British Journal of Cancer (1999) 81(7), 1097–1098 © 1999 Cancer Research Campaign Article no. bjoc.1999.0813 Editorial Prevention of hepatocellular cancer: one of the most cost-effective ways to reduce adult mortality? AJ Hall and PG Smith Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK In 1965, Blumberg, Alter and Visnich described a ‘new’ antigen in sera from patients with leukaemia, and in 1970, Prince and colleagues went on to show that this SH (serum hepatitis) antigen was associated with chronic hepatitis. A decade later, Beasley et al (1981), working in Taiwan, showed that the risk of developing liver cancer among men positive for this marker of persistent hepatitis B virus (HBV) infection was approximately 200 times greater than that among men without the marker. Although this relative risk fell with further follow-up to around 100 (Beasley and Hwang, 1991), the very strong association between the hepatitis B carrier state and the risk of hepatocellular cancer has been repli- cated in multiple case–control and cohort studies in various parts of the world (IARC, 1994). The strength and consistency of these findings, together with evidence of biological plausibility gained from animal models, led the International Agency for Research on Cancer to conclude that there is sufficient evidence for the carcino- genicity of chronic infection with HBV in humans (IARC, 1994). It has been estimated that at least 60% of cases of primary liver cancer worldwide and 67% in developing countries are attribut- able to persistent infection with HBV (Pisani et al, 1997). The burden of mortality due to chronic hepatitis and cirrhosis that is attributable to hepatitis B infection is much less clear due to a paucity of relevant studies but is likely to exceed that due to liver cancer. It has been estimated that around 40% of hepatitis B carriers will die as a result of the infection. Since approximately 20% of adults in China and sub-Saharan Africa are carriers, this signifies a major global public health problem. Only a minority of those infected with HBV become persis- tently infected, the major determinant being the age at first expo- sure to the virus (Edmunds et al, 1993). In China, where infection occurring around the time of birth from an infectious mother is common, about 40% of carriers are infected perinatally (IARC, 1994). There, about 90% of children born to carrier mothers are infected and perinatal infection is associated with about a 90% risk of becoming a carrier (Beasley et al, 1977; Mitusda et al, 1989). In many other parts of Asia and in sub-Saharan Africa, infection is most common in childhood. In The Gambia, for example, between 35% and 70% of children were found to have been infected by the age of 5 years (Whittle et al, 1990). Although the prevalence of infectious mothers in such populations is substantially lower than in China, the rates of chronic infection in the population are still Received 19 April 1999 Revised 1 May 1999 Accepted 18 May 1999 Correspondence to: PG Smith high, as the probability of becoming a carrier following infection in early childhood is around 20–30%. In contrast, the risk of becoming a carrier following infection in adolescence or adult life is less than 10%. This pattern makes the options for prevention clear. Either primary prevention of persistent infection must be undertaken early in life (particularly very early in life in China), or secondary prevention measures must be directed at reducing the risk associated with carriage later in life. Progress on these two possible intervention strategies has been unequal. Secondary prevention by modification of carriage can now be made by anti-viral therapy but is currently expensive and its long-term effectiveness has yet to be demonstrated. The high cost is a particularly important issue since the vast majority of carriers in the world live in Asia and Africa, where resources are very limited. Alcohol avoidance is likely to reduce the risks asso- ciated with carriage but this is a difficult intervention to imple- ment. The likely role of dietary aflatoxin has become clearer in recent years. Cohort studies in which stored samples have been analysed for biomarkers of aflatoxin exposure on a case–control basis indicate that aflatoxin exposure increases the risk of liver cancer by around twofold (Ross et al, 1992). However, because the risk appears to be multiplicative, the impact of such exposure among hepatitis B carriers, who are at high risk of liver cancer, may be substantial. This has led to more recent focus on the possi- bility of benefiting carriers by reducing their aflatoxin exposure. Oltipraz, an anti-schistosomal drug, induces aflatoxin metabo- lizing enzymes and has been shown to inhibit aflatoxin-induced hepatocarcinogenesis in animal models (Kensler et al, 1999). Whilst some trials of this chemotherapeutic agent in humans have been conducted (Wang et al, 1999), this does not represent a real- istic option in the affected resource-poor countries. A more attrac- tive agricultural approach is to reduce contamination of locally consumed foodstuff; however, field trials are needed using human biomarker exposure as the end point to assess their effectiveness, and ultimately intervention studies to assess whether simple, tech- nologically appropriate interventions can reduce the incidence of hepatocellular carcinoma. In contrast, great strides have been made in primary prevention. Hepatitis B vaccine has been available since 1980. Initial studies in the USA showed its effectiveness in preventing infection and acute hepatitis. More importantly, studies in China, Taiwan and West Africa demonstrated that vaccination at birth or in early childhood prevented the chronic carrier state: the efficacy in China was between 70% and 85% (Sun et al, 1986, 1991) but in Africa where perinatal transmission is less common it was over 90% (Fortuin et al, 1993). Recently, this protection has been shown to persist up to 9 years of age (Viviani et al, 1999), which is more 1097