The Natural History And Treatment Of Chronic Hepatitis C

目前正在对有充分记录的慢性丙型肝炎患者进行评估，以确定该疾病的长期自然病史和免疫发病机制，并评估治疗方法，特别是对传统治疗无效的患者。目前，慢性丙型肝炎的最佳治疗方法是聚乙二醇干扰素（每周一次皮下注射）和利巴韦林（口服，每天两次）联合治疗24至48周。该方案诱导血清中HCV RNA的持续清除，并改善血清转氨酶和50%至60%患者的潜在肝病。应答率高度依赖于HCV基因型。因此，基因2型和3型患者（约占感染患者的30%）的应答率为70 - 80%，可以用聚乙二醇干扰素和减少剂量的利巴韦林（每天800 mg）治疗24周。然而，基因1型患者（约占美国感染患者的70%）需要用全剂量的聚乙二醇干扰素和利巴韦林（每天1000至1200mg）治疗至少48周。此外，对于治疗无效而变为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提高当前治疗方法的安全性和有效性，并确定对丙型肝炎标准治疗无效的患者的治疗方法。因此，在从未接受过治疗的初发患者中，有两项关于病毒动力学和对聚乙二醇干扰素α -2a和利巴韦林治疗反应决定因素的前瞻性研究；一项研究针对基因型1的患者，另一项研究针对基因型2或3的患者。在基因1型患者中，进行了病毒动力学研究，比较了单独使用聚乙二醇干扰素与联合使用聚乙二醇干扰素和利巴韦林的效果。初步结果表明，利巴韦林增加第二阶段的病毒反应，但效果是最小的，在1个月。结果还表明，每周注射聚乙二醇干扰素之间的病毒水平反弹，表明给药方案是次优的。由于这些发现，该方案正在修订，以评估每周两次的聚乙二醇干扰素剂量。在基因2型和3型患者中，在接受低剂量聚乙二醇干扰素的患者中进行病毒动力学研究（作为减少聚乙二醇干扰素治疗相当大的副作用的尝试）。早期结果表明，病毒动力学是次优的，副作用没有显著减少。共有28名患者入组，并将结果与历史对照组进行了持续病毒学应答率的比较。如果反应率不理想，研究将停止，所有患者给予全剂量的聚乙二醇干扰素和利巴韦林。目前正在进行三项独立的研究，评估对当前最佳治疗无效的患者的治疗方法。第一项研究是长期利巴韦林单药治疗，重点是抑制疾病活动和逆转肝纤维化。共有28名患者参加了这项研究，其中12名患者目前正在接受利巴韦林治疗，治疗时间为2至6年。随访肝活检显示疾病活动性、炎症和坏死明显减少，但纤维化无变化。第二项研究是长期聚乙二醇干扰素单药治疗对当前最佳治疗无效的患者。这项研究是niddk资助的多中心试验的一部分，称为HALT-C。肝脏疾病科是美国10个参与研究的中心之一。共有1050名患者入组，其中55名来自全国疾病预防与发展研究所肝病科。本研究的结果将确定聚乙二醇干扰素慢性治疗在慢性丙型肝炎中的作用，并有助于确定丙型肝炎的自然史和肝细胞癌筛查在该病治疗中的作用。第三项针对无应答患者的研究现已完成，重点是γ干扰素的使用，γ干扰素是一种T细胞细胞因子，在复制子组织培养系统中对HCV具有抗病毒活性。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γ干扰素治疗，同时监测HCV病毒水平的变化。在三种剂量的治疗过程中，HCV RNA水平在任何时候都没有改变。血清转氨酶也没有变化。这项研究现已结束，并已提交出版。最后，肝脏疾病科与输血医学部合作，参与慢性丙型肝炎的长期自然史和免疫学研究。发现患有慢性丙型肝炎的志愿献血者定期随访，并每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病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 (given once weekly by subcutaneous injection) and ribavirin(given orally, twice daily) 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 50 to 60% of patients. The rate of response is highly dependent upon HCV genotype. Thus, patients with genotypes 2 and 3 (accounting for about 30% of infected patients) have a 70 to 80% response rate and can be effectively treated with peginterferon and a reduced dose of ribavirin (800 mg per day) for 24 weeks. Patients with genotype 1 (accounting for approximately 70% of infected patients in the United States), however, require treatment with full doses of peginterferon and ribavirin (1000 to 1200 mg daily) for at least 48 weeks. Furthermore, for patients who do not respond to treatment by becoming HCV RNA negative, there are few other options. Current studies in the Liver Diseases Branch, NIDDK focus on improving the safety and efficacy of current therapies and identifying treatments for patients who fail to respond to the standard therapy of hepatitis C. Thus, there are two prospective studies of viral kinetics and determinants of response to therapy with peginterferon alfa-2a and ribavirin in naive patients who have never been treated; one study for patients with genotype 1 and a second study for patients with genotypes 2 or 3. In genotype 1 patients, viral kinetic studies are done comparing the effects of peginterferon alone to those of the combination of peginterferon and ribavirin. Preliminary results indicate that ribavirin increases the second phase of viral response but the effect is minimal at 1 month. Results also indicate a rebound in viral levels between the weekly injections of peginterferon, suggesting that the dosing regimen is suboptimal. As a result of these findings, this protocol is being amended to assess twice weekly dosing of peginterferon. In genotype 2 and 3 patients, viral kinetics are done in patients who receive a reduced dose of peginterferon (as an attempt to decrease side effects which are considerable with peginterferon therapy). Early results indicate that the viral kinetics are suboptimal and side effects are not significantly reduced. A total of 28 patients have been enrolled and results compared to historical controls for rates of sustained virological response. If response rates are suboptimal, the study will be discontinued and all patients given full doses of peginterferon with ribavirin. Three separate studies are underway assessing therapy of patients who fail to respond to the current optimal treatment of this disease. The first study is of long-term ribavirin monotherapy focusing on suppressing disease activity and reversing liver fibrosis. A total of 28 patients have been enrolled in this study and 12 are currently receiving ribavirin, the duration of therapy being 2 to 6 years. Follow up liver biopsies demonstrate a significant decrease in disease activity, inflammation and necrosis, but no change in fibrosis. A second study is of long-term peginterferon monotherapy of patients who fail to respond to the current optimal treatment of this disease. This study is a part of the multicenter NIDDK-funded trial known as HALT-C. The Liver Diseases Branch being one of 10 participating U.S. centers. A total of 1050 patients have been enrolled including 55 from the Liver Diseases Branch, NIDDK. Results of this study will define the role of chronic therapy with peginterferon in chronic hepatitis C and help define the natural history of hepatitis C and the role of screening for hepatocellular carcinoma in management of this disease. A third study of non-responder patients is now completed and focused on use of 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. This study has now ended and has been submitted for publication. Finally, the Liver Diseases Branch participates in long-term natural history and immunological 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.