Studies Of The Natural History And Treatment Of Chronic

正在对有充分证据的慢性丙型肝炎患者进行评估，以确定该疾病的长期自然史和免疫发病机制，并评估治疗方法，特别是对常规治疗无效的患者。目前，慢性丙型肝炎的最佳治疗方法是聚乙二醇干扰素和利巴韦林联合治疗24至48周。该方案诱导约55%患者血清中HCV RNA的持续清除以及血清转氨酶和基础肝病的改善。对于治疗后没有变成HCV RNA阴性的患者，几乎没有其他选择。NIDDK肝病科目前的研究重点是这些对丙型肝炎标准治疗无效的患者。在两项研究中，正在评估利巴韦林单药治疗的效果。对干扰素和利巴韦林联合治疗无效的患者随机接受安慰剂或利巴韦林单药治疗一年。在108例接受联合治疗的患者中，50例病毒清除无效，其中34例随机接受安慰剂（n=17）或利巴韦林（n=17）。治疗一年后，医学评估和肝活检显示血清转氨酶水平和肝活检证据显示利巴韦林治疗后坏死性炎症有所改善（p<0.01），但纤维化没有变化。在一项随访研究中，26名患者长期接受利巴韦林治疗，前8名患者在两年后的肝活检显示纤维化评分没有消退。这些研究将继续进行，直到至少有足够数量的患者接受了两年或两年以上的治疗，并进行了重复肝活检组织学检查。治疗无应答患者的第二种方法是用干扰素维持治疗。肝病科正在参与一项名为HALT-C的大型、多中心、随机对照试验，该试验侧重于聚乙二醇干扰素对慢性丙型肝炎的长期治疗。在这项试验中，患者首先用聚乙二醇干扰素和利巴韦林治疗24周;然后将没有变成HCV RNA阴性的患者随机接受长期聚乙二醇干扰素治疗或不治疗，每隔3个月随访一次，每两年进行一次肝活检。本研究是一项由NIDDK申办的多中心美国试验，在包括NIH临床中心在内的10个中心进行。本研究将入组1200例患者，NIH临床中心最多入组100例。到目前为止，已有47名患者在NIH登记。治疗无应答患者的第三种方法是使用新的抗病毒药物。肝病科正在评估γ干扰素，一种在复制子组织培养系统中对HCV具有抗病毒活性的T细胞细胞因子。20名对联合治疗无效的患者正在接受为期4周的增加剂量的γ干扰素治疗，同时监测HCV病毒水平的变化。迄今为止，已有11名患者接受了治疗。在较低剂量的γ-干扰素，HCV RNA水平变化最小，血清转氨酶。未来将对更高剂量进行评估。作为本研究和其他丙型肝炎自然史研究的一部分，患者接受血清和肝组织的免疫学和病毒学评估，重点是阐明疾病的发病机制以及进展和恢复的决定因素。

Patients with well-documented chronic hepatitis C are being evaluated to determine the long-term natural history and immune pathogenesis of this disease and to evaluate therapies, particularly in patients who fail to respond to conventional therapy. The current, optimal therapy for chronic hepatitis C is the combination of peginterferon and ribavirin given for 24 to 48 weeks. This regimen induces a sustained clearance of HCV RNA from serum and improvement in serum aminotransferases and the underlying the liver disease in approximately 55% of patients. For patients who do not become HCV RNA negative with therapy, there are few other options. Current studies in the Liver Diseases Section, NIDDK focus upon these patients who fail to respond to the standard therapy of hepatitis C. In two studies, the effects of ribavirin monotherapy are being evaluated. Patients who fail to respond to the combination of interferon and ribavirin are randomized to receive either placebo or ribavirin monotherapy for one year. Among 108 patients treated with combination therapy, 50 failed to respond with clearance of virus of whom 34 were randomized to receive placebo (n=17) or ribavirin (n=17). After a year of treatment, medical evaluation and liver biopsies revealed improvements in serum aminotransferase levels and in liver biopsy evidence of necroinflammation with ribavirin therapy (p<.01), but no change in fibrosis. In a follow up study, 26 patients have been treated with ribavirin long-term and liver biopsies after two years in the first 8 patients show no regression of fibrosis scores. These studies will be continued until at least adequate numbers of patients have been treated for two years or more and have repeat liver biopsy histology. A second approach to treatment of non-responder patients is maintenance therapy with interferon. The Liver Diseases Section is participating in a large, multicenter, randomized controlled trial known as HALT-C, which focuses on long-term therapy of chronic hepatitis C with peginterferon. In this trial, patients are first treated with peginterferon and ribavirin for 24 weeks; patients who do not become HCV RNA negative are then randomized to receive long-term peginterferon therapy or no treatment, being followed at 3 month intervals and liver biopsy every two years. This study is a multicenter U.S. trial sponsored by NIDDK which is being conducted in 10 centers including the Clinical Center of the NIH. A total of 1200 patients will be enrolled in this study, up to 100 at the NIH Clinical Center. To date, 47 patients have been enrolled at the NIH. A third approach to therapy of non-responder patients is the use of new antiviral agents. The Liver Diseases Section is evaluating gamma interferon, a T cell cytokine that has antiviral activity against HCV in the replicon tissue culture system. Twenty patients who failed to respond to combination therapy are being treated with 4-week courses of increasing doses of gamma interferon while being monitored for changes in HCV viral levels. To date 11 patients have been treated. At the lower doses of gamma interferon, HCV RNA levels changed minimally as did serum aminotransferases. Higher doses will be evaluated in the future. As a part of this study and other natural history studies of hepatitis C, patients undergo immunological and virological assessment of the serum and liver tissue focusing upon elucidation of the pathogenesis of disease and the determinants of progression and of recovery.