A pilot assessment of miltefosine's efficacy and tolerability for treating cutaneous Leishmania tropica in Afghanistan

皮肤利什曼病（CL）是一种自圣经时代就存在的皮肤病。该病是由利什曼病寄生虫引起的，它通过沙蝇在人与人之间或小动物或狗之间传播给人类。历史上，利什曼病分为旧世界利什曼病和新世界利什曼病（OW或NWCL）。从地中海开始，横跨中东和高加索地区，一直延伸到印度西部。东非和西非也有受影响地区。NWCL分布在墨西哥、中美洲和南美洲的大多数国家（智利、阿根廷和乌拉圭除外）。世界卫生组织（WHO）估计，全世界每年CL病例数为600-90万例，其中90%发生在7个国家：阿富汗、阿尔及利亚、巴西、伊朗、秘鲁、沙特阿拉伯和叙利亚。在贫困、战争和大量人口流离失所的地方，伊斯兰教蓬勃发展。在叙利亚和阿富汗尤其如此。CL导致溃疡、结节和皮肤干燥结垢，尤其是面部，患者会感到不适。NWCL也可能侵入口腔、鼻子和喉咙，导致更难看和严重的疾病。这种形式在外劳中很少见，但据报道在叙利亚难民中也有，因为他们无法得到早期治疗。由于制药公司和政府对进行研究兴趣不大，因此对慢性淋巴细胞白血病的治疗仅限于使用有毒药物。这就是为什么利什曼病是世卫组织指定的一种被忽视的热带病。我们计划进行一项小规模的试点研究，看看一种名为米替福辛的药物对阿富汗的慢性粒细胞白血病是否有效。米替福辛对内脏利什曼病（影响内脏器官的利什曼病）和某些类型的NWCL有效。它可以口服，这比目前使用的治疗方法有很大的优势，但超过28天对患者来说可能是一个挑战。在阿富汗，CL是由人与人之间传播的热带利什曼原虫引起的。这解释了阿富汗和叙利亚的高病例数，以及为什么世卫组织建议治疗。stiboglusate钠（SSB）是阿富汗唯一可用于治疗CL的药物。它必须在20多天内注射到皮肤、静脉或肌肉中，这是痛苦和痛苦的，特别是对占25%的小孩。SSB是有毒的，可能影响肝脏、肾脏、胰腺、血液和心脏。因此，一些患者不得不尽早停止治疗。我们需要更好的替代方案。我们的初步研究将使用推荐剂量给予米替福辛和SSB，并随访患者6个月，看看他们的皮肤是否治愈；需要长时间的随访，因为即使皮肤看起来已经愈合，CL也可能复发。随着时间的推移，我们还将测量血液中的米特氟辛水平和皮肤中的利什曼原虫，并检查两者之间的关系。这是以前从未对热带乳杆菌做过的。我们还将询问患者对CL的了解，它如何影响他们的生活，以及他们愿意为他们更喜欢的治疗支付多少钱。如果我们的研究显示miltefosine有希望，我们将申请更多的资金来做一个比较14天和28天的miltefosine与SSB的大型研究。大规模的研究将使我们对结果有信心。如果米替福辛更受患者欢迎，我们愿意接受比SSB更低的治愈率（例如5-10%）。如果14天的米替福辛也非常有效，这将是一个很大的优势，因为米替福辛是昂贵的；世界卫生组织的价格分别为儿童和成人约70英镑和100英镑。拥有有效和流行的口服治疗，特别是超过14天的治疗，将大大方便诊所和患者，并将改善许多OWCL患者获得治疗的机会。

Cutaneous leishmaniasis (CL) is a skin disease that has been around since biblical times. The disease is caused by the leishmaniasis parasite, which is transmitted by sand flies between humans or between small animals or dogs to humans. Historically, CL is divided into Old and New World leishmaniasis (OW or NWCL). OWCL stretches from the Mediterranean Sea, across the Middle East and Caucasus region, to western India. There are also affected areas in east and west Africa. NWCL is found in Mexico, central and most countries in South America (except Chile, Argentina and Uruguay).The World Health Organization (WHO) estimates that the number of CL cases per year in the world is 600-900,000 with 90% occurring in seven countries: Afghanistan, Algeria, Brazil, Iran, Peru, Saudi Arabia, and Syria. CL thrives where there is poverty, war and large population displacements. This is particularly the case in Syria and Afghanistan. CL results in ulcers, nodules, and dry scaling of the skin especially on the face which patients find upsetting. NWCL may also invade the mouth, nose and throat leading to a more unsightly and severe disease. This form is rare in OWCL but has been reported in Syrian refugees because they have not been able to receive early treatment. Treatment for CL is limited to toxic drugs because there is little interest by drug companies and governments to conduct research. This is why leishmaniasis is a WHO-designated neglected tropical disease. We plan to conduct a small pilot study to see if a drug called miltefosine is effective in OWCL in Afghanistan. Miltefosine is effective for treating visceral leishmaniasis (leishmaniasis affecting our internal organs) and some types of NWCL. It can be given by mouth, a big advantage over currently used treatments, but over 28 days which may be a challenge for patients. In Afghanistan, CL is caused by the Leishmania tropica species which is transmitted between humans. This explains the high number of cases in Afghanistan and Syria and why the WHO recommends treatment. Sodium stibogluconate (SSB) is the only drug available for treating CL in Afghanistan. It has to be given over 20 days by injection into the skin, vein or muscle which is painful and distressing, especially for small children who make up about 25% of cases. SSB is toxic and may affect the liver, kidneys, pancreas, blood, and heart. As a result, some patients have to stop it early. Better alternatives are needed. Our pilot study will give miltefosine and SSB, using recommended doses, and follow patients for six months to see if their skin is cured; a long follow up is needed because CL can return even though the skin appears healed. We will also measure miltefosine levels in the blood and the leishmania parasites in the skin over time and examine the relationship between the two. This has never been done before for L. tropica. We will also ask patients about their knowledge of CL, how it affects their life, and how much they are willing to pay for a treatment that they prefer to SSB. If our study shows miltefosine has promise, we will apply for more money to do a large study comparing 14 and 28 days of miltefosine with SSB. A large study will give us confidence in the results. We are willing to accept a lower miltefosine cure rate (e.g. 5-10%) over SSB if it is more popular with patients. If 14 days of miltefosine is also very effective, this would be a big plus because miltefosine is expensive; the WHO price is about 70 and 100 pounds for children and adults, respectively. Having an effective and popular oral treatment, especially over 14 days, would be so much more convenient for clinics and patients and will improve access to treatment for many people with OWCL.