Studies Of The Natural History And Treatment Of Chronic

感染乙型肝炎病毒是全世界肝病的一个主要原因，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乙型肝炎，但一旦发生这种疾病，治疗方法的效力有限。干扰素是首个被证明对这种疾病有效的抗病毒药物，并于1993年获准用于这种适应症。许可的基础部分是由美国国立卫生研究院肝病科进行的研究。然而，干扰素对三分之一或更少的典型慢性乙型肝炎患者有效，其在非典型乙型肝炎中的作用尚不清楚。肝病科目前的活动重点是发展更好的治疗方法，以预防长期后果，并分析预测治疗结果或与治疗结果相关的免疫因素。拉米夫定（3-硫胞苷）治疗HBeAg阳性和抗hbe阳性慢性乙型肝炎的长期研究自1996年开始。共有49名患者被纳入本研究。几乎所有患者对每天一次的100毫克拉米夫定有血清生化、病毒学和组织学反应。然而，80%的初始HBeAg阳性患者和50%的初始抗- hbe阳性（和HBeAg阴性）患者出现了病毒耐药性的突破。治疗3 - 5年后进行的肝活检显示，维持病毒反应的患者有明显改善，但病毒耐药的患者几乎没有或没有长期改善。最引人注目的是对治疗长期维持反应的患者的纤维化消退，在某些情况下，肝活检恢复正常。一个核心问题是如何管理出现拉米夫定耐药性的患者。表现出疾病进展的耐药患者已接受α干扰素治疗，该治疗可引起短暂的改善，但没有清除HBeAg。已经制定了两项使用口服核苷酸类似物阿德福韦治疗慢性乙型肝炎的方案：一项是针对拉米夫定耐药患者（与NIAID免疫调节实验室合作开发），另一项是针对先前未接受治疗的患者，这些患者将随机接受拉米夫定和阿德福韦联合治疗或长期单独接受阿德福韦治疗，与接受拉米夫定单药治疗的患者进行类似的监测和随访。对接受乙肝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，许多患者没有T细胞反应。这些发现导致建议使用HBV疫苗来增强治疗患者的T细胞反应。目前正在制定使用疫苗免疫疗法的方案。这些研究将有助于确定长期、持续的乙肝抗病毒治疗的有效性和安全性。

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. 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.