阿扎那韦（每日两次，每次200毫克）联合拉替拉韦（每日两次，每次400毫克）双药方案在临床环境中的疗效、安全性及药代动力学
Efficacy, safety and pharmacokinetics of atazanavir (200mg twice daily) plus raltegravir (400mg twice daily) dual regimen in the clinical setting.
作者信息
Marinaro Letizia, Calcagno Andrea, Ripamonti Diego, Cenderello Giovanni, Pirriatore Veronica, Trentini Laura, Salassa Bernardino, Bramato Caterina, Orofino Giancarlo, D'Avolio Antonio, Rizzi Marco, Di Perri Giovanni, Rusconi Stefano, Bonora Stefano
机构信息
Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Ospedale Amedeo di Savoia, Torino, Italy.
Infectious Diseases Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
出版信息
J Clin Virol. 2017 Feb;87:30-36. doi: 10.1016/j.jcv.2016.11.015. Epub 2016 Dec 1.
BACKGROUND
Unboosted atazanavir with raltegravir has been investigated at 300mg twice daily showing frequent hyperbilirubinemia and selection of resistance-associated mutations.
OBJECTIVES
Atazanavir 200mg twice daily could increase tolerability and plasma exposure.
STUDY DESIGN
Patients on atazanavir/raltegravir (200/400 twice daily), with self-reported adherence >95% and no concomitant interacting drugs were retrospectively evaluated.
RESULTS
102 patients [72.5% male, age 46.4 years (42-54), BMI 24kg/m (22-26)] were included. CD4+ T lymphocytes were 417 cell/μL (302-704) and 76 patients (74.5%) had HIV-RNA <50 copies/ml. After 123 weeks 18.6% patients showed virological failure and 3.9% discontinued for intolerance. Available genotypes showed selection of major integrase (7/10 patients) and protease resistance-associated mutations (5/13 patients). In patients switching with dyslipidemia (n=67) total, LDL cholesterol and triglycerides significantly decreased. Patients switching with eCRCL<60ml/min (n=27) had no significant changes while patients with eCRCL >60ml/min showed significant decrease (-9.8ml/min, p=0.003) at 96-weeks. Atazanavir and raltegravir trough concentrations were 321ng/mL (147-720) and 412ng/mL (225-695). Self-reported non-adherence (n=4) was significantly associated with virological failure (p=0.02); patients with virological success had borderline longer previous virological control (33 vs. 18 months, p=0.07).
DISCUSSION
Switch to atazanavir/raltegravir was safe and well tolerated allowing optimal drugs' plasma exposure. However, a concerning rate (18.6%) failed with newly selected mutations and stopped ATV/RAL because of DDI and intolerance issues or were lost to follow-up. This regimen might be considered in selected patients, without history of protease inhibitors failure or HBV infection, showing optimal adherence and prolonged suppression.
背景
每日两次服用300mg未增强的阿扎那韦与拉替拉韦联合用药已被研究，结果显示频繁出现高胆红素血症以及耐药相关突变的选择。
目的
每日两次服用200mg阿扎那韦可提高耐受性并增加血浆暴露量。
研究设计
对接受阿扎那韦/拉替拉韦（每日两次，200/400）治疗、自我报告依从性>95%且无同时使用相互作用药物的患者进行回顾性评估。
结果
纳入102例患者[男性占72.5%，年龄46.4岁（42 - 54岁），体重指数24kg/m²（22 - 26）]。CD4 + T淋巴细胞为417个/μL（302 - 704），76例患者（74.5%）的HIV - RNA<50拷贝/ml。123周后，18.6%的患者出现病毒学失败，3.9%因不耐受而停药。可用基因型显示主要整合酶（7/10例患者）和蛋白酶耐药相关突变的选择（5/13例患者）。在伴有血脂异常的换药患者（n = 67）中，总胆固醇、低密度脂蛋白胆固醇和甘油三酯显著降低。估算肌酐清除率（eCRCL）<60ml/min的换药患者（n = 27）无显著变化，而eCRCL>60ml/min的患者在96周时显著下降（-9.8ml/min，p = 0.003）。阿扎那韦和拉替拉韦的谷浓度分别为321ng/mL（147 - 720）和412ng/mL（225 - 695）。自我报告的不依从（n = 4）与病毒学失败显著相关（p = 0.02）；病毒学成功的患者之前的病毒学控制时间略长（33个月对18个月，p = 0.07）。
讨论
换用阿扎那韦/拉替拉韦联合用药安全且耐受性良好，可实现最佳的药物血浆暴露量。然而，令人担忧的是，有18.6%的患者因新出现的突变而治疗失败，并因药物相互作用和不耐受问题或失访而停用阿扎那韦/拉替拉韦。对于无蛋白酶抑制剂治疗失败史或乙肝病毒感染史、依从性良好且病毒抑制时间延长的特定患者，可考虑使用该治疗方案。
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