Join Us | Latest Articles | Contact

Journal Home


Editorial Board


Archive


Submit to this journal


Current issue

Journal of Clinical Gastroenterology and Treatment





DOI: 10.23937/2469-584X/1510001



Expectations for Hepatitis B Universal Vaccination for Hepatitis B Virus Eradication

Toru Ishikawa*


Department of Gastroenterology, Saiseikai Niigata Daini Hospital, Japan


*Corresponding author: Toru Ishikawa, Department of Gastroenterology, Saiseikai Niigata Daini Hospital, 280-7 Teraji, Niigata 950-1104, Japan, Tel: +81-25-233-6161, E-mail: toruishi@ngt.saiseikai.or.jp
J Clin Gastroenterol Treat, JCGT-1-001, (Volume 1, Issue 1), Review Article; ISSN: 2469-584X
Received: July 21, 2015 | Accepted: August 24, 2015 | Published: August 26, 2015
Citation: Ishikawa T (2015) Expectations for Hepatitis B Universal Vaccination for Hepatitis B Virus Eradication. J Clin Gastroenterol Treat 1:001. 10.23937/2469-584X/1510001
Copyright: © 2015 Ishikawa T. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



Abstract

Context: To control hepatitis B virus (HBV) infection, we discuss in this review the expectations for a universal vaccination to eradicate HBV from the perspective of preventing hepatocarcinogenesis and hepatitis due to HBV. HBV infections are broadly classified into "acute infection" and "persistent infection" (HBV carrier state). Most adults who acquire HBV will only experience the "acute infection" that eventually heals, while nursing infants without adequately developed immune function and adults with immune dysfuncstion who contract HBV will be unable to eradicate the virus and will thus develop the "persistent infection." Hepatitis B virus is difficult to treat, but is simple to prevent through means such as vaccination. However, hepatitis B universal vaccination was not performed through 2014 in Japan.

Evidence acquisitions: The relevant English and non-English published papers were searched using online databases of PubMed, ISI Web of Science, SCOPUS, Science Direct and EMBASE from January 1985 to April 2015. We summarized the findings of 28 relevant studies in this review.

Results: In response to the demand for universal vaccination, the Immunization and Vaccination Committee of the Health Sciences Council decided to implement universal vaccination of HBV for newborns because in January 2015 confirmation was reached of the horizontal infection of HBV in children and the effectiveness of vaccination in different genotypes.

Conclusions: In this review, we discuss the expectations for hepatitis B universal vaccination for hepatitis B virus eradication.


Keywords

Hepatitis B universal vaccination, Antiviral treatment, Hepatocellular carcinoma


Abbreviations

HCC: Hepatocellular Carcinoma, HBV: Hepatitis B Virus, CHB: Chronic Hepatitis B, HBV: Hepatitis B Virus, HBsAg: Hepatitis B Virus Surface Antigen, Nucleos(t)ide: Nucleoside/Nucleotide; HBeAg: hepatitis B Virus Envelope Antigen


Introduction

The incidence of hepatitis B virus (HBV)-related HCC has not declined for the past several decades. HBV is essentially a disease that could potentially be eradicated by a vaccine. According to the World Health Organization (WHO), two billion people (one-third of the global population) have been infected with HBV worldwide, and more than 240 million are chronic carriers (4-6% of the world population) [1].

On the other hand, hepatitis C virus (HCV) is the leading infectious disease in Japan, but due to therapeutic advances, sustained viral response rates (SVRs), even among patients with refractory liver disease, have improved to 80-90% [2]. Therapeutic response is particularly good [3-5], even among the elderly and patients with progressive hepatic fibrosis, who are at very high risk for HCV-related hepatocellular carcinoma (HCC). Even after HCC treatment, interventions involving aggressive antiviral therapy can yield improved survival [6-8], suggesting that HCV-related HCC may be finally eradicated in the future.

This review examines vaccination strategies, the current status of HBV infection, and unresolved issues related to controlling HBV infection. We discuss the expectations for a universal vaccination (i.e., a vaccine available to all citizens) to eradicate HBV from the perspective of preventing hepatocarcinogenesis and hepatitis due to HBV.


Epidemiology of Hepatitis B

Of the approximately 240 million people worldwide who are said to be infected with HBV, 10-15% have refractory liver disease in the form of chronic hepatitis, cirrhosis or HCC. Each year 600,000 people die from diseases caused by HBV infection, such as cirrhosis and HCC [9].

In Japan, approximately 1.3-1.5 million people (about 1% of the population in Japan) are estimated to have persistent infection, and there are currently an estimated 1,800 new inpatients with acute hepatitis B each year. When including mild and latent forms of the disease, the number of estimated new cases of infection exceeds 5,000 per year. In any event, HBV infection has the potential to progress from chronic hepatitis to cirrhosis, and even to HCC.


Infection with Hepatitis B Virus

HBV infections are broadly classified into "acute infection" and "persistent infection" (HBV carrier state). In "acute infection," the virus is removed from the body after a certain period following establishment of infection, and the hepatitis B viral infection is cured. Clinical features of acute infection typically consist of inapparent infection that heals without any subjective symptoms, or apparent infection in which acute hepatitis occurs and rarely becomes fulminant. Around 400 people are estimated to develop fulminant hepatitis each year, with 40% of these cases reportedly caused by HBV [10]. The risk of these acute cases of HBV infection becoming chronic is highest in nursing infants and preschool children. In "persistent infection" (HBV carrier state), on the other hand, the virus gradually settles within the body; mainly the liver. Most adults who acquire HBV will only experience the "acute infection" that eventually heals, while nursing infants without adequately-developed immune function and adults with immune dysfunction who contract HBV will be unable to eradicate the virus and will thus develop the "persistent infection." Recently, there has been an increase in HBV genotype A infection, which is characterized by a high rate of progression from acute to chronic hepatitis, giving rise to concerns that chronic hepatitis is spreading, even among adults [11,12].


Treatment and Prevention of Hepatitis B

While treatment of acute hepatitis B virus infection usually consists of symptomatic therapy or watchful waiting, chronic hepatitis B is mainly treated with antiviral drugs (nucleic acid analogs) [13] and interferon-based virus eradication therapy. However, unlike hepatitis C therapy, in which total elimination of the virus is possible, the response rate to interferon therapy is around 30-40% [14].

Treatments for HBV such as nucleotide analogues and interferon have improved, but HBV patients are often required to receive the lifelong treatments with high cost and cure is still a challenging goal.

Hepatitis B virus is difficult to treat, but is simple to prevent through means such as vaccination. Moreover, considering the need to address mother-to-child transmission as well as the risk of horizontal transmission, universal vaccination of all nursing infants has been highlighted as one of the most crucial initiatives. In 2013, 183 of the 194 member nations of the World Health Organization (WHO) had already launched a universal vaccination program to combat hepatitis B.


Main Transmission Routes of HBV

Transmission routes of HBV to children are mainly from mothers and sexual contact is the main route of transmission for adolescents or adults recently in Japan. Horizontal transmission comprises modes of infection other than mother-to-child transmission. Other routes are varied such as blood transfusion, blood products, hemodialysis, needle treatment, a tattoo, 'needlestick' injuries, and so on [11].

In 1985, the former Ministry of Health and Welfare in Japan began the Mother-to-Child Transmission Prevention Program, and in 1986 implemented a procedure to prevent transmission from HBe/HBs antigen-positive mothers to their newborns. In 1995 the program was reviewed and expanded to prevent infection of all infants from HBs antigen-positive mothers.

The benefits of these initiatives to prevent mother-to-child transmission of hepatitis B were that infant HCC rates decreased after starting the program in 1986, leading to a significant decrease from 2001 in the incidence of HBV-related HCC compared to that of HBV-nonrelated HCC [15]. Conversely, horizontal transmission is still an issue. Although Japan has a "selective vaccination" program to prevent transmission, targeting the children of the aforementioned HBV carrier mothers, universal vaccination would not only benefit the children being vaccinated, but also could prevent the horizontal transmission described below.

Horizontal transmission comprises modes of infection other than mother-to-child transmission. Other routes are varied such as blood transfusion, blood products, hemodialysis, needle treatment, a tattoo, 'needlestick' injuries, and so on.

Previously, the most frequent form of horizontal transmission was via blood transfusion, but this has since decreased dramatically due to better screening of donated blood samples. Needle sharing has been also decreased. Today the major transmission are between family members (other than mother-to-child), via nursery schools and other public facilities, and via sexual transmitted infection (STI) in adults. A recent study found that HBV-DNA is present in the saliva, sweat, tears, urine and other bodily fluids and excretory products of carriers, such that even bodily fluids (saliva, sweat and tears) are potential sources of HBV infection [16]. Tear specimens from a child were injected intravenously into 2 human hepatocyte-transplanted chimeric mice. One week after inoculation, both chimeric mice had serum positive for HBV DNA. Strict precautions should be taken against direct contact with body fluids from HBV carriers with high-level viremia [16]. Furthermore, a study in the 1970s inoculating chimpanzees with HBe-Antigen positive serum also showed that infection through intravenous inoculation still occurred when using serum that had been diluted 100 million times [17]. These findings demonstrate the potent infectivity of HBV, and suggest that current efforts aimed only at preventing mother-to-child transmission are incapable of controlling this infectious disease.


Father-to-child transmission and associated measures

In terms of father-to-child transmission, approximately 25% of children with carrier fathers become infected and approximately 10% become carriers themselves [18]. Komatsu et al. studied transmission routes in Japan, both before and after prevention of mother-to-child transmission became possible in 1985, and discovered that father-to-child transmission was increasing relatively rapidly [19]. Unlike mother-to-child transmission, new fathers are currently not subject to screening, so introduction of a hepatitis B vaccine as universal vaccination is indispensable in addressing the issue of father-to-child infections.


Transmission via nursery schools and associated measures

It is difficult to demonstrate how HBV is transmitted at nursery schools and other facilities. Hayashi et al. investigated the extent of HBV infection in 269 children (2.9 ± 1.4 y) at 5 nursery schools located in areas in Japan known to have a high carrier rate. Consequently, 10 cases of infection were discovered, of whom 6 children had acute infection and 4 were carriers [20]. Hayashi et al. concluded that hepatitis B transmission most probably occurs among children in nursery schools where there are HBsAg carriers with HBeAg, and therefore vaccination of susceptible children is necessary [21].

Furthermore, Hayashi et al. assessed the efficacy of an inactivated hepatitis B vaccine among children in nursery schools where there was at least one hepatitis B surface antigen-positive child with hepatitis B e antigen. Of the 496 children who completed the inactivated hepatitis B vaccination protocol, 243 (aged 2.7 +/- 1.1 years) children in six of the nursery schools received three injections of the vaccine. In five other nursery schools, 253 children (aged 2.3 +/- 1.0 years) did not receive the vaccine and were used as the control group. Although nine (4.4%) of the 203 children in the control group (whom the authors were able to follow for 24 months) were infected with HBV and two of them became carriers, none of the vaccine recipients became infected. Hayashi et al. concluded that the vaccine appears to be safe, immunogenic, and efficacious in preventing HBV infection in nursery schools.

As a result of these cases, hepatitis B vaccination in nursery schools was prescribed for the first time in the "2012 Amended Guidelines for Preventing Infectious Diseases in Nursery Schools." In recent years, there has been a rise in the number of facilities where children and teachers are proactively inoculated with the hepatitis B vaccine. Expectations are now growing for a universal vaccination program as a necessary measure to combat father-to-child transmission.


Benefits and Cost Benefits of Universal Vaccination

Hepatitis B (HB) vaccines, which are the first vaccines that have been proven to prevent HCC, have played a crucial role in preventing HBV infection worldwide since their development in the 1980s. In particular, the HB vaccines have been rapidly integrated into the national immunization programs of low-income countries since the Global Alliance for Vaccine and Immunization was launched in 2000. However, HBV has still not been eradicated.

In Taiwan, where a universal hepatitis B vaccination program was implemented as early as 1984, the virus carrier rate in children under age 5 years declined from 9.8% when the program started to 0.7% after 15 years [22]. Additionally, the mean annual incidence of HCC in children aged 6 to 14 years (per 100,000 members of the population) dropped significantly from 0.7% between 1981 and 1986 to 0.36% between 1990 and 1994 (p<0.01) [23]. Furthermore, Taiwan's mean infant mortality rate due to fulminant hepatitis from 1985 to 1998 (after implementation of the hepatitis B vaccination program) decreased to one third of the rate seen during 1975 to 1984 (prior to implementation) [24].

Recently, a case was reported in which two elderly Japanese patients with fulminant hepatitis B acquired HBV infection via interposal (most likely sexual) transmission during long-lasting marriages [25].

In terms of hepatocarcinogenesis, the high viral load of HBV-DNA is the most important HCC risk factor [26,27].

The need for prolonged antiviral therapy before and after HCC [28] could ultimately be perceived as a burden on the national health care expenditure. We believe that universal vaccination is currently the best way to prevent not only the onset of HBV-related hepatitis and its progression to chronic disease and HCC, but also the best way to present spread of the infection itself. Furthermore, universal vaccination is already a commonly-accepted practice around the world.

In the report of the Hepatitis B vaccine working team, the incremental total cost of HB vaccine for 1,078,000 million infants (birth cohort number in 2009) was about $155 million and medical expenses for HBV related disease (acute hepatitis, chronic hepatitis, fulminant hepatitis, cirrhosis, hepatocellular carcinoma) reduction was up to about $6.3 million under universal vaccination program because of low prevalence of these disease. That means the incremental cost becomes about $148 million. As a result of cost-effectiveness analysis, incremental cost per QALY gained by HB vaccine was about $149,000 and the cost-effectiveness of universal vaccination program was not described favorable in their report in 2011. So cost-benefit is still big issue.


Conclusion

Conventional wisdom in 1985 stipulated that successful prevention of mother-to-child transmission should have allowed us to control hepatitis B in Japan. However, 30 years later, there are still no signs that HBV will be eradicated soon. Although not covered in the present study, new problems such as de novo hepatitis have emerged. Although there are issues surrounding cost-benefit, now might be the time to consider a shift from "selective vaccination" to universal vaccination.

In response to the demand for such universal vaccination, the Immunization and Vaccination Committee of the Health Sciences Council decided to implement universal vaccination of HBV for newborns because confirmation was reached in January 2015 concerning horizontal infection of HBV in children and the effectiveness of vaccination on a different genotype. However, there are still other issues to be resolved, such as the vaccination schedule, additional doses, catch-up vaccination, and resources. We strongly expect a smooth introduction of a HBV universal vaccination program after 2016.


Financial Disclosure

The authors declare that they do not have any current financial arrangements or affiliations with any organization that may have a direct interest in their work.


References
  1. World Health Organization (2013) Media Centre. Hepatitis B.

  2. Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, et al. (2014) Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology 146: 430-441.

  3. Asahina Y, Tsuchiya K, Nishimura T, Muraoka M, Suzuki Y, et al. (2013) α fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C. Hepatology 58: 1253-1262.

  4. Ishikawa T, Abe S, Kojima Y, Horigome R, Sano T, et al. (2015) Telaprevir-based triple therapy after partial splenic arterial embolization for chronic hepatitis C with thrombocytopenia can reduce carcinogenesis and improve hepatic function reserve. Experimental and Therapeutic Medicine.

  5. Ishikawa T, Abe S, Kojima Y, Horigome R, Sano T, et al. (2015) Low dose telaprevir-based triple therapy for elderly patient with fibrosis type C contributes to improve hepatic functional reserve. Hepato Gastroenterolgy (in press).

  6. Ishikawa T (2008) Secondary prevention of recurrence by interferon therapy after ablation therapy for hepatocellular carcinoma in chronic hepatitis C patients. World J Gastroenterol 14: 6140-6144.

  7. Ishikawa T, Higuchi K, Kubota T, Seki K, Honma T, et al. (2012) Combination PEG-IFN a-2b/ribavirin therapy following treatment of hepatitis C virus-associated hepatocellular carcinoma is capable of improving hepatic functional reserve and survival. Hepatogastroenterology. 59: 529-532.

  8. Ishikawa T (2013) Strategy for improving survival and reducing recurrence of HCV-related hepatocellular carcinoma. World J Gastroenterol 19: 6127-6130.

  9. Goldstein ST, Zhou F, Hadler SC, Bell BP, Mast EE, et al. (2005) A mathematical model to estimate global hepatitis B disease burden and vaccination impact. Int J Epidemiol 34: 1329-1339.

  10. Oketani M, Ido A, Nakayama N, Takikawa Y, Naiki T, et al. (2013) Intractable Hepato-Biliary Diseases Study Group of Japan. Etiology and prognosis of fulminant hepatitis and late-onset hepatic failure in Japan: Summary of the annual nationwide survey between 2004 and 2009. Hepatol Res 43: 97-105.

  11. Suzuki Y, Kobayashi M, Ikeda K, Suzuki F, Arfase Y, et al. (2005) Persistence of acute infection with hepatitis B virus genotype A and treatment in Japan. J Med Virol 76: 33-39.

  12. Kobayashi M, Ikeda K, Arase Y, Suzuki F, Akuta N, et al. (2008) Change of hepatitis B virus genotypes in acute and chronic infections in Japan. J Med Virol 80: 1880-1884.

  13. Liaw YF (2002) Management of patients with chronic hepatitis B. J Gastroenterol Hepatol 17: 406-408.

  14. Dogan UB, Golge N, Akin MS (2013) The comparison of the efficacy of pegylated interferon α-2a and α-2b in chronic hepatitis B patients. Eur J Gastroenterol Hepatol 25: 1312-1316.

  15. Tajiri H, Tanaka H, Brooks S, Takano T (2011) Reduction of hepatocellular carcinoma in childhood after introduction of selective vaccination against hepatitis B virus for infants born to HBV carrier mothers. Cancer Causes Control 22: 523-527.

  16. Komatsu H, Inui A, Sogo T, Tateno A, Shimokawa R, et al. (2012) Tears from children with chronic hepatitis B virus (HBV) infection are infectious vehicles of HBV transmission: experimental transmission of HBV by tears, using mice with chimeric human livers. J Infect Dis 206: 478-485.

  17. Shikata T, Karasawa T, Abe K, Uzawa T, Suzuki H, et al. (1977) Hepatitis B e antigen and infectivity of hepatitis B virus. J Infect Dis 136: 571-576.

  18. Hirota T, Ohno M, Yano K (1987) Father-to-child transmission of hepatitis B virus. Kanzo 28:427-432.

  19. Komatsu H, Inui A, Sogo T, Hiejima E, Kudo N, et al. (2009) Source of transmission in children with chronic hepatitis B infection after the implementation of a strategy for prevention in those at high risk. Hepatol Res 39: 569-576.

  20. Hayashi J, Kashiwagi S, Nomura H, Kajiyama W, Ikematsu H (1987) Hepatitis B virus transmission in nursery schools. Am J Epidemiol 125: 492-498.

  21. Hayashi J, Kashiwagi S, Nomura H, Kajiyama W, Ikematsu H (1987) The control of hepatitis B virus infection with vaccine in Japanese nursery schools. Am J Epidemiol 126: 474-479.

  22. Chang MH (2010) Breakthrough HBV infection in vaccinated children in Taiwan: surveillance for HBV mutants. Antivir Ther 15: 463-469.

  23. Chang MH, Chen CJ, Lai MS, Hsu HM, Wu TC, et al. (1997) Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 336: 1855-1859.

  24. Kao JH, Hsu HM, Shau WY, Chang MH, Chen DS (2001) Universal hepatitis B vaccination and the decreased mortality from fulminant hepatitis in infants in Taiwan. J Pediatr 139: 349-352.

  25. Okamoto D, Nakayama H, Ikeda T, Ikeya S, Nagashima S, et al. (2014) Molecular analysis of the interspousal transmission of hepatitis B virus in two Japanese patients who acquired fulminant hepatitis B after 50 and 49 years of marriage. J Med Virol 86: 1851-1860.

  26. Ishikawa T, Ichida T, Yamagiwa S, Sugahara S, Uehara K, et al. (2001) High viral loads, serum alanine aminotransferase and gender are predictive factors for the development of hepatocellular carcinoma from viral compensated liver cirrhosis. J Gastroenterol Hepatol 16: 1274-1281.

  27. Ishikawa T (2010) Clinical features of hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol 16: 2463-2467.

  28. Ishikawa T (2013) Anti-viral therapy to reduce recurrence and improve survival in hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol 19: 8861-8866.

International Journal of Anesthetics and Anesthesiology (ISSN: 2377-4630)
International Journal of Blood Research and Disorders   (ISSN: 2469-5696)
International Journal of Brain Disorders and Treatment (ISSN: 2469-5866)
International Journal of Cancer and Clinical Research (ISSN: 2378-3419)
International Journal of Clinical Cardiology (ISSN: 2469-5696)
Journal of Clinical Gastroenterology and Treatment (ISSN: 2469-584X)
Clinical Medical Reviews and Case Reports (ISSN: 2378-3656)
Journal of Dermatology Research and Therapy (ISSN: 2469-5750)
International Journal of Diabetes and Clinical Research (ISSN: 2377-3634)
Journal of Family Medicine and Disease Prevention (ISSN: 2469-5793)
Journal of Genetics and Genome Research (ISSN: 2378-3648)
Journal of Geriatric Medicine and Gerontology (ISSN: 2469-5858)
International Journal of Immunology and Immunotherapy (ISSN: 2378-3672)
International Journal of Medical Nano Research (ISSN: 2378-3664)
International Journal of Neurology and Neurotherapy (ISSN: 2378-3001)
International Archives of Nursing and Health Care (ISSN: 2469-5823)
International Journal of Ophthalmology and Clinical Research (ISSN: 2378-346X)
International Journal of Oral and Dental Health (ISSN: 2469-5734)
International Journal of Pathology and Clinical Research (ISSN: 2469-5807)
International Journal of Pediatric Research (ISSN: 2469-5769)
International Journal of Respiratory and Pulmonary Medicine (ISSN: 2378-3516)
Journal of Rheumatic Diseases and Treatment (ISSN: 2469-5726)
International Journal of Sports and Exercise Medicine (ISSN: 2469-5718)
International Journal of Stem Cell Research & Therapy (ISSN: 2469-570X)
International Journal of Surgery Research and Practice (ISSN: 2378-3397)
Trauma Cases and Reviews (ISSN: 2469-5777)
International Archives of Urology and Complications (ISSN: 2469-5742)
International Journal of Virology and AIDS (ISSN: 2469-567X)
More Journals

Contact Us

ClinMed International Library | Science Resource Online LLC
3511 Silverside Road, Suite 105, Wilmington, DE 19810, USA
Email: contact@clinmedlib.org
 

Feedback

Get Email alerts
 
Creative Commons License
Open Access
by ClinMed International Library is licensed under a Creative Commons Attribution 4.0 International License based on a work at https://clinmedjournals.org/.
Copyright © 2017 ClinMed International Library. All Rights Reserved.