Hepatitis B Virus Reactivation Research Articles

Novel strategies for the early diagnosis of hepatitisB virus reactivation.

HepatitisB virus (HBV) reactivation under systemic chemotherapy or immunosuppressive therapy is a serious complication among HBV-resolved patients. Some medications, such as more than 2weeks of corticosteroid therapy, can influence HBV reactivation; therefore, screening tests that measure hepatitisB surface antigen (HBsAg), hepatitisB core antibody, and hepatitis B surface antibody before therapy are required. Additionally, because HBV reactivation has been reported in patients positive for HBsAg treated with immune checkpoint inhibitors (ICIs), the prophylactic administration of nucleos(t)ide analogues prior to administering ICIs is recommended for HBsAg-positive patients. Under these circumstances, highly sensitive novel biomarkers are expected to be used for the early diagnosis of HBV reactivation. A fully automated high-sensitivity HBsAg assay (detection limit: 5mIU/ml) by Lumipulse HBsAg-HQ, with 10-fold higher sensitivity than that of conventional assays, is currently used. Furthermore, ultra-sensitive HBsAg assays using a semi-automated immune complex transfer chemiluminescence enzyme immunoassay (ICT-CLEIA; detection limit: 0.5mIU/ml) have been developed. Recently, a fully automated, novel high-sensitivity hepatitisB core-related antigen assay (iTACT-HBcrAg; cut-off value: 2.1LogU/mL) has been developed and reported. The utility of ICT-CLEIA and iTACT-HBcrAg for the diagnosis of HBV reactivation appears comparable to the use of HBV DNA. In this review, we provide the latest information related to medications that influence HBV reactivation and recently developed novel biomarkers that predict and monitor HBV reactivation.

Clinical practice of hepatitis B screening in patients starting with chemotherapy: A survey among Dutch oncologists.

ObjectiveScreening for hepatitis B virus (HBV) before chemotherapy is recommended by international guidelines; still, the HBV screening rate is low, and patients remain at risk for HBV reactivation (HBVr). Because HBVr is a serious and preventable condition, we conducted a survey to evaluate the screening behaviour of oncologists in the Netherlands.MethodsWe conducted an anonymous digital survey by email to all practicing medical oncologists. The surveys were sent in two session, the first one in 2017 and the second one in 2019. Questions included HBV screening procedures, reasons for screening and experience with HBVr.ResultsAmong the 110 respondents, 29 (27%) followed a standardised protocol. Overall, 13 (12%) oncologists screened all patients, 76 (70%) only screened patients they considered as high risk and 19 (18%) did not screen anyone. Fourteen percent of the respondents experienced a HBVr in one of their patients.ConclusionThis survey suggests that universal HBV screening is not common practice and usually patients considered as at risk for HBVr are screened, while this group is not always properly identified. Introduction of a national protocol for HBV screening and adjustment of the Dutch oncology guidelines might contribute to a reduction of HBVr during chemotherapy.

Prevention of hepatitis B reactivation in patients requiring chemotherapy and immunosuppressive therapy.

Hepatitis B virus (HBV) reactivation can lead to severe acute hepatic failure and death in patients with HBV infection. HBV reactivation (HBVr) most commonly develops in patients undergoing cancer chemotherapy, especially B cell-depleting agent therapy such as rituximab and ofatumumab for hematological or solid organ malignancies and that receiving hematopoietic stem cell transplantation without antiviral prophylaxis. In addition, the potential consequences of HBVr is particularly a concern when patients are exposed to either immunosuppressive or biologic therapies for the management of rheumatologic diseases, inflammatory bowel disease and dermatologic diseases. Thus, screening with HBV serological markers and prophylactic or pre-emptive antiviral treatment with nucleos(t)ide analogues should be considered in these patients to diminish the risk of HBVr. This review discusses the clinical manifestation, prognosis and management of HBVr, risk stratifications of cancer chemotherapy and immunosuppressive therapy and international guideline recommendations for the prevention of HBVr in patients with HBV infection and resolved hepatitis B.

Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients.

Lamivudine, also widely known as 3TC belongs to a family of nucleotide/nucleoside analogues of cytidine or cytosine that inhibits the Reverse Transcriptase (RT) of retroviruses such as HIV. Lamivudine is currently indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection or for chronic Hepatitis B (HBV) virus infection associated with evidence of hepatitis B viral replication and active liver inflammation. HBV reactivation in patients with HBV infections who receive anticancer chemotherapy can be a life-threatening complication during and after the completion of chemotherapy. Lamivudine is used, as well as other antiretrovirals, to prevent the reactivation of the Hepatitis B virus during and after chemotherapy. In addition, Lamivudine has been shown to sensitize cancer cells to chemotherapy. Lamivudine and other similar analogues also have direct positive effects in the prevention of cancer in hepatitis B or HIV positive patients, independently of chemotherapy or radiotherapy. Recently, it has been proposed that Lamivudine might be also repurposed against SARS-CoV-2 in the context of the COVID-19 pandemic. In this review we first examine recent reports on the re-usage of Lamivudine or 3TC against the SARS-CoV-2, and we present docking evidence carried out in silico suggesting that Lamivudine may bind and possibly work as an inhibitor of the SARS-CoV-2 RdRp RNA polymerase. We also evaluate and propose assessment of repurposing Lamivudine as anti-SARS-CoV-2 and anti-COVID-19 antiviral. Secondly, we summarize the published literature on the use of Lamivudine or (3TC) before or during chemotherapy to prevent reactivation of HBV, and examine reports of enhanced effectiveness of radiotherapy in combination with Lamivudine treatment against the cancerous cells or tissues. We show that the anti-cancer properties of Lamivudine are well established, whereas its putative anti-COVID effect is under investigation. The side effects of lamivudine and the appearance of resistance to 3TC are also discussed.

Effects of programmed death receptor-1 antibody in patients with hepatitis B-associated liver cancer

Objective: To investigate the effect of programmed death receptor (PD)-1 antibody therapy in patients with hepatitis B-associated liver cancer. Methods: Data of 29 chronically infected HBV patients with liver cancer who received PD-1 antibody combined with tyrosine kinase inhibitor in the Department of Infectious Diseases of the Fifth Medical Center of PLA General Hospital from March 2020 to January 2021 were selected. At the same time, all of the above-mentioned hepatitis B virus (HBV) patients were treated with nucleos(t)ide analogues. Patients clinical diagnostic data, laboratory test results, tumor response and the incidence of adverse reactions were collected retrospectively to understand the overall safety, therapeutic anti-tumor effect, HBV changes condition and the correlation between HBV changes and anti-tumor PD-1 antibody efficacy, high viral load treatment condition, and HBV reactivation safety issues. Statistical analysis was performed by non-parametric rank sum test. Results: Therapeutic anti-tumor effect and safety profile were good in patients. The complete remission rate was reached 27.6%. Adverse reactions were mostly mild, and the incidence of serious adverse reactions was low. After 12 weeks of follow-up, HBV DNA and hepatitis B surface antigen (HBsAg) was quantitatively decreased (P < 0.05). HBV DNA and HBsAg were decreased more significantly in patients with progressive disease (PD), stable disease (SD) and partial response (PR) (P < 0.05). Five patients with HBV DNA ≥ 10(4) IU/ml had responded well to the tumor treatment without serious adverse reactions. One patient had a slight increase in HBV DNA and alanine aminotransferase, while there was no HBV reactivation and correlated liver damage. Conclusion: Patients with HBV-associated liver cancer who received combined therapy have good anti-tumor efficacy and safety profile. PD-1 treatment has a certain effect on HBV. Compared with non-responders, patients with tumor response have better antiviral treatment efficacy. The safety of treatment in patients with high viral load is manageable, and there are no safety issues related to HBV reactivation.

Effect of Low-Dose Corticosteroid Use on HBV Reactivation in HBsAg-positive Rheumatoid Arthritis Patients

Background: It is well known that the use of corticosteroids (CS) results in increased viral replication and elevated alanine aminotransferase in hepatitis B virus (HBV) patients. However, only a few studies have investigated the effect of low-dose CS on HBV reactivation. In addition, there are few studies on the effects of synthetic disease-modifying anti-rheumatic drugs on HBV reactivation. Objective: We investigated the reactivation of HBV in rheumatoid arthritis (RA) patients treated with long-term low-dose corticosteroids. In addition, we analyzed factors affecting HBV reactivation, including disease-modifying anti-rheumatic drugs. Methods: We retrospectively reviewed medical records and analyzed the incidence of HBV reactivation in RA patients who were hepatitis B surface antigen (HBsAg) positive and who were receiving ≤10 mg of prednisolone over 4 weeks. Logistic regression analysis was performed to investigate the factors that increase the risk of HBV reactivation. Results: A total of 141 patients were included in the study, out of which 24 (17.0%) patients had HBV reactivation. The administration of low-dose corticosteroids did not affect HBV reactivation in HBsAg-positive RA patients (odds ratio: 0.807, 95% confidence interval: 0.143–4.546, p = 0.808), nor did the duration of corticosteroid administration, average daily corticosteroid dose, and cumulative corticosteroid dose. Administration of leflunomide was found to significantly increase the risk of HBV reactivation (odds ratio: 3.851, 95% confidence interval: 1.026–14.459, p = 0.046). Conclusion: The administration of low-dose corticosteroids did not affect the rate of HBV reactivation, suggesting that it can be used safely. Leflunomide may increase the risk of HBV reactivation; therefore, HBV patients should be carefully monitored when receiving this drug.

Management of hepatitis B virus infection in patients with inflammatory bowel disease under immunosuppressive treatment.

Hepatitis B remains a significant global clinical problem, despite the implementation of safe and effective vaccination programs. The prevalence of hepatitis B virus (HBV) in patients with inflammatory bowel disease (IBD) largely follows the regional epidemiologic status. Serological screening with hepatitis B surface antigen (HBsAg), and antibodies to hepatitis B surface (anti-HBs) and core (anti-HBc) proteins is a key element in the management of IBD patients and, ideally, should be performed at IBD diagnosis. Stratification of individual cases should be done according to the serologic profile and the IBD-specific treatment, with particular emphasis in patients receiving immunosuppressive regimens. In patients who have not contracted HBV, vaccination is indicated to accomplish protective immunity. Vaccination in immunosuppressed patients, however, is a challenging issue and several strategies for primary and revaccination have been proposed. The risk of HBV reactivation in patients with IBD should be considered in both HBsAg-positive and HBsAg-negative/anti-HBc-positive patients, when immunosuppressive therapies are administered. HBV reactivation is preventable via the administration of prophylactic nucleot(s)ide analogues and should be the standard approach in HBsAg-positive patients. HBsAg-negative/anti-HBc-positive patients represent a non-homogeneous group and bear a significantly lower risk of HBV reactivation. Biochemical, serological and molecular monitoring is currently the recommended approach for anti-HBc patients. Acute HBV infection is rarely reported in IBD patients. In the present review, we outline the problems associated with HBV infection in patients with IBD and present updated evidence for their management.

Role of quantitative hepatitis B surface antibodies in preventing hepatitis B virus-related hepatitis in patients treated with rituximab

Hepatitis B virus (HBV) reactivation is a well-known complication after rituximab-based chemotherapy in patients with B cell lymphoma (BCL) who have resolved HBV infection. This retrospective cohort study used electronic medical records from the Kaohsiung Chang Gung Memorial Hospital. There were 128 patients with BCL and resolved HBV infection treated with 1st-line rituximab-containing therapy from 2008 to 2013. No patient received antiviral prophylaxis. Patients with high pretreatment hepatitis B surface antibody (anti-HBs titer ≥100 mIU/mL), had significantly less HBV reactivation (2.0%, 1/49) than patients with low (10–100 mIU/mL, 10.8%, 4/37) or negative anti-HBs (<10 mIU/mL, 23.8%, 10/42) (p = 0.001). No patient in the high group vs. 1 (2.7%) low group vs. 6 (14.3%) negative group developed HBV-related hepatitis (p = 0.002). Patients with high pretreatment anti-HBs have a low risk of HBV-related complications and may not require antiviral prophylaxis. We propose an algorithm for the management of HBV reactivation risk in BCL.

HBV Reactivation During the Treatment of Non-Hodgkin Lymphoma and Management Strategies.

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.

Association of hepatitis B virus infection status with outcomes of non-small cell lung cancer patients undergoing anti-PD-1/PD-L1 therapy.

BackgroundThe aim of this study was to evaluate the safety and survival outcomes of anti-programmed cell death (PD)-1/programmed cell death-ligand 1 (PD-L1) monotherapy in patients with advanced non-small cell lung cancer (NSCLC) and different hepatitis B virus (HBV) infection status.MethodsPatients with advanced NSCLC and both chronic and/or resolved HBV infection who were treated with anti-PD-(L)1 monotherapy were retrospectively enrolled. The primary endpoint was the safety of PD-1/PD-L1 monotherapy, while the secondary endpoints included the survival outcomes.ResultsOf the 62 eligible patients, 10 (16.1%) were hepatitis B surface antigen (HBsAg) positive [chronic hepatitis B (CHB) infection] and 52 (83.9%) were HBsAg negative and HBcAb positive [resolved hepatitis B (RHB) infection]; 42 (67.7%) patients had at least 1 treatment-related adverse event (AE), with 4 patients (6.5%) developing grade 3 AEs and 6 (9.7%) developing hepatic AEs. One CHB patient experienced HBV reactivation during anti-PD-1 immunotherapy due to the interruption of antiviral prophylaxis. The objective response rate and durable clinical benefit (DCB) rate were 17.7% and 29.0%, respectively. Median overall survival (OS) and progression-free survival (PFS) were 23.6 months [95% confidence interval (CI): 14.4–32.8] and 2.1 months (95% CI: 1.2–3.0), respectively. The DCB rate was significantly higher in the CHB group than in the RHB group (60% vs. 23.1%; P=0.048). Patients with CHB experienced a longer PFS (8.3 vs. 2.0 months; P=0.103) and OS (35.0 vs. 18.2 months, P=0.119) than did RHB patients.ConclusionsAnti-PD-(L)1 monotherapy was safe and effective in patients with NSCLC and HBV infection. This population should not be excluded from receiving immunotherapy in routine clinical practice or within clinical trials if HBV biomarkers are monitored and antiviral prophylaxis is properly used.

Efficacy of entecavir verses lamivudine prophylaxis in preventing hepatitis B virus reactivation in patients with allogeneic stem cell transplant

Immunosuppressive therapy has been the main stay of treatment in patients with hematological malignancies. Reactivation of occult hepatitis B infection (HBV), is commonly encountered with stem cell transplant recipients with anti CD20 agents, with history of resolved HBV infection. We aimed to find the efficacy of nucleos(t)ide analogues lamivudine (LVD) and entecavir (ETV) in preventing the HBV flare up when given prophylactically. Patients who received allogeneic stem cell transplant were evaluated. Sixty patients, thirty in each group who received LVD or ETV prophylaxis were included in the study. All the baseline and post-transplant data was evaluated which includes anti -CD20 agent exposure, duration of prophylaxis of each drugs and clinical and virological follow up post transplantation. Serum ALT, HBsAg, anti HBs and HBV DNA were the parameters measured. The median clinical and virological follow up in each group was 24 months. LVD or ETV was given during the entire follow up period. There was no reactivation during the prophylaxis period, however 2 patients in LVD group showed detectable viral DNA post prophylaxis withdrawal. The clinical outcome of both LVD and ETV reveals equal efficacy in preventing HBV reactivation. However screening is mandatory before chemotherapy. HBs Ag-negative/anti-HBc-positive patients require ALT monitoring during the entire chemotherapy.

Abatacept is second to rituximab at risk of HBsAg reverse seroconversion in patients with rheumatic disease

BackgroundHepatitis B surface antigen (HBsAg) reverse seroconversion (RS) can happen in patients with rheumatoid arthritis (RA) with resolved hepatitis B (RHB) undergoing biological disease-modifying antirheumatic drugs (bDMARDs). But the incidence...

Risk of Hepatitis B Virus Reactivation in Patients Treated With Immunotherapy for Anti-cancer Treatment

Background & AimsHepatitis B virus (HBV) reactivation is a well-known complication in patients with chronic hepatitis B treated with cytotoxic chemotherapy. However, the risk of HBV reactivation through use of immune checkpoint inhibitors (ICIs) is not well understood. Therefore, we aimed to evaluate the risk of HBV reactivation and hepatic adverse events in patients with cancer receiving ICIs according to cancer type and virologic serology. MethodsThis historical cohort study included 3465 patients with cancer treated with ICIs between January 2015 and September 2020. The primary outcome was the occurrence of HBV reactivation, and the secondary outcome was presence of hepatic adverse events during ICI treatment. ResultsThe mean patient age was 62.2 years, and 68.8% of patients were men. Of the 3465 eligible patients, 511 (14.7%) showed hepatitis B surface antigen (HBsAg) positivity. The incidence rates of HBV reactivation of the total patients, HBsAg-positive patients, and HBsAg-negative patients were 0.14% (5/3465), 1.0% (5/511), and 0.0% (0/2954), respectively. Among HBsAg-positive patients, HBV reactivation occurred at a rate of 0.5% (2/409) and 2.9% (3/102) in patients with and without hepatocellular carcinoma, respectively. The HBV reactivation rates were 0.4% (2/464) and 6.4% (3/47) in patients with and without antiviral prophylaxis, respectively. Grade 3–4 hepatitis occurred in 23 (4.5%) HBsAg-positive, and 218 (7.4%) HBsAg-negative patients. No HBV-related fatality occurred. Only 2 patients (0.4%) experienced HBsAg seroclearance after ICI treatment among HBsAg-positive patients. ConclusionsIn general, HBV reactivation was rarely observed in patients with antiviral prophylaxis while undergoing ICI treatment. However, HBV reactivation may occur in HBsAg-positive patients without antiviral prophylaxis or noncompliant with antiviral prophylaxis.

Managing the Risk of Hepatitis B Virus Reactivation in Patients with B-Cell Lymphomas Treated with Obinutuzumab or Rituximab Immunochemotherapy

Introduction: Reactivation of hepatitis B virus (HBV) is an identified risk associated with immunochemotherapy for non-Hodgkin lymphoma (NHL) in patients (pts) with resolved HBV infection. This study aimed to evaluate the risk of HBV reactivation and explore risk factors in NHL pts with resolved HBV infection who received anti-CD20 antibody (obinutuzumab or rituximab)-containing immunochemotherapy in the phase III GOYA and GALLIUM studies (involving pts with previously untreated diffuse large B-cell lymphoma [DLBCL] and indolent NHL, respectively). Methods: Pts were randomized to receive induction with either obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, and day 1 of cycles 2‒8) or rituximab (375 mg/m2 on day 1 of each cycle) in combination with CHOP (GOYA and GALLIUM), CVP (GALLIUM), or bendamustine (GALLIUM) for 6-8 cycles. In GALLIUM, induction was followed by obinutuzumab or rituximab maintenance. Baseline screening was performed locally for hepatitis B surface antigen (HBsAg) and antibody against hepatitis B core antigen (anti-HBc). Pts positive for HBsAg were excluded, while those with resolved HBV infection (HBsAg-negative but anti-HBc-positive) could be enrolled if they had baseline HBV DNA Results: Of 2797 evaluable pts (GOYA, 1407; GALLIUM, 1390), 326 pts were seropositive for anti-HBc (207 were seropositive for antibodies against HBsAg) and 11 had detectable but non-quantifiable HBV DNA (10 to Conclusions: HBV DNA monitoring-guided preemptive NAT was effective in preventing HBV-related hepatitis during treatment with obinutuzumab- or rituximab-containing immunochemotherapy. Antiviral prophylaxis was effective in preventing HBV reactivation and may be an appropriate option for pts with resolved HBV infection and multiple risk factors. Disclosures Kusumoto: Chugai: Honoraria, Other: GALLIUM and GOYA are sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing support, under the direction of Shigeru Kusumoto, was provided by Cheryl Wright of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding. Arcaini: Celgene, Roche, Sandoz: Consultancy; Gilead: Research Funding; Pfizer, Celgene, Bayer, Roche: Membership on an entity9s Board of Directors or advisory committees. Kim: JJ Takeda: Research Funding; Celltrion, Inc: Consultancy, Honoraria; Novartis: Research Funding; Roche: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; Kyowa-Kirin: Research Funding. Peters: Genentech, Merck: Honoraria; Roche: Honoraria. Tanaka: BMS: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; GSK: Honoraria, Research Funding. Zelenetz: Celgene: Consultancy; Amgen: Consultancy. Kuriki: Chugai: Employment. Fingerle-Rowson: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Nielsen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ueda: Chugai: Employment. Piper-Lepoutre: Roche: Employment. Sellam: Roche: Employment. Tobinai: Daiichi Sankyo Co., Ltd: Consultancy, Honoraria; AbbVie: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; HUYA Bioscience: Honoraria; Chugai: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Janssen: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Servier: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria.

The Incidence of HBV Reactivation in Patients Receiving First-Line R-CHOP Chemotherapy: Three-Year Follow-up Results from a Prospective, Observational Study

Background:Due to the high rate of chronic hepatitis B virus (HBV) infection in China, hepatitis B surface antigen (HBsAg) can be detected among 25-61% of patients with diffuse large B-cell lymphoma (DLBCL) and 20-40% with follicular lymphoma (FL), while HBsAg- negative (neg) /HBcAb-positive (pos) can be detected among 20-44% of patients with DLBCL (Chinese Society of Hematology, 2013). When these patients receive immune-suppressing treatment, they are at an increased risk of HBV reactivation which may lead to hepatic mortality and interrupt the rituximab-based chemotherapy. For patients and their physicians, HBV infection management plays a crucial role for achieving optimal survival outcomes without compromising safety. This multicenter, single-arm, prospective, non-interventional study was conducted at 24 centers in China between January 17, 2011 and October 31, 2016. Previously untreated CD20-positive DLBCL patients who were eligible to receive rituximab plus chemotherapy (R-chemo) (CHOP or non-CHOP) as first-line treatment were enrolled with no specific exclusion criteria. We investigated the risk of HBV reactivation in patients with CD20+ DLBCL or FL which received R-chemo as first-line treatment.Methods:Patients who received at least one dose of R-chemo were included in the analysis. Data were collected and analyzed from medical records for 3 years since the last R dose was administered. The evaluation of HBV infection management included HBV infection and liver function screening before R-chemo, viral replication monitoring during and after R-chemo, antiviral prophylaxis use and HBV reactivation rates. HBsAg-pos patients had HBV reactivation if HBV DNA increased ≥1 log10 from baseline, if HBV DNA appeared (above the lower limit of detection) or if HBeAg appeared in HBeAg- neg patients. HBsAg-neg/HBcAb-pos patients had HBV reactivation if there was appearance of either HBsAg or HBV DNA (above the lower limit of detection). The HBV reactivation was determined by SAP and investigator's judgment. This study was registered in clincialtrials.gov (NCT01340443).Results:In total, 282 DLBCL patients and 31FL patients were included in the analysis. HBV screening data were available from 271 enrolled patients. At baseline, 26 patients were HBsAg-pos, 79 were HBsAg- neg/HBcAb-pos and 166 were double neg. HBV infection status was undefined for 42 patients. During the study, HBV reactivation was detected in 8 patients, which was only in the DLBCL group. Seven cases were observed in treatment period, while 1 case occurred during 3-year follow-up. None of them led to study termination, temporary termination, or dose adjustment.Cox univariate regression analysis in DLBCL patients showed that baseline type of hepatitis B correlated with overall response rate (ORR) and complete response (CR) but had no effect on progression-free survival (PFS).In term of HBV infection management, in DLBCL group, 25 patients with HBsAg-pos or HBsAg-neg/ HBcAb-pos receiving antiviral prophylaxis. In FL group, only 3 patients received antiviral treatment. Lamivudine was mostly administered by Chinese investigators. Details on treatment, duration and infection status are listed in Table 1.Summary:In this prospective, observational study, we followed the patients with DLBCL or FL for 3 years to investigate the risk of HBV reactivation after they received R-chemo. Our study showed that, in real-world setting, the incidence of HBV reactivation in patients with a history of hepatitis, particularly those positive for HBsAg is acceptable, baseline type of hepatitis B had no effect on PFS. Close monitoring and antiviral prophylaxis would be beneficial to the patients with DLBCL or FL combined with hepatitis B infection while they receive R-chemo. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Low Risk for Viral Reactivation during Induction for Acute Myeloid Leukemia in Hepatitis B Silent Carriers Who Are Negativefor Hepatitis B Surface Antigen

Introduction: Latent hepatitis B virus (HBV) infection is a well-recognized risk factor for viral reactivation and life-threatening hepatitis during chemotherapy. Chronic HBV carriers, identified by the presence of hepatitis B antigen (HBsAg) in their serum, have a well-established high risk for reactivation. Patients, exposed to HBV, who have not become true carriers [HBsAg-negative, but anti-hepatitis B core antigen (HBc)-positive] are usually considered to have a “resolved” HBV infection. Current recommendations state that during chemotherapy all patients exposed to HBV in the past are to receive anti-HBV prophylaxis. However, these recommendations are based on data mainly driven from unselected series of cancer patients previously exposed to HBV. It has been clearly demonstrated that HBV reactivation is common in cases where immune suppressive therapy is applied (e.g., patients treated with corticosteroids and/or rituximab or those undergoing stem cell transplantation). Information regarding the incidence and risk factors of HBV reactivation in patients treated for acute myeloid leukemia (AML) is scarce. While some data support prophylaxis for chronic HBV carriers (HbSAg-positive) during chemotherapy for AML, it remains debatable whether this approach is required in AML patients with “resolved” HBV infection undergoing intensive chemotherapy.Methods: The current study reviewed medical files of 1200 patients who were diagnosed with AML between the years 2000-2017 and treated in three large hematology departments in Israel - at the Rambam Health Care Campus, Tel Aviv Sourasky Medical Center and Shaare Zedek Medical Center. Clinical characteristics and laboratory data were retrospectively analyzed. Each patient, diagnosed with AML, was tested for HbSAg, HbSAb, anti-HBc, anti-hepatitis C virus (HCV). Only patients who had not received prophylaxis with anti-HBV agents were included in the analysis.Results: A total of 38 patients with “resolved” HBV infection at the time of leukemia diagnosis were identified, including 15 females (39.5%) and 23 males (60.5%), with a median age of 59.5 years (range 35-80). Six (15.7%) patients were diagnosed with AML secondary to myelodysplastic syndromes (MDS). The following induction regimens were used: daunorubicin + cytarabine (“7+3”) in 34 patients (89.5%), clofarabine in two patients, and high-dose cytarabine (HIDAC) in two patients. Nine patients received re-induction with “7+3”. Twenty seven patients (71%) received consolidation - 26 with HIDAC and one with clofarabine (Table 1). Within 90 days following induction + consolidation therapy, no HBV reactivation was documented in any of the 38 patients. There was a mild and asymptomatic elevation in the levels of hepatocellular liver enzymes (up to 2.5 times the upper limit of normal) in some patients, which could also be attributed to other causes, such as drugs, sepsis, etc. In our cohort of patients, overall survival (OS) was identical to that observed in historical AML patients from our medical centers who were not HBV carriers (Fig. 1).Conclusions: AML patients with previous HBV infection (HBsAg-negative and anti-HBc-positive) undergoing intensive chemotherapy are not at an increased risk for virus reactivation. In the current study, none of the 38 patients had HBV reactivation, suggesting that omission of anti-HBV prophylaxis during induction and consolidation chemotherapy could be considered in select AML patients. Notably, two groups of AML patients with a higher risk of HBV reactivation, i.e., recipients of allogeneic stem cell transplantation and HbSAg-positive patients, were not included in the present study and the conclusions drawn are not applicable to these patient subsets. Larger studies are warranted to explore the role of HBV prophylaxis in “silent” carriers. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

HBV Care Map for Patients Receiving Anti-CD20 Therapy

Background:Chronic Hepatitis B Virus (HBV) and so-called “resolved” HBV infections (HBsAg negative and anti-HBc positive) can be reactivated secondary to anti-CD20 therapy mediated immunosuppression used in the treatment of cancer and many non-malignant conditions. HBV reactivation can lead to delays in curative chemotherapy as well as HBV specific complications including liver failure and death. Appropriate screening, monitoring and treatment of HBV is integral to the safe administration of anti-CD20 therapies. However, current available guidelines for the management of HBV in patients receiving anti-CD20 therapies rely on a weak body of evidence and provide recommendations that do not adequately address all aspects of care.Objective:To provide a unified care map for the management of HBV in patients undergoing treatment with anti-CD20 therapies.Methods:A Delphi consensus technique was applied to a multidisciplinary panel of 10 North American experts in HBV or anti-CD20 therapy. The processed occurred over a 20-month period culminating in November 2014. To achieve a comprehensive overview, pharmacists, physicians and a nurse practitioner were included as team members. A preliminary HBV care map was generated based on literature review in conjunction with iterative questionnaires completed by panel members. Panelists were asked to rate their level of agreement across multiple domains of HBV care including screening, treatment and monitoring of patients. Consensus was achieved when there was greater than 75% agreement for all HBV care map elements. The HBV care map was subsequently revised and approved by all members at a face-to-face panel meeting.Results:The HBV care map recommends universal screening for all patients receiving anti-CD20 therapy. Patients with positive screening results are stratified into parallel, chronic and resolved HBV tracks. Both patients with chronic and resolved HBV should be started on antiviral treatment (or prophylaxis) prior to beginning anti-CD20 therapy. Entecavir is recommended as first line therapy over tenofovir disoproxil fumarate or lamuvidine. Where cost is a major factor, lamuvidine may be acceptable with close monitoring for viral resistance. Patients require routine monitoring for HBV reactivation (q3-6 months depending on care approach) from the initiation of anti-CD20 therapy until at least one year following discontinuation of immunosuppression. HBV DNA is recommended as the optimal test for HBV reactivation status as it is sensitive and can identify early reactivation events. Monitoring for HBsAg reverse seroconversion can also be used in resolved HBV but is not prioritized in the care map due to limited data demonstrating the safety of this approach.Conclusion:The HBV care map incorporates best available evidence and expert consensus building to provide clear and pragmatic guidance to clinicians managing HBV in patients receiving anti-CD20 therapies. In the rapidly changing clinical environment there is a need to quickly respond to growing risks associated with the development of new immunosuppressive treatments. The development of specific and valid guidelines in areas with limited published studies is an i2mportant step in improving the safe delivery of cancer care. This will also serve as the foundation for current and future prospective studies in the care of HBV among immunosuppressed patients. [Display omitted] DisclosuresCrump:Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Ortho: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hwang:Gilead Sciences: Research Funding; Merck: Research Funding. Yim:Gilead Sciences: Consultancy, Honoraria. Zelenetz:Celgene: Consultancy; Amgen: Consultancy. Feld:Gilead Sciences: Research Funding. Hicks:Gilead Sciences: Research Funding.

Hepatitis B Virus Seropositivity in Chronic Myeloid Leukemia Patients Receiving Tyrosine Kinase Inhibitors: Preliminary Results of a Single-Center Cross-Sectional Study

Background: Hepatitis B virus (HBV) infection is a global public health issue, and Turkey is intermediately endemic with 4.5% and 30.6% HbsAg and anti-HBc IgG prevalences, respectively. The HBV infection can be problematique in patients (pts) with hematological malignancies. Tyrosine kinase inhibitors (TKIs) are the mainstay of chronic myeloid leukemia (CML) management, and screening of CML pts for HBV prior to TKI initiation and the management of isolated anti-HBc IgG positivity among these pts are controversial.Aim: To evaluate the frequency and outcome of HbsAg and anti-HBc IgG positivity in CML pts receiving TKIs.Patients and methods: Seventy-four pts with CML in chronic phase (CML-CP) were tested for HBV markers (HbsAg, anti-Hbs, anti-Hbc IgG, HBV DNA) and serum alanine aminotransferase (ALT) levels out of a total of 240 pts as a part of an ongoing study. Pts' characteristics, TKI therapies and durations, response rates, and follow-up periods were noted retrospectively.Results: Pts' characteristics are summarized in Table 1. Fifty-six pts received imatinib (IM) and nilotinib (NIL) was administered in one patient as first-line treatments, whereas the remaining 17 pts had two or more lines of TKI. Median duration of follow-up was 104 months (mos) (range, 3-215 mos). Only one patient was screened for HBV prior to TKI therapy. The median time from TKI initiation to HBV screening was 98 mos (range, 2-179 mos).Fourty-three pts were either HBV naive or anti-Hbs negative. Nineteen pts had anti-Hbc IgG positivity, of whom 10 were also positive for anti-Hbs. Among anti-Hbc IgG positive cases, HBV DNA was negative in twelve pts, and the HBV DNA results of the remaining 7 cases are still pending. None of the pts with isolated anti-Hbc IgG positivity received antiviral prophylaxis for HBV. Four pts (5%) had elevated ALT levels at the time of analysis. One of these pts was HbsAg positive (ALT: 65 IU/ml) (Table 2, case 1); the other was anti-Hbc IgG positive but had negative anti-Hbs and HBV DNA (ALT: 54 IU/ml) receiving IM, whereas the remaining two were HBV negative. Of these two cases, one had grade I (ALT: 57 IU/ml) and the other had grade II (ALT: 101 IU/ml) hepatotoxicity most probably due to dasatinib and NIL, respectively.Two pts were HbsAg positive, and the clinical features of these cases are shown in Table 2. First case had elevated ALT levels (174 IU/ml), positive HbeAg and high HBV DNA which were detected one mo after IM initiation. Tenofovir was started and he had decline in HBV DNA. The patient is still under IM with MMR. The other case experienced HBV reactivation 28 months after IM therapy. With lamivudine treatment, HBV DNA became negative and he is still under IM maintaining MMR.Discussion: The risk of HBV reactivation under TKI therapy and thus, the necessity of screening for HBV prior to TKI initiation are still debating. HBV screening before TKI therapy is not recommended in the ESMO and ELN guidelines, whereas the most recent NCCN guideline and EMA document recommended testing for HBV infection before TKI administration due to some case reports of HBV reactivation after TKI initiation. In our patient cohort the percentages of HbsAg and anti-Hbc IgG positivities were 3% and 26% among the tested cases which were consistent with the prevalences for our general population. Although the nature of our study is cross-sectional and the results are preliminary, the risk of HBV reactivation with TKI use seems to be low in pts with resolved HBV infection and with isolated anti-Hbc IgG positivity and negative HBV DNA among our cohort. Longitudinal studies with serial testing for HBV markers are needed in order to answer these questions in CML pts receiving TKI therapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Study of hepatitis B virus infection, reactivation among patients with chronic hepatitis C infection treated by direct antiviral agents (DAAs)

BackgroundHepatitis B virus (HBV) may reactivate when treating chronic hepatitis C (CHC) with direct-acting antivirals (DAA). We aimed to investigate the risk of HBV infection and reactivation during DAA therapy by performing a prospective observational study carried on 200 patients positive for chronic HCV who were candidates for treatment by DAA therapy according to the Egyptian guidelines from February 2019 to December 2019; the patients identified to carry HBsAg at baseline or with positive HBc Abs were further assessed for other HBV markers: hepatitis B e antigen at baseline, and serum HBV DNA quantitative measurement at baseline, week 4 of treatment, end of treatment. On the other hand, recent infection by HBV among those patients was observed.ResultsOf all participants, 49% were males and 51% were females, aged above 18 years. There is a highly statistically significant difference (p-value < 0.05) between HCV RNA PCR (at the beginning, at the end of 4 weeks, and at the end of 12 weeks) in studied patients. There was a highly statistically significant difference found between the liver function tests at the beginning, at the end of 4 weeks, and at the end of 12 weeks of treatment where it shows improvement except for serum albumin. At beginning of the study, there were 34 patients who are co-infected with HCV and HBV with quantitative PCR test for HBV DNA ≥ 20 IU/ml. After 1 month of DAA therapy, reactivation was detected in 6 cases (4 occult cases show reverse seroconversion (became HBs Ag positive), and 2 co-infected cases show increased HBV DNA > 1000 IU/L above the baseline level). In addition, 3 new cases acquired recent infection with the positivity of HBc IgM and detectable levels of HBV DNA. After 3 months of study, reactivation was detected in one patient with co-infection (where increased HBV DNA > 1000 IU/L above the baseline level), and 5 new cases acquired recent infection late in the study.ConclusionScreening for HBV infection prior to DAA therapy is required to detect recent infection of reactivation of previous infection during or after DAA therapy.

Determination of reactivation rate and risk factors for Hepatitis B virus reactivation in low-positive cases: A retrospective cohort study

IntroductionIn quantitative assays for hepatitis B virus (HBV) DNA, although the amplification reaction signal is detected for low-positive cases, quantification remains challenging. HBV reactivation has been reported in many studies, but only a few have focused on HBV low-positive cases. This study aimed to determine the reactivation rate and risk factors for HBV reactivation in low-positive cases. MethodsIn this retrospective cohort study, we analyzed 7498 patients who had their HBV DNA measured at Sapporo Medical University Hospital between April 2008 and November 2020. Patient selection criteria were defined as follows: hepatitis B surface antigen was negative; HBV DNA was detectable but not quantifiable at least once. HBV DNA was monitored according to the guidelines for HBV reactivation. ResultsIn total, 49,086 HBV DNA quantitative tests were performed. HBV DNA levels of 2578 tests were detectable but not quantifiable. Eighty patients met the criteria in this study. The median observation period was 497 days, and the 2-year reactivation rate was 15%. Ten patients had low HBV DNA positivity at baseline. Malignant lymphoma was observed in 15 patients; chemotherapy was used to treat other solid tumors in 35 patients, and immunosuppressive therapy was used in 30 patients. Multivariate analysis revealed that HBV DNA detected below the quantification level at baseline was an independent risk factor for HBV reactivation (adjusted hazard ratio 5.82; P = 0.010). ConclusionsPatients with low HBV DNA positivity, especially at baseline, are at high risk for HBV reactivation and therefore require closer monitoring.