Immunologic And Virologic Approaches To HIV-1 Therapeutics

作为艾滋病毒研究诊所，我们的重点继续解决以下问题的几个重要方面：如何以最佳方式使用和管理多类联合抗逆转录病毒治疗；如何在进行中的抗逆转录病毒治疗的框架内整合基于免疫的治疗；如何确定启动抗逆转录病毒策略的最佳时间，以保存和重建免疫功能，同时最大限度地减少长期抗逆转录病毒毒副作用，以及在服用和停用抗逆转录病毒药物的情况下，进行性艾滋病毒感染不良后果发展的一些预测因素。 卫生与公众服务部先前的抗逆转录病毒指南建议对CD_4细胞数为500个/L或以下的艾滋病毒感染者启动HAART，但也强烈建议考虑开始抗逆转录病毒治疗，即使是CD_4细胞数较高的人。然而，这些建议是有争议的，因为它们是基于大型观察性试验的结果和专家意见，而不是基于随机临床试验的数据。在免疫调节实验室的临床研究部(CRS)，我们为“START”研究(抗逆转录病毒治疗的战略时机)的成功完成做出了贡献，该研究旨在确定在以前未接受治疗的患者中及早引入抗逆转录病毒疗法是否会转化为更好的临床结果。为了更严格和明确地解决这个问题，并消除专家意见的潜在偏见，START试验是一项大型的多国试验，招募CD_4细胞数超过500个/L的抗逆转录病毒初治HIV感染者，并随机分配他们要么立即开始HAART，要么推迟开始HAART，直到CD_4细胞数降至350个/L以下。这项为期4-5年的试验的主要目标是比较这两种药物在可归因于HIV进行性感染或HAART本身毒性的不良后果(艾滋病相关和非艾滋病相关)的累积发生率。START试验招募了4685名感染艾滋病毒的男性和女性，年龄在18岁或以上(中位数为36岁)，他们的CD4+T细胞数量超过500个/mm3，没有艾滋病毒感染的症状，并且从未接受过抗逆转录病毒治疗。27%的参与者是女性，大约一半是男同性恋。2015年春，数据安全监测委员会透露，削减战略武器条约的主要终点已经实现。数据分析显示，与延期治疗组相比，早期治疗组患严重艾滋病、严重非艾滋病或死亡的风险降低了57%。这种下降不受年龄、性别、基线CD4+细胞计数、地理区域或国家收入水平的影响。研究中观察到的最常见的事件是通常影响老年人的非艾滋病事件。在直接组和延期组中，最常见的两种个人严重非艾滋病事件是心血管疾病(分别有12名和14名有事件的参与者)和非艾滋病定义的癌症(分别有9名和18名有事件的参与者)。大多数结核病发生在非洲研究地点的参与者中(26项活动中有16项)，那里的结核病和艾滋病毒/艾滋病都是地方病。 通过这项和我们的其他艾滋病毒试验，我们还继续努力通过外联努力改善当地少数群体获得临床试验的机会，其中包括与医疗服务不足人群的当地诊所建立密切关系。

Our focus as an HIV research clinic continues to address several important aspects of the following questions: how to optimally use and administer multi-class combination anti-retroviral therapy; how to integrate immune based therapies within a framework of ongoing antiretroviral therapy; how to determine the optimal time for initiation of antiretroviral strategy in order to preserve and reconstitute immune function while at the same time minimizing long-term antiretroviral toxicities, and what are some of the predictive factors for the development of adverse consequences of progressive HIV infection both on and off antiretroviral medications. Prior Department of Health and Human Services Antiretroviral Guidelines recommended the initiation of HAART for HIV-infected individuals with CD4 cell counts of 500 cells/L or less, but also strongly recommended consideration of initiating antiretroviral treatment even in those with higher CD4 cell counts. However, these recommendations were controversial in that they were based upon the outcomes of large observational trials and expert opinion rather than on data from a randomized clinical trial. In the Clinical Research Section (CRS) of the Laboratory of Immunoregulation we contributed to the successful completion of the "START" study (Strategic Timing of AntiRetroviral Treatment) aimed at determining whether early introduction of ART in previously untreated patients translates into better clinical outcomes. In order to address this question more rigorously and definitively and remove the potential bias of expert opinion, the START trial is a large multi-national trial that enrolled antiretroviral-naive HIV-infected individuals with CD4 cell counts above 500 cells/L and randomly assigned them either to begin HAART immediately or to delay the start of HAART until the CD4 cell count falls below 350 cells/L. The primary goal of this 4-5 year trial was to compare the two arms in terms of the cumulative incidence of adverse consequences (both AIDS-related and non-AIDS related) ascribable either to progressive HIV infection or to the toxicities of HAART itself. The START trial enrolled 4,685 HIV-infected men and women ages 18 years or older (median age of 36 years) who had CD4+ T-cell counts above 500 cells/mm3, no symptoms of HIV infection, and had never taken antiretroviral therapy. Twenty-seven percent of the participants were women, and approximately half were gay men. In the spring of 2015 the Data Safety Monitoring Board revealed that the primary endpoint of START had been achieved. Data analysis revealed that the risk of developing serious AIDS, serious non-AIDS, or death was reduced by 57 percent among those in the early treatment group compared to those in the deferred group. This reduction was seen regardless of age, sex, baseline CD4+ cell counts, geographic region or country income level. The most common events observed in the study were non-AIDS events that typically affect older individuals. The two most common individual serious non-AIDS events in the immediate and deferred groups were cardiovascular disease (12 and 14 participants with events, respectively) and non-AIDS-defining cancer (9 and 18 participants with events, respectively). Most of the tuberculosis occurred among participants at study sites in Africa (16 of 26 events), where both TB and HIV/AIDS are endemic. With this and with our other HIV trials we also continue our efforts to improve access to clinical trials by local minority populations through outreach efforts that includes a close relationship with local clinics for medically under-served populations.