干扰素对丙型肝炎病毒Ⅱ型和Ⅲ型的治疗反应

当前，α－干扰素（α－ＩＦＮ）是治疗丙型肝炎病毒（ＨＣＶ）感染的唯一有效药物，在影响α－ＩＦＮ治疗反应的诸多因素中ＨＣＶ基因型是最重要的因素。我们应用α－ＩＦＮ治疗ＨＣＶⅡ型和Ⅲ型感染者，从治疗后血清ＨＣＶＲＮＡ阴转为疗效判断指标，从而探讨α－ＩＦＮ...     

再生障碍性贫血与丙型和戊型肝炎病毒相关性的研究

目的和方法：采用ＲＴ／ＰＣＲ和定量酶标标准化的测定方法,检测了先患（丙型或戊型）肝炎后患再生障碍性贫血和先患再生障碍性贫血后患丙型（或戊型）肝炎的阳性率,并与对照组比较。结果：血清组中ＨＣＶ－ＲＮＡ的阳性率分别是５７９％和２８９％,二者差异显著（Ｐ＜００５）;ＨＥＶ－ＲＮＡ阳性率分别是２４％和２５９％,二者差异不显著（Ｐ＞００５）。在单个核细胞组中ＨＣＶ－ＲＮＡ阳性率分别为１１８％和１０５％;ＨＥＶ－ＲＮＡ的阳性率分别为０％和３７％;ＨＥＶ－ＲＮＡ在粪便中的阳性率３２％和３７％,均无显著差异。结论：丙型和戊型肝炎病毒不直接影响造血细胞的基因表达,仅使造血微环境有一定改变,引起患者自身免疫反应,对造血有一定的影响     

丙型肝炎病毒感染慢性化的分子生物学机制

丙型肝炎病毒（ＨＣＶ）感染有较高的慢性化比例。ＨＣＶ的核心蛋白对于淋巴毒素β受体（ＬＴ－βＲ）,肿瘤坏死因子α受体（ＴＮＦαＲ）,包膜糖蛋白Ｅ２对Ｔ细胞受体（ＴＣＲ）,非结构蛋白ＮＳ５Ａ对双链ＲＮＡ结合蛋白ＰＫＲ和干扰素α（ＩＦＮα）诱导的抗病毒蛋白ＭｘＡ等机体免疫系统的调变作用是ＨＣＶ感染慢性化的主要分子生物学机制。     

丙型肝炎病毒基因型与血清HCV RNA含量关系及与干扰素应答的研究

目的探讨丙型肝炎病毒（ＨＣＶ）基因型与血清ＨＣＶＲＮＡ含量的关系及其对干扰素应答的影响。方法应用定量荧光ＰＣＲ（Ａｍｐｌｉｓｅｎｓｏｒ－ＰＣＲ）技术检测了１３５例不同基因型ＨＣＶ感染的慢性丙型肝炎患者血清ＨＣＶＲＮＡ含量，另对其中７７例进行干扰素治疗并随访１２个月以上。结果ＨＣＶ－Ⅱ型感染血清ＨＣＶＲＮＡ水平（１０７．８±３．４拷贝／ｍｌ）显著高于ＨＣＶ－Ⅲ型感染（１０６．３±２．５拷贝／ｍｌ）（Ｐ＜０．０１），Ⅲ型感染的应答率（７／１３，５３．８％）显著高于Ⅱ型感染（２０／６４，３１．３％）（Ｐ＜０．０５）。应答组治疗前血清ＨＣＶＲＮＡ含量（１０６．８±２．７拷贝／ｍｌ）显著低于无应答组（１０８．３±３．２拷贝／ｍｌ）（Ｐ＜０．０１）。ＨＣＶＲＮＡ含量低于１０６．５拷贝／ｍｌ者，无论何种型别ＨＣＶ感染均应答较好，而ＨＣＶＲＮＡ高于１０８．０拷贝／ｍｌ者则应答极差。结论ＨＣＶ基因型及病毒血症水平是预测干扰素疗效的重要因素，且后者比前者意义更大。Ⅱ型感染病毒血症水平较高可能是影响其疗效的原因之一。     

丙型肝炎病毒1b型NS5 A区基因结构变异与α干扰？…

目的 观察丙型肝炎患者丙型肝炎病毒（ＨＣＶ）１ｂ型基因组部分ＮＳ５ Ａ区核苷酸,氨基酸的变异情况并探讨其与α干扰素疗效的相关性。方法 患者干扰素治疗前,中,后留血标本,用聚合酶链反应（ＰＣＲ）扩增ＨＣＶ病毒ＮＳ５ Ａ区部分基因片段并用直接测序法测序。与ＨＣＶ－Ｊ株及ＨＣＶ－河北株（ＨＣＶ－ＨＢ）比较核苷酸及氨基酸序列的同源性,根据α干扰素疗效分析ＨＣＶ１ｂ是否存在干扰素敏感决定区。     

聚合酶链反应鉴定丙型肝炎病毒母婴传播的状态及其意义

采用多种方法，动态检测了１１例丙型肝炎病毒（ＨＣＶ）感染的孕妇所生的婴儿血抗－ＨＣＶ和ＨＣＶＲＮＡ。发现用合成肽酶联免疫吸附试验（ｓｐＥＬＩＳＡ）检测婴儿抗－ＨＣＶ阳性率（２３．５２％）显著低于第二代重组抗原ＥＬＩＳＡ（２ｎｄＥＬＩＳＡ）（４１．１８％）（Ｐ＜０．０５）；用２ｎｄＥＬＩＳＡ检测，６例婴儿脐血和静脉血抗－ＨＣＶ阳性，５例持续１～５月阴转，１例阳性持续１３个月。经重组免疫印迹试验（ＲＩＢＡ）鉴定，４例阳性，２例可疑阳性。用逆转录聚合酶链反应（ＲＴ－ＰＣＲ）检测ＨＣＶＲＮＡ，５例阳性，３例于生后１～６个月自然阴转，２例持续阳性分别达９个月和１３个月。提示检测抗－ＨＣＶ判断ＨＣＶ母婴传播的状态受到婴儿抗－ＨＣＶ产生水平低下、母体抗－ＨＣＶ的被动输入和不同检测方法的影响，用ＲＴ－ＰＣＲ检测ＨＣＶＲＮＡ是判断母婴传播更可靠的指标。     

丙型肝炎病毒感染的血清学检测

目的了解丙型肝炎病毒（ＨＣＶ）感染及病毒血症存在情况。方法用酶联免疫吸附试验（ＥＬＩＳＡ）和聚合酶链反应（ＰＣＲ）对不同人群的血清标本做了抗－ＨＣＶ、抗－ＨＣＶＩｇＭ和ＨＣＶＲＮＡ的检测，并对三项指标间的关系进行了对比分析。结果抗－ＨＣＶ在普通成年人、献血员、急性肝炎和肝硬化患者中的检出率分别是３５７％，８５８％，６２５％和４８３８％；与ＨＣＶＲＮＡ的符合率分别是１１４３％，６１１１％，８００％和７３３３％。相同人群抗－ＨＣＶＩｇＭ与ＨＣＶＲＮＡ的符合率分别是７５％，９０９％，８１８１％和１００％。结论抗－ＨＣＶＩｇＭ比抗－ＨＣＶ能更客观地反映ＨＣＶ病毒血症的情况，个别抗－ＨＣＶ阴性血清检测到了抗－ＨＣＶＩｇＭ和ＨＣＶＲＮＡ。     

丙型肝炎病毒RNA基因型与肝病临床转归的初步观察

丙型肝炎病毒ＲＮＡ基因型与肝病临床转归的初步观察李岱王宇基于不同的丙型肝炎病毒（ＨＣＶ）克隆间核苷酸序列同源性的差异，全世界ＨＣＶ基因型至少有１０余种之多，广泛分布的有五个基因型：Ⅰ／Ｉａ、Ⅱ／Ｉｂ、Ⅲ／２ａ、Ⅳ／２ｂ和Ⅴ／３ａ型，我国至今为止除了Ⅱ...     

输血后丙型肝炎病毒感染的前瞻性研究

对６４例受血者进行了半年前瞻性调查，发生输血后丙型肝炎（ＰＴ－ＨＣ）８例，亚临床（ＰＴ－ＨＣ）１例，丙型肝炎病毒（ＨＣＶ）隐性感染３例，ＨＣＶ总感染率为１８７５％，丙氨酸转氨酶（ＡＬＴ）首次异常时间为输血后２８～９１（５１９±２０９）天；抗－ＨＣＶ首次阳转为输血后２３～７６（４２４±１５９）天。发生巨细胞病毒（ＣＭＶ）感染２例，病原待定的非乙、非丙ＡＬＴ异常者５例。     

聚合酶链反应鉴定丙型肝炎病毒母婴传播的状态及其…

采用多种方法,动态检测了１１例丙型肝炎病毒感的孕妇所生的婴儿血抗－ＨＣＶ和ＨＣＶＲＮＡ。发现用合成肽酶联免疫吸附试验检测婴儿抗－ＨＣＶ阳性率显著低于第二低重组抗原ＥＬＩＳＡ;用２ｎｄＥＬＩＳＡ检测,６例婴儿脐血和静脉血抗－ＨＣＶ阳性,５例持续１－５月阴转,１例阳性持续１３个月。     

PEG—IFN α-2a治疗慢性丙型肝炎的临床分析

目的观察PEG-IFN α-2a小剂量长疗程治疗慢性丙型肝炎患者的病毒学应答。方法选择2004年9月至2006年9月住院的慢性丙型肝炎患者92例,根据对干扰素耐受情况将其分为A组（PEG—IFN α-2a 67．5μg／周）、B组（PEG—IFN α-2a 90μg／周）及C组（PEG-IFN α-2a 180μg／周）,同时联合利巴韦林（900～1200mg／d）。A组和B组中HCV基因1b型患者疗程延长至96周,2a型疗程48周;C组HCV基因1b型疗程48周,2a型疗程24周,均随访24周;分别观察各组患者的快速病毒学应答（RVR）、早期病毒学应答（EVR）及持续病毒学应答（SVR）率。结果三组RVR、EVR、SVR率之间无统计学差异（P〉0．05）,基因1b型患者的RVR、EVR和SVR率明显低于2a型（P〈0．05）,经logistic回归分析,HCV基因型为SVR独立预测因子（OR=12．78,95％CI=11．97—82．89,P=0．0075）。结论小剂量长疗程PEG—IFN α-2a联合利巴韦林与标准方案治疗慢性丙型肝炎病毒学应答状况相当;基因型是SVR的独立预测因素。     

慢性丙型肝炎患者血清细胞因子水平的变化及意义

目的:检测慢性丙型肝炎患者血清细胞因子IL-2、IFN-г、IL-5、IL-6、IL-12P70和P40水平,探讨其与患者血清ALT水平、HVC RNA载量、HCV基因型及干扰素疗效的关系。方法:检测30例健康对照者和30例慢性丙型肝炎患者干扰素治疗前后血清IL-2、IFN-г、IL-5、IL-6、IL-12P70和P40的含量,比较干扰素治疗应答组和无应答组之间细胞因子水平的差异及上述细胞因子水平与血清ALT水平、HCV基因型、HCVRNA载量等的关系。血清细胞因子检测应用ELISA法,HCV基因分型应用直接测序法,HCVRNA载量采用荧光定量PCR法。结果:与健康对照组相比,慢性丙型肝炎患者血清IL-2含量明显降低,IL-5和IL-12P40明显生高;血清IL-6含量与血清ALT水平呈正相关,与RNA载量呈负相关;HCV基因型1型患者血清IL-6含量明显高于2型,其他基因型和亚型之间细胞因子水平均无显著性差异;干扰素治疗的持续应答率为46.7%,应答组和无应答组治疗前血清细胞因子水平均无显著性差异,但应答组治疗结束时IFN-γ含量较治疗前明显升高。结论:血清Th1/Th2细胞因子水平失衡与丙型肝炎的慢性化和肝脏炎症活动相关;干扰素治疗前血清Th1/Th2细胞因子水平与干扰素治疗效果无关,不能对疗效进行预测,干扰素诱导的Th1细胞优势反应与持续应答有关。     

HCV RNA in patients with chronic hepatitis C treated with interferon-α

In order to assess the efficacy of interferon-α on hepatitis C viral RNA in patients with chronic hepatitis C, we analyzed the levels of HCV RNA in sera and liver tissues of 16 patients pre- and posttreatment using a semiquantitative polymerase chain reaction method. Fifteen of 16 patients were positive for anti-HCV antibodies by four-antigen recombinant immunoblot assay (4-RIBA). Only two patients demonstrated normalization of ALT in response to interferon; three patients showed a partial response. Only one patient from the partial responder group displayed a significant reduction of HCV RNA level posttreatment. In the nonresponder group, several patients, although their ALTs remained elevated, demonstrated significant decreases in HCV RNA levels in either serum or liver in response to interferon. Our data suggest that interferon treatment of chronic hepatitis C may not be effective in eradicating HCV infection and a reduction in ALT is infrequently associated with a decrease in HCV RNA level in either serum or liver. Cessation of treatment is frequently associated with the recrudescence of HCV replication and disease. © 1993 Wiley-Liss, Inc.     

A pilot study of daily subcutaneous interleukin-10 in patients with chronic hepatitis C infection.

The Th1/Th2 cytokine balance is important in persistence of infection and liver injury in chronic hepatitis C. The aim of this study was to administer the anti-inflammatory cytokine, recombinant human interleukin-10 (rHuIL-10), for 28 days in patients with chronic hepatitis C and to assess the safety and measure the effect on alanine aminotransferase (ALT, a marker of hepatic inflammation) levels and serum hepatitis C virus (HCV) RNA values. Three treatment-naive and 13 interferon (IFN) nonresponder patients (total 16 patients) with compensated chronic HCV infection were enrolled in this study. Patients were randomized to receive rHuIL-10 at a dose of 4 or 8 microg/kg/day as a single daily subcutaneous injection for 28 days. ALT values and serum HCV RNA were measured at days 0, 1, 3, 8, 15, 22, and 28 during therapy and at follow-up 2 and 4 weeks after cessation of the 4-week treatment period. ALT values normalized in 9 of 16 patients during therapy and remained normal until the end of treatment in 8 patients. The decreases in ALT values occurred in both the 4 microg and 8 microg dosage groups and were seen in both IFN naive and nonresponder patients. Mean ALT values fell significantly during the study period but usually returned to pretreatment levels by the end of the 4-week follow-up period (p < 0.05). HCV RNA concentrations did not vary significantly during or after therapy. (No patient had either an increase or a decrease in HCV RNA levels of > or =1.5 log during the study.) The drug was well tolerated, with no adverse symptoms noted. Platelet counts fell transiently to 73,000 and 63,000 in 2 patients. No other toxicity was observed, and no patients discontinued therapy. In chronic hepatitis C, short-term therapy with IL-10 was well tolerated and caused transient normalization of ALT values in 50% of patients, which returned to pretreatment levels on cessation of treatment. There were no significant changes observed in serum HCV RNA concentrations during the study. These immunomodulatory effects are similar to those observed with ribavirin monotherapy in chronic hepatitis C. Further study of rHuIL-10 alone or in combination with antiviral agents in chronic hepatitis C is warranted.     

丙型肝炎病毒基因分型及其与干扰素治疗应答的关系

目的为了解山西省丙型肝炎病毒的基因型和基因型对干扰素疗效的预示价值。方法用ＨＣＶ５’ＮＣ区酶切分型方法对９４例丙型肝炎病人进行基因分型，并观察其中４５例患者对干扰素α１ｂ治疗的应答。结果显示ＨＣＶⅠ组（Ⅰ、Ⅱ型）感染８０例（８５１％），ＨＣＶⅡ组（Ⅲ、Ⅳ型）感染１２例（１２８％），ＨＣＶⅠ／Ⅱ组混合感染２例（２１％）。在接受干扰素治疗的病例中，ＨＣＶⅠ组感染（３５例）的应答率为３７１％，持续应答率为１７１％，而Ⅱ组感染（１０例）的应答率为８０％，持续应答率为６０％，两组相比，有显著性差异（Ｐ＜００５，Ｐ＜００２５）。结论表明山西省以ＨＣＶⅠ组感染为主，干扰素对ＨＣＶⅡ组感染的疗效优于ＨＣＶⅠ组感染，ＨＣＶ基因型有预测干扰素疗效的意义。     

Loss of serum HCV RNA at week 4 of interferon-α therapy is associated with more favorable long-term response in patients with chronic hepatitis C

To determine the virological factors associated with a favorable long-term response to interferon-α (IFN) therapy in chronic hepatitis C virus (HCV) infection, 61 Japanese patients with chronic HCV infection were treated with IFN for 24 weeks (780 million units in total) and followed for 8 to 16 months after cessation of therapy. Ten patients dropped out because of severe side effects. Of the 51 patients who completed IFN therapy, 23 showed complete and sustained response (CR→SR), 13 complete response with early relapse (CR→Rel), and 15 no response to IFN (NR). For the pretreatment serum HCV RNA level, 20/23 who had CR→SR had <l0⁶ eq/ml compared to 3/13 CR→Rel and 1/15 NR (P< 0.01). Serologically defined HCV type 2 infection was also associated with a better opportunity to develop CR→SR compared to CR→Rel of NR (P<0.01). Loss of serum HCV RNA at week 4 of IFN therapy was also associated with a more favorable long-term response [17/19 CR→SR were HCV RNA negative compared to 3/11 CR→Rel (P<0.01)and2/13NR(P<0.01)]. n contrast, normalization of serum alanine ami-notransferase (ALT) levels at week 4 was found in 9/19 CR→SR compared to 8/11 CR→Re1 (P= NS), and 0/13 in NR (P<0.01). Six months after cessation of IFN therapy, 3/25 CR→SR patients were HCV RNA positive despite normalization of serum ALT levels. These data indicated that in addition to pretreatment serum HCV RNA levels and HCV type, the kinetics of response to IFN (at week 4) were also predictive of subsequent long-term response to IFN in patients with chronic HCV infection. © 1995 Wiley-Liss, Inc. © 1995 Wiley-Liss, Inc.     

干扰素α-2b对慢性乙型肝炎患者氧化损伤状态的影响

目的探讨不同基因型慢性乙型肝炎患者干扰素α-2b(IFNα-2b)治疗前后氧化损伤状态的变化及其与抗病毒疗效的关系。方法35例符合干扰素治疗指征的慢性乙型肝炎患者,分别给予IFNα-2b300万U,肌内注射,每周3次,疗程12周。治疗前后化学比色法测定患者血清丙二醛和总抗氧化能力指标的变化,同时在治疗过程中定期复查患者肝功、胆红素、血常规、HBV DNA及病毒标志物的变化,核酸杂交-酶联免疫吸附法测定乙肝病毒基因分型,18例健康人作为正常对照。结果慢性乙型肝炎患者血清丙二醛浓度明显高于健康对照组(P<0.05),总抗氧化能力明显低于健康对照组(P<0.05)。不同基因型患者血清丙二醛水平及总抗氧化能力无显著差别(P>0.05)。干扰素治疗后患者血清丙二醛水平明显低于治疗前水平(P<0.05),无效组治疗后的丙二醛浓度仍高于健康对照(P<0.05)。干扰素治疗前有效组的血清总抗氧化能力明显高于无效组(P<0.05),治疗后血清总抗氧化能力明显升高(P<0.05)。结论IFNα-2b治疗可以明显改善慢性乙型肝炎患者的氧化-抗氧化损伤平衡障碍,抗病毒治疗中适当应用抗氧化剂可能有助于提高临床疗效。     

Alanine Aminotransferase Elevation during Peginterferon Alpha-2a or Alpha-2b plus Ribavirin Treatment

Alanine aminotransferase (ALT) elevation was occassionally observed during the treatment with combination peginterferon alpha plus ribavirin. Two forms of peginterferon are currently available as a standard of care with or without direct-acting antivirals against hepatitis C virus (HCV). Until the appearance of interferon-sparing regimen, peginterferon alpha plus ribavirin will play a central role in the eradication of HCV. In the present study, we compared ALT elevations in response to peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin in HCV genotype-1-infected patients. There were no significant differences in ALT elevations between treatments with the two peginterferons, but in a comparison of the proportions of patients with transient ALT elevation from baseline between the two groups, transient ALT elevation was observed more in sustained virological response (SVR) patients treated with peginterferon alpha-2a than with peginterferon alpha-2b. However, no patients discontinued treatment due to ALT elevation. Patients with transient ALT elevation from baseline during the treatment had less favorable IL28B rs8099917 genotype in the peginterferon alpha-2b group. Patients achieving SVR tended to have lower ALT levels, although some had persistent ALT elevation during treatment. In conclusion, clinicians should pay attention to possible ALT elevation during the treatment of chronic hepatitis C patients.     

67例慢性丙型肝炎治疗过程及随访中血清ALT、病毒载量及肝纤维化指标的变化

目的 观察聚乙二醇干扰素α-2b联合利巴韦林治疗慢性丙型肝炎过程中肝功能、病毒复制及肝纤维化指标的改变情况.方法 检测67例慢性丙型肝炎患者在干扰素联合利巴韦林治疗开始（0周）、结束（48周）和停药12周（60周）时血清丙氨酸转氨酶（ALT）、丙肝病毒核糖核酸（HCV RNA）、透明质酸（HA）、Ⅲ型前胶原肽（PCⅢ）、Ⅳ型胶原（Ⅳ-C）和层粘连蛋白（LN）水平.结果 治疗后完全应答组（CR-S,43/67） ALT、HCV RNA及血清4项纤维化指标均显著下降（P ＜0.05或P＜0.01）,部分应答组（CR-R,13/67）和无应答组（NR,11/67） ALT、HCV RNA及血清4项纤维化指标变化不明显,反跳甚至更高.结论 聚乙二醇干扰素α-2b联合利巴韦林治疗慢性丙型肝炎约65％患者完全应答,随着肝细胞炎症的改善,病毒RNA滴度、肝纤维化指标水平明显下降,表明干扰素联合利巴韦林能抑制HCV RNA复制,调节机体免疫功能,减轻肝脏炎症反应,改善肝功能,减少肝纤维化.     

Impaired response to alpha interferon in patients with an inapparent hepatitis B and hepatitis C virus coinfection

Summary.  The possibility of hepatitis B virus (HBV) infection in HBsAg-negative patients has been shown. However, an “inapparent” coinfection by HBV in hepatitis C virus (HCV)-positive patients generally is not taken into account in clinical practice. Mechanisms responsible for resistance to interferon (IFN) have not been completely clarified. The aim of this study was to investigate whether an “inapparent” coinfection by HBV in anti-HCV-positive chronic liver disease patients may influence IFN response. Fourteen anti-HCV positive, HBsAg-negative but serum HBV DNA-positive patients by PCR and 111 anti-HCV-positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis were treated with 3 MU of recombinant α-2a IFN 3 times weekly for 12 months. Serum HBV DNA and HCV RNA were determined before treatment, after 6–12 months and in coincidence with ALT flare-up by PCR. HBV PCR was performed using primers specific for the S region of the HBV genome and HCV PCR with primers localised in the 5′NC region of HCV genome. IgM anti-HBc was tested using IMx Core-M Abbott assay. By the end of treatment, ALT values had become normal in 4/14 HBV DNA-positive patients (28%), but all “responders” (4/4) relapsed between 2 and 5 months after therapy. All but one patient were HCV RNA-positive before treatment, 6 were also both HBV DNA and HCV RNA-positive during ALT flare-ups. In 5 patients, only HBV DNA and in 3 patients, only HCV RNA was detected when transaminase values increased. All patients remained HBsAg-negative and anti-HCV-positive. IgM anti-HBc was detected both before treatment and during ALT elevation in 3 patients and only during ALT relapse in 3 others. Of the 111 anti-HCV positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis, a biochemical response to IFN treatment was observed in 54% of the cases. Relapse of ALT values was observed in 47% of the cases during a follow-up of 1 year after treatment. “Inapparent” HBV/HCV coinfection may be implicated in cases of resistance to IFN treatment. In addition, HBV replication may persist in patients in whom HCV replication was inhibited by IFN treatment. The pathogenic role of HBV in liver disease was confirmed by detection of IgM anti-HBc in some cases; the appearance of these antibodies only after IFN treatment suggests that IFN may exert a selective role in favour of HBV. Further studies will show the effect of different treatment schedules. HBV DNA and/or IgM anti-HBc detection with very sensitive methods may be important both as a prognostic factor and as a tool for better understanding interviral relationships and mechanisms involved in multiple hepatitis virus infections.