, until recently, this vaccine has been beyond the budgets of governments in the poorest countries; donors who supplied older vaccines were unwilling to pay for HB vaccine. In addition to the financial constraints, delivery services in the poorest countries were unable to access large parts of their populations with any vaccines. Both of these impediments are being overcome by the creation, in the last 3 years, of GAVI and The Vaccine Fund. It is believed that the comprehensive use of HB vaccine will prevent about 1,000,000 deaths per year from PHC and cirrhosis of the liver (each year) in future birth cohorts. There has already been a significant impact on the prevalence of chronic HB infection in immunized birth cohorts in more than 135 countries, including China, southeast Asia, and sub-Saharan Africa where most PHC occurs. The report in this journal, measuring the decline in PHC after immunization in Taiwan, is the latest in a remarkable series of studies in Taiwan dating back to the 1970s, in which much of the epidemiology of chronic HB infection, its link to cancer, and its prevention with HB vaccine were worked out. Before these studies, many researchers thought that aflatoxin from moldy groundnuts (peanuts) was the primary etiologic agent for PHC in developing countries. Whereas aflatoxin may be a cofactor in some countries, the Taiwanese studies showed that chronic HB infection is a necessary and sufficient cause of PHC, and that HB vaccine can prevent the development of chronic infection, strongly suggesting that routine HB immunization would be sufficient to prevent most PHC on a global basis (1). In one of the most important epidemiological studies of the 20th century, Beasley et al. (2) followed 22,000 male Taiwanese health workers for more than a decade with almost complete follow-up. Rates of PHC were approximately 100 times higher among men who were HBsAg (hepatitis B surface antigen)positive (495 per 100,000 per year) than among those who were HBsAg negative (5 per 100,000 per year). The validity of this association has now been confirmed in dozens of other studies; these are well reviewed in a monograph published by the IARC (3), which also discussed other confirmatory lines of evidence based on DNA integration and liver cancer in animals chronically infected with related hepadnaviruses. It is now generally accepted that prevention of the HBcarrier state with HB vaccine will prevent PHC, and the global immunization strategy is based on this assumption. In the early 1980s, a major study in The Gambia was designed to measure directly the reduction in PHC in immunized cohorts, a task that many believed would take about 25 years. Using an innovative and controversial step-wedge design, most Gambian newborns were recruited into the study over a period of 4 years in a way that generated comparable vaccinated and control groups. The Gambia study has been remarkably thorough in documenting a 90% success in prevention of the chronic carrier state, following a cohort for almost 20 years showing an unexpectedly (to many) long duration of protection of the vaccine, maintaining one of the most important cancer registries in Africa, and proving to many other African countries what can be achieved with HB immunization (4). However, it is still too early to measure a direct impact on PHC from this study. Thus, the first reports directly measuring an impact on PHC in immunized cohorts of adolescents in Taiwan came as a surprise to most of the hepatitis community (5, 6). Adolescent PHC is rare, and only in a population with high rates of PHC and with careful disease surveillance could such a finding be established. The Taiwanese researchers must be commended: Taiwan continues to generate cutting edge research in the field of hepatitis. In parallel and subsequent studies in Taiwan, researchers worked out the epidemiology of perinatal transmission of HB, showed that most perinatal transmission led to the chronic carrier state, and began a series of studies to explore how it could be prevented. First using HB immune globulin (HBIG), then HBIG plus HB vaccine, then HB vaccine alone, these studies, now confirmed by many others globally, have become an important basis for global public-health recommendations (7). It is estimated that more than 2 billion people have serological evidence of current or prior HB infection, resulting in a pool of more than 350 million chronic HB carriers. Most of these carriers live in the high endemicity areas of Asia and Africa, where more than 8% of the populations are chronically infected. The use of HB vaccine in infants can reduce the carrier prevalence in immunized birth cohorts to less than 2% (low endemicity), and often to less than 1%. This has been demonstrated in Taiwan (8), Shanghai, rural China, Indonesia, Thailand, Gambia, Senegal, South Africa, American Samoa, in Alaska Natives, and in many other populations (9). Although safe and effective HB vaccines have been available since 1982, immunization policies, economic constraints, and poor delivery infrastructure (in developing countries) have been impediments to the introduction of these vaccines. In the 1980s, the cost of a three-dose adult series of HB vaccine was more than $100, Received 11/10/02; accepted 11/11/02. 1 To whom requests for reprints should be addressed, at Program for Appropriate Technology in Health, 1455 Northwest Leary Way, Seattle, WA 98107-5136. 2 The abbreviations used are: HB, hepatitis B; PHC, primary hepatocellular carcinoma; GAVI, (the) Global Alliance for Vaccines and Immunization. 2 Vol. 12, 2–3, January 2003 Cancer Epidemiology, Biomarkers & Prevention