PACTG P1038

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 -目标和方法(提供完整议定书的研究设计/统计分析部分的页面参考) -目标：第37-38页 这是一项“概念验证”研究，旨在研究用大剂量LPV/r治疗含PI的HAART失败的受试者的可行性。该研究的主要目标是估计LPV/r和SQV的药代动力学参数(见第9节)，并检查在本方案第5节规定的剂量下LPV/r和SQV的安全性。PACTG P1038是一项I/II期的大剂量洛比那韦/利托那韦(LPV/r)开放标签研究，旨在评估在使用或不使用沙奎那韦(SQV)的情况下，使用或不使用沙奎那韦(SQV)的LPV/r在HIV感染儿童和青少年中的安全性、耐受性和药代动力学，这些儿童和青少年有至少六个月的PI经历，并且目前的抗逆转录病毒治疗失败(血浆HIV RNA 5000拷贝/毫升)。这项研究将寻求纳入48名受试者=2岁至15岁。这些因素中的每一项都与可能影响治疗成功的其他影响相互交织：目前正在接受NNRTI治疗的一些受试者将接受更高剂量的LPV/r治疗，以补偿与NNRTI联合服用时LPV/r浓度的降低，而智商达不到15的受试者将在他们的方案中加入沙奎那韦，前提是他们可以吞下沙奎那韦胶囊(见方案)。在下面描述的分析中，达到IQ=15预测长期病毒学和免疫学成功的程度可能会被NNRTI或沙奎那韦的使用混淆，这可能成功地补偿未能达到LPV/r IQ=15，从而消除那些确实符合这一标准的人的潜在病毒学优势。协方差分析将被用来试图控制这些潜在的混杂因素，但不可能完全调整混杂因素 这项研究将使用比标准剂量更高的洛比那韦。这样做的理由是，对大多数抗病毒药物的“抗药性”是一个相对的现象，即即使在体外“抗药性”的HIV-1毒株也很少是100%抗药性的。如果使用更高剂量的药物，病毒复制即使在“抗药性”克隆中也能被抑制。最终的结果将是更多的病毒粒子被抑制。这一策略已经成功地应用于其他传染病(用更高剂量的氟康唑治疗念珠菌，用更高剂量的阿昔洛韦治疗更长时间的慢性抑制)和肿瘤学(用更高剂量的氟康唑可以消除耐多药癌细胞)。事实上，“剂量强度”(即每单位时间给药的量)是癌症化疗的基本原则(50，51)。标准的肿瘤学教科书警告说：“剂量的特别调整是对药物敏感的人类肿瘤患者进行第一次化疗失败的主要原因”(50)。 治疗的目标是长期控制艾滋病毒复制，以预防或扭转艾滋病毒相关症状，或免疫系统抑制。与三种或三种以上抗逆转录病毒药物联合治疗优于单一治疗或仅使用两种抗逆转录病毒药物(5-12)，目前建议将三种药物联合治疗艾滋病毒感染患者(13-18)。有效的多种药物治疗可以减少病毒复制(4，19，20)，将血浆病毒载量降低到敏感分析(BLQ)的定量限度以下，扭转艾滋病毒感染的症状(21-26)，促进生长(27-31)，并导致免疫系统功能的改善，包括增加CD4+细胞计数，降低CD8+细胞计数，以及提高对疫苗接种的反应(32-37)。虽然在大多数HIV感染者中，有效的方案最初可以将病毒载量降低到低于检测定量限度，但30%到80%的接受治疗的受试者将在一年内方案失败并返回可检测到的血浆病毒(8、9、38、39)。在一些受试者中，失去对艾滋病毒复制的控制可能是良性的，他们的CD4+细胞计数将保持在高水平或不断上升，没有机会感染的风险，也没有艾滋病毒感染的症状(40-43)。然而，在其他受试者中，血浆病毒血症的恢复可能与CD4+细胞计数的减少、耐药病毒的选择以及艾滋病毒或机会性感染症状的恢复有关(38)。 进度报告将提供给参与网站。在P1038中登记的前六个受试者的安全性数据将在第六个受试者接受治疗4周后进行审查。将应用以下算法来确定是否应该对安全数据进行密集审查，有可能停止研究的应计或停止研究中登记的所有受试者的研究治疗： 1)如果一个或多个受试者有与药物有关的危及生命的毒性，则失败 2)如果3个或更多的受试者有与药物有关的、非危及生命的3级或4级毒性，则不合格 如果安全失败的任何一个标准被满足，研究的收益将被暂停，等待一个委员会对安全数据进行彻底调查，该委员会将包括：主席、副主席、医务人员、统计学家、来自P1038的临床试验专家、来自初级治疗RAC的代表以及雅培和罗氏的代表 到目前为止，还没有这项研究的成果发表。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. -Goals and Methods (provide the page reference to the research design/statistical analysis section of the full protocol) - Goals: Pages 37-38 This is a "proof of concept" study, designed to examine the feasibility of treating subjects who have failed PI-containing HAART therapy with high doses of LPV/r. The primary objectives of the study are to estimate pharmacokinetic parameters for LPV/r and SQV (see section 9), and to examine the safety of LPV/r and SQV at the doses specified in section 5 of this protocol. PACTG P1038 is a Phase I/II, open label study of high dose lopinavir/ritonavir (LPV/r) to assess the safety, tolerability, and pharmacokinetics of LPV/r with or without saquinavir (SQV) in HIV-infected children and adolescents who have at least six months of prior PI experience and are failing their current antiretroviral therapy (plasma HIV RNA 5000 copies/mL). The study will seek to enroll 48 subjects = 2 years to 15. Each of these factors is intertwined with other effects which may affect treatment success: some subjects currently on an NNRTI will be treated at higher doses of LPV/r to compensate for the reduction of LPV/r concentrations when co-dosed with NNRTIs, and subjects failing to achieve IQ = 15 will have saquinavir added to their regimens, provided that they can swallow the saquinavir capsules (see schema). In the analyses described below, the extent to which achieving an IQ = 15 predicts long term virologic and immunologic success may be confounded by use of NNRTIs or saquinavir, which may successfully compensate for failure to achieve a LPV/r IQ = 15, thereby eliminating the potential virologic advantage of those who do meet this criteria. Co-variance analyses will be used in an attempt to control for these potentially confounding factors, but complete adjustment for confounding will not be possible This study will use a higher than standard dose of lopinavir. The rationale for this is that "resistance" to most antivirals is a relative phenomenon, i.e. even in vitro "resistant" strains of HIV-1 are rarely 100% resistant. If higher doses of the drug are used, viral replication can be suppressed even in "resistant" clones. The net result will be the suppression of a greater number of virions. This strategy has been successfully employed in other infectious diseases (higher doses of fluconazole to treat candida, higher acyclovir doses for longer chronic suppression) and oncology (multi-drug resistant cancer cells can be eliminated with higher doses). In fact "dose intensity" (i.e. the amount of drug given per unit time) is a fundamental principle in cancer chemotherapy (50, 51). Standard oncology textbooks warn "ad hoc adjustment of dosing is a major reason for treatment failure in patients with drug-sensitive human tumors undergoing their first chemotherapy treatment" (50). The goal of therapy is long-lasting control of HIV replication to prevent or reverse HIV-related symptoms, or immune system suppression. Combination therapy with three or more antiretroviral medications is better than therapy with monotherapy or therapy with only 2 antiretrovirals (5-12), and triple-drug therapy is currently recommended for treatment of patients with HIV infection (13-18). Potent multi-drug therapy can decrease virus replication (4, 19, 20), reduce plasma virus load to below limits of quantitation on sensitive assays (BLQ), reverse symptoms of HIV infection (21-26), improve growth (27-31), and lead to improved immune system function, including increased CD4+ cell count, decreased CD8+ cell count, and improved response to vaccination (32-37). While potent regimens can initially reduce virus load to below assay quantitation limits in the majority of persons with HIV infection, 30% to 80% of treated subjects will have regimen failure and return of detectable plasma virus within one year (8, 9, 38, 39). Loss of control of HIV replication can be benign in some subjects, who will have sustained high or rising CD4+ cell counts, no risk of opportunistic infection, and no symptoms of HIV infection (40-43). However, in other subjects, return of plasma viremia may be associated with a decrease in CD4+ cell count, selection of drug-resistant virus, and return of symptoms of HIV or opportunistic infection (38). Progress report will be made available to the participating sites. The safety data from the first six subjects enrolled in P1038 will be reviewed when the sixth subject has been on treatment for 4 weeks. The following algorithm will be applied to determine whether an intensive review of safety data, with the potential for stopping accrual to the study or stopping study treatment for all subjects enrolled in the study, should be performed: 1) Fail, if 1 or more subjects have drug related life threatening toxicity 2) Fail, if 3 or more subjects have drug related, non-life-threatening Grade 3 or 4 toxicity If either of the criteria for safety failure is met, accrual to the study will be suspended, pending a thorough investigation of the safety data by a committee which will include: the Chair, Vice Chairs, Medical Officers, Statisticians, Clinical Trials Specialist from P1038, a representative from the Primary Therapy RAC, and Abbott and Roche representatives There are no publications to date that have resulted from this study.