Bustos Maria D, Wongsrichanalai Chansuda, Delacollette Charles, Burkholder Brent
WHO Country Office, Bangkok, Thailand.
Southeast Asian J Trop Med Public Health. 2013;44 Suppl 1:201-30; discussion 306-7.
In vivo Therapeutic Efficacy Studies (TES) have been routinely conducted in the Greater Mekong Subregion (GMS) for decades. Results from the last 10 years have contributed to update national antimalarial drug policies, to identify hotspots of multi-drug resistance and from 2008 onwards, to stimulate ambitious multi-country programs and innovative research projects to contain and eliminate artemisinin resistant Plasmodium falciparum strains in the subregion. This paper describes the results of TES of first-line antimalarials in six countries of the GMS from 2008-2010 using the WHO in vivo standard protocol. A total of 91 studies were conducted at 32 sentinel sites testing dihydroartemisinin-piperaquine (DHA-PIP), artesunate+mefloquine (A+M), and artemether-lumefantrine (AL) against P. falciparum malaria, as well as chloroquine and DHA-PIP against P vivax. Overall, artemisinin-based combination therapies (ACTs) remained efficacious against falciparum malaria with some exceptions. The 42-day adequate clinical and parasitological response (ACPR) for DHA-PIP dropped significantly to 73% (95% CI 53-87) in 2010 in the same hotspot area of western Cambodia known to harbor artemisinin resistant P. falciparum strains. Because P falciparum sensitivity to artemisinin is a major concern, especially on the Cambodia-Thailand border, attempts were also made to strengthen the monitoring of parasite clearance time elsewhere in the region and globally. The proportion of patients still blood-smear positive on Day 3 above 10% is considered a proxy indicator to strongly suspect the appearance of falciparum resistance to artesunate. This has led to substantial extra measures to confirm the suspicion and eventually set up interventions to eliminate artemisinin resistant parasites. Notably, increasing proportions (>10%) of Day 3 positives among falciparum malaria patients treated with DHA-PIP have been observed in western Cambodia, Myanmar, Viet Nam and China from 2008. Percent Day 3 parasitemia associated with A+M has increased along the Thailand-Myanmar border to surpass 10% at several sites, adding to the known pool of sites with 'suspected' artemisinin resistance in the GMS. Chloroquine remains highly effective against P. vivax except for northeastern and north-central Cambodia. TES results from this subregional-wide monitoring of antimalarial efficacy have influenced the changes of 1st line drugs against both P. falciparum and P. vivax in Cambodia, against P. falciparum in selected areas in Thailand, and pinpointed hotspot areas elsewhere that should be closely monitored in order to take action in a timely manner.
几十年来，体内治疗效果研究（TES）一直在大湄公河次区域（GMS）定期开展。过去10年的研究结果为更新各国抗疟药物政策、确定多重耐药热点地区做出了贡献，并且从2008年起，推动了雄心勃勃的多国项目和创新性研究项目，以控制和消除该次区域对青蒿素耐药的恶性疟原虫菌株。本文描述了2008 - 2010年期间，在GMS六个国家使用世界卫生组织体内标准方案对一线抗疟药物进行的TES结果。在32个哨点共开展了91项研究，测试双氢青蒿素 - 哌喹（DHA - PIP）、青蒿琥酯 + 甲氟喹（A + M）和蒿甲醚 - 本芴醇（AL）治疗恶性疟原虫疟疾的效果，以及氯喹和DHA - PIP治疗间日疟原虫的效果。总体而言，以青蒿素为基础的联合疗法（ACTs）对恶性疟原虫疟疾仍然有效，但有一些例外情况。在柬埔寨西部已知存在对青蒿素耐药的恶性疟原虫菌株的同一热点地区，2010年DHA - PIP的42天充分临床和寄生虫学反应（ACPR）显著降至73%（95%置信区间53 - 87）。由于恶性疟原虫对青蒿素的敏感性是一个主要关注点，特别是在柬埔寨 - 泰国边境，还尝试加强对该区域其他地方以及全球寄生虫清除时间的监测。第3天血涂片仍呈阳性的患者比例超过10%被视为强烈怀疑恶性疟原虫对青蒿琥酯产生耐药性的替代指标。这导致采取了大量额外措施来确认这种怀疑，并最终建立干预措施以消除对青蒿素耐药的寄生虫。值得注意的是，从2008年起，在柬埔寨西部、缅甸、越南和中国，接受DHA - PIP治疗的恶性疟原虫疟疾患者中第3天阳性比例不断增加（>10%）。与A + M相关的第3天寄生虫血症百分比在泰国 - 缅甸边境沿线有所增加，在几个地点超过了10%，这使得GMS中已知的“疑似”青蒿素耐药地点增多。除柬埔寨东北部和中北部外，氯喹对间日疟原虫仍然高度有效。该次区域范围内抗疟疗效监测的TES结果影响了柬埔寨针对恶性疟原虫和间日疟原虫的一线药物变化、泰国部分地区针对恶性疟原虫的一线药物变化，并确定了其他应密切监测的热点地区，以便及时采取行动。
