Dermal leishmaniasis is widely distributed throughout Latin America, where Leishmania of the Viannia subgenus predominate. In Colombia, reported cases have almost doubled from 5,000 annually to close to 10,000 in 2003 excluding cases in military personnel. Dermal leishmaniasis in the New World is generally considered a zoonosis. However, changing demographic patterns have led to the "domestication" of transmission in and around households of settlements in previously undeveloped areas and the periphery of urban centers. This phenomenon has contributed to both a large increase, and a shift in the age distribution of reported cases. Children now constitute a large proportion of cases. The trend of domestication of transmission has been recognized in several areas, among them, the Departments of Huila, Boyaca, Tolima and Narino. Children constitute a high proportion of cases and have been shown to have a poor response to treatment with pentavalent antimonial drugs. In new and especially in old areas of transmission, recurrent disease among previously infected inhabitants is an important cause of new incident disease. Therefore control measures must address the human host response and more effective treatment, as well as vector targeted interventions. The projects in this research program will address three current problems of human dermal leishmaniasis in Colombia and the region: 1) The lack of an effective treatment in children;2) The domestication of transmission and the need for effective intervention measures;3) Persistent infection, chronic and recurrent disease, and the limited understanding of the role of host response in these manifestations. To achieve these goals, the program will draw together the strengths in public health, epidemiology, leishmaniasis, vector biology, and immunology of individuals from the State Health Service of Tolima, the Institute Nacional de Salud (Bogata), Centro Internacional de Entrenamiento e Investigaciones Medicas (CIDEIM) and Yale University School of Medicine. PROJECT 1: Miltefosine in Pediatric Cutaneous Leishmaniasis (McMahon-Pratt, D.) PROJECT 1 DESCRIPTION (provided by applicant): This multicenter clinical trial will be conducted in Colombia, under the Centro Internacional de Entrenamiento e Investigaciones Medicas (CIDEIM) coordination in collaboration with Lyda Osorio, MD, PhD, as Project 1 of the ICIDR program. This study will compare the efficacy and tolerability of the new oral drug, miltefosine with the standard drug therapy, Glucantime in children with cutaneous leishmaniasis (CL) caused by Leishmania of the Viannia subgenus. Pentavalent antimonials have been the standard treatment for CL for more than 50 years in spite of its parenteral use, high toxicity, and relative high costs. On the other hand, children constitute a highly vulnerable population since more than 23% of the cases in the major Colombian endemic regions are patients under 12 years of age. Children also have a lower response to antimonial treatment explained by the different pharmacokinetic behaviour in these ages, where approximately half of the exposure to the drug is observed as a result of having twice the clearance rate as compared to adults. These data, along with the different immune response, make children below 12 years a population at high risk of treatment failure, increased morbidity, aesthetically deleterious scars or mucosal involvement. One hundred and twenty children below 12 years will be enrolled. Half of the randomized patients will receive Glucantime 20 mg/kg/day for 20 days (standard treatment), and the other half will receive miltefosine 2.5 mg/kg/day for 28 days. A 60% efficacy of antimonials and 90% efficacy of miltefosine is expected. Clinical response will be assessed at the end of the treatment, and at 13 and 26 weeks. Also the presence of adverse events will be identified by clinical and laboratory examination. Ethical approval from the Institutional Review Boards at CIDEIM and other participating institutions will be obtained. The availability of an efficacious, tolerable, orally administrable treatment for dermal leishmaniasis would revolutionize the treatment and perhaps even the prevention of this disease.
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