Parasitological Clearance Rates and Drug Concentrations of a Fixed Dose Combination of Azithromycin-Chloroquine in Asymptomatic Pregnant Women with Plasmodium Falciparum Parasitemia: An Open-Label, Non-Comparative Study in Sub-Saharan Africa

Background
Malaria remains one of the most important causes of morbidity and mortality in pregnant women and their newborn babies in sub-Saharan Africa. Intermittent preventive treatment in pregnancy (IPTp) is recommended by the World Health Organization (WHO) to reduce the burden of disease and improve maternal and neonatal survival and general health. Due to the growing resistance to sulfadoxine-pyrimethamine (SP), the current WHO-recommended drug for IPTp, identification of new and effective drugs is an urgent priority.
Methods and Findings
This was an open-label, non-comparative study (NCT01103713) in 5 countries in East and sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) to assess parasitological response and drug concentrations of a single, 3-day course of four tablets of a fixed-dose combination of azithromycin-chloroquine (AZCQ) 250/155 mg given during the second or third trimester to women with asymptomatic Plasmodium falciparum parasitemia in their first or second pregnancy. Parasitemia was determined by microscopy and molecular genotyping was performed to characterize parasites relative to the baseline infection. Weekly follow-up visits took place until day 42 after first dose and additional follow-up occurred after delivery. Systemic concentrations of azithromycin (AZ), chloroquine (CQ), and the CQ metabolite, desethyl CQ (DECQ) were evaluated at Day 0 (pre-dose), at Day 2 (pre-dose, 2 and 8 hours) and randomly at Days 7 and 14. Systemic concentrations of CQ and DECQ were also measured randomly at Day 21 and Day 28. In total, 404 women were screened for eligibility and 168 were treated, 155 of whom completed the study. PCR-adjusted parasitological response in the modified intent-to-treat population at day 28 (the primary efficacy endpoint) was estimated by the Kaplan-Meier method as 99.35% (95% confidence interval [CI]: 97.76, 100.00). PCR-adjusted parasitological response remained high at day 42 (95.19%; 95% CI: 91.35, 99.03). In general, the mean concentrations of serum AZ, plasma CQ, and plasma DECQ showed large CV% values (ranges of 33–156%, 42–228%, and 57–109%, respectively). There were 157 live births, three stillbirths, and eight pregnancies of unknown outcome: 7 due to withdrawal of participant consent and 1 lost to follow-up. The most frequent treatment-emergent adverse events were vomiting (20.8%) and dizziness (19.6%).
Conclusions
These results suggest that a 3-day course of AZCQ can lead to an adequate 28-day parasitological response.

背景
疟疾仍是撒哈拉以南非洲地区孕妇及其新生儿发病与死亡的最主要诱因之一。世界卫生组织（World Health Organization, WHO）推荐采用妊娠期间歇性预防性治疗（Intermittent Preventive Treatment in Pregnancy, IPTp）以减轻疾病负担，改善孕产妇及新生儿的生存状况与整体健康水平。鉴于当前作为WHO推荐IPTp一线用药的磺胺多辛-乙胺嘧啶（sulfadoxine-pyrimethamine, SP）耐药性日益凸显，研发新型有效抗疟药物已成为亟待解决的优先事项。
方法与结果
本研究为一项开放标签、非对照临床试验（临床试验注册号：NCT01103713），在东非及撒哈拉以南非洲的5个国家（贝宁、肯尼亚、马拉维、坦桑尼亚、乌干达）开展，旨在评估针对首次或二次妊娠且伴无症状恶性疟原虫血症的孕妇，在妊娠中晚期给予3天疗程、每日4片规格为250mg/155mg的阿奇霉素-氯喹（azithromycin-chloroquine, AZCQ）固定剂量复方制剂后的寄生虫学应答情况与药物浓度。研究通过显微镜检测判定寄生虫血症，并采用分子基因分型技术对比基线感染特征对寄生虫进行分型鉴定。受试者自首次给药后至第42天每周接受随访，产后追加随访评估。分别于给药前（第0天）、第2天给药前（及给药后2小时、8小时）检测阿奇霉素（AZ）、氯喹（CQ）及其代谢产物去乙基氯喹（desethyl CQ, DECQ）的全身药物浓度，并在第7天、第14天随机采样检测；另于第21天、第28天随机采样检测CQ与DECQ的全身浓度。本研究共筛查合格受试者404名，最终纳入治疗队列168名，其中155名完成全部研究流程。采用Kaplan-Meier法估算改良意向治疗人群第28天的PCR校正寄生虫学应答率（主要疗效终点）为99.35%（95%置信区间[CI]：97.76, 100.00）；第42天时PCR校正寄生虫学应答率仍维持较高水平（95.19%；95% CI：91.35, 99.03）。整体而言，血清AZ、血浆CQ及血浆DECQ的平均浓度变异系数（CV%）分别为33%~156%、42%~228%及57%~109%，波动幅度较大。本研究共获得157例活产儿、3例死胎，另有8例妊娠结局不明：其中7例因受试者撤回知情同意，1例失访。最常见的治疗期间出现的不良事件为呕吐（20.8%）与头晕（19.6%）。
结论
本研究结果表明，3天疗程的AZCQ可实现良好的28天寄生虫学应答。