Since 1990 Ukraine has seen a steady decline in the incidence of acute hepatitis B (HB) in all age groups. The highest HB incidence has been registered among adults. After routine HB vaccination of newborn children was introduced in 2000, the maximum incidence decrease rate was observed among children of 0-2 and 3-6 years of age. The reduction of HB incidence among adults (over 14 years old) can be explained by an increase in asymptomatic forms of the disease and is not associated with immunization of newborns. During 2004-2008 in Kiev, children under the age of 2 were primarily infected with acute HB by perinatal transmission due to incomplete vaccination of children born to HBsAg positive women. Despite the system of pre-delivery screening in Ukraine, results of the screening have not always been taken into account during HB immunoprophylaxis. Thus screening pregnant women for antibodies to HB core antigen (anti-HBc) is warranted. It is recommended that children born to women with this marker be vaccinated against HB in the maternity hospital. Immunization is also necessary for the newborns whose mothers were not screened before labour. The current epidemiological situation in Ukraine makes it vital to include HB vaccination of teenagers in the national vaccination schedule.
Hepatitis B is a major public health problem. WHO estimates that as many as 2 billion people have serological markers of either past or current hepatitis B virus (HBV) infection, and that 360 million people suffer from chronic infection. Every year 600 thousand people die from HB sequelae including hepatic cirrhosis (HC) and hepatocellular carcinoma (HCC). One third of all cases of HC and approximately two thirds of HCC cases are presumed to have been caused by chronic HBV infection [1,2].
Patients who get infected with HBV in early childhood have the most severe sequelae of the disease: more than 25% of infected children have either HC or HCC. In general, the lifetime risk of HCC for these children is 100-300 times higher than for non-infected children . Perinatal infection entails the highest risk for a child to suffer from chronic hepatic disorders. As many as 90% of children infected in the prenatal and natal periods become chronic virus carriers. Thus, vaccination that is the most effective means of protection against HB is primarily used for prophylaxis of perinatal infection. The efficiency of universal vaccination of newborns was vividly demonstrated in countries with a high incidence rate of HBV infection [4,5] because perinatal infection is a prevailing transmission route for the virus in endemic regions [6,7]. In the regions of middle or low HBV infection endemicity (including most of European countries, the US, Canada and Australia) perinatal transmission is not as significant as sexual transmission or injecting drug use [8,9].
The transmission routes define age categories of risk groups that may vary in different regions depending on HB epidemic intensity. The endemic areas usually show high HBV prevalence among children, while adults more often have markers of past infection. In countries with middle or low HB prevalence, people among older age categories have infection markers more often than younger people. However, acute HB is most prevalent among young patients as they primarily become infected via injecting drug use or sexual contact. At present, active involvement of young adults into the epidemic process is quite typical in Ukraine as well [10, 11].
The decrease of HBV infection incidence and a lower rate of chronic hepatitis and HCC prevalence achieved by the implementation of universal immunization programmes for newborns in highly HB endemic countries formed the basis for recommendations to include vaccination against HB into national vaccination schedules. As a result, by 2004 the universal HB vaccination of children was started in 150 of 192 WHO countries . In accordance with the WHO documentation, the final decision concerning the HB vaccination strategy needs to take into account the current epidemiological situation in a particular country .
The article provides some general information about the current trends of HB epidemiology in Ukraine and about the effect of vaccination of newborns on epidemiology of this infection.
Materials and Methods
The materials contained in official statistical forms from 1991 to 2008 of the Ministry of Health of Ukraine and the Central Sanitary Epidemiological Station were analyzed. A special form of the Ministry of Health entitled “Report on Separate Infectious and Parasitic Diseases” presents data on HB prevalence including the number of registered cases, general incidence rate per 100,000 population of Ukraine and incidence rates for adults and children of 0-2, 3-6 and 7-14 years of age. Prior to 1970, all cases of viral hepatitides in the country were registered as a common nosological form. Since 1970, cases of acute hepatitis A and acute hepatitis B have been registered separately. From 2003 acute hepatitis C has been registered. In Ukraine, all cases of viral hepatitis clinically diagnosed by medical officers are registered. In most cases, the diagnosis is confirmed by serological laboratory tests.
At the national level, vaccination data includes vaccination schedules for various population groups and implementation plans, and vaccination coverage of children under the age of 2 in different regions of the country. These data are registered in the corresponding statistical forms (Forms No.5 and No.6).
At present, some population groups in Ukraine are screened for HBV infection markers for surveillance and diagnostic purposes. Results of tests performed in 27 regions of Ukraine are sent for general analysis to the virology laboratory of the Central Sanitary Epidemiological Station and presented in the corresponding report form. The surveillance system prescribes checking all known HBV risk groups as well as blood donors, pregnant women, children born by women who are HBsAg carriers, children placed in orphanages. Pregnant women and blood donors are tested for HB markers (mainly for HBsAg) at the government’s expense. Pregnant women are tested twice during pregnancy, when they are registered at the antenatal clinic and in the third trimester.
Each case of viral hepatitis in our country is investigated in order to identify the probable infection source and transmission routes. Information is registered on the epidemiological investigation card. To define the share of perinatal infection in the general structure of HBV transmission routes among young children in Kiev, we analyzed epidemiological investigation cards for cases of HB among children at the age of 0-2 years during 2001-2008.
Data analysis was conducted using Microsoft Excel 2003.
To reveal the role of HB vaccination in reducing the incidence among children and adults, the incidence dynamics was analyzed starting from 1991 in different age groups. The period before vaccination (1991-2001) and vaccination period (2001-2008) were analyzed separately.
In 1970-1989 the HB epidemic process in Ukraine was characterized by a rapid increase in the number of cases of acute HB (from 6.8 to 31.5 per 100,000 population). This increase was presumably caused by active HBV transmission via medical parenteral operations (including blood transfusions) performed in medical and preventive institutions . From 1990, the registered incidence showed a steady decline and trend can still be observed. In 1991 the infection rate in Ukraine was 26.1 per 100,000 population and was 23.4, 7.8 and 7.7 in 1996, 2006 and 2008, respectively. In 2000 HB immunization of newborns was included in the vaccination schedule during the period when a stable incidence was observed. All newborn children should be vaccinated on the first day of life according to the standard scheme (0-1-6 months). During the first years after introduction of the scheduled vaccination program, the vaccination coverage of newborns was quite low (3.6%), but it gradually grew and reached 97.5% in 2005 (Fig. 1). From 2003 the vaccination coverage against HB (72.4%) has been considered sufficient to ensure herd immunity that influences the HB incidence.
Fig.1. Hepatitis B vaccination coverage of newborns in Ukraine, 2000-2008
The results of the analysis show that, before HB vaccination started in 1991-2000, a reduction in the incidence of HB had been observed in all age groups of the population. The reduction was primarily evident among children aged 3-6 years, and in 2000 the lowest incidence of 3.7 per 100,000 children of this age group and the highest incidence decrease (10.5%) was demonstrated in this age group. At the same time, the incidence among children aged 0-2 years showed the lowest decrease of 0.3%. At the start of the monitoring period in 1991 the incidence in this age group was the lowest at 7.1 per 100,000 population and in 2000 it moved to the third position at 5.2 per 100,000 population (Fig.2).
Fig. 2. Incidence of hepatitis B in different age groups before vaccination period 1991-2000
During the “vaccination period” after 2000, the highest decrease in HB incidence, was as in the previous period among children at the age of 3-6 years (13.8%). The incidence decrease in this age group can be explained by the effective vaccination of newborns during 2003-2005. At the same time, the incidence decrease among children under the age of two was lower (11.7%), but still was somewhat higher than among children aged 3-6 years. This may indicate the low efficiency of preventive measures including vaccination against the perinatal HBV infection.
Fig. 3. Incidence of hepatitis B in different age groups during vaccination period, 2001-2008
HBV screening of pregnant women is the most important preventive measure against perinatal HBV infection since it allows identifying newborns belonging to the risk group and providing the necessary preventive measures. Targeted vaccination of children at higher risk of infection has been replaced by universal HB vaccination of newborns in Ukraine . As a result, infected mothers’ children did not receive the specific immunoglobulin when they were born. Some of these children did not even receive the full course of vaccination. Investigations of HB cases among children aged 0-2 years in Kiev from 2001 support these statements. During this period, all children aged 0-2 years with HB did not receive the required vaccination course. Retrospective analysis of epidemiological investigation cards from 2004-2008 in Kiev showed that 5 children had acute HB and that 3 of these children were infected perinataly. In one additional case perinatal infection could not be excluded because the child’s mother who was an injecting drug user (IDU).was not tested.
In general, the positive role of HB vaccination in Ukraine is evident. From 2004, HBsAg was less frequently detected among children in orphanages and the incidence decreased from 3.6% to 1.7% in 2008 (Fig. 4).
Fig. 4. Frequency of HВsAg detection in specific population groups, 1996-2008
Children in orphanages are commonly born into families with problems and often belong to the perinatal infection risk group. In addition, all orphans face a higher risk of horizontal infection. Therefore, all orphans in Ukraine receive mandatory HB vaccination. In order to examine the immunization results for this group, the data for orphans was compared with data on children born to HBsAg-positive women. Information concerning 2010 children born to HBsAg-positive women was collected and recorded in official statistical forms during 2008. The HBsAg detection frequency was 4.6% among children born to HBsAg-positive women and thus indicated that these children are more often infected with HBV than children living in orphanages. It is worth noting that less than half of all children born to HBsAg-positive women were tested and those tested were only screened for HBsAg. Thus the test results do not provide a reliable estimate of the actual frequency of perinatal transmission of HBV in Ukraine.
The prevalence decreased among children living in orphanages, while HBsAg-detection among healthy adults (blood donors and pregnant women) remained stable (Fig. 4). At the same time, the registered incidence of acute HB among adults in Ukraine decreased steadily. We calculated the correlation between the HBsAg carriers and the acute HB incidence among adults per 100,000 population. For example, in 2001 HBsAg was detected among 1.4% of pregnant women (1400 per 100,000 population), and the incidence among adults was 22.4 per 100,000 adults. Thus, the correlation between HBsAg carriers and the registered incidence of acute HB was 62.5. During 1996 to 2002 there were 60 cases of HBsAg detected among pregnant women for every case of acute HB among adults in Ukraine. From 2003 this value grew rapidly and reached 184.6 in 2008 (Fig. 5).
Fig. 5. Correlation between HBsAg detection rate among pregnant women and acute HB incidence among adults in Ukraine, 1996-2008
The procedure for testing pregnant women did not change during this period (table below). During 2001-2008 an average of 1.28 HBsAg screenings of pregnant women for every child born were registered. In accordance with regulations, pregnant women in Ukraine should be screened for HBsAg during the first and third trimesters. The number of tests per pregnant woman indicates that the guidelines were not followed. Since the screening coverage of pregnant women did not change during the period, the population of healthy women covered by the screening is likely to be more or less homogeneous. Therefore, it is possible to draw a conclusion about the dominance of latent HB forms. Latent cases are not registered in any reports addressing the HB incidence, which creates an illusion of positive dynamics with HB prevalence decrease in Ukraine.
Table. HBsAg Screening Coverage of Pregnant Women, 2001-2008
The official statistics show a steady decline in the registered HB incidence in Ukraine from 1991 to 2008. A similar trend has been reported in many other European countries. For example, in the Russian Federation the incidence of acute HB declined from 42.5 to 7.0 per 100,000 population from 2000 to 2006. Hepatitis C demonstrated a similar tendency, with the incidence going down from 20.9 to 4.1 . It is thus possible to conclude that there may have been a general factor that influenced the incidence. The HB incidence registered in EU countries also declined from 6.7 per 100,000 population in 1995 to 1.5 in 2006 . Interestingly, Italian investigators  found that the HB incidence decreased most rapidly, from 41.0 to 0.5 per 100,000 population, among 15-24 year olds, the age group that previously had the highest incidence. Among children under the age of 14, the HB incidence reduced most drastically in 1985-1987 before the implementation of large-scale vaccination of newborns. The authors believe that HB incidence dynamics in Italy was influenced not only by vaccination, but by a number of other factors including a lowered risk of infection via blood transfusions and invasive medical procedures, sexual contacts and drug use .
The actual prevalence of HBV infection is demonstrated by results of seroepidemiological surveys. In many countries, the surveillance system does not require mandatory screening of the healthy population and risk groups. In accordance with a special order of the Ministry of Health in Ukraine, the particular groups of population are screened regularly at frequencies defined for each group individually. For example, pregnant women are screened in the first and third trimester; patients with chronic hepatic disorders and patients with any other chronic pathologies are tested when admitted to the hospital; children living in orphanages are tested when admitted to these institutions; and patients at narcological dispensaries are screened when they are registered and every year thereafter. Tracing changes in the dynamics of the epidemic process is based on the general screening results for various population groups. The choice of population groups for screening is subject to revision in accordance with the current situation. In addition, the scale of screening scale is insufficient in many regions. However, seromonitoring data yields adequate information about the current trends of the development of HBV infection epidemic process. Screening data from pregnant women and blood donors show that the proportion of asymptomatic forms is increasing in the structure of HBV infection incidence among adults. The reduced number of registered cases of acute HB cannot be viewed as indicator of an epidemiologically favourable situation. Asymptomatic carriers of the virus may develop chronic hepatic disorders, a tendency indicated by the rising incidence rate of chronic hepatitis in Ukraine.
The reduced incidence of clinically active forms of acute HB can be explained by changes in the structure of HBV transmission routes. At present the epidemic process is primarily fueled by transmission via sexual contacts. The universal vaccination of newborns that has been conducted in Ukraine for the last 10 years does not influence the intensity of HB epidemic process among adults (people of the age over 14 years). Vaccination has resulted in a lower incidence among children aged of 3-6 years. However, vaccination of all newborns did not effectively prevent perinatal transmission of HBV. Judging by the proportion of pregnant women with HBsAg (1.4% on average in 2000-2008), less than 1% of newborns in Ukraine are infected via perinatal transmission. It is worth mentioning that perinatal transmission prevailed among children under the age of 2 with acute HB in Kiev during 2004-2006.
The immunoprophylaxis of perinatal HB is known to be difficult and is never 100% effective. Reducing the number of virus carriers among women of the childbearing age seems to be the most promising preventive strategy. In our opinion, this goal can be achieved through vaccination of teenagers. The duration of immunological memory among people vaccinated against HB needs to be investigated. It is believed that a booster dose of HB vaccine is unnecessary due to the sufficient duration of immunological memory characteristic for people who have received the complete course of vaccination [17, 18]. The results of various surveys show that even with a undetectable level of antibodies an adequate immune response can be achieved within several days. However, the duration of immunological memory has not been established and it is not clear if a patient can be infected when the immune system is being activated. At present, WHO and CDC do not recommend using a booster dose of the HB vaccine [19, 20]. Recently, a number of reports indicate that markers of past infection (anti-HBc) have been detected among people vaccinated against HB at birth although these people have never experienced symptoms of chronic infection . The efficiency of universal HB vaccination was studied in Gambia fifteen years after introduction. Approximately 20% of vaccinated children became anti-HBs-positive and it was presumed that the infections were a result of sexual transmission. The authors concluded that the recommendation not to administer a booster dose of the HB vaccine lacked credibility . Another investigation demonstrated that a lowered efficiency of vaccination among teenagers was observed at the start of sexual activity. It was shown that an undetectable level of antibodies prior to seroconversion of anti-HBs did not confer protection and resulted in a much higher risk of infection . Consequently, there is still no definitive answer as to whether the booster vaccination is required after immunization of newborns. Since there is no evidence that HB vaccination can provide a strong lifelong immunity as well as in case of vaccination against smallpox, it is reasonable to apply various strategies for HB immunoprophylaxis depending on the epidemiological situation and availability of serological monitoring in a particular country.
In Ukraine, there are regulatory documents and resources to provide HBV seroepidemiological monitoring. These regulatory documents need to be substantially upgraded and resources extended. However, full use of the available resources may provide effective epidemiological surveillance over HBV infection by various methods, including immunization. The improved system of pre-delivery screening of pregnant women will allow increasing efficiency of prophylaxis of perinatal infection. We suggest the introduction of routine screening of pregnant women for anti-HBc. All children born to women with anti-HBc marker need to be vaccinated at the maternity hospital. Immunization of newborns is also necessary when the mothers have not been screened before labour. In accordance with the current immunization schedule, HB vaccination can be introduced in Ukraine under particular epidemic conditions. Vaccination is introduced to people who contact a virus carrier or a patient suffering from HB, to patients at high risk of infection during medical parenteral operations and blood transfusions, and among groups with professional and behavioural risk, to children living in orphanages. Thus children who were not vaccinated at birth are vaccinated when at risk of HBV infection, while vaccination of newborns is mainly targeted at prevention of perinatal infection.
In summary, these data indicate that the most effective strategy corresponding to the HB surveillance and epidemiological situation in Ukraine includes vaccination of newborns at risk groups and vaccination of teenagers. Vaccination of these groups may prevent the further spread of HBV infection in vulnerable groups in the population and may result in a considerable reduction in the number of perinatal infection sources in the foreseeable future.
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