Combination Therapy for Leishmaniases

Abstract

After more than 50 years of antimonial treatment of visceral leishmaniasis (VL), new drugs recently available include miltefosine, paromomycin, and amphotericin-B deoxycholate (Ampho) and its liposomal formulations (LamB). Miltefosine requires 28 days of treatment, is potentially teratogenic, and causes gastrointestinal disturbances. Because of its high cost, side effects, and because patients feel relieved from VL symptoms after a few days of treatment, compliance is low and increased resistance is highly anticipated. Paromomycin is inexpensive, but requires 3 weeks of daily injections with mild or moderate pain that can result in low compliance, and thereby increase the probability of resistance. Strains resistant to miltefosine or paromomycin have already been isolated from patients refractory to monotherapy with these 2 drugs. Ampho is effective if patients can tolerate it, but requires 15 intravenous infusions during 30 days of hospitalization. LamB is highly effective with minimal side effects and can cure more than 95 % of VL patients with a single infusion, but is very expensive. Hence, the Drugs for Neglected Diseases initiative in collaboration with the Indian Medical Research Council and the Kala-azar Medical Research Center initiated studies to assess the safety and efficacy of short-course, 2-drug combination therapies for the treatment of VL in India. The results are better than expected, with high tolerability and higher efficacy than that seen with any monotherapy. In addition to better safety, the duration of treatment is shorter (7–11 days) with the combination of low-dose LamB plus paromomycin or miltefosine than with either drug alone.