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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 来自新的和现有的ARV类别的药物的可用性将提高在经历过三个类别的患者中实现病毒学抑制的能力。 卫生和人类服务部（DHHS）治疗指南建议使用至少两种可能在重度治疗经验丰富的患者中有效的药物，因为如果仅将一种活性药物添加到失败的方案中，HIV耐药性将迅速发展。使用另一种活性剂，如ENF与TPV或DRV，显着增加了病毒学成功率（2.0可以构建。 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。对耐药病毒具有活性的多种新药的可用性实际上可能会改变严重抗逆转录病毒治疗患者的治疗模式，从强调维持免疫功能到预期实现血浆HIV-1 RNA抑制至2.0的可能性很高，而不是增加NRTI，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的受试者中。由于无法获得16岁以下患者的试验药物安全性和药代动力学数据，因此本研究将招募至少16岁的受试者。 在高度治疗经验的受试者中，两种药物方案不太可能导致持续的病毒抑制，可能的例外是两种新类别的药物，如整合酶抑制剂+ENF或整合酶抑制剂+MVC。在临床试验中，如果ENF也用作初治药物，则含有DRV或TPV的方案的活性增加，可能是因为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数据不可用，但推测ENF方案的活性小于cPSS 2.0。在这些试验中，病毒抑制率仍然不超过约60%。在BENCHMRK试验中，在第16周，如果在RAL之外使用一种或两种新药物，则病毒学抑制率较高（90%或更高）。需要更长时间的随访，以确认在高度治疗经验丰富的人群中这种高度病毒抑制的持久性。A5241将招募与RESIST、POWER、BENCHMRK、MOTIVATE和TORO研究相似的患者人群，目标是高发生率（即，75%）的病毒学成功。使用cPSS为2.0的方案（2种活性药物，或1种活性药物和2种部分活性药物，平均每种0.5，或3种部分活性药物，平均每种0.666）不太可能实现该目标。尽管如此，完全抑制方案需要多少活性尚不清楚。cPSS为2.0（而不仅仅是=2.0）将需要整个方案的更高活性，并排除了双药方案。事实上，研究受试者可能会接受cPSS为2.1 - 3.0的方案;因此，将探索cPSS（在一定范围内）与治疗应答的相关性。 此外，本研究将检验以下假设：在活性新型治疗方案的背景下，排除NRTI不会是劣效方法。受试者被随机分组，从预期具有实质性病毒学应答的新方案中排除NRTI，更有可能实现这一目标。 随机化和分析将按照NRTI易感性进行分层，该分层因素分为2个水平：对任何NRTI均不易感或对一种或多种NRTI易感。将使用表型敏感性试验报告中的信息定义敏感性。

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.