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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级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具有三个类别经验的患者中实现病毒学抑制的能力。卫生与公众服务部(DHHS)的治疗指南建议至少使用两种可能对治疗经验丰富的患者有效的药物，因为如果在失败的方案中只添加一种活性药物，艾滋病毒耐药性将迅速发展。使用另一种活化剂，如与TPV或DRV一起使用ENF，显著提高了病毒学成功率(可构建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推出，实际上可能会改变对经验丰富的抗逆转录病毒患者的治疗模式，从强调维持免疫功能转变为在具有三类抗逆转录病毒经验和预期多重药物交叉耐药的受试者中，实现血浆HIV-1RNA抑制到2.0而不是不添加NRTI的可能性很高。由于研究药物不能从16岁以下的患者那里获得安全性和药代动力学数据，因此这项研究将招募至少16岁的受试者。 在一个有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，可能的例外是来自两种新类别的药物，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也被用作普通药物，则含有DRV或TPV的方案的活性会增加，这可能是因为ENF添加了完全有效的试剂(CPSS为1.0)。这些试验中任何一种PI的活性或CPSS的数据都不可用，但据推测，使用ENF的方案的活性低于CPSS 2.0。这些试验中的病毒抑制率仍未超过60%左右。在BENCHMRK试验中，在第16周，如果在RAL之外使用一种或两种新的药物，则可以看到更高的病毒学抑制率(90%或更高)。需要更长的随访时间来证实这种高度的病毒抑制在高度治疗经验的人群中的持久性。A5241将招募类似于REST、POWER、BENCHMRK、MONTATE和TORO研究的患者群体，目标是在48周内实现高病毒学成功率(即75%)。这一目标不太可能在CPSS2.0(2个活性制剂，或1个活性和2个部分活性制剂，每个平均为0.5%，或三个部分活性制剂，每个平均为0.666)的方案下实现。尽管如此，一种完全抑制的养生法需要多少活动才能知道。CPSS为2.0(而不仅仅是=2.0)将要求整个方案具有更高的活性，并排除了两种药物方案。事实上，研究对象可能会接受CPSS从2.1到3.0的治疗方案；因此，将探索CPSS(超过一系列值)与治疗反应的关联。 此外，这项研究还将检验这样一种假设，即在一种有效的新疗法的设定中，排除NRTI将不会是一种次要的方法。从预期有实质性病毒学反应的新疗法中随机排除NRTI的受试者将更有可能实现这一目标。 随机化和分析将根据NRTI易感性进行分层，该分层因素有两个水平：对任何一种NRTI易感与对一种或多种NRTI易感。将使用表型敏感性分析报告中的信息来定义敏感性。

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.