A pilot study evaluating the tolerability and effectiveness of miltefosine and sodium stibogluconate for the treatment of cutaneous leishmaniasis in Kandahar, Afghanistan.

BACKGROUND: Oral miltefosine (MF) achieves per-protocol cure rates of 68-77% against Leishmania tropica in Iran and Pakistan, but it has never been compared with the standard of care in Afghanistan, where only intralesional (IL) or intramuscular (IM) antimonials are used. We, therefore, assessed the 6-month efficacy and tolerability of sodium stibogluconate (SSG) and MF, including MF pharmacokinetics, in L. tropica-predominant Kandahar city.

METHODS: This single-centre, open-label, pilot trial randomised patients aged ≥5 years to either SSG or 28-day, partially supervised MF that was allometrically scaled from the adult dose of 2.5 mg/kg/day. For the SSG group, patients were treated with either IL-SSG ×1/week ×5 doses or IM-SSG 20 mg/kg/day x20d for IL-inaccessible lesions. All children < 5 years received MF in an observational arm. Epithelialisation of ulcerated lesions or return to normal skin for other lesions, with resolution of signs of acute inflammation, defined cure.

RESULTS: Of 103 recruited patients (65 males), 15 were randomised to IL-SSG, 27 to IM-SSG, and 37 to MF; 24 under-5 s received MF. Respective median (interquartile range) ages were: 11.9 (7.2-13.8), 9.9 (8.2-15.1), 10 (7.8-12.5) and 4.3 (2.9-4.9) years. A total of 113/191 (59.2%) lesions were located on the face. 66 patients completed the 6-month follow-up. Combining the MF groups, the Kaplan-Meier cure rates (95% confidence intervals) were MF 25.3 (14.7‒40.9)%, IL-SSG 65.0 (36.0‒91.5)% (p=0.019 vs. MF), and IM-SSG 77.3 (53.7‒94.3)% (p=0.001 vs. MF). Median MF exposures0-180d were similar in failed (629 µg*day/mL) and cured (555 µg*day/mL) patients. 52/61 (85.2%) MF recipients reported mild (n=50)/moderate nausea/vomiting and 35/52 (67.3%) received domperidone. Laboratory adverse events were mostly grade 1 ALT(n=19)/AST(n=36) increases in the IM-SSG and MF arms. Transient stage 1/2 acute kidney injury affected 11/24 (45.8%) under-5 s vs. 5/37 (13.5%) ≥5 years MF patients (p=0.007).

CONCLUSIONS: SSG was effective by both routes, but partially supervised MF was ineffective. More work is needed to determine factors affecting MF effectiveness against L. tropica in Kandahar. Clinical trial number The clinical trial number is TCTR20180710007, dated 10/07/2018.