Treatment failure in leishmaniasis: drug-resistance or another (epi-) phenotype?

Abstract

Two major leishmaniasis treatments have shown a significant decrease in effectiveness in the last few decades, mostly in the Indian subcontinent but also in other endemic areas. Drug resistance of Leishmania correlated only partially to treatment failure (TF) of pentavalent antimonials, and has so far proved not to be important for the increased miltefosine relapse rates observed in the Indian subcontinent. While other patient- or drug-related factors could also have played a role, recent studies identified several parasite features such as infectivity and host manipulation skills that might contribute to TF. This perspective aims to discuss how different parasitic features other than drug resistance can contribute to TF of leishmaniasis and how this may vary between different epidemiological contexts.

Keywords::

• drug resistance
• leishmania
• leishmaniasis
• miltefosine
• pentavalent antimonials
• treatment failure

Financial & competing interests disclosure

The authors were supported by funds of the European Commission (Kaladrug-R, FP7-222895), the Belgian Development Cooperation (FA3 II VL control and FA3 project 95502), the Belgian Science Policy Office (TRIT, P7/41), the Flemish Fund for Scientific Research (G.0.B81.12), the Alexander von Humboldt Foundation (CDCH-UCV PI-09-8717-2013/1) and the Universidad Central de Venezuela Council for Research (PG-09-8646-2013/1). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Drug resistance (DR) is commonly considered as the main pathogen-related phenotype that contributes to treatment failure (TF) in the patient.

• In Leishmania donovani, the infectivity of the parasite correlates better with TF in the patient than DR.

• Recent studies indicate that host manipulation skills of the parasite may also contribute to TF.

• Parasite adaptations favoring TF may already be present in the sand fly stage.

• Other parasitic factors unrelated to DR may play a role in TF and should be further explored: localization in preserved niches, quiescence, presence of virus in the parasites.

• Pathogen phenotypes other than DR should also be standardly assessed in TF studies.

• A better insight into how these epiphenotypes evolved under drug pressure is crucial to revise current strategies by which drugs are designed and applied in the field.