King Jennifer R, Nachman Sharon, Yogev Ram, Hodge Janice, Aldrovandi Grace, Hughes Michael D, Chen Jie, Wiznia Andrew, Damle Bharat, Acosta Edward P
University of Alabama at Birmingham, Birmingham, USA.
Pediatr Infect Dis J. 2005 Oct;24(10):880-5. doi: 10.1097/01.inf.0000180508.21918.8a.
Few combinations of highly active antiretrovirals have been studied in nucleoside reverse transcription inhibitor (NRTI)-experienced, human immunodeficiency virus (HIV)-infected children. We tested the efficacy, tolerability and pharmacokinetics of 2 combination therapies containing an NRTI, protease inhibitors +/- a nonnucleoside reverse transcription inhibitor (NNRTI).
This was a phase II, randomized, multicenter study. Forty-one children and youths between 5 months and 21 years with prior NRTI and no prior NNRTI or protease inhibitor experience received either nelfinavir (NFV) 30 mg/kg twice daily (bid), ritonavir (RTV) 400 mg/m bid and buffered didanosine (ddI) 240 mg/m daily (arm A) or NFV 50-55 mg/kg bid, nevirapine (NVP) 120 mg/m bid and stavudine (d4T) 1 mg/kg bid (arm B). Patients were evaluated clinically for 48 weeks after initiation of therapy. Intensive pharmacokinetic sampling occurred after 4 weeks of therapy.
: The proportion of children with HIV-1 RNA < or =400 copies/mL and on randomized treatment at 48 weeks was 65% among children assigned NFV + RTV + ddI versus 28% among those assigned NFV + NVP + d4T (P = 0.039). No significant difference in median CD4% change from baseline to week 48 was found (3% versus 1%). No significant differences in safety or tolerability between children randomized to NFV + RTV + ddI versus NFV + NVP + d4T were identified. However, a trend toward a higher rate of permanent discontinuation of study treatment was noted among children assigned to NFV + NVP + d4T compared with NFV + RTV + ddI [7 of 20 (35%) versus 2 of 21 (10%); P = 0.12]. NFV pharmacokinetic measurements were not statistically different between the treatment groups, yet exposure to the NFV metabolite, M8, was significantly higher in subjects receiving RTV. The pharmacokinetics for NVP, RTV and d4T were similar to those of previously reported data.
: Combination therapy containing NFV + RTV + ddI appears more efficacious in NRTI-experienced children than a regimen containing NFV + NVP + d4T. Differences in tolerability between the 2 treatment groups were not identified. Systemic exposure of these drugs was similar to that reported in other HIV-infected children and adults.
在接受过核苷类逆转录酶抑制剂（NRTI）治疗的人类免疫缺陷病毒（HIV）感染儿童中，很少有高效抗逆转录病毒药物组合被研究过。我们测试了两种含NRTI、蛋白酶抑制剂+/-非核苷类逆转录酶抑制剂（NNRTI）的联合疗法的疗效、耐受性和药代动力学。
这是一项II期随机多中心研究。41名年龄在5个月至21岁之间、曾接受过NRTI治疗但未接受过NNRTI或蛋白酶抑制剂治疗的儿童和青少年，被随机分为两组，一组接受奈非那韦（NFV）30mg/kg每日两次（bid）、利托那韦（RTV）400mg/m² bid和缓冲去羟肌苷（ddI）240mg/m²每日一次（A组），另一组接受NFV 50 - 55mg/kg bid、奈韦拉平（NVP）120mg/m² bid和司他夫定（d4T）1mg/kg bid（B组）。治疗开始后对患者进行48周的临床评估。治疗4周后进行密集药代动力学采样。
在接受NFV + RTV + ddI治疗的儿童中，48周时HIV-1 RNA≤400拷贝/mL且仍在随机治疗的儿童比例为65%，而在接受NFV + NVP + d4T治疗的儿童中这一比例为28%（P = 0.039）。从基线到第48周，两组儿童的CD4%中位数变化无显著差异（分别为3%和1%）。随机接受NFV + RTV + ddI与NFV + NVP + d4T治疗的儿童在安全性或耐受性方面未发现显著差异。然而，与NFV + RTV + ddI组相比，NFV + NVP + d4T组儿童中研究治疗永久停药率有升高趋势[20例中有7例（35%），而21例中有2例（10%）；P = 0.12]。治疗组之间NFV药代动力学测量无统计学差异，但接受RTV治疗的受试者中，NFV代谢物M8的暴露量显著更高。NVP、RTV和d4T的药代动力学与先前报道的数据相似。
在接受过NRTI治疗的儿童中，含NFV + RTV + ddI的联合疗法似乎比含NFV + NVP + d4T的方案更有效。未发现两种治疗组在耐受性方面的差异。这些药物的全身暴露与其他HIV感染儿童和成人中报道的相似。
