A pilot assessment of miltefosine's efficacy and tolerability for treating cutaneous Leishmania tropica in Afghanistan
Lead Research Organisation:
University of Oxford
Department Name: Tropical Medicine
Abstract
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.
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.
Technical Summary
Background. Cutaneous leishmaniasis (CL) is a neglected tropical disease par excellence and attracts scant attention from the global research community, pharma, and governments. It is an unsightly disease that scars and causes misery, psychological distress, and poor quality of life. Old World (OW) CL, caused by Leishmania tropica and L. major, is a significant public health challenge in the Middle East and west Asia, notably in Afghanistan, Palestine, Syria, and Yemen (Karimkhani 2016). The WHO estimates a case burden of ~500,000/year and war related epidemics are well documented in Afghanistan and in Syrian refuges (Al-Salem 2016). Treatment options for OWCL are limited. Most countries rely on toxic pentavalent antimonials that must be given by injection (intralesion or parenterally). Better tolerated oral alternatives are needed. Miltefosine, a 28-day, effective oral treatment for visceral leishmaniasis, has variable efficacy in New World CL, and appears promising in OWCL case reports. There has never been a study to assess simultaneously clinical cure and the miltefosine parasite clearance relationship.
Methods. Our randomised pilot trial will assess efficacy and tolerability of miltefosine (n=50) and SSB (n=50) in Afghan patients aged 1 year or more with L. tropica CL needing chemotherapy. Miltefosine will be dosed allometrically (Dorlo 2012). Follow up is 6 months. The primary end point is cure (complete re-epithelisation of ulcers/return to normal skin). Key secondary endpoints include quality of life and the modelled relationship between miltefosine pharmacokinetics and parasite clearance.
Results & future direction. A miltefosine cure rate similar to that of SSB or at least 70% defines success for designing a large randomised noninferiority trial of 14 and 28-day miltefosine vs. SSB, including an economic analysis. We will work with WHO, and the Afghan MoPH to promote positive results and advocate for more research on OWCL.
Methods. Our randomised pilot trial will assess efficacy and tolerability of miltefosine (n=50) and SSB (n=50) in Afghan patients aged 1 year or more with L. tropica CL needing chemotherapy. Miltefosine will be dosed allometrically (Dorlo 2012). Follow up is 6 months. The primary end point is cure (complete re-epithelisation of ulcers/return to normal skin). Key secondary endpoints include quality of life and the modelled relationship between miltefosine pharmacokinetics and parasite clearance.
Results & future direction. A miltefosine cure rate similar to that of SSB or at least 70% defines success for designing a large randomised noninferiority trial of 14 and 28-day miltefosine vs. SSB, including an economic analysis. We will work with WHO, and the Afghan MoPH to promote positive results and advocate for more research on OWCL.
Planned Impact
Old World cutaneous leishmaniasis (OWCL), the focus of our research, is a neglected tropical disease that affects poor people and thrives during wars. This was graphically illustrated in the early 2000s in Afghanistan (where the burden has increased year on year since then) and in recent years in Syrian refugees. OWCL is a disabling disease that leads to disfigurement, usually on the face and hands, reduced quality of life, and social stigma, particularly for women and children.
In terms of case numbers, the EMRO estimates these to be up to ~500,000 per year in countries that are poor with weak health systems and with limited capacity to meet the costs and other challenges of treating patients. Our goal is to determine whether miltefosine has an important therapeutic role in the treatment of predominantly Leishmania tropica OWCL. This requires a pilot study first before embarking on a large, costly, randomised trial with the aim of demonstrating noninferiority of miltefosine (dosed for 14 or 28 days) to the current standard drug, sodium stibogluconate, a toxic pentavalent antimonial.
If we assume that miltefosine is effective in OWCL, tolerated and liked by patients, and makes economic sense, the potential impact will be far reaching. The population at risk in the EMRO region is huge. In Afghanistan alone, the WHO estimates the population at risk of OWCL is 20 million (http://www.emro.who.int/afg/afghanistan-news/leishmaniasis-neglected-disease.html). In the ongoing conflict in Syria, millions of people have been displaced and are at risk of OWCL, especially in overcrowded refugee camps where person-to-person transmission is enhanced.
OWLC sufferers should benefit from our research on miltefosine because:
- It is a well tolerated oral treatment that can be taken at home or in transit to a place of safety
- Little monitoring will be required, unlike the toxic pentavalent antimonials
- Patients will not run the risk of serious systemic toxicity often seen with the pentavalent antimonials
- Painful and distressing injections will be a thing of the past
- Trained staff will not be needed to administer these injections, thus saving valuable resources
- NGOs treating refugees and internally displaced persons will have a good option in challenging environments
- Leishmaniasis control programmes will be able offer greater choice and access to treatment for their CL affected populations
We hope to raise the awareness of OWCL and work with advocacy groups for more investment in research and control. In the long term this could lead to new drugs for OWCL as well as New World CL.
One important issue is the price of miltefosine. Even at the discounted, WHO negotiated price, an adult course cost about 100 pounds sterling. Greater advocacy might persuade the manufacturer to reduce further the cost of miltefosine and, if in our planned large trial, 14 days of miltefosine is effective, it could be used for OWCL. This would make adherence easier and the treatment less costly for patients and health systems.
In terms of case numbers, the EMRO estimates these to be up to ~500,000 per year in countries that are poor with weak health systems and with limited capacity to meet the costs and other challenges of treating patients. Our goal is to determine whether miltefosine has an important therapeutic role in the treatment of predominantly Leishmania tropica OWCL. This requires a pilot study first before embarking on a large, costly, randomised trial with the aim of demonstrating noninferiority of miltefosine (dosed for 14 or 28 days) to the current standard drug, sodium stibogluconate, a toxic pentavalent antimonial.
If we assume that miltefosine is effective in OWCL, tolerated and liked by patients, and makes economic sense, the potential impact will be far reaching. The population at risk in the EMRO region is huge. In Afghanistan alone, the WHO estimates the population at risk of OWCL is 20 million (http://www.emro.who.int/afg/afghanistan-news/leishmaniasis-neglected-disease.html). In the ongoing conflict in Syria, millions of people have been displaced and are at risk of OWCL, especially in overcrowded refugee camps where person-to-person transmission is enhanced.
OWLC sufferers should benefit from our research on miltefosine because:
- It is a well tolerated oral treatment that can be taken at home or in transit to a place of safety
- Little monitoring will be required, unlike the toxic pentavalent antimonials
- Patients will not run the risk of serious systemic toxicity often seen with the pentavalent antimonials
- Painful and distressing injections will be a thing of the past
- Trained staff will not be needed to administer these injections, thus saving valuable resources
- NGOs treating refugees and internally displaced persons will have a good option in challenging environments
- Leishmaniasis control programmes will be able offer greater choice and access to treatment for their CL affected populations
We hope to raise the awareness of OWCL and work with advocacy groups for more investment in research and control. In the long term this could lead to new drugs for OWCL as well as New World CL.
One important issue is the price of miltefosine. Even at the discounted, WHO negotiated price, an adult course cost about 100 pounds sterling. Greater advocacy might persuade the manufacturer to reduce further the cost of miltefosine and, if in our planned large trial, 14 days of miltefosine is effective, it could be used for OWCL. This would make adherence easier and the treatment less costly for patients and health systems.
