Prognosis of HIV-positive patients treated with antiretroviral therapy: comparative analyses and treatment strategies

目前，对艾滋病毒阳性患者可采用由不同药物组合组成的高效治疗，自1996年推出以来，已大大降低了获得性免疫缺陷综合征（艾滋病）和死亡的风险。越来越多的患者已经接受了多年的治疗，但这些人的结果仍然不清楚，死亡原因的模式已经改变，新的预测结果的因素正在出现。随机临床试验是检验治疗效果的最佳方法，但该领域的大多数试验依赖于血液测试的结果（而不是患者和医生更感兴趣的艾滋病和死亡），并招募少量患者进行短时间随访。试验通常排除病情较重的患者，并且无法估计药物在重要亚组中的有效性，如妇女、年龄在50岁至50岁之间的人或少数民族。许多与治疗策略有关的问题在试验中不能或没有得到回答。因此，关于患者亚组的长期结果和治疗效果的信息必须在很大程度上依赖于艾滋病毒队列的大规模合作——在这些研究中，艾滋病毒阳性人群被长期跟踪。这项申请为抗逆转录病毒治疗队列合作（ART- cc）寻求资助，这是一项国际合作，结合了来自欧洲和北美的19项艾滋病毒队列研究的数据。它由布里斯托尔大学的一个小小组协调，并由具有艾滋病毒医学、临床流行病学和医学统计专业知识的贡献研究的代表和患者代表组成的指导委员会管理。我们将在欧洲和北美的区域合作中开展工作，这将提供可观的资金价值，因为我们可以利用他们的数据管理系统，并确保我们有一个独特的研究议程。我们希望结合至少10万名患者的数据。我们将与南部和西非的合作组织合作，以便比较在这些治疗和保健资源有限的环境中接受治疗的患者的结果与在欧洲和北美接受治疗的患者的结果。我们将在申请期间每年更新我们的数据集。我们的目标是：(A)审查艾滋病患者治疗后的预后、各种原因导致的死亡和特定原因导致的死亡，重点是多年后的预后、预测艾滋病和死亡的新因素的作用以及开始治疗后若干年的预后；(B)审查各区域和环境之间的预后差异，包括性别和族裔群体的作用；(C)估计预期寿命，定义为从开始治疗时起一个人将活的平均额外年数，并分别为具有不同特征的患者组；(D)在低收入环境，例如大多数艾滋病毒阳性患者居住的撒哈拉以南非洲，开展关于预后的合作工作。我们将使用统计学方法模拟使用队列数据的随机试验：(E)研究血液中可检测到HIV-1病毒的患者的方案修改（转换）策略，并根据方案改变的类型检查风险因素和预后；(F)估计错过剂量或中断治疗对临床结果的不利影响；(G)检查在免疫系统受损并影响中枢神经系统的其他特定感染也需要治疗的患者开始治疗艾滋病毒的最佳时间。根据我们过去的经验，我们期望这项研究的结果与艾滋病毒阳性患者的护理直接相关，并将其纳入治疗指南。我们将在研究网站上提供在线风险和预期寿命计算器，以及患者摘要。

Highly effective treatments consisting of combinations of different drugs are now available for HIV-positive people and have dramatically reduced the risk of acquired immune deficiency syndromes (AIDS) and death since their introduction in 1996. Increasing numbers of patients have been treated for many years, but outcomes in these people remain unclear, patterns of cause of death have changed, and new predictors of outcomes are emerging. Randomised clinical trials are the best way to examine treatment effects, but most trials in the field rely on outcomes that are measurements from blood tests (rather than AIDS and death, which are of more interest to patients and doctors) and recruit small numbers of patients followed for a short length of time. Trials often exclude sicker patients, and cannot estimate the effectiveness of drugs in important subgroups such as women, those aged >50 years, or ethnic minorities. Many questions relating to treatment strategies cannot be, or have not been, answered in trials. Therefore information about long term outcomes and effects of treatment in patient subgroups must largely rely on large collaborations of HIV cohorts - studies in which groups of HIV positive people are followed over time. This application seeks funding for the ART Cohort Collaboration (ART-CC), an international collaboration that combines data from 19 HIV cohort studies from Europe and North America. It is coordinated by a small team at Bristol University, and administered by a steering committee of representatives from the contributing studies with expertise in HIV medicine, clinical epidemiology and medical statistics, and patient representatives. We will work within European and North American regional collaborations, which will provide considerable value for money because we can take advantage of their data management systems, and also ensure that we have a distinct and unique research agenda. We expect to combine data on at least 100,000 patients. We will work with collaborations in Southern and West Africa in order to compare outcomes among patients treated in these settings, in which resources for treatment and health care are limited, with outcomes among patients treated in Europe and North America. We will update our datasets annually during the period covered by the application.Our objectives are: (A) Examine the prognosis of patients on treatment for AIDS, deaths from all causes and deaths from specific causes, focusing on prognosis over many years, the role of new factors that predict AIDS and death, and prognosis from some years after starting treatment; (B) Examine differences in prognosis between regions and settings including the roles of gender and ethnic group; (C) Estimate life expectancy, defined as the average number of additional years a person will live, from the time of starting treatment and separately for groups of patients with different characteristics; (D) Conduct collaborative work on prognosis in low income settings, such as sub-Saharan Africa, where the majority of HIV-positive people live. We will use statistical methods that mimic randomised trials using cohort data to: (E) Investigate strategies for regimen modification (switching) in patients in whose blood HIV-1 virus can be detected, and examine risk factors for and prognosis according to the type of regimen change; (F) Estimate the adverse effects of missed doses or interruptions to treatment on clinical outcomes; (G) Examine the best time to start treatment for HIV in patients who also require treatment for other specific infections that occur when the immune system has been damaged and that affect the central nervous system.Based on our past experience, we expect the results of this research to be of direct relevance to the care of HIV-positive people and to be incorporated into treatment guidelines. We will provide online risk and life expectancy calculators, as well as summaries for patients, on the study web site.