ORIGINAL ARTICLE
Efficacy of Hepatitis A Vaccination and Factors Impacting on Seroconversion in Patients with Inflammatory Bowel Disease Sang Hyoung Park, MD,* Suk-Kyun Yang, MD,* Soo-Kyung Park, MD,* Jong Wook Kim, MD,* ,† Dong-Hoon Yang, MD,* Kee Wook Jung, MD,* Kyung-Jo Kim, MD,* Byong Duk Ye, MD,* Jeong-Sik Byeon, MD,* Seung-Jae Myung, MD,* and Jin-Ho Kim, MD*
Background: Little is known about the immune response to hepatitis A virus (HAV) vaccinations in patients with inflammatory bowel disease (IBD). We therefore assessed the immunogenicity of HAV vaccine in patients with IBD and evaluated the impact on vaccination efficacy of immunosuppressants, including corticosteroids, thiopurines, and anti–tumor necrosis factor (anti-TNF) agents.
Methods: This open prospective study evaluated the efficacy of HAV vaccination in 419 anti–HAV-negative adult patients with IBD. Patients were vaccinated against HAV at 0 and 6 to 12 months, with seroconversion (anti-HAV immunoglobulin G) measured 1 to 3 months after the second dose.
Results: Of the 419 vaccinated patients who finished the study protocol (mean age, 26.9 yr), 355 (84.7%) had Crohn’s disease and 64 (15.3%) had ulcerative colitis. The overall seroconversion rate was 97.6% (409/419) but was significantly lower in patients treated with the anti-TNF monoclonal antibody infliximab or adalimumab than in those not treated (92.4% [85/92] versus 99.1% [324/327], P ¼ 0.001). In addition, the seroconversion rate was significantly lower in patients treated with $2 than with ,2 immunosuppressants (92.6% [50/54] versus 98.4% [359/365], P ¼ 0.03). When comparing anti-TNF alone with anti-TNF and other immunosuppressants, there was no significant difference in seroconversion rates (odds ratio, 1.2; 95% confidence interval, 0.2–5.6; P ¼ 0.83). The sample/cutoff ratio was significantly lower in patients who did receive anti-TNF therapy than in those who did not (5.5 versus 9.6; P , 0.001).
Conclusions: Although HAV vaccination is generally effective in patients with IBD, the seroconversion rate is lower in patients receiving anti-TNF agents (ClinicalTrials.gov registration number NCT01341808). (Inflamm Bowel Dis 2014;20:69–74) Key Words: hepatitis A virus, inflammatory bowel disease, vaccination, immunosuppression
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mmunosuppressive drugs, including corticosteroids, immunomodulators such as azathioprine, 6-mercaptopurine, and methotrexate, and biologics such as infliximab, adalimumab, certolizumab, and natalizumab, are increasingly used to treat patients with inflammatory bowel disease (IBD). Although effective, these medications predispose patients with IBD to a variety of infections, the outcomes of which may be severe or fatal. Because vaccinations can prevent many of these infections,1 guidelines were developed for vaccinations in patients with IBD.2,3 Little is known, however, about immune responses of these patients to routine vaccinations, and
Received for publication September 12, 2013; Accepted October 22, 2013. From the *Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; and †Division of Gastroenterology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Gyeonggi-do, Korea. Supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A120176). Suk-Kyun Yang has received a research grant from Janssen Korea Ltd. The remaining authors have no conflicts of interest to disclose. Reprints: Suk-Kyun Yang, MD, Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea (e-mail: [email protected]). Copyright © 2013 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/01.MIB.0000437736.91712.a1 Published online 26 November 2013.
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many patients with IBD are still not being vaccinated appropriately.4 Moreover, only a few studies to date have evaluated the impact of immunosuppressive therapies on immune responses in patients with IBD to vaccination against tetanus,5,6 influenza,7,8 hepatitis A,9 and hepatitis B.10 Preliminary estimates by the World Health Organization suggest a global increase in the number of individuals with acute hepatitis A, from 177 million in 1990 to 212 million in 2005.11 Unlike hepatitis B or C, hepatitis A does not cause chronic liver disease, but acute fulminant hepatitis A, while rare, is associated with high mortality rates. The estimated fatality rates of hepatitis A vary with age, ranging from 0.1% in children younger than 15 years to 0.3% in people aged 15 to 39 years, and to 2.1% in adults aged $40 years.12 In addition, immunosuppressed patients and those with chronic liver disease are at increased risk for fulminant hepatitis A. In Korea, the annual incidence of adult hepatitis A has progressively increased over the past several decades due to improving socioeconomic conditions.13,14 Also, we recently reported that the prevalence of chronic hepatitis B virus infection in Korean patients with IBD is high (4.1%).15 Hepatitis A virus (HAV) vaccination is especially essential in patients with risk factors for fulminant hepatitis.16 Similarly, HAV vaccination may be considered for patients with IBD with risk factors.4 www.ibdjournal.org |
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To date, only 2 studies, including 1 letter, have assessed the efficacy of HAV vaccination in pediatric patients with IBD,9,17 with none assessing HAV vaccination in adults. Therefore, the aim of this study was to evaluate the immunogenicity of HAV vaccine in adult patients with IBD. In addition, we evaluated the impact of various factors, mainly treatment with immunosuppressants, on the efficacy of HAV vaccination. Our hypothesis is that immunogenicity of HAV vaccine in adult patients with IBD will be diminished by immunosuppressants.
PATIENTS AND METHODS Patients Consecutive patients with Crohn’s disease (CD) or ulcerative colitis (UC) treated at the IBD center of Asan Medical Center, a tertiary hospital in Seoul, between April 2011 and March 2012 were prospectively enrolled. CD and UC were diagnosed on the basis of conventional clinical, radiological, endoscopic, and histopathologic criteria.18 Patients were included if they were (1) seronegative for immunoglobulin G (IgG) antibodies against hepatitis A antigen (anti-HAV IgG) within 6 months before the first vaccination and (2) at least 16 years old at the time of the first vaccination. The exclusion criteria were (1) age older than 40 years, (2) history of HAV infection, (3) previous vaccination against HAV, (4) any medical condition known to cause immunosuppression, (5) malignancy, and (6) pregnancy. We excluded patients aged older than 40 years because this age group showed a high rate of seropositivity (.90%) for anti-HAV IgG in Korea.13 The study protocol was approved by the Institutional Review Board of the Asan Medical Center. All patients provided written informed consent before enrollment in this study (ClinicalTrials.gov registration number NCT01341808).
Baseline Data Collection Characteristics recorded for each patient at baseline included age, sex, IBD type (CD or UC), and body weight at the time of first vaccination. CD activity index for patients with CD and partial Mayo score for patients with UC were determined at the first vaccination and 1 to 3 months after the second vaccination. Baseline disease activity was stratified as active (CD activity index $ 150 for CD and partial Mayo score . 1 for UC) or remission (CD activity index , 150 for CD and partial Mayo score # 1 for UC). Blood tests performed at the time of vaccination included a complete blood count, serum albumin and C-reactive protein concentrations, and erythrocyte sedimentation rate. In addition, treatment with immunosuppressive agents, including corticosteroids, azathioprine/6-mercaptopurine, infliximab, or adalimumab, before or concomitant with vaccination was assessed. Patients were considered to receive immunosuppressants if they received the daily equivalent of $20 mg prednisolone for $2 weeks and/or the daily equivalent of $0.75 mg/kg azathioprine and/or the induction or maintenance of anti–tumor necrosis factor (anti-TNF) agents within 3 months before the first vaccination.
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Vaccination A virosome-formulated vaccine (Epaxal; Berna Biotech, Berna, Switzerland), composed of formalin-inactivated HAV (strain RG-SB) adsorbed to the surface of special liposomes (virosomes), was used. The vaccine was stored between 28C and 88C and was removed from the refrigerator immediately before use. Vaccination was administered intramuscularly into the left deltoid muscle19 according to the recommended 2-dose schedule, consisting of a primary dose followed by a booster dose 6 to 12 months later. All study patients were instructed to contact the medical staff immediately if they experienced any adverse reactions including a lifethreatening event. The presence of anti-HAV IgG was assessed before the first dose of vaccine and 1 to 3 months after the second dose with a chemiluminescent microparticle immunoassay method (Architect HAVAb-IgG; Abbott, Wiesbaden, Germany). Anti-HAV IgG sample/cutoff (S/CO) ratios ,1 and $1 were defined as negative and positive, respectively. The S/CO ratios 1 to 3 months after the second dose of vaccine were compared between groups.
Statistical Analysis Continuous variables were expressed as medians and ranges and discrete data as numbers and percentages. Fisher’s exact test and the Mann–Whitney test were used to compare categorical and quantitative variables, respectively, in patients with and without seroconversion. A P value ,0.05 was considered statistically significant.
RESULTS Study Demographics During the study period, 493 subjects were enrolled, 412 with CD and 81 with UC. Of these, 74 dropped out, mainly because they did not show up for follow-up or wished to withdraw. The entire study protocol (2 doses of vaccine and 2 serum samples) was completed by 419 subjects: 355 with CD and 64 with UC (Fig. 1). Their baseline characteristics are presented in Table 1. Median body weight at first vaccination was 58 kg (ranges, 36.5–116.4 kg). Thirty patients (7.2%) were on corticosteroids, 193 (46.1%) were on azathioprine or 6-mercaptopurine, and 92 (22.0%) were on infliximab (85 patients) or adalimumab (7 patients) within 3 months before the first vaccination. Of the 419 patients, 162 (38.7%) received no immunosuppressants, 203 (48.4%) were on 1 immunosuppressant, and 54 (12.9%) were on $2 immunosuppressants. Disease activity score (CDAI or partial Mayo score) increased in 173 patients (41.3%) and decreased in 246 (58.7%) between at first vaccination and the follow-up visit after the second vaccination.
Seroconversion Rate and S/CO Ratio Overall, the rate of seroconversion after the second dose of vaccine was 97.6% (409/419). The distribution of the study variables according to seroconversion status is summarized in Table 2. A higher percentage of patients without seroconversion than with were receiving anti-TNF treatment (70.0% versus
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HAV Vaccination in IBD
FIGURE 1. Flowchart of subjects’ progress through the study.
20.8%; P ¼ 0.001) and $2 immunosuppressants (40.0% versus 12.2%; P ¼ 0.03). Use of corticosteroids or azathioprine/ 6-mercaptopurine and the abnormal blood test results, including anemia, leukocytosis, thrombocytopenia, hypoalbuminemia, and elevated C-reactive protein/erythrocyte sedimentation rate, did not differ between patients with and without seroconversion. The 4 patients who did not seroconvert while receiving azathioprine were receiving daily azathioprine doses of 0.85, 1.07, 1.40, and
TABLE 1. Baseline Characteristics of Study Subjects Characteristics Sex Male Female Age at IBD diagnosis, median (range), yr Age at first dose of vaccine, median (range), yr Montreal classification of CD Ileum Colon Ileocolon Disease extent of UC Proctitis Left-sided colitis Extensive colitis Concomitant treatment Corticosteroids Azathioprine/6mercaptopurine Infliximab/adalimumab
CD (n ¼ 355)
UC (n ¼ 64)
255 (71.8%) 100 (28.2%) 20 (9–37)
44 (68.8%) 20 (31.2%) 21 (11–39)
27 (16–38)
27 (17–39)
47 (13.2%) 15 (4.2%) 293 (82.5%) 23 (35.9%) 21 (32.8%) 20 (31.3%) 26 (7.3%) 179 (50.4%)
4 (6.3%) 14 (21.9%)
85 (23.9%)
7 (10.9%)
1.92 mg/kg, respectively. Seroconversion rates were not associated with azathioprine dose, being 97.5% (117/120) in patients receiving 0.75 to 1.5 mg/kg/d azathioprine, 97.6% (41/42) in those receiving 1.5 to 2 mg/kg/d, and 100% (31/31) in patients receiving $2 mg/kg/d (P ¼ 1.0). Rates of seroconversion were similar in patients who were and were not receiving immunosuppressants (96.5% [248/257] versus 99.4% [161/162], P ¼ 0.1). However, seroconversion rates were significantly lower in patients who were receiving anti-TNF therapy than in those who were not (92.4% [85/92] versus 99.1% [324/327], P ¼ 0.001), and in patients receiving $2 than ,2 immunosuppressants (92.6% [50/54] versus 98.4% [359/365], P ¼ 0.03). When comparing anti-TNF alone with anti-TNF and other immunosuppressants using a binary logistic regression model, there was no significant difference in seroconversion rates (odds ratio, 1.2; 95% confidence interval, 0.2–5.6; P ¼ 0.83). The mean S/CO ratio was significantly lower in patients who were receiving anti-TNF therapy than in those who were not (5.5 versus 9.6, P , 0.001) (Fig. 2).
DISCUSSION This prospective study of patients with IBD vaccinated for HAV showed that the vaccine was highly immunogenic in this population. The seroconversion rate (97.6%) was comparable with those observed in a healthy population20–23 and in pediatric patients with IBD.9 However, the response rate tended to be slightly lower in patients with IBD who were on immunosuppressive therapies (96.5%) than in those who were not (99.4%), with this rate being significantly lower in patients who were receiving anti-TNF therapy (92.4%) than in those who were not (99.1%). To our knowledge, this study was the first to evaluate the effectiveness of HAV vaccine in adult patients with IBD, and, with the exception of a letter17 reporting the effectiveness of HAV vaccine in 12 pediatric patients with IBD on anti-TNF therapy, the only study to assess the impact of anti-TNF therapy on the immune response to HAV vaccination in patients with any disorder in which anti-TNF agents are used. In the absence of immunosuppressants, an adequate response to vaccination is anticipated in patients with IBD.2 Following vaccination for hepatitis B virus (HBV), patients with IBD being treated with immunosuppressants showed lower peak concentrations of antibodies to hepatitis B surface antigen (anti-HBs) than immunocompetent individuals.10,24 In addition, the effectiveness of the HBV vaccine was affected by the type and number of immunosuppressants.25,26 Similarly, serologic responses to influenza and pneumococcal vaccines are reduced in patients receiving immunosuppressants.7,8,27 However, seroprotection against some influenza strains was similar in nonimmunosuppressed and immunosuppressed patients with IBD.8 Therefore, the effect of immunosuppression on the effectiveness of vaccines may vary by type of vaccine. Only 2 previous studies have assessed the effectiveness of the HAV vaccine in pediatric patients with IBD. One study, involving 66 patients with IBD vaccinated at 0 and 6 to 12 months, www.ibdjournal.org |
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TABLE 2. Univariate Analysis of Factors Associated With Seroconversion to HAV Vaccine
Leukocytosisb Anemiac Thrombocytosisd Hypoalbuminemiae Elevated ESRf Elevated CRPg IBD type (CD/UC), % Active disease at baselineh Corticosteroids (CS) Azathioprine/6-mercaptopurine (AZA) Infliximab/adalimumab (anti-TNF) Any immunosuppressive therapy Combined immunosuppressive therapy CS + AZA + anti-TNF CS + AZA CS + anti-TNF AZA + anti-TNF
Patients Without Seroconversion (n ¼ 10)
Patients With Seroconversion (n ¼ 409)
Pa
0 (0.0%) 2 (20.0%) 3 (30.0%) 0 (0.0%) 6 (60.0%) 3 (30.0%) 90/10 1 (10.0%) 2 (20.0%) 4 (40.0%) 7 (70.0%) 9 (90.0%) 4 (40.0%) 0 (0.0%) 1 (10.0%) 1 (10.0%) 2 (20.0%)
22 (5.4%) 125 (30.6%) 62 (15.2%) 30 (7.3%) 266 (65.0%) 148 (36.2%) 85/15 94 (23.0%) 28 (6.8%) 189 (46.2%) 85 (20.8%) 248 (60.6%) 50 (12.2%) 4 (1.0%) 17 (4.2%) 4 (1.0%) 25 (6.1%)
1.00 0.73 0.19 1.00 0.75 1.00 1.00 0.47 0.16 0.76 0.001 0.10 0.03 1.00 0.36 0.11 0.13
a
Determined using the Fisher’s exact test. Defined as white blood cell count .10,000/mm3. c Defined as hemoglobin ,13 g/dL in male, ,12 g/dL in female. d Defined as platelet count .350,000/mm3. e Defined as albumin ,3.4 g/dL. f Defined as ESR .9 mm/h in male, .20 mm/h in female. g Defined as CRP $0.6 mg/dL. h Defined as CD activity index $150 for CD and partial Mayo score .1 for UC. CRP, C-reactive proterin; ESR, erythrocyte sedimentation rate. b
found that steroid monotherapy significantly reduced seroconversion at 4 weeks after the second dose.9 None of those patients, however, were being treated with any anti-TNF agents such as infliximab or adalimumab. Although the second study reported
FIGURE 2. S/CO ratio in relation to treatment with anti-TNF agents.
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that 11 of 12 pediatric patients (92%) seroconverted while receiving infliximab for IBD, few patients were assessed and these patients were not compared with those not receiving anti-TNF agents.17 Because these studies included only pediatric patients and the seroconversion rate after vaccination may vary according to age,28,29 a study investigating the efficacy of the HAV vaccine in adult patients with IBD was needed. In our study, which included 92 patients treated and 327 not treated with anti-TNF agents, the seroconversion rate after vaccination was significantly lower in the former. Although the seroconversion rate was also lower in patients receiving $2 than ,2 immunosuppressive agents, multivariate analysis showed that the only factor significantly associated with nonresponse (no seroconversion) was antiTNF therapy. As patients with IBD are likely in need of anti-TNF agents during the course of their disease, the best time to immunize these patients may be at the IBD diagnosis.4 Our study provides further support for the theory that response to vaccination in patients with IBD is diminished by immunosuppressants rather than by the disease itself.9 IBD itself, however, may be partially responsible for the low rate of response to HBV vaccine because only 63% of naive patients who were not receiving immunosuppressants or biologic treatment showed responses.10 We found that abnormal results on blood tests,
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including complete blood counts, erythrocyte sedimentation rate, and albumin and C-reactive protein concentrations, had no effect on response to HAV vaccine, whereas anti-TNF therapy decreased the rate of seroconversion. In patients being treated with azathioprine, we defined immunosuppression as treatment with $0.75 mg/kg/d (usually 50 mg/d) of this agent, lower than the recommended therapeutic dose (2.0 to 3.0 mg/kg/d) in Western countries.30 Many Asian patients, however, cannot tolerate this dose, with higher percentages of Asian than of Caucasian patients experiencing leukopenia at lower doses.31–33 Doses of 50 mg/d were found to be effective and safe for maintenance of remission in Japanese patients with IBD.31 All 4 of our patients not experiencing seroconversion while receiving azathioprine were on ,2 mg/kg/d of this agent. Testing for the presence of anti-HBs antibodies 1 to 3 months after administration of the last dose of vaccine has been recommended in high-risk and immunocompromised patients, including those with IBD, vaccinated for HBV, because their subsequent clinical management depends on knowledge of their immune status.34 However, as shown here, post-vaccination testing for anti-HAV IgG is generally unnecessary because the seroconversion rate in the entire cohort was very high. This study has several limitations. First, we did not compare seroconversion rates in healthy controls and patients with IBD because the former were not included. However, this comparison may be unnecessary because the seroconversion rate in patients with IBD was very high. Second, since we used a semiquantitative test to analyze immune responses to the HAV vaccine, we could not quantitatively compare antibody titers between groups of patients. Third, we did not measure anti-HAV IgG between the 2 doses of vaccine; thus, we did not determine the seroconversion rate after the first dose. Fourth, although we observed a high seroconversion rate, we could not determine whether the persistence of vaccine-induced immunity would be affected by the disease itself and/or by immunosuppressive treatments. In conclusion, we found that the seroconversion rate after HAV vaccination was very high in adult patients with IBD, although this rate was lower in patients receiving anti-TNF agents. Therefore, the best time to vaccinate these patients for HAV may be at the diagnosis of IBD. Additional controlled studies are needed to assess the long-term response and effectiveness of the HAV vaccine in adult patients with IBD.
REFERENCES 1. Viget N, Vernier-Massouille G, Salmon-Ceron D, et al. Opportunistic infections in patients with inflammatory bowel disease: prevention and diagnosis. Gut. 2008;57:549–558. 2. Sands BE, Cuffari C, Katz J, et al. Guidelines for immunizations in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2004;10: 677–692. 3. Rahier JF, Ben-Horin S, Chowers Y, et al. European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2009;3:47–91. 4. Wasan SK, Baker SE, Skolnik PR, et al. A practical guide to vaccinating the inflammatory bowel disease patient. Am J Gastroenterol. 2010;105: 1231–1238.
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5. Stevens R, Oliver M, Brogan M, et al. Defective generation of tetanusspecific antibody-producing B cells after in vivo immunization of Crohn’s disease and ulcerative colitis patients. Gastroenterology. 1985;88:1860–1866. 6. Brogan MD, Shanahan F, Oliver M, et al. Defective memory B cell formation in patients with inflammatory bowel disease following tetanus toxoid booster immunization. J Clin Lab Immunol. 1987;24:69–74. 7. Mamula P, Markowitz JE, Piccoli DA, et al. Immune response to influenza vaccine in pediatric patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5:851–856. 8. Lu Y, Jacobson DL, Ashworth LA, et al. Immune response to influenza vaccine in children with inflammatory bowel disease. Am J Gastroenterol. 2009;104:444–453. 9. Radzikowski A, Banaszkiewicz A, Lazowska-Przeorek I, et al. Immunogenecity of hepatitis A vaccine in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2011;17:1117–1124. 10. Gisbert JP, Villagrasa JR, Rodriguez-Nogueiras A, et al. Efficacy of hepatitis B vaccination and revaccination and factors impacting on response in patients with inflammatory bowel disease. Am J Gastroenterol. 2012; 107:1460–1466. 11. WHO. Evidence Based Recommendations for Use of Hepatitis A Vaccines in Immunization Services: Background Paper for SAGE Discussions, WHO Strategic Advisory Group of Experts on Immunization, 2011. Geneva, Switzerland: World Health Organization; 2011. Available at: http://www.who.int/immunization/sage/previous_november2011/en/. Accessed March 4, 2013. 12. Hollinger FB, Ticehurst JR. Hepatitis A virus. In: Fields Virology. 3rd ed. Philadelphia, PA: Lippincott-Raven; 1996: 735–782. 13. Jung YK, Kim JH. Epidemiology and clinical features of acute hepatitis A: from the domestic perspective [in Korean]. Korean J Hepatol. 2009; 15:438–445. 14. Kim YJ, Lee HS. Increasing incidence of hepatitis A in Korean adults. Intervirology. 2010;53:10–14. 15. Park SH, Yang SK, Lim YS, et al. Clinical courses of chronic hepatitis B virus infection and inflammatory bowel disease in patients with both diseases. Inflamm Bowel Dis. 2012;18:2004–2010. 16. CDC. Recommended vaccinations indicated for adults based on medical and other indications. Available at: http://www.cdc.gov/vaccines/schedules/ hcp/imz/adult-conditions.html. Accessed September 10, 2013. 17. Moses J, Alkhouri N, Shannon A, et al. Response to hepatitis A vaccine in children with inflammatory bowel disease receiving infliximab. Inflamm Bowel Dis. 2011;17:E160. 18. Lennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol Suppl. 1989;170:2–6; discussion 16–19. 19. Bovier PA. Epaxal: a virosomal vaccine to prevent hepatitis A infection. Expert Rev Vaccines. 2008;7:1141–1150. 20. Ambrosch F, Wiedermann G, Jonas S, et al. Immunogenicity and protectivity of a new liposomal hepatitis A vaccine. Vaccine. 1997;15:1209–1213. 21. Bovier PA, Althaus B, Glueck R, et al. Tolerance and immunogenicity of the simultaneous administration of virosome hepatitis A and yellow fever vaccines. J Travel Med. 1999;6:228–233. 22. Bovier PA, Farinelli T, Loutan L. Interchangeability and tolerability of a virosomal and an aluminum-adsorbed hepatitis A vaccine. Vaccine. 2005;23:2424–2429. 23. Loutan L, Bovier P, Althaus B, et al. Inactivated virosome hepatitis A vaccine. Lancet. 1994;343:322–324. 24. Altunoz ME, Senates E, Yesil A, et al. Patients with inflammatory bowel disease have a lower response rate to HBV vaccination compared to controls. Dig Dis Sci. 2012;57:1039–1044. 25. Wagner D, Wagenbreth I, Stachan-Kunstyr R, et al. Failure of vaccination against hepatitis B with Gen H-B-Vax-D in immunosuppressed heart transplant recipients. Clin Investig. 1992;70:585–587. 26. Worns MA, Teufel A, Kanzler S, et al. Incidence of HAV and HBV infections and vaccination rates in patients with autoimmune liver diseases. Am J Gastroenterol. 2008;103:138–146. 27. Melmed GY, Agarwal N, Frenck RW, et al. Immunosuppression impairs response to pneumococcal polysaccharide vaccination in patients with inflammatory bowel disease. Am J Gastroenterol. 2010;105:148–154. 28. Ramsay ME, Farrington CP, Miller E. Age-specific efficacy of pertussis vaccine during epidemic and non-epidemic periods. Epidemiol Infect. 1993;111:41–48. www.ibdjournal.org |
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29. Westerink MA, Schroeder HW Jr, Nahm MH. Immune responses to pneumococcal vaccines in children and adults: rationale for age-specific vaccination. Aging Dis. 2012;3:51–67. 30. Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130:940–987. 31. Hibi T, Naganuma M, Kitahora T, et al. Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis. J Gastroenterol. 2003;38:740–746.
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32. Andoh A, Tsujikawa T, Ban H, et al. Monitoring 6-thioguanine nucleotide concentrations in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol. 2008;23:1373–1377. 33. Lee HJ, Yang SK, Kim KJ, et al. The safety and efficacy of azathioprine and 6-mercaptopurine in the treatment of Korean patients with Crohn’s disease. Intest Res. 2009;7:22–31. 34. Hepatitis B vaccines: WHO position paper. Wkly Epidemiol Rec. 2009;84: 405–420. Available at: http://www.who.int/wer/2009/wer8440/en/index. html. Accessed September 10, 2013.
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Efficacy of Hepatitis A Vaccination and Factors Impacting on Seroconversion in Patients with Inflammatory Bowel Disease Sang Hyoung Park, MD,* Suk-Kyun Yang, MD,* Soo-Kyung Park, MD,* Jong Wook Kim, MD,* ,† Dong-Hoon Yang, MD,* Kee Wook Jung, MD,* Kyung-Jo Kim, MD,* Byong Duk Ye, MD,* Jeong-Sik Byeon, MD,* Seung-Jae Myung, MD,* and Jin-Ho Kim, MD*
Background: Little is known about the immune response to hepatitis A virus (HAV) vaccinations in patients with inflammatory bowel disease (IBD). We therefore assessed the immunogenicity of HAV vaccine in patients with IBD and evaluated the impact on vaccination efficacy of immunosuppressants, including corticosteroids, thiopurines, and anti–tumor necrosis factor (anti-TNF) agents.
Methods: This open prospective study evaluated the efficacy of HAV vaccination in 419 anti–HAV-negative adult patients with IBD. Patients were vaccinated against HAV at 0 and 6 to 12 months, with seroconversion (anti-HAV immunoglobulin G) measured 1 to 3 months after the second dose.
Results: Of the 419 vaccinated patients who finished the study protocol (mean age, 26.9 yr), 355 (84.7%) had Crohn’s disease and 64 (15.3%) had ulcerative colitis. The overall seroconversion rate was 97.6% (409/419) but was significantly lower in patients treated with the anti-TNF monoclonal antibody infliximab or adalimumab than in those not treated (92.4% [85/92] versus 99.1% [324/327], P ¼ 0.001). In addition, the seroconversion rate was significantly lower in patients treated with $2 than with ,2 immunosuppressants (92.6% [50/54] versus 98.4% [359/365], P ¼ 0.03). When comparing anti-TNF alone with anti-TNF and other immunosuppressants, there was no significant difference in seroconversion rates (odds ratio, 1.2; 95% confidence interval, 0.2–5.6; P ¼ 0.83). The sample/cutoff ratio was significantly lower in patients who did receive anti-TNF therapy than in those who did not (5.5 versus 9.6; P , 0.001).
Conclusions: Although HAV vaccination is generally effective in patients with IBD, the seroconversion rate is lower in patients receiving anti-TNF agents (ClinicalTrials.gov registration number NCT01341808). (Inflamm Bowel Dis 2014;20:69–74) Key Words: hepatitis A virus, inflammatory bowel disease, vaccination, immunosuppression
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mmunosuppressive drugs, including corticosteroids, immunomodulators such as azathioprine, 6-mercaptopurine, and methotrexate, and biologics such as infliximab, adalimumab, certolizumab, and natalizumab, are increasingly used to treat patients with inflammatory bowel disease (IBD). Although effective, these medications predispose patients with IBD to a variety of infections, the outcomes of which may be severe or fatal. Because vaccinations can prevent many of these infections,1 guidelines were developed for vaccinations in patients with IBD.2,3 Little is known, however, about immune responses of these patients to routine vaccinations, and
Received for publication September 12, 2013; Accepted October 22, 2013. From the *Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; and †Division of Gastroenterology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Gyeonggi-do, Korea. Supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A120176). Suk-Kyun Yang has received a research grant from Janssen Korea Ltd. The remaining authors have no conflicts of interest to disclose. Reprints: Suk-Kyun Yang, MD, Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea (e-mail: [email protected]). Copyright © 2013 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/01.MIB.0000437736.91712.a1 Published online 26 November 2013.
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many patients with IBD are still not being vaccinated appropriately.4 Moreover, only a few studies to date have evaluated the impact of immunosuppressive therapies on immune responses in patients with IBD to vaccination against tetanus,5,6 influenza,7,8 hepatitis A,9 and hepatitis B.10 Preliminary estimates by the World Health Organization suggest a global increase in the number of individuals with acute hepatitis A, from 177 million in 1990 to 212 million in 2005.11 Unlike hepatitis B or C, hepatitis A does not cause chronic liver disease, but acute fulminant hepatitis A, while rare, is associated with high mortality rates. The estimated fatality rates of hepatitis A vary with age, ranging from 0.1% in children younger than 15 years to 0.3% in people aged 15 to 39 years, and to 2.1% in adults aged $40 years.12 In addition, immunosuppressed patients and those with chronic liver disease are at increased risk for fulminant hepatitis A. In Korea, the annual incidence of adult hepatitis A has progressively increased over the past several decades due to improving socioeconomic conditions.13,14 Also, we recently reported that the prevalence of chronic hepatitis B virus infection in Korean patients with IBD is high (4.1%).15 Hepatitis A virus (HAV) vaccination is especially essential in patients with risk factors for fulminant hepatitis.16 Similarly, HAV vaccination may be considered for patients with IBD with risk factors.4 www.ibdjournal.org |
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To date, only 2 studies, including 1 letter, have assessed the efficacy of HAV vaccination in pediatric patients with IBD,9,17 with none assessing HAV vaccination in adults. Therefore, the aim of this study was to evaluate the immunogenicity of HAV vaccine in adult patients with IBD. In addition, we evaluated the impact of various factors, mainly treatment with immunosuppressants, on the efficacy of HAV vaccination. Our hypothesis is that immunogenicity of HAV vaccine in adult patients with IBD will be diminished by immunosuppressants.
PATIENTS AND METHODS Patients Consecutive patients with Crohn’s disease (CD) or ulcerative colitis (UC) treated at the IBD center of Asan Medical Center, a tertiary hospital in Seoul, between April 2011 and March 2012 were prospectively enrolled. CD and UC were diagnosed on the basis of conventional clinical, radiological, endoscopic, and histopathologic criteria.18 Patients were included if they were (1) seronegative for immunoglobulin G (IgG) antibodies against hepatitis A antigen (anti-HAV IgG) within 6 months before the first vaccination and (2) at least 16 years old at the time of the first vaccination. The exclusion criteria were (1) age older than 40 years, (2) history of HAV infection, (3) previous vaccination against HAV, (4) any medical condition known to cause immunosuppression, (5) malignancy, and (6) pregnancy. We excluded patients aged older than 40 years because this age group showed a high rate of seropositivity (.90%) for anti-HAV IgG in Korea.13 The study protocol was approved by the Institutional Review Board of the Asan Medical Center. All patients provided written informed consent before enrollment in this study (ClinicalTrials.gov registration number NCT01341808).
Baseline Data Collection Characteristics recorded for each patient at baseline included age, sex, IBD type (CD or UC), and body weight at the time of first vaccination. CD activity index for patients with CD and partial Mayo score for patients with UC were determined at the first vaccination and 1 to 3 months after the second vaccination. Baseline disease activity was stratified as active (CD activity index $ 150 for CD and partial Mayo score . 1 for UC) or remission (CD activity index , 150 for CD and partial Mayo score # 1 for UC). Blood tests performed at the time of vaccination included a complete blood count, serum albumin and C-reactive protein concentrations, and erythrocyte sedimentation rate. In addition, treatment with immunosuppressive agents, including corticosteroids, azathioprine/6-mercaptopurine, infliximab, or adalimumab, before or concomitant with vaccination was assessed. Patients were considered to receive immunosuppressants if they received the daily equivalent of $20 mg prednisolone for $2 weeks and/or the daily equivalent of $0.75 mg/kg azathioprine and/or the induction or maintenance of anti–tumor necrosis factor (anti-TNF) agents within 3 months before the first vaccination.
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Vaccination A virosome-formulated vaccine (Epaxal; Berna Biotech, Berna, Switzerland), composed of formalin-inactivated HAV (strain RG-SB) adsorbed to the surface of special liposomes (virosomes), was used. The vaccine was stored between 28C and 88C and was removed from the refrigerator immediately before use. Vaccination was administered intramuscularly into the left deltoid muscle19 according to the recommended 2-dose schedule, consisting of a primary dose followed by a booster dose 6 to 12 months later. All study patients were instructed to contact the medical staff immediately if they experienced any adverse reactions including a lifethreatening event. The presence of anti-HAV IgG was assessed before the first dose of vaccine and 1 to 3 months after the second dose with a chemiluminescent microparticle immunoassay method (Architect HAVAb-IgG; Abbott, Wiesbaden, Germany). Anti-HAV IgG sample/cutoff (S/CO) ratios ,1 and $1 were defined as negative and positive, respectively. The S/CO ratios 1 to 3 months after the second dose of vaccine were compared between groups.
Statistical Analysis Continuous variables were expressed as medians and ranges and discrete data as numbers and percentages. Fisher’s exact test and the Mann–Whitney test were used to compare categorical and quantitative variables, respectively, in patients with and without seroconversion. A P value ,0.05 was considered statistically significant.
RESULTS Study Demographics During the study period, 493 subjects were enrolled, 412 with CD and 81 with UC. Of these, 74 dropped out, mainly because they did not show up for follow-up or wished to withdraw. The entire study protocol (2 doses of vaccine and 2 serum samples) was completed by 419 subjects: 355 with CD and 64 with UC (Fig. 1). Their baseline characteristics are presented in Table 1. Median body weight at first vaccination was 58 kg (ranges, 36.5–116.4 kg). Thirty patients (7.2%) were on corticosteroids, 193 (46.1%) were on azathioprine or 6-mercaptopurine, and 92 (22.0%) were on infliximab (85 patients) or adalimumab (7 patients) within 3 months before the first vaccination. Of the 419 patients, 162 (38.7%) received no immunosuppressants, 203 (48.4%) were on 1 immunosuppressant, and 54 (12.9%) were on $2 immunosuppressants. Disease activity score (CDAI or partial Mayo score) increased in 173 patients (41.3%) and decreased in 246 (58.7%) between at first vaccination and the follow-up visit after the second vaccination.
Seroconversion Rate and S/CO Ratio Overall, the rate of seroconversion after the second dose of vaccine was 97.6% (409/419). The distribution of the study variables according to seroconversion status is summarized in Table 2. A higher percentage of patients without seroconversion than with were receiving anti-TNF treatment (70.0% versus
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FIGURE 1. Flowchart of subjects’ progress through the study.
20.8%; P ¼ 0.001) and $2 immunosuppressants (40.0% versus 12.2%; P ¼ 0.03). Use of corticosteroids or azathioprine/ 6-mercaptopurine and the abnormal blood test results, including anemia, leukocytosis, thrombocytopenia, hypoalbuminemia, and elevated C-reactive protein/erythrocyte sedimentation rate, did not differ between patients with and without seroconversion. The 4 patients who did not seroconvert while receiving azathioprine were receiving daily azathioprine doses of 0.85, 1.07, 1.40, and
TABLE 1. Baseline Characteristics of Study Subjects Characteristics Sex Male Female Age at IBD diagnosis, median (range), yr Age at first dose of vaccine, median (range), yr Montreal classification of CD Ileum Colon Ileocolon Disease extent of UC Proctitis Left-sided colitis Extensive colitis Concomitant treatment Corticosteroids Azathioprine/6mercaptopurine Infliximab/adalimumab
CD (n ¼ 355)
UC (n ¼ 64)
255 (71.8%) 100 (28.2%) 20 (9–37)
44 (68.8%) 20 (31.2%) 21 (11–39)
27 (16–38)
27 (17–39)
47 (13.2%) 15 (4.2%) 293 (82.5%) 23 (35.9%) 21 (32.8%) 20 (31.3%) 26 (7.3%) 179 (50.4%)
4 (6.3%) 14 (21.9%)
85 (23.9%)
7 (10.9%)
1.92 mg/kg, respectively. Seroconversion rates were not associated with azathioprine dose, being 97.5% (117/120) in patients receiving 0.75 to 1.5 mg/kg/d azathioprine, 97.6% (41/42) in those receiving 1.5 to 2 mg/kg/d, and 100% (31/31) in patients receiving $2 mg/kg/d (P ¼ 1.0). Rates of seroconversion were similar in patients who were and were not receiving immunosuppressants (96.5% [248/257] versus 99.4% [161/162], P ¼ 0.1). However, seroconversion rates were significantly lower in patients who were receiving anti-TNF therapy than in those who were not (92.4% [85/92] versus 99.1% [324/327], P ¼ 0.001), and in patients receiving $2 than ,2 immunosuppressants (92.6% [50/54] versus 98.4% [359/365], P ¼ 0.03). When comparing anti-TNF alone with anti-TNF and other immunosuppressants using a binary logistic regression model, there was no significant difference in seroconversion rates (odds ratio, 1.2; 95% confidence interval, 0.2–5.6; P ¼ 0.83). The mean S/CO ratio was significantly lower in patients who were receiving anti-TNF therapy than in those who were not (5.5 versus 9.6, P , 0.001) (Fig. 2).
DISCUSSION This prospective study of patients with IBD vaccinated for HAV showed that the vaccine was highly immunogenic in this population. The seroconversion rate (97.6%) was comparable with those observed in a healthy population20–23 and in pediatric patients with IBD.9 However, the response rate tended to be slightly lower in patients with IBD who were on immunosuppressive therapies (96.5%) than in those who were not (99.4%), with this rate being significantly lower in patients who were receiving anti-TNF therapy (92.4%) than in those who were not (99.1%). To our knowledge, this study was the first to evaluate the effectiveness of HAV vaccine in adult patients with IBD, and, with the exception of a letter17 reporting the effectiveness of HAV vaccine in 12 pediatric patients with IBD on anti-TNF therapy, the only study to assess the impact of anti-TNF therapy on the immune response to HAV vaccination in patients with any disorder in which anti-TNF agents are used. In the absence of immunosuppressants, an adequate response to vaccination is anticipated in patients with IBD.2 Following vaccination for hepatitis B virus (HBV), patients with IBD being treated with immunosuppressants showed lower peak concentrations of antibodies to hepatitis B surface antigen (anti-HBs) than immunocompetent individuals.10,24 In addition, the effectiveness of the HBV vaccine was affected by the type and number of immunosuppressants.25,26 Similarly, serologic responses to influenza and pneumococcal vaccines are reduced in patients receiving immunosuppressants.7,8,27 However, seroprotection against some influenza strains was similar in nonimmunosuppressed and immunosuppressed patients with IBD.8 Therefore, the effect of immunosuppression on the effectiveness of vaccines may vary by type of vaccine. Only 2 previous studies have assessed the effectiveness of the HAV vaccine in pediatric patients with IBD. One study, involving 66 patients with IBD vaccinated at 0 and 6 to 12 months, www.ibdjournal.org |
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TABLE 2. Univariate Analysis of Factors Associated With Seroconversion to HAV Vaccine
Leukocytosisb Anemiac Thrombocytosisd Hypoalbuminemiae Elevated ESRf Elevated CRPg IBD type (CD/UC), % Active disease at baselineh Corticosteroids (CS) Azathioprine/6-mercaptopurine (AZA) Infliximab/adalimumab (anti-TNF) Any immunosuppressive therapy Combined immunosuppressive therapy CS + AZA + anti-TNF CS + AZA CS + anti-TNF AZA + anti-TNF
Patients Without Seroconversion (n ¼ 10)
Patients With Seroconversion (n ¼ 409)
Pa
0 (0.0%) 2 (20.0%) 3 (30.0%) 0 (0.0%) 6 (60.0%) 3 (30.0%) 90/10 1 (10.0%) 2 (20.0%) 4 (40.0%) 7 (70.0%) 9 (90.0%) 4 (40.0%) 0 (0.0%) 1 (10.0%) 1 (10.0%) 2 (20.0%)
22 (5.4%) 125 (30.6%) 62 (15.2%) 30 (7.3%) 266 (65.0%) 148 (36.2%) 85/15 94 (23.0%) 28 (6.8%) 189 (46.2%) 85 (20.8%) 248 (60.6%) 50 (12.2%) 4 (1.0%) 17 (4.2%) 4 (1.0%) 25 (6.1%)
1.00 0.73 0.19 1.00 0.75 1.00 1.00 0.47 0.16 0.76 0.001 0.10 0.03 1.00 0.36 0.11 0.13
a
Determined using the Fisher’s exact test. Defined as white blood cell count .10,000/mm3. c Defined as hemoglobin ,13 g/dL in male, ,12 g/dL in female. d Defined as platelet count .350,000/mm3. e Defined as albumin ,3.4 g/dL. f Defined as ESR .9 mm/h in male, .20 mm/h in female. g Defined as CRP $0.6 mg/dL. h Defined as CD activity index $150 for CD and partial Mayo score .1 for UC. CRP, C-reactive proterin; ESR, erythrocyte sedimentation rate. b
found that steroid monotherapy significantly reduced seroconversion at 4 weeks after the second dose.9 None of those patients, however, were being treated with any anti-TNF agents such as infliximab or adalimumab. Although the second study reported
FIGURE 2. S/CO ratio in relation to treatment with anti-TNF agents.
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that 11 of 12 pediatric patients (92%) seroconverted while receiving infliximab for IBD, few patients were assessed and these patients were not compared with those not receiving anti-TNF agents.17 Because these studies included only pediatric patients and the seroconversion rate after vaccination may vary according to age,28,29 a study investigating the efficacy of the HAV vaccine in adult patients with IBD was needed. In our study, which included 92 patients treated and 327 not treated with anti-TNF agents, the seroconversion rate after vaccination was significantly lower in the former. Although the seroconversion rate was also lower in patients receiving $2 than ,2 immunosuppressive agents, multivariate analysis showed that the only factor significantly associated with nonresponse (no seroconversion) was antiTNF therapy. As patients with IBD are likely in need of anti-TNF agents during the course of their disease, the best time to immunize these patients may be at the IBD diagnosis.4 Our study provides further support for the theory that response to vaccination in patients with IBD is diminished by immunosuppressants rather than by the disease itself.9 IBD itself, however, may be partially responsible for the low rate of response to HBV vaccine because only 63% of naive patients who were not receiving immunosuppressants or biologic treatment showed responses.10 We found that abnormal results on blood tests,
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including complete blood counts, erythrocyte sedimentation rate, and albumin and C-reactive protein concentrations, had no effect on response to HAV vaccine, whereas anti-TNF therapy decreased the rate of seroconversion. In patients being treated with azathioprine, we defined immunosuppression as treatment with $0.75 mg/kg/d (usually 50 mg/d) of this agent, lower than the recommended therapeutic dose (2.0 to 3.0 mg/kg/d) in Western countries.30 Many Asian patients, however, cannot tolerate this dose, with higher percentages of Asian than of Caucasian patients experiencing leukopenia at lower doses.31–33 Doses of 50 mg/d were found to be effective and safe for maintenance of remission in Japanese patients with IBD.31 All 4 of our patients not experiencing seroconversion while receiving azathioprine were on ,2 mg/kg/d of this agent. Testing for the presence of anti-HBs antibodies 1 to 3 months after administration of the last dose of vaccine has been recommended in high-risk and immunocompromised patients, including those with IBD, vaccinated for HBV, because their subsequent clinical management depends on knowledge of their immune status.34 However, as shown here, post-vaccination testing for anti-HAV IgG is generally unnecessary because the seroconversion rate in the entire cohort was very high. This study has several limitations. First, we did not compare seroconversion rates in healthy controls and patients with IBD because the former were not included. However, this comparison may be unnecessary because the seroconversion rate in patients with IBD was very high. Second, since we used a semiquantitative test to analyze immune responses to the HAV vaccine, we could not quantitatively compare antibody titers between groups of patients. Third, we did not measure anti-HAV IgG between the 2 doses of vaccine; thus, we did not determine the seroconversion rate after the first dose. Fourth, although we observed a high seroconversion rate, we could not determine whether the persistence of vaccine-induced immunity would be affected by the disease itself and/or by immunosuppressive treatments. In conclusion, we found that the seroconversion rate after HAV vaccination was very high in adult patients with IBD, although this rate was lower in patients receiving anti-TNF agents. Therefore, the best time to vaccinate these patients for HAV may be at the diagnosis of IBD. Additional controlled studies are needed to assess the long-term response and effectiveness of the HAV vaccine in adult patients with IBD.
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32. Andoh A, Tsujikawa T, Ban H, et al. Monitoring 6-thioguanine nucleotide concentrations in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol. 2008;23:1373–1377. 33. Lee HJ, Yang SK, Kim KJ, et al. The safety and efficacy of azathioprine and 6-mercaptopurine in the treatment of Korean patients with Crohn’s disease. Intest Res. 2009;7:22–31. 34. Hepatitis B vaccines: WHO position paper. Wkly Epidemiol Rec. 2009;84: 405–420. Available at: http://www.who.int/wer/2009/wer8440/en/index. html. Accessed September 10, 2013.
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