Effect of antiviral treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis B

Chronic hepatitis B (CHB) is a major risk factor for hepatocellular carcinoma (HCC). The prevention of HCC is of paramount importance in patients with CHB, particularly in those with cirrhosis. Antiviral treatment can potentially reduce the risk for HCC since it suppresses viral replication, induces HBeAg seroconversion and improves liver histology. However, most evidence supporting a protective effect of antiviral treatment originates from non-randomized or retrospective studies and is limited to conventional interferon and lamivudine. There is a paucity of data on the effects of pegylated interferon and "newer" oral agents (telbivudine, tenofovir, entecavir) on HCC risk. However, it should be emphasized that the existing randomized control studies in patients with CHB were relatively short-term and not designed to assess the effects of antiviral treatment on HCC risk. Since viral load directly correlates with HCC risk, it is reasonable to hypothesize that the reduction in viral load with antiviral treatment will also lower the risk of HCC. This benefit might become more readily apparent with the newer agents used in the management of CHB which are more effective and have a more favorable resistance profile.     

Choice of drugs in the treatment of chronic hepatitis B in pregnancy

The selection of antiviral drugs for chronic hepatitis B(CHB) treatment in pregnancy is very difficult since none of the drugs have been approved for use in pregnancy.Transmission from mother to newborn remains the most frequent route of infection in mothers with high viral load and positive hepatitis B e antigen status,even with the use of appropriate prophylaxis with hepatitis B virus(HBV) immunoglobulin and HBV vaccination.We read from the article written by Yi et al that lamivudine treatment in early pregnancy was safe and effective.However,we could not understand why adefovir dipivoxil(ADV) was used in three pregnancy cases,since ADV has been classified as pregnancy category C.In pregnancy,telbivudine or tenofovir should be selected when the treatment of CHB is necessary,since these drugs have been classified as Food and Drug Administration pregnancy risk category B.     

Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies

AIM: To evaluate the long-term efficacy adefovir(ADV)-based combination therapies in entecavir(ETV)-resistant chronic hepatitis B(CHB) patients. METHODS: F i fty CHB pat ient s wi t h genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV(ADV/ETV,n = 23) or ADV plus lamivudine(LMV)(ADV/LMV,n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus(HBV) DNA levels were measured by realtime PCR and logarithmically transformed for analysis. Cumulative rates of virologic response(VR; HBV DNA 20 IU/m L) were calculated using the Kaplan-Meier method,and the difference was determined by a logrank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR,respectively.RESULTS: Baseline median HBV DNA levels were 5.53(2.81-7.63) log10 IU/m L. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27(12-45) mo. Overall,cumulative VR rates at 6,12,24,and 36 mo were 26%,36%,45%,and 68%,respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates(35%,43%,65%,and 76%,respectively) than those with the ADV/LAM combination(18%,30%,30%,and 62%,respectively; P = 0.048). In the multivariate analysis,low baseline HBV DNA levels( 5.2 log10 IU/m L) and initial virologic response at 3 mo(IVR-3; HBV DNA 3.3 log10 IU/m L after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period,the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors.CONCLUSION: If tenofovir is not available,ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers,and may becontinued if IVR-3 is achieved.     

Pegylated IFN-α 2b added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B

AIM: To investigate the role of pegylated-interferon (IFN) alpha-2b in the management of patients with lamivudine-resistant chronic hepatitis B.METHODS: Twenty consecutive anti-HBe positive patients were treated with pegylated IFN alpha-2b (100 mug sc once weekly) for 12 mo. There was no interruption in lamivudine therapy. Hematology, liver biochemistry, serum HBV DNA levels were detected by PCR, and vital signs were also assessed. Liver histology was assessed in some patients at entry and at wk 52 for comparison.RESULTS: Nine patients (45%) had a partial virological end-treatment response; seven patients (35%) showed complete virological end-treatment response. Eight patients (40%) showed biochemical end-treatment response. There was a trend for higher virological response rates in patients who had previously responded to IFN and relapsed compared to IFN non-responders (four out of seven patients vs none out of six patients, respectively; P=0.1). Patients without virological end-treatment response showed significant worsening of fibrosis [median score 2 (range, 1 to 3) vs median score 3 (range, 1 to 4)], in the first and second biopsy respectively (P=0.014), whereas necroinflammatory activity was not significantly affected. Patients with complete or partial virological end-treatment response did not show any significant changes in histological findings, possibly due to the small number of patients with paired biopsies (n=5). Nevertheless, after 12 mo of follow-up, only one patient (5%) showed sustained virological response and only 2 patients (10%) showed sustained biochemical response. Two patients (10%) discontinued pegylated IFN both after 6 mo of treatment due to flu-like symptoms.CONCLUSION: Pegylated IFNalpha-2b, when added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B, induces sustained responses only in a small minority of cases.     

Pegylated IFN-α 2b added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B

AIM: To investigate the role of pegylated-interferon (IFN)α-2b in the management of patients with lamivudineresistant chronic hepatitis B.METHODS: Twenty consecutive anti-HBe positive patients were treated with pegylated IFN α-2b (100 μg sc once weekly) for 12 mo. There was no interruption in lamivudine therapy. Hematology, liver biochemistry,serum HBV DNA levels were detected by PCR, and vital signs were also assessed. Liver histology was assessed in some patients at entry and at wk 52 for comparison.RESULTS: Nine patients (45%) had a partial virological end-treatment response; seven patients (35%)showed complete virological end-treatment response.Eight patients (40%) showed biochemical end-treatment response. There was a trend for higher virological response rates in patients who had previously responded to IFN and relapsed compared to IFN non-responders (four out of seven patients vs none out of six patients,respectively; P=0.1). Patients without virological endtreatment response showed significant worsening of fibrosis [median score 2 (range, 1 to 3) vs median score 3 (range, 1 to 4)], in the first and second biopsy respectively (P=0.014), whereas necroinflammatory activity was not significantly affected. Patients with complete or partial virological end-treatment response did not show any significant changes in histological findings, possibly due to the small number of patients with paired biopsies (n = 5). Nevertheless, after 12 mo of follow-up, only one patient (5%) showed sustained virological response and only 2 patients (10%) showed sustained biochemical response. Two patients (10%) discontinued pegylated IFN both after 6 mo of treatment due to flu-like symptoms.CONCLUSION: Pegylated IFNα-2b, when added to ongoing lamivudine therapy in patients with lamivudineresistant chronic hepatitis B, induces sustained responses only in a small minority of cases.     

Hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy

Patients with chronic hepatitis B are at increased risk of hepatocellular carcinoma(HCC),while the inhibition of viral replication can represent a reasonable target for HCC prevention.Interferon-αtherapy results in decreased HCC risk,which is more evident in patients with high baseline HCC risk.The majority of chronic hepatitis B patients are treated with a nucleos(t)ide analogue(NA)for several reasons including the nonsustained response after interferon-α.The effect of the first licensed and low genetic barrier NA,lamivudine,on HCC incidence,has been repeatedly evaluated.Lamivudine,compared to no treatment,reduces the HCC incidence,which may increase again in cases with lamivudine resistance.Emerging data with the currently first-line NAs,entecavir and tenofovir,suggest that they also reduce the HCC incidence.The treatment benefit in reduction of the HCC incidence is always greater in patients with high baseline HCC risk,particularly cirrhotics,and without virological remission under entecavir/tenofovir.However,the HCC risk is not eliminated even in the vast majority of patients who remain in virological remission under entecavir/tenofovir.Therefore,patients at increased baseline HCC risk should continue to undergo HCC surveillance even if they have achieved complete long-term inhibition of viral replication and improvements in liver histology.     

Future prospectives for the management of chronic hepatitis B

Chronic hepatitis B virus infection affects about 400 million people around the globe and causes approximately one million deaths a year. Since the discovery of interferon-α as a therapeutic option the treatment of hepatitis B has evolved fast and management has become increasingly complicated. The amount of viral replication reflected in the viral load (HBV-DNA) plays an important role in the development of cirrhosis and hepatocellular carcinoma. The current treatment modalities for chronic hepatitis B are immunomodulatory (interferons) and antiviral suppressants (nucleoside and nucleotide analogues) all with their own advantages and limitations. An overview of the treatment efficacy for both immunomodulatory as antiviral compounds is provided in order to provide the clinician insight into the factors influencing treatment outcome. With nucleoside or nucleotide analogues suppression of viral replication by 5-7 log10 is feasible, but not all patients respond to therapy. Known factors influencing treatment outcome are viral load, ALT levels and compliance. Many other factors which might influence treatment are scarcely investigated. Identifying the factors associated with response might result in stopping rules, so treatment could be adapted in an early stage to provide adequate treatment and avoid the development of resistance. The efficacy of compounds for the treatment of mutant virus and the cross- resistance is largely unknown. However, genotypic and phenotypic testing as well as small clinical trials provided some data on efficacy in this population. Discontinuation of nucleoside or nucleotide analogues frequently results in viral relapse; however, some patients have a sustained response. Data on the risk factors for relapse are necessary in order to determine when treatment can be discontinued safely. In conclusion: chronic hepatitis B has become a treatable disease; however, much research is needed to tailor therapy to an individual patient, to predict the sustainability of response and determine thebest treatment for those failing treatment.     

Extended treatment with lamivudine and adefovir dipivoxil in chronic hepatitis B patients with lamivudine resistance

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 ≤10⁵ copies or >2 log₁₀ 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 log₁₀ 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.     

阿德福韦酯联合拉米夫定治疗拉米夫定耐药的慢性乙型肝炎患者48周疗效观察

目的 观察阿德福韦酯（ADV）联合拉米夫定（LAM）治疗LAM耐药的慢性乙型肝炎患者的临床疗效。方法 2011年1月～2013年6月我科诊治的对LAM耐药的慢性乙型肝炎患者85例,43例接受ADV组治疗,42例接受ADV联合LAM治疗,观察治疗48 w时的疗效。结果 在治疗24 w和48 w时,联合治疗组患者肝功能指标改善情况优于阿德福韦治疗组（P<0.05）;在治疗24 w和48 w时,联合治疗组患者血清HBV DNA阴转率分别为54.7%（23/42）和92.8%（39/42）,显著高于阿德福韦治疗组[分别为37.2%（16/43）和67.4%（29/43）,P<0.05];在治疗48 w时,联合治疗组血清HBeAg阴转率为24.1%（7/29）,显著高于阿德福韦组的[3.2%（1/31）,P<0.05]。结论 ADV联合LAM治疗LAM耐药的慢性乙型肝炎患者有较好的临床疗效。     

Telbivudine： A new treatment for chronic hepatitis B

Three hundred and fifty million people worldwide are estimated to be chronically infected with hepatitis B virus. 15%-40% of these subjects will develop cirrhosis, liver failure or hepatocellular carcinoma during their life. The treatment of chronic hepatitis B has improved dramatically over the last decade merits to the advent of nucleoside/nucleotide analogues and the use of pegylated interferons. Approved drugs for chronic hepatitis B treatment include： standard interferon- alpha 2b, pegylated interferon-alpha 2a, lamivudine, adefovir dipivoxil, and entecavir. Unfortunately, these agents are not effective in all patients and are associated with distinct side effects. Interferons have numerous side effects and nucleoside or nucleotide analogues, which are well tolerated, need to be used for prolonged periods, even indefinitely. However, prolonged treatment with nucleoside or nucleotide analogues is associated with a high rate of resistance. Telbivudine is a novel, orally administered nucleoside analogue for use in the treatment of chronic hepatitis B. In contrast to other nucleoside analogues, Telbivudine has not been associated with inhibition of mammalian DNA polymerase with mitochondrial toxicity. Telbivudine has demonstrated potent activity against hepatitis B with a significantly higher rate of response and superior viral suppression compared with lamivudine, the standard treatment. Telbivudine has been generally well tolerated, with a low adverse effect profile, and at its effective dose, no dose- limiting toxicity has been observed. Telbivudine is one of the most potent antiviral agents for chronic hepatitis B virus and was approved by the FDA in late 2006.     

阿德福韦酯治疗对拉米夫定耐药的HBeAg阳性慢性乙型肝炎患者48周临床疗效

目的评价阿德福韦酯治疗对拉米夫定耐药的HBeAg阳性慢性乙型肝炎患者的临床疗效。方法 75例对拉米夫定耐药的HBeAg阳性慢性乙型肝炎患者,联合组（48例）加用阿德福韦酯（10 mg/d）治疗48周;单药组（27例）改用阿德福韦酯（10 mg/d）治疗48周,分别检测治疗前及治疗12周、24周和48周时患者血清HBVDNA定量、HBV血清标志物及肝功能。结果治疗48周时,联合组与单药组HBVDNA阴转率分别为62.5%和29.6%（P〈0.01）,HBeAg阴转率分别为31.3%和11.1%（P〈0.05）,HBeAg血清转换率为16.7%和7.4%（P〉0.05）,ALT复常率分别为91.7%和88.9%（P〉0.05）。治疗48周无肾脏安全性问题发生。结论加用阿德福韦酯可作为对拉米夫定耐药患者治疗的首选方案之一。     

替比夫定联合阿德福韦酯治疗高病毒载量HBeAg阳性慢性乙型肝炎的疗效观察

对慢性乙型肝炎(CHB)初治患者选择无交叉耐药的药物联合治疗是重要的策略[1-2].但联合用药的临床疗效和安全性尚缺乏长期的循证医学证据,尤其是对于高病毒载量(HBV DNA＞7 log10拷贝/ml)的CHB患者,尚鲜有报道.我们对64例高病毒载量HBeAg阳性CHB患者分别采用替比夫定(LDT)联合阿德福韦酯(ADV)与拉米夫定(LAM)联合ADV治疗,观察两组患者初治联合的临床疗效及安全性,现报道如下.     

Combination therapy of lamivudine and adefovir in Japanese patients with chronic hepatitis B

Purpose  This study aimed to clarify the long-term efficacy of the lamivudine treatment in Japanese patients with chronic hepatitis B either with or without lamivudine resistance or with or without adefovir add-on treatment. Methods  We followed 110 patients who received lamivudine for more than 12 months, including 67 hepatitis B e antigen (HBeAg)-positive and 43 HBeAg-negative patients. Results  The median follow-up after the onset of lamivudine was 48 (range = 12–86) months. In all the patients with or without lamivudine resistance, the level of alanine aminotransferase (ALT) normalization decreased from 70.0% at 1 year to 36.4% at 5 years and the loss of serum HBV DNA level decreased from 72.7% at 1 year to 31.8% at 5 years. Sixty patients (54.6%) developed a lamivudine-resistant mutation, and this occurrence was more frequently observed in those who were HBeAg-positive (P < 0.01), those with a low level of ALT (P < 0.05), and those with a high level of serum HBV DNA (P < 0.01). Thirty-six of 60 patients received adefovir in addition to lamivudine to treat breakthrough hepatitis. A Cox proportional hazards model analysis revealed the level of baseline HBV DNA to be the best predictive factor for the virus recrudescence (risk ratio = 0.466, 95% confidence interval [CI]: 0.246–0.842, P = 0.011) and the breakthrough hepatitis (risk ratio = 0.444, 95% CI: 0.218–0.879, P = 0.019). We carefully monitored the efficacy of this treatment both in patients who received adefovir and in those who did not since the beginning of the lamivudine treatment. The normalization level of ALT was 61.4% at 5 years and the loss of serum HBV DNA was 61.4% at 5 years since lamivudine was started. A histologic improvement was observed in patients with ALT levels less than two times the upper limit of normal at the time of a second liver biopsy. Conclusions  Although the efficacy of lamivudine is limited because of breakthrough hepatitis, adefovir was used as a salvage treatment of patients with lamivudine-resistant chronic hepatitis B. In addition, lamivudine was used for the treatment of Japanese patients with chronic hepatitis B with or without lamivudine resistance, and was found to be useful regarding the long-term virologic and biochemical responses. An erratum to this article can be found at     

阿德福韦治疗HBeAg阴性慢性乙型肝炎患者的初步观察

目的观察阿德福韦治疗HBeAg阴性、HBV DNA阳性慢性乙型肝炎的疗效。方法选择HBeAg阴性、HBV DNA阳性慢性乙型肝炎患者46例和HBeAg阳性、HBV DNA阳性慢性乙型肝炎47例。两组病例均口服阿德福韦10毫克,每日1次,治疗2年(实际平均完成11.8个月)。结果HBeAg阴性组和HBeAg阳性组病例ALT复常率在治疗结束时为82.6%(38/46)、85.1%(40/47),停药3个月时为32.6%(15/46)、31.9%(15/47)。HBV DNA阴转率在治疗结束时为30.4%(15/46)、29.8%(14/47),停药3个月时为13%(6/46)、12.8%(6/47),两组之间无显著性差异(P>0.05)。结论阿德福韦治疗HBeAg阴性和HBeAg阳性慢性乙型肝炎的近期疗效一致,但是在停药后两组大部分病例都复发。     

替比夫定与恩替卡韦治疗HBeAg阳性慢性乙型肝炎4年随访观察

目的比较替比夫定(LdT)和恩替卡韦(ETV)治疗HBeAg阳性的CHB,哪一个能较早地实现有限疗程。方法 60例HBeAg阳性的CHB患者随机分为LdT组和ETV组。在服药后第12周、24周及以后每24周复查,直至治疗和随访结束(4年,192周),检测血清HBV DNA定量、HBV血清标志物、肝功能、血清肌酸激酶。观察两组192周治疗结束时应答率及持续应答率以及患者达到停药标准所需的时间及费用。结果 192周时LdT组和ETV组治疗结束时应答率及持续应答率为43.3%(13/30)vs 16.7%(5/30)、36.7%(11/30)vs 10.0%(3/30),差异有统计学意义(P<0.05)。达到停药标准LdT组平均治疗时间为167.2周,费用28 089.6元,而ETV组平均治疗时间为186.4周,费用50 887.2元。结论治疗HBeAg阳性的CHB患者,实现有限疗程LdT更具有优势。     

Review of the pharmacological management of hepatitis B viral infection before and after liver transplantation

The progress in treatment against hepatitis B virus(HBV)with the development of effective and well tolerated nucleotide analogues(NAs)has improved the outcome of patients with HBV decompensated cirrhosis and has prevented post-transplant HBV recurrence.This review summarizes updated issues related to the management of patients with HBV infection before and after liver transplantation(LT).A literature search using the PubMed/Medline databases and consensus documents was performed.Pre-transplant therapy has been initially based on lamivudine,but entecavir and tenofovir represent the currently recommended first-line NAs for the treatment of patients with HBV decompensated cirrhosis.After LT,the combination of HBV immunoglobulin(HBIG)and NA is considered as the standard of care for prophylaxis against HBV recurrence.The combination of HBIG and lamivudine is related to higher rates of HBV recurrence,compared to the HBIG and entecavir or tenofovir combination.In HBIG-free prophylactic regimens,entecavir and tenofovir should be the first-line options.The choice of treatment for HBV recurrence depends on prior prophylactic therapy,but entecavir and tenofovir seem to be the most attractive options.Finally,liver grafts from hepatitis B core antibody(anti-HBc)positive donors can be safely used in hepatitis B surface antigen negative,preferentially anti-HBc/anti-hepatitis B surface antibody positive recipients.     

替比夫定与阿德福韦酯治疗HBeAg阳性慢性乙型肝炎的疗效观察

目的比较替比夫定与阿德福韦酯治疗HBeAg阳性慢性乙型肝炎的疗效和安全性。方法 175例HBeAg阳性慢性乙型肝炎患者被随机分为替比夫定组（85例）和阿德福韦酯组（90例）,比较两组在治疗后48周时的疗效。结果治疗后12周、24周、36周和48周时,替比夫定治疗患者HBV DNA水平低于阿德福韦酯组（P〈0.01）,HBV DNA转阴率和ALT复常率均高于阿德福韦酯组（P〈0.05或P〈0.01）;治疗后12周、24周和36周HBeAg转阴或血清学转换率和完全应答率也高于阿德福韦酯组（P〈0.05或P〈0.01）;治疗48周,替比夫定组有2例,阿德福韦酯组有1例出现病毒学反弹;两组均有良好的安全性。结论替比夫定较阿德福韦酯有更强的抑制HBV作用,其治疗可提高HBeAg转阴或血清学转换率和完全应答率。     

拉米夫定和阿德福韦酯初始联合与恩替卡韦单药治疗慢性乙型肝炎的疗效和安全性比较

目的 观察拉米夫定(LAM)和阿德福韦酯(ADV)初始联合与恩替卡韦(ETV)单药治疗慢性乙型肝炎的疗效,并比较两者的安全性.方法 选择我院2007年6月-2008年1月符合抗病毒治疗的未曾使用核苷(酸)类似物的初治慢性乙型肝炎患者120例,分为联合组60例和单药组60例,联合组应用LAM 100 mg,ADV 10 mg,每日1次;单药组应用ETV 0.5 mg,每日1次.分别在基线、12、24、48、96周时留取血清,采用全自动分析生物化学仪检测肝功能、肾功能、血生物化学指标;采用化学发光法定量检测HBsAg和HBeAg;采用实时荧光定量PCR检测HBV DNA水平;采用PCR产物直接测序法检测病毒耐药基因.组间比较采用配对t检验,率的比较采用χ2检验.结果 (1)联合组54例,单药组50例完成了48周随访,联合组51例,单药组48例完成了96周随访.两组治疗前性别、年龄、血清ALT、血肌酐、HBV DNA、HBsAg水平及HBeAg阳性率,差异无统计学意义,具有可比性.(2)两组在治疗12周和24周时,HBV DNA＜300拷贝/ml和HBV DNA＜1000拷贝/ml的比率,差异无统计学意义.治疗12周时,单药组和联合组HBV DNA下降＜1 log10拷贝/ml的分别为3.7%(2/54)和18.0%(9/50),两组比较,χ2=5.556,P＜0.05,差异有统计学意义.(3)治疗48周时,单药组和联合组的ALT复常率、HBVDNA＜1000拷贝/ml的比率、HBeAg血清转换率以及与基线比较HBV DNA下降绝对值,差异均无统计学意义.联合组与单药组HBV DNA＜300拷贝/ml的患者分别为90.7%(49/54)和76.0%(38/50),两组比较,χ2=4.125,P＜0.05,差异有统计学意义.(4)治疗96周时,HBV DNA＜300拷贝/ml、HBV DNA＜1000拷贝/ml患者比率和HBeAg血清转换率,联合组分别为96.1%(49/51)、98.0%(50/51)、41.7%(15/36),单药组分别为79.2%(38/48)、87.5%(42/48)、16.7%(6/36),两组比较,χ2值分别为6.639、4.180、5.445,P值均＜0.05,差异有统计学意义;但两组患者与基线比较HBV DNA和HBsAg下降绝对值以及ALT复常率差异无统计学意义.(5)治疗96周时,联合组未见病毒学突破和耐药发生,而单药组累计发生病毒学突破4例,其中3例(6.3%,3/48)检测到ETV相关耐药基因变异位点,2例患者在基线时存在LAM相关耐药基因变异位点(rtL180M+M204V).(6)治疗48、96周时,联合组与单药组患者血肌酐水平及治疗前后血肌酐升高水平差异无统计学意义.在治疗期间,两组均无血清肌酐水平超过正常上限或由于肌酐升高0.5 mg/dl而调整剂量的患者.结论 LAM和ADV初始联合治疗,在减少病毒学突破和耐药发生,以及提高HBeAg血清转换率方面优于ETV单药治疗.

Abstract：

Objective To compare the efficacy and safety of Lamivudine (LAM) plus Adefovir dipivoxil (ADV) combination therapy and Entecavir(ETV) monotherapy for chronic hepatitis B patients.Methods 120 patients with chronic hepatitis B managed in a single-centre clinical practice (median 96 weeks)were split into 2 cohorts,one was treated with de-novo combination Lamivudine (100 mg/day) plus Adefovir (10 mg/day) (LAM+ADV),thc other with Entecavir (0.5 mg/day) monotherapy.Serum levels of ALT,creatinine,HBsAg,HBeAg and HBV viral load,together with genotypic resistence were analyzed at 0,12,24,48,96 weeks,respectively.HBV DNA was determined by real-time PCR.HBsAg and HBeAg were assessed by chemiluminescence.Serum levels of ALT and creatinine were detected by automatic biochemical analyzer.HBV genotypic resistence was tested by direct sequencing.Results (1) At the time point of 96 weeks,a total of 99 patients(51 cases in combination therapy cohort and 48 case in monotherapy cohort) were compared.The baseline characteristics as for HBV viral load,median age,serum levels of ALT and creatinine were compatible between combination therapy cohort and monotherapy cohort.(2) The rates of HBV DNA ＜300 copies/ml and HBV DNA ＜ 1000 copies/ml had no significant difference between LAM + ADV and ETV cohorts by the 12 and 24 weeks (P ＞ 0.05).(3) At the time point of 48 weeks,the rates of HBV DNA＜1000copies/ml,HBeAg seroconversion,and ALT normalization were similar in both cohorts,though the rate of HBV DNA ＜ 300 copies/ml was obviously higher in combination therapy cohort than that of monotherapy cohort (90.7% vs 76%,P ＜ 0.05).(4) At the time point of 96 weeks,the rates of HBV DNA ＜ 300 copies/ml (96.1% vs 79.2%),HBV DNA ＜ 1000 copies/ml (98% vs 87.5%) and the HBeAg seroconversion (41.7% vs 16.7%) were markedly higher in combination therapy cohort than those of monotherapy cohort statistically (P ＜ 0.05 for all).The mean values of decreases for HBV viral loads and HBsAg levels were smilar in both cohorts at 48 and 96 weeks.(5) Elevated serum creatinine not be found in both cohorts at the end of treatment.(6) No virological breakthrough occurred in combination therapy cohort at the end of treatment.Four patients in monotherapy cohort were found with virological breakthrough at 96 weeks and three cases among were confirmed to be of variants associated with ETV resistance (rtLl80M + T184L + M204V).Conclusions Present study suggests that Lamivudine plus Adefovir dipivoxil de-novo combination therapy was more efficacious than Entecavir monotherapy for CHB patients and the tolerance is compatible.     

乙型肝炎病毒YMDD变异的治疗对策

目的 探讨慢性乙型肝炎患者发生YMDD病毒变异后的治疗策略. 方法 2005年6月-2007年6月在门诊和住院的经拉米夫定治疗后出现YMDD变异的慢性乙型肝炎患者120例,随机分为4组,A组单用阿德福韦酯10 mg/d,治疗48周;B组采用阿德福韦酯10 mg/d,拉米夫定100 mg/d,联合治疗12周,后单用阿德福韦酯10mg/d治疗36周;C组采用阿德福韦酯10mg/d、拉米夫定100mg/d,联合治疗48周;D组接受恩替卡书1 mg/d,治疗48周.根据资料不同,分别采用方差分析、q检验和χ2检验.结果 4组患者治疗12周内ALT水平进一步反弹升高的患者比例分别为30.0%(9/30)、10.0%(3/30)、6.7%(2/30)、10.0%(3/30)(A组与B组、D组间比较χ2=3.750,P=0.053;A组与C组比较χ2=5.455,P<0.05).A组1例患者出现重型肝炎;治疗12周时4组患者YMDD变异株检测阳性率分别为17.2%、0、0、0;治疗48周时4组患者间ALT水平、HBeAg阳性患者血清转换率比较,差异均无统计学意义.C组、D组患者ALT复常率、HBVDNA达到检测水平以下的百分率与A组患者比较,χ2值分别为7.131、5.516、5.260、6.748,P值均<0.05,差异有统计学意义.4组患者的基因型耐药率分别为6.9%(2/29)、6.7%(2/30)、0、0,A组2例耐药患者测序为rtN236T变异,B组rtA181V和rtN236T变异各1例.结论 YMDD变异后采用阿德福韦酯与拉米夫定联合治疗或恩替卡韦治疗更安全有效.     

拉米夫定联合阿德福韦酯与换用恩替卡韦单药治疗拉米夫定应答不佳患者的疗效对比

目的 观察分别利用拉米夫定和阿德福韦酯联合治疗与换用恩替卡韦单药治疗拉米夫定应答不佳慢性乙型肝炎患者的临床疗效.方法 80例拉米夫定应答不佳的慢性乙型肝炎患者采用随机数字表法分为联合组和单药组,联合组服用拉米夫定100 mg/d和阿德福韦酯10mg/d;单药组服用恩替卡韦0.5 mg/d,观察两组患者治疗48周时的疗效.结果 治疗48周后,联合组的HBV DNA应答率、HBeAg转换率、ALT复常率分别为90.0％、40.0％和95.0％,远高于单药组的70.0％、15.0％和80.0％,两组比较差异均有统计学意义(P＜0.05).治疗48周后,联合组未出现病毒学突破病例;单药组共有2例患者出现病毒学突破.结论 对于拉米夫定应答不佳的慢性乙型肝炎患者,加用阿德福韦酯联合治疗的疗效优于换用恩替卡韦单药治疗,且可降低病毒耐药的发生率.