ANTIVIRAL & ANTIFIBROTIC LIVER THERAPY OF HCV+ DRINKERS

我们计划评估抗病毒、抗纤维化和抗氧化联合治疗在迄今为止排除的丙型肝炎患者即饮酒者肝病进展中的作用。戒酒者或饮酒者将接受最先进的抗病毒治疗（聚乙二醇干扰素+利巴韦林），为期24-48周。该建议的另一个创新方面是补充抗纤维化剂，即从大豆中提取的聚乙烯磷脂酰胆碱（PPC），或安慰剂，服用3年（与抗病毒治疗同时服用，此后服用）。目前的治疗忽视了一个事实，即导致主要医学症状并最终导致患者死亡的是肝纤维化，由此导致的肝硬化和相关并发症，包括肝细胞癌。如果纤维化过程能够被阻止，甚至被预防，丙型肝炎病毒对健康的影响将大大减少。现有的抗纤维化药物毒性太大，不能用于患者，除了一种，即PPC，在各种实验模型中显示其具有显著的抗纤维化作用，并且最近发现它对HCV+患者的循环转氨酶水平有益。没有评估纤维化，但PPC对HCV+患者纤维化的影响的文献正在被提出。值得注意的是，PPC还被发现具有显著的抗氧化作用。这可能对HCV+患者很重要，因为现在各种研究表明HCV与氧化应激有关。另一个创新的方面是纳入了饮酒者，他们到目前为止被排除在标准的抗病毒治疗之外，主要是因为担心精神障碍的恶化，可靠性和依从性。然而，后一种反对意见现在已经被聚乙二醇化干扰素的可用性所克服，聚乙二醇化干扰素可以由治疗师以受控的方式每周给药一次。对于PPC和利巴韦林，依从性将通过纳入标记物来监测，如核黄素，可以在尿液中测量。此外，还将抽查PPC中主要的磷脂酰胆碱（dilinoleoylphospatidyolcholine， DLPC）的血液水平。因此，要求支持一项双盲、随机安慰剂对照研究，以评估这种新方法治疗HCV+酒精消费者或戒酒者肝病的疗效。所要求的经费用于特殊实验室化验、研究护士、参加会议的旅费、病人监测费用和一个核心办公室。

We plan to evaluate a combined antiviral, antifibrotic and antioxidant treatment in the progression of liver disease of heretofore excluded patients with hepatitis C namely alcohol drinkers. Abstainers or alcohol consumers will be given state- of-the-art antiviral treatment (pegylated interferon + ribavirin) for 24-48 weeks. Another innovative aspect of this proposal is the supplemention with an anti-fibrotic agent, namely polyenylphosphatidylcholine (PPC) extracted from soybeans, or placebo, administered for 3 years (concomitantly with the antiviral treatment and thereafter). Current therapy neglects the fact that what causes the major medical symptoms and eventually the demise of the patient is liver fibrosis, resulting cirrhosis and associated complications, including hepatocellular carcinoma. If the fibrotic process could be stopped or even prevented, the hepatitis C virus would lose much of its impact on health. Available anti-fibrotic agents are too toxic to be used in patients, except for one, namely PPC, which has been shown in various experimental models to have striking anti-fibrotic actions, and which was found recently to be beneficial in HCV+ patients in terms of their circulating levels of transaminases. Fibrosis was not assessed, but documentation of the effects of PPC on fibrosis in HCV+ patients is being proposed here. It is noteworthy that PPC was discovered to have also significant anti- oxidant effects. This may be important in HCV+ patients since various studies have now indicated that HCV is associated with an oxidative stress. Another innovative aspect is the inclusion of drinkers who thus far were excluded from standard antiviral treatment, mainly because of concerns about exacerbation of mental disorders, reliability and compliance. However, the latter objection has now been overcome by the availability of pegylated interferon which can be administered once a week by the therapist in a controlled fashion. For both PPC and ribavirin, compliance will be monitored by incorporation of markers, such as riboflavin, that can be measured in the urine. Spot checks of blood levels of dilinoleoylphosphatidylcholine (DLPC, the main phosphatidylcholine species of PPC) will also be performed. Accordingly, support is requested for a a double-blind, randomized placebo controlled study to assess the efficacy of this novel approach for the treatment of liver disease in HCV+ alcohol consumers or abstainers. Funds are requested for special laboratory tests, study nurses, travel to meetings, patient monitoring expenses and a core office.