Studies Of The Natural History And Treatment Of Chronic

慢性病的自然史和治疗研究

• 批准号: 7152964
• 负责人: JAY H. HOOFNAGLE
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7152964
• 关键词: active immunization; adefovir; antiviral agents; chronic disease /disorder; combination chemotherapy; disease /disorder etiology; disease /therapy duration; drug resistance; hepatitis B; hepatitis B virus group; hepatitis vaccine; human subject; human therapy evaluation; interferon alpha; lamivudine; longitudinal human study; microorganism disease chemotherapy; patient oriented research; therapy design /development

Infection with hepatitis B virus is a major cause of liver disease worldwide and accounts for 5-10 per cent of chronic liver disease and cirrhosis in the United States. Safe and effective vaccines are available for prevention of hepatitis B, but therapies for the disease once it has occurred are limited in efficacy. Alpha interferon was the first antiviral agent shown to be effective in this disease and was licensed for this indication in 1993. A modified, long-acting form of interferon -peginterferon- was licensed for use in hepatitis B in 2005. The basis for licensure were, in part, studies conducted by the Liver Diseases Section, NIH. However, alpha interferon is effective in one-third or less of patients with typical chronic hepatitis B and its role in atypical forms remains unclear. More recently, several nucleoside and nucleotide agents have been shown to be effective in treating chronic hepatitis B and have now been licensed for use in the United States. These include lamivudine, adefovir and entecavir. These agents are safe and cause suppression of HBV DNA to low levels and improvements in biochemical and histologic evidence of disease. However, withdrawal of nucleos(t)ide therapy is almost always followed by relapse and return of disease activity. Furthermore, long-term therapy can lead to antiviral resistance and loss of potency. Current activities in the Liver Diseases Section are focused on developing better therapies to prevent long-term consequences and analysis of immunological factors that predict or correlate with outcome of treatment. A longterm study of lamivudine (3-thiacytidine) for both HBeAg positive and anti-HBe positive chronic hepatitis B has been underway since 1996 and was recently modified to allow for continued therapy. A total of 49 patients were enrolled into this study. Virtually all patients had a serum biochemical, virological and histological response to lamivudine in a dose of 100 mg once daily. However, breakthrough with viral resistance has occurred in 80% of patients who were initially HBeAg positive and 50% of those initially anti-HBe positive (and HBeAg negative). Liver biopsies taken after 3 to 5 years of therapy show marked improvements in patients who maintained a viral response, but little or no long-term improvement in those with viral resistance. Most striking has been a resolution of fibrosis in patients with a long-term maintained response to therapy and, in some cases, return of the liver biopsy to normal despite persistence of HBsAg in serum. These patients appear to be tolerant of hepatitis B and lack T cell responsiveness to HBV antigens. A current protocol will focus upon transient withdrawal of lamivudine therapy in patients with a long-term response with frequent monitoring of viral levels, serum aminotransferases, and immunological responses to HBV antigens. Transient withdrawal of viral suppression may lead to triggering of immune reactivity to HBV and clearance of virus and HBsAg. Another central issue is how to manage patients who develop lamivudine resistance. Patients with resistance demonstrating progression of disease have been treated with alpha interferon which has induced transient improvements but without clearance of HBeAg. Two protocols have been developed to use the oral nucleotide analogue, adefovir for chronic hepatitis B: one for patients with lamivudine resistance (developed in collaboration with the Laboratory of Immune Regulation, NIAID) and one for previously untreated patients who will be randomized to receive either the combination of lamivudine and adefovir or adefovir alone longterm with similar monitoring and follow up as done for patients who received lamivudine monotherapy. A total of 32 patients have been enrolled into this study. Results to date indicate similar rates of response to adefovir alone as to adefovir and lamivudine in combination, but the combination provides more potent inhibition of HBV DNA levels (5.94 vs 3.88 log decrease) and a virologic response in all patients, compared to only two-thirds of patients treated with adefovir alone. The relative efficacy of long-term therapy will continue to be evaluated, and a total of 40 patients will be needed to adequately power this analysis of combination versus monotherapy with adefovir. These studies will help define the efficacy and safety of long-term, continuous antiviral therapy of hepatitis B.

丙型肝炎病毒感染是全球肝病的主要原因，在美国占慢性肝病和肝硬化的5-10％。安全有效的疫苗可用于预防丙型肝炎，但是一旦发生这种疾病的疗法，疗效的疗法受到限制。阿尔法干扰素是证明在该疾病中有效的第一种抗病毒剂，并于1993年获得该迹象。一种经过修改的长效形式的干扰素 - peginterferon-被许可在2005年获得用于乙型肝炎的使用。在2005年。然而，α干扰素在典型的慢性肝炎患者中有效，在三分之一或更少的患者中，其在非典型形式中的作用尚不清楚。最近，已经证明了几种核苷和核苷酸剂可有效治疗慢性丙型肝炎，并且现在已在美国使用许可。这些包括拉米夫丁，阿德菲维尔和恩塞韦尔。这些药物是安全的，并导致HBV DNA抑制至低水平，并改善了疾病的生化和组织学证据。然而，几乎总是戒断核（T）IDE治疗后，随后是复发和疾病活性的回归。此外，长期治疗可以导致抗病毒药耐药性和效力丧失。肝脏疾病部分中的当前活动集中于开发更好的疗法，以防止对预测或与治疗结果相关的免疫因素的长期后果和分析。自1996年以来，对HBEAG阳性和抗HBE阳性慢性肝炎B的长期研究（3-噻二啶）已经进行了，最近进行了修改以进行持续治疗。这项研究共有49名患者。几乎所有患者的生化，病毒学和组织学对拉米丁的反应均以每天100 mg的剂量为单位。但是，在最初呈HBEAG阳性的80％的患者中，有80％的患者发生了与病毒抗性的突破，最初抗HBE阳性的患者中有50％（以及HBEAG阴性）。经过3至5年治疗后进行的肝活检表明，维持病毒反应的患者的改善明显改善，但病毒抗性的患者几乎没有或没有长期改善。大多数引人注目的是在长期保持对治疗反应的患者中的纤维化解决，尽管在血清中HBSAG持续存在，但在某些情况下，肝活检恢复正常。这些患者似乎耐受性丙型肝炎，缺乏对HBV抗原的T细胞反应。当前的方案将集中于在长期反应的患者中暂时戒断拉米夫定疗法，并经常监测病毒水平，血清氨基转移酶和对HBV抗原的免疫反应。病毒抑制的短暂戒断可能导致对HBV的免疫反应性以及病毒和HBSAG的清除。另一个核心问题是如何管理产生lamivudine耐药性的患者。表现出疾病进展的耐药性患者已用α干扰素治疗，该患者已诱导短暂改善，但没有清除HBEAG。 Two protocols have been developed to use the oral nucleotide analogue, adefovir for chronic hepatitis B: one for patients with lamivudine resistance (developed in collaboration with the Laboratory of Immune Regulation, NIAID) and one for previously untreated patients who will be randomized to receive either the combination of lamivudine and adefovir or adefovir alone longterm with similar monitoring and follow up as done for patients who received lamivudine单一疗法。这项研究总共已入学32名患者。迄今为止的结果表明，仅对Adefovir和对Adefovir的反应率与对Adefovir和Lamivudine的组合相似，但是与仅使用Adefovir治疗的三分之二的患者相比，所有患者的HBV DNA水平（5.94 vs 3.88对数降低）提供了更有效的HBV DNA水平（5.94 vs 3.88对数降低）和病毒学反应。长期治疗的相对疗效将继续进行评估，总共需要40名患者来充分利用这种组合与Adefovir的单一疗法的分析。这些研究将有助于确定乙型肝炎的长期连续抗病毒疗法的功效和安全性。

项目成果

Denying the wolf access to sheep's clothing.

不让狼接触到羊皮。

• DOI: 10.1172/jci19417
• 发表时间: 2003
• 期刊: The Journal of clinical investigation
• 作者: Heller,Theo;Hoofnagle,JayH
• 通讯作者: Hoofnagle,JayH

Resolution of chronic hepatitis B-associated autoimmune neutropenia with interferon-alpha therapy.

用干扰素-α 治疗解决慢性乙型肝炎相关的自身免疫性中性粒细胞减少症。

• DOI: 10.1097/00005176-200301000-00027
• 发表时间: 2003
• 期刊: Journal of pediatric gastroenterology and nutrition
• 影响因子: 2.9
• 作者: Soza,Alejandro;Lau,DarylT-Y;Khokhar,MuhammadFarooq;Conjeevaram,Hari;Park,Yoon;Hoofnagle,JayH
• 通讯作者: Hoofnagle,JayH

Challenges in therapy of chronic hepatitis B.

慢性乙型肝炎治疗的挑战。

• DOI: 10.1016/s0168-8278(03)00332-5
• 发表时间: 2003
• 期刊: Journal of hepatology
• 影响因子: 25.7
• 作者: Hoofnagle,JayH