Oña Leonardo, Kouyos Roger D, Lachmann Michael, Bonhoeffer Sebastian
Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, Leipzig, Germany.
Theor Biol Med Model. 2013 Jul 11;10:44. doi: 10.1186/1742-4682-10-44.
The application of highly active antiretroviral therapy (HAART) against HIV can reduce and maintain viral load below detection limit in many patients. Continuous HAART, however, can have severe side effects. In this context, structured treatment interruptions (STI) were considered to be a promising strategy. However, using CD4 cell count to guide intermittent therapy starting and stopping points, the SMART study (strategies for management of antiretroviral therapy), revealed that STI were associated with increased risk of AIDS and other complications. Additionally, short-term periodic (e.g. one week on / one week off) interruption therapies have shown virus rebound exceeding a given "failure threshold", without any evidence for the evolution of drug resistance. Currently, the only hypothesis explaining the failure of STI is the "resonance hypothesis", which posits that treatment failure is due to a resonance effect between the drug treatment and the viral population. In the present study we used a mathematical model to analyse the parameters affecting the output of drug treatment interruption and the premises of the resonance hypothesis.
We used a population dynamic model of HIV infection. Simulations and analytical approximations of deterministic and stochastic versions of the model were studied.
The present study examines the roles of the most important parameters affecting the viral rebound, responsible for drug failure. We related these findings to the resonance hypothesis, and showed that the degree of sustainability of damping oscillations present in the model after the acute phase is strongly linked to their amplitude, which determines the resonance level. Stochastic simulations of the same model even revealed sustained oscillations in virus population for small virus population sizes. Given that pronounced viral load oscillations have not been observed in HIV-1 patients, the link between oscillations and resonance level suggests that treatment failure due to a resonance effect is not plausible. Moreover, the failure threshold is attained before the virus population crosses the set point while growing. As the maximum virus population is reached even after the set point is crossed, the role of resonance effects in the context of treatment interruptions cannot explain drug failure.
高效抗逆转录病毒疗法（HAART）应用于抗HIV治疗时，可使许多患者的病毒载量降低并维持在检测限以下。然而，持续进行HAART可能会产生严重的副作用。在此背景下，结构化治疗中断（STI）被认为是一种有前景的策略。然而，在“抗逆转录病毒治疗管理策略”（SMART）研究中，使用CD4细胞计数来指导间歇性治疗的起始和终止点时发现，STI与艾滋病及其他并发症风险增加相关。此外，短期周期性（如一周用药/一周停药）中断治疗已显示病毒反弹超过给定的“失败阈值”，且没有任何耐药性演变的证据。目前，唯一能解释STI失败的假说是“共振假说”，该假说认为治疗失败是由于药物治疗与病毒群体之间的共振效应所致。在本研究中，我们使用数学模型来分析影响药物治疗中断结果的参数以及共振假说的前提。
我们使用了HIV感染的群体动力学模型。研究了该模型确定性和随机性版本的模拟及解析近似。
本研究考察了影响病毒反弹（导致药物治疗失败）的最重要参数的作用。我们将这些发现与共振假说相关联，并表明急性期后模型中存在的阻尼振荡的可持续程度与其振幅密切相关，而振幅决定了共振水平。同一模型的随机模拟甚至显示，对于较小的病毒群体规模，病毒群体存在持续振荡。鉴于在HIV - 1患者中未观察到明显的病毒载量振荡，振荡与共振水平之间的联系表明，由共振效应导致的治疗失败似乎不太合理。此外，在病毒群体增长过程中，在其超过设定点之前就达到了失败阈值。由于即使在超过设定点之后仍能达到最大病毒群体数量，因此共振效应在治疗中断情况下的作用无法解释药物治疗失败。
