Real-Time Predictions of Reservoir Size and Rebound Time during Antiretroviral Therapy Interruption Trials for HIV
Real-Time Predictions of Reservoir Size and Rebound Time during Antiretroviral Therapy Interruption Trials for HIV
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DOI：
10.1371/journal.ppat.1005535
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发表时间：
2016-04-01
期刊：
影响因子：
6.7
通讯作者：
Henrich, Timothy J.
中科院分区：
文献类型：
--
作者：
Hill, Alison L.;Rosenbloom, Daniel I. S.;Henrich, Timothy J.
监测减少HIV病毒的新型治疗方法的有效性具有挑战性。对潜伏感染进行采样和定量的能力有限，这意味着通常需要进行有监督的抗逆转录病毒治疗（ART）中断研究。在这里，我们介绍了一套数学和统计建模工具，以帮助ART中断试验的设计和解释。我们展示了如何通过将实验室检测的输出与储层动力学和反弹模型的见解相结合，随着患者继续停止治疗，剩余储层的可能大小可以实时更新。我们设计了一个中断期间病毒载量采样的最佳时间表，从而可以减少随访的频率，因为患者继续停止ART而不会反弹。虽然该方案可以最大限度地降低成本时，访问之间的反弹的机会是低的，我们发现，水库将几乎完全restriated之前检测到反弹，除非采样发生至少每两周和最敏感的病毒载量测定。我们使用模拟数据来预测临床试验规模，以估计在面对高度可变的患者结局和不完善的储库检测时的治疗效果。我们的研究结果表明，需要大量的患者（在40到150之间）来可靠地估计新疗法的降血脂潜力，并比较不同干预措施的效果。作为一个例子，我们将这些方法应用于两个“波士顿患者”，接受异基因造血干细胞移植的患者，他们经历了潜伏感染的大幅减少并经历了ART中断。我们认为，考虑到治疗停止前的可用信息，病毒反弹的时间并不特别令人惊讶。此外，我们还展示了其他临床数据如何用于估计受体中剩余的HIV+细胞与来自供体的新感染细胞对最终导致反弹的残留储库的相对贡献。总之，这些工具将帮助艾滋病毒研究人员评估针对潜在水库的新的潜在治疗策略。
Monitoring the efficacy of novel reservoir-reducing treatments for HIV is challenging. The limited ability to sample and quantify latent infection means that supervised antiretroviral therapy (ART) interruption studies are generally required. Here we introduce a set of mathematical and statistical modeling tools to aid in the design and interpretation of ART-interruption trials. We show how the likely size of the remaining reservoir can be updated in real-time as patients continue off treatment, by combining the output of laboratory assays with insights from models of reservoir dynamics and rebound. We design an optimal schedule for viral load sampling during interruption, whereby the frequency of follow-up can be decreased as patients continue off ART without rebound. While this scheme can minimize costs when the chance of rebound between visits is low, we find that the reservoir will be almost completely reseeded before rebound is detected unless sampling occurs at least every two weeks and the most sensitive viral load assays are used. We use simulated data to predict the clinical trial size needed to estimate treatment effects in the face of highly variable patient outcomes and imperfect reservoir assays. Our findings suggest that large numbers of patients-between 40 and 150-will be necessary to reliably estimate the reservoir-reducing potential of a new therapy and to compare this across interventions. As an example, we apply these methods to the two "Boston patients", recipients of allogeneic hematopoietic stem cell transplants who experienced large reductions in latent infection and underwent ART-interruption. We argue that the timing of viral rebound was not particularly surprising given the information available before treatment cessation. Additionally, we show how other clinical data can be used to estimate the relative contribution that remaining HIV+ cells in the recipient versus newly infected cells from the donor made to the residual reservoir that eventually caused rebound. Together, these tools will aid HIV researchers in the evaluating new potentially-curative strategies that target the latent reservoir.