Risk of Hepatitis B Virus (HBV) Reactivation in Patients with Immune-Mediated Inflammatory Diseases Receiving Biologics: Focus on the Timing of Biologics after Anti-HBV Treatment

Hepatitis B virus (HBV) infection can result in a spectrum of outcomes from immune-mediated control to disease progression, cirrhosis, and liver cancer. The host molecular pathways that influence and contribute to these outcomes need to be defined. Using an immunocompetent mouse model of chronic HBV infection, we identified some of the host cellular and molecular factors that impact on infection outcomes. Here, we show that cellular inhibitor of apoptosis proteins (cIAPs) attenuate TNF signaling during hepatitis B infection, and they restrict the death of infected hepatocytes, thus allowing viral persistence. Animals with a liver-specific cIAP1 and total cIAP2 deficiency efficiently control HBV infection compared with WT mice. This phenotype was partly recapitulated in mice that were deficient in cIAP2 alone. These results indicate that antagonizing the function of cIAPs may promote the clearance of HBV infection.

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Hepatitis B Virus Reactivation Induced by Infliximab Administration in a Patient with Crohn’s Disease

Case Reports in Hepatology ◽

10.1155/2013/461879 ◽

2013 ◽

Vol 2013 ◽

pp. 1-4 ◽

Cited By ~ 3

Author(s):

Yuka Miyake ◽

Aki Hasebe ◽

Tetsuya Tanihira ◽

Akiko Shiraishi ◽

Yusuke Imai ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Crohn’S Disease ◽

Hepatitis B Virus ◽

Crohn's Disease ◽

Hepatitis B ◽

Bowel Disease ◽

Hbv Dna ◽

Hbv Reactivation ◽

B Virus ◽

Inflammatory Bowel

A 47-year-old man diagnosed with Crohn’s disease was treated with infliximab. He tested negative for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) but positive for anti-HB core antibody (anti-HBc). He tested positive for hepatitis B virus (HBV-) DNA 3 months after treatment and was administered entecavir. HBV-DNA test showed negative results 1 month later. ALT was persistently within the normal range, and HBV-DNA was persistently negative thereafter despite the continuation of infliximab every 8 weeks. In our hospital, 14 patients with inflammatory bowel disease, who tested negative for HBsAg, were treated with infliximab; 2 of them tested positive for anti-HBs and/or anti-HBc, and HBV reactivation was observed in 1 patient (the present patient). The present case and these findings highlight that careful follow-up is needed in patients with inflammatory bowel disease treated with infliximab who test positive for anti-HBc and/or anti-HBs.

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Evaluation of a Hepatitis B Virus Reactivation Prevention Program in Lymphoma Patients Receiving Immunochemotherapy

Blood ◽

10.1182/blood.v128.22.1801.1801 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1801-1801

Author(s):

Blanca Sanchez-Gonzalez ◽

Montserrat Garcia-Retortillo ◽

Teresa Murcia ◽

Mariana Ferraro ◽

Francesc Garcia-Pallarols ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Hbv Dna ◽

Hbv Reactivation ◽

Antiviral Prophylaxis ◽

B Virus ◽

Group A ◽

Chronic Hbv ◽

Group B

Abstract INTRODUCTION Chemotherapy-induced hepatitis B virus (HBV) reactivation is a well-recognized complication and is a potentially life-threatening condition in cancer patients with chronic HBV (hepatitis B surface antigen [HBsAg]-positive). Rituximab has been associated with an increase in HBV reactivation in chronic HBV patients (45%) and even in patients with resolved infection (HBsAg negative and hepatitis B core antibody [anti-HBc]-positive (22%); however, the reported frequency varies among different studies. Current guidelines for management of chronic HBV recommend routine antiviral HBV prophylaxis with lymphoma before starting chemotherapy. In contrast, there is little evidence-based consensus regarding patients with resolved HBV infection. Aim: To analyze the incidence of HBV reactivation and the role of antiviral HBV prophylaxis in lymphoma patients with chronic HBV or resolved HBV treated with chemotherapy, immunotherapy or immunochemotherapy managed according to our institutional HBV guidelines. Secondary endpoints were to analyze the incidence of HBV in this population and HBV guidelines adherence. PATIENTS AND METHODS Lymphoma patients with chronic HBV or resolved HBV in a single center. HBV viral status definitions: Active Chronic HBV infection: HBsAg positive, anti-HBc positive and HBV DNA >2000 IU/mL; Inactive Carriers: HBsAg positive, Anti-HBc positive, HBV DNA undetectable or <2000 IU/mL with normal transaminases; Resolved HBV: HBsAg negative, anti-HBc positive, HBV DNA undetectable. HBV reactivation was defined as increased serum HBV DNA (≥1 log10), regardless of liver biochemistry or HBsAg status. Institutional HBV guidelines: serum samples were collected at baseline for HBsAg and anti-HBc testing in all lymphoma patients. Patients were evaluated by a hepatologist if any of them fulfilled HBV viral status definition. Baseline at screening and monitoring every 3 months during therapy and up to 24 months after completing therapy (assessment of liver biochemistry, serum HBV DNA, HBsAg and anti-HBs levels). Specific prophylaxis strategies according to HBV status: Group A (Active chronic HBV): treatment for HBV; Group B (Inactive carriers): antiviral HBV prophylaxis; Group C (Resolved HBV): antiviral HBV prophylaxis if rituximab containing-therapy or follow-up only if rituximab-free therapy. HBV antiviral prophylaxis was started before therapy and finished 12 months after completing therapy. RESULTS From January 2012 to January 2015, 227 lymphoma patients received chemotherapy or immunochemotherapy. 142 (63%) patients received rituximab-containing therapy. 43 (19%) patients were anti-HBc positive. Group A: 2 (1%) patients; Group B: 2 (1%) patients; Group C: 39 (17%) patients. 14 (6%) patients have coinfection with hepatitis C virus and 12 (5%) patients co-infection with human immunodeficiency virus (HIV). Adherence to HBV guidelines was 90%. Patients in Group A (n=2) and B (n=2) received antiviral treatment/prophylaxis before starting therapy. In the Group C, 16 (41%) patients underwent only follow-up and 23 (59%) patients received HBV antiviral prophylaxis (lamivudine in 4, entecavir in 8 and tenofovir in 11). Median duration of HBV prophylaxis was 18 months (95% CI: 16-19 months). After a median follow-up of 21 months, 2 patients developed HBV reactivation during lymphoma treatment: 1 from group B (reactivation rate of 50%) and 1 from group C (reactivation rate of 3%). Both patients had received rituximab-containing treatment and both developed HBV reactivation (without hepatitis flare) within the first 6 months after finishing antiviral HBV prophylaxis (delayed HBV reactivation). Outcome was favorable in both patients. Characteristics of HBV reactivation patients are shown in table I. Cumulative incidence of HBV reactivation at 12 and 24 months were 0% and 8%, respectively. CONCLUSION Our strategy of close monitoring patients with chronic HBV or resolved HBV that receive chemotherapy and adding antiviral HBV prophylaxis only in selected patients clearly decrease HBV reactivation. Nevertheless, this strategy may not fully protect patients from late HBV reactivations. Larger validation studies are needed to confirm our data and to establish the best cost-effective strategy in this lymphoma population, especially in the new era of inmunomodulatory drugs of their real involvement in HBV reactivation is unknown. Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.

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Rituximab increases the risk of hepatitis B virus reactivation in non-Hodgkin lymphoma patients who are hepatitis B surface antigen-positive or have resolved hepatitis B virus infection in a real-world setting: a retrospective study

PeerJ ◽

10.7717/peerj.7481 ◽

2019 ◽

Vol 7 ◽

pp. e7481 ◽

Cited By ~ 5

Author(s):

Yu-Fen Tsai ◽

Ching-I Yang ◽

Jeng-Shiun Du ◽

Ming-Hui Lin ◽

Shih-Hao Tang ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Hodgkin Lymphoma ◽

Hepatitis B Surface Antigen ◽

Hbv Infection ◽

Hbv Reactivation ◽

Virus Reactivation ◽

Non Hodgkin Lymphoma ◽

B Virus ◽

Hepatitis Flare

Background Hepatitis B virus (HBV) reactivation with a hepatitis flare is a common complication in lymphoma patients treated with immunotherapy and/or chemotherapy. Anti-HBV prophylaxis is suggested for non-Hodgkin lymphoma (NHL) patients undergoing rituximab therapy, even those with resolved HBV infection. Since anti-HBV prophylaxis for patients with resolved HBV infection is not covered by national health insurance in Taiwan, a proportion of these patients receive no prophylaxis. In addition, late HBV reactivation has emerged as a new issue in recent reports, and no consensus has been reached for the optimal duration of antiviral prophylaxis. Thus, the aim of our study was to investigate the incidence and outcomes of HBV reactivation in NHL patients in a real-world setting and to study the frequency of late HBV reactivation. Materials Non-Hodgkin lymphoma patients who received rituximab and/or chemotherapy at our institute between January 2011 and December 2015 and who were hepatitis B surface antigen (HBsAg)- or hepatitis B core antibody (HBcAb)-positive were reviewed retrospectively. Results A total of 388 patients were screened between January 2011 and December 2015. In total, 196 patients were excluded because HBsAg was not assessed, HBcAb was negative or not assessed, or they were not treated with immunosuppressive therapy. Finally, the retrospective study included 62 HBsAg-positive NHL patients and 130 NHL patients with resolved HBV infection (HBsAg-negative and HBcAb-positive). During a median 30.5-month follow-up period, seven patients experienced HBV reactivation, five of whom had a hepatitis flare. The incidence of HBV reactivation did not significantly differ between the HBsAg-positive patients and the resolved HBV infection population without anti-HBV prophylaxis (4.8% vs. 3.1%, P = 0.683). All patients with HBV reactivation were exposed to rituximab. Notably, late HBV reactivation was not uncommon (two of seven patients with HBV reactivation events, 28.6%). Hepatitis B virus reactivation did not influence the patients’ overall survival. An age ≥65 years and an advanced disease stage were independent risk factors for poorer overall survival. Conclusion The incidence of HBV reactivation was similar between the HBsAg-positive patients with antiviral prophylaxis and the resolved HBV infection population without anti-HBV prophylaxis. All HBV reactivation events occurred in NHL patients exposed to rituximab. Late reactivation was not uncommon. The duration of regular liver function monitoring for more than 1 year after immunosuppressive therapy or after withdrawal of prophylactic antiviral therapy should be prolonged. Determining the exact optimal duration of anti-HBV prophylaxis is warranted in a future prospective study for NHL patients treated with rituximab-containing therapy.

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Randomized Controlled Trial of Entecavir Prophylaxis for Rituximab-Associated Hepatitis B Virus Reactivation in Patients With Lymphoma and Resolved Hepatitis B

Journal of Clinical Oncology ◽

10.1200/jco.2012.48.5938 ◽

2013 ◽

Vol 31 (22) ◽

pp. 2765-2772 ◽

Cited By ~ 202

Author(s):

Yi-Hsiang Huang ◽

Liang-Tsai Hsiao ◽

Ying-Chung Hong ◽

Tzeon-Jye Chiou ◽

Yuan-Bin Yu ◽

...

Keyword(s):

Viral Load ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Hepatitis B Surface Antigen ◽

Controlled Trial ◽

Control Group ◽

Hbv Reactivation ◽

Antiviral Prophylaxis ◽

B Virus ◽

To Receive

Purpose The role of antiviral prophylaxis in preventing hepatitis B virus (HBV) reactivation before rituximab-based chemotherapy in patients with lymphoma and resolved hepatitis B is unclear. Patients and Methods Eighty patients with CD20+ lymphoma and resolved hepatitis B were randomly assigned to receive either prophylactic entecavir (ETV) before chemotherapy to 3 months after completing chemotherapy (ETV prophylactic group, n = 41) or to receive therapeutic ETV at the time of HBV reactivation and hepatitis B surface antigen (HBsAg) reverse seroconversion since chemotherapy (control group, n = 39). Results Fifty-eight patients (72.5%) were positive for hepatitis B surface antibody, and HBV DNA was undetectable in 50 patients (62.5%). During a mean 18-month follow-up period, one patient (2.4%) in the ETV prophylactic group and seven patients (17.9%) in the control group developed HBV reactivation (P = .027). The cumulative HBV reactivation rates at months 6, 12, and 18 after chemotherapy were 8%, 11.2%, and 25.9%, respectively, in the control group, and 0%, 0%, and 4.3% in the ETV prophylactic group (P = .019). Four patients (50%) in the control group had HBsAg reverse seroconversion after HBV reactivation. The cumulative HBsAg reverse seroconversion rates at months 6, 12, and 18 since chemotherapy were 0%, 6.4%, and 16.3% in the control group, respectively, which were significantly higher than those in the ETV prophylactic group (P = .032). Patients with detectable or undetectable viral load could develop HBV reactivation and HBsAg reverse seroconversion. Conclusion Undetectable HBV viral load before chemotherapy did not confer reactivation-free status. Antiviral prophylaxis can potentially prevent rituximab-associated HBV reactivation in patients with lymphoma and resolved hepatitis B.

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Hepatitis B virus (HBV) reactivation-The potential role of direct-acting agents for hepatitis C virus (HCV)

Reviews in Medical Virology ◽

10.1002/rmv.1984 ◽

2018 ◽

Vol 28 (4) ◽

pp. e1984 ◽

Cited By ~ 5

Author(s):

Jason T. Blackard ◽

Kenneth E. Sherman

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Potential Role ◽

Hbv Reactivation ◽

B Virus ◽

Direct Acting

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288. Hepatitis B Virus Reactivation in Patients with Hematologic Malignancies after Anticancer Therapy Which Included Ibrutinib

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.363 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S156-S157 ◽

Cited By ~ 1

Author(s):

Alexandre Malek ◽

Yago Nieto ◽

Ariel D Szvalb ◽

Shaheer Siddiqui ◽

Mehnaz A Shafi ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Liver Failure ◽

Lymphocytic Leukemia ◽

Hbv Infection ◽

Temporal Association ◽

Hbv Reactivation ◽

Guidance Document ◽

Cell Transplant ◽

B Virus

Abstract Background Several cases of severe bacterial, fungal, and viral infections have been reported following ibrutinib therapy. Here, we report a case of a patient with non-Hodgkin lymphoma who developed hepatitis B virus (HBV)–associated liver failure after anti-cancer treatment most recently with ibrutinib. We also review reported cases of HBV reactivation (HBVr) after ibrutinib. Methods We searched the Medline and Embase databases and identified 5 patients with HBVr related to ibrutinib for a total of 6 study patients, including our case (figure). HBV-related outcomes were defined according to the 2018 AASLD HBV guidance document. Results All 6 patients were men and most (5 or 83%) had chronic lymphocytic leukemia and past HBV infection (table). Three patients (50%) developed HBV-related hepatitis and 2 of them progressed to liver failure. Four patients (67%) had a remote history (≥24 months) of other potential risk factors besides ibrutinib that could contribute to HBVr, including the use of direct-acting antivirals for hepatitis C co-infection (1 pt), hematopoietic cell transplant (HCT) (1 pt) and rituximab use (4 patients). HBVr occurred at least 6 months after initiation of ibrutinib in most patients (4 or 67%), with a median of 9.7 months (range, 1.5–42). In all 4 patients pretreated with rituximab, that treatment was completed at least 24 months before HBVr. Two of these patients received anti-HBV prophylaxis that was stopped 12 months after the completion of rituximab; the other 2 patients were only monitored without antivirals. The HCT recipient received anti-HBV prophylaxis per guidelines. None of the 6 patients treated with ibrutinib were receiving anti-HBV prophylaxis at the time of HBVr, but 5 patients were started on anti-HBV drugs at the first sign of HBVr. Four received entecavir and 1, tenofovir. All treated patients recovered from HBVr. No pt died of HBVr. Conclusion Life-threatening HBVr can occur following ibrutinib therapy in patients with past or chronic HBV infection. The temporal association between ibrutinib therapy and reactivation indicates that ibrutinib is the likely cause of the HBVr, and clinicians should be aware of the risk of HBVr in these patients. A provisional approach could be HBV monitoring at regular intervals with initiation of antiviral therapy at the earliest sign of HBV reactivation. Disclosures All authors: No reported disclosures.

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