ZIDOVUDINE METABOLISM: REBRETRON TREATED HUMAN PATIENTS

描述(由申请人提供)：我们的长期目标是了解 抗逆转录病毒药物的细胞内药理学。这个 目的研究恩巴韦林在体内的作用。 人类免疫缺陷病毒-丙型肝炎病毒共感染患者ZDV的磷酸化过程这个 需要检验的中心假设是REBETRON(利巴韦林+α干扰素) 会在体内与ZDV拮抗，减少ZDV的形成 细胞内代谢产物(ZDV-MP和ZDV-TP)，通过增加胸苷 抑制胸腺嘧啶核苷的三磷酸(DTTP)细胞内浓度 这些事件可能会影响HIV-丙型肝炎病毒混合感染患者的临床结局 患者，因为瑞贝隆治疗后dTTP/ZDV-TP比率会更高 从而降低了ZDV的有效性。建议的理由是 应用依赖于体外研究显示80%的减少 ZDV-MP和ZDV-TP在不同细胞系中的浓度 同时使用利巴韦林。如果这些观察结果保持在 体内，我们可能正在降低ZDV活性成分的浓度 (ZDV-TP)达到未知水平，我们将增加dTTP(内源性 HIV逆转录酶的竞争者)胞内浓度。因此， 在dTTP/ZDV-TP比率急剧增加的情况下，我们可能会从 HAART中的三种药物疗法(ZDV+包括一种蛋白酶在内的其他两种药物 抑制剂)改为两种药物疗法(包括一种蛋白酶在内的另外两种药物 抑制剂)增加了抗药性发展的可能性 突变。为了实现本应用程序的目标，我们将实现两个目标 具体目标：(1)比较不同负荷下的稳态面积 ZDV-MP、ZDV-TP、ZDV-TP在0~12小时内的浓度-时间曲线(AUC0.12) 外周血单个核细胞(PBMCs)和血浆中的奈非那韦 HIV型丙型肝炎病毒混合感染患者接受瑞贝隆治疗前后的变化 对照组为HIV感染的丙型肝炎病毒阴性患者，(2)描述 瑞贝隆对丙型肝炎病毒滴度、肝组织学、丙氨酸氨基转移酶、CD4+和 人类免疫缺陷病毒与丙型肝炎病毒混合感染患者治疗24周后的HIV-RNA病毒滴度 治疗。在研究项目完成后，我们预计将进行观察 ZDV-MP和ZDV-TP至少减少20%(保守估计)。 此外，我们将测定dTTP在体内的百分比增加 瑞贝隆疗法。因此，我们将能够确定 DTTP/ZDV-TP比率在该患者人群中HIV进展中的作用。 此外，由于目前还没有确定的治疗范围 ZDV-TP的胞内浓度，我们将确定ZDV-TP 浓度高于体外估计的50%抑制值 对于HIV以及在REBETRON治疗后是否持续暴露(AUC约2)。 这一信息将为类似的临床疗效提供强有力的支持 两种方案(REBETRON前后)。此外，这些数据将提供 对受试者间和受试者内细胞内变异性的有价值的洞察 ZDV-MP、ZDV-TP和dTTP。最后，我们将描述REBETRON在 丙型肝炎的进展(肝脏组织学、丙型肝炎病毒RNA滴度和丙氨酸氨基转移酶 在合并感染丙型肝炎病毒的患者中)。

DESCRIPTION (provided by applicant): Our long-range goal is to understand the intracellular pharmacology of antiretroviral drugs used against HIV. The objective in this application is to investigate the in vivo effect of nbavirin on the phosphorylation process of ZDV in HIV-HCV co-infected patients. The central hypothesis to be tested is that REBETRON (ribavirin + interferon alpha) will antagonize in vivo with ZDV, diminishing the formation of ZDV intracellular metabolites (ZDV-MP and ZDV-TP), by increasing thymidine triphosphate (dTTP) intracellular concentrations which inhibits thymidine kinase 1. These events may affect HIV clinical outcomes in HIV-HCV co-infected patients, since the dTTP/ZDV-TP ratio will be higher after REBETRON therapy thereby diminishing ZDV effectiveness. The rationale behind the proposed application relies on the in vitro studies showing an 80 percent reduction of ZDV-MP and ZDV-TP intracellular concentrations in different cell lines with the concurrent treatment of ribavirin. If these observations are maintained in vivo, we might be diminishing the concentrations of the active component of ZDV (ZDV-TP) to unknown levels and we will be increasing dTTP (endogenous competitor for HIV reverse transcriptase) intracellular concentrations. Thus, in the dTTP/ZDV-TP ratio increases dramatically, we might be changing from a three-drug therapy in HAART (ZDV + two other drugs including a protease inhibitor) to a two-drug therapy (two other drugs including a protease inhibitor) increasing the possibilities for the development of resistant mutations. To accomplish the objectives of this application, we will pursue two specific aims: (1) To compare the steady state area under the concentration-time-curve between 0 and 12 hours (AUC0.12) of ZDV-MP, ZDV-TP, and dTTP in peripheral blood mononuclear cells (PBMCs) and nelfinavir in plasma from HIV-HCV co-infected patients before and after REBETRON therapy with a control group of HIV infected HCV-negative patients, and (2) To describe the effect of REBETRON in HCV-RNA viral titers, liver histology, ALT, CD4+, and HIV-RNA viral titers in HIV-HCV coinfected patients after 24 weeks of treatment. After the completion of the research project, we expect to observe at least a 20 percent reduction (conservative estimate) of ZDV-MP and ZDV-TP. Furthermore, we will determine the in vivo percent increase of dTTP after REBETRON therapy. Thus, we will be in a position to determine the effect of the dTTP/ZDV-TP ratio in the progression of HIV in this patient population. Furthermore, since there are no established therapeutic ranges for intracellular concentrations of ZDV-TP, we will determine if ZDV-TP concentrations are above the estimated in vitro 50 percent inhibitory values for HIV and if the exposure (AUC about2) is sustained after REBETRON therapy. This information would provide strong support for similar clinical efficacy for both regimens (before and after REBETRON). Moreover, these data will provide valuable insight into the inter- and intra-subject variability of intracellular ZDV-MP, ZDV-TP, and dTTP. Finally, we will describe the effect of REBETRON in the progression of HCV disease (liver histology, HCV-RNA viral titers and ALT level) in HCV-HIV co-infected patients.