# Acute hepatitis B virus infection despite vaccination in a patient treated by infliximab: a case report

Juliette Besombes, Faouzi Souala, Guillaume] Bouguen, Dominique Guyader,

Claire Grolhier, Vincent Thibault, Charlotte Pronier

► To cite this version:

Juliette Besombes, Faouzi Souala, Guillaume] Bouguen, Dominique Guyader, Claire Grolhier, et al. Acute hepatitis B virus infection despite vaccination in a patient treated by infliximab: a case report. BMC Gastroenterology, 2022, 22 (1), pp.322. 10.1186/s12876-022-02397-5. hal-03763136

HAL Id: hal-03763136

https://hal.science/hal-03763136v1

Submitted on 29 Aug 2022

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
CASE REPORT

Open Access

<figure><img src="image_2.png" /></figure>

Check for
updates

# Acute hepatitis B virus infection despite vaccination in a patient treated by infliximab: a case report

Juliette Besombes<fnref n="1" />, Faouzi Souala², Guillaume Bouguen³, Dominique Guyader⁴, Claire Grolhier<fnref n="1" />, Vincent Thibault<fnref n="1" /> and Charlotte Pronier<fnref n="1" />* ID

**Abstract**

**Background:** Despite an effective vaccine, hepatitis B remains a major global health problem due to its significant morbidity and mortality. Vaccination in immunosuppressed patients such as those treated for an inflammatory bowel disease (IBD) can be less effective. This case describes an uncommon original diagnosis of an acute hepatitis B infection occurring in a vaccinated but immunocompromised IBD patient under long-term infliximab treatment. A low anti-HBs titer and the presence of HBsAg escape mutations are possible hypotheses to explain this unexpected infection.

**Case presentation:** A 28-year-old Caucasian male, regularly followed-up for a Crohn's disease treated by infliximab, was regularly screened for sexually transmissible infections because of at-risk behaviors. Despite a correct immunization scheme against hepatitis B virus (HBV), an active HBV infection was diagnosed during one of those screenings. Retrospective testing of a sample collected 6 months earlier was in favor of an evolution from an acute hepatitis B toward a chronic hepatitis B. The patient has always had a low anti-HBs antibody levels (near the threshold of 10 IU/L) possibly explaining his infection. In addition, HBV sequencing revealed a genotype A2 HBV strain, carrying the sD144A substitution on the S protein, known as a potential immune escape variant. Dual therapy combining tenofovir disoproxil fumarate and emtricitabine, active against HBV but also efficient as an HIV pre-exposure prophylaxis, was initiated. Ten months after treatment initiation, all surrogate biochemical and virological endpoints for HBV functional cure were achieved. Treatment and periodical monitoring are being maintained.

**Conclusion:** Emphasis should be placed on HBV screening, vaccination and regular monitoring of patients under long-term immunosuppressive therapy, particularly those with at-risk behaviors.

**Keywords:** Hepatitis B, Immunocompromised, Vaccination, Immune escape, Infliximab, Acute hepatitis

**Background**

Hepatitis B is a viral infection efficiently prevented by a safe and effective vaccine. Most of healthy adults with acute hepatitis B spontaneously resolve the infection

as a result of an efficient and timely innate and adaptive immune responses [1]. Yet, any immunosuppressive condition may jeopardize such spontaneous recovery. In patients undergoing immunosuppressive therapy, the risks of infection or reactivation largely depend on the type of administered drugs [2]. Thus, for non-immunized patients, vaccination against hepatitis B virus (HBV) is recommended before introduction of any immunosuppressive therapy [2, 3]. Here, we describe a case of a likely acute HBV infection occurring in a patient with an

<footnote>*Correspondence: charlotte.pronier@chu-rennes.fr</footnote>

<footnote n="1">¹ Department of Virology, INSERM, EHESP, IRSET - UMR_S 1085, Pontchaillou University Hospital, Univ Rennes, Rennes, France
Full list of author information is available at the end of the article</footnote>
inflammatory bowel disease (IBD) treated by infliximab and vaccinated in childhood, years prior to his immunosuppressive treatment initiation.

## Case presentation

A 28-year-old Caucasian male was regularly followed-up for a Crohn's disease (CD) treated by infliximab, an anti-tumor necrosis factor (TNF) therapy. Infliximab treatment had been initiated in August 2011 and maintained up to now. In 1997, he received a complete vaccination scheme of 3 doses of Engerix-B10 (0–1–6 months).

September 2010, a CD was diagnosed. In June 2011, serological HBV screening performed before infliximab initiation revealed the presence of a low anti-HBs titer of 15.4 IU/L without HBs antigen (HBsAg) (Table 1). At that time, the anti-HBc status was not determined. In April 2019, the HBV serology confirmed a protective anti-HBs antibodies (Ab) titer at 15 IU/L and the absence of anti-HBc Ab; a serological profile indicative of an efficient vaccine induced immunity. In parallel of his CD management, this patient, who had a high-risk of acquiring sexually transmissible infections (STI), has been receiving

<table><caption>**Table 1** Outcome of patient's biological analyses over several follow-ups</caption><thead><tr><th></th><th>June 2011<br>Pre-infliximab<br>evaluation</th><th>April 2019</th><th>January<br>2020 M-6</th><th>June 2020<br>HBV infection<br>Diagnosis D0</th><th>July<br>2020 M + 1</th><th>February<br>2021<br>Under HBV treatment (Since 09/2020)</th><th>September<br>2021</th><th>March 2022</th></tr><tr><th></th><th></th><th></th><th></th><th></th><th></th><th>M + 8</th><th>M + 15</th><th>M + 21</th></tr></thead><tbody><tr><td>Place of consultation</td><td>Gastroenterology</td><td>General practitioner</td><td>CeGIDD</td><td>CeGIDD</td><td>Infectious disease</td><td>Infectious disease</td><td>Infectious disease</td><td>Infectious disease</td></tr><tr><td>Infliximab treatment</td><td>—</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Serology and HBV markers</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>HBV</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>HBsAg</td><td>Negative</td><td>Negative</td><td>Positive*</td><td>Positive</td><td>Positive</td><td>ND</td><td>ND</td><td>ND</td></tr><tr><td>HBsAg (IU/mL)</td><td>ND</td><td>ND</td><td>Positive (3.3)*</td><td>Positive (18,000)*</td><td>Positive (18,000)</td><td>Positive (5,100)</td><td>Negative (&lt;0.03)</td><td>Negative (&lt;0.03)</td></tr><tr><td>Anti-HBs Ab (IU/L)</td><td>Positive (15.4)</td><td>Positive (15)</td><td>Negative (5.3)</td><td>Negative (&lt;2)</td><td>Negative (&lt;2)</td><td>Negative (&lt;2)</td><td>Negative (8.3)</td><td>Positive (17.4)</td></tr><tr><td>Anti-HBc Ab</td><td>ND</td><td>Negative</td><td>Negative*</td><td>Positive</td><td>Positive</td><td>ND</td><td>ND</td><td>ND</td></tr><tr><td>Anti-HBc IgM Ab</td><td>ND</td><td>ND</td><td>Negative*</td><td>Positive*</td><td>Positive</td><td>ND</td><td>ND</td><td>ND</td></tr><tr><td>HBeAg</td><td>ND</td><td>ND</td><td>Positive*</td><td>Positive*</td><td>Positive</td><td>Positive</td><td>Negative</td><td>Negative</td></tr><tr><td>Anti-HBe Ab</td><td>ND</td><td>ND</td><td>Negative*</td><td>Negative*</td><td>Negative</td><td>Negative</td><td>Positive</td><td>Positive</td></tr><tr><td>HBV-DNA VL (log<sub>10</sub> IU/mL)</td><td>ND</td><td>ND</td><td>5.0*</td><td>8.0*</td><td>8.2</td><td>3.84</td><td>&lt;1 Detected HBV-DNA</td><td>&lt;1 Not detected HBV-DNA</td></tr><tr><td>Anti-HDV Ab</td><td>ND</td><td>ND</td><td>ND</td><td>Negative*</td><td>Negative</td><td>Negative</td><td>ND</td><td>ND</td></tr><tr><td>Anti-HCV Ab</td><td>ND</td><td>ND</td><td>Negative</td><td>Negative</td><td>Negative</td><td>Negative</td><td>ND</td><td>Negative</td></tr><tr><td>Anti-HAV</td><td>ND</td><td>ND</td><td>ND</td><td>ND</td><td>Negative</td><td>Positive</td><td>ND</td><td>ND</td></tr><tr><td>Anti-HIV</td><td>ND</td><td>ND</td><td>Negative</td><td>Negative</td><td>Negative</td><td>Negative</td><td>Negative</td><td>Negative</td></tr><tr><td>Syphilis</td><td>ND</td><td>ND</td><td>ND</td><td>Prior syphilis treated or untreated, early syphilis or false positive</td><td></td><td>Negative</td><td>Negative</td><td>Negative</td></tr><tr><td>Liver function tests</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>ALT (ULN)</td><td>ND</td><td>ND</td><td>ND</td><td>4.2</td><td>3.8</td><td>3.4</td><td>1.1</td><td>1.8</td></tr><tr><td>AST (ULN)</td><td>ND</td><td>ND</td><td>ND</td><td>2.8</td><td>2</td><td>1.8</td><td>1</td><td>1.3</td></tr></tbody></table>

Qualitative HBs Antigen (Roche Cobas® Elecsys HBsAg II), Quantitative HBs Antigen (DiaSorin LIAISON® XL Murex HBsAg Quant), anti-HBs Antibodies (Roche Cobas® Elecsys Anti-HBs II), anti-HBc antibodies (Roche Cobas® Elecsys Anti-HBc II), anti-HBc antibodies IgM (Roche Cobas® Elecsys Anti-HBc IgM and DiaSorin LIAISON® XLHBC IgM), HBe Antigen and Antibodies (Roche Cobas® Elecsys HBeAg and anti-HBe). HBV viral load (HBV-VL) was determined by PCR (Xpert HBV viral load; Cepheid). Anti-HCV, HAV and HIV antibodies were detected using Elecsys anti-HCV II, anti-HAV II and HIV combi PT assays respectively (Roche Cobas®). Anti-HDV and syphilis antibodies were detected using Murex anti-HDV and Treponema screen assays respectively (DiaSorin LIAISON® XL)

ULN times over the upper limit of normal range. CeGIDD: free center for information, screening and diagnosis of HIV and STI; ND not determined

*Analyses added retrospectively after the HBV diagnosis in June 2020
regular STI screenings at a free sexual health center. In June 2020, HCV and HIV serologies were negative while the syphilis serology showed an inconclusive profile (Table 1). The HBV serological markers revealed an ongoing hepatitis B infection as documented by positive HBsAg and anti-HBc Ab but an absence of anti-HBs Ab. Liver function tests indicated a moderate hepatic cytolysis, with ALT around 4 times the upper limit of normal values. Additional hepatitis B markers were reactive for anti-HBc IgM, HBeAg and viral replication reaching 8 log IU/mL. Hepatitis Delta testing was negative. Interestingly, through retrospective testing of a sample collected 6 months earlier, the serological profile was already in agreement with an active HBV infection. HBV sequencing identified a genotype A2 strain carrying the sD144A substitution on the S protein. In July 2020, 1 month after HBV diagnosis and 7 months after the first evidence of a positive HBsAg, persistence of HBsAg and viral replication were in favor of a transition toward a chronic HBV infection. The FibroTest® result (F0–F1) did not support a significant fibrosis. To prevent the risk of HBV transmission and the development of liver lesions, a treatment by tenofovir disoproxil fumarate (TDF) and emtricitabine, active against HBV and also efficient as an HIV pre-exposure prophylaxis (PrEP), was initiated in September 2020. Five months after treatment initiation, HBeAg remained positive but a decline in HBV-DNA and HBsAg levels was recorded. Twelve months after treatment initiation, all surrogate virological endpoints for HBV functional cure were achieved. ALT levels remained slightly elevated while HBe seroconversion was observed. HBsAg became undetectable by both current and ultrasensitive HBsAg assays without anti-HBs seroconversion. HBV-DNA remained slightly detectable but below the limit of quantification of 10 IU/ml (Table 1). On the last control, 18 months after treatment initiation, HBV-DNA was undetectable in the blood and anti-HBs Ab appeared. However, ALT levels had increased again (1.8 ULN). Antiviral treatment and periodical STI monitoring are being maintained, in front of high-risk behaviors and to ascertain durable HBsAg loss.

## Discussion and conclusion

This original case reports an acute HBV infection, with a putative escape variant, despite a full HBV vaccination, in an immunocompromised patient treated with infliximab [4]. Different practitioners both for his digestive disease and for his at-risk sexual behavior regularly followed the patient. His acute HBV infection was diagnosed in favor of regular STI screening visits. The retrospective analysis of a sample collected 6 months earlier indicated the evolution of this acute hepatitis B toward a chronic hepatitis B as documented by the persistence over 6 months

of the HBsAg. Any immunosuppressive condition, either acquired or treatment-induced, is associated with a risk of HBV chronicity or reactivation. This is particularly observed during inhibition of TNF-α-mediated biological effects [1, 5]. The mechanism is not fully explained but TNF-α and related cytokines are involved both in the regulation of the adaptive immune system responsible for HBV immune surveillance and the control of covalently closed circular DNA transcriptional activity [6]. While cases of HBV reactivation under infliximab therapy for chronic inflammatory diseases have already been described, our clinical case indicates that these treatments may also be associated with an impaired vaccine efficacy and the risk of an evolution toward chronicity [7, 8]. The weakened immune system may also explain the delayed appearance of anti-HBc IgM that were negative on the first HBsAg positive serum. However, the lack of anti-HBc IgM can also be observed at the very early stage of acute HBV infection, at the very onset of liver cytolysis.

Screening for hepatitis B before starting an immunosuppressive therapy is widely recommended to prevent any risk of viral reactivation in infected patients (HBsAg positive) or those with past-infection serological imprint (i.e. anti-HBc positive) [3, 6]. In anti-HBc positive patients, antiviral prophylaxis can be proposed particularly for treatments at high risk of reactivation [3, 9]. Non-immunized patients should be proposed vaccination at the time of IBD diagnosis and before initiating immunomodulatory treatment [2, 10]. Yet, this patient benefited from a correct full vaccine scheme a few years earlier as reported in his medical file. In addition, stable anti-HBs titers were documented from 2011 to 2019. As only HBsAg and anti-HBs Ab had been tested before the initiation of infliximab treatment in our patient, it was not possible to formally conclude on a past infection or a vaccine serological status. Indeed, the first available anti-HBc testing was performed in 2019, when the patient was already receiving infliximab. The possibility that the immunosuppressive treatment had decreased anti-HBc to undetectable level cannot be formally ruled out [11]. Yet, anti-HBs had remained at similar levels as those detected earlier and the patient had no history of clinically significant conditions related to his immunosuppression. The need to propose a reinforced vaccine boost strategy in such patient should probably be discussed especially when no proof of a high level of immunity following vaccination (anti-HBs > 100 IU/L) exists. Early vaccination, before immunosuppressive treatment initiation is preferable as the HBV vaccine response rate in patients using immunomodulators is dramatically decreased, in particular in infliximab-users, even with high dose vaccine [12,
13]. An anti-HBs titer above 10 IU/L such as recommended in healthy individuals may not be sufficient for IBD patient; the definition of a minimal threshold in such situation would be useful [10]. Thus, efforts should be made to vaccinate IBD patients against HBV or to give a booster dose to maintain high anti-HBs Ab levels before immune suppressive therapy. Under such treatments, periodical monitoring of anti-HBs titers, to ascertain efficacy, should also be promoted especially in patients at high risk of acquiring hepatitis B. Interestingly, sequencing of the HBV strain revealed a known HBsAg escape variant (sD144A), that may also have contributed to a reduced vaccine induced Ab neutralization potency [4]. This substitution, along with others located within the ‘a’ determinant (residues 124–147), are known as vaccine escape substitutions that may also jeopardize HBsAg detection by assays [14]. Fortunately, these substitutions do not impair efficacy of current nucleoside/nucleotide analogues used for HBV treatment [15]. In front of a high viral load in an immunocompromised patient, the clinical staff decided to initiate a treatment by a TDF-emtricitabine (Truvada®) association, that also comply with an HIV PrEP strategy considering the patient’s at-risk behavior [3]. One year after treatment initiation, the patient achieved HBeAg and HBsAg losses, considered for this latter as the hallmark of functional cure. Considering the undetectable HBV viral load and the functional cure serological profile, persisting subnormal ALT levels were attributed to a possible infliximab side effect.

In conclusion, this case highlights some difficulties encountered in patients under long-term immunosuppressive therapy, particularly those with at-risk behaviors. This case conveys several messages:

* A full screening based on detection of the three HBV markers (HBsAg, anti-HBs Ab, anti-HBc Ab) should be performed before starting an immunosuppressive treatment. Anti-HBc Ab are essential to establish a history of previous HBV infection linked to a risk of reactivation;

* Vaccination should be promoted and vaccine efficacy controlled to consider a potential booster dose in patients with anti-HBs titer less than 100 IU/L before starting an immunosuppressive therapy [9];

* Patients who are at-risk of infection need a recurrent follow-up in order to prevent and to early diagnose any infection. Special attention should be paid to patients wandering between different practitioners and those who are particularly vulnerable.

**Abbreviations**

Ab: Antibody; Ag: Antigen; ALT: Alanine aminotransferase; CD: Crohn's disease; HBV: Hepatitis B virus; HIV: Human immunodeficiency virus; IBD: Inflammatory bowel disease; IU: International unit; PrEp: Pre-exposure prophylaxis; STI: Sexually transmissible infections; TDF: Tenofovir disoproxil fumarate; TNF: Tumor necrosis factor.

**Acknowledgements**

Not applicable.

**Author contributions**

JB, CG, VT, CP performed diagnostic tests, collected data, performed the literature review and wrote the first draft of the article. FS, GB, DG took care of the patient and raised critical comments on the article. All authors have read and approved the manuscript.

**Funding**

No specific funding has been received for this work.

**Availability of data and material**

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

**Declarations**

**Ethics approval and consent to participate**

Not applicable.

**Consent for publication**

Written informed consent was obtained from the case patient for publication of this report. A copy of the written consent is available for review by the Editor of this journal.

**Competing interests**

The authors declare that they have no competing interests.

**Author details**

¹Department of Virology, INSERM, EHESP, IRSET - UMR_S 1085, Pontchaillou University Hospital, Univ Rennes, Rennes, France. ²Infectious Diseases and Intensive Care Unit, Pontchaillou University Hospital, Rennes, France.

³Department of Hepato-Gastroenterology, UMR 991, Pontchaillou University Hospital, Univ Rennes, Rennes, France. ⁴Department of Liver Diseases (SMF), UMR 1241, Pontchaillou University Hospital, Univ Rennes, Rennes, France.

Received: 20 January 2022 Accepted: 15 June 2022

Published online: 29 June 2022

**References**

1. Hyams KC. Risks of chronicity following acute hepatitis B virus infection: a review. Clin Infect Dis. 1995;20(4):992–1000. https://doi.org/10.1093/clini ds/20.4.992.

2. Pol S. Management of HBV in immunocompromised patients. Liver Int. 2013;33:182–7. https://doi.org/10.1111/liv.12055.

3. Lampertico P, Agarwal K, Berg T, Buti M, Janssen HLA, Papatheodoridis G, et al. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98. https://doi.org/ 10.1016/j.jhep.2017.03.021.

4. Ni F, Fang D, Gan R, Li Z, Duan S, Xu Z. A new immune escape mutant of hepatitis B virus with an Asp to Ala substitution in aa144 of the envelope major protein. Res Virol. 1995;146(6):397–407. https://doi.org/10.1016/ 0923-2516(96)80899-5.

5. Baddley JW, Cantini F, Goletti D, Gómez-Reino JJ, Mylonakis E, San-Juan R, et al. ESCMID study group for infections in compromised hosts (ESGICH) consensus document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [J]: anti-tumor necrosis factor-α agents). Clin Microbiol Infect. 2018;24:S10- 20. https://doi.org/10.1016/j.cmi.2017.12.025.
6. Loomba R, Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology. 2017;152(6):1297–309. https://doi.org/10.1053/j.gastro.2017.02.009.

7. Esteve M. Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis. Gut. 2004;53(9):1363-5. https://doi.org/10.1136/gut.2004.040675.

8. Ueno Y, Tanaka S, Shimamoto M, Miyanaka Y, Hiyama T, Ito M, et al. Infliximab therapy for crohn's? Disease in a patient with chronic hepatitis B. Dig Dis Sci. 2005;50(1):163-6. https://doi.org/10.1007/s10620-005-1295-8.

9. Reddy KR, Beavers KL, Hammond SP, Lim JK, Falck-Ytter YT. American gastroenterological association institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015;148(1):215-9. https://doi.org/10.1053/j.gastro.2014.10.039.

10. Axiaris G, Zampeli E, Michopoulos S, Bamias G. Management of hepatitis B virus infection in patients with inflammatory bowel disease under immunosuppressive treatment. World J Gastroenterol. 2021;27(25):3762-79. https://doi.org/10.3748/wjg.v27.i25.3762.

11. Hall AJ. Boosters for hepatitis B vaccination? Need for an evidence-based policy. Hepatology. 2010;51(5):1485-6. https://doi.org/10.1002/hep.23674.

12. Haykir SA, Eser F. High dose hepatitis B vaccine is not effective in patients using immunomodulatory drugs: a pilot study. Hum Vaccines Immunother. 2019;15(5):1177-82. https://doi.org/10.1080/21645515.2019.1574151.

13. Pratt PK, David N, Weber HC, Little FF, Kourkoumpetis T, Patts GJ, et al. Antibody response to hepatitis B virus vaccine is impaired in patients with inflammatory bowel disease on infliximab therapy. Inflamm Bowel Dis. 2018;24(2):380-6. https://doi.org/10.1093/ibd/izx001.

14. Thibault V, Servant-Delmas A, Ly TD, Roque-Afonso A-M, Laperche S. Performance of HBsAg quantification assays for detection of hepatitis B virus genotypes and diagnostic escape-variants in clinical samples. J Clin Virol. 2017;89:14-21. https://doi.org/10.1016/j.jcv.2017.02.001.

15. Revill PA, Tu T, Netter HJ, Yuen LKW, Locarnini SA, Littlejohn M. The evolution and clinical impact of hepatitis B virus genome diversity. Nat Rev Gastroenterol Hepatol. 2020;17(10):618-34. https://doi.org/10.1038/s41575-020-0296-6.

**Publisher's Note**

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Ready to submit your research? Choose BMC and benefit from:

* fast, convenient online submission

* thorough peer review by experienced researchers in your field

* rapid publication on acceptance

* support for research data, including large and complex data types

* gold Open Access which fosters wider collaboration and increased citations

* maximum visibility for your research: over 100M website views per year

At BMC, research is always in progress.

Learn more biomedcentral.com/submissions

<figure><img src="image_3.png" /></figure>