Long term failure of miltefosine in the treatment of refractory visceral leishmaniasis in AIDS patients

Abstract

We carried out a retrospective and descriptive study of 4 HIV infected patients with relapsing visceral leishmaniasis (VL) seen at 2 tertiary-care hospitals in Spain during the last 6 y, in whom miltefosine was used as a compassionate use treatment at a dosage of 50 mg b.i.d. Patients had a medium CD4 lymphocyte count of 69 cells/microl and were C stage. All patients received at least 2 different anti-leishmanial drugs and had at least 3 relapses before miltefosine treatment (range 3-7). Three patients were treated with miltefosine at a standard dose of 50 mg b.i.d. for 28 d, and the other during 12 months. Despite an initial symptomatic improvement, miltefosine treatment failed to eradicate the infection in all cases. We conclude that the use of miltefosine alone is not strong enough to cure relapsing VL in HIV-1 controlled infected patients.

Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

“…Of note, it has been long recognized from studies in experimental VL that the efficacy of the antimonial drugs is exquisitely dependent upon host immune function, being modulated by a number of key T cell-derived cytokines (11,14,44). Although amphotericin B is less immune dependent in its mode of action in mice (11), clinical experience in the treatment of VL in HIV-infected patients, using this drug (72) as well as miltefosine (73), suggest that in humans, all antileishmanial drugs in current use probably have some degree of dependency on host immune effector mechanisms, particularly when measured in terms of the frequency of relapse. Hence, we believe that the restoration of immune competence described here could prove beneficial in combination with a variety of established therapeutic modalities.…”

Spread of Vector-borne Diseases and Neglect of Leishmaniasis, Europe

“…Because dogs are never cured parasitologically and given the long half-life of the drug, the lack of European policy might contribute to the emergence of parasites resistant to miltefosine. This resistance could be a problem for European human patients, as miltefosine is being used on a compassionate basis in several European AIDS coinfected patients unresponsive to amphotericin B or pentavalent antimonials (28,29). Furthermore, if dogs infected with miltefosine-resistant strains were to migrate to Latin America, where several countries have registered the drug for human use (currently Colombia, Guatemala, Argentina, Venezuela, Paraguay, Ecuador, and Honduras; 30), the impact might be greater.…”

The putrescine analogue 1,4-diamino-2-butanone affects polyamine synthesis, transport, ultrastructure and intracellular survival in Leishmania amazonensis

“…Nevertheless miltefosine cure rates in mucosal disease range from only 50 % (Soto et al, 2004) to 70 % (Soto & Toledo, 2007), and 58 % in severe clinical forms. In addition, miltefosine is not as rapid as the antimonials (Soto et al, 2008), not effective in HIV-infected patients (Troya et al, 2008) and permits relapses in diffuse cutaneous forms (Zerpa et al, 2007) as well as displaying limited efficacy against Brazilian cutaneous infection (Tuon et al, 2008). Furthermore, the prolonged treatments and half-life of the compound, especially in an oral therapy with variable adherence, may promote resistance (DupouyCamet, 2004;Janvier et al, 2008), and miltefosine-resistant parasites have been readily obtained in vitro (Ouellette et al, 2004).…”