Gianotti Nicola, Seminari Elena, Guffanti Monica, Boeri Enzo, Villani Paola, Regazzi Mario, Bigoloni Alba, Schira Giulia, Tiberi Simon, Fusetti Giuliana, Lazzarin Adriano, Castagna Antonella
Clinic of Infectious Diseases, Vita-Salute San Raffaele University, Milan, Italy.
New Microbiol. 2005 Apr;28(2):119-25.
The objective of this study was to evaluate virological and pharmacological determinants of a 24-week virological response to unboosted atazanavir (ATV) in highly drug-experienced HIV-infected patients. Among patients enrolled in the ATV Expanded Access Program, those with HIV-RNA >1000 copies/mL, a genotype performed within three months from the baseline (BL), and who completed 24 weeks of treatment, were included. They received at least three antiretrovirals, including ATV 400 mg once daily without boosting. ATV plasma levels were evaluated after four weeks of treatment by high performance liquid chromatography (HPLC). ATV genotypic inhibitory quotient (GIQ) was calculated as the ratio between ATV Ctrough and the number of the BL ATV-related protease resistance mutations (among the following: 10I/V/F, 20R/M/I, 24I, 331/F/V, 36I/L/V, 46I/L, 48V, 54V/L, 63P, 71V/T/I, 73C/S/T/A, 82A/F/S/T, 84V, and 90M). Thirty-five subjects were included. At baseline, median (interquartile range) CD4+ T-lymphocytes, HIV-RNA, and ATV resistance mutations were 232.5 (106-303)/microL, 4.7 (4.2-5.1) log10 copies/mL, 2 (1-6), respectively. Thirteen (37.1%) subjects were off-therapy and 11 (31.4%) showed no PI mutation at baseline. Median steady-state ATV Ctrough was 230 ng/mL (87-520), for an ATV GIQ of 86.5 (25.5-165.5). Median HIV-RNA changes from baseline at weeks 4, 12 and 24 were -1.76 (from -0.44 to -2.12), -1.41 (from -0.41 to -2.81) and -1.44 (from -0.42 to -2.71) log10, respectively. The HIV-RNA changes were correlated to the number of ATV resistance mutations at each time point (P < 0.05), whereas no correlation was found between ATV Ctrough or ATV GIQ and HIV-RNA changes. In conclusion, the number of ATV resistance mutations is the only correlate to virological response through 24 weeks of treatment with unboosted atazanavir 400 mg once daily.
本研究的目的是评估在具有丰富药物治疗经验的HIV感染患者中，未加用增效剂的阿扎那韦（ATV）治疗24周的病毒学和药理学决定因素。在参加ATV扩大可及项目的患者中，纳入HIV-RNA>1000拷贝/mL、在距基线（BL）三个月内进行过基因型检测且完成24周治疗的患者。他们接受至少三种抗逆转录病毒药物，包括每日一次400mg的ATV且未加用增效剂。治疗四周后通过高效液相色谱法（HPLC）评估ATV血浆水平。ATV基因型抑制商（GIQ）计算为ATV谷浓度与BL时ATV相关蛋白酶耐药突变数量（以下突变：10I/V/F、20R/M/I、24I、331/F/V、36I/L/V、46I/L、48V、54V/L、63P、71V/T/I、73C/S/T/A、82A/F/S/T、84V和90M）之比。共纳入35名受试者。基线时，CD4+T淋巴细胞、HIV-RNA和ATV耐药突变的中位数（四分位间距）分别为232.5（106 - 303）/μL、4.7（4.2 - 5.1）log10拷贝/mL、2（1 - 6）。13名（37.1%）受试者停止治疗，11名（31.4%）受试者在基线时未出现蛋白酶抑制剂突变。ATV稳态谷浓度中位数为230ng/mL（87 - 520），ATV GIQ为86.5（25.5 - 165.5）。第4、12和24周时HIV-RNA相对于基线的变化中位数分别为-1.76（范围-0.44至-2.12）、-1.41（范围-0.41至-2.81）和-1.44（范围-0.42至-2.71）log10。各时间点HIV-RNA变化与ATV耐药突变数量相关（P<0.05），而未发现ATV谷浓度或ATV GIQ与HIV-RNA变化之间存在相关性。总之，ATV耐药突变数量是每日一次400mg未加用增效剂的阿扎那韦治疗24周病毒学反应的唯一相关因素。
