Cromer Deborah, Pinkevych Mykola, Rasmussen Thomas A, Lewin Sharon R, Kent Stephen J, Davenport Miles P
Kirby Institute for Infection and Immunity, University of New South Wales (UNSW) Australia, Sydney, Australia.
Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
J Virol. 2017 Nov 30;91(24). doi: 10.1128/JVI.01395-17. Print 2017 Dec 15.
A number of treatment strategies are currently being developed to promote antiretroviral therapy-free HIV cure or remission. While complete elimination of the HIV reservoir would prevent recurrence of infection, it is not clear how different remission lengths would affect viral rebound and transmission. In this work, we use a stochastic model to show that a treatment that achieves a 1-year average time to viral remission will still lead to nearly a quarter of subjects experiencing viral rebound within the first 3 months. Given quarterly viral testing intervals, this leads to an expected 39 (95% uncertainty interval [UI], 22 to 69) heterosexual transmissions and up to 262 (95% UI, 107 to 534) homosexual transmissions per 1,000 treated subjects over a 10-year period. Thus, a balance between high initial treatment levels, risk of recrudescence, and risk of transmission should be considered when assessing the "useful" or optimal length of antiretroviral therapy-free HIV remission to be targeted. We also investigate the trade-off between increasing the average duration of remission versus the risk of treatment failure (viral recrudescence) and the need for retreatment. To minimize drug exposure, we found that the optimal target of antilatency interventions is a 1,700-fold reduction in the size of the reservoir, which leads to an average time to recrudescence of 30 years. Interestingly, this is a significantly lower level of reduction than that required for complete elimination of the viral reservoir. Additionally, we show that when shorter periods are targeted, there is a real probability of viral transmission occurring between tests for viral rebound. Current treatment of HIV involves patients taking antiretroviral therapy to ensure that the level of virus remains very low or undetectable. Continuous therapy is required, as the virus persists in a latent state within cells, and when therapy is stopped, the virus rebounds, usually within 2 weeks. A major question is how to reduce the amount of persistent virus and therefore allow a delay or remission until the virus returns after ceasing therapy. In this work, we consider the probability that HIV will still rebound even after this reduction and ask what the likelihood of viral transmission would be in this case.
目前正在开发多种治疗策略，以促进无抗逆转录病毒治疗的HIV治愈或缓解。虽然完全消除HIV储存库可防止感染复发，但尚不清楚不同的缓解时长将如何影响病毒反弹和传播。在这项研究中，我们使用一个随机模型表明，一种实现平均1年病毒缓解时间的治疗方法仍将导致近四分之一的受试者在头3个月内出现病毒反弹。给定每季度一次的病毒检测间隔，这导致每1000名接受治疗的受试者在10年期间预计有39次（95%不确定区间[UI]，22至69次）异性传播以及多达262次（95% UI，107至534次）同性传播。因此，在评估无抗逆转录病毒治疗的HIV缓解的“有效”或最佳时长目标时，应考虑高初始治疗水平、复发风险和传播风险之间的平衡。我们还研究了延长缓解平均持续时间与治疗失败（病毒复发）风险以及再次治疗需求之间的权衡。为了使药物暴露最小化，我们发现抗潜伏干预的最佳目标是将储存库大小减少1700倍，这会导致平均复发时间为30年。有趣的是，这一减少水平显著低于完全消除病毒储存库所需的水平。此外，我们表明，当针对较短时间段时，在病毒反弹检测之间确实存在病毒传播的可能性。目前HIV的治疗方法是让患者服用抗逆转录病毒疗法，以确保病毒水平保持非常低或检测不到。由于病毒在细胞内处于潜伏状态，所以需要持续治疗，而当治疗停止时，病毒通常会在2周内反弹。一个主要问题是如何减少持续存在的病毒量，从而延迟或缓解直到停止治疗后病毒再次出现。在这项研究中，我们考虑了即使在这种减少之后HIV仍会反弹的概率，并询问在这种情况下病毒传播的可能性有多大。
