A randomized trial of HAART in acute/early HIV Infection

描述（由申请人提供）：本修订申请中研究的总体目标是改善关于早期HIV感染者启动高效抗逆转录病毒治疗（HAART）的适当时间的临床决策。目前的指南建议，应考虑对感染后6-12个月内发现的艾滋病毒感染者进行抗逆转录病毒治疗。然而，没有随机研究提供数据支持早期治疗艾滋病毒感染作为长期管理该疾病的有效治疗策略，也没有数据证明截止值的合理性，该截止值将确定如何为该策略的目的最好地定义“早期”感染。因此，本申请的具体目的1是在感染后一年内被确定为HIV感染的人中进行HAART与无治疗的随机试验，并分为急性期和急性期。（<2个月）和早期（2-12个月）感染，以确定治疗是否上级不治疗，在随后的病毒学控制艾滋病毒和治疗是否在感染后2个月内，上级优于2-12个月的治疗。为了回应审查者对我们解决这些问题的统计能力的担忧，我们将招募受试者的研究中心数量从2个增加到5个（巴尔的摩，MD和温哥华，BC，维多利亚，BC，蒙特利尔，PQ和多伦多，ON，加拿大），预计在2年内招募120至180例受试者，从而大大提高了统计能力。入组者将随机接受HAART治疗一年或不接受治疗。第一年随访后，受试者将再随访4年，主要研究终点将是所有治疗受试者与未治疗受试者在首次就诊后24个月的血浆病毒载量比较。如果我们的假设是正确的，早期治疗将导致病毒抑制和宿主免疫反应的保留，这将反映在随后几年的较低病毒载量中。（根据目前的慢性HIV感染治疗指南，这些较低的病毒载量预计将转化为改善的无艾滋病生存期和无治疗时间，尽管这些终点可能发生在本申请的5年期限之后。这些研究结果将对急性和早期艾滋病毒感染的治疗和监测产生重大影响，并将导致治疗费用和发病率的降低，以及在有限的时间内对急性/早期艾滋病毒感染的治疗采取急需的基于数据库的办法。由于我们的研究人群还将包括高比例的注射毒品使用者（IDUs），研究结果也将有助于设计新的方法来治疗这一重要的艾滋病毒感染风险人群的急性/早期艾滋病毒感染。在具体目标2中，我们将监测所有研究受试者中原发性耐药的患病率，并监测其在未经治疗的受试者中随时间推移的稳定性。与携带敏感分离株的未治疗受试者进行比较，将使我们能够评估原发性耐药对HIV疾病进展的贡献（阳性或阴性）。

DESCRIPTION (provided by applicant): The overall objective of the study in this revised application is to improve clinical decision-making regarding the appropriate time to initiate highly active antiretroviral therapy (HAART) among persons with early HIV infection. Current guidelines suggest that antiretroviral therapy be considered for HIV-infected people who are identified within the first 6-12 months of infection. However, there are no randomized studies that have provided data supporting early treatment of HIV infection as a valid therapeutic strategy for the long-term management of the disease, nor are there are data to justify a cut-off that would establish how "early" infection should be best defined for the purposes of this strategy. Therefore, Specific Aim 1 of this application is to conduct a randomized trial of HAART vs. no therapy in people who are identified as HIV-infected within one year of becoming infected, and divided into periods of acute (<2 months) and early (2-12 months) infection, to determine whether therapy is superior to no therapy in terms of subsequent virologic control of HIV and whether treatment within 2 months of infection is superior to treatment with 2-12 months. In response to reviewers' concern about our statistical power to address these questions, we have increased the number of sites at which we will accrue participants from two to five (Baltimore, MD and Vancouver, BC, Victoria, BC, Montreal, PQ, and Toronto, ON, Canada) and the anticipated enrollment from 120 to 180 subjects over a 2-year period, yielding substantially improved statistical power. Enrollees will be randomized to receive HAART for one year or no therapy. After the initial year of follow-up, subjects will be followed for up to 4 more years and the principal study endpoint will be a comparison of the plasma viral load 24 months after initial presentation in all treated vs. untreated subjects. If our hypothesis is correct, early treatment will lead to viral suppression and preservation of host immune responses that will be reflected in lower viral loads in subsequent years. (These lower viral loads would be expected to translate into improved AIDS-free survival and time remaining therapy-free according to current guidelines for therapy of chronic HIV infection, although these endpoints because they would likely occur later than the 5-year term of this application.) Such findings would have a major impact on treatment of and surveillance for acute and early HIV infection and would result in reduced costs and morbidity of therapy as well as a much-needed databased approach to treatment of acute/early HIV infection for a limited period of time. Since our study population will also include a high proportion of injecting drug users (IDUs), the findings will also help in the design of new approaches for treatment of acute/early HIV infection in this important group of people at risk for HIV infection. In Specific Aim 2, we will monitor the prevalence of primary drug resistance in all study subjects and monitor its stability over time in untreated subjects. Comparison with untreated subjects carrying susceptible isolates will allow us to evaluate the contribution (positive or negative) of primary drug resistance on HIV disease progression.