National Centre for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
U.S. Naval Medical Research Unit 2, Phnom Penh, Cambodia.
Malar J. 2022 Sep 7;21(1):259. doi: 10.1186/s12936-022-04279-3.
Anti-malarial resistance remains an important public health challenge in Cambodia. The effectiveness of three therapies for uncomplicated falciparum malaria was evaluated in Oddar Meanchey province in Northern Cambodia from 2009 to 2011.
In this randomized, open-label, parallel group-controlled trial, 211 subjects at least 5 years old with uncomplicated falciparum malaria were treated with 3 days of directly observed therapy: 63 received artesunate-mefloquine (AS/MQ), 77 received dihydroartemisinin-piperaquine (DHA/PPQ), and 71 received atovaquone-proguanil (ATQ/PG). The subjects were followed for 42 days or until recurrent parasitaemia. Genotyping of msp1, msp2, and glurp among individual parasite isolates distinguished recrudescence from reinfection. Pfmdr1 copy number was measured by real-time PCR and half-maximal parasite inhibitory concentrations (IC) were measured in vitro by 48-h isotopic hypoxanthine incorporation assay.
The per-protocol PCR-adjusted efficacy (95% confidence interval) at 42 days was 80.6% (70.8-90.5%) for AS/MQ, 97.2% (93.3-100%) for DHA/PPQ, and 92.9% (86.1-99.6%) for ATQ/PG. On day 3, 57.9% remained parasitaemic in the AS/MQ and DHA/PPQ arms. At baseline, 46.9% had microscopic Plasmodium falciparum gametocytaemia. Both recurrences in the DHA/PPQ arm lost Pfmdr1 copy number amplification at recrudescence. All four recurrences in the ATQ/PG arm were wild-type for cytochrome bc. One subject withdrew from the ATQ/PG arm due to drug allergy.
This study was conducted at the epicentre of substantial multi-drug resistance that emerged soon thereafter. Occurring early in the national transition from AS/MQ to DHA/PPQ, both DHA/PPQ and ATQ/PG had acceptable efficacy against uncomplicated falciparum malaria. However, efficacy of AS/MQ was only 80% with apparent mefloquine resistance based on elevated Pfmdr1 copy number and IC. By 2009, there was already significant evidence of artemisinin resistance not previously reported at the Northern Cambodia-Thai border. This study suggests the basis for early development of significant DHA/PPQ failures within 3 years of introduction. Artemisinin resistance likely occurred on the Northern border concurrently with that reported along the Western border in Pailin. Trial registration This legacy trial was conducted prior to International Committee of Medical Journal Editors' requirements for preregistration on ClinicalTrials.gov. The full protocol has been provided.
抗疟药耐药性仍然是柬埔寨的一个重要公共卫生挑战。本研究于 2009 年至 2011 年在柬埔寨北部的奥多棉芷省评估了三种治疗无并发症恶性疟的疗效。
在这项随机、开放标签、平行组对照试验中，211 名年龄至少 5 岁的无并发症恶性疟患者接受 3 天的直接观察治疗：63 名患者接受青蒿琥酯-甲氟喹（AS/MQ）治疗，77 名患者接受双氢青蒿素-哌喹（DHA/PPQ）治疗，71 名患者接受阿托伐醌-磺胺多辛（ATQ/PG）治疗。随访 42 天或直至寄生虫复发。通过个体寄生虫分离物的 msp1、msp2 和 glurp 基因分型区分复燃与再感染。通过实时 PCR 测量 Pfmdr1 拷贝数，并通过 48 小时同位素次黄嘌呤掺入测定法测量半最大寄生虫抑制浓度（IC）。
42 天时按方案 PCR 校正的疗效（95%置信区间）分别为 AS/MQ 组 80.6%（70.8%-90.5%）、DHA/PPQ 组 97.2%（93.3%-100%）和 ATQ/PG 组 92.9%（86.1%-99.6%）。第 3 天，AS/MQ 和 DHA/PPQ 组仍有 57.9%的患者寄生虫血症。基线时，46.9%的患者有疟原虫配子体血症。DHA/PPQ 组的所有 4 次复发均在复燃时失去 Pfmdr1 拷贝数扩增。ATQ/PG 组的 4 次复发均为细胞色素 bc 的野生型。1 名患者因药物过敏而退出 ATQ/PG 组。
本研究在随后很快出现的多药耐药性的中心进行。DHA/PPQ 和 ATQ/PG 均具有良好的疗效，可用于治疗无并发症恶性疟，这发生在全国从 AS/MQ 向 DHA/PPQ 过渡的早期。然而，AS/MQ 的疗效仅为 80%，这表明根据 Pfmdr1 拷贝数和 IC 升高，存在明显的甲氟喹耐药性。到 2009 年，在柬埔寨北部-泰国边境已经有了明显的青蒿素耐药证据，这在以前没有报道过。本研究表明，DHA/PPQ 在引入后 3 年内就出现了显著失败的早期基础。青蒿素耐药性可能与在西部边境报告的耐药性同时发生。
本研究是在国际医学期刊编辑委员会要求在 ClinicalTrials.gov 上进行预注册之前进行的。已提供完整的方案。
