STUDIES OF THE NATURAL HISTORY AND TREATMENT OF CHRONIC HEPATITIS B

感染B型肝炎病毒是世界范围内肝病的主要原因，在美国占慢性肝病和肝硬化的5- 10%。 目前已有安全有效的疫苗预防B型肝炎。然而，一旦疾病发生，其治疗是不令人满意的。 α干扰素是第一个被证明对这种疾病有效的抗病毒药，并于1993年在美国获得许可用于这种适应症。 获得许可的部分依据是NIH肝病科进行的研究。 然而，α干扰素仅对三分之一的典型慢性B型肝炎患者有效，其在非典型形式的这种疾病中的作用仍不清楚。肝病科目前的活动集中在开发更好的治疗方法以预防长期后果。拉米夫定（3-硫代胞苷）治疗HBeAg阳性和抗-HBe阳性慢性B型肝炎的长期研究自1996年以来一直在进行。事实上，所有慢性B型肝炎患者在服用拉米夫定100 mg每日一次后，血清生化、病毒学和组织学均有所反应。 然而，在最初HBeAg阳性的患者中，75%的患者出现了病毒耐药的突破，但在最初抗-HBe阳性（和HBeAg阴性）的患者中，只有10%的患者出现了病毒耐药的突破。 治疗3 - 5年后进行的肝活检显示，所有维持病毒学应答的患者都有明显改善，但病毒耐药患者没有改善或恶化。 一些维持应答的患者清除了所有感染标志物（HBeAg、HBsAg和HBV DNA）。 其他人保持HBsAg阳性，但肝活检正常。 事实上，一些活组织检查显示先前的纤维化消退。 一个中心问题是如何管理拉米夫定耐药的患者。 耐药且显示疾病进展的患者将接受α干扰素治疗，试图诱导长期缓解。对这种方法没有反应的患者或尽管有耐药性但病情轻微的患者将被纳入未来的新抗病毒药物（阿德福韦）单独或与拉米夫定联合治疗的试验。 对抗病毒治疗有长期反应的患者将评估病毒是否仅被抑制并且仍然以低水平存在或被根除并且即使在肝脏中也不再可检测到。 将在长期应答者和无应答者之间比较对肝炎抗原的免疫应答，以试图剖析从B型肝炎恢复的免疫学和病毒学决定因素。

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.