Treatment failure and drug resistance
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Antimonials such as SSG are still the first-line drugs in many countries worldwide and for all clinical forms of leishmaniasis. Treatment is prolonged, not devoid of adverse side-effects and expensive due to the need for hospitalization. Treatment failure is well documented for SSG. Most alarming reports came from Bihar (India), where over 60% of VL-patients are unresponsive to SSG-treatment, while in Nepal, recent reports indicate an unresponsiveness rate of up to 24% in one district. In the New World, cutaneous leishmaniasis are associated to many Leishmania species and it has been shown that the aetiology of the infection might influence SSG treatment outcome.
In the frame of the Kala-Azar elimination programme in the Indian sub-continent, it has been recently decided to replace SSG by Miltefosine (MIL) as a first line treatment in the region. This alkyl-phosphocholine, originally developed as an anticancer drug, is the first oral drug that has proven to be highly effective against VL, including antimony-resistant cases. This drug will be used in monotherapy, despite (i) a doubling of MIL failure rate from phase III (3%) to phase IV (6%) observed in clinical trials in India, as well as 11 % treatment failures (almost all relapses) recently observed in Nepal and (ii) the danger of rapid emergence of resistance (see below).
Paromomycin (PMM), the latest antileishmanial drug on the market, was approved by the Indian government in August 2006 for the treatment of patients with VL in a phase III trial and appears to be safe, effective, and very cheap. The drug will be used soon in a large phase IV trial sponsored by the Institute of One World Health.
Amphotericin B (AmB) is generally used as second line drug, except in Bihar, India, where it was used as first line drug; in areas with SSG resistance. There has been no treatment failure reported so far, but it is expensive, requires prolonged hospitalisation, is toxic, and thus requires close monitoring.
Combination therapy was only introduced recently in trials. SSG+PMM, MIL+AmB, PMM+AmB, MIL+PMM represent very attractive candidates, but beneficial effects of these combinations may depend on the background of resistance to each individual drug. There are few other drugs in the drug development pipeline.