RESEARCH PAPER Human Vaccines & Immunotherapeutics 11:12, 2806--2810; December 2015; © 2015 Taylor & Francis Group, LLC

Missed opportunities for Hepatitis B vaccination among diabetic patients Lale Ozisik1,*, Mine Durusu Tanriover1, Nursel Calik Basaran1, S Gul Oz1, and Serhat Unal2 1

Department of Internal Medicine; Hacettepe University Faculty of Medicine, Ankara, Turkey; 2Department of Infectious Diseases and Clinical Microbiology; Hacettepe University Faculty of Medicine, Ankara, Turkey

Keywords: diabetes, hepatitis B vaccine, hepatitis B, seroprevalance, vaccination

Many infectious diseases in adults can be prevented by a ‘life-long vaccination strategy’. Hepatitis B disease burden was shown to be higher in diabetic patients. American Advisory Committee on Immunization Practices recommends to vaccinate diabetic patients against hepatitis B since 2011. In this study, we aimed to determine hepatitis B virus serology status to determine the rates of diabetic patients who have indications for hepatitis B vaccination. The electronic database of the hospital was searched to identify adult patients aged above 18 years and with hemoglobin A1C levels of 6.5% or above, who have been seen at General Medicine Outpatient Clinics of a university hospital during a 3-year period. A total of 5187 patients were included in the study. After exclusion of patients with an incomplete serological panel, 1358 patients were included for further analyses. Twenty-nine percent of the patients had indication for hepatitis B vaccination, whereas only 8% were vaccinated. This study showed that nearly one third of patients who had hepatitis B serological data had an indication for hepatitis B vaccination and this is a clear reflection of the need to keep a lifelong vaccination log and inquire vaccination data.

Introduction Although chronic diseases have become the leading public health problem in the 21st century, infectious diseases can still have devastating effects.1 Many infectious diseases in adults can be prevented by a ‘life-long vaccination strategy’ with vaccines designated to certain age groups and comorbid conditions. However, despite efforts to increase the awareness on adult vaccination and to implement solid vaccination strategies through frequently updated guidelines, vaccination rates are still not at the desired levels.2-4 Adults with chronic diseases are prone to certain infections and their complications such as influenza and invasive pneumococcal diseases.5,6 Among the chronic diseases with a high burden of morbidity and mortality, diabetes poses a risk for more severe and fatal course for many infectious diseases.7 Hence, diabetic patients make up a challenging risk group regarding adult vaccination.3 Particularly, hepatitis B infections require attention: hepatitis B prevalence and hepatitis B related hospital admissions were shown to be higher in diabetic patients.8-10 American Advisory Committee on Immunization Practices recommended to vaccinate all diabetic patients aged 19–60 years against hepatitis B as soon as they are diagnosed with diabetes and to vaccinate those above 60 years after risk assessment in the 2011 update11. Standard dose vaccination should be carried out at months 0, 1 and 6. American Diabetes Society has also adopted this recommendation.12

Both type 2 diabetes and hepatitis B have considerably high prevalences in Turkey. The ‘Turkish Diabetes, Hypertension, Obesity and Endocrinological Diseases Prevalence Study-II (TURDEP-II Study)’ revealed that in 2011 the diabetes prevalence has risen to 13.7%.13 Our country is among the moderately endemic regions regarding hepatitis B virus infections. Although there are differences among the regions within the country, the prevalence of hepatitis B superficial antigen positivity is thought to be 4.57% in the general population and approximately 3–3.3 million people are thought to be infected with hepatitis B.14,15 In Turkey, there is neither documented vaccination recommendations specific for diabetic patients nor is hepatitis B vaccine reimbursement for diabetics. Nevertheless, there is a National Immunization Schedule for Adults that was documented in 2009. According to National Immunization Recommendations influenza and pneumococcal vaccines are recommended for all diabetic patients as well as Td vaccine.4 Regarding the recent recommendation of vaccinating all diabetic patients aged 19–60 years against hepatitis B, our literature search did not reveal any study from Turkey to indicate the number of infected diabetic patients and patients who are hepatitis B na€ıve, hence having an indication for hepatitis B vaccination. In this study, we aimed to determine hepatitis B virus serological status of adult diabetic patients seen at the general medical outpatient clinic to determine the rates of diabetic patients who have indications for hepatitis B vaccination.

*Correspondence to: Lale Ozisik; Email: [email protected] Submitted: 05/15/2015; Revised: 06/16/2015; Accepted: 07/03/2015 http://dx.doi.org/10.1080/21645515.2015.1070999

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during January 1st, 2010 and December 31st, 2012 were included. Of those, 3254 patients were excluded since they had no antibodies or antigens studied in the defined time period or test panels were not sufficient to make a comment on the hepatitis B serological status. Additional 575 patients were excluded because HBsAg and AntiHBs were negative, but AntiHBc was not studied. Remaining 1358 patients were divided into groups for further analyses. The mean age of the patients was 64.0 § 0.4 years and 51.3% of them (n D 696) were males. The proportion of patients over 60 years of age was 65.6% (n D 891). HbsAg was positive in 6.7% (n D 90), anti HBs was positive in 57.8% (n D 785) and antiHBc was Figure 1. Hepatitis B immune status and vaccination indication of all the patients in the study group positive in 45.8% (n D 423) of the with regards to HBsAg, AntiHBs and AntiHBc levels. patients. When the antigen and antibody results were evaluated to identify the vaccine indication status of the patients, 28.6% (n D 389) had indication for vaccination (seronegative) Methods (Fig. 1). Nearly 30% were in the group with indeterminate antiThe electronic database of the hospital was searched to iden- body results, the immune group without indication for vaccinatify adult patients aged above 18 years and with hemoglobin tion (Fig. 1). In this group, HbsAg was negative, AntiHBs was A1C (HbA1C) levels of 6.5% or above, who have been seen in positive but it could not be determined whether they had gained the General Medicine Outpatient Clinics of a tertiary care uni- immunity through vaccination or were naturally immune since versity hospital during a 3-year period (January 1st, 2010- antiHBc was not studied. December 31st, 2012). The Hospital Administration approved When the patients were divided as below and above 60 years the use of the data and the study. Patient data were retrospec- of age, 10.5% of patients below 60 years (n D 49) were vaccitively reviewed from the prospectively recorded electronic data nated whereas only 6.8% of patients (n D 61) above 60 years registration system. Patient age, gender, levels of the latest were vaccinated (Fig. 2). Hepatitis B vaccine was indicated for HbA1C, creatinine, hepatitis B surface antigen (HBsAg), hepati- 27.3% (n D 243) of the patients aged 60 years or more, whereas tis B surface antigen antibodies (AntiHBs), total hepatitis B core 31.3% (n D 146) of the patients aged 19–59 years were seronegantigen antibody (AntiHBc total) were recorded. Patients were ative (Fig. 2). classified as those who had an indication for hepatitis B vaccination, those who have encountered the virus (immune or infected), those who have been vaccinated and those who had an Discussion unspecified status with regards to the level of antibodies and antigens (those with no indication for vaccination but the evidence Our country is among moderately endemic countries regardwhether he/she was vaccinated or encountered the virus is ing hepatitis B virus, and approximately 3 million people are lacking). thought to be infected with hepatitis B.14 There are many studies on the prevalence of hepatitis B with variable results depending on age and region. According to the report of hepatitis B consenStatistical analysis Statistical analysis was carried out using the “SPSS (Standard sus meeting of 2007, the mean rate of HBsAg carriers is 4–5% 15 Package for Social Sciences) 21.0 for Windows” commercial soft- among the Turkish population. World Health Organization ware program. Descriptive variables were expressed as mean § reported that the prevalence of HBsAg positivity in blood donors in Turkey was estimated as 1–2% and prevalence in the general standard deviation (SD) or numbers and percentages. population as 3–4%, and a total of 1,834,600 people were estimated to be infected with hepatitis B in 2013.16 These results suggest that hepatitis B prevalence has been decreasing and this Results decrease is more marked outside the endemic regions. However, A total of 5187 patients above 18 years were seen within the in endemic regions as Eastern Anatolia-Southeastern Anatolia 3 year time period with HbA1C levels  6.5 %. First visits and partly Inner Anatolia, hepatitis B is still a problem. The

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Figure 2. Hepatitis B immune status and vaccination indication of the patients (in percentages) aged 19–59 years (n D 467, 34.4%) and 60 years (n D 891, 65.6% ) and above with regard to HBsAg, AntiHBs and AntiHBc levels.

decrease in the general population can be attributed to the decreased prevalence in children and adolescents with the inclusion of hepatitis B vaccine in the pediatric immunization program in 1998.17 However, since these patients still have not reached adult age, the impacts of hepatitis B vaccination are not evident in the adult population yet.18 Additionally, there is no study showing vaccination rates in adults. Hepatitis B prevalence and hepatitis B related hospital admissions were found to be higher in diabetic patients.8,9 The incidence of occult hepatitis B was significantly higher in patients with type 2 diabetes compared with the control group (11% vs 3%, respectively)19. Hepatitis B is a virus that can live for a long time on surfaces.20 Epidemics have been reported in institutions with the transmission of hepatitis B virus through blood glucose measurement devices and commonly used insulin pens.11 Moreover, diabetic patients are known to have a tendency for infections because of abnormalities in their immune system and this tendency might be one of the reasons why they are prone to HBV infections.21 In patients with poor metabolic control, impairment of T cell transformation, decrease in the total number of T cells and specifically decrease in CD4 phenotype can be seen.22 In diabetics, serum immunoglobulin levels are also lower than healthy individuals. Antibody response against hepatitis B antigens is weak in individuals with prolonged type 1diabetes who have undergone hepatitis B vaccination. Impaired humoral and cellular immune response can be partly attributed to

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impairment in recognizing the antigens.22 Consequently, such immune system abnormalities seen in patients with type 2 DM can be effective in the development of hepatitis B. Our study showed that, in a daily encounter of patients, we might have chances for adult vaccination. Our study population was a selected adult patient population in a tertiary care setting and the results were evaluated retrospectively among those who have been ordered serological tests. Hence, it is impossible to extrapolate the results of this study to the entire Turkish population. Still, nearly one third of patients who had hepatitis B serological data in this study had an indication for hepatitis B vaccination and this is a clear reflection of the need to keep a lifelong vaccination log and inquire vaccination data. Moreover, this may be an underestimation given the number of patients excluded because of the lack of serological tests. Our literature search did not reveal any study from Turkey to indicate the proportion of diabetic patients who are hepatitis B na€ıve, hence having an indication for hepatitis B vaccination. In this sense, we believe this study presents important preliminary findings for a country with high prevalence of diabetes and hepatitis B. Surveillance studies carried out prior to updated vaccination recommendations have shown that rate of hepatitis B vaccination was very low in diabetic patients. Regarding data from the United States of America, it is seen that 19.5% of diabetic patients have been administered 1 dose of hepatitis B vaccine, and only 16.6% have completed the recommended 3 doses of

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the vaccination protocol.23 In another study published in Spain, 4.2% of the diabetic patients were vaccinated.24 The reasons for the low hepatitis B vaccination coverage among diabetics in our study maybe physicians’ basic medical knowledge and attitudes; patients’ perceptions and attitudes about vaccination; low health literacy; financial barriers; caveats of the health care system and lack of vaccine coverage data. Lack of basic knowledge and current recommendations about adult vaccination, inconsistent assessment of vaccination status and insufficient time spent on communicating the benefits of hepatitis B vaccine are doctor related barriers to vaccination.25 Recommendations which are not supported through public funding mechanisms may decrease the uptake of the vaccine.26 Health care system related factors such as lack of reminder-recall systems, immunization records, computerized vaccine registries and vaccine delivery systems might be other factors that contribute to low vaccine coverage rates.27 A review evaluating the effectiveness of interventions to improve targeted vaccination coverage for influenza, pneumococcal, and hepatitis B vaccines reported that provider reminder systems were the only strategy identified to be effective when implemented alone.28 Finally, at the national level, lack of vaccination coverage surveillance data and lack of References 1. Lang PO, Govind S, Michel JP, Aspinall R, Mitchell WA. Immunosenescence: Implications for vaccination programmes in adults. Maturitas 2011; 68:322-30; PMID:21316879; http://dx.doi.org/10.1016/j. maturitas.2011.01.011 2. Centers for Disease C, Prevention. Impact of vaccines universally recommended for children-United States, 1990-1998. MMWR 1999; 48:243-8; PMID:10220251 3. Centers for Disease C, Prevention. Recommended adult immunization schedule – United States, 2014. J Midwifery & Women’s Health 2014; 59:205-9; PMID:24618112; http://dx.doi.org/10.1111/ jmwh.12184 4. Eri¸s kin a¸s ılama €onerileri. Turkish Society of Internal Medicine, 2009. 5. Ortqvist A, Hedlund J, Kalin M. Streptococcus pneumoniae: epidemiology, risk factors, and clinical features. Semin Respir Crit Care Med 2005; 26:563-74; PMID:16388428; http://dx.doi.org/10.1055/s-2005925523 6. Nicholson KG, Wood JM, Zambon M. Influenza. Lancet 2003; 362:1733-45; PMID:14643124; http://dx. doi.org/10.1016/S0140-6736(03)14854-4 7. Gupta S, Koirala J, Khardori R, Khardori N. Infections in diabetes mellitus and hyperglycemia. Infect Dis Clin North Am 2007; 21:617-38, vii; PMID:17826615; http://dx.doi.org/10.1016/j.idc.2007.07.003 8. Schillie SF, Xing J, Murphy TV, Hu DJ. Prevalence of hepatitis B virus infection among persons with diagnosed diabetes mellitus in the United States, 19992010. J Viral Hepatit 2012; 19:674-6; PMID:22863272; http://dx.doi.org/10.1111/j.13652893.2012.01616.x 9. Byrd KK HR, Mehal, J, Murphy TV Chronic liver disease-associated hospitalizations among adults with diabetes-United States, 2001-2008. Abstracts of the American Association for the study of liver diseases 62nd annual meeting. November 4–8, 2011. San Francisco, California, USA. Hepatology 2011; 54 Suppl:360A-1513A. 10. Reilly ML, Schillie SF, Smith E, Poissant T, Vonderwahl CW, Gerard K, Baumgartner J, Mercedes L, Sweet K, Muleta D, et al. Increased risk of acute hepatitis B among adults with diagnosed diabetes mellitus. J

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documented vaccination recommendations are obstacles while improving vaccination strategies for a country.27 Current data show that hepatitis B vaccine is moderately cost effective in diabetic patients aged 20–59 years.29 Since the treatment of patients with chronic hepatitis is economically rather costly, it would be suitable to emphasize once more the importance of preventive measures and widespread hepatitis B vaccination regarding both individual healthcare and country’s resources.30 In conclusion, this preliminary study showed that hepatitis B vaccination history and/or seroprevalence data should be checked at every encounter with diabetic patients in daily practice. Although our study population was a selected adult patient population in a tertiary care setting, nearly one third of patients who had hepatitis B serological data had an indication for hepatitis B vaccination and this is a clear reflection of the need to keep a lifelong vaccination log and inquire vaccination data.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Diabetes Sci Technol 2012; 6:858-66; PMID:22920812; http://dx.doi.org/10.1177/ 193229681200600417 Centers for Disease C, Prevention. Use of hepatitis B vaccination for adults with diabetes mellitus: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morbidity and mortality weekly report 2011; 60:1709-11; PMID:22189894 Kirkman MS, Schaffner W. Another shot to protect people with diabetes: add hepatitis B vaccination to the checklist. Diabetes Care 2012; 35:941-2; PMID:22517936; http://dx.doi.org/10.2337/dc120164 Satman I. TURDEP II sonu¸c larının €ozeti. 2011. Toy M, Onder FO, Wormann T, Bozdayi AM, Schalm SW, Borsboom GJ, van Rosmalen J, Richardus JH, Yurdaydin C. Age- and region-specific hepatitis B prevalence in Turkey estimated using generalized linear mixed models: a systematic review. BMC infectious diseases 2011; 11:337; PMID:22151620; http://dx.doi.org/10.1186/14712334-11-337 Akarca US. Chronic hepatitis B. A guideline to diagnosis, approach, management, and follow-up 2007. Turk J Gastroenterol 2008; 19:207-30 Hope VD, Eramova I, Capurro D, Donoghoe MC. Prevalence and estimation of hepatitis B and C infections in the WHO European Region: a review of data focusing on the countries outside the European Union and the European Free Trade Association. Epidemiology and infection 2014; 142:270-86; PMID:23714072; http://dx.doi.org/10.1017/ S0950268813000940 Kanra G, Tezcan S, Badur S, Turkish National Study T. Hepatitis B and measles seroprevalence among Turkish children. The Turkish journal of pediatrics 2005; 47:105-10; PMID:16052847 Tosun S. Viral hepatitlerin u €lkemizdeki degi¸s en epidemiyolojisi. ANKEM Derg 2013; 27:128-34 Demir M, Serin E, Gokturk S, Ozturk NA, Kulaksizoglu S, Ylmaz U. The prevalence of occult hepatitis B virus infection in type 2 diabetes mellitus patients. Eur J Gastroenterol Hepatol 2008; 20:668-73; PMID:18679070; http://dx.doi.org/10.1097/ MEG.0b013e3282f55e1e

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20. Bond WW, Favero MS, Petersen NJ, Gravelle CR, Ebert JW, Maynard JE. Survival of hepatitis B virus after drying and storage for one week. Lancet 1981; 1:550-1; PMID:6111645; http://dx.doi.org/10.1016/ S0140-6736(81)92877-4 21. Marhoffer W, Stein M, Maeser E, Federlin K. Impairment of polymorphonuclear leukocyte function and metabolic control of diabetes. Diabetes Care 1992; 15:256-60; PMID:1547682; http://dx.doi.org/ 10.2337/diacare.15.2.256 22. Pozzilli PSA, Leslie RDG. Infections, immunity and diabetes. In: Pickup JWG, ed. Text book of diabetes: Oxford: Blackwell Science Ltd., 1997:1231-41. 23. Byrd KK, Lu PJ, Murphy TV. Baseline hepatitis B vaccination coverage among persons with diabetes before implementing a U.S. recommendation for vaccination. Vaccine 2012; 30:3376-82; PMID:22472793; http://dx.doi.org/10.1016/j. vaccine.2012.03.055 24. Esparza-Martin N, Hernandez-Betancor A, SuriaGonzalez S, Batista-Garcia F, Braillard-Pocard P, Sanchez-Santana AY, Guerra-Rodriguez R, RamirezPuga A, Checa-Andres MD. Serology for hepatitis B and C, HIV and syphilis in the initial evaluation of diabetes patients referred for an external nephrology consultation. Nefrologia 2013; 33:124-7; PMID:23364635 25. Hurley LP, Bridges CB, Harpaz R, Allison MA, O’Leary ST, Crane LA, Brtnikova M, Stokley S, Beaty BL, Jimenez-Zambrano A, et al. U.S. physicians’ perspective of adult vaccine delivery. Ann Intern Med 2014; 160:161; PMID:24658693; http://dx.doi.org/ 10.7326/M13-2332 26. Yi S, Nonaka D, Nomoto M, Kobayashi J, Mizoue T. Predictors of the uptake of A (H1N1) influenza vaccine: findings from a population-based longitudinal study in Tokyo. PLoS One 2011; 6:e18893; PMID:21556152; http://dx.doi.org/10.1371/journal. pone.0018893 27. Kanitz EE, Wu LA, Giambi C, Strikas RA, Levy-Bruhl D, Stefanoff P, Mereckiene J, Appelgren E, D’Ancona F. Variation in adult vaccination policies across Europe: an overview from VENICE network on vaccine recommendations, funding and coverage. Vaccine 2012; 30:5222-8; PMID:22721901; http://dx.doi.org/ 10.1016/j.vaccine.2012.06.012

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29. Hoerger TJ, Schillie S, Wittenborn JS, Bradley CL, Zhou F, Byrd K, Murphy TV. Cost-effectiveness of hepatitis B vaccination in adults with diagnosed diabetes. Diabetes Care 2013; 36:63-9; PMID:22933435; http://dx.doi.org/10.2337/dc12-0759

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_ 30. Tosun SAM, Isbir B. Hepatit B Virus infeksiyonu ile sava¸s ımda €ulke kaynaklarının ekonomik kullanımı. Viral Hepatit Dergisi 2007; 12:137-41

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Missed opportunities for Hepatitis B vaccination among diabetic patients.

Many infectious diseases in adults can be prevented by a 'life-long vaccination strategy'. Hepatitis B disease burden was shown to be higher in diabet...
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