影响拉米夫定治疗慢性乙型肝炎持续性病毒学应答因素的Cox回归分析

目的通过Cox回归分析，探讨影响拉米夫定治疗慢性乙型肝炎持续性病毒学应答的相关因素。方法回顾性和前瞻分析72例应用拉米夫定治疗的慢性乙型肝炎患者的临床、实验室检查及HBV基因型资料。将基线ALT水平、基线病毒载量等10个可能影响因素用Cox比例风险模型进行单因素和多因素分析。结果基线ALT水平（X4）、基线病毒载量（X5）、应答时间（X8）及疗程（X9）是拉米夫定持续性病毒学应答的独立影响因素，得回归方程为：h（t）=hO（t）·exp（-0．488X4＋0．332X5＋1．309X8-5．480X9）。结论获得早期病毒学应答、基线病毒载量低、治疗前ALT水平高和治疗疗程较长的慢性乙型肝炎患者在拉米夫定治疗后有望获得持久的病毒学应答。     

Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B

BACKGROUND/AIMS: We aimed to evaluate nucleoside/nucleotide combination therapy in treatment-na?ve 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.     

End-of-treatment virologic response does not predict relapse after lamivudine treatment for chronic hepatitis B

AIM: Attaining hepatitis B e antigen (HBeAg) seroconversion during lamivudine treatment is associated with fewer relapses in HBeAg-positive patients. In HBeAg-negative patients, predictors for post-treatment relapse remain largely unknown. We therefore studied whether end-of-treatment virologic response correlated with relapse after lamivudine treatment. METHODS: We prospectively analyzed 12 HBeAg-negative patients and 14 HBeAg-positive patients with chronic hepatitis B, who received at least 9 mo of lamivudine treatment and were followed up for 12 mo post-treatment. Relapse of hepatitis B activity was defined by an elevation of serum ALT level above twice the upper limit of normal as well as reappearance of serum HBV DNA by the branched DNA assay or HBeAg during the follow-up period. The serum viral loads during and at the end of treatment were further determined by a quantitative real-time polymerase chain reaction assay. RESULTS: Relapse occurred in 6 (50.0%) HBeAg-negative patients within 12 mo post-treatment. Two relapsers had end-of-treatment serum viral load <1 000 copies/mL, the proportion was not significantly different from that in the 6 non-relapsers (33.3% vs 16.7%; P = 1.00). Hepatitis B virus (HBV) DNA levels did not correlate with post-treatment relapse in HBeAg-positive patients either. However, genotype C patients tended to have a lower relapse rate than genotype B patients (14.3% vs 57.9%, P = 0.08). CONCLUSION: Our results suggest that end-of-treatment virologic response cannot predict post-treatment relapse in patients with HBeAg-negative or -positive chronic hepatitis B. The impact of HBV genotype on the response to lamivudine treatment awaits further studies.     

Intrahepatic hepatitis B virus covalently closed circular DNA can be a predictor of sustained response to therapy

BACKGROUND & AIMS: This study aimed to determine whether intrahepatic hepatitis B virus (HBV) covalently closed circular (ccc) DNA and total HBV DNA levels at the end of therapy would predict sustained response to therapy. METHODS: Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients receiving either lamivudine monotherapy or combination of peginterferon and lamivudine had liver biopsy at the end of 1 year therapy and were followed for 52 more weeks after cessation of therapy. Serum HBV DNA, intrahepatic HBV ccc DNA, and total HBV DNA levels were determined. RESULTS: Forty-seven patients, including 34 males and 13 females, were studied. Twenty-seven patients received combination therapy, and 20 patients received lamivudine monotherapy. Twenty-nine patients had end-of-treatment virologic response, and 15 patients had sustained response 52 weeks after therapy. At the end of treatment, log serum HBV DNA levels correlated well with log intrahepatic HBV cccDNA and log intrahepatic total HBV DNA levels. Log intrahepatic cccDNA and log intrahepatic total DNA levels were significantly lower among patients with sustained virologic response. The adjusted odds ratio for log cccDNA was 5.3 (95% CI: 1.5-18.2, P = .009) and, for log intrahepatic HBV DNA, was 4.4 (95% CI: 1.3-14.7, P = .015) to predict sustained virologic response. Using log cccDNA at -0.80 copies/genome equivalent as cutoff, the sensitivity, specificity, and positive and negative predictive values and accuracy of predicting sustained virologic response were 73%, 78%, 56%, 86%, and 77% respectively. CONCLUSIONS: Intrahepatic HBV cccDNA and intrahepatic total HBV DNA levels at the end of therapy are superior to serum HBV DNA as surrogates of sustained virologic response.     

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.     

Tenofovir versus tenofovir plus entecavir for chronic hepatitis B with lamivudine resistance and entecavir resistance

We compared the viral suppressive efficacy of tenofovir disoproxil fumarate (TDF) mono‐rescue therapy (TDF group) and TDF plus entecavir (ETV) combination‐rescue therapy (TDF + ETV group) in chronic hepatitis B (CHB) patients with lamivudine resistance and entecavir resistance. One hundred and thirty‐three CHB patients with lamivudine and entecavir resistance were investigated. Ninety‐six patients were treated with TDF and 37 with TDF + ETV for at least 6 months. We compared the virologic response rate (HBV DNA level <20 IU/mL) between the two groups and identified the predictive factors of treatment outcome. There were no significant differences between the two groups in demographic characteristics. Up to 24 months [median: 18 (range 6‐24) months], 85.4% and 89.2% of the TDF group and TDF + ETV group, respectively, achieved a virologic response (P=.068). Only the HBV DNA level at baseline was significantly associated with a virologic response in the multivariate analysis. In a subanalysis of patients with HBV DNA levels ≥4 log (IU/mL) at baseline, a higher proportion of patients in the TDF + ETV group than the TDF group achieved a virologic response (92.9% vs 68.3%; P<.001), while 90% of patients with HBV DNA (IU/mL) levels <4 log in all both TDF and TDF + ETV groups achieved a virologic response. TDF mono‐rescue therapy is a reasonable option in patients with lamivudine resistance and entecavir resistance. However, the combination strategy should be considered in patients with high baseline HBV DNA levels.     

Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus

BACKGROUND AND AIMS: Prolonged lamivudine therapy is associated with treatment-resistant YMDD mutant hepatitis B virus (HBV). We evaluated the efficacy and safety of adding adefovir dipivoxil to lamivudine in 135 patients with chronic hepatitis B (CHB) and YMDD mutant HBV. METHODS: Ninety-five patients with compensated CHB (group A) were randomized to adefovir 10 mg daily (n = 46) or placebo (n = 49) for 52 weeks while continuing treatment with lamivudine. Forty patients with decompensated hepatitis B or post-liver transplantation (group B) received adefovir and lamivudine. The primary end point was a decline in serum HBV DNA level to 10(5) copies/mL or a >2 log(10) reduction from baseline at weeks 48 and 52. RESULTS: HBV DNA response occurred in 85% of patients (39 of 46) in group A given combined therapy versus 11% (5 of 46) receiving lamivudine alone (P < 0.001), with a significant change in HBV DNA level from baseline (P < 0.001) between treatment groups (median, -4.6 vs. +0.3 log(10) copies/mL, respectively). Normalization of alanine aminotransferase levels occurred in 31% of patients (14 of 45) receiving combined therapy versus 6% (3 of 48) receiving lamivudine alone (P = 0.002). Ninety-two percent of patients (36 of 39) in group B had an HBV DNA response (median change of -4.6 log(10) copies/mL) and improved liver chemistries (P < or = 0.001). Both treatment regimens were well tolerated, and renal function abnormalities were not observed in either group. CONCLUSIONS: The addition of adefovir dipivoxil to lamivudine in patients with CHB with compensated or decompensated liver disease due to YMDD mutant HBV is associated with virologic and biochemical improvement during 52 weeks of treatment and is well tolerated.     

Long-term lamivudine treatment for chronic hepatitis B in Japanese patients： A project of Kyushu University Liver Disease Study

AIM:To determine the efficacy of long-term lamivudinetreatment of a large number of Japanese patients withchronic hepatitis B.METHODS:In this retrospective,multi-center trial,318 Japanese patients with chronic hepatitis B received100 mg of lamivudine daily for up to 36(median 21)mo.Virological response was a decline to a serumHBV DNA level less than 3.7 log copies/mL.Virological breakthrough was defined as the reappearance of aserum HBV DNA level to more than 10-fold the minimumduring treatment.RESULTS:Lamivudine produced virological responsein 86.8% of the 318 patients at 6 mo,in 80.2% of252 patients at 12 mo,in 69.2% of 133 patients at 24mo,and in 53.6% of 28 patients at 36 mo.Forwardstepwise logistic regression analysis showed an HBV DNAlevel less than 6.8 log copies/mL(P<0.0001),HBeAgnegativity(P<0.0001),a platelet count of 100×10~9/L ormore(P=0.0162)at baseline,and a decline of the HBVDNA level of more than 3.2 log copies/mL as comparedwith the baseline level at 3 mo after the start oftreatment(P=0.0003)to be significantly associated withvirological response.Among patients with a virologicalresponse,virological breakthrough was seen in 5.3%of 19 patients who responded virologically at 1 mo,in20.7% of 203 patients at 3 mo,in 27.5% of 51 patientsat 6 mo,in 33.3% of 12 patients at 9 mo,and in 100%of 3 patients at≥15 mo.A virological breakthrough wasfound significantly more often in patients with delayedvirological response.CONCLUSION:Lamivudine treatment could suppressserum HBV DNA in most of the tested Japanese patients.Long-term efficacy might be seen in patients withoutHBeAg at baseline,in the absence of cirrhosis,and inpatients with a decline in HBV DNA level soon after thestart of treatment.     

Long-term efficacy of entecavir in adefovir-refractory chronic hepatitis B patients with prior lamivudine resistance

This study aimed to evaluate the long-term efficacy of entecavir (ETV) in adefovir (ADV)-refractory chronic hepatitis B (CHB) patients with prior lamivudine (LMV) resistance. A total of 55 ADV-refractory CHB patients with prior LMV resistance, who received rescue therapy with ETV 1 mg daily for at least 12 months, were consecutively enrolled and analysed. Forty-four patients were men, and their median age was 47 (25-69). Ten patients had liver cirrhosis and 46 patients were positive for hepatitis B e antigen (HBeAg). Median hepatitis B virus DNA levels were 6.6 (4.3-8.0) log(10) copies/mL, and the median duration of ETV therapy was 24 (12-47) months. Cumulative virologic response rates at 6, 12, 24 and 36 months were 18%, 29%, 58% and 75%, respectively. HBeAg loss occurred in 10 (21.7%) of 46 HBeAg-positive patients. In multivariate analysis, only initial virologic response at 3 months remained as an independent predictor for virologic response (RR 3.143; 95% CI 1.387-7.120; P = 0.006). The patients with a virological response at 3 months had not only a significantly higher probability of achieving a virologic response (P < 0.001) but also lower probability of experiencing a virologic breakthrough (P = 0.043) than the patients without an early response. Viral breakthrough was observed in 29 patients during the follow-up period. Cumulative breakthrough rates at 6, 12, 24 and 36 months were 0%, 15%, 45% and 73%, respectively. ETV monotherapy may be considerably efficacious in cases with an initial virological response but its efficacy is attenuated by frequent emergence of ETV resistance in ADV-refractory CHB patients with prior LMV resistance.     

拉米夫定治疗慢性乙型肝炎的疗效影响因素

目的 探讨拉米夫定治疗慢性乙型肝炎患者的疗效影响因素,并初步评价基线特征、24周早期病毒学应答及治疗方案对疗效和病毒学突破(VB)发生率的影响.方法 对接受拉米夫定治疗的233例慢性乙型肝炎患者(其中90例治疗期间加用或换用阿德福韦酯)的专科门诊病历资料进行回顾性分析,采用聚合酶链反应法、酶联免疫吸附法分别检测HBV DNA水平与HBsAg、抗-HBs,HBeAg,抗-HBe水平.用SPSS17.0统计软件通过Kaplan-Meier法描述生存时间分布,并分析基线HBV DNA水平,HBeAg状态、ALT水平和疗效的关系.计量资料用t检验分析,计数资料用x2检验.结果 HBeAg阳性与HBeAg阴性患者HBV DNA阴转率分别为63.4%和84.6%,ALT复常率分别为83.8%和81.3%,VB发生率分别为31.0%和14.3%;60.6%的HBeAg阳性患者出现HBeAg阴转,28.9%出现HBeAg/抗-HBe血清学转换.HBeAg阳性患者中,与基线ALT<2.5×正常值上限(ULN)者比较,≥2.5×ULN者HBV DNA阴转率无明显变化(P>0.05),而HBeAg阴转率(66.7%与45.0%)和HBeAg血清学转换率(33.3%与17.5%)明显升高(P值均<0.05),VB发生率则明显下降(34.3%与50.0%,P<0.05),基线HBV DNA<1×106拷贝/ml者VB发生率为23.4%,与HBV DNA≥1×106拷贝/ml者的46.3%比较,差异有统计学意义(P<0.05).HBeAg阳性患者24周有初始病毒学应答(IVR)者的HBV DNA阴转率(76.3%与45.5%)、HBeAg阴转率(72.4%与43.9%)和HBeAg血清学转换率(40.8%与12.1%)均明显高于无IVR者(P值均<0.01),VB发生率较低(28.9%与45.5%,P<0.05).出现VB后,与单一拉米夫定组比较,加药或换药组中HBeAg阳性者HBV DNA阴转率(40.6%与16.7%)、HBeAg血清学转换率(21.9%与0)较高,HBeAg阴转率(37.5%与41.7%)较低,ALT复常率无差别(均为75%);而HBeAg阴性患者的HBV DNA阴转率、ALT复常率较高.结论 拉米夫定抗病毒疗效确切,基线ALT≥2.5×ULN和(或)HBV DNA水平<1×106拷贝/ml的患者疗效较好,VB发生率较低,24周IVR对拉米夫定疗效有预测价值;出现VB后,加用或者换用阿德福韦酯比继续单用拉米夫定治疗的效果好.     

A three-month course of lamivudine therapy in HBeAg-positive hepatitis B patients with normal aminotransferase levels.

BACKGROUND/AIMS: HBeAg-positive patients with normal ALT levels are unlikely to respond to current therapy. In addition, there is a high risk of hepatocellular carcinoma in HBeAg-positive patients in the natural course of HBV infection. For this purpose, we aimed to investigate the clinical efficacy and safety of a three-month course of lamivudine therapy in HBeAg-positive hepatitis B patients with normal aminotransferase levels for assessing a more practical and economical approach to these patients. METHODS: Forty-six patients were prospectively randomized into two groups. Group A consisted of 13 patients treated with lamivudine 100 mg/day, for 12 weeks [7 males, mean age 23.30+/-5.82 years, median ALT of 27 IU/L (21-40), median HBV DNA of 4116 pg/ml (2885-6628)]. Group B consisted of 33 patients without treatment [18 males, mean age 24.75+/-6.92 years, median ALT of 30 IU/L (19-39), median HBV DNA of 4094 pg/ml (782-7387)]. Main outcome measure was sustained virologic response, which was defined as loss of HBV DNA in serum with HBeAg seroconversion at least 12 months thereafter. Follow-up lasted 12 months after the first dose. RESULTS: No significant effects were observed in the treated population in the reduction of HBV DNA to undetectable levels, in HBeAg/anti-HBe seroconversion, or in transaminase levels. At the end of follow-up, sustained virologic response was almost similar in the study as well as control group (7.6% vs. 3.0%, p=0.502). None of the 13 patients who received lamivudine therapy had HBeAg seroconversion during the study period. In addition, the suppression of serum HBV DNA was temporary; prolonged suppression could be achieved in only one patient in the follow-up period. The median levels of HBV DNA and ALT values between baseline and month 12 did not differ significantly between groups. All patients remained HBsAg positive and none developed anti-HBs. The therapy was well tolerated and post-therapy flare was not observed in any patient after stopping lamivudine therapy. CONCLUSIONS: A short course of lamivudine therapy resulted mostly in only temporarily depressed serum HBV DNA levels without significant change in viral clearance. Whether permanent suppression of HBV DNA can be achieved in this special population of HBsAg carriers by long-term treatment with lamivudine awaits further controlled trials. New and safe modalities of therapy are needed for the satisfactory treatment of these asymptomatic but viremic patients.     

阿德福韦酯单药挽救治疗对拉米夫定耐药的慢性乙型肝炎患者3年疗效观察

目的总结阿德福韦酯(ADV)单药挽救治疗拉米夫定(LAM)耐药慢性乙型肝炎患者效果,分析疗效影响因素,探讨单药挽救LAM耐药的可行性。方法 60例慢性乙型肝炎应用LAM耐药后入组挽救治疗。收集患者的基本特征:如年龄、性别、肝生化指标、HBV DNA及HBV M。纪录治疗持续时间及应答,并进行分组对照。结果 60例中,HBV DNA定量反弹≥1log10拷贝/ml 20例,HBV DNA测序rtM204I/V、rtL180M位点变异40例。生化学突破的LAM耐药患者,给予ADV单药治疗。完成156周治疗者42例。HBV DNA低复制组(基线水平HBV DNA 103～105拷贝/ml)治疗后第12至156周HBV DNA转阴率均为80.0%,高复制组(基线水平HBV DNA≥106拷贝/ml)转阴率为40.7%～44.7%,两组相比差异有统计学意义(P<0.01)。HBV DNA转阴率随治疗时间延长渐增加。治疗156周时,HBeAg阳性血清学转换率24.1%。4例因检测出rtA181V/I/S位点变异改用恩替卡韦(ETV)。结论 ADV单药挽救治疗LAM耐药慢性乙型肝炎,具有一定的疗效,且更适合于低病毒载量患者。     

Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation

BACKGROUND/AIMS: The susceptibility of adefovir-resistant hepatitis B virus (HBV) mutants is only reduced by 3-10-fold in in vitro studies, suggesting that virologic breakthrough and clinical deterioration are unlikely. The aim of this study was to describe the clinical course of patients with adefovir-resistant HBV infection. METHODS: Testing for adefovir-resistant mutations was performed on patients who had a suboptimal response or virologic breakthrough on adefovir. Adefovir-resistant mutations were detected using a line probe assay and direct sequencing of the HBV P-gene. RESULTS: Eight male patients with pre-existing lamivudine resistance or breakthrough (mean age 47+/-13 years) were found to have adefovir-resistant mutations rtA181V/T or rtN236T. Baseline median ALT was 66 IU/L (range, 27-1161) and median HBV DNA 7.9 log10 copies/ml (range, 6-8.3). At the time of adefovir resistance (mean of 20+/-9 months), HBV DNA increased to > or = 5 log10 copies/ml in 7 patients. After detection of adefovir resistance, hepatic decompensation occurred in 2 patients, 1 of whom died. Salvage therapy with lamivudine, entecavir or tenofovir was given to 7 patients and a reduction in HBV DNA by > or = 3 log10 was seen in 3 patients. CONCLUSIONS: In conclusion, adefovir resistance can be associated with significant viral rebound and hepatic decompensation which may be fatal.     

Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B

BACKGROUND AND AIMS: Adefovir dipivoxil possesses potent in vitro and in vivo antiviral activity in wild-type hepatitis B. This study assessed the safety and efficacy of adefovir dipivoxil alone and in combination with lamivudine compared with ongoing lamivudine therapy in patients with chronic hepatitis B with compensated liver disease and lamivudine-resistant hepatitis B virus (HBV). METHODS: Fifty-nine hepatitis B e antigen (HBeAg)-positive patients with genotypic evidence of lamivudine-resistant HBV, serum alanine aminotransferase (ALT) level > or =1.2 times the upper limit of normal, and serum HBV DNA level > or =6 log(10) copies/mL despite ongoing treatment with lamivudine were randomized to adefovir dipivoxil 10 mg, lamivudine 100 mg, or addition of adefovir dipivoxil to ongoing lamivudine daily. The primary end point was the time-weighted average change from baseline in serum HBV DNA level (DAVG) up to week 16. RESULTS: Rapid reductions in serum HBV DNA level were seen by 4 weeks in all recipients of adefovir dipivoxil; DAVG(16) was -0.07 in the lamivudine group compared with -2.45 and -2.46 log(10) copies/mL in the adefovir dipivoxil/lamivudine and adefovir dipivoxil monotherapy groups, respectively (P < 0.001). Median change from baseline in serum HBV DNA level at week 48 was 0.0, -3.59, and -4.04 log(10) copies/mL in the lamivudine, adefovir dipivoxil/lamivudine, and adefovir dipivoxil groups, respectively. ALT level normalized in 10 of 19 (53%) and 9 of 18 (47%) recipients of adefovir dipivoxil/lamivudine and adefovir dipivoxil, respectively, compared with 1 of 19 (5%) recipients of lamivudine. Three patients receiving adefovir dipivoxil or adefovir dipivoxil/lamivudine and none receiving lamivudine monotherapy were HBeAg negative at week 48 and one became hepatitis B surface antigen negative. CONCLUSIONS: These data, limited to patients with compensated liver disease, indicate that adefovir dipivoxil alone or in combination with ongoing lamivudine therapy provides effective antiviral therapy in patients with lamivudine-resistant HBV.     

Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks

In hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients who were refractory to current lamivudine therapy, switching to entecavir was superior to continued lamivudine at week 48 for histologic improvement, viral load reduction by polymerase chain reaction and alanine aminotransferase normalization. We assessed the efficacy, safety, and resistance profile of entecavir through 96 weeks of treatment. A total of 286 patients were randomized and treated with entecavir 1 mg (n = 141) or continued lamivudine 100 mg (n = 145). At week 52, 77 entecavir-treated patients who had a protocol-defined virologic response (HBV branched DNA [bDNA] < 0.7 MEq/mL but HBeAg-positive) continued blinded therapy for up to 96 weeks. Patients were assessed for efficacy, safety, and emerging resistance. Cumulative proportions of all treated patients who achieved confirmed efficacy endpoints were also analyzed. Between week 48 and the end of dosing, the proportions of patients with HBV DNA <300 copies/mL by polymerase chain reaction increased from 21% to 40%, and alanine aminotransferase normalization (< or =1x upper limit of normal) increased from 65% to 81%. In the second year, HBeAg seroconversion was achieved by 10% of patients. Of the 77 patients in the second year treatment cohort, entecavir resistance emerged in six patients, and seven experienced virologic breakthrough (five with genotypic resistance acquired before year 2). The safety profile of entecavir in the second year of therapy was consistent with that reported during year 1. CONCLUSION: Through 96 weeks of treatment, 1 mg entecavir resulted in continued clinical benefit in lamivudine-refractory HBeAg-positive chronic hepatitis B patients with a safety profile comparable to lamivudine.     

Effects of antiviral agents and HBV genotypes on intrahepatic covalently closed circular DNA in HBeAg-positive chronic hepatitis B patients

AIM： To evaluate the effects of antiviral agents and HBV genotypes on intrahepatic covalently closed circular DNA （ccc DNA） in HBeAg-positive chronic hepatitis B patients.
METHODS： Seventy-one patients received lamivudine （n = 35）, or sequential therapy with lamivudine- interferon alpha 2b （IFN-α 2b, n = 24） for 48 wk, or IFN-α 2b （n = 12） for 24 wk. All subjects were followed up for 24 wk. Intrahepatic ccc DNA was measured quantitatively by PCR. HBV genotypes were analyzed by PCR-RFLP.
RESULTS： Sequential lamivudine- INF-α therapy, lamivudine and INF-α monotherapy reduced ccc DNA of 1.7 log, 1.4 log and 0.8 log, respectively （P 〈 0.05）. Seventeen out of the 71 patieots developed HBeAg seroconversion, the reduction of ccc DNA in the HBeAg seroconversion patients was more significant than that in the HBeAg positive patients （3.0 log vs 1.6 log, P = 0.0407）. Twenty-four weeks after antiviral therapy withdrawal, 16 patients had a sustained virological response, the baseline intrahepatic ccc DNA in the patients with a sustained virological response was significantly lower than that in the patients with virological rebound （4.6 log vs 5.4 log, P = 0.0472）. HBV genotype C accounted for 85.9% （n = 61）, and genotype B for 14.1% （n = 10）, respectively, in the 71 patients. There was no significant difference in the change of ccc DNA level between HBV genotypes C and B （2.1 log vs 1.9 log）.
CONCLUSION： Forty-eight week sequential lamivudine- INF-α therapy and lamivudine monotherapy reduce ccc DNA more significantly than 24-wk INF-α monotherapy. Low baseline intrahepatic ccc DNA level may predict the long-term efficacy of antiviral treatment. HBV genotypes C and B have no obvious influence on ccc DNA load.     

拉米夫定治疗慢性乙型肝炎的耐药分析及处理

目的 探讨拉米夫定长期治疗慢性乙型肝炎(CHB)患者的耐药因素及其耐药后处理措施,为合理应用拉米夫定提供依据.方法 2001年9月-2010年1月应用拉米夫定初治的CHB患者383例,治疗观察满1年.其中发生病毒学突破或反弹患者129例,分为换用阿德福韦酯治疗组和加用阿德福韦酯治疗组.疗效评估包括血清HBV病毒学、血清HBV免疫学、血生物化学应答,观察时间至少1年.定性资料采用X2检验,反弹时间分布关系用生存分析曲线描述.结果383例CHB患者3个月、半年、1、2、3年以及3年后HBV DNA阴转率分别为40.7%、55.6%、59.5%、56.7%、55.9%和55.6%.HBeAg血清学转换62例,占22.6%.原发耐药12例,突破反弹129例,累计耐药率为36.8%,累计反弹率为34.8%.基线高病毒载量、基线ALT水平<2倍正常值上限、治疗24周时的病毒学低应答,与较高的反弹率相关,X2值分别为35.716、8.728和43.534,P值均<0.01.病毒学突破反弹发生在1年半内112例(86.8%),2年内123例(95.3%),5年以后未再发现病毒学突破反弹患者.129例病毒学突破反弹的患者予以换用阿德福韦酯或加用阿德福韦酯继续治疗,换药和加药后的再次阴转率分别为22.7%(15/66)和58.7%(37/63),病毒学应答率分别为59.1%(39/66)和87.3%(55/63),x2值分别为17.364和12.975,P值均<0.01,差异有统计学意义.结论拉米夫定初始治疗的CHB患者,耐药反弹主要发生在2年以内,对于拉米夫定耐药的CHB患者,拉米夫定联合阿德福韦酯比单用阿德福韦酯治疗可取得更好的疗效.

Abstract：

Objective To study the factors influencing the long-term usage of lamivudine(LAM)in chronic hepatitis B(CHB)patients and the management after drug-resistance.Methods 383 cases of naive CHB patients in our outpatient clinic were treated with lamivudine (100mg/d)and followed up for at least over 1 year from 2001 to 2010.129 cases encountered lamivudine-resistance and were then divided into two groups:patients in group A were switched to adefovir dipivoxil(ADV)alternative treatment and those patients in group B were added with ADV for continuous treatment.Efficacy assessment factors included serum HBV markers,HBV DNA,ALT,AFP and other biochemical indicators.Results Among the 383 cases,patients with HBV DNA negative conversion(PCR below test line)at 3 months,6 months,1 year,2 years,3years and>3 years after initial treatment were respectively 156 cases(40.7%),213 cases(55.6%),228 cases (59.5%),217cases(56.7%),214 cases(55.9%)and 213 cases(55.6%).HBeAg/HBeAb seroconversion occurred in 62 cases(22.6%).12 cases were found with primary LAM resistance,129 cases with HBV breakthrough and rebound.the cumulative resistance rate was 36.8%and the cumulative rebomad rate was 34.8%.High baseline viral load,baseline ALT levels < 2 ULN,Lower virologic response rate at week 24 were associated with a higher rebound rate ( x2 is 35.716,8.728,43.534,respectively,all with P < 0.01).Viral breakthrough and rebound occurred in 112 patients (86.8%) within 1 year and a haf,123 patients (95.3%)occurred at the end of 2 years and no patient with viral breakthrough and rebound after 5 years. For the patients with viral rebound in group A and group B,the rates of HBV DNA loss were 22.7% (15/66)and 58.7% (37/63) respectively,and the viral response rates were 59.1% (39/66) and 87.3% (52/63)respectively,with x2 values equaled 17.364 and 12.975 respectively (P < 0.01). Conclusion For the chronic hepatitis B patients on initial treatment with lamivudine,the viral rebound occurred mainly within 2 years. LAM combined with ADV is more effective than ADV alone for lamivudine-resistant patients.     

Low efficacy of entecavir therapy in adefovir‐refractory hepatitis B patients with prior lamivudine resistance

Summary. We determined the virologic response, incidence of entecavir resistance, and evolution of lamivudine and adefovir‐resistant mutants during entecavir (ETV) therapy in adefovir‐refractory patients with prior lamivudine resistance. Forty adefovir‐refractory chronic hepatitis B patients with prior lamivudine resistance who had received entecavir for ≥6 months were included and monitored for virologic response and entecavir resistance. Ten per cent of patients achieved HBV DNA < 50 copies/mL by PCR after 24 weeks of ETV therapy, and an initial virologic response was observed in 12 of 40 patients (30%). Higher pretreatment ALT (P = 0.039) and the presence of the rtL180M mutation (P = 0.038) were associated with an initial virologic response. During a mean follow‐up of 11.4 months, four patients (10%) experienced virologic breakthrough, while ETV‐resistant mutants were detected in six patients (15%). YMDD and adefovir‐resistant mutants were detected in 57 and 35% of patients at baseline, respectively. At 48 weeks of therapy, 96 and 4% of patients had YMDD and adefovir‐resistant mutants, respectively. These data suggest an early development of ETV resistance and low antiviral response during ETV therapy in adefovir‐refractory patients with prior lamivudine resistance.     

拉米夫定治疗慢性乙型肝炎患者3年疗效观察

目的初步探讨LAM长期治疗HBeAg阳性和HBeAg阴性的两组慢性乙型肝炎(CHB)患者生化学、病毒学指标的变化及临床转归的差异。方法对63例诊断为CHB的患者均给予拉米夫定100mg,每日一次,进行3年的随访观察,动态检测患者的HBV血清标志物,HBV DNA,ALT、AFP、YMDD变异、B超等指标。结果拉米夫定治疗HBeAg阳性和HBeAg阴性的CHB患者3年时,HBeAg阳性组ALT复常率、HBV DNA阴转率、肝细胞癌发生率及HBsAg阴转率分别为64.7%、64.7%、0%、0%;HBeAg阴性组ALT复常率、HBV DNA阴转率、肝细胞癌发生率及HBsAg阴转率分别为70.4%、77.8%、0%、0%。两组间ALT复常率、HBV DNA阴转率、肝细胞癌发生率及HBsAg阴转率两组差异均无统计学意义(P0.05);HBeAg阳性组YMDD变异率(43.3%)显著高于HBeAg阴性组(18.2%),x2=4.720,P0.05;HBeAg阴性组肝硬化患者(37.0%)显著高于HBeAg阳性组(5.9%),x2=3.866,P0.05。结论拉米夫定治疗HBeAg阳性CHB患者较HBeAg阴性患者更容易发生YMDD变异,HBeAg阴性CHB患者较HBeAg阳性患者更易发生肝硬化。     

Diagnosis and treatment of chronic hepatitis B: an update

The diagnosis of chronic hepatitis B virus (HBV) infection is made using a combination of serological, virologic, biochemical, and histologic markers. The natural history of HBV infection can be divided into four phases: immune tolerance, immune clearance (HBeAg-positive chronic hepatitis B), inactive HBsAg carrier, and reactivation (HBeAg-negative chronic hepatitis B). Patients in the immune clearance and reactivation phases, with elevated alanine aminotransferase (ALT) and HBV DNA levels, are candidates for antiviral therapy. The primary goal of therapy for chronic hepatitis B is suppression of viral replication, which has been shown to reduce hepatic necroinflammation and retard progression of hepatic fibrosis. Long-term suppression of serum HBV DNA is likely to reduce progression to cirrhosis and hepatic decompensation and decrease the risk of hepatocellular carcinoma. Current antiviral therapy for chronic hepatitis B includes interferon alfa, peginterferon alfa-2a, lamivudine, adefovir, entecavir, and telbivudine. In patients with HBeAg-positive chronic hepatitis B, antiviral treatment is indicated when the serum HBV DNA level is = or > 10(5) copies/mL (20,000 IU/mL) and the ALT level is elevated. For HBeAg-negative patients, the threshold for initiation of therapy is lower, i.e., a serum HBV DNA level = or > 10(4) copies/mL (2,000 IU/mL) in association with an elevated ALT level. The presence of at least moderate necroinflammation and the presence of fibrosis on liver biopsy, which is optional and not mandatory before therapy, may be useful in supporting the decision to initiate therapy, particularly in patients with normal ALT levels. While undergoing therapy, patients require monitoring every 3 to 6 months to ensure compliance and to test for the development of resistance if an oral agent is used. Issues that remain controversial or need to be studied further are the necessity of a baseline liver biopsy, the HBV DNA and ALT thresholds for initiation of therapy, the optimal duration of antiviral therapy, selection of one agent over another, and the role of combination therapy.