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Susceptibility of Drug Resistant Hepatitis B Virus Mutants to Besifovir. Biomedicines 2022; 10:biomedicines10071637. [PMID: 35884942 PMCID: PMC9312910 DOI: 10.3390/biomedicines10071637] [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] [Received: 06/06/2022] [Revised: 07/04/2022] [Accepted: 07/04/2022] [Indexed: 12/02/2022] Open
Abstract
Currently, interferon alpha and nucleos(t)ide analogues (NAs) are clinically available to treat hepatitis B virus (HBV) infection. Several NAs, including lamivudine (LMV), adefovir (ADV), entecavir (ETV) and tenofovir (TDF or TAF) have been approved and administered to chronic hepatitis B (CHB) patients. NAs inhibit HBV DNA synthesis by targeting the reverse transcriptase (RT) domain of HBV polymerase. Several mutations in the RT domain which lead to drug resistance against NAs have been reported, even for TDF and TAF which are highly potent with very low resistance rate. Besifovir (BFV) is a new antiviral dGMP analogue able to be used as a new NA drug for the control of CHB infection. Drug resistance to BFV is not well known due to its shorter duration of clinical use. Recently, we reported that rtL180M (M) and rtM204V (V) mutations, already resistant to LMV, are associated with BFV resistance. However, the susceptibility to BFV of previously known HBV mutants resistant to various drugs has not been studied. To investigate this, we performed in vitro drug susceptibility assays using natural and artificial mutants that are associated with resistance to LMV, ADV, ETV or TDF. As a result, LMV-resistant mutants were not susceptible to BFV and ETV-resistant clones showed partial resistance against BFV as well. However, ADV-resistant mutants were highly sensitive to BFV. In case of tenofovir-resistant mutations, the HBV mutants harboring primary mutations to tenofovir resistance were susceptible to BFV. Therefore, our study revealed that BSV may serve as an alternative drug for patients with ADV-, ETV-, TDF- or TAF-resistance.
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Identification and Characterization of Besifovir-Resistant Hepatitis B Virus Isolated from a Chronic Hepatitis B Patient. Biomedicines 2022; 10:biomedicines10020282. [PMID: 35203489 PMCID: PMC8868672 DOI: 10.3390/biomedicines10020282] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/17/2022] [Accepted: 01/23/2022] [Indexed: 01/05/2023] Open
Abstract
Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B (CHB) infection is a major health problem with nearly 300 million individuals infected worldwide. Currently, nucleos(t)ide analogs (NAs) and interferon alpha are clinically approved treatments for HBV infection. NAs are potent antiviral agents that bind to HBV polymerase and block viral reverse transcription and replication. Besifovir dipivoxil maleate (BSV) is a newly developed NA against HBV in the form of acyclic nucleotide phosphonate that is available for oral administration similar to adefovir and tenofovir. Until now, resistance to BSV treatment has not been reported. In this study, we found a CHB patient who showed viral breakthrough after long-term treatment with BSV. The isolated HBV DNA from patient’s serum were cloned into the replication-competent HBV 1.2 mer and the sequence of reverse transcriptase (RT) domain of HBV polymerase were analyzed. We also examined the drug susceptibility of generated clones in vitro. Several mutations were identified in HBV RT domain. A particular mutant harboring ten RT mutations showed resistance to BSV treatment in vitro. The ten mutations include rtV23I (I), rtH55R (R), rtY124H (H), rtD134E (E), rtN139K (K), rtL180M (M), rtM204V (V), rtQ267L (L), rtL269I (I) and rtL336M (M). To further identify the responsible mutations for BSV resistance, we performed in vitro drug susceptibility assay on several artificial clones. As a result, our study revealed that rtL180M (M) and rtM204V (V) mutations, already known as lamivudine-resistant mutations, confer resistance to BSV in the CHB patient.
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Song JE, Park JY. Besifovir dipivoxil maleate: a novel antiviral agent with low toxicity and high genetic barriers for chronic hepatitis B. Expert Opin Pharmacother 2021; 22:2427-2433. [PMID: 34392744 DOI: 10.1080/14656566.2021.1967321] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Chronic hepatitis B is an important public health concern. Introduction of oral nucleos(t)ide analogs (NAs), inhibitors of hepatitis B virus (HBV) polymerase, was a milestone that lowered the high viral loads associated with an increased risk of liver-related complications. AREAS COVERED Although the currently available NAs are effective in suppressing viral replication, anti-HBV treatment in principle requires lifelong drug administration, and some patients have limitations such as the incidence of liver cancer and the likelihood of toxicities following long-term treatment despite viral suppression. Besifovir dipivoxil maleate (BSV), an oral nucleotide analog, is a prodrug that is metabolized to its active form. It has consistent and well-characterized pharmacokinetics in animals and human. In clinical studies, BSV exhibits significant and potent viral suppression of HBV replication with maintenance of antiviral efficacy for over 192 weeks without resistance, or renal and bone toxicities. Herein, the authors discuss the data of BSV and provide the reader with their expert opinion. EXPERT OPINION BSV is a newly developed antiviral agent against HBV. This new agent has strong antiviral activity with low toxicity and a high barrier to resistance. Because there is concern that patients treated with a high dose of BSV require carnitine supplementation, BSV with carnitine supplementation is recommended during antiviral therapy.
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Affiliation(s)
- Jeong Eun Song
- Department Of Internal Medicine, Daegu Catholic University School Of Medicine, Daegu, 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.,Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
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Groaz E, De Jonghe S. Overview of Biologically Active Nucleoside Phosphonates. Front Chem 2021; 8:616863. [PMID: 33490040 PMCID: PMC7821050 DOI: 10.3389/fchem.2020.616863] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 11/30/2020] [Indexed: 12/25/2022] Open
Abstract
The use of the phosphonate motif featuring a carbon-phosphorous bond as bioisosteric replacement of the labile P–O bond is widely recognized as an attractive structural concept in different areas of medicinal chemistry, since it addresses the very fundamental principles of enzymatic stability and minimized metabolic activation. This review discusses the most influential successes in drug design with special emphasis on nucleoside phosphonates and their prodrugs as antiviral and cancer treatment agents. A description of structurally related analogs able to interfere with the transmission of other infectious diseases caused by pathogens like bacteria and parasites will then follow. Finally, molecules acting as agonists/antagonists of P2X and P2Y receptors along with nucleotidase inhibitors will also be covered. This review aims to guide readers through the fundamentals of nucleoside phosphonate therapeutics in order to inspire the future design of molecules to target infections that are refractory to currently available therapeutic options.
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Affiliation(s)
- Elisabetta Groaz
- Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
| | - Steven De Jonghe
- Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
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Yim HJ, Kim W, Ahn SH, Yang JM, Jang JY, Kweon YO, Cho YK, Kim YJ, Hong GY, Kim DJ, Jung YK, Um SH, Sohn JH, Lee JW, Park SJ, Lee BS, Kim JH, Kim HS, Yoon SK, Kim MY, Lee KS, Lim YS, Lee WS, Han KH. Besifovir Dipivoxil Maleate 144-Week Treatment of Chronic Hepatitis B: An Open-Label Extensional Study of a Phase 3 Trial. Am J Gastroenterol 2020; 115:1217-1225. [PMID: 32355123 PMCID: PMC7402376 DOI: 10.14309/ajg.0000000000000605] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 02/26/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Chronic hepatitis B (CHB) remains a major worldwide public health concern. Besifovir dipivoxil maleate (BSV) is a new promising treatment for CHB. However, long-term efficacy and safety have not yet been evaluated. Therefore, the goal of the study is to determine the antiviral efficacy and safety of BSV treatment over a 144-week duration (BSV-BSV) in comparison with those of a sequential treatment with tenofovir disoproxil fumarate (TDF) followed by a 96-week duration BSV administration (TDF-BSV). METHODS After 48 weeks of a double-blind comparison between BSV and TDF treatments, patients continued the open-label BSV study. We evaluated antiviral efficacy and drug safety up to 144 weeks for BSV-BSV and TDF-BSV groups. The primary endpoint was a virological response (hepatitis B virus DNA < 69 IU/mL). RESULTS Among the 197 patients enrolled, 170 and 158 patients entered the second-year and third-year open-label phase extensional study, respectively, whereas 153 patients completed the 144-week follow-up. The virological response rate over the 144-week period was 87.7% and 92.1% in BSV-BSV and TDF-BSV groups, respectively (P = 0.36). The rates of ALT normalization and HBeAg seroconversion were similar between the groups. No drug-resistant mutations to BSV were noted. Bone mineral density and renal function were well preserved in the BSV-BSV group and were significantly improved after switching therapy in TDF-BSV patients. DISCUSSION This extensional study of a phase 3 trial (NCT01937806) suggests that BSV treatment is efficacious and safe for long-term use in treatment-naïve and TDF-experienced patients with CHB.
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Affiliation(s)
- Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jin Mo Yang
- Department of Internal Medicine, Catholic University Medical College St. Vincent, Suwon, Korea
| | - Jae Young Jang
- Department of Internal Medicine, College of Medicine, Soonchunhyang University, Seoul, Korea
| | - Yong Oh Kweon
- Department of Internal Medicine, Kyungpook National University College of Medicine, Daegu, Korea
| | - Yong Kyun Cho
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Gun Young Hong
- Department of Internal Medicine, Kwangju Christian Hospital, Gwangju, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Soon Ho Um
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Joo Hyun Sohn
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Jin Woo Lee
- Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea
| | - Sung Jae Park
- Department of Internal Medicine, Paik Hospital, Inje University, Busan, Korea
| | - Byung Seok Lee
- Department of Gastroenterology and Hepatology, Chungnam National University School of Medicine, Daejeon, Korea
| | - Ju Hyun Kim
- Department of Internal Medicine, Gacheon University College of Medicine, Incheon, Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Seung Kew Yoon
- Department of Internal Medicine, Catholic University of Korea, Seoul, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Kwan Sik Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Young Suk Lim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Wan Sik Lee
- Department of Internal Medicine, Chonnam University Medical School, Gwangju, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Pierra Rouviere C, Dousson CB, Tavis JE. HBV replication inhibitors. Antiviral Res 2020; 179:104815. [PMID: 32380149 PMCID: PMC7293572 DOI: 10.1016/j.antiviral.2020.104815] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 04/22/2020] [Accepted: 04/28/2020] [Indexed: 12/21/2022]
Abstract
Chronic Hepatitis B Virus infections afflict >250 million people and kill nearly 1 million annually. Current non-curative therapies are dominated by nucleos(t)ide analogs (NAs) that profoundly but incompletely suppress DNA synthesis by the viral reverse transcriptase. Residual HBV replication during NA therapy contributes to maintenance of the critical nuclear reservoir of the HBV genome, the covalently-closed circular DNA, and to ongoing infection of naive cells. Identification of next-generation NAs with improved efficacy and safety profiles, often through novel prodrug approaches, is the primary thrust of ongoing efforts to improve HBV replication inhibitors. Inhibitors of the HBV ribonuclease H, the other viral enzymatic activity essential for viral genomic replication, are in preclinical development. The complexity of HBV's reverse transcription pathway offers many other potential targets. HBV's protein-priming of reverse transcription has been briefly explored as a potential target, as have the host chaperones necessary for function of the HBV reverse transcriptase. Improved inhibitors of HBV reverse transcription would reduce HBV's replication-dependent persistence mechanisms and are therefore expected to become a backbone of future curative combination anti-HBV therapies.
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Affiliation(s)
| | - Cyril B Dousson
- Ai-biopharma, Medicinal Chemistry Department, Montpellier, France.
| | - John E Tavis
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
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Spyrou E, Smith CI, Ghany MG. Hepatitis B: Current Status of Therapy and Future Therapies. Gastroenterol Clin North Am 2020; 49:215-238. [PMID: 32389360 PMCID: PMC7444867 DOI: 10.1016/j.gtc.2020.01.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Despite the availability of a protective vaccine for over 3 decades, the number of persons with chronic hepatitis B virus (HBV) infection remains high. These persons are at risk for cirrhosis and hepatocellular carcinoma. Current treatment is effective at inhibiting viral replication and reducing complications of chronic HBV infection, but is not curative. There is a need for novel, finite therapy that can cure chronic HBV infection. Several agents are in early-phase development and can be broadly viewed as agents that target the virus directly or indirectly or the host immune response. This article highlights key developments in antiviral/immunomodulatory therapy, the rationale for these approaches, and possible therapeutic regimens.
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Affiliation(s)
- Elias Spyrou
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC, USA,Nazih Zuhdi Transplant Institute, INTEGRIS Baptist Medical Center, Oklahoma City, OK, USA
| | - Coleman I. Smith
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC, USA
| | - Marc G. Ghany
- Liver Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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Jung YW, Kim M, Kim BK, Park JY, Kim DY, Ahn SH, Han KH, Kim SU. Influence of Besifovir Dipivoxil Maleate Combined with L-Carnitine on Hepatic Steatosis in Patients with Chronic Hepatitis B. J Korean Med Sci 2020; 35:e104. [PMID: 32356416 PMCID: PMC7200179 DOI: 10.3346/jkms.2020.35.e104] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 02/26/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Besifovir dipivoxil maleate (BSV) with L-carnitine is the first-line antiviral agent for chronic hepatitis B (CHB) infection. We investigated whether BSV combined with L-carnitine improves hepatic steatosis (HS). METHODS Treatment-naïve patients with CHB who were initiated on antiviral therapy (AVT) were enrolled. The magnitude of HS was assessed using hepatic steatosis index (HSI), and HS improvement was defined as a ≥ 10% reduction in the HSI score from the baseline. RESULTS The mean age of the study patients was 56 years with a male predominance (n = 178, 64.7%). The mean body mass index (BMI), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelet count were 23.5 kg/m², 49.6 IU/L, 49.0 IU/L, and 191.3 × 10⁹/L, respectively. The mean HSI and fibrosis (FIB)-4 index were 32.6 and 0.5, respectively. After 6 months of AVT, platelet count (mean, 191.3→167.0 × 10⁹/L), fasting glucose (mean, 113.1→105.9 mg/dL), AST (mean, 49.6→28.0 IU/L), ALT (mean, 49.0→33.9 IU/L), and total cholesterol (mean, 170.0→162.1 mg/dL) levels significantly decreased (all P < 0.05). In the BSV group, AST (mean, 95.2→30.2 IU/L) and ALT (mean, 81.1→31.1 IU/L) levels significantly reduced (all P < 0.05), whereas HSI and FIB-4 index were maintained (all P > 0.05). In the univariate analysis, age, BMI, diabetes, cirrhosis, fasting glucose level, and ALT were significantly associated with HS improvement (all P < 0.05). CONCLUSION BSV with L-carnitine did not show any improvement of HS in patients with CHB. Further prospective randomized controlled studies are needed to validate the potential beneficial effects of BSV with L-carnitine in CHB infection.
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Affiliation(s)
- Yeon Woo Jung
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Moonhyun Kim
- 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
- Yonsei Liver Center, Severance Hospital, 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
- Yonsei Liver Center, Severance Hospital, 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
- Yonsei Liver Center, Severance Hospital, 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
- Yonsei Liver Center, Severance Hospital, 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
- Yonsei Liver Center, Severance Hospital, 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
- Yonsei Liver Center, Severance Hospital, Seoul, Korea.
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9
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Ahn SH, Kim W, Jung YK, Yang JM, Jang JY, Kweon YO, Cho YK, Kim YJ, Hong GY, Kim DJ, Um SH, Sohn JH, Lee JW, Park SJ, Lee BS, Kim JH, Kim HS, Yoon SK, Kim MY, Yim HJ, Lee KS, Lim YS, Lee WS, Park NH, Jin SY, Kim KH, Choi W, Han KH. Efficacy and Safety of Besifovir Dipivoxil Maleate Compared With Tenofovir Disoproxil Fumarate in Treatment of Chronic Hepatitis B Virus Infection. Clin Gastroenterol Hepatol 2019; 17:1850-1859.e4. [PMID: 30448598 DOI: 10.1016/j.cgh.2018.11.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 10/24/2018] [Accepted: 11/02/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Besifovir dipivoxil maleate (BSV) has activity against hepatitis B virus (HBV). We performed a phase 3 study to compare the antiviral efficacy and safety of BSV vs tenofovir disoproxil fumarate (TDF) in patients with chronic HBV infection in Korea. METHODS We conducted a double-blind, non-inferiority trial of 197 patients with chronic HBV infection at 22 sites in South Korea, from November 2013 through February 2016. Patients were randomly assigned to groups given BSV (150 mg, n = 99) or TDF (300 mg, n = 98) for 48 weeks. We evaluated virologic responses to therapy (HBV DNA <69 IU/mL or 400 copies/ml), bone mineral density (BMD), and renal outcomes for safety analysis. The main efficacy endpoint was the proportion of patients with a virologic response at week 48. After 48 weeks, TDF was switched to BSV (150 mg) for an additional 48 weeks. RESULTS After 48 weeks of treatment, 80.9% of patients given BSV and 84.9% of patients given TDF met the efficacy endpoint, indicating the non-inferiority of BSV to TDF. At week 96, 87.2% of patients in the BSV-BSV and 85.7% of patients in the TDF-BSV had a virologic response. At week 48, changes in hip and spine BMD differed significantly between the BSV and TDF groups, whereas the estimated glomerular filtration rate in the TDF group was significantly lower than that in the BSV group. However, at 96 weeks, there were no significant differences in BMD and estimated glomerular filtration rate between the BSV-BSV and TDF-BSV groups. CONCLUSIONS BSV has antiviral efficacy comparable to that of TDF after 48 weeks of treatment, with durable effects for 96 weeks. BSV has a better safety profile than TDF, in terms of bone and renal outcomes. ClinicalTrials.gov no: NCT01937806.
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Affiliation(s)
- Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jin Mo Yang
- Department of Internal Medicine, Catholic University Medical College St Vincent's Hospital, Suwon, Korea
| | - Jae Young Jang
- Department of Internal Medicine, College of Medicine, Soonchunhyang University, Seoul, Korea
| | - Yong Oh Kweon
- Department of Internal Medicine, Kyungpook National University College of Medicine, Daegu, Korea
| | - Yong Kyun Cho
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Gun Young Hong
- Department of Internal Medicine, Kwangju Christian Hospital, Gwangju, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Soon Ho Um
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Joo Hyun Sohn
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Jin Woo Lee
- Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea
| | - Sung Jae Park
- Department of Internal Medicine, Paik Hospital, Inje University, Pusan, Korea
| | - Byung Seok Lee
- Department of Gastroenterology and Hepatology, Chungnam National University School of Medicine, Daejeon, Korea
| | - Ju Hyun Kim
- Department of Internal Medicine, Gacheon University College of Medicine, Incheon, Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Seung Kew Yoon
- Department of Internal Medicine, Catholic University of Korea, Seoul, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Kwan Sik Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Young Suk Lim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Wan Sik Lee
- Department of Internal Medicine, Chonnam University Medical School, Gwangju, Korea
| | - Neung Hwa Park
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan, Korea
| | - So Young Jin
- Department of Internal Medicine, College of Medicine, Soonchunhyang University, Seoul, Korea
| | - Kyun-Hwan Kim
- Department of Pharmacology, School of Medicine, Konkuk University, Korea
| | - Won Choi
- Ildong Pharmaceutical Co, Ltd, Seoul, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
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Abstract
An estimated 240 million people worldwide are chronically infected with the hepatitis B virus (HBV). Despite readily available vaccination, HBV infections remain highly prevalent. As established HBV infections constitute a strong risk factor for developing hepatocellular carcinoma their treatment is a major task for the health system. Unfortunately, HBV is not curable with today's medicine. Approximately 15 million HBV patients have developed a hepatitis delta (HDV) infection on top of their HBV infection. The patients superinfected with this satellite virus suffer from a more severe disease development. The knowledge of the viruses, their classifications, clinical implications, treatment options and efforts to increase the drug variety are compiled in this review. The current standard therapies include nucleosidic reverse transcriptase inhibitors and interferon. As the known treatments fail to cure HBV and HDV, targeted treatment is highly warranted. The focus of this review is set on the drugs currently under clinical investigation. Furthermore, strategies for the development of targeted treatment, and compounds with novel mode of action are described.
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Abstract
With high morbidity and mortality worldwide, there is great interest in effective therapies for chronic hepatitis B (CHB) virus. There are currently several dozen investigational agents being developed for treatment of CHB. They can be broadly divided into two categories: (1) direct-acting antivirals (DAAs) that interfere with a specific step in viral replication; and (2) host-targeting agents that inhibit viral replication by modifying host cell function, with the latter group further divided into the subcategories of immune modulators and agents that target other host functions. Included among the DAAs being developed are RNA interference therapies, covalently closed circular DNA (cccDNA) formation and transcription inhibitors, core/capsid inhibitors, reverse transcriptase inhibitors, hepatitis B surface antigen (HBsAg) release inhibitors, antisense oligonucleotides, and helioxanthin analogues. Included among the host-targeting agents are entry inhibitors, cyclophilin inhibitors, and multiple immunomodulatory agents, including Toll-like receptor agonists, immune checkpoint inhibitors, therapeutic vaccines, engineered T cells, and several cytokine agents, including recombinant human interleukin-7 (CYT107) and SB 9200, a novel therapy that is believed to both have direct antiviral properties and to induce endogenous interferon. In this review we discuss agents that are currently in the clinical stage of development for CHB treatment as well as strategies and agents currently at the evaluation and discovery phase and potential future targets. Effective approaches to CHB may require suppression of viral replication combined with one or more host-targeting agents. Some of the recent research advances have led to the hope that with such a combined approach we may have a functional cure for CHB in the not distant future.
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Affiliation(s)
- Altaf Dawood
- Department of Internal Medicine, Section of Gastroenterology, University of Nevada School of Medicine, Las Vegas, NV, USA
| | - Syed Abdul Basit
- Department of Internal Medicine, Section of Gastroenterology, University of Nevada School of Medicine, Las Vegas, NV, USA
| | - Mahendran Jayaraj
- Department of Internal Medicine, Section of Gastroenterology, University of Nevada School of Medicine, Las Vegas, NV, USA
| | - Robert G Gish
- Department of Internal Medicine, Section of Gastroenterology, University of Nevada School of Medicine, Las Vegas, NV, USA.
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA.
- Hepatitis B Foundation, Doylestown, PA, USA.
- Asian Pacific Health Foundation, San Diego, CA, USA.
- National Viral Hepatitis Roundtable, Washington, DC, USA.
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Feng S, Gao L, Han X, Hu T, Hu Y, Liu H, Thomas AW, Yan Z, Yang S, Young JAT, Yun H, Zhu W, Shen HC. Discovery of Small Molecule Therapeutics for Treatment of Chronic HBV Infection. ACS Infect Dis 2018; 4:257-277. [PMID: 29369612 DOI: 10.1021/acsinfecdis.7b00144] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The chronic infection of hepatitis B virus (HBV) inflicts 250 million people worldwide representing a major public health threat. A significant subpopulation of patients eventually develop cirrhosis and hepatocellular carcinoma (HCC). Unfortunately, none of the current standard therapies for chronic hepatitis B (CHB) result in a satisfactory clinical cure rate. Driven by a highly unmet medical need, multiple pharmaceutical companies and research institutions have been engaged in drug discovery and development to improve the CHB functional cure rate, defined by sustainable viral suppression and HBsAg clearance after a finite treatment. This Review summarizes the recent advances in the discovery and development of novel anti-HBV small molecules. It is believed that an improved CHB functional cure rate may be accomplished via the combination of molecules with distinct MoAs. Thus, certain molecules may evolve into key components of a suitable combination therapy leading to superior outcome of clinical efficacy in the future.
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Affiliation(s)
- Song Feng
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Lu Gao
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Xingchun Han
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Taishan Hu
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Yimin Hu
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Haixia Liu
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Andrew W. Thomas
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Zhipeng Yan
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Song Yang
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - John A. T. Young
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Hongying Yun
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Wei Zhu
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
| | - Hong C. Shen
- Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, 720 Cailun Road, Shanghai, 201203, China
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Mak LY, Seto WK, Lai CL, Yuen MF. Pharmacokinetic evaluation of besifovir for the treatment of HBV infection. Expert Opin Drug Metab Toxicol 2017; 14:101-106. [PMID: 29237296 DOI: 10.1080/17425255.2018.1417983] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Besifovir (LB80380) is a relatively new oral acyclic nucleotide phosphonate. We reviewed the pharmacokinetic characteristics of LB80380 and discussed its role in the treatment of chronic hepatitis B infection. Areas covered: LB80380 is a prodrug of LB80331 and LB80317. It is rapidly absorbed when taken orally. Escalating doses of besifovir produce linear increase of the plasma concentration. Doses above 60mg are effective for inhibiting HBV in human. Using 60mg as an example, the maximal concentration of LB80331 in plasma is 397 ng/mL. The time required to reach maximal concentration in plasma and elimination half-life are 2.0 and 3.0 h, respectively. Besifovir and its metabolites are mainly excreted via the kidneys. Its antiviral efficacy is non-inferior to ETV 0.5mg daily. It is generally safe in terms of renal and bone toxicity. The most common adverse event is carnitine depletion which affects almost all patients on besifovir requiring carnitine supplementation. Expert opinion: Besifovir demonstrated predictable pharmacokinetic characteristics in human subjects. Few clinical studies on besifovir have been conducted. More data are expected particularly for special populations. The adverse events upon long term exposure should be monitored. Large scale head-to-head trials comparing besifovir with existing NA, especially tenofovir alafenamide, should be conducted.
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Affiliation(s)
- Lung-Yi Mak
- a Department of Medicine , The University of Hong Kong, Queen Mary Hospital , Hong Kong , China
| | - Wai-Kay Seto
- a Department of Medicine , The University of Hong Kong, Queen Mary Hospital , Hong Kong , China.,b State Key Laboratory for Liver Research , The University of Hong Kong , Hong Kong , China
| | - Ching-Lung Lai
- a Department of Medicine , The University of Hong Kong, Queen Mary Hospital , Hong Kong , China.,b State Key Laboratory for Liver Research , The University of Hong Kong , Hong Kong , China
| | - Man-Fung Yuen
- a Department of Medicine , The University of Hong Kong, Queen Mary Hospital , Hong Kong , China.,b State Key Laboratory for Liver Research , The University of Hong Kong , Hong Kong , China
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14
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Novel therapies and potential therapeutic targets in the management of chronic hepatitis B. Eur J Gastroenterol Hepatol 2017; 29:987-993. [PMID: 28538269 DOI: 10.1097/meg.0000000000000911] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Chronic hepatitis B is a persistent and progressive inflammatory liver disease caused by infection with the hepatitis B virus (HBV). More than 240 million individuals are infected with HBV worldwide and hepatitis B accounts for an estimated 650 000 deaths annually. Approximately up to 30% of chronically infected patients will develop complications of HBV infection including, but not limited to, liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Currently approved therapies have improved clinical outcomes, but have a considerable side-effect profile, elevated cost, and a finite course of treatment. This has led to a growing interest in research for new therapies. As the mechanisms for HBV replication are becoming better understood, new potential targets have been discovered, leading to the development of new therapies. In this article, we describe the promising therapies that are under evaluation, showing their mechanisms of action, effects, and stage of development.
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Abstract
Chronic hepatitis B treatment is available for a long period, allowing disease control and infection suppression, but it is rarely responsible for HBsAg clearance. None of the drugs available aim at cccDNA, the obstacle in HBV infection eradication. Complications related to CHB, such as liver insufficiency, cirrhosis, and hepatocellular carcinoma are reduced in conditions of good viremia suppression, but still exist even after HBsAg seroclearance, what makes a need for urgent forthcoming of new therapeutics. Recent years brought promising and interesting results of experimental approaches, which are directed against different phases of HBV life cycle, target ccc DNA, or boost, and restore host immune response. Unfortunately, encouraging results in vitro and on animal models are not always reflected in human. Nevertheless, the multiplicity of novel antivirals allows to expect that at least some of them will enter clinical practice and relieve patients from chronic hepatitis B, fatal and devastating disease.
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Chang BW, Kaung A, Robbins L, Tran TT. Hepatitis B: Working Towards a Cure. Curr Gastroenterol Rep 2016; 17:35. [PMID: 26275560 DOI: 10.1007/s11894-015-0460-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
First-line oral therapies for hepatitis B are effective at viral suppression, and treatment can lead to biochemical improvement and histologic regression. Unfortunately, recommended endpoints of treatment such as HBeAg loss and seroconversion may not be durable, with high rates of seroreversion, requiring monitoring, and unfortunately, low rates of HBsAg loss/seroconversion. Additionally, meeting these endpoints requires years or even indefinite administration, leading to concerns regarding cost, side effects, and high rates of nonadherence. This article will review defined endpoints of therapy and their durability, the risks of long-term therapy, and the evolving new therapies aimed at a viral cure.
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Affiliation(s)
- Bianca W Chang
- Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, USA
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17
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18
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Block TM, Rawat S, Brosgart CL. Chronic hepatitis B: A wave of new therapies on the horizon. Antiviral Res 2015; 121:69-81. [PMID: 26112647 DOI: 10.1016/j.antiviral.2015.06.014] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 06/21/2015] [Indexed: 02/07/2023]
Abstract
This year marks the 50th anniversary of the discovery of the Australia antigen (Blumberg et al., 1965), which in 1967 was identified to be the hepatitis B virus (HBV) surface antigen. Even though several antiviral medications have been in use for the management of chronic HBV infection for more than 20years, sustained clearance of HBsAg, similar to the sustained viral response (SVR) or cure in chronic hepatitis C, occurs in only a minority of treated patients. Moreover, even after 10years of effective suppression of HBV viremia with current therapy, there is only a 40-70% reduction in deaths from liver cancer. Recent success in developing antivirals for hepatitis C that are effective across all genotypes has renewed interest in a similar cure for chronic HBV infection. In this article, we review a wave of newly identified drug targets, investigational compounds and experimental strategies that are now under clinical evaluation or in preclinical development. The paper forms part of a symposium in Antiviral Research on "An unfinished story: From the discovery of the Australia antigen to the development of new curative therapies for hepatitis B."
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Affiliation(s)
- Timothy M Block
- Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA.
| | - Siddhartha Rawat
- Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, PA 18902, USA
| | - Carol L Brosgart
- University of California, San Francisco, School of Medicine, Departments of Medicine, Epidemiology and Biostatistics, USA
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19
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Yuen MF, Ahn SH, Lee KS, Um SH, Cho M, Yoon SK, Lee JW, Park NH, Kweon YO, Sohn JH, Lee J, Kim JA, Lai CL, Han KH. Two-year treatment outcome of chronic hepatitis B infection treated with besifovir vs. entecavir: results from a multicentre study. J Hepatol 2015; 62:526-32. [PMID: 25450709 DOI: 10.1016/j.jhep.2014.10.026] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 10/14/2014] [Accepted: 10/14/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS We aimed to compare the viral suppression, safety and rate of drug resistance between besifovir (a new acyclic nucleotide analogue) and entecavir. METHODS Treatment-naïve chronic hepatitis B patients receiving besifovir 90 mg (n=31), 150 mg (n=28) and entecavir 0.5 mg (n=30) were monitored for liver biochemistry, viral serology, HBV DNA levels, development of drug resistance mutations, and adverse events throughout 96 weeks of treatment. RESULTS The mean decline of HBV DNA levels from baseline to week 96 were 5.29, 5.15, and 5.67 logs IU/ml for patients receiving besifovir 90 mg, 150 mg and entecavir 0.5 mg, respectively (p>0.05). Undetectable HBV DNA (<20 IU/ml) were achieved in 80.7%, 78.6%, and 80%; ALT normalization in 90.3%, 78.6%, and 93.3%; and loss of HBeAg in 20%, 21.4%, and 22.2% of patients respectively (all p>0.05). One patient receiving besifovir 90 mg had a virological breakthrough due to drug non-compliance. No patient developed drug resistance mutations. Ten patients had serious adverse events, which were not related to the study medications. The most common side effect related to besifovir was carnitine depletion. Carnitine supplements were prescribed to 83.9% and 100% of patients, who had low carnitine level for any one time during follow-up, receiving besifovir 90 mg and 150 mg respectively. No patient had increased creatinine>0.5 mg/dl from baseline. CONCLUSIONS Besifovir had the same antiviral property as compared to entecavir over 96 weeks of treatment for chronic hepatitis B patients. Besifovir was well tolerated and also had a good clinical safety profile.
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Affiliation(s)
- Man-Fung Yuen
- Department of Medicine, University of Hong Kong, Hong Kong
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kwan Sik Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soon Ho Um
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Mong Cho
- Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea
| | - Seung Kew Yoon
- Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jin-Woo Lee
- Department of Internal Medicine, Inha University College of Medicine, Incheon, Republic of Korea
| | - Neung Hwa Park
- Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Young-Oh Kweon
- Department of Internal Medicine, Kyungpook National University College of Medicine, Daegu, Republic of Korea
| | - Joo Hyun Sohn
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Jiyoon Lee
- LG Life Sciences, Ltd., Seoul, Republic of Korea
| | - Jeong-Ae Kim
- LG Life Sciences, Ltd., Seoul, Republic of Korea
| | - Ching-Lung Lai
- Department of Medicine, University of Hong Kong, Hong Kong.
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Pradere U, Garnier-Amblard E, Coats SJ, Amblard F, Schinazi RF. Synthesis of nucleoside phosphate and phosphonate prodrugs. Chem Rev 2014; 114:9154-218. [PMID: 25144792 PMCID: PMC4173794 DOI: 10.1021/cr5002035] [Citation(s) in RCA: 418] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Indexed: 01/29/2023]
Affiliation(s)
- Ugo Pradere
- Center
for AIDS Research, Laboratory of Biochemical Pharmacology, Department
of Pediatrics, Emory University School of
Medicine, and Veterans Affairs Medical Center, Atlanta, Georgia 30322, United States
| | | | | | - Franck Amblard
- Center
for AIDS Research, Laboratory of Biochemical Pharmacology, Department
of Pediatrics, Emory University School of
Medicine, and Veterans Affairs Medical Center, Atlanta, Georgia 30322, United States
| | - Raymond F. Schinazi
- Center
for AIDS Research, Laboratory of Biochemical Pharmacology, Department
of Pediatrics, Emory University School of
Medicine, and Veterans Affairs Medical Center, Atlanta, Georgia 30322, United States
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21
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Wang XY, Chen HS. Emerging antivirals for the treatment of hepatitis B. World J Gastroenterol 2014; 20:7707-7717. [PMID: 24976708 PMCID: PMC4069299 DOI: 10.3748/wjg.v20.i24.7707] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with hepatitis B virus (HBV) constitutes a major global public health threat, causing substantial disease burdens such as liver cirrhosis and hepatocellular carcinoma, thus representing high unmet medical needs. Currently available therapies are safe, well tolerated, and highly effective in decreasing viremia and improving measured clinical outcomes with low rates of antiviral resistance. However, long-term management remains a clinical challenge, mainly due to the slow kinetics of HBV surface antigen clearance. In this article, we review emerging antivirals directed at novel targets derived from mechanisms of viral cellular entry, viral replication, viral assembly, and the host immune response, leading to preclinical and clinical trials for possible future therapeutic intervention. The recent therapeutic advances in the development of all categories of HBV inhibitors may pave the way for regimens of finite duration that result in long-lasting control of chronic hepatitis B infection.
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22
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Lai CL, Ahn SH, Lee KS, Um SH, Cho M, Yoon SK, Lee JW, Park NH, Kweon YO, Sohn JH, Lee J, Kim JA, Han KH, Yuen MF. Phase IIb multicentred randomised trial of besifovir (LB80380) versus entecavir in Asian patients with chronic hepatitis B. Gut 2014; 63:996-1004. [PMID: 23979965 DOI: 10.1136/gutjnl-2013-305138] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Besifovir (LB80380) is an acyclic nucleotide phosphonate effective in hepatitis B virus (HBV) DNA suppression for both treatment-naive and lamivudine-resistant chronic hepatitis B (CHB) patients in preliminary studies. DESIGN We aimed to compare the safety and antiviral activity of two doses of besifovir (90 mg and 150 mg daily) with entecavir 0.5 mg daily in CHB patients. 114 patients were randomised to receive besifovir 90 mg daily (n=36), besifovir 150 mg daily (n=39) or entecavir 0.5 mg daily (n=39). HBV DNA and liver biochemistry, including serum L-carnitine levels, were monitored. RESULTS At week 48, in the intention-to-treat population, the proportion of patients achieving undetectable HBV DNA (<20 IU/mL) were 63.6%, 62.9% and 58.3%, respectively (p>0.05). The serum mean log10 HBV DNA changes from baseline for the HBeAg-positive patients were -5.84, -5.91 and -6.18, respectively; and for the HBeAg-negative patients were -4.65, -4.55 and -4.67, respectively (p>0.05). There were no differences in the proportions of patients achieving normalisation of alanine aminotransferase (91.7%, 76.9%, 89.7%, respectively) and HBeAg seroconversion (11.11%, 15%, 9.52%, respectively) among all three groups. None of the patients had resistant mutations or increase in serum creatinine of >0.5 mg/dL from baseline. 64 (94.1%) patients on besifovir had lowering of serum L-carnitine (not tested in entecavir patients). L-carnitine levels returned to normal with carnitine supplement. CONCLUSIONS At 48 weeks, 90 mg and 150 mg daily of besifovir were non-inferior to entecavir 0.5 mg daily in treatment-naive CHB patients. The only significant side effect of besifovir was L-carnitine depletion, requiring carnitine supplementation.
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Affiliation(s)
- Ching-Lung Lai
- Department of Medicine, University of Hong Kong, Hong Kong, Hong Kong
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Tang CM, Yau TO, Yu J. Management of chronic hepatitis B infection: current treatment guidelines, challenges, and new developments. World J Gastroenterol 2014; 20:6262-6278. [PMID: 24876747 PMCID: PMC4033464 DOI: 10.3748/wjg.v20.i20.6262] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 11/24/2013] [Accepted: 01/19/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) virus infection is a global public health problem, affecting more than 400 million people worldwide. The clinical spectrum is wide, ranging from a subclinical inactive carrier state, to progressive chronic hepatitis, cirrhosis, decompensation, and hepatocellular carcinoma. However, complications of hepatitis B virus (HBV)-related chronic liver disease may be reduced by viral suppression. Current international guidelines recommend first-line treatment of CHB infection with pegylated interferon, entecavir, or tenofovir, but the optimal treatment for an individual patient is controversial. The indications for treatment are contentious, and increasing evidence suggests that HBV genotyping, as well as serial on-treatment measurements of hepatitis B surface antigen and HBV DNA kinetics should be used to predict antiviral treatment response. The likelihood of achieving a sustained virological response is also increased by extending treatment duration, and using combination therapy. Hence the paradigm for treatment of CHB is constantly evolving. This article summarizes the different indications for treatment, and systematically reviews the evidence for the efficacy of various antiviral agents. It further discusses the shortcomings of current guidelines, use of rescue therapy in drug-resistant strains of HBV, and highlights the promising clinical trials for emerging therapies in the pipeline. This concise overview presents an updated practical approach to guide the clinical management of CHB.
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24
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Qiu LP, Chen L, Chen KP. Antihepatitis B therapy: a review of current medications and novel small molecule inhibitors. Fundam Clin Pharmacol 2013; 28:364-81. [DOI: 10.1111/fcp.12053] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2012] [Revised: 09/14/2013] [Accepted: 09/30/2013] [Indexed: 12/18/2022]
Affiliation(s)
- Li-Peng Qiu
- Institute of Life Sciences; Jiangsu University; Zhenjiang Jiangsu Province 212013 China
| | - Liang Chen
- Institute of Life Sciences; Jiangsu University; Zhenjiang Jiangsu Province 212013 China
| | - Ke-Ping Chen
- Institute of Life Sciences; Jiangsu University; Zhenjiang Jiangsu Province 212013 China
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Brooks J, Gelson W, Rushbrook SM. Therapeutic advances in the management of chronic hepatitis B infection. Ther Adv Chronic Dis 2013; 4:157-66. [PMID: 23819019 DOI: 10.1177/2040622313484647] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B virus (HBV) is a small nonenveloped DNA virus that is a member of the Hepadnaviridae family. Chronic HBV infection is estimated to effect more than 350 million people worldwide with over 2 billion people being exposed to the virus. Risk factors for chronic infection include age of exposure to the virus, concurrent immunosuppression and HIV infection. Individuals chronically infected are 200 times more likely to develop hepatocellular carcinoma (HCC) than uninfected individuals and are at risk of developing cirrhosis and the risks of decompensated liver disease. This article focuses on the recent therapeutic advances that reduce the risk of developing these complications, those that prevent the spread of HBV and strategies for the prevention of post-liver-transplantation recurrence of HBV.
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Affiliation(s)
- Johanne Brooks
- Gastroenterology Department, Norfolk and Norwich Hospital, Colney Lane, Norwich NR4 7UY, UK
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26
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Hu Y, Zhu W, Tang G, Mayweg AV, Yang G, Wu JZ, Shen HC. Novel Therapeutics in Discovery and Development for Treatment of Chronic HBV Infection. ANNUAL REPORTS IN MEDICINAL CHEMISTRY 2013. [DOI: 10.1016/b978-0-12-417150-3.00017-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Karayiannis P. Direct acting antivirals for the treatment of chronic viral hepatitis. SCIENTIFICA 2012; 2012:478631. [PMID: 24278700 PMCID: PMC3820491 DOI: 10.6064/2012/478631] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 10/08/2012] [Indexed: 06/02/2023]
Abstract
The development and evaluation of antiviral agents through carefully designed clinical trials over the last 25 years have heralded a new dawn in the treatment of patients chronically infected with the hepatitis B and C viruses, but not so for the D virus (HBV, HCV, and HDV). The introduction of direct acting antivirals (DDAs) for the treatment of HBV carriers has permitted the long-term use of these compounds for the continuous suppression of viral replication, whilst in the case of HCV in combination with the standard of care [SOC, pegylated interferon (PegIFN), and ribavirin] sustained virological responses (SVRs) have been achieved with increasing frequency. Progress in the case of HDV has been slow and lacking in significant breakthroughs.This paper aims to summarise the current state of play in treatment approaches for chonic viral hepatitis patients and future perspectives.
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Affiliation(s)
- Peter Karayiannis
- Section of Hepatology and Gastroenterology, Department of Medicine, Imperial College, St Mary's Campus, London W2 1PG, UK
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28
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Abstract
Vaccination for hepatitis B virus (HBV) infection and treatment for chronic hepatitis B, while effective for primary prevention and control of the disease, still have their limitations. Global coverage of HBV immunization needs improvement. Several patient populations are noted to have suboptimal seroprotective rates after HBV vaccination. There are currently several potential new vaccines undergoing animal and human studies, most notably vaccines containing immunostimulatory DNA sequences. Long-term nucleoside analogue therapy is necessary in achieving permanent virologic suppression. Potential new treatments explore new mechanisms of action, including the inhibition of hepatitis B surface antigen release, targeting antifibrotic mechanism, and immunomodulation through novel interferons and therapeutic vaccines. The clinical application of potential new vaccines and therapies would enhance the prevention of HBV infection and treatment of chronic hepatitis B.
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Abstract
Large volume of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2008. These include further studies in asymptomatic subjects with chronic HBV infection and community-based cohorts, the role of HBV genotype/naturally occurring HBV mutations, the application of non-invasive assessment of hepatic fibrosis and quantitation of HBV surface antigen and new drug or new strategies towards more effective therapy. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings was discussed and debated. The earlier "Asian-Pacific consensus statement on the management of chronic hepatitis B" was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patients receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.
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Abstract
INTRODUCTION Chronic hepatitis B virus (HBV) infection continues to represent a global health concern with an estimated 350 - 400 million people infected worldwide. Current treatment options are either of two IFN-based therapies or either of five oral nucleos(t)ide analogs which are used as monotherapy or in combination. Control of viral replication can be achieved basically in all patients today. However, despite the clinical efficacy of antivirals, long-term management remains a clinical challenge mainly due to the slow kinetics of HBsAg clearance. Emergence of viral resistance has been a challenge in the past with some but not all oral therapies. The development of novel therapeutic agents with different mechanisms of action might provide new opportunities to clear HBsAg and achieve HBsAg seroconversion which could be maintained off therapy. The long-term efficacy of combinations of IFN and/or nucleos(t)ide analogs might achieve antiviral synergy, preventing drug resistance and clearing viral covalently close circular DNA and infected cells. AREAS COVERED This article provides a review of recent data on the safety and efficacy of existing and emerging agents for the treatment of chronic hepatitis B infection. EXPERT OPINION Currently, entecavir and tenofovir offer a safe and effective treatment option for patients with chronic HBV with minimal to no resistance. Although entecavir and tenofovir are able to suppress replication in essentially all patients, achieving HBsAg seroconversion remains suboptimal among all antiviral therapy. There are a number of new therapies in the pipeline for the treatment of chronic HBV infection as well as revisiting IFN combined or sequential to antiviral therapy.
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Affiliation(s)
- Natravis Cox
- Duke University Medical Center, Durham, NC 27710, USA
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32
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Abstract
PURPOSE OF REVIEW We review here new developments in chronic hepatitis B (CHB) treatment, based on review of published articles between December 2009 and November 2010. RECENT FINDINGS It is estimated that two-thirds of US CHB patients have not been identified, evaluated and appropriately treated, largely due to lack of knowledge and awareness of CHB among medical professionals and at-risk populations. Seven medications have been approved to treat CHB in adults, but only four medications have been approved to treat CHB in children.Hepatitis B e antigen (HBeAg) seroconversion is still an important treatment endpoint in HBeAg-positive patients. Durability of nucleoside analogue treatment-related HBeAg seroconversion is still questionable. Hepatitis B surface antigen (HBsAg) seroclearance has been achieved in some patients with antiviral therapy. HBsAg quantitation and kinetics is now being studied to determine its role in the natural history of CHB and whether these measures may predict future response to current antiviral therapy. SUMMARY Great advances have been made in understanding the HBeAg seroconversion durability. The clinical significance of serum HBsAg kinetics has been recognized in naive CHB patients and patients with antiviral therapy. More education programs are needed to improve the public awareness of the importance of CHB to the health of whole population.
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Grimm D, Thimme R, Blum HE. HBV life cycle and novel drug targets. Hepatol Int 2011; 5:644-53. [PMID: 21484123 DOI: 10.1007/s12072-011-9261-3] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Accepted: 02/04/2011] [Indexed: 12/19/2022]
Abstract
With up to 400 million affected people worldwide, chronic hepatitis B virus (HBV) infection is still a major health care problem. During the last decade, several novel therapeutic approaches have been developed and evaluated. In most regions of the world, interferon-α, and nucleos(t)ide analogues (NUCs) are currently approved. Despite major improvements, none of the existing therapies is optimal since viral clearance is rarely achieved. Recently, a better understanding of the HBV life cycle and the development of novel model systems of HBV infection have led to the development of novel antiviral strategies and drug targets. This review will focus on current and potential future drug targets in the HBV life cycle and strategies to modulate the virus-host interaction.
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Affiliation(s)
- Daniel Grimm
- Department of Medicine II, University of Freiburg, Freiburg, Germany
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Abstract
There has been a recent paradigm shift in the indications and endpoints of treatment for chronic hepatitis B (CHB). Hepatitis B e antigen (HBeAg)-negative disease is being increasingly recognized. Antiviral treatment for both HBeAg-positive and HBeAg-negative patients should aim at long-term suppression of HBV DNA, with the ultimate ideal endpoint of hepatitis B surface antigen (HBsAg) seroconversion. Conventional interferon alpha (IFN-α), the only agent licensed in 1991, has been superseded by pegylated IFN-α. HBeAg seroconversion using pegylated IFN-α is 33%, with only 25% of HBeAg-positive patients achieving undetectable HBV DNA by polymerase chain reaction (PCR) assay. Five nucleoside/nucleotide analogues have been licensed since 1998. Lamivudine, an L-nucleoside, is limited by the development of resistance in 76% of patients after 5 years of therapy. Telbivudine, another L-nucleoside, is more potent than lamivudine but resistance still develops in 25% of HBeAg-positive and 11% HBeAg-negative patients after 2 years. Adefovir, an acyclic phosphonate, is relatively weak, but is effective against lamivudine- and telbivudine- resistant mutations, for which it should be used in combination (add-on therapy) rather than substituted. Resistance to adefovir develops slowly, rising to 29% for HBeAg-negative patients by year 5, but more rapidly when used alone for lamivudine-resistant HBV. Currently the two first line nucleoside/nucleotides are entecavir and tenofovir. Entecavir, a cyclopentane (D-nucleoside), is very potent, with 94% of patients having undetectable HBV DNA after 5 years. Resistance develops in only 1.2% of treatment-naïve patients. Tenofovir, another acyclic nucleotide, is more potent with less renal toxicity compared to adefovir. It is effective against lamivudine-resistant mutations when used alone. No resistance to tenofovir has been described after its use for 3 years or longer, often for patients with human immunodeficiency virus/HBV co-infection. With these current, potent antiviral agents associated with very low rates of resistance, long-term HBV DNA suppression and possibly even reversal of cirrhosis can now be achieved in a proportion of patients. In addition, long-term treatment with these antiviral agents is associated with a reduced risk of development of hepatocellular carcinoma.
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Affiliation(s)
- Man-Fung Yuen
- Department of Medicine, the University of Hong Kong, Queen Mary Hospital, China.
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Kim KH, Kim ND, Seong BL. Discovery and development of anti-HBV agents and their resistance. Molecules 2010; 15:5878-908. [PMID: 20802402 PMCID: PMC6257723 DOI: 10.3390/molecules15095878] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2010] [Revised: 08/24/2010] [Accepted: 08/26/2010] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a prime cause of liver diseases such as hepatitis, cirrhosis and hepatocellular carcinoma. The current drugs clinically available are nucleot(s)ide analogues that inhibit viral reverse transcriptase activity. Most drugs of this class are reported to have viral resistance with breakthrough. Recent advances in methods for in silico virtual screening of chemical libraries, together with a better understanding of the resistance mechanisms of existing drugs have expedited the discovery and development of novel anti-viral drugs. This review summarizes the current status of knowledge about and viral resistance of HBV drugs, approaches for the development of novel drugs as well as new viral and host targets for future drugs.
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Affiliation(s)
- Kyun-Hwan Kim
- Department of Pharmacology, School of Medicine, and Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University, Seoul 143-701, Korea
- Research Institute of Medical Sciences, Konkuk University, Seoul 143-701, Korea
- Author to whom correspondence should be addressed; E-Mail: (K.H.K.); Tel.: +82 2 2030 7833; Fax: +82 2 2049 6192; E-Mail: (B.L.S.); Tel.: +82 2 2123 2885; Fax: +82 2 392 3582
| | - Nam Doo Kim
- R&D Center, Equispharm Inc., 11F Gyeonggi Bio-Center, 864-1 Iui-Dong, Yeongtong-gu, Suwon-Shi, Gyeonggi-Do 443-766, Korea
| | - Baik-Lin Seong
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea
- Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea
- Author to whom correspondence should be addressed; E-Mail: (K.H.K.); Tel.: +82 2 2030 7833; Fax: +82 2 2049 6192; E-Mail: (B.L.S.); Tel.: +82 2 2123 2885; Fax: +82 2 392 3582
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