STUDIES OF THE NATURAL HISTORY AND TREATMENT OF CHRONIC HEPATITIS B

慢性乙型肝炎的自然史和治疗的研究

• 批准号: 6432156
• 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/6432156
• 关键词: chronic disease /disorder; clinical research; combination chemotherapy; hepatitis B; human subject; human therapy evaluation; immunopathology; interferon alpha; lamivudine; liver disorder chemotherapy; nucleoside analog

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 now available for prevention of hepatitis B. However, therapies for the disease once it has occurred are unsatisfactory. Alpha interferon was the first antiviral agent shown to be effective in this disease and was licensed for this indication in the United States in 1993. The basis for licensure were, in part, studies conducted in the Liver Diseases Section of NIH. However, alpha interferon is effective in only one-third of patients with typical chronic hepatitis B and its role in atypical forms of this disease remain unclear. Current activities in the Liver Diseases Section are focused on developing better therapies to prevent long-term consequences. A longterm study of lamivudine (3-thiacytidine) for both HBeAg positive and anti-HBe positive chronic hepatitis B has been underway since 1996. Virtually all patients with chronic hepatitis B have 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 75% of patients who were initially HBeAg positive but in only 10% of those initially anti-HBe positive (and HBeAg negative). Liver biopsies taken after 3 to 5 years of therapy show marked improvements in all patients who maintained a virological response, but no improvement or worsening in those with viral resistance. Some patients with a maintained response have cleared all markers of infection (HBeAg, HBsAg and HBV DNA). Others remain HBsAg positive but have normal liver biopsies. Indeed, some biopsies show resolution of previous fibrosis. A central issue is how to manage patients who develop lamivudine resistance. Patients with resistance demonstrating progression of disease will be treated with alpha interferon in an attempt to induce a longterm remission. Patients who fail to respond to this approach or who have mild disease despite resistance will be enrolled in future trials of new antivirals (adefovir) alone or in combination with lamivudine. Patients who have had a long term response to antiviral therapy will be evaluated for whether the virus is merely suppressed and is still present in low level or is eradication and no longer detectable even in liver. Immune responses to hepatitis antigens will be compared between long term responders and non responders to attempt to dissect out the immunology and virologic determinants of recovery from 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％。 现在可以使用安全有效的疫苗来预防丙型肝炎。但是，该疾病发生的疗法并不令人满意。 阿尔法干扰素是证明在该疾病中有效的第一位抗病毒剂，并于1993年在美国获得了该迹象。许可的基础部分是在NIH的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只有三分之一的患者有效，并且其在该疾病的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致力于开发更好的疗法以防止长期后果。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-吡啶丁胺）进行了。几乎所有的慢性肝炎B患者均患有血清生物化学，病毒学和组织学对100 mg兰氨维地的反应。 但是，在最初呈HBEAG阳性的患者中，有75％的患者发生了与病毒抗性的突破，但最初只有抗HBE阳性的患者中只有10％（和HBEAG阴性）。 3至5年治疗后进行的肝活检表明，所有维持病毒学反应但病毒抗性患者没有改善或恶化的患者的改善明显改善。 一些具有维持反应的患者清除了所有感染标记（HBEAG，HBSAG和HBV DNA）。 其他人则保持HBSAG阳性，但具有正常的肝活检。 确实，一些活检显示了先前纤维化的分辨率。 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将用α干扰素治疗，以试图诱导长期缓解。未能对这种方法反应或尽管有抵抗力患有轻度疾病的患者将在以后的新抗病毒药（Adefovir）进行试验中，或与拉米夫丁（Lamivudine）结合使用。 对抗病毒疗法有长期反应的患者将被评估，以评估该病毒是否仅被抑制并且仍处于低水平或根除，即使在肝脏中也无法检测到。 将比较长期反应者和非反应者之间对丙型肝炎抗原的免疫反应，以试图从乙型肝炎中剖析恢复的免疫学和病毒学决定因素。