Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1
Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1
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DOI：
10.1073/pnas.1406663111
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发表时间：
2014-09-16
影响因子：
11.1
通讯作者：
Siliciano, Robert F.
中科院分区：
文献类型：
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作者：
Hill, Alison L.;Rosenbloom, Daniel I. S.;Siliciano, Robert F.
目前正在进行大量研究工作，以开发治疗 HIV 感染的方法，使患者能够停止终身联合抗逆转录病毒治疗 (ART)。新的潜伏期逆转剂（LRAs）可能能够清除静息记忆CD4+T细胞中持续存在的潜伏病毒库，但治愈所需的病毒库减少程度仍不清楚。在这里，我们使用感染动态的随机模型来估计 ART 中断后防止病毒反弹所需的 LRA 的功效。我们结合临床数据来估计人群水平的参数分布和结果。我们的研究结果表明，需要减少大约 2,000 倍才能允许大多数患者中断 ART 1 年而不出现反弹，并且反弹可能会在多年后突然发生。可能需要减少超过 10,000 倍才能完全防止反弹。我们的结果预测 LRA 治疗后的反弹时间会有很大变化，这将使临床管理变得复杂。该模型为将 LRA 从实验室转移到临床提供了基准，并有助于临床试验的设计和解释。这些结果也适用于减少潜伏病毒库的其他干预措施，并可以解释最近骨髓移植受者和立即治疗的新生儿在明显治愈数月后观察到的病毒血症的复发。
Massive research efforts are now underway to develop a cure for HIV infection, allowing patients to discontinue lifelong combination antiretroviral therapy (ART). New latency- reversing agents (LRAs) may be able to purge the persistent reservoir of latent virus in resting memory CD4(+) T cells, but the degree of reservoir reduction needed for cure remains unknown. Here we use a stochastic model of infection dynamics to estimate the efficacy of LRA needed to prevent viral rebound after ART interruption. We incorporate clinical data to estimate population-level parameter distributions and outcomes. Our findings suggest that similar to 2,000-fold reductions are required to permit a majority of patients to interrupt ART for 1 y without rebound and that rebound may occur suddenly after multiple years. Greater than 10,000-fold reductions may be required to prevent rebound altogether. Our results predict large variation in rebound times following LRA therapy, which will complicate clinical management. This model provides benchmarks for moving LRAs from the laboratory to the clinic and can aid in the design and interpretation of clinical trials. These results also apply to other interventions to reduce the latent reservoir and can explain the observed return of viremia after months of apparent cure in recent bone marrow transplant recipients and an immediately-treated neonate.