Hepatitis B Virus Reactivation Research Articles

THU450 - The low incidence of HBV reactivation among anti-HBc+ subjects on immunotherapy reduces the impact of suboptimal screening rate

THU450 - The low incidence of HBV reactivation among anti-HBc+ subjects on immunotherapy reduces the impact of suboptimal screening rate

THU394 - Benign course of HBV reactivations during DAAs in untreated ENI with HBV-HCV co-infections correlates with different HBsAg kinetics compared to NAs treated CHB patients

THU394 - Benign course of HBV reactivations during DAAs in untreated ENI with HBV-HCV co-infections correlates with different HBsAg kinetics compared to NAs treated CHB patients

Hepatitis B virus reactivation in patients undergoing immune checkpoint inhibition: systematic review with meta-analysis.

Immune checkpoint inhibitors (ICIs) have been explored as first-line treatment in various types of previously untreatable malignancies, while limited evidence is available on the management of hepatitis B virus (HBV) in patients undergoing immunotherapy. We systematically reviewed data concerning challenges of hepatic adverse events including HBV reactivation and hepatitis in patients with chronic HBV infection undergoing immunotherapy. A systematic search was conducted in Medline, web of science, Embase and Cochrane library up to May 31, 2022. Studies reporting the safety profile of ICIs in patients with HBV infection were eligible. Meta-analyses were conducted to generate odds ratios (ORs) with 95% confidence intervals (CIs). A total of 13 studies including 2561 patients were included for meta-analysis. The overall incidence rates of HBV reactivation in patients with chronic HBV infection and past HBV infection were 1.0% (95% CI 0-3%) and 0% (95% CI 0-0%), respectively. Among patients with chronic HBV infection, the incidence rates of HBV reactivation were 1.0% (95% CI 0-2%) and 10.0% (95% CI 4-18%) for patients with and without antiviral prophylaxis, respectively. Patients with chronic HBV infection were at a higher risk of HBV reactivation compared with those with past HBV infection [OR = 8.69, 95% CI (2.16-34.99)]. Antiviral prophylaxis significantly reduced the risk of HBV reactivation [OR = 0.12, 95% CI (0.02-0.67)] and HBV-associated hepatitis [OR = 0.05, 95% CI (0.01-0.28)] in patients with chronic HBV infection. Prophylactic antiviral therapy should be administered to patients with chronic HBV infection undergoing anticancer immunotherapy. Patients with past HBV infection are at lower risk of HBV reactivation compared with those with chronic HBV infection, they could be initiated with antiviral prophylaxis or monitored with the intent of on-demand antiviral therapy.

Drugs and hepatitis B virus reactivation

Drugs may induce hepatitis B virus (HBV) reactivation (HBV-R). Here we have reviewed the definition and harm of HBV-R, the risk drugs and their underlying mechanism, the influence factors, as well as the early intervention measures. It is shown that multiple drugs, including chemotherapy drugs, immunotherapy drugs, directly acting antivirals, cell therapy, etc., can induce HBV-R by affecting host immunity or directly activating HBV transcription factors. HBV-R could cause severe liver damage, even interruption of treatment of original diseases, affecting the prognosis of patients. Through precisely identifying risk drugs, monitoring the influence factors, and prescribing preventive anti-HBV regimen if necessary, the incidence of HBV-R can be significantly reduced. It is also suggested that clinical physicians should not only pay attention to the early identification and intervention of HBV-R, but also further study the mechanism of HBV-R in depth, especially the underlying mechanism between host, HBV and risk factors. This will help to promote the discovery of more valuable markers for risk prediction and targets for early intervention, and to further reduce the risk of HBV-R and improve the prognosis of patients.

Prognostic value of plasma level of superoxide dismutase in HBV-related acute-on-chronic liver failure

BackgroundHepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is the most prevalent type of ACLF in China. The mortality rate of HBV-ACLF has decreased in recent years due to advances in treatment therapies; however, it is still above 50%. Many cases of HBV-ACLF are caused by HBV reactivation due to discontinuation of nucleoside analog treatment. The present study focused on plasma levels of superoxide dismutase (SOD) in HBV-ACLF patients and investigated whether the plasma level of SOD is a useful biomarker in assessing disease severity and predicting outcomes of HBV-ACLF patients, including patients treated with Entecavir (ETV) and patients who were withdrawn from ETV treatment.MethodsPlasma samples and clinical data from 200 HBV-ACLF patients and from age- and sex-matched cirrhotic and healthy controls were collected and analyzed. Plasma levels of SOD were measured using an ELISA commercial kit.ResultsAmong the HBV-ACLF patients, in the ETV withdrawal group, the mortality rate was higher than in the ETV group (69.95% vs 46.71%, P < 0.05). Moreover, HBV-DNA and SOD plasma levels were higher in the ETV withdrawal group than in the ETV group (Log10(HBV-DNA): 6.49 ± 0.24 vs 4.79 ± 0.14, P < 0.01; SOD: 463.1 ± 27.61 U/mL vs 397.2 ± 10.97 U/mL, P < 0.05). The mortality and liver transplantation rates were significantly higher in HBV-ACLF patients with plasma levels of SOD > 428 U/mL than in patients with plasma SOD levels ≤ 428 U/mL.ConclusionsReactivation of HBV and elevated oxidative stress caused by discontinuation of ETV treatment are crucial factors in the pathogenesis of HBV-ACLF. Plasma level of SOD may serve as a useful biomarker in estimating disease severity and predicting outcomes of HBV-ACLF patients who stop ETV treatment.

P1234: REAL-WORLD EXPERIENCE OF OUTCOMES WITH GLOFITAMAB SALVAGE THERAPY FOR RELAPSE/REFRACTORY B-CELL LYMPHOMA IN TAIWAN: MINIMAL SAFETY CONCERN WITH HEPATITIS B REACTIVATION

Background: Glofitamab, a T-cell-engaging bispecific antibody (Ab) with a novel 2:1 configuration conferring robust bivalency for CD20 and monovalency for CD3, has recently shown promising activity in its phase I/II trial as a salvage therapy in various major subtypes of B-cell lymphoma. Few studies, however, have described the use of glofitamab in a real-world clinical setting. Aims: We aimed to depict the efficacy and safety profiles of glofitamab as a salvage therapy for patients with diffuse large B-cell lymphoma (DLBCL) and other subtype of B-cell lymphoma in the real-world setting with a special focus on the risk of hepatitis B virus (HBV) reactivation. Methods: The clinical data of patients with DLBCL or other B-cell lymphomas who had received ≥3 lines of prior therapies and received glofitamab salvage therapy in a compassionate use program in Nov. 2020 - Dec. 2021 were retrospectively analyzed. The treatment protocol included obinutuzumab pretreatment 1000mg given 7 days before the first glofitamab dose, followed by step-up dose of glofitamab administration: 2.5mg on Day 1 and 10mg on Day 8 of cycle 1, and then 30mg on Day 1 of cycle 2-12 (21-day cycles). Results: As of the end of 2021, 26 patients from two medical centers in Taiwan, 11(43%) of whom were females, were enrolled. Among them, 18 were diagnosed with de novo DLBCL, 3 with transformed large B-cell lymphoma, and 5 with other subtypes of B-cell lymphoma. The median age was 57 years (26-75). Among the 18 cases with de novo DLBCL, 10(56%) had non-germinal center subtype, and 9(50%), double-hit/triple-hit lymphoma. Extra-nodal lesions were observed in 12(46%) patients, and 7(27%), marrow involvement. Elevated LDH levels occurred in 15 (58%) patients. Median prior therapies were 5 (3–10) with 24(92%) patients having received ≥4 prior therapies. All patients had received prior rituximab therapy, 6(23%), autologous or allogeneic stem cell transplantation (SCT), and 9(35%), polatuzumab salvage. Nineteen (79%) patients were refractory to their most recent regimen. Median cycles of glofitamab treatment were 5 (1-12). With the median follow-up of 9 months, the median overall survival was 6 months. The overall response and complete response rates were 50% and 23%, respectively. The remissions are durable (Figure 1): among 13 responders, 8 are continuing the treatment, 1 finished the planned 12 cycles of therapy, 1 had consolidated autologous SCT in remission status, and 2 passed away because of infections in remission status; only one case had disease relapse after achieving remission. No case has had disease progression after achieving an initial response. Cytokine releasing syndrome (CRS) occurred in 15(58%) patients; most of them occurred in the initial two cycles and were mostly of grade 1/2 severity except two cases (8%) with grade 3 CRS, both resulted from transaminitis. No grade 4/5 CRS, neurological toxicity, or fatal toxicity was observed. In terms of HBV infection, 7 patients were HBs antigen(+) and 6 of them had concurrent prophylactic HBV therapy during glofitamab treatment, whereas 11 patients were anti-HBc antibody(+)/HBs antigen(-) and 2 of them received prophylactic HBV therapy. No HBV reactivation event was observed in this cohort of patients. Image:Summary/Conclusion: In the real-world setting, glofitamab remains an effective salvage treatment for patients with heavily pretreated relapse/refractory DLBCL and B-cell lymphomas. No new safety issues were observed. With optimal prophylaxis, the risk of HBV reactivation would not be of concern during glofitamab treatment.

Clinical implication of immune checkpoint inhibitor on the chronic hepatitis B virus infection.

The risk of hepatitis B virus (HBV) reactivation with immune checkpoint inhibitors (ICIs) is an important issue that has not yet been fully investigated. ICI is also expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect. We herein investigated the risk of HBV reactivation and the antiviral effect of ICI administration. This study included 892 patients on ICIs between September 2014 and May 2021 at our hospital. The frequency of HBV reactivation and antiviral effects were investigated. Among the 892 patients who underwent ICI, 27 were hepatitis B surface antigen (HBsAg) positive. HBV reactivation was evaluated in 24 cases, among which 4.1% (1/24) had HBV reactivation. Nucleic acid analog prophylaxis was not administered to patients with reactivation. In a study of 15 cases, the amount of HBsAg decreased from baseline; 2.18±0.77 log to 48weeks later; 1.61±1.38 log (p=0.17). Forty-eight weeks after the start of ICI, disappearance of HBsAg was observed in two out of 15 cases (13.3%), and one case each with and without nucleic acid analog. In rare cases, HBsAg-positive patients may be reactivated by ICI administration. On the other hand, when ICI is administered, it is expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect, and future drug development is expected.

Hepatitis B screening to reduce the risk of viral reactivation in gynecologic oncology patients receiving chemotherapy at a regional tertiary cancer center: A quality improvement initiative.

e18628 Background: In 2020, ASCO released a Provisional Clinical Opinion recommending universal hepatitis B virus (HBV) screening prior to systemic chemotherapy to reduce the risk of reactivation and associated morbidities. There is limited data for HBV prevalence and risk factors in gynecologic oncology. In gynecologic oncology patients at the Juravinski Cancer Centre, median baseline screening rate over 6 months was 0%. Our aim was to increase the rate of HBV screening to 70% in gynecologic oncology patients initiating chemotherapy over 6 months and compare real-world efficacy of risk factor-based vs. universal screening. Methods: We performed an interrupted time series study using the Model for Improvement methodology. Four interventions were introduced to address identified screening barriers: provider education, standardization of a testing protocol, integration with existing clinical workflow, and biweekly feedback reports. These were modified in response to outcomes and stakeholder feedback in Plan-Do-Study-Act cycles. Process and outcome measures data were collected by chart review and analyzed on statistical process control and run charts. Retrospective chart review collected demographic and disease data including Centers for Disease Control (CDC) hepatitis risk factors. Results: From Dec 1/20 to Nov 30/21, there were 381 new chemotherapy initiations in gynecology patients. The proportion of physicians screening increased significantly from 0% to 85%, and HBV monthly screening rates increased significantly from 0% to 72.2% by month 8 and were sustained for 4 months at last analysis. The integrated clinic screening protocol and feedback report interventions were each associated with increased screening rates. Of 330 unique patients initiating chemotherapy, 175 were screened (53%). Although ≥95% lacked data for 4 CDC hepatitis risk factors, 60.9% had ≥1 risk factor, and 11.2% had ≥2. HBV surface antigen (HBSAg) was non-reactive in all screened patients, but anti-HBV core (HBc) antibody was reactive in 5 (2.9%), indicative of prior infection. Real world risk factor-based screening in those with ≥1 CDC risk factor would have only identified 3/5 seropositive patients. In the screened population, risk-factor based screening had sensitivity 60%, specificity 38.8%, PPV 2.8%, NPV 97.1%. There were no HBV reactivations. Conclusions: Implementation of 4 interventions to increase HBV screening in gynecologic oncology patients receiving chemotherapy significantly improved screening rates, achieving our target at 8 months with sustained improvement. Risk-factor based screening lacks sensitivity compared to universal screening which may impact management. Lessons learned from this initiative may be applicable to other interventions to reduce infectious morbidity in oncologic populations.

Frequency of Hepatitis B Markers in Systemic Lupus Erythematosus Patients in Iran.

Background:Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Hepatitis B virus is the causative agent for chronic, acute, cirrhosis, and hepatocellular carcinoma. SLE patients with chronic or occult hepatitis B infection undergoing immunosuppressive drugs may become reactive and develop fatal hepatitis. Therefore, this study was conducted to determine HBV markers in SLE patients before the administration of immunosuppressive drugs in Ahvaz city, Iran. Materials and methods:The sera of 92 SLE patients were tested for HBs Ag and anti-HBc using ELISA, HBV DNA (by Nested PCR) testes. Real-time PCR was performed for the patients with positive anti-HBc and negative HBsAg. The positive HBV DNA samples were checked for HBV genotype and HBV subtypes. Results: Among the 92 SLE patients, three (3.3%) were males and 89 (96.7%) females . The patients’ ages ranged from 14 to 70 years [mean age of 38.9±10.1]. Three of 92 (3.26%) subjects [2/3 males and 1/89 female] were positive for HBsAg, anti-HBc Ab, and HBV DNA detected with PCR (p=0.000003)]. Five of 89 (5.61%) subjects [1 male and 4/88 females were only positive for anti-HBc and negative for HBs Ag, HBV DNA(PCR) using Real-time PCR (p=0.05). The results of the nucleotide data and phylogenetic tree showed all three HBV patients were genotype D1. The results of amino acid sequencing revealed all three HBV patients were HBV subtype ayw2. Conclusion:This study proved that 3.26% of SLE patients were positive for overt HBV infection (positive for anti-HBc, HBsAg and HBV-DNA using PCR). All the three isolated HBV were genotype D1 and subtype ayw2. The fact that 5.61% of the patients were only positive for anti-HBc characterized the occult hepatitis B infection (OBI) although further investigation is needed. To prevent HBV or OBI reactivation for SLE patients before immunosuppression treatment, HBV markers including anti-HBc, HBsAg, HBV-DNA should be implemented using PCR and Real-time PCR .

Clinical outcomes in patients (pts) with previously treated advanced hepatocellular carcinoma (HCC) experiencing hepatitis B virus (HBV) DNA increases during tislelizumab (TIS) treatment in RATIONALE-208.

e16181 Background: The effect of checkpoint inhibitor therapy on HBV infection is uncertain. TIS, an anti-PD-1 antibody, was clinically active and well tolerated in pts with previously treated advanced HCC in the Phase 2 RATIONALE-208 study (NCT03419897). Objective response rate by independent committee review (IRC) in pts with a history of HBV infection was consistent with the overall population (12.5% vs 13.3%, respectively). We explored whether TIS treatment was associated with increased HBV DNA and the clinical significance of HBV DNA elevations. Methods: Pts with ≥ 1 prior systemic therapy for advanced HCC received TIS 200 mg IV Q3W. Pts with inactive, chronic, or active HBV were eligible if HBV DNA levels were &lt; 500 IU/mL at screening (pts with detectable hepatitis B surface antigen [HBsAg] or detectable HBV DNA were required to be managed per treatment guidelines). HBV DNA testing was conducted every 4 cycles if HBV DNA was detectable at screening, or when clinically indicated. Results: Among 249 enrolled pts, 128 had a history of HBV infection. Of these pts, 114 were HBsAg positive at baseline (BL), 36 had detectable HBV DNA at BL, and 32 had detectable HBV DNA and HBsAg at BL. Clinically significant increases in HBV DNA levels from BL were reported in 7 pts, with no pattern relative to the time of TIS initiation (Table). All 7 pts were HBsAg positive at BL and had been receiving antiviral treatment for ≥ 3 months before the first dose of TIS. Six out of the 7 pts had increases in alanine transaminase (ALT) from BL during the study (Table), 4 of whom had ≥ 3-fold increases in ALT which were observed concurrently or soon after HBV DNA increases. IRC-assessed best overall response (BOR) was partial response (PR) for 1 pt with increased HBV DNA and progressive disease for the remaining 6. HBV-related treatment-emergent adverse events (TEAEs) were reported in 6 of the 7 pts (2 pts had a Grade 3 TEAE of hepatitis B; 2 pts had a Grade 2 TEAE of HBV reactivation; 2 pts had a TEAE of increased HBV DNA, with one Grade 1 and one Grade 3 event). All HBV-related TEAEs were non-serious and did not result in discontinuation of TIS. Conclusions: Clinically significant increases in HBV DNA from BL were reported in a small number of pts, which does not suggest that TIS is associated with increased HBV DNA. Tumor responses in these pts were consistent with the overall population and HBV-related TEAEs were manageable and did not require discontinuation of TIS, demonstrating that HBV DNA increases did not impact treatment. The effects of TIS in pts with HBV infection will be further investigated in an ongoing Phase 3 trial (NCT03412773). Clinical trial information: NCT03419897. [Table: see text]

Hepatitis B Virus Infection Flare Induced Acute-on-chronic Liver Failure After COVID-19 Vaccination: A Case Report

Introduction: During the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 vaccination is essential for controlling the outbreak and preventing severe disease. However, there are still uncertainties about the safety of COVID-19 vaccination in individuals with chronic liver disease. Case Presentation: Three patients with hepatitis B virus (HBV) infection presented to our hospital with acute-on-chronic liver failure (ACLF) due to HBV flare after COVID-19 vaccination (mRNA-1273 and ChAdOx1 nCoV-19). Their COVID-19 antibodies were tested by Elecsys Anti-SARS-CoV-2 S immunoassay, which showed good response after full two-dose course of vaccine. One patient refused the test. The patients’ clinical conditions deteriorated during hospitalization. Patient 1 received Entecavir (Baraclude) 1 mg/day upon presentation, but the serum bilirubin level and international normalized ratio (INR) kept increasing. He was comatose in one week and underwent urgent living donor liver transplantation. Patient 2 was on regular Entecavir (Baraclude) 0.5 mg/day and was increased to 1 mg/day upon admission. The serum bilirubin level and INR kept increasing, and he developed grade 3 hepatic encephalopathy in three weeks. The patient then received urgent living donor liver transplantation. Patient 3 received Entecavir (Baraclude) 1 mg/day upon presentation. Her serum bilirubin and INR kept increasing, and her mental status altered in a week. She did not undergo liver transplantation for her old age. Conclusions: It is unclear whether there is a cause-and-effect relationship between COVID-19 vaccination and HBV infection flare. Furthermore, the mechanism of COVID-19 vaccine-induced HBV reactivation is not established. Further studies are needed in this regard. However, during the COVID-19 pandemic, prophylactic antiviral therapy for HBV infection before COVID-19 vaccination should be considered.

Long-Term Safety of Rituximab in DLBCL Patients With Hepatitis B-Related Cirrhosis: A Retrospective Case Series

ObjectiveChemotherapy regimens containing rituximab (RTX) have been extensively used to treat diffuse large B cell lymphoma (DLBCL). However, data looking at long-term safety of DLBCL patients with hepatitis B-related cirrhosis are still lacking. This study aims to report the safety and outcomes of RTX administration in DLBCL patients with hepatitis B-related cirrhosis.MethodsA retrospective case series was designed and implemented, using data from January 1, 2011 to December 31, 2020. Consecutive patients who were diagnosed with DLBCL and hepatitis B-related cirrhosis receiving RTX treatment were included. The primary outcomes included HBV reactivation, hepatitis flares or abnormal liver function. Survival status, the secondary outcome measure, was observed until death, loss to follow-up, or the end of follow-up, whichever occurred first.ResultsA total of 8 DLBCL patients combined with hepatitis B-related cirrhosis were included in this study [4 men; median age 62.5 years (range, 44–77 years); median RTX-containing regimen course 5 (range, 2–11)]. Of them, 6 patients had current HBV infection with HBsAg-positive and anti-HBc-positive, whereas 2 patients had previously resolved HBV infection with HBsAg-negative and anti-HBc-positive. The HBV reactivation was observed in only one patient, who received 11 courses of RTX-containing immunochemotherapies within 15 months. No hepatitis flares or abnormal liver function occurred in any patients included. All patients received standardized antiviral therapy for a lifelong time. Of 8 patients included, 3 patients died, and 1 patient was lost to follow-up, and the median overall survival among patients was 39 months (range, 7–82 months).ConclusionThe findings provide support for the concept that, on the premise of standardized and valid management strategy, RTX containing regimens may be a safe option for use as the treatment of DLBCL patients combined with hepatitis B-related cirrhosis.

Correlation of HBV DNA and Hepatitis B Surface Antigen Levels With Tumor Response, Liver Function and Immunological Indicators in Liver Cancer Patients With HBV Infection Undergoing PD-1 Inhibition Combinational Therapy.

BackgroundThus far, few studies have investigated the safety and efficacy of programmed death-1 (PD-1) immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) antibodies in patients with hepatitis B virus (HBV)-related liver cancer.ObjectiveTo investigate the effect of combination therapy with programmed death-1 (PD-1) immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) on HBV-related liver cancer.MethodsUntil January 31, 2022, liver cancer patients with hepatitis B surface antigen (HBsAg) or HBV DNA positivity, treated with PD-1 ICIs and TKIs combined with nucleoside analogs (NAs), were retrospectively reviewed. The correlation between the change in HBV DNA and HBsAg levels and tumor response was analyzed using the χ2 test. Cox univariate and multivariate survival analyses and Kaplan–Meier curves were used to identify and compare risk factors and overall survival (OS).ResultsA total of 48 patients were enrolled in the study, with an objective response rate (ORR) of 31.3%, a disease control rate (DCR) of 66.7%; the incidence of adverse events was mostly mild. A significant decrease in HBV DNA and HBsAg levels was observed at 12 and 24 weeks compared with the baseline (p < 0.05). Compared to patients with progressive disease (PD), patients with disease control showed a more significant decrease in HBV DNA and HBsAg levels at 12 and 24 weeks (p < 0.001). Eleven patients showed elevations in HBV DNA level and one of them showed HBV reactivation; however, the reactivation was not associated hepatitis. Moreover, eight patients showed elevation in HBsAg. Elevation in HBV DNA level was associated with poor tumor response (P=0.001, OR=18.643 [95% CI: 3.271–106.253]). Cox survival analysis suggested that HBV DNA increase (P=0.011, HR=4.816, 95% CI: 1.439–16.117) and HBsAg increase (P=0.022, HR=4.161, 95% CI: 1.224–16.144) were independent risk factors associated with survival time. Kaplan–Meier curves suggested that patients who exhibited an increase in HBV DNA (6.87 months vs undefined, log-rank test: p= 0.004) and HBsAg (8.07 months vs undefined, log-rank test: p= 0.004) levels had a shorter median survival time (MST). Patients without increased HBsAg showed better baseline liver function and routine blood tests (p<0.05) than patients with increased HBsAg. An increase in C-reactive protein (CRP) and interleukin-6 (IL-6), and a decrease in T lymphocytes, CD4+ T lymphocytes, and B lymphocytes at 1-week post-treatment associated with HBsAg well-controlled.ConclusionHBV-related liver cancer patients treated with combination therapy showed improved efficacy and safety profiles. Combination therapy has some effect on HBV infection, and a correlation between tumor response and antiviral efficacy was found. Elevation of HBV DNA and HBsAg levels may indicate poorer tumor response and survival time. Better baseline liver function and early immune activation may be associated with decline in HBsAg levels.

POS1179 SYSTEMATIC LITERATURE REVIEW ON THE SCREENING AND PROPHYLAXIS OF CHRONIC AND OPPORTUNISTIC INFECTIONS

BackgroundOpportunistic and chronic infections can arise in the context of treatment used for Autoimmune Rheumatic Diseases (ARDs). Although it is recognized that screening procedures and prophylactic measures must be followed, clinical practice is largely heterogeneous, with relevant recommendations not currently developed or disparately located across the literature.ObjectivesTo conduct a systematic literature review (SLR) focusing on the screening and prophylaxis of opportunistic and chronic infections in ARDs. This is preparatory work done by members of the respective EULAR task force (TF).MethodsFollowing the EULAR standardised operating procedures, we conducted an SLR with the following 5 search domains; 1) Infection: infectious agents identifed by a scoping review and expert opinion (TF members), 2) Rheumatic Diseases: all ARDs, 3) Immunosuppression: all immunosuppressives/immunomodulators used in rheumatology, 4) Screening: general and specific (e.g mantoux test) terms, 5) Prophylaxis: general and specific (e.g trimethoprim) terms. Articles were retrieved having the terms from domains 1 AND 2 AND 3, plus terms from domains 4 OR 5. Databases searched: Pubmed, Embase, Cochrane. Exclusion criteria: post-operative infections, pediatric ARDs, not ARDs (e.g septic arthritis), not concerning screening or prophylaxis, Covid-19 studies, articles concerning vaccinations and non-Εnglish literature. Quality of studies included was assessed as follows: Newcastle Ottawa scale for non-randomized controlled trials (RCTs), RoB-Cochrane tool for RCTs, AMSTAR2 for SLRs.Results5641 studies were initially retrieved (Figure 1). After title and abstract screening and removal of duplicates, 568 full-text articles were assessed for eligibility. Finally, 293 articles were included in the SLR. Most studies were of medium quality. Reasons for exclusion are shown in Figure 1. Results categorized as per type of microbe, are as follows: For Tuberculosis; evidence suggests that tuberculin skin test (TST) is affected by treatment with glucocorticoids and conventional synthetic DMARDs (csDMARDs) and its performance is inferior to interferon gamma release assay (IGRA). Agreement between TST and IGRA is moderate to low. Conversion of TST/IGRA occurs in about 10-15% of patients treated with biologic DMARDs (bDMARDs). Various prophylactic schemes have been used for latent TB, including isoniazide for 9 months, rifampicin for 4 months, isoniazide/rifampicin for 3-4 months. For hepatitis B (HBV): there is evidence that risk of reactivation is increased in patients positive for hepatitis B surface antigen. These patients should be referred for HBV treatment. Patients who are positive for anti-HBcore antibodies, are at low risk for reactivation when treated with glucocorticoids, cDMARDs and bDMARDs but should be monitored periodically with liver function tests and HBV-viral load. Patients treated with rituximab display higher risk for HBV reactivation especially when anti-HBs titers are low. Risk for reactivation in hepatitis C RNA positive patients, treated with bDMARDs is low. However, all patients should be referred for antiviral treatment and monitored periodically. For pneumocystis jirovecii: prophylaxis with trimethoprim/sulfamethoxazole (alternatively with atovaquone or pentamidine) should be considered in patients treated with prednisolone: 15-30mg/day for more than 4 weeks. Few data exist for screening and prophylaxis from viruses like EBV, CMV and Varicella Zoster Virus. Expert opinion supports the screening of rare bugs like histoplasma and trypanosoma in patients considered to be at high risk (e.g living in endemic areas).Figure 1.SLR flowchartConclusionThe risk of chronic and opportunistic infections should be considered in all patients prior to treatment with immunosuppressives/immunomodulators. Different screening and prophylaxis approaches are described in the literature, partly determined by individual patient and disease characteristics. Collaboration between different disciplines is important.AcknowledgementsWe would like to thank all members of the EULAR Task Force for the screening and prophylaxis of chronic and opportunistic infections in Autoimmune Rheumatic Diseases.Disclosure of InterestsNone declared

Prophylactic effect of tenofovir on viral reactivation in immunocompromised pregnant women living with hepatitis B virus.

The appropriate prophylaxis for hepatitis B virus reactivation (HBVr) during gestation for immunocompromised pregnant women has yet to be determined. The prophylactic efficacy and safety of tenofovir disoproxil fumarate (TDF) in hepatitis B surface antigen (HBsAg)–positive patients and the HBVr risk in hepatitis B core antibody (HBcAb)–positive patients during gestation were investigated. Eligible pregnant women were diagnosed with rheumatic diseases and were administered prednisone (≤10 mg daily) with permitted immunosuppressants at screening. HBsAg‐positive participants were instructed to take TDF; those unwilling to take TDF were followed up as the control group. Propensity score matching was applied to control for differences in confounding factors between the HBcAb‐positive and uninfected groups. Hepatopathy, maternal, pregnancy, and safety outcomes were documented as endpoints. A cohort of 1292 women was recruited from 2017 to 2020, including 58 HBsAg‐positive patients (29 in each group). A total of 120 pairs in the HBcAb‐positive and noninfection groups were analyzed. Among HBsAg‐positive patients, 6 (20.7%) cases of hepatitis flare (hazard ratio [HR]: 7.44; 95% confidence interval [CI]: 1.50–36.89; p = 0.014) and 12 (41.4%) cases of HBVr (HR: 8.71; 95% CI: 2.80–27.17; p < 0.001) occurred in the control group, while 0 occurred in the TDF prophylaxis group. The HBV level at delivery was the lowest (1.6 log10 IU/ml) for those who received TDF during the pregestation period with a good safety profile. More adverse maternal outcomes were observed in the control group (odds ratio: 0.19, 95% CI: 0.05–0.77, p = 0.021), including one death from fulminant hepatitis and two cases of vertical transmission. No HBVr was recorded in HBcAb‐positive participants. Among immunocompromised pregnant women, prophylactic TDF during pregestation was necessary for HBsAg‐positive women, whereas regular monitoring was recommended for HBcAb‐positive women.

Viral Hepatitis B and Chemotherapy

Patients with chronic hepatitis B treated with chemotherapy or immunotherapy are at risk of viral reactivation, which can have serious or even fatal consequences [1]. Patients treated with chemotherapy for haematological disease have a known risk of hepatitis B virus (HBV) reactivation with an estimated incidence of 14-72% [2]. The majority of chemotherapy drugs can induce HBV reactivation in patients with HBs-positive antigen [3]. HBs testing should therefore be recommended prior to chemotherapy. Preventive antiviral treatment will reduce the risk of HBV reactivation.

Prevention of HBV Reactivation in Hemato-Oncologic Setting during COVID-19.

Onco-hematologic patients are highly susceptible to SARS-CoV-2 infection and, once infected, frequently develop COVID-19 due to the immunosuppression caused by tumor growth, chemotherapy and immunosuppressive therapy. In addition, COVID-19 has also been recognized as a further cause of HBV reactivation, since its treatment includes the administration of corticosteroids and some immunosuppressive drugs. Consequently, onco-hematologic patients should undergo SARS-CoV-2 vaccination and comply with the rules imposed by lockdowns or other forms of social distancing. Furthermore, onco-hematologic facilities should be adapted to new needs and provided with numerically adequate health personnel vaccinated against SARS-CoV-2 infection. Onco-hematologic patients, both HBsAg-positive and HBsAg-negative/HBcAb-positive, may develop HBV reactivation, made possible by the support of the covalently closed circular DNA (cccDNA) persisting in the hepatocytic nuclei of patients with an ongoing or past HBV infection. This occurrence must be prevented by administering high genetic barrier HBV nucleo(t)side analogues before and throughout the antineoplastic treatment, and then during a long-term post-treatment follow up. The prevention of HBV reactivation during the SARS-CoV-2 pandemic is the topic of this narrative review.

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

SummaryBackgroundAbatacept 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.MethodsUsing 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.FindingsDuring 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).InterpretationWe 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.FundingThis work was supported by the Fundamental Research Funds for Central Universities (xjh012019063).

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

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. 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. 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. 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.

Cost-effectiveness of managing HBV reactivation in patients with resolved HBV infection treated with anti-CD20 antibody for B-cell non-Hodgkin lymphoma.

There is no universal recommendation for managing the reactivation of HBV in patients with resolved HBV infection treated with anti-CD20 monoclonal antibodies for B-cell non-Hodgkin lymphoma. This study compared the cost-effectiveness of two commonly used strategies: prophylactic anti-HBV nucleos(t)ide analog therapy (Pro NAT), and HBV DNA monitoring followed by on-demand antiviral therapy (HBV DNA monitoring). Using a decision tree model, the incremental cost-effectiveness ratio (ICER) expressed as cost per quality-adjusted life-year (QALY) gained was calculated. The threshold for cost-effectiveness was set at 5,000,000 JPY, equivalent to 45,662 USD. In a base–case analysis, HBV DNA monitoring was found to be more cost-effective based on the calculation of ICER as 132,048 USD per QALY, a value that far exceeds 45,662 USD. The same results were consistently obtained by a one-way deterministic sensitivity analysis, even after changing each parameter value within the predetermined range. A probabilistic sensitivity analysis with 10,000 simulations also revealed that HBV DNA monitoring is more cost-effective than Pro NAT in 96.8% of cases. Therefore, this study suggests that HBV DNA monitoring is an appropriate managing measure in Japan from a cost-effectiveness perspective.