Robbins Brian L, Capparelli Edmund V, Chadwick Ellen G, Yogev Ram, Serchuck Leslie, Worrell Carol, Smith Mary Elizabeth, Alvero Carmelita, Fenton Terence, Heckman Barbara, Pelton Stephen I, Aldrovandi Grace, Borkowsky William, Rodman John, Havens Peter L
St Jude Children's Research Hospital, Memphis, Tennessee, USA.
Antimicrob Agents Chemother. 2008 Sep;52(9):3276-83. doi: 10.1128/AAC.00224-08. Epub 2008 Jul 14.
Human immunodeficiency virus (HIV)-infected children and adolescents who are failing antiretrovirals may have a better virologic response when drug exposures are increased, using higher protease inhibitor doses or ritonavir boosting. We studied the pharmacokinetics and safety of high-dose lopinavir-ritonavir (LPV/r) in treatment-experienced patients, using an LPV/r dose of 400/100 mg/m(2) orally every 12 h (p.o. q12h) (without nonnucleoside reverse transcriptase inhibitor [NNRTI]), or 480/120 mg/m(2) p.o. q12h (with NNRTI). We calculated the LPV inhibitory quotient (IQ), and when the IQ was <15, saquinavir (SQV) 750 mg/m(2) p.o. q12h was added to the regimen. We studied 26 HIV-infected patients. The median age was 15 years (range, 7 to 17), with 11.5 prior antiretroviral medications, 197 CD4 cells/ml, viral load of 75,577 copies/ml, and a 133-fold change in LPV resistance. By treatment week 2, 14 patients had a viral-load decrease of >0.75 log(10), with a median maximal decrease in viral load of -1.57 log(10) copies/ml at week 8. At week 2, 19 subjects showed a median LPV area under the concentration-time curve (AUC) of 157.2 (range, 62.8 to 305.5) microg x h/ml and median LPV trough concentration (C(trough)) of 10.8 (range, 4.1 to 25.3) microg/ml. In 16 subjects with SQV added, the SQV median AUC was 33.7 (range, 4.4 to 76.5) microg x h/ml and the median SQV C(trough) was 2.1 (range, 0.2 to 4.1) microg/ml. At week 24, 18 of 26 (69%) subjects remained in the study. Between weeks 24 and 48, one subject withdrew for nonadherence and nine withdrew for persistently high virus load. In antiretroviral-experienced children and adolescents with HIV, high doses of LPV/r with or without SQV offer safe options for salvage therapy, but the modest virologic response and the challenge of adherence to a regimen with a high pill burden may limit the usefulness of this approach.
对于抗逆转录病毒治疗失败的人类免疫缺陷病毒（HIV）感染儿童和青少年，增加药物暴露量（使用更高剂量的蛋白酶抑制剂或利托那韦增强治疗）可能会产生更好的病毒学反应。我们研究了高剂量洛匹那韦 - 利托那韦（LPV/r）在有治疗经验患者中的药代动力学和安全性，使用的LPV/r剂量为每12小时口服400/100 mg/m²（每12小时一次口服）（不使用非核苷类逆转录酶抑制剂[NNRTI]），或每12小时口服480/120 mg/m²（使用NNRTI）。我们计算了LPV抑制商（IQ），当IQ<15时，将每12小时口服750 mg/m²的沙奎那韦（SQV）添加到治疗方案中。我们研究了26例HIV感染患者。中位年龄为15岁（范围7至17岁），之前接受过11.5种抗逆转录病毒药物治疗，CD4细胞计数为197个/ml，病毒载量为75,577拷贝/ml，LPV耐药性有133倍的变化。到治疗第2周时，14例患者的病毒载量下降>0.75 log₁₀，第8周时病毒载量最大中位下降为-1.57 log₁₀拷贝/ml。在第2周时，19名受试者的LPV浓度 - 时间曲线下面积（AUC）中位值为157.2（范围62.8至305.5）μg·h/ml，LPV谷浓度（C(trough)）中位值为10.8（范围4.1至25.3）μg/ml。在添加了SQV的16名受试者中，SQV的AUC中位值为33.7（范围4.4至76.5）μg·h/ml，SQV的C(trough)中位值为2.1（范围0.2至4.1）μg/ml。到第24周时，26名受试者中有18名（69%）仍在研究中。在第24周到48周之间，1名受试者因不依从退出，9名受试者因病毒载量持续高而退出。在有抗逆转录病毒治疗经验的HIV感染儿童和青少年中，高剂量的LPV/r联合或不联合SQV为挽救治疗提供了安全的选择，但适度的病毒学反应以及坚持高 pill 负担治疗方案的挑战可能会限制这种方法的实用性。
