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Wang D, Fu B, Shen X, Guo C, Liu Y, Zhang J, Sun R, Ye Y, Li J, Tian Z, Wei H. Restoration of HBV-specific CD8 + T-cell responses by sequential low-dose IL-2 treatment in non-responder patients after IFN-α therapy. Signal Transduct Target Ther 2021; 6:376. [PMID: 34737296 PMCID: PMC8569154 DOI: 10.1038/s41392-021-00776-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
Patients with chronic hepatitis B (CHB) undergoing interferon (IFN)-α-based therapies often exhibit a poor HBeAg serological response. Thus, there is an unmet need for new therapies aimed at CHB. This study comprised two clinical trials, including 130 CHB patients, who were treatment-naïve; in the first, 92 patients were systematically analyzed ex vivo for interleukin-2 receptor (IL-2R) expression and inhibitory molecules expression after receiving Peg-IFN-α-2b therapy. In our second clinical trial, 38 non-responder patients, in whom IFN-α therapy had failed, were treated with or without low-dose IL-2 for 24 weeks. We then examined the hepatitis B virus (HBV)-specific CD8+ T-cell response and the clinical outcome, in these patients. Although the majority of the participants undergoing Peg-IFN-α-2b therapy were non-responders, we observed a decrease in CD25 expression on their CD4+ T cells, suggesting that IFN-α therapy may provide a rationale for sequential IL-2 treatment without increasing regulatory T cells (Tregs). Following sequential therapy with IL-2, we demonstrated that the non-responders experienced a decrease in the numbers of Tregs and programmed cell death protein 1 (PD-1) expression. In addition, sequential IL-2 administration rescued effective immune function, involving signal transducer and activator of transcription 1 (STAT1) activation. Importantly, IL-2 therapy significantly increased the frequency and function of HBV-specific CD8+ T cells, which translated into improved clinical outcomes, including HBeAg seroconversion, among the non-responder CHB patients. Our findings suggest that sequential IL-2 therapy shows efficacy in rescuing immune function in non-responder patients with refractory CHB.
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Affiliation(s)
- Dongyao Wang
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Binqing Fu
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Xiaokun Shen
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Chuang Guo
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Yanyan Liu
- Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230027, China
| | - Junfei Zhang
- Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230027, China
| | - Rui Sun
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230001, China
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Ying Ye
- Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230027, China
| | - Jiabin Li
- Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230027, China.
| | - Zhigang Tian
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230001, China.
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230001, China.
| | - Haiming Wei
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medicine and Medical Center, University of Science and Technology of China, Hefei, Anhui, 230001, China.
- Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, Anhui, 230001, China.
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Wu Z, Gong Y, Peng J, Zhang X, Tang L. Correlation Between Serum Entecavir Concentration and Virological Response in Patients with Chronic Type B Hepatitis. Med Sci Monit 2019; 25:6998-7004. [PMID: 31530794 PMCID: PMC6765337 DOI: 10.12659/msm.916553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Background This study was conducted to investigate the relationship between trough concentrations of serum entecavir and the virological response of patients with chronic type B hepatitis (CHB). Material/Methods A total of 59 CHB patients who had been receiving antiviral therapy with entecavir for >3 months were included in this study. Serum entecavir concentrations, HBV DNA levels, and other biochemical indicators were determined after drug treatments. Results The serum entecavir concentrations in the good response and poor response groups were 0.58±0.38 and 0.43±0.15 ng/mL, respectively. The antiviral efficacy was 52.38%, 65.63%, and 100% in low, middle, and high entecavir groups, respectively. The baseline HBV DNA level among the patients with poor response was significantly higher than in the group with good response. Among the 14 patients with a high viral load, 5 patients showed a good response and had a higher entecavir concentration than the other 9 patients with poor response. Entecavir in patients with cirrhosis was higher than in those without cirrhosis (0.63±0.45 ng/mL vs. 0.46±0.16 ng/mL), and the virological response rate in patients with cirrhosis was higher than in those without cirrhosis (83.33 vs. 51.43%). Cirrhosis progression was reversed in 3 patients with high serum entecavir concentration. Conclusions Serum entecavir concentrations vary among individuals, and higher serum entecavir concentration is correlated with more efficient viral clearance. Therefore, for patients with poor response, high doses may be beneficial for viral clearance.
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Affiliation(s)
- Zhengjie Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Yiwen Gong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland)
| | - Jun Peng
- Hangzhou Biozon Medical Institute, Hangzhou, Zhejiang, China (mainland)
| | - Xiao Zhang
- Hangzhou Biozon Medical Institute, Hangzhou, Zhejiang, China (mainland)
| | - Lingling Tang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China (mainland)
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Şahin A, Namıduru M, Balkan A, Karaoğlan İ, Gülşen MT. Assessment of histopathological alterations in patients with chronic hepatitis B infection following long-term oral antiviral therapy. Saudi Med J 2019; 39:999-1005. [PMID: 30284582 PMCID: PMC6201023 DOI: 10.15537/smj.2018.10.23056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objectives: To evaluate the histopathological changes in the liver after oral antiviral therapy in patients with chronic hepatitis B. Methods: A total of 79 HBeAg-negative and positive patients who had been on lamivudine, entecavir, or tenofovir disoproxil for at least 3 years prior to inclusion were enrolled between March 2015 and 2016, retrospectively. There were 23 patients on lamivudine, 21 patients on entecavir, and 35 on tenofovir. All patients underwent a follow-up liver biopsy. Biochemical, serological, virological and histopathological data were recorded in all patients and were compared after at least 3 years of treatment with oral antiviral agents. Results: Histological activity index scores were reduced in patients who received lamivudine (p=0.011), entecavir (p=0.002), and tenofovir (p=0.001). Also, in contrast with a significant improvement in fibrosis scores in lamivudine (p=0.033) and tenofovir (p=0.001) groups no improvements were found in patients who received entecavir (p=0.090). Conclusion: Long term treatment with oral antiviral agents was associated with biochemical, virological, serological, and histopathological improvements. Long-term use of anti-viral agents as well as continuous suppression of HBV DNA are prerequisites for histopathological improvement.
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Affiliation(s)
- Ahmet Şahin
- Department of Infectious Diseases and Clinical Microbiology, Çankırı State Hospital, Çankırı, Turkey. E-mail:.
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Xing T, Xu H, Cao L, Ye M. HBeAg Seroconversion in HBeAg-Positive Chronic Hepatitis B Patients Receiving Long-Term Nucleos(t)ide Analog Treatment: A Systematic Review and Network Meta-Analysis. PLoS One 2017; 12:e0169444. [PMID: 28107377 PMCID: PMC5249087 DOI: 10.1371/journal.pone.0169444] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 12/17/2016] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND HBeAg seroconversion is an important intermediate outcome in HBeAg-positive chronic hepatitis B (CHB) patients. This study aimed to compare the effect of nucleos(t)ide analogs (NAs) on HBeAg seroconversion in treating CHB with lamivudine, adefovir, telbivudine, entecavir, and tenofovir. METHODS Network meta-analysis of NA treatment-induced HBeAg seroconversion after 1-2 years of treatment was performed. In addition, NA treatment-induced HBeAg seroconversion after 3-5 years of treatment was systematically evaluated. RESULTS A total of 31 articles were included in this study. Nine and five studies respectively reporting on 1- and 2-year treatment were included in our network meta-analysis. In addition, 6, 5, and 5 studies, respectively reporting on 3-, 4-, and 5-year treatment were included in our systematic evaluation. Telbivudine showed a significantly higher HBeAg seroconversion rate after a 1 year treatment period compared to the other NAs (odds ratio (OR) = 3.99, 95% CI 0.68-23.6). This was followed by tenofovir (OR = 3.36, 95% CI 0.70-16.75). Telbivudine also showed a higher seroconversion rate compared to the other NAs after a 2 year treatment period, (OR = 1.38, 95% CI 0.92-2.22). This was followed by entecavir (OR = 1.14, 95% CI 0.72-1.72). No significant difference was observed between spontaneous induction and long-term telbivudine treatment-induced HBeAg seroconversion. However, entecavir and tenofovir treatment-induced HBeAg seroconversions were significantly lower than spontaneous seroconversion. CONCLUSION Long-term treatment with potent anti-HBV drugs, especially tenofovir and entecavir, may reduce HBeAg seroconversion compared with spontaneous HBeAg seroconversion rate. Telbivudine treatment, whether short term or long term, is associated with higher HBeAg seroconversion compared with the other NAs. However, the high rates of drug resistance likely limit the application of telbivudine.
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Affiliation(s)
- Tongjing Xing
- Department of Infectious Diseases, Taizhou People’s Hospital, Taizhou, Jiangsu Province, China
| | - Hongtao Xu
- Department of Infectious Diseases, Taizhou People’s Hospital, Taizhou, Jiangsu Province, China
| | - Lin Cao
- Department of Infectious Diseases, Taizhou People’s Hospital, Taizhou, Jiangsu Province, China
| | - Maocong Ye
- Department of Infectious Diseases, Taizhou People’s Hospital, Taizhou, Jiangsu Province, China
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Treatment Outcomes With First-line Therapies With Entecavir and Tenofovir in Treatment-Naive Chronic Hepatitis B Patients in a Routine Clinical Practice. J Clin Gastroenterol 2016; 50:169-74. [PMID: 26018133 DOI: 10.1097/mcg.0000000000000345] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Given their high efficacy, entecavir (ETV) and tenofovir (TDF), are the recommended first-line therapies for chronic hepatitis B, but it is not clear whether the efficacy reported from pivotal trials is similar to the outcomes seen in routine practice. GOALS Our goal was to examine the treatment outcomes of antiviral therapy in such setting. PATIENTS AND METHODS We conducted a retrospective study of 557 consecutive treatment-naive patients who started either ETV (n=443) or TDF (n=114) at 3 US liver clinics between January 2005 and 2012. Primary study endpoint was complete viral suppression (CVS) rate (hepatitis B virus DNA<40 IU/mL). RESULTS The majority of patients in both ETV and TDF groups were Asians, hepatitis B e antigen (HBeAg) negative, male, and with similar pretreatment alanine aminotransferase and hepatitis B virus DNA levels. Similar proportions of patients in the ETV and TDF groups achieved CVS at 24 months: 87.7% versus 87.0%, respectively. Cumulative rates of virological breakthrough in the ETV and TDF groups were 1.0% versus 4.8% (P=0.26) and 3.7% versus 9.8% (P=0.04) at month 12 and 24, respectively; and all were associated with medication nonadherence. Cumulative rate of medication nonadherence was lower in the ETV than TDF group: 4.6% versus 7.8% at month 12 and 8.9% versus 16.9% at month 24, respectively. CONCLUSIONS Patients treated with either ETV or TDF achieve a similar rate of CVS at 24 months. The primary contributor to suboptimal response was medication nonadherence. Attention to medication adherence is needed in a routine clinical setting.
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Lin CC, Bair MJ, Chen CJ, Lee KH, Chen MJ, Liu CY, Chang CW, Hu KC, Liou TC, Lin SC, Wang HY, Chu CH, Shih SC, Wang TE. Off-treatment efficacy of 3-year nucleos(t)ide analogues in chronic hepatitis B patients. Kaohsiung J Med Sci 2016; 32:10-15. [PMID: 26853169 DOI: 10.1016/j.kjms.2015.11.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 11/12/2015] [Accepted: 11/23/2015] [Indexed: 12/30/2022] Open
Abstract
Lamivudine, telbivudine, and entecavir are the first-line drugs covered by the Taiwan National Health Insurance as 3-year treatments for patients with chronic hepatitis B virus (HBV), but the optimal treatment duration of each remains unclear. We aimed to detect HBV treatment-cessation durability, and compare the predictors in patients with and without clinical relapse. In this retrospective cohort study, 210 patients with chronic HBV who tested hepatitis B e-antigen positive or hepatitis B e-antigen negative were treated for 3 years with a nucleos(t)ide analogue. Of these, 102 patients continued therapy after 3 years, while 88 patients stopped treatment and were followed for 1 year due to financial difficulties. Efficacy was assessed in terms of alanine aminotransferase (ALT) level normalization, HBV DNA clearance, virus breakthrough, clinical relapse, and liver decompensation. The durability predictors were evaluated by host factors, HBV DNA, and drug differences. Eighty patients (14 on lamivudine, 19 on telbivudine, and 47 on entecavir) were recruited. There was no difference in clinical-relapse rate among lamivudine, telbivudine, and entecavir (35.7% vs. 36.8% vs. 31.9%, respectively; p = 0.916), and liver decompensated hepatitis was absent. In baseline clinical characteristics, there were no differences between the clinical-relapse and nonrelapse groups in age, sex, cirrhosis, prior treatment, HBV DNA, pretreatment ALT, or hepatitis B e-antigen (HBeAg). The mean 3(rd) year serum ALT level differed significantly between clinical-relapse and nonrelapse patients (37.5 U/L vs. 27.7 U/L, respectively; p = 0.044). The 3-year nucleos(t)ide analogue off-treatment in patients with chronic HBV delivered according to the Taiwan National Health Insurance guidelines had an overall 33.8% 1-year clinical-relapse rate without any decompensated hepatitis flare-ups.
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Affiliation(s)
- Ching-Chung Lin
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Medical College, New Taipei City, Taiwan
| | - Ming-Jong Bair
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taitung Branch, Taitung, Taiwan; Department of Nursing, Meiho University, Pingtung, Taiwan
| | - Chih-Jen Chen
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | | | - Ming-Jen Chen
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Chia-Yuan Liu
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Medical College, New Taipei City, Taiwan
| | - Chen-Wang Chang
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Kuang-Chun Hu
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Tai-Cherng Liou
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Medical College, New Taipei City, Taiwan
| | - Shee-Chan Lin
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Medical College, New Taipei City, Taiwan
| | - Horng-Yuan Wang
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Cheng-Hsin Chu
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Shou-Chuan Shih
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan
| | - Tsang-En Wang
- Division of Gastroenterology, Department of Internal Medicine and Liver Medical Center, Mackay Memorial Hospital, Taipei, Taiwan; Mackay Medical College, New Taipei City, Taiwan.
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Xu Y, Zhang YG, Wang X, Qi WQ, Qin SY, Liu ZH, Jiao J, Wang JB. Long-term antiviral efficacy of entecavir and liver histology improvement in Chinese patients with hepatitis B virus-related cirrhosis. World J Gastroenterol 2015; 21:7869-76. [PMID: 26167087 PMCID: PMC4491974 DOI: 10.3748/wjg.v21.i25.7869] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Revised: 03/04/2015] [Accepted: 05/11/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the clinical outcomes of 240-wk treatment with entecavir (0.5 mg) in Chinese nucleoside-naive patients with cirrhosis. METHODS A total of 204 nucleoside-naive patients with compensated (n = 96) or decompensated (n = 108) hepatitis B virus (HBV)-induced cirrhosis at the Department of Gastroenterology of the China-Japan Union Hospital (Jilin University, Changchun, China) who were treated with entecavir (0.5 mg) for 240 wk were enrolled in this study. Liver biopsy samples obtained from 38 patients prior to treatment (baseline) and at week 240 were evaluated by different independent histopathologists. Efficacy assessments included the proportions of patients who achieved an HBV DNA level < 500 copies/mL, the association of interleukin-28B genetic variation with antivirus therapy, clinical outcomes, and histologic improvement. Changes in liver disease severity were analyzed, and liver histologic evaluation was performed in 38 patients with paired biopsies. Student t tests were used to compare the means of continuous variables between the groups, and the proportions of patients who achieved the endpoints were compared using the χ(2) test. RESULTS At week 240, 87.5% of the patients with compensated cirrhosis and 92.6% of the patients with decompensated cirrhosis achieved a HBV DNA level < 500 copies/mL. Three patients had genotypic entecavir resistance within the 240-wk period. No significant association was observed between virologic response and interleukin-28 genotype (CT, 88.2% vs CC, 90.6%). The proportion of patients with Child-Pugh class A disease was significantly increased at week 240 (68%) from the baseline (47%; P < 0.01). The proportion of patients with Child-Pugh class B disease was significantly decreased at week 240 (25%) from the baseline (39%; P = 0.02). In the patients with paired liver biopsies, the mean reduction in the Knodell necroinflammatory score from the baseline was 3.58 ± 1.03 points (7.11 ± 1.80 vs 3.53 ± 1.35, P < 0.01). The mean reduction in Ishak fibrosis score from the baseline was 1.26 ± 0.64 points (5.58 ± 0.50 vs 4.32 ± 0.81, P < 0.01). CONCLUSION Entecavir is an effective treatment option for patients with HBV-related compensated or decompensated cirrhosis that can result in sustained virologic suppression and histologic improvement.
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Ha NB, Ha NB, Chaung KT, Trinh HN, Nguyen HA, Nguyen KK, Nguyen MH. Similar response to entecavir 0.5 and 1.0 mg in treatment-naïve chronic hepatitis B patients: a case-control study. Dig Dis Sci 2014; 59:168-73. [PMID: 24248420 DOI: 10.1007/s10620-013-2940-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2013] [Accepted: 10/29/2013] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND AIMS The dose recommendation for entecavir (ETV) is 0.5 mg daily for treatment-naïve chronic hepatitis B (CHB) patients and 1.0 mg daily for lamivudine-refractory patients; however, few data are available for the efficacy of a 1.0-mg daily dose in treatment-naïve CHB patients. Our goal is to examine the treatment outcome of treatment-naïve patients placed on ETV 0.5 mg or ETV 1.0 mg daily through week 48. METHODS Cases were 40 consecutive hepatitis B e antigen (HBeAg)-positive CHB patients treated with ETV 1.0 mg daily between January 2005 and September 2010, and controls were 40 consecutive CHB patients treated with ETV 0.5 mg daily between January 2005 and September 2010 at three US gastroenterology/liver clinics. Controls were matched for age (±5 years), sex, HBeAg, and baseline hepatitis B virus (HBV) DNA (±0.5 log10 IU/ml). Complete viral suppression was defined as undetectable HBV DNA by polymerase chain reaction (<100 IU/ml). RESULTS Both groups had similar distributions of age (38 ± 11 years), male patients (55 %), and mean HBV DNA (7.7 ± 1.1 log10 IU/ml). The complete viral suppression rate was similar in both cases and controls through week 24 (15 vs. 15 %, p = 1.00) and week 48 (22 vs. 36 %, p = 0.17). Non-adherence was reported in three patients in the ETV 1.0 mg daily cohort at week 48. CONCLUSIONS There were no significant differences in the proportion of patients with complete viral suppression in patients treated with ETV 0.5 mg daily or the higher daily dose of 1.0 mg.
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Affiliation(s)
- Nghiem B Ha
- School of Medicine, University of California, Davis, Sacramento, CA, USA
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Wang J. Clinical utility of entecavir for chronic hepatitis B in Chinese patients. DRUG DESIGN DEVELOPMENT AND THERAPY 2013; 8:13-24. [PMID: 24376343 PMCID: PMC3865082 DOI: 10.2147/dddt.s41423] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The People's Republic of China has one of the highest rates of hepatitis B virus (HBV) infection. This review summarizes recent data from studies of entecavir, one of the recommended first-line oral therapies for treating chronic hepatitis B, in Chinese HBV-infected patients. Long-term treatment with entecavir is efficacious and well tolerated, and studies comparing entecavir with other nucleos(t)ide therapies, such as lamivudine, adefovir, and telbivudine, demonstrate superior antiviral effects for entecavir therapy and comparable safety profiles. Entecavir monotherapy and combination treatment with other nucleos(t) ide analogs has been shown to be efficacious in the treatment of lamivudine-resistant and adefovir-resistant patients with HBV infection, as well as in patients with multidrug-resistant disease. Entecavir has also been shown to be effective in patients with HBV-associated clinical morbidity, including cirrhosis and liver failure, as well as in preventing recurrence of HBV following liver transplantation and in preventing reactivation of HBV after immunosuppres-sive therapy. Although the cost of anti-HBV therapy is a particular concern in the People's Republic of China, a number of studies have recently demonstrated that entecavir (particularly long-term therapy) represents a more cost-effective treatment strategy compared with other nucleos(t)ide therapies. Further research is required to assess the effects of entecavir combination therapy on hepatitis B surface antigen clearance, and in drug-resistant patients in the People's Republic of China.
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Affiliation(s)
- Jiyao Wang
- Zhongshan Hospital, Fudan University, Shanghai, Key Laboratory of Medical, Molecular Virology of MOE/MOH, Shanghai, People's Republic of China
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Wang J, Ma K, Han M, Guo W, Huang J, Yang D, Zhao X, Song J, Tian D, Qi J, Huang Y, Ning Q. Nucleoside analogs prevent disease progression in HBV-related acute-on-chronic liver failure: validation of the TPPM model. Hepatol Int 2013. [PMID: 26202407 DOI: 10.1007/s12072-013-9485-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE This study aimed to evaluate the efficacy and safety of entecavir, lamivudine and telbivudine for treating patients with HBV-ACLF and to validate the Tongji prognostic predictor model (TPPM) in these patients. METHODS In this retrospective study, we enrolled 283 patients with HBV-ACLF (100 treated with entecavir, 98 treated with lamivudine and 85 treated with telbivudine). There were no significant differences in baseline clinical and virological characteristics among patients treated with entecavir, telbivudine or lamivudine. RESULTS There were no significant differences in the 4- and 12-week survival rates of entecavir-, telbivudine- and lamivudine-treated patients (79.00, 81.18 and 86.73 %, respectively, at 4 weeks; 67.00, 65.88 and 73.47 %, respectively, at 12 weeks). Patients in all three groups achieved an improvement in the model for end-stage liver disease (MELD) score. Using the Hosmer-Lemeshow test, the validation of the TPPM score for HBV-ACLF demonstrated a good degree of fit with disease prognosis. Based on this unique group of patients, the TPPM score with an AUC of 0.787 was superior to the MELD score, which had an AUC of 0.736 in the prediction of 12-week mortality. The TPPM had an AUC of 0.733, and the MELD score had an AUC of 0.672 in the prediction of 4-week mortality. Using a cutoff value of 0.22 for 12-week mortality prediction by the TPPM, the positive predictive value was 49.66 %, with a negative predictive value of 89.55 %. CONCLUSION Treatment with nucleoside analogs including entecavir, lamivudine and telbivudine prevented disease progression and increased the survival of patients with HBV-ACLF. Validation of the established TPPM scoring system in this study confirmed its superior predictive value for HBV-ACLF patients when compared with the MELD system.
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Affiliation(s)
- Junshuai Wang
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Ke Ma
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Meifang Han
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Wei Guo
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Jiaquan Huang
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Daofeng Yang
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Xiping Zhao
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Jiangxin Song
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Deying Tian
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Junying Qi
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Yuancheng Huang
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China.
| | - Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China.
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Response to higher dose of entecavir 1.0 mg daily in patients with partial response to entecavir 0.5 mg daily. J Clin Gastroenterol 2013; 47:461-5. [PMID: 23090046 DOI: 10.1097/mcg.0b013e318266fd31] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Despite its high potency against hepatitis B virus (HBV), entecavir (ETV) 0.5 mg daily may not be sufficient to induce complete viral suppression in some patients with very high pretreatment viremia. It is not clear whether ETV 1.0 mg daily would have additive effect in such patients. GOALS Our goal was to examine virologic outcome of ETV 1.0 mg daily in patients with partial response to ETV 0.5 mg daily. METHODS We retrospectively studied 31 consecutive treatment-naive patients who were switched to ETV 1.0 mg daily after partial response [reduction of HBV DNA ≥2 log10 IU/mL but with detectable HBV DNA levels (>100 IU/mL) after 24 weeks of therapy or longer] with ETV 0.5 mg daily from January 2005 to January 2010 at 2 clinics. RESULTS All patients were Asians and 90% had positive hepatitis B e antigen. Mean HBV DNA was 8.04±0.65 log10 IU/mL before therapy and 3.64±0.91 log10 IU/mL at the time of switch. Overall rate of complete viral suppression were 29% (n=9/31) after 24 weeks of ETV 1.0 mg daily and 22% (n=5/23) after 48 weeks. Complete viral suppression after 24 weeks with ETV 1.0 mg daily was significantly higher in patients with lower HBV DNA (<3 log10 IU/mL) at time of switch: 75% versus 5%, P<0.0001. CONCLUSIONS The majority of patients with partial response to ETV 0.5 mg daily did not achieve complete viral suppression with the higher dose of ETV 1.0 mg daily except those with minimal residual viremia (HBV DNA <3 log10 IU/mL).
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12
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Lin B, Ha NB, Liu A, Trinh HN, Nguyen HA, Nguyen KK, Ahmed A, Keeffe EB, Garcia RT, Garcia G, Nguyen MH. Low incidence of hepatitis B e antigen seroconversion in patients treated with oral nucleos(t)ides in routine practice. J Gastroenterol Hepatol 2013; 28:855-60. [PMID: 23278507 DOI: 10.1111/jgh.12108] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/18/2012] [Indexed: 12/28/2022]
Abstract
BACKGROUND AND AIM Treatment end-point of therapy for patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) includes HBeAg seroconversion, which ranges from 15% to 22% after 1 year of oral nucleos(t)ides according to clinical trials. Our goal was to determine the incidence and predictors of HBeAg seroconversion in such patients in routine clinical practice because they may differ than reported rates. METHODS We conducted a retrospective cohort study of 333 consecutive treatment-naïve HBeAg-positive patients who were treated for CHB between 1/2000 and 6/2010 at three gastroenterology and liver clinics in the USA. Primary study end-point was HBeAg seroconversion-loss of HBeAg and antibody to HBeAg (anti-HBe) development. RESULTS The majority of patients were Asian (96%). Median treatment duration prior to HBeAg seroconversion was 50 (range 26-52) weeks. Of the 333 study patients, 25% received lamivudine, 16% adefovir, 51% entecavir, and 8% tenofovir. HBeAg seroconversion at month 12 was 8.2%. On multivariate analysis inclusive of age, gender, and antiviral agents, independent predictors for HBeAg seroconversion at month 12 were hepatitis B virus DNA < 7.5 log10 IU/mL (hazard ratio [HR] = 2.59 [1.04-6.44]), P = 0.041) and alanine transaminase (ALT) > 1.5 × upper normal limit (HR = 2.86 [1.05-7.81], P = 0.040), but not the choice of nucleos(t)ides. CONCLUSIONS The HBeAg seroconversion rate seen in clinical settings for oral nucleos(t)ides appears much lower than those reported in pivotal trials, especially in patients with lower ALT and higher HBV DNA levels. HBeAg-positive patients should be counseled about the high possibility of the long treatment duration required to achieve recommended treatment end-points.
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Affiliation(s)
- Brian Lin
- Pacific Health Foundation, California, USA
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Wang Y, Jia J. Control of hepatitis B in China: prevention and treatment. Expert Rev Anti Infect Ther 2011; 9:21-5. [PMID: 21171874 DOI: 10.1586/eri.10.143] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
A high rate of chronic HBV infection in China is mainly the result of perinatal or early childhood transmission. Therefore, universal vaccination against HBV in infants has been very successful in the control of chronic HBV infection, with the prevalence of hepatitis B surface antigen decreasing from nearly 10% to approximately 7% in the general population. Adoption of Good Clinical Practice and proper conduction of well-designed clinical trials on conventional and pegylated interferons and nucleos(t)ide analogs have generated important clinical data. The publication and promotion of the evidence-based national guidelines have greatly improved the standard of clinical practice on the prevention and treatment of chronic hepatitis B. The ongoing national key scientific projects on the optimization of vaccination strategy and current anti-HBV therapy will yield important clinical evidence. Inclusion of conventional and pegylated interferons and nucleos(t)ides into the new national reimbursement list will increase the availability and affordability of anti-HBV therapies, thereby further decreasing the morbidity and mortality associated with chronic HBV infection.
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Affiliation(s)
- Yu Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Colombo GL, Gaeta GB, Viganò M, Di Matteo S. A cost-effectiveness analysis of different therapies in patients with chronic hepatitis B in Italy. CLINICOECONOMICS AND OUTCOMES RESEARCH 2011; 3:37-46. [PMID: 21935331 PMCID: PMC3169981 DOI: 10.2147/ceor.s16655] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2011] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Chronic hepatitis B (CHB) is a prevalent disease associated with high morbidity, mortality, and impact on health care costs. Antiviral therapy is aimed at reducing hepatitis B virus replication in order to limit progressive liver disease and improve the natural history of the disease. This study estimates the cost-effectiveness of lamivudine, adefovir, telbivudine, entecavir, tenofovir, and pegylated interferon in patients with CHB. METHODS A Markov model was developed to evaluate the costs and benefits of antivirals in a cohort of patients with CHB (hepatitis B e antigen [HBeAg]-positive and HBeAg-negative) and cirrhosis over a period of 10 years. Different rescue therapies were considered, according to current guidelines. Data on efficacy and changes in quality of life were derived from clinical trials and epidemiological Italian data. Direct costs were assessed from the perspective of the Italian National Health Service. RESULTS Tenofovir was associated with lower costs and higher efficacy compared with entecavir, telbivudine, and adefovir, as shown by their incremental cost-effectiveness ratios (ICER) per quality-adjusted life-year (QALY) gained: tenofovir €30,959, entecavir €45,971, telbivudine €62,051, and adefovir €82,824. Even following 1 year of pegylated interferon therapy, tenofovir had a more favourable ICER per QALY gained compared with the other rescue options. The analysis of patients with cirrhosis confirms the results obtained with the CHB cohort though with higher ICERs. Sensitivity analyses on the main variables confirm the results of the base case scenario. CONCLUSION Within the Italian health care system, in patients with CHB, tenofovir is a cost-effective strategy compared with other available therapies. Public health care authorities would benefit from mathematical models designed to estimate the future burden of CHB infection together with the impact of treatment and drug resistance.
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A comparison of treatment with adefovir and entecavir for chronic hepatitis B in China: The 2-year results of a prospective study: Adefovir versus Entercavir for Chronic Hepatitis B. HEPATITIS MONTHLY 2011; 11:27-31. [PMID: 22087113 PMCID: PMC3206656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2010] [Revised: 09/27/2010] [Accepted: 10/01/2010] [Indexed: 11/12/2022]
Abstract
BACKGROUND The reduction of hepatitis B virus replication to minimal levels is emerging as key therapeutic goal in chronic hepatitis B (CHB). OBJECTIVES This study aimed to evaluate and compare the efficacies of adefovir (ADV) and entecavir (ETV) in CHB. PATIENTS AND METHODS In this prospective study, 100 naïve patients were assigned to treatment with ADV (33 HBeAg-positive and 19 HBeAg-negative patients) or ETV (32 HBeAg-positive and 16 HBeAg-negative patients). The primary efficacy outcome was ALT normalization, reduction in HBV DNA, and seroconversion of HBeAg. Second efficacy outcomes included resistance and safety. Comparisons of quantitative and qualitative variables between groups were analyzed by student t-test and chi-square test (or Fisher's exact test), respectively. RESULTS Among HBeAg-positive patients, ETV was superior to ADV with respect to mean reduction in HBV DNA (-7.5 versus -6.3, respectively, at Month 24, p = 0.003) and the percentage of those with HBV DNA < 103 copies/mL at Month 24 [96.9% (31/32) vs. 69.7% (23/33), respectively, p = 0.002] and < 300 copies/mL at Month 24 [84.4% (27/32) vs. 54.5% (18/33), respectively, p = 0.004]. But, the rates of ALT normalization and HBeAg seroconversion between the groups were similar [87.9% (29/33) vs. 96.9% (31/32), respectively, p=0.355; and 24.2% (8/33) vs. 25.0% (8/32), respectively, p = 0.943]. In HBeAg-negative patients who received ETV or ADV, the reduction in HBV DNA (-6.8 versus -5.9, respectively, p = 0.192), percentage of ALT normalization [100% (16/16) vs. 78.9% (15/19), respectively, p=0.109], HBV DNA < 103 copies/mL [100% (16/16) vs. 89.5% (17/19), respectively, p = 0.489], and HBV DNA < 300 copies/mL [100% (16/16) vs. 84.2% (16/19), respectively, p = 0.234] were similar. No ETV- or ADV-associated mutations were observed, and both agents were well tolerated. CONCLUSIONS ETV and ADV are effective therapies for CHB. In HBeAg-positive patients, the efficacy of ETV is significantly superior to that of ADV, and in HBeAg-negative patients, the agents effect similar biochemical and virological responses.
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Pradeep KS, Medhi S, Asim M, Das BC, Gondal R, Kar P. Evaluation of adefovir & lamivudine in chronic hepatitis B: correlation with HBV viral kinetic, hepatic-necro inflammation & fibrosis. Indian J Med Res 2011; 133:50-6. [PMID: 21321419 PMCID: PMC3100146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND & OBJECTIVES Chronic hepatitis B is an important cause of morbidity and mortality. We conducted a study comparing the efficacy of adefovir and lamivudine with respect to their impact on serum and hepatic viral DNA clearance, and improvement in hepatic necro-inflammatory score, in naive patients of chronic hepatitis B. METHODS This prospective randomized pilot study was conducted in Lok Nayak Hospital, New Delhi, involving 30 patients of chronic hepatitis B (both e antigen positive and negative); 15 were randomly selected to receive either adefovir or lamivudine for a period of 6 months. Quantification of serum and hepatic HBV DNA levels was done by real time PCR and liver biopsy was done at the beginning and end of 6 months. RESULTS Serum ALT was elevated to 2 or more times normalized in both the groups. In the adefovir group, two patients became HBeAg negative. In the lamivudine group, one patient became HBeAg negative. After therapy HBV DNA was negative in 26.7 per cent patients from adefovir group and 13.3 per cent patients from lamivudine group. Serum HBV DNA levels were correlated with the hepatic levels before therapy (r=0.843; P<0.001) and after therapy (r=0.713, P<0.001) showing strong correlation. There was a median reduction of 1.92 and 2.06 log copies per ml in serum HBV DNA load after adefovir and lamivudine therapy, respectively. The mean reduction in the histology activity index (HAI) score was 2 and 1.53, fibrosis score was 2.33 and 3.06 after adefovir and lamivudine therapy respectively. INTERPRETATION & CONCLUSIONS Adefovir and lamivudine treatment caused biochemical and serological improvement when administered for about 6 months with significant reduction in HBV DNA, serum and hepatic viral load without completely clearing the virus from either serum or liver. It also helped in reduction of the necro-inflammatory and fibrosis score of patients with chronic hepatitis B. Our study also showed significant correlation between serum and hepatic HBV DNA levels both before and after therapy. There was not enough evidence to show therapeutic advantage of one drug over the other in any of the parameters measured.
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Affiliation(s)
- Kumar S Pradeep
- Department of Medicine, Maulana Azad Medical College, New Delhi, India
| | - Subhash Medhi
- Department of Medicine, Maulana Azad Medical College, New Delhi, India
| | - Mohammad Asim
- Department of Medicine, Maulana Azad Medical College, New Delhi, India
| | - Bhudev C Das
- Department of Medicine, Ambedkar Centre for Biomedical Research, University of Delhi, Delhi India
| | - Ranjana Gondal
- Department of Pathology, G.B. Pant Hospital, New Delhi, India
| | - Premashis Kar
- Department of Medicine, Maulana Azad Medical College, New Delhi, India
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Hynicka LM, Yunker N, Patel PH. A Review of Oral Antiretroviral Therapy for the Treatment of Chronic Hepatitis B. Ann Pharmacother 2010; 44:1271-86. [DOI: 10.1345/aph.1m590] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Objective: To describe the current evidence for the use of oral antiretroviral (ARV) agents in the treatment of chronic hepatitis B (CHB). Data Sources: A search from 1950 to April 2010 was conducted using the databases PubMed and MEDLINE with the search terms chronic hepatitis B, lamivudine, entecavir, adefovir, telbivudine, tenofovir, emtricitabine, clevudine, and pradefovir. The search was limited to trials conducted in humans that were published in the English language. Study Selection and Data Extraction: Studies were included if they evaluated the use of oral ARVs in patients with CHB infection who were not coinfected with hepatitis C, hepatitis D, or HIV. Data Synthesis: Oral ARVs have revolutionized the treatment of CHB. Studies conducted comparing ARVs have favored entecavir and tenofovir with respect to their ability to decrease hepatitis B virus DNA viral load while minimizing the development of resistance. However, low seroconversion rates, recurrent viremia when ARV therapy is discontinued, and increased resistance rates with longer treatment durations limit the benefit of oral ARVs in the treatment of CHB. Combination therapy has been a suggested solution; however, studies have yet to prove additional benefit over currently recommended monotherapy. Conclusions: Oral ARVs should continue to be used in the treatment of CHB; however, research is needed to define the optimal duration of therapy, evaluate the utility of combination therapy, and explore novel targets within the hepatitis B life cycle.
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Affiliation(s)
| | - Nancy Yunker
- School of Pharmacy, Virginia Commonwealth University, Richmond, VA
| | - Punam H Patel
- Solid Organ Transplant, Virginia Commonwealth University Health System
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18
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Lau GKK. Current treatments for patients with HBeAg-positive chronic hepatitis B virus infection: a comparison focusing on HBeAg seroconversion. Liver Int 2010; 30:512-20. [PMID: 20102511 DOI: 10.1111/j.1478-3231.2009.02198.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
HBeAg seroconversion, in association with undetectable levels of hepatitis B virus DNA as determined by polymerase chain reaction, is an important goal in the treatment of patients with HBeAg-positive chronic hepatitis B (CHB). Achievement of sustained HBeAg seroconversion at an early age (<40 years) is associated with a reduced incidence of hepatic complications, increased rates of HBsAg loss and seroconversion and improved survival rates, whether the seroconversion is spontaneous or treatment induced. Patients with HBeAg-positive CHB who achieve sustained HBeAg seroconversion and complete 6-12 months of consolidation therapy are eligible for stopping therapy. In randomized clinical studies involving patients with HBeAg-positive CHB, treatment with pegylated interferon (PegIFN)-alpha is associated with higher and more durable HBeAg seroconversion rates than are lamivudine and adefovir. More recently, newer generation oral nucleos(t)ide analogs (NAs) have become available. These include entecavir, telbivudine and tenofovir, and they demonstrate superior antiviral potency and efficacy. This review examines the importance of HBeAg seroconversion as an end point for therapy in the treatment of patients with HBeAg-positive CHB, and examines the rates and durability of HBeAg seroconversion with PegIFN and oral NA therapy. The mechanisms for enhanced HBeAg seroconversion rates with new-generation NAs are also discussed.
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Affiliation(s)
- George K K Lau
- Clinical Trial Center, LKS Faculty of Medicine, The University of Hong Kong, Humanity and Health GI and Liver Clinic, Hong Kong, SAR.
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19
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20
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Yao GB, Ren H, Xu DZ, Zhou XQ, Jia JD, Wang YM, Chen CW. Virological, serological and biochemical outcomes through 3 years of entecavir treatment in nucleoside-naive Chinese chronic hepatitis B patients. J Viral Hepat 2010; 17 Suppl 1:51-8. [PMID: 20586934 DOI: 10.1111/j.1365-2893.2010.01271.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hepatitis B virus (HBV) infection has a high prevalence in China. Entecavir has shown superior efficacy over lamivudine in Chinese nucleoside-naive chronic hepatitis B (CHB) patients over 48 weeks, with continued clinical benefit to 96 weeks. The present study evaluates the long-term efficacy of entecavir in Chinese CHB patients who continued entecavir treatment for 144 weeks. Patients receiving either entecavir 0.5 mg/day (n = 258) or lamivudine 100 mg/day (n = 261) entered the initial 96-week randomized, double-blind, controlled efficacy study. Patients who did not achieve a consolidated response [HBV DNA <0.7 MEq/mL; alanine aminotransferase (ALT) <1.25 x upper limit of normal; and if hepatitis B e antigen (HBeAg) positive at baseline, loss of HBeAg for ≥ 24 weeks] or who experienced viral breakthrough or relapse entered a 48-week entecavir rollover study. A total of 160 patients received continuous entecavir for 144 weeks; of these, 89% had undetectable serum HBV DNA, 86% showed ALT normalization, 20% reported HBeAg loss and 8% experienced HBeAg seroconversion. The cumulative rates of HBeAg loss and seroconversion were 36% and 27% at Week 144, respectively. The development of resistance was low, with three patients up to Week 96 and an additional two patients in Weeks 96-144 showing evidence of associated genotypic mutations. Entecavir was well tolerated. Adverse event rates were similar to those in lamivudine-treated patients, but patients receiving entecavir experienced fewer ALT flares. This study demonstrates that entecavir provides durable, long-term suppression of HBV DNA and ALT normalization in Chinese CHB patients, and is associated with low rates of emerging resistance. The results are consistent with the findings using entecavir globally and in Japan.
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Affiliation(s)
- G B Yao
- Clinical Immunology Research Center, Department of Gastroenterology and Hepatology, Shanghai Jing An Central Hospital, Shanghai, China.
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Abstract
Chronic hepatitis B infection is a significant health problem throughout the world, and particularly in China. It is estimated that more than half a million Chinese people die annually from end-stage hepatitis B complications, which is associated with huge healthcare costs and a heavy socioeconomic burden. In China, the implementation of a hepatitis B vaccination programme has come into effect, and there has been a one-third decrease of the hepatitis B virus (HBV) carrier population since 1992. This great achievement changes China from a highly endemic area for HBV infection to an intermediate one. The predominant HBV genotypes in China are B and C, which might predispose patients to a poor antiviral response. Patients and physicians from China have been actively involved in the global research into and development of new antiviral agents. Patients have been recruited for global and domestic clinical trials on antiviral agents, including lamivudine, adefovir dipivoxil, entecavir, telbivudine and two pegylated interferon-alpha. In the future, more important data, focussing on optimization of the efficacy of antiviral agents, will be released from China, based on the newly launched National Eleven Five Plan Project on Hepatitis Research. Both economic development and healthcare system reform, including a new reimbursement policy, will make antiviral agents more accessible to Chinese patients. Ultimately, this will allow physicians greater opportunities to follow international and Chinese treatment recommendations.
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Affiliation(s)
- J Sun
- Hepatology Unit and Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
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22
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Abstract
Entecavir (Baraclude), a nucleoside analogue, is rapidly phosphorylated to the active intracellular 5'-triphosphate form that inhibits replication of hepatitis B virus (HBV). Oral entecavir is approved in the US, EU and several countries worldwide for the treatment of chronic HBV infection in adults (> or =16 years of age) with evidence of active viral replication and persistently elevated serum ALT and/or AST levels, and/or histological evidence of active disease. In several randomized, double-blind, multicentre trials, oral entecavir was an effective and generally well tolerated treatment in nucleoside-naive and lamivudine-refractory adult patients with chronic HBV infection, irrespective of whether patients were hepatitis B e antigen (HBeAg)-positive or -negative. Furthermore, it was more efficacious, associated with a lower risk of resistance, and more cost effective than lamivudine in these patient populations, with both drugs having a similar tolerability profile. In the EARLY trial, entecavir was significantly more effective than and as well tolerated as adefovir dipivoxil therapy in nucleoside-naive patients. In addition, in a double-blind, multicentre trial, entecavir plus lamivudine-based highly active antiretroviral therapy (HAART) was more effective than placebo plus lamivudine-based HAART in patients co-infected with HBV and HIV. Although the exact position of entecavir relative to other agents, such as tenofovir disoproxil fumarate and adefovir dipivoxil, for the treatment of chronic HBV infection remains to be fully determined, an important aspect in this positioning is the emergence of drug resistance. Hence, entecavir therapy provides a valuable first-line option in nucleoside-naive patients with chronic HBV infection and is a useful alternative in lamivudine-refractory patients.
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Affiliation(s)
- Lesley J Scott
- Wolters Kluwer Health/Adis, 41 Centorian Drive, Mairangi Bay, North Shore 0754, Auckland, New Zealand.
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Affiliation(s)
- Ching-Lung Lai
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China
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