Infectious Diseases, 2015; Early Online: 1–6
Original article
Hepatitis B infection and vaccination coverage in men who have sex with men consulting a Danish venereal disease clinic
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Ulla Schierup Nielsen1, Anne Birgitte Simonsen2, Lars Halkier-SØrensen2, Carsten Schade Larsen1 & Christian Erikstrup3 From the 1Department of Infectious Diseases, 2Department of Dermatology, and 3Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
Abstract Background: Vaccination guidelines from the Danish Health and Medicines Authority recommend vaccination of all men who have sex with men (MSM) against hepatitis B virus (HBV). The only existing data on HBV infection in Danish MSM stem from 1984: 58% of MSM attending venereal clinics in Copenhagen had a prior and 4% had a chronic HBV infection. The aim of this study was to provide up-to-date data on the prevalence of HBV infection and vaccination coverage among Danish MSM. Methods: At the venereal clinic at Aarhus University Hospital, 1525 consecutive patients received a questionnaire covering risk group and vaccination status; moreover, HBV serology was performed. Prevalence proportions of serological signs of vaccination, infection, etc. were stratified according to self-reported risk group and vaccination status. Results: In total, 141 patients were MSM. Among these, 14% (CI 9–21%) were vaccinated, 7% (CI 3–13%) had a prior infection and 1.4% (CI 0.2–5%) were HBsAg positive. In patients recalling three doses of vaccination, 18% (CI 11–26%) were anti-HBs negative and 0.8% (CI 0.02–5%) were HBsAg positive. Similar data for other risk groups and the total clientele are presented. Conclusions: This study presents the first Scandinavian data on the prevalence of HBV infection and vaccination among MSM since the introduction of the vaccine. Danish health authorities should evaluate whether a carrier frequency of 1.4% and a vaccination coverage of 14% in MSM is acceptable or warrants intensified focus on vaccination. Prospective vaccination campaigns should consider prevaccination testing, since 18% of patients recalling three doses of vaccination were anti-HBs negative.
Keywords: Hepatitis B, immunization, prevalence, homosexuals, risk
Introduction An effective vaccine against hepatitis B virus (HBV) has existed for 25 years [1]. Five Scandinavian countries, including Denmark, refrain from universal childhood vaccination against HBV infection [2], since infected individuals in low-incidence countries mostly belong to four well-known risk groups: men who have sex with men (MSM), immigrants from HBV-endemic countries, intravenous drug users (IDUs) and sex workers. Irrespective of universal childhood vaccination, programmes targeting these risk groups will be needed during the next decades, due to the older unvaccinated generations. However, strategies on how to secure sufficient vaccination coverage in these risk groups vary and have been
criticized as being ineffective in achieving sufficient coverage in the target populations [3]. Vaccination guidelines from the Danish Health and Medicines Authority recommend HBV vaccination of all MSM as well as IDUs [4]. Since 2005, a national campaign has focused on free of charge vaccination of IDUs in Danish prisons/IDU clinics; no such campaign has been targeted at Danish MSM, who must ask their general practitioner for the vaccine and pay for it themselves. No data exist on the current prevalence of HBV infection and vaccination coverage in the group of Danish MSM. The only existing data stem from 1984, i.e. before the vaccine was introduced and before behavioural changes due to the human immunodeficiency virus
Correspondence: Ulla Schierup Nielsen, Department of Infectious Diseases, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark. E-mail: [email protected] (Received 9 August 2014; accepted 24 February 2015) ISSN 2374-4235 print/ISSN 2374-4243 online © 2015 Informa Healthcare DOI: 10.3109/23744235.2015.1026932
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(HIV) epidemic. At that time, 58% of MSM attending venereal disease clinics in Copenhagen had serological signs of prior HBV infection, and 4% were chronically infected [5]. The purpose of this study was to estimate the current prevalence of HBV infection and vaccination coverage, and thus evaluate the current vaccination strategy among MSM and other risk groups visiting a venereal disease clinic in Denmark.
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Materials and methods The study design was a retrospective prevalence study based on data retrieved from patient records. Patients visiting the venereal disease clinic at Aarhus University Hospital between 25 November 2010 and 9 February 2012 were included. Aarhus is the second largest city in Denmark, and the clinic services a population of approximately 1.3 million. Aarhus has a high concentration of university students, which is reflected in the clientele. The clinic is an open venereal disease clinic; patients visit on their own initiative, either requesting a venereal screening or because they suspect a specific sexually transmitted disease. Before examination, the patients fill in a standardized questionnaire to uncover whether they have had any previous venereal diseases, belong to any risk group(s), and whether they were previously vaccinated against hepatitis A and/or B as well as the number of doses received. All patients underwent a standard venereal disease examination and blood test. In total, 1899 individuals visited the clinic during the study period; however, some of these patients only came for repeated treatment of genital warts, etc., and had already been screened before the study period; thus, blood tests were not performed. A total of 1525 patients filled in the questionnaire and underwent a full HBV serology within the study period and were included in the study. Patients with more than one screening visit during the study period were only recorded in the database once, i.e. at their last screening visit. All numbers refer to individuals, not visits. All blood samples were screened with commercially available chemiluminescence assays, anti-HAV, anti-HBc, anti-HBs, HBsAg, anti-HCV and HIV antibody/antigen combo test, on the Architect platform (Architect, Abbott Laboratories, Abbott Park, IL, USA). HBsAg reactive samples were subsequently tested for the presence of HBeAg and anti-HBe. The main focus of the study was MSM, but data from other risk groups and the general venereal clientele are presented for comparison. Categorization into risk groups was based on responses in the questionnaire. The wording in the questionnaire
was: ‘Are you, or have you ever been: an IV drug user? a sex worker? another ethnic origin than Danish (write country)? Are your sexual partners usually: men? women? men and women?’. Four risk groups were defined: MSM, IDUs, sex workers and immigrants from countries outside Western Europe and the USA. Individuals belonging to more than one risk group were included in all relevant risk groups. In the present study, of 141 MSM, 0 were both MSM and IDU, 2 were MSM and sex worker, and 12 were MSM and immigrants. These numbers did not allow estimation of prevalence of infection and vaccination coverage in these subgroups of the MSM population. We also defined a comparison group of patients who would not be recommended vaccination, i.e. patients stating that they were not MSM/IDU/sex worker/immigrant (‘not MISI’). Verification of their answers was not possible and under-reporting of risk group status cannot be excluded; however, regardless of possible underreporting, in a clinical setting this ‘not MISI’ group de facto constitutes a group of people that would not be recommended HBV vaccination according to the Danish national guidelines. The serological results were interpreted as follows. Prior infection anti-HBc positive, anti-HBe/s positive and HBsAg negative.Current infection HBsAg positive. Core-only anti-HBc positive, anti-HBeand anti-HBs negative, and HBsAg negative. Vaccinated anti-HBc negative, anti-HBs 10 mIU/ml and HBsAg negative. Susceptible anti-HBc negative, anti-HBs negative and HBsAg negative. Prevalence proportions were calculated and are presented with confidence intervals (CIs) using a 5% significance level. Vaccination coverage was calculated as number of vaccinated/total population. Proportions were compared using the chi-squared test and presented as risk ratios (RRs). The data analysis was done using the statistical software programme STATA 12.0. The project was approved by the Danish Data Protection Agency (journal no. 2010-41-5299). Results A total of 1525 patients were included in the study. Patient characteristics are shown in Table I. The median age was 27 years (range 15–80 years, interquartile range 23–36 years); 60% of patients were males and the vast majority of patients were young, heterosexual Danes. Among the 1525 patients, 14% (CI 13–16%) belonged to one of the four predefined risk groups. MSM constituted 9% (CI 8–11%) of all patients and 15% (CI 13–18%) of male patients.
Hepatitis B infection and vaccination coverage in MSM
susceptible to HBV infection. The RR of having a prior or current HBV infection was higher in all four risk groups compared with this ‘not MISI’ group; MSM, RR 6 (CI 3–13); IDU, RR 37 (CI 9–161); sex worker, RR 11 (CI 3–45); immigrant, RR 14 (CI 7–27); total risk group, RR 9 (CI 3–13). The vaccination coverage was lower in all four risk groups compared to the ‘not MISI’ group, although numbers were too small to reach statistical significance in most groups: MSM, RR 0.7 (CI 0.5–1.05); IDU, RR 0; sex worker, RR 0; immigrant, RR 0.5 (CI 0.3–0.99); total risk group, RR 0.6 (CI 0.4–0.9). Table III shows patients’ recall of vaccination status versus HBV serology and reveals large discrepancies between patient recall and actual serological signs of immunity. Of the patients who believed they were vaccinated, 43% (CI 38–48%) were anti-HBs negative and 1% (CI 0.5–3%) were HBsAg positive; even if people recalled having received three doses, 18% (CI 11–26%) were anti-HBs negative and 0.8% (CI 0.02–5%) were HBsAg positive. Antigen carrier status was three times more frequent among those claiming to be vaccinated than among those claiming not to be vaccinated; however, this finding was not statistically significant: RR 3 (CI 0.7–11). Only four patients reported being previously infected with HBV, but according to the serology, 44 had a prior or current infection and a further 11 were core-only. Thus, screening of 1525 persons during a 15-month period resulted in 40 new diagnoses of HBV infection, of which 8 were HBsAg positive.
Table I. Patient characteristics. n (%).
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Characteristic Age and gender Median age, years (IQR) Males Females Ethnicity Danes Immigrants Western Europe/USA Not western Europe/USA Africa/East Asia/Middle East Latin America Eastern Europe/Turkey/Russia Canada/Greenland Other No answer on ethnicity Risk group status Risk groupa MSM IV drug user Sex worker Immigrant, not Western Europe/USA Not MISIb Female not MISI Male not MISI No answer on risk group Total no. of patients
27 (23–36) 915 (60) 610 (40) 1341 138 62 76 46 2 25 3 0 46
(88) (9) (4) (5) (3) (0.1) (2) (0.2) (0) (3)
217 141 2 13 76 1,264 553 711 44 1525
(14) (9) (0.1) (1) (5) (83) (36) (47) (3) (100)
aPatients
may belong to more than one risk group. stating that they are not MSM/IDU/sex worker/ immigrant. bPatients
Table II shows the HBV serology in the different risk groups. Among the 141 patients who reported being MSM, 14% (CI 9–21%) were vaccinated, 7% (CI 3–13%) had a prior infection, 1.4% (CI 0.2–5%) were HBsAg positive and 77% (CI 69–83%) were susceptible to HBV infection. Among the 1264 patients who reported that they were not MSM, IDU, sex worker or immigrant, 20% (CI 18–23%) were vaccinated, 0.9% (CI 0.4– 1.6%) had a prior infection, 0.5% (CI 0.2–1.0%) were HBsAg positive and 77% (CI 75–80%) were
Discussion This study presents the first Scandinavian data on prevalence of HBV infection and vaccination coverage among MSM since the introduction of the HBV
Table II. Hepatitis B serology in different risk groups, n (%). Prior infection: anti-HBc (), anti-HBe/s (), HBsAg (–)
Group Risk groupa MSM Sex workers Drug users Immigrants Not MISIb No answer Total
22 10 2 1 12 11 0 33
(10) (7) (15) (50) (16) (0.9) (2)
Current infection: HBsAg () 4 (2) 2 (1.4) 0 0 2 (2.6) 6 (0.5) 1 (2) 11 (0.7)
aPatients may belong to more than one risk group. bPatients
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Core-only: anti-HBc (), anti-HBe/s (–), HBsAg (–) 1 1 0 0 0 9 1 11
stating that they are not MSM/IDU/sex worker/immigrant.
(0.5) (0.7)
(0.7) (2) (0.7)
Vaccinated: anti-HBc (–), anti-HBs (), HBsAg (–) 28 20 0 0 8 259 9 296
(13) (14)
(11) (20) (20) (19)
Susceptible: anti-HBc (–), anti-HBs (–), HBsAg (–) 162 108 11 1 54 979 33 1174
(75) (77) (85) (50) (72) (77) (75) (77)
No. tested 217 141 13 2 76 1264 44 1525
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U. S. Nielsen et al.
Table III. Hepatitis B serology versus patient recall of vaccination, n (%).
Patient recall
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‘No, I’m not vaccinated’ ‘Don’t remember if I’m vaccinated’ ‘Yes, I am vaccinated’ ‘1 dose’ ‘2 doses’ ‘3 doses’ ‘Don’t remember the number of doses’ No answer Total
Prior infection: anti-HBc (), anti-HBe/s (), HBsAg (–)
Current infection: HBsAg ()
Core-only: anti-HBc (), anti-HBe/s (–), HBsAg (–)
Vaccinated: anti-HBc (–), anti-HBs (), HBsAg (–)
Susceptible: anti-HBc (–), anti-HBs (–), HBsAg (–)
No. tested
16 (3)
3 (0.5)
6 (1)
11 (2)
575 (94)
611
13 (3)
2 (0.4)
3 (0.7)
46 (10)
391 (86)
455
6 2 2 1 1
(1.4) (3) (3) (0.8) (0.6)
1 (0.2) 0 0 1 (0.8) 0
187 42 23 21 101
(43) (55) (29) (18) (64)
433 77 80 118 158
0 11 (0.7)
1 (4) 11 (0.7)
21 (81) 1.174 (77)
26 1525
3 (0.7) 0 0 2 (2) 1 (0.6) 1 (4) 33 (2)
vaccine in 1988. In our study, only 14% of MSM consulting a venereal disease clinic had serological signs of vaccination against HBV, and when comparing MSM and other risk groups with a large group of people stating that they did not belong to any risk group, vaccination coverage was significantly lower (RR 0.7 for MSM), while HBV infection was more prevalent (RR 6 for MSM) in the risk groups. This questions the efficacy of the Danish vaccination strategy; it seems as if the people who choose to ask their general practitioner for HBV vaccination are those with the lowest risk of infection. The proportion of MSM infected with HBV in the present study is lower than that found by the only previous Danish study from Copenhagen in 1984, which may indicate a decline in the prevalence of HBV infection among Danish MSM [5]: from 58% to 7% (prior infection) and from 4% to 1.4% (HBsAg positive). The two studies had similar designs and are thus comparable. However, the estimates cannot be statistically compared, keeping in mind that the clientele in Copenhagen venereal disease clinics may differ from the clientele in Aarhus, and may change over time. In spite of the decline, MSM still have an increased risk (RR 6) of infection compared with other people attending the clinic in our study. If authorities wish to introduce vaccination campaigns in venereal disease clinics, it is important to keep in mind the study results on discrepancies between claims to be vaccinated and actual serological immunity. When 18% of those who claim to be vaccinated with three doses against HBV are in fact anti-HBs negative, healthcare professionals must either perform prevaccination tests or choose to vaccinate everybody regardless of claims of previous vaccination. The choice between these two strategies can be guided by the fact that 1.4% of all people claiming to be vaccinated were HBsAg
236 33 55 93 55
(55) (43) (69) (79) (35)
3 (12) 296 (19)
positive, perhaps making prevaccination testing worthwhile. It is worth noting that the study data showed a much better concordance between patient recall and actual serological immunity regarding hepatitis A (data not shown). We speculate that the reason for the poor concordance regarding HBV is caused by patients confusing HBV with hepatitis A, and perhaps low immunological response rates after HBV vaccination among the clientele visiting a venereal disease clinic. Supporting this latter theory, a study from Birmingham, UK, showed significantly lower immunological response rates (75.4% vs 97.9%, p 0.001) even after several boosters in healthy MSM compared with heterosexual males [6]. The present study also provides data allowing rough cost–benefit considerations regarding the general screening of clients at venereal disease clinics. Screening of 1525 persons attending the clinic during a 15-month period resulted in 40 new diagnoses of HBV infection, of which 8 were antigen carriers. Thus, ‘numbers needed to screen’ (NNS) 38 for finding 1 patient with a previously undiagnosed prior or current HBV infection, and NNS 190 for finding 1 previously undiagnosed carrier (these estimates apply to the current study and may not be generalizable to other settings). Since Rituximab and other immunosuppressants/oncological treatments are known to reactivate prior HBV infections (including fulminant hepatitis with lethal outcome), discovery of a prior infection with HBV is meaningful in modern medicine [7]. Although vaccination of the MSM population is recommended by all European countries and the USA [8,9], the necessary vaccination coverage needed to achieve herd immunity has not been determined; only the UK has a set target (90%) for vaccination coverage among MSM [10]. This may be an
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Hepatitis B infection and vaccination coverage in MSM
ambitious target, and lower coverage levels (30–50%) seem sufficient to prevent significant transmission of acute HBV, as reported in studies from Amsterdam and Melbourne [11,12]. A recent study indicates that the combined efforts of national screening programmes with subsequent vaccination and treatment of infected MSM has helped in halving the number of reported cases of acute HBV infection in MSM since 2004 in The Netherlands [13]. The present study has limitations. First of all, this study was carried out at a single venereal disease clinic in Denmark and results are thus not generalizable to the general MSM population in Denmark. Second, the reliance on self-reported risk group status carries a risk of misclassification. Concerning generalizability, our primary purpose was to examine the efficacy of the Danish vaccination strategy. The subgroup of MSM who choose to consult a venereal disease clinic is likely to have a higher level of sexual risk behaviour than other MSM, and if this subgroup presents with poor vaccination coverage, then the national target of vaccinating those at highest risk has failed. Thus, even though the estimates cannot be extrapolated to the general MSM population, they can be used to evaluate the national vaccination strategy. Risk group status was based on self-reports, which carries a risk of misclassification; we believe that men who admit to having sex with men are probably not misclassified, but the ‘not MISI’ group is likely to include a certain amount of MSM, sex workers and IDUs, and even immigrants. However, in a clinical setting, decisions of whether or not to recommend vaccination are based on patient reports, not facts. The ‘not MISI’ group de facto represents all the patients who are considered to be at low risk (and thus not recommended vaccination) in a typical clinical setting, when following national guidelines. Our results confirm that the ‘not MISI’ group had a significantly lower prevalence of HBV infection (Table II), indicating an association between self-reported data on risk group status and actual risk behaviour. In other words, patient reports on risk group status were a predictor of overall HBV risk despite any misclassification. The fact that the ‘not MISI’ group had a higher vaccination coverage than any of the risk groups thus shows that the people at lowest risk of infection have the highest vaccination coverage and vice versa. National guidelines should be followed, and our study shows that this is not the case. Danish health authorities should evaluate whether the current vaccination coverage (14% in the present study) is sufficient, relative to the current prevalence of disease (1.4% in the present study), when keeping in mind the morbidity of HBV and vaccine costs. If not, intensified focus on vaccination of MSM by active national outreach campaigns is necessary.
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Conclusions Although this was a single-centre study, it seems fair to conclude that the proportion of MSM infected with HBV has declined considerably compared with the 1980s. Danish health authorities should evaluate whether a carrier frequency of 1.4% and a vaccination coverage of 14% in MSM consulting a venereal disease clinic is acceptable or if it warrants intensified focus on national vaccination campaigns. If such campaigns are initiated, they should consider the cost–benefit of prevaccination testing, since 18% of patients recalling three doses of vaccination were anti-HBs negative.
Acknowledgments The study was carried out in a collaboration between the following departments at Aarhus University Hospital: the venereal disease clinic at the Department of Dermatology, Department of Infectious Diseases and Department of Clinical Immunology. There was no external funding or other financial involvement. We wish to thank the management of all three departments for allocating time and resources to make this study possible.
Declaration of interest: Carsten Schade Larsen has received standard fees for lectures from GlaxoSmith-Kline, SBL-Crucell Vaccines and Sanofi Pasteur MSD. The authors alone are responsible for the content and writing of the paper. References [1] Danish Medicines Agency. Summary of product characteristics for Engerix-B. 2012. [2] World Health Organization. WHO-UNICEF estimates of HepB3 coverage. Available at: http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tswucoveragehepb3.html. 2013. [3] van Houdt R, Koedijk FD, Bruisten SM, Coul EL, Heijnen ML, Waldhober Q, et al. Hepatitis B vaccination targeted at behavioural risk groups in the Netherlands: does it work? Vaccine 2009;27:3530–5. [4] Sundhedsstyrelsen. Vejledning om HIV (human immundefekt virus), hepatitis B og C virus. 2013. [5] Petersen CS, Seier KS, Kroon S. Hepatitis B blandt et venerologisk klientel i København. Ugeskrift for Laeger 1984;146:1273–76. [6] Das S, Brassington M, Drake SM, Boxall E. Response to hepatitis-B vaccination in healthy homosexual individuals: retrospective case control study. Vaccine 2003; 21:3701–5. [7] Mitka M. FDA: Increased HBV reactivation risk with ofatumumab or rituximab. JAMA 2013;310:1664. [8] Mereckiene J, Cotter S, Lopalco P, D’Ancona F, Levy-Bruhl D, Giambi C, et al. Hepatitis B immunisation programmes in
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European Union, Norway and Iceland: where we were in 2009? Vaccine 2010;28:4470–7. [9] Mast EE, Weinbaum CM, Fiore AE, Alter MJ, Bell BP, Finelli L, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep 2006;55(RR-16):1–33; quiz CE1–4. [10] Adler MW, French P, McNab A, Smith C, Wellsteed S. The national strategy for sexual health and HIV: implications for genitourinary medicine. Sex Transm Infect 2002;78:83–6.
[11] Gamagedara N, Weerakoon AP, Zou H, Fehler G, Chen MY, Read TR, et al. Cross-sectional study of hepatitis B immunity in MSM between 2002 and 2012. Sex Transm Infect 2014;90:41–5. [12] van Rijckevorsel G, Whelan J, Kretzschmar M, Siedenburg E, Sonder G, Geskus R, et al. Targeted vaccination programme successful in reducing acute hepatitis B in men having sex with men in Amsterdam, the Netherlands. J Hepatol 2013;59:1177–83. [13] Hahne S, van Houdt R, Koedijk F, van Ballegooijen M, Cremer J, Bruisten S, et al. Selective hepatitis B virus vaccination has reduced hepatitis B virus transmission in the Netherlands. PLoS One 2013;8:e67866.
Original article
Hepatitis B infection and vaccination coverage in men who have sex with men consulting a Danish venereal disease clinic
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Ulla Schierup Nielsen1, Anne Birgitte Simonsen2, Lars Halkier-SØrensen2, Carsten Schade Larsen1 & Christian Erikstrup3 From the 1Department of Infectious Diseases, 2Department of Dermatology, and 3Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark
Abstract Background: Vaccination guidelines from the Danish Health and Medicines Authority recommend vaccination of all men who have sex with men (MSM) against hepatitis B virus (HBV). The only existing data on HBV infection in Danish MSM stem from 1984: 58% of MSM attending venereal clinics in Copenhagen had a prior and 4% had a chronic HBV infection. The aim of this study was to provide up-to-date data on the prevalence of HBV infection and vaccination coverage among Danish MSM. Methods: At the venereal clinic at Aarhus University Hospital, 1525 consecutive patients received a questionnaire covering risk group and vaccination status; moreover, HBV serology was performed. Prevalence proportions of serological signs of vaccination, infection, etc. were stratified according to self-reported risk group and vaccination status. Results: In total, 141 patients were MSM. Among these, 14% (CI 9–21%) were vaccinated, 7% (CI 3–13%) had a prior infection and 1.4% (CI 0.2–5%) were HBsAg positive. In patients recalling three doses of vaccination, 18% (CI 11–26%) were anti-HBs negative and 0.8% (CI 0.02–5%) were HBsAg positive. Similar data for other risk groups and the total clientele are presented. Conclusions: This study presents the first Scandinavian data on the prevalence of HBV infection and vaccination among MSM since the introduction of the vaccine. Danish health authorities should evaluate whether a carrier frequency of 1.4% and a vaccination coverage of 14% in MSM is acceptable or warrants intensified focus on vaccination. Prospective vaccination campaigns should consider prevaccination testing, since 18% of patients recalling three doses of vaccination were anti-HBs negative.
Keywords: Hepatitis B, immunization, prevalence, homosexuals, risk
Introduction An effective vaccine against hepatitis B virus (HBV) has existed for 25 years [1]. Five Scandinavian countries, including Denmark, refrain from universal childhood vaccination against HBV infection [2], since infected individuals in low-incidence countries mostly belong to four well-known risk groups: men who have sex with men (MSM), immigrants from HBV-endemic countries, intravenous drug users (IDUs) and sex workers. Irrespective of universal childhood vaccination, programmes targeting these risk groups will be needed during the next decades, due to the older unvaccinated generations. However, strategies on how to secure sufficient vaccination coverage in these risk groups vary and have been
criticized as being ineffective in achieving sufficient coverage in the target populations [3]. Vaccination guidelines from the Danish Health and Medicines Authority recommend HBV vaccination of all MSM as well as IDUs [4]. Since 2005, a national campaign has focused on free of charge vaccination of IDUs in Danish prisons/IDU clinics; no such campaign has been targeted at Danish MSM, who must ask their general practitioner for the vaccine and pay for it themselves. No data exist on the current prevalence of HBV infection and vaccination coverage in the group of Danish MSM. The only existing data stem from 1984, i.e. before the vaccine was introduced and before behavioural changes due to the human immunodeficiency virus
Correspondence: Ulla Schierup Nielsen, Department of Infectious Diseases, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark. E-mail: [email protected] (Received 9 August 2014; accepted 24 February 2015) ISSN 2374-4235 print/ISSN 2374-4243 online © 2015 Informa Healthcare DOI: 10.3109/23744235.2015.1026932
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(HIV) epidemic. At that time, 58% of MSM attending venereal disease clinics in Copenhagen had serological signs of prior HBV infection, and 4% were chronically infected [5]. The purpose of this study was to estimate the current prevalence of HBV infection and vaccination coverage, and thus evaluate the current vaccination strategy among MSM and other risk groups visiting a venereal disease clinic in Denmark.
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Materials and methods The study design was a retrospective prevalence study based on data retrieved from patient records. Patients visiting the venereal disease clinic at Aarhus University Hospital between 25 November 2010 and 9 February 2012 were included. Aarhus is the second largest city in Denmark, and the clinic services a population of approximately 1.3 million. Aarhus has a high concentration of university students, which is reflected in the clientele. The clinic is an open venereal disease clinic; patients visit on their own initiative, either requesting a venereal screening or because they suspect a specific sexually transmitted disease. Before examination, the patients fill in a standardized questionnaire to uncover whether they have had any previous venereal diseases, belong to any risk group(s), and whether they were previously vaccinated against hepatitis A and/or B as well as the number of doses received. All patients underwent a standard venereal disease examination and blood test. In total, 1899 individuals visited the clinic during the study period; however, some of these patients only came for repeated treatment of genital warts, etc., and had already been screened before the study period; thus, blood tests were not performed. A total of 1525 patients filled in the questionnaire and underwent a full HBV serology within the study period and were included in the study. Patients with more than one screening visit during the study period were only recorded in the database once, i.e. at their last screening visit. All numbers refer to individuals, not visits. All blood samples were screened with commercially available chemiluminescence assays, anti-HAV, anti-HBc, anti-HBs, HBsAg, anti-HCV and HIV antibody/antigen combo test, on the Architect platform (Architect, Abbott Laboratories, Abbott Park, IL, USA). HBsAg reactive samples were subsequently tested for the presence of HBeAg and anti-HBe. The main focus of the study was MSM, but data from other risk groups and the general venereal clientele are presented for comparison. Categorization into risk groups was based on responses in the questionnaire. The wording in the questionnaire
was: ‘Are you, or have you ever been: an IV drug user? a sex worker? another ethnic origin than Danish (write country)? Are your sexual partners usually: men? women? men and women?’. Four risk groups were defined: MSM, IDUs, sex workers and immigrants from countries outside Western Europe and the USA. Individuals belonging to more than one risk group were included in all relevant risk groups. In the present study, of 141 MSM, 0 were both MSM and IDU, 2 were MSM and sex worker, and 12 were MSM and immigrants. These numbers did not allow estimation of prevalence of infection and vaccination coverage in these subgroups of the MSM population. We also defined a comparison group of patients who would not be recommended vaccination, i.e. patients stating that they were not MSM/IDU/sex worker/immigrant (‘not MISI’). Verification of their answers was not possible and under-reporting of risk group status cannot be excluded; however, regardless of possible underreporting, in a clinical setting this ‘not MISI’ group de facto constitutes a group of people that would not be recommended HBV vaccination according to the Danish national guidelines. The serological results were interpreted as follows. Prior infection anti-HBc positive, anti-HBe/s positive and HBsAg negative.Current infection HBsAg positive. Core-only anti-HBc positive, anti-HBeand anti-HBs negative, and HBsAg negative. Vaccinated anti-HBc negative, anti-HBs 10 mIU/ml and HBsAg negative. Susceptible anti-HBc negative, anti-HBs negative and HBsAg negative. Prevalence proportions were calculated and are presented with confidence intervals (CIs) using a 5% significance level. Vaccination coverage was calculated as number of vaccinated/total population. Proportions were compared using the chi-squared test and presented as risk ratios (RRs). The data analysis was done using the statistical software programme STATA 12.0. The project was approved by the Danish Data Protection Agency (journal no. 2010-41-5299). Results A total of 1525 patients were included in the study. Patient characteristics are shown in Table I. The median age was 27 years (range 15–80 years, interquartile range 23–36 years); 60% of patients were males and the vast majority of patients were young, heterosexual Danes. Among the 1525 patients, 14% (CI 13–16%) belonged to one of the four predefined risk groups. MSM constituted 9% (CI 8–11%) of all patients and 15% (CI 13–18%) of male patients.
Hepatitis B infection and vaccination coverage in MSM
susceptible to HBV infection. The RR of having a prior or current HBV infection was higher in all four risk groups compared with this ‘not MISI’ group; MSM, RR 6 (CI 3–13); IDU, RR 37 (CI 9–161); sex worker, RR 11 (CI 3–45); immigrant, RR 14 (CI 7–27); total risk group, RR 9 (CI 3–13). The vaccination coverage was lower in all four risk groups compared to the ‘not MISI’ group, although numbers were too small to reach statistical significance in most groups: MSM, RR 0.7 (CI 0.5–1.05); IDU, RR 0; sex worker, RR 0; immigrant, RR 0.5 (CI 0.3–0.99); total risk group, RR 0.6 (CI 0.4–0.9). Table III shows patients’ recall of vaccination status versus HBV serology and reveals large discrepancies between patient recall and actual serological signs of immunity. Of the patients who believed they were vaccinated, 43% (CI 38–48%) were anti-HBs negative and 1% (CI 0.5–3%) were HBsAg positive; even if people recalled having received three doses, 18% (CI 11–26%) were anti-HBs negative and 0.8% (CI 0.02–5%) were HBsAg positive. Antigen carrier status was three times more frequent among those claiming to be vaccinated than among those claiming not to be vaccinated; however, this finding was not statistically significant: RR 3 (CI 0.7–11). Only four patients reported being previously infected with HBV, but according to the serology, 44 had a prior or current infection and a further 11 were core-only. Thus, screening of 1525 persons during a 15-month period resulted in 40 new diagnoses of HBV infection, of which 8 were HBsAg positive.
Table I. Patient characteristics. n (%).
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Characteristic Age and gender Median age, years (IQR) Males Females Ethnicity Danes Immigrants Western Europe/USA Not western Europe/USA Africa/East Asia/Middle East Latin America Eastern Europe/Turkey/Russia Canada/Greenland Other No answer on ethnicity Risk group status Risk groupa MSM IV drug user Sex worker Immigrant, not Western Europe/USA Not MISIb Female not MISI Male not MISI No answer on risk group Total no. of patients
27 (23–36) 915 (60) 610 (40) 1341 138 62 76 46 2 25 3 0 46
(88) (9) (4) (5) (3) (0.1) (2) (0.2) (0) (3)
217 141 2 13 76 1,264 553 711 44 1525
(14) (9) (0.1) (1) (5) (83) (36) (47) (3) (100)
aPatients
may belong to more than one risk group. stating that they are not MSM/IDU/sex worker/ immigrant. bPatients
Table II shows the HBV serology in the different risk groups. Among the 141 patients who reported being MSM, 14% (CI 9–21%) were vaccinated, 7% (CI 3–13%) had a prior infection, 1.4% (CI 0.2–5%) were HBsAg positive and 77% (CI 69–83%) were susceptible to HBV infection. Among the 1264 patients who reported that they were not MSM, IDU, sex worker or immigrant, 20% (CI 18–23%) were vaccinated, 0.9% (CI 0.4– 1.6%) had a prior infection, 0.5% (CI 0.2–1.0%) were HBsAg positive and 77% (CI 75–80%) were
Discussion This study presents the first Scandinavian data on prevalence of HBV infection and vaccination coverage among MSM since the introduction of the HBV
Table II. Hepatitis B serology in different risk groups, n (%). Prior infection: anti-HBc (), anti-HBe/s (), HBsAg (–)
Group Risk groupa MSM Sex workers Drug users Immigrants Not MISIb No answer Total
22 10 2 1 12 11 0 33
(10) (7) (15) (50) (16) (0.9) (2)
Current infection: HBsAg () 4 (2) 2 (1.4) 0 0 2 (2.6) 6 (0.5) 1 (2) 11 (0.7)
aPatients may belong to more than one risk group. bPatients
3
Core-only: anti-HBc (), anti-HBe/s (–), HBsAg (–) 1 1 0 0 0 9 1 11
stating that they are not MSM/IDU/sex worker/immigrant.
(0.5) (0.7)
(0.7) (2) (0.7)
Vaccinated: anti-HBc (–), anti-HBs (), HBsAg (–) 28 20 0 0 8 259 9 296
(13) (14)
(11) (20) (20) (19)
Susceptible: anti-HBc (–), anti-HBs (–), HBsAg (–) 162 108 11 1 54 979 33 1174
(75) (77) (85) (50) (72) (77) (75) (77)
No. tested 217 141 13 2 76 1264 44 1525
4
U. S. Nielsen et al.
Table III. Hepatitis B serology versus patient recall of vaccination, n (%).
Patient recall
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‘No, I’m not vaccinated’ ‘Don’t remember if I’m vaccinated’ ‘Yes, I am vaccinated’ ‘1 dose’ ‘2 doses’ ‘3 doses’ ‘Don’t remember the number of doses’ No answer Total
Prior infection: anti-HBc (), anti-HBe/s (), HBsAg (–)
Current infection: HBsAg ()
Core-only: anti-HBc (), anti-HBe/s (–), HBsAg (–)
Vaccinated: anti-HBc (–), anti-HBs (), HBsAg (–)
Susceptible: anti-HBc (–), anti-HBs (–), HBsAg (–)
No. tested
16 (3)
3 (0.5)
6 (1)
11 (2)
575 (94)
611
13 (3)
2 (0.4)
3 (0.7)
46 (10)
391 (86)
455
6 2 2 1 1
(1.4) (3) (3) (0.8) (0.6)
1 (0.2) 0 0 1 (0.8) 0
187 42 23 21 101
(43) (55) (29) (18) (64)
433 77 80 118 158
0 11 (0.7)
1 (4) 11 (0.7)
21 (81) 1.174 (77)
26 1525
3 (0.7) 0 0 2 (2) 1 (0.6) 1 (4) 33 (2)
vaccine in 1988. In our study, only 14% of MSM consulting a venereal disease clinic had serological signs of vaccination against HBV, and when comparing MSM and other risk groups with a large group of people stating that they did not belong to any risk group, vaccination coverage was significantly lower (RR 0.7 for MSM), while HBV infection was more prevalent (RR 6 for MSM) in the risk groups. This questions the efficacy of the Danish vaccination strategy; it seems as if the people who choose to ask their general practitioner for HBV vaccination are those with the lowest risk of infection. The proportion of MSM infected with HBV in the present study is lower than that found by the only previous Danish study from Copenhagen in 1984, which may indicate a decline in the prevalence of HBV infection among Danish MSM [5]: from 58% to 7% (prior infection) and from 4% to 1.4% (HBsAg positive). The two studies had similar designs and are thus comparable. However, the estimates cannot be statistically compared, keeping in mind that the clientele in Copenhagen venereal disease clinics may differ from the clientele in Aarhus, and may change over time. In spite of the decline, MSM still have an increased risk (RR 6) of infection compared with other people attending the clinic in our study. If authorities wish to introduce vaccination campaigns in venereal disease clinics, it is important to keep in mind the study results on discrepancies between claims to be vaccinated and actual serological immunity. When 18% of those who claim to be vaccinated with three doses against HBV are in fact anti-HBs negative, healthcare professionals must either perform prevaccination tests or choose to vaccinate everybody regardless of claims of previous vaccination. The choice between these two strategies can be guided by the fact that 1.4% of all people claiming to be vaccinated were HBsAg
236 33 55 93 55
(55) (43) (69) (79) (35)
3 (12) 296 (19)
positive, perhaps making prevaccination testing worthwhile. It is worth noting that the study data showed a much better concordance between patient recall and actual serological immunity regarding hepatitis A (data not shown). We speculate that the reason for the poor concordance regarding HBV is caused by patients confusing HBV with hepatitis A, and perhaps low immunological response rates after HBV vaccination among the clientele visiting a venereal disease clinic. Supporting this latter theory, a study from Birmingham, UK, showed significantly lower immunological response rates (75.4% vs 97.9%, p 0.001) even after several boosters in healthy MSM compared with heterosexual males [6]. The present study also provides data allowing rough cost–benefit considerations regarding the general screening of clients at venereal disease clinics. Screening of 1525 persons attending the clinic during a 15-month period resulted in 40 new diagnoses of HBV infection, of which 8 were antigen carriers. Thus, ‘numbers needed to screen’ (NNS) 38 for finding 1 patient with a previously undiagnosed prior or current HBV infection, and NNS 190 for finding 1 previously undiagnosed carrier (these estimates apply to the current study and may not be generalizable to other settings). Since Rituximab and other immunosuppressants/oncological treatments are known to reactivate prior HBV infections (including fulminant hepatitis with lethal outcome), discovery of a prior infection with HBV is meaningful in modern medicine [7]. Although vaccination of the MSM population is recommended by all European countries and the USA [8,9], the necessary vaccination coverage needed to achieve herd immunity has not been determined; only the UK has a set target (90%) for vaccination coverage among MSM [10]. This may be an
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Hepatitis B infection and vaccination coverage in MSM
ambitious target, and lower coverage levels (30–50%) seem sufficient to prevent significant transmission of acute HBV, as reported in studies from Amsterdam and Melbourne [11,12]. A recent study indicates that the combined efforts of national screening programmes with subsequent vaccination and treatment of infected MSM has helped in halving the number of reported cases of acute HBV infection in MSM since 2004 in The Netherlands [13]. The present study has limitations. First of all, this study was carried out at a single venereal disease clinic in Denmark and results are thus not generalizable to the general MSM population in Denmark. Second, the reliance on self-reported risk group status carries a risk of misclassification. Concerning generalizability, our primary purpose was to examine the efficacy of the Danish vaccination strategy. The subgroup of MSM who choose to consult a venereal disease clinic is likely to have a higher level of sexual risk behaviour than other MSM, and if this subgroup presents with poor vaccination coverage, then the national target of vaccinating those at highest risk has failed. Thus, even though the estimates cannot be extrapolated to the general MSM population, they can be used to evaluate the national vaccination strategy. Risk group status was based on self-reports, which carries a risk of misclassification; we believe that men who admit to having sex with men are probably not misclassified, but the ‘not MISI’ group is likely to include a certain amount of MSM, sex workers and IDUs, and even immigrants. However, in a clinical setting, decisions of whether or not to recommend vaccination are based on patient reports, not facts. The ‘not MISI’ group de facto represents all the patients who are considered to be at low risk (and thus not recommended vaccination) in a typical clinical setting, when following national guidelines. Our results confirm that the ‘not MISI’ group had a significantly lower prevalence of HBV infection (Table II), indicating an association between self-reported data on risk group status and actual risk behaviour. In other words, patient reports on risk group status were a predictor of overall HBV risk despite any misclassification. The fact that the ‘not MISI’ group had a higher vaccination coverage than any of the risk groups thus shows that the people at lowest risk of infection have the highest vaccination coverage and vice versa. National guidelines should be followed, and our study shows that this is not the case. Danish health authorities should evaluate whether the current vaccination coverage (14% in the present study) is sufficient, relative to the current prevalence of disease (1.4% in the present study), when keeping in mind the morbidity of HBV and vaccine costs. If not, intensified focus on vaccination of MSM by active national outreach campaigns is necessary.
5
Conclusions Although this was a single-centre study, it seems fair to conclude that the proportion of MSM infected with HBV has declined considerably compared with the 1980s. Danish health authorities should evaluate whether a carrier frequency of 1.4% and a vaccination coverage of 14% in MSM consulting a venereal disease clinic is acceptable or if it warrants intensified focus on national vaccination campaigns. If such campaigns are initiated, they should consider the cost–benefit of prevaccination testing, since 18% of patients recalling three doses of vaccination were anti-HBs negative.
Acknowledgments The study was carried out in a collaboration between the following departments at Aarhus University Hospital: the venereal disease clinic at the Department of Dermatology, Department of Infectious Diseases and Department of Clinical Immunology. There was no external funding or other financial involvement. We wish to thank the management of all three departments for allocating time and resources to make this study possible.
Declaration of interest: Carsten Schade Larsen has received standard fees for lectures from GlaxoSmith-Kline, SBL-Crucell Vaccines and Sanofi Pasteur MSD. The authors alone are responsible for the content and writing of the paper. References [1] Danish Medicines Agency. Summary of product characteristics for Engerix-B. 2012. [2] World Health Organization. WHO-UNICEF estimates of HepB3 coverage. Available at: http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tswucoveragehepb3.html. 2013. [3] van Houdt R, Koedijk FD, Bruisten SM, Coul EL, Heijnen ML, Waldhober Q, et al. Hepatitis B vaccination targeted at behavioural risk groups in the Netherlands: does it work? Vaccine 2009;27:3530–5. [4] Sundhedsstyrelsen. Vejledning om HIV (human immundefekt virus), hepatitis B og C virus. 2013. [5] Petersen CS, Seier KS, Kroon S. Hepatitis B blandt et venerologisk klientel i København. Ugeskrift for Laeger 1984;146:1273–76. [6] Das S, Brassington M, Drake SM, Boxall E. Response to hepatitis-B vaccination in healthy homosexual individuals: retrospective case control study. Vaccine 2003; 21:3701–5. [7] Mitka M. FDA: Increased HBV reactivation risk with ofatumumab or rituximab. JAMA 2013;310:1664. [8] Mereckiene J, Cotter S, Lopalco P, D’Ancona F, Levy-Bruhl D, Giambi C, et al. Hepatitis B immunisation programmes in
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European Union, Norway and Iceland: where we were in 2009? Vaccine 2010;28:4470–7. [9] Mast EE, Weinbaum CM, Fiore AE, Alter MJ, Bell BP, Finelli L, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep 2006;55(RR-16):1–33; quiz CE1–4. [10] Adler MW, French P, McNab A, Smith C, Wellsteed S. The national strategy for sexual health and HIV: implications for genitourinary medicine. Sex Transm Infect 2002;78:83–6.
[11] Gamagedara N, Weerakoon AP, Zou H, Fehler G, Chen MY, Read TR, et al. Cross-sectional study of hepatitis B immunity in MSM between 2002 and 2012. Sex Transm Infect 2014;90:41–5. [12] van Rijckevorsel G, Whelan J, Kretzschmar M, Siedenburg E, Sonder G, Geskus R, et al. Targeted vaccination programme successful in reducing acute hepatitis B in men having sex with men in Amsterdam, the Netherlands. J Hepatol 2013;59:1177–83. [13] Hahne S, van Houdt R, Koedijk F, van Ballegooijen M, Cremer J, Bruisten S, et al. Selective hepatitis B virus vaccination has reduced hepatitis B virus transmission in the Netherlands. PLoS One 2013;8:e67866.
