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Wong WWL, Pechivanoglou P, Wong J, Bielecki JM, Haines A, Erman A, Saeed Y, Phoon A, Tadrous M, Younis M, Rayad NZ, Rac V, Janssen HLA, Krahn MD. Antiviral treatment for treatment-naïve chronic hepatitis B: systematic review and network meta-analysis of randomized controlled trials. Syst Rev 2019; 8:207. [PMID: 31426837 PMCID: PMC6699129 DOI: 10.1186/s13643-019-1126-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 08/04/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Chronic hepatitis B (CHB) infection poses a significant burden to public health worldwide. Most cases are clinically silent until late in the disease course. The main goal of current therapy is to improve survival and quality of life by preventing disease progression to cirrhosis and liver failure, and consequently hepatocellular carcinoma development. The objective of this review is to provide a contemporary and comprehensive evaluation of the effectiveness of treatment options. METHODS We performed a systematic review of peer-reviewed literature for randomized controlled trials involving treatment-naïve CHB adult population who received antiviral therapy. The endpoints were virologic response (VR), normalization of alanine aminotransferase (ALT norm), HBeAg loss, HBeAg seroconversion, and HBsAg loss for the HBeAg-positive population; and VR and ALT norm for the HBeAg-negative population. Network meta-analysis (NMA) was performed to synthesize evidence on the efficacy of treatment. RESULTS Forty-two publications were selected. Twenty-three evaluated HBeAg-positive population, 13 evaluated HBeAg-negative population, and six evaluated both. We applied NMA to the efficacy outcomes of the two populations separately. Treatment strategies were ranked by the probability of achieving outcomes, and pairwise comparisons calculated from NMA were reported in odds ratios (OR). For HBeAg-positive population, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) were the best for VR; OR vs adefovir = 14.29, 95% CI 7.69-25 and 12.5, 95% CI 4.35-33.33 respectively. TAF was the best for achieving ALT norm (OR vs placebo = 12.5, 95% CI 4.55-33.33), HBeAg loss, and seroconversion (OR vs entecavir/TDF combination = 3.03, 95% CI 1.04-8.84 and 3.33, 95% CI 1.16-10 respectively). In the HBeAg-negative population, TDF and TAF were the best for VR (OR vs adefovir = 9.79, 95% CI 2.38-42.7 and 11.71, 95% CI 1.03-150.48 respectively). Telbivudine and TAF were the best for ALT norm. Certain nucleos(t)ide combinations also had high probability of achieving positive outcomes. CONCLUSIONS Our results are consonant with current clinical guidelines and other evidence reviews. For both HBeAg-positive and HBeAg-negative populations, TDF and TAF are the most effective agents for virologic suppression, and TAF is effective across all outcomes.
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Affiliation(s)
- William W L Wong
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada. .,University of Waterloo, School of Pharmacy, Waterloo, ON, Canada. .,University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON, Canada.
| | - Petros Pechivanoglou
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada.,The Hospital for Sick Children, Toronto, ON, Canada
| | - Josephine Wong
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada
| | - Joanna M Bielecki
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada
| | - Alex Haines
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada
| | - Aysegul Erman
- University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON, Canada
| | - Yasmin Saeed
- University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON, Canada
| | - Arcturus Phoon
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada
| | - Mina Tadrous
- University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON, Canada.,The Ontario Drug Policy Research Network, St. Michael's Hospital, Toronto, ON, Canada
| | - Mona Younis
- University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON, Canada
| | - Noha Z Rayad
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada.,BioPharma Services Inc, Toronto, ON, Canada
| | - Valeria Rac
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada.,Ted Rogers Centre for Heart Research at Peter Munk Cardiac Centre, Toronto General Hospital Research Institute (TGHRI), University Health Network (UHN), Toronto, Canada.,Institute of Health Policy, Management and Evaluation (IHPME), Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.,Diabetes Action Canada, CIHR SPOR Network, Toronto, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada
| | - Murray D Krahn
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University of Toronto and University Health Network, Toronto, ON, Canada.,University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, ON, Canada
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Lee HW, Park JY, Ahn SH. An evaluation of entecavir for the treatment of chronic hepatitis B infection in adults. Expert Rev Gastroenterol Hepatol 2016; 10:177-86. [PMID: 26610256 DOI: 10.1586/17474124.2016.1125781] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Entecavir is a nucleoside analogue of 2'-deoxyguanosine whose intracellular triphosphate form inhibits replication of the hepatitis B virus. Entecavir is recommended as a first-line monotherapy option for nucleos(t)ide-naïve patients with HBeAg-positive or -negative chronic hepatitis B infection. Entecavir has a three-step mechanism of action: It maintains viral suppression with a greater than 90% chance of undetectable hepatitis B virus DNA during continuous therapy, improves liver histology, and reduces the risk of liver failure or hepatocellular carcinoma development. The safety profile of long-term entecavir therapy is favorable; however, its optimal treatment duration is unknown. Entecavir monotherapy is not a rescue option for patients with lamivudine/adefovir resistance or baseline lamivudine-resistant mutants; rather, combination treatment is recommended for patients with lamivudine/adefovir resistance.
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Affiliation(s)
- Hye Won Lee
- a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.,b Yonsei Liver Center , Severance hospital , Seoul , Korea
| | - Jun Yong Park
- a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.,b Yonsei Liver Center , Severance hospital , Seoul , Korea.,c Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Korea
| | - Sang Hoon Ahn
- a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.,b Yonsei Liver Center , Severance hospital , Seoul , Korea.,c Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Korea.,d Brain Korea 21 Project for Medical Science , Seoul , Korea
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Chen EQ, Dai J, Bai L, Tang H. The efficacy of zinc finger antiviral protein against hepatitis B virus transcription and replication in tansgenic mouse model. Virol J 2015; 12:25. [PMID: 25889209 PMCID: PMC4334851 DOI: 10.1186/s12985-015-0245-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 01/19/2015] [Indexed: 02/05/2023] Open
Abstract
Aim The zinc finger antiviral protein (ZAP) is a mammalian host restriction factor, and it could inhibit HBV RNA synthesis in vitro experiments. However, the role of ZAP against HBV in vivo environment is unclear. This study aimed to investigate whether ZAP could act against HBV transcription and replication in ZAP tansgenic mouse model. Methods HBV-replication-competent plasmid pHBV4.1 was transferred to ZAP transgenic ICR mouse via the tail vein using a hydrodynamic in vivo transfection procedure, and ICR mouse were used as controls. HBV RNA and HBV DNA replication intermediates in the liver were respectively analyzed by Northern blotting and Southern blotting. The expression of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) in the liver tissue was detected by immunohistochemical staining. Results As compared to ICR control mouse, the levels of 3.5 kb mRNA in ZAP transgenic mouse were decreased by 8.4%; while the level of HBV DNA replication intermediates was decreased by 82%. In addition, the expression of HBsAg and HBcAg in ZAP transgenic mouse liver were both significantly less than that of ICR control mouse. Conclusions Our findings suggest that ZAP could inhibit HBV replication in vivo in mice, which offers a new target for anti-HBV drug development.
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Affiliation(s)
- En-Qiang Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China. .,Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610041, China.
| | - Jie Dai
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China. .,Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610041, China.
| | - Lang Bai
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China. .,Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610041, China.
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China. .,Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 610041, China.
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Ahn SS, Chon YE, Kim BK, Kim SU, Kim DY, Ahn SH, Han KH, Park JY. Tenofovir disoproxil fumarate monotherapy for nucleos(t)ide-naïve chronic hepatitis B patients in Korea: data from the clinical practice setting in a single-center cohort. Clin Mol Hepatol 2014; 20:261-6. [PMID: 25320729 PMCID: PMC4197174 DOI: 10.3350/cmh.2014.20.3.261] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 09/02/2014] [Accepted: 09/11/2014] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND/AIMS This study assessed the antiviral efficacy and safety of tenofovir disoproxil fumarate (TDF) for up to 12 months in Korean treatment-naïve chronic hepatitis B (CHB) patients. METHODS A total of 411 treatment-naïve CHB patients who had been treated with TDF for at least 3 months (median 5.6) were consecutively enrolled. Clinical, biochemical, virological parameters and treatment adherence were routinely assessed every 3 months. RESULTS The median age was 51.3 years, 63.0% of the patients were male, 49.6% were HBeAg (+), and 210 patients had liver cirrhosis. The median baseline HBV DNA was 5.98 (SD 1.68) log10 IU/mL. Among the patients completing week 48, 83.3% had a complete virologic response (CVR, <12 IU/mL by HBV PCR assay), and 88.2% had normalized levels of alanine aminotransferase (ALT). The cumulative probabilities of CVR at 3, 6, 9 and 12 months were 22.8%, 53.1%, 69.3% and 85.0%. During the follow-up period, 9.8% patients achieved HBeAg loss and 7.8% patients achieved HBeAg seroconversion. There was no virological breakthrough after initiating TDF. The most common TDF-related adverse event was gastrointestinal upset, and three patients discontinued TDF therapy. However, no serious life-threatening side effect was noted. CONCLUSIONS In a clinical practice setting, TDF was safe and highly effective when administered for 12 months to Korean treatment-naïve CHB patients.
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Affiliation(s)
- Sung Soo Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Young Eun Chon
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. ; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. ; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. ; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. ; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. ; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. ; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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Chen EQ, Tang H. Optimization therapy for the treatment of chronic hepatitis B. World J Gastroenterol 2014; 20:5730-5736. [PMID: 24914334 PMCID: PMC4024783 DOI: 10.3748/wjg.v20.i19.5730] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 12/17/2013] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) is currently medically managed with either interferon-alpha or one of the five nucleos(t)ide analogs. However, there are still a large number of CHB patients whose response to the above therapies remains less than satisfactory, and their incomplete or non-response to antiviral therapies has plagued clinicians worldwide. In recent years, a newly proposed optimization therapy has provided us with a new approach to solve this problem. The key points in this optimization therapy are to initiate antiviral therapy with an appropriate agent at the correct time point, and to adjust treatments in patients with poor early responses by adding a second agent or switching to another more potent agent. In this review, we summarize recent developments in optimization therapy for the treatment of CHB, and provide an outlook for future research in this field.
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Chon YE, Park JY, Ahn SH, Kim DY, Han KH, Chon CY, Choi A, Kim SU. Partial virological response to adefovir add-on lamivudine rescue therapy in patients with lamivudine-resistant chronic hepatitis B. Digestion 2014; 87:196-203. [PMID: 23689059 DOI: 10.1159/000348853] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Accepted: 02/12/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS In patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB) receiving adefovir (ADV) add-on LAM therapy, insufficient viral suppression or the appearance of additional ADV resistance has remained unresolved. This study determined the partial virological response (PVR) criteria to predict a virological response (VR) at week 96 in these patients. METHODS 96 patients with LAM-resistant CHB (ADV add-on LAM therapy >2 years) were analyzed. For predicting VR at week 96, the area under the receiver operating characteristic curve values at different time points were compared to establish the optimal time point, and the maximal Youden index was calculated to determine the optimal cut-off hepatitis B virus (HBV) DNA level. RESULTS 50 (52.1%) patients achieved VR at 2 years after ADV add-on LAM therapy. The optimal PVR criteria were determined to be HBV DNA 500 IU/ml at week 48. 44 (45.8%) patients who met optimal PVR criteria showed a significantly higher risk for detectable HBV DNA levels at week 96 than those with a favorable VR (HBV DNA <500 IU/ml) at week 48. CONCLUSIONS This study suggested optimal PVR criteria in patients with LAM-resistant CHB receiving ADV add-on LAM therapy. Modification of the antiviral agent regimen should be considered if the serum HBV DNA level exceeds 500 IU/ml at week 48.
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Affiliation(s)
- Young Eun Chon
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Park H, Park JY, Kim SU, Kim DY, Han KH, Chon CY, Ahn SH. Efficacy of switching to telbivudine plus adefovir in suboptimal responders to lamivudine plus adefovir. World J Gastroenterol 2013; 19:7671-7679. [PMID: 24431895 PMCID: PMC3837266 DOI: 10.3748/wjg.v19.i43.7671] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2013] [Revised: 08/11/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the efficacy of telbivudine (LdT) + adefovir (ADV) vs continuation of lamivudine (LAM) + ADV in patients with LAM-resistant chronic hepatitis B (CHB) who show a suboptimal response to LAM + ADV.
METHODS: This was a randomized, active-control, open-label, single-center, parallel trial. All eligible patients were enrolled in this study in Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea, between March 2010 and March 2011. Hepatitis Be antigen (HBeAg)-positive CHB patients whose serum hepatitis B virus (HBV) DNA remained detectable despite at least 6 mo of LAM + ADV therapy were included. Enrolled patients were randomized to either switching to LdT (600 mg/d orally) plus ADV (10 mg/d orally) (LdT + ADV group) or to continuation with LAM (100 mg/d orally) plus ADV (10 mg/d orally) (LAM + ADV group), and were followed for 48 wk. One hundred and six patients completed the 48-wk treatment period. Serum HBV DNA, HBeAg status, liver biochemistry and safety were monitored at baseline and week 12, 24, 36 and 48.
RESULTS: The duration of prior LAM + ADV treatment was 18.3 (LdT + ADV) and 14.9 mo (LAM + ADV), respectively (P = 0.131). No difference was seen in baseline serum HBV DNA between the two groups [3.66 (LdT + ADV) vs 3.76 (LAM + ADV) log10 IU/mL, P = 0.729]. At week 48, although there was no significant difference in the mean reduction of serum HBV DNA from baseline between LdT + ADV group and LAM + ADV group (-0.81 vs -0.47 log10 IU/mL, P = 0.167), more patients in the LdT + ADV group had undetectable HBV DNA levels compared to those in the LAM + ADV group (30.2% vs 11.5%, P = 0.019). Three patients with LdT + ADV treatment and 2 patients with LAM + ADV treatment achieved HBeAg loss. The patients in both groups tolerated the treatment well without serious adverse events. The proportion of patients with estimated glomerular filtration rate ≥ 90 mL/min per 1.73 m2 in the LdT + ADV group increased from 49.1% (26/53) at baseline to 58.5% (31/53) at week 48, while that in the LAM + ADV group decreased from 37.7% (20/53) at baseline to 30.2% (16/53) at week 48.
CONCLUSION: The switch to LdT + ADV in suboptimal responders to LAM + ADV showed a significantly higher rate of virologic response at week 48. These results suggest that LdT + ADV could be a therapeutic option for patients who are unable to use enofovir disoproxil fumarate for any reason.
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Kwon DH, Kim IH, Choung BS, Ahn DS, Yoo SH, Park SB, Lee S, Kim SH, Kim SW, Im YJ. Continuous long-term entecavir therapy in naïve chronic hepatitis B patients showing partial virologic response. Gut Liver 2013; 7:712-8. [PMID: 24312713 PMCID: PMC3848542 DOI: 10.5009/gnl.2013.7.6.712] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 03/20/2013] [Accepted: 03/27/2013] [Indexed: 12/18/2022] Open
Abstract
Background/Aims We investigated the efficacy of continuous long-term entecavir 0.5 mg treatment in naïve chronic hepatitis B patients showing a partial virologic response (PVR). Methods A total of 227 patients were included. PVR was defined as a more than 1 log10 IU/mL decline in detectable serum hepatitis B virus (HBV) DNA by polymerase chain reaction (PCR; ≥20 IU/mL) at week 48. A complete virologic response (CVR) was defined as undetectable serum HBV DNA by PCR (<20 IU/mL) at week 48. Results At week 48, the rate of the PVR was 64/227 (28.2%). Among patients with PVR, the cumulative rates of virologic response (serum HBV DNA <20 IU/mL) at weeks 96 and 144 were 45.2% and 73.8%, respectively. The cumulative rates of genotypic resistance were not significantly different between patients with a PVR and patients with a CVR (p=0.057). However, the cumulative rates of virologic breakthrough were higher in patients with PVR than in patients with CVR (4% vs 0% and 11.2% vs 0% at weeks 96 and 144, respectively; p<0.001). Conclusions Long-term continuous entecavir 0.5 mg treatment in patients with a PVR resulted in an additional virologic response without a significant increase in genotypic resistance. However, the rate of virologic breakthrough was higher in the partial responders.
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Affiliation(s)
- Dae Hun Kwon
- Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, Korea
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Jun DW, Kim BI, Cho YK, Kim HJ, Kwon YO, Park SY, Han SY, Baek YH, Jung YJ, Kim HY, Kim W, Heo J, Woo HY, Hwang SG, Rim KS, Choi JY, Bae SH, Lee YS, Lim YS, Cheong JY, Cho SW, Lee BS, Kim SH, Sohn JH, Kim TY, Paik YH, Kim JK, Lee KS. Efficacy and safety of entecavir plus carnitine complex (GODEX®) compared to entecavir monotherapy in patient with ALT elevated chronic hepatitis B: randomized, multicenter open-label trials. The GOAL study. Clin Mol Hepatol 2013; 19:165-72. [PMID: 23837141 PMCID: PMC3701849 DOI: 10.3350/cmh.2013.19.2.165] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Revised: 05/31/2013] [Accepted: 06/03/2013] [Indexed: 02/07/2023] Open
Abstract
Background/Aims Carnitine and vitamin complex (Godex®) is widely used in patients with chronic liver disease who show elevated liver enzyme in South Korea. The purpose of this study is to identify the efficacy and safety of carnitine from entecavir combination therapy in Alanine aminotransferase (ALT) elevated Chronic Hepatitis B (CHB) patients. Methods 130 treatment-naïve patients with CHB were enrolled from 13 sites. The patients were randomly selected to the entecavir and the complex of entecavir and carnitine. The primary endpoint of the study is ALT normalization level after 12 months. Results Among the 130 patients, 119 patients completed the study treatment. The ALT normalization at 3 months was 58.9% for the monotherapy and 95.2% for the combination therapy (P<0.0001). ALT normalization rate at 12 months was 85.7% for the monotherapy and 100% for the combination group (P=0.0019). The rate of less than HBV DNA 300 copies/mL at 12 months was not statistically significant (P=0.5318) 75.9% for the monotherapy, 70.7% for the combination and it was. Quantification of HBsAg level was not different from the monotherapy to combination at 12 months. Changes of ELISPOT value to evaluate the INF-γ secretion by HBsAg showed the increasing trend of combination therapy compare to mono-treatment. Conclusions ALT normalization rate was higher in carnitine complex combination group than entecavir group in CHB. Combination group was faster than entecavir mono-treatment group on ALT normalization rate. HBV DNA normalization rate and the serum HBV-DNA level were not changed by carnitine complex treatment.
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Affiliation(s)
- Dae Won Jun
- Department of Internal medicine, Hanyang University College of Medicine, Seoul, Korea
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Heo J, Park JY, Lee HJ, Tak WY, Um SH, Kim DY, Yoon KT, Park SY, Seo YS, Han KH, Cho M, Ahn SH. A 96-week randomized trial of switching to entecavir in chronic hepatitis B patients with a partial virological response to lamivudine. Antivir Ther 2013; 17:1563-70. [PMID: 22872647 DOI: 10.3851/imp2277] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/09/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Growing numbers of chronic hepatitis B (CHB) patients in the Asia-Pacific region have failed first-line therapy with low genetic barrier drugs. This prospective, 96-week study investigated the antiviral efficacy, safety and tolerability of switching to entecavir versus maintaining lamivudine in CHB patients with a partial virological response to lamivudine. METHODS A total of 72 hepatitis B e antigen (HBeAg)-positive patients, with serum HBV DNA≥60 IU/ml after ≥6 months lamivudine monotherapy were randomized 1:1 to receive either entecavir 1.0 mg/day, or continued lamivudine 100 mg/day. RESULTS Mean duration of prior lamivudine treatment was 15.1 months in the lamivudine-maintained patients and 16.1 months in the entecavir-switch patients, with mean baseline HBV DNA levels of 4.66 and 4.55 log(10) IU/ml, respectively. A greater proportion of entecavir-switch than lamivudine-maintained patients achieved undetectable HBV DNA at all time points (67.6% versus 11.4% at week 96; P<0.001). Entecavir-switch patients achieved a greater mean decrease in HBV DNA level by week 4, maintained through week 96. Entecavir-switch patients with baseline HBV DNA<5 log(10) IU/ml were more likely to achieve a virological response at week 96. A total of 6 (17.6%) entecavir-switch and 2 (5.7%) lamivudine-maintained patients achieved HBeAg loss, and 3 (8.8%) entecavir and 1 (2.9%) lamivudine patients achieved HBeAg seroconversion. Genotypic resistance to the assigned intervention emerged in 82.9% (29/35) of lamivudine-maintained patients, and in 3% (1/34) of entecavir-switch patients after 96 weeks. CONCLUSIONS Switching to entecavir in patients with a partial virological response to lamivudine resulted in increased virological efficacy and lower rates of antiviral resistance than maintaining lamivudine.
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Affiliation(s)
- Jeong Heo
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Republic of Korea
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Park MS, Kim BK, Kim KS, Kim JK, Kim SU, Park JY, Kim DY, Baartarkhuu O, Han KH, Chon CY, Ahn SH. Antiviral efficacies of currently available rescue therapies for multidrug-resistant chronic hepatitis B. Clin Mol Hepatol 2013; 19:29-35. [PMID: 23593607 PMCID: PMC3622853 DOI: 10.3350/cmh.2013.19.1.29] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2012] [Revised: 10/19/2012] [Accepted: 11/02/2012] [Indexed: 01/03/2023] Open
Abstract
Background/Aims The incidence of multidrug-resistant (MDR) chronic hepatitis B (CHB) during sequential lamivudine (LAM) and adefovir dipivoxil (ADV) treatment is increasing. We investigated the antiviral efficacies of various rescue regimens in patients who failed sequential LAM-ADV treatment. Methods Forty-eight patients (83.3% of whom were HBeAg-positive) who failed sequential LAM-ADV treatment were treated with one of the following regimens: entecavir (ETV) (1 mg) monotherapy (n=16), LAM+ADV combination therapy (n=20), or ETV (1 mg)+ADV combination therapy (n=12). All patients had confirmed genotypic resistance to both LAM and ADV and were evaluated every 12 weeks. Results The baseline characteristics and treatment duration did not differ significantly among the study groups. During the treatment period (median duration: 100 weeks), the decline of serum HBV DNA from baseline tended to be greatest in the ETV+ADV group at all-time points (week 48: -2.55 log10 IU/mL, week 96: -4.27 log10 IU/mL), but the difference was not statistically significant. The ETV+ADV group also tended to have higher virologic response rates at 96 weeks compared to the ETV monotherapy or LAM+ADV groups (40.0% vs. 20.0% or 20.0%, P=0.656), and less virologic breakthrough was observed compared to the ETV monotherapy or LAM+ADV groups (8.3% vs. 37.5% or 30.0%; P=0.219), but again, the differences were not statistically significant. HBeAg loss occurred in one patient in the ETV+ADV group, in two in the ETV monotherapy group, and in none of the LAM+ADV group. The safety profiles were similar in each arm. Conclusions There was a nonsignificant tendency toward better antiviral efficacy with ETV+ADV combination therapy compared to LAM+ADV combination therapy and ETV monotherapy for MDR CHB in Korea, where tenofovir is not yet available.
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Affiliation(s)
- Mi Sung Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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13
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Luo J, Li X, Wu Y, Lin G, Pang Y, Zhang X, Ao Y, Du Z, Zhao Z, Chong Y. Efficacy of entecavir treatment for up to 5 years in nucleos(t)ide-naïve chronic hepatitis B patients in real life. Int J Med Sci 2013; 10:427-33. [PMID: 23471472 PMCID: PMC3590603 DOI: 10.7150/ijms.5472] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 02/22/2013] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE To analyze the efficacy and safety of entecavir (ETV) treatment for up to 5 years in nucleos(t)ide-naïve chronic hepatitis B patients in real life. METHODS We retrospectively analyzed 230 nucleos(t)ide naïve chronic hepatitis B patients who received ETV 0.5 mg/day monotherapy for at least 3 months, of whom 113 were HBeAg positive and 117 were HBeAg negative. The primary endpoints was cumulative probability of achieving a virological response (undetectable serum HBV DNA, <100IU/mL). Secondary endpoints were rates of ALT normalization (ALT < upper limit of normal), HBeAg seroconversion, resistance, and safety. RESULTS The median follow-up duration was 27.5 months (3-73 months) and mean age was 42 years. With 230, 214, 180, 142, 88, 42 and 11 patients followed-up for at least 3 months,6 months, 1, 2, 3, 4 and 5 years, respectively. In all, Incremental increases were observed in the rates of undetectable HBV DNA. 67.0%, 85.0%, 89.4%, 94.4%, 95.5%, 97.6%, 100% had undetectable HBV DNA at month 3, month 6, 1 year, 2 years, 3 years, 4 years and 5 years. Proportions of patients achieving normal ALT were 73.9%, 85.5%, 82.8%, 89.4%, 80.7%, 85.7%, 100%, respectively. The rate of HBeAg seroconversion reached 21.4% and 15.4% at year2, 3, respectively. One patient achieved HBsAg seroclearance after 1 year, and achieved anti-HBs seroconversion at year 3. Of 180 patients, HBV DNA was detectable (partial virological response, PVR) in 19 patients at year 1 of follow-up, twelve of 14 (85.7%) patients with PVR need more than 1 year of continuous ETV therapy to achieved VR. At baseline, no ETV-resistance was detected in 25 ETV-naïve patients. One patient developed ETV-resistance mutations due to noncompliance. No serious adverse event was reported. CONCLUSION Long-term ETV treatment of nucleos(t)ide-naïve was effective and safe in real life. Adjustment of ETV monotherapy in nucleos(t)ide-naïve patients with a partial virological response at 1 year may be unnecessary.
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Affiliation(s)
- Jie Luo
- Department of Infectious Diseases, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
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14
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Shin HS, Kim SU, Park JY, Kim DY, Han KH, Chon CY, Baatarkhuu O, Ahn SH. Antiviral efficacy of lamivudine versus entecavir in patients with hepatitis B virus-related advanced hepatocellular carcinoma. J Gastroenterol Hepatol 2012; 27:1528-34. [PMID: 22497450 DOI: 10.1111/j.1440-1746.2012.07145.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM Little information is available about the antiviral efficacy of lamivudine (LAM) and entecavir (ETV) in patients with hepatitis B virus (HBV)-related advanced hepatocellular carcinoma (HCC). Thus, we compared the antiviral efficacy of LAM and ETV in these patients. METHODS The medical records of 134 antiviral therapy-naïve patients with HBV-related advanced HCC (modified Union for International Cancer Control [UICC] Tumor, Nodes, and Metastases [TNM] stages III-IV) treated between January 2005 and September 2009 were reviewed. After HCC diagnosis, 87 (64.9%) and 47 (35.1%) patients received LAM and ETV, respectively. RESULTS The mean age of patients (115 men, 19 women) was 53 years. Sixty-five (48.5%) and 69 (51.5%) patients had TNM stages III and IV HCC, respectively. Treatment outcomes during follow-up, including virologic, biochemical, and serologic responses and appearance of antiviral resistance, were similar in the LAM and ETV groups (all P>0.05). Multivariate analysis identified Child-Pugh class, α-fetoprotein, and TNM stage as independent predictors of overall survival (all P<0.05). Antiviral agent type (LAM vs ETV) did not influence overall survival (median 9.6 months in LAM vs 13.6 months in ETV group; P=0.493). HCC treatment was not interrupted due to HBV flare up in any patient. CONCLUSIONS The antiviral efficacy of LAM and ETV was similar and the type of antiviral agent did not influence overall survival in patients with HBV-related advanced HCC. Thus, LAM, which is less expensive than ETV in Korea, might be sufficient to control HBV in these patients.
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Affiliation(s)
- Hye Sun Shin
- Department of Internal Medicine, Yonsei University College of Medicine, Korea Institute of Gastroenterology, Yonsei University College of Medicine, Korea Liver Cirrhosis Clinical Research Center, Korea Brain Korea 21 Project for Medical Science, Seoul, Korea Department of Infectious Disease, Health Sciences University, Ulaanbaatar, Mongolia
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15
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Abstract
UNLABELLED The guideline on the management of chronic hepatitis B (CHB) was first developed in 2004 and revised in 2007 by the Korean Association for the Study of the Liver (KASL). Since then there have been many developments, including the introduction of new antiviral agents and the publications of many novel research results from both Korea and other countries. In particular, a large amount of knowledge on antiviral resistance--which is a serious issue in Korea--has accumulated, which has led to new strategies being suggested. This prompted the new guideline discussed herein to be developed based on recent evidence and expert opinion. TARGET POPULATION The main targets of this guideline comprise patients who are newly diagnosed with CHB and those who are followed or treated for known CHB. This guideline is also intended to provide guidance for the management of patients under the following special circumstances: malignancy, transplantation, dialysis, coinfection with other viruses, pregnancy, and children.
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MESH Headings
- Acute Disease
- Adolescent
- Adult
- Aged
- Alanine Transaminase/blood
- Antiviral Agents/therapeutic use
- Asian People
- Aspartate Aminotransferases/blood
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/etiology
- Child
- Child, Preschool
- Coinfection/drug therapy
- DNA, Viral/blood
- Drug Resistance, Viral
- Drug Therapy, Combination
- Female
- Hepatitis B Surface Antigens/blood
- Hepatitis B e Antigens/blood
- Hepatitis B virus/genetics
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/drug therapy
- Humans
- Immunosuppression Therapy
- Infectious Disease Transmission, Vertical/prevention & control
- Liver/pathology
- Liver/physiology
- Liver Cirrhosis/physiopathology
- Liver Neoplasms/diagnosis
- Liver Neoplasms/etiology
- Liver Transplantation
- Male
- Middle Aged
- Pregnancy
- Renal Dialysis
- Republic of Korea
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Song JC, Min BY, Kim JW, Kim JY, Kim YM, Shin CM, Lee SH, Hwang JH, Jeong SH, Kim N, Lee DH. Pretreatment serum HBsAg-to-HBV DNA ratio predicts a virologic response to entecavir in chronic hepatitis B. THE KOREAN JOURNAL OF HEPATOLOGY 2012; 17:268-73. [PMID: 22310791 PMCID: PMC3304662 DOI: 10.3350/kjhep.2011.17.4.268] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background/Aims Decay of hepatitis B surface antigen (HBsAg) titers has previously been shown to be predictive of a virologic response (VR), especially during peginterferon-alpha therapy. However, the role of HBsAg levels in predicting a VR to nucleos(t)ide analog therapy has not yet been established. In this study we sought to determine whether the VR can be predicted from HBsAg titers in nucleos(t)ide-naïve chronic hepatitis B (CHB) patients treated with entecavir. Methods CHB patients who started entecavir as an initial antiviral therapy were enrolled in this study. Serum hepatitis B virus (HBV) DNA, HBsAg, and alanine aminotransferase levels were measured every 3 months during treatment. A VR was defined as undetectable serum HBV DNA titer by real-time PCR assay (<60 IU/mL). Results Fifty-two patients were enrolled, and the median duration of treatment was 26 months (range 7-35 months). Forty-five patients achieved a VR; the cumulative VR rates at 3, 6, 12, and 24 months were 40%, 71.2%, 81.5%, and 88%, respectively. Baseline HBV DNA levels were significantly lower in patients with VR, whereas the HBsAg levels did not differ significantly between patients with or without VR. In a univariate analysis the cumulative VR rate was significantly higher in HBeAg negative patients and patients with an HBsAg/HBV DNA ratio above 0.56. However, in a multivariate analysis only an HBsAg/HBV DNA ratio above 0.56 was an independent predictor of VR (P=0.003). The area under the receiver operating characteristic curve was larger for the HBsAg/HBV DNA ratio than for either HBV DNA or HBsAg. Conclusions Pretreatment HBsAg/HBV DNA ratio can predict a long-term VR to entecavir therapy in nucleos(t)ide-naïve CHB patients.
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Affiliation(s)
- Joon Chang Song
- Department of Internal Medicine, Seoul National University College of Medicine, Seongnam, Korea
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17
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Partial Response to Entecavir and Tenofovir in Naïve Patients with Chronic Hepatitis B: Clinical Relevance and Management. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/s11901-012-0127-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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