Bienczak Andrzej, Denti Paolo, Cook Adrian, Wiesner Lubbe, Mulenga Veronica, Kityo Cissy, Kekitiinwa Addy, Gibb Diana M, Burger David, Walker Ann S, McIlleron Helen
aDivision of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa bMRC Clinical Trials Unit at University College London, London, United Kingdom cDepartment of Paediatrics and Child Health, University Teaching Hospital, Lusaka, Zambia dJoint Clinical Research Centre eBaylor College of Medicine Bristol Myers Squibb Children's Clinical Centre of Excellence, Kampala, Uganda fGulu Regional Centre of Excellence, Gulu, Uganda gDepartment of Pharmacy, Radboud University Medical Centre, Nijmegen, The Netherlands. *Ann S. Walker and Helen McIlleron contributed equally to the article.
AIDS. 2017 Apr 24;31(7):905-915. doi: 10.1097/QAD.0000000000001376.
Nevirapine is the only nonnucleoside reverse transcriptase inhibitor currently available as a paediatric fixed-dose-combination tablet and is widely used in African children. Nonetheless, the number of investigations into pharmacokinetic determinants of virological suppression in African children is limited, and the predictive power of the current therapeutic range was never evaluated in this population, thereby limiting treatment optimization.
We analysed data from 322 African children (aged 0.3-13 years) treated with nevirapine, lamivudine, and either abacavir, stavudine, or zidovudine, and followed up to 144 weeks. Nevirapine trough concentration (Cmin) and other factors were tested for associations with viral load more than 100 copies/ml and transaminase increases more than grade 1 using proportional hazard and logistic models in 219 initially antiretroviral treatment (ART)-naive children.
Pre-ART viral load, adherence, and nevirapine Cmin were associated with viral load nonsuppression [hazard ratio = 2.08 (95% confidence interval (CI): 1.50-2.90, P < 0.001) for 10-fold higher pre-ART viral load, hazard ratio = 0.78 (95% CI: 0.68-0.90, P < 0.001) for 10% improvement in adherence, and hazard ratio = 0.94 (95% CI: 0.90-0.99, P = 0.014) for a 1 mg/l increase in nevirapine Cmin]. There were additional effects of pre-ART CD4 cell percentage and clinical site. The risk of virological nonsuppression decreased with increasing nevirapine Cmin, and there was no clear Cmin threshold predictive of virological nonsuppression. Transient transaminase elevations more than grade 1 were associated with high Cmin (>12.4 mg/l), hazard ratio = 5.18 (95% CI 1.95-13.80, P < 0.001).
Treatment initiation at lower pre-ART viral load and higher pre-ART CD4 cell percentage, increased adherence, and maintaining average Cmin higher than current target could improve virological suppression of African children treated with nevirapine without increasing toxicity.
奈韦拉平是目前唯一可作为儿科固定剂量组合片剂使用的非核苷类逆转录酶抑制剂，在非洲儿童中广泛应用。尽管如此，针对非洲儿童病毒学抑制的药代动力学决定因素的研究数量有限，且从未在该人群中评估当前治疗范围的预测能力，从而限制了治疗的优化。
我们分析了322名接受奈韦拉平、拉米夫定和阿巴卡韦、司他夫定或齐多夫定治疗的非洲儿童（年龄0.3 - 13岁）的数据，并随访了144周。在219名最初未接受抗逆转录病毒治疗（ART）的儿童中，使用比例风险模型和逻辑模型测试了奈韦拉平谷浓度（Cmin）及其他因素与病毒载量高于100拷贝/ml和转氨酶升高超过1级之间的关联。
ART前病毒载量、依从性和奈韦拉平Cmin与病毒载量未被抑制相关[ART前病毒载量每升高10倍，风险比 = 2.08（95%置信区间（CI）：1.50 - 2.90，P < 0.001）；依从性提高10%，风险比 = 0.78（95% CI：0.68 - 0.90，P < 0.001）；奈韦拉平Cmin每升高1mg/l，风险比 = 0.94（95% CI：0.90 - 0.99，P = 0.014）]。ART前CD4细胞百分比和临床地点也有额外影响。随着奈韦拉平Cmin升高，病毒学未被抑制的风险降低，且没有明确的Cmin阈值可预测病毒学未被抑制。超过1级的短暂转氨酶升高与高Cmin（>12.4mg/l）相关，风险比 = 5.18（95% CI 1.95 - 13.80，P < 0.001）。
在较低的ART前病毒载量和较高的ART前CD4细胞百分比时开始治疗、提高依从性以及维持平均Cmin高于当前目标，可改善接受奈韦拉平治疗的非洲儿童的病毒学抑制，且不增加毒性。
