Studies Of The Natural History And Treatment Of Chronic

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%。安全有效的疫苗可用于预防B型肝炎，但一旦发生这种疾病的治疗效果有限。α干扰素是第一种被证明对这种疾病有效的抗病毒药，并于1993年获得许可用于这种适应症。一种改良的长效干扰素-聚乙二醇干扰素-在2005年被批准用于治疗B型肝炎。获得许可的部分依据是美国国立卫生研究院肝病科进行的研究。然而，α干扰素在三分之一或更少的典型慢性B型肝炎患者中有效，其在非典型形式中的作用仍不清楚。最近，几种核苷和核苷酸药物已被证明对治疗慢性B型肝炎有效，并且现已在美国获得许可使用。这些药物包括拉米夫定、阿德福韦和恩替卡韦。这些药物是安全的，可将HBV DNA抑制到低水平，并改善疾病的生化和组织学证据。然而，停止核苷（酸）治疗后几乎总是伴随着疾病活动的复发和恢复。此外，长期治疗可能导致抗病毒药物耐药性和效力丧失。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和分析预测或与治疗结果相关的免疫因素。拉米夫定（3-硫代胞苷）治疗HBeAg阳性和抗-HBe阳性的慢性B型肝炎的长期研究自1996年以来一直在进行，最近进行了修改，以允许继续治疗。共有49例患者入组本研究。几乎所有的患者在拉米夫定100毫克每日一次的剂量下都有血清生化、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（和HBeAg阴性）的患者发生了病毒耐药的突破。治疗3至5年后进行的肝活检显示，维持病毒应答的患者有明显改善，但病毒耐药患者的长期改善很少或没有。最引人注目的是对治疗有长期维持反应的患者的纤维化消退，在某些情况下，尽管血清中HBsAg持续存在，但肝活检恢复正常。这些患者似乎对B型肝炎具有耐受性，并且缺乏对HBV抗原的T细胞反应性。目前的方案将集中在拉米夫定治疗的长期反应与频繁监测病毒水平，血清转氨酶和HBV抗原的免疫反应的患者短暂停药。短暂撤销病毒抑制可能导致触发对HBV的免疫反应性以及病毒和HBsAg的清除。另一个中心问题是如何管理拉米夫定耐药的患者。耐药患者表现为疾病进展，已用α干扰素治疗，该干扰素诱导了短暂的改善，但没有清除HBeAg。已经开发了两种方案来使用口服核苷酸类似物阿德福韦治疗慢性B型肝炎：一种用于拉米夫定耐药患者（与免疫调节实验室合作开发，NIAID）另一组为既往未接受治疗的患者，他们将随机接受拉米夫定和阿德福韦酯联合治疗或阿德福韦酯单药治疗，长期监测和随访与接受拉米夫定治疗的患者相似单一疗法。共有32例患者入组本研究。迄今为止的结果表明，阿德福韦单药治疗的应答率与阿德福韦和拉米夫定联合治疗的应答率相似，但联合治疗对HBV DNA水平的抑制作用更强（5.94对3.88 log下降），所有患者均出现病毒学应答，而阿德福韦单药治疗的患者中只有三分之二出现病毒学应答。长期治疗的相对疗效将继续进行评估，总共需要40例患者才能充分把握阿德福韦酯联合治疗与单药治疗的分析。这些研究将有助于确定长期持续抗病毒治疗B型肝炎的有效性和安全性。

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. A modified, long-acting form of interferon -peginterferon- was licensed for use in hepatitis B in 2005. 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. More recently, several nucleoside and nucleotide agents have been shown to be effective in treating chronic hepatitis B and have now been licensed for use in the United States. These include lamivudine, adefovir and entecavir. These agents are safe and cause suppression of HBV DNA to low levels and improvements in biochemical and histologic evidence of disease. However, withdrawal of nucleos(t)ide therapy is almost always followed by relapse and return of disease activity. Furthermore, long-term therapy can lead to antiviral resistance and loss of potency. 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 and was recently modified to allow for continued therapy. A total of 49 patients were 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 despite persistence of HBsAg in serum. These patients appear to be tolerant of hepatitis B and lack T cell responsiveness to HBV antigens. A current protocol will focus upon transient withdrawal of lamivudine therapy in patients with a long-term response with frequent monitoring of viral levels, serum aminotransferases, and immunological responses to HBV antigens. Transient withdrawal of viral suppression may lead to triggering of immune reactivity to HBV and clearance of virus and HBsAg. Another 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 32 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 the combination provides more potent inhibition of HBV DNA levels (5.94 vs 3.88 log decrease) and a virologic response in all patients, compared to only two-thirds of patients treated with adefovir alone. The relative efficacy of long-term therapy will continue to be evaluated, and a total of 40 patients will be needed to adequately power this analysis of combination versus monotherapy with adefovir. These studies will help define the efficacy and safety of long-term, continuous antiviral therapy of hepatitis B.