Efficacy of Miltefosine for Bolivian Cutaneous Leishmaniasis

Oral miltefosine (2.5 mg/kg/d for 28 days) was compared with intramuscular antimony (20 mg/kg/d for 20 days) in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis in Palos Blancos, Bolivia. The cure rates with 6 months of follow-up were statistically similar: 36 of 41 evaluable miltefosine patients (88%) versus 15 of 16 (94%) evaluable antimony patients. However, antimony cured more rapidly, because, by 1 month after therapy, 31 of 44 miltefosine patients (70%) compared with 16 of 16 antimony patients (100%) had achieved cure. The two conclusions from this work are that oral miltefosine can be used for cutaneous disease in this part of Bolivia and that miltefosine was more effective for L. braziliensis in this region than for L. braziliensis in Guatemala. Chemotherapy needs to be evaluated in each endemic region, even if the "same" species of Leishmania causes disease in these locales. Cutaneous leishmaniasis is typically treated with the par- enteral product pentavalent antimony. Because the disease generally self-cures in 2-15 months depending on the endemic region in which it was obtained, 1 parenteral therapy is inher- ently unattractive, and the primary chemotherapeutic need is an effective oral or, if appropriate, topical regimen. Miltefos- ine is an oral agent, originally shown to be > 95% curative for Indian visceral leishmaniasis, 2 which underwent evaluation for cutaneous and mucosal disease of the New World. A 91% cure rate for Leishmania panamensis disease in Colombia compared with a 38% cure rate for placebo led to the regis- tration of this drug in Colombia. 3 However, miltefosine was not impressively effective in Guatemala, in which the infect- ing species are L. braziliensis and L. mexicana. In Guatemala, 50% of the miltefosine group were cured compared with 20% of the placebo group, and for patients with documented L. braziliensis disease, only 5 of 15 patients (33%) cured in the miltefosine group compared with 1 of 12 cases (8%) in the placebo group. 3 In contrast, antimony routinely cures > 90% of patients in Guatemala, and it seemed as if miltefosine should not be recommended for L. braziliensis cutaneous disease. The possibility that L. braziliensis in Guatemala is unusual in its low response to miltefosine led us to study miltefosine for Bolivian leishmaniasis, 94% of which is caused by L. bra- ziliensis. 4 We first studied mucosal leishmaniasis. In a single- group trial, the cure rate for miltefosine was similar to that of historic values for antimony. 5 It could be argued, however, that antimony might have been superior had a randomized study been performed, and that at any rate, the mucosal data might not pertain to cutaneous leishmaniasis, which is by far the most prevalent presentation. To directly evaluate the rela- tive efficacy of miltefosine to antimony for L. braziliensis cutaneous disease in this region of Bolivia, we compared the drugs in a randomized study of cutaneous leishmaniasis at the same site at which we had conducted the mucosal trial. Our study patients lived in the same Bolivian provinces of Beni or La Paz from which we recruited mucosal patients 5 and were treated at the community clinic of Palos Blancos. The inclusion/exclusion criteria for this cutaneous study were similar to that used in the Colombian/Guatemalan cutaneous study 3 : a skin ulcer confirmed to be caused by leishmania by ing; either sex; 12 years of age; without mucosal disease or anti-leishmanial therapy for at least 6 months; without signifi- cant concomitant disease by history, physical examination, or blood tests; without pregnancy or lactation. Eighty-one pa- tients were seen at this facility during the time of the trial but not entered because they were too young or it seemed un- likely that they would comply with follow-up. The number of patients and patient allocation (2 miltefos- ine:1 antimony) was chosen based on resource constraints and the desire to provide more patients for the experimental (miltefosine) group. The patients were randomized to open- label treatment with a standard course of oral miltefosine (2.5 mg/kg/d for 28 days; Impavido; Zentaris, Frankfurt-am-Main, Germany) or of intramuscular pentavalent antimony (20 mg/ kg/d for 20 days; glucantime; Aventis, Paris, France) in a 2:1 allocation. Both treatments were observed. Drug-appropriate laboratory tests and symptoms were used to evaluate drug tolerance. For all patients, hemoglobin, white cell count, platelet count, serum glutamic oxaloacetic transaminase (SGOT), and blood urea nitrogen (BUN) were ascertained at the beginning and end of treatment. Miltefosine patients were queried daily during therapy for vomiting, diarrhea, nausea,