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Ward JW, Wanlapakorn N, Poovorawan Y, Shouval D. Hepatitis B Vaccines. PLOTKIN'S VACCINES 2023:389-432.e21. [DOI: 10.1016/b978-0-323-79058-1.00027-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Liu H, Wan Z, She L, Zhu Y, Cai Z, Wu B, Zhuang Q, Ke P, Wu X, Li Z, Huang X. Inflammation Pharmacological Reaction and YMDD Mutational Patterns in Lamivudine Therapeutics Hepatitis B Virus. Front Pharmacol 2021; 12:648170. [PMID: 33935748 PMCID: PMC8081950 DOI: 10.3389/fphar.2021.648170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 02/19/2021] [Indexed: 02/05/2023] Open
Abstract
Background/Aims: Emergence of tyrosine-methionine-aspartate-aspartate (YMDD) motif in reverse transcriptase is a serious problem in chronic hepatitis B(CHB) patients after Lamivudine (LAM) therapy. However, the relationship between inflammation pharmacological reaction and YMDD mutational patterns of CHB has not been well-characterized. The aim of this study was to investigate the inflammation pharmacological reaction and different YMDD mutants patterns of CHB patients. Methods: We investigated the inflammation pharmacological reaction and YMDD mutational patterns through biochemical, serological and virological detection among 83 CHB patients, including 25 YMDD mutants, 25 under detection, and 33 control patients without YMDD mutants. Results: Prevalence of YMDD mutation patterns is different. Among 25 YMDD mutants patients, YIDD was the dominant mutation (72%), followed YVDD (16%) and the hybrid YIDD + YVDD (12%). The time course during the YMDD mutations was also different. 52.4% patients developed the mutation less than 12 months after the LAM therapy. Serum hepatitis B virus (HBV) DNA level in patients with YMDD mutants were significantly higher than that in control and negative groups. Serum HbsAg and HbeAg in patients with YMDD mutants were also higher than those in control and negative groups, despite no significant difference was found forserum HbeAb. ALT and AST levels were also significantly higher in mutants group. Conclusions: Illuminating inflammation pharmacological reaction and YMDD mutational patterns of CHB during pathological process may have implications for future therapy in YMDD mutation patients. This may have impact on the choice of treatment strategies for lamivudine-resistant HBV.
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Affiliation(s)
- Hongcan Liu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Hongcan Liu, ; Zhuo Li, ; Xianzhang Huang,
| | - Zemin Wan
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lanhui She
- Department of Infectious Diseases, Guangzhou Women and Children’s Medical Center, Guangzhou, China
| | - Yajuan Zhu
- Department of Ultrasound, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Zhiliang Cai
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bin Wu
- Genetic Testing Lab, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qizhen Zhuang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Peifeng Ke
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xinzhong Wu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhuo Li
- Genetic Testing Lab, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Hongcan Liu, ; Zhuo Li, ; Xianzhang Huang,
| | - Xianzhang Huang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Hongcan Liu, ; Zhuo Li, ; Xianzhang Huang,
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Lenci I, Milana M, Grassi G, Manzia TM, Gazia C, Tisone G, Angelico R, Baiocchi L. Hepatitis B virus recurrence after liver transplantation: An old tale or a clear and present danger? World J Gastroenterol 2020; 26:2166-2176. [PMID: 32476783 PMCID: PMC7235198 DOI: 10.3748/wjg.v26.i18.2166] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/12/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) recurrence after liver transplantation (LT) has been described more than 50 years ago. Similarly, to other clinical conditions, in which impairment of host immune defense favors viral replication, early reports described in details recurrence and reactivation of HBV in liver transplant recipients. The evidence of a possible, severe, clinical evolution of HBV reappearance in a significant percentage of these patients, allowed to consider, for some years, HBV positivity a contraindication for LT. Moving from the old to the new millennium this picture has changed dramatically. Several studies contributed to establish efficient prophylactic protocols for HBV recurrence and with the advent of more potent anti-viral drugs an increased control of infection was achieved in transplanted patients as well as in the general immune-competent HBV population. Success obtained in the last decade led some authors to the conclusion that HBV is now to consider just as a "mere nuisance". However, with regard to HBV and LT, outstanding issues are still on the table: (1) A standard HBV prophylaxis protocol after transplant has not yet been clearly defined; (2) The evidence of HBV resistant strains to the most potent antiviral agents is claiming for a new generation of drugs; and (3) The possibility of prophylaxis withdrawal in some patients has been demonstrated, but reliable methods for their selection are still lacking. The evolution of LT for HBV is examined in detail in this review together with the description of the strategies adopted to prevent HBV recurrence and their pros and cons.
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Affiliation(s)
- Ilaria Lenci
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | - Martina Milana
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | - Giuseppe Grassi
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
| | - Tommaso M Manzia
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Carlo Gazia
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Giuseppe Tisone
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Roberta Angelico
- Hepato-Pancreato-Biliary and Transplant, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
| | - Leonardo Baiocchi
- Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
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Structural Insights into HIV Reverse Transcriptase Mutations Q151M and Q151M Complex That Confer Multinucleoside Drug Resistance. Antimicrob Agents Chemother 2017; 61:AAC.00224-17. [PMID: 28396546 DOI: 10.1128/aac.00224-17] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 03/28/2017] [Indexed: 12/26/2022] Open
Abstract
HIV-1 reverse transcriptase (RT) is targeted by multiple drugs. RT mutations that confer resistance to nucleoside RT inhibitors (NRTIs) emerge during clinical use. Q151M and four associated mutations, A62V, V75I, F77L, and F116Y, were detected in patients failing therapies with dideoxynucleosides (didanosine [ddI], zalcitabine [ddC]) and/or zidovudine (AZT). The cluster of the five mutations is referred to as the Q151M complex (Q151Mc), and an RT or virus containing Q151Mc exhibits resistance to multiple NRTIs. To understand the structural basis for Q151M and Q151Mc resistance, we systematically determined the crystal structures of the wild-type RT/double-stranded DNA (dsDNA)/dATP (complex I), wild-type RT/dsDNA/ddATP (complex II), Q151M RT/dsDNA/dATP (complex III), Q151Mc RT/dsDNA/dATP (complex IV), and Q151Mc RT/dsDNA/ddATP (complex V) ternary complexes. The structures revealed that the deoxyribose rings of dATP and ddATP have 3'-endo and 3'-exo conformations, respectively. The single mutation Q151M introduces conformational perturbation at the deoxynucleoside triphosphate (dNTP)-binding pocket, and the mutated pocket may exist in multiple conformations. The compensatory set of mutations in Q151Mc, particularly F116Y, restricts the side chain flexibility of M151 and helps restore the DNA polymerization efficiency of the enzyme. The altered dNTP-binding pocket in Q151Mc RT has the Q151-R72 hydrogen bond removed and has a switched conformation for the key conserved residue R72 compared to that in wild-type RT. On the basis of a modeled structure of hepatitis B virus (HBV) polymerase, the residues R72, Y116, M151, and M184 in Q151Mc HIV-1 RT are conserved in wild-type HBV polymerase as residues R41, Y89, M171, and M204, respectively; functionally, both Q151Mc HIV-1 and wild-type HBV are resistant to dideoxynucleoside analogs.
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Li H, Zhou C, Zhou L, Chen Z, Yang L, Bai H, Wu X, Peng H, Zhao Y. In vitro antiviral activity of three enantiomeric sesquiterpene lactones from Senecio species against hepatitis B virus. ACTA ACUST UNITED AC 2016; 16:277-82. [PMID: 16130525 DOI: 10.1177/095632020501600407] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Three enantiomeric sesquiterpene lactones were isolated under the bioguidance of the suppression of hepatitis B virus (HBV) surface antigen (HBsAg) from Senecio species, a widely distributed Chinese medicinal herb traditionally used for the treatment of hepatitis B, dermatosis and inflammation. The anti-HBV activity of the purified compounds was measured; all of them showed suppressive activity on the expression of HBsAg and HBV e antigen (HBeAg) in the HepG2.2.15 cell line. Realtime quantitative PCR analysis showed that the studied compounds decreased the number of infectious virions released, but did not inhibit the intracellular HBV DNA. The results suggest that enantiomeric sesquiterpene lactones may possess the potential to work synergistically with other antiviral compounds for the treatment of HBV infection.
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Affiliation(s)
- Haibo Li
- Department of Traditional Chinese Medicine and Natural Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Abstract
Hepatitis B virus (HBV) infection constitutes a worldwide public health problem, causing both acute and chronic liver infections. Although a vaccine has been developed that is effective in preventing HBV infection, this is of no benefit to the estimated 350 million carriers of the virus. Chronic hepatitis B infection may lead to cirrhosis of the liver and hepatocellular carcinoma. Therefore, there is a clear need for antiviral therapy. Alpha interferon was the first therapeutic agent used against HBV infection. However, its lack of efficacy in many patients and significant adverse event profile has prompted the development of alternative therapies. Nucleoside analogues are currently being investigated as potential anti-HBV agents, with two compounds, famciclovir and lamivudine, undergoing Phase III clinical trials of long-term use. In preclinical studies using the Pekin duck model for hepatitis B, both compounds have been found to reduce the amount of serum duck HBV DNA to sub-detectable levels during therapy. However, once therapy was stopped, the virus returned to pretreatment levels, making long-term treatment necessary. In clinical studies in chronic hepatis B patients, treatment with these agents also resulted in a significant reduction of HBV DNA levels but, again, the return of HBV DNA after discontinuing treatment indicates the need for long-term therapy. The need for long-term treatment means that the virus may develop resistance to the antiviral agents. Resistance mutations to both famciclovir and lamivudine are now being reported after treatment of chronic HBV infection with these agents. Combination therapy may be a strategy to overcome the development of resistance. Therapeutic vaccines and new antiviral agents are also being developed.
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Affiliation(s)
- S Bowden
- Victorian Infectious Diseases Reference Laboratory, Yarra Bend Road, Fairfield PO Box 65, Fairfield, Victoria 3078, Australia
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Pierra C, Benzaria S, Dukhan D, Loi AG, La Colla P, Bridges E, Mao J, Standring D, Sommadossi JP, Gosselin G. Synthesis, Physicochemical and Pharmacokinetic Studies of Potential Prodrugs of β-L-2′-Deoxycytidine, a Selective and Specific Anti-HBV Agent. ACTA ACUST UNITED AC 2016; 15:269-79. [PMID: 15535049 DOI: 10.1177/095632020401500506] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
β-L-2′-Deoxycytidine (β-L-dC) is a potent, selective and specific anti-hepatitis B virus (HBV) agent. To improve its oral bioavailability, several derivatives involving sugar or base acylation, as well as N4-derivatization with an N,N-(dimethyl-amino)methylene function, were synthesized. The physicochemical characteristics (including chemical stabilities, solubilities and distribution coefficient values) and pharmacokinetics of these compounds were determined and compared with those of the parent drug, β-L-dC. Presented in part at the 14th International Conference on Antiviral Research, Seattle, Washington, USA, 8–13 April 2001. Antiviral Reseach 2001; 50:A79.
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Affiliation(s)
- Claire Pierra
- Laboratoire Coopératif Idenix-CNRS-Université Montpellier II, Montpellier, France
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Lok ASF. Hepatitis B: 50 years after the discovery of Australia antigen. J Viral Hepat 2016; 23:5-14. [PMID: 26280668 DOI: 10.1111/jvh.12444] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 07/16/2015] [Indexed: 12/13/2022]
Abstract
It is an honour to be invited to recount the progress in our understanding and management of hepatitis B 50 years after the discovery of Australia antigen (Au Ag). During this half century, we have gone from identifying the causative agent--hepatitis B virus (HBV), understanding its biology and the disease it causes, to having vaccines that can prevent HBV infection and antiviral therapy that can suppress HBV replication and prevent progression of HBV-related liver disease. As a result of the progress, prevalence of HBV infection and morbidity and mortality from chronic HBV infection has declined.
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Affiliation(s)
- A Suk-Fong Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
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Menéndez-Arias L, Álvarez M, Pacheco B. Nucleoside/nucleotide analog inhibitors of hepatitis B virus polymerase: mechanism of action and resistance. Curr Opin Virol 2014; 8:1-9. [PMID: 24814823 DOI: 10.1016/j.coviro.2014.04.005] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 04/14/2014] [Accepted: 04/16/2014] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) polymerase and human immunodeficiency virus (HIV) reverse transcriptase are structurally related. However, the HBV enzyme has a protein priming activity absent in the HIV enzyme. Approved nucleoside/nucleotide inhibitors of the HBV polymerase include lamivudine, adefovir, telbivudine, entecavir and tenofovir. Although most of them target DNA elongation, guanosine and adenosine analogs (e.g. entecavir and tenofovir, respectively) also impair protein priming. Major mutational patterns conferring nucleoside/nucleotide analog resistance include the combinations rtL180M/rtM204(I/V) (for lamivudine, entecavir, telbivudine and clevudine) and rtA181V/rtN236T (for adefovir and tenofovir). However, development of drug resistance is very slow for entecavir and tenofovir. Novel nucleoside/nucleotide analogs in advanced clinical trials include phosphonates similar to adefovir or tenofovir, and new tenofovir derivatives with improved pharmacological properties.
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Affiliation(s)
- Luis Menéndez-Arias
- Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), c/Nicolás Cabrera, 1, Campus de Cantoblanco, Madrid 28049, Spain.
| | - Mar Álvarez
- Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), c/Nicolás Cabrera, 1, Campus de Cantoblanco, Madrid 28049, Spain
| | - Beatriz Pacheco
- Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), c/Nicolás Cabrera, 1, Campus de Cantoblanco, Madrid 28049, Spain
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Identification of a novel Orthohepadnavirus in pomona roundleaf bats in China. Arch Virol 2014; 160:335-7. [PMID: 25193071 PMCID: PMC7087111 DOI: 10.1007/s00705-014-2222-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 08/30/2014] [Indexed: 11/27/2022]
Abstract
Bats in Myanmar, Gabon, and Panama have been found to harbor diverse hepadnaviruses. Here, we report a novel hepadnavirus in 4 of 20 pomona roundleaf bats from Yunnan province, China. This virus contains 3,278 nucleotides (nt) in the full circularized genome, with four predicted open frames (ORFs) reading in the same direction. Full genomic sequence comparisons and evolutionary analysis indicate that this virus is a member of a new species within the genus Orthohepadnavirus
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Wedemeyer H. EASL Recognition Awardee for 2014: Prof. Geoff-Dusheiko. J Hepatol 2014; 61:466-8. [PMID: 24972753 DOI: 10.1016/j.jhep.2014.05.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Accepted: 05/25/2014] [Indexed: 12/04/2022]
Affiliation(s)
- Heiner Wedemeyer
- Dept. of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
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Kasraianfard A, Watt KD, Lindberg L, Alexopoulos S, Rezaei N. HBIG Remains Significant in the Era of New Potent Nucleoside Analogues for Prophylaxis Against Hepatitis B Recurrence After Liver Transplantation. Int Rev Immunol 2014; 35:312-324. [PMID: 24911598 DOI: 10.3109/08830185.2014.921160] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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In vitro evaluation of 9-(2-phosphonylmethoxyethyl)adenine ester analogues, a series of anti-HBV structures with improved plasma stability and liver release. Arch Pharm Res 2013; 37:1416-25. [PMID: 24338503 DOI: 10.1007/s12272-013-0300-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Accepted: 11/06/2013] [Indexed: 01/30/2023]
Abstract
Chronic hepatitis B virus (HBV) infection may lead to liver cirrhosis and hepatocellular carcinoma, but few drugs are available for its treatment. Acyclic nucleoside phosphonates (ANPs) have remarkable antivirus activities but are not easily absorbed from the gastrointestinal tract and accumulate in the kidneys, resulting in nephrotoxicity. Therefore, there is a need to find effective liver site-specific prodrugs. The dipivaloyloxymethyl ester of 9-(2-phosphonylmethoxyethyl)adenine (PMEA)-adefovir dipivoxil (ADV)-is a first-line therapy drug for chronic hepatitis B with a low therapeutic index because of renal toxicity and low hepatic uptake. In this study, a series of PMEA derivatives were synthesized to enhance plasma stability and liver release. The metabolic stability of ADV (Chemical I) and its two analogues (Chemicals II and III) was evaluated in rat plasma and liver homogenate in vitro. An ion-pair reverse-phase HPLC-UV method and a hybrid ion trap and high-resolution time-of-flight mass spectrometry (LC-IT-TOF-MS) were used to evaluate the degradation rate of the analogues and to identify their intermediate metabolites, respectively. Chemicals I and II were hydrolyzed by cleavage of the C-O bond to give monoesters. Sufficient enzymatic activation in the liver homogenate through a relatively simple metabolic pathway, in addition to a favorable stability profile in rat plasma, made Chemical II an optimal candidate. Next, six analogues based on the structure of Chemical II were synthesized and evaluated in plasma and liver homogenate. Compared to Chemical II, these compounds generated less active PMEA levels in rat liver homogenate. Therefore, chemical modification of Chemical II may lead to new promising PMEA derivatives with enhanced plasma stability and liver activation.
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Long-term effects of prophylactic and therapeutic lamivudine treatments in hepatitis B surface antigen-positive renal allograft recipients. Clin Exp Nephrol 2013; 18:144-50. [PMID: 23605388 DOI: 10.1007/s10157-013-0807-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 04/07/2013] [Indexed: 01/07/2023]
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Delaney WE. Molecular virology of chronic hepatitis B and C: parallels, contrasts and impact on drug development and treatment outcome. Antiviral Res 2013; 99:34-48. [PMID: 23602852 DOI: 10.1016/j.antiviral.2013.04.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Revised: 03/29/2013] [Accepted: 04/09/2013] [Indexed: 12/17/2022]
Abstract
Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are highly prevalent worldwide, causing significant liver disease and thus representing high unmet medical needs. Accordingly, substantial pharmaceutical and clinical research efforts have been made to develop and improve treatments for these viruses. While HBV and HCV are both hepatotropic viruses that can cause similar disease in chronically infected patients, they belong to different viral families. There are substantial differences in the molecular virology of HBV and HCV that have profound implications for therapeutic strategy. In particular, HBV has a long-lived nuclear form of its genome (covalently closed circular DNA) that is able to persist in the face of potent inhibition of viral replication. In contrast, HCV does not have a long-lived genome form and depends on active replication to maintain infection; HCV is therefore much more susceptible to eradication by potent antiviral agents. Additional differences between HBV and HCV with therapeutic implications include the size, structure and heterogeneity of their respective viral genomes. These factors influence the number of targets available for therapeutic intervention, response to therapy among viral genotypes and the emergence of viral resistance. Substantial progress has been made in treating each infection, but unique challenges remain. In this review, key differences in the molecular virology of hepatitis B and C will be presented, highlighting their impact on antiviral therapy (particularly with respect to direct-acting antivirals) and the challenges they present to the cure of each disease.
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Zheng Y, Zhang S, Tan Grahn HM, Ye C, Gong Z, Zhang Q. Prophylactic Lamivudine to Improve the Outcome of Breast Cancer Patients With HBsAg Positive During Chemotherapy: A Meta-Analysis. HEPATITIS MONTHLY 2013; 13:e6496. [PMID: 23805156 PMCID: PMC3693540 DOI: 10.5812/hepatmon.6496] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Revised: 11/10/2012] [Accepted: 12/31/2012] [Indexed: 12/11/2022]
Abstract
CONTEXT Raising the chemotherapy-induced HBV reactivation is parallel to the increment of chemotherapy treatments in breast cancer patients. This meta-analysis aims to evaluate the efficacy of prophylactic use of lamivudine in breast cancer patients with HBsAg positive during chemotherapy. EVIDENCE ACQUISITION MEDLINE, Pubmed, Ovid and Embase were used to search for clinical studies comparing with or without prophylactic use of lamivudine for HBV reactivation in breast cancer patients receiving chemotherapy. Outcomes of interest were the rate of HBV reactivation, incidence of hepatitis and incidence of hepatitis attributable to HBV reactivation, severity of hepatitis and severity of hepatitis attributable to HBV reactivation, the rate of chemotherapy disruption, and the rate of chemotherapy disruption attributable to HBV reactivation, overall mortality, and mortality attributable to HBV reactivation. RESULTS Four studies with 285 patients were included in this meta-analysis. The rate of HBV reactivation, incidence of hepatitis and incidence of hepatitis related to HBV reactivation were reduced by use of prophylactic lamivudine compared to control group. Pooled Odds Ratios (ORs) were 0.09 (95% confidence intervals [CI] 0.03-0.26; P < 0.0001), 0.23 (95% CI 0.06-0.92; P = 0.04), and 0.10 (95% CI 0.03-0.32; P < 0.0001) respectively. There was a reduction in chemotherapy disruption related to HBV reactivation by use of prophylactic lamivudine (pooled OR = 0.11; 95% CI 0.02-0.58; P = 0.01). Chemotherapy disruption, overall mortality, and mortality attributable to HBV reactivation were not significantly different between two groups. Pooled ORs were 0.42 (95% CI 0.11-1.58; P = 0.20), 0.37 (95% CI 0.07-2.04; P = 0.25), and 0.25 (95% CI 0.01-6.82; P = 0.41) respectively. Lamivudine was well-tolerated, and no additional toxicity was observed. CONCLUSIONS Use of prophylactic lamivudine may have positive effect on the outcome of breast cancer patients with HBsAg positive during chemotherapy.
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Affiliation(s)
- Yihu Zheng
- Department of General Surgery, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China
| | - Shengchu Zhang
- Department of General Surgery, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China
- Department of General Surgery, Yichang Central People’s Hospital, The First Clinical Medical College of Three Gorges University, Yichang, China
| | - Hooi Min Tan Grahn
- Metabolism, Obesity/Diabetes, Department of Biochemistry, Boston University School of Medicine, Boston, USA
| | - Chao Ye
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Zheng Gong
- Department of General Surgery, Yichang Central People’s Hospital, The First Clinical Medical College of Three Gorges University, Yichang, China
| | - Qiyu Zhang
- Department of General Surgery, The First Affiliated Hospital, Wenzhou Medical College, Wenzhou, Zhejiang, China
- Corresponding author: Qiyu Zhang, Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical College, NO. 453 Ward, No. 4 Building, Nan Bai Xiang Street, Ouhai District, Wenzhou, Zhejiang, China. Tel.: +86-57788288181, Fax: 86-57788069555, E-mail:
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Dusheiko G. Treatment of HBeAg positive chronic hepatitis B: interferon or nucleoside analogues. Liver Int 2013; 33 Suppl 1:137-50. [PMID: 23286858 DOI: 10.1111/liv.12078] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Interferon alpha has restricted efficacy in as much as only a proportion of patients show a response. However, in appropriately selected HBeAg-positive and HBeAg-negative patients, sustained suppression of viral replication can be achieved, and HBeAg or even HBsAg seroconversion can be attained. Thus, finite course of interferon alpha can be successful, and offer an advantage to patient. Interferon (IFN) remains a benchmark therapy for chronic hepatitis B. The main advantages of IFN-α over nucleoside analogues are the absence of resistance and the possibility of immune-mediated clearance of hepatitis B. Unfortunately, side effects preclude the use of interferon alpha in substantial proportions of patients, and prolonged maintenance therapy to suppress hepatitis B virus (HBV) is not feasible. Nucleoside analogues are given by mouth, once per day, and the safety, potency and efficacy have improved and facilitated treatment. However, maintenance of long-term suppression is required for the majority of patients. In general, treatment of chronic hepatitis B should target patients with active disease and viral replication, preferably before the signs and symptoms of cirrhosis or significant injury has occurred. Current EASL guidelines suggest that treatment be based on the evaluation of three criteria: Serum aminotransferase levels, serum HBV DNA levels and histological grade and stage. Many questions remain unanswered on the optimal treatment of patients with chronic hepatitis B with a nucleoside vs interferon alpha. Both forms of treatment have benefits and the choice should be selected and tailored. Stopping or futility rules can be implemented in patients who fail interferon. Recent data suggest the safety and efficacy of nucleoside analogues in the third trimester of pregnancy to reduce the risk of transmission from mothers to their children.
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Affiliation(s)
- Geoffrey Dusheiko
- UCL Division of Liver and Digestive Health, University College London Medical School, and Royal Free Hospital, London, UK.
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Hepatitis B vaccines. Vaccines (Basel) 2013. [DOI: 10.1016/b978-1-4557-0090-5.00025-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
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Abstract
Viral diseases are leading cause of deaths worldwide as WHO report suggests that hepatitis A virus (HAV) infects more than 80 % of the population of many developing countries. Viral hepatitis B (HBV) affects an estimated 360 million people, whereas hepatitis C affects 123 million people worldwide, and last but not least, at current, India has an HIV/AIDS population of approximately 2.4 million people and more than 30 million in whole world and now it has become a reason for 1.8 million death globally; thus, millions of people still struggle for their lives. The progress in medical science has made it possible in overcoming the various fatal diseases such as small pox, chicken pox, dengue, etc., but human immunodeficiency viruses, influenza, and hepatitis virus have renewed challenge surprisingly. The obstacles and challenges in therapy include existence of antibiotic resistance strains of common organisms due to overuse of antibiotics, lack of vaccines, adverse drug reaction, and last but not least the susceptibility concerns. Emergence of pharmacogenomics and pharmacogenetics has shown some promises to take challenges. The discovery of human genome project has opened new vistas to understand the behaviors of genetic makeup in development and progression of diseases and treatment in various viral diseases. Current and previous decade have been engaged in making repositories of polymorphisms (SNPs) of various genes including drug-metabolizing enzymes, receptors, inflammatory cells related with immunity, and antigen-presenting cells, along with the prediction of risks. The genetic makeup alone is most likely an adequate way to handle the therapeutic decision-making process for previous regimen failure. With the introduction of new antiviral therapeutic agents, a significant improvement in progression and overall survival has been achieved, but these drugs have shown several adverse responses in some individuals, so the success is not up to the expectations. Research and acquisition of new knowledge of pharmacogenomics may help in overcoming the prevailing burden of viral diseases. So it will definitely help in selecting the most effective therapeutic agents, effective doses, and drug response for the individuals. Thus, it will be able to transform the laboratory research into the clinical bench side and will also help in understanding the pathogenesis of viral diseases with drug action, so the patients will be managed more properly and finally become able to fulfill the promise of the future.
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Affiliation(s)
- Debmalya Barh
- Centre for Genomics & Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Purba Medinipur, West Bengal India
| | - Dipali Dhawan
- Institute of Life Sciences, B.V. Patel Pharmaceutical Education and Research Development Centre, Ahmedabad University, Ahmedabad, Gujarat India
| | - Nirmal Kumar Ganguly
- Policy Centre for Biomedical Research, Translational Health Science and Technology Institute (Department of Biotechnology Institute, Government of India), Office @ National Institute of Immunology, New Delhi, India
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Sueki R, Maekawa S, Miura M, Kadokura M, Komase K, Shindo H, Kanayama A, Ohmori T, Shindo K, Amemiya F, Nakayama Y, Uetake T, Inoue T, Sakamoto M, Enomoto N. Correlation between pretreatment viral sequences and the emergence of lamivudine resistance in hepatitis B virus infection. J Med Virol 2012; 84:1360-8. [PMID: 22825814 DOI: 10.1002/jmv.23314] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The emergence of amino acid or nucleotide substitutions leads to lamivudine resistance in hepatitis B virus (HBV) infected patients. The aim of this study was to investigate whether viral sequences help predict the emergence of lamivudine resistance. The study subjects comprised 59 consecutive patients infected with HBV treated with daily therapy of 100 mg lamivudine. Among those, 32 patients with adequate pretreatment serum preservation were investigated for the correlation between viral amino acid substitutions and the appearance of lamivudine resistance with consideration of clinical background by determining dominant HBV full open reading frames. Viral resistance to lamivudine emerged in 28 of 59 patients (47%) in a median period of 2.45 years. Sequence comparisons of HBV genomes between patients who later developed lamivudine resistance and patients who did not revealed the existence of significant differences between the two groups in the pre-S1 84 (P = 0.042), pre-S2 1 (P = 0.017) and 22 (P = 0.015), and polymerase tp 95 (P = 0.046), judged by a log-rank test. Viral sequence analyses revealed the presence of amino acid substitutions in HBV pre-S1 and pre-S2 that may be associated with the emergence of lamivudine resistance during chronic HBV infection.
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Affiliation(s)
- Ryota Sueki
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
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Du Y, Su T, Ding Y, Cao G. Effects of antiviral therapy on the recurrence of hepatocellular carcinoma after curative resection or liver transplantation. HEPATITIS MONTHLY 2012; 12:e6031. [PMID: 23166535 PMCID: PMC3500771 DOI: 10.5812/hepatmon.6031] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2011] [Revised: 01/09/2012] [Accepted: 02/02/2012] [Indexed: 02/07/2023]
Abstract
CONTEXT Hepatocellular carcinoma (HCC) is a fatal disease. Chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection is the major cause of HCC. High viral replication rate and related hepatic/systematic inflammation are the major risk factors in HCC recurrence after hepatectomy or liver transplantation. EVIDENCE ACQUISITION Some of the carcinogenesis-related HBV mutations are also associated with poor prognosis for HCC patients. Antiviral therapy is an option for improving HCC prognosis after surgery. In case of HBV-associated HCC, treatment with interferon and nucleos(t)ide analogues (NAs), especially interferon, is effective in improving the prognosis. However, long-term use of NAs increases the possibility of developing drug-resistant viral mutations such as the HBV rtA181T/sW172 mutation, which increases the risk of HCC recurrence. RESULTS In cases of HCV-associated HCC, standard interferon with or without ribavirin therapy is effective in improving the prognosis of HCV-associated HCC; however, some HCV mutations, such as the amino acid substitution M91L, are associated with treatment failure and a poor prognosis. Therapeutic efficacy needs to be confirmed using largescale, randomized, placebo-controlled clinical trials. CONCLUSIONS Surveillance of viral mutations during antiviral treatment and a better understanding of the associations of HCC recurrence with viral load, inflammation-associated signaling, and environmental factors can aid the development of more effective strategies for the prevention of HCC recurrence after surgery.
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Affiliation(s)
- Yan Du
- Department of Epidemiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, China
| | - Tong Su
- Department of Epidemiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, China
| | - Yibo Ding
- Department of Epidemiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, China
| | - Guangwen Cao
- Department of Epidemiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, Shanghai, China
- Corresponding author: Guangwen Cao, Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China. Tel.: +86-2181871060, Fax: +86-2181871060, E-mail:
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Mello FCA, Lago BV, Lewis-Ximenez LL, Fernandes CA, Gomes SA. Detection of mixed populations of wild-type and YMDD hepatitis B variants by pyrosequencing in acutely and chronically infected patients. BMC Microbiol 2012; 12:96. [PMID: 22672436 PMCID: PMC3395561 DOI: 10.1186/1471-2180-12-96] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2011] [Accepted: 06/06/2012] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Lamivudine (LAM) is associated with the highest known rate of resistance mutations among nucleotide analogs used to treat chronic hepatitis B virus (HBV) infection. Despite this, LAM continues in widespread use, especially in combination therapies. The primary LAM resistance mutation (rtM204V/I) occurs in the YMDD motif of HBV polymerase. The aim of this study was to characterize Brazilian HBV isolates from acute and chronic cases by direct sequencing, and to identify HBV quasispecies in the YMDD motif using a pyrosequencing method capable of detecting single-nucleotide polymorphisms. HBV DNA from serum samples of 20 individuals with acute HBV infection and 44 with chronic infection undergoing antiviral therapies containing LAM were analyzed by direct sequencing and pyrosequencing methods. RESULTS Phylogenic analyses of direct-sequenced isolates showed the expected genotypes (A, D and F) for the Brazilian population in both acute and chronic infections. However, within genotype A isolates, subgenotype A2 was more frequently detected in acute cases than in chronic cases (P = 0.012). As expected, none of the individuals with acute hepatitis B had LAM-resistant isolates as a dominant virus population, whether detected by direct sequencing or pyrosequencing. However, pyrosequencing analyses showed that 45% of isolates (9/20) had minor subpopulations (4-17%) of LAM-resistant isolates. Among chronic patients undergoing LAM treatment, YMDD mutants were frequently found as a dominant virus population. In cases where wild-type virus was the dominant population, subpopulations of YMDD variants were usually found, demonstrating the complexity of HBV quasispecies. CONCLUSIONS YMDD variants were frequently detected as a minor population in acute HBV infection. The occurrence of pre-existing variants may lead to a high frequency of resistant mutants during antiviral therapy in the chronic phase. In chronic infection, detection of YMDD variants before virological or biochemical breakthrough might contribute to making better therapy choices and thus improving treatment outcome.
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Michailidis E, Kirby KA, Hachiya A, Yoo W, Hong SP, Kim SO, Folk WR, Sarafianos SG. Antiviral therapies: focus on hepatitis B reverse transcriptase. Int J Biochem Cell Biol 2012; 44:1060-71. [PMID: 22531713 DOI: 10.1016/j.biocel.2012.04.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2012] [Revised: 04/04/2012] [Accepted: 04/05/2012] [Indexed: 12/20/2022]
Abstract
Hepatitis B virus (HBV) is the etiologic agent of mankind's most serious liver disease. While the availability of a vaccine has reduced the number of new HBV infections, the vaccine does not benefit the approximately 350 million people already chronically infected by the virus. Most of the drugs approved by the FDA for the treatment of hepatitis B target the reverse transcriptase (RT or P gene product) and are nucleoside RT inhibitors (NRTIs) that suppress viral replication. However, prolonged monotherapies directed against a single target result in the emergence of viral resistance. HBV genotypic differences affect NRTI resistance, and because the reading frames of the S (surface antigen) and P genes partially overlap, genomic differences that affect the surface of the virus may also alter the viral polymerase sequence, function and drug susceptibility. The scope of this review is to assess the effects of HBV genotypic variation on the development of drug resistance to NRTIs. Some RT residues that vary among different genotypes are in the vicinity of residues that mutate and give rise to NRTI resistance. Interactions between these amino acids can help explain the effect of HBV genotype on the development of NRTI resistance during antiviral therapies, and might help in the design of improved therapeutic strategies.
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Affiliation(s)
- Eleftherios Michailidis
- Christopher S. Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65211, USA
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Li SY, Qin L, Zhang L, Song XB, Zhou Y, Zhou J, Lu XJ, Cao J, Wang LL, Wang J, Ying BW. Molecular epidemical characteristics of Lamivudine resistance mutations of HBV in southern China. Med Sci Monit 2012; 17:PH75-80. [PMID: 21959623 PMCID: PMC3539467 DOI: 10.12659/msm.881965] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Lamivudine (LMV), as the preferred oral drug for use in treatment of HBV, always results in development of resistance mutations after long-term treatment. In this study we investigated chronic hepatitis B (CHB) patients in southern China to determine whether different HBV genotypes affect the incidence of LMV resistance mutations. MATERIAL/METHODS The study recruited 185 CHB patients living in southern China. Enzyme-linked immunosorbent assay was used to test for HBV serological markers, and HBV DNA was quantified by real-time PCR. Sequencing was performed to detect HBV genotypes and mutations. RESULTS There were 49.19% (91/185) CHB patients with HBV resistant to LMV. Only 2 genotypes were found: B and C; 62.16% (115/185) of patients were infected with genotype B HBV and 37.84% (70/185) of patients were infected with genotype C HBV. The incidence rate of LMV resistance was not significantly different between genotype B and C (49.57% vs. 48.57%, P>0.05). For the mean age and sex ratio, no significant difference was found. The pattern of rtM204I alone was predominantly observed (36.26%, 33/91), followed by rtM204V+rtL180M (23.08%, 21/91). The overall incidence rate of rtM204I mutation in genotype B (45.61%, 26/57) was more frequent than that in genotype C (20.59%, 7/34) (45.61% vs. 20.59%, P<0.05), but the incidence rate of other mutation patterns was not significantly different between genotypes B and C. CONCLUSIONS Our results emphasize that a LMV resistance test before treatment is of great importance in rational and optimal CHB therapy.
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Affiliation(s)
- Si-Yue Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Sichuan Province, China
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Hasosah MY, Ghandourah HS, Alsahafi AF, Sukkar GA, Jacobson K. Seroconversion of hepatitis B envelope antigen (HBeAg) by entecavir in a child with chronic hepatitis B. Saudi J Gastroenterol 2012; 18:217-20. [PMID: 22626803 PMCID: PMC3371426 DOI: 10.4103/1319-3767.96465] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a worldwide health problem. Consensus guidelines for the treatment of chronic HBV in children have not been established, and indications for antiviral therapy in adults with chronic HBV infection may not be applicable to children. The medications that are Food and Drug Administration approved for the treatment of children with HBV include interferon (IFN)-alpha and lamivudine. Nondetectable serum HBV deoxyribonucleic acid, Hepatitis B envelope antigen (HBeAg) loss, and HBeAg seroconversion following 1 year duration of entecavir treatment. A review of the literature of entecavir treatment of chronic hepatitis B in children is also provided.
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Affiliation(s)
- Mohammed Y. Hasosah
- Department of Pediatric Gastroenterology, King Saud Bin Abdulaziz University for Health Sciences/National Guard Health Affairs, Jeddah, Saudi Arabia,Address for correspondence: Dr. Mohammed Y. Hasosah, King Saud Bin Abdulaziz University for Health Sciences/National Guard Health Affairs, Department of Pediatric Gastroenterology, King Abdul-Aziz Medical City, National Guard Hospital, Jeddah, PO Box: 8202, Jeddah - 21482, Saudi Arabia. E-mail:
| | - Heba S. Ghandourah
- Department of Pediatric Gastroenterology, King Saud Bin Abdulaziz University for Health Sciences/National Guard Health Affairs, Jeddah, Saudi Arabia
| | - Ashraf F. Alsahafi
- Department of Pediatric Gastroenterology, King Saud Bin Abdulaziz University for Health Sciences/National Guard Health Affairs, Jeddah, Saudi Arabia
| | - Ghassan A. Sukkar
- Department of Pediatric Gastroenterology, King Saud Bin Abdulaziz University for Health Sciences/National Guard Health Affairs, Jeddah, Saudi Arabia
| | - Kevan Jacobson
- Department of Pediatric Gastroenterology, British Colombia Children's Hospital, University of British Columbia, Vancouver, BC, Canada
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Deng L, Tang H. Hepatitis B virus drug resistance to current nucleos(t)ide analogs: Mechanisms and mutation sites. Hepatol Res 2011; 41:1017-24. [PMID: 21917087 DOI: 10.1111/j.1872-034x.2011.00873.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Nucleos(t)ide analogs (NAs) have become the mainstream drugs for the treatment of chronic hepatitis B virus infection. Drug resistance to NAs, however, has posed a major obstacle in obtaining sustained viral suppression. Standardized definitions of terms and nomenclature in discussing NAs resistance have been proposed. Drug resistance to NAs is produced by a combination of viral, host and antiviral drug factors. A detailed understanding of the mechanisms and effects of mutation sites that cause resistance to NAs is important for the design of rational treatment and management of patients with existing drug resistance.
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Affiliation(s)
- Lihui Deng
- Center of Infectious Diseases, West China Hospital of Sichuan University Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan Province, China
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The therapeutic response of antiviral therapy in HBsAg-positive renal transplant recipients and a long-term follow-up. Hepatol Int 2011; 6:449-56. [PMID: 21744310 DOI: 10.1007/s12072-011-9295-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Accepted: 06/21/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND Early prediction of lamivudine (LAM) response by individualized monitoring of serum HBV DNA like roadmap concept, and investigation of the outcome after LAM discontinuation in renal transplant recipients (RTRs) with chronic hepatitis B (CHB). METHODS We conducted a study on 19 RTRs with HBV infection receiving LAM treatment for 2 years from 2004 to 2007. HBV DNA level was assessed at baseline, 12, 24, 52, and 104 weeks after treatment. Risk factors of tyrosine-methionine-aspartate-aspartate (YMDD) mutation on treatment and relapse rate of HBV after LAM discontinuation were analyzed. RESULTS HBV DNA levels became undetectable in 32, 37, 63, and 53% of patients after 12, 24, 52, and 104 weeks of LAM treatment, respectively. Overall, three (16%) and five (33%) patients were detected with YMDD mutations at week 52 and 104, respectively. In the concept of roadmap, of the seven patients with inadequate virologic response (IAVR) at week 24, five had YMDD mutations. There was no significant association of YMDD mutations with age, gender, genotype, cirrhosis, HBeAg status, baseline HBV DNA, precore/core promoter mutations, and primary response, except IAVR at week 24 (P = 0.001). The relapse rate of HBV after LAM discontinuation was high (75%) during a median follow-up of 65 weeks. CONCLUSIONS The rate of LAM resistance in RTRs is similar to immunocompetent CHB patients in a 2-year therapy. By roadmap concept, RTRs with IAVR require a change in therapy to prevent viral resistance. Relapse after LAM withdrawal is frequent. Long-term antiviral therapy is crucial for immunosuppressed patients.
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Hsu CW, Yeh CT. Emergence of hepatitis B virus S gene mutants in patients experiencing hepatitis B surface antigen seroconversion after peginterferon therapy. Hepatology 2011; 54:101-8. [PMID: 21503942 DOI: 10.1002/hep.24363] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
UNLABELLED With anti-hepatitis B virus (anti-HBV) therapy using peginterferon, the seroconversion of hepatitis B surface antigen (HBsAg), which is considered a cure of the disease, can be achieved in a small percentage of patients. Eight of 245 consecutive patients (3.27%) with chronic hepatitis B who received peginterferon therapy at our center achieved HBsAg seroclearance. Surprisingly, two of the eight patients remained viremic according to standard HBV DNA assays. The coding regions of the HBV pre-S/S gene, which were derived from serial serum samples, were analyzed. Site-directed mutagenesis experimentation was performed to verify the phenotypic alterations in Huh-7 cells. In patient 1, an sT125A mutant developed during the HBsAg-negative stage and constituted 11.2% of the viral population. The HBV DNA level was 2.73 × 10(4) IU/mL at the time of detection. This mutant was not detectable in the HBsAg-positive stages. A phenotypic study of Huh-7 cells showed a significant reduction of antigenicity. In patient 2, an sW74* truncation mutation was found during the HBsAg-negative stage and constituted 83.1% of the viral population. The HBV DNA level was 4.12 × 10(4) IU/mL at the time of detection. A phenotypic study of Huh-7 cells showed a complete loss of antigenicity. Patient 2 subsequently experienced an episode of hepatitis relapse 7 months after the end of treatment and was negative for HBsAg throughout the hepatitis flare. CONCLUSION During antiviral therapy with peginterferon, the achievement of HBsAg seroconversion does not necessarily indicate viral eradication. The emergence of S gene mutants is another possibility, and a relapse with HBsAg-negative hepatitis can occur.
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Affiliation(s)
- Chao-Wei Hsu
- Liver Research Center, Chang Gung Memorial Hospital, Taipei, Taiwan
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Long M, Jia W, Li S, Jin L, Wu J, Rao N, Feng H, Chen K, Deng H, Liu F, Su F, Song E. A single-center, prospective and randomized controlled study: Can the prophylactic use of lamivudine prevent hepatitis B virus reactivation in hepatitis B s-antigen seropositive breast cancer patients during chemotherapy? Breast Cancer Res Treat 2011; 127:705-12. [PMID: 21445574 DOI: 10.1007/s10549-011-1455-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Accepted: 03/11/2011] [Indexed: 12/14/2022]
Abstract
Over the past four decades, chemotherapy has played an important role in prolonging survival in breast cancer patients. However, it may also result in undesirable side effects such as hepatitis B virus (HBV) reactivation seen in this study. With the increasing use of chemotherapy paralleling the rise in breast cancer incidence, the occurrence of HBV reactivation is likely to further increase. Several strategies use lamivudine to deal with this problem. Initially, lamivudine had been used to treat patients who developed alanine transaminase elevation attributable to HBV reactivation during chemotherapy. However, using this strategy, fatal reactivation has also been reported. Later studies have suggested that prophylactic lamivudine significantly reduces HBV reactivation and its associated morbidity. However, these studies were based mainly on patients with lymphoma, whereas studies on breast cancer patients were few. Moreover, these studies were retrospective. Recently, a prospective study has recommended that deferred preemptive lamivudine could be a comparable alternative to the prophylactic strategy. However, it was not a randomized controlled study. In this study, it was examined the efficacy of the prophylactic strategy in hepatitis B s-antigen seropositive breast cancer patients during chemotherapy using a prospective, randomized controlled study. Two groups were studied. One group consisted of 21 patients who were treated with prophylactic lamivudine, the other group consisted of 21 patients who were not treated with prophylactic lamivudine. The results showed that the prophylactic lamivudine strategy significantly decreased the incidence of HBV reactivation (0 vs. 28.6%, P = 0.021). It was conclude that the prophylactic lamivudine strategy significantly reduces the incidence of HBV reactivation for hepatitis B s-antigen seropositive breast cancer undergoing chemotherapy.
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Affiliation(s)
- Meijun Long
- Department of Breast Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
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Inoue J, Ueno Y, Wakui Y, Niitsuma H, Fukushima K, Yamagiwa Y, Shiina M, Kondo Y, Kakazu E, Tamai K, Obara N, Iwasaki T, Shimosegawa T. Four-year study of lamivudine and adefovir combination therapy in lamivudine-resistant hepatitis B patients: influence of hepatitis B virus genotype and resistance mutation pattern. J Viral Hepat 2011; 18:206-215. [PMID: 20367795 DOI: 10.1111/j.1365-2893.2010.01301.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
To investigate the efficacy of long-term lamivudine (3TC) and adefovir dipivoxil (ADV) combination therapy in 3TC-resistant chronic hepatitis B virus (HBV) infected patients, we analysed 28 3TC-resistant patients treated with the combination therapy during 47 months (range, 9-75). At 12, 24, 36, and 48 months, the rates of virological response with undetectable HBV DNA (≤ 2.6 log copies/mL) were 56, 80, 86, and 92%, respectively. Among 17 hepatitis B e antigen (HBeAg)-positive patients, HBeAg disappeared in 24% at 12 months, 25% at 24 months, 62% at 36 months, and 88% at 48 months. When HBV genotypes were compared, patients with genotype B achieved virological response significantly more rapidly than those with genotype C (P=0.0496). One patient developed virological breakthrough after 54 months, and sequence analysis of HBV obtained from the patient was performed. An rtA200V mutation was present in the majority of HBV clones, in addition to the 3TC-resistant mutations of rtL180M+M204V. The rtN236T ADV-resistant mutation was observed in only 25% clones. In vitro analysis showed that the rtA200V mutation recovered the impaired replication capacity of the clone with the rtL180M+M204V mutations and induced resistance to ADV. Moreover, rtT184S and rtS202C, which are known entecavir-resistant mutations, emerged in some rtL180M+M204V clones without rtA200V or rtN236T. In conclusion, 3TC+ADV combination therapy was effective for most 3TC-resistant patients, especially with genotype B HBV, but the risk of emergence of multiple drug-resistant strains with long-term therapy should be considered. The mutation rtA200V with rtL180M+M204V may be sufficient for failure of 3TC+ADV therapy.
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Affiliation(s)
- J Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
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Minemura M, Tokimitsu Y, Tajiri K, Nakayama Y, Kawai K, Kudo H, Hirano K, Atarashi Y, Yata Y, Yasumura S, Takahara T, Sugiyama T. Development of osteomalacia in a post-liver transplant patient receiving adefovir dipivoxil. World J Hepatol 2010; 2:442-446. [PMID: 21191520 PMCID: PMC3010514 DOI: 10.4254/wjh.v2.i12.442] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Revised: 10/11/2010] [Accepted: 10/18/2010] [Indexed: 02/06/2023] Open
Abstract
We report the case of a patient treated with living donor-related liver transplantation who suffered from osteomalacia during adefovir dipivoxil (ADV)-containing antiviral therapy for lamivudine-resistant hepatitis B virus infection. The patient had generalized bone pain, with severe hypophosphatemia after 20 mo of ADV therapy. Radiographic studies demonstrated the presence of osteomalacia. The peak plasma ADV level was 38 ng/mL after administration of ADV at 10 mg/d. It was also found that ADV affected the metabolism of tacrolimus, a calcineurin-inhibitor, and caused an increase in the plasma levels of tacrolimus. The disability was reversed with the withdrawal of ADV and with mineral supplementation. ADV can cause an elevation of plasma tacrolimus levels, which may be associated with renal dysfunction. High levels of ADV and tacrolimus can cause nephrotoxicity and osteomalacia. This case highlights the importance of considering a diagnosis of osteomalacia in liver transplantation recipients treated with both ADV and tacrolimus.
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Affiliation(s)
- Masami Minemura
- Masami Minemura, Yoshiharu Tokimitsu, Kazuto Tajiri, Yasuhiro Nakayama, Kengo Kawai, Hiroshi Kudo, Katsuharu Hirano, Yoshinari Atarashi, Yutaka Yata, Satoshi Yasumura, Terumi Takahara, Toshiro Sugiyama, Third Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan
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Yu Y, Pandeya DR, Liu ML, Liu MJ, Hong ST. Expression and purification of a functional human hepatitis B virus polymerase. World J Gastroenterol 2010; 16:5752-8. [PMID: 21128327 PMCID: PMC2997993 DOI: 10.3748/wjg.v16.i45.5752] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify a method for efficient large-scale purification of functional hepatitis B virus polymerase (HBV-Pol) without addition of cellular factors.
METHODS: Full-length HBV-Pol (843 amino acids) tagged with 5’ end Polyhistidine was expressed at a high level in an Escherichia coli (E. coli) system. Sodium dodecyl sulfate lysis buffer was utilized to dissolve insoluble HBV-Pol, and Ni-NTA resin affinity chromatography was utilized for HBV-Pol purification. Most recombinant HBV-Pol was eluted with 100 mmol/L imidazole in the presence of NP-40, a weak detergent that keeps HBV-Pol in solution. A reducing agent was utilized throughout the purification steps to keep soluble HBV-Pol from redundant disulfide bond formation.
RESULTS: The large-scale production of functional intact human HBV-Pol was achieved in an E. coli expression system. Purified HBV-Pol showed stable reverse transcriptase activity and DNA polymerase activity. The purified protein was of high purity and had stable reverse transcriptase activity.
CONCLUSION: Large-scale production of HBV-Pol in pure form should facilitate crystallization and detailed analysis of the structure and mechanism of HBV-Pol. Ability of this purification approach to obtain human HBV-Pol in an enzymatically active form should be helpful for development of drugs for treatment of chronic hepatitis B.
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Yağci M, Ozkurt ZN, Yeğin ZA, Aki Z, Sucak GT, Haznedar R. Hepatitus B virus reactivation in HBV-DNA negative and positive patients with hematological malignancies. ACTA ACUST UNITED AC 2010; 15:240-4. [PMID: 20670484 DOI: 10.1179/102453309x12583347114059] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Reactivation of hepatitis B virus (HBV) is a frequent complication of chemotherapy (CT) in patients with HBsAg carriers. In this prospective study, we documented CT induced HBV reactivation risk in patients with hematological malignancies. HBV reactivation risk is influenced by baseline viral load. Therefore, we divided our study population into two groups according to HBV-DNA status. HBV-DNA negative patients (n=18) were treated with nucleoside analogues once HBV reactivation was observed. HBV-DNA positive patients (n=12) commenced lamivudine before the initiation of the CT. In HBV-DNA negative patients HBV reactivation was found in 10 patients (55.5%). HBV reactivation was significantly more frequent in chronic lymphocytic leukemia (CLL) patients (P=0.008) and in patients receiving rituximab containing chemotherapy regimens (P=0.06). Eight patients (80.0%) responded to antiviral treatment after HBV reactivation. Two CLL patients experienced a flare-up after the withdrawal of antiviral therapy. In HBV-DNA positive patients, HBV reactivation was observed in four patients (33.3%) during lamivudine treatment and in two patients after lamivudine withdrawal. This study demonstrated the increased risk of CT-induced HBV reactivation in CLL patients, for the first time.
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Affiliation(s)
- Münci Yağci
- Department of Hematology, Faculty of Medicine, Gazi University, Ankara, Turkey
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Wei C, Chong YT, Wen JZ, Li YW, Li G. Characterization of hepatitis virus B isolated from a multi-drug refractory patient. Virus Res 2010; 155:254-8. [PMID: 20970466 DOI: 10.1016/j.virusres.2010.10.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2010] [Revised: 10/14/2010] [Accepted: 10/14/2010] [Indexed: 01/03/2023]
Abstract
Prolonged treatment of chronic hepatitis B (CHB) with nucleoside analogues (NAs) almost invariably engenders viral resistance, and sequential NAs monotherapy can promote multi-drug resistance. This study aimed to investigate the molecular characteristics and the mutation profile of multi-drug resistant hepatitis B virus (HBV). The complete genome of HBV isolated from a multi-drug refractory patient was amplified and cloned, and 22 clones were selected for sequencing. The homology of the full-length genome between clones ranged from 98.7% to 99.9%. A precore stop codon mutation of G1896A and basic core promoter (BCP) mutations A1762T/G1764A were detected in a majority of clones. A phylogenetic analysis showed that all clones were classified as subgenotype B2. Three mutations in the surface (S) antigen region, sC76Y, sP120T and sI195M, were detected in 100%, 100% and 77.3% of the clones, respectively. In the core (C) antigen region, a mutation at codon 135 (cP135Q) was detected in 100% of clones. Lamivudine (LAM)-resistant mutations, rtL180M and rtM204V/I were detected in 86.4% of clones. Adefovir (ADV) or entecavir (ETV)-resistant mutations were not detected. Several novel mutations, such as rtT128N, rtA222T, rtS256G, rtL271M, rtS332R, and rtN/T337D, were present in a majority of clones. Furthermore, six pairs of mutations in the overlapping reverse transcriptase (RT) gene and S gene were detected. In conclusion, the complex HBV mutation profile detected in the multi-drug refractory patient highlights the problems associated with the ongoing selection of mutations, including further compensatory mutations as well as potential cross-resistance mutations.
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Affiliation(s)
- Chen Wei
- Medical Research Center, The Third Affiliated Hospital of Sun Yat-sen University, No 600, Tianhe Road, Guangzhou, Guangdong, China.
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Xu G, You Q, Pickerill S, Zhong H, Wang H, Shi J, Luo Y, You P, Kong H, Lu F, Hu L. Application of PCR-LDR-nucleic acid detection strip in detection of YMDD mutation in hepatitis B patients treated with lamivudine. J Med Virol 2010; 82:1143-9. [PMID: 20513076 DOI: 10.1002/jmv.21811] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Abstract
Liver transplantation is now widely recognised as an effective treatment option for patients with advanced liver disease. Many units now achieve greater than 85% survival at 1 year, with the majority of patients having a high quality of life. The maintenance of a high quality of life requires careful clinical management to ensure that the continued maintenance of excellent liver graft function is not achieved at the expense of immunosuppressive drug complications or morbidity. Acute liver rejection will occur in between 30 to 45% of patients, although with modern immunosuppressive protocols, usually combining one of the calcineurin agents, either cyclosporin or tacrolimus, with both azathioprine and corticosteroids (prednisolone) ensures that relatively few grafts are lost from severe acute rejection. While the incidence and severity of acute rejection may be one factor in raising the risk of chronic rejection, it may not be the principal one in many patients. It is important to recognise that the frequency of rejection also varies with the primary underlying liver disease, with patients with hepatitis B or alcoholic liver disease having relatively low rejection rates, compared with patients with primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC), which range between 20 to 70%. Chronic rejection will account for some 5% of grafts lost in the first 3 to 5 years. Indeed, there is some evidence that the incidence of chronic rejection is actually declining over the past few years. While the reason for this apparent decline is uncertain, and it could relate to better immunosuppression management, or more likely to the growing recognition that chronic graft dysfunction may be due to recurrent liver disease, such as autoimmune hepatitis, PBC, PSC, or recurrent hepatitis C. The differentiation of recurrent primary liver disease from chronic rejection can prove to be very difficult in clinical practice. Thus, the clinician must carefully monitor liver and graft function, evaluate any biochemical changes, and try to reach a clear diagnosis before considering any modification of immunosuppressive schedules.
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Affiliation(s)
- R F Garcia
- Liver Unit, Queen Elizabeth Hospital, Birmingham, England
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Walsh AW, Langley DR, Colonno RJ, Tenney DJ. Mechanistic characterization and molecular modeling of hepatitis B virus polymerase resistance to entecavir. PLoS One 2010; 5:e9195. [PMID: 20169198 PMCID: PMC2820545 DOI: 10.1371/journal.pone.0009195] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2009] [Accepted: 01/06/2010] [Indexed: 01/25/2023] Open
Abstract
Background Entecavir (ETV) is a deoxyguanosine analog competitive inhibitor of hepatitis B virus (HBV) polymerase that exhibits delayed chain termination of HBV DNA. A high barrier to entecavir-resistance (ETVr) is observed clinically, likely due to its potency and a requirement for multiple resistance changes to overcome suppression. Changes in the HBV polymerase reverse-transcriptase (RT) domain involve lamivudine-resistance (LVDr) substitutions in the conserved YMDD motif (M204V/I ± L180M), plus an additional ETV-specific change at residues T184, S202 or M250. These substitutions surround the putative dNTP binding site or primer grip regions of the HBV RT. Methods/Principal Findings To determine the mechanistic basis for ETVr, wildtype, lamivudine-resistant (M204V, L180M) and ETVr HBVs were studied using in vitro RT enzyme and cell culture assays, as well as molecular modeling. Resistance substitutions significantly reduced ETV incorporation and chain termination in HBV DNA and increased the ETV-TP inhibition constant (Ki) for HBV RT. Resistant HBVs exhibited impaired replication in culture and reduced enzyme activity (kcat) in vitro. Molecular modeling of the HBV RT suggested that ETVr residue T184 was adjacent to and stabilized S202 within the LVDr YMDD loop. ETVr arose through steric changes at T184 or S202 or by disruption of hydrogen-bonding between the two, both of which repositioned the loop and reduced the ETV-triphosphate (ETV-TP) binding pocket. In contrast to T184 and S202 changes, ETVr at primer grip residue M250 was observed during RNA-directed DNA synthesis only. Experimentally, M250 changes also impacted the dNTP-binding site. Modeling suggested a novel mechanism for M250 resistance, whereby repositioning of the primer-template component of the dNTP-binding site shifted the ETV-TP binding pocket. No structural data are available to confirm the HBV RT modeling, however, results were consistent with phenotypic analysis of comprehensive substitutions of each ETVr position. Conclusions Altogether, ETVr occurred through exclusion of ETV-TP from the dNTP-binding site, through different, novel mechanisms that involved lamivudine-resistance, ETV-specific substitutions, and the primer-template.
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Affiliation(s)
- Ann W. Walsh
- Research and Development, Bristol-Myers Squibb Inc., Wallingford, Connecticut, United States of America
| | - David R. Langley
- Research and Development, Bristol-Myers Squibb Inc., Wallingford, Connecticut, United States of America
- * E-mail: (DRL); (DJT)
| | - Richard J. Colonno
- Research and Development, Bristol-Myers Squibb Inc., Wallingford, Connecticut, United States of America
| | - Daniel J. Tenney
- Research and Development, Bristol-Myers Squibb Inc., Wallingford, Connecticut, United States of America
- * E-mail: (DRL); (DJT)
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Main J, Thomas HC. Hepatitis. ANTIBIOTIC AND CHEMOTHERAPY 2010:608-616. [DOI: 10.1016/b978-0-7020-4064-1.00048-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Huang H, Cai Q, Lin T, Lin X, Liu Y, Gao Y, Peng R. Lamivudine for the prevention of hepatitis B virus reactivation after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for patients with advanced or relapsed non-Hodgkin's lymphoma single institution experience. Expert Opin Pharmacother 2009; 10:2399-406. [PMID: 19761353 DOI: 10.1517/14656560903251710] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE Hepatitis B virus (HBV) reactivation is a well-known complication in cancer patients receiving cytotoxic chemotherapy, resulting in varying degrees of liver damage. The objective of this study was to investigate the efficacy of lamivudine for the prevention of HBV reactivation in non-Hodgkin's lymphoma (NHL) patients undergoing high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT). RESEARCH DESIGN AND METHODS Thirty-two patients with NHL who were HBV surface antigen (HBsAg)-positive were enrolled in this pilot study. They were divided into two groups: 20 patients received prophylactic oral lamivudine 100 mg/day before, and until at least 6 months after transplantation. The historical control group comprised 12 patients who received high-dose chemotherapy and AHSCT without lamivudine. The incidence and severity of hepatitis due to HBV reactivation, as well as other adverse clinical outcomes, were compared between the two groups. RESULTS Most baseline clinical characteristics were similar in the two groups, except for HBV e-antigen (HBeAg)-positive status (85% in the lamivudine group vs 33.3% in the control group, p = 0.006) and the type of AHSCT. There was a lower incidence of hepatitis due to HBV reactivation in the lamivudine group than in the control group (10 vs 50%, p = 0.030), less severe hepatitis (0 vs 25%, p = 0.009), and lower mortality (0 vs 25%, p = 0.236). An HBV variant with tyrosine methionine aspartate aspartate (YMDD) mutation was detected in one patient in the lamivudine group (5%) after administration of lamivudine for 9 months. No significant adverse events were associated with the use of prophylactic lamivudine, and hematopoietic reconstitution was not affected by the intervention. CONCLUSIONS Prophylactic lamivudine may reduce the incidence and severity of chemotherapy-related HBV reactivation and hepatitis-related mortality in HBsAg-positive NHL patients receiving high-dose chemotherapy and AHSCT. Additional randomized, multicenter trials are warranted.
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Affiliation(s)
- Huiqiang Huang
- Sun Yat-sen University, Cancer Center, Department of Medical Oncology, Guangzhou 510060, PR China.
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Li XK, Zhou ZH, Jin Q, Du B, Shi YG, Fang SH, Liu W, Zhang SY. Prevalence of lamivudine-resistant hepatitis B virus strains in patients with acute hepatitis B virus infection. Shijie Huaren Xiaohua Zazhi 2009; 17:2631-2634. [DOI: 10.11569/wcjd.v17.i25.2631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the prevalence of lamivudine-resistant hepatitis B virus (HBV) strains (YIDD/YVDD variants) in patients with acute HBV infection (AHB).
METHODS: A total of 321 patients with HBV infection (HBV DNA ≥ 1.0 × 107 copies/L) were included in the study, of which 100 had AHB and underwent no treatment, and 221 had chronic HBV infection (CHB) and were treated with lamivudine (100 mg/d). Serum specimens were taken from these patients and used to identify wild-type and YMDD motif mutant HBV strains by fluorescent hybridization biprobe-based polymerase chain reaction (PCR) and melting curve assay (FH-PCR-MC).
RESULTS: Only wild-type HBV was detected in patients with AHB (YMDD, 100%). Both wild-type and YMDD motif mutant HBV strains were detected in patients with CHB. The YMDD mutation rate in CHB patients was 63.4%. Of all YMDD mutations detected, YIDD variant accounted for 52.1%, YVDD variant 37.9%, and the mixed type (YIDD + YVDD) 10.0%. The YMDD mutation rates in CHB patients treated with lamivudine for < 1 year, 1-2 years, 2-3 years, 3-4 years and > 4 years were 45%, 66%, 77%, 75% and 40%, respectively. There was a significant difference in the YMDD mutation rate between the two groups of patients (χ2 = 112.3, P = 0.00).
CONCLUSION: Lamivudine-resistant HBV strains are not detected in patients with acute HBV infection.
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Antiviral activity, dose-response relationship, and safety of entecavir following 24-week oral dosing in nucleoside-naive Japanese adult patients with chronic hepatitis B: a randomized, double-blind, phase II clinical trial. Hepatol Int 2009; 3:445-52. [PMID: 19669249 DOI: 10.1007/s12072-009-9135-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2009] [Accepted: 05/07/2009] [Indexed: 01/04/2023]
Abstract
PURPOSE A randomized, double-blind, multicenter study (ETV-047) was conducted to evaluate the dose-response relationship of entecavir and compare its antiviral activity and safety with lamivudine in Japanese patients with chronic hepatitis B (CHB). METHODS One hundred thirty-seven nucleoside-naive adult patients with CHB were randomized to once-daily oral doses of entecavir 0.01, 0.1, or 0.5 mg or lamivudine 100 mg for 24 weeks. The primary efficacy end point used to evaluate the dose-response relationship was mean change from baseline in serum hepatitis B virus (HBV) DNA level at week 22, as determined by polymerase chain reaction assay. RESULTS Entecavir demonstrated a clear dose-response relationship, with mean change from baseline in serum HBV DNA level of -3.11, -4.77, and -5.16 log(10) copies/ml with entecavir 0.01, 0.1, and 0.5 mg, respectively. Entecavir 0.5 mg was superior to lamivudine 100 mg for the mean change in HBV DNA level (-5.16 vs. -4.29 log(10) copies/ml; P = 0.007). The overall incidence of adverse events was comparable between treatment groups. Two patients discontinued treatment because of adverse events (one with liver cirrhosis [entecavir 0.5 mg] and one with grade 4 serum alanine aminotransferase (ALT) elevation, nausea, and malaise [lamivudine 100 mg]). Serum ALT flares were observed in four patients; flares were associated with 2 log(10) reductions or more in HBV DNA level and resolved without dose interruption. CONCLUSION Entecavir 0.01-0.5 mg is well tolerated and produces a dose-dependent reduction in viral load in nucleoside-naive Japanese patients with CHB. Compared with lamivudine 100 mg, entecavir 0.1 mg demonstrated noninferiority and entecavir 0.5 mg was superior in this population.
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Abstract
Hepatitis B virus (HBV) infection is a worldwide problem and can cause acute liver failure, acute hepatitis, chronic hepatitis, liver cirrhosis, and liver cancer. In areas of high prevalence such as in Asia, Africa, southern Europe, and Latin America, the hepatitis B surface antigen positive rate ranges from 2% to 20%.In endemic areas, HBV infection occurs mainly during infancy and early childhood. Mother-to-infant transmission accounts for approximately half of the chronic HBV infections. In contrast to infection in adults, HBV infection during early childhood results in a much higher rate of persistent infection and long-term serious complications such as liver cirrhosis and HCC.Three phases of chronic hepatitis B have been identified: the immune-tolerant phase, the immune-active phase, and the inactive hepatitis B phase. These phases of infection are characterized by variations in viral replication, hepatic inflammation, spontaneous clearance, and response to antiviral therapy.The optimal goal of antiviral therapy for chronic HBV infection is to eradicate HBV and to prevent its related liver complications. However, due to the limited effect of available therapies in viral eradication, the goal of treatment is to reduce viral replication, to minimize liver injury, and to reduce infectivity. In this review the current recommendations for monitoring and treating chronic HBV infection in children are reviewed.
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Sarin SK, Kumar A, Almeida JA, Chawla YK, Fan ST, Garg H, de Silva HJ, Hamid SS, Jalan R, Komolmit P, Lau GK, Liu Q, Madan K, Mohamed R, Ning Q, Rahman S, Rastogi A, Riordan SM, Sakhuja P, Samuel D, Shah S, Sharma BC, Sharma P, Takikawa Y, Thapa BR, Wai CT, Yuen MF. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int 2009; 3:269-82. [PMID: 19669378 PMCID: PMC2712314 DOI: 10.1007/s12072-008-9106-x] [Citation(s) in RCA: 642] [Impact Index Per Article: 40.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2008] [Accepted: 09/26/2008] [Indexed: 02/06/2023]
Abstract
The Asian Pacific Association for the Study of the Liver (APASL) set up a working party on acute-on-chronic liver failure (ACLF) in 2004, with a mandate to develop consensus guidelines on various aspects of ACLF relevant to disease patterns and clinical practice in the Asia-Pacific region. Experts predominantly from the Asia-Pacific region constituted this working party and were requested to identify different issues of ACLF and develop the consensus guidelines. A 2-day meeting of the working party was held on January 22-23, 2008, at New Delhi, India, to discuss and finalize the consensus statements. Only those statements that were unanimously approved by the experts were accepted. These statements were circulated to all the experts and subsequently presented at the Annual Conference of the APASL at Seoul, Korea, in March 2008. The consensus statements along with relevant background information are presented in this review.
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Affiliation(s)
- Shiv Kumar Sarin
- Department of Gastroenterology, G. B. Pant Hospital, Affiliated to University of Delhi, Jawahar Lal Nehru Road, New Delhi, 110 002 India
| | - Ashish Kumar
- Department of Hepatology, Institute of Liver & Biliary Sciences (ILBS), D-1 Vasant Kunj, New Delhi, 110 070 India
| | - John A. Almeida
- Gastrointestinal and Liver Unit, The Prince of Wales Hospital and University of New South Wales, Barker Street, Randwick 2031, New South Wales, Australia
| | - Yogesh Kumar Chawla
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Sheung Tat Fan
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China
| | - Hitendra Garg
- Department of Gastroenterology, G. B. Pant Hospital, Affiliated to University of Delhi, Jawahar Lal Nehru Road, New Delhi, 110 002 India
| | - H. Janaka de Silva
- Department of Medicine, Faculty of Medicine, University of Kelaniya, P.O. Box 6, Thalagolla Road, Ragama, Sri Lanka
| | - Saeed Sadiq Hamid
- Section of Gastroenterology, Department of Medicine, The Aga Khan University Hospital, Stadium Road, P.O. Box 3500, Karachi , 74800 Pakistan
| | - Rajiv Jalan
- The University College London (UCL) Institute of Hepatology, Division of Medicine, University College London, 69-75 Chenies Mews, London, WC1E 6HX UK
| | - Piyawat Komolmit
- Department of Medicine, Faculty and Medicine, Chulalongkorn University, Bangkok , 10330 Thailand
| | - George K. Lau
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China
| | - Qing Liu
- Beijing Youan Hospital, Capital University of Medical Sciences, Beijing, China
| | - Kaushal Madan
- Department of Hepatology, Institute of Liver & Biliary Sciences (ILBS), D-1 Vasant Kunj, New Delhi, 110 070 India
| | - Rosmawati Mohamed
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603 Malaysia
| | - Qin Ning
- Laboratory of Infectious Immunology, Department of Infectious Disease, Institute of Immunology, Huazhong University of Science and Technology, Wuhan, China
| | - Salimur Rahman
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Archana Rastogi
- Department of Pathology, Institute of Liver & Biliary Sciences (ILBS), D-1 Vasant Kunj, New Delhi, 110 070 India
| | - Stephen M. Riordan
- Gastrointestinal and Liver Unit, The Prince of Wales Hospital and University of New South Wales, Barker Street, Randwick 2031, New South Wales, Australia
| | - Puja Sakhuja
- Department of Pathology, G. B. Pant Hospital, Affiliated to University of Delhi, Jawahar Lal Nehru Road, New Delhi, 110 002 India
| | - Didier Samuel
- INSERM Unité 785, AP-HP Hôpital Paul Brousse, Villejuif, 94800 France
| | - Samir Shah
- Department of Gastroenterology, Jaslok Hospital and Research Center, 15 - Dr. Deshmukh Marg, Pedder Road, Mumbai, 400 026 India
| | - Barjesh Chander Sharma
- Department of Gastroenterology, G. B. Pant Hospital, Affiliated to University of Delhi, Jawahar Lal Nehru Road, New Delhi, 110 002 India
| | - Praveen Sharma
- Department of Gastroenterology, G. B. Pant Hospital, Affiliated to University of Delhi, Jawahar Lal Nehru Road, New Delhi, 110 002 India
| | - Yasuhiro Takikawa
- Department of Gastroenterology and Hepatology, Iwate Medical University, 19-1 Uchimaru, Morioka, 020-8505 Japan
| | - Babu Ram Thapa
- Division of Pediatric Gastroenterology, Department of Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Chun-Tao Wai
- Asian Center for Liver Diseases and Transplantation, Gleneagles Hospital, Annexe Block #02-37, 6A Gleneagles Hospital, Singapore, 258500 Singapore
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China
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Okita R, Takahashi M, Narahara H, Sanada Y, Okada M, Kawakami Y, Chayama K, Okita K. Use of entecavir to prevent hepatitis B virus reactivation during cytotoxic chemotherapy for solid malignancy. Clin J Gastroenterol 2009; 2:214-217. [DOI: 10.1007/s12328-009-0063-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2008] [Accepted: 12/18/2008] [Indexed: 02/05/2023]
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Kobashi H, Takaguchi K, Ikeda H, Yokosuka O, Moriyama M, Imazeki F, Kage M, Seriu T, Omata M, Sakaguchi K, Shiratori Y. Efficacy and safety of entecavir in nucleoside-naive, chronic hepatitis B patients: phase II clinical study in Japan. J Gastroenterol Hepatol 2009; 24:255-61. [PMID: 19215336 DOI: 10.1111/j.1440-1746.2008.05593.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND AIM Entecavir has demonstrated clinical efficacy for chronic hepatitis B. This study evaluated the efficacy and safety of entecavir in nucleoside-naive Japanese chronic hepatitis B patients. METHODS In this multicenter, double-blind study, 66 nucleoside-naive Japanese chronic hepatitis B patients were randomized to 0.1 mg entecavir (n = 32) or 0.5 mg entecavir (n = 34) daily for 52 weeks. The primary endpoint was the proportion of patients whose serum hepatitis B virus (HBV) DNA decreased from baseline by > or =2 log(10) copies/mL or became undetectable (<400 copies/mL by polymerase chain reaction assay) at week 48. RESULTS One hundred percent of patients in both treatment groups achieved the primary efficacy endpoint, with 81% and 68% of patients achieving undetectable HBV DNA in the 0.1 mg and 0.5 mg treatment groups, respectively. Mean changes from baseline in HBV DNA were -4.49 log(10) and -4.84 log(10) copies/mL for the 0.1 mg and 0.5 mg groups, respectively. Significant improvements in necroinflammation were seen in both groups, as assessed by Knodell and New Inuyama classifications. Most adverse events were transient and classified as grade 1 or 2. There were no clinically significant differences in adverse events across the two treatment groups and no discontinuations due to adverse events in either group. CONCLUSIONS In Japanese nucleoside-naive patients with chronic hepatitis B, 0.1 mg or 0.5 mg entecavir daily provided excellent efficacy and was well tolerated. The 0.5 mg dose was selected for the treatment of nucleoside-naive patients.
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Affiliation(s)
- Haruhiko Kobashi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
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47
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Lai MW, Huang SF, Hsu CW, Chang MH, Liaw YF, Yeh CT. Identification of nonsense mutations in hepatitis B virus S gene in patients with hepatocellular carcinoma developed after lamivudine therapy. Antivir Ther 2009; 14:249-261. [PMID: 19430100 DOI: 10.1177/135965350901400216] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
BACKGROUND Lamivudine is widely used in patients with chronic hepatitis B virus (HBV) infection. In cirrhotic patients, long-term lamivudine therapy significantly reduced the risk of hepatocellular carcinoma (HCC). However, in a small but substantial portion of patients, HCC still developed despite lamivudine therapy. Prolonged usage of lamivudine led to mutations in the polymerase gene, where concurrent nonsense mutations in the HBV S gene occasionally occurred. The significance of such mutations in hepatocarcinogenesis remains elusive. Here, we aimed to understand the oncogenicity of HBV pre-S/S nonsense mutations identified in patients with HCC that developed after lamivudine therapy. METHODS Of 141 consecutive hepatitis B surface antigen-positive HCC patients, 8 developed HCC after receiving lamivudine therapy. The HBV pre-S/S sequences in their serum and tissue samples were analysed. A sex- and age-matched group of HCC patients who never received lamivudine therapy were included as controls. Site-directed mutagenesis experiments were performed to generate identified pre-S/S nonsense mutations in expression vectors for tumourigenicity analysis. RESULTS Seven of eight patients in the lamivudine-treated group harboured nonsense mutations in the S gene compared with none in the control group (P<0.001). Site-directed mutagenesis and transient transfection experiments revealed that these mutants could transactivate oncogene promoters. NIH3T3 cells stably expressing sL21*, sW156* and sW172* pre-S/S mutants had increased tumourigenicity in nude mice. CONCLUSIONS HCCs developed in lamivudine-treated patients who frequently carried nonsense mutations in the S gene. Such pre-S/S mutants are potentially oncogenic and might counteract the effect of lamivudine in preventing hepatocarcinogenesis.
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Affiliation(s)
- Ming-Wei Lai
- Liver Research Unit, Chang Gung Medical Center, Taipei, Taiwan
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48
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Alam S, Azam G, Mustafa G, Ahmad N, Islam B, Podder PK, Khan M. Pretreatment and on-treatment predictors of viral breakthrough in lamivudine therapy for chronic hepatitis B. Hepatol Int 2008; 2:494-497. [PMID: 19669325 PMCID: PMC2716900 DOI: 10.1007/s12072-008-9095-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2008] [Accepted: 08/07/2008] [Indexed: 01/17/2023]
Abstract
PURPOSE There are remarkable advances in the treatment of chronic hepatitis B (CHB) in the last few years. Unfortunately, prolonged antiviral treatment is associated with increasing risk of drug resistance/viral breakthrough (VBT), which may lead to flare-up and rapid decompensation. We have designed this study to predict the pretreatment and on-treatment factors responsible for development of VBT. METHODS This study was conducted during the period of February 2000 to November 2007. We have included 423 patients who received lamivudine (LAM) therapy for at least 1 year and at least 2 follow-ups at 6 months' interval. Follow-up period was 12-78 months. Chi-square test, student's t test, and logistic regression analysis were performed to prove the validity. RESULTS Of the 423 study cases, 367 (86.8%) were of male patients and 261 (61.7%) patients were HBeAg positive; the age of the patients was 30.8 +/- 12.9 years. Development of VBT was 4.4, 22.8, 45.3, and 74% at 1, 2, 3, and 4 or more years, respectively. Pretreatment high HBV DNA (P = 0.005) and female sex (P = 0.01) were associated with VBT and pretherapy ALT (P = 0.698), HBeAg status (P = 0.273), and age (P = 0.059) were not associated. Duration of treatment, failure to lose HBeAg at 1 year, and HBV DNA nonresponder at 6 months were significantly (P = 0.001) associated with development of VBT. CONCLUSION Persistence of HBeAg at 1 year and HBV DNA nonresponder at 6 months are good predictors of development of VBT.
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Affiliation(s)
- Shahinul Alam
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Golam Azam
- Department of Immunology, Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders, Shahbag, Dhaka, Bangladesh
| | - Golam Mustafa
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Nooruddin Ahmad
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Belalul Islam
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Provat Kumar Podder
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Mobin Khan
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
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Kuwahara R, Kumashiro R, Ide T, Koga Y, Hino T, Hisamochi A, Tanaka K, Ogata K, Koga H, Takao Y, Sata M. Predictive factors associated with the progression to hepatic failure caused by lamivudine-resistant HBV. Dig Dis Sci 2008; 53:2999-3006. [PMID: 18618250 DOI: 10.1007/s10620-008-0384-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2005] [Accepted: 07/12/2005] [Indexed: 02/07/2023]
Abstract
The aims of this study were to select the patients with a potential for progression to hepatic failure due to lamivudine-resistant HBV and to standardize the treatment for patients with lamivudine-resistant HBV. Patients (n = 47) with reactivated hepatitis due to lamivudine-resistant HBV were classified into two groups, with and without potential for progression to hepatic failure, according to the criteria using the data of serum bilirubin level and prothrombin activity after the reactivated hepatitis. Multivariate analysis showed that prothrombin activity at the initiation of lamivudine therapy was related to the deterioration of the liver function after the emergence of lamivudine-resistant HBV (P = 0.0025, 95%CI 0.8269-0.9601). We assume that earlier additional or substitutive treatment with other antiviral agent, such as adefovir dipivoxil, should be recommended when the lamivudine-resistant HBV is detected in patients with the history of decompensated liver disease before the administration of lamivudine, even when hepatitis has not been reactivated yet.
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Tchesnokov EP, Obikhod A, Schinazi RF, Götte M. Delayed chain termination protects the anti-hepatitis B virus drug entecavir from excision by HIV-1 reverse transcriptase. J Biol Chem 2008; 283:34218-28. [PMID: 18940786 DOI: 10.1074/jbc.m806797200] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Entecavir (ETV) is a potent antiviral nucleoside analogue that is used to treat hepatitis B virus (HBV) infection. Recent clinical studies have demonstrated that ETV is also active against the human immunodeficiency virus type 1 (HIV-1). Unlike all approved nucleoside analogue reverse transcriptase RT) inhibitors (NRTIs), ETV contains a 3'-hydroxyl group that allows further nucleotide incorporation events to occur. Thus, the mechanism of inhibition probably differs from classic chain termination. Here, we show that the incorporated ETV-monophosphate (MP) can interfere with three distinct stages of DNA synthesis. First, incorporation of the next nucleotide at position n + 1 following ETV-MP is compromised, although DNA synthesis eventually continues. Second, strong pausing at position n + 3 suggests a long range effect, referred to as "delayed chain-termination." Third, the incorporated ETV-MP can also act as a "base pair confounder" during synthesis of the second DNA strand, when the RT enzyme needs to pass the inhibitor in the template. Enzyme kinetics revealed that delayed chain termination is the dominant mechanism of action. High resolution foot-printing experiments suggest that the incorporated ETV-MP "repels" the 3'-end of the primer from the active site of HIV-1 RT, which, in turn, diminishes incorporation of the natural nucleotide substrate at position n + 4. Most importantly, delayed chain termination protects ETV-MP from phosphorolytic excision, which represents a major resistance mechanism for approved NRTIs. Collectively, these findings provide a rationale and important tools for the development of novel, more potent delayed chain terminators as anti-HIV agents.
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Affiliation(s)
- Egor P Tchesnokov
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada
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