麻烦翻译一下. 谢谢.

wwqm

请哪位帮忙翻译一下. 谢谢.

CASE REPORTS

Case 1.

The first Chinese patient, a 21-year-old male, was randomized to receive 100mg of lamivudine daily from the start of the trial (August 1997). He was found to be HBsAg positive during a routine checkup at age 16. He probably had chronic hepatitis B virus (HBV) infection since childhood, as his sister was also an HBV carrier. He had HBV genotype B (determined by the line probe assay INNO-LiPA HBV Genotyping; Innogenetics NV, Ghent, Belgium). The pretreatment liver biochemistry was as follows: albumin, 45 g/liter; bilirubin, 9 umol/liter; alanine aminotransferase (ALT), 398 U/liter. The HBV DNA level measured by the Cobas Amplicor HBV Monitor test (Roche Diagnostics, Branchburg, N.J.; lower limit of detection of 200 copies/ml) was 7.7 x 10 6 copies/ml. After reaching the peak ALT level of 554 U/liter at week 4 of lamivudine treatment, he had HBeAg seroconversion with undetectable HBV DNA level (<200 copies/ml) at month 3 of therapy (November 1997). He was maintained on lamivudine after HBeAg seroconversion. The HBV DNA level remained undetectable at month y of therapy. He had follow-up every 8 weeks under the trial protocol till week 48. From then on, he had regular follow-up every 3 to 6 months in the Hepatitis Clinic, Queen Mary Hospital, The University of Hong Kong, Hong Kong. The ALT levels were normal throughout the subsequent follow-up. HBsAg became negative at 24 months (at 23 years of age; July 1999). Anti-HBs first became positive, with a titer of 17 Mu/ml, at 65 months (at 26.4 years of age; January 2003). The liver biochemistry at the last follow-up (71.5 months; July 2003) was as follows: albumin 45 g/liter; bilirubin, 8 umol/liter; ALT, 37 U/liter. The serum HBV DNA remained undetectable. Liver biopsy showed minimal necroinflammation (grade 1 out of 18) and fibrosis (grade 1 out of 4) according to the Knodell scoring system (histologic activity index). Both the intrahepatic total HBV DNA and the covalently closed circular (ccc) DNA were undetectable, as measured by the Invader HBV DNA assay (Third Wave Technologies, Inc., Madison, Wis.; lower limits of detection for the relaxed circular and ccc forms of DNA were 10 5 and 10 4 copies/ml of DNA extract, respectively) With all these favorable results, the lamivudine was stopped at 71.5 months (august 2003). Six months after cessation of lamivudine (February 2004), the HBVDNA and HBsAg remained undetectable and the anti-HBs titer was 93 MU/ml.

Case 2.

The second Chinese patient was a 17-year-old male randomized to receive 500 mg famciclovir three times a day in September 1997 for 12 weeks, followed by 100 mg of lamivudine daily. He was found to be HBsAg positive by screening his blood for donation at age 16. He had HBV genotype C. The pretreatment liver biochemistry was as follows: albumin, 50 g/liter; bilirubin, 8 umol/liter; ALT, 59 U/liter. The HBV DNA level measured by the Cobas Amplicor HBV Monitor test was 6.7 x 10 6 copies/ml. The HBV DNA level decreased to 2.1 x 10 4 copies/ml at month 6 of therapy. He had follow-up every 8 weeks under the trial protocol till week 48. From then onwards, he had regular follow-up every 3 to 6 months in our Hepatitis Clinic, Queen Mary Hospital, The University of Hong Kong. He had fluctuating ALT levels, ranging from 29 to 132 U/liter before achieving HBeAg seroconversion at month 15 of therapy (December 1998). The HBV DNA level was undetectable at the time of HBeAg seroconversion. HBsAg became negative at 27 months (at 19.3 years of age; December 1999). Lamivudine was maintained after HBeAg seroconversion but was stopped after 30 months of therapy on the patient's own initiative (March 2000). Anti-HBs was detectable at the titer of 421.2 MU/liter at the last follow-up (71 months; at 22.9 years of age; August 2003). He had persistent normal ALT levels till the last follow-up. The latest liver biochemistry was as follows: albumin, 11 umol/liter; ALT, 12 U/liter. The serum HBV DNA was undetectable. The option of liver biopsy was declined by the patient.

liver411

以下是引用wwqm在2005-8-9 14:29:49的发言：

请哪位帮忙翻译一下. 谢谢.

CASE REPORTS病历报告

Case 1.病例一

The first Chinese patient, a 21-year-old male, was randomized to receive 100mg of lamivudine daily from the start of the trial (August 1997). He was found to be HBsAg positive during a routine checkup at age 16. He probably had chronic hepatitis B virus (HBV) infection since childhood, as his sister was also an HBV carrier. He had HBV genotype B (determined by the line probe assay INNO-LiPA HBV Genotyping; Innogenetics NV, Ghent, Belgium).

第一位中国患者, 21岁, 男性, 自1997年8月开始被任选接受每天100毫克拉米夫定治疗的临床试药. 他是在16岁一次理性体检中发现乙肝表面抗原阳性. 很有可能他自幼就感染了乙肝病毒HBV, 他的妹妹也是HBV的带原者. 他所感染的病毒基因是B型 (根据比利时NV Ghent, Innogenetics公司的线性探针检测乙肝病毒基因分析检验方法求证的)

The pretreatment liver biochemistry was as follows: albumin, 45 g/liter; bilirubin, 9 umol/liter; alanine aminotransferase (ALT), 398 U/liter. The HBV DNA level measured by the Cobas Amplicor HBV Monitor test (Roche Diagnostics, Branchburg, N.J.; lower limit of detection of 200 copies/ml) was 7.7 x 10 6 copies/ml. After reaching the peak ALT level of 554 U/liter at week 4 of lamivudine treatment, he had HBeAg seroconversion with undetectable HBV DNA level (<200 copies/ml) at month 3 of therapy (November 1997). He was maintained on lamivudine after HBeAg seroconversion.

在治疗前的肝脏生化检查是: 白蛋白 45g/liter, 胆红素 9umol/liter, ALT 398 U/liter. HBV DNA水平是用(新泽西州, Branchburg城市的罗氏生物制药公司生产最低监测限度为200拷贝/毫升)的Cobas Amplicor HBV Monitor方法, 为7.7X10 6 拷贝/毫升. 在服用拉米夫定之后4周ALT达到最高峰554U/liter, 在用药后三个月(1997年11月)其HBeAg转阴, HBV DNA监测不到(少于200拷贝/毫升). 他在HBeAg转阴后继续服用拉米夫定.

The HBV DNA level remained undetectable at month y of therapy. He had follow-up every 8 weeks under the trial protocol till week 48. From then on, he had regular follow-up every 3 to 6 months in the Hepatitis Clinic, Queen Mary Hospital, The University of Hong Kong, Hong Kong. The ALT levels were normal throughout the subsequent follow-up. HBsAg became negative at 24 months (at 23 years of age; July 1999). Anti-HBs first became positive, with a titer of 17 Mu/ml, at 65 months (at 26.4 years of age; January 2003). The liver biochemistry at the last follow-up (71.5 months; July 2003) was as follows: albumin 45 g/liter; bilirubin, 8 umol/liter; ALT, 37 U/liter. The serum HBV DNA remained undetectable. Liver biopsy showed minimal necroinflammation (grade 1 out of 18) and fibrosis (grade 1 out of 4) according to the Knodell scoring system (histologic activity index).

在治疗后的y(?)月份, HBV DNA持续监测不到. 之后根据试药规定他每8周复检一次, 直到第48周. 之后他每3-6个月去香港大学皇后玛利医院进行一次正常检查.ALT水平在之后的检查中都正常. HBsAg在第24个月的时候开始转阴(在23岁, 1999年7月时). 在第65个月的时候(在26.4岁, 2003年7月时)HBsAb呈现阳性, 其滴度为17Mu/ml. 肝脏生化在最后一次检查时候(71.5 个月; 2003年7月)是: 白蛋白45g/liter, 胆红素8umol/liter, ALT37U/liter. 血清HBV DNA仍然监测不到. 根据Knodell分级系统(HAI)肝穿显示微量坏死性炎症(18级分级为一级), 纤维化(4级中第一级)

Both the intrahepatic total HBV DNA and the covalently closed circular (ccc) DNA were undetectable, as measured by the Invader HBV DNA assay (Third Wave Technologies, Inc., Madison, Wis.; lower limits of detection for the relaxed circular and ccc forms of DNA were 10 5 and 10 4 copies/ml of DNA extract, respectively) With all these favorable results, the lamivudine was stopped at 71.5 months (august 2003). Six months after cessation of lamivudine (February 2004), the HBVDNA and HBsAg remained undetectable and the anti-HBs titer was 93 MU/ml.

利用Invader HBV DNA 检验方法(第三波技术公司, Madison, 威州发明, 最低监测cccDNA和HBV DNA提纯物分别为5个log和4个log拷贝/毫升)得到的结果为肝内HBV DNA和cccDNA均为监测不到. 基于所有这些好的结果, 在71.5个月(2003年8月)时候拉米夫定停药. 在停拉米夫定6个月后(2004年2月), HBV DNA和HBsAg仍然持续监测不到, HBsAb抗体滴度为93Mu/ml.

先草草弄第一个, 第二个明天或等等看...)) wwqm翻译这个做啥?

wwqm

非常感谢411先生. 这是上周日我们参加地坛医院网友见面会时, 蔡医生提供的资料, 我想翻译后放在拉米综合信息里作为长期使用拉米抗病毒治疗的一个参考. 再次表示感谢.

[此贴子已经被作者于2005-8-10 13:14:28编辑过]

liver411

Case 2.病理二

The second Chinese patient was a 17-year-old male randomized to receive 500 mg famciclovir three times a day in September 1997 for 12 weeks, followed by 100 mg of lamivudine daily. He was found to be HBsAg positive by screening his blood for donation at age 16.

第二名中国患者是一名17岁男性, 自1997年9月被任选临床试药服用泛昔洛韦500毫克每天三次, 为期12周, 之后改用拉米夫定100毫克每天一次. 他是在16岁一次献血筛检中检查到HBeAg阳性.

He had HBV genotype C. The pretreatment liver biochemistry was as follows: albumin, 50 g/liter; bilirubin, 8 umol/liter; ALT, 59 U/liter. The HBV DNA level measured by the Cobas Amplicor HBV Monitor test was 6.7 x 10 6 copies/ml. The HBV DNA level decreased to 2.1 x 10 4 copies/ml at month 6 of therapy. He had follow-up every 8 weeks under the trial protocol till week 48. From then onwards, he had regular follow-up every 3 to 6 months in our Hepatitis Clinic, Queen Mary Hospital, The University of Hong Kong.

他感染的HBV病毒基因是C型. 治疗前肝脏生化为: 白蛋白50g/liter, 单红素8umol/liter, ALT59U/liter. HBV DNA水平使用Cobas Amplicor HBV Monitor方法检验是6.7X 10 6 拷贝/毫升. HBV DNA水平在治疗后6个月时减低至2.1X10 4 拷贝/毫升. 之后, 根据试药规定每8周检查一次, 直到第48周为止. 从48周起, 他每3-6个月去香港大学附属皇后玛丽医院肝脏诊所复查一次.

He had fluctuating ALT levels, ranging from 29 to 132 U/liter before achieving HBeAg seroconversion at month 15 of therapy (December 1998). The HBV DNA level was undetectable at the time of HBeAg seroconversion. HBsAg became negative at 27 months (at 19.3 years of age; December 1999). Lamivudine was maintained after HBeAg seroconversion but was stopped after 30 months of therapy on the patient's own initiative (March 2000). Anti-HBs was detectable at the titer of 421.2 MU/liter at the last follow-up (71 months; at 22.9 years of age; August 2003).

在第15个月HBeAg转阴(1998年12月)前, 他的ALT属于上下波动, 持续在29-132U/liter之间. HBV DNA在HBeAg转换的时候监测不到. HBsAg在第27个月的时候(19.3岁, 1999年12月)转阴. 拉米在HBeAg转阴后继续服用, 直到30月时候在患者的要求下停药(2000年3月). HBsAb在最后一次检查(第71个月, 在22.9岁, 2003年8月)时候为421.2MU/liter.

He had persistent normal ALT levels till the last follow-up. The latest liver biochemistry was as follows: albumin, 11 umol/liter; ALT, 12 U/liter. The serum HBV DNA was undetectable. The option of liver biopsy was declined by the patient. 其ALT直到上次检查时候维持正常. 最后一次肝脏生化检查为: 白蛋白11umol/liter, ALT12U/liter. HBV DNA为监测不到. 给与患者感穿检查的机会被患者拒绝.

奇怪的是最后一次的白蛋白是否正确, 11? 应该求证那个Dr之后改掉再发表.

liver411

是否应该是51/41?

流浪花猫

啊啊啊，411老大，下次留给我啊[em21][em21]

liver411

SORRY! You may do this one, pretty good article...

Highlights in Hepatitis B Therapy -- Clinical Efficacy and Patterns of Viral Resistance

Disclosures

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.

Clinical Efficacy

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.

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.

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.

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

1. 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]
2. 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]
3. 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]
4. 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]
5. 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]
6. 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]
7. 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]
8. 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]

Copyright © 2004 Medscape.

55th Annual Meeting of the American Association for the Study of Liver Diseases

liver411

or this one about Hepsera...

Frequently Asked Questions About Hepsera
— What is the indication for Hepsera?
— What is the dosing for Hepsera?
— What are the efficacy data for Hepsera?
— What were the most common side effects for Hepsera in clinical trials?
— How many patients have participated in clinical trials for Hepsera?
— Has Hepsera been associated with drug resistance?
— Are there any significant drug interactions associated with Hepsera?
— Is Hepsera safe for use in children?
— Where can I learn more about Hepsera?

Is There Resistance to Hepsera?

Drug resistance is a primary concern of infectious disease specialists around the world. Any virus can develop drug resistance, and may even develop resistance to more than one drug. Resistance occurs when viruses acquire ways to survive the effects of the drugs that were designed to weaken them. Resistance to antiviral drugs presents an obstacle to providing effective long-term treatment of viral diseases, such as chronic hepatitis B.

Hepsera® was studied in clinical trials to find out whether or not resistance would develop. Through 144 weeks (about 3 years), resistance mutations were identified that may reduce the effectiveness of Hepsera. After 3 years of continuous treatment, 4/100 patients developed resistance to Hepsera in clinical trials.

In clinical trials, Hepsera was found to work well in people who had hepatitis B virus that was resistant to the currently approved chronic hepatitis B treatment, lamivudine.

Important Safety Information about Hepsera

Severe acute exacerbations of hepatitis have been reported with discontinuation of anti-hepatitis B therapy including Hepsera. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted. Patients with advanced liver disease or cirrhosis may be at a higher risk for hepatic decompensation. Although most events appear to have been self-limited or resolved with re-initiation of treatment, severe hepatitis exacerbations, including fatalities, have been reported.1

Chronic administration of Hepsera may result in nephrotoxicity in patients at risk of or having underlying renal dysfunction. These patients should be monitored closely for renal function and may require dose adjustment.

HIV resistance may emerge in chronic hepatitis B patients with unrecognized or untreated human immunodeficiency virus (HIV) infection treated with anti-hepatitis B therapies, such as therapy with Hepsera that may have activity against HIV.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals.

Frequently Asked Questions About Hepsera

Q: What is the indication for Hepsera?
A: Hepsera is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

This indication is based on histological, virological, biochemical and serological responses in adult patients with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver function, and in adult patients with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function.

Q: What is the dosing for Hepsera?
A: The dosing for Hepsera is one 10 mg tablet once daily, without regard to food. The optimal duration of treatment is unkown. Dose adjustments can be made for patients with renal impairment
(see table below).


The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearence < 10mL/min; therefore, no dosing recommendation is available for these patients.

Q: What are the efficacy data of Hepsera?
A: The efficacy and safety of Hepsera compared to placebo were evaluated in two large controlled clinical trials enrolling adult patients with chronic hepatitis B. In both studies, patients received Hepsera or matching placebo once a day for 48 weeks, with therapy extended for a second 48-week treatment period.

Q: What were the most common side effects for Hepsera in clinical trials?
A: The most common adverse events seen with Hepsera in clinical trials were headache, pharyngitis, asthenia, abdominal pain and flu syndrome; no patients discontinued drug due to these events. One percent of patients receiving Hepsera discontinued drug due to an adverse event.

Q: How many patients have participated in clinical trials for Hepsera?
A: To date, over 800 people have received Hepsera in clinical trials.

Q: Has Hepsera been associated with drug resistance?
A: Long-term resistance analyses (96–144 weeks) performed by genotyping samples from all adefovir dipivoxil-treated patients with detectable serum HBV DNA identified 2 adefovir resistance-associated mutations. The rtN236T mutation resulted in 4- to 14-fold reduced adefovir susceptibility in vitro and serum HBV DNA rebound in 6/6 patients who developed this mutation in their HBV. The rtA181V mutation conferred 2.5 to 3-fold reduced susceptibility to adefovir in vitro and serum HBV DNA rebound in 2/3 patients who developed this mutation in their HBV. There was a cumulative probability of 3.9% in developing adefovir resistance at year 3. At 96 weeks, 5.1% (4/79) of adefovir dipivoxil-treated patients experienced a confirmed increase of >1 log₁₀ HBV DNA copies/mL from nadir (Study 438).¹

Q: Are there any significant drug interactions associated with Hepsera?
A: No significant drug interactions have been observed with Hepsera. Hepsera has been evaluated in healthy volunteers in combination with lamivudine, trimethoprim/sulfamethoxazole, acetominophen, tenofovir disoproxil fumarate or ibuprofen. Hepsera was not found to alter the pharmacokinetics of any of these agents.¹

Q: Is Hepsera safe for use in children?
A: The safety and effectiveness of Hepsera in pediatric patients have not been established.

Q: Where can I find out more about Hepsera?
A: To find out more about Hepsera, you can
a) review the content of www.Hepsera.com, b) read the full prescribing information, or c) contact Gilead to speak with the clinical information department or set up a meeting with a Gilead Representative.

Adverse Events

Safety profile through 48 weeks

• Laboratory abnormalities occurred at similar rates with Hepsera vs placebo in placebo-controlled studies (Studies 437 and 438)
  
  
  
  

liver411

No patients developed a serum creatinine increase ≥ 0.5 mg/dL from baseline by week 48; increases in serum creatinine ≥ 0.3 mg/dL occurred in 4% of patients receiving Hepsera vs 2% with placebo by week 48

By week 96, increases in serum creatinine ≥ 0.3 mg/dL and ≥ 0.5 mg/dL from baseline occurred in 10% and 2%, respectively, of patients receiving Hepsera^†1

• Elevations in serum creatinine > 0.3 mg/dL from baseline resolved on continued treatment (20/29), remained unchanged (8/29), or resolved following treatment discontinuation (1/29). In total, only one patient discontinued treatment due to an increase in creatinine
  
  

Exacerbations of hepatitis (ALT ≥ 10 x ULN) occurred in up to 25% of patients after discontinuation of Hepsera

• Exacerbations were not generally accompanied by hepatic decompensation in HBeAg+ and HBeAg- patients with compensated liver function. Patients with advanced liver disease or cirrhosis may be at a higher risk for hepatic decompensation. Although most events appear to have been self-limited or resolved with re-initiation of treatment, severe hepatitis exacerbations, including fatalities, have been reported¹

It is important to monitor renal function for all patients during treatment with Hepsera, particularly for those with pre-existing or other risks for renal impairment. ¹

* No placebo control beyond 48 weeks.
^† Based on Kaplan-Meier estimates.

Discontinuation due to adverse events


Treatment-related adverse events

• The most common treatment-related adverse events occurred at rates similar to placebo¹
• Adverse events in patients receiving Hepsera beyond week 48 in Study 438 were similar in nature and severity to those reported through week 48. With increased Hepsera exposure, the incidence of adverse events related to treatment increased only slightly
  

Drug interactions

• Adefovir does not inhibit common cytochrome P450 enzymes; the potential for adefovir to induce cytochrome P450 enzymes is not known¹
• The effect of adefovir on cyclosporine and tacrolimus concentrations is not known¹
• Since adefovir is eliminated by the kidney, co-administration of Hepsera with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either adefovir and/or these co-administered drugs¹

Safety and tolerability in pre- and post-liver transplantation patients

• The most common treatment-related adverse events (2% or higher) with Hepsera were asthenia, abdominal pain, headache, fever, nausea, vomiting, diarrhea, flatulence, hepatic failure, increases in ALT and AST, abnormal liver function, increased cough, pharyngitis, sinusitis, pruritus, rash, increases in creatinine, renal failure, and renal insufficiency¹
• Increases in serum creatinine ≥ 0.3 mg/dL from baseline were observed in 26% of patients by week 48 and 37% by week 96^‡1
• Increases in serum creatinine ≥ 0.5 mg/dL from baseline were observed in 16% of patients by week 48 and 31% by week 96 (N=41) ^‡
  • Elevations in serum creatinine ≥ 0.5 mg/mL from baseline resolved on continued treatment (7/41), remained unchanged (18/41), or had not resolved (16/41) ¹
• Due to the presence of multiple concomitant risk factors for renal dysfunction at baseline or during treatment in these patients, the contributory role of Hepsera to these changes in serum creatinine is difficult to assess¹
• 1% (3/324) of patients discontinued Hepsera due to renal events
  
  Important safety information
  Severe acute exacerbations of hepatitis have been reported with discontinuation of anti-hepatitis B therapy including Hepsera. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted. Patients with advanced liver disease or cirrhosis may be at a higher risk for hepatic decompensation. Although most events appear to have been self-limited or resolved with re-initiation of treatment, severe hepatitis exacerbations, including fatalities, have been reported. ¹
  
  In patients at risk of or having underlying renal dysfunction, chronic administration of Hepsera may result in nephrotoxicity. These patients should be monitored closely for renal function and may require a dose adjustment.¹
  
  HIV resistance may emerge in chronic hepatitis B patients with unrecognized or untreated human immunodeficiency virus (HIV) infection treated with anti-hepatitis B therapies, such as therapy with Hepsera that may have activity against HIV. ¹
  
  Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals.¹
  

Dosing

The recommended dose of Hepsera® in chronic hepatitis B patients with adequate renal function is 10 mg once daily taken orally, without regard to food. The optimum duration of treatment is unknown.

Dose Adjustment in Renal Impairment:

Significantly increased drug exposures were seen when Hepsera was administered to patients with renal impairment. Therefore, the dosing interval of Hepsera should be adjusted in patients with baseline creatinine clearance < 50 mL/min using the following suggested guidelines (see table below). The safety and effectiveness of these dosing interval adjustment guidelines have not been clinically evaluated. Therefore, the clinical response to treatment and renal function should be closely monitored in patients with creatinine clearance below 50 mL/min.

*The pharmacokinetics of adefovir have not been evaluated in non-hemodialysis patients with creatinine clearance < 10 mL/min; therefore, no dosing recommendation is available for these patients.

† No dosing recommendation is available for non-hemodialysis patients with creatinine clearance
< 10 mL/min.

liver411

or you prefer case study too?