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Kothapalli Y, Jones RA, Chu CK, Singh US. Synthesis of Fluorinated Nucleosides/Nucleotides and Their Antiviral Properties. Molecules 2024; 29:2390. [PMID: 38792251 PMCID: PMC11124531 DOI: 10.3390/molecules29102390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/10/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
The FDA has approved several drugs based on the fluorinated nucleoside pharmacophore, and numerous drugs are currently in clinical trials. Fluorine-containing nucleos(t)ides offer significant antiviral and anticancer activity. The insertion of a fluorine atom, either in the base or sugar of nucleos(t)ides, alters its electronic and steric parameters and transforms the lipophilicity, pharmacodynamic, and pharmacokinetic properties of these moieties. The fluorine atom restricts the oxidative metabolism of drugs and provides enzymatic metabolic stability towards the glycosidic bond of the nucleos(t)ide. The incorporation of fluorine also demonstrates additional hydrogen bonding interactions in receptors with enhanced biological profiles. The present article discusses the synthetic methodology and antiviral activities of FDA-approved drugs and ongoing fluoro-containing nucleos(t)ide drug candidates in clinical trials.
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Affiliation(s)
| | | | - Chung K. Chu
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA; (Y.K.); (R.A.J.)
| | - Uma S. Singh
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA; (Y.K.); (R.A.J.)
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Squires KE, Ogilvie L, Jucov A, Anastasiy I, Ghicavii N, Huguet J, Melara R, Constantineau M, De La Rosa A, Mayers DL. A randomized phase 1b trial of the active site polymerase inhibitor nucleotide ATI-2173 in patients with chronic hepatitis B virus infection. J Viral Hepat 2023; 30:19-28. [PMID: 36201354 PMCID: PMC10092119 DOI: 10.1111/jvh.13753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 09/13/2022] [Accepted: 09/13/2022] [Indexed: 01/15/2023]
Abstract
ATI-2173 is an active site polymerase inhibitor nucleotide in development as part of a potentially curative regimen for chronic hepatitis B virus (HBV) infection. This study evaluated the safety, tolerability, pharmacokinetics (PK) and antiviral activity of ATI-2173. This was a phase 1b, randomized, double-blind, placebo-controlled trial in treatment-naive adults with chronic HBV infection conducted in the Republic of Moldova and Ukraine (ClinicalTrials.gov: NCT04248426). Patients positive for hepatitis B surface antigen were randomized 6:2 to receive once-daily oral doses of ATI-2173 10, 25, or 50 mg (n = 6 per dose) or placebo (n = 7) for 28 days, with off-treatment monitoring for 24 weeks. Endpoints included PK parameters of ATI-2173 and its metabolite clevudine, maximum reduction from baseline in HBV DNA, and safety and tolerability. Treatment-emergent adverse events occurred in eight patients (47%) receiving ATI-2173 and five (71%) receiving placebo; headache was the most common (n = 4). ATI-2173 PK was generally dose proportional. Systemic clevudine exposure with ATI-2173 dosing was substantially reduced compared with historical values observed with clevudine administration. On Day 28, mean changes from baseline in HBV DNA were -2.72 to -2.78 log10 IU/ml with ATI-2173 and +0.17 log10 IU/ml with placebo. Off-treatment sustained viral suppression and decreases in covalently closed circular DNA biomarkers were observed in most patients; one maintained undetectable HBV DNA at 24 weeks off treatment. In this 28-day monotherapy study, ATI-2173 demonstrated safety and antiviral activity, with sustained off-treatment effects and substantially reduced systemic clevudine exposure. These results support evaluation of ATI-2173 with tenofovir disoproxil fumarate in phase 2 studies.
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Affiliation(s)
| | | | - Alina Jucov
- ARENSIA Exploratory Medicine, Republican Clinical Hospital, Chisinau, Moldova.,Department of Infectious Diseases, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Moldova
| | - Igor Anastasiy
- Department of Infectious Diseases, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Moldova.,ARENSIA Exploratory Medicine, Kiev, Ukraine
| | - Nelli Ghicavii
- ARENSIA Exploratory Medicine, Republican Clinical Hospital, Chisinau, Moldova
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Yardeni D, Ghany MG. Review article: hepatitis B-current and emerging therapies. Aliment Pharmacol Ther 2022; 55:805-819. [PMID: 35224760 DOI: 10.1111/apt.16828] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 01/17/2022] [Accepted: 02/04/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND The hepatitis B virus (HBV) affects an estimated 290 million individuals worldwide and is responsible for approximately 900 000 deaths annually, mostly from complications of cirrhosis and hepatocellular carcinoma. Although current treatment is effective at preventing complications of chronic hepatitis B, it is not curative, and often must be administered long term. There is a need for safe, effective, finite duration curative therapy. AIM Our aim was to provide a concise, up to date review of all currently available and emerging treatment options for chronic hepatitis B. METHODS We conducted a search of PubMed, clinicaltrials.gov, major meeting abstracts and pharmaceutical websites for publications and communications on current and emerging therapies for HBV. RESULTS Currently approved treatment options for chronic hepatitis B include peginterferon alpha-2a and nucleos(t)ide analogues. Both options do not offer a 'complete cure' (clearance of covalently closed circular DNA (cccDNA) and integrated HBV DNA) and rarely achieve a 'functional cure' (hepatitis B surface antigen (HBsAg) loss). An improved understanding of the viral lifecycle, immunopathogenesis and recent advances in drug delivery technologies have led to many novel therapeutic approaches that are currently being evaluated in clinical trials including targeting of viral entry, cccDNA, viral transcription, core protein, and release of HBsAg and HBV polymerase. Additionally, novel immunological approaches that include targeting the innate and adaptive immune system and therapeutic vaccination are being pursued. CONCLUSION The breadth and scope of novel therapies in development hold promise for regimen/s that will achieve functional cure.
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Affiliation(s)
- David Yardeni
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Marc G Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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Gish RG, Asselah T, Squires K, Mayers D. Active site polymerase inhibitor nucleotides (ASPINs): Potential agents for chronic HBV cure regimens. Antivir Chem Chemother 2022; 30:20402066221138705. [PMID: 36423233 PMCID: PMC9703507 DOI: 10.1177/20402066221138705] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 10/06/2022] [Indexed: 10/03/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection affects 240 to 300 million people worldwide. In the nucleus of infected hepatocytes, the HBV genome is converted to covalently closed circular DNA (cccDNA), which persists and serves as a transcriptional template for viral progeny. Therefore, a long-term cure for chronic HBV infection will require elimination of cccDNA. Although currently available nucleos(t)ide analogues (eg, tenofovir disoproxil fumarate, tenofovir alafenamide, entecavir) effectively control HBV replication, they are seldom curative (functional cure rate ∼10%) and require lifelong treatment for most patients. As such, antiviral agents with novel mechanisms of action are needed. Active site polymerase inhibitor nucleotides (ASPINs) noncompetitively distort the HBV polymerase active site to completely inhibit all polymerase functions, unlike traditional chain-terminating nucleos(t)ide analogues, which only target select polymerase functions and are consumed in the process. Clevudine, a first-generation ASPIN, demonstrated potent and prolonged HBV suppression in phase 2 and 3 clinical studies, but long-term treatment was associated with reversible myopathy in a small number of patients. ATI-2173, a novel next-generation ASPIN, is structurally similar to clevudine but targets the liver and demonstrates potent anti-HBV activity on and off treatment, and may ultimately demonstrate an improved pharmacokinetic and safety profile by significantly reducing systemic clevudine exposure. Thus, ATI-2173 is currently in clinical development as an agent for HBV cure. Here, we review the mechanism of action and preclinical and clinical profiles of clevudine and ATI-2173 to support the role of ASPINs as part of curative regimens for chronic HBV infection.
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Affiliation(s)
- Robert G Gish
- Hepatitis B Foundation, Doylestown, PA, USA
- Robert G. Gish Consultants, LLC, La Jolla, CA, USA
| | - Tarik Asselah
- Université de Paris, Inserm U1149, Centre de Recherche sur l’inflammation, Paris, France
- Department of Hepatology, AP-HP, Hôpital Beaujon, Clichy, France
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ATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure Regimens. Antimicrob Agents Chemother 2020; 64:AAC.00836-20. [PMID: 32540975 PMCID: PMC7449170 DOI: 10.1128/aac.00836-20] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 06/06/2020] [Indexed: 01/05/2023] Open
Abstract
ATI-2173 is a novel liver-targeted molecule designed to deliver the 5′-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5′-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development. ATI-2173 is a novel liver-targeted molecule designed to deliver the 5′-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5′-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development. ATI-2173 was designed by modifying clevudine with a 5′-phosphoramidate to deliver the 5′-monophosphate to the liver. Bypassing the first phosphorylation step of clevudine, the 5′-monophosphate is converted to the active 5′-triphosphate in the liver. ATI-2173 is a selective inhibitor of HBV with an anti-HBV 50% effective concentration (EC50) of 1.31 nM in primary human hepatocytes, with minimal to no toxicity in hepatocytes, skeletal muscle, liver, kidney, bone marrow, and cardiomyocytes. ATI-2173 activity was decreased by viral polymerase mutations associated with entecavir, lamivudine, and adefovir resistance, but not capsid inhibitor resistance mutations. A single oral dose of ATI-2173 demonstrated 82% hepatic extraction, no food effect, and greatly reduced peripheral exposure of clevudine compared with equimolar oral dosing of clevudine. Despite reduced plasma clevudine exposure, liver concentrations of the 5′-triphosphate were equivalent following ATI-2173 versus clevudine administration. By selectively delivering the 5′-monophosphate to the liver, while retaining the unique anti-HBV activity of the 5′-triphosphate, ATI-2173 may provide an improved pharmacokinetic profile for clinical use, reducing systemic exposure of clevudine and potentially eliminating skeletal myopathy.
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Cho EY, Yim HJ, Jung YK, Suh SJ, Seo YS, Kim JH, Kim HS, Lee SH, Ahn SH, Lee JI, Jeong SH, Kim JW, Lee JW, Kim IH, Kim HS, Park SJ, Lee JM, Hwang SG. Management of Clevudine-Resistant Chronic Hepatitis B: A Multicenter Cohort Study. Gut Liver 2017; 11:129-135. [PMID: 27538443 PMCID: PMC5221870 DOI: 10.5009/gnl15597] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 01/24/2016] [Accepted: 03/22/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIMS Data are lacking regarding the management of chronic hepatitis B (CHB) with resistance to clevudine (CLV). This study evaluated the efficacy of different rescue therapies for CLV-resistant CHB. METHODS Patients with CLV-resistant CHB were enrolled in the cohort, and all patients developed virologic breakthrough during CLV therapy and had confirmed-genotypic resistance to CLV (rtM204I mutation) before enrollment. RESULTS Of the 107 patients, 12 received adefovir (ADV), 21 received a CLV plus ADV combination (CLV+ADV), 34 received a lamivudine plus ADV combination (LAM+ADV), and 40 received entecavir (ETV) therapy for 48 weeks. The CLV+ADV group had the lowest hepatitis B virus (HBV) DNA level (p<0.0001) and showed the greatest reduction of HBV DNA levels from baseline compared to all other groups (p=0.004) at week 48. HBV DNA was undetectable (<70 IU/mL) in 0%, 57.1%, 21.2%, and 27.5% (p=0.003) of the patients in each group, respectively, at week 48. At the end of the study, the mean alanine transaminase (ALT) level, rate of ALT normalization, and rate of hepatitis B envelope antigen loss or seroconversion did not differ between groups. CONCLUSIONS CLV+ADV combination therapy in patients with CLV-resistant CHB more effectively suppresses HBV replication than ETV, ADV, or LAM+ADV therapy.
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Affiliation(s)
- Eun Young Cho
- Department of Internal Medicine, Wonkwang University School of Medicine, Iksan,
Korea
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan,
Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan,
Korea
| | - Sang Jun Suh
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan,
Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul,
Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul,
Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan,
Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan,
Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
| | - Jeong Il Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
| | - Sook-Hyang Jeong
- Department of Internal Medicine, Seoul National University College of Medicine, Seongnam,
Korea
| | - Jin-Wook Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seongnam,
Korea
| | - Jin-Woo Lee
- Department of Internal Medicine, Inha University School of Medicine, Incheon,
Korea
| | - In Hee Kim
- Department of Internal Medicine, Chonbuk National University Medical School, Jeonju,
Korea
| | - Hyoung Su Kim
- Department of Internal Medicine, Hallym University College of Medicine, Seoul,
Korea
| | | | - Jeong Mi Lee
- Department of Public Health, Wonkwang University Graduate School, Iksan,
Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam,
Korea
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Manzoor S, Saalim M, Imran M, Resham S, Ashraf J. Hepatitis B virus therapy: What’s the future holding for us? World J Gastroenterol 2015; 21:12558-12575. [PMID: 26640332 PMCID: PMC4658610 DOI: 10.3748/wjg.v21.i44.12558] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 07/24/2015] [Accepted: 10/20/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B is one of the leading causes of liver cancer worldwide and unfortunately the number of people affected with hepatitis B virus (HBV) infection is still on the rise. Although the HBV has been known to cause fatal illness since decades but the population effected by this lethal virus have still only a few options for its management. The major treatment strategies include interferons and nucleos(t)ide analogues. These agents have so far produced unsatisfactory results in terms of complete virus eradication. Interferons cannot be used for long term therapy because of their potential side effects. Prolong treatment with nucleos(t)ide analogues has also been reported to cause serious side effects besides the increasing resistance by the virus. The need for new innovative solutions for treatment of HBV has been realized by global research institutes and pharmaceutical industry. Present review focuses in detail on the new ideas that are being transformed into therapeutic tools for use as future therapies in HBV infection. Modern drug designing and screening methods have made the drug discovery process shorter and more reliable. HBV therapeutics will take a new turn in coming years owing to these intelligent drug designing and screening methods. Future therapy of HBV is aiming to include the use of vaccines (both prophylactic and therapeutic), immunomodulators such as antibodies, non-nucleoside antivirals such as RNAi and inhibitors of viral life cycle.
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Clark DN, Hu J. Hepatitis B virus reverse transcriptase - Target of current antiviral therapy and future drug development. Antiviral Res 2015; 123:132-7. [PMID: 26408354 DOI: 10.1016/j.antiviral.2015.09.011] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 09/09/2015] [Accepted: 09/21/2015] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) infections rely on the proper functioning of the viral polymerase enzyme, a specialized reverse transcriptase (RT) with multiple activities. All currently approved antiviral drugs for the treatment of chronic HBV infection, except for interferon, target the RT and belong to the same chemical class - they are all nucleoside analogs. Viral DNA synthesis is carried out by the RT enzyme in several different steps, each with distinct RT conformational requirements. In principle, each stage may be targeted by distinct antiviral drugs. In particular, the HBV RT has the unique ability to initiate viral DNA synthesis using itself as a protein primer in a novel protein priming reaction. In order to help identify RT inhibitors and study their mechanisms of action, a number of experimental systems have been developed, each varying in its ability to dissect the protein priming stage and subsequent stages of viral DNA synthesis at the molecular level. Two of the most effective drugs to date, entecavir and tenofovir, can inhibit both the protein priming and the subsequent DNA elongation stages of HBV DNA synthesis. Interestingly, clevudine, a thymidine analog, can inhibit both protein priming and DNA elongation in a non-competitive manner and without being incorporated into the viral DNA. Thus, a nucleoside RT inhibitor (NRTI) can functionally mimic a non-NRTI (NNRTI) in its inhibition of the HBV RT. Therefore, novel NRTIs as well as NNRTIs may be developed to inhibit the DNA synthesis activity of the HBV RT. Furthermore, additional activities of the RT that are also essential to HBV replication, including specific recognition of the viral RNA and its packaging into viral nucleocapsids, may be exploited for antiviral development. To achieve a more potent inhibition of viral replication and ultimately cure chronic HBV infection, the next generation of anti-HBV therapies will likely need to include NRTIs, NNRTIs, and other agents that target the viral RT as well as other viral and host factors in various combinations. This article 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)
- Daniel N Clark
- Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.
| | - Jianming Hu
- Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
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You CR, Lee SW, Jang JW, Yoon SK. Update on hepatitis B virus infection. World J Gastroenterol 2014; 20:13293-13305. [PMID: 25309066 PMCID: PMC4188887 DOI: 10.3748/wjg.v20.i37.13293] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 03/18/2014] [Accepted: 04/05/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with hepatitis B virus (HBV) leads to the development of hepatocellular carcinoma and/or chronic liver failure. Despite extensive research, the immunopathogenesis is not completely understood. Viral persistence and clinical outcomes following HBV infection depend on viral factors and host factors; including genetic factors that determine a host's immune mechanisms. The primary goal of chronic hepatitis B (CHB) treatment is to eradicate HBV or to at least maintain suppression of HBV replication. Despite recent advances in anti-viral agents for chronic HBV infection, complete eradication of the virus has been difficult to achieve. Agents for the treatment of CHB are divided mainly into two groups: immunomodulating agents and antiviral nucleos(t)ide analogues (NAs). Although NAs are safe, effective and easily administered orally, their long-term use poses the risk of drug resistance. Currently, international evidence-based guidelines have been developed to support physicians in managing CHB patients. However, treatment of patients with drug resistance is still challenging, as only a few classes of anti-HBV drugs are available and cross-resistance between drugs can occur. In addition, as the currently available genotypic test for detection of drug resistance still has limitations in identifying the different substitutions present in the same viral genome, the development of a new virologic test to overcome this limitation is necessary. Among the predictive factors associated with response to pegylated interferon (PEG-IFN) therapy, hepatitis B surface antigen quantification is considered to be a surrogate marker for monitoring response to PEG-IFN. Current practice guidelines stress the importance of profound and durable HBV viral suppression in the treatment of CHB patients. To this end, it is essential to choose a potent antiviral drug with a low risk of resistance for initial treatment of CHB to achieve sustained virological response. This review highlights recent advances in the understanding of the immunopathogenesis of HBV and currently available and developing treatment strategies against HBV infection.
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Tak WY, Yang JM, Kim BI, Baik SK, Cheon GJ, Byun KS, Kim DY, Yoo BC. A randomized, open-label study comparing low-dose clevudine plus adefovir combination therapy with clevudine monotherapy in naïve chronic hepatitis B patients. Hepatol Int 2014; 8:375-81. [PMID: 25101150 PMCID: PMC4116600 DOI: 10.1007/s12072-014-9537-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 04/21/2014] [Indexed: 01/05/2023]
Abstract
Purpose Clevudine 30 mg showed potent antiviral activity with a marked post-treatment antiviral effect. However, long-term treatment with clevudine monotherapy induced resistance and myopathy in some cases. The objective of this study is to evaluate the preliminary efficacy and safety of the combination of clevudine 20 mg and adefovir compared to clevudine monotherapy. Methods Seventy-four patients were randomized to either a combination of clevudine 20 mg and adefovir or clevudine 20 or 30 mg and were treated for 2 years. The viral kinetics for 24 weeks, virological response [VR; hepatitis B virus (HBV) DNA less than 300 copies/ml], and the biochemical response [BR; normal alanine aminotransferase (ALT)] were assessed. Results There was no difference in baseline characteristics among the three groups. Viral kinetics study showed no statistically significant difference among them during 24 weeks. The combination group showed 95 % virological response with a statistically significant difference compared to the clevudine 30 mg (67 %) and 20 mg (71 %) groups (p = 0.0376). Biochemical response rates were similar in all groups (78–94 %). No resistance was reported in the combination group, while 20 % of patients treated with clevudine 30 mg or 20 mg reported resistance during 2 years. Muscle-related symptoms such as myalgia (1 in clevudine 30 mg, 1 in the combination group) and muscle weakness (1 in clevudine 30 mg, 2 in clevudine 20 mg) were reported in five patients (7 %); of these, three patients discontinued the study. Conclusion We concluded that the combination of clevudine 20 mg and adefovir produced a potent antiviral response together with a good resistance profile compared to clevudine monotherapy at 96 weeks in this pilot study.
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Affiliation(s)
- Won Young Tak
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Jin Mo Yang
- Department of Internal Medicine, The Catholic University Medical College St. Vincent’s Hospital, Suwon, Republic of Korea
| | - Byung Ik Kim
- Division of Gastroenterology and Hepatology, Kangbook Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Soon Koo Baik
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Gab Jin Cheon
- Department of Internal Medicine, GangNeung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea
| | - Kwan Soo Byun
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byung Chul Yoo
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Hardikar W, Schwarz KB. Treatment options for chronic hepatitis B and C infection in children. Expert Rev Anti Infect Ther 2014; 4:583-91. [PMID: 17009938 DOI: 10.1586/14787210.4.4.583] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
There has been a dramatic increase in treatment options for both chronic hepatitis B (CHB) and chronic hepatitis C (CHC) infection in adults over the past 5-10 years, resulting in standardized regimes for initial treatment, relapsers and even infection in the setting of recurrence post-liver transplantation. These regimes have resulted in the halting of the disease progression, reduction in the risk of hepatocellular carcinoma and removal of these infections as a contraindication for liver transplantation. However, treatment in children must be considered carefully in the context of the natural history of these infections and host factors, particularly the immunological mileu, which may affect response to therapy. The as yet unknown long-term effects of medications must also be balanced with the probability of significant life-long morbidity or mortality from chronic hepatitis and its complications. Furthermore, the development of drug resistance, particularly in the case of CHB, has significant implications for the pediatric patient who may exhaust effective therapeutic options at a relatively young age. For these reasons, initiation of therapy must be based on sound criteria. Based on the current data, we recommend that therapy should be offered to children with CHB who have an elevation in alanine aminotransferase (>2-3 x upper limit of normal) for more than 6 months. Therapy with interferon-alpha should be offered in the majority of cases with the aim of immune clearance as measured by early antigen seroconversion. By contrast, treatment indication for CHC in children remains controversial. If used, combination therapy with pegylated interferon and ribavirin is likely to produce the highest rates of sustained viral response.
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Affiliation(s)
- Winita Hardikar
- Royal Children's Hospital, Department of Gastroenterology and Nutrition, Melbourne, Australia.
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Noncompetitive inhibition of hepatitis B virus reverse transcriptase protein priming and DNA synthesis by the nucleoside analog clevudine. Antimicrob Agents Chemother 2013; 57:4181-9. [PMID: 23774432 DOI: 10.1128/aac.00599-13] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
All currently approved antiviral drugs for the treatment of chronic hepatitis B virus (HBV) infection are nucleos(t)ide reverse transcriptase inhibitors (NRTI), which inhibit the DNA synthesis activity of the HBV polymerase. The polymerase is a unique reverse transcriptase (RT) that has a novel protein priming activity in which HP initiates viral DNA synthesis using itself as a protein primer. We have determined the ability of NRTI-triphosphates (TP) to inhibit HBV protein priming and their mechanisms of action. While entecavir-TP (a dGTP analog) inhibited protein priming initiated specifically with dGTP, clevudine-TP (a TTP analog) was able to inhibit protein priming independently of the deoxynucleoside triphosphate (dNTP) substrate and without being incorporated into DNA. We next investigated the effect of NRTIs on the second stage of protein priming, wherein two dAMP nucleotides are added to the initial deoxyguanosine nucleotide. The obtained results indicated that clevudine-TP as well as tenofovir DF-DP strongly inhibited the second stage of protein priming. Tenofovir DF-DP was incorporated into the viral DNA primer, whereas clevudine-TP inhibited the second stage of priming without being incorporated. Finally, kinetic analyses using the HBV endogenous polymerase assay revealed that clevudine-TP inhibited DNA chain elongation by HP in a noncompetitive manner. Thus, clevudine-TP appears to have the unique ability to inhibit HBV RT via binding to and distorting the HP active site, sharing properties with both NRTIs and nonnucleoside RT inhibitors.
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Janmanchi D, Lin CH, Hsieh JY, Tseng YP, Chen TA, Jhuang HJ, Yeh SF. Synthesis and biological evaluation of helioxanthin analogues. Bioorg Med Chem 2013; 21:2163-76. [DOI: 10.1016/j.bmc.2012.11.037] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Revised: 11/20/2012] [Accepted: 11/21/2012] [Indexed: 12/18/2022]
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Kim BK, Ko SY, Kwon SY, Park E, Kim JH, Choe WH, Lee CH. Virological Response and Muscular Adverse Events during Long-Term Clevudine Therapy in Chronic Hepatitis B Patients. HEPATITIS MONTHLY 2013; 13:e6056. [PMID: 23805155 PMCID: PMC3693539 DOI: 10.5812/hepatmon.6056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2012] [Revised: 05/24/2012] [Accepted: 05/26/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recently, several reports issued clevudine induced myopathy in the long term use. OBJECTIVES The aim of this study was to investigate antiviral effects and adverse events of clevudine monotherapy in patients with chronic hepatitis B (CHB). PATIENTS AND METHODS The subjects were 110 treatment-naïve CHB patients. They were treated with 30 mg clevudine/day for more than six months. Virological and biochemical tests, including that for serum creatine kinase (CK), were monitored at baseline and at 3-month intervals during treatment period. RESULTS In HBeAg-positive patients, the cumulative rates of virological response were 74.0 %, 68.5 %, and 67.3 % after one, two, and three years of clevudine treatment, respectively. Cumulative rates of HBeAg loss or seroconversion were 17.8 %, 30 %, and 31.5 % after one, two and, three years of clevudine treatment, respectively. In HBeAg-negative patients, the cumulative rates of virological response were 97.3 %, 100 %, and 94.6 %, respectively. Virological breakthrough occurred in 27 patients. The rtM204I mutation in HBV polymerase was predominantly detected. Muscular adverse events were observed in 15 patients. All patients with myopathy recovered after the cessation of clevudine monotherapy. Fluctuations in CK level during the clevudine treatment period were frequently observed irrespective of development of myopathy. Multiple episodes of CK elevation were significantly related to the development of myopathy. CONCLUSIONS Long-term clevudine monotherapy is effective for suppression of serum HBV DNA level and normalization of serum alanine amino transaminase levels, but associated with occurrence of rtM204I mutation. Clevudine-induced muscular adverse events are not uncommon, although they are totally reversible after cessation of the treatment. Muscular adverse events and serum CK level should be carefully monitored during long-term treatment with clevudine.
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Affiliation(s)
- Byung Kook Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
| | - Soon Young Ko
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
- Corresponding author: So Young Kwon, Department of Internal Medicine, Konkuk University School of Medicine, Konkuk University Medical center, 4-12 Hwayang-dong, Gwangjin-gu, Seoul, 143-729, Korea. Tel.: +82-220305010, Fax: +82-220305029, E-mail:
| | - Eugene Park
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
| | - Jeong Han Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
| | - Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
| | - Chang Hong Lee
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 143-729, Korea
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Kim JH, Yim HJ, Jung ES, Jung YK, Kim JH, Seo YS, Yeon JE, Lee HS, Um SH, Byun KS. Virologic and biochemical responses to clevudine in patients with chronic HBV infection-associated cirrhosis: data at week 48. J Viral Hepat 2011; 18:287-93. [PMID: 20367793 DOI: 10.1111/j.1365-2893.2010.01304.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Clevudine shows high rates of virologic and biochemical responses in patients with chronic hepatitis B. However, the efficacy and safety of clevudine in patients with cirrhosis are unknown. The aims of this study were to evaluate the safety and to assess the virologic and the biochemical responses to clevudine in patients with cirrhosis with chronic hepatitis B virus (HBV) infection. We reviewed data from treatment-naïve patients with chronic hepatitis B with and without cirrhosis who started clevudine between April 2007 and March 2008 (n = 52, hepatitis B without cirrhosis n = 21 and chronic hepatitis B with cirrhosis n = 31) at Korea University Ansan/Guro Hospital. All of the patients were treated for more than 48 weeks. The mean age was older in the patients with cirrhosis. Baseline HBV DNA levels were 6.9 and 7.78 log copies/mL (P = 0.042), and alanine aminotransferase (ALT) levels were 104.9 and 147.4 IU/L (P = 0.204), for those with and without cirrhosis, respectively. Virologic response (HBV DNA <1000 copies/mL) (87.1%vs 71.4%, P = 0.24) and biochemical response (83.9%vs 80.9%, P = 0.99) at week 48 were not significantly different between the two groups. Early virologic response at week 12 was even higher in the patients with cirrhosis (61.3%vs 28.6%, P = 0.026). Neither ALT flare nor newly onset hepatic decompensation was found in the patients with cirrhosis, whereas ALT flare was transiently observed in 14.3% of the chronic hepatitis group. In conclusion, although clevudine may produce a transient elevation of ALT during the early treatment period, such findings were not observed in patients with cirrhosis and the virologic and biochemical responses of the groups were comparable.
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Affiliation(s)
- J H Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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Woo SM, Park JW, Lee WJ, Kim CM. Clinical and virological responses to clevudine therapy of hepatocelluar carcinoma patients with chronic hepatitis B. Gut Liver 2011; 5:82-7. [PMID: 21461078 DOI: 10.5009/gnl.2011.5.1.82] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2010] [Accepted: 12/13/2010] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIMS The clinical effects of clevudine have been reported in patients with chronic hepatitis B virus infections (CHIs). In this investigation, we assessed whether clevudine induced biochemical and virological improvements in hepatocellular carcinoma (HCC) patients with CHI. METHODS Fifty-four patients who received 30 mg clevudine for more than 24 weeks between 2007 and 2009 at the National Cancer Center Hospital, Korea, were enrolled. Among these cases, 39 had HCC (CHI/HCC group) and 15 did not (CHI group). RESULTS In relation to the CHI group, the CHI/HCC group was older (55.5 years.) and had a higher liver cirrhosis rate (79.5%) (p<0.05). Median changes in serum hepatitis B virus (HBV) DNA levels from baseline at weeks 12, 24, and 36 of treatment in the CHI/HCC group were not significantly different from those of the CHI group (-2.3, -2.7, -2.6 vs -1.7, -1.8, -2.4, respectively). HBV DNA <2,000 copies/mL was achieved in 76.5% of the CHI/HCC group at 24 weeks. Rates of ALT normalization in the CHI/HCC and CHI groups were 62.5% and 66.7%, respectively (p>0.05). Liver function was preserved with clevudine treatment in patients displaying response or stable disease under anti-cancer therapy. Four patients (7.4%) developed viral resistance during clevudine therapy. Among these, one was naïve, and three had previously received antiviral therapy. One CHI/HCC patient (1.9%) discontinued clevudine treatment due to symptomatic myopathy. CONCLUSIONS Our findings clearly indicate that clevudine has comparable antiviral and biochemical effects in patients with CHI and with CHI/HCC and preserves the underlying liver function in HBV-related HCC patients.
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Affiliation(s)
- Sang Myung Woo
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
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Yang HW, Lee BS, Lee TH, Lee HY, Nam KW, Kang YW, Chae HB, Kim SH, Kim SB, Lee HI, Kim AN, Song IH, Lee SH, Kim HS. Efficacy of initial treatment with clevudine in naive patients with chronic hepatitis B. Korean J Intern Med 2010; 25:372-6. [PMID: 21179274 PMCID: PMC2997965 DOI: 10.3904/kjim.2010.25.4.372] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2009] [Revised: 01/22/2010] [Accepted: 09/14/2010] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND/AIMS Clevudine, a pyrimidine nucleoside analogue, has potent antiviral effects in patients with chronic viral hepatitis B (CHB). We report the efficacy of initial treatment with clevudine in naïve patients with CHB living in Daejeon and Chungcheong Province, South Korea. METHODS One hundred five adults with CHB were administered 30 mg of clevudine per day for an average of 51 weeks. We evaluated viral markers and liver biochemistry retrospectively every 3 months. RESULTS Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatitis B virus (HBV) DNA before the treatment were 184 ± 188 IU/L, 150 ± 138 IU/L, and 7.1 ± 1.2 log copies/mL, respectively. Undetectable rates (< 60 IU/mL) of DNA were 36.2%, 68.9%, 83.6%, 76.2%, and 75.8% at 12, 24, 36, 48, and 60 weeks, respectively. Seroconversion rates were 9.1%, 13.6%, 24.6%, 26.5%, and 26.1% and ALT normalization rates were 64.5%, 78.1%, 87.9%, 90.0% at 12, 24, 36, and 48 weeks, respectively. Six patients (5.7%) had a viral breakthrough. CONCLUSIONS Clevudine is a useful drug in the initial treatment of patients with CHB, with a potent antiviral effect and low incidence of viral breakthrough.
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Affiliation(s)
- Hyeon Woong Yang
- Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea
| | - Byung Seok Lee
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Tae Hee Lee
- Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea
| | - Heon Young Lee
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Kwan Woo Nam
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Young Woo Kang
- Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea
| | - Hee Bok Chae
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Seok Hyun Kim
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Seok Bae Kim
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
| | - Hyang Ie Lee
- Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea
| | - An Na Kim
- Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea
| | - Il Han Song
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Hong Su Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
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Tak WY, Park SY, Cho CM, Jung MK, Jeon SW, Kweon YO, Park JY, Sohn YK. Clinical, biochemical, and pathological characteristics of clevudine-associated myopathy. J Hepatol 2010; 53:261-6. [PMID: 20466447 DOI: 10.1016/j.jhep.2010.03.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2009] [Revised: 03/04/2010] [Accepted: 03/09/2010] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The aim of this study was to define the clinical, biochemical, and pathological characteristics of myopathy developed during clevudine therapy. METHODS We prospectively enrolled 36 consecutive myopathy patients who were receiving clevudine therapy for the treatment of chronic hepatitis B (CHB). We evaluated patients with a complete medical history, neurologic examination with a questionnaire on neuromuscular diseases, laboratory tests, electrophysiology studies, and muscle biopsies. RESULTS The median duration of clevudine therapy was 18.0 months (ranging from 9 to 24 months). The chief complaint was weakness of the lower extremities in 30 patients (83.3%) and asthenia in five patients (13.9%). One patient (2.8%) had only persistently elevated serum muscle enzyme without any symptoms. Weakness of the lower extremity mainly involved proximal muscle group of the lower extremity, characterized by difficulty in climbing stairs (83.3%), a decrease in exercise capacity (75.0%) and difficulty in walking (55.6%). All patients showed an elevation of more than two of serum creatine kinase, lactate dehydrogenase, and lactate levels. Muscle biopsies performed in 23 patients revealed myopathic features with abnormal mitochondria in 21 patients, and nonspecific myositis in two patients. Motor weakness gradually improved after discontinuation of clevudine. CONCLUSIONS Myopathy associated with clevudine is characterized by a weakness in proximal muscles of the lower extremities with elevated muscle enzymes and presumably caused by mitochondrial toxicities. Careful medical and serologic examinations are essential for the early detection and management of this potential adverse reaction in CHB patients under clevudine therapy.
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Affiliation(s)
- Won Young Tak
- Department of Internal Medicine, Liver Research Institute, Graduate School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
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Hynicka LM, Yunker N, Patel PH. A Review of Oral Antiretroviral Therapy for the Treatment of Chronic Hepatitis B. Ann Pharmacother 2010; 44:1271-86. [DOI: 10.1345/aph.1m590] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Objective: To describe the current evidence for the use of oral antiretroviral (ARV) agents in the treatment of chronic hepatitis B (CHB). Data Sources: A search from 1950 to April 2010 was conducted using the databases PubMed and MEDLINE with the search terms chronic hepatitis B, lamivudine, entecavir, adefovir, telbivudine, tenofovir, emtricitabine, clevudine, and pradefovir. The search was limited to trials conducted in humans that were published in the English language. Study Selection and Data Extraction: Studies were included if they evaluated the use of oral ARVs in patients with CHB infection who were not coinfected with hepatitis C, hepatitis D, or HIV. Data Synthesis: Oral ARVs have revolutionized the treatment of CHB. Studies conducted comparing ARVs have favored entecavir and tenofovir with respect to their ability to decrease hepatitis B virus DNA viral load while minimizing the development of resistance. However, low seroconversion rates, recurrent viremia when ARV therapy is discontinued, and increased resistance rates with longer treatment durations limit the benefit of oral ARVs in the treatment of CHB. Combination therapy has been a suggested solution; however, studies have yet to prove additional benefit over currently recommended monotherapy. Conclusions: Oral ARVs should continue to be used in the treatment of CHB; however, research is needed to define the optimal duration of therapy, evaluate the utility of combination therapy, and explore novel targets within the hepatitis B life cycle.
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Affiliation(s)
| | - Nancy Yunker
- School of Pharmacy, Virginia Commonwealth University, Richmond, VA
| | - Punam H Patel
- Solid Organ Transplant, Virginia Commonwealth University Health System
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Kim IH, Lee S, Kim SH, Kim SW, Lee SO, Lee ST, Kim DG, Choi CS, Kim HC. Treatment outcomes of clevudine versus lamivudine at week 48 in naïve patients with HBeAg positive chronic hepatitis B. J Korean Med Sci 2010; 25:738-745. [PMID: 20436711 PMCID: PMC2858834 DOI: 10.3346/jkms.2010.25.5.738] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2009] [Accepted: 09/28/2009] [Indexed: 12/21/2022] Open
Abstract
The authors assessed the efficacy and antiviral resistance of 48-week clevudine therapy versus lamivudine in treatment of naïve patients with HBeAg positive chronic hepatitis B. In this retrospective study, a total of 116 HBeAg positive patients, who received 30 mg of clevudine once daily (n=53) or 100 mg of lamivudine once daily (n=63) for 48 weeks, were included. At week 48, clevudine therapy produced a significantly greater mean reductions in serum HBV DNA levels from baseline than lamivudine therapy (-5.2 vs. -4.2 log(10)IU/mL; P=0.005). Furthermore, a significantly higher proportion of patients on clevudine achieved negative serum HBV DNA by PCR (<13 IU/mL) at week 48 (60.4% vs. 38.1%; P=0.025). The incidence of virologic breakthrough in the clevudine group was significantly lower than in the lamivudine group (9.4% vs. 25.4%; P=0.031). However, rates of alanine aminotransferase normalization and HBeAg loss or seroconversion were similar in the two groups (83.0% vs. 81.0%, 11.3% vs. 11.1%; P=0.813, 1.000, respectively). In conclusion, clevudine is more potent for viral suppression and lower for antiviral resistance at week 48 than lamivudine in treatment of naïve patients with HBeAg positive chronic hepatitis B.
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Affiliation(s)
- In Hee Kim
- Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Korea
- The Research Institute for Medical Science, Chonbuk National University Medical School and Hospital, Jeonju, Korea
| | - Seok Lee
- Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Korea
- The Research Institute for Medical Science, Chonbuk National University Medical School and Hospital, Jeonju, Korea
| | - Seong Hun Kim
- Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Korea
- The Research Institute for Medical Science, Chonbuk National University Medical School and Hospital, Jeonju, Korea
| | - Sang Wook Kim
- Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Korea
- The Research Institute for Medical Science, Chonbuk National University Medical School and Hospital, Jeonju, Korea
| | - Seung Ok Lee
- Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Korea
- The Research Institute for Medical Science, Chonbuk National University Medical School and Hospital, Jeonju, Korea
| | - Soo Teik Lee
- Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Korea
- The Research Institute for Medical Science, Chonbuk National University Medical School and Hospital, Jeonju, Korea
| | - Dae Ghon Kim
- Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Korea
- The Research Institute for Medical Science, Chonbuk National University Medical School and Hospital, Jeonju, Korea
| | - Chang Soo Choi
- Department of Internal Medicine, Wonkwang University College of Medicine and Hospital, Iksan, Korea
| | - Haak Cheoul Kim
- Department of Internal Medicine, Wonkwang University College of Medicine and Hospital, Iksan, Korea
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Janmanchi D, Tseng YP, Wang KC, Huang RL, Lin CH, Yeh SF. Synthesis and the biological evaluation of arylnaphthalene lignans as anti-hepatitis B virus agents. Bioorg Med Chem 2010; 18:1213-26. [DOI: 10.1016/j.bmc.2009.12.038] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2009] [Revised: 12/10/2009] [Accepted: 12/11/2009] [Indexed: 12/11/2022]
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Fleischer RD, Lok ASF. Myopathy and neuropathy associated with nucleos(t)ide analog therapy for hepatitis B. J Hepatol 2009; 51:787-91. [PMID: 19665816 DOI: 10.1016/j.jhep.2009.06.011] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The development of clevudine as a treatment for hepatitis B was terminated recently because of case reports of myopathy. In each case, the onset of symptoms occurred between 8 and 13 months after the initiation of treatment. Electromyography and muscle biopsy confirmed the presence of myonecrosis. One report also found evidence of mitochondrial toxicity. The delayed onset and the finding of mitochondrial damage are reminiscent of fialuridine toxicity. Telbivudine has also been reported to be associated with myopathy and neuropathy, particularly when used in combination with pegylated interferon. These findings serve as a sober reminder of the lack of data on long-term safety of nucleos(t)ide analogs for hepatitis B, the importance of balancing benefits versus risks before initiating treatment, and the need for more stringent post-marketing surveillance for drug toxicities.
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Affiliation(s)
- Russell D Fleischer
- Division of Antiviral Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
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Kim BK, Oh J, Kwon SY, Choe WH, Ko SY, Rhee KH, Seo TH, Lim SD, Lee CH. Clevudine myopathy in patients with chronic hepatitis B. J Hepatol 2009; 51:829-34. [PMID: 19615776 DOI: 10.1016/j.jhep.2009.04.019] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Revised: 03/23/2009] [Accepted: 04/20/2009] [Indexed: 12/14/2022]
Abstract
Clevudine (L-FMAU) is a thymidine l-nucleoside analogue that was recently introduced for the treatment of chronic hepatitis B virus infection. Previous studies showed that clevudine has potent and sustained antiviral activity without causing viral resistance. No severe adverse event occurred during clinical trials. We describe two cases of drug-induced myopathy during long-term treatment of chronic hepatitis B with clevudine.
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Affiliation(s)
- Byung Kook Kim
- Department of Internal Medicine, Konkuk University School of Medicine, 4-12 Hwayang-dong, Gwangjin-gu, Seoul 143-729, Republic of Korea
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Scarsi KK, Darin KM. Chronic Hepatitis B Infection: Principles of Therapy. J Pharm Pract 2009; 22:359-387. [DOI: 10.1177/0897190008328692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Chronic hepatitis B is a global health concern in many resource-limited settings due to perinatal or pediatric hepatitis B virus transmission. In the United States, pediatric infection has been virtually eliminated due to maternal screening during pregnancy and the availability of an effective vaccine. However, young adults remain an at-risk group for hepatitis B virus infection due to sexual transmission and injection drug use. The frequency of progression from acute hepatitis B virus infection to chronic hepatitis B infection depends on multiple factors, including host immune function and age at time of hepatitis B virus infection. Fortunately, there are 7 currently approved therapies for chronic hepatitis B infection, and several emerging therapies that show promise. Despite the availability of these agents, many clinical questions still surround chronic hepatitis B therapy including when to start therapy, which agent is ideal for first and second line therapy, the appropriate duration of therapy, and the role of combination antiviral therapy. This review focuses on agents available for chronic hepatitis B management, including pharmacology, safety and efficacy data, monitoring parameters, and the role for each in chronic hepatitis B therapy in adult patients.
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Affiliation(s)
- Kimberly K. Scarsi
- Northwestern University Feinberg School of Medicine, Division of Infectious Diseases, Chicago,
| | - Kristin M. Darin
- Northwestern University Feinberg School of Medicine, Division of Infectious Diseases, Chicago
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Clevudine for Chronic Hepatitis B. INFECTIOUS DISEASES IN CLINICAL PRACTICE 2009. [DOI: 10.1097/ipc.0b013e318198d88d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Stein LL, Loomba R. Drug targets in hepatitis B virus infection. Infect Disord Drug Targets 2009; 9:105-16. [PMID: 19275699 DOI: 10.2174/187152609787847677] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus infection (HBV) is a significant global health problem. Despite the success of universal hepatitis B vaccination in many countries, more than 350 million individuals worldwide are chronically infected and 15- 40% of those will develop cirrhosis and/or hepatocellular carcinoma if left untreated. Available therapies for chronic hepatitis B (CHB) infection are effective at decreasing viremia and improving measured clinical outcomes, however, no single therapy is optimal. As such, alternative drug therapies and the investigation of their role in the management of CHB are warranted. Significant improvements in the understanding of the HBV life cycle, viral genomics, and virus-host interactions continue to lead to the development of novel viral targets and immune modulators. Currently, two major classes of agents are utilized in CHB: the interferons and the nucleos(t)ide analogues. Each agent has individual advantages and drawbacks. The development of specific antiviral therapy has led to the emergence of HBV drug-resistant strains that has limited the long-term therapeutic potential of available agents. This necessitates the development of new agents that target both wild-type and drug-resistant strains. Further understanding of the basic mechanisms and clinical nuances of drug therapy is warranted. As most novel therapies are in the earliest stages of clinical development and testing, in the near future, treatment will continue to be long-term and likely involve the use of combination therapies to prevent viral resistance. In this review, we will highlight the HBV life cycle and genome, focusing in on current and potential novel antiviral drug targets as well as the benefits and clinical challenges with these therapies.
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Affiliation(s)
- Lance L Stein
- Division of Gastroenterology, Department of Medicine, University of California - San Diego, CA, USA
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Ko SY, Kwon SY, Choe WH, Kim BK, Kim KH, Lee CH. Clinical and Virological Responses to Clevudine Therapy in Chronic Hepatitis B Patients: Results at 1 Year of an Open-Labelled Prospective Study. Antivir Ther 2009. [DOI: 10.1177/135965350901400401] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background A previous clinical study of oral clevudine monotherapy for 24 weeks demonstrated that it has potent sustained antiviral effects without inducing drug resistance. The aim of this study was to evaluate the antiviral effects and safety of clevudine monotherapy for 12 months. Methods In this open-labelled prospective study, 45 treatment-naive chronic hepatitis B patients treated with 30 mg clevudine once daily for 12 months were monitored at baseline and at 3-month intervals during treatment. Results At baseline, the mean age of patients was 42 years, 32 were hepatitis B e antigen (HBeAg)-positive and 15 had liver cirrhosis. After 12 months of clevudine therapy, the mean serum hepatitis B virus (HBV) DNA level in HBeAg-positive patients had decreased by 4.6 log10 IU/ ml. Serum HBV DNA was undetectable in 68.7% of patients. HBeAg loss or seroconversion was observed in five patients (15.6%) and serum alanine aminotransferase (ALT) level had normalized after 12 months of treatment in 75% of patients. In all 13 HBeAg-negative patients, serum HBV DNA level was undetectable after 12 months of therapy and ALT level was normal in 61.5% of patients. Viral breakthrough occurred in one patient after 9 months of clevudine treatment. This patient had an HBV polymerase mutation, rtM204I. There were no serious adverse events. Conclusions One-year clevudine therapy is effective for suppressing serum HBV DNA level and for normalization of ALT level. Viral breakthrough associated with the rtM204I mutation in the HBV polymerase gene occurs during long-term clevudine treatment.
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Affiliation(s)
- Soon Young Ko
- Department of Internal Medicine, Konkuk University School of Medicine, Konkuk University Medical Center, Seoul, South Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Konkuk University Medical Center, Seoul, South Korea
| | - Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Konkuk University Medical Center, Seoul, South Korea
| | - Byung Kook Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Konkuk University Medical Center, Seoul, South Korea
| | - Kyun-Hwan Kim
- Department of Pharmacology, Konkuk University School of Medicine, Seoul, South Korea
| | - Chang Hong Lee
- Department of Internal Medicine, Konkuk University School of Medicine, Konkuk University Medical Center, Seoul, South Korea
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Yim HJ. [Hepatitis B virus genetic diversity and mutant]. THE KOREAN JOURNAL OF HEPATOLOGY 2009; 14:446-64. [PMID: 19119240 DOI: 10.3350/kjhep.2008.14.4.446] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) is a partially double stranded DNA virus with genetic diversity represented by eight genotypes (A to H). Natural course and response to treatment could be affected by HBV genotypes. HBV shows high rates of turn over in the absence of proof-reading ability. As a result, large amounts of quasispecies are produced naturally or antiviral-associated. HBV consists of four open reading frames, namely preS/S gene, precore/core gene, polymerase gene, and X gene. Mutations on preS gene can result in undetectable HBsAg even in case that HBV is replicating. Surface gene mutation leads to decreased binding affinity to anti-HBs, which is associated with a vaccine escape mutant. Precore mutation abolishes HBeAg whereas mutations on basal core promoter gene down-regulate the HBeAg production. Mutations on basal core promoter are associated with increased HBV replication and high incidence of progressive liver diseases such as liver cirrhosis and hepatocellular carcinoma. Mutations on polymerase genes are often induced by antiviral therapy. Emergence of antiviral-resistant mutation is the major cause of treatment failure. Furthermore, existence of prior antiviral-resistant mutations limits the options of subsequent antiviral agents. Therefore, judicious use of antivirals and selection of the most potent drug with the lowest resistance rate are of the utmost importance for the prevention of antiviral-associated mutants. Detailed knowledge and understanding of HBV genetic diversity and mutant would be critical to establish strategies for the diagnosis and management of HBV infection.
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Affiliation(s)
- Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Ansan, Korea.
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Gupta S, Altice FL. Hepatitis B virus infection in US correctional facilities: a review of diagnosis, management, and public health implications. J Urban Health 2009; 86:263-79. [PMID: 19184447 PMCID: PMC2648882 DOI: 10.1007/s11524-008-9338-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2008] [Accepted: 11/12/2008] [Indexed: 12/22/2022]
Abstract
Among the blood-borne chronic viral infections, hepatitis B virus (HBV) infection is one that is not only treatable but also preventable by provision of vaccination. Despite the availability of HBV vaccine for the last 15 years, more than 1.25 million individuals in the USA have chronic HBV infection, and about 5,000 die each year from HBV-related complications. From a societal perspective, access to treatment of chronic viral infections, like HIV and viral hepatitis, is highly cost-effective and has lasting benefits by reducing risk behaviors, morbidity, mortality, as well as disease transmission in the community. Individuals in correctional facilities are specially predisposed to such chronic viral infections because of their high-risk behaviors. The explosion of incarceration in the USA over the last few decades and the disproportionate burden of morbidity and mortality from chronic infections among the incarcerated have put incredible strains on an overcrowded system that was not originally designed to provide comprehensive medical care for chronic illnesses. Recently, there has been a call to address medical care for individuals with chronic medical conditions in correctional settings, including those with infectious diseases. The economic and public health burden of chronic hepatitis B and its sequelae, including cirrhosis and hepatocellular carcinoma, is felt most prominently in managed care settings with limited budgets, like correctional facilities. Prevalence of HBV infection among the incarcerated in the USA is fivefold that of the general population. We present a review of diagnosis, prevention, and the recently streamlined treatment guidelines for management of HBV infection in correctional settings, and discuss the implications and public health impact of these measures.
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Affiliation(s)
- Shaili Gupta
- Section of Infectious Diseases, AIDS Program, Yale University School of Medicine, New Haven, CT 06510-2283, USA.
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30
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Kim JY, Yoon YS, Park KD, Koo H. Myopathy due to Chronic Clevudine Therapy - A Case Report -. KOREAN JOURNAL OF PATHOLOGY 2009. [DOI: 10.4132/koreanjpathol.2009.43.6.575] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Jee Young Kim
- Department of Neurology, Ewha Medical Reseach Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Young Shin Yoon
- Department of Neurology, Ewha Medical Reseach Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Kee Duk Park
- Department of Neurology, Ewha Medical Reseach Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Heasoo Koo
- Department of Pathology, Ewha Medical Reseach Institute, Ewha Womans University School of Medicine, Seoul, Korea
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31
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Asselah T, Lada O, Moucari R, Marcellin P. Clevudine: a promising therapy for the treatment of chronic hepatitis B. Expert Opin Investig Drugs 2008; 17:1963-74. [PMID: 19012511 DOI: 10.1517/13543780802535760] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Feitelson MA, Clayton MM, Reis HM, Wu G, Lu EP. Pharmacotherapy of chronic viral hepatitis and hepatocellular carcinoma. Expert Opin Pharmacother 2008; 9:2233-45. [PMID: 18710349 DOI: 10.1517/14656566.9.13.2233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) is a major etiologic agent of chronic liver disease (CLD) and hepatocellular carcinoma. Drugs have been developed and shown to be effective against HBV replication. These treatments are often associated with the resolution of CLD. However, they are too expensive, not well tolerated, and result in the development of resistance when given as mono or salvage therapies. In addition, most of these drugs target only the virus polymerase. OBJECTIVE To revitalize the field, drugs with other targets and combination therapies need to be developed. METHODS Major advances in HBV and liver cancer drug development over the past decade, focusing on Phase III trials and FDA-approved compounds, are presented. RESULTS/DISCUSSION A number of potent nucleoside/nucleotide analogs are now available for treatment, but for the long-term management of CLD, the development of combination therapies will probably be required. Development of compounds with new virus targets will enhance the utility of combination therapies. Development of compounds to host targets altered prior to or after the development of liver cancer, as demonstrated by sorafenib, need to be developed. The goal is to devise drug cocktails that will yield sustained virus responses and halt disease progression and tumor development.
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Affiliation(s)
- Mark A Feitelson
- Temple University, Department of Biology, College of Science and Technology, Suite 409, BioLife Science Building, 1900 North 12th Street, Philadelphia, PA 19122, USA.
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Affiliation(s)
- Peng Liu
- The University of Georgia, College of Pharmacy, Athens, GA 30602
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Sharon A, Chu CK. Understanding the molecular basis of HBV drug resistance by molecular modeling. Antiviral Res 2008; 80:339-53. [PMID: 18765256 DOI: 10.1016/j.antiviral.2008.07.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2008] [Revised: 07/25/2008] [Accepted: 07/29/2008] [Indexed: 12/30/2022]
Abstract
Despite the significant successes in the area of anti-HBV agents, resistance and cross-resistance against available therapeutics are the major hurdles in drug discovery. The present investigation is to understand the molecular basis of drug resistance conferred by the B and C domain mutations of HBV-polymerase on the binding affinity of five anti-HBV agents [lamivudine (3TC, 1), adefovir (ADV, 2), entecavir (ETV, 3), telbivudine (LdT, 4) and clevudine (l-FMAU, 5)]. In this regard, homology modeled structure of HBV-polymerase was used for minimization, conformational search and induced fit docking followed by binding energy calculation on wild-type as well as on mutant HBV-polymerases (L180M, M204V, M204I, L180M+M204V, L180M-M204I). Our studies suggest a significant correlation between the fold resistances and the binding affinity of anti-HBV nucleosides. The binding mode studies reveals that the domain C residue M204 is closely associated with sugar/pseudosugar ring positioning in the active site. The positioning of oxathiolane ring of 3TC (1) is plausible due the induced fit orientation of the M204 residue in wild-type, and further mutation of M204 to V204 or I204 reduces the final binding affinity which leads to the drug resistance. The domain B residue L180 is not directly close ( approximately 6A) to the nucleoside/nucleoside analogs, but indirectly associated with other active-site hydrophobic residues such as A87, F88, P177 and M204. These five hydrophobic residues can directly affect on the incoming nucleoside analogs in terms of its association and interaction that can alter the final binding affinity. There was no sugar ring shifting observed in the case of adefovir (2) and entecavir (3), and the position of sugar ring of 2 and 3 is found similar to the sugar position of natural substrate dATP and dGTP, respectively. The exocyclic double bond of entecavir (3) occupied in the backside hydrophobic pocket (made by residues A87, F88, P177, L180 and M204), which enhances the overall binding affinity. The active site binding of LdT (4) and l-FMAU (5) showed backward shifting along with upward movement without enforcing M204 residue and this significant different binding mode makes these molecules as polymerase inhibitors, without being incorporated into the growing HBV-DNA chain. Structural results conferred by these l- and d-nucleosides, explored the molecular basis of drug resistance which can be utilized for future anti-HBV drug discovery.
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Affiliation(s)
- Ashoke Sharon
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA
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35
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Abstract
Three nucleotide/nucleoside analogs are used for chronic hepatitis B (HBV): lamivudine, adefovir dipivoxil, and entecavir. Lamivudine and adefovir are advantageous for oral administration and safety but induce a sustained response after withdrawal of therapy in only a minority of patients. Thus, the treatment should be given in trials in a majority of patients for a long period of time. In addition, the long-term efficacy of lamivudine is limited by the frequent emergence of drug-resistant HBV mutants. Adefovir is associated with a low frequency of resistance, but its antiviral effect is not optimal. Entecavir, a cyclopentyl guanosine analog, is a potent inhibitor of HBV-DNA polymerase and it inhibits both priming and elongation steps of viral DNA replication. In phase II and III clinical trials, entecavir was found to be superior to lamivudine for all primary end points evaluated in both nucleoside-naive and lamivudine-resistant patients, and it was effective in both HBeAg-positive and HBeAg-negative nucleoside-naive patients. Only one trial has shown cases of viral resistance to this drug. The approved dosage in treatment-naive patients is 0.5 mg per day orally, whereas in patients who have failed lamivudine therapy or who are known to harbor lamivudine-resistant mutants, the approved dosage is 1.0 mg per day. Recent preliminary results show that clevudine, telbivudine, and emtricitabine may be potent analogs available for the treatment of HBV. Further studies are being conducted to assess the long-term efficacy and safety of these drugs.
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Abstract
Among current treatment options for chronic hepatitis B, nucleoside/nucleotide analog therapy has better tolerability and most patients respond to the therapy, while interferon (IFN) therapy has rather severe side-effects and a lower response rate. However, nucleoside/nucleotide analog therapies have problems of the emergence of drug resistance and poor sustainability of response after discontinuation. After the first nucleoside/nucleotide analog lamivudine, adefovir and entecavir are now utilized in many countries. Adefovir has efficacy for lamivudine resistant patients and current data suggests that adding adefovir to ongoing lamivudine is better than switching to adefovir in terms of viral suppression and the occurrence of resistance. Entecavir can be the first choice for naïve patients, although cross-resistance has been known for lamivudine resistant patients and mutational screening should take place before using entecavir with such patients. Many other new nucleoside/nucleotide analogs are being developed such as telbivudine, clevudine and tenofovir; the details of each drug will be disclosed in near future.
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Affiliation(s)
- Mari Inada
- Department of Medicine and Clinical Oncology, Postgraduate School of Medicine, Chiba University, Chiba, Japan
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Leung N. Recent data on treatment of chronic hepatitis B with nucleos(t)ide analogues. Hepatol Int 2008; 2:163-78. [PMID: 19669301 PMCID: PMC2716844 DOI: 10.1007/s12072-008-9061-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2007] [Accepted: 01/25/2008] [Indexed: 12/13/2022]
Abstract
Forty years ago in 1967, Professor Blumberg discovered the Australian Antigen, later known as the hepatitis B surface antigen, and was awarded the Nobel Prize. This discovery enables the diagnosis of hepatitis B virus (HBV) infection and defines its epidemiology. Viral hepatitis B infection affects global health situation, and chronic hepatitis B (CHB) is particularly serious in the Asia-Pacific region. HBV vaccines created the first breakthrough in HBV prevention. Through universal HBV vaccination program for the newborns, promoted since the mid-1980s, the main route that perpetuates chronic infection from mother to child is curbed. Most children and young adults now have immunity against HBV infection. The next breakthrough comes with therapy for CHB. This prevents progression to cirrhosis and hepatocellular carcinoma. Standard interferon therapy with modest efficacy has been largely replaced by therapy with nuclos(t)ide analogues or pegylated interferons alfa-2a and -2b. Lamivudine was approved by the FDA USA in 1998, followed by adefovir dipivoxil in 2002, entecavir in 2005, and telbivudine in 2006. Clevudine, tenofovir, and many promising candidates are in different stages of development and clinical trial. This paper critically reviews recent data published or presented since the APASL Consensus and Guideline Update of 2005. Clinical efficacy mostly in patients with raised serum alanine aminotransferase will be analyzed.
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Affiliation(s)
- Nancy Leung
- Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Room 65, J6, 11 Chuen On Road, Taipo, NT, Hong Kong,
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38
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Lim SG, Leung N, Hann HWL, Lau GKK, Trepo C, Mommeja-Marin H, Moxham C, Sorbel J, Snow A, Blum MR, Rousseau F, Marcellin P. Clinical trial: a phase II, randomized study evaluating the safety, pharmacokinetics and anti-viral activity of clevudine for 12 weeks in patients with chronic hepatitis B. Aliment Pharmacol Ther 2008; 27:1282-1292. [PMID: 18363895 DOI: 10.1111/j.1365-2036.2008.03686.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Clevudine is a polymerase inhibitor that has the unusual feature of delayed viral rebound after therapy in some patients which may be related to its pharmacokinetics. AIM To characterize pharmacokinetic and pharmacodynamic profile of clevudine, a potent hepatitis B polymerase inhibitor. METHODS A multicenter, randomized study comparing 10, 30 and 50 mg clevudine once daily for 12 weeks with 24 weeks off-treatment follow-up. Patients had chronic HBV infection, were nucleoside-naïve without co-infection. HBV viral load (VL) was assayed using Digene Hybrid Capture II with a lower limit of detection of 4700 copies/mL (940 IU/mL). Clevudine levels were measured using a liquid chromatography/mass spectrometery method. RESULTS A total of 31 patients were enrolled into the 10 mg (n = 10), 30 mg (n = 11) and 50 mg (n = 10) groups, respectively. At week 12, the median VL change was -3.2, -3.7 and -4.2 log(10) copies/mL (-0.64, -0.74 and -0.84 log(10) IU/mL) in the 10, 30 and 50 mg groups, respectively (P = 0.012). At week 12, one of 10, five of 11 and two of 10 patients had VL below the assay lower limit of detection. Clevudine was well tolerated with no severe/serious adverse events. The mean plasma half-life of clevudine was 70 h and consequently is not the cause of the delayed viral rebound seen in some patients. Through modelling, 97% of the maximal treatment effect was reached with a 30 mg daily dose. Six patients had genomic changes without viral rebound. CONCLUSION Clevudine appears to be a potent and tolerable (over 12 weeks) anti-viral and the optimal dosage appears to be 30 mg once daily.
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Affiliation(s)
- S G Lim
- Department of Gastroenterology and Hepatology, National University Hospital, Yong Yoo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Rd, Singapore 119074.
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Wang GF, Shi LP, Zuo JP. Anti-hepatitis B virus drugs in clinical and preclinical development. Virol Sin 2008. [DOI: 10.1007/s12250-008-2945-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Lim SG. Telbivudine: a hepatitis B-specific antiviral. Expert Rev Clin Pharmacol 2008; 1:217-29. [PMID: 24422647 DOI: 10.1586/17512433.1.2.217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Telbivudine, a l-nucleoside enantiomer, is a potent specific inhibitor of hepatitis B virus (HBV) polymerase. It recently completed Phase III trials and has been licensed in most countries worldwide. It has shown superior efficacy compared with lamivudine in therapeutic response, reduction in HBV DNA, proportion of patients with undetectable HBV DNA, reduced primary treatment failure and reduced viral resistance over 2 years, in Hepatitis B e antigen-positive and -negative patients. Further studies show that switching to telbivudine in lamivudine-suboptimal responders improves the reduction in HBV DNA at week 24 and shows superiority compared with adefovir in reduction of HBV DNA at week 24. Multivariate analysis showed that week 24 HBV DNA best predicted outcomes at 2 years and a 'hepatitis B roadmap' concept has been proposed to manage patients based on this. Thus, telbivudine is a useful addition to the current landscape of hepatitis B therapeutic agents.
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Affiliation(s)
- Seng Gee Lim
- Department of Gastroenterology and Hepatology, National University Hospital, Department of Medicine, Yong Yoo Lin School of Medicine, National University of Singapore, Singapore and Principal Investigator, Immunovirology group, Centre for Molecular Medicine, Co-Principal Investigator, Institute of Molecular and Cell Biology, Biopolis, Singapore.
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Abstract
Four oral antiviral agents have been approved by the United States Food and Drug Administration (FDA) for the treatment of chronic hepatitis B: lamivudine, adefovir, entecavir, and telbivudine. This article reviews the durability of response, dose regimen, predictors of response, safety, and problems with resistance of these four agents and of promising agents currently in phase III clinical trials for the treatment of patients who have hepatitis B e antigen-positive and -negative chronic hepatitis B.
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Affiliation(s)
- Albert D Min
- Division of Digestive Diseases, Beth Israel Medical Center, First Avenue at 16th Street, New York, NY 10003, USA
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42
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Yoo BC, Kim JH, Kim TH, Koh KC, Um SH, Kim YS, Lee KS, Han BH, Chon CY, Han JY, Ryu SH, Kim HC, Byun KS, Hwang SG, Kim BI, Cho M, Yoo K, Lee HJ, Hwang JS, Kim YS, Lee YS, Choi SK, Lee YJ, Yang JM, Park JW, Lee MS, Kim DG, Chung YH, Cho SH, Choi JY, Kweon YO, Lee HY, Jeong SH, Yoo HW, Lee HS. Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off-therapy viral suppression. Hepatology 2007; 46:1041-8. [PMID: 17647293 DOI: 10.1002/hep.21800] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
UNLABELLED Clevudine is a pyrimidine analog with potent and sustained antiviral activity against HBV. In the present study, we evaluated the safety and efficacy of clevudine 30 mg daily for 24 weeks and assessed the durability of antiviral response for 24 weeks after cessation of dosing in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e-CHB). We randomized a total of 86 patients (3:1) to receive clevudine 30 mg (n = 63) or placebo (n = 23) daily for 24 weeks. We followed patients for an additional 24 weeks after withdrawal of treatment. The median changes in HBV DNA from baseline were -4.25 and -0.48 log(10) copies/mL at week 24 in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained after withdrawal of therapy, with 3.11 log(10) reduction at week 48. At week 24 and week 48, 92.1% and 16.4% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (<300 copies/mL). The proportion of patients who achieved ALT normalization was 74.6% and 33.3% in the clevudine and placebo groups at week 24, respectively (P = 0.0006). ALT normalization in the clevudine group was well-maintained during the post-treatment follow-up period. The incidence of adverse events was similar in the 2 groups. No resistance to clevudine was detected during treatment. CONCLUSION A 24-week clevudine therapy was well-tolerated and showed potent and sustained antiviral effect without evidence of viral resistance in e-CHB patients. However, treatment for longer than 24 weeks would be needed to achieve durable remission.
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Affiliation(s)
- Byung Chul Yoo
- Sungkyunkwan University Samsung Medical Center, Seoul, South Korea
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Pardo M, Bartolomé J, Carreño V. Current therapy of chronic hepatitis B. Arch Med Res 2007; 38:661-77. [PMID: 17613358 DOI: 10.1016/j.arcmed.2006.12.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2006] [Accepted: 12/04/2006] [Indexed: 12/24/2022]
Affiliation(s)
- Margarita Pardo
- Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain
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44
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Lee KS, Byun KS, Chung YH, Paik SW, Han JY, Yoo K, Yoo HW, Yoo BC, Lee HS. Clevudine Therapy for 24 Weeks Further Reduced Serum Hepatitis B Virus DNA Levels and Increased ALT Normalization Rates without Emergence of Viral Breakthrough than 12 Weeks of Clevudine Therapy. Intervirology 2007; 50:296-302. [PMID: 17622789 DOI: 10.1159/000105442] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2006] [Accepted: 03/30/2007] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVES The objectives of the study were to evaluate the safety and antiviral activity of 24-week treatment with clevudine 30 mg in HBeAg(+) chronic hepatitis B patients. Biochemical and serological responses were also assessed. METHOD Twenty-one patients received clevudine 30 mg for 24 weeks and were followed up for another 24 weeks off therapy. RESULTS Median decreases from baseline in HBV DNA were 4.65 and 1.96 log(10) copies/ml at week 24 (end of treatment) and week 48 (24 weeks off therapy), respectively. Analysis of individual data showed that HBV DNA levels were below the lower limit of detection (300 copies/ml) by Amplicor PCR assay in 19, 57, 19 and 0% at week 12, 24, 34 and 48, respectively. The proportion of patients with normal ALT were 67, 81 and 75% at week 24 (end of treatment), 34 and 48 (24 weeks off therapy), respectively. The rates of HBeAg loss were 24 and 20% at week 24 and 48, respectively. No viral breakthrough during treatment was observed. CONCLUSION Clevudine 30 mg treatment for 24 weeks was well tolerated and exhibited more potent antiviral activity and a higher ALT normalization rate than 12-week treatment with durable efficacy at week 24 off therapy.
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45
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Abstract
PURPOSE OF REVIEW Coinfection with HIV and hepatitis B virus has a significant impact on the natural history of hepatitis B disease with faster rates of progression to cirrhosis and end stage liver disease. An increasing number of hepatitis B virus active drugs are now available, many of which have dual anti-HIV activity. This review highlights the most important recent developments in the management of HIV and hepatitis B virus coinfection. RECENT FINDINGS Natural history studies continue to confirm the increased rate of liver-related mortality in coinfected individuals and the importance of hepatocellular carcinoma in this population. The most recent studies of adefovir and tenofovir in open label use in coinfected individuals are discussed and new data on the activity of emtricitabine, entecavir and pegylated interferon are presented. Strategies for use of these new options for anti-hepatitis B virus therapy in coinfected individuals are discussed. SUMMARY Prevention of end stage liver disease and hepatocellular carcinoma in the coinfected population is vital and the increasing availability of drugs with potent anti-hepatitis B activity is encouraging. Appropriate diagnosis and monitoring of hepatitis B, coupled with better understanding of the mechanisms of drug resistance, will enable clinicians to manage coinfection more effectively.
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Affiliation(s)
- Gail Matthews
- Viral Hepatitis Clinical Research Program, National Centre in HIV Epidemiology and Clinical Research, Sydney, New South Wales, Australia.
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Yoo BC, Kim JH, Chung YH, Lee KS, Paik SW, Ryu SH, Han BH, Han JY, Byun KS, Cho M, Lee HJ, Kim TH, Cho SH, Park JW, Um SH, Hwang SG, Kim YS, Lee YJ, Chon CY, Kim BI, Lee YS, Yang JM, Kim HC, Hwang JS, Choi SK, Kweon YO, Jeong SH, Lee MS, Choi JY, Kim DG, Kim YS, Lee HY, Yoo K, Yoo HW, Lee HS. Twenty-four-week clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology 2007; 45:1172-8. [PMID: 17464992 DOI: 10.1002/hep.21629] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
UNLABELLED Clevudine is a pyrimidine analogue with potent and sustained antiviral activity against HBV. The present study evaluated the safety and efficacy of 30 mg clevudine once daily for 24 weeks and assessed the durable antiviral response for 24 weeks after cessation of dosing. A total of 243 hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients were randomized (3:1) to receive clevudine 30 mg once daily (n=182) or placebo (n=61) for 24 weeks. Patients were followed for a further 24 weeks off therapy. Median serum HBV DNA reductions from baseline at week 24 were 5.10 and 0.27 log10 copies/mL in the clevudine and placebo groups, respectively (P<0.0001). Viral suppression in the clevudine group was sustained off therapy, with 3.73 log10 reduction at week 34 and 2.02 log10 reduction at week 48. At week 24, 59.0% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (less than 300 copies/mL). The proportion of patients who achieved normalization of alanine aminotransferase (ALT) levels was 68.2% in the clevudine group and 17.5% in the placebo group at week 24 (P<0.0001). ALT normalization in the clevudine group was well maintained during post-treatment follow-up period. The incidence of adverse events (AEs) was similar between the clevudine group and the placebo group. No resistance to clevudine was detected with 24 weeks of administration of drug. CONCLUSION A 24-week clevudine therapy was well tolerated and showed potent and sustained antiviral effect without evidence of viral resistance during treatment period in HBeAg-positive chronic hepatitis B.
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Affiliation(s)
- Byung Chul Yoo
- Samsung Medical Center, Sungkyunkwan University, and Yonsei University Hospital, Seoul, Korea
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Pár A, Tornai I, Szalay F. Experiences on antiviral treatment for chronic viral B and C hepatitis patients in Hungary. 1998–2004. Orv Hetil 2007; 148:819-26. [PMID: 17468063 DOI: 10.1556/oh.2007.28114] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Az utolsó évtizedben számos multicentrikus, randomizált vizsgálat bizonyította az előrehaladást a krónikus vírushepatitisek kezelésében. Ugyanakkor csak korlátozott számú és ellentmondásos adatokat közöltek az antivirális terápia reális értékéről a mindennapos rutin klinikai gyakorlatában.
Cél:
Retrospektív felmérést végeztünk a terápia hatékonyságának megállapítására krónikus B- és C-hepatitisben, egy 7 éves periódus alatt kezelt országos populációban. Emellett bemutatjuk még egy hazai prospektív vizsgálat néhány adatát is.
Módszerek:
220 krónikus B-hepatitises beteget kezeltünk, közülük 112 standard interferon-, 23 pegilált interferon-, 85 lamivudin-terápiában részesült, akikben a HbeAg-szerokonverzió és/vagy HBV-DNS-negatívvá válás arányát vizsgáltuk. A retrospektív elemzésben szereplő 2442 krónikus C-hepatitises közül 333 standard interferon-monoterápiát, 1122 standard interferon + ribavirin kombinációt és 987 pegilált interferon + ribavirin-kezelést kapott. A prospektív vizsgálatban 69 HCV1-beteg pegilált interferon α-2a + ribavirin terápiában részesült 6–12 hónapon át. A tartós virológiai válasz mellett vizsgáltuk a kedvező kimenetel prediktorait és a mellékhatások előfordulását.
Eredmények:
Krónikus B-hepatitisben a standard interferon 31%-os, a pegilált interferon 30%-os, a lamivudin 31–33%-os tartós vírusnegativitáshoz vezetett. Krónikus C-hepatitisben a tartós virológiai válasz aránya az interferon-monoterápiával észlelt 13%-ról a pegilált interferon + ribavirin mellett 31%-ra nőtt, a prospektív vizsgálatban ez 48% volt. A jó prognózis prediktora a rapid (4 hetes) és a korai (12 hetes) virológiai válasz, a női nem, az életkor, BMI és az adherencia volt. A betegek 9%-ában fordult elő mellékhatás, leggyakrabban cytopenia, haemolysis és depresszió.
Következtetés:
A krónikus B-hepatitisszel ellentétben, a hepatitis C-vírusinfekció kezelésének effektivitása hazánkban is fokozatosan javult. A mindennapi gyakorlat országos adatai azonban elmaradnak a prospektív vizsgálat sikerességétől. A jövőben hatékonyabb terápiás stratégiák szükségesek, beleértve az individualizált dozírozást és az új antivirális szerek alkalmazását.
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Affiliation(s)
- Alajos Pár
- Pécsi Tudományegyetem, Altalános Orvostudományi Kar I. Belgyógyászati Klinika, Pécs.
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Yerly D, Di Giammarino L, Bihl F, Cerny A. Targets of emerging therapies for viral hepatitis B and C. Expert Opin Ther Targets 2007; 10:833-50. [PMID: 17105371 DOI: 10.1517/14728222.10.6.833] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Viral hepatitis B and C, structurally two completely different viruses, commonly infect human hepatocytes and cause similar clinical manifestations. Since their discovery, IFN has been a pillar in the treatment. However, because of the different natures of the viruses, therapeutic approaches diverge and new treatment targets are tailored specifically for each virus. Herein, the authors analyse therapeutic approaches for hepatitis B virus (HBV) and hepatitis C virus (HCV) and focus on emerging concepts that are under clinical evaluation. In particular, promising viral inhibitors for HBV and HCV are reviewed and the current status of research for gene therapy for HCV is described. Immune therapy is a fast-moving field with fascinating results which include therapeutic vaccines and toll-like receptor agonists that could improve tomorrow's treatment approaches.
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Affiliation(s)
- Daniel Yerly
- University of Bern, Clinic for Rheumatology and Clinical Immunology/Allergology, CH-3010 Bern, Switzerland
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Abstract
Conventional treatment of chronic hepatitis B with interferon alfa-2b, lamivudine, and adefovir is limited by low rates of sustained hepatitis B virus DNA suppression and hepatitis B e antigen (HBeAg) seroconversion, increasing rates of drug resistance to the oral agents, and poor tolerability of interferon. Recently several promising new antiviral agents have emerged that possess potent antiviral effects, less toxicity, and have little or no risk of drug resistance. Two new agents, entecavir and peginterferon alfa-2a, have received recent approval by regulatory authorities in the United States and several other countries for the treatment of adults with chronic hepatitis B. In large phase III clinical trials, these agents have demonstrated superior efficacy over lamivudine in both HBeAg-positive and HBeAg-negative patients. Drug resistance occurs at a low rate in lamivudine-refractory patients treated with entecavir or is, to date, nonexistent in nucleoside-naïve patients treated with entecavir and all patients receiving peginterferon. In addition, several novel agents in clinical development, such as emtricitabine, clevudine, telbivudine, valtorcitabine, and tenofovir, have shown promising clinical profiles in patients with chronic hepatitis B. This review summarizes the recent clinical studies of these new agents and discusses the implications of these data for the management of chronic hepatitis B.
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Affiliation(s)
- Emmet B Keeffe
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA.
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Abstract
Currently approved treatments for hepatitis B virus (HBV) infection include the immunomodulatory agent, IFN-α, and nucleos(t)ide analogues. Their efficacy is limited by their side effects, as well as the induction of viral mutations that render them less potent. It is thus necessary to develop drugs that target additional viral antigens. Chemicals and biomaterials by unique methods of preventing HBV replication are currently being developed, including novel nucleosides and newly synthesized compounds such as capsid assembling and mRNA transcription inhibitors. Molecular therapies that target different stages of the HBV life cycle will aid current methods to manage chronic hepatitis B (CHB) infection. The use of immunomodulators and gene therapy are also under consideration. This report summarizes the most recent treatment possibilities for CHB infection. Emerging therapies and their potential mechanisms, efficacy, and pitfalls are discussed.
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Affiliation(s)
- Guo-Yi Wu
- Hepatology Institute, People's Hospital, Peking University, Beijing 100044, China
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