Sustained Responses in Chronic Hepatitis B Patients with Nucleos(t)ide Analogue Drug-resistance after Peg-interferon Alfa-2a Add-on Treatment:A Long-term Cohort Study

Background and Aims:The use of additional nucleos(t)ide analogues(NAs)without cross-resistance to previously used NAs as a rescue therapy is recommended by most international guidelines for chronic hepatitis B patients with NAresistance.We aimed to investigate the efficacy and safety of combination therapy of peg-interferon(PegIFN)alfa-2a and NA in these patients,comparing to those who switch to an alternative NA therapy without cross-resistance.Methods:In this prospective,comparative and cohort study,data were collected from the patients'hospital records.Eligible patients were those with hepatitis B e antigen(HBeAg)positivity and resistance to one or more NAs.All patients were treated with alternative NA alone or in combination with PegIFN alfa-2a for 52 weeks or 72 weeks,respectively.HBeAg seroconversion was measured at the end of follow-up(EOF;more than 104 weeks after the end of treatment).Results:Sixty-three patients were recruited to the cohort study(NAtherapy group=31 patients;combination therapy group of NA and PegIFN alfa-2a=32 patients).At the EOF,significantly more patients in the combination therapy group(13/27,48.2%)achieved primary outcome of HBeAg seroconversion than those in the NA therapy group(4/32,12.5%)(p=0.003).Four patients(14.8%)in the combination therapy group achieved hepatitis B surface antigen(HBsAg)loss and HBsAg seroconversion,but none in the NA therapy group did(p=0.039).In the combination therapy group,16 patients(51.6%)achieved HBeAg seroconversion at the end of treatment,of which,11 patients(68.8%)maintained the response until EOF.Conclusions:Adding on PegIFN alfa-2a in combination with NA therapy might be an appropriate rescue treatment option for patients who have prior NA resistance.In addition,combination therapy induced sustained off-treatment biochemical responses in these patients.

Peginterferon alfa-2a for the treatment of chronic hepatitis C in the era of direct-acting antivirals

BACKGROUND: The availability of novel direct-acting antivirals (DAAs) represents a new era of curative hepatitis C virus (HCV) treatment, with over 95% of patients infected with HCV genotype 1 achieving sustained virological response (SVR). Nevertheless, the majority of patients globally are unable to access these treatments because of cost and infrastructure constraints and, thus, remain untreated and uncured. DATA SOURCE: Relevant articles of peginterferon (PegIFN)-based treatments in HCV and sofosbuvir-based treatments, simeprevir, daclatasvir/asunaprevir, ritonavir-boosted paritaprevir/ombitasvir/dasabuvir, and grazoprevir/elbasvir, were searched in PubMed database, including general population and special population. RESULTS: PegIFN in combination with ribavirin remains an important and relevant option for some patients, achieving SVR rates of up to 79% in genotype 1 and 89% in genotype 2 or 3 infections, which increases for patients with favorable IL28B genotypes. Triple therapy of DAA plus PegIFN/ribavirin is effective in treating difficult-to-cure patients infected with HCV genotype 3 or with resistance-associated variants. Owing to its long history in HCV management, the efficacy, tolerability and long-term outcomes associated with PegIFN alfa-2a are well established and have been validated in large-scale studies and in clinical practice for many populations. Furthermore, emerging data show that IFN-induced SVR is associated with lower incidences of hepatocellular carcinoma compared with DAAs. On the contrary, novel DAAs have yet to be studied in special populations, and long-term outcomes, particularly tumor development and recurrence in patients with cirrhosis and/or hepatocellular carcinoma, and reactivation of HBV in dually infected patients, are still unclear. CONCLUSION: In this interferon-free era, PegIFN-based regimens remain a safe and effective option for selected HCV patients.

Serum proteins in chronic hepatitis B patients treated with peginterferon alfa-2b

AIM: To study the differential protein profile in serum of hepatitis B patients.METHODS: Serum samples were obtained from patients with chronic hepatitis B who were receiving peginterferon alfa-2b.The serum samples were subjected to albumin depletion and analyzed by two-dimensional gel electrophoresis(2-DE).Differentially expressed protein spots were identified by electrospray ionizationquadrupole time-of-flight mass spectrometry.Alpha2-HS-glycoprotein,complement component C3c and CD5 antigen were further analyzed by an enzymelinked immunosorbent assay and immunonephelometry.RESULTS: Nineteen patients with HBeAg-positive chronic hepatitis B(CHB) were studied.These patients were followed for at least 1 year after treatment and were classified according to their treatment response: responders(n = 9) and non-responders(n = 10).2-DE and MS/MS analysis were performed to compare the serum proteins before initiating peginterferon alfa2b.From the quantitative analysis of the 2-D gel,7 proteins were detected between the two groups at different levels before treatment.Among these potential candidates,serum levels of alpha-2-HS-glycoprotein,complement component C3c and CD5 antigen-like precursor were further analyzed.In the validation phase,23 subjects,9 sustained responders and 14 nonresponders,were recruited.Interestingly,the levels of alpha-2-HS-glycoprotein and complement component C3c were elevated in the serum of the non-responders compared to the responders.CONCLUSION: Serum alpha-2-HS-glycoprotein and complement component C3c may be potential serum biomarkers in predicting the treatment response of peginterferon alfa-2b in patients with CHB prior to treatment.

Pericarditis and chronic inflammatory demyelinating polyneuropathy during therapy with pegylated interferon alfa-2a for chronic hepatitis C

We report a case of pericarditis and chronic inflam- matory demyelinating polyneuropathy with biological signs of a lupus-like syndrome due to pegylated interferon alfa-2a therapy during treatment for chronic hepatitis C.The patient developed moderate weakness in the lower limbs and dyspnea.He was hospitalized for congestive heart failure.An electrocardiogram showed gradual ST-segment elevation in leads V1 through V6 without coronary artery disease.A transthoracic cardiac ultrasonographic study revealed moderate pericardial effusion with normal left ventricular function.Anti-DNA antibody and anti-ds DNA IgM were positive.Neu ro logical examination revealed a symmetrical predomina ntly sensory polyneuropathy with impairment of light touch and pin prick in globe and stoking-like distribution.Treatment with prednisolone improved the pericarditis and motor nerve disturbance and the treatment with intravenous immunoglobulin improved the sensory nerve disturbance.

Pegylated interferon alfa-2b plus ribavirin for treatment of chronic hepatitis C

AIM: To study the safety and efficacy of pegylated interferon alfa-2b, indigenously developed in India, plus ribavirin in treatment of hepatitis C virus(HCV). METHODS: One-hundred HCV patients were enrolled in an open-label, multicenter trial. Patients were treated with pegylated interferon alfa-2b 1.5 μg/kg per week subcutaneously plus oral ribavirin 800 mg/d for patients with genotypes 2 and 3 for 24 wk. The same dose of peginterferon plus weight-based ribavirin(800 mg/d for ≤ 65 kg; 1000 mg/d for > 65-85 kg; 1200 mg/d for > 85-105 kg; 1400 mg/d for > 105 kg body weight) was administered for 48 wk for patients with genotypes 1 and 4. Serological and biochemical responses of patients were assessed.RESULTS: Eighty-two patients(35 in genotypes 1 and 4 and 47 in 2 and 3), completed the study. In genotype 1, 25.9% of patients achieved rapid virologic response(RVR): while the figures were 74.1% for early virologic response(EVR) and 44.4% for sustained virologic response(SVR). For genotypes 2 and 3, all patients bar one belonged to genotype 3, and of those, 71.4%, 87.5%, and 64.3% achieved RVR, EVR, and SVR, respectively. In genotype 4, 58.8%, 88.2%, and 52.9% of patients achieved RVR, EVR, and SVR, respectively. The majority of patients attained normal levels of alanine aminotransferase by 4-12 wk of therapy. Most patients showed a good tolerance for the treatment, although mild-to-moderate adverse events were exhibited; only two patients discontinued the study medication due to serious adverse events(SAEs). Eleven SAEs were observed in nine patients; however, only four SAEs were related to study medication.CONCLUSION: Peginterferon alfa-2b, which was developed in India, in combination with ribavirin, is a safe and effective drug in the treatment of HCV.

聚乙二醇干扰素α-2a注射液不良反应报告分析

目的:探讨聚乙二醇干扰素α-2a注射液不良反应发生的特点及相关因素,为临床安全用药提供参考。方法:收集某省药品不良反应监测中心2004～2011年自发呈报系统上报的1 606例聚乙二醇干扰素α-2a注射液的不良反应(ADR)报告,对ADR所涉及的患者年龄、性别,以及ADR年份、类型、结果、临床表现等进行统计分析。结果:1606例报告中,男883例,女723例,30～60岁患者最多(72.6%);发生严重不良反应243例,新的严重ADR 86例;临床表现以血液系统损害为主占59.95%,其次为肝胆系统损害占10.76%。结论:临床在运用聚乙二醇干扰素α-2a治疗丙肝的过程中,应密切观察其ADR,制定周密的护理计划,积极干预和防治,以有效减少和防止ADR发生。

聚乙二醇干扰素α-2a治疗新疆地区不同HBV基因分型乙肝患者的临床疗效

目的探讨聚乙二醇干扰素α-2a治疗新疆地区不同HBV基因分型乙型肝炎(乙肝)患者的临床疗效。方法选择56例符合纳入和排除标准的慢性乙型肝炎患者,均采用聚乙二醇干扰素α-2a抗病毒治疗,疗程为6个月。检测所有患者的基因型,并对不同基因型患者乙肝表面抗原(HBsAg)、乙肝e抗原(HBeAg)、血清HBeAg定量、乙肝病毒基因(HBV-DNA)定量、谷丙转氨酶(ALT)、HBsAg阴转率、HBeAg阴转率、血清HBeAg转换率、HBV-DNA阴转率以及ALT复常率进行比较。结果 18例HBeAg阳性患者中HBsAg阴转2例,血清HBeAg转换4例,血清学转换率为22.22%;56例患者HBV基因型以C型为主,共36例,其余为B型,C型患者HBVDNA显著高于B型,差异有统计学意义(P<0.05);随着治疗时间的延长,两组患者的HBV-DNA阴转率以及ALT复常率成显著升高趋势,差异有统计学意义(P<0.05),HBsAg阴转率、HBeAg阴转率以及血清HBeAg转换率无明显改变(P>0.05),且相同时间点B型和C型患者上述指标差异均无统计学意义(P>0.05);与治疗前比较,治疗后两组HBsAg定量均无明显差异,2种基因型相同时间点HBsAg定量比较差异无统计学意义(P>0.05)。结论新疆地区乙肝患者聚乙二醇干扰素α-2a抗病毒治疗HBsAg阴转率降低,应答情况不理想,疗效欠佳,且基因型对疗效无明显影响。

α-2b干扰素抑制动脉粥样硬化的实验研究

目的 :探讨α - 2b干扰素 (IFNα- 2b)抑制动脉粥样硬化 (AS)的体内机制。方法 :随机将家兔分为空白对照 (NC)组、动脉粥样硬化 (AS)组、病毒感染动脉粥样硬化 (V)组、干扰素治疗非病毒感染动脉粥样硬化 (IFN -Ⅰ )组、干扰素治疗病毒感染动脉粥样硬化 (IFN -Ⅱ )组。复制AS模型 ,于第 1、3、5、7周酶法测血清总胆固醇、甘油三脂。 7周后主动脉苏丹Ⅳ染色测AS斑块面积 /总面积 ,HE染色观察主动脉形态学改变。用免疫组化法测胸主动脉中的增殖细胞核抗原 (PCNA)和单纯疱疹病毒Ⅰ型 (HSV -Ⅰ )的表达 ,用原位杂交法测血小板衍生生长因子 β(PDGF - β)的表达程度。 结果 :NC组、IFN -Ⅰ组、IFN -Ⅱ组主动脉粥样硬化斑块面积小于AS组 (P <0 .0 5) ,AS组小于V组 (P <0 .0 5)。NC组、IFN -Ⅰ组、IFN -Ⅱ组PDGF -B的表达低于AS组、V组 (P <0 .0 5)。结论 :病毒可能是AS的始动因素 ,PDGF - β可能是促使血管平滑肌细胞 (VSMC)增生、AS进展的主要因素。IFNα- 2b通过抑制病毒和下调PDGF - βmRNA抑制VSMC的增生 ,可能是其抑制AS的形成及发展的重要机制之一。

α2b干扰素治疗慢性丙肝患者的临床研究

目的 探讨α2 b干扰素对慢性丙肝患者外周血单个核细胞 (PBMC)内 HCV的治疗效果。方法 采用国产α 2 b干扰素 (30 0 MU / d)治疗 ,3个月为一疗程 ,共 2个疗程 ,并设常规治疗组(Vit C、门冬氨酸 )为对照。于疗程结束后分别检测患者 PBMC内 HCV- RNA和血清内 HCV- RNA、抗 - HCV。结果 α 2 b干扰素治疗组 2个疗程后慢性丙肝患者 PBMC、血清内 HCV - RNA和抗 -HCV转阴率分别为 4 2 .31% (11/ 2 6 )、5 7.6 9% (15 / 2 6 )、6 5 .38% (17/ 2 6 ) ,常规治疗组慢性丙肝患者 PBMC、血清内 HCV- RNA和抗 - HCV转阴率分别为 13.6 4 % (3/ 2 2 )、2 2 .73% (5 / 2 2 )、2 7.2 7%(6 / 2 2 ) ,两组相比 ,差异有显著性 (P <0 .0 5 )。结论 α 2 b干扰素对 PBMC内 HCV- RNA具有肯定的治疗作用 ,其疗效优于常规治疗组。

Heat shock protein 72 normothermic ischemia,and the impact of congested portal blood reperfusion on rat liver

INTRODUCTIONFrom the technical aspect of liver surgery ,control of bleeding during hepatic parenchymal resection is one of the most important procedures in hepatectomy .Pringle,s maneuver ,a temporary cross-clamping of the hepatoduodnal ligament ,has often been used for this purpose[1],This is the simplest and userul technique to reduce intraoperative blood loss .

The Change of Quantitative of HBeAg Can Predict the Efficacy of Peg-IFN-α 2a in HBeAgpositive CHB Patients

Objective To investigate the quantitation of hepatitis B e antigen (HBeAg) at week 24 in predicting the efifcacy of pegylated-interferon alfa-2a (Peg-IFN-α2a) in HBeAg-positive chronic hepatitis B (CHB) patients at week 48 and to find a useful predictor for treatment efficacy and investigate individualized treatment of antiviral therapy. Methods Ninety-six HBeAg-positive CHB patients with detectable HBeAg who were treated with Peg-IFN-α2a were enrolled in this trial. They were categorized into 3 groups according to the changes of HBeAg in week 24:HBeAg decline>2 log10 group (group A), HBeAg decline between 1 1og10-2 log10 (group B), HBeAg decline<1 log10 group (group C), and group C was randomly distributed into C1 and C2. The patients in group A, group B, and group C1 continued the original therapy and the patients in group C2 were given lamivudine plus Peg-IFN-α2a for 24 weeks. At week 48, the treatment efifcacy and hepatitis B virus covalently closed circular DNA (HBV cccDNA) in liver biopsies were analyzed. Results At week 48, mean reduction of serum HBV DNA:group A:5.8 log10 copies/ml, group B:3.8 log10 copies/ml, group C1:2.8 log10 copies/ml, group C2:5.7 log10 copies/ml, the reduction of HBV DNA in group A was greater than groups B and C1 (P<0.01), that in group C1 was greater than group C2 (P<0.01), the difference between groups B and C1 had no statistical signiifcance (P=0.19). Mean reduction of HBeAg:group A:2.7 log10S/CO, group B:1.9 log10S/CO, group C1:0.9 log10S/CO, group C2:1.5 log10S/CO, the difference among groups A, B and C1 and between groups C1 and C2 were statistically signiifcant (P<0.01). At week 48, HBV DNA undetectable rate in group A, group B, group C1 and group C2 were 87.5%, 34.5%, 17.4%and 81.9%, respectively, the rate in group A was greater than groups B and C1 (P<0.01),that in group C1 was greater than group C2 (P<0.01). HBeAg seroconversion rate were 75.0%, 24.1%, 13.0%and 22.7%, respectively, that in group A was greater than groups B and C1 (P<0.01). Group A had lower cccDNA in liver tissue than group B and group C1 (P<0.01). The difference of HBV cccDNA between groups B and C1 and that between groups C1 and C2 had no statistical signiifcance. Conclusions HBeAg decline > 2 log10 at week 24 in Peg-IFN-α 2a-treated hepatitis B patients suggested a better efficacy at week 48; HBeAg decline < 2 log10 at week 24 suggests a worse efficacy at week 48, the combined therapy of Peg-IFN-α and lamivudine could improve the clinical responses. The change of quantitative of HBeAg at week 24 may be used as a predictor of treatment effects at week 48.

慢性丙型肝炎的治疗：2000-2005最新进展（下）

不良反应 与α干扰素和长效干扰素相关的不良反应包括疲劳、流行性感冒样症状、胃肠道紊乱、血液学异常、神经精神病学反应（明显的抑郁症）、甲状腺机能异常和皮肤用药反应，例如脱发和瘙痒症。利巴韦林主要的不良反应是溶血性贫血。虽然某些不良反应的出现可能不同，但α干扰素和长效干扰素之间出现的不良反应大体相似。在Fried等人的研究中，与α干扰素组相比较，长效干扰素alfa-2a组出现的流感样症状、头痛、脱发和抑郁（最低限度5％）较少。Manns等人发现，与Q干扰素组相比较，使用长效干扰素alfa-2b的流感样症状和一些胃肠道反应（例如恶心、腹泻和体重减轻）的发生率较高（≥5％）。针对不良反应的策略包括降低药物剂量或中断治疗，虽然这些策略可降低疗效，上述问题也被注意到。在大部分长效干扰素／利巴韦林的试验中，血液学异常是减少药物剂量的最常见的原因；然而，这很少会造成治疗的中断（≤3％的患者）。胃肠的不良反应、神经精神方面的影响和流感样症状是减少药物剂量或中断治疗的另外的常见原因。

慢性丙型肝炎的治疗：2000-2005最新进展（中）

持续和剂量维持的作用 持续抗HCV治疗和剂量维持的干扰素／长效干扰素和利巴韦林治疗对达到最高SVR已经变得更重要了。研究人员对一项来自干扰素alfa-2b或长效干扰素alfa-2b加利巴韦林的3组随机试验进行了回顾性分析以评价持续治疗对SVR的作用。通过对药物配方／反馈记录以及患者每日剂量的观察决定所给予的各种药物的数量。为了进行该项分析，患者被分为两组：（1）接受两种总计剂量干扰素和利巴韦林的80喊以上以及治疗时间在预期的治疗时间的80％或以上的患者，（2）患者接受了降低的剂量（小于一种或两种药物的8096，预期的治疗时间≥8096）。该分析排除了早期退出该研究的患者。

聚乙二醇干扰素治疗HBeAg阳性慢性乙型肝炎患者外周血NKT细胞的变化及疗效预测

目的研究聚乙二醇干扰素α-2a(Peg-INFα-2a)治疗乙型肝炎e抗原(HBeAg)阳性慢性乙型肝炎(CHB)患者,其外周血NKT细胞表达率和疗效预测相关性。方法选取2010年1—12月在中南大学湘雅三医院住院和门诊接受治疗的HBeAg阳性CHB患者63例,予Peg-INFα-2a18MIU肌内注射,1次/周,共48周。检测各时段外周血NKT数量占外周血T淋巴细胞的百分比、血清乙型肝炎5项定量及乙型肝炎病毒(HBV)DNA载量。结果 Peg-INFα-2a治疗HBeAg阳性CHB患者48周后,显效(完全病毒学应答)26例,有效(部分病毒学应答)21例,无效(无病毒学应答)16例。外周血NKT细胞占T淋巴细胞百分比:显效组治疗前及治疗后4、8、12、16、24周,较有效组和无效组均明显升高(均P<0.01);在治疗48周和停药24周,显效组较有效组NKT表达水平明显升高(分别t=32.0,P<0.01;t=27.6,P<0.01)。显效组治疗后前4周,NKT表达水平上升速度最快,12周时达最高峰,其后逐渐下降,到24周比治疗前水平稍高,一直维持到48周;有效组12周时NKT表达水平达最高峰,较治疗前显著增高(t=12.83,P<0.05)。显效组患者肝功能基本在12周左右完全恢复正常,且持续维持在正常水平,其HBVDNA载量亦逐步下降;而有效组和无效组患者的肝功能波动在(1～2)×ULN。监测至停药24周后,共有27例患者出现HBeAg血清学转换。结论 Peg-INFα-2a治疗HBeAg阳性CHB患者,其外周血中NKT的表达对疗效有一定预测作用。

α-2-HS-糖蛋白对聚乙二醇干扰素alfa-2b治疗慢性乙型肝炎患者e抗原血清转换预测作用的研究

利用干扰素治疗慢性乙型肝炎仅在约1/3的患者中取得了满意的治疗效果.采用基于双向电泳的血清蛋白质组学技术,寻找慢性乙型肝炎患者干扰素治疗时发生e抗原血清学转换的预测标志物.对发生/未发生血清学转换组的患者基线和治疗24周血清进行差异蛋白的筛选和鉴定,并对筛选得到的α-2-HS-糖蛋白在训练组和验证组患者个体中进行了基线和第4周的进一步验证实验.结果发现,α-2-HS-糖蛋白从治疗基线至治疗第4周的变化趋势对慢性乙型肝炎患者干扰素alfa-2b治疗过程中e抗原血清学转换具有预测意义.

丙型肝炎病毒基因Ⅱ型感染对干扰素治疗的应答反应

对 31例丙肝病人进行基因分型及干扰素治疗。其中 2 7例 HCV基因 型感染病人治疗结束时的应答率为92 .6 % (生化 )及 6 3% (病毒 ) ,一年的稳定应答率为 2 6 % (生化及病毒学 ) ,不应答率为 8.4%。结论 :国人 HCV 型感染对干扰素治疗有良好的近期应答 ,如何提高稳定应答率 ,减少复发是临床研究应注意的问题。