Virologic, serologic, and biochemical outcomes through 2 years of treatment with entecavir and lamivudine in nucleoside-naïve Chinese patients with chronic hepatitis B: a randomized, multicenter study

Purpose

Entecavir demonstrated superior virologic and biochemical benefits over lamivudine at 48 weeks in nucleoside-naïve Chinese patients with chronic hepatitis B (CHB). We evaluated the effect of continued entecavir and lamivudine treatment in patients who continued treatment in year 2 and the off-treatment durability of patients who achieved a protocol-defined consolidated response at week 48.

Methods

Chinese adults (n = 519) with CHB were randomized to a minimum of 52 weeks of treatment with entecavir 0.5 mg/day or lamivudine 100 mg/day. Patients with a consolidated response at week 48 (HBV DNA <0.7 MEq/ml for ≥24 weeks, ALT <1.25 times ULN, and, if HBeAg(+) at baseline, loss of HBeAg for at least 24 weeks) stopped treatment at week 52 and were followed off-treatment. Patients with a partial response at week 48 (HBV DNA <0.7 MEq/ml in the absence of other criteria for a consolidated response) could continue blinded treatment for up to 96 weeks. Patients were assessed for HBV DNA, ALT normalization, safety, and, if HBeAg(+) at baseline, for HBe seroconversion. Cumulative proportions of all treated patients who ever achieved these responses were also analyzed.

Results

Among patients treated during year 2 (entecavir: n = 193; lamivudine: n = 145), 74% of entecavir-treated and 41% of lamivudine-treated patients had HBV DNA <300 copies/ml by PCR at end of dosing and 96% of entecavir-treated and 82% of lamivudine-treated patients normalized ALT. Eleven percent of entecavir-treated versus 19% of lamivudine-treated patients underwent HBe seroconversion during year 2. Cumulative confirmed analysis for all treated patients through 96 weeks showed that 79% of entecavir-treated versus 46% of lamivudine-treated patients (p < 0.0001) achieved HBV DNA <300 copies/ml by PCR. Similar proportions of entecavir- and lamivudine-treated patients achieved confirmed ALT normalization and HBe seroconversion. Safety profile was comparable for both treatment groups.

Conclusions

Through 96 weeks of treatment, entecavir resulted in continued clinical benefit in nucleoside-naïve Chinese patients with CHB, with a safety profile comparable with lamivudine.     

恩替卡韦联合复方甘草酸苷治疗代偿期活动性乙型肝炎肝硬化患者的临床研究

目的观察ETv分散片联合复方甘草酸苷治疗代偿期活动性乙型肝炎肝硬化患者的临床疗效并探讨其作用机制,为进一步提高代偿期活动性乙型肝炎肝硬化临床疗效提供依据。方法将60例代偿期活动性乙型肝炎肝硬化患者随机分为研究组和对照组,对照组应用ETV分散片0．5mg／次,1次,d,晨起空腹口服。治疗组在对照组基础上联合复方甘草酸苷片75mg／次,37次／d,口服。两组患者疗程均为48周。比较两组患者治疗前后肝功能、血清肝纤维化指标、肝硬度指标、血清病毒学（HBVDNA、HBeAg及抗．HBe）指标,运用彩色多普勒超声检查比较肝脏、脾脏和门静脉内径变化。结果两组患者治疗48周肝功能指标（ALT、AST、ALB、TBil）、血清肝纤维化指标（HA、LN、PCIII、IV．C）和肝硬度指标比较差异均有显著统计学意义（P均=0．000）;两组患者治疗前后血清HBVDNA水平比较差异均有显著统计学意义（P均=O．000）,但组间比较差异均无统计学意义（P=0．490、0．630）。对照组治疗48周发生HBeAg低于检测下限的比率为30．8％、血清学转换率23．1％;治疗组治疗48周发生HBeAg低于检测下限的比率为50．0％、血清学转换率为35．7％。两组患者HBeAg低于检测下限的比率和血清学转换率比较,差异均有统计学意义（P=0．029、0．040）。两组患者治疗前后门静脉内径、脾脏长径、脾脏厚度、脾静脉宽度比较差异均无统计学意义（P=0．830、0．350、0．870、0．490）。结论ETv联合复方甘草酸苷对代偿期乙型肝炎肝硬化患者治疗有协同作用,其作用机制可能与抗-HBV、抗肝纤维化、改善肝功能、免疫调节等有关。     

Continuous Long-Term Entecavir Therapy in Na?ve Chronic Hepatitis B Patients Showing Partial Virologic Response

Background/Aims

We investigated the efficacy of continuous long-term entecavir 0.5 mg treatment in naïve chronic hepatitis B patients showing a partial virologic response (PVR).

Methods

A total of 227 patients were included. PVR was defined as a more than 1 log₁₀ IU/mL decline in detectable serum hepatitis B virus (HBV) DNA by polymerase chain reaction (PCR; ≥20 IU/mL) at week 48. A complete virologic response (CVR) was defined as undetectable serum HBV DNA by PCR (<20 IU/mL) at week 48.

Results

At week 48, the rate of the PVR was 64/227 (28.2%). Among patients with PVR, the cumulative rates of virologic response (serum HBV DNA <20 IU/mL) at weeks 96 and 144 were 45.2% and 73.8%, respectively. The cumulative rates of genotypic resistance were not significantly different between patients with a PVR and patients with a CVR (p=0.057). However, the cumulative rates of virologic breakthrough were higher in patients with PVR than in patients with CVR (4% vs 0% and 11.2% vs 0% at weeks 96 and 144, respectively; p<0.001).

Conclusions

Long-term continuous entecavir 0.5 mg treatment in patients with a PVR resulted in an additional virologic response without a significant increase in genotypic resistance. However, the rate of virologic breakthrough was higher in the partial responders.     

拉米夫定及恩替卡韦治疗非何杰金淋巴瘤相关性HBV再激活的疗效对比研究

目的对比观察拉米夫定、恩替卡韦在预防和治疗非何杰金淋巴瘤(NHL)合并慢性乙型肝炎病毒(HBV)感染的患者化疗期间出现HBV再激活的有效性。方法 2006年6月~2010年6月期间,共收集NHL合并HBV感染患者84例,在化疗同时服用拉米夫定(100 mg/d)或恩替卡韦(0.5 mg/d),对病毒学突破率,原发性无应答率、病毒学突破相关性肝炎突发等方面进行对比。结果抗乙肝病毒治疗前HBV DNA<103copies/mL组,服用拉米夫定或恩替卡韦的病毒学突破率、肝炎突发率无统计学差异(P>0.05)。抗乙肝病毒治疗前HBV DNA>103copies/mL组,服用拉米夫定的患者病毒学突破率为34.2%,原发耐药率为10.5%,肝炎突发率为26.3%,肝衰竭发生率为2.6%;服用恩替卡韦的患者上述指标分别为4.2%,0%,0%,0%,两者病毒学突破率及肝炎突发率有统计学差异(P<0.05)。结论 NHL并HBV感染患者抗乙肝病毒治疗前HBVDNA<103copies/mL,拉米夫定和恩替卡韦疗效相当;抗乙肝病毒治疗前HBV DNA>103copies/mL的患者恩替卡韦有更低的病毒学突破率及肝炎突发率,能更好地保证化疗的顺利进行。     

恩替卡韦治疗拉米夫定失效的慢性乙型肝炎患者5年的临床疗效

目的 评价恩替卡韦(ETV)对重庆地区拉米夫定治疗失效的慢性乙型肝炎(CHB)患者5年的疗效和安全性.方法 选取拉米夫定治疗失效的CHB患者32例,随机分为ETV组(剂量1.0 mg/d)28例和安慰剂组4例,完成12周的双盲治疗后,患者均接受开放的ETV(剂量1.0 mg/d)治疗,持续治疗至240周.分别检测治疗2、4、8、12、24、48、96、144、168、240周时患者的血清HBV DNA水平、HBsAg与HBeAg状态和肝功能情况.双盲阶段HBV DNA水平变化情况经Mauchly"球对称"检验后采用重复测量数据方差分析;连续性变量的统计描述用均数±标准差(x±s)表示.结果 在接受ETV治疗后,12周时ETV组患者血清HBV DNA水平平均下降4.05 log10拷贝/ml,安慰剂组平均下降0.08 log10拷贝/ml(P<0.05).治疗240周时,ETV组患者HBV DNA水平均值下降至2.58 log10拷贝/ml.HBV DNA<3 log10拷贝/ml患者的百分比在治疗前为0,从第8周开始上升(6.25%),24周时为15.6%,尤其在96周明显上升(50%),到240周末为57.14%.240周末有2例出现HBsAg血清学转换,4例出现HBeAg血清学转换.服用ETV后ALT水平下降较迅速,12周后均数达正常水平,且5年持续低于40 U/L.5年治疗期间,患者不良事件发生率为21%,有1例出现严重不良事件. 结论 ETV(1.0 mg/d)治疗拉米夫定失效的CHB患者具有显著的抗病毒和临床疗效,且安全性及耐受性良好.     

阿德福韦酯联合拉米夫定与单纯恩替卡韦对乙肝患者抗病毒效果的对比分析

目的 探讨对乙肝患者应用阿德福韦酯联合拉米夫定与单纯恩替卡韦的抗病毒效果比较。方法 选取笔者医院2011年1月～2012年1月收治的乙型肝炎患者136例,随机将样本分为对照组66例与观察组70例,对照组给予阿德福韦酯与拉米夫定的联合治疗,观察组给予单纯恩替卡韦治疗,观察两组患者的肝功能及乙肝病毒标志物的变化情况,并开展比较分析。结果 治疗后12个月与24个月,观察组患者在ALT复常率、HBV-DNA转阴率、HBeAg与HBeAb转换率3项指标中,均显著好于对照组,差异具有统计学意义（P＜0.01）。观察组患者治疗12个月的总应答率为77.1％,治疗24个月的总应答率为84.3％,均显著好于对照组,差异有统计学意义（P＜0.01）。结论 应用单纯恩替卡韦治疗乙型肝炎患者,能够更有效的清除乙肝病毒,改善患者的临床症状与体征,具有确切的临床疗效。     

恩替卡韦治疗失代偿期乙型肝炎肝硬化48周疗效观察

目的 观察恩替卡韦治疗失代偿期乙型肝炎肝硬化48周的疗效。方法 96例失代偿期乙型肝炎肝硬化患者被随机分为治疗组48例和对照组48例,其中治疗组给予恩替卡韦治疗48周。观察治疗前、治疗后24周和48周时的病毒学、生化学指标的变化情况。结果 患者在接受恩替卡韦治疗后24周和48周时血清HBV DNA水平小于1000 copies／ml比率分别为73．9％（34／46）和85．7％（36／42）,与对照组比较差别有显著性意义（P值分别等于0．009和0．004）;血清丙氨酸氨基转移酶复常率分别为84．8％（39146）和88．0％（37／42）,高于对照组的52．5％（21140）和44．1％（15／34）,差别有显著性意义（P值均为0．000）;Child-Pugh计分分别为8．42±2．78和8．92±2．76,较治疗前明显下降,也比对照组的10．75±3．14和11．41±2．69明显降低（P值分别为0．018和0．044）。结论 恩替卡韦治疗乙型肝炎肝硬化患者能有效地抑制病毒复制,降低HBV DNA水平,同时可以改善肝功能及Child-Pugh计分等指标。     

应用Cox比例风险模型分析抗病毒治疗对慢性乙型重型肝炎预后的影响

目的应用Cox比例风险模型分析核苷（酸）类似物抗病毒治疗对慢性乙型重型肝炎预后的影响。方法选择219例慢性乙型重型肝炎患者,采用Cox比例风险模型对可能影响其预后的因素进行单变量和多变量回归分析。重点分析核苷（酸）类似物抗病毒治疗对慢性乙型重型肝炎预后的影响。结果多变量回归分析结果显示：年龄、肝性脑病、总胆红素、白蛋白、凝血酶原活动度、血尿素氮、核苷（酸）类似物抗病毒治疗具有独立的预后意义（P〈0．05）。纠正混杂因素后,在多变量Cox比例风险模型中比较拉米夫定与恩替卡韦两种药物对慢性乙型重型肝炎预后的影响程度,两者无显著性差异（P〉0．05）;比较在慢性乙型重型肝炎的早期、中期和晚期抗病毒治疗对预后的影响程度,结果在早期和中期抗与不抗病毒治疗有显著性差异（P〈0．05）,但晚期抗与不抗病毒治疗已无显著性差异（P〉0．05）。结论核苷（酸）类似物抗病毒治疗是影响慢性乙型重型肝炎预后的独立因素。较早开始抗病毒治疗可以改善预后。拉米夫定和恩替卡韦均可选用于对这种患者的治疗。     

Combination treatment in HBeAg-negative chronic hepatitis B

Chronic hepatitis B (CHB) represents an important public health problem. HBeAg-negative CHB is frequently associated with advanced liver disease and its prevalence is increasing. Monotherapy with either interferon (conventional or pegylated) or nucleoside/nucleotide analogues has its limitations. It has been suggested that a combination of these agents might increase antiviral efficacy. However, existing data do not support this hypothesis, even though combination treatment appears to reduce the risk for emergence of lamivudine resistance. Nevertheless, most existing combination studies are small, and it is possible that they have not been designed to detect significant differences between combination treatment and monotherapies. Another limitation of these studies is that, in most of them, lamivudine treatment was discontinued after 1 year, a strategy that is not followed in clinical practice. It was thought to be interesting to evaluate the combination of a short course of interferon (particularly pegylated) with the long-term administration of nucleotide or nucleoside analogues. The efficacy of combining pegylated interferon with the newer nucleotide or nucleoside analogues or of nucleotide with nucleoside analogues could also be evaluated. However, findings show that until more data are available, combination therapy cannot be recommended as first-line treatment in patients with CHB. On the other hand, add-on therapy with adefovir or tenofovir is the treatment of choice in patients who develop resistance to lamivudine. In patients with cirrhosis, a combination of lamivudine/adefovir may also be used as initial treatment; another option would be to add tenofovir in patients with an insufficient response to entecavir.     

聚乙二醇干扰素α-2a治疗丙氨酸转氨酶异常但＜2倍正常值上限的HBeAg阳性慢性乙型肝炎患者24周临床研究

目的 观察聚乙二醇干扰素α-2a(Peg-IFN α-2a)治疗ALT＜2倍正常值上限(ULN)且肝组织学炎症活动度(G)≥2的HBeAg阳性慢性乙型肝炎患者的临床疗效.方法采用随机、开放、对照的研究方法,将55例ALT＜2×ULN且G≥2的HBeAg阳性慢性乙型肝炎患者分为Peg-IFN α-2a治疗组27例和恩替卡韦对照组28例,接受48周治疗,数据行卡方检验和t检验.结果治疗24周时,Peg-IFN α-2a组有8例患者HBeAg被清除,占29.6%(χ2=9.71,P＜0.01),其中6例HBeAg血清转换,占22.2%(χ2=6.98,P＜0.01);2例HBsAg被清除,占7.4%.Peg-IFN α-2a组与恩替卡韦组HBeAg滴度分别下降(1179.8±582.6) PEIU/mL和(441.5±258.8) PEIU/mL(t=2.66,P=0.01).恩替卡韦组和Peg-IFN α-2a组分别与其基线相比,HBV DNA分别下降(4.520±0.694)lg拷贝/mL和(3.520±1.442)lg拷贝/mL(t=2.45,P=0.029).Peg-IFN α-2a组G3患者较G2患者有更高的HBeAg阴转率(χ2=4.23,P=0.041).结论治疗24周时,Peg-IFN α-2a在HBeAg阴转、HBeAg血清转换、HBeAg滴度下降较恩替卡韦有明显优势,恩替卡韦降低HBV DNA载量更为有效.在基线肝组织炎症活动度较高患者中,Peg-IFN α-2a可能有更高的HBeAg清除率.