Drug resistance and treatment failure in leishmaniasis: A 21st century challenge

Abstract

Reevaluation of treatment guidelines for Old and New World leishmaniasis is urgently needed on a global basis because treatment failure is an increasing problem. Drug resistance is a fundamental determinant of treatment failure, although other factors also contribute to this phenomenon, including the global HIV/AIDS epidemic with its accompanying impact on the immune system. Pentavalent antimonials have been used successfully worldwide for the treatment of leishmaniasis since the first half of the 20th century, but the last 10 to 20 years have witnessed an increase in clinical resistance, e.g., in North Bihar in India. In this review, we discuss the meaning of “resistance” related to leishmaniasis and discuss its molecular epidemiology, particularly for Leishmania donovani that causes visceral leishmaniasis. We also discuss how resistance can affect drug combination therapies. Molecular mechanisms known to contribute to resistance to antimonials, amphotericin B, and miltefosine are also outlined.

Author summary

Chemotherapy is central to the control and management of leishmaniasis. Antimonials remain the primary drugs against different forms of leishmaniasis in several regions. However, resistance to antimony has necessitated the use of alternative medications, especially in the Indian subcontinent (ISC). Compounds, notably the orally available miltefosine (MIL), parenteral paromomycin, and amphotericin B (AmB), are increasingly used to treat leishmaniasis. Although treatment failure (TF) has been observed in patients treated with most anti-leishmanials, its frequency of appearance may be important in patients treated with MIL, which has replaced antimonials within the kala-azar elimination program in the ISC. AmB is highly efficacious, and the associated toxic effects—when administered in its free deoxycholate form—are somewhat ameliorated in its liposomal formulation. Regrettably, laboratory experimentation has demonstrated a risk of resistance towards AmB as well. The rise of drug resistance impacts treatment outcome, and understanding its causes, spread, and impact will help us manage the risks it imposes. Here, we review the problem of TF in leishmaniasis and the contribution of drug resistance to the problem. Molecular mechanisms causing resistance to anti-leishmanials are discussed along with the appropriate use of additional available drugs, as well as the urgent need to consolidate strategies to monitor drug efficacy, epidemiological surveillance, and local policies. Coordination of these activities in national and international programs against leishmaniasis might represent a successful guide to further research and prevention activities.