Universal hepatitis B vaccination (De Wit et
al., 2007) Voor literatuurreferenties zie rapport.
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Hepatitis B is a contagious viral infection caused by hepatitis B virus (HBV). HBV is transmitted via blood, body fluids or at birth. The course of an acute infection varies, from temporary to fatal, from asymptomatic to symptoms as tiredness, fever, joint complaints and jaundice. Acute infection can lead to a persistent chronic infection with clinical symptoms (caused by liver damage), or, more frequently, to a sub-clinical form of the disease (Van de Laar et al., 2005). There is a strong relation between age and the course of an acute infection: 1-10% of infected young children (<6) and 30-40% of older children and adults have symptoms (Van de Laar et al., 2005). Young children are at greatest risk of a chronic infection; over 90% of those children infected at birth develop a chronic infection. Chronic carriers stay infectious to others and have an increased chance of developing long term sequelae, such as cirrhosis and hepatocellular carcinoma (Van de Laar et al., 2005).
Worldwide, about 350 to 400 million people are chronically infected with HBV (Kowdley, 2004) and every year more than a million people die of hepatitis B infection. However, the regional prevalence of HBV varies tremendously. In Southeast and Far East Asia countries over 10% of the population is infected, while in Western Europe and North America this is less than 2% (Kowdley, 2004).
The prevalence of chronic hepatitis B in the Netherlands is generally low (about 0.4%), but is higher in risk groups such as drug users, men having sex with men and prostitutes. Also, the prevalence is alleviated in certain immigrant groups from countries with intermediate or high prevalence, e.g. mediterranean countries (Boot et al., 2005). In 2003, hepatitis B was 1,877 times reported (319 acute and 1,445 chronic infections) and the incidence of acute hepatitis B was 2.0 per 100,000 inhabitants; 3.1 for men and 0.9 for women (Van de Laar and Op de Coul, 2004; Koedijk et al., 2005).
Prevention of hepatitis B is possible by vaccinating those groups of people not yet exposed to the virus. Since 1986, safe and effective vaccines are available. The vaccine used nowadays in the western world is a recombinant sub-unit vaccine of the hepatitis B (pre)-Surface protein (HBsAg). Adverse events of hepatitis B vaccination are usually mild, of short duration and have the same frequency as in placebo recipients (Boot et al., 2005). Standard hepatitis B vaccination consists of three vaccinations with an interval of respectively one and at least five months between the consecutive vaccination doses. In 90-95% of vaccinated cases, this leads to an adequate and lasting (> 15 years, possibly lifelong) protection.
There are two different ways of vaccination: universal (a whole cohort receives vaccination regardless of individual risks) and selective (only high risk groups). In 1992, the WHO recommended that universal vaccination against HBV (of infants or adolescents) should be integrated into all national immunization programmes. Most European countries have done so, but the Netherlands and some other countries with a very low (<1%) HBV carrier prevalence (United Kingdom, Ireland and the Scandinavian countries) decided not to start an universal vaccination programme. It was estimated that in the Netherlands universal immunization of infants could only prevent 5-10% of new carriers of HBV, because most newly infected persons came from abroad (Kretzschmar et al., 2002).
The current Dutch hepatitis B prevention policy consists of four (voluntary and for free) selective programmes:
Screening of all pregnant women and vaccination of children of infected mothers (since 1989). Vaccination of persons who are at increased risk to be infected or to infect others with hepatitis B through work-related situations (e.g. surgeons, nurses, dentists) or through their living circumstances (e.g. mentally disabled people living in institutions) (since 2000). Vaccination of all newborn children with one or two parents from a medium or high HBV prevalence region. This is integrated into the National Immunization Programme (since 2003). Vaccination of four high risk groups, namely men having sex with men, heterosexual persons who change sex-partners frequently, hard drug users and commercial sex-workers. This programme started in 2002 as a catch-up campaign for a four-year period, intended to reach as many members of target groups as possible. Recently, it was decided that this programme will be continued for a longer period.
In spite of the four selective programmes, at this moment the vast majority of the Dutch population is not protected against hepatitis B. As part of its permanent advisory role on the contents and organisation of the National Immunization Programme, the Health Council of the Netherlands is expected to review the current Dutch hepatitis B prevention policies in the near future.
The description of the cost-effectiveness of universal hepatitis B vaccination is based on seven studies. Six of them are European studies, one is from the Netherlands. All studies are based on simulation models, but the assumptions, time span and methodology used in the studies differ, and therefore, results differ as well. Outcome measures used were life years gained (LYG) or cases prevented.
The studies compared universal vaccination (infants, schoolchildren, adolescents or combinations of these) with prenatal screening (De Wit et al., 2000; Wiebe et al., 1997) vaccination of risk-groups (Zurn et al., 2000; Garuz et al., 1997; Mangtani et al., 1995) or no vaccination at all (Fenn et al., 1996; Antonanzas et al., 1995).
All studies, except the Dutch study, showed that universal immunization is a cost-effective strategy in comparison with prenatal screening, vaccination of high risk groups or no vaccination at all. However there were differences in the universal strategy that was primarily recommended from a cost-effectiveness perspective. In the studies of Wiebe et al. (1997) and Fenn et al. (1996) immunization of infants is the most cost-effective strategy. The results were 15,900 Canadian Dollars per LYG respectivily 5,234 (undiscounted) or 227,130 (discounted) UK Pounds per LYG. Four studies found that immunization of adolescents is the most cost-effective strategy. Both the results of Garuz et al. (1997) and Antonanzas et al. (1995) were presented per cases prevented and were 603 (undiscounted) or 850 (discounted) US Dollars, respectivily 49,000 (undiscounted) or 82,000 (discounted) Spanish Pesetas. In the study of Zurn et al. (2000) universal vaccination of adolescents costs 53,970 Swiss Francs per LYG. This is 2,824 (undiscounted) or 51,817 (discounted) UK dollars per LYG in the study of Mangtani et al. (1995).
The Dutch study modelled the cost-effectiveness of adding universal vaccination of infants to the prenatal screening programme. Due to the relative high percentage of HBV infections imported by immigrants, universal vaccination of infants had almost no effect on the prevalence and infection pressure on susceptible persons and only a small impact on prevention of long-term complications of hepatitis B. So in this study, universal vaccination was not a cost-effective strategy.
All studies included some form of sensitivity analysis to assess the effects of key parameters on the estimated outcomes. In general, sensitivity analyses indicated that vaccination costs, the effectiveness of vaccination, prevalence and the discount rate had the largest impact on the cost-effectiveness. In the Dutch study universal immunization of infants became more cost-effective with lower vaccine costs and lower discount rate of health benefits in the future (De Wit et al., 2000). At present, the Dutch cost-effectiveness analysis is being updated. Several major changes in assumptions are now made compared to the study that was published in 2000, including (much) lower costs of vaccination, lower discount rates for effects of vaccination, and the inclusion of a third route of transmission, namely horizontal transmission at children's age. Preliminary results of the updated analyses show that universal vaccination of both infants and adolescents have cost-effectiveness ratio's that remain below the threshold of € 20,000 per QALY (De Wit et al., in preparation).
Beutels (2001) reviewed recent (1994-2000) economic studies of hepatitis B vaccination. He concludes that economic evaluations of vaccination in very low-endemic areas have yielded contradictory results and therefore evidence is inconclusive. Beutels makes clear that the different results are partly determined by differences in modelling techniques and differences in assumptions made in the different studies. For example, using a static model to estimate the effectiveness of vaccination at population level underestimates the cost-effectiveness of vaccination in comparison to a situation where cost-effectiveness is modelled using a dynamic model. According to Beutels (2001) vaccination of adolescents seems most cost-effective for low-endemic countries, because the period between vaccination and start of sexual activity (the major route of infection in low-endemic countries) is relatively short.
Translation of the foreign studies to the Dutch situation has several limitations. First and most important, the countries of the study differ in endemicity. The level of prevalence of hepatitis B in a country is a key-parameter in determining the cost-effectiveness of universal immunization, because vaccination is by definition more cost-effective in high-prevalence regions. The prevalence in the Netherlands is very low, less than 1%. Only in the two studies of the United Kingdom, the prevalence is comparable to the Dutch situation. In the other countries, in particular Spain, the prevalence is higher so universal immunization has more effect and is more cost-effective than in the Netherlands. Besides the prevalence, the countries studied differ in other aspects (e.g. transmission route and vaccination rate) from the Dutch situation. In the Netherlands nowadays most HBV is transmitted by male homosexual contact, while in some other countries intravenous drug use is still an important transmission route. In addition, since the studies were published, vaccine prices dropped considerably. Also, immigration patterns, and therefore the proportion of imported infections, changed. These differences between countries have major impact on the estimated cost-effectiveness of vaccination strategies. The ongoing Dutch evaluation study of hepatitis B vaccination strategies takes these changes into account (De Wit et al., in preparation).
At present, the Health Council of the Netherlands discusses the necessity of changing the current risk-based strategy to prevent hepatitis B to a strategy that includes universal vaccination, either of infants or of adolescents. Vaccination of newborns from infected mothers and infants with one or two parents from a medium or high HBV prevalence region is already integrated in the National Immunization Programme (NIP). Until April 2006, this used to be done with three separate injections of hepatitis B vaccine. However, since April 2006, universal infant pneumococcal vaccination was introduced in the National Immunization Programme. To avoid giving three different injections to a child at any one moment, a combination vaccine containing DTP-IPV-HepB-Hib is being used for those children with one or two parents from endemic regions. This commercial combination vaccine is relatively expensive in comparison with the DTP-IPV-Hib vaccine that was used before. The undesirability of three different vaccinations at one moment and the relatively high price of the commercial combination vaccine including hepatitis B vaccine might hamper the introduction of hepatitis B vaccination for all infants in the short term.
As the Dutch National Immunization Programme traditionally was targeted at infants and young school children, universal vaccination of adolescents would require the introduction of an entirely different age group within the NIP. Many issues surround such a major change in the NIP. At this moment, it is unclear how a succesfull vaccination programme for adolescents can be achieved and preserved. Should it be organized through schools or through municipal health services? Who needs to give informed consent, only parents or the adolescent as well? Will vaccination against a (mainly) sexually transmitted disease be accepted widely? Will the acceptance of and compliance with vaccination be sufficient to decrease transmission of the virus at population level? These and other issues need to be resolved before a major change in the NIP can be implemented. Because other vaccines, such as pertussis vaccine and human papilloma virus vaccine, also qualify for vaccination of adolescents, it is expected that the Health Council committee will reflect upon the possibility of implementation of adolescent vaccination in the Netherlands.
Hepatitis B is a contagious viral infection transmitted via blood, body fluids or at birth. In the Netherlands the prevalence of hepatitis B is generally low, but higher among some groups (men having sex with men, prostitutes, drugusers) and some immigrant groups. Because of the very low endemicity, the Dutch government decided not to implement universal vaccination, but to implement risk-based prevention policies, including vaccination of risk-groups. Economic evaluations in very low-endemic areas have yielded contradictory results on the cost-effectiveness of such policies, therefore evidence is inconclusive. For low-endemic countries, vaccination of adolescents seems more cost-effective than vaccination of infants. Because the Netherlands differs from the countries studied in for example prevalence, transmission route and vaccination rate, translation from the international results to the Dutch situation is difficult. However, preliminary results of an ongoing study on cost-effectiveness of different vaccination strategies for the Netherlands show that both infant vaccination and adolescent vaccination are cost-effective. Implementation of universal vaccination in the Netherlands is not without problems. The undesirability of three different vaccinations at one moment and the relativily high price of the commercial combination (DTP-IPV-HepB-Hib) vaccine might hamper the introduction of hepatitis B vaccination for all infants. Universal vaccination of adolescents would require the introduction of an entirely different age group within the NIP. Such a major change in the NIP is surrounded with many issues that need to be resolved