ZIDOVUDINE METABOLISM: REBRETRON TREATED HUMAN PATIENTS

描述（由申请人提供）：我们的长期目标是了解 抗艾滋病毒的抗逆转录病毒药物的细胞内药理学。的 本申请的目的是研究恩巴韦林的体内作用 对HIV-HCV共感染患者中ZDV磷酸化过程的影响。的 待检验的中心假设是REBETRON（利巴韦林+干扰素α） 将在体内拮抗ZDV，减少ZDV的形成 细胞内代谢产物（ZDV-MP和ZDV-TP），通过增加胸苷 抑制胸苷的三磷酸盐（dTTP）细胞内浓度 激酶1。这些事件可能会影响HIV-HCV合并感染者的HIV临床结局。 患者，因为REBETRON治疗后dTTP/ZDV-TP比值会更高 从而降低ZDV的有效性。建议的理由 应用依赖于体外研究，显示80%的减少， ZDV-MP和ZDV-TP在不同细胞系中的细胞内浓度， 同时使用利巴韦林治疗。如果这些观察保持在 在体内，我们可能会减少ZDV活性成分的浓度， （ZDV-TP）至未知水平，我们将增加dTTP（内源性 HIV逆转录酶的竞争者）细胞内浓度。因此，在本发明中， 在dTTP/ZDV-TP比率急剧增加的情况下，我们可能正在从一个 HAART中的三种药物疗法（ZDV +包括蛋白酶在内的两种其他药物 抑制剂）到两种药物疗法（包括蛋白酶的两种其他药物 抑制剂）增加了耐药性发展的可能性 突变。为了实现本申请的目标，我们将寻求两个 具体目的：（1）比较稳态下的面积 ZDV-MP、ZDV-TP、 外周血单核细胞（PBMC）中的dTTP和血浆中的奈非那韦 在REBETRON治疗前后， 对照组HIV感染者HCV阴性患者，（2）描述 REBETRON对HCV-RNA病毒滴度、肝组织学、ALT、CD 4+和 24周后HIV-HCV合并感染患者的HIV-RNA病毒滴度 治疗研究项目完成后，我们希望观察 ZDV-MP和ZDV-TP至少降低20%（保守估计）。 此外，我们将确定在给药后dTTP的体内增加百分比。 REBETRON治疗。因此，我们将能够确定 dTTP/ZDV-TP比值在该患者人群中HIV进展中的作用。 此外，由于没有确定的治疗范围， ZDV-TP的细胞内浓度，我们将确定ZDV-TP是否 浓度高于体外估计的50%抑制值 对于HIV，如果暴露（AUC约2）在REBETRON治疗后持续。 该信息将为类似的临床疗效提供强有力的支持， 两种方案（REBETRON之前和之后）。这些数据将提供 有价值的见解之间和受试者内的变异性细胞内 ZDV-MP、ZDV-TP和dTTP。最后，我们将描述REBETRON的效果， HCV疾病的进展（肝组织学、HCV-RNA病毒滴度和ALT 水平）。

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.