Journal of Neurology https://doi.org/10.1007/s00415-023-11973-y ORIGINAL COMMUNICATION Hepatitis B reactivation is a rare event among patients with resolved infection undergoing anti‑CD20 antibodies in monotherapy without antiviral prophylaxis: results from the HEBEM study Blanca Marzo1,2 · Angela Vidal‑Jordana3 · Joaquín Castilló3 · Miguel‑Angel Robles‑Sanchez3,4 · Susana Otero‑Romero3,5 · Mar Tintore3 · Xavier Montalban3 · Maria Buti1,2,6 · Mar Riveiro‑Barciela1,2,6 Received: 4 July 2023 / Revised: 25 August 2023 / Accepted: 26 August 2023 © The Author(s) 2023 Abstract Introduction Prospective data on the risk of hepatitis B reactivation (HBVr) among patients with resolved HBV infection undergoing anti-CD20 antibodies monotherapy is scarce. We aimed to assess the risk of HBVr in patients with resolved HBV infection treated with rituximab or ocrelizumab in monotherapy for multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) without antiviral prophylaxis. Methods HEBEM is a prospective study that included all consecutive adults HBsAg-negative/anti-HBc-positive who initi- ated anti-CD20 antibodies for MS or NMOSD at Cemcat. Inclusion criteria encompassed undetectable HBV-DNA, absence of other immunosuppressants or antiviral therapy. Every 6 months HBsAg, ALT and HBV-DNA were performed to rule out HBVr (defined by 2-log increase in HBV-DNA or seroconversion to HBsAg+). Results From August/2019 to August/2022, 540 subjects initiated anti-CD20 antibodies, 28 (5.2%) were anti-HBc-positive and were included. Twenty-two received rituximab and 6 ocrelizumab. The majority (89.3%) had previously received ≥ 1 immunomodulatory drug, with corticosteroids (82.1%) and interferon (42.9%) as the most common. At inclusion, all pre- sented normal transaminases and undetectable HBV-DNA. Median anti-HBs levels were 105.5 mIU/mL (IQR 0–609). Median follow-up was 3.1 years (2.1–4.0). Median number of cycles of anti-CD20 antibodies was 6 (3–7), with a cumulative dose of 8.5 g (5.8–11.2) of rituximab and 3 g (1.8–3.8) of ocrelizumab. Neither cases of HBVr nor changes in anti-HBs titers were observed per 83.6 patient-years treated with monotherapy with anti-CD20 antibodies. Conclusions In this cohort of patients with MS or NMOSD and resolved HBV infection, anti-CD20 monotherapy was not associated with detectable risk of HBV reactivation despite the lack of antiviral prophylaxis. Keywords Rituximab · Ocrelizumab · Hepatitis B · Reactivation · Anti-CD20 antibodies · Multiple Sclerosis 4 * Mar Riveiro‑Barciela Grup d’Investigació Multidisciplinari d’Infermeria, Vall mar.riveiro@gmail.com d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain 1 Department of Medicine, Universitat Autònoma de 5 Servei de Medicina Preventiva i Epidemiologia. Hospital Barcelona (UAB), Bellaterra, Spain Universitari Vall d’Hebron, Universitat Autònoma de 2 Liver Unit, Internal Medicine Department, Hospital Barcelona, Barcelona, Spain Universitari Vall d’Hebron, Vall d’Hebron Barcelona 6 Centro de Investigación Biomédica en Red de Enfermedades Hospital Campus, Barcelona, Spain Hepáticas y Digestivas (CIBERehd), Instituto de Salud 3 Servei de Neurologia. Centre d’Esclerosi Múltiple de Carlos III, Madrid, Spain Catalunya (Cemcat). Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain 13 Vol.:(0123456789) Journal of Neurology Introduction increased [9]. In this population, these drugs are given in monotherapy for long periods, providing a homogeneous and According to the World Health Organization (WHO), 296 well-characterized population for addressing the real risk of million people are living with chronic hepatitis B [23]. Yet, HBVr associated with rituximab monotherapy. the statistics for subjects with evidence of resolved hepa- The aim of our study was to assess the risk of HBVr in titis B virus (HBV) infection is even higher, ranging from patients with evidence of resolved HBV infection (anti-HBc 3.5% in Western countries to more than 20% population in positive/HBsAg negative/undetectable HBV-DNA) treated high-endemicity areas [17, 19]. Patients with current HBV with monotherapy with anti-CD20 antibodies (rituximab or infection are at risk of reactivation when they are exposed ocrelizumab) for MS or NMOSD, in the absence of antiviral to immunosuppressant drugs, as well as those with resolved prophylaxis. HBV infection, though the risk is lower. The relevance of HBV reactivation (HBVr) lies in the potential risk of devel- oping acute hepatitis that can progress to chronic hepatitis Patients and methods and even liver failure with a high mortality rate [13]. The development of HBVr can also lead to a transient or per- Study design sistent discontinuation of immunosuppressant drugs which might negatively impact on the overall and progression-free HEBEM is an interventional prospective study that included survival rate of patients [10]. Risk of reactivation varies all consecutive adults with MS or NMOSD undergoing treat- according to the HBV status and the type of immunosup- ment with anti-CD20 monoclonal antibodies (rituximab, pressive treatment [15]. Rituximab-containing regimens ocrelizumab) with evidence of resolved HBV infection. account for the highest incidence of HBVr, with up to 55% of From August 2019 to August 2022, all patients with MS haematological patients, especially if undergoing R-CHOP, or NMOSD attended at the Centre d’Esclerosi Múltiple de experiencing increases in HBV-DNA levels or reverse sero- Catalunya (Cemcat) were tested for viral hepatitis B markers conversion to HBsAg in those with resolved HBV infection prior to starting anti-CD20 in monotherapy. Ocrelizumab [11]. This fact has turned up in the accepted worldwide rec- was administered as a single 600 mg IV infusion every ommendation of antiviral prophylaxis for onco-hematolog- 6 months, except for the initial 600 mg dose that is adminis- ical subjects on rituximab, regardless of whether they are tered as two separate IV infusions of 300 mg. Rituximab was HBsAg carriers or just anti-HBc-positive individuals [1, 20]. administered at a dose of 2000 mg (two courses of 1000 mg Chronic HBV individuals or those with occult HBV infec- IV infusions separated by 2 weeks); usually, after the first tion treated with rituximab seem to present a high incidence year of treatment, if the response was considered adequate, of HBVr even in non-haematological settings [6, 7, 25]. patients were maintained with a lower dose (1000 mg every However, regarding patients with resolved HBV infection, 6 months). later data have pointed out that the hazard associated with The HBV markers encompassed HBsAg and anti-HBc. anti-CD20 monoclonal antibodies in non-haematological Moreover, anti-HBs and HBV-DNA were also tested in subjects may be quite low [3, 22]. For instance, a cohort all anti-HBc positive subjects. The inclusion criteria were including all anti-HBc-positive/HBsAg-negative subjects patients with resolved HBV infection (defined by the pres- treated with rituximab from 2009 to 2013 reported cases of ence of anti-HBc positive and HBsAg negative with or with- reactivation just in those with underlying lymphoma treated out anti-HBs and undetectable HBV-DNA) monotherapy with polychemotherapy, without cases among other indi- with anti-CD20 monoclonal antibodies for MS or NMOSD cations for rituximab [8]. Nevertheless, results from anti- [1]. Exclusion criteria encompassed concomitant use of HBc-positive individuals derive from retrospective studies other immunosuppressant drugs than anti-CD20 agents, including a limited and heterogeneous cohort of patients, including any dose of daily corticosteroids except for pulses, mainly affected by rheumatological disorders and treated and antiviral prophylaxis with any nucleos(t)ide analogue, with a highly variable number and types of immunosup- including TDF-containing regimens for human immunode- pressant drugs [12]. ficiency virus (HIV) infection. All included patients under- Multiple sclerosis (MS) is the most common inflam- went a clinical and blood test evaluation every 6 months in matory-demyelinating disease of the central nervous sys- order to assess the risk of HBVr in this population. tem. It has been estimated that more than 2 million people HBV reactivation was defined by a 2-log increase in worldwide are suffering from MS or a neuromyelitis optica HBV-DNA levels or reverse seroconversion to positive spectrum disorder (NMOSD) [21]. In recent years, the use HBsAg [2]. Pre-emptive antiviral therapy was to be started of B-cell–targeted agents, mainly rituximab and ocreli- in all patients who met the criteria for HBVr during follow- zumab, to treat these neurological disorders has dramatically up, regardless of the ALT values or liver function tests. 13 Journal of Neurology This study was approved by the Vall d’Hebron Hospi- Results tal ethics committee and the Spanish Agency of Medicines and Medical Devices (Code: MMR-RIT-2019-01; Date Characteristics of all patients treated with anti‑CD20 02/10/2019), and was conducted in compliance with the antibodies principles of the Declaration of Helsinki, Good Clinical Practice guidelines and local regulatory requirements. All Overall, 540 patients with MS or NMOSD underwent anti- included patients signed the informed consent for participa- CD20 therapy during the period of study. The majority tion in the present study. (73.2%) received rituximab and 144 (26.6%) ocrelizumab. Three-hundred and forty-two were women (63.3%). The Methods mean age was 46.6 (SD 10.8) years and the main indication for anti-CD20 therapy was MS (92.9%). Baseline characteristics of the included patients were col- All patients tested negative for HBsAg, anti-HCV and lected and included age, gender, race, prior medical condi- HIV. Overall, 28 subjects were anti-HBc positive, therefore tions and surgical history, type of MS or NMOSD and previ- the prevalence of resolved HBV infection in the cohort was ous and current specific treatments. A blood test including 5.2%. Anti-HBc-positive subjects were older than those neg- HBV serologies (HBsAg, anti-HBc, anti-HBs), HBV-DNA ative (53.9 vs. 46.2 years, p < 0.001). Likewise, the preva- and liver biochemistry was performed. Prospective follow- lence of anti-HBc positivity was higher among individuals up every 6 months included analytical screening for HBVr, aged over 50 years in contrast to those younger (9.4% vs. and clinical events such as progression of the neurological 2.7%, p = 0.001). Moreover, anti-HBc-positive patients were disorder, need of pulses of corticosteroids, changes in spe- more frequently male, although this difference did not reach cific therapy (intermittent/permanent discontinuation and statistical significance (46.4% vs. 36.1%, p = 0.183). Race reason), development of adverse events, especially infec- distribution was slightly different in patients with resolved tious complications, death and lost to follow-up. In those HBV infection compared with those without evidence of patients who required discontinuation of anti-CD20 therapy, prior HBV, with a higher rate of non-Caucasian population screening of HBVr was continued for the next 12 months. (Caucasian: 89.3% vs. 95.9%, African: 7.1% vs. 1.4%, Asian: Serological markers for HBV (HBsAg, anti-HBc, and 3.6% vs. 1.4%, Hispanic: 0% vs. 1.4%, p = 0.085). Preferred anti-HBs) were analysed by commercial enzyme immuno- anti-CD20 agent did not differ in the group of anti-HBc- assays. The lower limit of quantification of anti-HBs was positive individuals in comparison with the overall cohort 3.10 mIU/mL and the upper limit, 1000 mIU/mL. Serum (rituximab: 78.6% vs. 73.0%, p = 0.346). The rate of subjects HBV-DNA was quantified by PCR (COBAS 6800 HBV test with baseline detectable anti-HBs titers was greater among (Roche Diagnostics, Mannheim, Germany): lower limit of those with resolved HBV infection in comparison with anti- quantification, 20 IU/mL and lower limit of detection, 10 IU/ HBc-negative subjects (75.0% vs. 23.9%, p < 0.001). mL. Baseline characteristics of patients with resolved Statistical analysis HBV infection treated with anti‑CD20 antibodies without antiviral prophylaxis Normally-distributed quantitative variables were com- pared with the paired Student t test and expressed as the Baseline characteristics of the 28 anti-HBc-positive indi- mean ± standard deviation (SD). Variables with a non-nor- viduals are summarized in Table 1. Briefly, 15 (53.6%) were mal distribution were analysed with the Mann–Whitney U female, median age 55 years and mainly Caucasian (89.3%). test and expressed as the median and interquartile range. All patients suffered from MS except two with NMOSD. Categorical variables were compared using the chi-square or Twenty-two (78.6%) subjects with resolved HBV infection Fisher exact test, as appropriate, and expressed as frequen- received therapy with rituximab and 6 (21.4%) ocrelizumab. cies and percentages. P values < 0.05 were considered statis- The majority of anti-HBc-positive subjects (96.4%) had tically significant. All analyses were carried out using Stata been previously treated with at least another immunomodu- version 16 (from StataCorp, College ​​Station, Texas, USA). latory drug prior to the anti-CD20 therapy, as summarized in Fig. 1A. The prior most common drugs were corticoster- oids pulses and interferon (Fig. 1B). Median time between the diagnosis of the neurological disease and the beginning of anti-CD20 therapy was 10.5 months. At the beginning of either rituximab or ocrelizumab, all patients presented normal aminotransferase levels and, according to the study 13 Journal of Neurology Table 1  Baseline characteristics of subjects with resolved HBV infec- Hepatitis B reactivation and clinical outcomes tion treated with anti-CD20 monoclonal antibodies of anti‑HBc‑positive patients Anti-HBc- positive subjects Median follow-up of the cohort of anti-HBc-positive sub- N = 28 jects was 3.1 years (IQR 2.1–4.0) and the median number Female gender 15 (53.6%) of cycles of anti-CD20 antibodies 6 (3–7) cycles, with a Age, years 55.0 (49.7–57.5) median cumulative dose of 8.5 g (IQR 5.8–11.2) of rituxi- Ethnicity mab and 3 g (IQR 1.8–3.8) of ocrelizumab. No cases of Caucasian 25 (89.3%) HBV reactivation were observed despite the lack of antiviral African 2 (7.1%) prophylaxis in this cohort including 83.6 patient-years at Asian 1 (3.6%) risk. The individual follow-up of anti-HBc-positive subjects Tobacco use 10 (34.5%) is shown in Fig. 2. Demyelinating disease One subject included in this study received a 3-dose cor- SPMS 13 (46.4%) ticosteroid pulse (dose of 1 gr per day) due to a potential RRMS 8 (28.6%) relapse of the disease (myelitis). Among the 22 patients PPMS 5 (17.9%) treated with rituximab, dose adjustment was carried out in NMOSD 2 (7.2%) 17 (77.3%) individuals, the majority according to protocol Comorbidities due to acceptable disease control, and in 2 patients due to Arterial hypertension 8 (27.6%) recurrent infections (one ophthalmic herpes during the first Dyslipidemia 6 (20.7%) cycle of rituximab; one due to recurrent urinary infections) Diabetes mellitus 2 (6.9%) and in one because of colitis as adverse event (Fig. 2). Depressive disorder 14 (48.3%) Overall, anti-CD20 therapy was permanently discon- Prior immunomodulatory therapy 27 (96.4%) tinued in 4 (14.3%): 1 due to pregnancy aspiration, 1 by Prior need of corticosteroids pulses 23 (82.1%) decision of the patient during the SARS CoV-2 pandemic, Number of previous pulses 6 (4–13) 1 due to recurrent urinary infections despite previous dose Time (months) from diagnosis of MS/ NMOSD 10.5 (5.5–18.0) adjustment and 1 because of adverse event (colitis). Main to anti-CD20 therapy outcomes and events associated with anti-CD20 are shown Current anti-CD20 agent in Table 2. During the period of study, no changes in anti- Rituximab 22 (78.6%) HBs titers were observed, including the rate of subjects Ocrelizumab 6 (21.4%) with anti-HBs over 10 mIU/mL (Table 3). Lymphocytes count, ×10E9/L 1.95 (1.60–2.38) Platetets, ×10E9/L 245 (211–288) AST, IU/mL 21 (17–25) Discussion ALT, IU/mL 20 (15–27) GGT, IU/mL 22 (15–59) Herein, we present data from a prospective study that Anti-HBs >10mIU/mL 21 (75.0%) follows 83.6 patient-years with resolved HBV infection Anti-HBs, mIU/L 105.5 (0–609.3) treated with anti-CD20 monoclonal antibodies in mono- therapy, and no cases of HBV reactivation were observed, Variables are expressed as n (%) or median (IQR) despite the lack of antiviral prophylaxis. MS multiple sclerosis, NMOSD neuromyelitis optica spectrum disor- der, PPMS primary progressive multiple sclerosis, RRMS remittent- The widespread use of rituximab and other anti-CD20 recurrent multiple sclerosis, SPMS secondary progressive multiple in multiple diseases, mainly autoimmune disorders such sclerosis, AST aspartate aminotransferase, ALT alanine aminotrans- as rheumatoid arthritis, systemic lupus erythematosus and ferase, GGT​gamma-gluamyltranferase. MS, has raised the question about the risk of HBVr linked with these drugs in non-hematological settings. These patients have a different profile, with a not so considerable degree of immunosuppression, and in most of the cases, with the anti-CD20 treatment being used as monotherapy. protocol, in all cases, HBV-DNA was undetectable at inclu- The progressive and profound B-cell depletion pro- sion. Median baseline anti-HBs titers were 105.5 mUI/mL, duced by the repeated treatment with anti-CD20 drugs with all patients but 7 presenting titers over the 10 mIU/mL is the supposed mechanism associated with HBVr [24]. cut-off. However, control of HBV infection is mainly driven by memory T-cell immunity [4], whose response is not so altered by these drugs [18]. 13 Journal of Neurology Fig. 1  Previous immunomodulatory drugs received by patients with resolved HBV infection. A Number of prior immunomodulatory drugs. B Type of prior immunomodulatory drugs received by subjects with resolved HBV infection Fig. 2  Individual follow-up of patients with resolved HBV infection treated with anti-CD20 antibodies without antiviral prophylaxis In order to assess the real risk of HBVr, patients with population usually receive either rituximab or ocrelizumab resolved HBV infection undergoing anti-CD20 agent to in monotherapy; the high efficacy of the drug precludes the treat MS or NMOSD are an excellent group of study: this use of corticosteroids as shown in our cohort where only 13 Journal of Neurology Table 2  Clinical events in the cohort of subjects with resolved HBV our study. Despite the fact the follow-up of the included infection treated with anti-CD20 monoclonal antibodies without anti- subjects was three years, which is a relatively short period viral prophylaxis of time considering some infections associated with rituxi- Anti-HBc-positive mab [16], patients were exposed to repeated doses of the individuals N = 28 drugs and based on data from hematological cohorts, risk Anti-CD20 therapy duration of HBVr is especially relevant after the second anti-CD20 Months of therapy 37.9 (25.6–48.5) exposure [14]. Number of cycles 6 (3–7) The strengths of our study are that this is the first prospec- HBV reactivation 0 (0%) tive study in a very homogeneous group of patients with Need of corticosteroids pulses 1 (3.6%) resolved HBV infection undergoing anti-CD20 monotherapy, Infectious complications 3 (10.7%) without HBV prophylaxis. Another merit was the centralized Permanent discontinuation of therapy 4 (14.3%) diagnosis and follow-up of patients at the CEMCAT unit, Rituximab dose adjustment due to infections/side 3 (13.6%) and the periodical 6-month supervision by the Liver Unit in effects (N = 22) order to ensure proper ruling out of HBV reactivation. In summary, in our cohort anti-CD20 monoclonal treat- Variables are expressed as n (%) or median (IQR) ment used in monotherapy was not associated with risk of HBV reactivation in subjects with resolved HBV infection Table 3  Evolution of anti-HBs titters in the cohort of subjects with and multiple sclerosis or diseases of the spectrum of optic resolved HBV infection treated with anti-CD20 agents without anti- neuromyelitis at medium term follow-up, despite the lack viral prophylaxis of antiviral prophylaxis. Our results suggest the possibility Baseline Last follow-up p value of pre-emptive management of HBV reactivation in these patients, although our findings need to be confirmed in a Anti-HBs (mUI/mL) titers 105.5 (0–609.3) 92 (13–493.5) 0.502 multicentric cohort including more patients and a longer Anti-HBs > 10mUI/mL 21 (75.0%) 22 (78.6%) 0.749 follow-up. Variables are expressed as n (%) or median (IQR) Acknowledgements English writing support was provided by Fidelma Greaves. one subject developed a relapse of the neurological disor- Funding Open Access Funding provided by Universitat Autonoma de der requiring methylprednisolone pulses; and the underly- Barcelona. The authors did not receive support from any organization for the submitted work. ing degree of immunosuppression is low since the previous use of immunomodulatory drugs is frequent whereas prior Data availability The data that support the findings of this study are immunosuppression is rare. Moreover, inclusion criteria available from the corresponding author upon request. for entering our study encompassed a baseline undetect- able HBV-DNA in order to avoid the risk linked to the Declarations occult hepatitis B state. Our results are especially relevant Conflicts of interest The authors have no relevant financial or non- in view of the low rate of screening for HBVr in patients financial interests to disclose. with MS undergoing rituximab-containing regimens. A recently published multicentre study including 53 anti- Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- HBc-positive subjects showed that 21 received antiviral tion, distribution and reproduction in any medium or format, as long prophylaxis, and only 13 had HBV DNA monitoring dur- as you give appropriate credit to the original author(s) and the source, ing therapy for assessment of HBVr [5]. provide a link to the Creative Commons licence, and indicate if changes In view of our results, in patients with resolved HBV were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated infection and MS or NMOSD treated with anti-CD20 anti- otherwise in a credit line to the material. If material is not included in bodies, we recommend monitoring for HBsAg and HBV- the article's Creative Commons licence and your intended use is not DNA every 6 months and HBV therapy only in case of permitted by statutory regulation or exceeds the permitted use, you will evidence of reactivation. need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. Our study has some limitations. Firstly, the relatively limited number of subjects included, since this was a uni- centric study. However, the CEMCAT is the reference center in all Catalonia for patients with MS and NMOSD leading to more than 500 subjects treated with anti-CD20 antibodies during the 3-year period of study, including 28 with resolved HBV infection who were recruited for 13 Journal of Neurology References HBcAb(+) carriers receiving rituximab for rheumatoid arthritis. Sci Rep 10:2456 13. 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