Liposomal Amphotericin B drug access for the treatment of leishmaniasis in Brazil.

Abstract

The social and economic impact of leishmaniasis in Brazil is underestimated. The country has a population of 207.5 million; the annual incidence rates of visceral and cutaneous leishmaniasis are 1.58 and 11.86 per 100 000 inhabitants, respectively 1. Overall, 90% of leishmaniasis cases reported from Latin America between 1979 and 2009 occurred in Brazil; 45 402 of the 700 000 cases reported in Brazil were hospitalised 1. By applying a mathematical model, it was recently estimated that by the end of this century, the hospitalisation rate may increase by up to 15%, with a rise in costs of leishmaniasis-related hospitalisations of 57% 2. Low-income persons from endemic areas comprise the majority of individuals diagnosed with leishmaniasis in Brazil, and they are treated by the public health system. Treatment follows the guidelines of the Brazilian Ministry of Health that recommend pentavalent antimony (SbV) as first-line therapy. Amphotericin B deoxycholate (AmB-D) is recommended as the second-line drug, while the liposomal formulation of amphotericin B (L-AmB) is restricted to a few special conditions (e.g. children <1 year and elderly persons) and treating patients who are contraindicated or fail to respond to first- and second-line treatments 3. The use of SbV for the treatment of leishmaniasis has been falling worldwide due to the increase in the number of patients with therapeutic failure or renal and cardiac toxicity 4. AmB-D is significantly more effective than SbV, but it is associated with rates of nephrotoxicity ranging from 30% to 80% 5. Both SbV and AmB-D require intravenous administration, close monitoring and either hospitalisation or daily access to health facilities for 30 days on average. In contrast, the use of high doses of L-AmB formulations (Ambisome and Fungisome) as a very short-term treatment for both cutaneous and visceral leishmaniasis was associated with an insignificant number of serious adverse reactions 6. The cure rates of L-AmB formulations are very high – up to 90% in reported series of treated patients 6, 7. In developing countries such as Brazil, the main obstacle to widening access to L-AmB for the treatment of leishmaniasis is the high cost of the formulation. The use of SbV and AmB-D as initial therapies for leishmaniasis in Brazil is therefore understandable. These treatments are preconised despite disadvantages such as longer treatment time (inpatient or outpatient settings), need for re-treatment, drug switching due to adverse effects, treatment of adverse effects, absence from work and apparent lower effectiveness – all of which improve substantially when patients are treated with L-AmB 8, 9. The superiority of L-AmB in efficacy, safety and time in treating leishmaniasis has raised questions over whether the overall cost of treatment would be lower than SbV or AmB-D if L-AmB were used as first-line treatment. It is thought that a pharmacoeconomic study which takes these measures into account may demonstrate that the total cost of the treatment with L-AmB would be at least equal to that of SbV and AmB-D. Despite a scarcity of studies aiming to answer this question, there is some evidence in the literature to support the use of L-AmB formulations for the initial treatment of leishmaniasis. A pharmacoeconomic analysis in the Indian subcontinent showed that L-AmB used in a cumulative dose of 10 mg/kg was the dominant option of all evaluated treatment schemes 8, 10. However, there is a lack of good-quality comparative clinical studies with reliable economic analysis to support the health authorities in Brazil and other developing countries to change their treatment guidelines for leishmaniasis in favour of an expensive drug 9, 11. Some initiatives aim to expand access to lipid formulations of amphotericin B in the treatment of leishmaniasis. In 2013, the Brazilian government launched an incentive grant to stimulate local production of important medications by official laboratories, of which L-AmB is one 12. Efforts to minimise adverse reactions of amphotericin B deoxycholate are also under evaluation, such as dilution in lipid emulsion. Preliminary studies have shown promising results in reducing the nephrotoxicity, maintenance of efficacy and use of high doses in a single-day treatment schedule, with significantly lower cost than for L-AmB 5, 7. Further pharmacoeconomic studies are warranted to underpin policy changes to improve access to the safest and most effective treatments, allowing better control of endemic tropical diseases in resource-limited countries.