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Year : 2004  |  Volume : 1  |  Issue : 1  |  Page : 25-59
Prophylaxis of viral hepatitis: A global perspective


Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

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How to cite this article:
Chongsrisawat V, Chatchatee P, Poovorawan Y. Prophylaxis of viral hepatitis: A global perspective. Hep B Annual 2004;1:25-59

How to cite this URL:
Chongsrisawat V, Chatchatee P, Poovorawan Y. Prophylaxis of viral hepatitis: A global perspective. Hep B Annual [serial online] 2004 [cited 2019 Jul 18];1:25-59. Available from: http://www.hepatitisbannual.org/text.asp?2004/1/1/25/27918


Viral hepatitis usually refers to an infection with one of the hepatotrophic viruses, hepatitis viruses A, B, C, D, E, G, TT, and SEN. Viral hepatitis may range from a mild subclinical infection with nonspecific symptoms to an overwhelming multisystem fulminant disease with a high mortality rate. Hepatitis B, C, and D may cause chronic infection after either overt or inapparent acute infection. Chronic viral hepatitis may be associated with a chronic carrier state, progression to cirrhosis, and development of hepatocellular carcinoma (HCC). There have been a lot of advances in the understanding of the epidemiology, pathogenesis, molecular biology, and immunoprophylaxis of these infections. Remaining challenges include the application of this knowledge to treatment and ultimately to prevention of viral hepatitis. This article focuses on only hepatitis A and B, for which there have been extensive investigations regarding prophylaxis against these viruses.

Hepatitis A

Hepatitis A virus (HAV) is a 27-32 nm diameter, icosahedral-shaped, nonenveloped RNA virus of the genus Hepatovirus within the Picornaviridae family. This 7474 nucleotides long virus is divided into three regions: 5' noncoding or untranslated region (UTR) which contains an internal ribosomal entry site; a single long, open reading frame (ORF) which encodes a long polypeptide of 2227 amino acids; and a short 3' noncoding region which terminates as a polyadenylated tract of variable length. The structural protein-encoding region P1 yields four capsid proteins (VP1, VP2, VP3, VP4), while nonstructural protein-encoding regions P2 and P3 yield three and four nonstructural proteins, respectively, including the 5' terminal protein, a protease, and an RNA-dependent RNA polymerase.

Only one serotype has been recognized although genotypic differences have been found in isolates from various geographic sites.[1] Human strains may now be classified into four genotypes. The HAV epitope that stimulates the formation of protective antibody is common to all genotypes, so that polyvalent vaccine made from one strain provides protection against all strains.[2]

Transmission

The major mode of transmission is person to person via the fecal-oral route. The virus replicates in the liver and is transported through the bile to the stool in high titers. Because it is relatively resistant to degradation by environmental conditions, the virus is spread easily when there is close personal contact and difficulty in maintaining adequate hygiene, as in day care centers, military camps, and residential institutions for the developmentally disabled. The virus can be spread from asymptomatic young children to other young children and to adult contacts. Young children are thus considered to be a principal reservoir and the dominant source of transmission in the community. The virus may also be transmitted before symptoms occur, given that the virus appears in the stool substantially before the onset of illness. Common-source outbreaks occur with contamination of water or food. Consumption of contaminated uncooked or undercooked food, and foods that are contaminated by an infected food handler has led to outbreaks of disease that affect large numbers of people. Contamination of water supplies may occur in areas with inadequate sewage disposal systems. In developing countries, waterborne transmission leads to widespread infection at an early age. With inadequate hygiene and sanitation, HAV infection is endemic, and most children are infected in the first years of life.[3] In developed countries, infection early in life is uncommon, and serologic evidence of infection gradually increases with age.[3] In these regions, there are cyclic outbreaks of HAV that correspond to changing susceptibility patterns. During community outbreaks, the highest rates of infection occur in children, adolescents, and young adults.[4] However, lack of infection early in life, with its consequent lifelong immunity, leads to a population of susceptible adults in which the clinical illness of acute HAV infection is more severe.

Because the period of viremia is generally short (1-2 weeks) and the concentration of virus in blood is relatively low, transmission through nonsterile needle sharing occurs only rarely. Perinatal transmission of hepatitis A is extremely uncommon.[5]

Prevention

Prevention requires attention to public and personal health measures. The virus is inactivated by boiling, chlorination (concentration-dependent), ultraviolet light, and a 1:4000 formalin mixture. Strict adherence to handwashing in the hospital, daycare, and institutional setting is important in preventing person-to-person spread. Travelers to endemic areas should be advised to avoid drinking water or beverages with ice from sources of unknown purity, and eating uncooked or undercooked food.

Passive immunoprophylaxis

Passive immunization is recommended for several high-risk groups, including travelers to endemic areas and household contacts of index cases with HAV infection. Administration of immune globulin (IG) before exposure will prevent infection in 85% to 95% of exposed persons, administration within 1 to 2 weeks of exposure will prevent or attenuate infection, while administration beyond 2 weeks is ineffective.[6] The dose that has been shown to be consistently protective is 0.02 mL/kg. The duration of protection appears to be dose related, with the 0.02 mL/kg and 0.05 mL/kg doses providing protection for approximately 3 months and 4 to 6 months, respectively.[6] However, if travel to an endemic area is anticipated by at least 2 to 4 weeks, active prophylaxis with vaccine is recommended. IG has a good safety record, the main side effect being local discomfort. IG may be given simultaneously with a vaccine, at a different site. Although antibody titers are somewhat lower with this technique, they are well within the protective range and a booster dose of vaccine is recommended in persons who receive this combination.[4]

Although the secondary attack rates are highest among children, adults are at greatest risk of symptomatic disease, and therefore contacts of all ages should be given IG. Contacts outside the home (i.e., at work or school) do not require passive immunoprophylaxis unless repeated cases are occurring, suggesting the presence of a common-source outbreak. For containment of HAV outbreaks in nursing homes or other institutions, administration of IG may be required in addition to strict adherence to preventive measures.

Active immunoprophylaxis

Vaccination against HAV has been used to shorten the duration of community outbreaks. It is currently recommended for members of high-risk groups [Table - 1]. Three different strategies have been utilized in vaccine development: a live attenuated vaccine, an inactivated vaccine, and a recombinant polypeptide vaccine.

Live attenuated vaccines

The live attenuated vaccine is produced by serial passage of HAV in cell culture to create a virus with reduced infectivity but with retained antigenicity. The vaccines induce the development of anti-HAV in more than 90% of vaccinees, with persistence of neutralizing antibody for 3 to 6 months. Adverse effects are minimal. However, these vaccines are available only in China.[7]

Inactivated vaccines

For inactivated vaccines, the virus is grown in cell culture and then inactivated by exposure to formalin. These vaccines are highly immunogenic, with 90% to 100% seroconversion rates after a single dose and a 100% seroconversion rate after booster.[8],[9],[10] Using model-based estimation, the proportion of subjects estimated to lose their detectable antibodies 25 years after the first vaccine dose never exceeds 12%, even in those subjects with the lowest antibody level just before the second vaccination. Thus, vaccine-induced anti-HAV antibodies can be expected to persist even longer than estimated previously.[11],[12],[13] Postvaccination testing for a serologic response is not indicated because of the high rate of vaccine response in normal subjects.[11]

The vaccine is considered to be very safe. Reported adverse events have included soreness at the injection site, headache, and fever.[14] The only contraindication to vaccination is a previous allergic reaction to either of the vaccines or sensitivity to any vaccine component.

The association between severe HAV infection and underlying chronic liver disease has led to the recommendation that patients with chronic liver disease be vaccinated against HAV.[11] Recent data have provided evidence that supports the efficacy and immunogenicity of the HAV vaccine in patients with mild-to-moderate chronic liver disease.[15] However, HAV vaccination is less immunogenic in patients with advanced liver disease,[15],[16] in liver transplant recipients,[17] and in immunocompromised persons.[18] In these groups, postvaccination testing is recommended. Although scarce, available data suggest that testing for anti-HAV in patients with chronic liver disease before vaccination is cost-effective in light of the high prevalence of anti-HAV in this patient population (approximately 50%-75%).[19]

The Advisory Committee on Immunization Practices (ACIP) has concluded that the best strategy for decreasing hepatitis A incidence is routine vaccination of young children.[11] However, studies in infants who had passively-transferred maternal anti-HAV at the time of vaccination suggests that giving the vaccine to infants may result in significantly lower antibodies levels among those with passively-transferred maternal anti-HAV and potentially decreased protection from hepatitis A within 6 years of vaccination.[20],[21] Therefore, hepatitis A vaccine should not be administered to children younger than 1 year of age.

Recombinant polypeptide vaccines

The development of immunogenic recombinant polypeptides offers the potential advantage of large-scale production of a highly purified, safe, and potentially less expensive product. Sequences from the VP0, VP1, and VP3 proteins have been inserted into expression vectors to generate the corresponding polypeptides, and further progress with both attenuated and recombinant polypeptide vaccines can be anticipated.

Cost benefit of HAV vaccination

As the incidence of hepatitis A declines in many parts of the world, there is an increasing number of susceptible adolescents and adults. Severe HAV infection, which is associated with greater morbidity and mortality, is more likely to develop in such persons than in younger persons. Current recommendations of ACIP for use of HAV vaccine target high-risk persons and those with underlying chronic liver disease. Even though inactivated hepatitis A vaccine has proven highly immunogenic and efficacious, one important factor that has to be considered is cost-effectiveness. In Israel, the cost-benefit analysis of a nationwide infant immunization programme against hepatitis A in an area of intermediate endemicity has shown the policy both medically and economically justifiable.[22] A study in Germany showed the strategy of vaccinating 11-15-year-olds to be the most cost-effective, but it would leave a large percentage of the population at high risk of HAV infection.[23] A study conducted among healthcare workers and the general population at risk in Ireland has shown the most cost-effective strategy related to target group immunity. Where HAV immunity amounts to 45% or less, vaccination is the strategy of choice and when immunity exceeds 45%, screening should be performed before vaccination.[24] Analysis of cost-effectiveness of various vaccination strategies in healthy adults in the USA has proven the vaccination strategy to be cost-effective when one dose of vaccine costs $7 or less (baseline $57).[25] Cost-effectiveness of HAV vaccination in the general population in Thailand showed that the benefit of universal vaccination to the general population aged between 3 and 40 years old would not justify the expense incurred.[26] Furthermore, the recommendation to vaccinate patients with underlying chronic liver disease was recently questioned in a study that showed a lack of cost-effectiveness for this approach, with a current annual incidence of hepatitis A of only 0.01%.[27] Therefore cost effectiveness of hepatitis A vaccination would depend on the endemicity of the disease and the socioeconomic status of individual country.

Hepatitis B

Hepatitis B virus (HBV) infection is a major global health problem and is the most common cause of chronic liver disease worldwide. Roughly 2 billion people, or one third of the world's population, have serological evidence of past or continuing infection with the virus.[28] HBV belongs to the Hepadnaviridae family. It contains partially double-stranded DNA that is surrounded by an outer lipoprotein envelope and an inner core composed of nucleocapsid proteins. Intact HBV virions are 40-42 nm in diameter and can be visualized by electron microscopy. HBV is a compact virus with four open reading frames (ORF) (S, P, C, and X) that encode four major proteins (surface, polymerase, core, and X protein, respectively).[29],[30] HBsAg, or S protein is the major envelope protein of the virus. The viral envelope contains three distinct components, large, middle, and major (or small) proteins that are synthesised by beginning transcription with pre-S1, pre-S2, or S gene alone, respectively. The pre-S1 and pre-S2 proteins are perhaps the more immunogenic components of HBsAg. Within the envelope is a 27-nm structure known as the nucleocapsid core, which consists of 180 copies of the viral core protein, or hepatitis B core antigen (HBcAg), surrounding the viral DNA and the virally encoded polymerase. This icosahedral structure protects the viral DNA from degradation by exogenous nucleases. The nucleic acid itself is a relaxed circular molecule that consists of a 3.2-kB minus strand and a smaller, complementary DNA plus strand of variable length. The circular structure of HBV is maintained by hydrogen bonds between 250 bp at the two 5' ends of the plus and minus strands. The 5' ends of the DNA strands are each linked covalently to additional structures that are essential for the initiation of DNA synthesis: the polymerase, which is bound to the 5' end of the minus strand, and an oligo RNA, which is linked to the 5' end of the plus strand. Two short repeat sequences known as DR1 and DR2, which are present at the 5' ends of the plus and minus strands, are important for the initiation of DNA synthesis.

Four major HBV serological subtypes (adw, ayw, adr, and ayr) and nine minor subtypes are identified by the antigenic determinants of HBsAg. Seven HBV genotypes (A to G) are defined by divergence in the entire HBV genomic sequence of more than 8%.[31],[32],[33],[34] Anti-HBs is directed against this "a" determinant and provides protection against all serotypes. Most viral genomes carry more than one mutation, and most individuals are infected with more than one variant. Some of the mutations are believed to contribute to viral latency, low-level infection, severity of liver disease, and vaccine escape. The best-studied group is the precore mutants, which result in a lack of HBeAg production, even in the presence of active viral replication the so called e-minus HBV infection. In contrast to the situation in persons with wild-type virus, in whom the absence of HBeAg usually signifies absent HBV replication and mild liver disease, in e-minus infection, HBV DNA levels are high, antibody to HBe Ag (anti-HBe) is detected, and liver disease may be severe.[35] Sporadic cases and outbreaks of fulminant HBV infection have been attributed to precore mutants.[36]

Transmission

HBV is parenterally transmitted via blood or blood products or by sexual or perinatal exposure. Viral particles are detectable in body secretions, including semen and saliva. Thus, contact with mucous membranes and their secretions is likely to be a mode of transmission of HBV.[37]

Perinatal and early childhood transmission

HBV is most prevalent in people born in regions of high HBV endemicity and their descendants. High levels of virus in serum (signified by HBV DNA and HBeAg positivity) have been associated with an increased risk of transmission by vertical routes. Infants born to HBeAg-positive mothers who have high levels of viral replication have a 70% to 90% risk of perinatal acquisition in the absence of interventions. In contrast, the risk of mother-to-infant transmission from HBeAg-negative mothers is substantially lower (10%-40%).[38],[39] Infection occurs through occult inoculation of the infant at the time of birth or shortly thereafter. IgM anti-HBc is not detectable in cord blood, so that intrauterine infection is unlikely to have occurred. Even with active and passive immunization, 5% to 10% of babies may acquire HBV infection at birth.[38]

Children of HBsAg-positive mothers who are not infected at birth remain at high risk of early childhood infection; 60% become infected by the age of 5 years.[40] The mechanism of this later infection, which is neither perinatal nor sexual, is unknown. Although HBsAg can be detected in breast milk, breast-feeding is not believed to be an important mode of transmission. It is well established that the likelihood of HBV infection becoming chronic is inversely proportional to the patient's age at acquisition.[41]

Sexual transmission

Sexual activity is probably the single most important mode of HBV transmission in developed countries, where the prevalence of infection is low. From 1980 to 1985, men who had sex with men were at particularly high risk of HBV infection and accounted for 20% of all reported cases of HBV infection.[42] Factors associated with a high risk of viral acquisition in this patient population included multiple sexual partners, anal-receptive intercourse, and duration of sexual activity. Recently, the risk has fallen markedly, probably because of modifications of sexual behavior in response to the acquired immunodeficiency syndrome (AIDS) epidemic.[43] Heterosexual sex now accounts for the majority of cases of HBV infection in developed countries. In heterosexuals, factors associated with an increased risk of HBV infection include duration of sexual activity, number of sexual partners, a history of sexually transmitted diseases, and positive serologic results for syphilis.[42] Sexual partners of intravenous drug users, prostitutes, and clients of prostitutes are at particularly high risk for HBV infection.[42]

Sexual partners of persons infected with HBV are at risk for infection, even in the absence of high-risk behavior. The risk of heterosexual transmission is greater when the infected person is female than when the infected person is male. A study of intrafamilial transmission of HBV revealed that 70% of husbands of female HBV carriers were HBsAg positive.[44] Because many patients with chronic HBV infection are unaware of their infection and are silent carriers, sexual transmission is likely to be an important mode of transmission worldwide. As with perinatal transmission, sexual transmission is facilitated by active viral replication in the infected person. The use of condoms appears to reduce the risk of sexual transmission.

Intravenous drug use

In developed countries, intravenous drug use remains a very important mode of HBV transmission.[43] The risk of HBV infection increases with duration of drug use, so that serologic markers of ongoing or prior HBV infection are almost universal after 5 years of drug use.

Other modes of transmission

Other risk factors for HBV infection include working in a health-care setting, transfusions and dialysis, acupuncture, tattooing, travel abroad, and residence in an institution.[43] Although the risk of transfusion-associated HBV infection has been greatly reduced with the screening of blood as well as exclusion of donors who engage in high-risk activities, transfusion should not be neglected as a cause of HBV transmission. Acupuncture has been associated with outbreaks of HBV infection. Nosocomial spread of HBV infection in hospitals, particularly in dialysis units as well as in dental units, has been well described, even when current infection control practices are followed. HBV infection has been linked to multiple-use heparin vials. As with other modes of transmission, high viral titers in serum have been related to an increased risk of transmission. HBV remains infectious in the environment for 7 days or longer, so that contaminated surfaces may account for transmission in the absence of a known exposure.

Prevention

Currently, the comprehensive hepatitis B prevention strategies should include (1) prevention of perinatal HBV transmission, (2) hepatitis B vaccination at critical ages to interrupt transmission, and (3) prevention of nosocomial HBV transmission.[45] Behavior modification to prevent disease transmission is also crucial. Public-health measures such as immunization and public education demand considerable co-operation from society, the government, and health professionals, both locally and internationally.

Behavior modification

Changes in sexual practices in response to HIV infection have probably contributed to the falling incidence of HBV infection, and improved screening measures of blood products in blood banks have reduced the risk of transfusion-associated hepatitis B. Other primary preventive measures, such as needle exchange programs in intravenous drug users are more difficult to implement. Behavior modification is unlikely to be beneficial in developing countries where neonates and young children are at greatest risk of acquiring infection. In these groups, immunoprophylaxis, both passive and active, will be most effective.

Passive immunoprophylaxis

Hepatitis B immune globulin (HBIG) is prepared by cold ethanol fractionation of pooled plasma from donors seropositive for anti-HBs and contains high titers (> 100,000) of this antibody. It has been proven to be efficacious in postexposure passive prophylaxis of HBV infection in clinical settings, such as accidental needle-stick contact, sexual contact, perinatal exposure, and recurrence of hepatitis B after liver transplantation. HBIG provides protection for only 3 to 6 months. Therefore if more prolonged or repeated exposure is expected, such as from employment in a medical occupation, living in a household with a chronic HBV carrier, homosexual or promiscuous sexual behavior, or an ongoing requirement for blood transfusions, prophylaxis should include hepatitis B vaccine.

Immunoprophylaxis is currently recommended for all infants born to HBsAg-positive mothers. Current dosing recommendations are 0.13 mL/kg (maximum dose 0.5 mL; 200 unit/mL) of HBIG immediately after delivery, or within 12 hours after birth, in combination with the first dose of the recombinant vaccine, followed by the remainder of the vaccine series. This combination results in a greater than 90% level of protection against perinatal acquisition of HBV.[46],[47] Between 3% and 15% of infants still acquire HBV infection perinatally from HBV-infected mothers.[48] Failure of passive and active immunoprophylaxis in this setting may be the result of in utero transmission of HBV infection, perinatal transmission related to a high inoculum, or the presence of surface gene escape mutants.

After sexual or needlestick exposure, current recommendations are to administer HBIG in a dose of 0.05 to 0.07 mL/kg (maximum dose 5 mL) as soon after exposure as possible, preferably within 48 hours of exposure and no more than 7 days after exposure. A second dose 30 days later may decrease the risk of transmission of HBV.[49],[50] Active immunization should be administered concurrently.

Active immunoprophylaxis

The principal objective of hepatitis B immunization strategies is to prevent chronic HBV infections which result in chronic liver disease later in life. By preventing chronic HBV infections, the major reservoir for transmission of new infections is also reduced. Effective and safe vaccines against HBV infection have been available since the early to mid-1980s. The first commercially available HBV vaccines were plasma-derived HBsAg subunit vaccines, but concern about transmission of other infectious agents led to the development of recombinant vaccines. The early plasma-derived vaccines are no longer routinely available. Recombinant vaccines are made by incorporating the surface gene of HBV into different expression vectors (yeast,  Escherichia More Details coli, or mammalian cell lines). The yeast-derived recombinant vaccines are most widely available. Current recommendations are to administer the vaccine by intramuscular injection in the deltoid muscle for adults and in the lateral aspect of the thigh in children. HBV vaccines have a protective efficacy of 90-95%.[51] Prevaccination testing of patients is not usually cost-effective in areas where the prevalence of markers for HBV infection is less than 20%.


  Hepatitis B immunization strategies Top


Routine infant vaccination

In countries of intermediate and high endemicity of HBV infection, universal vaccination of all infants is the best way to control HBV infection because the majority of chronic infections are acquired during early childhood. In countries where a lower proportion of chronic infections is acquired perinatally (e.g. Africa), the highest priority is to achieve high DTP3 and HepB3 vaccine coverage among infants. In these countries, use of a birth dose may also be considered after disease burden, cost-effectiveness, and feasibility are evaluated.

Prevention of perinatal HBV transmission

In order to prevent perinatal HBV transmission, the first dose of hepatitis B vaccine should be given as soon as possible after birth, preferably within 24 hours, especially in countries where a high proportion of chronic infections is acquired perinatally (e.g. South-East Asia). It is usually most feasible to give hepatitis B vaccine at birth when infants are born in hospitals. Efforts should also be made in these countries to give hepatitis B vaccine as soon as possible after delivery to infants delivered at home.

The efficacy of the vaccination programme in interrupting perinatal HBV transmission was shown by the fact that the proportion of babies who became carriers born to highly infectious carrier mothers decreased from 86-96% to approximately 10%; the decrease was from 10-12% to less than 5% for babies of less infectious HBsAg carrier mothers.[38],[39]

Catch-up vaccination of older age groups

In countries with a high endemicity of chronic HBV infection (HBsAg prevalence >8%), catch-up immunization is not usually recommended because most chronic infections are acquired among children <5 years of age. In countries with lower endemicity of chronic HBV infection, a higher proportion of chronic infections may be acquired among older children, adolescents and adults; catch-up immunization for these groups may be considered. Possible target groups for catch-up immunization include age-specific cohorts (e.g. routine immunization of young adolescents) and persons with risk factors for acquiring HBV infection.

The establishment of surveillance for acute hepatitis B and the performance of seroprevalence studies on HBV infection can assist in determining the groups at highest risk of acquiring HBV infection, e.g. clients and staff of institutions for the developmentally disabled, intravenous drug users, men who have sex with men, and persons with multiple sex partners. Vaccination and other prevention efforts may be targeted at these groups.

Impact of the universal hepatitis B immunization on the control of HBV infection

The efficacy of a hepatitis B immunization programme can be assessed at various stages. The effect of routine infant and childhood hepatitis B immunization programmes is usually not apparent because almost all HBV infections in infants and young children are asymptomatic, and HBV related sequelae as a result of the long-term consequences of chronic infection usually manifest after middle age. The effectiveness of immunization programmes can be evaluated by studying their influence on chronic HBV infection rate, HBV-related diseases such as acute hepatitis and HCC.

Chronic HBV infection rate

In endemic countries where the carrier rate of HBsAg in the general population is as high as 15-20%, about half of these chronic HBsAg carriers are infected by perinatal transmission. Comparison of the prevalence of HBsAg in different age groups before and after the vaccination programme showed that the carrier rate decreased in all age groups of children, but was most marked in the younger children. Thus, universal vaccination substantially reduces the HBV carrier rate and the infection rate, especially in children and adolescents covered by the programme. Studies from Italy, Gambia, Saudi Arabia, Samoa, Alaska, Federated States of Micronesia, Saipan, Indonesia, Taiwan, and Thailand have all shown the effectiveness of routine infant immunization, with marked reductions of the prevalence of HBsAg carriage in children [Table - 2].

HBV-related diseases

Hepatitis B vaccination not only protects children from becoming carriers but also protects them from HCC, acute as well as chronic hepatitis, and fulminant hepatitis. HBV is second only to tobacco use as a cause of cancer in humans. Hepatitis B vaccine is the first anticancer vaccine. After universal hepatitis B immunization in Taiwan, the incidence of HCC in children has reduced. The average annual incidence of HCC in children 6-14 years of age declined from 0.70 to 0.36 per 100,000 children between 1981-1986 and 1990-1994 respectively.[61] Given the estimates that approximately 70% of HCC in developing countries are attributable to HBV, universal vaccination could prevent more than 500,000 cases per year in these areas.[62]

A survey in Alaska, an area hyperendemic for HBV and comparable to Southeast Asia, revealed the decline in prevalence of acute symptomatic HBV infection from 215 to 14 cases per 100,000 population after complete immunization of 90% of susceptible persons.[63] A recent analysis in Taiwan showed that the mortality due to fulminant hepatitis in infants has declined significantly following the institution of the country's universal hepatitis B vaccination program. The average mortality from fulminant hepatitis in infants from 1975 to 1984 and from 1985 to 1998 was 5.36 and 1.71 per 100,000 infants respectively.[64]

Taken together, these data prove that preventing HBV infection leads to a reduction in HBV-related morbidity and mortality, and justify advocacy for universal hepatitis B vaccination programmes worldwide.

Coverage of HBV vaccine

The impact of immunization cannot be directly assessed through disease surveillance because the actual impact of immunization on the prevalence of chronic HBV infection will only be seen many years after immunization. The primary method for monitoring hepatitis B immunization is through routine coverage data.

Although the World Health Organization (WHO) set a goal for all countries to integrate hepatitis B vaccination into their universal childhood vaccination programmes by 1997, as of June 2001, 129 countries had universal infant and/or adolescent hepatitis B immunization programmes.[65] As of May 2003, a total of 151 (79%) of 192 WHO member states had adopted universal childhood hepatitis B vaccination policies, including six that have policies for vaccinating adolescents.[66] Of the 137 member states that have adopted universal childhood hepatitis B vaccination and for which data are available, 76 (55%) have a policy for administering the first dose of vaccine soon after birth (birth dose).

Most countries with intermediate or high hepatitis B endemicity, such as those in the Pacific, Asia, Middle East, as well as Southern and Eastern Europe, have universal infant hepatitis B immunization programmes with about 75-100% vaccination coverage.[67] African countries, such as The Gambia, Tunisia, Egypt, Mauritius and the Seychelles islands have over 90% vaccination coverage where as the figure in Caribbean and Latin American countries is around 50%.[67] Through these programmes, an estimated 32% of children aged <1 year were vaccinated fully with the 3-dose hepatitis B vaccination series. In the six WHO regions, the proportion of children aged <1 year who were vaccinated fully was 65% in the Western Pacific Region, 58% in the Americas Region, 45% in the European Region, 41% in the Eastern Mediterranean Region, 9% in the South-East Asian Region, and 6% in the African Region.[68]

In areas of the world with high endemicity of HBV infection, current recommendations are for universal vaccination. The major difficulty in implementing these recommendations is the high cost to developing countries of vaccinating large populations. Support from the Global Alliance for Vaccines and Immunization (GAVI), which began in 1999, and the Vaccine Fund (VF) make vaccines available in developing countries.[69] GAVI's major agencies are WHO, UNICEF, World Bank, the Bill and Melinda Gates Children's Vaccine Program at PATH, the Rockefeller Foundation, some country governments, and industry. These international organizations can enable more developing countries to afford hepatitis B vaccines and make it possible to control the disease on a global scale. As of May 2003, of 75 countries eligible for GAVI/VF support, 48 (64%) had received funding for hepatitis B vaccination introduction.(66)

The goals for global hepatitis B vaccination are introduction of the vaccine in all countries by 2007, and 90% coverage with the 3-dose hepatitis B vaccination series by the year 2010.[70]

Vaccination in special circumstances

Non-responders


There is evidence that vaccine response is genetically determined. A dominant immune-response gene in the MHC determines vaccine response. Immunocompetent patients who are homozygous for this gene have a low response rate. The seroconversion rate after hepatitis B vaccination is lower in smokers, the elderly, and immunocompromised people. Approaches for non-responders including intradermal injection or addition of vaccine adjuvants such as granulocyte macrophage colony-stimulating factor have recently been explored to increase the efficacy of the vaccine.[71],[72] In addition, a third-generation recombinant hepatitis B vaccine has been reported to be effective for the revaccination of at-risk people who have responded inadequately to single-antigen hepatitis B vaccines.[73]

HBV mutants

Immune escape from neutralizing antibodies occurs in a region of HBV known as the "a" determinant of the HBV S gene. This hydrophilic region from amino acids 124 to 147 is highly conserved between the subtypes of HBV and is believed to be important in eliciting protection against infection. Most amino acid changes of the variants cluster in residues 125-129 and 140-149.[74] Because of the very compact nature of the genomic organization of HBV, changes in the "a" determinant have the potential to alter the function of the HBV polymerase, an enzyme essential for viral replication. 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 immunoprophylaxis.[75] Despite protective levels of antibody, babies who contracted these "vaccine-escape" mutants became HBsAg positive and developed chronic liver disease. In Taiwan, the prevalence of "a" determinant mutants increased from 7.8% HBV DNA-positive children just before, to 28.1% 10 years after universal vaccination.[76] The presence of these mutants was higher in those fully vaccinated than in the unvaccinated.[77] These vaccinated children may contract variant infections through vertical or horizontal transmission. Emergence of surface gene mutants in liver transplant recipients receiving monoclonal HBIG therapy has also been described.

Accordingly, universal vaccination may accelerate an accumulation of HBsAg "a" determinant mutants with amino acid changes critical for immune escape in vaccinated children who become carriers. However, recent studies have shown that immunization of chimpanzees with currently available recombinant hepatitis B vaccines can induce adequate anti-HBs, which is broadly reactive and can confer protection against the infection with a surface gene mutant of HBV.[78],[79] More evidence is needed whether HBV vaccines should incorporate both wild-type and mutated S proteins. The development of more immunogenic, potent adjuvants or naked DNA to overcome the problems of S gene mutants should continue.

Premature infants

HBV vaccine induces poor immunogenicity in premature infants. Therefore, those born to HBsAg-positive mothers should receive HBIG and vaccine at birth and subsequent 3 more doses of vaccine according to the routine schedule. For those born to HBsAg-negative women, initiation of vaccination may be delayed until hospital discharge or a weight of 1,700 g.[80]

Immunocompromised patients

Immunocompromised patients, including those on hemodialysis, have a reduced chance of mounting a protective immune response after vaccination. Additional doses of the vaccine appear to increase the response rate. Patients over the age of 40 years also exhibit a decreased response rate. For immunocompromised patients, regular testing for anti-HBs, and a booster injection when the titer falls below 10 mIU/mL, is advised.[81]

Booster immunizations

Long-term protection against clinically significant breakthrough HBV infection and chronic carriage depends on immunological memory, which allows a protective anamnestic antibody response to antigen challenge. Memory seems to last for up to 10-15 years in immunocompetent individuals.[60],[82],[83],[84] The need for booster doses of hepatitis B vaccine in immunocompetent individuals after a primary vaccine series has been the subject of debate. To date, vaccine advisory groups do not recommend routine booster doses in people who have responded to vaccination, even in high-risk infants.[81] Nonetheless, several countries currently have a policy of administering booster doses to certain risk groups to provide reassurance of protective immunity.[81]

Combination vaccine

Combination vaccines are a widely accepted means of effective childhood vaccination. The reduced number of injections adds to the benefit in terms of increased compliance, time, cost savings, and decreased amount of space required for cold chain storage and transport. Hepatitis B vaccine is available in monovalent formulations that protect only against HBV infection and also in combination formulations that protect against HBV and other diseases. Tetravalent (DTP-HB) and hexavalent (DTaP-IPV-PRP-T-HB) vaccines have been demonstrated to be highly immunogenic and provided long-term protection against all antigens.[85],[86] Monovalent hepatitis B vaccines must be used for the birth dose. Combination vaccines must not be used to give the birth dose of hepatitis B vaccine because DTP and Hib vaccines should not be administered at birth. Either monovalent or combination vaccines may be used for later doses in the hepatitis B vaccine schedule.

Adverse effects of hepatitis B vaccine

Hepatitis B vaccine is very safe. Mild transient side-effects that may occur after immunization include soreness at the injection site, fatigue, headache, irritability, and fever. These transient side-effects usually start within a day after the vaccine has been given and last from one to three days. When hepatitis B vaccine is given at the same time as DTP vaccine, the rate of fever and/or irritability is no higher than when DTP is given alone. Serious allergic reactions to the vaccine, i.e. hives, difficulty in breathing and shock are rare. Recombinant HBV vaccines have rarely been associated with immunologic reactions such as vasculitis, immune-mediated thrombocytopenia, and arthritis, but casual relationship yet has not yet been established.[87],[88],[89],[90] There have been concerns that HBV vaccination could precipitate the onset of multiple sclerosis in previously healthy people 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 seem to increase the short-term risk of exacerbation in multiple sclerosis.[91],[92] Moreover, an association between hepatitis B immunization and demyelinating diseases has not been shown.[93],[94]

Thimerosal is a preservative containing small amounts of ethylmercury that is used in routine vaccines for infants and children including hepatitis B vaccine. It was suggested that thimerosal is a risk factor for the development of autism. However, the discontinuation of thimerosal-containing vaccines in Denmark in 1992 was followed by an increase in the incidence of autism. These data do not support a correlation between thimerosal-containing vaccines and the incidence of autism.[95] Besides, the administration of vaccines containing thimerosal does not seem to raise blood concentrations of mercury above safe values in infants.[96] Ethylmercury seems to be eliminated from blood rapidly via the stools after parenteral administration of thimerosal in vaccines. There is little doubt that the benefits of hepatitis B vaccine overall far outweigh its risks.

Necessity of pregnant women screening for HBV infection

The CDC recommended immunoprophylaxis for all infants born to HBsAg-positive mothers in combination with universal screening of all pregnant women.[97] The purpose of the screening for HBsAg and HBeAg is to identify individuals at risk and thus have a plan giving HBIG and vaccine to neonates within 24 hours after birth. However, screening all pregnant women is expensive and time-consuming. Furthermore, studies in endemic countries revealed that universal hepatitis B vaccination in neonates without screening of pregnant women has been highly effective.[52] Cost-benefit studies ought to be performed to evaluate the potential benefits of this screening.

Future prospects

Because of the complexity and expense of HBV immunization, some areas of the world may not be able to have their own programmes. Thus different approaches may have to be considered. HBV antivirals such as lamivudine can be considered in areas where the cold chain of vaccine delivery cannot be maintained, or in those instances in which intrauterine infection is likely to occur. In highly viremic mothers, lamivudine in the last month of pregnancy may be an effective measure to reduce vaccination breakthrough HBV infection.[98] However, large controlled trials should be conducted to ensure the antivirals used are harmless to the fetus.

Although safe and effective, the conventional vaccine still has some drawbacks; for example, a small yet significant proportion of individuals do not respond adequately to the vaccine. Recently, a third-generation recombinant hepatitis B vaccine containing pre-S1, pre-S2, and S antigenic components of viral surface antigen subtypes adw and ayw has been developed.[99] Pre-S1 and pre-S2 domains of the virus are thought to increase anti-HBs responses. Also, these domains stimulate cellular immune responses and can help bypass genetic nonresponsiveness to the S antigen. This novel vaccine was developed to produce a superior immune response to that of the currently approved vaccines. Clinical trials have confirmed that the vaccine is well tolerated in human beings and that a 20 µg dose is adequate and effective for vaccination of both naive subjects as well as patients who are not responsive to standard vaccines.[100] Other potential approaches are DNA-based vaccine, use of new adjuvants or live recombinant vectors, and oral vaccines.[101] Although attractive, more needs to be established concerning their efficacy, safety, and cost. Unless proven to be far better than the currently used vaccines, there will be little need to change the present program.

Conclusion

Because the relative importance of the various modes of transmission of hepatitis A and B differs by country, the choice of specific prevention and control strategies depends primarily on the epidemiology of infection in a given country. Implementation of worldwide vaccination against HAV and HBV requires more time to overcome the social and economic obstacles. Evaluation of hepatitis B immunization programme in each country should include coverage of immunization, serological survey of HBV infection, surveillance of the incidence of acute hepatitis B as well as monitoring of the incidence of chronic hepatitis B, cirrhosis, and HCC. Global control of HAV and HBV infection remains an important and challenging task that needs to be continued in the future.

Acknowledgements

We are grateful to the Thailand Research Fund and Center of Excellence, Viral Hepatitis Research Unit, Chulalongkorn University for supporting our studies on viral hepatitis.

 
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Correspondence Address:
Voranush Chongsrisawat
Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok
Thailand
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