Recent Development of Visceral Leishmaniasis Treatments: Successes, Pitfalls, and Perspectives

Abstract

SUMMARYResearch in visceral leishmaniasis in the last decade has been focused on how better to use the existing medicines as monotherapy or in combination. Systematic research by geographical regions has shown that a universal treatment is far from today's reality. Substantial progress has been made in the elimination of kala-azar in South Asia, with a clear strategy on first- and second-line therapy options of single-dose liposomal amphotericin B and a combination of paromomycin and miltefosine, respectively, among other interventions. In Eastern Africa, sodium stibogluconate (SSG) and paromomycin in combination offer an advantage compared to the previous SSG monotherapy, although not exempted of limitations, as this therapy requires 17 days of painful double injections and bears the risk of SSG-related cardiotoxicity. In this region, attempts to improve the combination therapy have been unsuccessful. However, pharmacokinetic studies have led to a better understanding of underlying mechanisms, like the underexposure of children to miltefosine treatment, and an improved regimen using an allometric dosage. Given this global scenario of progress and pitfalls, we here review what steps need to be taken with existing medicines and highlight the urgent need for oral drugs. Furthermore, it should be noted that six candidates belonging to five new chemical classes are reaching phase I, ensuring an optimistic near future.

Eliminating visceral leishmaniasis in South Asia: the road ahead

“…The current drug regimens, while allowing progress towards eliminating kala-azar, will probably be inadequate for the post-elimination phase. 25 Based on WHO recommendations, the kala-azar elimination programme replaced miltefosine with a single dose infusion of liposomal amphotericin B (AmBisome) as first line treatment in 2013. AmBisome has shown greater efficacy and improved compliance, but it requires a strict cold chain.…”

Visceral leishmaniasis: a global overview

“…Overall, the development of VL treatments globally has had successes but also many pitfalls. 105,106…”

“…127 In 2003 the Drugs for Neglected Disease Initiative (DNDi) organized a network of stakeholders bringing together Ethiopia, Kenya, Sudan and Uganda together to create the Leishmaniasis East Africa Platform (LEAP). 128 The main work of the group has been, in furtherance of DNDi's mission which is, as the name suggests, to develop better treatment for NTDs, 106,129 A powerful approach to address VL, especially in the sub-Saharan Africa region with highest burden of infectious diseases, is to use integrated interventions. One study has assessed the integration landscape in 25 countries from all NTDs endemic region.…”

“…157 Although not reportedly a widespread problem, resistance of the parasite to antimonials as well Miltefosine and AmB has been reported in parts of India reducing treatment outcomes. 4,158 Such a concern led to a call for development of a policy to monitor drug resistance, 159 and needs for pharmacovigilance 92,106 as well as continued drug development. 5,106,128…”

“…4,158 Such a concern led to a call for development of a policy to monitor drug resistance, 159 and needs for pharmacovigilance 92,106 as well as continued drug development. 5,106,128…”