A5241 (VERSION 10) THE OPTIMIZED TREATMENT THAT INCLUDES OR OMITS NRTIS

A5241（版本 10）包括或省略 NRTIS 的优化治疗

• 批准号: 8356712
• 负责人: William Thomas Shearer
• 金额: $ 0.53万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356712
• 关键词: 16 year old; Biological Assay; Clinical Research; Clinical Trials; Data; Drug Kinetics; Enrollment; Funding; Goals; Grant; Guidelines; HIV drug resistance; HIV-1; Immunologics; Inferior; Integrase Inhibitors; Maintenance; National Center for Research Resources; New Agents; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Population; Predisposition; Principal Investigator; RNA; Randomized; Regimen; Reporting; Research; Research Infrastructure; Resistance; Resources; Safety; Source; Stratification Factors; Study Subject; Testing; United States Dept. of Health and Human Services; United States National Institutes of Health; Viral; Virus; cost; experience; follow-up; improved; novel; patient population; response; success; treatment response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT The availability of agents from new and existing ARV classes will improve the ability to achieve virologic suppression in triple class-experienced patients. The Department of Health and Human Services (DHHS) treatment guidelines recommend using at least two agents that are likely to be active in heavily treatment-experienced patients because HIV drug resistance will develop quickly if only one active agent is added to a failing regimen. Using another active agent such as ENF with TPV or DRV significantly increased the rate of virologic success (2.0 can be constructed. Achieving virologic suppression remains the goal for all patients starting or changing therapy. The availability of multiple new agents with activity against resistant virus may actually change the treatment paradigm for heavily ARV-experienced patients from one that emphasizes maintenance of immunologic function to one that expects a high likelihood of achieving suppression of plasma HIV-1 RNA to 2.0 versus not adding NRTIs, in subjects with triple-class ARV experience and expected multiple drug cross resistance. Because safety and pharmacokinetic data are not available from patients younger than 16 years for investigational agents, the study will enroll subjects of at least 16 years of age. In a highly treatment-experienced subject, a two-drug regimen is not likely to result in sustained viral suppression with the possible exception of drugs from two new classes such as integrase inhibitor plus ENF or integrase inhibitor plus MVC. In clinical trials, the activity of a DRV- or TPV-containing regimen was increased if ENF was also used as a na¿ve drug, presumably because ENF added a completely active agent (a cPSS of 1.0). Data on the activity or cPSS of either PI in these trials are not available but presumably the activity of the regimen with ENF was less than a cPSS of 2.0. The rates of viral suppression in these trials still did not exceed about 60%. In the BENCHMRK trials, at week 16, higher rates of virologic suppression (90% or more) were seen if one or two new agents were used in addition to RAL. Longer follow-up is needed to confirm the durability of this high degree of viral suppression in a highly treatment-experienced population. A5241 will enroll a patient population similar to the RESIST, POWER, BENCHMRK, MOTIVATE, and TORO studies with the goal of high rates (i.e., 75%) of virologic success at 48 weeks. This goal is unlikely to be achieved with a regimen that has a cPSS of 2.0 (2 active agents, or 1 active and 2 partially active agents averaging 0.5 each, or three partially active agents averaging 0.666 each). Nonetheless, how much activity is needed for a completely suppressive regimen is not known. A cPSS of 2.0 (and not just =2.0) will require higher activity of the entire regimen and precludes a two-drug regimen. In fact, study subjects will likely take regimens with cPSS from 2.1 to 3.0; therefore, the association of cPSS (over a range of values) to treatment response will be explored. In addition, the study will test the hypothesis that excluding NRTIs will not be an inferior approach in the setting of an active novel regimen. Subjects randomized to exclude NRTIs from a novel regimen that is expected to have a substantial virologic response would be more likely to achieve this goal. Randomization and analysis will be stratified by NRTI susceptibility with 2 levels for this stratification factor: susceptible to none of the NRTIs versus susceptible to one or more NRTIs. Susceptibility will be defined using information from the phenotype sensitivity assay report.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 抽象的 新的和现有的 ARV 类别药物的可用性将提高对三类药物经验丰富的患者实现病毒学抑制的能力。 美国卫生与公众服务部 (DHHS) 治疗指南建议至少使用两种可能对经历过大量治疗的患者有效的药物，因为如果在失败的治疗方案中只添加一种活性药物，HIV 耐药性就会迅速发展。使用另一种活性剂（例如 ENF）与 TPV 或 DRV 显着提高了病毒学成功率（可以构建 2.0）。 实现病毒学抑制仍然是所有开始或改变治疗的患者的目标。多种具有抗耐药病毒活性的新药物的出现，实际上可能会改变对经历过多次抗逆转录病毒药物治疗的患者的治疗模式，从强调维持免疫功能的治疗模式，转变为在具有三级抗逆转录病毒治疗经验和预期多重药物交叉耐药性的受试者中，与不添加 NRTI 相比，更有可能将血浆 HIV-1 RNA 抑制至 2.0 的治疗模式。由于尚无 16 岁以下患者的研究药物的安全性和药代动力学数据，因此该研究将招募至少 16 岁的受试者。 对于治疗经验丰富的受试者，两种药物方案不太可能导致持续的病毒抑制，但两种新类别的药物可能除外，例如整合酶抑制剂加 ENF 或整合酶抑制剂加 MVC。在临床试验中，如果 ENF 也用作原始药物，则含有 DRV 或 TPV 的方案的活性会增加，大概是因为 ENF 添加了完全活性的药物（cPSS 为 1.0）。这些试验中任一 PI 的活性或 cPSS 数据均不可用，但推测 ENF 方案的活性低于 2.0 的 cPSS。这些试验中的病毒抑制率仍然没有超过60%左右。在 BENCHMRK 试验中，第 16 周时，如果除 RAL 之外还使用一种或两种新药，则会出现更高的病毒学抑制率（90% 或更高）。需要更长时间的随访来确认这种高度病毒抑制在治疗经验丰富的人群中的持久性。 A5241 将招募类似于 RESIST、POWER、BENCHMRK、MOTIVATE 和 TORO 研究的患者群体，目标是在 48 周时获得高病毒学成功率（即 75%）。使用 cPSS 为 2.0 的治疗方案（2 种活性药物，或 1 种活性药物和 2 种部分活性药物，平均各 0.5，或 3 种部分活性药物，平均各 0.666）不太可能实现这一目标。尽管如此，完全抑制疗法需要多少活性尚不清楚。 cPSS 为 2.0（而不仅仅是 =2.0）将需要整个方案更高的活性，并且排除两种药物方案。事实上，研究对象可能会采用 cPSS 2.1 至 3.0 的治疗方案；因此，将探讨 cPSS（在一定范围内的值）与治疗反应的关联。 此外，该研究还将检验以下假设：在积极的新型治疗方案中，排除 NRTI 不会是一种劣等方法。随机将 NRTI 排除在预计会产生显着病毒学反应的新疗法之外的受试者更有可能实现这一目标。 随机化和分析将根据 NRTI 敏感性进行分层，该分层因素有 2 个水平：对任何 NRTI 均不敏感与对一种或多种 NRTI 敏感。将使用表型敏感性测定报告中的信息来定义易感性。