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Rajput MK. Mutations and methods of analysis of mutations in Hepatitis B virus. AIMS Microbiol 2020; 6:401-421. [PMID: 33364535 PMCID: PMC7755589 DOI: 10.3934/microbiol.2020024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/23/2020] [Indexed: 12/13/2022] Open
Abstract
Immunization programmes against hepatitis-B are being carried out since more than three decades but still HBV is a major public health problem. Hepatitis B virus (HBV) genome consists of circular and partial double stranded DNA. Due to partial double stranded DNA, it uses an RNA intermediate during replication. This replicative strategy of HBV and lack of polymerase proofreading activity give rise to error occurrences comparable to retroviruses. The low fidelity of polymerase, overlapping reading frames and high replication rate produces many non-identical variants at every cycle of replication. Therefore, HBV spreads with mutations and variations. The mutations have been reported both in non-structural as well as structural genes of HBV genome. Recent advances in molecular biology have made easier to analyse these mutations. Hepatitis B antiviral therapy and immunization are all influenced by genetic variability. The analysis and understanding of these mutations are important for therapy against hepatitis B and updating of diagnostic tools. The present review discusses about mutations occurring in whole HBV genome. The mutation occurring both in structural and non-structural genes and non-coding regions have been described in details. It is much more informative because most of literature available, covers only individual gene or DNA regions of HBV.
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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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Zhou M, Zhang RH, Wang M, Xu GB, Liao SG. Prodrugs of triterpenoids and their derivatives. Eur J Med Chem 2017; 131:222-236. [DOI: 10.1016/j.ejmech.2017.03.005] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 03/01/2017] [Accepted: 03/03/2017] [Indexed: 12/12/2022]
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Motaleb MA, Abo-Kul M, Ibrahim SM, Saad SM, Arafat M. Synthesis of (125) I-lamivudine and (125) I-lamivudine-ursodeoxycholic acid codrug. J Labelled Comp Radiopharm 2016; 59:451-3. [PMID: 27561199 DOI: 10.1002/jlcr.3434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 07/20/2016] [Accepted: 07/25/2016] [Indexed: 11/07/2022]
Abstract
The preparation of (125) I-lamivudine ((125) I-3TC) and (125) I-lamivudine-ursodeoxycholic acid codrug ((125) I-3TC-UDCA), suitable for comparative biodistribution studies, is described. The synthesis of the unlabeled precursor 3TC-UDCA proceeds in an 11.6% yield, and the radiolabelling yields for (125) I-3TC and (125) I-3TC-UDCA were 89 and 92%, respectively. The final products are radiochemically pure (greater than 98%).
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Affiliation(s)
- M A Motaleb
- Labelled Compounds Department, Hot Labs Centre, Atomic Energy Authority, Cairo, 13759, Egypt.
| | - M Abo-Kul
- Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, 44519, Zagazig, Egypt
| | - Samy M Ibrahim
- Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, 44519, Zagazig, Egypt
| | - Shokry M Saad
- Cyclotron Project, Nuclear Research Centre, Atomic Energy Authority, Cairo, 13759, Egypt
| | - Muhammad Arafat
- Cyclotron Project, Nuclear Research Centre, Atomic Energy Authority, Cairo, 13759, Egypt
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Devunuri N, Amminabavi N, Chennuri BK, Losetty V, Gardas RL. The structural effect on volumetric and acoustic properties of aqueous anti-HIV drugs (Emtricitabine and Lamivudine) at various temperatures. J Mol Liq 2016. [DOI: 10.1016/j.molliq.2015.12.084] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Liang CC, Liu CH, Chung CS, Lin CK, Su TH, Yang HC, Liu CJ, Chen PJ, Chen DS, Kao JH. Advanced hepatic fibrosis and steatosis are associated with persistent alanine aminotransferase elevation in chronic hepatitis C patients negative for hepatitis C virus RNA during pegylated interferon plus ribavirin therapy. J Infect Dis 2014; 211:1429-36. [PMID: 25387585 DOI: 10.1093/infdis/jiu630] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 10/20/2014] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Clinical implications of persistent alanine aminotransferase (ALT) elevation and associated factors in chronic hepatitis C (CHC) patients who achieved undetectable hepatitis C virus (HCV) RNA during pegylated interferon plus ribavirin (peg-IFN/RBV) therapy remain unknown. METHODS A total of 1113 CHC patients with undetectable HCV RNA during peg-IFN/RBV therapy were enrolled. Baseline characteristics associated with persistent on-treatment ALT elevation (POAE), and its impact on treatment outcomes, were investigated. RESULTS Of 1113 CHC patients, 254 (22.8%) had POAE. Among patients with HCV genotype 1 (HCV-1) who had complete early virologic response (EVR) and received 48 weeks of therapy, patients with POAE had a lower rate of sustained virologic response (SVR) than those without POAE (44.1% vs 74.0%; P = .0002). Multivariate analyses showed that body mass index ≥ 27 kg/m(2), ALT level ≥3 times the upper limit of normal, aspartate aminotransferase to platelet ratio index score ≥1.5, hepatic fibrosis ≥F3, and hepatic steatosis ≥S2 were independent factors associated with POAE after viral clearance. CONCLUSIONS POAE is common in CHC patients during therapy. HCV-1 patients with POAE have a lower SVR rate to 48-week therapy if they achieve complete EVR. Advanced hepatic fibrosis, obesity, and steatosis are factors associated with POAE in these patients.
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Affiliation(s)
- Cheng-Chao Liang
- Department of Internal Medicine, Far Eastern Memorial Hospital Oriental Institute of Technology
| | - Chen-Hua Liu
- Department of Internal Medicine Hepatitis Research Center, National Taiwan University Hospital Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine
| | | | - Cheng-Kuan Lin
- Department of Internal Medicine, Far Eastern Memorial Hospital
| | - Tung-Hung Su
- Department of Internal Medicine Hepatitis Research Center, National Taiwan University Hospital Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine
| | - Hung-Chih Yang
- Hepatitis Research Center, National Taiwan University Hospital Department of Microbiology, National Taiwan University College of Medicine and National Taiwan University Hospital
| | - Chun-Jen Liu
- Department of Internal Medicine Hepatitis Research Center, National Taiwan University Hospital Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine
| | - Pei-Jer Chen
- Department of Internal Medicine Hepatitis Research Center, National Taiwan University Hospital Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine
| | - Ding-Shinn Chen
- Department of Internal Medicine Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine Hepatitis Research Center, National Taiwan University Hospital Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine
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High dose of Lamivudine and resistance in patients with chronic hepatitis B. HEPATITIS RESEARCH AND TREATMENT 2014; 2014:615621. [PMID: 25349729 PMCID: PMC4199074 DOI: 10.1155/2014/615621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 08/10/2014] [Accepted: 08/28/2014] [Indexed: 11/23/2022]
Abstract
Background. Lamivudine is the most affordable drug used for chronic hepatitis B and has a high safety profile. With the daily dose of 100 mg there is progressive appearance of resistance to lamivudine therapy. In our study we used 150 mg of lamivudine daily as a standard dose which warrants further exploration for the efficacy of the drug. Aims of the Study. To assess the efficacy of lamivudine 150 mg daily on resistance in patients with chronic hepatitis B. Methods. This retrospective study consists of 53 patients with chronic hepatitis B treated with 150 mg of lamivudine daily. The biochemical and virological response to the treatment were recorded at a 1-year and 2-, 3-, 4-, and 5-year period and time of emergence of resistance to the treatment was noted. Results. The mean age of the patients was 54 years with 80% being males. The resistance to lamivudine 150 mg daily at 1 year and 2, 3, and 5 years was 12.5%, 22.5%, 37.5%, and 60%, respectively, which is much less compared to the standard dose of 100 mg of lamivudine. Conclusions. Lamivudine is safe and a higher dose of 150 mg daily delays the resistance in patients with chronic hepatitis B.
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Majid F, Jahan M, Lutful Moben A, Tabassum S. Comparison of Hybrid Capture 2 Assay with Real-time-PCR
for Detection and Quantitation of Hepatitis B Virus DNA. Euroasian J Hepatogastroenterol 2014; 4:31-35. [PMID: 29264316 PMCID: PMC5736953 DOI: 10.5005/jp-journals-10018-1093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Accepted: 12/26/2013] [Indexed: 11/30/2022] Open
Abstract
Background Both real-time-polymerase chain reaction (PCR) and hybrid capture 2 (HC2) assay can detect and quantify hepatitis B virus (HBV) DNA. However, real-time-PCR can detect a wide range of HBV DNA, while HC2 assay could not detect lower levels of viremia. The present study was designed to detect and quantify HBV DNA by real-time-PCR and HC2 assay and compare the quantitative data of these two assays. Materials and methods A cross-sectional study was conducted in between July 2010 and June 2011. A total of 66 serologically diagnosed chronic hepatitis B (CHB) patients were selected for the study. Real-time-PCR and HC2 assay was done to detect HBV DNA. Data were analyzed by statistical Package for the social sciences (SPSS). Results Among 66 serologically diagnosed chronic hepatitis B patients 40 (60.61%) patients had detectable and 26 (39.39%) had undetectable HBV DNA by HC2 assay. Concordant results were obtained for 40 (60.61%) out of these 66 patients by real-time-PCR and HC2 assay with mean viral load of 7.06 ± 1.13 log10 copies/ml and 6.95 ± 1.08 log10 copies/ml, respectively. In the remaining 26 patients, HBV DNA was detectable by real-time-PCR in 20 patients (mean HBV DNA level was 3.67 ± 0.72 log10 copies/ml. However, HBV DNA could not be detectable in six cases by the both assays. The study showed strong correlation (r = 0.915) between real-time-PCR and HC2 assay for the detection and quantification of HBV DNA. Conclusion HC2 assay may be used as an alternative to real-time-PCR for CHB patients. How to cite this article: Majid F, Jahan M, Moben AL, Tabassum S. Comparison of Hybrid Capture 2 Assay with Real-time-PCR for Detection and Quantitation of Hepatitis B Virus DNA. Euroasian J Hepato-Gastroenterol 2014;4(1):31-35.
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Affiliation(s)
- Farjana Majid
- Department of Microbiology, Tairunnessa Memorial Medical College, Tongi, Gazipur, Bangladesh
| | - Munira Jahan
- Department of Virology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Ahmed Lutful Moben
- Department of Medicine, Shaheed Suhrawardy Medical College Hospital, Dhaka, Bangladesh
| | - Shahina Tabassum
- Department of Virology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
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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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Tan YW, Ge GH, Zhao W, Gan JH, Zhao Y, Niu ZL, Zhang DJ, Chen L, Yu XJ, Yang LJ. YMDD motif mutations in chronic hepatitis B antiviral treatment naïve patients: a multi-center study. Braz J Infect Dis 2012. [PMID: 22729192 DOI: 10.1016/s1413-8670(12)70319-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE This study aimed to determine the natural prevalence of variants of tyrosine-methionine-aspartic acid-aspartic acid (YMDD) motif in patients with chronic hepatitis B (CHB), and to explore its relation with demographic and clinical features, hepatitis B virus (HBV) genotypes, and HBV DNA levels. METHODS A total of 1,042 antiviral treatment naïve CHB patients (including with lamivudine [LAM]) in the past year were recruited from outpatient and inpatient departments of six centers from December 2008 to June 2010. YMDD variants were analyzed using the HBV drug resistance line probe assay (Inno-Lipa HBV-DR). HBV genotypes were detected with polymerase chain reaction (PCR) microcosmic nucleic acid cross-ELISA, and HBV deoxyribonucleic acid (DNA) was quantitated with real-time PCR. All serum samples underwent tests for HBV, HCV, and HDV with ELISA. RESULTS YMDD variants were detected in 23.3% (243/1042) of CHB patients. YMDD mutation was accompanied by L180M mutation in 154 (76.9%) patients. Both wild-type HBV and YMDD variant HBV were present in 231 of 243 patients. Interestingly, 12 patients had only YIDD and/or YVDD variants without wild YMDD motif. In addition, 27.2% (98/359) of HbeAg-positive patients had YMDD mutations, which was higher than that in HbeAg-negative patients (21.2%, 145/683). The incidence of YMDD varied among patients with different HBV genotypes, but the difference was not significant. Moreover, the incidence of YMDD in patients with high HBV DNA level was significantly higher than that in those with low HBV DNA level. CONCLUSION Mutation of YMDD motif was detectable at a high rate in CHB patients in this study. The incidence of YMDD may be correlated with HBeAg and HBV DNA level.
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Affiliation(s)
- You-Wen Tan
- Department of Liver Diseases, No. 3 Hospital of Zhenjiang, Zhenjiang, Jiangsu, China.
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Karayiannis P. Direct acting antivirals for the treatment of chronic viral hepatitis. SCIENTIFICA 2012; 2012:478631. [PMID: 24278700 PMCID: PMC3820491 DOI: 10.6064/2012/478631] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 10/08/2012] [Indexed: 06/02/2023]
Abstract
The development and evaluation of antiviral agents through carefully designed clinical trials over the last 25 years have heralded a new dawn in the treatment of patients chronically infected with the hepatitis B and C viruses, but not so for the D virus (HBV, HCV, and HDV). The introduction of direct acting antivirals (DDAs) for the treatment of HBV carriers has permitted the long-term use of these compounds for the continuous suppression of viral replication, whilst in the case of HCV in combination with the standard of care [SOC, pegylated interferon (PegIFN), and ribavirin] sustained virological responses (SVRs) have been achieved with increasing frequency. Progress in the case of HDV has been slow and lacking in significant breakthroughs.This paper aims to summarise the current state of play in treatment approaches for chonic viral hepatitis patients and future perspectives.
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Affiliation(s)
- Peter Karayiannis
- Section of Hepatology and Gastroenterology, Department of Medicine, Imperial College, St Mary's Campus, London W2 1PG, UK
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Kim HJ, Park JH, Park DI, Cho YK, Sohn CI, Jeon WK, Kim BI. The influence of YMDD mutation patterns on clinical outcomes in patients with adefovir add-on lamivudine combination treatment. Liver Int 2012; 32:303-10. [PMID: 22098177 DOI: 10.1111/j.1478-3231.2011.02647.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2011] [Accepted: 08/22/2011] [Indexed: 12/22/2022]
Abstract
BACKGROUND/AIM The aim of this study was to assess the patterns of lamivudine (LAM)-resistant mutations and the influence on biochemical and virological responses to adefovir (ADV) add-on LAM combination therapy in patients with LAM-resistant chronic hepatitis B (CHB). METHODS Seventy-eight CHB patients with confirmed genotypic resistance to LAM, who initiated ADV add-on LAM combination treatment, were enrolled at our institution between April 2007 and April 2009. RESULTS The baseline tyrosine-methionine-aspartate-aspartate (YMDD) mutation patterns were as follows: rtM204I 45 (57.7%); and rtM204V + rtM204I/V 33 (42.3%). The decrease in the mean ± standard deviation (SD) serum log(10) HBV-DNA level did not differ between the patients carrying the rtM204I vs. rtM204IV +rtM204I/V mutations at 3, 6 and 12 months after the initiation of ADV add-on LAM combination treatment. The proportion of patients who achieved ALT normalization (<40 IU/L) 12 months after the initiation of ADV add-on LAM combination treatment were significantly higher in patients with a rtM204I mutation than rtM204V+ rtM204I/V mutations (39 [86.7%] vs. 22 [66.7%], P = 0.05). The proportion of patients in whom the log(10) HBV-DNA decreased <2 log(10) copies/ml, 6 months after the initiation of ADV add-on LAM combination treatment (non-responders), was significantly higher in patients with a rtM204V + rtM204I/V mutations than rtM204I mutation (7 [21.2%] vs. 2 [4.4%], P = 0.032). CONCLUSION Biochemical response at 12 months from baseline was better in patients with a rtM204I mutation than rtM204V+ rtM204I/V mutations. In addition, early treatment failure was more common in patients with rtM204V+ rtM204I/V mutations than a rtM204I mutation.
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Affiliation(s)
- Hong J Kim
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, Korea.
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Zhong Y, Dai Z, Xu Y, Teng Y, Wu B. Synthesis, stability and pharmacological evaluation of a novel codrug consisting of lamivudine and ursolic acid. Eur J Pharm Sci 2012; 45:110-5. [PMID: 22085635 DOI: 10.1016/j.ejps.2011.10.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Revised: 10/29/2011] [Accepted: 10/29/2011] [Indexed: 10/15/2022]
Abstract
A novel codrug (LMX) was obtained from lamivudine (LMV) and ursolic acid (UA) coupled with ethyl chloroacetate through an amide and ester linkage. The structure of LMX was confirmed by ¹H NMR, ¹³C NMR, IR and HRMS. Herein, the in vitro non-enzymatic and enzymatic hydrolysis and in vivo pharmacological activities of LMX were studied. The kinetics of hydrolysis of LMX was studied in aqueous solution of pH 1-10, 80% buffered human plasma and in the presence of lipase from Porcine pancreas (EC 3.1.1.3) at 37°C. It is found that LMX hydrolysis rate was significantly faster in lipase with half-life of 1.4h compared to pH 7.4 phosphate buffer (t(1/2) 11.2h) and buffered human plasma (t(1/2) 5.4h). The decomposition rates in aqueous solution (pH 1-10) showed a U-shaped curve. LMX was comparatively stable between pH 3 and 6 (half-life >40 h). Pharmacological studies indicated that LMX had the dual action of anti-hepatitis B virus activity and hepatoprotective effects against acute liver injury. These findings suggest that LMX could be a promising candidate agent for the treatment of hepatitis.
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Affiliation(s)
- Yan Zhong
- School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210096, PR 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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Chopra GS, Gupta PK, Anand AC, Varma PP, Nair V, Rai R. Real Time-PCR HBV-DNA Analysis: Significance and First Experience in Armed Forces. Med J Armed Forces India 2011; 61:234-7. [PMID: 27407767 DOI: 10.1016/s0377-1237(05)80161-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2003] [Accepted: 04/27/2004] [Indexed: 10/18/2022] Open
Abstract
BACKGROUND HBV DNA quantitation is used extensively world wide for the diagnosis and monitoring of treatment of Hepatitis B virus (HBV) infection. However, it has still to be popular in India. The aim of this study was to quantitate HBV - DNA by Real time - PCR method in Hepatitis B and in immuno-compromised patients, to compare the results with HBeAg detection and to monitor the response to therapy of chronic Hepatitis B patients to antivirals. METHODS Ninety one serum samples of Hepatitis group of patients (all HBsAg positive), 41 samples from immuno-compromised patients (all HBsAg negative) and 49 patients of Chronic Hepatitis B group (all HBsAg positive) were the subjects of this first ever study in Armed Forces. Twenty serum samples from healthy volunteers and non-hepatitis B patients served as negative controls. The amplification detection was carried out in a Rotor-Gene 2000-sequence detector. RESULTS Amongst Hepatitis B group, 33% (30/91) of the samples were positive for HBV-DNA and 26% (24/91) of samples were positive for HBeAg. In the immuno-compromised group of patients 14.6% (6/11) of samples were positive for HIV-DNA and 9.7% (4/41) were positive for HBeAg. Of the Chronic Hepatitis B patients on treatment, all (100%) were positive by HBV-DNA, whereas 29/49 (59.2%) were positive by HBeAg before treatment. After treatment with antivirals, 06/49 (12.2%) were positive by both tests and 11/49 (22.5%) were positive only by HBV-DNA. 32/49 (65.3%) patients became negative serologically after therapy. CONCLUSION HBeAg status did not necessarily reflect HBV-DNA level in the serum, as 10/91 (11%) in the Hepatitis B group, 2/41 (4.9%) in the immuno compromised group and 20/49 (40.8%) patients in the Chronic Hepatitis B group were positive for HBV-DNA but negative for HBeAg. HBV-DNA was not found to be positive amongst any of the negative controls. Real time - PCR is a sensitive and reproducible assay for HBV-DNA quantitation and may be started in Armed Forces referral centers in the near future.
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Affiliation(s)
- G S Chopra
- Senior Advisor (Pathology and Immunology), Army Hospital (R and R), Delhi Cantt
| | - P K Gupta
- Reader, Department of Blood Transfusion, Armed Forces Medical College, Pune
| | - A C Anand
- Professor and Head, Department of Medicine, Armed Forces Medical College, Pune
| | - P P Varma
- Senior Advisor (Medicine and Nephrology), Army Hospital (R and R), Delhi Cantt
| | - V Nair
- Senior Advisor, (Medicine and Haematology), Army Hospital (R and R), Delhi Cantt
| | - Ramji Rai
- Director General Medical Services (Army), Army Head Quarters, New Delhi
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Ghandehari F, Pourazar A, Zadeh MS, Tajedin N. Probing rate of YMDD motif mutant in lamivudine treatment of Iranian patients with chronic hepatitis B virus infection. Asian J Transfus Sci 2011; 5:32-4. [PMID: 21572712 PMCID: PMC3082713 DOI: 10.4103/0973-6247.75982] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Background: Lamivudine is an analog nucleoside used for the treatment of chronic hepatitis B virus (CHV) infection. Studies showed that prolonged therapy could induce lamivudine resistance hepatitis B virus (HBV) variants (YMDD motif). In this study, the rate of YMDD motif mutants is determined in lamivudine-treated CHV patients in Iran. Materials and Methods: Thirty-three serum specimens of patients with chronic hepatitis who had been treated with lamivudine were included in the study. Serum samples of patients were tested by PCR flash and RFLP as well as tested for HBeAg, HBsAg, and liver enzymes (ALT and AST). Results: Out of the 33 patients enrolled in this study, 82% were male and 18% female, respectively. Mean ALT levels were between 20 and 100 IU/1. HBeAg was positive in 76% of the patients whereas HBs was positive only in 61% of the patients. Furthermore, in 28 patients liver biopsy grade was between 2 and 17 having the stage of 1–6. Moreover, HBsAg negative and HBeAg positive were observed in 30% of the patients. Conclusion: During therapy, it was found that patients with lamivudine incidence YMDD mutation were approximately 14%. The ALT levels were also reduced in these patients. This study revealed that there was a significant difference between HBeAg, grade, and YMDD mutation whereas no significant different was observed between HBsAg and HBV DNA PCR. Conclusively, it was found that a significant difference exists between YMDD mutation and lamivudine therapy (17% of patients were HBsAg negative and PCR positive).
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Affiliation(s)
- Freshte Ghandehari
- Department of Microbiology and Genetics, Islamic Azad University Fellavarjan Branch, Isfahan, Iran
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17
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Wang K, Tan W, Tang Y, Deng G. Numerical diagnoses of superinfection in chronic hepatitis B viral dynamics. Intervirology 2011; 54:349-56. [PMID: 21242660 DOI: 10.1159/000321454] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2010] [Accepted: 09/15/2010] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVES Fluctuation profile has been observed in chronic hepatitis B patients who are untreated or interrupt therapy. A mathematical model and its parameters could be used to diagnose the assumption of superinfection of hepatocytes and to understand the causes for the spontaneous fluctuation pattern of HBV DNA loads in chronically infected patients. METHODS We propose a new conceptual model in terms of chemical kinetics, which is based on the assumption that hepatocytes can be superinfected with hepatitis B virus (HBV). Minimizing the sum of squares of the deviations, we fitted the model to the HBV DNA trajectories from clinical data and obtained the model parameters. RESULTS The model with the fitted parameters can capture the tendency of HBV DNA trajectories. The mean value of the fitted number of virions that enter a single hepatocyte at the beginning stage of an invasion is 2.10 ± 0.18. The dynamics patterns may correlate with the clinical phenotypes of patients and the value of clinical parameters, such as α-fetoprotein, hepatitis B e-antigen, hepatitis B e-antibody, total bilirubin and alanine transaminase. CONCLUSIONS The superinfection scenario is possible in HBV infection and it may induce HBV DNA fluctuation in the host.
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Affiliation(s)
- Kaifa Wang
- Department of Medical Device and Equipment, School of Biomedical Engineering and Medical Imaging, Chongqing, P.R. China
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18
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You CR, Jang JW, Choi JK, Bae SH, Yoon SK, Kay CS, Choi JY. Hepatic Failure Caused by Reactivation of YMDD Mutants Occurring during Preemptive Lamivudine Therapy. Gut Liver 2010; 4:262-5. [PMID: 20559533 DOI: 10.5009/gnl.2010.4.2.262] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2009] [Accepted: 10/07/2009] [Indexed: 12/21/2022] Open
Abstract
Reactivation of hepatitis B virus (HBV) replication is a frequent phenomenon in patients receiving immunosuppressants or chemotherapy. It was recently reported that regional therapy, such as transarterial chemotherapy (TAC) or radiotherapy, can also induce HBV reactivation in patients with hepatocellular carcinoma (HCC), and this can be prevented by preemptive lamivudine treatment. We report an unusual case of fatal hepatitis caused by reactivation of the tyrosine-methionine-aspartate-aspartate (YMDD) lamivudine-resistant strain in a 51-year-old male patient with HCC who was receiving preemptive lamivudine therapy. This patient received combined helical tomotherapy and TAC for the treatment of HCC with pulmonary metastasis. HBV reactivation and hepatitis exacerbation occurred after 2 months of therapy, but preemptive antiviral therapy was continued. Laboratory tests showed that the serum HBV DNA level had increased by more than 10,000-fold and a severe elevation of the aminotransferase level to 1,060 U/L. Although adefovir was added to lamivudine immediately after detecting the YMDD mutants, the patient eventually died of hepatic failure. Our experience suggests that for preemptive therapy, the use of potent antiviral drugs with a low risk of drug resistance as well as close viral monitoring are important for chronic HBV carriers undergoing intensive anticancer therapy.
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Affiliation(s)
- Chan Ran You
- Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Incheon, Korea
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19
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Yuefeng M, Weili F, Wenxiang T, Ligang X, Guiling L, Hongwei G, Wencai L, Xiaoguang W, Wei M, Zhongyi F. Long-term outcome of patients with lamivudine after early cessation of hepatitis B immunoglobulin for prevention of recurrent hepatitis B following liver transplantation. Clin Transplant 2010; 25:517-22. [PMID: 20560989 DOI: 10.1111/j.1399-0012.2010.01290.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND The aim of this study is to examine the efficacy of long-term prophylaxis with lamivudine (LAM) after a course of post-operative hepatitis B immunoglobulin (HBIG) in patients who underwent liver transplantation (LT) for hepatitis B virus (HBV)-related disease. RESULT The medical records of HBV-infected patients who underwent a LT in our institution between July 2001 and May 2005 were reviewed. There were 15 liver transplant recipients who were administered HBIG for <18 months and used LAM as a maintenance prophylaxis regime enrolled in this study. At enrollment, all patients were hepatitis B surface antigen (HBsAg) positive and three patients were HBeAg positive. There were 13 patients who were HBV DNA positive with a mean viral load of 5.4 log copies/mL, and among them, 12 recipients were on antiviral therapy with LAM (100 mg/d orally) for 12-168 d, resulting in HBV DNA negative levels in nine patients prior to their transplant. HBV recurrence post-LT was noted in two patients who had very high-HBV DNA levels pre-LT. Both of these patients showed LAM-resistant mutation at the time of recurrence. The 11 patients who were HBV DNA negative before LT (low-risk patients) had no HBV recurrence during a follow-up at a median of 58 months post-LT. This included five patients who had intermittent low-level HBV DNA post-LT (HBsAg negative), of whom two had YMDD mutation and these two were given adefovir in addition to LAM. CONCLUSION Our retrospective study demonstrated excellent long-term outcomes in the low-risk patients treated with LAM after a short course of HBIG.
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Affiliation(s)
- M Yuefeng
- Department of Hepatobiliary Surgery, Dalian Institute of Hepatobiliary Surgery, Dalian Friendship Hospital, Dalian, China
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20
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Kobayashi M, Suzuki F, Akuta N, Yatsuji H, Hosaka T, Sezaki H, Kobayashi M, Kawamura Y, Suzuki Y, Arase Y, Ikeda K, Mineta R, Iwasaki S, Watahiki S, Kumada H. Correlation of YMDD mutation and breakthrough hepatitis with hepatitis B virus DNA and serum ALT during lamivudine treatment. Hepatol Res 2010; 40:125-34. [PMID: 19788696 DOI: 10.1111/j.1872-034x.2009.00565.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
AIM Continuous lamivudine treatment is associated with high frequency of drug resistance. We analyzed the incidence of tyrosine-methionine-aspartate-aspartate (YMDD) motif mutant and breakthrough hepatitis (BTH) in hepatitis B virus (HBV) DNA positive patients receiving lamivudine for > 1 year and correlated it with HBV DNA and alanine aminotransferase (ALT) levels to evaluate if these measurements can provide a practical option for monitoring patients in clinical practice and define early switch from lamivudine therapy. METHODS Of the 929 patients receiving lamivudine for > 1 year, 359 patients who maintained an ALT level of </= 40 IU/L during the course of lamivudine treatment were stratified into two groups based on the duration of lamivudine treatment - one receiving lamivudine for < 3 years and the other for >/= 3 years. RESULTS The incidence of YMDD motif in patients receiving lamivudine for < 3 years was 27% in patients with ALT </= 20 IU/L, 58% with ALT </= 30 IU/L, and 63% with ALT </= 40 IU/L, (P = 0.002). The corresponding incidence of BTH was 2%, 7%, and 48% (P < 0.001). The incidence of YMDD motif and BTH in these patients was 7% and 2% with HBV DNA < 2.6 (log copies/mL) and ALT </= 20 IU/L, while with ALT at 21-30, the YMDD motif mutant was 16% and BTH was 0%. CONCLUSION Correlation of ALT and HBV DNA levels with YMDD motif mutant and BTH indicates that these measurements can be used in clinical practice for deciding early switch from lamivudine to other suitable antiviral therapies.
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Affiliation(s)
- Mariko Kobayashi
- Research Institute for Hepatology, Toranomon Hospital, Tokyo, Japan
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21
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Kim JH, Lee SJ, Joo MK, Kim CH, Choi JH, Jung YK, Yim HJ, Yeon JE, Park JJ, Kim JS, Bak YT, Byun KS. Durability of antiviral response in HBeAg-positive chronic hepatitis B patients who maintained virologic response for one year after lamivudine discontinuation. Dig Dis Sci 2009; 54:1572-7. [PMID: 18975080 DOI: 10.1007/s10620-008-0508-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2008] [Accepted: 08/22/2008] [Indexed: 12/13/2022]
Abstract
The purpose of this study is to determine the long-term relapse rate and associated risk factors in HBeAg-positive chronic hepatitis B (CHB) patients who had maintained virologic response (VR) for 1 year after lamivudine (LMV) discontinuation. We enrolled 55 treatment-naive HBeAg-positive CHB patients who achieved and maintained VR until 1 year after LMV discontinuation. Delayed relapse was defined as an elevation of HBV DNA after sustained VR for 1 year. During follow-up, 16 of 55 patients (29%) showed delayed relapse. Beginning 1 year after LMV discontinuation, the cumulative rates of relapse after 2 and 4 years were 29 and 44%, respectively. In multivariate analysis, age (P = 0.029) and >2,000 copies/ml HBV DNA 3 months after LMV discontinuation (P = 0.047) were significant predictors of delayed relapse. Delayed relapse is not infrequent, even in patients who maintain VR for 1 year after LMV discontinuation. Therefore, LMV maintenance therapy might be considered in HBeAg-positive CHB patients who achieve VR.
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Affiliation(s)
- Ji Hoon Kim
- Department of Internal Medicine, Guro Hospital, Korea University College of Medicine, 97, Guro-Dong Gil, Guro-Dong, Guro-Ku, Seoul, 152-703, South Korea
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22
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Heipertz RA, Starkey JL, Miller TG, Hu J, Isom HC. trans-Complementation of HBV rtM204I mutant replication by HBV wild-type polymerase. Virology 2009; 388:57-67. [PMID: 19383566 DOI: 10.1016/j.virol.2009.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2008] [Revised: 12/17/2008] [Accepted: 03/23/2009] [Indexed: 10/20/2022]
Abstract
The function of the hepatitis B virus (HBV) wild-type (WT) polymerase (pol) expressed alone or in the context of the intact genome when interacting with HBV rtM204I in HepG2 cells was compared. We show that WT pol expression from a packaging-defective RNA can complement defective rtM204I pol activity resulting in increased levels of HBV replicative intermediates (RI). Analysis of the genetically marked genomes showed that this restoration resulted from trans-complementation, rather than recombination. In contrast, we demonstrate that enhanced levels of total HBV RI observed when cells were cotransduced with both WT and rtM204I baculoviruses were predominantly WT RI. In this case, WT pol was produced from a full-length pregenomic RNA (pgRNA). We conclude that the WT pol has the capacity to trans-complement the replication defect of rtM204I; however, when expressed from an authentic pgRNA, as in a mixed infection, pol may not trans-complement efficiently.
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Affiliation(s)
- Richard A Heipertz
- Department of Microbiology and Immunology, Milton S. Hershey Medical Center, The Penn State College of Medicine, Hershey, PA 17033, USA
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23
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Liu P, Li Y, Sun CM. Correlations of Serum Hepatitis C Virus RNA and Alanine Transaminase With Liver Histopathological Changes in Patients With Chronic Hepatitis C. Lab Med 2009. [DOI: 10.1309/lm5xqbwg0qmlnnpc] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Suzuki Y, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Hosaka T, Akuta N, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Miyakawa Y, Kumada H. Efficacy of entecavir treatment for lamivudine-resistant hepatitis B over 3 years: histological improvement or entecavir resistance? J Gastroenterol Hepatol 2009; 24:429-35. [PMID: 19226381 DOI: 10.1111/j.1440-1746.2008.05760.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND AIMS Long-term lamivudine therapy is required for patients with chronic hepatitis B, because hepatitis reappears frequently after it has withdrawn. However, hepatitis B virus (HBV) mutants resistant to lamivudine emerge frequently accompanied by breakthrough hepatitis. METHODS Effects of entecavir were evaluated in 19 patients who had developed breakthrough hepatitis during lamivudine therapy for longer than 5 years. This study is a subgroup analysis of a previously reported study. Entecavir, in either 0.5 or 1.0 mg/day doses, was given to 10 and nine patients for 52 weeks, respectively, and then all received 1.0 mg/day entecavir for an additional 68-92 weeks. RESULTS There were no differences in biochemical and virological responses in the two groups of patients with respect to the two different initial doses of entecavir. Serum levels of alanine aminotransferase were normalized in 17 (90%) patients, and hepatitis B e antigen (HBeAg) disappeared from the serum in two (14%) of the 14 patients who were HBeAg-positive before. Furthermore, a decrease in histological activity index score greater than 2 points was achieved in nine of the 11 (82%) patients in whom annual liver biopsies were performed during 3 years while they received entecavir. HBV mutants resistant to entecavir emerged in five of the 19 (26%) patients, and hepatitis flare occurred in two of them (40%). CONCLUSION Entecavir in the long term would be useful for histological improvement of breakthrough hepatitis induced by lamivudine-resistant HBV mutants in patients with chronic hepatitis B. However, the relatively high rate of entecavir resistance is a concern, and other strategies need to be considered when available.
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Affiliation(s)
- Yoshiyuki Suzuki
- Department of Hepatology, Toranomon Hospital, Takatsu-ku, Kawasaki City, Japan.
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Hur WH, Woo HY, Jeong SW, You CR, Bae SH, Choi JY, Yoon SK. [A case report of treatment with pegylated interferon alpha for lamivudine-resistant chronic hepatitis B virus infection]. THE KOREAN JOURNAL OF HEPATOLOGY 2009; 14:513-8. [PMID: 19119246 DOI: 10.3350/kjhep.2008.14.4.513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The wide use of lamivudine in chronic hepatitis B has produced a monotonic increase in patients with lamivudine resistance. Therefore, treating lamivudine resistance in chronic hepatitis B is a major concern in clinical practice for the treatment of hepatitis B virus (HBV). There is conflicting evidence on the outcome of pegylated interferon alpha (PEG-IFN alpha) therapy against lamivudine-resistant HBV, which is due to mutations in the YMDD motif. We experienced a patient with chronic hepatitis B who was successfully treated with PEG-IFN alpha-2a after the development of virologic and biochemical breakthrough during lamivudine therapy. Virologic breakthrough was associated with the emergence of YMDD mutants 48 months after starting lamivudine therapy. Treatment with PEG-IFN alpha-2a for 12 months resulted in an undetectable serum level of HBV DNA and the resolution of hepatitis, and the virologic response was maintained over 16 months after cessation of PEG-IFN alpha-2a.
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Affiliation(s)
- Won Haing Hur
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, WHO Collaborating Center of Viral Hepatitis, Seoul, Korea
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Okushin H, Ohnishi T, Morii K, Uesaka K, Yuasa S. Short-term intravenous interferon therapy for chronic hepatitis B. World J Gastroenterol 2008; 14:3038-43. [PMID: 18494055 PMCID: PMC2712171 DOI: 10.3748/wjg.14.3038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [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 therapeutic efficacy of short-term, multiple daily dosing of intravenous interferon (IFN) in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B.
METHODS: IFN-β was intravenously administered at a total dose of 102 million international units (MIU) over a period of 28 d in 26 patients positive for HBeAg and HBV-DNA. IFN-beta was administered at doses of 2 MIU and 1 MIU on d 1, 3 MIU twice daily from d 2 to d 7, and 1 MIU thrice daily from d 8 to d 28. Patients were followed up for 24 wk after the end of treatment.
RESULTS: Six months after the end of the treatment, loss of HBV-DNA occurred in 13 (50.0%) of the 26 patients, loss of HBeAg in 9 (34.6%), development of anti-HBe in 10 (38.5%), HBeAg seroconversion in 8 (30.8%), and normalization of alanine aminotransferase (ALT) levels in 11 (42.0%).
CONCLUSION: This 4-wk long IFN-β therapy, which was much shorter than conventional therapy lasting 12 wk or even more than 1 year, produced therapeutic effects similar to those achieved by IFN-α or pegylated-IFN-α (peg-IFN). Fewer adverse effects, greater efficacy, and a shorter treatment period led to an improvement in patients’ quality of life. IFN-β is administered intravenously, whereas IFN-α is administered intramuscularly or subcutaneously. Because both interferons are known to bind to an identical receptor and exert antiviral effects through intracellular signal transduction, the excellent results of IFN-β found in this study may be attributed to the multiple doses allowed by the intravenous route.
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Zhao YL, Cai GM, Hong X, Shan LM, Xiao XH. Anti-hepatitis B virus activities of triterpenoid saponin compound from Potentilla anserine L. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2008; 15:253-8. [PMID: 18337074 DOI: 10.1016/j.phymed.2008.01.005] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
The Tibetan herb Potentilla anserina L. has been widely used in China for many thousands of years to treat hepatitis-B. Bioassay-guided fractionation of the ethanol extract of the rhizomes led to the isolation of a triterpenoid saponin (TS) that was determined to be 2alpha,3beta,19alpha-trihydroxyurs-12-en-28-oic acid beta-D-glucopyranosyl ester. Using models of HBV infection, this compound was evaluated for its effect on HBV antigene expression in the 2.2.15 cell line in vitro and anti-hepatitis B virus (HBV) activities in Peking ducklings in vivo. Results showed that it could decrease the expression levels of HBsAg, HBeAg and HBVDNA in the 2.2.15 cell culture and the inhibitory effect was not due to the cytotoxity of the triterpenoid saponin. The antiviral study in vivo on Peking ducklings also demonstrated that this compound inhibits duck hepatitis B virus (DHBV) DNA replication.
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Affiliation(s)
- Y-L Zhao
- Institute of Traditional Chinese Material Medica, People's Liberation Army, Beijing 100039, PR China.
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28
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Okanoue T, Itoh Y, Minami M, Hashimoto H, Yasui K, Yotsuyanagi H, Takehara T, Kumada T, Tanaka E, Nishiguchi S, Izumi N, Sata M, Onji M, Yamada G, Okita K, Kumada H. Guidelines for the antiviral therapy of hepatitis C virus carriers with normal serum aminotransferase based on platelet counts. Hepatol Res 2008; 38:27-36. [PMID: 18039201 DOI: 10.1111/j.1872-034x.2007.00217.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM We aimed to identify the candidates for antiviral therapy, among patients who are hepatitis C virus (HCV) carriers with normal serum aminotransferase (ALT), focused on the inhibition of hepatocellular carcinoma (HCC). METHODS Four hundred and sixty-four HCV carriers with normal serum ALT and 129 HCV carriers with persistently normal ALT (PNALT) and platelet (PLT) counts >/=150 000/muL who received liver biopsies were enrolled. HCV carriers with normal serum ALT were divided into four groups according to their ALT levels (</=30 U/L or 31-40 U/L) and PLT counts (>/=150 000/muL or <150 000/muL). RESULTS In 129 HCV carriers with PNALT, the rate of progression of fibrosis stage was 0.05/year and no HCC was detected during the follow up for 10 years. Approximately 20% of patients with ALT </=40 U/L and PLT counts >/=150 000/muLwere at stage F2-3; however, approximately 50% of patients with ALT </= 40 U/L and PLT counts <150 000/muL were at stage F2-4. An algorithm for the management of HCV carriers with normal serum ALT was advocated based on ALT and PLT counts. CONCLUSION The combination of ALT and PLT counts is useful for evaluating the fibrosis stage in HCV carriers with normal serum ALT. Most patients with PLT counts <150 000/muL are candidates for antiviral therapy, especially those with ALT levels >/=31 U/L when we focus on the inhibition of the development of HCC.
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Affiliation(s)
- Takeshi Okanoue
- Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Abstract
PURPOSE Lamivudine is known to be very effective in suppressing hepatitis B virus replication and virus induced necroinflammation. The aim of this study was to evaluate lamivudine therapy efficacy, predictive factors, breakthrough, prevalence of YMDD mutation, and relapse rate in Korean children with chronic hepatitis B. MATERIALS AND METHODS Between August 1999 and February 2005, 60 children on lamivudine therapy for chronic hepatitis B were enrolled. Treatment response was defined as alanine aminotransferase (ALT) normalization, and HBeAg and HBV-DNA disappearance. RESULTS Seroconversion rates of HBeAg and HBV- DNA were 42% and 53%, respectively, and ALT normalization rate was 88%. Seroconversion rates of HBeAg (60.0%) and anti-HBe (60.0%) were higher in patients younger than 6 years. Seroconversion rate of HBV-DNA (68.4%) and normalization rate of serum ALT (94.7%) were highest in patients between 6 and 12 years. Seroconversion rates of all HBV markers were lowest in patients older than 12 years. Predicted 3 year cumulative seroconversion rates, were 70%, 68% for HBeAg, HBV-DNA, respectively. These were calculated by Kaplan-Meier method. Cox proportional hazard regression model showed that pre-treatment ALT was a positive predictive factor for seroconversion of HBeAg and HBV-DNA. Breakthrough phenomenon was noted in 6 patients, and 3 had a YMDD mutation. CONCLUSION Lamivudine therapy had a significant effect on HBeAg seroconversion and HBV-DNA disappearance, and ALT normalization for Korean children with chronic hepatitis B.
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Affiliation(s)
- Hong Koh
- Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Korea
| | - Seoung Yon Baek
- Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Korea
| | - Ki Sup Chung
- Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Korea
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Farinati F, Cardin R, Bortolami M, Burra P, Russo FP, Rugge M, Guido M, Sergio A, Naccarato R. Hepatitis C virus: from oxygen free radicals to hepatocellular carcinoma. J Viral Hepat 2007; 14:821-9. [PMID: 18070284 DOI: 10.1111/j.1365-2893.2007.00878.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Epidemiological evidence clearly identifies chronic infection with hepatitis C virus (HCV) as a major risk factor for the development of hepatocellular carcinoma (HCC). Among the mechanisms that have been implicated in the pro-carcinogenic effect of HCV infection, an increased production of reactive oxygen species in the liver seems to have a major pathogenetic role in leading from chronic inflammation to cancer. Recent data have also demonstrated that HCV is capable of inducing this active production of free radicals per se, not just through inflammation, a feature peculiar to this virus and the specific activity of its core protein. This paper provides an overview of the inter-relationships between HCV, liver damage, free radical production and HCC, describing at least in part the complex network involving DNA oxidative damage, cytokine synthesis, proto-oncogene activation and oestrogen receptor expression, that may all be deeply involved in liver carcinogenesis.
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Affiliation(s)
- F Farinati
- Dipartimento di Scienze Chirurgiche e Gastroenterologiche, Sezione di Gastroenterologia, Policlinico Universitario, Università di Padova, Padova, Italy.
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Kobayashi M, Suzuki F, Akuta N, Hosaka T, Sezaki H, Yatsuji H, Yatsuji H, Kobayashi M, Suzuki Y, Arase Y, Ikeda K, Watahiki S, Iwasaki S, Miyakawa Y, Kumada H. Loss of hepatitis B surface antigen from the serum of patients with chronic hepatitis treated with lamivudine. J Med Virol 2007; 79:1472-7. [PMID: 17705186 DOI: 10.1002/jmv.20994] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Although loss of hepatitis B e antigen (HBeAg) from the serum is sought by treatment with lamivudine, clearance of hepatitis B surface antigen (HBsAg) is the eventual goal of any antiviral therapy. In a single hepatology center in the Metropolitan Tokyo, 486 patients with chronic hepatitis B were followed up for longer than 3 years after they started treatment with lamivudine. HBsAg disappeared from the serum in 17 (3.5%). Age >or=50 years and low HBsAg levels (hemagglutination titer <or=2(7)) at the start of lamivudine were significantly more frequent in the patients who did than did not lose HBsAg from the serum. Except for these two factors, there were no differences between the two groups of patients in the prevalence of HBeAg and HBV DNA levels at the baseline, as well as the development of YMDD mutants and breakthrough hepatitis during lamivudine treatment. Using multivariate analysis, age >or=50 years at the start of lamivudine was the only factor predicting the loss of HBsAg (hazard ratio: 2.96 [95% confidence interval: 1.14-7.68], P = 0.028). By the method of Kaplan-Meier performed on the 486 patients, the loss of HBsAg was estimated to occur in 3% and 13% of patients, respectively, who had received lamivudine therapy for 5 and 10 years. These results indicate that loss of HBsAg occurs in a minority (3.5%) of patients with chronic hepatitis B who receive lamivudine therapy and more frequently in those with lower HBsAg titers and older ages at the start of treatment.
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Affiliation(s)
- Mariko Kobayashi
- Research Institute for Hepatology, Toranomon Hospital, Tokyo, Japan.
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Abstract
The global prevalence of chronic hepatitis B and its associated serious sequelae demand technologically advanced techniques of management. Nucleic acid testing (NAT) plays a key role in the diagnosis, surveillance, and treatment of chronic hepatitis B. NAT includes quantitative PCR-based HBV DNA assays, HBV genotyping, tests for mutations associated with resistance to antiviral medications, and assays to detect precore and core promoter mutations. This article reviews the uses of NAT in the diagnosis and management of chronic hepatitis B.
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Affiliation(s)
- Robert G Gish
- California Pacific Medical Center, 2340 Clay St., Room 223, San Francisco, CA 94115, USA.
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Pan XP, Li LJ, Du WB, Li MW, Cao HC, Sheng JF. Differences of YMDD mutational patterns, precore/core promoter mutations, serum HBV DNA levels in lamivudine-resistant hepatitis B genotypes B and C. J Viral Hepat 2007; 14:767-74. [PMID: 17927612 DOI: 10.1111/j.1365-2893.2007.00869.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The aims of this study were to investigate the viral differences among lamivudine-resistant hepatitis B virus (HBV) genotypes B and C in vivo. Fifty-three patients carrying lamivudine-resistant HBV were enrolled in this study. HBV genotypes, Levels of alanine aminotransferase (ALT), HBV DNA levels were monitored during therapy. The polymerase and precore/core promoter genes were amplified by polymerase chain reaction and their products were sequenced directly. Among 53 patients resistant HBV genotypes B and C accounted for 41.50% and 58.50%, respectively. The occurrence of reverse transcriptase rt204I mutants was lower in genotype B (36.36%) than that in genotype C (87.10%), whereas rt204V mutants was higher in genotype B (63.64%) than that in genotype C (12.90%). The occurrence of precore mutation (nt1896A) was higher in genotype B (77.27%) than that in genotype C (32.26%). Serum HBV DNA levels after emergence of lamivudine resistance were higher in genotype C (7.71 +/- 0.80 Log copies/mL) compared with genotype B (6.97 +/- 0.77 Log copies/mL). Multivariate analysis identified pretreatment HBV DNA levels, HBeAg status and HBV genotype as independent factors associated with a shorter time to lamivudine resistance(P = 0.035, P = 0.006 and P = 0.001, respectively). Multivariate analysis showed that HBV genotype (P = 0.004) and pretreatment ALT levels (P = 0.01) was independently associated with YMDD mutational patterns. The results showed that the YMDD mutational patterns, precore mutation and serum HBV DNA levels differ between lamivudine-resistant HBV genotypes B and C in vivo. It is valuable for treatment of lamivudine-resistant HBV in clinic.
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Affiliation(s)
- X P Pan
- Key Laboratory of Infectious Diseases, Ministry of Public Health, Department of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Vassiliadis T, Tziomalos K, Patsiaoura K, Zagris T, Giouleme O, Soufleris K, Grammatikos N, Theodoropoulos K, Mpoumponaris A, Dona K, Zezos P, Nikolaidis N, Orfanou-Koumerkeridou E, Balaska A, Eugenidis N. Lamivudine/pegylated interferon alfa-2b sequential combination therapy compared with lamivudine monotherapy in HBeAg-negative chronic hepatitis B. J Gastroenterol Hepatol 2007; 22:1582-8. [PMID: 17683500 DOI: 10.1111/j.1440-1746.2007.05103.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND AND AIM Monotherapy has been proven insufficient in achieving sustained control of chronic hepatitis B. We aimed to assess the efficacy of combined sequential administration of lamivudine and pegylated interferon alfa-2b in patients with hepatitis Be antigen (HBeAg)-negative chronic hepatitis B. METHODS Eighteen patients were given sequential combination treatment starting with 3 months of lamivudine monotherapy followed by 9 months of pegylated interferon alfa-2b (after a 3-month period of concomitant administration of the two drugs) and 24 patients received lamivudine monotherapy. RESULTS At the end of treatment, 88.9% of the patients who received sequential combination treatment and 70.8% of those who received lamivudine monotherapy had hepatitis B virus (HBV) DNA levels below 400 copies/mL (P = not significant). At the end of treatment, 72.2% of the patients who received sequential combination treatment and 70.8% of those who received lamivudine monotherapy achieved alanine aminotransferase normalization (P = not significant). After 12 months of follow up, 33.3% of the patients who received sequential combination treatment and 16.7% of those who received lamivudine monotherapy had HBV-DNA levels below 400 copies/mL (P = 0.4). After 12 months of follow up, 72.2% of the patients who received sequential combination treatment and 25.0% of those who received lamivudine monotherapy had normal alanine aminotransferase levels (P < 0.01). Twenty-five percent of the patients in the lamivudine monotherapy group had virological breakthrough compared to none in the sequential combination treatment group (P = 0.06). CONCLUSIONS Sequential combination treatment is able to improve sustained biochemical response rates and prevent the emergence of lamivudine-resistant mutants in patients with HBeAg-negative chronic hepatitis B.
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Affiliation(s)
- Themistoklis Vassiliadis
- 2nd Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
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Manning DS, Sheehan KM, Byrne MF, Kay EW, Murray FE. Cyclooxygenase-2 expression in chronic hepatitis C and the effect of interferon alpha treatment. J Gastroenterol Hepatol 2007; 22:1633-7. [PMID: 17845691 DOI: 10.1111/j.1440-1746.2007.04869.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIM Cyclooxygenase-2 (COX-2), a target of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), is upregulated in chronic hepatitis B and may have a role in hepatocellular carcinoma. Little is known about the expression of COX-2 in chronic hepatitis C (HCV) infection. The aim the present study was to evaluate the extent of COX-2 expression in liver biopsies in patients with HCV infection and to determine the effect of treatment with interferon alpha (IFN). METHODS Percutaneous liver biopsy specimens were retrieved. Following formalin fixation and paraffin embedding, the biopsies were histologically evaluated for inflammation and fibrosis. The extent of COX-2 expression was measured by the avidin biotin immunohistochemical technique using a monoclonal COX-2 antibody. The extent of COX-2 expression was graded according to the number of hepatocytes expressing COX-2. Data were analyzed using Student's t-test. RESULTS Liver biopsies from 10 patients before and after treatment with IFN were obtained and compared with nine normal liver biopsies. All of the liver biopsies showed some COX-2 expression. COX-2 expression was confined to hepatocytes and bile duct epithelium and was not detected in vascular endothelium or inflammatory cells. The extent of COX-2 expression was greater in hepatitis C infected liver biopsies than in normal biopsies. Following treatment with IFN, there was a greater than threefold reduction in COX-2 expression (P < 0.01). This result was independent of the sustained virological response. CONCLUSION In this small pilot study we have shown that COX-2 is overexpressed in liver biopsies infected with HCV and COX-2 expression is reduced following treatment with IFN.
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Affiliation(s)
- Diarmuid S Manning
- Department of Clinical Pharmacology/Gastroenterology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland
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Kim JH, Yu SK, Seo YS, Yim HJ, Yeon JE, Park JJ, Kim JS, Bak YT, Lee CH, Byun KS. Clinical outcomes of chronic hepatitis B patients with persistently detectable serum hepatitis B virus DNA during lamivudine therapy. J Gastroenterol Hepatol 2007; 22:1220-5. [PMID: 17532786 DOI: 10.1111/j.1440-1746.2007.04921.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM A small proportion of chronic hepatitis B patients have persistently detectable serum hepatitis B virus (HBV) DNA despite lamivudine therapy. The incidence and clinical outcomes of patients who persistently have detectable serum HBV-DNA during lamivudine therapy was investigated. METHOD We enrolled 221 chronic hepatitis B patients who underwent lamivudine therapy for more than 6 months. Among them, 180 were HBeAg positive. Serum HBV-DNA, HBeAg, anti-HBe and alanine aminotransferase (ALT) levels were serially monitored. The study groups were defined, using a hybridization assay, as patients with reductions in serum HBV-DNA below the detectable level (group I) or patients with persistently detectable serum HBV-DNA (group II) during the initial 6 months of lamivudine therapy. RESULTS The incidence of patients who had persistently detectable HBV-DNA was 7.7%. After the first year, the rates of viral breakthrough, HBeAg loss and serum ALT normalization of group I versus group II were 21% versus 63%, 38% versus 0%, and 71% versus 28%, respectively (P < 0.001). The log(10) reduction of serum HBV-DNA at 6 months was -4.58 log(10) for group I and -1.97 log(10) for group II (P < 0.001, bDNA assay). There were no pretreatment lamivudine-resistant mutants in group II. CONCLUSION Lamivudine had little effect on serum HBV-DNA suppression, viral breakthrough suppression and rate of HBeAg loss and ALT normalization in chronic hepatitis B patients with persistently detectable serum HBV-DNA during the initial 6 months of therapy. Early termination of lamivudine therapy is advocated for these patients.
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Affiliation(s)
- Ji H Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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Abstract
A focused meeting on hepatitis B virus (HBV) infection was held at the United States National Institutes of Health in Washington, DC, in April 2006. This meeting focused on new and historical data and served as a review for basic scientists and clinicians, as well as representatives from the pharmaceutical industry. Understanding HBV disease must include up-to-date information concerning virology, immunology, animal models, natural history, prevalence, and transmission risk, as well as an understanding of the evolving therapies for this life-threatening infection. Serious outcomes such as advanced fibrosis, cirrhosis, liver failure and hepatocellular carcinoma from hepatitis B infection appear to be closely tied to both historical and current serum levels of HBV DNA, and elevated serum levels of liver enzymes. Decreasing risk events and vaccinating susceptible individuals are key steps in managing this global scourge. New oral treatments for patients withchronic hepatitis B infection characterized by more potent antiviral effects, less toxicity, and minimal or no risk of resistance were reviewed and emphasized. Entecavir and pegylated interferons have recently been approved for treatment of chronic hepatitis B. Further expansion of our information about lamivudine and adefovir were highlighted. Several other new anti-HBV agents are also in phase II or III clinical trials or have been submitted for licensing including LdT (telbivudine). The NIH review meeting is summarized in this review and new and emerging areas of information are highlighted.
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Affiliation(s)
- Robert G Gish
- Departments of Medicine and Transplantation, Division of Hepatology and Complex GI, Physicians Foundation, California Pacific Medical Center, San Francisco, California, USA
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38
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Suzuki F, Kumada H. Interferon and lamivudine monotherapy on chronic hepatitis B in Japan. Hepatol Res 2007; 37:S42-6. [PMID: 17627635 DOI: 10.1111/j.1872-034x.2007.00104.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM We show data of interferon (IFN) and lamivudine monotherapy on chronic hepatitis B in Japan. METHODS Data collected from sixty-six chronic hepatitis B (CHB) Japanese patients who were treated with IFN for 6 months were analyzed. The efficacy of long-term IFN therapy in 52 patients with e-antigen positive CHB, and data from 290 chronically HBV-infected patients who were treated with lamivudine for more than 3 years, were analyzed. RESULTS Six-month IFN therapy: among 45 patients with HBeAg at commencement of IFN therapy, nine (20%) were responders. Young patients especially those with high serum alanine aminotransferase (ALT) levels were much more likely to respond to IFN therapy. Twelve-month IFN therapy: theresponse rate was 31% among 52 patients with HBeAg. Long-term lamivudine therapy: YMDD motif mutation was detected in 167 of 290 patients (58%) during lamivudine treatment. Breakthrough hepatitis from lamivudine resistant virus was detected in 93 of 290 patients (32%). Finally, 813 patients were treated by lamivudine between September 1995 and February 2006. Fifteen patients lost HBsAg during and after lamivudine therapy. CONCLUSION Long-term interferon therapy has a better response than short-term interferon therapy. Some patients lost HBsAg during and after lamivudine therapy.
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Suzuki F, Suzuki Y, Akuta N, Yatsuji H, Sezaki H, Arase Y, Kawamura Y, Hosaka T, Kobayashi M, Ikeda K, Kobayashi M, Watahiki S, Kumada H. Changes in viral loads of lamivudine-resistant mutants during entecavir therapy. Hepatol Res 2007; 38:132-40. [PMID: 17573951 DOI: 10.1111/j.1872-034x.2007.00144.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Entecavir therapy is effective against lamivudine-resistant virus in patients with hepatitis B virus infection. We investigated viral load changes of YMDD mutant virus (rtM204I [YIDD sequence], rtM204V [YVDD]) in serial serum samples during entecavir treatment for lamivudine-resistant virus and determined changes in viral precore and core promoter mutants. METHODS Nineteen patients were treated in randomized, double-blind phase II clinical trials of entecavir at 0.5 or 1.0 mg for breakthrough hepatitis due to lamivudine-resistant virus. Viral changes in YMDD mutants (rtM204I, rtM204V), amino acid changes in the polymerase reverse transcriptase region and precore/core promoter mutations at 52 weeks were determined in 18 patients. RESULTS Changes in viral loads of rtM204I and rtM204V were similar. No differences in load changes were seen betweenthe 0.5 and 1.0 mg groups. However, load changes for rtM204I alone were greater than those for the rtM204I + rtM204V mixed-type (P = 0.042, at both 40 and 52 weeks). Load changes in rtM204I and rtM204V with G1896A tended to be greater than those without. Moreover, G1896A was replaced by wild-type virus in two patients at 52 weeks. CONCLUSION RtM204I only or the existence of precore mutation was more sensitive to entecavir therapy against lamivudine-resistant virus.
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Kawaoka T, Suzuki F, Akuta N, Suzuki Y, Arase Y, Sezaki H, Kawamura Y, Hosaka T, Kobayashi M, Ikeda K, Kumada H. Efficacy of lamivudine therapy in elderly patients with chronic hepatitis B infection. J Gastroenterol 2007; 42:395-401. [PMID: 17530365 DOI: 10.1007/s00535-007-2015-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2006] [Accepted: 01/29/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND The aim of this study was to evaluate the efficacy of lamivudine therapy in elderly patients with chronic HBV infection. METHODS Patients aged >or=60 years (n = 40) received lamivudine monotherapy between February 1995 and September 2005 at Toranomon Hospital. We compared the efficacy of lamivudine therapy in these patients and in 639 patients aged <60 years, including 80 patients aged <60 years matched for sex, hepatitis B e antigen (HBeAg) status, and hepatitis B virus (HBV) DNA level. RESULTS The rates of normalization of alanine aminotransferase (ALT) level in 40 patients aged >or=60 years and 639 patients aged <60 years were 85% versus 76%, and 86% versus 73% at 1 and 3 years, respectively. The respective rates of loss of HBV-DNA were 74% versus 74%, and 76% versus 68% at 1 and 3 years. The respective cumulative emergence rates of the YMDD mutant were 16% and 17% at 1 year, and 46% and 49% at 3 years. In 80 patients <60 years old matched for sex, HBeAg status, and HBV-DNA level, the rates of normalization of the ALT level and loss of HBV-DNA were similar to those in the 639 patients aged <60 years. The emergence rate of YMDD mutants in patients aged >or=60 years were similar to those in matched patients aged <60 years. Multivariate analyses identified low serum bilirubin (<1 mg/dl) as an independent factor associated with the emergence of the YMDD motif mutation in patients aged >or=60 years. CONCLUSIONS Our results suggest that treatment with lamivudine is both well tolerated and efficacious in elderly patients with chronic HBV infection.
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Affiliation(s)
- Tomokazu Kawaoka
- Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Tokyo 105-8470, Japan
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Kim DY, Kim HJ, Lee CK, Suh JH, Kim DH, Cho YS, Won SY, Park BK, Park IS. Efficacy of adefovir dipivoxil in the treatment of lamivudine-resistant hepatitis B virus genotype C infection. Liver Int 2007; 27:47-53. [PMID: 17241380 DOI: 10.1111/j.1478-3231.2006.01407.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Adefovir dipivoxil (ADV) is a nucleotide analogue that is known to be effective for lamivudine-resistant hepatitis B virus (HBV) mutants as well as wild-type HBV. The aim of this study is to assess the efficacy of ADV against lamivudine-resistant genotype C HBV mutants. METHODS Thirty-five patients with breakthrough hepatitis due to lamivudine-resistant HBV received ADV 10 mg daily with discontinuation of lamivudine. Quantitative HBV DNA, HBeAg, liver function test including alanine aminotransferase (ALT) was checked every 4-12 weeks to evaluate the efficacy of ADV. RESULTS ADV was administered for a median of 48 weeks (range: 24-120 weeks). The rate of serum HBV DNA loss was 68.6%, 80.0%, 84.0%, and 88.2% at weeks 12, 24, 36, and 48, respectively. The rate of serum HBeAg seroconversion was 8.3% and 14.3% at weeks 24 and 48, respectively. The rate of serum ALT normalization at week 48 was 70.6%. Within 32 weeks after stopping ADV therapy, serum HBV DNA levels increased to a median of 378.9 pg/ml in 88.9% of patients, who were treated for a median of 40 weeks. Moreover, in some patients, the ALT level increased to more than five times the upper limit of normal. CONCLUSIONS Administration of ADV is an effective option for the treatment of patients with lamivudine-resistant genotype C HBV infection.
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Affiliation(s)
- Do Young Kim
- Department of Internal Medicine, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea
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Heipertz RA, Miller TG, Kelley CM, Delaney WE, Locarnini SA, Isom HC. In vitro study of the effects of precore and lamivudine-resistant mutations on hepatitis B virus replication. J Virol 2007; 81:3068-76. [PMID: 17215289 PMCID: PMC1866076 DOI: 10.1128/jvi.02341-06] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Understanding the consequences of mutation in the hepatitis B virus (HBV) genome on HBV replication is critical for treating chronic HBV infection. In this study, HBV replication in HepG2 cells initiated by transduction with precore (PC), rtM204I, and wild-type (wt) HBV recombinant baculoviruses was compared. The pattern and magnitude of HBV replication initiated by the PC HBV recombinant baculovirus were similar to those observed for wt HBV throughout the time course examined. In contrast, when the rtM204I mutation was introduced into wt HBV, by day 10 postinfection the levels of intra- and extracellular HBV DNA were markedly reduced compared to those for wt HBV. Although the rtM204I mutation reduced the production of HBV replicative intermediates, no effect on the level of covalently closed circular DNA or HBV transcripts was observed at late time points. Coinfection studies with different ratios of wt and rtM204I baculoviruses showed that the rtM204I variant did not produce a product that inhibited HBV replication. However, the combination of the wt and rtM204I baculoviruses yielded HBV DNA levels at late time points that were greater than those for the wt alone, suggesting that wt polymerase may function in trans to boost rtM204I replication. We concluded that the rtM204I mutation generates a polymerase that is not only resistant to lamivudine but also replicates nucleic acids to lower levels in vitro.
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Affiliation(s)
- Richard A Heipertz
- Milton S. Hershey Medical Center, The Penn State College of Medicine, 500 University Drive, P.O. Box 850, Hershey, PA 17033, USA
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von Wagner M, Lee JH, Kronenberger B, Friedl R, Sarrazin C, Teuber G, Herrmann E, Zeuzem S. Impaired health-related quality of life in patients with chronic hepatitis C and persistently normal aminotransferase levels. J Viral Hepat 2006; 13:828-34. [PMID: 17109682 DOI: 10.1111/j.1365-2893.2006.00772.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
A significant impact of hepatitis C virus (HCV) infection on health-related quality of life (HRQOL) has been previously described. However, comprehensive data on the quality of life in patients with chronic hepatitis C and persistently normal aminotransferase levels (PNAL) are currently not available. One hundred fifteen patients with chronic hepatitis C (45 with persistently normal aminotransferases and 70 with elevated aminotransferases) and 50 healthy subjects were enrolled. Emotional and psychological states were assessed by Profile of Mood States (POMS) scale and HRQOL was assessed by the 'Everyday Life' questionnaire (EDLQ), a validated questionnaire related to the SF-36 Health Survey. An impairment in HRQOL was observed in patients with chronic hepatitis C showing PNAL compared with healthy subjects with significant differences for the factor scores depression and anger in the POMS scale as well as for the items body, relationship to partner, self-confidence and zest of life in the EDLQ. No differences in any questionnaire were observed between patients with chronic hepatitis C showing PNAL or elevated aminotransferase levels except of a worse mean level for factor score anger in POMS scale in patients with persistently normal aminotransferases. No association of quality of life with severity of liver disease was found. Impairment of HRQOL by chronic infection with HCV is similar in patients with PNAL and those with elevated aminotransferase levels.
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Affiliation(s)
- M von Wagner
- Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg, Saar, Germany
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Akarsu M, Sengonul A, Tankurt E, Sayiner AA, Topalak O, Akpinar H, Abacioglu YH. YMDD motif variants in inactive hepatitis B carriers detected by Inno-Lipa HBV DR assay. J Gastroenterol Hepatol 2006; 21:1783-8. [PMID: 17074014 DOI: 10.1111/j.1440-1746.2006.04567.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Mutations of hepatitis B virus (HBV) polymerase, especially occurring at the highly conserved YMDD region, are related to resistance to lamivudine. Although these mutations are frequently secondary to lamivudine use, they can also occur naturally. The aim of the present study was to determine the prevalence of YMDD variants that exist naturally in patients who are inactive HBV carriers. METHODS Seventy-one adult inactive HBV carriers were studied. All of the patients were confirmed to have maintained normal alanine aminotransferase (ALT) values for one or more years by monitoring serum ALT levels at 3-monthly intervals. None of the patients received interferon or antiviral agents. YMDD variants were analyzed by the HBV Drug Resistance Line Probe assay (Inno-Lipa HBV-DR). RESULTS YMDD variants were detected in 13 (18.3%) of the 71 anti-HBe positive inactive HBV carriers. Of the 13 patients, 10 (76.9%) also had accompanying L180M mutation. The combination of wild type and YMDD variant HBV was present in 11 of 13 patients. In two patients, only YIDD and/or YVDD variants plus L180M were detected without the presence of wild YMDD motif. CONCLUSION Naturally occurring YMDD motif variants were detected at a high rate in a group of lamivudine-untreated inactive HBV carriers.
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Affiliation(s)
- Mesut Akarsu
- Department of Gastroenterology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
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Liu CH, Lin JW, Tsai FC, Yang PM, Lai MY, Chen JH, Kao JH, Chen DS. Noninvasive tests for the prediction of significant hepatic fibrosis in hepatitis C virus carriers with persistently normal alanine aminotransferases. Liver Int 2006; 26:1087-94. [PMID: 17032409 DOI: 10.1111/j.1478-3231.2006.01355.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND The diagnostic value of Doppler and various noninvasive indices in predicting significant hepatic fibrosis in hepatitis C virus (HCV) carriers with persistently normal alanine aminotransferases (PNALT) is unknown. METHODS Seventy-nine treatment-naïve HCV carriers with PNALT, who received Doppler ultrasonography and percutaneous liver biopsies, were enrolled in the study. Doppler indices, including portal vein velocity (PVV), hepatic arterial resistive index (HARI), hepatic arterial pulsatility index (HAPI), splenic arterial resistive index (SARI), and splenic arterial pulsatility index (SAPI), were compared with known biochemical indices used in HCV carriers with elevated ALT levels, including aspartate aminotransferase (AST) to platelet ratio index (APRI), age-platelet index (API), and AST to ALT ratio (AAR), for the diagnostic accuracy of significant hepatic fibrosis. RESULTS SAPI was the most discriminatory index among the Doppler indices (P<0.001). By comparing areas under the receiver-operating characteristic (AUROC) of SAPI with various biochemical indices, SAPI was superior to APRI, API, and AAR for predicting significant fibrosis (> or =F2) (0.862 vs. 0.673, 0.639, 0.504). SAPI set at 0.85 and 1.10 had a sensitivity of 96.7% and 66.7%, a specificity of 44.6% and 96.0%, a positive predictive value of 41.4% and 87.1%, and an negative predictive value of 97% and 87.7% in predicting significant fibrosis. CONCLUSIONS This study indicates that SAPI is the most useful index among Doppler and biochemical indices for the detection of significant hepatic fibrosis in HCV carriers with PNALT levels.
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Affiliation(s)
- Chen-Hua Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Zeuzem S, Alberti A, Rosenberg W, Marcellin P, Diago M, Negro F, Prati D, Puoti C, Roberts SK, Shiffman ML. Review article: management of patients with chronic hepatitis C virus infection and "normal" alanine aminotransferase activity. Aliment Pharmacol Ther 2006; 24:1133-49. [PMID: 17014573 DOI: 10.1111/j.1365-2036.2006.03073.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Hepatitis C virus infection, a major cause of chronic liver disease, occurs with normal serum alanine aminotransferase activity in approximately 25% of patients. These patients have historically remained untreated but substantial evidence indicates liver damage, progression of disease and impaired quality of life in some individuals. AIM To review the current management of patients with chronic hepatitis C and normal alanine aminotransferase activity. METHODS This review represents the summary of discussions at a Clinical Workshop with a comprehensive literature searching of available databases (PubMed and Embase). RESULTS Current limits defining normal serum alanine aminotransferase activity are not representative of a "healthy" status. Most patients with hepatitis C and normal alanine aminotransferase levels have histologically proven liver damage that, although generally mild, may be significant (> or =F2) in up to 20% of patients and progresses at approximately 50% of the rate in patients with elevated alanine aminotransferase levels. Some patients have persistently normal alanine aminotransferase activity and may have a more benign outcome, but a significant proportion (> or =20%) experience periods of increased serum alanine aminotransferase activity which may be associated with enhanced disease progression. CONCLUSIONS A treatment approach that considers host and virus-related variables and optimizes patient and cost benefits may therefore provide more effective management of patients with chronic hepatitis C and normal alanine aminotransferase activity.
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Affiliation(s)
- S Zeuzem
- Department of Internal Medicine, , Saarland University Hospital, 66421 Homburg/Saar, Germany.
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Kobayashi M, Suzuki F, Akuta N, Suzuki Y, Arase Y, Ikeda K, Hosaka T, Sezaki H, Kobayashi M, Iwasaki S, Sato J, Watahiki S, Miyakawa Y, Kumada H. Response to long-term lamivudine treatment in patients infected with hepatitis B virus genotypes A, B, and C. J Med Virol 2006; 78:1276-83. [PMID: 16927289 DOI: 10.1002/jmv.20701] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Response to lamivudine treatment longer than 1 year was compared in 15 patients persistently infected with hepatitis B virus (HBV) genotype A, 38 with genotype B, and 449 with genotype C. Patients with genotype A were younger (median age 37 [range 24-49] vs. 47 [24-67] or 44 [18-73], P = 0.015), possessed hepatitis B e antigen (HBeAg) more frequently (73% vs. 21% or 56%, P < 0.001) and HBV DNA in higher levels (8.6 [6.1-8.7] vs. 6.5 [<3.7-8.7] or 6.5 [<3.7-8.7] log genome equivalents (LGE)/ml, P = 0.024) than those with genotype B or C. During lamivudine, YMDD mutants (89% vs. 53% or 42%, P = 0.0001) and breakthrough hepatitis developed more often (47% vs. 21% or 29%, P = 0.023) in patients with genotype A than B or C. YMDD mutants elicited more frequently in patients with genotype A than B or C who were positive (82% [9/11] vs. 25% [2/8] or 48% [117/245], P = 0.037) or negative for HBeAg (75% [3/4] vs. 30% [9/30] or 33% [68/204], P = 0.003). HBeAg (hazard ratio 2.1 [95% confidence interval 1.53-2.92], P < 0.001) and genotype A (2.78 [1.08-7.12], P = 0.034) enhanced the emergence of YMDD mutants by the Cox proportional hazard model. The risk for breakthrough hepatitis was increased by the baseline alanine aminotransferase level <500 IU/L (2.56 [1.82-5.50], P = 0.018), HBeAg (2.11 [1.40-3.16], P < 0.001), cirrhosis (1.92 [1.24-2.97], P = 0.004) and HBV DNA > or =8.0 LGE/ml (1.57 [1.04-2.36], P = 0.03); it was influenced by genotypes only in patients with HBeAg. In conclusion, HBV genotypes help in predicting response to long-term lamivudine treatment and development of YMDD mutants in patients with chronic hepatitis B.
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Affiliation(s)
- Mariko Kobayashi
- Research Institute for Hepatology, Toranomon Hospital, Tokyo, Japan.
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48
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Hosseini SY, Sabahi F, Amini-Bavil-Olyaee S, Alavian SM, Merat S. A novel accurate ACRS-PCR method with a digestion internal control for identification of wild type and YMDD mutants of hepatitis B virus strains. J Virol Methods 2006; 137:298-303. [PMID: 16962669 DOI: 10.1016/j.jviromet.2006.07.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2006] [Revised: 06/29/2006] [Accepted: 07/04/2006] [Indexed: 12/11/2022]
Abstract
As a consequence of the point mutation in the YMDD motif of the hepatitis B virus (HBV) polymerase gene, lamivudine-resistant mutants have been reported in chronic hepatitis B patients who underwent lamivudine therapy. The objective of the study was to develop a novel accurate artificially created restriction site (ACRS) method with a digestion internal control for identification of YMDD, YIDD and YVDD HBV strains. Three conserved, specific and diagnostic primers introducing NdeI, SspI and AleI cleavage sites were designed in order to identify YMDD, YIDD and YVDD strains, respectively; while, their reverse primers also modified with the above recognition sites in order to enzyme correctness monitoring and false outcome avoiding. Thirty-two chronic hepatitis B patients who had taken lamivudine for 1-3 years and checked by the Inno-LiPA HBV DR kit, were evaluated by the ACRS method and then compared to sequencing data. The results of the ACRS method revealed the YMDD mutant strain in 20 patients, YMDD plus YIDD pattern in 1 patient, YMDD plus YVDD in 4 patients, the YIDD in 4 patients and mixed infection with each three strains in 1 patient. The sequencing and Inno-LiPA results were in agreement with the ACRS results. The novel ACRS method is a reliable, rapid and a cost-effective technique for determination of HBV strains with the wild type and YMDD mutant patterns.
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Affiliation(s)
- Seyed Younes Hosseini
- Virology Department, Faculty of Medical Sciences, Tarbiat Modarres University, Tehran, Iran
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49
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Bruce MG, Bruden D, McMahon BJ, Christensen C, Homan C, Sullivan D, Deubner H, Hennessy T, Williams J, Livingston S, Gretch D. Hepatitis C infection in Alaska Natives with persistently normal, persistently elevated or fluctuating alanine aminotransferase levels. Liver Int 2006; 26:643-9. [PMID: 16842319 DOI: 10.1111/j.1478-3231.2006.01281.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND/AIMS An estimated one-third of patients with chronic hepatitis C virus (HCV) infection have persistently normal alanine transaminase (PNALT); however, in many previous studies alanine aminotransferase (ALT) levels were followed for < or = 12 months. METHODS We analyzed data from a population-based cohort of 935 Alaska Natives with HCV, recruited from 1994 to 2005, to determine the proportion of persons with PNALT, persistently elevated ALT (PEALT), and fluctuating ALT (FLUXALT) to determine factors for each ALT state. We selected persons with two positive HCV RNA results > or = 1 year apart and > or = 6 ALT levels measured over the subsequent 3 years with at least 1 month between ALT measurements (n = 265). We defined a person as having PNALT, PEALT, or FLUXALT when all six ALT levels were normal, elevated, or did not fit either of the above two categories, respectively, during the 3-year follow-up period. RESULTS Among 208 persistently HCV RNA-positive persons, 13 had PNALT, 121 PEALT, 74 FLUXALT. Among 77 persons who underwent liver biopsy, those with PEALT were more likely to have Ishak fibrosis scores > 2 compared with persons with FLUXALT (44% vs. 10%, OR 7.0, 95% CI: 1.5-33.2). No statistically significant differences were found in ALT classification by age, gender, infection duration, median body mass index, alcohol consumption, residence, risk behavior, RNA level, or genotype. CONCLUSIONS Only 6% of persons with chronic HCV had PNALT. Persons with PEALT were significantly more likely to have higher fibrosis scores on liver biopsy than those with FLUXALT. Previous studies with short follow-up periods may have overestimated the proportion of persons with normal ALT levels.
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Affiliation(s)
- Michael G Bruce
- Arctic Investigations Program, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Anchorage, Alaska.
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Umeoka F, Iwasaki Y, Matsumura M, Takaki A, Kobashi H, Tatsukawa M, Shiraha H, Fujioka SI, Sakaguchi K, Shiratori Y. Early detection and quantification of lamivudine-resistant hepatitis B virus mutants by fluorescent biprobe hybridization assay in lamivudine-treated patients. J Gastroenterol 2006; 41:693-701. [PMID: 16933008 DOI: 10.1007/s00535-006-1834-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2005] [Accepted: 04/08/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND Long-term lamivudine treatment induces the emergence of lamivudine-resistant hepatitis B virus (HBV). The objective of this study was to develop a fluorescent biprobe hybridization (FBH) assay for the detection and quantification of HBV mutants in the clinical course of lamivudine-treated patients and to evaluate its clinical usefulness. METHODS We developed an FBH assay to detect mutations in the HBV DNA polymerase gene. The assay's detection sensitivity was determined using a dilution series of wild-type/mutant plasmid DNA. Blood samples obtained from 27 lamivudine-treated patients were analyzed. RESULTS Mutant DNA levels as low as 10% of total HBV DNA were detected (sensitivity = 100%, specificity = 80%). HBV mutants were detected in five of the 27 patients during an average follow-up of 20 months after lamivudine administration. In one of the five patients, the YIDD mutant was detected at the initiation of lamivudine treatment, while the remaining four patients were identified as having YIDD mutants within 3 months after beginning lamivudine administration. Of the five patients with an HBV mutant, four developed breakthrough hepatitis more than 10 months after the detection of HBV mutants, following the reappearance or a re-increase of HBV DNA, characterized by a predominance of the mutant. The YIDD mutant was detected in one patient, even when the titer of the serum HBV DNA was below the detection limit of commercially available quantitative polymerase chain reaction. CONCLUSIONS The FBH assay is an efficient method for detecting and quantifying HBV mutants, as early as 3 months after lamivudine administration.
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Affiliation(s)
- Fumi Umeoka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
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