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，28名患者长期接受利巴韦林治疗，前14名患者在2至4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4年或更长时间的治疗，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。共有1000名患者被随机分配到本研究中，其中包括NIH临床中心的55名患者。目前至少有10名患者接受了两年的随访评估和肝活检。本研究的结果将明确聚乙二醇干扰素长期治疗慢性丙型肝炎的作用。治疗无应答患者的第三种方法是使用新的抗病毒药物。肝病科已经评估了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。11名对联合治疗无效的患者接受了为期4周的三种不同剂量的γ干扰素治疗，同时监测HCV病毒水平的变化。HCV RNA水平在三种剂量中的任何一种治疗期间的任何时间都没有变化。血清转氨酶也无变化。作为这些研究的结果，我们已经停止了对γ干扰素的评估。另外两项临床研究正在慢性丙型肝炎中进行：一项侧重于HCV基因型1的患者，另一项侧重于基因型2和3的患者。在基因型1的患者中，在多达25例接受聚乙二醇干扰素和利巴韦林治疗的患者、25例单独接受聚乙二醇干扰素治疗的患者和25例同时患有丙型肝炎和终末期肾病且单独接受聚乙二醇干扰素治疗的患者中，在治疗期间进行了仔细的病毒动力学研究。迄今为止，已招募了24名患者。比较三组的病毒动力学、副作用和治疗结果。这些研究将确定利巴韦林在降低HCV RNA水平中的作用，以及肾脏疾病的存在是否会改变病毒的动力学反应。最后，基因型2和3患者的治疗研究将集中于使用缩短的疗程和低剂量的聚乙二醇干扰素（半剂量）和利巴韦林（800 mg，而不是每天1000-1200 mg）。本研究将试图确定较低和耐受性较好的聚乙二醇干扰素和利巴韦林剂量是否足以治疗基因型2和3型HCV感染（通常对治疗有高应答率（75-80%））。最后，肝病科与输血医学科合作参与慢性丙型肝炎的长期自然史研究。定期对发现患有慢性丙型肝炎的志愿献血者进行随访，并每隔5年进行一次肝活检。这项研究将有助于确定丙型肝炎的自然史和预测疾病进展的临床相关因素。

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, 28 patients have been treated with ribavirin long-term and liver biopsies after two to four years in the first 14 patients show no regression of fibrosis scores. These studies will be continued until at least adequate numbers of patients have been treated for four 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 1000 patients have been randomized into this study, including 55 at the NIH Clinical Center. At least 10 patients have now undergone the two year follow up evaluation and liver biopsy. Results of this study will define the role of chronic therapy with peginterferon in chronic hepatitis C. A third approach to therapy of non-responder patients is the use of new antiviral agents. The Liver Diseases Section has evaluated gamma interferon, a T cell cytokine that has antiviral activity against HCV in the replicon tissue culture system. Eleven patients who failed to respond to combination therapy were treated with a 4-week course of three different doses of gamma interferon while being monitored for changes in HCV viral levels. HCV RNA levels did not change at any time during therapy with any of the three doses. Serum aminotransferases were also unchanged. As a result of these studies, we have discontinued evaluation of gamma interferon. Two other clinical studies are being conducted in chronic hepatitis C: one focusing on patients with HCV genotype 1 and one on patients with genotypes 2 and 3. In patients with genotype 1, careful viral kinetics are being performed during therapy in up to 25 patients treated with peginterferon and ribavirin, 25 patients treated with peginterferon alone, and 25 patients with both hepatitis C and end-stage renal disease treated with peginterferon alone. To date 24 patients have been enrolled. The viral kinetics, side effects and outcome of treatment will be compared in the three groups. These studies will define the role of ribavirin in decreasing HCV RNA levels and whether the presence of renal disease alters viral kinetic responses. Finally a study of therapy in patients with genotypes 2 and 3 will focus on use of an abbreviated course of treatment and low doses of both peginterferon (half dose) and ribavirin (800 mg instead of 1000-1200 mg daily). This study will attempt to define whether lower and better tolerated doses of peginterferon and ribavirin will be adequate to treat genotype 2 and 3 HCV infections (which typically have a high rate of response to therapy (75-80%). Finally, the Liver Diseases Section participates in long-term natural history studies of chronic hepatitis C in collaboration with the Division of Transfusion Medicine. Volunteer blood donors found to have chronic hepatitis C are followed at regular intervals and undergo liver biopsy at 5 year intervals. This study will help define the natural history of hepatitis C and the clinical correlates that predict disease progression.