Overview 

Leishmaniasis (pronounced " leesh-muh-NAI-uh-suhs") is categorised as a neglected tropical disease that is caused by parasites spreading through the bite of infected sandflies. It is typically found in warm, tropical parts of the world including regions in East Africa, Brazil and even the Mediterranean basin. Once an infection takes place, it can cause disfiguring skin lesions and even life-threatening complications if left untreated. It is more than just sickness affecting the individual, it affects entire communities leading to severe social and economic challenges.¹  

Miltefosine was the first effective oral treatment for leishmaniasis despite being originally developed for cancer. Its convenience of administration and efficacy has made it a cornerstone in the fight against this neglected disease.

Miltefosine was originally developed as an anti-cancer treatment, emerging as the first effective oral treatment for leishmaniasis. Due to its convenience of administration and efficacy has made it an important aspect of the fight against this neglected tropical disease especially in the endemic regions.² 

What is leishmaniasis?

Leishmaniasis is caused by parasites from the leishmania genus, transmitted by infected female sandflies. When the sandflies bites a person for a bloodmeal, the parasite enters the body and causes illness.³  

There are three major types:

• Cutaneous leishmaniasis leads to painful skin ulcers, whereas visceral leishmaniasis can cause fever, weight loss, enlargement of the spleen and liver, and death in up to 95% of untreated cases—compelling reasons for prompt diagnosis and treatment
• Mucocutaneous leishmaniasis which involves mucus membranes and damages the nose, mouth and throat
• Visceral leishmaniasis which mainly affects internal organs and when untreated can be fatal. With up to a fatality rate of up to 95%

According to the World Health Organisation, there are up to 1 million new cases annually and are  found in 99 countries. As well as being very prevalent in poor, rural areas with an estimated 20,000 to 30,000 deaths each year globally.⁴

What is Miltefosine

Miltefosine is a medication that was developed in the 1980s with the purpose to treat cancer. After a while, scientists found that it could be effective to treat leishmaniasis by interfering with the cell structure of parasites which make it harder for them to survive and multiply.⁵

Approved in the year 2002 for visceral leishmaniasis in India, It became the first oral drug to treat the disease effectively. Its ease of use offers a significant advantage over traditional injectable therapies like amphotericin B or pentavalent antimonials which is dependent on hospitalisation and therefore careful monitoring.⁶

Evidence supporting Miltefosine use

Clinical trials and efficacy

Multiple clinical studies have shown that miltefosine is effective in treating the different forms of leishmaniasis:

• Visceral Leishmaniasis: In India, it showed cure rates of up to 94% in immunocompetent patients.⁷ The standard regime of treatment is a 28 day course of oral miltefosine⁸
• Cutaneous Leishmaniasis: Trials in Iran and Colombia have shown moderate to high efficacy depending on the species of Leishmania involved⁹
• Mucocutaneous Leishmaniasis: Miltefosine shows promise although response rates are lower and treatment duration may need adjustment¹⁰

Guidelines

Organisation like the world health organisation has included Miltefosine in its list of Essential Medicines and recommends it as a first-line treatment for VL in certain regions.¹¹ While national programs in India and Nepal have widely adopted it due to its oral administration and satisfactory safety profile.¹²

Practical  experience and real-world use

Implement in endemic regions

Miltefosine has been integrated into public health programs in endemic areas with notable success :

• India elimination programme: Miltefosine played a crucial role in reducing VL incidence significantly over the past two decades. This was reliant on community based distribution and oral dosing enhanced treatment adherence¹³
• Brazil and Latin America: used primarily for cutaneous and mucocutaneous forms through access and efficacy vary¹⁴

Challenges in Real-World use

Despite its benefits, real-world use reveals several challenges:

• Adherence: completing the 28 day course can be difficult to complete, especially without close monitoring. This can be difficult in remote or low-resource settings
• Cost and availability: Although cost-effective compared to hospital-based therapies, miltefosine remains unaffordable for some communities¹⁵
• Resistance development: emerging resistance is a major concern. In India, studies had shown decreasing sensitivity over time which could be due to widespread monotherapy and non-compliance

Side effects and safety profile

Miltefosine is generally well-tolerated but some side effects can limit its use:

• Gastrointestinal effects: Nausea, vomiting and diarrhoea are common especially in the first few days of treatment
• Liver and kidney function: Mild to moderate increases in liver enzymes and kidney makers have been reported in some patients
• Teratogenicity: Miltefosine is contraindicated in pregnancy due to its teratogenic effects. Women of reproductive age are advised to use contraception during and for several months after treatment⁵

Close monitoring and patient education are essential to minimize risks and ensure safety during therapy.

Future direction and alternatives

Combating resistance

To address emerging resistance, combination therapy strategies are being explored, pairing Miltefosine with drugs like paromomycin or liposomal amphotericin B. These combinations may shorten treatment duration and reduce the risk of resistance.¹⁰

Research and development

• New oral compound and lipid formulations: are under development to improve absorption and reduce toxicity⁶
• Biomarkers are being investigated for treatment and treatment responses are also being investigated

Vaccines and vector control

While miltefosine remains a key therapeutic option, integrated control strategies including vector control and vaccine development are important for long-term elimination goals.

Miltefosine is the most effective when integrated with other control strategies such as:

• Vector control through insecticide-treated nets and indoor residual spraying
• Vaccine development efforts in endemic countries⁴

Summary

Miltefosine has revolutionized the treatment landscape for leishmaniasis, offering an effective oral alternative to traditional therapies. Its inclusion in global and national treatment guidelines underscores its value. However, challenges such as resistance, cost, and side effects require ongoing attention.

In the context of global efforts to eliminate leishmaniasis, Miltefosine remains a critical tool, particularly in resource-limited settings. Continued research, policy support, and community engagement are essential to sustain its effectiveness and broaden its impact.