Studies Of The Natural History And Treatment Of Chronic

慢性病的自然史和治疗研究

• 批准号: 6983966
• 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/6983966
• 关键词: active immunization; adefovir; chronic disease /disorder; combination chemotherapy; disease /disorder etiology; 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

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. 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. 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. A total of 49 patients have been 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. A 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 28 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 only 16 patients have completed a year of treatment and differences in these regimens will probably require 2 to 3 years to become evident. Immunological studies have been carried out on patients receiving therapy for their hepatitis B. A striking finding has been that patients on long-term therapy have decreased T cell responses to HBV antigens and many have no T cell reactions. These findings have led to the proposal to use HBV vaccination to augment T cell responses in treated patients. Protocols incorporating use of vaccine immunotherapy are being developed. 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。阿尔法干扰素是第一个证明在该疾病中有效的抗病毒剂，并于1993年获得该适应症的许可。许可的基础部分是由NIH肝脏疾病部分进行的研究。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。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-噻吩丁胺）进行了。总共有49名患者参与了这项研究。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，在某些情况下，肝活检恢复到正常。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。总共有28名患者参加了这项研究。迄今为止的结果表明，仅对Adefovir的反应率与Adefovir和Lamivudine的组合相似，但是只有16名患者完成了一年的治疗，并且在这些方案中的差异可能需要2至3年才能证明。对接受肝炎的治疗的患者进行了免疫学研究。一个惊人的发现是，长期治疗的患者对HBV抗原的T细胞反应降低了，许多人没有T细胞反应。这些发现导致了该提议使用HBV疫苗接种来增加治疗患者的T细胞反应。正在开发结合使用疫苗免疫疗法的方案。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。