A randomized trial of HAART in acute/early HIV Infection

描述（由申请人提供）：本次修订申请中研究的总体目标是改善早期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。目前的指导方针建议考虑对感染后6-12个月内确诊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艾滋病毒感染的早期治疗作为一种有效的长期治疗策略，也没有数据证明一个临界值是合理的，该临界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Specific Aim 1是在感染后一年内确诊为HIV感染者的人群中进行HAART与不治疗的随机试验，并将其分为急性（<2个月）和早期（2-12个月）感染期，以确定在随后的HIV病毒学控制方面治疗是否优于不治疗，以及感染后2个月内治疗是否优于2-12个月治疗。为了回应审稿人对我们的统计能力的担忧，我们将参与者的数量从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），并在2年的时间内预计入组人数从120个增加到180个，大大提高了统计能力。参与者将被随机分配接受一年的HAART治疗或不接受治疗。在最初一年的随访后，将对受试者进行长达4年的随访，主要研究终点将是对所有治疗与未治疗受试者首次就诊后24个月的血浆病毒载量进行比较。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存，这将反映在随后几年的较低病毒载量。（根据目前的慢性HIV感染治疗指南，这些较低的病毒载量有望转化为改善的无艾滋病生存和剩余的无治疗时间，尽管这些终点可能发生在该应用的5年期限之后。）这些发现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，并将降低治疗的费用和发病率，并在有限的时间内为急性/早期艾滋病毒感染的治疗提供急需的基于数据库的方法。由于我们的研究人群还将包括高比例的注射吸毒者（IDUs），因此研究结果也将有助于设计治疗这一重要的艾滋病毒感染风险人群的急性/早期艾滋病毒感染的新方法。在具体目标2中，我们将监测所有研究对象中原发性耐药性的流行情况，并监测未经治疗的受试者的耐药性随时间的稳定性。与携带敏感分离株的未经治疗的受试者进行比较，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.