Drug resistance in Indian visceral leishmaniasis

Throughout the world, pentavalent antimonial compounds (Sb-v) have been the mainstay of antileishmanial therapy for more than 50 years. Sb-v has been highly effective in the treatment of Indian visceral leishmaniasis (VL: kala-azar) at a tow dose (10 mg/kg) for short durations (6-10 days). But in the early 1980s reports of its ineffectiveness emerged, and the dose of Sb-v was eventually raised to 20 mg/kg for 30-40 days. This regimen cures most patients with VL except in India, where the proportion of patients unresponsive to Sb-v has steadily increased. In hyperendemic districts of north Bihar, 50-65% patients fail treatment with Sb-v. Important reasons are rampant use of subtherapeutic doses, incomplete duration of treatment and substandard drugs. In vitro experiments have established emergence of Sb-v resistant strains of Leishmania donovani, as isolates from unresponsive patients require 3-5 times more Sb-v to reach similarly effectiveness against the parasite as in Sb-v responders. Anthroponotic transmission in India has been an important factor in rapid increase in the Sb-v refractoriness. Pentamidine was the first drug to be used and cured 99% of these refractory patients, but over time even with double the amount of initial doses, it cures only 69-78% patients now and its use has largely been abandoned in India. Despite several disadvantages, amphotericin B is the only drug available for use in these areas and should be used as first-line drug instead of Sb-v. The new oral antileishmanial drug miltefosine is likely to be the first-line drug in future. Unfortunately, development of newer antileishmanial drugs is rare; two promising drugs, aminosidine and sitamaquine, may be developed for use in the treatment of VL. Lipid associated amphotericin B has an excellent safety and efficacy profile, but remains out of reach for most patients because of its high cost.