de Requena Daniel Gonzalez, Bonora Stefano, Castagna Antonella, Hasson Hamid, Marucco Diego Aguilar, D'Avolio Antonio, Sciandra Mauro, Trentini Laura, Calcagno Andrea, Lazzarin Adriano, Di Perri Giovanni
Department of Infectious Diseases, University of Turin, Turin, Italy.
J Antimicrob Chemother. 2008 Aug;62(2):384-7. doi: 10.1093/jac/dkn192. Epub 2008 May 16.
Early virological response (VR) to enfuvirtide-based salvage regimens at week 12 has been described as a predictor of long-term therapeutic success. The relationship between enfuvirtide plasma exposure and VR has not yet been investigated in the clinical setting. Our aim was to investigate the role of enfuvirtide plasma exposure as a determinant of early VR in the clinical setting.
Forty-two multidrug-experienced patients starting a salvage enfuvirtide-based regimen were prospectively evaluated over a 12 week period. HIV-RNA levels and enfuvirtide C(trough) were regularly measured. VR was considered as achievement of viral load (VL) undetectability and/or a decrease of more than 1 log at week 12.
Optimized background score (OBS) and enfuvirtide C(trough) concentrations were associated with VL decrease at week 12. An OBS > or =2 and enfuvirtide C(trough) >2100 ng/mL were associated with VR. The pharmacokinetic/pharmacodynamic (PK/PD) analysis confirmed this exposure-response relationship both in the total population and in different groups according to OBS <2 or > or =2. Higher estimates of IC(50) were calculated for the OBS <2 group when compared with the OBS > or =2 group (7551 versus 2330 ng/mL, respectively), without a marked difference in I(0) (0.31 versus 0.21 log) and I(max) (-2.64 versus -3.33 log).
Enfuvirtide plasma exposure and OBS were found to significantly influence the magnitude and rate of early VR. The PK/PD modelling of enfuvirtide concentrations was different in our clinical setting, compared with previous data obtained under trial conditions. Therefore, optimization of enfuvirtide plasma exposure could deserve further evaluation as a determinant of therapeutic response in HIV-positive patients.
基于恩夫韦肽的挽救治疗方案在第12周时的早期病毒学反应（VR）已被描述为长期治疗成功的预测指标。在临床环境中，尚未对恩夫韦肽血浆暴露与VR之间的关系进行研究。我们的目的是在临床环境中研究恩夫韦肽血浆暴露作为早期VR决定因素的作用。
对42名开始基于恩夫韦肽的挽救治疗方案的多药耐药患者进行了为期12周的前瞻性评估。定期测量HIV-RNA水平和恩夫韦肽C（谷值）。VR被定义为在第12周时实现病毒载量（VL）不可检测和/或下降超过1 log。
优化背景评分（OBS）和恩夫韦肽C（谷值）浓度与第12周时的VL下降相关。OBS≥2且恩夫韦肽C（谷值）>2100 ng/mL与VR相关。药代动力学/药效学（PK/PD）分析在总体人群以及根据OBS<2或≥2划分的不同组中均证实了这种暴露-反应关系。与OBS≥2组相比，OBS<2组计算出的IC50估计值更高（分别为7551和2330 ng/mL），I0（0.31对0.21 log）和I max（-2.64对-3.33 log）无明显差异。
发现恩夫韦肽血浆暴露和OBS对早期VR的幅度和速率有显著影响。与先前在试验条件下获得的数据相比，我们临床环境中恩夫韦肽浓度的PK/PD模型有所不同。因此，作为HIV阳性患者治疗反应的决定因素，优化恩夫韦肽血浆暴露值得进一步评估。
