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，该方案已被修订，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，病毒动力学是在接受低剂量聚乙二醇干扰素（每周90微克而不是180微克）的患者中进行的，目的是减少聚乙二醇干扰素治疗中相当大的副作用。现在的结果表明，随着聚乙二醇干扰素剂量的减少，第一阶段的病毒动力学不是最佳的，而且副作用没有显著减少。最重要的是，治疗后复发率高，持续病毒学应答率仅为50%，而基因2型和3型患者的应答率较低（其应答率应为80%）。由于这些原因，进一步的招募被停止，新的慢性丙型肝炎和基因2型和3型患者将接受180微克聚乙二醇干扰素α -2a和利巴韦林的标准方案治疗，并比较减少方案的反应率、副作用和病毒动力学。

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.