’Original article Impact of immunosuppressive therapy on hepatitis B vaccination in inflammatory bowel diseases Arthur Bellea, Cédric Baumannb, Marc-André Bigarda, Camille Zallota, Emmanuel Gizarda, Jean-Louis Guéanta, Jean-Pierre Bronowickia and Laurent Peyrin-Birouleta Background and aims The vaccination rate against hepatitis B virus (HBV) is low in inflammatory bowel disease (IBD) patients. The Consensus from the European Crohn’s and Colitis Organisation on opportunistic infections recommends testing all IBD patients for HBV at diagnosis and vaccinating all HBV-negative patients. We compared the efficacy of HBV vaccine between IBD patients and healthy controls and investigated the impact of immunosuppressive therapy on vaccine response in IBD patients. Materials and methods IBD patients and healthy adult workers were vaccinated against HBV following a standard protocol (at 0, 1, and 6 months; Engerix B). The efficacy of vaccination was evaluated at 8 months by a titer of antibodies against hepatitis B surface antigen (anti-HBs). Results Among 164 participants (96 with IBD and 68 healthy workers), the level of anti-HBs was greater than 10 IU/l in 80.2 and 94.1% (P = 0.0115) of IBD patients and healthy controls, respectively, and anti-HBs levels greater than 100 IU/l were seen in 45.8 versus 77.9% (P < 0.0001) of IBD patients and healthy controls, respectively. The median level of anti-HBs was significantly higher in healthy controls (497.0 ± 386.2) than in IBD patients (253.9 ± 34.5) (P < 0.0001). None of the baseline characteristics of IBD patients, including immunomodulators and antitumor necrosis factor therapy, influenced the vaccine response. In the multivariate analysis, ileal disease was the only factor associated with a lower response to the vaccine (odds ratio = 3.2; 95% confidence interval = 1.0–9.7; P = 0.049). Conclusion The response rate to HBV vaccination is significantly lower in IBD patients than in the general population. Immunosuppressive therapy for IBD did not influence the vaccine response. Eur J Gastroenterol Hepatol 27:877–881 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Introduction

Hepatitis B infection is one of the most commonly occurring viral infections worldwide. About one-third of the world’s population has serological evidence of past or present hepatitis B virus (HBV) infection, and more than 350 million people may be affected by chronic HBV infection (1 and 2). In addition, chronic HBV infection is the primary cause of cirrhosis and hepatic cellular carcinoma worldwide, and it is among the top 10 causes of death; about 1.5 million people may die annually from these complications [1,2]. Several cases of reactivation of HBV infection have been reported among patients receiving antitumor necrosis factor (anti-TNF) agents for inflammatory bowel diseases (IBD) [3–5]. Patients with IBD are being increasingly treated with immunomodulators such as thiopurines and anti-TNF therapy [6,7]. Therefore, reactivation of HBV European Journal of Gastroenterology & Hepatology 2015, 27:877–881 Keywords: hepatitis B, immunosuppressive, inflammatory bowel disease, vaccination a Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy and bESPRI Unit, Clinical epidemiology, CHU de Nancy, Lorraine University, Vandoeuvre-lès-Nancy, France

Correspondence to Laurent Peyrin-Biroulet, MD, PhD, Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy-Brabois, Université de Lorraine, Allée du Morvan, 54511 Vandoeuvre-lès-Nancy, France Tel: + 33 3 83 15 36 31; fax: + 33 3 83 15 36 33; e-mail: [email protected] Received 15 January 2015 Accepted 17 March 2015

infection is a major concern among physicians managing IBD patients on immunosuppressive therapy [8–16]. Although recent reports have indicated that the prevalence of HBV infection in IBD patients is similar to that of the general population [17–20], less than half of IBD patients are vaccinated for HBV [17–20]. The Consensus from the European Crohn’s and Colitis Organisation on opportunistic infections recommends testing all IBD patients for HBV at diagnosis and vaccinating all HBVnegative patients [21]. HBV vaccination is safe and effective in 95% of the general adult population [22–25]. Three recent studies showed that the response rate to HBV vaccination is lower in IBD patients than in the general population [26–28]. The seroconversion rate was higher among patients vaccinated with the double dose than with the standard dose [26]. The impact of immunosuppressive therapy on vaccine response to HBV in patients with IBD is controversial [26–30]. The aims of our study were therefore to (i) compare the efficacy of HBV vaccine between IBD patients and healthy controls and (ii) determine the impact of immunosuppressive therapy on the efficacy of HBV vaccination in IBD patients. Materials and methods Study sample and hepatitis B virus vaccination

All consecutive adult patients from the IBD cohort of our center (Centre Hospitalo-Universitaire de Nancy, France)

0954-691X Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

DOI: 10.1097/MEG.0000000000000370

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who were vaccinated for HBV between June 2009 and June 2013 were retrospectively included in this study. Information about the Nancy IBD cohort is reported to the Commission Nationale Informatique et Libertés (no. 1404720), which supervises the implementation of the act regarding data processing, maintenance of data files, and individual liberties. It came into effect on 6 January 1978 and was amended on 6 August 2004 to protect the personal data of individuals [31–33]. All included IBD patients had titer antibodies against hepatitis B surface antigen (anti-HBs) less than 10 IU/l and were seronegative against both antibodies to hepatitis B core protein (anti-HBc) and hepatitis B surface antigen (HBsAg) before HBV vaccination. Controls without IBD were healthy adult workers from the Department of Preventive Medicine of the same hospital center and were included retrospectively. Inclusion criteria were as follows: no IBD; no known morbidity; anti-HBs titer less than 10 IU/l; and seronegativity against both anti-HBc and HBsAg before HBV vaccination. The exclusion criteria for both groups were as follows: (i) history of viral hepatitis; (ii) other inflammatory/autoimmune disease; (iii) active infection; (iv) any medical condition known to cause immunosuppression (e.g. HIV infection or chronic renal failure); (v) liver cirrhosis; and (vi) pregnancy. Patients were vaccinated against HBV following a standard protocol (current standard of care) consisting of three intramuscular doses (1.0 ml, 20 μg recombinant HBsAg) of the commercial HB vaccine Engerix-B (GlaxoSmithKline, Evreux, France) administered at 0, 1, and 6 months. The vaccine was administered by intramuscular injection into the deltoid muscle at 0, 1, and 6 months. All included IBD patients and healthy workers have completed the vaccination protocol. The demographic characteristics collected for each patient were age, sex, size, weight, renal function, IBD type [Crohn’s disease (CD) or ulcerative colitis (UC)], immunosuppressive treatment (thiopurine, methotrexate) concomitant with administration of the vaccine, and anti-TNF treatment (infliximab, adalimumab) concomitant with administration of the vaccine. Anti-HBs titers were measured 2 months after the third dose. The response rate to the vaccine (seroprotection rate) was analyzed considering two different anti-HBs titers as cutoff: more than 10 IU/l (according to the standard definition for seroconversion) and more than 100 IU/l (according to the standard definition of efficacy for the protocol of vaccination). The level of anti-HBs titers was also collected for each patient. Statistical analysis

Continuous variables were described as mean ± SD and median, and categorical variables as percentage with 95% confidence interval (CI). Comparisons between groups were made using χ2 and Mann–Whitney U-tests. Bivariate and multivariate logistic regression models were used to identify factors associated with the probability of nonresponse to vaccine in IBD patients. Variables with a P value less than 0.2 in bivariate analysis were candidates in the multivariate model. We applied a stepwise variable selection with significance level for entry into the model at

0.2 and with significance level for staying in the model at 0.05. Analysis was performed using SAS version 9.3 (SAS Institute Inc., Cary, North Carolina, USA). Results Characteristics of inflammatory bowel disease patients and controls

A total of 164 patients were included in this case–control study. Of them, 96 had IBD and 68 were healthy controls. Their characteristics are summarized in Table 1. The mean age of patients with IBD (44.9 ± 13.4) was significantly higher than that of healthy controls (31.0 ± 8.3) (P < 0.0001). There was no difference between IBD patients and healthy controls regarding BMI and sex. In the IBD group 53% of patients were female, 80% had CD, and 20% had UC. Seventy-three patients (76%) were on anti-TNF drugs (infliximab or adalimumab), 48 patients (50%) were on immunomodulators (thiopurine or methotrexate), and 42 patients (43.8%) were on anti-TNF therapy in combination with an immunomodulator at study inclusion (Table 1). Among patients receiving anti-TNF drugs (n = 73), 59 were on infliximab and 14 on adalimumab. Of those receiving an immumomodulator (n = 48), 43 were on thiopurine and five on methotrexate. Efficacy of hepatitis B vaccination in inflammatory bowel disease patients versus controls

The response rate for anti-HBs of more than 10 IU/l (standard definition for seroconversion) was 80.2 and 94.1% (P = 0.0115) for IBD patients and controls, respectively, and 45.8 versus 77.9% (P < 0.0001) for antiHBs more than 100 IU/l (standard definition for efficacy of the protocol of vaccination). The median rate of anti-HBs titers was significantly higher in healthy controls (497.0 ± 386.2) than in IBD patients (253.9 ± 342.5) (P < 0.0001) (Table 2). In multivariate analysis, the probability of no response was significantly higher in IBD patients regardless of the Table 1. Characteristics of IBD patients and controls

Sex (female) [n (%)] Age (mean ± SD) BMI (mean ± SD) Localization of IBD [n (%)] UC E1 (proctitis) E2 (left-sided) E3 (pancolitis) CD L1 (ileum) L2 (colon) L3 (ileocolon) L4 (upper GI) Treatment of IBD [n (%)] IFX ADA Thiopurine MTX Combination therapy No therapy

IBD (N = 96)

Controls (N = 68)

P

51 (53.1) 44.9 ± 13.4 24.6 ± 6.1

31 (70.5) 31.0 ± 8.3 23.9 ± 4.4

0.0623 < 0.0001 0.2143

19 5 4 10 77 19 17 40 3

(19.8) (5.2) (4.2) (10.4) (80.2) (19.8) (17.7) (41.7) (3.1)

– – – – – – – – –

– – – – – – – – –

59 14 43 5 42 16

(61.5) (14.6) (44.8) (5.2) (43.8) (16.7)

– – – – – –

– – – – – –

ADA, adalimumab; CD, Crohn’s disease; GI, gastrointestinal tract; IBD, inflammatory bowel disease; IFX, infliximab; UC, ulcerative colitis.

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Hepatitis B vaccination in IBD Belle et al.

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reference; patients on immunomodulators (thiopurine or methotrexate) (N = 48); patients on anti-TNF drugs (infliximab or adalimumab) (N = 73); and patients on combination therapy (N = 42). There was no difference in terms of vaccine response rate between these four subgroups when using anti-HBs more than 10 IU/l or more than 100 IU/l to define vaccine response. Moreover, the median titers of anti-HBs did not differ between these four subgroups, being, respectively, 246.25 ± 330.88, 275.93 ± 369.99, 273.54 ± 357.58, and 306.91 ± 385.49 (Table 5).

Table 2. Comparison between IBD patients and controls regarding the vaccine response

Anti-HBs > 10 UI/l [n (%)] Anti-HBs > 100 UI/l [n (%)] Median rate of anti-HBs (mean ± SD)

IBD (N = 96)

Controls (N = 68)

P

77 (80.2) 44 (45.8) 253.9 ± 342.5

64 (94.1) 53 (77.9) 497.0 ± 386.2

0.0115 < 0.0001 < 0.0001

879

Anti-HBs, antibodies against hepatitis B surface antigen; IBD, inflammatory bowel disease.

anti-HBs cutoff (10 and 100 UI/l), compared with healthy controls (OR = 3.9; 95% CI = 1.3–12.2; P = 0.0080 and OR = 4.2; 95% CI = 2.1–8.4; P < 0.0001, respectively) (Table 3).

Discussion

The rate of vaccination against HBV remains low among IBD patients [17–20]. The Consensus from the European Crohn’s and Colitis Organisation on opportunistic infections recommends testing all IBD patients for HBV at diagnosis and vaccinating all HBV-negative patients [21]. Several studies in children and adults have demonstrated that the response rate against HBV was significantly lower among IBD patients than among healthy controls [17–20]. A prospective study by Altunöz et al. [28] found that the response rate in 102 IBD patients was significantly lower (76%) than that in 52 controls (100%) (P < 0.001). The response rate was similar between patients with CD and UC (P = 0.302) after following a standard protocol. A study by Melmed et al. [34] using a questionnaire reported that only three of nine patients (33%) responded to HBV vaccination. Vida Perez et al. [35] reported that 34.1% of the 129 IBD patients had vaccine response. In the pediatric population, the overall seroprotection rates were 96% in controls as compared with 85.1% in IBD patients after the hepatitis B vaccination standard protocol (95% CI = 0.83–0.95, P = 0.08) [29]. Gisbert et al. demonstrated among 241 patients that the HBV vaccination response was only 59% [26]. We could confirm that the vaccination response rate was significantly lower in patients with IBD than in the control group when considering the standard definition for seroconversion, anti-HBs more than 10 IU/l, as well as when using 100 IU/l as the cutoff. Interestingly, it is the first study to show that the median level of anti-HBs titers was significantly higher in controls (497.0 ± 386.2) than in IBD patients (253.9 ± 342.5) (P < 0.0001). The vaccination protocol may influence the vaccine response. Gisbert et al. [26] showed that administration of a double dose was associated with a higher response rate compared with a simple dose protocol: 75% (95% CI = 65–85%) versus 41% (95% CI = 29–54%) (P < 0.001). In the multivariate analysis, vaccination with

Association of baseline characteristics (except medications) with efficacy of hepatitis B vaccination among inflammatory bowel disease patients

Sex, age, BMI, and type of IBD (UC vs. CD) did not influence the vaccine response in univariate analysis for either anti-HBs of more than 10 UI/l or anti-HBs more than 100 UI/l. The only subgroup with a different response was the topography of CD: CD located in the terminal ileum (L1) had lower response to vaccination both for anti-HBs more than 10 UI/l (63 vs. 84%, P = 0.0490) and for anti-HBs more than 100 UI/l (21.1 vs. 51.9%, P = 0.0125) (Table 4). Multivariate analysis revealed the response rate to be lower among patients with ileal disease both for anti-HBs of more than 10 UI/l (OR, 3.2; 95% CI = 1.0–9.7; P = 0.049) and for anti-HBs of more than 100 UI/l (OR, 4.1; 95% CI = 1.2–13.3; P = 0.0125). Impact of immunosuppressive therapy on the efficacy of hepatitis B vaccination among inflammatory bowel disease patients

In univariate analysis, no medications influenced the vaccine response rate, whether anti-TNF drugs (P = 0.7897), immunomodulators (thiopurine or methotrexate) (P = 0.7978), or combination therapy (P = 0.8717), for anti-HBs more than 10 UI/l. Similar results were observed for anti-HBs of more than 100 UI/l: anti-TNF drugs (P = 0.7947); immunomodulators (thiopurine or methotrexate) (P = 1); and combination therapy (P = 0.7568) (Table 4). We next investigated the impact of immunosuppressive therapy on vaccine response by comparing four predefined subgroups of IBD patients: IBD patients with no immunomodulator and no anti-TNF therapy (N = 16) as

Table 3. Factors associated with nonresponse to vaccine in inflammatory bowel disease patients versus controls Response to the vaccine: univariate analysis Anti-HBs > 10 UI/l

Response to the vaccine: multivariate analysis

Anti-HBs > 100 UI/l

Anti-HBs > 10 UI/l

Anti-HBs > 100 UI/l

Factors

OR

95% CI

P

OR

95% CI

P

OR

95% CI

P

OR

95% CI

P

Sex Age BMI No IBD

1.1 3.9 2.1 3.3

0.5–2.8 0.9–17.3 0.8–5.8 1.3–12.2

NS 0.0384 NS 0.0080

1.6 1.2 1.0 5.5

0.8–3.4 0.6–2.7 0.5–2.3 1.7–17.8

NS NS NS 0.0004

– – – 4.2

– – – 2.1–8.4

– – – < 0.0001

– – – 4.2

– – – 2.1–8.4

– – – 0.0004

Anti-HBs, antibodies against hepatitis B surface antigen; CI, confidence interval; IBD, inflammatory bowel disease; OR, odds ratio.

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Table 4. Factors associated with nonresponse to vaccine in inflammatory bowel disease patients Response to the vaccine: univariate analysis Anti-HBs > 10 UI/l

Response to the vaccine: multivariate analysis

Anti-HBs > 100 UI/l

Anti-HBs > 10 UI/l

Anti-HBs > 100 UI/l

Factors

OR

95% CI

P

OR

95% CI

P

OR

95% CI

P

OR

95% CI

P

Sex Age BMI IBD UC E1 UC E2 UC E3 CD L1 CD L2 CD L3 Anti-TNF MTX or thiopurine Combination therapy

1.0 2.1 1.6 0.7 – 1.4 1.0 3.2 2.3 0.4 0.9 1.1 0.9

0.4–2.8 0.2–17.8 0.5–5.3 0.2–2.8 – 0.1–14.0 0.2–5.2 1.0–9.7 0.7–7.1 0.1–1.2 0.3–2.5 0.4–3.1 0.3–2.5

NS NS NS NS – NS NS 0.0490 NS NS NS NS NS

1.3 0.9 0.5 0.7 0.2 0.8 1.3 4.1 1.2 0.6 0.9 1.0 0.9

0.6–2.9 0.2–3.7 0.2–1.5 0.3–1.9 0–1.8 0.1–6.2 0.3–5.0 1.2–13.3 0.4–3.3 0.3–1.4 0.3–2.3 0.4–2.2 0.4–2.0

NS NS NS NS NS NS NS 0.0125 NS NS NS NS NS

– – – – – – – 3.2 – – – – –

– – – – – – – 1.0–9.7 – – – – –

– – – – – – – 0.049 – – – – –

– – – – – – – 4.1 – – – – –

– – – – – – – 1.2–13.3 – – – – –

– – – – – – – 0.0125 – – – – –

Anti-HBs, antibodies against hepatitis B surface antigen; CD, Crohn’s disease; CI, confidence interval; IBD, inflammatory bowel disease; OR, odds ratio; TNF, tumor necrosis factor; UC, ulcerative colitis.

Table 5. Comparison between therapies in inflammatory bowel disease patients regarding the vaccine response

Anti-HBs > 10 UI/l [n (%)] Anti-HBs > 100 UI/l [n (%)] Median rate of anti-HBs (mean ± SD)

Anti-TNF (n = 73)

MTX or thiopurine (n = 48)

Combination therapy (n = 42)

No therapy (n = 16)

P

59 (80.82) 34 (46.58) 273.54 ± 357.58

38 (79.17) 22 (45.83) 275.93 ± 369.99

34 (80.95) 20 (47.62) 306.91 ± 385.49

13 (81.25) 7 (43.75) 246.25 ± 330.88

NS NS NS

Anti-HBs, antibodies against hepatitis B surface antigen; TNF, tumor necrosis factor.

the double dose was the only factor associated with a better response to the vaccine (OR, 4; 95% CI = 2.0–8.0; P

Impact of immunosuppressive therapy on hepatitis B vaccination in inflammatory bowel diseases.

The vaccination rate against hepatitis B virus (HBV) is low in inflammatory bowel disease (IBD) patients. The Consensus from the European Crohn's and ...
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