Recent updates in hepatitis vaccination and the prevention of hepatocellular carcinoma
Journal
International Journal of Cancer
Journal Volume
97
Journal Issue
3
Pages
269-271
Date Issued
2002
Author(s)
Abstract
With an estimated 1 million cases per year, hepatocellular carcinoma (HCC) is the fifth most common cancer in the world with 80% of cases occurring in developing countries.1 Symptomatic HCC usually runs a rapidly progressive course with low rate of resectability and poor response to nonsurgical therapy and thus has a very poor prognosis.2 The risk factors associated with the development of HCC include chronic infection with either hepatitis B virus (HBV) or hepatitis C virus (HCV),3 the presence of cirrhosis, carcinogen exposure especially to alfatoxin B1 (AFB1), alcohol abuse, genetic factors, male gender, cigarette smoking and advanced age.4 Among these risk factors, chronic hepatitis virus infection, particularly those who already reached the stage of cirrhosis, bears the strongest association with the development of HCC.2-6 The mass vaccination program against HBV in Taiwan has reduced the incidence of HCC in children,7 and such programs are likely to yield comparable benefits elsewhere. Recently, however, there is evidence that the incidence of HCC is rising in developed countries.8 This appears to be likely related to the increasing prevalence and duration of HCV infection in these countries. In our article, the recent advances in hepatitis vaccination and prevention of HCC are reviewed. The first commercially available HBV vaccines were plasma-derived hepatitis B surface antigen (HBsAg) subunit vaccines. At present, the plasma-derived vaccines are almost totally replaced by recombinant vaccines. All these vaccines are safe and have a protective efficacy of 90–95%. Several different studies in Alaska, China, Taiwan, Italy and Gambia have all demonstrated the effectiveness of routine infant immunization,9-13 with dramatic reductions of the prevalence of HBsAg carriage. A recent analysis in Taiwan further demonstrated that the mortality of fulminant hepatitis in infants has also declined significantly since the institution of the country's mass hepatitis B vaccination.14 In brief, the data on the mortality of fulminant hepatitis in infants in Taiwan from 1975–1998 were retrieved from the National Mortality Registry System. The difference of average mortality from fulminant hepatitis in infants before (1975–1984) and after (1985–1998) the implementation of the mass hepatitis B vaccination was assessed by using the Poisson regression analysis. The results showed that the ratio of yearly mortality from 1975–1998 was 1.10 (p < 0.001), representing progressive decrease of the cases. The average mortality of fulminant hepatitis in infants from 1975–1984 and from 1985–1998 was 5.36 and 1.71 per 100,000 infants, respectively, and the ratio of the average mortality in the period from 1985–1998 to that in the period from 1975–1984 was thus 0.32 (p < 0.001).14 The seroconversion rate after hepatitis B vaccination is lower in smokers, elderly and immunocompromised subjects. Approaches including intradermal application or addition of vaccine adjuvants such as granulocyte-macrophage colony-stimulating factor (GM-CSF) have been recently explored to enhance the efficacy of the vaccination.15, 16 HBV with mutations in the surface (S) gene may affect the antigenicity of S protein leading to breakthrough infections in successfully vaccinated individuals and to false-negative results in HBV screening tests.17 A glycine to arginine change at amino acid 145 (G145R) is the first and by far the most commonly encountered variant, and such a mutation has been claimed to be responsible for the failure of the immunoprophylaxis. Thus it is suggested that the currently available HBV vaccines may be changed to incorporate both wild-type and mutated S proteins. However, recent demonstrations that immunization of chimpanzees with currently available recombinant hepatitis B vaccines can stimulate anti-HBs, which is broadly reactive and can confer protection against the infection with a surface gene mutant of HBV.18, 19 Therefore, the mutated S proteins may not be needed in current HBV vaccination. Nevertheless, development of more immunogenic, potent adjuvants or naked DNA to overcome the problems of S gene mutants should continue.17 There has been concern that HBV vaccination may precipitate the onset of multiple sclerosis in previously healthy subjects or lead to relapses of patients with multiple sclerosis. However, two large surveys have documented that hepatitis B vaccination is not associated with the development of multiple sclerosis and does not appear to increase the short-term risk of relapse in multiple sclerosis.20, 21 Long-term protection against clinically significant breakthrough HBV infection and chronic carriage depends on immunologic memory, which allows a protective anamnestic antibody response to antigen challenge. Memory seems to last for at least 15 years in immunocompetent individuals. The need for booster doses of hepatitis B vaccine in immunocompetent individuals after a primary vaccine series has been the subject of debate. Currently, vaccine advisory groups do not recommend routine booster doses in persons who have responded to vaccination. Nonetheless, several countries and individuals currently have a policy of administering booster doses to certain risk groups. Boosters may be used to provide reassurance of protective immunity against benign breakthrough infection. For immunocompromised patients, regular testing for anti-HBs and a booster injection when the titer falls below 10 mIU/mL are advised.22 Many countries in the world still cannot afford vaccination programs against HBV, and these countries are often populous and highly endemic for HBV infection. In the developing countries, HBV infection in early childhood is the main cause of chronic HBV carriage, and thus universal vaccination of all infants is the best way to control HBV infection. To achieve the goal of universal infant vaccination, public education should be done in parallel with education of health professionals and propagation of the control measures.23 Global control of HBV infection no doubt remains the most important and challenging task that needs to be continued in the beginning of the new millennium. The quasispecies nature and variation of amino acid sequences on the envelope proteins of HCV may allow the virus to escape the neutralizing antibodies and then establish persistent infection.24, 25 As confirmed in chimpanzee experiments, antibody against E2 after vaccination is found either to confer only transient protection against HCV infection or to ameliorate the severity of clinical hepatitis if these animals are infected.26 In addition, the lack of protective immunity against reinfection with heterotypic or homotypic HCV infection in an already infected host is documented in both chimpanzee experiments and human observations.27-30 Taken together, these findings reveal a major obstacle to the design of an effective preventive vaccine as it does with hepatitis A virus or HBV. Hepatitis D virus (HDV), a defective RNA virus that requires the provision of HBsAg from HBV for package and transmission,31 plays an important role in fulminant hepatitis and the progression of chronic liver damage in patients with chronic hepatitis B.32 In addition, chronic HDV infection has been claimed to be associated with the development of HCC. Currently, there is no effective vaccine to protect HBV carriers from HDV superinfection. A recent study has suggested that DNA vaccines against HDV can induce significant cellular immune responses with a T-helper 1 (Th1) preference in a mouse model.33 Thus the DNA-based immunization may be a promising tool not only in the prevention of HDV superinfection in HBV carriers but also in the treatment of chronic HDV infection. More animal studies are needed to further evaluate the safety and therapeutic effects of this vaccine. On the other hand, since the universal HBV vaccination has effectively decreased the HBV carrier rate in the general population, the development of HDV vaccine is therefore not so compelling. A safe and effective vaccine to prevent HBV infection is well developed, and a mass vaccination program against HBV in Taiwan has been shown to reduce the incidence of HCC in children,7 especially in boys.34 The average annual incidence of HCC in children 6 to 14 years of age declined from 0.70 per 100,000 children in 1981–1986 to 0.57 in 1986–1990 and further to 0.36 in 1990–1994 (p < 0.01).7 Taken together, these data suggest the effect of the HBV mass vaccination program in controlling HBV-related HCC has begun to be seen in the Taiwanese children and very likely can also be seen in young adults soon. An 80–85% decrease of HCC in the Taiwanese adults 3–4 decades later is anticipated. The decrease of HCC in children after the implementation of universal vaccination against HBV not only represents a practical prevention of a human cancer by vaccination for the first time in history, but also strengthens the etiologic role of HBV in causing HCC in man. Given estimates that approximately 70% of HCC in developing countries is attributable to HBV, mass vaccination could prevent more than 500,000 cases per year in these areas. Nevertheless, the HBV vaccine is still not incorporated into many national immunization programs. Thus the major challenge now is to ensure the availability of the vaccine in all countries with endemic infection. Unfortunately, development of a vaccine against HCV is more problematic due to the genetic heterogeneity of the virus.3 Nevertheless, with 24% of HCC in developing countries attributable to HCV (approximately 93,000 cases per year),35 preclusion of HCV infection would make a major contribution to cancer prevention. Until effective immunoprophylaxis is available, interruption of transmission routes such as implementation of blood donor screening for anti-HCV, adequate sterilization of surgical instruments or the use of disposable medical instruments and avoidance of sharing personal tools remains the mainstay in preventing HCV infection.36 Reduction of exposure to aflatoxins can be addressed at the community level, either pre- or postharvest by limiting fungal contamination of crops. Approaches may involve low technology postharvest measures to limit fungal growth or genetic engineering of crops to become resistant to fungal infection or toxin biosynthesis.37 An alternative measure is using chemopreventive agents to modulate the metabolism of aflatoxins once ingested. Unfortunately, the resources available in countries with endemic hepatitis infection and fungal contamination of foods are often severely limited. The currently recommended therapy of chronic hepatitis B is a 4–6 month course of interferon alfa in doses of 5–10 million units 3 times a week; a regimen that results in sustained clearance of serum HBV DNA and HBeAg in approximately 25–40% of patients and a loss of HBsAg in 10% of Western patients.38 Long-term follow-up of patients who respond to interferon alfa treatment with clearance of HBeAg indicates that the majority ultimately clear HBsAg as well, have continued remission of liver disease and are usually associated with improved clinical outcomes.39 Recently, several oral nucleoside analogues that possess potent activity against HBV have been developed. Among them, lamivudine (3-thiacytidine) was extensively studied and can induce marked reduction of serum HBV DNA levels and improvement in serum aminotransferase activities as well as hepatic histology.40 However, whether these therapeutic effects persist and eventually lower the incidence of cirrhosis or even HCC needs to be seen after further long-term observation. Future approaches of therapy for hepatitis B should focus on combinations with other regimens, such as interferon alfa, other antiviral nucleoside analogues or therapeutic vaccines. For chronic hepatitis C, the currently recommended 6–12-month course of combination therapy with interferon alfa and ribavirin can clear HCV RNA and normalize serum aminotransferase levels as well as liver histology in 40–50% of patients.41, 42 Sustained responses are associated with marked improvements in hepatic histology, and long-term studies indicate that the majority of patients remain free of virus in serum and liver, suggesting a “cure” of the infection.43 Recent studies have indicated that patients with chronic hepatitis C have a significantly lower risk of HCC and mortality if treated with interferon than those who were not treated.44, 45 Preliminary observations have also suggested that the occurrence of HCC was decreased in those successfully treated with the combination of interferon and ribavirin (authors' unpublished data). Search for other antiviral compounds is in progress, and the combination of long-acting interferon (pegylated IFN) with ribavirin has been shown to be more effective in clearing the virus, with the overall sustained virologic response rate of 60%.46 Curcumin, a food additive widely used as a spice and coloring agent, is found to possess chemopreventive effects against several cancers. The chemopreventive effect of curcumin on murine hepatocarcinogenesis was recently reported.47 Whether curcumin or other compounds is feasible in the chemoprevention of HCC in high-risk patients needs to be further explored.
SDGs
Other Subjects
aflatoxin; curcumin; hepatitis B vaccine; hepatitis vaccine; recombinant alpha interferon; ribavirin; cancer incidence; cancer prevention; disease association; hepatitis B; Hepatitis B virus; hepatitis C; Hepatitis C virus; Hepatitis delta virus; human; liver cell carcinoma; multiple sclerosis; primary prevention; priority journal; secondary prevention; short survey; Carcinoma, Hepatocellular; Female; Hepacivirus; Hepatitis; Hepatitis Delta Virus; Hepatitis Viruses; Humans; Male; Prognosis; Risk Factors; Sex Factors; Vaccines
Type
short survey