ANTIRETROVIRAL ACTIVITY OF HYDROXYUREA ALONE AND IN COMBINATION WITH DDI

目的：本研究的目的是确定羟基脲在单独使用和与ddI联合使用两种剂量下是否安全且耐受性良好，以及ddI和羟基脲联合使用是否比单独使用更有利的抗病毒效果。脱氧核糖核苷酸三磷酸（dNTPs）是细胞DNA的组成部分，在细胞内从头合成。因此，细胞DNA合成依赖于核糖核苷酸还原酶（RR），它催化所有四种核糖核苷酸还原为还原的脱氧形式。通过干扰dNTPs的浓度可以减少HIV的复制。羟基脲抑制RR活性，从而停止细胞DNA合成，降低HIV逆转录效率。该活性与核苷类RT抑制剂具有协同作用。体外实验表明，羟基脲与DDI的协同作用大于与ZDV的协同作用。方法：这是一项为期24周、I/II期、随机、双盲、剂量范围研究，研究对象是CD4淋巴细胞计数在200-500之间的hiv感染成人。将有两个12周的治疗期和5个研究组。将对所有受试者进行药代动力学监测。将在第2、4、8、12和24周获得定量HIV RNA水平、CD4+/CD8+淋巴细胞计数和dATP测量的标本。最初为期12周的研究旨在收集数据，用于进行抗逆转录病毒活性分析。抗逆转录病毒活性分析中使用的主要比较将是羟基脲+ ddI联合治疗组和ddI单药治疗组之间的比较。第8周血浆HIV RNA水平将用于该比较。在第12周完成后，联合治疗的受试者将继续使用当前的治疗方法；接受ddI单药治疗的受试者将继续服用ddI，并按指定剂量（1:1随机化）添加羟基脲，即1000 mg qd或1500 mg qd。在研究开始时，将ddI单药治疗组的受试者随机分配为低剂量或高剂量羟基脲+ ddI联合治疗。因此，所有受试者将在第12周至第24周接受联合治疗，其中一半接受羟脲剂量为1000 mg / d，一半接受羟脲剂量为1500 mg / d。在第12周至第24周期间，所有的研究药物都是开放标签的，没有安慰剂。以下临床和实验室评估将在预定的时间间隔进行。在第4、8、12、18和24周根据新的和持续的体征或症状进行有针对性的体检；第4、12、24周体重；妊娠12周和24周有生育潜力的妇女的Karnofsky状态、尿镜检查和血清β - hcg检测CBC伴MCV、差异和血小板；电解质、肝功能、淀粉酶、碱性磷酸酶和总胆红素将在第2、4、8、12、18和24周进行检查。结果和未来计划：该研究仍在进行中，治疗组仍为盲法，因此研究结论和意义尚不能讨论。该研究目前已结束，但仍在继续对患者进行随访。目前正在考虑一个较长期的后续阶段。

Purpose: The purpose of this study is to determine whether hydroxyurea is safe and well tolerated at the two doses that will be examined alone and in combination with ddI, and whether there will be a more favorable antiviral effect when ddI and hyroxyurea are used in combination as compared to either one used as monotherapy Rationale Deoxyribonucleotide triphosphates (dNTPs) are the building blocks for cellular DNA and are synthesized de novo within the cell. Therefore, cellular DNA synthesis is dependent on the enzyme ribonucleotide reductase (RR), which catalyzes all four ribonucleotides to the reduced deoxy-form. HIV replication can be decreased by interfering with the concentration of dNTPs. Hydroxyurea inhibits RR activity and thus halts cellular DNA synthesis, and decreases the efficiency of HIV reverse transcription. This activity is synergistic with nucleoside RT inhibitor. In vitro testing shows greater synergy between hydroxyurea and DDI than with ZDV. Methods: This is a 24 week, phase I/II, randomized, double-blind, dose-ranging study in HIV-infected adults, whose CD4 lymphocyte count is between 200-500. There will be two 12-week treatment periods and 5 study arms. Pharmacokinetic monitoring will be performed on all subjects. Specimens for quantitative HIV RNA levels, CD4+/CD8+ lymphocyte counts, and dATP measurements will be obtained on weeks 2, 4, 8, 12 and 24. The initial 12-week portion of the study is designed to gather data that will be used to perform an antiretroviral activity analysis. The principal comparison used in the antiretroviral activity analysis will be between the hydroxyurea + ddI combination therapy arms and the ddI monotherapy arm. The Week 8 plasma HIV RNA levels will be used in this comparison. After the completion of Week 12, subjects on combination therapy will remain on their current therapy; and subjects on ddI monotherapy will remain on ddI and have hydroxyurea added at an assigned dose (1:1 randomization) of 1000 mg qd or 1500 mg qd. Randomization of subjects in the ddI monotherapy arm to low or high dose hydroxyurea + ddI combination therapy at Week 12 will have occurred at study entry. Therefore, all subjects will receive combination therapy during Weeks 12 to 24, with half receiving hydroxyurea at a dose of 1000 mg qd and half receiving hydroxyurea at a dose of 1500 mg qd. During Weeks 12 to 24, all study medication will be open label with no placebos. The following clinical and laboratory evaluations will be performed at scheduled intervals. Targeted physical exam based on new and ongoing signs or symptoms at Weeks 4, 8, 12, 18, and 24; weight at Weeks 4, 12, 24; Karnofsky status, urinalysis with microscopic examination, and serum beta-HCG test for women of child-bearing potential at Weeks12 and 24; CBC with MCV, differential and platelets; electrolytes, liver function tests, amylase, alkaline phosphatase and total bilirubin will be done at Weeks 2, 4, 8, 12, 18 and 24. Results and Future Plans: The study is ongoing and treatment arms remain blinded, therefore study conclusions and significance can not yet be discussed. The study is currently closed to accrual, though patients are continuing to be followed. A longer-term follow-up phase is being contemplated.