TABLE OF CONTENTS

1.       Introduction

2.       Hepatitis B

2.1 Virology of hepatitis B virus

2.2 Clinical features of hepatitis B

2.3 Hepatitis B vaccines

2.4 Prevention and control policies

2.5 Epidemiology of hepatitis B

2.5.1 Global morbidity and mortality

2.5.2 The epidemiology of hepatitis B in the region

2.5.2.1 Prevalence and incidence data

2.5.2.2 Overall picture

2.5.2.3 Low prevalence countries

2.5.2.4 Intermediate prevalence countries

2.5.2.5 High endemicity countries

2.5.2.6 Hospital-acquired infection

2.6 Strategies for prevention of hepatitis B

2.6.1 General preventive measures

2.6.2 Standard precautions

2.6.3 Vaccination strategies

2.6.3.1 Selective vaccination

2.6.3.2 Universal vaccination

(a) Adolescents

(b) Infants

(c) Infants, adolescents and those at high risk

2.6.4 Promoting vaccination

2.7 Priority setting

2.7.1 Disease burden

2.7.2 Cost effectiveness

2.7.3 Information and education

2.7.4 Strategy

2.7.5 Disease burden in Issyk-Kul, Kyrgyzstan

2.8 Health economics

2.9 Resource mobilization

2.9.1 Increased government financing

2.9.2 Setting priorities for funding and services

2.9.3 Affordability

2.9.4 Support
 

2.10 Workshops

2.10.1 Resource mobilization

2.10.2 Monitoring and surveillance

2.10.2.1 Lack of comparability of surveillance data between countries

2.10.2.2 Assessing the burden of disease due to hepatitis B virus infections

2.10.2.3 Monitoring the effectiveness of hepatitis B vaccination programmes

2.10.3 Vaccines and immunization

2.10.4 Vaccine production, quality control and regulatory issues

2.10.5 Nosocomial transmission

2.10.6 Diagnostics

2.10.6.1 Sensitivity of assays

2.10.6.2 Specificity of assays

2.10.6.3 Rapid, instrument-independent assays

2.10.6.4 Reduction in post-transfusion hepatitis B

3.  Consensus and conclusion

3.1 Data

3.2 Constraints

3.3 Immunization programme

3.4 Consensus

Annexes:

          Annex 1 : consensus statement (Russian version)

          Annex 2 : consensus statement (English version)

          Annex 3 : List of participants

Table 1:        Endemicity of hepatitis B virus infection in central and eastern Europe and the Newly Independent States in terms of prevalence of HBsAg

Table 2:        Data on demography, markers of hepatitis B virus infection and immunization policy in central and eastern Europe and the Newly Independent States

Table 3:        Sustainable vaccine supply: banding of counties for global targeting strategy

Table 4:        Relative sensitivities of assays for the detection of HBsAg

Table 5:        Performance characteristics of flow-through and lateral-flow devices

Table 6:        Comparison of test characteristics

Table 7:        Post-transfusion hepatitis B in regions of different HBV endemicity with and without flow-through screening of blood donations

Fig 1             Prevalence of HBsAg in central and eastern Europe and the Newly Independent States

Fig 2             Sustainable vaccine supply: global targeting strategy for central and eastern Europe and the Newly Independent States

1.   INTRODUCTION

The prevention and control of hepatitis B constitute a major policy priority especially in the countries of central and eastern Europe and the Newly Independent States, many of which report high prevalence rates of hepatitis B virus (HBV) infection and of clinical disease. For some 15 years safe and effective vaccines against hepatitis B have been available. Previous attempts to prevent and control the disease have rested on the strategy of immunizing  people at highest risk of infection, such as health-care workers, but no country has succeeded in controlling HBV infection with this strategy. This failure has led to the recommendation of universal childhood immunization as the most effective way to decrease infection rates and to lower the amount of acute infection.

The Viral Hepatitis Prevention Board jointly organized with the World Health Organization and the US Centers for Disease Control and Prevention (CDC) a meeting to bring together managers of immunization programmes, national hepatitis experts and senior officials from ministries of health. The meeting was held with the active support of the Hungarian Ministry of Health in Siófok, Lake Balaton, Hungary, on 6-9 October 1996.

The aim of the meeting, on which this report is based, was two-fold: to put the prevention of hepatitis B on the political agenda and to speed the progress of the countries in central and eastern Europe and the Newly Independent States towards the implementation of universal childhood immunization against hepatitis B. In particular, its objectives were to summarize and share available data, to identify what is necessary for the implementation of a strong programme against hepatitis B, and to highlight the main constraints against such action in the region.

This conference was the first to focus on hepatitis B control and prevention with the inclusion of all the countries in the region, and afforded a major opportunity to raise awareness of hepatitis B with decision-makers and to discuss with them the introduction of hepatitis B vaccination into universal immunization programmes. The high level of participation - in many cases Deputy Ministers of Health or Deputy Chief Medical Officers attended - testifies to the importance accorded to the matter by the health authorities of the countries concerned. The joint sponsorship of the meeting attested to the willingness of the organizing bodies to help in the implementation of prevention and control programmes and to assist in the identification of donors to help secure supplies of vaccine.

In 1991 the WHO called for all countries to implement hepatitis B into their immunization programmes and so far more than 85 have done so. This figure includes only 5 of the 25 countries in the region under discussion. The VHPB, an independent, international and multidisciplinary group of experts set up to consider, make recommendations and encourage action to improve the control and prevention of viral hepatitis in the WHO European region, has been actively supporting the WHO’s position. The CDC have been committed to the control of viral hepatitis world-wide for several years and have worked to provide technical assistance to countries that request help in the areas of prevention and control.

Following the dissolution of the USSR, many countries who had received their routine vaccines (DTP, polio, measles and BCG) from Russia found themselves without a supply of vaccines which they could afford. Although donors were found to supply infant routine vaccines, no provisions were made for hepatitis B vaccines, even though the burden of disease from HBV infection was greater than that of other vaccine-preventable diseases in many areas. This situation prompted the convening of the Siófok meeting to consider ways of facilitating the inclusion of routine hepatitis B immunization in national immunization programmes of these 25 countries in the region (no representatives from Bosnia and Herzegovina and from Yugoslavia attended the Siófok meeting).

2.   HEPATITIS B

2.1 Virology of hepatitis B virus

Hepatitis B is caused by hepatitis B virus, a DNA virus of the genus hepadnavirus containing a partially double-stranded circular DNA genome and three major antigens: hepatitis B surface antigen (HBsAg), the core antigen (HBcAg) and a derivative of the latter, namely the e antigen (HBeAg). It also contains a DNA polymerase. The icosahedral viral particle has a diameter of 42 nm. Although four subtypes of HBV due to antigenic variation in HBsAg are known, infection with one strain confers resistance against all strains.

HBV is mainly hepatotropic; it attaches through its HBsAg to liver cells in which its DNA is converted into RNA, from which new DNA viral particles are synthesized and released by budding. The virus is not cytopathic but triggers liver damage through the immune response to infected hepatocytes. Symptoms of infection appear after a lengthy incubation period of 1-3 months.

The virus itself is robust. It can survive on surfaces such as surgical instruments, chairs and work benches for as long as one week at room temperature. It is about 100 times more infectious than HIV.

The natural hosts of HBV are human beings; there is no other reservoir. HBV is present in high concentrations in blood, serum and wound exudate. It may also be present in moderate concentrations in semen, vaginal fluids and saliva. It is either undetectable or present in small amounts in urine, faeces, sweat, tears and breast milk. Thus, the main routes of transmission are parenteral, sexual, from mother to child (vertical or perinatal) and horizontal.

Transfusion of blood from HBsAg-positive donors is one of the most efficient means of transmitting HBV. A WHO study in 1990 indicated that more than 43% of the world’s population lives in regions where blood is never or only sometimes screened for HBsAg, and for another 11% of the world’s population no data are available on blood screening practices. In the WHO’s European Region only 28% of blood donations were always tested for HBsAg, with no information on the testing practices for the remaining 72%.[1] The high cost of importing sensitive and specific tests such as enzyme-linked immunosorbent assays is probably the biggest constraint on testing of blood.

Among health-care workers exposed to needlestick injuries the minimum volume of blood from a patient infected with HBV needed to transmit infection is 0.04 µl. The risk of infection after a needlestick injury with a HBV-positive patient lies between 7% and 30% or higher, the rate depending on whether the blood is positive for HBeAg. (A CDC study showed that 37-62% of health-care workers exposed to HBeAg-positive blood showed markers of infection and 22-31% developed clinical acute hepatitis.) The average volume of blood inoculated during a needlestick injury with a 22 gauge needle is about 1 µl which can contain up to 100 infectious doses of HBV.

Contaminated equipment such as used in tattooing, earpiercing and acupuncture can lead to transmission. Heterosexual transmission occurs, and may be facilitated by the presence of genital ulcers. High rates of infection are seen in injecting drug users, homosexual men and in the general population in many developing countries as a result of sexual transmission. Horizontal transmission between children also occurs and in Asia transmission from mothers to children (vertical transmission) is even more prevalent, and represents therefore a serious problem.

2.2 Clinical features of hepatitis B

HBV infection has different clinical manifestations depending on the person’s age at infection, immune status and the stage at which the disease is recognized.

In infants and young children most HBV infections are asymptomatic; only some 5-10% of neonates show symptoms. Irrespective of the development of symptoms, most infections (70-90%) progress to the chronic carrier state, with about 30-50% of these people developing chronic liver disease: cirrhosis and primary liver cancer.

Although about a third of adults infected with HBV are completely without symptoms, another third present with a ‘flu-like illness without jaundice; in them HBV infection is rarely diagnosed. The rest of those infected present with typical signs and symptoms of viral hepatitis, including jaundice, dark urine, extreme fatigue and pain in the right upper quadrant. Activities of liver enzymes, for example alanine aminotransferase, are often much greater than normal and the serum concentration of bilirubin is also markedly raised. Among those with symptomatic infection less than 1% develop fulminant hepatitis, but this condition carries a very high mortality.

Most infected adults recover completely and develop lifelong immunity against the virus, but some 6-10% fail to eradicate HBV and become chronic carriers and thus infectious, often for life. In about a quarter of those who become carriers chronic HBV infection can lead to progressive liver disease. Progression to chronic hepatitis depends on continuing viral replication in the liver and on the host response. When HBV replicates chronic active hepatitis develops and can lead to cirrhosis. Chronic infection can also cover a long stage of quiescent liver disease, with primary liver cancer developing 20-30 years after infection with HBV.

When a person is infected with both HBV and hepatitis D virus[2], the latter infection may be self-limited as the virus cannot outlive the transient HBV infection. However, superinfection of a chronic carrier of HBV with HDV may lead to fulminant disease, but severe chronic hepatitis with an accelerated progression to cirrhosis is more likely.

The most important factor predisposing to the development of the chronic carrier state is age at infection. During perinatal infection maternal HBV antigen and antibodies may suppress the infant’s own immune response which in any case will be immature and unlikely to mount an effective response against HBV antigens. Other factors include male gender, immunosuppression through use of steroids or other immunosuppressive drugs and immunodeficient conditions such as cancer and HIV infection. Immunodeficient people infected with HBV tend to develop a milder disease but are more likely to become carriers than immunocompetent ones.

2.3 Hepatitis B vaccines

Hepatitis B vaccine consists of HBsAg. The first-generation vaccines were derived from the plasma of chronic HBV carriers. The reason for this unusual approach to a vaccine is that HBV could not, and still cannot, be grown in cell culture. The various difficulties raised by the production of a vaccine from human plasma spurred the search for alternatives. The gene for HBsAg can be expressed now in both yeast and mammalian cells, producing a protein identical to that in the plasma-derived vaccine except that it is not glycosylated. Nevertheless, as a vaccine, the immunogenicity, efficacy and safety of this recombinant protein are the same as those of the natural product.

Despite the experience of their use over 15 years, some questions about the use of hepatitis B vaccines remain unanswered. How long does protection last? Are booster doses needed? What is the position regarding people who do not respond to hepatitis B vaccination? How can we protect against mutant forms of HBV?

Antibodies to HBsAg peak about 4-6 weeks after the final dose of vaccine and decrease in concentration rapidly at first but progressively more slowly. Immunization produces neutralizing antibodies that protect against HBV infection but it also induces efficient and long-lasting immunological memory that allows protective responses after antibodies have disappeared. Thus immunity lasts longer than the persistence of antibodies. Recommendations for revaccination to boost immunity can be relaxed. In general there is no clear evidence of the need for booster doses after primary series of vaccination has been completed. Long-term studies  (field experience extends to 10-12 years) in high-risk newborns demonstrate that protection against acute disease and development of a chronic carrier state lasts beyond the fall of antibody levels. However, booster doses are recommended in the package insert accompanying the vaccine in some countries, and may be indicated in particular situations such as immunocompromised patients or health-care workers.  Testing for anti-HBs after vaccination may be recommended for health-care workers who need to know whether they are protected.

Some 3-5% of people vaccinated do not produce specific antibodies after a normal course of immunization. Although some immunodeficient people have seroconverted when interleukin-2 has been administered with the vaccine, the procedure is ineffective in immunocompetent subjects. Additional doses of vaccine can induce immunity. With up to three additional doses, about half of the non-responders eventually seroconvert.

Several escape mutants of HBV have been discovered but most have no biological or medical significance. Some, however, especially those with mutations in the a determinant of HBsAg, may resist the immune response. Consequently some doubt has been cast on the effectiveness of present HBV vaccines, but these mutants do not appear to be new or to pose any real danger. “Real” escape mutants have not been observed.

2.4  Prevention and control policies

Prevention and control of HBV infection are now major health priorities, especially since safe and effective vaccines have been available for more than a decade. In 1991 the WHO called for all countries to include hepatitis B vaccination in their national immunization programmes by 1997. Routine immunization of infants is recommended for countries with a prevalence of chronic HBV infection of 2% or higher, and countries with lower rates may adopt immunization of adolescents instead of or in addition to infant immunization. So far, more than 85 countries world-wide have included hepatitis B vaccination in their national programmes.

In the WHO European Region more than a million people acquire hepatitis B each year, of whom about 90,000 will become chronic carriers of HBV. In the 25 countries in central and eastern Europe and the Newly Independent States (NIS), many of which have high incidence rates of HBV infection, only five have yet included HBV in their national immunization programmes. The other countries have failed to do so mainly because of economic constraints.

2.5 Epidemiology of hepatitis B

2.5.1  Global morbidity and mortality

Globally at least 2000 million people have been infected with HBV at some time in their lives and about 350 million are chronically infected. The general public recognize HBV as a cause of jaundice but it is not widely known that the virus is the major cause of death from cirrhosis and chronic liver disease including liver cancer. Chronic hepatitis B infection is responsible for at least 60 million cases of liver cirrhosis world-wide, more than the number of cases caused by alcohol. HBV infection is responsible for more than one million deaths a year, and most of these result from its chronic manifestations. According to a study in women in Taiwan the relative risk of developing liver cancer is 10 times greater than that of smokers developing lung cancer.

2.5.2  The epidemiology of hepatitis B in the region

2.5.2.1  Prevalence and incidence data

Several epidemiological measures are used to describe the burden of disease for HBV infection. The most commonly used indicators are the prevalence of HBV carriers in the population and the incidence of acute clinical hepatitis B. Three categories of prevalence have been described: low (with <2% of the population carrying the HBsAg marker), intermediate (2-8%) and high (>8%). The prevalence of carriers indicates the size of the pool of infectious people and those at risk of the chronic sequelae of HBV infection, namely cirrhosis and primary liver cancer. The distribution of prevalences in the European region is shown in Table 1 and Fig 1.

Prevalence data need to be interpreted with care, for some of the studies used to determine prevalence rates may be seriously biased. For instance, data on blood donors are readily available but this group may be very unrepresentative of the general population because of donor self-selection, socio-economic or cultural bias about who donates blood, prior screening to eliminate HBsAg-positive people from the donor pool, or the use of paid donors.

Incidence data for acute clinical hepatitis B are even more unreliable than data on the prevalence of carriers of HBsAg. No two countries, even in Western Europe, measure the incidence in the same way and there is no comparable standard case definition across Europe.[3] The type and nature of reporting vary widely. Differences in reporting criteria range from countries that report jaundice cases without serological differentiation to countries that report hepatitis A, B, C, D, and E. Some countries mix reporting of HBsAg carriers with that of cases of acute clinical hepatitis B. Many countries do not have reagents available to differentiate types of viral hepatitis and diagnosis is based on physicians’ instincts or guesses. Some countries base their reporting on clinical cases whereas others rely on laboratory reports. Still others use sentinel surveillance systems. The degree of under-reporting is significant and differs for each country. As hepatitis B is mainly an asymptomatic infection,  this will play an additional role in the under-reporting.

TABLE 1        Endemicity of hepatitis B virus infection in central and eastern Europe and the Newly Independent States in terms of prevalence of HBsAg (no data available for Bosnia and Herzegovina and for Yugoslavia)

*           Hepatitis B vaccination included in national immunization programme

+          Hepatitis B vaccination included in national immunization programme but implementation subject to financial constraints

2.5.2.2  Overall picture

Most countries of northern and western Europe have very low prevalences of HBV infection (with rates of less than 0.5% of the population carrying HBsAg). Incidence rates too are very low, being less than 1/100,000 in the general population in Scandinavia, Ireland and the UK. The rates increase southwards (incidence rates rising to about 6/100,000) but eastwards and south-eastwards the picture is very different. The virus is highly endemic in some eastern European countries and the Newly Independent States, especially the Central Asian Republics; carriage rates of HBsAg rise to 2-7% in central and eastern Europe and more than 8% (high endemicity) in the Central Asian Republics. Table 2 summarizes more detailed data acquired through questionnaires distributed to participants before the meeting.

Hepatitis D infection is present; in Central Asian Republics up to 20% of cases of HBV infection also have D infection. Here little HBV-related carcinoma is seen, for the simple reason that people die of D superinfection (and short life expectancy) before the carcinoma can develop. Rough estimates put the number of deaths from HBV-related cirrhosis and hepatocellular carcinoma at about 200 a year in north-west Europe but about 18,600 in central and Eastern Europe.

2.5.2.3  Low prevalence countries

The lowest prevalence rates outside western European countries are seen in the northern parts of Central and Eastern Europe, the Baltic republics and Armenia (see Table 2). Reported incidence rates in these regions range from 1 to 25 cases per 100,000 population a year. Although this is called  ‘low’ endemicity relative to other areas of the world, this does not imply a low burden of disease, and hepatitis B continues to be a major infectious disease problem.

Screening of blood donors in Croatia has shown a falling prevalence of HBsAg positivity, from 1.53% in 1982 to 0.34% in 1991 and, after a rise, to 0.32% in 1995. There, immunization is compulsory for health workers exposed to infection as well as for at-risk people. The Czech and Slovak Republics as well as Hungary have HBsAg prevalence rates of less than 1%. Higher rates are seen in Armenia, Poland, Ukraine and Slovenia but in several countries the rates are declining. For instance, whereas the incidence rate of acute hepatitis B in the general population in Slovenia in 1992 was about 6/100,000 it fell to 0.9/100,000 by October 1996. Data for Ukraine for 1993-95 show an incidence of hepatitis B of 24-25 cases/100,000 population, with highest rates in the under-1 year and 20-30 age groups. HBsAg carriage was 1.1% among blood donors but 2.3% among at-risk groups such as health workers and injecting drug users. In Armenia screening of blood donors identified 1.25% carrying HBsAg in the first 9 months of 1996, a figure similar to that in the previous 6 years, whereas the incidence of acute hepatitis B fell from 23.1/100,000 in 1990 to 9.7/100,000 in 1996.

2.5.2.4  Intermediate prevalence countries

Intermediate prevalence rates of 2–7% are seen in the southern and eastern parts of central and eastern Europe, a finding not appreciated in the West until the fall of communism in this area. According to the national participants at the meeting, both the acute and chronic sequelae of hepatitis B make it one of the most important infectious disease problems in their countries. Most experts believe that perinatal transmission is uncommon and that horizontal, sexual and especially nosocomial transmission accounts for incidence rates that range from 25 to 100 per 100,000 population a year.

In The Former Yugoslav Republic of Macedonia blood-donor screening showed a prevalence of 2.0% in the years 1992-95 while the incidence of all viral hepatitides was 109/100,000. In Bulgaria HBsAg carrier prevalence is 3-5% and 20% of the population have evidence of exposure to HBV. The incidence rate of chronic HBV infection is high, 30.3/100,000, with a mortality rate for chronic liver disease and primary liver cancer of 24/100,000.  Belarus recorded some 4100 carriers of HBsAg by August 1996 (39.8/100,000). Georgia has seen a decline in reported cases of all hepatitides, the total falling to about 7000 in 1994, with 19% due to hepatitis B or D, but it is recognized that the decline is almost certainly an artefact of reporting, consequent on the disruptions around independence and continuing through unaffordability of medical care for many people. The extent of transmission of hepatitis B, C and D through injecting drug use, occupational exposure among health-care workers, blood transfusion and unsafe sex is "anybody's guess".

In the Russian Federation generally, the proportion of cases of hepatitis B among all reported viral hepatitides is steadily increasing, reaching about 30% in the first 8 months of 1996. Incidence rates have doubled between 1992 and 1995. Low and intermediate prevalences are found across the huge country; HBsAg carriage rates range from 0.3% in the Tula oblast to 6.4% in the Tyva republic. Among newborns across Russia in 1994 3.1% were carriers of HBsAg. In far-eastern Russia the prevalence rate of HBsAg carriage is considered to be 5%.

Before Romania introduced hepatitis B immunization into the national immunization programme in 1995 the prevalence of HBsAg in the general population was 5.95% (with an anti-HBc prevalence of 31.0%) and the incidence rate of hepatitis B infections was 24.4/100,000. By mid-1996 the incidence rate had fallen to 9.96/100,000, with a more than 2.5-fold reduction in the 1-14 year age group.

2.5.2.5  High endemicity countries

While endemicity and morbidity due to hepatitis B lie in the intermediate range in central Russia, in some regions such as central and eastern Siberia, the Caucasian regions and the Central Asian Republics they are high, with prevalence rates of HBsAg of 11.1% in Kyrgyzstan in 1994 and 15.6% in Turkmenistan in 1995. Reported incidence rates of hepatitis B vary from 23.6/100,000 in Kazakhstan in 1994 (rising to 26.8/100,000 in 1995) and 98.5/100.000 in Uzbekistan in 1995 to 300-400 cases/100,000 in eastern Siberia and about 400/100,000 in Turkmenistan in 1994 (where the peak rate was reached in 1984 when about 1% of the population had jaundice due to HBV). One can only guess at the number of subclinical cases in these regions. Transmission patterns vary too. A study in  Ashgabat  (Turkmenistan) in 1994 revealed that in 70% of cases of hepatitis B there had been no known parenteral exposure. In Moscow in contrast no parenteral exposure was determined in only 13% of cases.

In Albania the HBV situation was described as very grave and dangerous, with prevalence rates similar to those in the hyperendemic countries of Asia and Africa. The Albanian Ministry of Health at the time of the meeting concluded that the only effective intervention is universal vaccination.

TABLE 2:         Data on demography , markers of hepatitis B virus infection and immunization policy in central and eastern Europe and the Newly Independent States