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Thi EP, Ye X, Snead NM, Lee ACH, Micolochick Steuer HM, Ardzinski A, Graves IE, Espiritu C, Cuconati A, Abbott C, Jarosz A, Teng X, Paratala B, McClintock K, Harasym T, Rijnbrand R, Lam AM, Sofia MJ. Control of Hepatitis B Virus with Imdusiran, a Small Interfering RNA Therapeutic. ACS Infect Dis 2024; 10:3640-3649. [PMID: 39306863 DOI: 10.1021/acsinfecdis.4c00514] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
Chronic hepatitis B is a global health concern with a high risk of end-stage liver disease. Current standard-of-care agents have low cure rates, and new therapies are needed. Small interfering RNAs (siRNAs) that target viral RNAs fulfill a gap not addressed by standard-of-care agents and may contribute to a functional cure. Here, we describe the preclinical characterization of imdusiran (AB-729), a novel, pan-genotypic siRNA therapeutic that effectively reduces HBsAg, viral antigens, and viral replication in chronic hepatitis B patients and is currently in Phase 2 clinical studies. In hepatitis B virus (HBV) cell-based systems, imdusiran possessed pan-genotypic nanomolar potency and retained activity against HBV target site polymorphisms. Imdusiran was active against nucleos(t)ide analogue- and capsid assembly modulator-resistant HBV isolates, and combination with standard-of-care agents was additive. In an HBV adeno-associated virus mouse model, HBsAg was reduced up to 3.7 log10 after a single imdusiran dose, with sustained suppression for 10 weeks. Imdusiran did not intrinsically stimulate cytokine release in healthy donor human whole blood, supportive of its mechanism of action as a direct acting RNA interference antiviral. Taken together, these data support imdusiran in combination treatment approaches toward chronic hepatitis B functional cure.
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Affiliation(s)
- Emily P Thi
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Xin Ye
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Nicholas M Snead
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Amy C H Lee
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | | | - Andrzej Ardzinski
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Ingrid E Graves
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Christine Espiritu
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Andrea Cuconati
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Cory Abbott
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Agnes Jarosz
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Xiaowei Teng
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Bhavna Paratala
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Kevin McClintock
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Troy Harasym
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Rene Rijnbrand
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Angela M Lam
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
| | - Michael J Sofia
- Arbutus Biopharma Inc. 701 Veterans Circle, Warminster, Pennsylvania 18974, United States
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Chu C, Liang Y, Lin X, Liu Y, Liu S, Guo J, Wang D, Wang J, Liu H, Qiu B. Hypofractionated Radiation Therapy Combined With Weekly Chemotherapy in Patients With Unresectable or Recurrent Thymic Epithelial Tumor: A Prospective, Single-Arm Phase 2 Study (GASTO-1042). Int J Radiat Oncol Biol Phys 2022; 114:89-98. [PMID: 35598797 DOI: 10.1016/j.ijrobp.2022.05.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 04/16/2022] [Accepted: 05/10/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE This prospective phase 2 study aimed to evaluate the efficacy and safety of hypofractionated radiation therapy (HRT) combined with concurrent weekly chemotherapy in patients with unresectable or recurrent thymic epithelial tumors (TETs). METHODS AND MATERIALS Patients with unresectable or recurrent intrathoracic TETs that could be encompassed within the radiation fields were enrolled. HRT using intensity modulated radiation therapy (IMRT) technique was administered with 3 different levels of radiation doses (51 Gy/17 fractions (fx), 48 Gy/12 fx, and 45 Gy/9 fx; biologically effective dose of 66.3-67.5Gy), combined with weekly docetaxel (25 mg/m2) and nedaplatin (25 mg/m2). Weekly thymosin α1 (1.6 mg) was administered from the start to 2 months after radiation therapy. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), health-related quality of life (QOL), and toxicity were recorded. RESULTS Fifty eligible patients enrolled from August 1, 2018, to July 1, 2020, were analyzed. Most patients (82.0%) had stage IVB tumors. Patients had IMRT-HRT (36-51 Gy in 9-17 fx, median biologically effective dose of 67.2 Gy) and concurrent weekly docetaxel/nedaplatin (2-4 cycles). During a median follow-up of 25.0 months (14.0-40.0), the ORR was 83.7%, the 2-year PFS was 59.1%, and the 2-year OS was 90.0%. There was 1 (2.0%) in-field recurrence while 19 (38.0%) patients developed out-of-field recurrence. Grade 3 pneumonitis was observed in 1 patient (2.0%). The ORR, 2-year PFS, 2-year OS, and toxicity were similar among 3 dose levels. Fourteen (28.0%) patients had 2 to 4 courses of radiation therapy because of recurrent diseases. Only 1 suffered from grade 1 pulmonary fibrosis during follow-up. Most patients (88%) maintained a stable QOL within 1 year after radiation therapy. CONCLUSIONS IMRT-HRT and concurrent weekly docetaxel/nedaplatin was effective and well tolerated in unresectable or recurrent TETs. Considering the common out-of-field recurrence, this combined regimen could be an option for repeated radiation therapy. Thymosin α1 might help lower the incidence of pneumonitis and maintain the QOL.
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Affiliation(s)
- Chu Chu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine; Lung Cancer Institute, Sun Yat-sen University, Guangzhou, China; Guangdong Association Study of Thoracic Oncology, Guangzhou, China
| | - Ying Liang
- State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine; Lung Cancer Institute, Sun Yat-sen University, Guangzhou, China; Guangdong Association Study of Thoracic Oncology, Guangzhou, China; Departments of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiaosheng Lin
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine; Lung Cancer Institute, Sun Yat-sen University, Guangzhou, China; Guangdong Association Study of Thoracic Oncology, Guangzhou, China
| | - Yimei Liu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine; Lung Cancer Institute, Sun Yat-sen University, Guangzhou, China; Guangdong Association Study of Thoracic Oncology, Guangzhou, China
| | - Songran Liu
- State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine; Lung Cancer Institute, Sun Yat-sen University, Guangzhou, China; Guangdong Association Study of Thoracic Oncology, Guangzhou, China; Departments of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jinyu Guo
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine; Lung Cancer Institute, Sun Yat-sen University, Guangzhou, China; Guangdong Association Study of Thoracic Oncology, Guangzhou, China
| | - Daquan Wang
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine; Lung Cancer Institute, Sun Yat-sen University, Guangzhou, China; Guangdong Association Study of Thoracic Oncology, Guangzhou, China
| | - Junye Wang
- State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine; Lung Cancer Institute, Sun Yat-sen University, Guangzhou, China; Guangdong Association Study of Thoracic Oncology, Guangzhou, China; Departments of Thoracic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hui Liu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine; Lung Cancer Institute, Sun Yat-sen University, Guangzhou, China; Guangdong Association Study of Thoracic Oncology, Guangzhou, China.
| | - Bo Qiu
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine; Lung Cancer Institute, Sun Yat-sen University, Guangzhou, China; Guangdong Association Study of Thoracic Oncology, Guangzhou, China.
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Liu F, Qiu B, Xi Y, Luo Y, Luo Q, Wu Y, Chen N, Zhou R, Guo J, Wu Q, Xiong M, Liu H. Efficacy of thymosin α1 in management of radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy: A Phase 2 Clinical Trial (GASTO-1043). Int J Radiat Oncol Biol Phys 2022; 114:433-443. [PMID: 35870709 DOI: 10.1016/j.ijrobp.2022.07.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 06/26/2022] [Accepted: 07/03/2022] [Indexed: 10/31/2022]
Abstract
PURPOSE To evaluate the efficacy of thymosin α1 in management of radiation pneumonitis (RP) in patients with locally advanced non-small cell lung cancer (LANSCLC) treated with concurrent chemoradiotherapy (CCRT). METHODS AND MATERIALS This phase II, single-arm trial enrolled patients with unresectable LANSCLC of 18 to 75 years' old and an Eastern Cooperative Oncology Group performance status of 0 to 1. Eligible patients received definitive CCRT and weekly thymosin α1 from the start of CCRT till 2 months after CCRT. Patients were administered 51 Gy in 17 daily fractions or 40 Gy in 10 daily fractions in the first course followed by a re-evaluation and those patients without disease progression had an adaptive plan of 15 Gy in 5 daily fractions or 24 Gy in 6 daily fractions as a boost. Concurrent chemotherapy consisted of weekly docetaxel (25 mg/m2) and nedaplatin (25 mg/m2) during radiation therapy. The primary endpoint was the incidence of Grade (G) ≥2 RP. Secondary endpoints included the incidence of late pulmonary fibrosis, total lymphocyte count (TLC), serum C-reactive protein (CRP) levels, and the composition of gut microbiota. TLC and CRP data were collected at baseline, 2-3 weeks during CCRT, the end of CCRT, 2 and 6 months after CCRT. Fecal samples were collected at baseline and the end of CCRT. Patients treated with CCRT but without thymosin α1 intervention during the same period were selected as the control group by the propensity score matching method. RESULTS Sixty-nine patients were enrolled in the study, and another 69 patients were selected as the control group. The incidence of G≥2 RP was lower in the study group compared with control cases (36.2% vs 53.6%, P=0.040). G1 late pulmonary fibrosis occurred in 2 (3.7%) patients of the control group compared with no event in the study group (P=0.243). Compared with the control group, the incidence of G3-4 lymphopenia (19.1% vs. 62.1%, P<0.001) was lower, and the median TLC nadir (0.51 k/µL vs. 0.30 k/µL, P<0.001) was higher in the study group. The proportion of patients with maximum CRP≥100 mg/L was lower in the study group (13.8% vs. 29.7% P=0.029). The diversity and community composition of the gut microbiota were not significantly different between the two groups. CONCLUSIONS Administration of thymosin α1 during and after CCRT was associated with significant reductions in G≥2 RP and G3-4 lymphopenia in patients with LANSCLC compared to historic controls.
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Affiliation(s)
- Fangjie Liu
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‑sen University Cancer Center, Guangzhou, China
| | - Bo Qiu
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‑sen University Cancer Center, Guangzhou, China
| | - Yu Xi
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China; School of biology and biological engineering, South China University of Technology, Guangzhou. China
| | - Yifeng Luo
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou
| | - Qiaoting Luo
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‑sen University Cancer Center, Guangzhou, China
| | - Yingjia Wu
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‑sen University Cancer Center, Guangzhou, China
| | - Naibin Chen
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‑sen University Cancer Center, Guangzhou, China
| | - Rui Zhou
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‑sen University Cancer Center, Guangzhou, China
| | - Jinyu Guo
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‑sen University Cancer Center, Guangzhou, China
| | - Qingping Wu
- Guangdong Provincial Key Laboratory of Microbial Safety and Health, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
| | - Mai Xiong
- Department of Cardiac Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou
| | - Hui Liu
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat‑sen University Cancer Center, Guangzhou, China.
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Qi Q, Qian X, Zhu X, Cai J, Xia R, Zhang Q. Perioperative Transfusion is Related to the Length of Hospital Stays in Primary Liver Cancer Patients. Cancer Manag Res 2021; 13:4947-4954. [PMID: 34188547 PMCID: PMC8233480 DOI: 10.2147/cmar.s296022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 06/11/2021] [Indexed: 11/23/2022] Open
Abstract
Purpose Blood loss may be corrected with red blood cell transfusion, but may ultimately contribute to negative impacts. This study was a retrospective analysis to assess the impact of perioperative blood transfusion on hospital stay days in liver cancer patients. Methods We retrospectively examined data from patients with primary liver cancer who underwent curative resection. Patients were divided into perioperative blood transfusion (PBT) and non-PBT groups. Data were given as means and SDs for continuous variables and as counts and percentage for categorical variables. The correlation between blood transfusion and hospital stay days was analyzed by Fisher's exact test. Multivariable logistic regression analyses were used to identify independent predictors of length of hospital stays. Results Totally 206/1031 patients (20.3%) were given perioperative transfusion. The mean length of hospital stay was 17.8 days in PBT and 13.9 days in non-PBT groups. Our multivariable logistic regression showed transfusion, total bilirubin, indirect bilirubin, and the ratio of albumin to bilirubin were all indicators of the length of hospital stay days. Perioperative transfusion was also associated with prolonged length of hospital stays (95% CI: 0.395-0.811, p = 0.002). Transfusion also affected intrinsic coagulation factors (activated partial thromboplastin time, fibrinogen, platelet), inflammatory index (neutrocyte to lymphocyte ratio, monocyte), albumin and bilirubin levels. Conclusion Perioperative transfusion of blood was associated with a significantly increased length of hospital stays probably via changing intrinsic coagulation and inflammatory factors and bilirubin levels in plasma.
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Affiliation(s)
- Qi Qi
- Department of Transfusion Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
| | - Xuemeng Qian
- Department of Transfusion Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
| | - Xinfang Zhu
- Department of Transfusion Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
| | - Jiajing Cai
- Department of Transfusion Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
| | - Rong Xia
- Department of Transfusion Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
| | - Qi Zhang
- Department of Transfusion Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
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Evaluating the clinical value of MRI multi-model diffusion-weighted imaging on liver fibrosis in chronic hepatitis B patients. Abdom Radiol (NY) 2021; 46:1552-1561. [PMID: 33051757 DOI: 10.1007/s00261-020-02806-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 09/21/2020] [Accepted: 09/30/2020] [Indexed: 12/24/2022]
Abstract
PURPOSE To explore the value of various diffusion parameters obtained from monoexponential, biexponential, and stretched exponential in assessing liver fibrosis in chronic hepatitis B (CHB). METHODS DWI and intravoxel incoherent motion (IVIM) MRI were performed prospectively on liver for 146 patients with CHB and 21 healthy volunteers. ADC values were obtained from monoexponential model imaging. Diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) obtained by biexponential model imaging, and stretched exponential model to obtain diffusion distribution coefficient (DDC) and diffusion heterogeneity index (α). Blood draw were performed on patients to obtain AST, ALT, and PLT, and then APRI and FIB-4 index were determined based on the serological diagnostic models. The fibrosis stage was staged (S0-S4) according to the pathology of liver puncture. Independent sample t test was used to compare the parameter values between liver fibrosis group and control group. One-way ANOVA was used to compare the parameters of different liver fibrosis grades. Bonferroni test was used for correcting multiple comparisons. Spearman correlation was used to analyze the correlation between each parameter and liver fibrosis grades. ROC was used to predict the diagnostic power of each parameter for liver fibrosis stages ≥ S2 and ≥ S3. RESULTS ADC, D, D*, f, and DDC values were significantly different between normal control group and hepatic fibrosis group (P < 0.05). There were significant differences in ADC, D*, f, and DDC value among liver fibrosis groups (P < 0.05). D* and DDC values were moderately negatively correlated with the grades of liver fibrosis (r = - 0.483, P < 0.001; r = - 0.622, P < 0.001). ADC and f values were slightly negatively correlated with the grades of liver fibrosis (r = - 0.295, P < 0.001; r = - 0.312, P < 0.001). DDC values have the highest diagnostic efficiency in liver fibrosis stages ≥ S2 and ≥ S3. The areas under ROC curve (AUC) were 0.813 and 0.832 for ≥ S2 and ≥ S3, respectively, the sensitivity is 83.72% and 73.53%, and the specificity of 83.33% and 66.04%, which were better than APRI and FIB-4. CONCLUSION D* obtained from biexponential and DDC obtained from stretched exponential DWI have better value in evaluating the degree of liver fibrosis in CHB.
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Chen L, Lin L, Zhou H, Tang W, Wang H, Cai W, Bao S, Guo S, Xie Q. Peginterferon and Entecavir Combination Therapy Improves Outcome of Non-Early Response Hepatitis B e Antigen-Positive Patients. Open Forum Infect Dis 2020; 7:ofaa462. [PMID: 33889654 PMCID: PMC8050793 DOI: 10.1093/ofid/ofaa462] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 09/25/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The efficacy of nucleot(s)ide analogs (NAs) and pegylated interferon (PegIFN) combination therapy for hepatitis B e antigen-positive (HBeAg+) patients is still controversial. Whether PegIFN and entecavir (ETV) combination therapy could provide a greater benefit for HBeAg+ patients was assessed. METHODS Treatment-naïve HBeAg+ patients initiated on PegIFN alfa-2a (PegIFNα-2a) for 24 weeks without early response (early response: HBsAg <1500 IU/mL and hepatitis B virus [HBV] DNA <105 copies/mL) were recruited in the current study. Among total of 94 patients, 51 were continued on PegIFNα-2a monotherapy, and 43 were offered PegIFNα-2a and ETV combined therapy. RESULTS Better outcomes in response to the combined therapy, compared with that of the monotherapy, were demonstrated, including more HBsAg decline and loss and HBV DNA decline and HBeAg clearance. Importantly, the patients with HBsAg levels between 1500 and 20 000 IU/mL initially or between 5000 and 20 000 IU/mL after 24 weeks of PegIFNα-2a benefitted more from the combined therapy, compared with those on monotherapy. CONCLUSIONS Combined therapy of PegIFNα-2a and ETV is more efficacious for HBeAg+ patients without early response to PegIFN monotherapy, and HBsAg levels are a good predictor of treatment outcomes.
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Affiliation(s)
- Lu Chen
- Department of Infectious Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lanyi Lin
- Department of Infectious Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huijuan Zhou
- Department of Infectious Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiliang Tang
- Department of Infectious Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Wang
- Department of Infectious Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Cai
- Department of Infectious Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shisan Bao
- Discipline of Pathology, School of Medical Science, Charles Perkins Centre, The Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Simin Guo
- Department of Infectious Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Xie
- Department of Infectious Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Shen XX, Qiu FZ, Shen LP, Yan TF, Zhao MC, Qi JJ, Chen C, Zhao L, Wang L, Feng ZS, Ma XJ. A rapid and sensitive recombinase aided amplification assay to detect hepatitis B virus without DNA extraction. BMC Infect Dis 2019; 19:229. [PMID: 30836947 PMCID: PMC6402085 DOI: 10.1186/s12879-019-3814-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 02/13/2019] [Indexed: 12/13/2022] Open
Abstract
Background Hepatitis B virus (HBV) infection is the major public health problem worldwide. In clinical practice, serological and molecular assays are the most commonly used diagnostic methods to detect HBV infection in clinical practices. Methods Here we present a rapid and sensitive recombinase aided amplification assay (RAA) to detect HBV at 39.0 °C for 30 min without DNA extraction from serum samples. The analytical sensitivity of RAA assay was 100 copies per reaction and showed no cross reaction with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The universality of RAA assay was validated by testing of 41 archived serum samples with predefined HBV genotypes (B, C and D). Results A total of 130 archived suspected HBV infected serum samples were detected by commercial qPCR with DNA extraction and RAA assay without DNA extraction (heat-treatment). Compared with qPCR assay as a reference, the RAA assay obtained 95.7% sensitivity and 100% specificity and a kappa value of 0.818. Conclusions We developed a rapid, convenient, highly sensitive and specific method to detect HBV without DNA extraction in clinical samples. This RAA method of HBV detection is very suitable for clinical testing.
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Affiliation(s)
- Xin-Xin Shen
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China
| | - Fang-Zhou Qiu
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.,Hebei Medical University, Shijiazhuang, 050031, Hebei, China
| | - Li-Ping Shen
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China
| | - Ten-Fei Yan
- Myasthenia Gravis Research Institute, The First Hospital of Shijiazhuang, Shijiazhuang, 050011, Hebei, China
| | - Meng-Chuan Zhao
- Children's Hospital of Hebei Province, Shijiazhuang, 050031, Hebei, China
| | - Ju-Ju Qi
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.,Hebei Medical University, Shijiazhuang, 050031, Hebei, China
| | - Chen Chen
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China
| | - Li Zhao
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.,Hebei Medical University, Shijiazhuang, 050031, Hebei, China
| | - Le Wang
- Children's Hospital of Hebei Province, Shijiazhuang, 050031, Hebei, China
| | - Zhi-Shan Feng
- Children's Hospital of Hebei Province, Shijiazhuang, 050031, Hebei, China.
| | - Xue-Jun Ma
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
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Liu J, Yao N, Zhao Y. Improvement of telbivudine on renal function and massive proteinuria: A case report. J Viral Hepat 2017; 24 Suppl 1:75-77. [PMID: 29082647 DOI: 10.1111/jvh.12789] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 08/24/2017] [Indexed: 12/19/2022]
Abstract
The quality of life and extended survival of patients with chronic hepatitis B (CHB), especially those with decompensated liver cirrhosis, has been improved markedly with nucleos(t)ide analogs treatment. In such conditions, the influence of hepatitis B virus (HBV) infection and antiviral agents on renal function becomes a consideration with long-term use and ageing. Membranous glomerulonephritis has been confirmed as the most common histological renal lesion. In this study, we reported a CHB patient with decompensated cirrhosis showing a significant improvement in massive proteinuria along with elevation of estimated glomerular filtration rate (eGFR) after 1 year treatment with telbivudine. However, a well-designed study should be performed to confirm the causal association, and the molecular mechanism needs further investigation.
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Affiliation(s)
- J Liu
- Department of Infectious Disease, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Institution of Hepatitis, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - N Yao
- Department of Infectious Disease, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Institution of Hepatitis, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Y Zhao
- Department of Infectious Disease, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China.,Institution of Hepatitis, Xi'an Jiaotong University, Xi'an, Shaanxi, China
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张 从, 鄢 金, 张 志, 左 维. 聚乙二醇干扰素α-2a联合胸腺肽α1治疗慢性乙型肝炎疗效的系统评价. Shijie Huaren Xiaohua Zazhi 2017; 25:1869-1876. [DOI: 10.11569/wcjd.v25.i20.1869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
目的 系统评价聚乙二醇干扰素α-2a(pegylated interferon α-2a, Peg-IFNα-2a)联合胸腺肽α1(thymosin α 1, Tα1)与单用Peg-IFNα-2a治疗慢性乙型肝炎(chronic hepatitis B, CHB)的疗效及安全性.
方法 检索PubMed、EMBASE、The Cochrane Library、CBM、CNKI、VIP和WanFang Data, 查找Peg-IFNα-2a联合Tα1治疗CHB的随机对照试验(randomized controlled trial, RCT), 检索年限从建库至2016-10, 由2位评价员根据纳入与排除标准独立筛选文献, 从纳入的文献中提取资料并进行质量评价, 采用RevMan5.3软件进行Meta分析.
结果 最终纳入7个RCT, 包括640例患者. Meta分析结果显示: 与单用Peg-IFNα-2a治疗CHB相比, 联合Tα1治疗结束时明显提高了血清ALT复常率(OR = 2.94, 95%CI: 1.59-5.44, P = 0.0006)、HBV-DNA阴转率(OR = 2.53, 95%CI: 1.76-3.64, P<0.00001)、乙型肝炎e抗原(hepatitis B e antigen, HBeAg)阴转率(OR = 2.21, 95%CI: 1.43-3.40, P = 0.0003)、HBeAg血清转换率(OR = 2.53, 95%CI: 1.48-4.30, P = 0.0006)、乙型肝炎表面抗原阴转率(OR = 2.67, 95%CI: 1.07-6.69, P = 0.04). 联合治疗后不增加Peg-IFNα-2a的不良反应(流感样症状)发生率, 差异无统计学意义(OR = 0.8, 95%CI: 0.24-2.63, P = 0.71).
结论 Peg-IFNα-2a联合Tα1治疗CHB结束时的疗效优于单用Peg-IFNα-2a, 其安全性良好, 但受纳入研究数量和质量的限制, 停药后的长期效果如何尚缺乏证据, 需开展更多高质量的RCT进一步研究.
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Xu H, Wang L, Zheng P, Liu Y, Zhang C, Jiang K, Song H, Ji G. Elevated serum A20 is associated with severity of chronic hepatitis B and A20 inhibits NF-κB-mediated inflammatory response. Oncotarget 2017; 8:38914-38926. [PMID: 28473659 PMCID: PMC5503582 DOI: 10.18632/oncotarget.17153] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 04/03/2017] [Indexed: 12/14/2022] Open
Abstract
A20 is a powerful suppressor for inflammatory response. This study aims to determine A20 level in patients with chronic hepatitis B (CHB), and analyze its association with the disease severity. The role of A20 in inflammatory response was further investigated in vivo and in vitro. Our results showed significantly higher A20 in both serum and liver tissues in CHB patients than in health controls. Serum A20 level was positively correlated with ALT, AST and TNF-α. To induce hepatitis with inflammation and liver injury, mice were injected intraperitoneally with D-galactosamine (D-GalN), resulting in rapid increase of A20 in serum and liver tissues. Consistently, HepG2 and Huh-7 cells exposed to Lipopolysaccharide (LPS) or D-GalN were promoted to express A20. Moreover, overexpression or knockdown of A20 inhibited or increased TNF-α secretion separately. A20 significantly reduced pro-inflammatory cytokines expression and down-regulated phospho-IκBα and phospho-p65 in both cells. In conclusion, elevated A20 expression is involved in the severity of CHB, suggesting A20 to be a possible serological biomarker for the disease prognosis. Additionally, the inflammatory response is attenuated by A20 through inhibiting NF-κB activity, which partially contributes to the hepato-protective function of this molecule. Thus, up-regulating A20 might be a potential strategy for preventing the progress of CHB.
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Affiliation(s)
- Hanchen Xu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Lei Wang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Peiyong Zheng
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- China-Canada Centre of Research for Digestive Diseases, Shanghai 200032, China
| | - Yang Liu
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Chunlei Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Kaiping Jiang
- Department of Hepatology, Foshan Hospital of Traditional Chinese Medicine, Foshan 528000, China
| | - Haiyan Song
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- China-Canada Centre of Research for Digestive Diseases, Shanghai 200032, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- China-Canada Centre of Research for Digestive Diseases, Shanghai 200032, China
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Efficacy of prophylactic antiviral therapy and outcomes in HBsAg-negative, anti-HBc-positive patients receiving chemotherapy: a real-life experience. Eur J Gastroenterol Hepatol 2017; 29:56-60. [PMID: 27669175 DOI: 10.1097/meg.0000000000000749] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE The aim of this study is to evaluate the outcomes of hepatitis B surface antigen (HBsAg)-negative, anti-HBc-positive patients who received immunosuppressive therapies. PATIENTS AND METHODS We retrospectively evaluated the medical records of HBsAg-negative, anti-HBc-positive patients with hematological diseases or solid tumors who underwent immunosuppressive therapies and were referred because of positive baseline hepatitis B virus (HBV) serology or HBV reactivation. The referral date was according to the judgment of the treating physician at the time of identification of any signs of HBV infection. RESULTS We included 55 HBsAg-negative, anti-HBc-positive patients. Of these, 31 received antiviral prophylaxis (group 1), whereas 24 patients did not receive any anti-HBV agent (group 2). The majority of patients [49/55 (89%)] had hematological malignancies and most of them 39/55 (71%) received rituximab-containing regimens. Lamivudine was used as antiviral prophylaxis in 13/31 (42%) patients of group 1. One patient in this group experienced HBV reactivation and was treated successfully with tenofovir add-on therapy. All patients in the second group experienced HBV reactivation and most of them [19/24 (79%)] were treated with tenofovir or entecavir as rescue therapy. Two of these patients (one of the tenofovir/entecavir subgroup and one of the lamivudine subgroup) eventually died because of hepatic failure despite rescue treatment. CONCLUSION Patients with serological markers of previous HBV infection are still at risk for HBV reactivation. Screening of both anti-HBs and anti-HBc is mandatory before chemotherapy. Pre-emptive antiviral prophylaxis, including lamivudine, is highly effective in all subgroups of such patients, whereas deferring treatment upon HBV reactivation is not enough to rescue all cases.
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Effect of Cytotoxic T Lymphocytes Induced by Recombinant Adeno-Associated Virus on Different Hepatitis B Virus Genes. HEPATITIS MONTHLY 2016. [DOI: 10.5812/hepatmon.42685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Park CH, Kim HY, Lee SW, Song DS, Song MJ, Kwon JH, You CR, Jang JW, Kim CW, Choi SW, Bae SH, Choi JY, Yoon SK. On-treatment and off-treatment efficacy of entecavir in a real-life cohort of chronic hepatitis B patients. Eur J Gastroenterol Hepatol 2016; 28:1179-1187. [PMID: 27428552 DOI: 10.1097/meg.0000000000000691] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Entecavir (ETV) is a potent nucleoside analogue with high genetic barrier to resistance. In this study, real-life clinical experiences in the long-term use of ETV and the durability of its off-treatment effectiveness were analyzed. MATERIALS AND METHODS This study was based on a large real-life cohort of 2240 chronic hepatitis B patients treated with ETV between January 2006 and December 2012 using a centralized electronic data repository. RESULTS Among 2240 patients, 804 patients were treatment naive and underwent ETV monotherapy. Their mean treatment duration was 712±493 days, with a cumulative proportion of patients achieving HBV DNA less than 300 copies/ml in 85.8, 95.7, and 97.6% at years 1, 2, and 3, respectively. Predictors for earlier virologic response were female sex, lower HBV DNA, higher alanine transaminase, lower platelet count, and HBeAg negativity at baseline. In patients who achieved virologic response and HBeAg loss, the cumulative relapse rate was 91.3% in 2 years after the cessation of treatment. During the treatment, 34 patients developed hepatocellular carcinoma, among whom 30 patients had cirrhosis before treatment initiation. ETV treatment showed efficient virologic response as the treatment duration was extended, but off-treatment efficacy was not durable, and the antiviral treatment showed some limitation in preventing hepatocellular carcinoma among liver cirrhosis patients, implying that treatment cessation should be taken into consideration more carefully. CONCLUSION This study from a real-life cohort may provide data on treating chronic hepatitis B patients more close to everyday clinical practice.
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Affiliation(s)
- Chung-Hwa Park
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Nakaya A, Fujita S, Satake A, Nakanishi T, Azuma Y, Tsubokura Y, Hotta M, Yoshimura H, Ishii K, Ito T, Nomura S. Delayed HBV reactivation in rituximab-containing chemotherapy: How long should we continue anti-virus prophylaxis or monitoring HBV-DNA? Leuk Res 2016; 50:46-49. [PMID: 27665181 DOI: 10.1016/j.leukres.2016.09.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 09/14/2016] [Accepted: 09/15/2016] [Indexed: 01/01/2023]
Abstract
Reactivation of hepatitis B virus (HBV) infection is a well-recognized and potentially fatal complication in patients treated with chemotherapy for lymphoid malignancies. Although several guidelines recommend antiviral prophylaxis and/or monitoring for HBV-DNA, there is no consensus over what time period these should occur. Clinically, we have encountered delayed reactivation of HBV infections and have reported 12 cases of reactivation in patients. Among them, five patients developed HBV reactivation more than a year after they completed their chemotherapy. This means there can be a delayed HBV reactivation and prolonged monitoring of more than a year after cessation of chemotherapy may be needed. Hence, the current recommendation of stopping antiviral prophylaxis 6-12 months after the cessation of chemotherapy may not fully protect all patients from HBV reactivation. The optimal duration of follow-up needs to be determined, and until better guidelines are set, there is no choice but to keep monitoring patients for reactivation for as long as practicable.
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Affiliation(s)
- Aya Nakaya
- First Department of Internal Medicine, Kansai Medical University, Japan.
| | - Shinya Fujita
- First Department of Internal Medicine, Kansai Medical University, Japan
| | - Atsushi Satake
- First Department of Internal Medicine, Kansai Medical University, Japan
| | | | - Yoshiko Azuma
- First Department of Internal Medicine, Kansai Medical University, Japan
| | - Yukie Tsubokura
- First Department of Internal Medicine, Kansai Medical University, Japan
| | - Masaaki Hotta
- First Department of Internal Medicine, Kansai Medical University, Japan
| | - Hideaki Yoshimura
- First Department of Internal Medicine, Kansai Medical University, Japan
| | - Kazuyoshi Ishii
- First Department of Internal Medicine, Kansai Medical University, Japan
| | - Tomoki Ito
- First Department of Internal Medicine, Kansai Medical University, Japan
| | - Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, Japan
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Wang ML, Zhou QL, Chen EQ, Du LY, Yan LB, Bai L, He M, Tang H. Low Ratio of Treg to Th17 Cells After 36 Weeks of Telbivudine Therapy Predict HBeAg Seroconversion. Viral Immunol 2016; 29:332-342. [PMID: 27104358 DOI: 10.1089/vim.2016.0007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Changes of Treg/Th17 cells ratio and their associated cytokines have some correlations with an immune modulatory effect of Telbivudine treatment. The aim of our study was to investigate the role of the dynamic ratio of Treg/Th17 cells in the mechanism of LdT therapy and their relationships with the clinical responses. We detected the frequency and cytokines production of Treg and Th17 cells in 28 hepatitis B envelope antigen (HBeAg)-positive CHB patients at 0, 12, 24, 36, 48, and 96 weeks after initial LdT therapy. LdT could upregulate the frequency of Th17 cells and Th17 cells associated cytokines, downregulated the frequency of Treg cells and level of TGF-β, which leads to the decrease of Treg/Th17 ratio in HBeAg-positive CHB patients. Treg/Th17 ratio at treatment week 36 could independently predict HBeAg seroconversion in the first 2 years of Telbivudine treatment. Telbivudine therapy can decrease Treg/Th17 ratio, which may predict HBeAg seroconversion during treatment.
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Affiliation(s)
- Meng-Lan Wang
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - Qiao-Ling Zhou
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - En-Qiang Chen
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - Ling-Yao Du
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - Li-Bo Yan
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - Lang Bai
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - Min He
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
| | - Hong Tang
- 1 Center of Infectious Diseases, West China Hospital of Sichuan University , Chengdu, China
- 2 Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University , and Collaborative Innovation Center for Biotherapy , Chengdu, China
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Song PP, Xia JF, Inagaki Y, Hasegawa K, Sakamoto Y, Kokudo N, Tang W. Controversies regarding and perspectives on clinical utility of biomarkers in hepatocellular carcinoma. World J Gastroenterol 2016; 22:262-274. [PMID: 26755875 PMCID: PMC4698491 DOI: 10.3748/wjg.v22.i1.262] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 07/27/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
The prevalence of hepatocellular carcinoma (HCC) worldwide parallels that of persistent infection with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV). According to recommendations by the World Health Organization guidelines for HBV/HCV, alpha-fetoprotein (AFP) testing and abdominal ultrasound should be performed in routine surveillance of HCC every 6 mo for high-risk patients. These examinations have also been recommended worldwide by many other HCC guidelines over the past few decades. In recent years, however, the role of AFP in HCC surveillance and diagnosis has diminished due to advances in imaging modalities. AFP was excluded from the surveillance and/or diagnostic criteria in the HCC guidelines published by the American Association for the Study of Liver Diseases in 2010, the European Association for the Study of the Liver in 2012, and the National Comprehensive Cancer Network in 2014. Other biomarkers, including the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-γ-carboxyprothrombin, Dickkopf-1, midkine, and microRNA, are being studied in this regard. Furthermore, increasing attention has focused on the clinical utility of biomarkers as pre-treatment predictors for tumor recurrence and as post-treatment monitors. Serum and tissue-based biomarkers and genomics may aid in the diagnosis of HCC, determination of patient prognosis, and selection of appropriate treatment. However, further studies are needed to better characterize the accuracy and potential role of these approaches in clinical practice.
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Qiu Q, Duan XW, Li Y, Yang LK, Chen Y, Li H, Duan ZP, Wang L. Impact of partial reimbursement on hepatitis B antiviral utilization and adherence. World J Gastroenterol 2015; 21:9588-9597. [PMID: 26327766 PMCID: PMC4548119 DOI: 10.3748/wjg.v21.i32.9588] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 04/28/2015] [Accepted: 06/15/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the impact of partial reimbursement for antivirals on antiviral utilization and adherence for chronic hepatitis B patients. METHODS This was a retrospective cohort study. Two separate cohorts were enrolled, including 14163 and 16288 chronic hepatitis B outpatients, respectively. These patients were referred to Beijing You'an Hospital before and after the new partial reimbursement for antivirals, which was implemented on July 1, 2011. Demographic characteristics (including medical insurance status), routine biochemical, virological and serology laboratory test results, and antiviral agents' prescription information were collected from an electronic database. Patients were also defined as new and existing patients according to treatment history. Antiviral utilization, medication possession ratio and persistence rate were calculated and compared among the patients with different characteristics. A questionnaire survey was conducted among 212 randomly sampled outpatients from the same hospital to confirm the validity of the electronic database. Propensity score matching was used to adjust the distribution of patient's characteristics which may influence the antiviral utilization. χ(2) test or ANOVA was adopted and multivariate logistic regression was used to determine the factors associated with antiviral utilization and good adherence. RESULTS A total of 13364 outpatients from each cohort were enrolled after the propensity score matching. The antiviral utilization rate for the insured patients increased from 57.4% to 75.9% (P < 0.0001) after the reimbursement, and the rate among those who paid out-of-pocket increased from 54.9% to 56.7% (P = 0.028). Approximately 71% of the patients had a medication possession ratio of more than 80% in each cohort before reimbursement. This increased to 79.2% and 73.1% for insured patients and those who paid out-of-pocket, respectively (P < 0.0001). Insured patients and those who paid out-of-pocket had the similar persistence rates before reimbursement. But after reimbursement, insured patients had higher persistence rates than those who paid out-of-pocket at 6 (86.5% vs 81.5%, P < 0.0001), 9 (79.7% vs 69.9%, P < 0.0001), 12 (73.4% vs 61.9%, P < 0.0001), and 15 mo (66.6% vs 53.1%, P < 0.0001). The reimbursement could significantly improve adherence for the insured patients than those who paid out-of-pocket even after adjusting other covariates, with an interaction odds ratio of 1.422 (95%CI: 1.220-1.657, P < 0.0001). The questionnaire survey supported the validity of the electronic database. CONCLUSION The reimbursement policy shows a positive impact on antiviral utilization as well as adherence for insured chronic hepatitis B patients.
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Characterization of Full-Length Genomes of Hepatitis B Virus Quasispecies in Sera of Patients at Different Phases of Infection. J Clin Microbiol 2015; 53:2203-14. [PMID: 25926495 DOI: 10.1128/jcm.00068-15] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 04/24/2015] [Indexed: 12/17/2022] Open
Abstract
Hepatitis B virus (HBV) infection results in different clinical presentation due to different levels of immune response. Our study aimed to characterize HBV full-length genome quasispecies (QS) in patients with different phases of infection to better understand its pathogenesis. Forty treatment-naive HBV-infected patients were enrolled, including 10 cases of acute hepatitis B (AHB), 9 cases of immunotolerant (IT) HBV carriers, 11 cases of chronic hepatitis B (CHB), and 10 cases of acute-on-chronic liver failure (ACLF). The present study was conducted by clone-based sequencing. QS heterogeneity within each open reading frame was calculated. The mutation frequency index (MFI) and amino acid variations within the large HBsAg, HBcAg, and HBxAg regions were analyzed based on the different infection phases. In total, 606 HBV full-length sequences were obtained. HBV QS had higher heterogeneity in ACLF and CHB than that in IT among chronically infected individuals. AHB patients had the lower QS heterogeneity at onset than those with chronic infection. ACLF patients had the highest frequency of mutations in the core promoter and precore region. A triple mutation (A1762T/G1764A/G1896A) was observed more frequently in genotype C than in genotype B. The MFI indicated that specific peptides of the studied regions had more frequent mutations in ACLF. Furthermore, several amino acid variations, known as T- and B-cell epitopes, were potentially associated with the immunoactive phase of infection. More HBV genome mutations and deletions were observed in patients with more severe diseases, particularly in specific regions of the core and preS regions, the clinical significance and mechanism of which need to be further investigated.
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Poon RTP, Cheung TTT, Kwok PCH, Lee AS, Li TW, Loke KL, Chan SL, Cheung MT, Lai TW, Cheung CC, Cheung FY, Loo CK, But YK, Hsu SJ, Yu SCH, Yau T. Hong Kong consensus recommendations on the management of hepatocellular carcinoma. Liver Cancer 2015; 4:51-69. [PMID: 26020029 PMCID: PMC4439785 DOI: 10.1159/000367728] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is particularly prevalent in Hong Kong because of the high prevalence of chronic hepatitis B (CHB) infection; HCC is the fourth commonest cancer in men and the seventh commonest in women, and it is the third leading cause of cancer death in Hong Kong. The full spectrum of treatment modalities for HCC is available locally; however, there is currently no local consensus document detailing how these modalities should be used. SUMMARY In a series of meetings held between May and October 2013, a multidisciplinary group of Hong Kong clinicians - liver surgeons, medical oncologists, clinical oncologists, hepatologists, and interventional radiologists - convened to formulate local recommendations on HCC management. These recommendations consolidate the most current evidence pertaining to HCC treatment modalities, together with the latest thinking of practicing clinicians engaged in HCC management, and give detailed guidance on how to deploy these modalities effectively for patients in various disease stages. KEY MESSAGES Distinct from other regional guidelines, these recommendations provide guidance on the use of antiviral therapy to reduce the incidence of HCC in CHB patients with cirrhosis and to reduce recurrence of CHB-related HCC.
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Affiliation(s)
- Ronnie Tung-Ping Poon
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR (China),*Ronnie Tung-Ping Poon, MBBS, MS, PhD, FRCS (Edin), FRCSEd (General Surgery), FCSHK, FHKAM (General Surgery), Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102, Pokfulam Raod, Pokfulam, Hong Kong, SAR (China), Tel. +852 2255 3025 / 2255 5907, E-Mail
| | - Tom Tan-To Cheung
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR (China)
| | - Philip Chong-Hei Kwok
- Department of Radiology and Imaging, Queen Elizabeth Hospital, Hong Kong, SAR (China)
| | - Ann-Shing Lee
- Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong, SAR (China)
| | - Tat-Wing Li
- Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, SAR (China)
| | - Kwok-Loon Loke
- Department of Radiology and Organ Imaging, United Christian Hospital, Hong Kong, SAR (China)
| | - Stephen Lam Chan
- Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, SAR (China)
| | - Moon-Tong Cheung
- Department of Surgery, Queen Elizabeth Hospital, Hong Kong, SAR (China)
| | - Tak-Wing Lai
- Department of Surgery, Princess Margaret Hospital, Hong Kong, SAR (China)
| | | | - Foon-Yiu Cheung
- Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Hong Kong, SAR (China)
| | - Ching-Kong Loo
- Department of Medicine and Geriatrics, Kwong Wah Hospital, Hong Kong, SAR (China)
| | - Yiu-Kuen But
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR (China)
| | - Shing-Jih Hsu
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR (China)
| | - Simon Chun-Ho Yu
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, SAR (China)
| | - Thomas Yau
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR (China)
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Chong CCN, Wong GLH, Wong VWS, Ip PCT, Cheung YS, Wong J, Lee KF, Lai PBS, Chan HLY. Antiviral therapy improves post-hepatectomy survival in patients with hepatitis B virus-related hepatocellular carcinoma: a prospective-retrospective study. Aliment Pharmacol Ther 2015; 41:199-208. [PMID: 25413146 DOI: 10.1111/apt.13034] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Revised: 09/15/2014] [Accepted: 11/04/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND The effect of antiviral therapy on the post-hepatectomy long-term survival in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains uncertain. AIM To evaluate the effect of antiviral therapy on post-hepatectomy survival and recurrence in patients with HBV-related HCC. METHODS This was a prospective-retrospective study of a total of 404 patients who underwent hepatectomy for HBV-related HCC in a tertiary academic hospital. Data on patient and tumour characteristics, tumour recurrence, treatment for recurrence and survival were compared between antiviral and no antiviral groups. RESULTS Patient's and tumour characteristics were comparable between the two groups, except a higher proportion of patients with cirrhosis in the antiviral group. With a mean follow-up time of 52.4 months, antiviral group had a better 5-year overall survival (66.7% vs. 56.0%, P = 0.001) while there was no significant difference in the 5-year disease-free survival (44.7% vs. 38.1%, P = 0.166). Use of antiviral therapy was associated with better liver function reserve at the time of recurrence and a greater proportion of patients could receive curative treatment for recurrence (38.5% vs. 24.3%, P = 0.041). There was no significant different in the hazard ratios of patients who started antiviral therapy before or after operation (P = 0.054). CONCLUSIONS Use of antiviral therapy improves the long-term post-hepatectomy survival in patients with HBV-related HCC. With a better liver function reserve at the time of recurrence, a greater proportion of patients in antiviral group could receive curative treatment for recurrence.
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Affiliation(s)
- C C N Chong
- Division of Hepato-biliary and Pancreatic Surgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
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Yapali S, Talaat N, Fontana RJ, Oberhelman K, Lok AS. Outcomes of patients with chronic hepatitis B who do not meet criteria for antiviral treatment at presentation. Clin Gastroenterol Hepatol 2015; 13:193-201.e1. [PMID: 25041863 PMCID: PMC4268235 DOI: 10.1016/j.cgh.2014.07.019] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 06/10/2014] [Accepted: 07/03/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The availability of potent, well-tolerated, oral antivirals with low rates of resistance has led many experts to recommend liberalizing indications for the treatment of chronic hepatitis B (CHB). This study sought to determine the rate of transitions to an active phase of infection, the frequency of treatment initiation, and the clinical outcomes of patients with CHB who did not meet treatment criteria at presentation. METHODS We reviewed medical records of patients with CHB, seen in the liver clinics at the University of Michigan Health System from 1999 through 2010, who did not receive antiviral treatment within 6 months of presentation. We collected data on transitions between different phases of CHB, hepatitis B e antigen (HBeAg) seroconversion, loss of hepatitis B surface antigen (HBsAg), and the development of hepatocellular carcinoma (HCC). Data analyses were censored or truncated at the time of treatment initiation or development of an outcome. RESULTS Of the 234 patients analyzed, 52.1% were men (median age, 35 y), 72.2% were Asian, and 81.2% were HBeAg-negative. During a median follow-up period of 51 months, 19.2% of patients transitioned to a more active disease phase and 18.8% started antiviral therapy. Of the 44 HBeAg-positive patients, 4 patients (9%) had spontaneous HBeAg seroconversion. Nine HBeAg-negative patients but none of the HBeAg-positive patients lost HBsAg. The cumulative probability of HBsAg loss among HBeAg-negative patients was 1% at year 5 and 21% by year 10. No patients had flares of icteric hepatitis or hepatic decompensation. None of the HBeAg-positive patients developed HCC, whereas 2 HBeAg-negative patients developed HCC. CONCLUSIONS Careful monitoring of patients with CHB who did not meet treatment criteria at presentation permits timely initiation of treatment, with a low risk of adverse clinical outcomes, based on a retrospective study with a median follow-up period of 4.3 years. These findings indicate that current guidelines for initiating treatment are appropriate.
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Affiliation(s)
- Suna Yapali
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, Michigan
| | - Nizar Talaat
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, Michigan
| | - Robert J Fontana
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, Michigan
| | - Kelly Oberhelman
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, Michigan
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, Michigan.
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Antiviral treatment among pregnant women with chronic hepatitis B. Infect Dis Obstet Gynecol 2014; 2014:546165. [PMID: 25548510 PMCID: PMC4274824 DOI: 10.1155/2014/546165] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 10/23/2014] [Accepted: 10/23/2014] [Indexed: 12/15/2022] Open
Abstract
Objective. To describe the antiviral treatment patterns for chronic hepatitis B (CHB) among pregnant and nonpregnant women. Methods. Using 2011 MarketScan claims, we calculated the rates of antiviral treatment among women (aged 10–50 years) with CHB. We described the pattern of antiviral treatment during pregnancy and ≥1 month after delivery. Results. We identified 6274 women with CHB during 2011. Among these, 64 of 507 (12.6%) pregnant women and 1151 of 5767 (20.0%) nonpregnant women received antiviral treatment (P < 0.01). Pregnant women were most commonly prescribed tenofovir (73.4%) and lamivudine (21.9%); nonpregnant women were most commonly prescribed tenofovir (50.2%) and entecavir (41.3%) (P < 0.01). Among 48 treated pregnant women with an identifiable delivery date, 16 (33.3%) were prescribed an antiviral before pregnancy and continued treatment for at least one month after delivery; 14 (29.2%) started treatment during the third trimester and continued at least one month after delivery. Conclusion. Among this insured population, pregnant women with CHB received an antiviral significantly less often than nonpregnant women. The most common antiviral prescribed for pregnant women was tenofovir. These data provide a baseline for assessing changes in treatment patterns with anticipated increased use of antivirals to prevent breakthrough perinatal hepatitis B virus infection.
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Liu CJ, Chen PJ. Updates on the treatment and outcomes of dual chronic hepatitis C and B virus infection. World J Gastroenterol 2014; 20:2955-2961. [PMID: 24659886 PMCID: PMC3961993 DOI: 10.3748/wjg.v20.i11.2955] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 10/25/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
Dual hepatitis C virus (HCV)/hepatitis B virus (HBV) infection is found in HBV or HCV endemic areas, and in specific populations exhibiting a high risk of parenteral viral transmission. Clinical observations have revealed that HCV/HBV dually infected patients demonstrate a higher risk of liver disease progression compared with HBV or HCV monoinfected patients. The viral activity responsible for liver disease progression can be determined by examining the viral loads of HCV and HBV and by conducting liver biopsy examinations. Recent trials have confirmed that the combination therapy of peginterferon alpha-2a or 2b and ribavirin for dual hepatitis patients with HCV dominance appears to be as effective and safe as it is in patients with HCV monoinfections. Strikingly, approximately 60% of dually infected patients with inactive hepatitis B before treatment develop HBV reactivation after the clearance of the HCV. The clinical significance of this HBV reactivation and the strategy to prevent and treat this event should be determined. Furthermore, approximately 30% of dually infected patients lost hepatitis B surface antigen (HBsAg) within 5 years after the start of peginterferon-based therapy, and 40% of them harbored occult HBV infection. The underlying mechanisms of their accelerating HBsAg seroclearance and the development of occult HBV await further investigations. Moreover, the optimal treatment strategies for dually infected patients who are seropositive for the hepatitis B e antigen must be explored. Finally, the advent of new direct-acting antiviral-based anti-HCV therapy may change the optimal therapies for patients with dual hepatitis in the near future, which warrants further clinical trials.
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