Sleeping sickness in West and Central Africa: is eradication just skin deep?
Sleeping sickness in West and Central Africa: is eradication just skin deep?
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DOI：
10.1016/s1474-4422(19)30082-1
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发表时间：
2019-04-01
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通讯作者：
Burton, Adrian
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作者：
Burton, Adrian
根据去年公布的临床试验结果，被忽视疾病药物倡议（DNDi）于2018年11月16日宣布，非洲昏睡病（或人类非洲锥虫病）的第一种口服治疗药物非昔硝唑已收到欧洲药品管理局的积极意见。这种新药是DNDi、赛诺菲和非洲合作伙伴十年来研发的成果，人们希望这种新药不仅能使昏睡病更容易治疗，而且还能与成功针对其采采蝇媒介的项目一起，最终帮助根除昏睡病。但昏睡病有一种方法，就在你认为它已经永远消失的时候，它会卷土重来。一组研究人员现在相信它已经找到了原因，这可能只是暂时搁置任何庆祝活动。2019年1月30日，刚果民主共和国批准了非昔硝唑，这意味着其他西非和中非国家可能很快就会效仿，这些国家总共发生了约97%的非洲昏睡病病例。这将首次为卫生工作者提供一种简单，安全，口服的治疗方法，用于治疗具有惊人神经症状的疾病：舞蹈病样、手足徐动样、四肢或躯干的振荡运动、肌束震颤、运动无力、共济失调、运动不能、言语障碍和口周反射和手口反射，伴有不可抗拒的日间嗜睡、夜间失眠、幻觉、谵妄、暴力行为，激动愤怒和狂躁最终导致死亡由布氏冈比亚锥虫（在西非和中非遇到的寄生虫致病剂）引发的疾病的第一阶段（外周寄生虫血症）的治疗迄今为止依赖于注射或输注喷他脒，这种治疗可能具有令人不快的副作用，包括突然的低血压、低血糖、低钙血症和心动过速，并且需要一些医疗基础设施来管理。直到最近，对第二阶段疾病（即中枢神经系统受累）的治疗仅限于使用含砷化合物美拉胂醇，其毒性如此之大，以至于10%接受治疗的患者出现治疗后脑病，其中一半死亡。20世纪90年代出现的一种更安全的替代品依氟鸟氨酸需要56次静脉注射，这在许多非洲地区是不切实际的。2009年，开始使用硝呋替莫氟鸟氨酸联合治疗（NECT），仅需7天内输注14次，再加上10天的进一步口服治疗，但仍需要患者住院10天。在这种背景下，非昔硝唑是一个游戏规则的改变者。在10天内服用24片，它可以治愈第一阶段和第二阶段的疾病，尽管对于晚期第二阶段的疾病，它不如NECT有效，NECT仍然是最严重的神经系统症状患者的治疗选择。此外，它还没有在幼儿或患有非常晚期疾病的人中进行过测试。尽管听起来令人鼓舞，但它可能不是对抗昏睡病的最终解决方案。“就在你认为发病率如此之低，以至于你已经打破了传播周期，并且从数学上讲，这种疾病必须灭绝时，数字可以回升，”格拉斯哥大学寄生虫学教授Annette麦克劳德解释说。“目前，非洲每年报告的新病例不到1500例，这证明了消除这种疾病的努力。但我们在20世纪60年代也遇到了类似的情况，在消除措施变得令人望而却步之后，昏睡病又卷土重来。
Following the results of clinical trials published last year, the Drugs for Neglected Diseases initiative (DNDi) announced on Nov 16, 2018, that fexinidazole, the first oral treatment for African sleeping sickness (or human African trypanosomiasis), had received a positive opinion from the European Medicines Agency. The product of a decade of development by the DNDi, Sanofi, and African partners, there is hope that this new drug will not only make sleeping sickness much easier to treat, but that it will also, alongside programmes that have successfully targeted its tsetse-fly vector, finally help eradicate it. But sleeping sickness has a way of coming back just when you think it has disappeared forever. A group of researchers now believes it has discovered why—and it might just put any celebrations on hold for a while. The approval of fexinidazole in the Democratic Republic of the Congo, communicated Jan 30, 2019, means that other West and Central African countries, where collectively about 97% of all cases of African sleeping sickness occur, might soon follow suit. This would arm health workers for the first time with a simple, safe, orally administered treatment for a condition with alarming neurological symptoms: choreiform, athetoid, oscillatory movements of the limbs or trunk, muscle fasciculation, motor weakness, ataxia, akinesia, speech disorder, and perioral and cheiro-oral reflexes, accompanied by irresistible daytime somnolescence, night-time insomnia, hallucinations, delirium, violent behaviour, agitation, rage, and mania, eventually leading to death. Treatment for the first stage of the disease (peripheral parasitaemia), as triggered by Trypanosoma brucei gambiense—the parasitic causal agent encountered in West and Central Africa—has until now relied on injected or infused pentamidine, a treatment that can have unpleasant side effects, including sudden hypotension, hypoglycaemia, hypocalcaemia, and tachycardia, and requiring some medical infrastructure to administer. Treatment for second-stage disease (ie, with CNS involvement) was until recently limited to the use of the arsenical compound melarsoprol—which is so toxic that 10% of patients thus treated developed post-treatment encephalopathy, half of whom died. A safer alternative that became available in the 1990s, eflornithine, demanded 56 intravenous infusions—which is impractical in many African settings. In 2009, nifurtimoxeflornithine combination therapy (NECT) started to be used, needing only 14 infusions over 7 days plus 10 days of further oral treatment, but still requiring that patients spend 10 days in hospital. Against this backdrop, fexinidazole is something of a gamechanger. Administered as 24 tablets over a 10-day period, it can be curative for both first-stage and second-stage disease, although for late second-stage disease it is less effective than NECT, which remains the treatment of choice for patients with the most serious neurological symptoms. Furthermore, it has not been tested in small children or in people with very advanced disease. Encouraging as it sounds, however, it might not be the definitive solution against sleeping sickness.“Just when you think the incidence is so low that you’ve broken the transmission cycle, and that mathematically the disease has got to die out, the numbers can go back up”, explains Annette MacLeod, professor of parasitology at the University of Glasgow (Glasgow, UK).“Right now, fewer than 1500 new cases are being reported from Africa per year, a testimony to the effort to eliminate the disease. But we reached a similar situation back in the 1960s, and sleeping sickness sprang back after elimination measures became prohibitive for …