Studies Of The Natural History And Treatment Of Chronic

正在对有充分记录的慢性丙型肝炎患者进行评估，以确定这种疾病的长期自然史和免疫发病机制，并评估治疗方法，特别是对这种常见形式的慢性肝病常规治疗无效的患者。最近的研究已经确定了慢性丙型肝炎的标准，最佳治疗方法为α干扰素和利巴韦林的联合治疗24至48周。该方案诱导约40%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肝病科目前进行的治疗研究集中在这些对丙型肝炎标准治疗无效的患者身上。在一项长期利巴韦林的研究中，患者最初接受α干扰素和利巴韦林的联合治疗：那些在联合治疗24周后没有变成HCV RNA阴性的患者然后随机接受利巴韦林或安慰剂，并停止干扰素治疗。共有108例患者入组本研究，90例完成参与（18个月的治疗和随访）。总共有35名患者参加了研究的第二阶段，接受利巴韦林或安慰剂，其中24名患者完成了一年的疗程和随访。利巴韦林治疗组患者的肝脏组织学得到改善，但安慰剂组患者的肝脏组织学保持不变。接受利巴韦林治疗的患者纤维化评分没有变化，但接受安慰剂治疗的患者纤维化评分恶化。对利巴韦林有有益反应的患者（如转氨酶水平的改善和肝组织学的改善所证明的）将在开放标签研究中接受长期利巴韦林治疗，每两年进行一次随访肝活检。第二项治疗无应答者的研究是一项多中心、随机对照试验，称为Halt-C，重点是用聚乙二醇干扰素长期治疗慢性丙型肝炎。聚乙二醇化干扰素是一种α干扰素，其通过与聚乙二醇共价键合进行修饰，从而允许延迟活性分子的清除和持续的作用持续时间。聚乙二醇干扰素每周一次（而不是常规干扰素每周三次），并提供更严格和持续的抗病毒活性。在该试验中，患者首先用聚乙二醇干扰素和利巴韦林联合治疗24周。然后，没有成为HCV RNA阴性的患者随机接受长期聚乙二醇干扰素治疗或不接受治疗，每隔3个月随访长达4年，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个地理位置分散的医疗中心进行。本研究将入组1200例患者，NIH临床中心最多入组100例。迄今为止，已有27名患者在NIH入组。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 of this common form of chronic liver disease. Recent studies have defined the standard, optimal therapy for chronic hepatitis C as the combination of alpha interferon 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 40% of patients. For patients who do not become HCV RNA negative with therapy, there are few other options. Current studies of therapy done by the Liver Diseases Section, NIDDK focus upon these patients who fail to respond to the standard therapy of hepatitis C. In one study of long-term ribavirin, patients are initially treated with the combination of alpha interferon and ribavirin: those patients who do not become HCV RNA negative after 24 weeks of combination therapy are then randomized to receive either ribavirin or placebo and to stop interferon treatment. A total of 108 patients have been enrolled in this study and 90 have completed participation (18 months of therapy and follow up). In all, 35 patients have been enrolled in the second phase of the study receiving either ribavirin or placebo and 24 of these have completed the one year course and follow up. Liver histology improved in the ribavirin treated patients, but remained unchanged in the placebo recipients. Fibrosis scores did not change in ribavirin recipients, but worsened in those on placebo. Patients who have a beneficial response to ribavirin (as demonstrated by improvements of aminotransferase levels and improvement in liver histology) will then be treated with long-term ribavirin in an open-label study with follow up liver biopsies every two years. A second study of therapy of non-responders is a multicenter, randomized controlled trial known as Halt-C, which focuses on long-term therapy of chronic hepatitis C with pegylated interferon. Pegylated interferon is an alpha interferon that has been modified by convalent linkage with polyethylene glycol which allows for delayed clearance of the active molecule and a sustained duration of action. Pegylated interferon is given once weekly (instead of three times weekly as for regular interferon) and provides more rigorous and sustained antiviral activity. In this trial, patients are first treated with the combination of pegylated interferon and ribavirin for 24 weeks. Patients who do not become HCV RNA negative are then randomized to receive long-term pegylated interferon therapy or no treatment, being followed at 3 month intervals for up to four years and undergoing liver biopsy every two years. This study is a multicenter U.S. trial sponsored by NIDDK which is being conducted in 10 geographically dispersed medical 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, 27 patients have been enrolled at the NIH. 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.