Natural History And Treatment Of Chronic Hepatitis C

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（每周一次皮下注射）和利巴韦林（口服，每日两次）联合使用24至48周。该方案诱导持续清除血清中的HCV RNA，并改善血清转氨酶和50 - 60%患者的潜在肝脏疾病。应答率高度依赖于HCV基因型。因此，基因型2和3的患者（约占感染患者的30%）有70 - 80%的应答率，可以有效地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，基因型1的患者（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（每日1000至1200 mg）治疗至少48周。此外，对于那些对治疗没有反应的HCV RNA阴性患者，几乎没有其他选择。NIDDK肝病分支的当前研究重点是提高当前治疗的安全性和有效性，并确定对丙型肝炎标准治疗无效的患者的治疗方法。因此，有两个前瞻性研究的病毒动力学和决定因素的治疗与聚乙二醇干扰素α-2a和利巴韦林的初治患者谁从来没有治疗;一个研究的患者基因型1和第二个研究的患者基因型2或3。在基因1型患者中，进行了病毒动力学研究，比较了聚乙二醇干扰素单独使用与聚乙二醇干扰素和利巴韦林联合使用的效果。初步结果表明，利巴韦林增加病毒反应的第二阶段，但在1个月的影响是最小的。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，对该方案进行了修订，以评估聚乙二醇干扰素每周两次给药。在基因型2和3患者中，在接受减少剂量的聚乙二醇干扰素（每周90 mcg而不是180 mcg）的患者中进行病毒动力学研究，以减少聚乙二醇干扰素治疗的副作用。现在的结果表明，第一阶段的病毒动力学与聚乙二醇干扰素的剂量减少是次优的，副作用并没有显着减少。最重要的是，治疗后的复发率很高，持续的病毒学应答率仅为50%，这对于基因型2和3的患者来说很低（其中应答率应该为80%）。出于这些原因，停止进一步招募，新的慢性丙型肝炎患者和基因型2和3将接受180微克聚乙二醇干扰素α-2a和病毒唑的标准方案治疗，并比较缓解率、副作用和病毒动力学。减少方案。 三项独立的研究正在进行中，评估对目前这种疾病的最佳治疗无效的患者的治疗。第一项研究是长期利巴韦林单一疗法，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10名目前正在接受利巴韦林治疗，治疗持续时间为3至6年。随访肝活检显示疾病活动、炎症和坏死显著减少，但纤维化无变化。第二项研究是对目前这种疾病的最佳治疗无效的患者进行长期聚乙二醇干扰素单药治疗。这项研究是NIDDK资助的多中心试验HALT-C的一部分。肝病分支是美国10个参与中心之一。共入组了1050例患者，其中55例来自NIDDK肝病分支。本研究的结果将明确聚乙二醇干扰素长期治疗在慢性丙型肝炎中的作用，并有助于明确丙型肝炎的自然史和肝细胞癌筛查在治疗这种疾病中的作用。目前的分析集中在对1050名患者的横断面分析上，如疾病严重程度的决定因素、纤维化和肝癌的生物标志物以及生活质量。第三项针对无应答患者的研究现已完成，重点是使用γ干扰素，这是一种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。最后，肝病分支科与输血医学科合作，参与慢性丙型肝炎的长期自然史和免疫学研究。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。最近的分析集中在疾病进展的预测因素上。这些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性。

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 has been 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 (90 mcg instead of 180 mcg weekly) as an attempt to decrease side effects which are considerable with peginterferon therapy. Results now indicate that the first phase of viral kinetics are suboptimal with the reduced dosages of peginterferon, and that side effects are not significantly reduced. Most importantly, the relapse rate following therapy is high and the sustained virological response rate was only 50%, which is low for patients with genotypes 2 and 3 (in whom the response rate should be 80%). For these reasons, further enrollment was stopped and new patients with chronic hepatitis C and genotypes 2 and 3 will be treated with the standard regimen of 180 mcg of peginterferon alfa-2a and ribavirin with comparison of response rates, side effects and viral kinetics to the reduced regimen. 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 10 are currently receiving ribavirin, the duration of therapy being 3 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. Analyses are now focusing upon cross-sectional analyses of the 1050 patients for issues such as determinants of disease severity, biomarkers for fibrosis and liver cancer and quality of life. 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. 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. Recent analysis have focused on predictors of disease progression. These studies will help define the natural history of hepatitis C and the clinical correlates that predict disease progression.