A Study for Safety and Efficacy of Miltefosine for Treatment of Children and Adolescents With Post-Kala-azar Dermal Leishmaniasis (PKDL) in Bangladesh and Association of Serum Vitamin E and Exposure to Arsenic With PKDL

Background:

Visceral leishmaniasis also known as kala-azar is a neglected tropical disease affecting the poorest of the poor living in the rural areas of Bangladesh, Nepal, India, South Sudan, Sudan and Brazil with an annual incidence of 500,000 new cases with 10% mortality. Since 2008, the first oral drug Miltefosine (MF) has been introduced for the treatment of VL in Bangladesh, India and Nepal as part of the National VL / Kala-azar (KA) Elimination Program (NKEP) in these three countries. The duration of treatment is 28 days at a dose of 100 mg / day or 50 mg / day for adult with body weight ≥25 KG and< 25 Kg respectively. For children, it is ≤ 2 mg/Kg/24h. The efficacy of MF for VL is 87%, but we have observed that 15% of those develop Post-kala-azar Dermal (PKDL) Leishmaniasis with an annual incidence of about 300 cases, mostly in the Mymensingh district of Bangladesh (the most VL endemic district in the country). The clinical manifestation of PKDL is macular/papular/nodular /mixed lesions. Children and adolescents with PKDL are otherwise clinically healthy, but these patients continue to carry the parasites for years and can transmit the parasites to others through sand fly bite. In this way these patients play a role as inter-epidemic reservoirs and can initiate new outbreaks of VL in the community. The only current treatment option is 120 injections with SSG (one injection per day for 20 consecutive days in a month for 6 months). Injections are very painful and associated with risks including sudden heart failure from cardiac arrhythmias and death. Therefore, PKDL patients usually do not seek treatment and the compliance is very low, when they take treatment with SSG. Thus, a safe and effective treatment which can ensure better compliance is urgently needed. Recent studies in India showed that 12 weeks treatment with MF of adult PKDL patients is effective (94%) and safe. However, the study reported only 24 adult PKDL cases. Similar results have been observing with adult PKDL patients in Nepal. There is no information about the safety and efficacy of 12 weeks MF treatment of children with PKDL and about pharmacokinetics of MF among these children. It is established that exposure to MF in VL children was less to oral MF at conventional dose of 2.5mg/Kg/day, thus allometric dosing of MF is now recommended by experts. A study is therefore urgently needed for efficacy and safety of allometric daily dose of MF for 12 weeks for treatment of PKDL in children.

Risk factors for PKDL are poorly investigated. Younger age of VL patients and genetic susceptibility to PKDL are found to contribute to PKDL. Exposure to arsenic through drinking water and protein-energy malnutrition are public health problem in Bangladesh. Both arsenic and vitamin E and other nutrients deficiency may contribute to PKDL directly or in combination, because they inhibit innate and adaptive immunity to infections.

Hypothesis(es) and Aims:

1. Oral treatment with Miltefosine in children with PKDL at allometric daily dose for 12 weeks is safe with a cure rate of ≥95%; 2. Development of PKDL in children and adolescent is genetically predisposed and is associated with IL-10 & IFN-gamma gene polymorphism causing high serum level of IL-10 and low serum level of IFN-gamma; 3. Nutritional & environmental factors such as low serum vitamin E & arsenic exposure are associated with PKDL .