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Kim TH, Kim M, Yim HJ, Suh SJ, Jung YK, Seo YS, Um SH, Lee JI, Lee SH, Kim SG, Kim IH, Kim HS, Cho EY, Kim TY, Hwang SG. Telbivudine Plus Adefovir Versus Lamivudine Plus Adefovir for Lamivudine-Resistant Chronic Hepatitis B: TeSLA Randomized Trial. HEPATITIS MONTHLY 2022; 21. [DOI: 10.5812/hepatmon.121627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Background: In countries with unavailable tenofovir, a combination of lamivudine (LMV) and adefovir (ADV) is recommended for the treatment of LMV-resistant chronic hepatitis B (CHB). Considering that telbivudine (L-dT) was demonstrated to be superior to LMV in previous studies, L-dT and ADV combination therapy is expected to show better antiviral efficacy than the combination of LMV and ADV in patients with LMV-resistant CHB. Methods: This was a prospective randomized multicenter study. The primary endpoint was Hepatitis B Virus (HBV) DNA reduction after 52 weeks of treatment. The secondary endpoints were HBV DNA undetectability, hepatitis B e antigen seroconversion, the incidence of virological and biochemical breakthroughs, and safety during the study period. Results: A total of 43 LMV-resistant CHB patients were enrolled. Twenty-one were treated with LMV + ADV and 22 with L-dT + ADV. After 52 weeks of antiviral treatment, the HBV DNA reduction showed no significant intergroup difference (-4.54 ± 1.23 log IU/mL in the LMV + ADV group, -4.24 ± 1.46 log IU/mL in the L-dT + ADV group, P = 0.475). There were no significant intergroup differences in HBV DNA undetectability rates, mean HBV DNA level, or hepatitis B e antigen seroconversion rate at 13, 26, 39, and 52 weeks of treatment. In terms of safety, the mean creatine phosphokinase level was significantly higher in the L-dT + ADV group. Conclusions: In the treatment of LMV-resistant CHB, the combination of L-dT and ADV did not show any clinical benefit compared to the combination of LMV and ADV.
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A novel method for nucleos(t)ide analogues susceptibility assay of hepatitis B virus by viral polymerase transcomplementation. Antiviral Res 2015; 126:99-107. [PMID: 26738784 DOI: 10.1016/j.antiviral.2015.12.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 12/18/2015] [Accepted: 12/22/2015] [Indexed: 02/06/2023]
Abstract
Nucleos(t)ide analogues (NUCs) susceptibility assay is important for the study of hepatitis B virus (HBV) drug resistance. The purpose of susceptibility assay is to test the sensitivity of a specific HBV variant to NUCs in vitro, by which assesses if and to what extent the mutant virus is resistant to a specific NUC. Among the existing susceptibility assay methods, stable cell line expressing the specific variant is one of the commonly used assessment systems based on its high repeatability. However, establishment of stable cell lines expressing individual variant is laborious and time-consuming. In the present study, we developed a novel strategy for rapidly establishing HBV replicating stable cell lines. We first established an acceptor cell line stably transfected with a polymerase-null HBV 1.1mer genome DNA, then lentiviruses expressing different mutant HBV polymerases were transduced into the acceptor cell line respectively. Stable cell lines replicating HBV DNA with the trans-complemented HBV polymerases were established by antibiotics selection. Lamivudine and entecavir susceptibility data from these polymerase-complementing cell lines were validated by comparing with other assays. Taken together, this transcomplementation strategy for establishment of stable cell lines replicating HBV DNA with clinically isolated HBV polymerase provides a new tool for NUC susceptibility assay of HBV.
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Comparison of lamivudine plus adefovir therapy versus entecavir with or without adefovir therapy for adefovir-resistant chronic hepatitis B. J Clin Gastroenterol 2014; 48:889-95. [PMID: 24440937 DOI: 10.1097/mcg.0000000000000066] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND GOALS Data regarding the management of adefovir (ADV) resistance are still limited. The aim of this study is to investigate treatment outcomes of rescue therapy in ADV-resistant chronic hepatitis B (CHB) patients. STUDY CHB patients who began rescue therapy due to documented genotypic resistance mutations to ADV between October 2006 and July 2012 were retrospectively reviewed. RESULTS Sixty-three patients were included in this study. Most patients had history of lamivudine (LAM) resistance. Treatment response was evaluated at 3-month intervals up to 12 months. The cumulative rate of complete virologic response (CVR) in hepatitis B virus (HBV)-infected patients (HBV DNA<60 IU/mL) was 15.9%, 27.2%, 28.9%, and 31.7% after 3, 6, 9, and 12 months of rescue therapy. Thirty-five patients were treated with a combination of LAM plus ADV (LAM+ADV group) and 28 patients were treated with entecavir (ETV)-based therapy (ETV with or without ADV therapy, ETV±ADV group). The cumulative CVR rate was significantly higher in the ETV±ADV group than in the LAM+ADV group at month 12 (46.4% vs. 20.6%, respectively, P=0.040). Multivariate analysis showed that pretreatment serum HBV DNA levels at <6 log10 IU/mL (hazard ratio: 34.109, P=0.001) and type of rescue therapy (hazard ratio: 4.944, P=0.036) were associated with CVR. CONCLUSIONS Lower baseline HBV DNA level and ETV±ADV therapy were the important predictive factors for CVR in ADV-resistant CHB patients. This study suggests the need of early switching to a rescue therapy such as ETV±ADV at the time of low-level viremia.
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Menéndez-Arias L, Álvarez M, Pacheco B. Nucleoside/nucleotide analog inhibitors of hepatitis B virus polymerase: mechanism of action and resistance. Curr Opin Virol 2014; 8:1-9. [PMID: 24814823 DOI: 10.1016/j.coviro.2014.04.005] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 04/14/2014] [Accepted: 04/16/2014] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) polymerase and human immunodeficiency virus (HIV) reverse transcriptase are structurally related. However, the HBV enzyme has a protein priming activity absent in the HIV enzyme. Approved nucleoside/nucleotide inhibitors of the HBV polymerase include lamivudine, adefovir, telbivudine, entecavir and tenofovir. Although most of them target DNA elongation, guanosine and adenosine analogs (e.g. entecavir and tenofovir, respectively) also impair protein priming. Major mutational patterns conferring nucleoside/nucleotide analog resistance include the combinations rtL180M/rtM204(I/V) (for lamivudine, entecavir, telbivudine and clevudine) and rtA181V/rtN236T (for adefovir and tenofovir). However, development of drug resistance is very slow for entecavir and tenofovir. Novel nucleoside/nucleotide analogs in advanced clinical trials include phosphonates similar to adefovir or tenofovir, and new tenofovir derivatives with improved pharmacological properties.
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Affiliation(s)
- Luis Menéndez-Arias
- Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), c/Nicolás Cabrera, 1, Campus de Cantoblanco, Madrid 28049, Spain.
| | - Mar Álvarez
- Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), c/Nicolás Cabrera, 1, Campus de Cantoblanco, Madrid 28049, Spain
| | - Beatriz Pacheco
- Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), c/Nicolás Cabrera, 1, Campus de Cantoblanco, Madrid 28049, Spain
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Lu JJ, Liu K, Ma YJ, Wang J, Chen EQ, Tang H. Efficacy and safety of telbivudine plus adefovir dipivoxil combination therapy and entecavir monotherapy for HBeAg-positive chronic hepatitis B patients with resistance to adefovir dipivoxil. J Viral Hepat 2013; 20 Suppl 1:40-45. [PMID: 23458523 DOI: 10.1111/jvh.12062] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Accepted: 12/09/2012] [Indexed: 02/05/2023]
Abstract
The objective of this study was to compare the efficacy and safety of two rescue strategies for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients with resistance to adefovir dipivoxil (ADV). This prospective study included 58 HBeAg-positive CHB patients with resistance to ADV; 30 patients underwent telbivudine (LdT) plus ADV combination therapy and 28 patients switched to entecavir (ETV) monotherapy. After 48 weeks of treatment, the rates of hepatitis B virus (HBV) DNA <3 log10 copies/mL in the LdT plus ADV group and the ETV group were not significantly different (73.3% vs 57.1%, P = 0.195). Six patients receiving LdT plus ADV had HBeAg seroconversion, while none of the patients receiving ETV alone had HBeAg seroconversion (20% vs 0%, P = 0.039). During the 48-week treatment period, two patients in the ETV monotherapy group had viral breakthrough and the strains were confirmed to be of a variant associated with ETV resistance (rtM204V+ rtL180M+ rtT184G), while one patient receiving LdT plus ADV had viral breakthrough and an LdT-associated resistance mutation (rtM204I) was detected. For the majority of the patients, both LdT plus ADV combination treatment or ETV monotherapy were generally well tolerated, and no serious side effects were observed. Both LdT plus ADV combination therapy and ETV monotherapy led to significant decreases in serum HBV DNA in HBeAg-positive CHB patients with resistance to ADV, and LdT plus ADV combination therapy exhibited a significantly higher rate of HBeAg seroconversion compared with ETV monotherapy.
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Affiliation(s)
- Jia-Jie Lu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Svarovskaia ES, Curtis M, Zhu Y, Borroto-Esoda K, Miller MD, Berg T, Lavocat F, Zoulim F, Kitrinos KM. Hepatitis B virus wild-type and rtN236T populations show similar early HBV DNA decline in adefovir refractory patients on a tenofovir-based regimen. J Viral Hepat 2013; 20:131-40. [PMID: 23301548 DOI: 10.1111/j.1365-2893.2012.01638.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hepatitis B virus (HBV) pol/RT mutations that confer clinical resistance to tenofovir disoproxil fumarate (TDF) have not been detected to date. In vitro, the rtN236T adefovir dipivoxil (ADV)-associated resistance mutation confers low-level cross-resistance to tenofovir: 3- to 13-fold changes in EC(50) from wild type. This study evaluated the clinical response of rtN236T mutant viruses by comparing their early viral load decay kinetics to wild-type viruses in chronic HBV monoinfected patients harbouring rtN236T prior to initiating TDF or emtricitabine (FTC)/TDF therapy. Baseline samples (n = 105) from adefovir refractory patients were tested for the presence of rtN236T using a highly sensitive allele-specific PCR assay with an rtN236T detection cut-off of 0.5%. The rtN236T mutation was detected at baseline in 14.3% (14/98) of analysable patient samples (0.5-93.2%, rtN236T percentage range). The median change in total HBV DNA at week 24 was comparable for patients with rtN236T detected at baseline (-3.7 log(10) copies/mL, n = 14) as compared to patients with wild-type HBV (-3.2 log(10) copies/mL, n = 90). In patients with rtN236T, wild-type and rtN236T mutant virus showed similar rates of HBV DNA decline with no statistically significant difference observed at week 4. Moreover, the proportion of rtN236T remained unchanged in patients in either arm of the study during treatment. In conclusion, the rtN236T mutant virus showed similar HBV DNA decline kinetics to wild-type virus in adefovir refractory patients who switched to TDF or FTC/TDF. Despite low levels of cross-resistance in vitro, TDF similarly suppresses wild-type and rtN236T mutant viruses in vivo.
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Pharmacokinetic Properties of Single-Dose Lamivudine/Adefovir Dipivoxil Fixed-Dose Combination in Healthy Chinese Male Volunteers. Clin Ther 2013; 35:68-76. [PMID: 23274144 DOI: 10.1016/j.clinthera.2012.12.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Revised: 12/04/2012] [Accepted: 12/04/2012] [Indexed: 02/07/2023]
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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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Evaluation of single and combination therapies with tenofovir disoproxil fumarate and emtricitabine in vitro and in a robust mouse model supporting high levels of hepatitis B virus replication. Antimicrob Agents Chemother 2012; 56:6186-91. [PMID: 22985879 DOI: 10.1128/aac.01483-12] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Next-generation therapies for chronic hepatitis B virus (HBV) infection will involve combinations of established and/or experimental drugs. The current study investigated the in vitro and in vivo efficacy of tenofovir disoproxil fumarate (TDF) and/or emtricitabine [(-)-FTC] alone and in combination therapy for HBV infection utilizing the HepAD38 system (human hepatoblastoma cells transfected with HBV). Cellular pharmacology studies demonstrated increased levels of (-)-FTC triphosphate with coincubation of increasing concentrations of TDF, while (-)-FTC had no effect on intracellular tenofovir (TFV) diphosphate levels. Quantification of extracellular HBV by real-time PCR from hepatocytes demonstrated the anti-HBV activity with TDF, (-)-FTC, and their combination. Combination of (-)-FTC with TDF or TFV (ratio, 1:1) had a weighted average combination index of 0.7 for both combination sets, indicating synergistic antiviral effects. No cytotoxic effects were observed with any regimens. Using an in vivo murine model which develops robust HBV viremia in nude mice subcutaneously injected with HepAD38 cells, TDF (33 to 300 mg/kg of body weight/day) suppressed virus replication for up to 10 days posttreatment. At 300 mg/kg/day, (-)-FTC strongly suppressed virus titers to up to 14 days posttreatment. Combination therapy (33 mg/kg/day each drug) sustained suppression of virus titer/ml serum (<1 log(10) unit from pretreatment levels) at 14 days posttreatment, while single-drug treatments yielded virus titers 1.5 to 2 log units above the initial virus titers. There was no difference in mean alanine aminotransferase values or mean wet tumor weights for any of the groups, suggesting a lack of drug toxicity. TDF-(-)-FTC combination therapy provides more effective HBV suppression than therapy with each drug alone.
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Chen CH, Wang JH, Lu SN, Hu TH, Hung CH, Chang MH, Changchien CS, Lee CM. Treatment response and evolution of HBV resistance during lamivudine plus adefovir or entecavir therapy in patients with adefovir-resistant mutants. Antivir Ther 2012; 17:701-9. [PMID: 22358132 DOI: 10.3851/imp2074] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/01/2011] [Indexed: 12/25/2022]
Abstract
BACKGROUND Here, we investigated the treatment response and evolution of HBV resistance during lamivudine (LAM) plus adefovir (ADV) and entecavir (ETV) monotherapy in patients with ADV-resistant mutants. METHODS Of the 53 patients with ADV-resistant mutants, 25 received combined LAM plus ADV therapy (LAM+ADV group) and 28 received ETV monotherapy (ETV group) for at least 12 months (median 24 months and range 12-67 months). RESULTS During 24 months therapy, no significant difference was noted in HBV DNA reduction from baseline, HBV DNA<200 copies/ml, hepatitis B e antigen loss and ALT normalization between the two groups. In the LAM+ADV group, patients with single rtN236T resistant mutation had higher rates of undetectable HBV DNA than those with the double mutant rtA181T/V+rtN236T at months 3-18 of therapy. No virological breakthrough occurred except for one patient with rtN236T resistant mutation who experienced virological and biochemical breakthrough after the emergence of an additional rtA181T mutant under LAM+ADV therapy. Of the 28 patients receiving ETV monotherapy, ETV-resistant mutants developed in 8. The cumulative rates of ETV-resistant mutations and virological breakthrough at months 12, 24 and 36 were 3.6%, 25.7% and 46.8%, respectively. ADV-resistant mutations were rapidly replaced by LAM-resistant mutations (median 12 months) followed by ETV-resistant mutations. CONCLUSIONS There was no significant difference in virological response between the LAM+ADV and ETV groups in patients with ADV-resistant mutants. LAM+ADV were less effective in patients with the double mutant rtA181T/V+rtN236T than the single rtN236T mutation. The incidence of ETV-resistant mutation was high in patients with LAM/ADV-resistant mutants treated with ETV monotherapy.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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Gish R, Jia JD, Locarnini S, Zoulim F. Selection of chronic hepatitis B therapy with high barrier to resistance. THE LANCET. INFECTIOUS DISEASES 2012; 12:341-53. [PMID: 22326017 DOI: 10.1016/s1473-3099(11)70314-0] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Antiviral drug resistance is a crucial factor that frequently determines the success of long-term therapy for chronic hepatitis B. The development of resistance to nucleos(t)ide analogues has been associated with exacerbations in liver disease and increased risk of emergence of multidrug resistance. The selection of a potent nucleos(t)ide analogue with a high barrier to resistance as a first-line therapy, such as entecavir or tenofovir, provides the best chance of achieving long-term treatment goals and should be used wherever possible. The barrier to resistance of a given nucleos(t)ide analogue is influenced by genetic barrier, drug potency, patient adherence, pharmacological barrier, viral fitness, mechanism of action, and cross-resistance. In countries with limited health-care resources, the selection of a therapy with a high barrier to resistance is not always possible and alternative strategies for preventing resistance might be needed, although limited data are available to support these strategies.
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Affiliation(s)
- Robert Gish
- Center for Hepatobiliary Disease and Abdominal Transplantation, UC San Diego Health System, San Diego, CA, USA
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12
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Lee YS, Chung YH, Kim JA, Jin YJ, Park WH, Kim SE, Lee D, Shim JH, Kim KM, Lim YS, Lee HC, Lee YS, Suh DJ. rtL180M mutation of hepatitis B virus is closely associated with frequent virological resistance to adefovir dipivoxil therapy. J Gastroenterol Hepatol 2012; 27:300-5. [PMID: 21777282 DOI: 10.1111/j.1440-1746.2011.06853.x] [Citation(s) in RCA: 10] [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
BACKGROUND AND AIM We intended to investigate the effects of pre-existing mutations at reverse transcriptase region of hepatitis B virus (HBV) on the occurrence of virological breakthrough (VB) to adefovir dipivoxil (ADV) in patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB). METHODS Ninety-seven patients with LAM-resistant CHB were treated with ADV at a dose of 10 mg daily, and were followed for a median period of 13 months. Just before the initiation of ADV therapy, the whole length of reverse transcriptase region of serum HBV-DNA was sequenced using direct sequencing. RESULTS All patients had genotype C HBV and mutations in the YMDD motif, specifically, YIDD (65%), YVDD (28%), or both (7%). The rtL180M and rtL80V/I mutations were identified in 68% and 69%, respectively. The cumulative probability of VB was 19% and 27% at 1 and 2 years, respectively. There was no difference in the occurrence of VB with regard to types of YMDD mutation or rtL80V/I. However, interestingly, patients carrying rtL180M experienced VB during ADV monotherapy more frequently than those not carrying rtL180M (2-year cumulative probability of VB: 37% vs 3% at 2 years, P < 0.01). On multivariate Cox proportional hazards analysis, rtL180M (hazard ratio [HR]: 8.62, 95% confidence interval: 1.08-69.09, P = 0.042) and decrease in HBV-DNA for 1 year of treatment (HR: 0.69, 95% CI: 0.51-0.95, P = 0.024) are independently associated with VB. CONCLUSIONS The rtL180M mutation of HBV, as well as a small decrease in HBV-DNA after 1 year of treatment might be closely associated with frequent occurrence of virological resistance to ADV in patients with LAM-resistant CHB.
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Affiliation(s)
- Yoon-Seon Lee
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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Viganò M, Lampertico P, Colombo M. Drug safety evaluation of adefovir in HBV infection. Expert Opin Drug Saf 2011; 10:809-18. [PMID: 21671843 DOI: 10.1517/14740338.2011.593507] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Several nucleos(t)ide analogs (NUC) are available for the management of patients with chronic hepatitis B (CHB). In most patients, NUC need to be administered on a long-term basis, thus increasing the risk of adverse effects. Adefovir dipivoxil (ADV), the first nucloeotide analog developed to treat CHB, may indeed cause nephrotoxicity. AREAS COVERED The pharmacokinetic mechanism of action, potential mechanism of renal damage and long-term safety profile of ADV in CHB patients have been reported. The current monitoring modalities, together with dosage adjustments, treatment of patients with ADV-related kidney impairment and the therapeutic algorithm in place at the authors' Liver Center are also summarized. Although, in short-term clinical trials, a daily dose of 10 mg of ADV was safe owing to a low rate of negligible nephrotoxic effects, the same dose may be associated with a usually reversible, proximal renal tubular toxicity as reflected by hypophosphatemia and elevated creatinine levels. Occasionally, Fanconi syndrome occurred in ADV-treated patients. EXPERT OPINION Renal function at baseline and during treatment should be carefully assessed in all patients receiving ADV to adjust the dose according to creatinine clearance, aimed to prevent or minimize nephrotoxicity.
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Affiliation(s)
- Mauro Viganò
- A. M. and A. Migliavacca Center for Liver Disease, 1st Gastroenterology Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Università di Milano, Via F. Sforza 35, 20122 Milan, Italy
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14
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Perrillo RP, Hann HW, Schiff E, Mutimer D, Willems B, Leung N, Lee WM, Dixon S, Woessner M, Brosgart CL, Condreay LD, Gardner SD. Extended treatment with lamivudine and adefovir dipivoxil in chronic hepatitis B patients with lamivudine resistance. Hepatol Int 2011; 5:654-663. [PMID: 21484148 PMCID: PMC3090563 DOI: 10.1007/s12072-010-9228-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2010] [Accepted: 11/25/2010] [Indexed: 01/11/2023]
Abstract
PURPOSE We and others have reported that adding adefovir dipivoxil (adefovir) to lamivudine results in virological and biochemical improvement in cases of lamivudine resistance. The current study assessed the efficacy and safety of combined therapy after 104 weeks of combined treatment and analyzed the frequency of persistent lamivudine resistant HBV. METHODS A total of 78 patients with compensated CHB (Group A) were maintained on either adefovir 10 mg daily (n = 38) or placebo (n = 40) while continuing lamivudine. An additional 38 patients with decompensated cirrhosis or post liver transplantation (Group B) received lamivudine plus adefovir. The primary endpoint was HBV DNA response at year 2. RESULTS At week 104 of therapy, a significantly greater proportion of patients in Group A on combination therapy (76%) had a decline in serum HBV DNA to ≤10(5) copies or >2 log(10) reduction from baseline compared to those receiving lamivudine alone (13%; p < 0.001). Fifty-two percent of Group A patients on combination treatment continued to have the M204V/I HBV mutation compared to 92% receiving lamivudine alone (p = 0.0013). Virologic response occurred less frequently in patients expressing persistent lamivudine resistant HBV. In Group B, 87% of patients had HBV DNA response at week 104 (median change from baseline of -5.84 log(10) copies/mL). CONCLUSIONS The combination of lamivudine and adefovir for 2 years generally proved effective in lamivudine-resistant cases, but there was a persistently high rate of detection of lamivudine resistant mutants and impaired virologic response in compensated patients.
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Kumar A, Dwivedi M, Misra SP, Narang S, Tiwari BK, Pandey R. Clinical profile, genotype and management updates of hepatitis B virus. INDIAN JOURNAL OF VIROLOGY : AN OFFICIAL ORGAN OF INDIAN VIROLOGICAL SOCIETY 2011; 22:1-10. [PMID: 23637496 PMCID: PMC3550728 DOI: 10.1007/s13337-011-0037-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2010] [Accepted: 05/07/2011] [Indexed: 12/18/2022]
Abstract
Hepatitis B virus (HBV) is a well known agent of acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Around 400 million people worldwide carrier of HBV of which more than 250 million reside in Asia, and 1-2 million people have died from it. It has a partially double-stranded DNA, having 3.2-kb genome size and replicate via reverse transcription of RNA intermediate. In the natural history or during the antiviral therapy of chronic HBV infection, seroconversion from HBeAg to anti-HBeAg is usually accompanied by a decrease in viral replication and remission of liver disease. Based on genomic sequence data HBV is classified into eight genotypes A-H and four major serotypes ayw, ayr, adw and adr on the basis of complete genome and S gene sequence analysis. Genotypes and serotypes are useful tools in understanding the epidemiology of HBV infection. HBV genotypes have distinct geographical distributions. The HBV variants appear during HBeAg seroconversion and they bring mutations in the precore region (PC) that prevent HBeAg synthesis. Another common HBeAg variant is the basal core promoter mutant (BCP) characterized by point mutation in the promoter of both HBeAg mRNA and core protein mRNA. The most frequent core promoter mutation is the double A1762T and G1764A nucleotide exchange, which results in a substantial decrease in HBeAg expression but enhanced viral genome replication. The approved antiviral drugs such as Interferon, lamivudine, adefovir dipivoxil, entecavir and telbivudine for purpose of treating chronic HBV infection is to prevent or stop the progression of liver injury by suppressing viral replication or eliminating infection. Sustained losses of viral markers of active viral replication (HBeAg and HBV DNA) are the standard end point of the therapies.
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Affiliation(s)
- Ajay Kumar
- />Centre for Biotechnology, Allahabad Central University, Allahabad, India
- />Department of Gastroenterology, MLN Medical College, Allahabad, India
| | - Manisha Dwivedi
- />Department of Gastroenterology, MLN Medical College, Allahabad, India
| | - S. P. Misra
- />Department of Gastroenterology, MLN Medical College, Allahabad, India
| | - Sushil Narang
- />Department of Gastroenterology, MLN Medical College, Allahabad, India
| | | | - Renu Pandey
- />Centre for Biotechnology, Allahabad Central University, Allahabad, India
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16
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Initial virological response and viral mutation with adefovir dipivoxil added to ongoing Lamivudine therapy in Lamivudine-resistant chronic hepatitis B. Dig Dis Sci 2011; 56:1207-14. [PMID: 20927588 DOI: 10.1007/s10620-010-1423-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2010] [Accepted: 09/03/2010] [Indexed: 12/24/2022]
Abstract
BACKGROUND Although adefovir dipivoxil (ADV) has been used for antiviral treatment of lamivudine (LAM)-resistant chronic hepatitis B (CHB) patients, the long-term efficacy of this treatment is not well understood. Initial virological response (IVR) has been reported to be an important factor in relation to the development of ADV-resistance. AIMS We therefore examined the factors associated with IVR and ADV mutation in these patients. METHODS Forty-nine LAM-resistant CHB patients with ADV add-on LAM therapy, 47% of whom were hepatitis B e-antigen (HBeAg)-positive with median treatment duration of 23 months, were enrolled in this study. Patients were classified into IVR and non-IVR groups on the basis of viral suppression status. Mutational analysis of the HBV polymerase/reverse transcriptase (rt) domain was performed by PCR-direct sequencing. RESULTS Serum HBV DNA was undetectable (<2.6 log10 copies/mL) in 67, 82, and 84% of patients at 24, 48, and 96 weeks, respectively, after ADV add-on LAM therapy. IVR was achieved in 82% of patients, and ALT normalized at week 24 in 90% of IVR and 78% of non-IVR patients. The lower pretreatment HBV DNA level and virus-containing mutations other than double mutation of rtL180M + rtM204V were significantly associated with IVR (P=0.002 and P=0.014, respectively). ADV-resistant mutations in the RT motif, reported previously, were not detected. CONCLUSION IVR is useful for predicting the antiviral efficacy of ADV and LAM combination therapy in LAM-resistant CHB.
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17
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Chen CH, Wang JH, Lu SN, Hu TH, Hung CH, Chang MH, Changchien CS, Lee CM. Characteristics of adefovir resistance in patients with or without lamivudine-resistant hepatitis B virus treated with adefovir: a 4-year experience. Liver Int 2011; 31:206-14. [PMID: 21143368 DOI: 10.1111/j.1478-3231.2010.02416.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIM We investigated the 4-year incidence and predictors of adefovir resistance in chronic hepatitis B patients with or without lamivudine (LAM)-resistance treated with adefovir dipivoxil with or without short-term LAM overlapping. METHODS One hundred and two LAM-resistant patients and 79 without LAM resistance (36 naïve and 43 prior LAM exposure) treated with adefovir for >12 months were prospectively examined. RESULTS Cumulative incidences of adefovir resistance at month 12, 24, 36 and 48 were 3.9, 21.1, 31.8 and 43% respectively in LAM-resistant patients. Cirrhosis was a significant risk factor for adefovir resistance. A similar rate of adefovir resistance was observed for LAM-resistant patients and those with prior LAM exposure without resistance. Regarding LAM-resistant patients, compared with those having hepatitis B virus (HBV) DNA levels <300 copies/ml, patients having HBV DNA levels >10(4) copies/ml at week 24 of therapy had a hazard ratio (HR) of 9.8 for adefovir resistance development, while those without LAM resistance having the same HBV DNA levels at week 48 had a similar HR (9.5). Multidrug-resistant (LAM+adefovir) variants were detected by direct sequencing in three of 35 LAM-resistant patients treated with a switch to adefovir. Two of them had resistant mutations to both drugs on the same viral genome as determined by molecular cloning and sequencing. CONCLUSION The incidence of adefovir resistance was high in LAM-resistant patients treated with sequential adefovir. High HBV DNA levels at week 24 and 48 of therapy were the strongest predictors for adefovir resistance development in patients with and without LAM resistance respectively.
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Affiliation(s)
- Chien-Hung Chen
- Department of Internal Medicine, Division of Hepatogastroenterology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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18
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Th1 and Th2 immune response in chronic hepatitis B patients during a long-term treatment with adefovir dipivoxil. Mediators Inflamm 2010; 2010:143026. [PMID: 21127728 PMCID: PMC2994066 DOI: 10.1155/2010/143026] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2010] [Revised: 07/12/2010] [Accepted: 09/07/2010] [Indexed: 12/16/2022] Open
Abstract
Adefovir dipivoxil treatment has significantly improved the outcome of chronic hepatitis B virus (HBV) infection. However, it remains largely unknown how immune system responds to the treatment. Chronic HBV patients were treated with adefovir dipivoxil and examined for serum HBV DNA loads, cytokines, and T helper (Th1) and 2 (Th2) cytokine producing T cells during 104 weeks of the treatment. Th1/Th2 cytokines producing T cells were significantly lower in chronic HBV patients as compared to normal individuals. Adefovir dipivoxil treatment led to the increase of Th1/Th2 cytokines producing T cells and serum cytokine levels in association with the decline of HVB DNA load. In contrast, Th1/Th2 cytokines producing T cells remained lower in one patient detected with adefovir dipivoxil resistant HBV A181T/V mutation. This study has established inverse correlation of the increase of Th1/Th2 immunity and the decline of HBV DNA load in chronic HBV patients during adefovir dipivoxil treatment.
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19
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Te HS. Antiviral Therapy: Analysis of Long-term Efficacy and Safety. CURRENT HEPATITIS REPORTS 2010; 9:214-222. [DOI: 10.1007/s11901-010-0052-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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20
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Kim KH, Kim ND, Seong BL. Discovery and development of anti-HBV agents and their resistance. Molecules 2010; 15:5878-908. [PMID: 20802402 PMCID: PMC6257723 DOI: 10.3390/molecules15095878] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2010] [Revised: 08/24/2010] [Accepted: 08/26/2010] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a prime cause of liver diseases such as hepatitis, cirrhosis and hepatocellular carcinoma. The current drugs clinically available are nucleot(s)ide analogues that inhibit viral reverse transcriptase activity. Most drugs of this class are reported to have viral resistance with breakthrough. Recent advances in methods for in silico virtual screening of chemical libraries, together with a better understanding of the resistance mechanisms of existing drugs have expedited the discovery and development of novel anti-viral drugs. This review summarizes the current status of knowledge about and viral resistance of HBV drugs, approaches for the development of novel drugs as well as new viral and host targets for future drugs.
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Affiliation(s)
- Kyun-Hwan Kim
- Department of Pharmacology, School of Medicine, and Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University, Seoul 143-701, Korea
- Research Institute of Medical Sciences, Konkuk University, Seoul 143-701, Korea
- Author to whom correspondence should be addressed; E-Mail: (K.H.K.); Tel.: +82 2 2030 7833; Fax: +82 2 2049 6192; E-Mail: (B.L.S.); Tel.: +82 2 2123 2885; Fax: +82 2 392 3582
| | - Nam Doo Kim
- R&D Center, Equispharm Inc., 11F Gyeonggi Bio-Center, 864-1 Iui-Dong, Yeongtong-gu, Suwon-Shi, Gyeonggi-Do 443-766, Korea
| | - Baik-Lin Seong
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea
- Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Korea
- Author to whom correspondence should be addressed; E-Mail: (K.H.K.); Tel.: +82 2 2030 7833; Fax: +82 2 2049 6192; E-Mail: (B.L.S.); Tel.: +82 2 2123 2885; Fax: +82 2 392 3582
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21
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Jiang L, Yan LN. Current therapeutic strategies for recurrent hepatitis B virus infection after liver transplantation. World J Gastroenterol 2010; 16:2468-75. [PMID: 20503446 PMCID: PMC2877176 DOI: 10.3748/wjg.v16.i20.2468] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [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
Hepatitis B virus (HBV)-related liver disease is the leading indication for liver transplantation (LT) in Asia, especially in China. With the introduction of hepatitis B immunoglobulin (HBIG) and oral antiviral drugs, the recurrent HBV infection rate after LT has been evidently reduced. However, complete eradication of recurrent HBV infection after LT is almost impossible. Recurrent graft infection may lead to rapid disease progression and is a frequent cause of death within the first year after LT. At present, the availability of new oral medications, especially nucleoside or nucleotide analogues such as adefovir dipivoxil, entecavir and tenofovir disoproxil fumarate, further strengthens our ability to treat recurrent HBV infection after LT. Moreover, since combined treatment with HBIG and antiviral agents after liver re-transplantation may play an important role in improving the prognosis of recurrent HBV infection, irreversible graft dysfunction secondary to recurrent HBV infection in spite of oral medications should no longer be considered an absolute contraindication for liver re-transplantation. Published reviews focusing on the therapeutic strategies for recurrent HBV infection after LT are very limited. In this article, the current therapeutic strategies for recurrent HBV infection after LT and evolving new trends are reviewed to guide clinical doctors to choose an optimal treatment plan in different clinical settings.
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22
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Importance of serum concentration of adefovir for Lamivudine-adefovir combination therapy in patients with lamivudine-resistant chronic hepatitis B. Antimicrob Agents Chemother 2010; 54:3205-11. [PMID: 20498322 DOI: 10.1128/aac.01372-09] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Lamivudine (LMV)-adefovir pivoxil (ADV) combination therapy suppresses the replication of LMV-resistant hepatitis B virus (HBV), although its efficacy in suppressing HBV varies among patients. This study analyzed the clinical, virological, and pharmaceutical factors that influence the effect of the combination therapy. Patients negative for hepatitis B virus e antigen (HBeAg) and with low HBV DNA titers immediately prior to the combination therapy effectively cleared serum HBV DNA (P=0.0348 and P=0.0310, respectively). The maximum concentration of ADV in serum (ADV Cmax) was higher in patients who showed HBV DNA clearance (P=0.0392), and the cumulative clearance rates of HBV DNA were significantly higher in patients with ADV Cmax equal to or greater than 24 ng/ml (P=0.0284). HBeAg negativity and lower HBV DNA at the start of the combination therapy and higher ADV Cmax were found to be independent factors for serum HBV DNA clearance. Serum creatinine increased significantly during the combination therapy, and the ADV Cmax was higher in patients with low creatinine clearance rates. In conclusion, higher serum concentrations of ADV are associated with a good response to therapy based on clearance of HBV DNA in serum. However, care should be taken to prevent worsening of renal function due to high ADV serum concentrations.
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23
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Chen CH, Lee CM, Tung WC, Wang JH, Hung CH, Hu TH, Wang JC, Lu SN, Changchien CS. Evolution of full-length HBV sequences in chronic hepatitis B patients with sequential lamivudine and adefovir dipivoxil resistance. J Hepatol 2010; 52:478-85. [PMID: 20185198 DOI: 10.1016/j.jhep.2010.01.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2009] [Revised: 10/05/2009] [Accepted: 10/19/2009] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS The aim of this study was to determine the evolution of full-length hepatitis B virus (HBV) sequences in chronic hepatitis B (CHB) patients with sequential lamivudine (LAM) and adefovir (ADV) resistance. METHODS The full-length genomes of HBV were sequenced from 11 CHB patients before LAM treatment and at the emergence of LAM- and ADV-resistant HBV. RESULTS Besides the known LAM-resistant polymerase gene mutations, 10 of 11 patients who had LAM-resistant HBV variants had additional amino acid changes in the reverse transcriptase (RT) domain, and ADV therapy reversed these additional changes to pre-LAM therapy status. Furthermore, new amino acid changes in the RT domain, distinct from the known ADV-resistant HBV variants, were selected at the emergence of ADV resistance in six of 11 patients. Seven patients had amino acid changes within the known T-cell or B-cell epitopes of HBV surface and core antigens at the emergence of LAM and/or ADV resistance. The frequency of pre-S deletions between nucleotide 3037-56 was higher at the emergence of ADV resistance compared with that at the emergence of LAM resistance (7/11 vs. 1/11; p=0.024). Combined LAM-ADV resistance was detected in one of 11 patients. This patient had resistant mutations to both drugs on the same viral genome by molecular cloning (5/24 polymerase gene clones). CONCLUSIONS In addition to the known LAM- and ADV-resistant mutations accompanying the emergence of LAM and ADV resistance, the changes of nucleotide or amino acid sequences occurred commonly in the HBV surface antigen or RT domain and were scattered along the full-length HBV genomes.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan
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24
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Cha CK, Kwon HC, Cheong JY, Cho SW, Hong SP, Kim SO, Yoo WD. Association of lamivudine-resistant mutational patterns with the antiviral effect of adefovir in patients with chronic hepatitis B. J Med Virol 2009; 81:417-24. [PMID: 19152409 DOI: 10.1002/jmv.21402] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Adefovir has a potent antiviral activity as a rescue treatment against lamivudine-resistant strains. The aim of this study was to assess the patterns of lamivudine-resistant mutations and their influence on the virologic response to adefovir rescue therapy in patients with lamivudine-resistant chronic hepatitis B. Sixty-seven patients with lamivudine-resistant chronic hepatitis B were treated with adefovir monotherapy. Baseline blood samples were analyzed for lamivudine-resistant mutations via restriction fragment mass polymorphism. Virologic responses, ALT normalization and loss of HBeAg were assessed. Serum HBV DNA levels were measured using real-time PCR at baseline and 24 weeks of adefovir therapy. Of the 67 patients with chronic hepatitis B, 65 patients (97%) had lamivudine-resistant mutations in the YMDD motif [27 (41%) rtM204I, 22 (34%) rtM204V, and 16 (25%) rtM204I/V]. In addition to the YMDD mutations, the rtL180M, rtL80I, and rtV173L mutations were also present in 78%, 43%, and 11% of patients, respectively. The rtM204V mutation always accompanied rtL180M, and rtL80I was always observed in conjunction with rtM204I. Decrease in mean serum HBV did not differ between patients carrying the rtM204I versus rtM204V mutant at week 24 (-3.3 vs. -3.3 log(10) copies/ml, respectively; P = 0.303). The presence of the rtL180M, rtL80I, and rtV173L did not significantly affect viral load reduction during adefovir administration. These results demonstrate that the rtL80I mutant is co-selected with rtM204I as a compensatory mutation in the same manner as rtL180M with rtM204V, and that adefovir shows similar antiviral efficacy against all of the evaluated patterns of lamivudine-resistant HBV mutations.
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Affiliation(s)
- Choong Keun Cha
- Internal Medicine, CHA Biomedical Center, Pochon CHA University College of Medicine, Seoul, South Korea
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25
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Seifer M, Patty A, Serra I, Li B, Standring DN. Telbivudine, a nucleoside analog inhibitor of HBV polymerase, has a different in vitro cross-resistance profile than the nucleotide analog inhibitors adefovir and tenofovir. Antiviral Res 2008; 81:147-55. [PMID: 19028525 DOI: 10.1016/j.antiviral.2008.10.008] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2008] [Revised: 10/16/2008] [Accepted: 10/24/2008] [Indexed: 12/24/2022]
Abstract
Telbivudine, a nucleoside analog inhibitor of the viral polymerase of hepatitis B virus (HBV), has been approved for the treatment of chronic HBV infection, along with the nucleoside inhibitors lamivudine and entecavir, and the nucleotide inhibitors adefovir and tenofovir. The resistance profiles of these agents were investigated via drug treatment of HepG2 cells stably transfected with wild-type or mutant HBV genomes bearing known resistance mutations. Telbivudine was not active against HBV strains bearing lamivudine mutations L180M/M204V/I but remained active against the M204V single mutant in vitro, potentially explaining the difference in resistance profiles between telbivudine and lamivudine. Against HBV genomes with known telbivudine-resistance mutations, M204I and L80I/M204I, telbivudine, lamivudine and entecavir lost 353- to >1000-fold activity whereas adefovir and tenofovir exhibited no more than 3-5-fold change. Conversely, against HBV cell lines expressing adefovir resistance mutations N236T and A181V, or the A194T mutant associated with resistance to tenofovir, telbivudine remained active as shown by respective fold-changes of 0.5 (N236T) and 1.0 (A181V and A194T). These in vitro results indicate that nucleoside and nucleotide drugs have different cross-resistance profiles. The addition of telbivudine to ongoing adefovir therapy could provide effective antiviral therapy to patients who develop adefovir resistance.
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Affiliation(s)
- Maria Seifer
- Idenix Pharmaceuticals Inc., 60 Hampshire Street, Cambridge, MA 02139, USA
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26
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Menne S, Butler SD, George AL, Tochkov IA, Zhu Y, Xiong S, Gerin JL, Cote PJ, Tennant BC. Antiviral effects of lamivudine, emtricitabine, adefovir dipivoxil, and tenofovir disoproxil fumarate administered orally alone and in combination to woodchucks with chronic woodchuck hepatitis virus infection. Antimicrob Agents Chemother 2008; 52:3617-32. [PMID: 18676881 PMCID: PMC2565907 DOI: 10.1128/aac.00654-08] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2008] [Revised: 07/01/2008] [Accepted: 07/25/2008] [Indexed: 01/03/2023] Open
Abstract
Adefovir dipivoxil (ADV) and tenofovir disoproxil fumarate (TDF) are nucleotide analogs that inhibit the replication of wild-type hepatitis B virus (HBV) and lamivudine (3TC)-resistant virus in HBV-infected patients, including those who are coinfected with human immunodeficiency virus. The combination of ADV or TDF with other nucleoside analogs is a proposed strategy for managing antiviral drug resistance during the treatment of chronic HBV infection. The antiviral effect of oral ADV or TDF, alone or in combination with 3TC or emtricitabine (FTC), against chronic woodchuck hepatitis virus (WHV) infection was evaluated in a placebo-controlled study in the woodchuck, an established and predictive model for antiviral therapy. Once-daily treatment for 48 weeks with ADV plus 3TC or TDF plus FTC significantly reduced serum WHV viremia levels from the pretreatment level by 6.2 log(10) and 6.1 log(10) genome equivalents/ml serum, respectively, followed by TDF plus 3TC (5.6 log(10) genome equivalents/ml), ADV alone (4.8 log(10) genome equivalents/ml), ADV plus FTC (one survivor) (4.4 log(10) genome equivalents/ml), TDF alone (2.9 log(10) genome equivalents/ml), 3TC alone (2.7 log(10) genome equivalents/ml), and FTC alone (2.0 log(10) genome equivalents/ml). Individual woodchucks across all treatment groups also demonstrated pronounced declines in serum WHV surface antigen, characteristically accompanied by declines in hepatic WHV replication and the hepatic expression of WHV antigens. Most woodchucks had prompt recrudescence of WHV replication after drug withdrawal, but individual woodchucks across treatment groups had sustained effects. No signs of toxicity were observed for any of the drugs or drug combinations administered. In conclusion, the oral administration of 3TC, FTC, ADV, and TDF alone and in combination was safe and effective in the woodchuck model of HBV infection.
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MESH Headings
- Adenine/administration & dosage
- Adenine/analogs & derivatives
- Animals
- Antigens, Viral/blood
- Antiviral Agents/administration & dosage
- Antiviral Agents/toxicity
- DNA, Viral/blood
- DNA, Viral/genetics
- Deoxycytidine/administration & dosage
- Deoxycytidine/analogs & derivatives
- Disease Models, Animal
- Drug Therapy, Combination
- Emtricitabine
- Hepatitis B Virus, Woodchuck/drug effects
- Hepatitis B Virus, Woodchuck/genetics
- Hepatitis B Virus, Woodchuck/immunology
- Hepatitis B Virus, Woodchuck/physiology
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/pathology
- Hepatitis B, Chronic/veterinary
- Hepatitis B, Chronic/virology
- Humans
- Lamivudine/administration & dosage
- Liver/pathology
- Liver/virology
- Marmota
- Organophosphonates/administration & dosage
- RNA, Viral/genetics
- RNA, Viral/metabolism
- Rodent Diseases/drug therapy
- Rodent Diseases/pathology
- Rodent Diseases/virology
- Tenofovir
- Virus Replication/drug effects
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Affiliation(s)
- Stephan Menne
- Gastrointestinal Unit, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
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27
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Feitelson MA, Clayton MM, Sun B, Schinazi RF. Development of a novel mouse model to evaluate drug candidates against hepatitis B virus. Antivir Chem Chemother 2008; 18:213-23. [PMID: 17907379 PMCID: PMC7656857 DOI: 10.1177/095632020701800405] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Woodchuck hepatitis virus (WHV)-infected woodchucks have been used for preclinical development of drugs against hepatitis B virus (HBV). However, there is no simple in vivo model to evaluate small amounts of compounds against HBV. To develop such a model, HepAD38 cells, in which HBV replication is regulated by tetracycline (tet), were grown as subcutaneous tumours in nude mice. Mice developing viraemia were then left untreated or given tet in the drinking water. In some of the mice given tet, it was removed and the mice were injected intraperitoneally with phosphate buffer saline (PBS), lamivudine (3TC), clevudine (CLV) or tenofovir dipivoxil fumarate (TDF). Virus DNA titres were measured by real-time PCR during and after drug treatment. In water-fed and PBS-injected mice, virus titres reached approximately 10(9) copies/ml serum within 35 days of HepAD38 injection, whereas in tet-treated mice, virus titres remained at 10(4)-10(5) copies/ml. HBV DNA levels were suppressed by 3TC, TDF and CLV, with the latter two drugs showing more sustained virus suppression compared with 3TC. Combination therapy with CLV plus TDF was much more effective than either drug alone in suppressing virus titre for at least 3 weeks after the end of treatment. There was no demonstrable toxicity to HepAD38 cells in drug-treated mice. Hence, a robust tet-controlled system for HBV replication in vivo was demonstrated, validated with monotherapies against HBV and shown to be useful in assessing combination therapy. This system will be useful for preclinical assessment of small amounts of single or multiple compounds against HBV in vivo.
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Affiliation(s)
- Mark A Feitelson
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
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28
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Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. J Hepatol 2008; 48:728-35. [PMID: 18329126 DOI: 10.1016/j.jhep.2007.12.026] [Citation(s) in RCA: 122] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2007] [Revised: 12/10/2007] [Accepted: 12/11/2007] [Indexed: 01/05/2023]
Abstract
BACKGROUND/AIMS We aimed to evaluate nucleoside/nucleotide combination therapy in treatment-naïve HBeAg-positive patients with chronic hepatitis B (CHB). METHODS One hundred and fifteen HBeAg-positive patients received lamivudine 100 mg daily plus placebo (monotherapy) or lamivudine 100 mg plus adefovir dipoxil 10 mg daily (combination therapy) for 104 weeks in a randomized double-blind study. RESULTS Time-weighted average change in serum HBV DNA from baseline up to week 16 was -4.20 log(10)copies/mL for both groups (p=0.936). At week 104, median serum HBV DNA change from baseline (log(10)copies/mL) for monotherapy and combination therapy was -3.41 versus -5.22, respectively. HBV DNA breakthrough was detected in 44% of monotherapy and 19% of combination therapy patients. The M204V/I mutation was detected in 43% (15/35) and 15% (6/41) of each group, respectively. ALT normalization at week 100 and 104 was 34% (19/56) in the monotherapy group and 45% (23/51) in the combination therapy group (p=0.018). By week 104, HBeAg seroconversion occurred in 20% of monotherapy and 13% of combination therapy patients. Both regimens were well tolerated. CONCLUSIONS Lower rates of resistance to lamivudine, lower serum HBV DNA levels and higher rates of ALT normalization were seen in the combination therapy group after two years. However, serological outcomes were similar.
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29
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Gallego A, Sheldon J, García-Samaniego J, Margall N, Romero M, Hornillos P, Soriano V, Enrĺquez J. Evaluation of initial virological response to adefovir and development of adefovir-resistant mutations in patients with chronic hepatitis B. J Viral Hepat 2008. [PMID: 18221300 DOI: 10.1111/j.1365-2893.2008.00966.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The aims of the present study were to assess initial virological response (IVR) to adefovir (ADV) treatment for chronic hepatitis B, to identify patients with suboptimal response and to determine the incidence of ADV-resistant mutants. All patients treated with ADV for at least 12 months were evaluated for virological response and ADV resistance. IVR was defined as a reduction > or = 4 log10 IU/mL in hepatitis B virus (HBV)-DNA at month 6. Forty-two patients were analysed. Mean treatment duration was 23 +/- 7 months; 50% had prior lamivudine (LAM) therapy (LAM resistance 62%); 88% were hepatitis B e antigen (HBeAg)-negative; and 76% carried genotype D. IVR was seen in 40.5% of patients. Higher baseline ALT level was the only factor associated with IVR (P = 0.043). Patients with IVR achieved undetectable HBV-DNA at month 12 in 77% of cases compared with only 5% of those without IVR (P < 0.001). Five (12%) patients developed ADV-resistant mutations: rtN236T in four cases and one case with an rtV207L change, which has not been previously reported. This mutation was accompanied by viral rebound and alanine aminotransferase (ALT) flare. The cumulative probability of ADV-resistant mutations at 12 and 24 months was 5% and 17% respectively. IVR defined as a reduction > or = 4 log10 IU/mL in HBV-DNA at month 6 is a useful tool to predict virological response at month 12 and to identify patients with suboptimal response to ADV. Cumulative probability of ADV resistance is higher than previously reported for nucleos(t)ide-naïve patients.
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Affiliation(s)
- A Gallego
- Gastroenterology Department, Hospital Sta. Creu i St. Pau, Barcelona
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Gwak GY, Huh W, Lee DH, Choi MS, Lee JH, Koh KC, Kim SJ, Joh JW, Oh HY. The incidence and clinical outcome of YMDD mutants in hepatitis B surface antigen-positive renal allograft recipients after prolonged lamivudine therapy. Transplant Proc 2008; 39:3121-6. [PMID: 18089336 DOI: 10.1016/j.transproceed.2007.06.081] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2007] [Revised: 04/16/2007] [Accepted: 06/21/2007] [Indexed: 12/28/2022]
Abstract
Although lamivudine (LAM) is a potent inhibitor of hepatitis B virus (HBV), prolonged therapy may induce the development of LAM-resistant strains, YMDD mutants. Although YMDD mutants have impaired replication that leads to a benign clinical course compared with wild-type virus, some immunosuppressive agents may enhance replication of YMDD mutants, causing a severe hepatitis flare. We retrospectively investigated the incidence and clinical outcomes of YMDD mutants in renal allograft recipients on immunosuppressive treatment. Clinical records of 25 renal allograft recipients, who underwent renal transplantation between December 1997 and February 2006 were hepatitis B surface antigen positive at the time of transplantation, were reviewed. All patients received LAM treatment after renal transplantation. Over 9 to 98 months of follow-up, 16 patients (64.0%) maintained undetectable HBV DNA levels; however, 9 patients (36.0%) showed persistent or increased levels of HBV DNA. Seven were identified as having developed YMDD mutants. Although genotypic analysis was not performed, YMDD mutants were strongly suspected in another two patients, who developed severe hepatic dysfunction combined with high levels of HBV viremia at close to 2 years of LAM therapy. One patient recovered after hepatic transplantation and another patient died of hepatic failure. In conclusion, the incidence of YMDD mutants was similar to that of nonimmunosuppressed individuals; however, the presence of these mutants made it more likely for severe liver disease to develop in renal transplant recipients. Therefore, close monitoring for the development of YMDD mutants should be performed during LAM treatment, especially in this group of patients.
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Affiliation(s)
- G-Y Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Martyak LA, Taqavi E, Saab S. Lamivudine prophylaxis is effective in reducing hepatitis B reactivation and reactivation-related mortality in chemotherapy patients: a meta-analysis. Liver Int 2008; 28:28-38. [PMID: 17976155 DOI: 10.1111/j.1478-3231.2007.01618.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Hepatitis B viral (HBV) reactivation in patients undergoing chemotherapy is associated with significant morbidity and mortality. Lamivudine has been suggested to be useful as a prophylaxis for HBV reactivation; however, its impact on overall survival and HBV reactivation-related liver disease survival is unclear. OBJECTIVE To determine the effect of lamivudine prophylaxis on the rate of HBV reactivation, overall survival and HBV reactivation-related survival in patients with HBV undergoing chemotherapy. METHODS A comprehensive search of MEDLINE, Cochrane Collaboration Database, reference lists and abstracts from national meetings. Statistical analysis was performed using revman. RESULTS Eleven studies met the defined inclusion criteria and were included in the analysis. Two-hundred and twenty patients received lamivudine prophylaxis and 400 did not receive prophylaxis. Patients given lamivudine prophylaxis had an 87% decrease in HBV reactivation [risk ratio (RR) 0.13, 95% confidence interval (CI), 0.07-0.24] than patients not given prophylaxis [absolute risk reduction (ARR) -0.46, 95% CI, -0.61 to -0.31]. The number needed to treat to prevent one reactivation was 3. The Lamivudine prophylaxis group was also associated with a 70% reduction in reactivation-related mortality (RR 0.30, 95% CI, 0.1-0.94) compared with controls (ARR -0.03, 95% CI, 0.07-0.00). There was a reduction in treatment delays and premature termination of chemotherapy in the lamivudine prophylaxis arm (RR 0.41, 95% CI, 0.27-0.63; ARR -0.33, 95% CI, -0.33 to -0.15). There was no significant heterogeneity in the comparisons. CONCLUSION Lamivudine prophylaxis during chemotherapy is effective in reducing the rate of HBV reactivation, and reactivation-related liver mortality. Patients with lamivudine prophylaxis had less chemotherapy treatment delays and premature termination of their chemotherapy. Few patients need to be treated to prevent reactivation. Patients with HBV undergoing chemotherapy should be started on lamivudine prophylaxis.
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Affiliation(s)
- Lenna A Martyak
- Department of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
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Akyildiz M, Gunsar F, Ersoz G, Karasu Z, Ilter T, Batur Y, Akarca U. Adefovir dipivoxil alone or in combination with lamivudine for three months in patients with lamivudine resistant compensated chronic hepatitis B. Dig Dis Sci 2007; 52:3444-7. [PMID: 17431777 DOI: 10.1007/s10620-006-9718-8] [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: 10/19/2006] [Accepted: 12/03/2006] [Indexed: 12/31/2022]
Abstract
We studied clinical and laboratory effects of 3 months of lamivudine with adefovir combination and adefovir dipivoxil (AD) alone in the treatment of patients with lamivudine-resistant hepatitis B virus (HBV) infection. Eligible patients were hepatitis B surface antigen-positive men and women with compensated liver disease who were given lamivudine at least more than 6 months and had HBV polymerase gene mutation. Patients were assigned to receive adefovir 10 mg/day (Group 1) or adefovir 10 mg once daily and lamivudine 100 mg once daily combination during first 3 months, and then stopped lamivudine and continued adefovir (Group 2). Median age was 48 years (34 males and 20 females, and 35 were HBeAg-negative). Baseline median ALT, AST, and HBV DNA levels were 66 IU/l, 49 IU/l, and 6.7 log(10) copy/ml, respectively. Median adefovir therapy time and ALT normalization time were 9 and 3.5 months, respectively. There was no significant difference between groups according to the baseline HBV DNA, ALT, HBe Ag status, age, gender, and lamivudine resistance time. Virological and biochemical responses were similar in both groups during therapy. Two patients (8%) had ALT flare more than five times upper limit of normal without any clinical decompensation in Group 1. Mild ALT elevation according to baseline levels were found in 8 (27.6%) and 4 (17.4%) patients, respectively, in Group 2 and Group 1, and no statistically significance between two groups. In conclusion, this study showed that it is not necessary to continue lamivudine therapy while switching to AD therapy. Adefovir alone is effective in the treatment of patients with lamivudine resistant HBV infection and compensated liver disease, without significant clinical and laboratory flares. However, it is not easy to say that switching to AD with cessation of lamivudine is safe, because the study population is not enough for precise conclusion and resistance may be a considerable problem against AD in patients using long-term treatment.
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Affiliation(s)
- Murat Akyildiz
- Department of Gastroenterology, Ege University Medical School, Bornova, Izmir, Turkey.
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Akyildiz M, Karasu Z, Zeytunlu M, Aydin U, Ozacar T, Kilic M. Adefovir dipivoxil therapy in liver transplant recipients for recurrence of hepatitis B virus infection despite lamivudine plus hepatitis B immunoglobulin prophylaxis. J Gastroenterol Hepatol 2007; 22:2130-4. [PMID: 18031370 DOI: 10.1111/j.1440-1746.2006.04609.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Treatment of post-transplantation recurrence of hepatitis B virus (HBV) infection despite prophylaxis with hepatitis B immunoglobulin (HBIG) and lamivudine combination therapy is not easy. Because HBV reinfection has a severe course and could result in graft failure in liver transplant recipients, prompt medication is essential. Herein is reported the authors' experience with adefovir dipivoxil (AD) therapy in 11 liver transplant recipients who had HBV reinfection despite the administration of lamivudine and HBIG. METHOD Two-hundred and nine patients underwent liver transplantation (100 deceased donor liver transplantations [DDLT], 109 living donor liver transplantation [LDLT]) due to chronic hepatitis B infection between April 1997 and May 2005 in Ege University Medical School, Liver Transplantation Unit. Patients had prophylaxis with lamivudine and low-dose HBIG combination after liver transplantation. Treatment of recurrence consisted of AD 10 mg once a day and lamivudine 300 mg/daily and HBIG was discontinued in those patients. RESULTS In total there were 11 HBV recurrences: five occurred in DDLT recipients and six in LDLT recipients, at a median follow up of 18 months (range, 6-48 months). In one of 11 patients, pretransplant HBV-DNA and HBeAg were positive. Three patients had a severe course and one patient had fibrosing cholestatic hepatitis. After AD treatment, HBV-DNA level decreased in all patients and became negative in seven patients. Two patients died due to hepatocellular carcinoma recurrence after 12 and 14 months of follow up. Serum creatinine level increased mildly in one patient and no other side-effect was observed, and all patients continued therapy. CONCLUSION Adefovir dipivoxil is a safe, effective treatment option for post-transplant HBV recurrence even among patients with fibrosing cholestatic hepatitis caused by lamivudine-resistant HBV.
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Affiliation(s)
- Murat Akyildiz
- Department of Gastroenterology, Ege University Medical School, Bornova, Izmir, Turkey.
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Gérolami R, Borentain P, Colson P, Norguet E, Gérolami A, Tamalet C. Efficacy of hepatitis B virus (HBV) vaccination in treating lamivudine-resistant HBV reactivation following hepatitis B surface antigen seroconversion. Liver Int 2007; 27:1417-21. [PMID: 18036104 DOI: 10.1111/j.1478-3231.2007.01541.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: 02/13/2023]
Abstract
BACKGROUND HBsAg vaccination might help to control HBV replication following nucleos(t)ide analog therapy. We tested HBsAg vaccine in a patient who developed lamivudine resistance. PATIENT AND RESULTS An HBeAg negative HBV chronically-infected patient developed HBsAg seroconversion after 3 years of treatment by lamivudine. However, the control of HBV replication was transient and HBV DNA could be detected in the serum one year after lamivudine was stopped. Concurrently, the anti-HBs antibodies (HBsAb) titre had decreased from more than 100 IU/L to 23 IU/L. Due to the presence of rtM204V resistance mutation, lamivudine was not reintroduced and the patient was treated by HBsAg vaccination. After three injections, HBV DNA was no more detectable and the HBsAb titre reached more than 200 IU/L. CONCLUSION This observation suggests that a regular follow up of patients presenting HBsAg seroconversion following lamivudine therapy is necessary. In these patients, a low titre of HBsAb may not prevent from lamivudine-resistant HBV reactivation. Evaluation of HBsAg vaccination to maintain HBsAb at a high titre in these patients deserves further studies.
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Affiliation(s)
- René Gérolami
- Service d'Hépato-gastroentérologie, Centre Hospitalier Universitaire Conception, Marseille, France.
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Therapeutic strategies in the management of patients with chronic hepatitis B virus infection. THE LANCET. INFECTIOUS DISEASES 2007; 8:167-78. [PMID: 18053766 DOI: 10.1016/s1473-3099(07)70264-5] [Citation(s) in RCA: 156] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Currently available options for the treatment of chronic hepatitis B virus (HBV) infection include standard and pegylated interferon alfa and four oral antiviral agents (lamivudine, adefovir, entecavir, and telbivudine). These treatment strategies are either therapies of finite duration that aim to achieve sustained off-therapy responses, or long-term treatments that aim to maintain on-therapy remission. Pegylated interferon alfa may offer higher sustained off-therapy responses after 1 year, but most patients do not respond. Oral antivirals are the only candidates for long-term treatment of patients with chronic HBV infection. Viral suppression has favourable effects on patients' outcome and modifies the natural history of the disease. Viral resistance is the main drawback of long-term antiviral therapy. Lamivudine monotherapy is associated with higher resistance (year 1, 10-27%; year 2, 37-48%; year 4, 60-65%) than adefovir (year 1, 0%; year 2, 3%; year 5, 29%) or telbivudine (year 1, 3-4%; year 2, 9-22%). Entecavir resistance is rare in naive individuals (year 4, <1%), but increases over time in lamivudine-resistant patients (year 4, 43%). The best strategy for long-term therapy in chronic HBV infection has yet to be established.
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Lim SG, Marcellin P, Tassopoulos N, Hadziyannis S, Chang TT, Tong M, Sievert W, Hu P, Arterburn S, Brosgart CL. Clinical trial: effects of adefovir dipivoxil therapy in Asian and Caucasian patients with chronic hepatitis B. Aliment Pharmacol Ther 2007; 26:1419-28. [PMID: 17983369 DOI: 10.1111/j.1365-2036.2007.03506.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Two-thirds of the 350 million people infected with chronic hepatitis B virus live in the Asia-Pacific region. AIM To compare the effects of adefovir dipivoxil therapy between Asian and Caucasian patients with chronic hepatitis B. METHODS The safety and efficacy of 10 mg of adefovir dipivoxil was compared to placebo in 501 Asian (n = 259) or Caucasian (n = 242) HBeAg+ and HBeAg- chronic hepatitis B virus patients treated for 48 weeks in two randomized, double-blind, placebo-controlled studies. RESULTS At week 48, histological improvement was observed in 60% and 56% of Caucasian and Asian patients, respectively. Change in serum hepatitis B virus DNA from baseline to week 48 for the adefovir dipivoxil-treated patients was -3.89 and -3.70 log(10) copies/mL in Caucasian and Asian patients, respectively, while 34 per cent of Caucasian patients and 39 per cent of Asian patients had undetectable serum hepatitis B virus DNA (<400 copies/mL) at week 48. The percentage of patients achieving alanine aminotransferase (ALT) normalization at week 48 was similar in both groups (Caucasian 64 per cent, Asian 63 per cent). No patients developed resistance through week 48. No differences in adverse events or grade 3 or 4 laboratory abnormalities were observed between groups. CONCLUSIONS There were no significant differences in treatment response between Asians and Caucasians. Adefovir dipivoxil was well tolerated and no resistance developed up to week 48 in both racial groups.
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Affiliation(s)
- S G Lim
- National University Hospital, Singapore.
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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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Seo YS, Kim JH, Yeon JE, Park JJ, Kim JS, Byun KS, Bak YT, Lee CH. Antiviral efficacy of adefovir dipivoxil versus lamivudine in patients with chronic hepatitis B sequentially treated with lamivudine and adefovir due to lamivudine resistance. World J Gastroenterol 2007; 13:4072-9. [PMID: 17696224 PMCID: PMC4205307 DOI: 10.3748/wjg.v13.i30.4072] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare the antiviral efficacy of adefovir (ADV) in lamivudine (LMV)-resistant patients with LMV treatment in nucleoside-naïve patients, using serum samples collected sequentially during the course of treatment progressing from LMV to ADV.
METHODS: Forty-four patients with chronic hepatitis B (CHB) were included. The patients were initially treated with LMV and then switched to ADV when LMV resistance developed. Antiviral efficacy was assessed by measuring the following: reduction in serum HBV DNA from baseline, HBV DNA negative conversion (defined as HBV DNA being undectable by the hybridization assay), and HBV DNA response (either HBV DNA level ≤ 105 copies/mL or a ≥ 2 log10 reduction from baseline HBV DNA level).
RESULTS: After two and six months of treatment, HBV DNA reduction was greater with LMV compared to ADV treatment (P = 0.021). HBV DNA negative conversion rates were 64% and 27% after one month of LMV and ADV treatment respectively (P = 0.001). Similarly, HBV DNA response rates were 74% and 51% after two months of LMV and ADV treatment respectively (P = 0.026).
The time taken to HBV DNA negative conversion and to HBV DNA response were both delayed in ADV treatment compared with LMV.
CONCLUSION: The antiviral efficacy of ADV in LMV-resistant patients is slower and less potent than that with LMV in nucleoside-naïve patients during the early course of treatment.
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Affiliation(s)
- Yeon Seok Seo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
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Rizzetto M, Zoulim F. Viral Hepatitis. TEXTBOOK OF HEPATOLOGY 2007:819-956. [DOI: 10.1002/9780470691861.ch9a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Hosaka T, Suzuki F, Suzuki Y, Saitoh S, Kobayashi M, Someya T, Sezaki H, Akuta N, Arase Y, Ikeda K, Kumada H. Factors associated with the virological response of lamivudine-resistant hepatitis B virus during combination therapy with adefovir dipivoxil plus lamivudine. J Gastroenterol 2007; 42:368-74. [PMID: 17530361 DOI: 10.1007/s00535-007-2008-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2007] [Accepted: 01/17/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND The aim of this study was to investigate the factors associated with the response of lamivudine-resistant hepatitis B virus (HBV) during combination therapy with adefovir dipivoxil plus lamivudine. METHODS Sixty-three patients with breakthrough hepatitis received a 10-mg once-daily dose of oral adefovir dipivoxil. RESULTS The rates of undetectable serum HBV-DNA were 49.2% after 24 weeks, 61.9% after 48 weeks, and 67.2% after 72 weeks. The cumulative hepatitis B e antigen (HBeAg) loss rates in patients with alanine aminotransferase (ALT) levels of more than twice the upper limit of normal (ULN) were significantly higher than in patients with ALT less than twice the ULN (P = 0.0145). Multivariate analysis revealed that baseline ALT level (P = 0.003) and HBeAg status (P = 0.049) were associated with early virological response. CONCLUSIONS Baseline ALT level was associated with HBeAg loss and seroconversion, and baseline ALT level and HBeAg status were associated with the virological response of lamivudine-resistant HBV during combination therapy with adefovir dipivoxil plus lamivudine.
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Affiliation(s)
- Tetsuya Hosaka
- Department of Gastroenterology, 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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Abstract
Chronic hepatitis B virus infection afflicts 400 million people worldwide and untreated will progress to cirrhosis in 15-40% of individuals, with an associated increased risk for the development of hepatocellular carcinoma. The 'inactive carrier state' carries a benign prognosis with a very low risk of cirrhosis or hepatocellular carcinoma. However, the hepatitis B e antigen (HBeAg)-positive chronic hepatitis state is an active disease state with increased risk for progressing to cirrhosis and hepatocellular carcinoma. The HBeAg-negative mutant variety of chronic hepatitis B has been associated with a higher incidence of cirrhosis at initial presentation and more frequent progression to hepatocellular carcinoma compared with the wild-type hepatitis B. Five medications are currently approved by the US FDA for the treatment of chronic hepatitis B: interferon-alpha, lamivudine, adefovir dipivoxil, entecavir and peginterferon-alpha-2a. Interferon-alpha therapy has been shown to increase the rate of HBeAg and hepatitis B DNA loss with a small chance of hepatitis B surface antigen loss, but has significant adverse effects and is ineffective against the HBeAg-negative mutant. Lamivudine is a safely used, orally administered drug with good efficacy, but is associated with the development of a lamivudine-resistant (Lam-R) mutant in a large proportion of patients after long-term therapy. High relapse rates after lamivudine therapy make this medication less effective in the HBeAg-negative mutant also. Adefovir dipivoxil is a safely used, orally administered drug, which is effective against the Lam-R mutant. Adefovir dipivoxil is effective against the wild-type and HBeAg-negative hepatitis B and has a very low incidence of resistance development. Entecavir is a highly potent and selective new oral drug against hepatitis B. It has demonstrated no resistance development in treatment-naive patients, but a low incidence of resistance in patients infected with prior Lam-R mutants. Peginterferon-alpha-2a is administered once weekly and has improved efficacy compared with standard interferon-alpha and lamivudine. However, it has a similar adverse-effect profile to standard interferon-alpha. Pharmacoeconomic studies have demonstrated a cost benefit in treating chronic hepatitis B patients compared with no therapy. However, results have been conflicting, with earlier studies showing a cost advantage of lamivudine over interferon-alpha and a more recent, comprehensive study favouring interferon-alpha monotherapy in HBeAg-negative patients and adefovir dipivoxil 'salvage' after lamivudine resistance development in HBeAg-positive patients.
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Affiliation(s)
- Steven-Huy B Han
- David Geffen School of Medicine at UCLA, Los Angeles, California 90095-7302, USA.
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Karatayli E, Karayalçin S, Karaaslan H, Kayhan H, Türkyilmaz AR, Sahin F, Yurdaydin C, Bozdayi AM. A novel mutation pattern emerging during lamivudine treatment shows cross-resistance to adefovir dipivoxil treatment. Antivir Ther 2007; 12:761-768. [PMID: 17713159 DOI: 10.1177/135965350701200509] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
AIMS This study was conducted to clarify the resistance profile of a novel mutation pattern emerging during lamivudine (3TC) therapy and showing cross-resistance to adefovir dipivoxil (ADV) in a patient with chronic hepatitis B. METHODS AND RESULTS Successful suppression of hepatitis B virus (HBV) replication by sequential therapy of 9 MU thrice weekly interferon (IFN) and 3TC was followed by genotypical resistance detected at month 28 of therapy (month 19 of lamivudine treatment). ADV was added to 3TC therapy on month 44 of antiviral treatment. Neither alanine aminotransferase normalization nor a stable decrease in HBV viral load was observed, although ADV was used for more than 40 months. The HBV pol region was amplified from serum samples obtained before and after ADV treatment. The complete genome was cloned into a TA vector. PCR products and 7-10 clones from each cloned vector were sequenced. A novel mutation, A181S, in the reverse transcriptase gene leading to a conversion of W172C in the overlapping surface antigen gene was detected along with a M2041 mutation. The complete genome comprising the A181S+M2041 pattern was cloned into an expression vector and its in vitro susceptibility to 3TC, ADV, tenofovir (PMPA), clevudine (L-FMAU) and emtricitabine (FTC) were determined in transiently transfected Huh7 cells. This mutation pattern displayed more than 1000-fold resistance to the nucleoside analogues 3TC and FTC and approximately sixfold resistance to L-FMAU, while it confers 28.23- and 5.57-fold resistance for the nucleotide analogues ADV and PMPA, respectively. CONCLUSION A new mutation pattern, A181S+M2041, arising under lamivudine treatment confers cross-resistance to ADV both in vivo and in vitro.
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Peters MG, Andersen J, Lynch P, Liu T, Alston-Smith B, Brosgart CL, Jacobson JM, Johnson VA, Pollard RB, Rooney JF, Sherman KE, Swindells S, Polsky B. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology 2006; 44:1110-6. [PMID: 17058225 PMCID: PMC4114764 DOI: 10.1002/hep.21388] [Citation(s) in RCA: 129] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is an important cause of morbidity and mortality in subjects coinfected with HIV. Tenofovir disoproxil fumarate (TDF) and adefovir dipivoxil (ADV) are licensed for the treatment of HIV-1 and HBV infection, respectively, but both have in vivo and in vitro activity against HBV. This study evaluated the anti-HBV activity of TDF compared to ADV in HIV/HBV-coinfected subjects. ACTG A5127 was a prospective randomized, double-blind, placebo-controlled trial of daily 10 mg of ADV versus 300 mg of TDF in subjects with HBV and HIV coinfection on stable ART, with serum HBV DNA >/= 100,000 copies/mL, and plasma HIV-1 RNA </= 10,000 copies/mL. This study closed early based on results of a prespecified interim review, as the primary noninferiority end point had been met without safety issues. Fifty-two subjects were randomized. At baseline, 73% of subjects had a plasma HIV-1 RNA < 50 copies/mL, 86% were HBeAg positive, 94% were 3TC resistant, median serum ALT was 52 IU/L, and 98% had compensated liver disease. The mean time-weighted average change in serum HBV DNA from baseline to week 48 (DAVG(48)) was -4.44 log(10) copies/mL for TDF and -3.21 log(10) copies/mL for ADV. There was no difference in toxicity between the 2 treatment arms, with 11 subjects (5 ADV and 6 TDF) experiencing elevations of serum ALT on treatment. In conclusion, over 48 weeks, treatment with either ADV or TDF resulted in clinically important suppression of serum HBV DNA. Both drugs are safe and efficacious for patients coinfected with HBV and HIV.
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Affiliation(s)
- Marion G Peters
- University of California, San Francisco, San Francisco, CA, USA.
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Wen R, Wang J, Chen M, Yan M. Chinese medicine Jiangganlong combined with anti-virus medicine in long-term treatment of active liver cirrhosis and its effect on prognosis of patients. Shijie Huaren Xiaohua Zazhi 2006; 14:2860-2864. [DOI: 10.11569/wcjd.v14.i29.2860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the efficacy of Chinese medicine Jiangganlong combined with anti-virus medicine in the treatment of active liver cirrhosis (ALC).
METHODS: A total of 114 ALC patients were divided into treatment group and control group, named A and B, respectively. The patients in group A were treated with Jiangganlong and lamivudine (LAM). Jiangganlong decoction or pills were given a dose every three days, or 4.0 g (tid). LAM was administered 0.1 g per day. After the emergence of YMDD variations, adefovir (ADV) was added. LAM was stopped when HBV DNA YMDD variation became negative. The patients in group B received general and symptomatic treatment. The mean treatment therapeutic time was 36 months.
RESULTS: The rates of negative conversion for the serum HBV DNA were 75.4% (43/57) and 3.5% (2/57) in group A and B, respectively, and there was significant difference between them (P < 0.01). The cumulative rate of YMDD variations among patients of group A was 40.4% (23/57). After the emergence of YMDD variations, 20 patients received ADV treatment, 90% (18/20) of which were found YMDD variation-negative; there were 3 patients who did not receive ADV treatment, and they died of liver failure. The negative conversion rates of HBeAg were 44.4% (16/36), 16.7% (5/30) in group A, B, respectively, and there was marked difference between them (P < 0.05). The total bilirubin (TBIL) and alanine aminotransferase (ALT) returned to the normal level, and the albumin level, Child-Pugh score, and decompensation status were improved in group A. The rate of complications was dramatically lower in group A than that in group B [14.0% (8/57) vs 50.8% (29/57), P < 0.01]. The mortality rate was also decreased in group A as compared with that in group B [7.0% (4/57) vs 29.8% (17/57), P < 0.01], while the survival time was notably prolonged (3.3 ± 2.1 year vs 1.1 ± 1.0 year, P < 0.01).
CONCLUSION: Chinese medicine Jiangganlong combined with anti-virus medicine can inhibit the replication of HBV DNA, ameliorate liver function, decrease the rate of complications, reduce the mortality rate, and prolong the survival time as well as improve the prognosis of ALC patients.
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Thibault V. Where does adefovir stand amongst newly developed antivirals: from pharmacology to virology. Future Virol 2006. [DOI: 10.2217/17460794.1.5.553] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Adefovir, an acyclic nucleotide analog of adenosine monophosphate, has demonstrated potent activities against several viruses in vitro. Since 2002, the diester prodrug of this molecule, adefovir dipivoxil, has been approved as a well-tolerated and efficacious treatment for chronic hepatitis B. It is the first nucleotide analog to be approved for this indication and it is now challenged by several other molecules that also inhibit hepatitis B virus replication. In this article, we analyze the strengths and limitations of adefovir in the context of hepatitis B treatment and consider the other alternatives in the treatment of this difficult-to-treat chronic disease. Adefovir dipivoxil has offered a real opportunity for patients who developed lamivudine resistance and were facing a therapeutic deadlock; the next challenge for clinicians will be to offer the best therapeutic strategy to limit the inexorable selection of resistant strains.
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Affiliation(s)
- Vincent Thibault
- Laboratoire de Virologie, EA 2387, CERVI, Groupe Hospitalier Pitié-Salpêtrière (AP-HP), 91 Boulevard de l’Hôpital 75013 Paris, France
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Delaney WE, Ray AS, Yang H, Qi X, Xiong S, Zhu Y, Miller MD. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob Agents Chemother 2006; 50:2471-7. [PMID: 16801428 PMCID: PMC1489769 DOI: 10.1128/aac.00138-06] [Citation(s) in RCA: 193] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Tenofovir is an acyclic nucleotide analog with activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). Tenofovir disoproxil fumarate (tenofovir DF), a bis-alkoxyester prodrug of tenofovir, is approved for the treatment of HIV and is currently being developed to treat chronic hepatitis B. In this report, we further characterize the in vitro activity of tenofovir against HBV as well as its metabolism in hepatic cells. We show that tenofovir is efficiently phosphorylated to tenofovir diphosphate (TFV-DP) in both HepG2 cells and primary human hepatocytes. TFV-DP has a long intracellular half-life (95 h) and is a potent and competitive inhibitor of HBV polymerase (Ki = 0.18 microM). Tenofovir has a 50% effective concentration of 1.1 microM against HBV in cell-based assays, and potency is improved > 50-fold by the addition of bis-isoproxil progroups. Tenofovir has previously demonstrated full activity against lamivudine-resistant HBV in vitro and clinically. Here we show that the major adefovir resistance mutation, rtN236T, confers three- to fourfold-reduced susceptibility to tenofovir in cell culture; the clinical significance of this susceptibility shift has not yet been determined. The rtA194T HBV polymerase mutation recently identified in tenofovir DF-treated HIV/HBV-coinfected patients did not confer in vitro resistance to tenofovir as a single mutation or in a lamivudine-resistant viral background. Overall, the antiviral and metabolic profile of tenofovir supports its development for the treatment of chronic hepatitis B.
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Affiliation(s)
- William E Delaney
- Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
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Zeng M, Mao Y, Yao G, Wang H, Hou J, Wang Y, Ji BN, Chang CNP, Barker KF. A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B. Hepatology 2006; 44:108-16. [PMID: 16799983 DOI: 10.1002/hep.21225] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Four hundred and eighty Chinese subjects with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) were enrolled in a multicenter, double-blind, randomized, placebo-controlled study of adefovir dipivoxil (ADV) 10 mg once daily. There was a significant difference in reduction of serum hepatitis B virus (HBV) DNA after 12 weeks between subjects who received ADV and those who received the placebo (3.4 and 0.1 log10 copies/mL, respectively, P < .001). Further reductions in serum HBV DNA and increases in the proportion of subjects with an HBV DNA level of at most 10(5) copies/mL, with HBV DNA undetectable, and with ALT normalization were observed in ADV-treated subjects at week 52 (median HBV DNA reduction of 4.5 log(10) copies/mL, 67% with HBV DNA <or= 10(5) copies/mL, 28% with HBV DNA undetectable, and 79% with ALT normalization). Subjects who initially received ADV lost some treatment benefit after being rerandomized to the placebo in week 40. Subjects with YMDD mutant HBV at baseline had virological, biochemical, and serological responses to treatment that were similar to those of subjects with wild-type HBV. The incidence of clinically adverse events was similar in nature and severity between the treatment groups, and there was no evidence of renal toxicity. No adefovir-related HBV mutations were identified. In conclusion, treatment with ADV 10 mg daily over 52 weeks was safe and effective in Chinese subjects with HBeAg-positive CHB and did not lead to the emergence of drug resistance. The study is continuing for an additional 4 years with all subjects on open-label ADV 10 mg daily.
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Lee YS, Suh DJ, Lim YS, Jung SW, Kim KM, Lee HC, Chung YH, Lee YS, Yoo W, Kim SO. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology 2006; 43:1385-91. [PMID: 16729316 DOI: 10.1002/hep.21189] [Citation(s) in RCA: 254] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Although adefovir dipivoxil (ADV) has a unique profile of delayed and infrequent resistance in treatment-naïve chronic hepatitis B patients, the association of ADV resistance with previous lamivudine (LAM) resistance is not well understood. We compared the emergence of the ADV-resistant mutations rtA181V/T and rtN236T between LAM-resistant patients and treatment-naïve patients at 48 weeks of ADV monotherapy. Fifty-seven LAM-resistant patients and 38 treatment-naïve patients were treated with 10 mg/d ADV for more than 48 weeks. Both baseline and 48-week blood samples were analyzed for ADV-resistant mutations via restriction fragment mass polymorphism analysis. Antiviral responses were evaluated according to changes in serum HBV DNA (measured via real-time polymerase chain reaction) and alanine aminotransferase (ALT) levels and loss of hepatitis B e antigen (HBeAg). After 48 weeks, 10 (18%) of the 57 LAM-resistant patients were found to have developed ADV-resistant mutations, whereas none of the 38 treatment-naïve patients developed such mutations (P < .01). Among LAM-resistant patients, the reduction in serum HBV DNA levels was significantly lower in patients with ADV-resistant mutations than in those without such mutations (-1.04 vs. -2.63 log10 copies/mL) (P = .01). However, the rates of serum ALT normalization (60% vs. 55%) and HBeAg loss (14% vs. 21%) were not significantly different between the 2 groups (P > .05). In conclusion, the emergence of the rtA181V/T and rtN236T mutations was more common in LAM-resistant patients than in treatment-naïve patients after 48 weeks of ADV therapy and was associated with reduced antiviral efficacy to drug treatment.
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Affiliation(s)
- Yoon-Seon Lee
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
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Abstract
The worldwide burden of hepatitis B mandates accurate and timely diagnosis of patients infected with the hepatitis B virus (HBV) and the use of treatment strategies derived from evidence-based guidelines. HBV is a DNA virus that produces a series of viral protein products circulating HBV DNA. Serologic and nucleic acid testing are critical to disease prevention and treatment objectives. Information from such testing helps determine patients' infectivity and immune status, appropriate monitoring strategies, and the efficacy of treatment, as well as providing data that contributes to a better understanding of the natural history and epidemiology of the disease. This article reviews the clinical use of state-of-the-art serologic and nucleic acid tests, including the relevance of hepatitis B e antigen and antibody and HBV DNA measurements as markers of disease activity. Viral load can be used to distinguish between active and inactive disease, define response to therapy, and detect the development of antiviral resistance. Some recent reports have suggested that high viral load is associated with poorer patient outcomes (eg, more rapid progression to cirrhosis and a higher incidence of hepatocellular carcinoma). Durable suppression of HBV DNA is evolving to become the primary goal of therapy, although all currently licensed medications have used histology as the primary end point of therapy. Suggested frequencies for HBV DNA monitoring are presented.
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Affiliation(s)
- Robert G Gish
- Division of Hepatology and Complex GI, Physician Foundation, California Pacific Medical Center, San Francisco, California, USA.
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