Cases Of Hepatitis B Virus Reactivation Research Articles

Hepatitis B virus coinfection in patients treated for chronic hepatitis C: clinical characteristics, risk of reactivation with long-term follow-up, and effectiveness of antiviral therapy.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) share a similar transmission route, which increases coinfection odds and worsens clinical outcomes. Our aim was to investigate coinfected patients undergoing HCV treatment with direct-acting antivirals (DAAs) to understand their characteristics, risk of HBV reactivation, and effectiveness of the therapy. Our study comprehensively analyzed 1118 patients with chronic HCV infection, divided into 3 subgroups based on their HBV status. We documented that 0.7% of the analyzed population was positive for hepatitis B virus surface antigen (HBsAg), while 14.3% had evidence of a past HBV infection. The patients without HBV coinfection were less burdened with comorbidities, and were mostly treatment-naive, while the individuals suffering from coinfection were younger and more likely to have a history of a previous therapy. Infection with HCV genotype 3 was more common among the HBsAg-positive patients than in the other studied groups. Response to DAA therapy was comparable between the groups, and most patients completed the course of treatment as planned. Only 3 cases of HBV reactivation were observed, all of which achieved sustained virologic response after DAA therapy. Two were women on immunosuppressants with antihepatitis B core positive antibodies, and the third patient was an HBsAgpositive man. These patients remained in long-term follow-up. Neither the presence of HBV markers nor HBV reactivation during DAA treatment reduced effectiveness of the therapy. Our findings are important for future recommendations and guidelines on managing HBV/HCV coinfection.

Hepatitis B virus reactivation in seronegative occult hepatitis B patient receiving ibrutinib therapy

BackgroundIbrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor approved for the treatment for several mature B-cell malignancies. Reactivation of hepatitis B virus (HBV) is a well-described complication in patients with chronic HBV infection or prior HBV exposure undergoing cytotoxic or immunosuppressive chemotherapy for hematologic malignancies. This phenomenon has been frequently reported with rituximab. However, published data on the risk of HBV reactivation induced by ibrutinib are scarce. Cases of HBV reactivation in hematologic patients receiving ibrutinib therapy have recently been described, but limited only to overt hepatitis B patients or seropositive occult hepatitis B patients.Case presentationWe report the first case of HBV reactivation during ibrutinib treatment in an asymptomatic 82-year-old woman with seronegative occult hepatitis B patient (i.e., negative for HBsAg, anti-HBc and anti-HBs). Four months after ibrutinib treatment, her liver function test (LFT) was deranged, with seroconversion to HBsAg positivity. Serum hepatitis B virus DNA was quantified to be 1.92 × 108 IU/ml. Antiviral treatment was initiated, and viral load was gradually suppressed with improvement in LFT.ConclusionsOur case illustrated that in populations with a high incidence of HBV exposure, systematic screening for HBV exposure is essential prior to ibrutinib treatment, followed by serial monitoring of serologic and molecular markers of hepatitis B. There is a need for an international consensus to support the recommendation of antiviral prophylaxis against HBV reactivation in patients using ibrutinib.

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

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

Hepatitis B virus infection does not affect the clinical outcome of anti-programmed death receptor-1 therapy in advanced solid malignancies: Real-world evidence from a retrospective study using propensity score matching.

This study aimed to investigate the impact of hepatitis B virus (HBV) infection on the outcome of patients with advanced solid malignancies treated with programmed death receptor-1 (PD-1) inhibitors.We retrospectively included patients treated with PD-1 inhibitors between August 2018 and April 2020. Propensity score matching (PSM) was performed to match the characteristics of the HBV and non-HBV groups. Objective response rate (ORR) and disease control rate (DCR) were compared between HBV and non-HBV groups using χ2 or Fisher exact tests. Kaplan-Meier and log-rank tests were used to analyze overall survival (OS) and progression-free survival (PFS).A total of 120 patients, including 43 (35.8%) with HBV and 77 (64.2%) without HBV, were enrolled. Cases of HBV reactivation were not observed. In the entire study population, ORR and DCR did not significantly differ between both groups. After PSM, the study population comprised 39 patients, 15 with and 24 without HBV. The HBV group had an ORR of 55.6%, whereas the ORR in the non-HBV group was 36.8% (P = .35). Similarly, the DCR was 77.8% in the HBV group, as compared to 68.4% in the non-HBV group (P = .61). Additionally, HBV infection did not significantly affect OS (P = .54) and PFS (P = .64) in the unmatched cohort. Moreover, statistically significant differences regarding OS (P = .15) and PFS (P = .23) were also not detected after PSM.In conclusion, the HBV infection status did not impact the therapy response or prognosis of patients treated with PD-1 inhibitors. Further prospective studies are needed to corroborate these findings.

Hepatitis B reactivation with pembrolizumab, atezolizumab, and nivolumab: A pharmacovigilance study and literature review.

e15127 Background: Chronic Hepatitis B virus (HBV) impacts 257 million people worldwide. Chemo- and immunotherapies may predispose to HBV reactivation (HBVr), which can negatively impact oncologic outcomes. Programmed death (PD) and programmed death ligand (PDL)-1 inhibitors have been implicated in HBVr. The aim of this study is to report HBVr in patients who are treated with PD-1/PD L-1 inhibitors by utilizing the FDA Adverse Events Reporting System (FAERS) and literature review. Methods: This is a retrospective pharmacovigilance study using FAERS. We reviewed cases of HBVr reported in patients treated with pembrolizumab, atezolizumab, and nivolumab from 2016-2019. Signal disproportionality analysis was conducted using a reporting odds ratio (ROR). A systematic review using Ovid MEDLINE(R) was conducted for additional reports of HBVr and associated outcomes. Results: There were 15 cases of HBVr associated with the use of PD1/PDL1 inhibitors on FAERS (ROR 1.2, 95% CI [0.72-1.99]). Only pembrolizumab was shown to a have significant association with HBVr (ROR 2.93, 95% CI [1.57-5.46]) (Table). Moreover, 7 cases of HBVr were reported in the literature, 3 with pembrolizumab and 4 with nivolumab. Median time to diagnosis following initiation of immunotherapy was 12 (5-24) weeks and 8 (3-10.5) weeks for resolution of HBVr. Conclusions: Pembrolizumab was the only agent with a significant association of HBVr. Future institutional studies in both endemic and nonendemic areas are warranted to determine the true incidence and necessity of pretreatment screening for HBV in patients on PD-1/PDL-1 therapy. [Table: see text]

Hepatitis B Virus Reactivation: Risk Factors and Current Management Strategies.

Hepatitis B virus (HBV) is a global disease with significant morbidity and mortality. Worldwide, ~257 million people are chronically infected with HBV, defined as having a positive hepatitis B surface antigen, but millions more have prior HBV exposure indicated by positive hepatitis B core antibody. Reactivation of hepatitis B implies a sudden increase in viral replication in a patient with chronic HBV infection or prior HBV exposure. Hepatitis B virus reactivation (HBVr) can occur spontaneously, but it is more commonly triggered by immunosuppressive therapies for cancer, immunologic diseases, or transplantation. Elimination of hepatitis C virus (HCV) in HBV-HCV coinfected individuals treated with direct-acting antivirals (DAAs) has also been identified as an important cause of HBVr. Hepatitis B virus reactivation is an underappreciated but important complication of common medical therapies that can delay treatment or result in clinical episodes of hepatitis, hepatic failure, or death. In this review, factors associated with HBVr, particularly medication-related risks, are explored. We review data involving rituximab and ofatumumab, doxorubicin, corticosteroids, tumor necrosis factor antagonists, tyrosine kinases, bortezomib, hematologic stem cell transplantation, and DAAs for HCV treatment. In addition, we discuss screening strategies, choice of antiviral prophylaxis, and the optimal duration of therapy for HBVr. With additional awareness, screening, and appropriate antiviral therapy, it is expected that most cases of HBVr can be prevented.

Hepatitis B screening rates and reactivation in solid organ malignancy patients undergoing chemotherapy in Southern Thailand.

Background/AimsHepatitis B virus reactivation (HBVr) following chemotherapy (CMT) is well-known among hematologic malignancies, and screening recommendations are established. However, HBVr data in solid organ malignancy (SOM) patients are limited. This study aims to determine hepatitis B surface antigen (HBsAg) screening rates, HBV prevalence, and the rate of significant hepatitis caused by HBVr in SOM patients undergoing CMT.MethodsBased on the Oncology unit’s registration database from 2009–2013, we retrospectively reviewed records of all SOM patients ≥18 years undergoing CMT at Songklanagarind Hospital who were followed until death or ≥6 months after CMT sessions. Exclusion criteria included patients without baseline liver function tests (LFTs) and who underwent CMT before the study period. We obtained and analyzed baseline clinical characteristics, HBsAg screening, and LFT data during follow-up.ResultsOf 3,231 cases in the database, 810 were eligible. The overall HBsAg screening rate in the 5-year period was 27.7%. Screening rates were low from 2009–2012 (7.8–21%) and increased in 2013 to 82.9%. The prevalence of HBV among screened patients was 7.1%. Of those, 75% underwent prophylactic antiviral therapy. During the 6-month follow-up period, there were three cases of significant hepatitis caused by HBVr (4.2% of all significant hepatitis cases); all were in the unscreened group.ConclusionsThe prevalence of HBV in SOM patients undergoing CMT in our study was similar to the estimated prevalence in general Thai population, but the screening rate was quite low. Cases of HBVr causing significant hepatitis occurred in the unscreened group; therefore, HBV screening and treatment in SOM patients should be considered in HBV-endemic areas.

Incidence of hepatitis B reactivation during epidermal growth factor receptor tyrosine kinase inhibitor treatment in non–small-cell lung cancer patients

BackgroundReactivation of hepatitis B virus (HBV) is a documented risk during cytotoxic chemotherapy in patients with lung cancer. Cases of HBV reactivation in non–small-cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment have been reported; however, the incidence of HBV reactivation in patients treated with EGFR TKIs has not yet been reported. Materials and methodsWe enrolled 171 patients who were diagnosed as having NSCLC from 2011 through 2017 and who also had positive hepatitis B surface antigen (HBsAg). All patients had received EGFR TKIs as anticancer treatment for at least 2 weeks during their treatment course. Reactivation of HBV is defined as one of the following: an increase in HBV DNA by at least 10-fold compared to baseline or an absolute increase to >10ˆ5 IU/mL with abnormal liver function. ResultsThe median duration of EGFR TKI treatment was 10.5 months (95% confidence interval: 8.2–12.8). Sixteen (9.36%) patients met the criteria of HBV reactivation during EGFR TKI treatment, with an annual incidence of 7.86%. HBV reactivation occurred during erlotinib treatment in 6 patients, followed by 5 patients with gefitinib treatments, 3 patients with osimertinib treatment and 2 with afatinib treatment. No independent risk factor for HBV reactivation was identified. ConclusionNSCLC patients receiving EGFR TKI treatment may have a clinically meaningful risk of HBV reactivation during the treatment period. Thus, monitoring liver function, HBV viral load and serology of HBV (i.e., HBeAg and anti-HBc) during EGFR TKI therapy is recommended for NSCLC patients with positive HBsAg.

Real world data on follicular lymphoma patients treated by rituximab-containing immunochemotherapy and rituximab maintenance.

Background/AimsReal-world data about the treatment outcomes of patients receiving rituximab-containing immunochemotherapy followed by rituximab maintenance are required to understand better the treatment for follicular lymphoma (FL).MethodsA cross-sectional study analyzed FL patients who were treated with R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab maintenance.ResultsOf 139 patients, 85 patients received R-CVP and 54 received R-CHOP. The characteristics did not differ significantly between the groups. Only grade 3 of FL was more common in R-CHOP. The complete response rate did not differ significantly between R-CHOP (50/54, 92.6%) and R-CVP (77/85, 90.6%). The number of disease relapses during rituximab maintenance did not differ significantly between the groups (p = 0.798). Therefore, the comparison of progression-free survival (PFS) showed no significant difference: the 3-year PFS rates for R-CVP and R-CHOP were 77% and 85%, respectively (p = 0.567). Although five of 56 hepatitis B virus (HBV) core antibody (anti-HBc)-positive patients experienced HBV reactivation, all cases of HBV reactivation were identified during regular monitoring for HBV DNA in blood, and were successfully managed with antiviral treatment.ConclusionsThe survival outcomes of FL patients on rituximab maintenance after responding to R-CVP or R-CHOP were similar. Rituximab-containing immunochemotherapy followed by rituximab maintenance can be safely used for anti-HBc-positive patients if HBV DNA titer in blood can be regularly monitored.

Minimal Risk of HBV Reactivation in Resolved HBV-Infected Patients During Immunosuppressive Therapy

Background: Hepatitis B virus reactivation (HBVr) during immunosuppressive drug therapy (ISDT) is a growing concern; however, prospective long-term follow-up studies are rare. Methods: In this cross-sectional study, we analyzed two groups of patients showing hepatitis B surface antibody (anti-HBs) positivity/HBV surface antigen (HBsAg) negativity among 181 patients receiving immunosuppressive therapy and 141 patients receiving antineoplastic therapy in our tertiary care center. We also analyzed the associated factors and determined the necessity of prophylactic antiviral treatment. Findings: The mean follow-up time was 17.7 months. We did not detect any cases of HBVr, even among patients receiving rituximab, tumor necrosis factor inhibitors and antineoplastic therapy or in patients with only hepatitis B core antibody (anti-HBc) positivity. Furthermore, we did not find an association between anti-HBs changes and HBVr, although a role for anti-HBs in reactivation has previously been suggested. To examine the association between anti-HBs titers and HBVr, anti-HBs ( ) patients were divided into three subgroups: (i) anti-HBs>1000 mIU/mL (group A), (ii) anti-HBs between 100 and 1,000 mIU/mL (group B) and (iii) anti-HBs between 0 and 100 mIU/mL (group C). A subgroup analysis showed that during the study period, the antibody levels did not change in group A, changed nonsignificantly in group B (p=0.27) and significantly declined in group C (p=0.003). Interpretation: The risk of reactivation of HBV infection by immunosuppressive and antineoplastic therapy is lower than that suspected in published anecdotal reports. Funding: None Declarations of Interest: None Ethics Approval Statement: This study was performed in accordance with the principles of Good Clinical Practice, the principles of the Declaration of Helsinki and national laws. The study protocol was approved by the local ethics committee.

Outcome of patients with serology suggestive of past hepatitis B virus infection during antitumor necrosis factor therapy for psoriasis

Recently, the reactivation during treatment with tumor necrosis factor (TNF) blockers has exceptionally been described in patients with hepatitis B virus (HBV) antigen-negative (HBsAg). The objective was to evaluate the influence of anti-TNF agents in patients with psoriasis and serology suggesting past hepatitis B state. The inclusion criteria were chronic plaque psoriasis treated with anti-TNF therapy, HBsAg-negative, and HBcAb-positive. We gathered the demographic data and type and duration of anti-TNF agent. Serum aminotransferase levels and HBV serologic status were requested at baseline and during follow-up. We have included 13 patients (four women, nine men) (mean age of 62.1years). The agent was etanercept in seven cases, infliximab in four patients, and adalimumab in the other two. The mean duration of TNF therapy was 28.6months. None of them became HBsAg-positive. Neither signs nor symptoms of acute hepatitis were reported. The management of HBsAg-negative patients is unresolved. Only nine cases of HBV reactivation during treatment with TNF blockers have been reported. Despite the low risk of reactivation in these patients, we recommend the monitoring of serum aminotransferase levels, HBsAb titers, HBsAg and, if possible, viral load.

Hepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor

Hepatitis B virus (HBV) reactivation is a well-recognized complication in patients with chronic HBV infection receiving cytotoxic or immunosuppressive chemotherapy. Imatinib mesylate and nilotinib are selective Bcr/Abl tyrosine kinase inhibitors, which are now widely used in the treatment of patients with chronic myeloid leukemia. Although HBV reactivation induced by imatinib mesylate has been reported, nilotinib-related HBV reactivation has not been reported in the English literature. We report here 2 cases of HBV reactivation in chronic myeloid leukemia patients receiving imatinib mesylate and a novel case of nilotinib related HBV reactivation.

Risk of hepatitis B reactivation and the role of novel agents and stem-cell transplantation in multiple myeloma patients with hepatitis B virus (HBV) infection

The purpose of the study is to analyse the prevalence of hepatitis B virus (HBV) infection and its incidence of reactivation among multiple myeloma (MM) patients treated in the era of novel therapy in an endemic Asian setting. From 2000 to 2008, 273 patients with newly diagnosed MM were screened for the presence of hepatitis B virus surface antigen and HBV core antibody. HBV-infected patients were prospectively followed for reactivation with serial monitoring of serum alanine transferase and HBV DNA load. The patterns of HBV reactivation in relation to treatment received, exposure to high-dose therapy with autologous stem-cell transplantation (HDT/ASCT) and novel agents were studied. The prevalence of HBV infection was 5.5%. Three cases of HBV reactivation despite lamivudine prophylaxis were reported. Two patients reactivated 3-5 months after HDT/ASCT while receiving thalidomide maintenance and one reactivated 3 years after HDT/ASCT and shortly after bortezomib salvage therapy. Emergence of a mutant HBV strain was documented in one patient. Use of prophylaxis may reduce but will not preclude HBV reactivation. Highest risk occurs during immune reconstitution phase of HDT/ASCT. The role of immunomodulatory agents in HBV reactivation needs to be further elucidated. Separate HBV prophylaxis and surveillance guidelines ought to be developed for patients with MM.

Fatal hepatitis B reactivation treated with entecavir in an isolated anti-HBs positive lymphoma patient: A case report and literature review

Hepatitis B virus (HBV) reactivation is a well-recognized complication that occurs in lymphoma patients who undergo chemotherapy. Only very few cases of HBV reactivation in patients with isolated antibody against hepatitis B surface antigen (anti-HBs) have been reported. We present a case of a 78-year-old woman diagnosed with diffuse large B cell non-Hodgkin's lymphoma who only displayed a positive anti-HBs, as the single possible marker of occult HBV infection, before starting therapy. She was treated with several chemotherapeutic regimens (including rituximab) for disease relapses during 3 years. Forty days after the last cycle of chemotherapy, she presented with jaundice, markedly elevated serum aminotransferase levels, and coagulopathy. HBV serology showed positivity for HBsAg, anti-HBc and anti-HBs. HBV DNA was positive. Antiviral treatment with entecavir was promptly initiated, but the patient died from liver failure. A review of the literature of HBV reactivation in patients with detectable anti-HBs levels is discussed.

Reactivation of hepatitis B virus in a hepatitis B surface antigen-negative patient with rheumatoid arthritis treated with methotrexate

Immunosuppressive therapy can induce viral reactivation in patients with chronic hepatitis B virus (HBV) infection and, more rarely, in patients with resolved HBV infection. We report the case of a 57-year-old Japanese woman with rheumatoid arthritis (RA) who developed de-novo hepatitis B virus-related hepatitis after methotrexate (MTX) therapy. Entecavir and oral prednisolone following steroid pulse therapy were administered and her liver function recovered. MTX is widely used for RA for its efficiency and safety. But some cases of HBV reactivation caused by MTX, including de-novo hepatitis, have been reported. Considering these conditions, more attention should be paid when using MTX in patients with RA. And more studies are needed to determine who needs screening of HBV, monitoring of HBV-DNA, and prophylaxis with chemotherapy or immunosuppressive therapy.

Prise en charge du risque de réactivation du virus de l’hépatite B chez les patients traités par immunosuppresseurs et immunomodulateurs en médecine interne : données de l’enquête REACTI-B et proposition d’un algorithme de prise en charge

Propose This study aimed to evaluate the screening practices and management of the risk of hepatitis B virus (HBV) reactivation in patients receiving immunosuppressive and immunomodulatory agents in internal medicine departments and to propose a diagnostic and therapeutic algorithm. Methods Descriptive, cross-sectional survey of the 1350 members of the French Society of Internal Medicine, which took place in France in January 2011 using an electronic questionnaire. Experts in the field of HBV infection proposed a decisional algorithm. Results The overall response rate was 21.5%. Screening of HBV infection was performed in 44%, 68% and 76% of patients receiving or prior to initiating corticosteroids, immunosuppressive and immunomodulatory agents, respectively. Among participants, 35% had been confronted with one or several cases of HBV reactivation, mainly in patients receiving corticosteroids (54%), cyclophosphamide (34%) or rituximab (33%). Chronic, inactive carriers of HBV were considered to be at risk of reactivation in 89% of cases, while 41% of anti-HBc positive patients were considered at risk. In at-risk patients initiating immunosuppressive and/or immunomodulatory agents, 43% of practitioners consider the use of pre-emptive therapy, whereas 33% treat in case of confirmed reactivation. Systematic HBV vaccination of seronegative patients is planned in less than 50% of cases. Finally, 89% of participants feel they are not sufficiently educated regarding the risks of HBV reactivation and its prevention. Conclusion This survey highlights the need to improve the education of physicians regarding the risks of HBV reactivation prior to initiating corticosteroids, immunosuppressive and immunomodulatory agents, and to provide more specific guidelines for patients managed in internal medicine departments.

Three Cases of Radiation-Induced Hepatitis B Virus Reactivation after Hepatic Tomotherapy: Case Report

Radiation-induced liver disease (RILD) has been characterized as a veno-occlusive disease with anicteric elevation of alkaline phosphatase (ALP). However, some RILD patients present with elevated transaminase levels rather than with anicteric elevation of ALP, and these findings are common in the Asia-Pacific region where hepatitis B virus (HBV) infection is associated with 70∼90% of hepatocelluar carcinoma (HCC) cases. In addition, the development of RILD is more common in patients with hepatitis B virus-related HCC. These findings indicate that susceptibility to RILD might be different in HBV carriers and non-carriers, and moreover, RILD in patients with HBV-related HCC might be associated with another unique pathogenesis such as HBV reactivation. However, HBV reactivation after hepatic irradiation has been reported in only a few studies. This study reports three cases of HBV reactivation after hepatic tomotherapy for management of HCC.

Prospective Analysis of Hepatitis B Virus Reactivation In Patients with Diffuse Large B Cell Lymphoma After Rituximab Combination Chemotherapy

AbstractAbstract 3950Reactivation of hepatitis B virus (HBV) was reported in patients who were being treated with rituximab-combination chemotherapy (R-chemotherapy). HBV reactivation was a well-known complication in lymphoma patients who were positive for hepatitis B surface antigen (HBsAg) in the pre-rituximab era. Recently, it was reported that HBV reactivation can occur in HBsAg-negative patients with past infection of HBV, upon administering R-chemotherapy for B-cell lymphoma. The association between rituximab and HBV reactivation is still unknown. There have been cases of HBV reactivation in patients with past HBV infection during the course of chemotherapy and/or immunotherapy, sometimes proving fatal. Nevertheless, it remains uncertain whether diffuse large B-cell lymphoma (DLBCL) patients with past HBV infection are at substantial risk for reactivation of latent HBV.We prospectively studied the frequency of and risk factors for HBV reactivation in DLBCL patients who received R-chemotherapy. A total of 356 HBsAg-negative patients with DLBCL were treated with R-chemotherapy. Anti-HBs and anti-HBc tests were performed in all patients. In patients who were positive for anti-HBs and/or anti-HBc, serum HBV-DNA was measured. The serum HBV-DNA load was determined by quantitative RT-PCR [COBAS® AmpliPrep/COBAS® TaqMan® HBV-Test, Roche Diagnostics K.K. Tokyo, Japan].A total of 356 HBsAg-negative patients with DLBCL were enrolled in this study. Among the 51 (16.2%) HBV carriers, 6 patients developed HBV reactivation and 45 patients did not develop HBV reactivation during the study period. Exploratory analysis was conducted on potential factors associated with the development of HBV reactivation. Male gender and having a low anti-HBs titer before R-chemotherapy were significantly associated with HBV reactivation. Age, clinical stage, B symptoms, lactate dehydrogenase (LDH), performance status, international prognostic index, and chemotherapy regimen were not associated with HBV reactivation. Among the 51 HBV carriers, 8 patients (15.7%) were positive for only anti-HBs, 27 (53%) were positive for both anti-HBs and anti-HBc, and 16 (31.3%) were positive for only anti-HBc. HBV reactivation occurred during or after R-chemotherapy in the 6 patients (12%); two patients developed reactivation after three or seven cycles of R-CHOP, respectively, whereas four patients developed reactivation after completion of R-CHOP therapy at a median interval of 90 days (range, 20 to 143 days). All 6 patients who developed HBV reactivation were positive for anti-HBc, and 3 of them were also positive for anti-HBs. The pretreatment anti-HBs titer of the 6 patients was low (range, <2.0 to 40.2 mIU/ml). When HBV-DNA became detectable in the serum, entecavir administration was started and the serum HBV-DNA became negative within 13 weeks. Elevation of ALT and AST was not observed in any of the 6 patients. The serum HBV-DNA level did not increase after entecavir administration was started in any patient. When HBV reactivation occurred, the liver function did not become elevated and HBsAg remained negative in all six patients. After serum HBV-DNA became undetectable, R-chemotherapy was resumed. None of the 6 patients developed hepatitis B. In the 6 patients who developed HBV reactivation, the anti-HBs titer before R-chemotherapy and the anti-HBs titer at the time of HBV reactivation did not significantly differ. In the 45 patients who did not develop HBV reactivation, the anti-HBs titer before R-chemotherapy ranged from 11.6 to <1,000 mIU/ml. After the end of R-chemotherapy, the anti-HBs titer was lower in 42 of the 45 patients. The posttreatment anti-HBs titer of the 42 patients was 10.2–542 mIU/ml. The anti-HBs titer returned to the value before the start of R-chemotherapy 6–18 months after the end of R-chemotherapy.HBV reactivation occurred in some patients who had been anti-HBs-negative or had a low anti-HBs level. In addition, HBV reactivation occurred at an early stage of R-chemotherapy, but R-chemotherapy could be resumed after entecavir administration reduced the serum HBV-DNA level. Entecavir prophylaxis was not performed when R-chemotherapy was started, and it was thought that entecavir could be started when the serum HBV-DNA increased. Disclosures:No relevant conflicts of interest to declare.

Reactivation of hepatitis B virus in HBsAg-negative patients with multiple myeloma: two case reports

It was recently reported that hepatitis B virus (HBV) reactivation had occurred in HBsAg-negative lymphoma patients who received rituximab plus steroid combination chemotherapy. HBV reactivation in myeloma patients have not been reported extensively. We describe here two cases of HBV reactivation in HBsAg-negative myeloma patients receiving systemic chemotherapy: one from the medical records of 40 patients and another from 61 patients with prospective HBV-DNA monitoring. In the first case positive for anti-HBs, HBV reactivation was diagnosed when hepatitis developed during conventional chemotherapy such as MP and MCP regimen in a relapsed patient after autologous stem cell transplantation (APBSCT); in the second case positive for anti-HBc and anti-HBs, elevation of HBV-DNA was recognized by serial HBV-DNA monitoring performed prospectively following APBSCT. Interestingly, these two cases had the reduction of the titer of anti-HBs during the treatment, followed by HBV reactivation. These clinical data suggest that the HBV-DNA monitoring is necessary for not only HBsAg-positive but also HBsAg-negative myeloma patients with anti-HBc-positive and/or anti-HBs-positive following transplantation and after conventional chemotherapy in the salvage setting. Establishment of a standard strategy to prevent HBV reactivation is important for myeloma patients receiving systemic chemotherapy.

Hepatitis B reactivation induced by Rituximab maintenance therapy for lymphoma

Dear Editor, Hepatitis B virus (HBV) reactivation is a serious problem for patients with malignancy when receiving cytotoxic chemotherapy, especially for lymphoma patients [1]. Pei et al. [2] demonstrate that Rituximab-based chemotherapy regimen increases risk of HBV reactivation. For patients with positive HBV surface antigen (HBsAg), the consensus in Taiwan is prophylaxis with anti-HBV drugs during and 3 to 6 months after chemotherapy. With more evidence for use of Rituximab in 2-year maintenance therapy for follicular lymphoma [3] and for further treatment of diffused large B cell lymphoma, it remains unclear whether HBV prophylaxis during Rituximab maintenance therapy is indicated. Here, we present a 41-year-old woman with nonHodgkin's lymphoma (NHL) who died of HBV reactivation during Rituximab maintenance therapy. This patient was diagnosed as NHL, diffused large B cell stage IV, with initial presentation of abdominal fullness. Because of positive HBsAg, she received Lamivudine 100 mg per day during her six cycles of R-CHOP regimen (375 mg/M Rituximab, 750 mg/M cyclophosphamide, 50 mg/M Adriamycin, 1.4 mg/M vincristine, and 40 mg/ M prednisolone for 5 days). She achieved complete remission after this full course of chemotherapy, as shown by negative image findings of computer tomography and positron emission tomography. This patient received lamivudine daily for another 6 months after chemotherapy. She then entered a clinical trial of Rituximab maintenance therapy with schedule of 375 mg/M every 2 months for 2 years. Unfortunately, she suffered from reactivation of HBV, and fulminant hepatitis about 30 days after the ninth treatment with Rituximab. Her liver function is shown in Fig. 1. The patient's HBV DNA was 8.87×10 IU. There were no detectable mutations. We shifted her anti-HBV drug to Entecavir 1 mg per day, but she was not responsive. This patient eventually died of fulminant hepatitis. Rituximab-induced profound hypogammaglobulinemia and impaired humoral immune response have been demonstrated and might be responsible for HBV reactivation [4,5]. There is no consensus of HBV prophylaxis during Rituximab single therapy because only a few cases of HBV reactivation are reported [6,7]. Even if it is highly effective [8], one of the serious problems of HBV prophylaxis with lamivudine comes from its high resistance, which is about 25% annually [9]. For those receiving long-term Rituximab therapy, Entecavir may be a better option because it has minimal resistance rate after 5-years of use in patients with chronic hepatitis B [10]. C.-H. Cho :W.-L. Hwang :C.-L. Teng (*) Division of Hematology/Oncology, Department of Medicine, Taichung Veterans General Hospital, 160, Section 3, Chungkang Road, Taichung 407, Taiwan e-mail: drteng@vghtc.gov.tw