Department of Mathematics and Computer Science, Free University Berlin, Berlin, Germany.
PLoS One. 2012;7(7):e40382. doi: 10.1371/journal.pone.0040382. Epub 2012 Jul 11.
Antiviral pre-exposure prophylaxis (PrEP) through daily drug administration can protect healthy individuals from HIV-1 infection. While PrEP was recently approved by the FDA, the potential long-term consequences of PrEP implementation remain entirely unclear. The aim of this study is to predict the efficacy of different prophylactic strategies with the pro-drug tenofovir-disoproxil-fumarate (TDF) and to assess the sensitivity towards timing- and mode of TDF administration (daily- vs. single dose), adherence and the number of transmitted viruses. We developed a pharmacokinetic model for TDF and its active anabolite tenofovir-diphosphate (TFV-DP) and validated it with data from 4 different trials, including 4 distinct dosing regimes. Pharmacokinetics were coupled to an HIV model and viral decay following TDF mono-therapy was predicted, consistent with available data. Subsequently, a stochastic approach was used to estimate the % infections prevented by (i) daily TDF-based PrEP, (ii) one week TDF started either shortly before, or -after viral exposure and (iii) a single dose oral TDF before viral challenge (sd-PrEP). Analytical solutions were derived to assess the relation between intracellular TFV-DP concentrations and prophylactic efficacy. The predicted efficacy of TDF was limited by a slow accumulation of active compound (TFV-DP) and variable TFV-DP half-life and decreased with increasing numbers of transmitted viruses. Once daily TDF-based PrEP yielded [Formula: see text]80% protection, if at least 40% of pills were taken. Sd-PrEP with 300 mg or 600 mg TDF could prevent [Formula: see text]50% infections, when given at least before virus exposure. The efficacy dropped to [Formula: see text]10%, when given 1 h before 24 h exposure. Efficacy could not be increased with increasing dosage or prolonged administration. Post-exposure prophylaxis poorly prevented infection. The use of drugs that accumulate more rapidly, or local application of tenofovir gel may overcome the need for drug administration long before virus exposure.
抗病毒的暴露前预防（PrEP）通过每日药物治疗可以保护健康个体免受 HIV-1 感染。虽然 PrEP 最近已被 FDA 批准，但 PrEP 实施的潜在长期后果仍完全不清楚。本研究的目的是预测使用前药替诺福韦二异丙基富马酸酯（TDF）的不同预防策略的疗效，并评估 TDF 给药时间和模式（每日 vs. 单次剂量）、依从性和传播病毒数量的敏感性。我们开发了 TDF 及其活性代谢物替诺福韦二磷酸（TFV-DP）的药代动力学模型，并使用来自 4 项不同试验的数据进行了验证，其中包括 4 种不同的给药方案。药代动力学与 HIV 模型相结合，预测了 TDF 单药治疗后的病毒衰减情况，与现有数据一致。随后，采用随机方法来估计（i）基于每日 TDF 的 PrEP、（ii）在病毒暴露前或暴露后一周开始的 TDF 治疗 1 周以及（iii）在病毒攻击前口服 TDF 单剂量（sd-PrEP）预防的感染百分比。推导了分析解来评估细胞内 TFV-DP 浓度与预防疗效之间的关系。TDF 的预测疗效受到活性化合物（TFV-DP）缓慢积累的限制，以及 TFV-DP 半衰期的变化，并且随着传播病毒数量的增加而降低。如果至少服用 40%的药丸，每日一次的 TDF 为基础的 PrEP 可提供[公式：见正文]80%的保护。300mg 或 600mg TDF 的 sd-PrEP 可以在至少在病毒暴露前给药时预防[公式：见正文]50%的感染。如果在 24 小时暴露前 1 小时给药，疗效下降至[公式：见正文]10%。增加剂量或延长给药时间并不能提高疗效。暴露后预防也不能很好地预防感染。使用积累更快的药物，或局部应用替诺福韦凝胶，可能无需在病毒暴露前长时间给药。
