Studies Of The Natural History And Treatment Of Chronic

乙肝病毒感染是全球肝病的主要原因，占美国慢性肝病和肝硬变的5%至10%。安全有效的疫苗可用于预防乙肝，但这种疾病一旦发生，治疗效果有限。阿尔法干扰素是第一个被证明对这种疾病有效的抗病毒药物，并于1993年获得批准用于这一适应症。获得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，α干扰素对三分之一或更少的典型慢性乙肝患者有效，其在非典型形式中的作用尚不清楚。肝病科目前的活动侧重于开发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。自1996年以来，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一直在进行中。共有49名患者参加了这项研究。几乎所有的患者对拉米夫定每天100毫克的剂量都有血清生化、病毒学和组织学反应。然而，80%最初HBeAg阳性的患者和50%最初抗HBe阳性(HBeAg阴性)的患者出现了病毒耐药性的突破。治疗3到5年后的肝脏活检显示，保持病毒应答的患者显著改善，但对病毒耐药的患者长期改善很少或没有改善。最引人注目的是，对治疗有长期维持反应的患者的纤维化得到了解决，在某些情况下，肝脏活检恢复正常。一个中心问题是如何管理对拉米夫定产生耐药性的患者。表现出疾病进展的耐药患者接受了阿尔法干扰素治疗，这种治疗导致了短暂的改善，但没有清除HBeAg。已经开发了两个使用口服核苷酸类似物阿德福韦治疗慢性乙肝的方案：一个用于拉米夫定耐药患者(与免疫调节实验室NIAID合作开发)，另一个用于以前未接受治疗的患者，他们将随机接受拉米夫定和阿德福韦的联合治疗或阿德福韦单独治疗，与接受拉米夫定单一疗法的患者进行类似的监测和随访。共有28名患者参加了这项研究。到目前为止的结果表明，单用阿德福韦的有效率与阿德福韦和拉米夫定的联合有效率相似，但只有16名患者完成了一年的治疗，而且这些方案的差异可能需要2到3年才能显现出来。对接受乙肝治疗的患者进行了免疫学研究。一个引人注目的发现是，长期治疗的患者对乙肝病毒抗原的T细胞反应降低，许多人没有T细胞反应。这些发现导致了使用乙肝疫苗接种来增强接受治疗的患者的T细胞反应的提议。纳入疫苗免疫疗法使用的方案正在制定中。这些研究将有助于确定长期、持续的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.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.