This review will focus on the use of LAMB to treat VL. summarizes regimens involving LAMB for the treatment of VL, some of which have only been developed in the last 5 – 6 years. Data on the use of LAMB for other forms of leishmaniasis (CL, MCL and PKDL) are scarce and summarized in the .
Potential regimens of LAMB that have been developed for use against VL*.
Review of LAMB treatment for cutaneous, mucosal and post-kala azar leishmaniasis as leishmaniasis also refer back to cutaneous and mucosal.
A review of the literature was undertaken on PubMed/MEDLINE using the search terms ‘liposomal amphotericin B' and ‘visceral leishmaniasis' (search performed on 10 July 2012). Selection criteria were used to include the following: publications in English only, all clinical trials, observational studies (including cohort studies and case series) including over 10 patients. Of the 263 articles revealed in the original search, 27 studies and clinical trials were included. These studies are summarized in descending chronological order in
. The design and quality of the studies varied, and included two Phase III, nine dosing/Phase II and four other clinical trials, as well as eight retrospective and four prospective observational studies. Of the 27 studies, 25 were performed using the AmBisome™
formulation, and two using the Fungisome™
formulation (a generic LAMB formulation manufactured by Lifecare in India).
Summary of studies and clinical trials on LAMB use for VL.
Of note is that studies using non-liposomal lipid formulations of amphotericin B are not included in . Comparative studies report that different types of lipid amphotericin B formulations have proved to be superior to conventional amphotericin B formulation with higher drug concentrations in the liver and spleen and lower concentrations in kidneys and lungs, thus enhancing its efficacy and decreasing its toxicity 
. Nevertheless, LAMB has a better safety profile compared with lipid formulations [1,38]
Over the last 20 years, studies have focused on several areas of development. Initial studies (those published between 1994 and 1998) were early pivotal studies. Some of them were used for a New Drug Application (NDA) to the United States Food and Drug Administration (US FDA) [12,16]
. This led to the registration of AmBisome in 1997 for treatment of VL, as well as for use as empirical therapy for presumed fungal infections in febrile neutropenic patients, and treatment of patients with systemic fungal infections refractory to conventional amphotericin B 
. A critical finding in these early studies was that there appeared to be different dose requirements for LAMB in different endemic regions, with South Asia (India) requiring lower doses than Europe (Mediterranean), Latin America (Brazil) or East Africa (Sudan, Kenya) 
The next group of studies, those published between 1998 and 2005, focused on Phase II dose optimization studies, mainly in the Mediterranean region of Europe and India. The studies in Europe included separate groups of children (the traditional patient population of L. infantum
) and immunocompromised/HIV+ adults. These observational studies confirmed earlier studies showing that total doses of 18 – 20 mg/kg appeared effective, at least in non-immunocompromised individuals [14,18,23,35]
. However, longer-term outcomes of HIV co-infected individuals appeared to be poor. Recent use in high-dose monotherapy in HIV-positive VL patients in East Africa has shown similar poor outcomes 
. The second group of studies, conducted mainly in South Asia, were driven by the considerable interest in developing low-dose or single-dose regimens of LAMB, given the profile of the drug formulation: on the one hand safe and highly efficacious, and on the other, relatively complex to administer and extremely expensive (the WHO-negotiated price of AmBisome for treatment of VL was as high as US$50 per vial at that time) 
. These studies confirmed the results of the early Phase II clinical trial by Berman et al.
and demonstrated high efficacy (over 90%) with a dose as low as 5 mg/kg, as well as the feasibility and safety of use in high single doses [29,30,36]
Since 2005, two interesting strategies have been investigated, the first of which relied on developing combination treatments using LAMB (specifically AmBisome) together with other anti-leishmanial drugs. In India, trials were supported by both TDR and DNDi.
Phase II and III trials demonstrated extremely high efficacy of low-dose, short-course regimens involving only a single dose of LAMB [5,33,34]
. This led to the evaluation of LAMB combination regimens in both Africa and Latin America, where trials are still ongoing (in co-administration with MF and MA, respectively) [42,43]
The second strategy looked into the use of single-dose LAMB, specifically for the South Asia focus. A pivotal Phase III trial published in 2010 by Sundar et al.
demonstrated high efficacy (> 95%) and safety of a single 10 mg/kg dose of LAMB 
. This prompted the WHO expert committee on the control of leishmaniasis to recommend the regimen as first-line treatment for VL in South Asia that same year 
. Of additional interest, a trial in East Africa (Sudan and Ethiopia) involving single doses of LAMB (AmBisome) has recently been terminated 
. Results are due to be published soon; however, other recent data confirmed early findings that high doses of LAMB were required to achieve definitive cure (6 months) rates of even 90% [22,26]
It is difficult to predict if use of LAMB in single dose may increase the risk of drug resistance, as has occurred with SSG in India (where short course treatments of the drug were used). The mode of action of amphotericin B on membrane ergosterol is such that an organism would have to undergo significant changes in order to become resistant. Moreover, it is likely that the LAMB single-dose regimen will improve compliance and therefore reduce the risk of underdosing. There is evidence that resistance may not be easily generated in practice as was shown in a small study of 10 HIV-VL co-infected patients who were exposed to long-term treatment of LAMB, with no changes in drug susceptibility of the patient parasite isolates 
. By contrast, an earlier study has demonstrated a reduction in amphotericin B susceptibility (IC90
) in promastigote and intracellular amastigote forms of Leishmania
sp. in immunocompromised patients treated with a lipidic emulsion of amphotericin B 
. In addition, the recent exploration and in vitro
elaboration of mechanisms of L. donovani
resistance to amphotericin B suggest that there are indeed pathways to resistance