利妥昔时代和利妥昔后时代不同类型的靶向药对乙肝再激活的影响

Background and Aims: Immunosuppression can cause hepatitis B virus (HBV) reactivation, leading to severe outcomes in patients with “resolved” HBV infection. This multicenter, randomized, placebo-controlled trial assessed the efficacy of preemptive antiviral therapy in HBsAg-negative, anti–HBc-positive patients receiving rituximab-based chemotherapy for non-Hodgkin lymphoma (NHL). Methods: Patients were randomized 1:1 to tenofovir alafenamide (TAF)/placebo across 3 phases: chemotherapy plus TAF/placebo (phase 1), TAF/placebo post-chemotherapy (phase 2), and follow-up after therapy cessation (phase 3). The primary endpoint was HBsAg reverse seroconversion. HBsAg and ALT were monitored every 3–12 weeks, depending on treatment phase, and HBV DNA was measured post hoc. ClinicalTrials.gov (NCT02186574). Results: Among 42 patients (median age 65.2 years, 52.4% male, 52.4% aggressive lymphoma, 73.8% anti-HBs positive), 20 received TAF and 22 received a placebo. Median ALT was 20.0 U/L (IQR: 15.0–28.0) at baseline. Median follow-up was 69.4 weeks (IQR: 63.7–166), with 6.1 weeks (IQR: 4.7–8.3) between visits. During follow-up, 2 patients in the TAF arm, but none receiving placebo, experienced HBsAg reverse seroconversions: occurring in phase 3 at 62.3 weeks from baseline, and in phase 1 at 20.0 weeks from baseline. Neither patient experienced ALT >2× ULN. HBV DNA >1000 IU/mL was observed in 8 instances among 6 patients, 3 in each arm, with no associated hepatitis. Low-level DNA (<1000 IU/mL) was not indicative of reverse seroconversion, DNA increases, or ALT elevations. Conclusions: The use of preemptive TAF therapy did not reduce the risk of HBsAg reverse seroconversion; however, the findings should be interpreted with caution as the study was underpowered due to slow enrolment leading to early termination. Low-level HBV DNA elevations were not associated with HBV reactivation. Thus, close HBsAg and ALT monitoring are adequate in HBsAg-negative patients undergoing rituximab-based chemotherapy.

Abstract Hepatitis B virus (HBV) reactivation is a recognized complication of long-term immunosuppressive or cytotoxic therapy, typically occurring during immunosuppression or within a few months after treatment. To mitigate this risk, hepatological societies recommend the use of nucleos(t)ide analogues (NA) for HBV reactivation prophylaxis, along with post-treatment monitoring; though, these recommendations are not universally consistent across different guidelines. We present a case of late HBV reactivation in a 76-year-old male with occult HBV infection who received rituximab-based therapy for chronic lymphocytic leukemia. In accordance with HBV reactivation guidelines, the patient was prescribed entecavir 0.5 mg daily during chemotherapy and for 18 months following the completion of hematological treatment. Despite adherence to these recommendations, the patient developed HBV reactivation 2 years and 5 months after the cessation of rituximab-based therapy, which progressed to acute HBV hepatitis. Our case emphasizes the need for extended follow-up in patients undergoing rituximab-based immunosuppression. It highlights the critical importance of vigilance for HBV reactivation and the potential consequences of delayed treatment. This case supports evidence on the unpredictability of HBV reactivation timelines and underscores the need for standardized monitoring protocols.

Risk of hepatitis B virus (HBV) reactivation was assessed in B-cell non-Hodgkin lymphoma (NHL) patients with resolved HBV infection (hepatitis B surface antigen negative, hepatitis B core antibody positive) who received obinutuzumab- or rituximab-containing immunochemotherapy in the phase 3 GOYA and GALLIUM studies. HBV DNA monitoring was undertaken monthly to 1 year after the last dose of study drug. In case of HBV reactivation (confirmed, HBV DNA ≥29 IU/mL), immunochemotherapy was withheld and nucleos(t)ide analog treatment (preemptive NAT) started. Immunochemotherapy was restarted if HBV DNA became undetectable or reactivation was not confirmed, and discontinued if HBV DNA exceeded 100 IU/mL on NAT. Prophylactic NAT was allowed by investigator discretion. Among 326 patients with resolved HBV infection, 27 (8.2%) had HBV reactivation, occurring a median of 125 days (interquartile range, 85-331 days) after the first dose. In 232 patients without prophylactic NAT, 25 (10.8%) had HBV reactivation; all received preemptive NAT. Ninety-four patients received prophylactic NAT; 2 (2.1%) had HBV reactivation. No patients developed HBV-related hepatitis. On multivariate Cox analysis, detectable HBV DNA at baseline was strongly associated with an increased risk of reactivation (adjusted hazard ratio [HR], 18.22; 95% confidence interval [CI], 6.04-54.93; P < .0001). Prophylactic NAT was strongly associated with a reduced risk (adjusted HR, 0.09; 95% CI, 0.02-0.41; P = .0018). HBV DNA monitoring-guided preemptive NAT was effective in preventing HBV-related hepatitis during anti-CD20-containing immunochemotherapy in B-cell NHL patients with resolved HBV infection. Antiviral prophylaxis was also effective and may be appropriate for high-risk patients. These trials were registered at www.clinicaltrials.gov as NCT01287741 (GOYA) and NCT01332968 (GALLIUM).

To evaluate a surveillance protocol in managing the risk of hepatitis B virus (HBV) reactivation among lymphoma patients with resolved HBV infection receiving rituximab.

BACKGROUND & AIMS The purpose of this post hoc analysis was to evaluate the efficacy of an ultra-high sensitive HBsAg assay using prospectively stored samples of HBV DNA monitoring study for lymphoma patients with resolved HBV infection following anti-CD20 antibody, rituximab-containing chemotherapy (UMIN000001299). METHODS HBV reactivation defined as HBV DNA levels of 11 IU/mL or more was confirmed in 22 of 252 patients. Conventional HBsAg assay (ARCHITECT, cut-off value: 0.05 IU/mL) and ultra-high sensitive HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA, cut-off value: 0.0005 IU/mL) were measured at baseline, at confirmed HBV reactivation and monitored after HBV reactivation. RESULTS Baseline HBsAg was detected using ICT-CLEIA in 4 patients, in all of whom precore mutants with high replication capacity were reactivated. Of the 6 patients with HBV DNA detected below the level of quantification at baseline, 5 showed HBV reactivation and 3 of the 5 had precore mutations. Sensitivity for detection by ARCHITECT and ICT-CLEIA HBsAg assays at HBV reactivation or the next sampling after HBV reactivation was 18.2% (4 of 22) and 77.3% (17 of 22), respectively. Of the discrepant 5 patients undetectable by ICT-CLEIA, 2 patients resolved spontaneously. All 6 patients reactivated with precore mutations including preS deletion could be diagnosed by ICT-CLEIA HBsAg assay at an early stage of HBV reactivation. Multivariate analysis showed that an anti-HBs titer of less than 10 mIU/mL, detected HBV DNA below the level of quantification, and detected ICT-CLEIA HBsAg at baseline were independent risk factors for HBV reactivation (adjusted hazard ratios, 15.4, 31.2 and 8.7, respectively; p<0.05). CONCLUSIONS A novel ICT-CLEIA HBsAg assay would be an alternative method to diagnose HBV reactivation.

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We read with interest the meta-analysis by Poola et al., “Meta-Analysis: High anti-HBs Titers Are Associated with Significantly Reduced Risk of Hepatitis B Virus Reactivation During Rituximab Treatment.” [1] The authors showed a titre-dependent reduction in HBV reactivation among HBsAg-negative/anti-HBc–positive patients (27.3% in anti-HBs–negative patients, 13.8% with titers of 10–100 IU/L

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Hepatitis B virus reactivation (HBV-R), which can lead to HBV-related morbidity and mortality, is a common and well-known complication that occurs during the treatment of non-Hodgkin lymphoma (NHL) patients with current or past exposure to HBV infection. HBV-R is thought to be closely associated with chemotherapeutic or immunosuppressive therapies. However, immunosuppressive agents such as anti-CD20 antibodies (e.g., rituximab and ofatumumab), glucocorticoids, and hematopoietic stem cell transplantation (HSCT) administered to NHL patients during treatment can cause deep immunodepression and place them at high risk of HBV-R. In this review, we explore the current evidence, the guidelines of several national and international organizations, and the recommendations of expert panels relating to the definition, risk factors, screening and monitoring strategies, whether to use prophylaxis or pre-emptive therapy, and the optimal antiviral agent and duration of antiviral therapy for HBV-R.

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Hepatitis B virus reactivation (HBVr) can develop in HBV surface antigen (HBsAg) positive or HBsAg-negative and anti-hepatitis B core antigen antibodies (anti-HBc) positive (past HBV infection) patients receiving immuno-chemotherapy for hematological malignancies. A higher rate of HBVr is associated with the use of rituximab (R) in patients with past HBV infection, thus justifying an antiviral prophylaxis. In this study we evaluated the incidence of HBVr in a real-life cohort of 362 anti-HBc-positive subjects affected by non-Hodgkin lymphoma (NHL), mainly receiving lamivudine (LAM) prophylaxis (93%) and all undergoing a R-containing regimen. A retrospective, multicenter, observational study was conducted in 4 Italian Hematology Departments. The primary endpoint was the incidence of virologic (HBV DNA-positive), serologic (HBsAg-positive) and clinical (ALT increase > 3 × upper limit of normal) HBVr, which occurred in five, four and one patients, respectively, with a total HBVr rate of 1.4%. None of them had to discontinue the chemotherapy program, while two patients required a delay. Treatment-related adverse events (AEs) were reported during LAM prophylaxis in three patients (0.9%). In conclusion, this study confirms the efficacy and safety of LAM prophylaxis in anti-HBc-positive patients undergoing R-containing regimens.

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BACKGROUND & AIMS Absence or low anti-HBV surface antibody (anti-HBs) is associated with an increased risk of HBV reactivation in patients with lymphoma and resolved HBV infection receiving rituximab-containing chemotherapy. Quantification of anti-HBV core antibody (anti-HBc) is a new marker associated with the natural history and treatment response of chronic HBV infection. This study investigated whether baseline anti-HBc and anti-HBs levels may better predict HBV reactivation. METHODS We prospectively measured the HBV DNA levels of patients with lymphoma and resolved HBV infection receiving rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone-based chemotherapy and started an antiviral therapy upon HBV reactivation, defined as a greater than 10-fold increase in HBV DNA compared with previous nadir levels. Anti-HBs and anti-HBc were quantified by a double-sandwich assay. Receiver-operating-characteristic-curve analysis was used to determine the optimal baseline anti-HBc/anti-HBs levels for predicting HBV reactivation. RESULTS HBV reactivation occurred in 24 of the 197 patients enrolled, with an incidence of 11.6/100 person-years. For the 192 patients with enough serum samples for analysis, low anti-HBs (<56.48 mIU/ml) and high anti-HBc (≥6.41 IU/ml) at baseline were significantly associated with high risk of HBV reactivation (hazard ratio [HR] 8.48 and 4.52, respectively; p <0.01). The multivariate analysis indicated that (1) patients with both high anti-HBc and low anti-HBs at baseline (36 of 192 patients) had an HR of 17.29 for HBV reactivation (95% CI 3.92-76.30; p <0.001), and (2) HBV reactivation may be associated with inferior overall survival (HR 2.41; 95% CI 1.15-5.05; p = 0.02). CONCLUSIONS Baseline anti-HBc/anti-HBs levels may predict HBV reactivation in these patients with lymphoma and help optimize prophylactic antiviral therapy for high-risk patients. LAY SUMMARY In this study, we identified a subgroup of patients with lymphoma and resolved hepatitis B virus infection that had a high risk of hepatitis B virus reactivation after receiving rituximab-containing chemotherapy. These findings will help optimize a preventive strategy, especially in hepatitis B virus endemic regions with limited healthcare resources. Clinical trial number: NCT 00931229.

Hepatitis B virus (HBV) is an important public health problem that poses a serious threat to human health. HBV reactivation generally occurs in overt or occult HBV infection patients who suffered DDAs, chemotherapy, or immunosuppressive therapy, especially when some solid tumors and leukemia patients are using hormones such as prednisolone and imatinib. The approximate incidence of HBV reactivation ranged from about 10% to 40%. Scientists often explore the molecular mechanisms from both the virus and the host. But some studies have reported that some drugs (cisplatin, rituximab, imatinib, and glucocorticoid) could induce HBV reactivation directly. However, the specific molecular mechanisms were unclear. With the emergence of new antiviral drugs and molecular targeted drugs, the risk of HBV reactivation will increase significantly. Therefore this review was expected to be used to provide recommendations for future research in HBV reactivation.

Objective We started an information technology (IT) system that encodes the medical treatment status of hepatitis B virrus (HBV) with a 9-digit number, automatically checks for inappropriate situations occurring due to immunosuppression and chemotherapy that do not comply with the flowchart of the hepatitis B countermeasure guideline, and promotes correct HBV medical treatment in our hospital. We conducted a prospective study of HBV reactivation using this system. Methods Among 21,607 cases that were managed using this system, 1,206 patients who were HBs antigen-negative, HBc antibody- and/or HBs antibody-positive and in whom HBV DNA quantification was performed two times or more were examined for the occurrence of HBV reactivation. The study population included: malignant lymphoma patients using rituximab (n=40), patients with malignant tumors using anticancer agents (n=546), patients treated with steroids (n=274), rheumatoid arthritis (RA) patients (n=144), patients using immunosuppressants/biologics (n=26), and patients undergoing hepatitis C direct acting antiviral (DAA) treatment (n=176). Results HBV reactivation was observed in 27 cases undergoing treatment with the following agents: rituximab (n=6), anticancer agents (n=8), steroids (n=10), anti-RA agents (n=1), and hepatitis C DAA (n=2). Among the 40 patients who were using rituximab, 6 (18.2%) showed a high rate of reactivation. In 10 in which HBV reactivation occurred at a median of 10 (range, 4-32) months after steroid administration, 6 occurred after the 7th month, and 1 patient showed HBs antigen positivity and severe hepatitis. Conclusion Continuing of the operation of an automatic check system using coded medical information to check for the reactivation enabled this prospective study of HBV reactivation. Careful attention should be paid to patients using steroids, as well as malignant lymphoma patients who are treated with rituximab. The results of the present study suggest that the present IT encoding system would be useful for preventing HBV reactivation.

The study was undertaken in order to provide a snapshot from real clinical practice of virological presentation and outcome of patients developing immunosuppression‐driven HBV reactivation. Seventy patients with HBV reactivation were included (66.2% treated with rituximab, 10% with corticosteroids and 23.8% with other immunosuppressive drugs). Following HBV reactivation, patients received anti‐HBV treatment for a median (IQR) follow‐up of 31(13‐47) months. At baseline‐screening, 72.9% of patients were HBsAg‐negative and 27.1% HBsAg‐positive. About 71.4% had a diagnosis of biochemical reactivation [median (IQR) HBV DNA and ALT: 6.9 (5.4‐7.8) log IU/mL and 359 (102‐775) U/L]. Moreover, 10% of patients died from hepatic failure. Antiviral prophylaxis was documented in 57.9% and 15.7% of HBsAg‐positive and HBsAg‐negative patients at baseline‐screening (median [IQR] prophylaxis duration: 24[15‐33] and 25[17‐36] months, respectively). Notably, HBV reactivation occurred 2‐24 months after completing the recommended course of anti‐HBV prophylaxis in 35.3% of patients. By analysing treatment outcome, the cumulative probability of ALT normalization and of virological suppression was 97% and 69%, respectively. Nevertheless, in patients negative to HBsAg at baseline‐screening, only 27% returned to HBsAg‐negative status during prolonged follow‐up, suggesting the establishment of chronic infection. In conclusion, most patients received a diagnosis of HBV reactivation accompanied by high ALT and 10% died for hepatic failure, supporting the importance of strict monitoring for an early HBV reactivation diagnosis. Furthermore, HBV reactivation correlates with high risk of HBV chronicity in patients negative for HBsAg at baseline‐screening, converting a silent into a chronic infection, requiring long‐term antiviral treatment. Finally, a relevant proportion of patients experienced HBV reactivation after completing the recommended course of anti‐HBV prophylaxis, suggesting the need to reconsider proper duration of prophylaxis particularly in profound immunosuppression.

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Background Hepatitis B virus reactivation (HBVr) can occur in patients with resolved hepatitis B virus (HBV) infection receiving immunosuppressive therapy. The class of immunosuppression influences HBV reactivation (HBVr) risk, with B-cell depleting agents such as Rituximab conferring a higher risk. The presence of hepatitis B surface antibodies (HBsAb) may be protective against HBVr. Objective To compare the rates of HBVr amongst individuals with resolved HBV infection receiving rituximab and non-rituximab immunosuppressive therapy, without chemoprophylaxis. Our secondary objective was to explore the role of HBsAb in risk stratification for HBVr. Methods We retrospectively collected the data of patients with resolved HBV infection receiving immunosuppressants between 2014 and 2022. HBVr rates amongst patients receiving rituximab and non-rituximab therapy were compared. Logistic regression analysis was performed to identify risk factors for HBVr. Results 148 patients with resolved HBV infection did not receive chemoprophylaxis. Of the 20 (13.5%) patients who developed HBVr, none developed HBV flare. 42 of the 148 (28.3%) patients received rituximab-based therapy. Patients who received rituximab had a higher risk of HBVr, 12(28.6%) vs 8(7.5%), P = 0.001. This was confirmed on multivariable analysis (OR 4.19 [C.I. 1.47-11.9], P = 0.007). HBsAb titres of above 100 mIU/ml were protective against HBVr (OR 0.04 [CI 0.001-0.84], P = 0.039) in the rituximab exposed cohort, but not in the non-rituximab exposed cohort. Conclusion The risk of HBVr was higher in patients receiving rituximab; however, no patient developed HBV flare. In patients with resolved HBV infection, the presence of HBsAb titres above 100 mIU/ml may confer additional protection against HBVr and can be used as part of risk stratification for HBVr. In such patients, close surveillance with on-demand therapy instead of chemoprophylaxis may be considered.

We herein report a case of hepatitis B virus (HBV) reactivation in a female patient in her 70s with isolated anti-hepatitis B core (IAHBc) antibodies [HB surface antigen (HBsAg)-negative, HB surface antibody (HBsAb)-negative, and HB core antibody (HBcAb)-positive], receiving rituximab-based chemotherapy for follicular lymphoma. Her serum HBV DNA was negative. The patient was treated with rituximab for 21 months, and 33 months after completion of treatment, her HBV DNA level increased to 5.1 Log IU/mL, and the patient developed hepatic failure. Tenofovir alafenamide fumarate treatment was initiated for HBV reactivation, and DNA was not detected 9 months later.

Rituximab therapy is associated with a high risk of hepatitis B virus (HBV) reactivation. We aimed to assess whether the risk of reactivation differed among various underlying diseases and between hepatitis B surface antigen (HBsAg) carriers and patients with resolved HBV infection.

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Reactivation of hepatitis B virus (HBV) can occur in lymphoma patients infected with HBV when they receive chemotherapy or immunotherapy. Prophylactic administration of lamivudine (LAM) reduces the morbidity and mortality associated with HBV reactivation. However, what defines HBV reactivation and the optimal duration of treatment with LAM have not yet been clearly established. HBV reactivation may occur due to the cessation of prophylactic LAM, although re-treatment with nucleoside analogs may sometimes result in hepatitis B surface antigen (HBsAg) seroconversion, which is a satisfactory endpoint for the management of HBV infection. We report a case of HBV reactivation in a 68-year-old HBsAg-positive patient who received rituximab-based immunochemotherapy for follicular lymphoma. HBV reactivation developed following cessation of prophylactic LAM therapy. The patient subsequently received treatment with entecavir (ETV), which led to a rapid and sustained suppression of HBV replication and HBsAg seroconversion. We also appraised the literature concerning HBV reactivation and the role of ETV in the management of HBV reactivation in lymphoma patients. A total of 28 cases of HBV reactivation have been reported as having been treated with ETV during or after immunosuppressive chemotherapy in lymphoma patients. We conclude that ETV is an efficacious and safe treatment for HBV reactivation following LAM cessation in lymphoma patients treated with rituximab-based immunochemotherapy.

Human herpesvirus type 8 (HHV‐8) unrelated primary effusion lymphoma (PEL) like lymphoma (PEL‐LL) is an exceedingly rare non‐Hodgkin lymphoma with no characteristic symptoms and consensus on the optimal treatment. This case report presents a 55‐year‐old man with prior HBV‐related Child‐Pugh B liver cirrhosis and developing activity‐related dyspnea. A moderate amount of pleural effusion was identified without tumor masses, and cytological studies confirmed a diagnosis of PEL‐LL. The patient received rituximab and lenalidomide, albeit with HBV infection, and is currently on maintenance therapy with resolving symptoms but without HBV reactivation. Hence, the R2 protocol (rituximab and lenalidomide) might be clinically effective and safe for PEL‐LL patients with HBV infection and Child‐Pugh B liver cirrhosis.

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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.

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Biological drugs target immune or genetic mediators and are important treatment alternatives in rheumatology, especially in patients with inadequate response to the conventional treatment. Hepatitis B reactivation may emerge during the use of these agents. There is a higher risk of reactivation with rituximab (RTX) therapy. The frequency of hepatitis B reactivation with non-RTX biologics is unclear.Hepatitis B seroprevalence and reactivation frequency were evaluated in patients followed in Kocaeli University Faculty of Medicine rheumatology outpatient clinic and treated with non-RTX biological drugs.The HBsAg, anti-HBs, and anti-HBcIgG data of 170 patients who received non-RTX biological drug therapy for different indications between 2010 and 2022 were analyzed retrospectively. HBV DNA PCR, liver enzyme elevation and HBeAg reversion were evaluated for reactivation, especially in HBsAg and anti-HBcIgG positive patients. The patients were divided into 5 groups as HBsAg (+) patients (Group 1), HBsAg (-), anti-HBs (+) and anti-HBcIgG (+) patients (Group 2), anti-HBc IgG (+) patients (Group 3), whole serology negative patients (Group 4) and vaccine-immunized anti-HBs (+) patients (Group 5).The mean age of the study population was 47.4±10.6 years. 57.6% of the patients were ankylosing spondylitis (AS), 24.1% were rheumatoid arthritis, and 8.8% were psoriatic arthritis. Behçet’s disease and Takayasu arteritis were observed in 3.5% and 2.4% of patients, respectively. 3.5% of patients were consisting of a various of rheumatological diseases including Familial Mediterranean fever, giant cell arteritis, adult Still’s disease. In these patients, anti-tumor necrosis factor (TNF) and non-TNF biological drug (tocilizumab, abatacept, secukinumab) treatment use were 80% and 20%, respectively. Most of patients were in group 4 (n=114, 67.1%). The distribution of patients based on serology is shown in Table 1. The patients in group 1 were receiving antiviral treatment. Other groups did not receive any antiviral therapy. In group 3, reactivation was observed in a patient who was followed up with the diagnosis of AS and on infliximab treatment. After reactivation, this patient started to take the antiviral treatment. In a patient of which was classified in group 1, a non-significant increase in viral load (<1 log10 IU/mL) revealed. However, we did not consider this patient had reactivation due to the normal level of liver enzymes and the absence of HBeAg reversion.Patients using non-RTX biological treatments have a medium risk in terms of HBV reactivation. However, the usage of antiviral prophylaxis is quite low. In our study, HBV reactivation was observed less. On the other hand, patients should be carefully screened in terms of hepatitis serology in order to prevent the reactivation.Table 1.Data of Patients Receiving Non-Rituximab Biological TreatmentN(%)GenderFemale79(46,5)Male91(53,5)DiagnosisRheumatoid Arthritis41(24,1)Ankylosing spondylitis98(57,6)Psoriatic Arthritis15(8,8)Behcet ‘s disease6(3,5)Takayasu Arthritis4(2,4)Other6(3,5)Groups by Viral MarkersGroup 1 - HBsAg (+)5(2,9)Group 2 - HBsAg (-), anti-HBs (+), anti-HBcIgG (+)13(7,6)Group 3 - HBsAg (-), anti-HBs (-), anti-HBcIgG (+)14(8,2)Group 4 - HBsAg (-), anti-HBs (-), anti-HBcIgG (-)114(67,1)Group 5 - HBsAg (-), anti-HBs (+), anti-HBcIgG (-)24(14,1)Hepatitis B Reactivation RateGroup 1-Group 2-Group 31(7,1)NIL.NIL.None Declared.

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BACKGROUND Reactivation of Hepatitis B (HBVr) related to immunosuppressive drug therapy (ISDT) in patients with resolved and past infection is a challenging entity. The number of prospective long-term studies is limited. METHODS Two groups of patients with resolved and past HBV infection were analyzed prospectively. The patients were further categorized as 266 patients receiving ISDT (group 1) and 246 patients receiving antineoplastic therapy (group 2). RESULTS We did not detect any cases of HBVr among 108 patients receiving rituximab (71 of which were anti-HBc positive only), 111 patients receiving tumor necrosis factor inhibitors (66 of which were anti-HBc positive only), and 42 patients receiving high-dose glucocorticoids for more than 4 weeks (24 of which were anti-HBc positive only) during a mean follow-up time of more than 24 months. Subgroup analysis of the anti-HBs (+) patients showed that in group A (anti-HBs >1000 mIU/mL) the antibody levels did not change; in group B (anti-HBs between 100 and 1000 mIU/mL) the antibody levels changed non-significantly (P = .25), and in Group C (anti-HBs between 0 and 100 mIU/mL) the antibody levels declined significantly (P = .002). Furthermore, 16 patients in Group C had an anti-HBs loss during follow-up, but no HBVr was detected. CONCLUSION The risk of HBVr by immunosuppressive therapy in this group may be lower than that suspected in the literature and anti- HBs levels may not seem to correlate with the risk of reactivation.

Hepatitis B virus (HBV) infection is a worldwide distributing viral disease. Hepatitis caused by HBV reactivation may progress to chronic illness and associated with increased risk of hepatic failure and hepatocellular cancer. Rituximab (RTX) is an immunosuppressive agent, is particularly used in the treatment of non‐Hodgkin's Lymphoma. Patients have significant risk for HBV reactivation following chemotherapy with a RTX‐containing regimen. This study aimed to determine the HBV screening manner and reactivation rates in patients with haematological neoplasm following chemotherapy including Rituximab.

A 54-year-old woman underwent chemotherapy including rituximab and autologous peripheral blood stem cell transplantation (auto-PBSCT) for diffuse large B-cell lymphoma. Before the treatment, she exhibited a resolved hepatitis B virus (HBV) infection. She was diagnosed with HBV reactivation based on positive serum HBV-DNA test results, 55 months after her last treatment. Subsequently, he was treated with tenofovir alafenamide fumarate (TAF) therapy and her liver function improved. Patients undergoing chemotherapy including rituximab and auto-PBSCT are at a high risk of HBV reactivation. In such cases, careful and long-term observations may be required to detect HBV reactivation.

Background/Aims Rituximab is known to be associated with high hepatitis B virus (HBV) reactivation rate in patients with resolved HBV infection and hematologic malignancy. However, data regarding HBV reactivation (HBVr) in rheumatic patients receiving rituximab is limited. To assess the HBVr rate in hepatitis B surface antigen (HBsAg)-negative patients receiving rituximab for autoimmune diseases in a large real-world cohort. Methods From March 2006 to December 2019, 900 patients with negative HBsAg receiving at least one cycle of rituximab for autoimmune diseases in a tertiary medical center in Taiwan were retrospectively reviewed. Clinical outcome and factors associated with HBVr were analyzed. Results After a median follow-up period of 3.3 years, 21 patients developed HBVr, among whom 17 patients were positive for hepatitis B core antibody (anti-HBc) and four were negative. Thirteen patients had clinical hepatitis flare, while eight patients had HBsAg seroreversion without hepatitis. Old age, anti-HBc positivity, undetectable serum hepatitis B surface antibody level at rituximab initiation and a higher average rituximab dose were associated with a higher HBVr rate. There was no significant difference in the HBVr risk between rheumatoid arthritis and other autoimmune diseases. Among anti-HBc-negative patients, subjects without HBV vaccination at birth had an increased risk of HBVr (4/368, 1.1%) compared with those who received vaccination (0/126, 0%). Conclusions In HBV endemic areas where occult HBV is prevalent, anti-HBc-negative patients, may still be at risk for HBVr after rituximab exposure. HBVr may still be considered in HBsAg-negative patients developing abnormal liver function after rituximab exposure, even in patients with negative anti-HBc.

OBJECTIVE Hepatitis B virus (HBV) reactivation is a critical concern for patients with autoimmune disease undergoing immunosuppressive therapy. Despite data on HBV reactivation risks associated with biologics, the impact of this new targeted immunosuppressive agents-Janus kinase inhibitors (JAKi) - remains unclear. This study aimed to evaluate the risk of HBV reactivation among rheumatoid arthritis (RA) patients treated with JAK inhibitors, compared with those receiving TNF inhibitors or rituximab. METHOD We conducted a retrospective analysis of RA patients treated at National Taiwan University Hospital from 2015 to 2023. Patients with available baseline HBV status (HBsAg, anti-HBc, anti-HBs, HBV DNA) who received TNF inhibitors, rituximab, or JAKi (tofacitinib, baricitinib, upadacitinib) were included. The primary outcomes were hepatitis flare in HBsAg-positive patients and HBsAg seroreversion in HBsAg-negative/anti-HBc-positive patients. RESULTS We included 35 HBsAg-positive patients and 339 patients with resolved HBV infection (HBsAg-negative/anti-HBc-positive). Among those with resolved HBV infection, the reactivation risk was low with TNF inhibitors (0.9%, 2.8/1,000 person-years), higher with rituximab (3.2%, 15.1/1,000 person-years) and JAKi overall (2.9%, 10.3/1,000 person-years). Among individual JAK inhibitors, upadacitinib had the highest incidence (6.5%, 42.8/1,000 person-years), followed by baricitinib (4.7%, 19.2/1,000 person-years), and tofacitinib (1.0%, 2.7/1,000 person-years). Among HBsAg-positive patients, 50% of JAKi users developed a hepatitis flare, emphasizing the importance of vigilant monitoring and prophylaxis. CONCLUSIONS Our findings reveal a non-negligible risk of HBV reactivation among RA patients receiving JAKi therapy, particularly with the more JAK1-selective JAKi. Larger registry or prospective studies are needed to validate these findings.

Pegylated interferon-alpha (PEG-IFN-α) is an antiviral medication used to treat chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. It may result in rare but severe side effects, such as undifferentiated connective tissue disease (UCTD) and excessive dynamic airway collapse (EDAC), which can occur as delayed complications of PEG-IFN-α-induced UCTD. In cases where these complications arise, entecavir, employed for treating HBV infection, may be considered. A 49-year-old female patient, monitored for nine years with HCV and a viral load of 1.5 million, genotype 3, and normal liver function tests (LFTs), possibly acquired the infection from her HCV-positive husband. The patient was initially treated with PEG-IFN-α (IFN-α-2b, 100 µg/week subcutaneously) and ribavirin (RBV, 500 mg/twice daily). Following the sixth injection, the patient exhibited symptoms, including shortness of breath and cough, leading to limited daily activities. Subsequent high-resolution computed tomography (HRCT) showed interstitial pneumonitis (IP) signs. She was given a high dose of steroids. Over the next two to four weeks, the patient experienced Raynaud's phenomenon, skin tightening, joint pains, and dryness of the eyes and mouth. The antinuclear antibody (ANA) test was negative, while the extractable nuclear antigen (ENA) test showed equivocal anti-Smith antibodies (6.38). Rheumatoid factor (RA) factors were mildly positive, and pulmonary function tests (PFTs) indicated a restrictive pattern. The patient was intolerant to hydroxychloroquine (HCQ) and azathioprine (Imuran) 500 mg, subsequently receiving mycophenolate mofetil 500 mg/thrice daily. Despite four years of treatment, UCTD due to PEG-IFN-α remained difficult to control; however, IP responded well to steroids. Rituximab pulse therapy was planned before the initiation; serological tests showed positive anti-HBs with a titer of 17.02, positive anti-HBc, but negative HBsAg and undetectable HBV viral load, indicating immunity to HBV due to natural infection. Given the potential for rituximab to cause immunosuppression and HBV reactivation, entecavir treatment was started and continued for 18 months. The patient was followed for another five years, during which her LFTs and viral markers showed stability. However, after nine years of PEG-IFN-α-induced UCTD disorder, she experienced a reoccurring cough but was unresponsive to steroids that were against her suspicion of a flare of IP. A subsequent dynamic CT scan detected a 75% trachea collapse while in a supine position, indicating a potential complication termed EDAC. This EDAC could not be linked to PEG-IFN-α-induced UCTD disorder or EDAC after the use of entecavir in a patient with PEG-IFN-α-induced UCTD disorder. Treatment of such complex patients requires flexible, specific treatment plans and continuous monitoring. This case emphasizes the need for caution in patients with a history of IFN-induced disease and the possibility of late effects and possible effects of the use of entecavir in a patient with PEG-IFN-α-induced UCTD. To the best of our knowledge, this is the first case reported as EDAC, a possible delayed complication of PEG-IFN-α plus ribavirin or entecavir in a patient with PEG-IFN-α-induced UCTD.

To investigate the incidence and risk factors of hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)−/ HBV core antibody (HBcAb)+ patients who underwent rituximab (RTX) therapy for rheumatoid arthritis (RA). From January 2000 through December 2017, a total of 134 RA patients with various HBV serostatuses who received RTX at Dalin Tzu Chi Hospital were screened. Finally, 50 HBsAg−/HBcAb+ patients were enrolled in this retrospective study. Baseline characteristics, comedications, and the occurrence of HBV reactivation were recorded. Four HBsAg−/HBcAb+ RA patients (8%; 4/50) experienced HBV reactivation after treatment with RTX. Hepatitis flare-up occurred in 2 of these 4 patients, with a fatal outcome in one. HBV reactivation occurred approximately 1–4 years after the first dose of RTX and 0.5–1.5 years after the last one. In HBsAg−/HBcAb+ patients, HBV reactivation was significantly more common in those who were HBV surface antibody (HBsAb)− at baseline than in those who were HBsAb+ (30% vs 4%; p = 0.02). A history of adalimumab use was associated with HBV reactivation (100% vs 39%; p = 0.02). A moderate risk of HBV reactivation was observed in HBsAg−/HBcAb+ RA patients receiving RTX therapy. The reactivation may induce acute hepatitis and even death. To reduce the risk of HBV reactivation, regular monitoring of liver function is insufficient; monitoring of viral load and HBsAg or prophylaxis with antiviral therapy should be considered.