Impact of hepatitis B surface and core antibody levels on hepatitis B virus reactivation

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We examined the levels of HBV surface (HBsAb) and core antibodies (HBcAb) to assess the incidence of HBV-R in patients with solid and hematopoietic cancers. Retrospective cohort study was conducted in 590 patients with resolved HBV infection. The patients consisted of solid (n = 466) and hematopoietic cancers (n = 124), including lymphoma receiving rituximab-containing chemotherapy. The incidenceof HBV-R was evaluated 761.5 (range, 4–3,898) days after the start of chemotherapy. Of 590 patients, 13 (2.2%) developed HBV-R after the start of chemotherapy. All HBV-R patients exhibited a lower HBsAb (<100 mIU/mL) at baseline. A higher HBcAb (≥100 C.O.I.) was identified as a risk factor for HBV-R,with an incidence of 9.6%. The simultaneous presence of HBsAb <100 mIU/mL and HBcAb ≥100 C.O.I. increased the risk of HBV-R by 18.5%. Patients treated with rituximab-containing chemotherapy had a higher risk of HBV-R (18.4%) despite having HBcAb <100 C.O.I. Our results indicate that baseline levels of HBsAb <100 mIU/mL and HBcAb ≥100 C.O.I are risk factors for HBV-R, except for the patients receiving chemotherapy containing rituximab. Health sciences/Oncology/Cancer Biological sciences/Cancer/Cancer therapy/Chemotherapy Health sciences/Risk factors HBV-R Resolved HBV infection HBs-antibody HBc-antibody Cancer chemotherapy Rituximab Figures Figure 1 Figure 2 Introduction Hepatitis B virus (HBV) infection remains endemic to Asia and Africa, affecting more than 2% of the population in these continents [ 1 ]. Therefore, physicians and medical staff should consider the potential for HBV reactivation (HBV-R) during chemotherapy for cancer patients with resolved HBV infection. Chemotherapy-induced HBV-R can lead to severe hepatic dysfunction, resulting in the interruption of drug treatment [ 2 ]. In particular, B-cell depleting therapies, such as rituximab-containing regimens, increase the risk of HBV-R [ 3 – 26 ]. The Japan Society of Hepatology guidelines for the management of HBV infection recommended monitoring HBV-DNA levels in cancer patients with resolved HBV infection during and after chemotherapy [ 2 ]. Identifying patients at higher risk for HBV-R will optimize the monitoring interval of HBV-DNA levels to prevent HBV-R. Quantification of HBV surface antibody (HBsAb) and core antibody (HBcAb) is important for predicting HBV-R in patients with lymphoma [ 3 , 4 ]. A prospective observational study revealed that the risk of HBV-R is low in lymphoma patients with HBsAb levels ≥ 100 mIU/mL [ 5 ], because HBsAb neutralizes the virus and prevents HBV-R [ 27 , 28 ]. However, the effect of HBcAb levels on HBV-R in cancer patients receiving chemotherapy is controversial, [ 6 – 10 , 29 – 31 ] although antibody titers are associated with persistent viral infection [ 32 ]. In this study, we measured baseline HBsAb and HBcAb levels to predict the incidence of HBV-R in patients with resolved HBV infection after initiating chemotherapy for solid and hematopoietic cancers. The levels of HBsAb and HBcAb, and their impact on HBV-R was examined in patients with or without rituximab-containing chemotherapy. Results The characteristics of the 590 patients at baseline are listed in Table 1 . The mean age at the time of the first chemotherapy was 65.4 years (range, 15–92). The median duration of follow-up was 761.5 (range, 4–3,898) days. Lymphoma (14.6%), breast cancer (12.9%) and lung cancer (11.0%) accounted for the majority of the cases. Sixty-five patients with lymphoma were treated with rituximab-containing chemotherapy. Table 1 Characteristics of patients with resolved HBV infection Characteristics n = 590 Sex (male/female) 295/295 Age at first chemotherapy (years) 65.4 ± 12.1 (15–92) Baseline aspartate aminotransferase 25.2 ± 16.1 (8–162) Baseline alanine aminotransferase 21.7 ± 21.7 (3–539) Duration of follow-up (days) 761.5 (4–3,898) Primary disease at first chemotherapy Lymphoma 87 (14.6) Breast cancer 76 (12.9) Lung cancer 65 (11.0) Uterine neoplasms/Cervical cancer 49 (8.3) Colorectal cancer 45 (7.6) Esophageal cancer 32 (5.4) Pancreatic adenocarcinoma 30 (5.1) Ovarian cancer 27 (4.6) Leukemia 26 (4.4) Head and neck cancers 26 (4.4) Bladder tumor 23 (3.9) Gastric cancer 19 (3.2) Central nervous system cancers 18 (3.1) Others 67 (11.4) Data are presented as number (%), mean ± standard deviation (range), or median (range). Thirteen patients (2.2%) developed HBV-R 221 (92–1,654) days after starting chemotherapy. The cumulative incidence of HBV-R was compared between HBsAb-positive and -negative patients, and between HBcAb-positive and -negative patients (Fig. 1 ). Kaplan–Meier plots revealed that the incidence of HBV-R was significantly higher in HBsAb-negative versus positive patients (0.149 vs. 0.024, P = 0.0016). Conversely, the incidence rate of HBV-R tended to be higher in HBcAb-positive compared with negative patients, although the difference was not statistically significant (0.060 vs. 0.014, P = 0.24). HBsAb and HBcAb levels at baseline for the individual patients are shown in Fig. 2 . Closed squares and circles indicate the 13 patients with HBV-R (Fig. 2 ) and the details of these patients are listed in Table 2 . The baseline HBsAb levels were < 100 mIU/mL, 6.8 (1.1–74.2) mIU/mL, in all 13 patients with HBV-R (Fig. 2 , Table 2 ). The baseline HBcAb levels were 36.8 (0.1–717.0) C.O.I., with ≥ 100 C.O.I. in 5 cases and < 100 C.O.I. in 8 cases. Of the latter 8 cases, 7 (Case 6, 7, 8, 9, 10, 11, and 12) were treated with rituximab-containing chemotherapy (Fig. 2 , Table 2 ), and exhibited a shorter median time of 208 (92–1,654) days until HBV-R, compared with that of the remaining 5 cases, which required 898 (445–1321) days until HBV-R. None of the patients developed de-novo hepatitis, although the peak HBV-DNA levels reached 7.3 and 8.7 logIU/mL with elevated AST and ALT in cases 4 and 10, respectively. Table 2 Details of 13 patients with HBV-R Case Before chemotherapy Chemotherapies (cycle) until HBV-R Rituximab- containing HBV-R Age (years) Sex Tumor diagnosis HBsAb levels (mIU/mL) HBcAb levels (C.O.I.) Time until HBV-R (days) Peak HBV-DNA levels a Peak AST (U/L) Peak ALT (U/L) 1 67 M Colorectal cancer 2.4 717.0 FOLFOX + Bv (33), CapeOX + Bv (13), Irinotecan + panitumumab (4) No 1,321 2.3 32 10 2 37 M Bladder tumor, Renal pelvis carcinoma 6.8 440.2 Gemcitabine + cisplatin (7), Gemcitabine + cisplatin (2) No 832 1.8 32 50 3 68 M Multiple myeloma 1.7 329.8 VRD (4), VRD (1) No 445 2.4 26 23 4 62 F Acute lymphoblastic Leukemia 37.9 230.4 PSL + dasa (1), Hyper CVAD (2), Fludarabine + busulfan (1) No 898 7.3 136 395 5 66 F Acute myeloid leukemia 36.9 180.6 Azacitidine (4), Fludarabine + busulfan (1) No 1,037 1.4 25 26 6 73 M Diffuse large B-cell Lymphoma 3.9 69.9 R-CHOP (4), High dose methotrexate (2) Yes 221 2.5 28 21 7 74 M Intravascular lymphoma 1.3 36.8 R-CHOP (2) Yes 92 1.8 38 29 8 64 M Primary central nervous system lymphoma 74.2 12.7 Elderly protocol induction (1), Rit (3), Elderly protocol consolidation (2) Yes 170 1.2 19 23 9 75 M Follicular lymphoma 59.8 6.8 R-Benda (6) Yes 214 1.8 35 15 10 63 M Follicular lymphoma 1.4 5.2 R-Benda (5) Yes 133 8.7 143 109 11 63 F Follicular lymphoma 1.1 2.7 R-CHOP (6), R-cESHAP (4), HD-CPA (1), Rit (4), R-Benda (2) Yes 1,654 3.0 92 131 12 78 F Diffuse large B-cell Lymphoma 12.2 0.9 R-CHOP (8) Yes 208 1.9 22 12 13 61 F Myelodysplastic Syndrome 20.8 0.1 Azacitidine (2), Fludarabine + busulfan (1) No 118 2.8 26 9 a The HBV-DNA cutoff levels for HBV-R varied between two measurement methods: Cases 6, 11, and 13 , 2.1 log copies/mL; Cases 1–5, 7–10, and 12, 1.3 log IU/mL. CapeOX + Bv, capecitabine + oxaliplatin + bevacizumab; Elderly protocol induction, methotrexate + ranimustine + procarbazine + methylprednisolone sodium succinate + injection methotrexate + cytarabine into the spinal column; Elderly protocol consolidation, methotrexate + ranimustine + procarbazine + injection methotrexate + cytarabine into the spinal column; F, female; FOLFOX + Bv, fluorouracil + calcium levofolinate hydrate oxaliplatin + bevacizumab; HBV-R, hepatitis B virus reactivation; HD-CPA, high dose endoxan; Hyper CVAD, methotrexate + cytarabine + methylprednisolone sodium succinate + calcium folinate hydrate; M, male; PSL + dasa, prednisolone + dasatinib hydrate; R-Benda, rituximab + bendamustine; R-cESHAP, rituximab + carboplatin + etoposide + cytarabine; R-CHOP, rituximab + endoxan + doxorubicin hydrochloride + vincristine sulfate + prednisolone; Rit, rituximab only; VRD, bortezomib + lenalidomide + dexamethasone. The impact of baseline levels of HBsAb < 100 mIU/mL and HBcAb ≥ 100 C.O.I. on the incidence of HBV-R is summarized in Table 3 . HBV-R occurred more frequently in patients with HBcAb levels ≥ 100 C.O.I. compared with those < 100 C.O.I. (9.6% vs. 1.5%, P = 0.0030; Table 3 B). This difference was remarkable between patients with HBsAb ≥ 100 mIU/mL and HBsAb < 100 mIU/mL (2.5% vs. 18.5%, P = 0.0030; Table 3 C). Patients treated with rituximab-containing chemotherapy had a higher incidence of HBV-R compared with those treated with non-rituximab-containing chemotherapy (18.4% vs. 0.4%, P < 0.001; Table 3 D), irrespective of HBcAb levels < 100 C.O.I. Table 3 Baseline HBsAb and HBcAb levels in 13 patients with or without HBV-R HBV-R (%)* p -value A. HBsAb levels † 0.002 <100 ( n = 344) 13 (3.8%) ≥100 ( n = 246) 0 (0%) B. HBcAb levels †† 0.003 <100 ( n = 538) 8 (1.5%) ≥100 ( n = 52) 5 (9.6%) C. HBsAb levels of < 100 † 0.002 and HBcAb levels of < 100 †† ( n = 317) 8 (2.5%) and HBcAb levels of ≥ 100 †† ( n = 27) 5 (18.5%) D. HBsAb levels of < 100 † and HBcAb levels of < 100 †† < 0.001 and rituximab-containing chemotherapy ( n = 38) 7 (18.4%) and non-rituximab-containing chemotherapy ( n = 279) 1 (0.4%) * HBV-R incidence rate (%) HBV-R, hepatitis B virus reactivation; †, mIU/mL; ††, C.O.I. Discussion This study addresses the clinical implication of HBsAb and HBcAb titers to assess the risk of HBV-R in cancer patients treated with chemotherapy. The results show that a baseline HBsAb level ≥ 100 mIU/mL is a preventive factor against HBV-R (0%, Table 3 A), regardless of the type of cancer, solid or hematopoietic, and whether, or not the chemotherapy regimen includes rituximab. Baseline HBcAb levels of ≥ 100 C.O.I. were a risk factor for HBV-R (9.6%, Table 3 B). Using both HBsAb (< 100 mIU/mL) and HBcAb (≥ 100 C.O.I.) is a robust predictor of HBV-R (18.5%, Table 3 C). For patients receiving rituximab-containing chemotherapy, the incidence of HBV-R was still high (18.4%, Table 3 D) although the baseline HBcAb was < 100 C.O.I. A major aim of the present study was to confirm the role of HBsAb levels in assessing HBV-R risk in patients with solid and hematopoietic cancers. Previous studies demonstrated that a lower titer of HBsAb is associated with an increased risk for HBV-R in patients with lymphoma [ 3 , 4 ]. Our study confirmed that baseline HBsAb levels < 100 mIU/mL were indicative of increased HBV-R, regardless of whether the patients received rituximab (Fig. 2 , Tables 2 ). Because HBsAb acts as an HBsAg-neutralizing antibody protecting against HBV-R, [ 27 , 28 ] levels < 100 mIU/mL may not be sufficient to suppress HBV-R in patients experiencing chemotherapy-induced immunosuppression (Fig. 2 , Tables 2 ). These results are consistent with a previous study showing that HBsAb levels < 100 mIU/mL are an independent risk factor for HBV-R in lymphoma patients [ 5 ]. Baseline HBcAb titer is an indicator of previous or persistent HBV infection [ 32 ], and is associated with HBV-R in patients with lymphoma undergoing intensive rituximab treatment [ 3 , 4 ] and with malignant glioma undergoing temozolomide therapy [ 33 ]. However, it is unclear what levels of HBcAb affect the incidence of HBV-R in chemotherapy patients with or without rituximab. Our results indicate that HBcAb levels ≥ 100 C.O.I. could be a risk factor for HBV-R (9.6%, Table 3 B). We estimated this figure because 100 C.O.I. in CLEIA corresponds to 10.5 S/CO in chemiluminescent immunoassays (CLIA) [ 34 ] and 10.5 S/CO HBcAb levels were considered indicative of HBV-R in earlier studies [ 4 , 33 ]. The simultaneous presence of HBsAb < 100 mIU/mL and HBcAb ≥ 100 C.O.I. resulted in a high incidence of HBV-R (18.5%, Table 3 C); however, HBcAb ≥ 100 C.O.I. alone does not always indicate a high risk of HBV-R, especially in patients treated with rituximab-containing chemotherapies (Table 3 -D). Thus, HBcAb levels ≥ 100 C.O.I. are likely a high-risk factor for developing HBV-R, except when combined with rituximab-containing chemotherapy. Case 13 was ruled out because HBsAb status was positive without a history of HBV vaccination, and the patient developed HBV-R despite being HBcAb-negative (Fig. 2 , Table 2 ). This patient received intensive immunosuppressive therapy containing cyclosporine for hematopoietic stem cell transplantation. This observation is consistent with earlier reports showing HBV-R cases with positive HBsAb alone without a history of HVB vaccination [ 2 , 5 , 10 ]. In conclusion, this study confirmed that baseline HBsAb levels of < 100 mIU/mL are a risk factor for HBV-R in patients undergoing chemotherapy for solid or hematopoietic cancers. Furthermore, we found that a baseline HBcAb titer of ≥ 100 C.O.I. could be an additional risk factor for HBV-R, except in cases of rituximab-containing chemotherapy. Our findings show that determining viral antibody titers of HBsAb and HBcAb are important for identifying patients at higher risk for HBV-R, prior to the chemotherapy with or without rituximab. Methods 1) Patients and study design A total of 4,856 cancer patients who were treated with chemotherapy were screened from December 2015 to August 2020 in this retrospective cohort study. Of these patients, 590 with resolved HBV infection were evaluated. Patients with solid (n = 466) and hematopoietic cancers (n = 124), including lymphoma, who received rituximab-containing chemotherapy (n = 65) were examined. Exclusion criteria for the present study were as follows: positive for HBsAg (n = 51); negative for all of HBsAg, HBsAb and HBcAb before or after chemotherapy (n = 3,633); and missing data for HBsAg, HBsAb, or HBcAb before chemotherapy (n = 582). This study was approved by the Ethical Committee of the University of Tsukuba Hospital (H29-056) in accordance with Declaration of Helsinki. For data collection in this observational study, informed consent of the patients was obtained based on a waived requirement (opt-out style). 2) Measurement of HBV markers Serum HBsAg, HBsAb, and HBcAb levels were measured using chemiluminescent enzyme immunoassays (CLEIA) (HISCL®; Sysmex Corporation, Kobe, Japan) and a criteria for positivity of ≥ 0.03 IU/mL, ≥ 5.0 mIU/mL, and ≥ 1.0 cut off index (C.O.I.), respectively. HBV viral load was quantified using real-time polymerase chain reaction using a reference value of 2.1 log copies/mL and 1.0 log IU/mL in the COBAS TaqMan® HBV v2.0 and COBAS® 6800/8800 system HBV (Roche Diagnostics K.K., Tokyo, Japan) assays, respectively. Resolved HBV infection was defined as HBsAg-negative, and HBsAb- and/or HBcAb-positive based on the Guidelines of the Japan Society of Hepatology [ 2 ]. HBV-R was considered positive when HBV DNA levels were measured above the reference value after starting chemotherapy. Nucleos(t)ide analog agents were administered even if the detection of amplification reaction signals were below the reference values [ 2 ]. 3) Statistical Analysis Statistical analyses were performed using SPSS Statistics 28 software (IBM, Armonk, NY, USA). The cumulative incidence rates of HBV-R were evaluated using the Kaplan–Meier method and compared between the 2 groups using a log-rank test. Proportions were compared using a χ2 test or Fisher’s exact probability test. P values < 0.05 were considered statistically significant. Declarations Acknowledgements The authors are deeply indebted to Dr. Y. Mukai and S. Katsuyama for their insightful comments and discussion regarding this manuscript. Authors’ contributions M.O., Y.S., I.S., and M.H. contributed to the study conception. M.O., K.D., and M.H. performed the analyses. E.S. contributed to interpretation of the analyses. M.O. prepared figures and drafted the manuscript. E.S., K.D., Y.S., I.S., and M.H. editing the manuscript. All authors reviewed the manuscript. Data availability The data supporting this study’s findings are available from the first author, M.O., and the corresponding author, M.H., upon reasonable request. Competing interests The authors declare no competing interest. Consent to publish Not applicable. Funding JSPS KAKENHI supported this work: grant nos. [JP17H00540 to M.O., JP21H04226 to M.O.] References Ott, J. J., Stevens, G. A., Groeger, J. & Wiersma, S. T. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 30, 2212–2219 (2012). Drafting Committee for Hepatitis Management Guidelines, the Japan Society of Hepatology. Japan Society of Hepatology Guidelines for the Management of hepatitis B virus Infection: 2019 update. Hepatol. Res. 50, 892–923 (2020). Yang, H. C. et al . Quantification of HBV core antibodies may help predict HBV reactivation in patients with lymphoma and resolved HBV infection. J. Hepatol. 69, 286–292 (2018). Matsubara, T. et al . The combination of anti-HBc and anti-HBs levels is a useful predictor of the development of chemotherapy-induced reactivation in lymphoma patients with resolved HBV infection. Oncol. Lett. 14, 6543–6552 (2017). Kusumoto, S. et al . Monitoring of hepatitis B virus (HBV) DNA and risk of HBV reactivation in B-cell lymphoma: a prospective observational study. Clin. Infect. Dis. 61, 719–729 (2015). Matsue, K. et al . Reactivation of hepatitis B virus after rituximab-containing treatment in patients with CD20-positive B-cell lymphoma. Cancer 116, 4769–4776 (2010). Chen, K. L. et al. Hepatitis B virus reactivation and hepatitis in diffuse large B-cell lymphoma patients with resolved hepatitis B receiving rituximab-containing chemotherapy: risk factors and survival. Chin. J. Cancer 34, 225–234 (2015). Hsiao, L. T. et al . Risk of reverse seroconversion of hepatitis B virus surface antigen in rituximab-treated non-Hodgkin lymphoma patients: a large cohort retrospective study. Med. (Baltim.) 94, e1321 (2015). Watanabe, M. et al . Re-appearance of hepatitis B virus following therapy with rituximab for lymphoma is not rare in Japanese patients with past hepatitis B virus infection. Liver Int. 31, 340–347 (2011). Hui, C. K. et al . Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology 131, 59–68 (2006). Guo, Y. F., Pan, J. X. & Zhuang, W. H. Concurrent and reactivation of hepatitis B virus infection in diffuse large B-cell lymphoma: risk factors and survival outcome. Infect. Agent Cancer 13, 40 (2018). Cho, Y. et al . High titers of anti-HBs prevent rituximab-related viral reactivation in resolved hepatitis B patient with non-Hodgkin’s lymphoma. J. Med. Virol. 88, 1010–1017 (2016). Borentain, P. et al . Clinical and virological factors associated with hepatitis B virus reactivation in HBsAg-negative and anti-HBc antibodies-positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer. J. Viral Hepat. 17, 807–815 (2010). Wu, C. Y. et al. Lymphocyte/monocyte ratio and cycles of rituximab-containing therapy are risk factors for hepatitis B virus reactivation in patients with diffuse large B-cell lymphoma and resolved hepatitis B. Leuk. Lymphoma 56, 2357–2364 (2015). Lu, S. et al . The risk of hepatitis B virus reactivation and the role of antiviral prophylaxis in hepatitis B surface antigen negative/hepatitis B core antibody positive patients with diffuse large B-cell lymphoma receiving rituximab-based chemotherapy. Leuk. Lymphoma 56, 1027–1032 (2015). Seto, W. K. et al. Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study. J. Clin. Oncol. 32, 3736–3743 (2014). Hsu, C. et al . Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study. Hepatology. 59, 2092–2100 (2014). Kim, E. et al. Hepatitis B virus reactivation during anti-cancer chemotherapy in patients with past hepatitis B virus infection. Hepato-Gastroenterology. 61, 1704–1711 (2014). Huang, Y. H. et al . Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J. Clin. Oncol. 31, 2765–2772 (2013). Kim, S. J. et al. Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: analysis from the Asia Lymphoma Study Group. Eur. J. Cancer 49, 3486–3496 (2013). Koo, Y. X. et al. Hepatitis B virus reactivation and role of antiviral prophylaxis in lymphoma patients with past hepatitis B virus infection who are receiving chemoimmunotherapy. Cancer 116, 115–121 (2010). Ji, D. et al . Low incidence of hepatitis B virus reactivation during chemotherapy among diffuse large B-cell lymphoma patients who are HBsAg-negative/ HBcAb-positive: a multicenter retrospective study. Eur. J. Haematol. 85, 243–250 (2010). Francisci, D. et al . Management of hepatitis B virus reactivation in patients with hematological malignancies treated with chemotherapy. Infection 38, 58–61 (2010). Yeo, W. et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J. Clin. Oncol. 27, 605–611 (2009). Takahashi, H. et al . Multicenter cooperative case survey of hepatitis B virus reactivation by chemotherapeutic agents. Hepatol. Res. 45, 1220–1227 (2015). Oh, M. J. & Lee, H. J. A study of hepatitis B virus reactivation associated with rituximab therapy in real-world clinical practice: a single-center experience. Clin. Mol. Hepatol. 19, 51–59 (2013). Zhang, Z. H. et al . Elimination of hepatitis B virus surface antigen and appearance of neutralizing antibodies in chronically infected patients without viral clearance. J. Viral Hepat. 18, 424–433 (2011). Washizaki, A. et al . Neutralization of hepatitis B virus with vaccine-escape mutations by hepatitis B vaccine with large-HBs antigen. Nat. Commun. 13, 5207 (2022). Sugimoto, R. et al . Risk factors for de novo hepatitis B during solid cancer treatment. World J. Clin. Cases 8, 6264–6273 (2020). Hagiwara, S. et al . Characteristic pattern of reactivation of hepatitis B virus during chemotherapy for solid cancers. Dig. Dis. 30, 541–546 (2012). Kotake, T. et al . Prevalence and risk factors of hepatitis B virus reactivation in patients with solid tumors with resolved HBV infection. Asia Pac. J. Clin. Oncol. 15, 63–68 (2019). Caviglia, G. P. et al . Quantitation of HBV cccDNA in anti-HBc-positive liver donors by droplet digital PCR: A new tool to detect occult infection. J. Hepatol. 69, 301–307 (2018). Shoji, T. et al. Hepatitis B virus reactivation during temozolomide administration for malignant glioma. Int. J. Clin. Oncol. 26, 305–315 (2021). Brochure paper from SRL, Inc. (Clinical Laboratory Testing Company) SRL NEWS. https://www.srl-group.co.jp/assets/pdf/news/testing/2016-27.pdf (2016). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 09 May, 2024 Read the published version in Biological and Pharmaceutical Bulletin → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3386711","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":241136488,"identity":"df229895-d62a-4fd2-8907-0bc2d94c4225","order_by":0,"name":"Maki Ohkubo","email":"","orcid":"","institution":"University of Tsukuba","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maki","middleName":"","lastName":"Ohkubo","suffix":""},{"id":241136489,"identity":"d647d7bb-1481-41f9-b9ce-ac1e72938b50","order_by":1,"name":"Emiko Seo","email":"","orcid":"","institution":"University of Tsukuba","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Emiko","middleName":"","lastName":"Seo","suffix":""},{"id":241136490,"identity":"736e5cc7-0159-4be1-920c-9f327ff630d3","order_by":2,"name":"Kosuke Doki","email":"","orcid":"","institution":"University of Tsukuba","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kosuke","middleName":"","lastName":"Doki","suffix":""},{"id":241136491,"identity":"ec041678-7684-4d7b-895c-702d62a0314d","order_by":3,"name":"Yoshiharu Suzuki","email":"","orcid":"","institution":"University of Tsukuba","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yoshiharu","middleName":"","lastName":"Suzuki","suffix":""},{"id":241136492,"identity":"cd688289-b79b-4410-a5cf-6899918e7706","order_by":4,"name":"Ikuo Sekine","email":"","orcid":"","institution":"University of Tsukuba","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ikuo","middleName":"","lastName":"Sekine","suffix":""},{"id":241136493,"identity":"4c661655-fd9b-449c-9700-a989fefeffd6","order_by":5,"name":"Masato Homma","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIiWNgGAWjYPCCA3IMDAkgRgKDAUSEjYAGhgPGQNWMDSRpSWxA04Ib6LYff/j5Q8Wd9LXtCewPf7alJW5nP8D44QcDXx4uLWZncowlDpx5lrvtzAPGZt62nMSdPQnMkj0MbMU4tRzIYZA42HY4d9uNBMZmxraKxA0HEhikgX4BOhWHlvPPH/8Aakk3A2pp/AnScv4B82+8Wm4kmIFsSQBpaQA5bMONBDb8ttx4Y2Zx5sxhw21nHjbO5jmXZrxzxsM2yx4DPH45n/74RkXFYXmz48kHPv4oS5bdzp98+MaPimM4QwwJMDYgMQyOJRChBRXUkK5lFIyCUTAKhisAAJi8Z3LaCZSUAAAAAElFTkSuQmCC","orcid":"","institution":"University of Tsukuba","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Masato","middleName":"","lastName":"Homma","suffix":""}],"badges":[],"createdAt":"2023-09-26 02:44:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3386711/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3386711/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1248/bpb.b23-00907","type":"published","date":"2024-05-10T00:46:19+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":45103581,"identity":"fe5078e0-bdc6-4dfd-9dad-c2da7cd9c9ea","added_by":"auto","created_at":"2023-10-23 18:23:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47661,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier risk curves illustrating the cumulative rate of HBV-R in baseline HBsAb (A) and HBcAb (B) status. HBsAb and HBcAb were considered positive when the values were ≥5.0 mIU/mL and ≥1.0 C.O.I., respectively. The period between the first chemotherapy and HBV-R or the termination of observation was the follow-up duration.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3386711/v1/e8ee078e054b87d04b41227e.png"},{"id":45103582,"identity":"873fd29b-ebf4-4978-82b5-5f93c392250c","added_by":"auto","created_at":"2023-10-23 18:23:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":90941,"visible":true,"origin":"","legend":"\u003cp\u003eBaseline HBsAb and HBcAb status in patients treated with rituximab-containing (\u003cem\u003en\u003c/em\u003e= 65, squares) and nonrituximab-containing (\u003cem\u003en\u003c/em\u003e= 525, circles) chemotherapy regimens. Closed and opened points indicate patients with and without HBV-R, respectively.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3386711/v1/3f709b239f3afb946112f95f.png"},{"id":56209312,"identity":"1bb6bbc4-3b8e-4f69-a9a9-96fbad80d611","added_by":"auto","created_at":"2024-05-10 00:46:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":721391,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3386711/v1/9b06131a-9fe1-48d0-85c5-f88bc3261f13.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of hepatitis B surface and core antibody levels on hepatitis B virus reactivation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHepatitis B virus (HBV) infection remains endemic to Asia and Africa, affecting more than 2% of the population in these continents [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Therefore, physicians and medical staff should consider the potential for HBV reactivation (HBV-R) during chemotherapy for cancer patients with resolved HBV infection. Chemotherapy-induced HBV-R can lead to severe hepatic dysfunction, resulting in the interruption of drug treatment [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In particular, B-cell depleting therapies, such as rituximab-containing regimens, increase the risk of HBV-R [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The Japan Society of Hepatology guidelines for the management of HBV infection recommended monitoring HBV-DNA levels in cancer patients with resolved HBV infection during and after chemotherapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Identifying patients at higher risk for HBV-R will optimize the monitoring interval of HBV-DNA levels to prevent HBV-R.\u003c/p\u003e \u003cp\u003eQuantification of HBV surface antibody (HBsAb) and core antibody (HBcAb) is important for predicting HBV-R in patients with lymphoma [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. A prospective observational study revealed that the risk of HBV-R is low in lymphoma patients with HBsAb levels\u0026thinsp;\u0026ge;\u0026thinsp;100 mIU/mL [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], because HBsAb neutralizes the virus and prevents HBV-R [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, the effect of HBcAb levels on HBV-R in cancer patients receiving chemotherapy is controversial, [\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] although antibody titers are associated with persistent viral infection [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, we measured baseline HBsAb and HBcAb levels to predict the incidence of HBV-R in patients with resolved HBV infection after initiating chemotherapy for solid and hematopoietic cancers. The levels of HBsAb and HBcAb, and their impact on HBV-R was examined in patients with or without rituximab-containing chemotherapy.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe characteristics of the 590 patients at baseline are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean age at the time of the first chemotherapy was 65.4 years (range, 15\u0026ndash;92). The median duration of follow-up was 761.5 (range, 4\u0026ndash;3,898) days. Lymphoma (14.6%), breast cancer (12.9%) and lung cancer (11.0%) accounted for the majority of the cases. Sixty-five patients with lymphoma were treated with rituximab-containing chemotherapy.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of patients with resolved HBV infection\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;590\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (male/female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e295/295\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at first chemotherapy (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(15\u0026ndash;92)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline aspartate aminotransferase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.2\u0026thinsp;\u0026plusmn;\u0026thinsp;16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(8\u0026ndash;162)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline alanine aminotransferase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.7\u0026thinsp;\u0026plusmn;\u0026thinsp;21.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(3\u0026ndash;539)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of follow-up (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e761.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(4\u0026ndash;3,898)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary disease at first chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(14.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(12.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(11.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUterine neoplasms/Cervical cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(8.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eColorectal cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(7.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEsophageal cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(5.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePancreatic adenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(5.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOvarian cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(4.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(4.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHead and neck cancers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(4.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBladder tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(3.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastric cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(3.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCentral nervous system cancers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(3.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(11.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eData are presented as number (%), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (range), or median (range).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThirteen patients (2.2%) developed HBV-R 221 (92\u0026ndash;1,654) days after starting chemotherapy. The cumulative incidence of HBV-R was compared between HBsAb-positive and -negative patients, and between HBcAb-positive and -negative patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Kaplan\u0026ndash;Meier plots revealed that the incidence of HBV-R was significantly higher in HBsAb-negative versus positive patients (0.149 vs. 0.024, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0016). Conversely, the incidence rate of HBV-R tended to be higher in HBcAb-positive compared with negative patients, although the difference was not statistically significant (0.060 vs. 0.014, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.24).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHBsAb and HBcAb levels at baseline for the individual patients are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Closed squares and circles indicate the 13 patients with HBV-R (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) and the details of these patients are listed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The baseline HBsAb levels were \u0026lt;\u0026thinsp;100 mIU/mL, 6.8 (1.1\u0026ndash;74.2) mIU/mL, in all 13 patients with HBV-R (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The baseline HBcAb levels were 36.8 (0.1\u0026ndash;717.0) C.O.I., with \u0026ge;\u0026thinsp;100 C.O.I. in 5 cases and \u0026lt;\u0026thinsp;100 C.O.I. in 8 cases. Of the latter 8 cases, 7 (Case 6, 7, 8, 9, 10, 11, and 12) were treated with rituximab-containing chemotherapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), and exhibited a shorter median time of 208 (92\u0026ndash;1,654) days until HBV-R, compared with that of the remaining 5 cases, which required 898 (445\u0026ndash;1321) days until HBV-R. None of the patients developed \u003cem\u003ede-novo\u003c/em\u003e hepatitis, although the peak HBV-DNA levels reached 7.3 and 8.7 logIU/mL with elevated AST and ALT in cases 4 and 10, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDetails of 13 patients with HBV-R\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"16\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c16\" colnum=\"16\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c7\" namest=\"c3\"\u003e \u003cp\u003eBefore chemotherapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eChemotherapies (cycle) until HBV-R\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRituximab-\u003c/p\u003e \u003cp\u003econtaining\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c15\" namest=\"c12\"\u003e \u003cp\u003eHBV-R\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c16\" namest=\"c16\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003cp\u003e(years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTumor diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHBsAb\u003c/p\u003e \u003cp\u003elevels\u003c/p\u003e \u003cp\u003e(mIU/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eHBcAb\u003c/p\u003e \u003cp\u003elevels\u003c/p\u003e \u003cp\u003e(C.O.I.)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eTime until\u003c/p\u003e \u003cp\u003eHBV-R\u003c/p\u003e \u003cp\u003e(days)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003ePeak\u003c/p\u003e \u003cp\u003eHBV-DNA\u003c/p\u003e \u003cp\u003elevels \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003ePeak\u003c/p\u003e \u003cp\u003eAST\u003c/p\u003e \u003cp\u003e(U/L)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003ePeak\u003c/p\u003e \u003cp\u003eALT\u003c/p\u003e \u003cp\u003e(U/L)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eColorectal cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e717.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eFOLFOX\u0026thinsp;+\u0026thinsp;Bv (33), CapeOX\u0026thinsp;+\u0026thinsp;Bv (13),\u003c/p\u003e \u003cp\u003eIrinotecan\u0026thinsp;+\u0026thinsp;panitumumab (4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1,321\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBladder tumor,\u003c/p\u003e \u003cp\u003eRenal pelvis carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e440.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eGemcitabine\u0026thinsp;+\u0026thinsp;cisplatin (7),\u003c/p\u003e \u003cp\u003eGemcitabine\u0026thinsp;+\u0026thinsp;cisplatin (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e832\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMultiple myeloma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e329.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eVRD (4), VRD (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e445\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAcute lymphoblastic\u003c/p\u003e \u003cp\u003eLeukemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e230.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePSL\u0026thinsp;+\u0026thinsp;dasa (1), Hyper CVAD (2),\u003c/p\u003e \u003cp\u003eFludarabine\u0026thinsp;+\u0026thinsp;busulfan (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e898\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e7.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003e395\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAcute myeloid leukemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e180.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAzacitidine (4),\u003c/p\u003e \u003cp\u003eFludarabine\u0026thinsp;+\u0026thinsp;busulfan (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1,037\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDiffuse large B-cell\u003c/p\u003e \u003cp\u003eLymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e69.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR-CHOP (4),\u003c/p\u003e \u003cp\u003eHigh dose methotrexate (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e221\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIntravascular lymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e36.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR-CHOP (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePrimary central nervous\u003c/p\u003e \u003cp\u003esystem lymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e74.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eElderly protocol induction (1), Rit (3),\u003c/p\u003e \u003cp\u003eElderly protocol consolidation (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFollicular lymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e59.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR-Benda (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e214\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFollicular lymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR-Benda (5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e8.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003e109\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFollicular lymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR-CHOP (6), R-cESHAP (4),\u003c/p\u003e \u003cp\u003eHD-CPA (1), Rit (4), R-Benda (2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1,654\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003e131\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDiffuse large B-cell\u003c/p\u003e \u003cp\u003eLymphoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR-CHOP (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMyelodysplastic\u003c/p\u003e \u003cp\u003eSyndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAzacitidine (2),\u003c/p\u003e \u003cp\u003eFludarabine\u0026thinsp;+\u0026thinsp;busulfan (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"16\"\u003e\u003csup\u003ea\u003c/sup\u003e The HBV-DNA cutoff levels for HBV-R varied between two measurement methods: Cases 6, 11, and \u003cspan refid=\"FPar1\" class=\"InternalRef\"\u003e13\u003c/span\u003e, 2.1 log copies/mL; Cases 1\u0026ndash;5, 7\u0026ndash;10, and 12, 1.3 log IU/mL.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"16\"\u003eCapeOX\u0026thinsp;+\u0026thinsp;Bv, capecitabine\u0026thinsp;+\u0026thinsp;oxaliplatin\u0026thinsp;+\u0026thinsp;bevacizumab; Elderly protocol induction, methotrexate\u0026thinsp;+\u0026thinsp;ranimustine\u0026thinsp;+\u0026thinsp;procarbazine\u0026thinsp;+\u0026thinsp;methylprednisolone sodium succinate\u0026thinsp;+\u0026thinsp;injection methotrexate\u0026thinsp;+\u0026thinsp;cytarabine into the spinal column; Elderly protocol consolidation, methotrexate\u0026thinsp;+\u0026thinsp;ranimustine\u0026thinsp;+\u0026thinsp;procarbazine\u0026thinsp;+\u0026thinsp;injection methotrexate\u0026thinsp;+\u0026thinsp;cytarabine into the spinal column; F, female; FOLFOX\u0026thinsp;+\u0026thinsp;Bv, fluorouracil\u0026thinsp;+\u0026thinsp;calcium levofolinate hydrate oxaliplatin\u0026thinsp;+\u0026thinsp;bevacizumab; HBV-R, hepatitis B virus reactivation; HD-CPA, high dose endoxan; Hyper CVAD, methotrexate\u0026thinsp;+\u0026thinsp;cytarabine\u0026thinsp;+\u0026thinsp;methylprednisolone sodium succinate\u0026thinsp;+\u0026thinsp;calcium folinate hydrate; M, male; PSL\u0026thinsp;+\u0026thinsp;dasa, prednisolone\u0026thinsp;+\u0026thinsp;dasatinib hydrate; R-Benda, rituximab\u0026thinsp;+\u0026thinsp;bendamustine; R-cESHAP, rituximab\u0026thinsp;+\u0026thinsp;carboplatin\u0026thinsp;+\u0026thinsp;etoposide\u0026thinsp;+\u0026thinsp;cytarabine; R-CHOP, rituximab\u0026thinsp;+\u0026thinsp;endoxan\u0026thinsp;+\u0026thinsp;doxorubicin hydrochloride\u0026thinsp;+\u0026thinsp;vincristine sulfate\u0026thinsp;+\u0026thinsp;prednisolone; Rit, rituximab only; VRD, bortezomib\u0026thinsp;+\u0026thinsp;lenalidomide\u0026thinsp;+\u0026thinsp;dexamethasone.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe impact of baseline levels of HBsAb\u0026thinsp;\u0026lt;\u0026thinsp;100 mIU/mL and HBcAb\u0026thinsp;\u0026ge;\u0026thinsp;100 C.O.I. on the incidence of HBV-R is summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. HBV-R occurred more frequently in patients with HBcAb levels\u0026thinsp;\u0026ge;\u0026thinsp;100 C.O.I. compared with those\u0026thinsp;\u0026lt;\u0026thinsp;100 C.O.I. (9.6% vs. 1.5%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0030; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). This difference was remarkable between patients with HBsAb\u0026thinsp;\u0026ge;\u0026thinsp;100 mIU/mL and HBsAb\u0026thinsp;\u0026lt;\u0026thinsp;100 mIU/mL (2.5% vs. 18.5%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0030; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). Patients treated with rituximab-containing chemotherapy had a higher incidence of HBV-R compared with those treated with non-rituximab-containing chemotherapy (18.4% vs. 0.4%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD), irrespective of HBcAb levels\u0026thinsp;\u0026lt;\u0026thinsp;100 C.O.I.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline HBsAb and HBcAb levels in 13 patients with or without HBV-R\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eHBV-R (%)*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA. HBsAb levels \u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;100 (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;344)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(3.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;100 (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;246)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB. HBcAb levels \u003csup\u003e\u0026dagger;\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;100 (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;538)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(1.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;100 (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(9.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC. HBsAb levels of \u0026lt;\u0026thinsp;100 \u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eand HBcAb levels of \u0026lt;\u0026thinsp;100 \u003csup\u003e\u0026dagger;\u0026dagger;\u003c/sup\u003e (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;317)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(2.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eand HBcAb levels of \u0026ge;\u0026thinsp;100 \u003csup\u003e\u0026dagger;\u0026dagger;\u003c/sup\u003e (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(18.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD. HBsAb levels of \u0026lt;\u0026thinsp;100 \u003csup\u003e\u0026dagger;\u003c/sup\u003e and HBcAb levels of \u0026lt;\u0026thinsp;100 \u003csup\u003e\u0026dagger;\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eand rituximab-containing chemotherapy (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(18.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eand non-rituximab-containing chemotherapy (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;279)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e* HBV-R incidence rate (%)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eHBV-R, hepatitis B virus reactivation; \u0026dagger;, mIU/mL; \u0026dagger;\u0026dagger;, C.O.I.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study addresses the clinical implication of HBsAb and HBcAb titers to assess the risk of HBV-R in cancer patients treated with chemotherapy. The results show that a baseline HBsAb level\u0026thinsp;\u0026ge;\u0026thinsp;100 mIU/mL is a preventive factor against HBV-R (0%, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA), regardless of the type of cancer, solid or hematopoietic, and whether, or not the chemotherapy regimen includes rituximab. Baseline HBcAb levels of \u0026ge;\u0026thinsp;100 C.O.I. were a risk factor for HBV-R (9.6%, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Using both HBsAb (\u0026lt;\u0026thinsp;100 mIU/mL) and HBcAb (\u0026ge;\u0026thinsp;100 C.O.I.) is a robust predictor of HBV-R (18.5%, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). For patients receiving rituximab-containing chemotherapy, the incidence of HBV-R was still high (18.4%, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD) although the baseline HBcAb was \u0026lt;\u0026thinsp;100 C.O.I.\u003c/p\u003e \u003cp\u003eA major aim of the present study was to confirm the role of HBsAb levels in assessing HBV-R risk in patients with solid and hematopoietic cancers. Previous studies demonstrated that a lower titer of HBsAb is associated with an increased risk for HBV-R in patients with lymphoma [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Our study confirmed that baseline HBsAb levels\u0026thinsp;\u0026lt;\u0026thinsp;100 mIU/mL were indicative of increased HBV-R, regardless of whether the patients received rituximab (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Because HBsAb acts as an HBsAg-neutralizing antibody protecting against HBV-R, [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] levels\u0026thinsp;\u0026lt;\u0026thinsp;100 mIU/mL may not be sufficient to suppress HBV-R in patients experiencing chemotherapy-induced immunosuppression (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These results are consistent with a previous study showing that HBsAb levels\u0026thinsp;\u0026lt;\u0026thinsp;100 mIU/mL are an independent risk factor for HBV-R in lymphoma patients [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBaseline HBcAb titer is an indicator of previous or persistent HBV infection [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], and is associated with HBV-R in patients with lymphoma undergoing intensive rituximab treatment [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] and with malignant glioma undergoing temozolomide therapy [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. However, it is unclear what levels of HBcAb affect the incidence of HBV-R in chemotherapy patients with or without rituximab. Our results indicate that HBcAb levels\u0026thinsp;\u0026ge;\u0026thinsp;100 C.O.I. could be a risk factor for HBV-R (9.6%, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). We estimated this figure because 100 C.O.I. in CLEIA corresponds to 10.5 S/CO in chemiluminescent immunoassays (CLIA) [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] and 10.5 S/CO HBcAb levels were considered indicative of HBV-R in earlier studies [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The simultaneous presence of HBsAb\u0026thinsp;\u0026lt;\u0026thinsp;100 mIU/mL and HBcAb\u0026thinsp;\u0026ge;\u0026thinsp;100 C.O.I. resulted in a high incidence of HBV-R (18.5%, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC); however, HBcAb\u0026thinsp;\u0026ge;\u0026thinsp;100 C.O.I. alone does not always indicate a high risk of HBV-R, especially in patients treated with rituximab-containing chemotherapies (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e-D). Thus, HBcAb levels\u0026thinsp;\u0026ge;\u0026thinsp;100 C.O.I. are likely a high-risk factor for developing HBV-R, except when combined with rituximab-containing chemotherapy.\u003c/p\u003e \u003cp\u003eCase 13 was ruled out because HBsAb status was positive without a history of HBV vaccination, and the patient developed HBV-R despite being HBcAb-negative (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This patient received intensive immunosuppressive therapy containing cyclosporine for hematopoietic stem cell transplantation. This observation is consistent with earlier reports showing HBV-R cases with positive HBsAb alone without a history of HVB vaccination [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003c/p\u003e \u003cp\u003eIn conclusion, this study confirmed that baseline HBsAb levels of \u0026lt;\u0026thinsp;100 mIU/mL are a risk factor for HBV-R in patients undergoing chemotherapy for solid or hematopoietic cancers. Furthermore, we found that a baseline HBcAb titer of \u0026ge;\u0026thinsp;100 C.O.I. could be an additional risk factor for HBV-R, except in cases of rituximab-containing chemotherapy. Our findings show that determining viral antibody titers of HBsAb and HBcAb are important for identifying patients at higher risk for HBV-R, prior to the chemotherapy with or without rituximab.\u003c/p\u003e "},{"header":"Methods","content":" \u003cp\u003e1) Patients and study design\u003c/p\u003e \u003cp\u003eA total of 4,856 cancer patients who were treated with chemotherapy were screened from December 2015 to August 2020 in this retrospective cohort study. Of these patients, 590 with resolved HBV infection were evaluated. Patients with solid (n\u0026thinsp;=\u0026thinsp;466) and hematopoietic cancers (n\u0026thinsp;=\u0026thinsp;124), including lymphoma, who received rituximab-containing chemotherapy (n\u0026thinsp;=\u0026thinsp;65) were examined. Exclusion criteria for the present study were as follows: positive for HBsAg (n\u0026thinsp;=\u0026thinsp;51); negative for all of HBsAg, HBsAb and HBcAb before or after chemotherapy (n\u0026thinsp;=\u0026thinsp;3,633); and missing data for HBsAg, HBsAb, or HBcAb before chemotherapy (n\u0026thinsp;=\u0026thinsp;582). This study was approved by the Ethical Committee of the University of Tsukuba Hospital (H29-056) in accordance with Declaration of Helsinki. For data collection in this observational study, informed consent of the patients was obtained based on a waived requirement (opt-out style).\u003c/p\u003e \u003cp\u003e2) Measurement of HBV markers\u003c/p\u003e \u003cp\u003eSerum HBsAg, HBsAb, and HBcAb levels were measured using chemiluminescent enzyme immunoassays (CLEIA) (HISCL\u0026reg;; Sysmex Corporation, Kobe, Japan) and a criteria for positivity of \u0026ge;\u0026thinsp;0.03 IU/mL, \u0026ge;\u0026thinsp;5.0 mIU/mL, and \u0026ge;\u0026thinsp;1.0 cut off index (C.O.I.), respectively. HBV viral load was quantified using real-time polymerase chain reaction using a reference value of 2.1 log copies/mL and 1.0 log IU/mL in the COBAS TaqMan\u0026reg; HBV v2.0 and COBAS\u0026reg; 6800/8800 system HBV (Roche Diagnostics K.K., Tokyo, Japan) assays, respectively.\u003c/p\u003e \u003cp\u003eResolved HBV infection was defined as HBsAg-negative, and HBsAb- and/or HBcAb-positive based on the Guidelines of the Japan Society of Hepatology [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. HBV-R was considered positive when HBV DNA levels were measured above the reference value after starting chemotherapy. Nucleos(t)ide analog agents were administered even if the detection of amplification reaction signals were below the reference values [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e3) Statistical Analysis\u003c/p\u003e \u003cp\u003eStatistical analyses were performed using SPSS Statistics 28 software (IBM, Armonk, NY, USA). The cumulative incidence rates of HBV-R were evaluated using the Kaplan\u0026ndash;Meier method and compared between the 2 groups using a log-rank test. Proportions were compared using a χ2 test or Fisher\u0026rsquo;s exact probability test. \u003cem\u003eP\u003c/em\u003e values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are deeply indebted to Dr. Y. Mukai and S. Katsuyama for their insightful comments and discussion regarding this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eM.O., Y.S., I.S., and M.H. contributed to the study conception. M.O., K.D., and M.H. performed the analyses. E.S. contributed to interpretation of the analyses. M.O. prepared figures and drafted the manuscript. E.S., K.D., Y.S., I.S., and M.H. editing the manuscript. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting this study\u0026rsquo;s findings are available from the first author, M.O., and the corresponding author, M.H., upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJSPS KAKENHI supported this work: grant nos. [JP17H00540 to M.O., JP21H04226 to M.O.]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOtt, J. J., Stevens, G. A., Groeger, J. \u0026amp; Wiersma, S. T. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 30, 2212\u0026ndash;2219 (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDrafting Committee for Hepatitis Management Guidelines, the Japan Society of Hepatology. Japan Society of Hepatology Guidelines for the Management of hepatitis B virus Infection: 2019 update. Hepatol. Res. 50, 892\u0026ndash;923 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang, H. C. \u003cem\u003eet al\u003c/em\u003e. Quantification of HBV core antibodies may help predict HBV reactivation in patients with lymphoma and resolved HBV infection. J. Hepatol. 69, 286\u0026ndash;292 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsubara, T. \u003cem\u003eet al\u003c/em\u003e. The combination of anti-HBc and anti-HBs levels is a useful predictor of the development of chemotherapy-induced reactivation in lymphoma patients with resolved HBV infection. Oncol. Lett. 14, 6543\u0026ndash;6552 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKusumoto, S. \u003cem\u003eet al\u003c/em\u003e. Monitoring of hepatitis B virus (HBV) DNA and risk of HBV reactivation in B-cell lymphoma: a prospective observational study. Clin. Infect. Dis. 61, 719\u0026ndash;729 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsue, K. \u003cem\u003eet al\u003c/em\u003e. Reactivation of hepatitis B virus after rituximab-containing treatment in patients with CD20-positive B-cell lymphoma. Cancer 116, 4769\u0026ndash;4776 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen, K. L. \u003cem\u003eet al.\u003c/em\u003e Hepatitis B virus reactivation and hepatitis in diffuse large B-cell lymphoma patients with resolved hepatitis B receiving rituximab-containing chemotherapy: risk factors and survival. Chin. J. Cancer 34, 225\u0026ndash;234 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHsiao, L. T. \u003cem\u003eet al\u003c/em\u003e. Risk of reverse seroconversion of hepatitis B virus surface antigen in rituximab-treated non-Hodgkin lymphoma patients: a large cohort retrospective study. Med. (Baltim.) 94, e1321 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatanabe, M. \u003cem\u003eet al\u003c/em\u003e. Re-appearance of hepatitis B virus following therapy with rituximab for lymphoma is not rare in Japanese patients with past hepatitis B virus infection. Liver Int. 31, 340\u0026ndash;347 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHui, C. K. \u003cem\u003eet al\u003c/em\u003e. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology 131, 59\u0026ndash;68 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo, Y. F., Pan, J. X. \u0026amp; Zhuang, W. H. Concurrent and reactivation of hepatitis B virus infection in diffuse large B-cell lymphoma: risk factors and survival outcome. Infect. Agent Cancer 13, 40 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCho, Y. \u003cem\u003eet al\u003c/em\u003e. High titers of anti-HBs prevent rituximab-related viral reactivation in resolved hepatitis B patient with non-Hodgkin\u0026rsquo;s lymphoma. J. Med. Virol. 88, 1010\u0026ndash;1017 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorentain, P. \u003cem\u003eet al\u003c/em\u003e. Clinical and virological factors associated with hepatitis B virus reactivation in HBsAg-negative and anti-HBc antibodies-positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer. J. Viral Hepat. 17, 807\u0026ndash;815 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu, C. Y. \u003cem\u003eet al.\u003c/em\u003e Lymphocyte/monocyte ratio and cycles of rituximab-containing therapy are risk factors for hepatitis B virus reactivation in patients with diffuse large B-cell lymphoma and resolved hepatitis B. Leuk. Lymphoma 56, 2357\u0026ndash;2364 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLu, S. \u003cem\u003eet al\u003c/em\u003e. The risk of hepatitis B virus reactivation and the role of antiviral prophylaxis in hepatitis B surface antigen negative/hepatitis B core antibody positive patients with diffuse large B-cell lymphoma receiving rituximab-based chemotherapy. Leuk. Lymphoma 56, 1027\u0026ndash;1032 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeto, W. K. \u003cem\u003eet al.\u003c/em\u003e Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study. J. Clin. Oncol. 32, 3736\u0026ndash;3743 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHsu, C. \u003cem\u003eet al\u003c/em\u003e. Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study. Hepatology. 59, 2092\u0026ndash;2100 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim, E. \u003cem\u003eet al.\u003c/em\u003e Hepatitis B virus reactivation during anti-cancer chemotherapy in patients with past hepatitis B virus infection. Hepato-Gastroenterology. 61, 1704\u0026ndash;1711 (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang, Y. H. \u003cem\u003eet al\u003c/em\u003e. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J. Clin. Oncol. 31, 2765\u0026ndash;2772 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim, S. J. \u003cem\u003eet al.\u003c/em\u003e Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: analysis from the Asia Lymphoma Study Group. Eur. J. Cancer 49, 3486\u0026ndash;3496 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoo, Y. X. \u003cem\u003eet al.\u003c/em\u003e Hepatitis B virus reactivation and role of antiviral prophylaxis in lymphoma patients with past hepatitis B virus infection who are receiving chemoimmunotherapy. Cancer 116, 115\u0026ndash;121 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJi, D. \u003cem\u003eet al\u003c/em\u003e. Low incidence of hepatitis B virus reactivation during chemotherapy among diffuse large B-cell lymphoma patients who are HBsAg-negative/ HBcAb-positive: a multicenter retrospective study. Eur. J. Haematol. 85, 243\u0026ndash;250 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrancisci, D. \u003cem\u003eet al\u003c/em\u003e. Management of hepatitis B virus reactivation in patients with hematological malignancies treated with chemotherapy. Infection 38, 58\u0026ndash;61 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYeo, W. \u003cem\u003eet al.\u003c/em\u003e Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J. Clin. Oncol. 27, 605\u0026ndash;611 (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakahashi, H. \u003cem\u003eet al\u003c/em\u003e. Multicenter cooperative case survey of hepatitis B virus reactivation by chemotherapeutic agents. Hepatol. Res. 45, 1220\u0026ndash;1227 (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOh, M. J. \u0026amp; Lee, H. J. A study of hepatitis B virus reactivation associated with rituximab therapy in real-world clinical practice: a single-center experience. Clin. Mol. Hepatol. 19, 51\u0026ndash;59 (2013).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang, Z. H. \u003cem\u003eet al\u003c/em\u003e. Elimination of hepatitis B virus surface antigen and appearance of neutralizing antibodies in chronically infected patients without viral clearance. J. Viral Hepat. 18, 424\u0026ndash;433 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWashizaki, A. \u003cem\u003eet al\u003c/em\u003e. Neutralization of hepatitis B virus with vaccine-escape mutations by hepatitis B vaccine with large-HBs antigen. Nat. Commun. 13, 5207 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSugimoto, R. \u003cem\u003eet al\u003c/em\u003e. Risk factors for de novo hepatitis B during solid cancer treatment. World J. Clin. Cases 8, 6264\u0026ndash;6273 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHagiwara, S. \u003cem\u003eet al\u003c/em\u003e. Characteristic pattern of reactivation of hepatitis B virus during chemotherapy for solid cancers. Dig. Dis. 30, 541\u0026ndash;546 (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKotake, T. \u003cem\u003eet al\u003c/em\u003e. Prevalence and risk factors of hepatitis B virus reactivation in patients with solid tumors with resolved HBV infection. Asia Pac. J. Clin. Oncol. 15, 63\u0026ndash;68 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCaviglia, G. P. \u003cem\u003eet al\u003c/em\u003e. Quantitation of HBV cccDNA in anti-HBc-positive liver donors by droplet digital PCR: A new tool to detect occult infection. J. Hepatol. 69, 301\u0026ndash;307 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShoji, T. \u003cem\u003eet al.\u003c/em\u003e Hepatitis B virus reactivation during temozolomide administration for malignant glioma. Int. J. Clin. Oncol. 26, 305\u0026ndash;315 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrochure paper from SRL, Inc. (Clinical Laboratory Testing Company) SRL NEWS. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.srl-group.co.jp/assets/pdf/news/testing/2016-27.pdf\u003c/span\u003e\u003cspan address=\"https://www.srl-group.co.jp/assets/pdf/news/testing/2016-27.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2016).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"HBV-R, Resolved HBV infection, HBs-antibody, HBc-antibody, Cancer chemotherapy, Rituximab","lastPublishedDoi":"10.21203/rs.3.rs-3386711/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3386711/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHepatitis B virus reactivation (HBV-R) is a serious concern during cancer chemotherapy in patients with resolved HBV infection. We examined the levels of HBV surface (HBsAb) and core antibodies (HBcAb) to assess the incidence of HBV-R in patients with solid and hematopoietic cancers. Retrospective cohort study was conducted in 590 patients with resolved HBV infection. The patients consisted of solid (n = 466) and hematopoietic cancers (n = 124), including lymphoma receiving rituximab-containing chemotherapy. The incidenceof HBV-R was evaluated 761.5 (range, 4–3,898) days after the start of chemotherapy. Of 590 patients, 13 (2.2%) developed HBV-R after the start of chemotherapy. All HBV-R patients exhibited a lower HBsAb (\u0026lt;100 mIU/mL) at baseline. A higher HBcAb (≥100 C.O.I.) was identified as a risk factor for HBV-R,with an incidence of 9.6%. The simultaneous presence of HBsAb \u0026lt;100 mIU/mL and HBcAb ≥100 C.O.I. increased the risk of HBV-R by 18.5%. Patients treated with rituximab-containing chemotherapy had a higher risk of HBV-R (18.4%) despite having HBcAb \u0026lt;100 C.O.I. Our results indicate that baseline levels of HBsAb \u0026lt;100 mIU/mL and HBcAb ≥100 C.O.I are risk factors for HBV-R, except for the patients receiving chemotherapy containing rituximab.\u003c/p\u003e","manuscriptTitle":"Impact of hepatitis B surface and core antibody levels on hepatitis B virus reactivation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-23 18:23:35","doi":"10.21203/rs.3.rs-3386711/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"669a0202-2d1d-4e06-88b1-0b5b008f4ba9","owner":[],"postedDate":"October 23rd, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":25481848,"name":"Health sciences/Oncology/Cancer"},{"id":25481849,"name":"Biological sciences/Cancer/Cancer therapy/Chemotherapy"},{"id":25481850,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2024-05-10T00:46:20+00:00","versionOfRecord":{"articleIdentity":"rs-3386711","link":"https://doi.org/10.1248/bpb.b23-00907","journal":{"identity":"biological-and-pharmaceutical-bulletin","isVorOnly":true,"title":"Biological and Pharmaceutical Bulletin"},"publishedOn":"2024-05-10 00:46:19","publishedOnDateReadable":"May 10th, 2024"},"versionCreatedAt":"2023-10-23 18:23:35","video":"","vorDoi":"10.1248/bpb.b23-00907","vorDoiUrl":"https://doi.org/10.1248/bpb.b23-00907","workflowStages":[]},"version":"v1","identity":"rs-3386711","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3386711","identity":"rs-3386711","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}