SORRY! You may do this one, pretty good article...
Highlights in Hepatitis B Therapy -- Clinical Efficacy and Patterns of Viral Resistance
B型肝炎治疗会议文献——临床效益和病毒模式
George V. Papatheodoridis, MD
Boston, Massachusetts; Monday, November 1, 2004 -- Researchers and clinicians from all over the world presented many exciting original studies during this year’s meeting of the American Association for the Study of Liver Diseases. The management of chronic hepatitis B, which is a rapidly evolving field in hepatology, was the main focus of several emerging presentations. This commentary explores the key issues of these clinically important reports on the management of chronic hepatitis B, as presented during the core meeting proceedings.
马萨诸塞州,波士顿,2004年11月1日星期一,来自全球的临床医师和研究人员在今年的美国肝脏疾病研究协会的会议提出很多令人激动的新颖研究。慢性B型肝炎的处理, 这在肝脏病学里将是一个迅速逐步形成的领域, 介绍几个独特的主要焦点。会议核心审理评论探讨临床医生处理关于慢性乙型肝炎重要报告的关键问题。
Clinical Efficacy
临床效应
The development and approval of oral anti-hepatitis B virus (HBV) agents, lamivudine, and more recently adefovir dipivoxil, revolutionized the treatment of chronic hepatitis B and has offered effective therapeutic options for almost all patients with this disease. In addition to these 2 drugs, several newer agents are currently under evaluation, but today’s sessions only included the results of 2 studies on the clinical efficacy of anti-HBV agents, and therefore this commentary will address these reports.
正式批准用于治疗病毒性B肝(HBV)的药物,拉米夫定,和近期的阿德福韦,绝大部分B型慢性肝炎可在临床治疗上提示有效。
另外两只药,NEWER AGENTS仍在评估,但当日会议仅包括在抗-HBV的 2项研究的结果临床效应?(什么意思)因此这项评估加入报告。
Shouval and colleagues[1] presented the results of a 48-week, phase 3 trial of entecavir vs lamivudine in 648 patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. Entecavir (0.5 mg/day) compared with lamivudine (100 mg/day) was associated with more frequent histologic improvement (70% vs 61%; P = .014), greater reductions in serum HBV-DNA < 400 copies/mL (91% vs 73%; P < .0001), and with achievement of the composite endpoint (HBV-DNA < 700,000 Eq/mL and alanine aminotransferase [ALT] normalization [84% vs 78%; P = .04]). There was similar fibrosis improvement (36% vs 38%, entecavir vs lamivudine, respectively) among both treatment groups. No resistance to entecavir was detected. Thus, entecavir appears to offer a benefit over lamivudine in the treatment of HBeAg-negative chronic hepatitis B.
HOUVAL 和其同事提供一项48周的结果,在648位B型慢性肝炎,E抗原 (HBeAg)阴性患者的恩卡韦对拉米夫定的三个试药状态。恩卡韦每天0。5MG联合拉米夫定每天100MG发生组织改善,(70%VS61%),血清HBV-DNA < 400 copies/mL (91% vs 73%; P < .0001), 复合的终点?结果(HBV-DNA < 700,000 Eq/mL以及ALT正常。[84% vs 78%; P = .04]). 纤维化改善(36% vs 38%,分别为恩卡韦VS拉米夫定,)没有发现恩卡韦抗药性,因此,恩卡韦在B型慢性肝炎E抗原阴性治疗上有效益于拉米夫定。
Adefovir has been approved for the treatment of chronic hepatitis B in western countries, but is not yet approved in China. The initial results of a 5-year controlled trial of this agent in 480 Chinese patients with HBeAg-positive chronic hepatitis B were reported by Zeng and colleagues.[2] At 12 months, treatment with adefovir (10 mg/day) achieved reductions in serum HBV-DNA by 4.5 log10 copies/mL; HBV-DNA response (< 100,000 copies/mL) was achieved in 98% of patients, and ALT normalization was achieved in 79% of patients. Thus, the efficacy of adefovir was confirmed in Chinese patients with chronic hepatitis B, a population that is considered to represent a difficult-to-treat HBV clinical setting.
阿德福韦已在西方国家批准用于治疗慢性B型肝炎,但在中国仍未被核准。Zeng 和 同事的最初5年在480位中国B型慢性肝炎E抗原阳性患者试验结果报告上。阿德福韦每天10MG,治疗12个月,血清HBV DNA减少达到4.5 log10 copies/mL,患者HBV DNA应答达98%,ALT复常达79%,因此,证实阿德福韦对中国B型慢性肝炎患者有效。
Issues in HBV Resistance
The primary disadvantage of antiviral agents is that they have to be administered for long periods. In particular, in HBeAg-negative chronic hepatitis B, antiviral agents may have to be given indefinitely in order to maintain on-therapy remission, because relapses are observed in the majority of patients who discontinue treatment. Any form of long-term antiviral therapy, however, may be associated with development of viral resistance. The problem of resistance is very frequent and progressively increases with prolongation of lamivudine therapy (> 50% at 3 years), but is infrequent with adefovir therapy (approximately 6% at 3 years). Because emergence of resistant HBV mutants is the main factor limiting the efficacy of antiviral therapy, many investigators focus on the elucidation of this clinical issue.
In this setting, resistance to adefovir has been associated with emergence of the rtN236T or rtA181V mutation in the HBV polymerase gene, but the effects of these mutations on viral sensitivity have not been clarified. Locarnini and colleagues[3] used site-directed mutagenesis and created a panel of HBV mutants containing rtN236T or rtA181V with either wild or mutant (G1896 stop codon mutation) precore region. Both mutations caused small decreases in sensitivity to adefovir; the rtN236T mutation decreased sensitivity by 6.7-fold irrespective of the precore region and the rtA181V mutation by 1.6-fold in precore wild, and by 3.6-fold in precore mutant strains. All of these HBV strains remained relatively sensitive to lamivudine or tenofovir, with the rtN236T precore mutant strain being the least sensitive.
Bartholomeusz and colleagues[4] analyzed the mechanism of adefovir resistance using molecular modeling and in vitro functional analysis. They showed that adefovir resistance mutations clustered into 3 regions of the polymerase gene (D and A, B, C-D domain), which have differential effects on the structure of the HBV polymerase and its interaction with adefovir. All of these observations are expected to assist the clinician in selecting new and more effective anti-HBV agents.
Cross-resistance to lamivudine and adefovir has not been detected to date. To investigate the possibility of the emergence of an HBV strain with polymerase mutations conferring resistance to both of these agents, Brunelle and colleagues[5] constructed an HBV strain harboring the L180M+M204V+N236T mutations, which demonstrated resistance to both lamivudine and adefovir in vitro. In addition, they reported that they isolated such an HBV strain from a liver transplanted patient who had been treated with combination adefovir plus lamivudine for 42 months after development of lamivudine resistance. Based on these findings, it appears that multiple drug resistance may emerge more frequently in the future, with the more wide and prolonged use of combination therapies.
M204V or M204I and L180M are the most common HBV mutations associated with lamivudine resistance. In an in vitro study, Delaney and colleagues[6] determined the cross-resistance profiles of lamivudine, adefovir, and a number of other currently evaluated antiHBV agents. All L-nucleoside analogues (lamivudine and the unapproved/investigational agents [for HBV indication], emtricitabine, clevudine, L-deoxy-thymidine, L-deoxy-cytidine, L-deoxy-adenosine) demonstrated > 100-fold resistance to all lamivudine-resistant strains, while entecavir demonstrated variable resistance (37- to 471-fold) with M204I strains, exhibiting the greatest fold reduced susceptibility to entecavir. In contrast, acyclic phosphonate nucleotides (adefovir and the unapproved/investigational agents [for HBV indication] tenofovir and alamifovir) showed consistent activity against the wild-type and all patterns of lamivudine-resistant HBV strains.
There are very limited data regarding HBV resistance to entecavir, which was very recently described to be associated with rtM250V +/- I169T or rtT184G + rtS202I mutations of the HBV polymerase. Two sequential reports presented during these meeting proceedings set out to further address this issue. Warner and colleagues[7] showed that the first class of entecavir resistance mutations (rtM204V, rtI169T) affects the interaction between the incoming dNTP and the primer strand of HBV-DNA, whereas the second class (rt T184G, rtS202I) results in altered geometry of the nucleotide binding pocket of the polymerase near the YMDD motif. Moreover, these investigators found that all of these mutations interact cooperatively with the rtM204V/rtI LMV resistance mutation, which may explain the cross-resistance between the 2 agents. In the second study, Tenney and colleagues[8] reported that 4 or more combined mutations were required for maximal entecavir resistance and that such mutations emerged in a small proportion (6%) of chronic hepatitis B patients with preexisting lamivudine resistance treated with entecavir for 48 weeks, whereas no entecavir resistance was detected in 432 treatment-naive chronic hepatitis B patients receiving entecavir for 1 year or more.
Collectively, these data suggest that HBV resistance may affect the efficacy of all antiviral agents if they are given for a long enough period. Therefore, monotherapies, or, most probably, combinations of antiviral agents with potent antiviral efficacy and low resistance profiles, will have priority over other oral antiviral drugs, particularly in patients with advanced liver disease.
Concluding Remarks
It is hoped that the above discussion sheds light on the current challenges facing the physician treating the patient with chronic hepatitis B. Emergence of drug-resistant HBV is an ongoing clinical problem, as evidenced by the many studies presented above, and the path forward will require additional elucidation of these mechanisms to better optimize and individualize therapy.
References
- Shouval D, Lai C-L, Cheinquer H, et al. Entecavir demonstrates superior histologic and virologic efficacy over lamivudine in nucleoside-naive HBeAg(-) chronic hepatitis B: results of phase III trial ETV-027. Hepatology. 2004;40:728A. [Abstract #LB 07]
- Zeng MD, Yao GB, Wang YZ, et al. One year results from a multi-centre, double-blind, placebo (PLA)-controlled 5 year study of adefovir dipivoxil (ADV) in Chinese patients with HBeAg positive chronic hepatitis B (CHB). Hepatology. 2004;40:730A. [Abstract #LB 11]
- Locarnini S, Shaw T, Sozzi T, et al. HBV mutants associated with clinical resistance to adefovir dipivoxil display only small decreases in antiviral sensitivity in vitro. Hepatology. 2004;40:244A. [Abstract #182]
- Bartholomeusz A, Locarnini SA, Ayres A, et al. Molecular modelling of hepatitis B virus polymerase and adefovir resistance identifies three clusters of mutations. Hepatology. 2004;40:246A. [Abstract #185]
- Brunelle M-N, Jacquard A-C, Pichoud C, et al. Susceptibilty to antivirals of an HBV strain harboring polymerase mutations conferring resistance to both lamivudine and adefovir. Hepatology. 2004;40:265A. [Abstract #229]
- Delaney IV W, Yang H, Qi X, et al. In vitro cross-resistance testing of adefovir, lamivudine, telbivudine (L-DT), entecavir and other anti-HBV compounds against four major mutational patterns of lamivudine-resistant HBV. Hepatology. 2004;40:244A. [Abstract #181]
- Warner N, Locarnini SA, Edwards R, et al. Molecular modelling of entecavir resistant mutations in the hepatitis B virus polymerase selected during therapy. Hepatology. 2004;40:245A. [Abstract #183]
- Tenney DJ, Langley DR, Oliver AJ, et al. Hepatitis B virus resistance to entecavir involves novel changes in the viral polymerase. Hepatology. 2004;40:245A. [Abstract #184]
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55th Annual Meeting of the American Association for the Study of Liver Diseases