聚乙二醇干扰素初始联合核苷(酸)类似物治疗慢性乙型肝炎的疗效观察

[目的]观察聚乙二醇干扰素初始联合核苷(酸)类似物治疗e抗原阳性慢性乙型肝炎(CHB)患者的疗效。[方法]对60例慢乙肝治疗患者进行研究,A组患者(n=29)使用聚乙二醇干扰素α-2a(Peg-IFNα-2a)联合阿德福韦酯治疗48周,B组患者(n=31)使用Peg-IFNα-2a联合阿德福韦酯及拉米夫定治疗48周。观察治疗过程中12、24、48周时患者ALT复常率、HBV-DNA应答率、HBeAg、HBsAg的转阴率和转换率。[结果]2组治疗结束时ALT复常率分别为82.8%(24/29)、83.9%(26/31),HBV-DNA应答率分别为86.2%(25/29)、90.3%(28/31),HBeAg血清学转换率分别为34.5%(10/29)、35.5%(11/31),HBsAg血清学转换率6.9%(2/29)、6.5%(2/31),差异无统计学意义(P0.05)。[结论]Peg-IFNα-2a联合阿德福韦酯及拉米夫定治疗慢乙肝未显示疗效优势,初始全程Peg-IFNα-2a联合阿德福韦酯抗病毒治疗,可以提高病毒抑制的速度和血清学转换率。     

聚乙二醇干扰素α治疗核苷(酸)类似物经治慢性乙型肝炎患者专家会议纪要

随着对慢性乙型肝炎(CHB)抗病毒治疗研究的深入以及临床对CHB治疗经验的积累,越来越多的患者接受了抗病毒治疗.对于经过核苷(酸)类似物(NAs)规范治疗后未能获得病毒学或血清学应答,或在治疗中出现耐药以及达到治疗目标后停药复发的患者往往需要调整治疗策略.如何在这部分NAs经治患者中实现理想的治疗目标已经成为临床关注的热点,包括如何通过治疗策略的调整达到理想的治疗目标,如何实现停药后持久应答,以及如何对长期应用NAs应答不佳或者出现耐药的患者调整治疗方案等,仍是临床上尚未解决的问题.     

核苷(酸)类似物治疗慢性乙型肝炎部分应答后加用α干扰素继续治疗疗效分析

目的比较核苷(酸)类似物(NA)治疗慢性乙型肝炎(CHB)部分应答后加用α-干扰素组与未加用干扰素组的疗效。方法筛选出71例经NA抗病毒治疗后出现HBV DNA转阴,ALT复常半年以上,但持续未出现HBeAg血清转换的HBeAg阳性CHB患者,随机分为联合干扰素组(n=38例)和单用NA组(n=33例),观察治疗4、12、24、36和48周两组患者HBeAg阴转率、HBeAg血清转换率、生化及HBV DNA水平的变化。结果在治疗36周时,联合组HBeAg阴转率为36.8%,高于单用NA组的15.2%(P=0.039);在治疗48周时,联合组HBeAg阴转率和HBeAg血清转换率分别为42.1%和36.8%,明显高于单用NA组的18.2%和15.2%(P=0.030和0.039);治疗过程中两组均未出现ALT、HBV DNA波动及明显的不良反应。结论干扰素可辅助NA治疗,提高患者HBeAg血清转换率,是一种有效的治疗方法。     

不同核苷类似物序贯方案对干扰素治疗无应答伴肝功能损害慢性乙型肝炎的疗效比较

目的探讨核苷类似物序贯方案对干扰素治疗无应答伴肝脏损害慢性乙型肝炎的作用。方法随机选取我院2012年5月至2015年5月收治的90例干扰素治疗无应答伴肝脏损害慢性乙型肝炎患者,依据随机数字表法将患者分为替比夫定组(n=30)、恩替卡韦组(n=30)及阿德福韦酯组(n=30)3组。治疗后对三组患者的临床疗效及不良反应发生情况进行统计分析。结果替比夫定组和阿德福韦酯组患者的完全应答率均显著高于恩替卡韦组(P0.05),部分应答率均显著低于恩替卡韦组(P0.05),复发率均显著高于恩替卡韦组(P0.05),而替比夫定组患者的复发率又显著高于阿德福韦酯组(P0.05);替比夫定组患者的不良反应发生率显著高于恩替卡韦组和阿德福韦酯组(P0.05)。结论替比夫定、恩替卡韦、阿德福韦酯序贯治疗干扰素治疗无应答伴肝脏损害慢性乙型肝炎的效果均较好。     

干扰素治疗无应答的慢性乙型肝炎患者再治疗方法探讨

目的：探讨干扰素治疗无应答的慢性乙型肝炎患者再治疗的方法。方法选择病毒载量高（HBVDNA＞105 IU/mL）伴肝脏有损害的慢性乙型肝炎患者采用普通干扰素或聚乙二醇干扰素a-治疗24周～48周未达到持续无病毒核酸学（HBVDNA＞105 IU/ml或 HBVDNA下降小于2log）、无病毒血清学及生物化学指标应答效应的慢性乙型肝炎患者100例,进行核苷（酸）类似物（替比夫定、恩替卡韦、阿德福韦酯）序贯或联合治疗,疗程48周进行疗效评价,共随访240周。结果替比夫定组：40例中完全应答15例（37．5％）,部分应答25例（62．5％）,无应答0。恩替卡韦组：40例中完全应答6例（15％）,部分应答34例（85％）,无应答0。阿德福韦酯组：20例中完全应答15例（37．5％）,部分应答25例（62．5％）,无应答0。治疗结束时应答三组均100％。144周时持续应答恩替卡韦组及阿德福韦酯组均100％,理想应答0;替比夫定组持续应答35（87．5％）。复发5例（12．5％）进行基因耐药分析发现5例患者均为替比夫定耐药加用阿德福韦酯8周后病毒学应答;不作为疗效考核,无理想应答患者。192～240周时持续应答恩替卡韦组及阿德福韦酯组均100％,其中理想应答恩替卡韦组1例（2．5％）、阿德福韦酯组1例（5％）;替比夫定组持续应答40（100％）、理想应答2例（5％）。三组均未出现明显不良反应,替比夫定组10例肌酸激酶轻度升高未影响治疗,未发生末稍性神经炎。结论干扰素治疗无应答的慢性乙型肝炎患者进行核苷（酸）类似物序贯或联合治疗是最佳的选择。     

核苷(酸)类似物抗病毒治疗对慢性乙型肝炎患者细胞免疫功能的影响

我国是乙型肝炎病毒(hepatitis B virus,HBV)感染的高流行区,大样本的调查显示我国慢性HBV感染者高达1.2亿人之多.由于持续HBV感染及复制激发的免疫应答失调是慢性乙型肝炎(chronic hepatitis B,CHB)患者病情进展的根本原因,要阻止疾病进展,应进行有效的抗病毒治疗.核苷(酸)类似物是目前公认有效的抗HBV的药物之一,被广泛应用于临床,主要通过抑制DNA聚合酶的复制从而发挥抗HBV作用.其在有效抗病毒治疗的同时对机体细胞免疫功能有何影响.本文就近年来此方面的研究进展进行综述.     

拉米夫定和α-干扰素序贯联合治疗慢性乙型肝炎疗效观察

目的探讨拉米夫定与干扰素序贯联合治疗慢性乙型肝炎的疗效。方法30例慢性乙型肝炎患者接受拉米夫定100mg／13口服，直到血清HBVDNA转阴后，联合应用重组人IFN-α2b3MU肌肉注射24周，停拉米夫定，再单用IFN-α24周；对照组30例单用拉米夫定100mg口服，疗程1年。结果治疗结束时ALT复常率治疗组和对照组分别为90．0％和86．7％，两组差异无统计学意义（p〉0．05）。但随访6个月时ALT复常率治疗组和对照组分别为83．3％和56．7％，两组相比有显著性差异（P〈0．05）；治疗组治疗结束时及随访6个月时HBeAg阴转率分别为60．0％和56．7％，对照组阴转率分别为23．3％和20．0％（P〈0．01）；HBeAg转换率治疗组治疗结束时及随访6个月时分别为53．3％和53．3％，对照组分别为20．0％和20．0％（P〈0．01）；治疗结束时HBVDNA阴转率治疗组和对照组分别为86．7％和83．3％，两组差异无统计学意义（P〉0．05），但随访6个月时治疗组和对照组分别为70．0％和43．3％（P〈0．05）。结论拉米夫定与干扰素序贯联合治疗慢性乙型肝炎能明显提高抗病毒疗效，持续应答优于单用拉米夫定治疗者。     

恩替卡韦联合聚乙二醇干扰素α-2b治疗低水平血清HBsAg阳性的慢性乙型肝炎患者疗效研究

目的 探讨应用恩替卡韦(ETV)联合聚乙二醇干扰素α-2b(PEG-IFNα-2b)治疗血清低水平HBsAg阳性的慢性乙型肝炎(CHB)患者的临床疗效。方法 2018年1月～2020年1月我院收治的CHB患者96例,采用随机数字表法分成对照组48例和观察组48例,分别给予ETV或ETV联合PEG-IFNα-2b治疗观察48 w。采用荧光定量PCR法检测HBV DNA定量,采用电化学发光法检测血清HBsAg和HBeAg水平,使用流式细胞仪检测外周血CD3⁺、CD4⁺和CD8⁺细胞百分比,并计算CD4⁺/CD8⁺细胞比值。结果 在治疗48 w末,观察组血清HBsAg和HBeAg水平分别为(809.8±101.5)IU/mL和(193.4±24.5)IU/mL,均显著低于对照组【分别为(1201.7±204.9)IU/mL和(244.2±5.7)IU/mL,P<0.05】;观察组血清HBeAg转阴率为29.2%,显著高于对照组的4.2%(P<0.05),血清HBeAg转换...     

乙型肝炎e抗原阴性慢性乙型肝炎患者采用核苷(酸)类似物治疗停药的研究进展

强效、低耐药核苷(酸)类似物[nucleos(t)ide analogues,NAs]的应用已明显改善了慢性乙型肝炎(chronic hepatitis B,CHB)患者的预后,但是目前对乙型肝炎e抗原(hepatitis B e antigen,HBeAg)阴性CHB患者采用NAs治疗的停药问题尚存在较大争议。近年来...     

核苷(酸)类似物序贯干扰素治疗乙型肝炎病毒e抗原阳性慢性乙型肝炎患者的临床观察

目的 观察HBeAg阳性慢性乙型肝炎(CHB)患者在核苷(酸)类似物抗病毒治疗基础上序贯聚乙二醇干扰素α-2a(PEG IFNα-2a)治疗48周血清HBsAg的变化.方法 6例HBeAg阳性CHB患者中,3例采用核苷(酸)类似物序贯PEG IFNα-2a治疗48周,3例维持原核苷(酸)类似物治疗方案,每12周采用实时PCR定量检测HBV DNA,采用时间分辨免疫荧光分析法检测HBsAg、抗-HBs、HBeAg、抗-HBe及抗-HBc.结果 核苷(酸)类似物序贯PEG lFNα-2a治疗48周后,3例序贯治疗患者血清HBsAg均消失,而维持原核苷(酸)类似物治疗患者血清HBsAg效价为100～320 IU/mL.结论 对核苷(酸)类似物治疗产生较好应答反应且伴有血清HBsAg效价明显下降的HBeAg阳性CHB患者,在核苷(酸)类似物抗病毒治疗基础上序贯PEG IFNα-2a治疗48周能有效促进血清HBsAg下降,并出现血清HBsAg消失的现象.     

一线核苷(酸)类药物对慢性乙型肝炎患者脂质代谢的影响

慢性乙型肝炎(chronic hepatitis B,CHB)是我国重要的公共卫生问题.目前,核苷(酸)类似物[nucleos(t)ide analogs,NAs]是抗病毒治疗的一线用药,其长期服用的安全性问题也引起了临床医师的广泛关注.有研究表明,NAs抗病毒治疗可能影响脂质代谢,不同药物对脂质代谢的影响不同,脂质代...     

Exploration of nucleos(t)ide analogs cessation in chronic hepatitis B patients with hepatitis B e antigen loss

BACKGROUNDNucleos(t)ide analogs (NAs) cessation in chronic hepatitis B (CHB) patients remains a matter of debate in clinical practice. Current guidelines recommend that patients with hepatitis B e antigen (HBeAg) seroconversion discontinue NAs after relatively long-term consolidation therapy. However, many patients fail to achieve HBeAg seroconversion after the long-term loss of HBeAg, even if hepatitis B surface antigen (HBsAg) loss occurs. It remains unclear whether NAs can be discontinued in this subset of patients.AIMTo investigate the outcomes and factors associated with HBeAg-positive CHB patients with HBeAg loss (without hepatitis B e antibody) after cessation of NAs.METHODSWe studied patients who discontinued NAs after achieving HBeAg loss. The Cox proportional hazards model was used to identify predictors for virological relapse after cessation of NAs. The cut-off value of the consolidation period was confirmed using receiver operating characteristic curves; we confirmed the cut-off value of HBsAg according to a previous study. The log-rank test was used to compare cumulative relapse rates among groups. We also studied patients with CHB who achieved HBeAg seroconversion and compared their cumulative relapse rates. Propensity score matching analysis (PSM) was used to balance baseline characteristics between the groups.RESULTSWe included 83 patients with HBeAg loss. The mean age of these patients was 32.1 ± 9.5 years, and the majority was male (67.5%). Thirty-eight patients relapsed, and the cumulative relapse rate at months 3, 6, 12, 24, 36, 60, 120, and 180 were 22.9%, 36.1%, 41.0%, 43.5%, 45.0%, 45.0%, 45.0%, and 52.8%, respectively. Twenty-six (68.4%) patients relapsed in the first 3 mo after NAs cessation, and 35 patients (92.1%) relapsed in the first year after NAs cessation. Consolidation period (≥ 24 mo vs < 24 mo) (HR 0.506, P = 0.043) and HBsAg at cessation (≥ 100 IU/mL vs < 100 IU/mL) (HR 14.869, P = 0.008) were significant predictors in multivariate Cox regression. In the PSM cohort, which included 144 patients, there were lower cumulative relapse rates in patients with HBeAg seroconversion (P = 0.036).CONCLUSIONHBeAg-positive CHB patients with HBeAg loss may be able to discontinue NAs therapy after long-term consolidation, especially in patients with HBsAg at cessation < 100 IU/mL. Careful monitoring, especially in the early stages after cessation, may ensure a favorable outcome.     

Serum hepatitis B surface antigen levels predict treatment response to nucleos(t)ide analogues

Quantification of hepatitis B surface antigen(HBsAg)has been suggested to be helpful in the management of chronic hepatitis B(CHB)patients.Nucleos(t)ide analogs(NAs)are the therapy of choice for CHB and are used in the majority of CHB patients.NAs are able to induce hepatitis B virus(HBV)viral suppression,normalization of alanine aminotransferase(ALT)levels,and improvement in liver histology.Automated quantitative assays for serum HBsAg have recently become available,facilitating standardized quantification of serum HBsAg.This has led to increased interest in the clinical application of quantitative serum HBsAg for predicting therapeutic response to NAs.Recent studies have shown that a decline in serum HBsAg levels in patients receiving peginterferon may signal successful induction of immune control over HBV,and can therefore be used to predict therapeutic response.NA treatment typically induces a less rapid decline in HBsAg than interferon treatment;it has been estimated that full HBsAg clearance can require decades of NA treatment.However,a rapid HBsAg decline during NA therapy may identify patients who will show clearance of HBsAg.Currently,there is no consensus on the clinical utility of serum HBsAg monitoring for evaluating patient responses to NA therapy.This review focuses on recent findings regarding the potential application of HBsAg quantification in the management of CHB patients receiving NA therapy.     

核苷(酸)类似物抗乙型肝炎病毒应用进展及耐药新认识

核苷(酸)类似物是目前临床上治疗乙型肝炎的重要药物,但应用过程中可出现乙型肝炎病毒的变异,从而发生耐药。本文就核苷(酸)类似物在乙型肝炎治疗方面的进展以及病毒耐药的新认识作一综述。     

Pronounced decline of serum HBsAg in chronic hepatitis B patients with long-term effective nucleos(t)ide analogs therapy

Aims: This study aims to investigate the kinetics of serum HBsAg levels in chronic hepatitis B patients with long-term nucleos(t)ide analogs (NAs) therapy.

Methods: This was a retrospective clinical study. Serum HBsAg in serial samples of 94 patients, who received at least 8 years of NAs therapy, were measured using Elecsys^® HBsAg II Quant Assay.

Results: In this cohort, serum HBsAg levels reduced from 3.80 log10?IU/mL at baseline to 2.72 log10?IU/mL at year 8 (p?p?p?=?.001). As compared to patients with slow (0–1 log10?IU/mL) or steady HBsAg(≤0 log10?IU/mL) decline at year 1, patients with a rapid HBsAg (≥1 log10?IU/mL) decline had a significantly lower HBsAg levels from year 2 to 8. However, Cox regression analysis showed that only absolute HBsAg levels at year 1 was an independent predictor of subsequent HBsAg <1000?IU/mL at year 8 of antiviral therapy(HR 0.242, p?=?.004).

Conclusion: Pronounced HBsAg declines could be achieved in patients after long-term effective therapy with NAs, and on-treatment low serum HBsAg level at year 1 might be a predictor of serum HBsAg <1000?IU/mL at year 8.     

核苷(酸)类似物抗病毒治疗慢性乙型肝炎的优化策略

目前,我国有4种核苷(酸)类似物可用于慢性乙型肝炎(CHB)患者的抗病毒治疗,即拉米夫定、阿德福韦酯、恩替卡韦和替比夫定.但由于患者的性别、年龄、遗传背景、HBV感染途径、病毒基因型、病程长短、肝脏病变程度和对治疗药物敏感性等不同,即使有同样治疗适应证的患者按同样的规范方案治疗后,仍有相当一部分患者早期应答欠佳,从而影响了抗病毒治疗的长期疗效.如何进一步优化现有的治疗方案以提高远期疗效已成为国内外专家关注的热点问题.     

HBsAg clearance by Peg-interferon addition to a long-term nucleos(t)ide analogue therapy

The ideal endpoint of hepatitis B virus (HBV) antiviral therapy is HBsAg loss, a difficult goal to obtain, especially in HBeAg negative patients. Herein, we report the results obtained by the addition of peg-interferon α-2a to a long-lasting nucleos(t)ide analogue therapy in a HBeAg negative, genotype D patient with steadily HBV-DNA negative/HBsAg positive values. In 2002, our Caucasian 44-year-old male patient received lamivudine and, 4 years later, added adefovir because of a virological breakthrough. In 2011, considering his young age, liver stiffness (4.3 kPa) and HBsAg levels (3533 IU/mL), we added Peg-interferon α-2a for six months (3 in combination with nucleos(t)ide analogues followed by 3 mo of Peg-interferon α-2a monotherapy). A decrease of HBsAg levels was observed after 1 mo (1.21 log) of Peg-interferon and 3 mo (1.88 log) after the discontinuation of all drugs. Later, a complete clearance of HBsAg was obtained with steadily undetectable HBV-DNA serum levels (< 9 IU/mL). HBsAg clearance by the addition of a short course of Peg-interferon α-2a represents an important result with clinical and pharmaco-economic implications, considering that nucleos(t)ide analogues therapy in HBeAg negative chronic hepatitis B patients is considered a long-lasting/life-long treatment.     

Recent data on treatment of chronic hepatitis B with nucleos(t)ide analogues

Forty years ago in 1967, Professor Blumberg discovered the Australian Antigen, later known as the hepatitis B surface antigen, and was awarded the Nobel Prize. This discovery enables the diagnosis of hepatitis B virus (HBV) infection and defines its epidemiology. Viral hepatitis B infection affects global health situation, and chronic hepatitis B (CHB) is particularly serious in the Asia-Pacific region. HBV vaccines created the first breakthrough in HBV prevention. Through universal HBV vaccination program for the newborns, promoted since the mid-1980s, the main route that perpetuates chronic infection from mother to child is curbed. Most children and young adults now have immunity against HBV infection. The next breakthrough comes with therapy for CHB. This prevents progression to cirrhosis and hepatocellular carcinoma. Standard interferon therapy with modest efficacy has been largely replaced by therapy with nuclos(t)ide analogues or pegylated interferons alfa-2a and -2b. Lamivudine was approved by the FDA USA in 1998, followed by adefovir dipivoxil in 2002, entecavir in 2005, and telbivudine in 2006. Clevudine, tenofovir, and many promising candidates are in different stages of development and clinical trial. This paper critically reviews recent data published or presented since the APASL Consensus and Guideline Update of 2005. Clinical efficacy mostly in patients with raised serum alanine aminotransferase will be analyzed.