Reactivation of hepatitis B virus infection - an important aspect of multifaceted problem.

In this editorial we comment on the article published in the recent issue of the World Journal of Gastroenterology. We focus specifically on the problem of occult hepatitis B virus (HBV) infection, that is a result of previous hepatitis B (PHB) and a source for reactivation of HBV. The prevalence of PHB is underestimated due to the lack of population testing programs. However, this condition not only complicate anticancer treatment, but may be responsible for the development of other diseases, like cancer or autoimmune disorders. Here we unveil possible mechanisms responsible for realization of these processes and suggest practical approaches for diagnosis and treatment.

Impact of universal hepatitis B virus (HBV) screening using chemotherapy orders on the HBV reactivation in cancer patients.

INTRODUCTION: Hepatitis B virus (HBV) reactivation (HBVr) induced by chemotherapy in patients with resolved or chronic infection can lead to severe consequences. Despite recommendations, rates of HBV screening before chemotherapy are low due to poor recognition of risk factors by clinicians. The aim of the study is to assess whether routine HBV screening using universal HBV screening on chemotherapy orders (CO) could reduce HBVr incidence. METHODS: This is a 1-year retrospective single-center observational study of patients who received intravenous chemotherapy post implementation of CO. We compared the incidence of HBVr in three groups of patients: those screened through CO (group 1), those screened by the medical team (group 2), and those not screened (group 3). RESULTS: On a total of 1374 patients, 179 of 206 patients were screened as requested on CO (group 1) and 421 by the medical team (group 2), whereas 747 patients were not screened (group 3). Only one HBVr occurred, and no difference was seen on the incidence of HBVr between group 1 and group 3 (0% vs 0.1%; p = 1.00), probably because of a lack of follow-up after chemotherapy. Follow-up for HBVr was imperfect in group 1 and group 2 (16.7% vs 5.6%; p = 0.32). Screening was done for 92% of patients on anti-CD20 therapy. In group 3, 89 patients had ALT elevation during chemotherapy but only 17 (19%) were tested for HBVr. CONCLUSION: Systematic HBV detection requested on CO is an effective way to obtain a high percentage of patients with adequate screening, particularly when chemotherapy is at high risk of HBVr. Nevertheless, this screening method do not guarantee optimal follow-up and requires improvements.

Low risk of hepatitis B virus reactivation in membranous nephropathy patients with resolved infection undergoing rituximab-based regimens without antiviral prophylaxis.

INTRODUCTION: Patients with resolved hepatitis B virus infection undergoing rituximab are at risk of hepatitis B virus reactivation without antiviral prophylaxis. However, the risk in such patients treated with rituximab-based regimens for membranous nephropathy is not clear. We evaluated the risk of hepatitis B virus reactivation in membranous nephropathy patients with resolved infection undergoing rituximab-based regimens without antiviral prophylaxis. METHODS: Clinical data of 51 membranous nephropathy patients with resolved hepatitis B virus infection undergoing rituximab-based regimens without antiviral prophylaxis were retrospectively analyzed. Among these, 21 patients were followed for more than 1 year after rituximab discontinuation. The clinical data collected aimed to assess patients' responses and the risk of hepatitis B virus reactivation during and after rituximab treatment. RESULTS: 30/51 (58.8 %) patients reached complete or partial remission at 12 months. None of the patients experienced HBsAg seroreversion during rituximab treatment. Alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase and total bilirubin levels, as well as the numbers of patients who exceeded the upper limits of normal for alkaline phosphatase and prothrombin time, did not show any statistically significant difference during rituximab-based therapy. Neither did the anti-HBs level, the number of patients with protective anti-HBs titers exceeding 10 U/L, nor the levels of CD19+ B cells, CD4+ T cells, CD8+ T cells, and natural killer cells. Among the 21 patients followed for 12 (ranging from 12 to 19) months after rituximab discontinuation, no hepatitis B virus reactivation was observed. The mean anti-HBs level and the number of patients with anti-HBs titers over 10 U/L did not show any statistically significant difference during the extended follow-up of 33 patient-years. Neither did the CD4+ T cell, CD8+ T cell, nor the natural killer cell counts. One patient presented with an ALT level that exceeded the baseline value by three times and reached above 100 U/L, accompanied by elevations in AST, GGT, and ALP levels. Meanwhile, the anti-HBs titer was 816.09 U/L, and HBsAg was negative. CONCLUSION: The administration of rituximab-based regimens in membranous nephropathy patients with hepatitis B virus resolved infection leads to a low risk of hepatitis B virus reactivation without antiviral prophylaxis. Patient's immune status, drug combination, rituximab strategy should be fully evaluated when considering antiviral prophylaxis therapy.

Navigating the complex terrain of hepatitis B virus reactivation in the era of Bruton tyrosine kinase inhibitors.

In this editorial, we offer a summary of the risk associated with hepatitis B reactivation (HBVr) in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase (BTK) inhibitors, with insights derived from current studies. Furthermore, we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such treatments. This framework is essential for identifying those at increased risk of HBVr, enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy.

Impact of Hepatitis B Surface and Core Antibody Levels on Hepatitis B Virus Reactivation.

Hepatitis B virus reactivation (HBV-R) is a serious complication that can occur in patients with resolved HBV infection during cancer chemotherapy. We examined the levels of HBV surface antibody (HBsAb) and HBV core antibody (HBcAb) to assess the incidence of HBV-R in cancer patients including hematopoietic stem cell transplantation (HSCT) and rituximab administration. This retrospective cohort study included 590 patients with resolved HBV infection. The incidence of HBV-R was evaluated 761.5 (range, 90-3898) days after the inititiation of chemotherapy. Of the patients, 13 (2.2%) developed HBV-R after the start of chemotherapy. All 13 patients exhibited lower HBsAb (<100 mIU/mL) levels at baseline. A higher level of HBcAb (≥100 cut off index (C.O.I.)) was a possible risk factor for HBV-R as well as HSCT and rituximab administration. The simultaneous presence of HBsAb <100 mIU/mL and HBcAb ≥100 C.O.I. increased the risk of HBV-R by 18.5%. Patients treated with rituximab were at a higher risk of HBV-R (18.4%) despite having HBcAb <100 C.O.I. Our results suggest that assessment of HBsAb and HBcAb levels prior to the chemotherapy is important for identifying patients at high risk of HBV-R, especially in solid cancers without HSCT and rituximab administration.

Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies.

Hepatitis B virus (HBV) reactivation is a clinically significant challenge in disease management. This review explores the immunological mechanisms underlying HBV reactivation, emphasizing disease progression and management. It delves into host immune responses and reactivation's delicate balance, spanning innate and adaptive immunity. Viral factors' disruption of this balance, as are interactions between viral antigens, immune cells, cytokine networks, and immune checkpoint pathways, are examined. Notably, the roles of T cells, natural killer cells, and antigen-presenting cells are discussed, highlighting their influence on disease progression. HBV reactivation's impact on disease severity, hepatic flares, liver fibrosis progression, and hepatocellular carcinoma is detailed. Management strategies, including anti-viral and immunomodulatory approaches, are critically analyzed. The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation. In conclusion, this comprehensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation. With a dedicated focus on understanding its implications for disease progression and the prospects of efficient management strategies, this article contributes significantly to the knowledge base. The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches, ultimately enhancing disease management and elevating patient outcomes. The dynamic landscape of management strategies is critically scrutinized, spanning anti-viral and immunomodulatory approaches. The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.

Risk of hepatitis B virus reactivation in people with multiple sclerosis treated with ocrelizumab: an observational study from Turkey.

BACKGROUND: The risk of hepatitis B virus (HBV) reactivation remains unclear in people with multiple sclerosis (MS) receiving ocrelizumab. We aimed to assess HBV seroprevalence and reactivation risk in MS patients on ocrelizumab and to evaluate the effectiveness of antiviral prophylaxis against HBV reactivation. METHODS: In this single-center, cross-sectional study, 400 people with MS receiving ocrelizumab were screened for HBV at baseline and antiviral prophylaxis was implemented based on serological results. Patients were monitored for HBV reactivation, and outcomes were analyzed. RESULTS: Among 56 (14%) patients who had serology compatible with occult or resolved HBV infection, 49 (85.7%) received antiviral prophylaxis regularly and had no HBV reactivation during the follow-up. Reactivation of HBV occurred in 2 out of 7 (28.6%) patients who did not receive antiviral prophylaxis and in one patient who did not adhere to the prophylaxis regimen. All patients with reactivation had anti-HBs levels below 100 mIU/mL and the median titer was significantly lower than the patients with no HBV reactivation (p = 0.034). CONCLUSION: This study highlights a 14% anti-HBc positivity, indicating a potential risk for HBV reactivation in people with MS receiving ocrelizumab. This suggests the importance of vigilant monitoring and the implementation of prophylactic measures. Our recommendation emphasizes antiviral prophylaxis, particularly for patients with low anti-HBs, and a pre-emptive strategy for others.

Change in Hepatitis B Surface Antibody Titers After Chemotherapy in Patients With Hematological Malignancies.

Background The change in hepatitis B surface antibody (anti-HBs) titers after chemotherapy (CT) in patients with hematological malignancy, affecting factors, and its clinical implications have not been sufficiently understood. Therefore, we aim to evaluate the change in anti-HBs titers and hepatitis B virus reactivation (HBVr) after CT. Methods This retrospective study enrolled patients with hematological malignancies who received CT between 2013 and 2021. All patients were followed up for HBVr and a change in anti-HBs titers for one year. Results Overall, 192 patients were included. In total, 33.9% of the patients were anti-HBs (+) and 26% of the patients were anti-HBc (+) ± anti-HBs (+). Hepatitis B virus (HBV) prophylaxis was given to 35 (70%) of 50 Anti-HBc (+) patients. Tenofovir disoproxil fumarate and entecavir prophylaxis were initiated in 25 (71.4%) and 10 (28.6%) patients, respectively. A significant decrease was found in anti-HBs titers of all patients (p=0.017). A significant decrease was also found in anti-HBs titers of HBc IgG (+) patients and those who received four or more courses of CT (p=0.025; p=0.041). HBVr was not diagnosed in any of the patients. Conclusion Chemotherapeutic agents administered for hematological malignancy have serious immunosuppression effects. In these patients, anti-HBs titers may decrease or become negative one year after CT. Anti-HBs titer before CT or its change after CT may not constitute a risk for HBVr patients who received HBV prophylaxis in line with current guidelines and these recommendations.

Immune checkpoint inhibitor use and the incidence of hepatitis B virus reactivation or immune-related hepatitis in non-small cell lung cancer patients with chronic hepatitis B.

BACKGROUND: The safety of immune-checkpoint inhibitors (ICIs) has not been thoroughly investigated in non-small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B infection (OBI). The authors analyzed the incidence of hepatitis B virus (HBV) reactivation, immune-related hepatitis and jaundice in NSCLC patients in a real-world setting. METHODS: A total of 1277 NSCLC patients treated with ICIs were analyzed. Among them, 52 patients were hepatitis B surface antigen (HBsAg) (+) (group A, CHB), 759 patients were HBsAg (-)/hepatitis B core antibody immunoglobulin G (anti-HBc IgG) (+) (group B, OBI), and 466 patients were HBsAg (-)/anti-HBc IgG (-) (group C). Among the 52 patients with CHB, 38 (73.1%) were receiving antiviral therapy. The primary end point was HBV reactivation, immune-related hepatitis, and jaundice. The secondary end points included other immune-related adverse events and efficacy. RESULTS: HBV reactivation was observed in two patients (0.2%) who were both in group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed in 14.3% (2 of 14 patients). The incidences of immune-related hepatitis and jaundice were comparable among the three groups. The incidence of ≥grade 3 other immune-related adverse events and efficacy were all comparable among the three groups (p > .05 for all comparisons). CONCLUSIONS: In this large, real-world cohort study, the safety and efficacy of ICIs were comparable in patients with CHB and OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with OBI, the risk of HBV reactivation was minimal.

Hepatitis B reactivation in cancer patients receiving immune checkpoint inhibitors: a systematic review and meta-analysis.

BACKGROUND: Immunotherapy shows promise as a treatment option for various cancers. However, there is growing concern over potential complications from hepatitis B virus (HBV) reactivation after checkpoint blockade immunotherapy. Although most of the previous clinical trials on immune checkpoint inhibitors (ICIs) excluded patients with HBV, a few case reports and retrospective studies of HBV reactivation have been published. The aim of this study is to assess the risk of hepatitis B virus reactivation (HBVr) in patients receiving ICIs for advanced cancer. METHODS: English and Chinese language literature published prior to April 30, 2023, was searched in PubMed, EMBASE, Web of Science, Cochrane, SinoMed, CNKI and Wanfang Data for studies reporting HBVr rates in cancer patients treated with ICIs. A pooled risk estimate was calculated for HBVr rates with 95% confidence intervals (CI). RESULTS: Data from 34 studies including 7126 patients were retrieved and analyzed. The pooled HBVr rate in cancer patients treated with ICIs was 1.3% (I2 = 90.44%, 95% CI: 0.2-2.9%, P < 0.001). Subgroup analysis revealed that patients diagnosed with hepatocellular carcinoma (HCC), HBV carriers, and patients from Asian regions or in developing countries have a higher rate of HBVr. CONCLUSIONS: Our meta-analysis demonstrated a low risk of HBVr in patients treated with ICIs for advanced cancer. ICI treatment may be safely used in patients with existing HBV infection or chronic hepatitis B, accompanied by regular monitoring and appropriate antiviral prophylaxis if necessary.

HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) predicts a high risk of hepatitis B reactivation in patients with B-cell lymphoma receiving rituximab based immunochemotherapy.

Patterns of hepatitis B virus reactivation (HBV-R) in HBsAg (-)/HBcAb (+) patients with B-cell non-Hodgkin lymphoma (NHL) receiving rituximab based immunochemotherapy have not been well described. The retrospective study included 222 HBsAg (-)/HBcAb (+) NHL patients as training cohort and 127 cases as validation cohort. The incidence of HBV-R in HBsAg (-)/HBcAb (+) B-cell NHL patients was 6.3% (14/222), of which that in HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) population was 23.7% (9/38). Multivariate analysis showed that HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) correlated with a high risk of HBV-R in B-cell lymphoma patients (training phase hazard ratio [HR], 10.123; 95% confidence interval [CI], 3.389-30.239; p < 0.001; validation phase HR, 18.619; 95% CI, 1.684-205.906; p = 0.017; combined HR, 12.264; 95% CI, 4.529-33.207; p < 0.001). In the training cohort, the mortality rate of HBsAg (-)/HBcAb (+) B-cell NHL caused by HBV-R was 14.3% (2/14) while that for HBV reactivated HBsAg (-)/HBsAb (-)/HBeAg (-)/HBeAb (+)/HBcAb (+) population was up to 44.4% (4/9). As a high incidence of HBV-R and high mortality after HBV-R was found in HBsAg (-)/HBsAb (-)/HBcAb (+)/HBeAg (-)/HBeAb (+) patients with B-cell NHL receiving rituximab based immunochemotherapy, prophylactic antiviral therapy is recommended for these patients.

Hepatitis B virus reactivation associated with Janus kinase (JAK) inhibitors: a retrospective study of pharmacovigilance databases and review of the literature.

BACKGROUND: Recently, there have been clinical reports of hepatitis B virus reactivation (HBVr) related with Janus kinase (JAK) inhibitors. However, there were no studies to investigate the association between HBVr and different JAK inhibitors. RESEARCH DESIGN AND METHODS: This study was a retrospective review utilizing the FAERS pharmacovigilance database and a systematic literature search for all cases of HBVr reported with JAK inhibitors. Disproportionality analysis and Bayesian analysis were used in data detection to screen the suspected HBVr after the administration of different JAK inhibitors, based on the FDA Adverse Event Reporting System (FAERS) pharmacovigilance database from Q4 2011 to Q1 2022. RESULTS: There were a total number of 2097 (0.02%) reports of HBVr in FAERS, of which 41 (1.96%) were associated with JAK inhibitors. Baricitinib appeared to have the strongest signal among four JAK inhibitors, based on the highest reporting odds ratio (ROR = 4.45, 95% confidence interval [CI] 1.67-11.89). Ruxolitinib also showed signals, whereas no signals were detected among Tofacitinib and Upadacitinib. CONCLUSION: While there may be an association between JAK inhibitors and HBVr, it appears to be a numerically uncommon occurrence. Further studies are needed to optimize the safety profiles of JAK inhibitors.

A Hepatitis B Virus Reactivation Case Potentially Triggered by the Onset of Diffuse Large B Cell Lymphoma.

An 81-year-old man underwent rituximab-containing chemotherapy for chronic lymphocytic leukemia (CLL). Thirteen years after his last chemotherapy, he was diagnosed with hepatitis B virus (HBV) reactivation. He was then treated with entecavir, and improvement was seen in his liver injury. He developed diffuse large B cell lymphoma (DLBCL) after improvement in his hepatitis. Despite chemotherapy, he contracted the coronavirus disease 2019 (COVID-19) and died of COVID-19. We suspect that HBV reactivation was triggered by DLBCL. When HBV reactivation occurs a long time after chemotherapy has concluded, the onset of DLBCL should be considered.

Outcome of nucleos(t)ide analog cessation in patients with treatment for prevention of or against hepatitis B virus reactivation.

AIM: We retrospectively investigated patients with administration of nucleos(t)ide analogs (NAs) for prevention of or against hepatitis B virus (HBV) reactivation, and their clinical outcomes after cessation of the NA. METHODS: We enrolled 180 patients who were positive for HBsAg when they started immunosuppressive therapy or chemotherapy and an NA was administered to prevent HBV reactivation (HBV carrier group), and 82 patients with resolved HBV infection who started administration of an NA after HBV reactivation (de novo HBV group). Cessation of the NA depended on each physician's judgment without definite criteria. RESULTS: A total of 27 patients in the HBV carrier group and 22 in the de novo HBV group stopped NA therapy. In the HBV carrier group, 16 patients experienced virological relapse, which was defined as HBV DNA levels ≥20 IU/ml, and one with hematological disease had an alanine aminotransferase flare after cessation of NA. Of the 16 patients, the NA was reintroduced in three, whereas, the remaining 13 had low levels of HBV DNA and no alanine aminotransferase flare. In the de novo HBV group, virological relapse occurred in six patients, and one with hematological disease had an alanine aminotransferase flare after cessation of the NA. The NA was reintroduced in four of the six patients. CONCLUSIONS: We may be able to consider to cease NA therapy proactively in HBV carriers and resolved patients with non-hematological disease, if their primary diseases are under remission after completion of immunosuppressive therapy or chemotherapy. However, careful follow up is necessary after stopping NA therapy.

A case report of hepatitis B virus reactivation 19 months after cessation of chemotherapy with rituximab.

A 72-year-old woman presented to our hospital with elevation of serum transaminases. Her blood tests showed the hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) negative. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were given for the diffuse large B-cell lymphoma. She didn't receive anti- hepatitis B virus (HBV) drug for the isolated HBcAb positive. HBV reactivation confirmed based on the serum HBV DNA detectable until 19 months after stopping R-CHOP regimen. HBV DNA became undetectable after 4 weeks therapy with Tenofovir alafenamide fumarate (TAF). Serum transaminases went down to normal 3 months later after receiving TAF. HBV reactivation is a substantial risk for patients with isolated HBcAb positive receiving rituximab-containing chemotherapy without anti- HBV drug. Regular monitoring with a frequency of 1-3 months is the basis for timely diagnosis and treatment of HBV reactivation. Serum transaminases abnormalities may be the initial manifestation of HBV reactivation.

Hepatitis B Reactivation Following Eradication of HCV with Direct-Acting Antiviral Drugs (DAAs) in a Cohort of Patients from Different Institutions in Egypt.

Background: Concerns about HBV reactivation (HBVr) have been raised with the introduction of DAA for HCV treatment. The aim of the study was to assess the risk of HBVr in chronic HCV patients during or after DAA. Methods: A cohort of 166 chronic HCV patients who were treated with SOF-based DAA regimens and initially positive for HBcAb total were evaluated; 10 HBsAg-positive, 156 had past HBV exposure (HBsAg-negative/HBcAb-positive). Laboratory investigations, including liver functions tests, HBV-DNA, LSM by Transient elastography, and ARFI together with serum markers of fibrosis; APRI and FIB-4 were done at baseline and after 12 weeks of DAAs therapy. HBV-DNA levels and liver functions were monitored for assessment of HBVr. Results: Virological HBVr was diagnosed by ≥ 1 log10 IU/ml HBV-DNA levels in 2/166 patients (1.2%) among the whole HCV cohort, who were initially positive for HBsAg; 20%. Clinical HBVr (>3 folds liver enzyme elevation) was detected in one patient with virological HBVr. Conversely, none of past HBV-infected patients experienced HBVr. All patients achieved SVR12 and had a significant decline in serum transaminases, bilirubin, APRI, and LSM measurements after HCV eradication. Conclusion: HBVr might be considered after successful eradication of HCV following DAAs therapy, especially among patients who are positive for HBsAg, while past HBV infection does not seem to be a predisposing condition to HBVr.

Hepatitis B Virus Reactivation Increased the Risk of Developing Hepatic Failure and Mortality in Cirrhosis With Acute Exacerbation.

Background and Aims: Hepatitis B virus (HBV) reactivation is a serious condition and has been extensively described in chemotherapeutic immunosuppressive population. However, little is known about HBV reactivation in immunocompetent patients with chronic hepatitis B (CHB). In this study, we evaluated the prevalence and the clinical significance of HBV reactivation in CHB patients with acute exacerbations. Method: Patients were screened from two prospective multicenter observational cohorts (CATCH-LIFE cohort). A total of 1,020 CHB patients with previous antiviral treatment history were included to assess the prevalence, risk factors, clinical characteristics of HBV reactivation, and its influence on the progression of chronic liver disease. Results: The prevalence of HBV reactivation was 51.9% in CHB patients with acute exacerbations who had antiviral treatment history in our study. Among the 529 patients with HBV reactivation, 70.9% of them were triggered by discontinued antiviral treatment and 5.9% by nucleos(t)ide analogs (NUCs) resistance. The prevalence of antiviral treatment disruption and NUCs resistance in patients with HBV reactivation is much higher than that in the patients without (70.9% vs. 0.2%, and 5.9% vs. 0, respectively, both p < 0.001). Stratified and interaction analysis showed that HBV reactivation was correlated with high short-term mortality in cirrhosis subgroup (HR = 2.1, p < 0.001). Cirrhotic patients with HBV reactivation had a significantly higher proportion of developing hepatic failure (45.0% vs. 20.3%, p < 0.001), acute-on-chronic liver failure (ACLF; 31.4% vs. 21.8%, p = 0.005), and short-term death (14.0% vs. 5.9% for 28-day, and 23.3% vs. 12.4% for 90-day, both p < 0.001) than those without. HBV reactivation is an independent risk factor of 90-day mortality for cirrhosis patients (OR = 1.70, p = 0.005), as well as hepatic encephalopathy, ascites, and bacterial infection. Conclusion: This study clearly demonstrated that there was a high prevalence of HBV reactivation in CHB patients, which was mainly triggered by discontinued antiviral treatment. The HBV reactivation strongly increased the risk of developing hepatic failure, ACLF and short-term death in HBV-related cirrhotic patients, which may suggest that HBV reactivation would be a new challenge in achieving the WHO target of 65% reduction in mortality from hepatitis B by 2030.

Risk of hepatitis B virus reactivation following treatment with abatacept: A retrospective study of international pharmacovigilance databases.

Background: Abatacept is a selective T-cell costimulation modulator approved for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, and psoriatic arthritis. Reports were recently published on hepatitis B virus reactivation (HBVr) in patients who were treated with abatacept. However, the literature is limited to case reports and series, and no study has investigated the relationship between HBVr and abatacept using extensive population-based databases. Methods: Using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database, we collected all cases of HBVr between Jan 1, 2006 and June 30, 2021, for abatacept and other drugs. Disproportionality was analysed using the reporting odds ratio (ROR), which was considered significant when the lower limit of the 95% CI was >1. We also conducted a confirmatory analysis in the European pharmacovigilance database, EudraVigilance. Findings: During the study period, 77,669 adverse cases were reported for abatacept use. There were 2889 reports of HBVr with any drug during this period, of which 55 were reported with abatacept. The ROR for HBVr with abatacept was significantly elevated at 4·80 (95% CI 3·68-6·27). All 55 cases of HBVr with abatacept were reported as serious adverse events. Of them, six individuals were hospitalised and four died. Among 832 reports of HBVr with any drug in EudraVigilance, 43 were reported with abatacept; the ROR was 8·99 (95% CI 6·61-12·23). Interpretation: We identified a positive signal between abatacept exposure and HBVr. Future prospective studies should further confirm the relationship and provide evidence to develop strategies involving pre-treatment screening, monitoring, and utilisation of antiviral prophylaxis when using abatacept in patients with rheumatic diseases. Funding: This work was supported by the Fundamental Research Funds for Central Universities (xjh012019063).

Association Between Depression or Anxiety and the Risk of Hepatitis B Flares: A Nationwide Population-Based Cohort Study.

Purpose: Depression and anxiety have been reported to increase the risk of infectious diseases and reactivation of latent infection. We conducted a nationwide population-based retrospective cohort study to determine the relationship between hepatitis B flares and depression or anxiety, utilizing outpatient and inpatient data from the Taiwan National Health Insurance Research database collected from 2000 to 2015. Patients and Methods: A total of 12,992 patients with chronic hepatitis B and newly diagnosed anxiety/depression, without advanced liver disease, were propensity score-matched for age, sex, and comorbidities in a 1:4 ratio to 51,968 controls with chronic hepatitis B without depression/anxiety or advanced liver disease. Both groups were followed-up until December 31, 2015. Cox proportional hazards regression was used to determine the risk factors for hepatitis B flares. The Log rank test and Kaplan-Meier analysis were performed to assess differences in the cumulative incidence of hepatitis B flares according to anxiety/depression status. Results: The incidence of hepatitis B flares was higher in the depression/anxiety cohort than in the control cohort (log-rank; p < 0.001). Patients with depression/anxiety had a significantly higher incidence rate of hepatitis B flares than those without depression/anxiety (3017 per 105 person-years versus 2042 per 105 person-years, p = 0.003). After adjusting for age and comorbidities, anxiety/depression was independently associated with an increased risk of hepatitis B flares (hazard ratio, 1.173; 95% confidence interval, 1.033-1.277; p = 0.003). Conclusion: This analysis suggests that in patients with chronic hepatitis B without advanced liver disease, those with concomitant depression or anxiety may be at higher risk of hepatitis B flares.

Hepatitis B Virus Vaccination after Allogeneic Hematopoietic Cell Transplantation Prevents Post-Transplantation Hepatitis B Virus Reactivation.

Hepatitis B virus (HBV) reactivation in allogeneic hematopoietic cell transplantation (HCT) recipients with evidence of pretransplantation resolved HBV infection is an important cause of morbidity, usually occurring 1 year or later after HCT. We retrospectively studied a cohort of allogeneic HCT recipients with resolved HBV infection, some of whom were vaccinated for HBV following transplantation, to understand whether post-HCT HBV vaccination influenced the risk of HBV reactivation. The study included all patients with resolved HBV who underwent allogeneic HCT at our institution between January 1, 2000, and December 31, 2015, where HBV vaccination starting at 1 year after HCT became standard in 2012 and antiviral prophylaxis is not used. Resolved HBV infection was defined as positive HBV-core IgG (HBcAb), negative HBV-surface antigen (HBsAg), and undetectable HBV DNA before HCT. HBV reactivation was defined as the development of detectable HBsAg and HBV DNA after HCT. Follow-up for outcomes concluded on January 1, 2018. Among 136 patients with resolved HBV infection before HCT, 19 developed reactivation during follow-up (cumulative incidence, 14%). The median time to HBV reactivation was 21 months (range, 2 to 47 months). When accounting for competing risks, the cumulative incidence of HBV reactivation among HCT recipients who survived for 1 year or longer after transplantation without early HBV reactivation and were HBV vaccinated versus those who were unvaccinated was 2.9% versus 10.0% at 2 years post-HCT and 6.6% versus 26.5% at 4 years post-HCT (P = 0.03, Gray's test). In a time-dependent Cox model, the adjusted hazard ratio (aHR) of HBV reactivation in patients with a pretransplantation HBsAb level >10 IU/L was 0.34 (95% confidence interval [CI], 0.13 -0.90). The aHR of HBV reactivation in patients who were vaccinated with 2 or more doses of recombinant HBV vaccine after HCT was 0.18 (95% CI, 0.04-0.80) compared with those who received 1 or no post-HCT vaccine doses. HBV reactivation is a late complication of allogeneic HCT in at-risk recipients, particularly in those with low pre-HCT HBsAb. HBV vaccination starting at 1 year after HCT may be protective.