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      Current challenges in treatment options for visceral leishmaniasis in India: a public health perspective

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          Abstract

          Visceral leishmaniasis (VL) is a serious parasitic disease causing considerable mortality and major disability in the Indian subcontinent. It is most neglected tropical disease, particularly in terms of new drug development for the lack of financial returns. An elimination campaign has been running in India since 2005 that aim to reduce the incidence of VL to below 1 per 10,000 people at sub-district level. One of the major components in this endeavor is reducing transmission through early case detection followed by complete treatment. Substantial progress has been made during the recent years in the area of VL treatment, and the VL elimination initiatives have already saved many lives by deploying them effectively in the endemic areas. However, many challenges remain to be overcome including availability of drugs, cost of treatment (drugs and hospitalization), efficacy, adverse effects, and growing parasite resistance. Therefore, better emphasis on implementation research is urgently needed to determine how best to deliver existing interventions with available anti-leishmanial drugs. It is essential that the new treatment options become truly accessible, not simply available in endemic areas so that they may promote healing and save lives. In this review, we highlight the recent advancement and challenges in current treatment options for VL in disease endemic area, and discuss the possible strategies to improve the therapeutic outcome.

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          The online version of this article (doi:10.1186/s40249-016-0112-2) contains supplementary material, which is available to authorized users.

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          Most cited references140

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          Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis.

          Miltefosine is an alkylphosphocholine drug with demonstrated activity against various parasite species and cancer cells as well as some pathogenic bacteria and fungi. For 10 years it has been licensed in India for the treatment of visceral leishmaniasis (VL), a fatal neglected parasitic disease. It is the first and still the only oral drug that can be used to treat VL and cutaneous leishmaniasis (CL). The standard 28 day miltefosine monotherapy regimen is well tolerated, except for mild gastrointestinal side effects, although its teratogenic potential severely hampers its general use in the clinic and roll-out in national elimination programmes. The pharmacokinetics of miltefosine are mainly characterized by its long residence time in the body, resulting in extensive drug accumulation during treatment and long elimination half-lives. At the moment, different combination therapy strategies encompassing miltefosine are being tested in multiple controlled clinical trials in various geographical areas of endemicity, both in South Asia and East Africa. We here review the most salient pre-clinical and clinical pharmacological aspects of miltefosine, its mechanism of action against Leishmania parasites and other pathogens, and provide a systematic overview of the efficacy and safety data from all clinical trials of miltefosine, either alone or in combination, in the treatment of VL and CL.
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            Oral miltefosine for Indian visceral leishmaniasis.

            There are 500,000 cases per year of visceral leishmaniasis, which occurs primarily in the Indian subcontinent. Almost all untreated patients die, and all the effective agents have been parenteral. Miltefosine is an oral agent that has been shown in small numbers of patients to have a favorable therapeutic index for Indian visceral leishmaniasis. We performed a clinical trial in India comparing miltefosine with the most effective standard treatment, amphotericin B. The study was a randomized, open-label comparison, in which 299 patients 12 years of age or older received orally administered miltefosine (50 or 100 mg [approximately 2.5 mg per kilogram of body weight] daily for 28 days) and 99 patients received intravenously administered amphotericin B (1 mg per kilogram every other day for a total of 15 injections). The groups were well matched in terms of age, weight, proportion with previous failure of treatment for leishmaniasis, parasitologic grade of splenic aspirate, and splenomegaly. At the end of treatment, splenic aspirates were obtained from 293 patients in the miltefosine group and 98 patients in the amphotericin B group. No parasites were identified, for an initial cure rate of 100 percent. By six months after the completion of treatment, 282 of the 299 patients in the miltefosine group (94 percent [95 percent confidence interval, 91 to 97]) and 96 of the 99 patients in the amphotericin B group (97 percent) had not had a relapse; these patients were classified as cured. Vomiting and diarrhea, generally lasting one to two days, occurred in 38 percent and 20 percent of the patients in the miltefosine group, respectively. Oral miltefosine is an effective and safe treatment for Indian visceral leishmaniasis. Miltefosine may be particularly advantageous because it can be administered orally. It may also be helpful in regions where parasites are resistant to current agents. Copyright 2002 Massachusetts Medical Society
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              Single-dose liposomal amphotericin B for visceral leishmaniasis in India.

              Some 50% of patients with visceral leishmaniasis (kala-azar) worldwide live in the Indian state of Bihar. Liposomal amphotericin B is an effective treatment when administered in short courses. We wanted to determine whether the efficacy of a single infusion of liposomal amphotericin B was inferior to conventional parenteral therapy, consisting of 15 alternate-day infusions of amphotericin B deoxycholate. In this open-label study, we randomly assigned 412 patients in a 3:1 ratio to receive either liposomal amphotericin B (liposomal-therapy group) or amphotericin B deoxycholate (conventional-therapy group). Liposomal amphotericin B (at a dose of 10 mg per kilogram of body weight) was given once, and patients were discharged home 24 hours later. Amphotericin B deoxycholate, which was administered in 15 infusions of 1 mg per kilogram, was given every other day during a 29-day hospitalization. We determined the cure rate 6 months after treatment. A total of 410 patients--304 of 304 patients (100%) in the liposomal-therapy group and 106 of 108 patients (98%) in the conventional-therapy group--had apparent cure responses at day 30. Cure rates at 6 months were similar in the two groups: 95.7% (95% confidence interval [CI], 93.4 to 97.9) in the liposomal-therapy group and 96.3% (95% CI, 92.6 to 99.9) in the conventional-therapy group. Adverse events in the liposomal-therapy group were infusion-related fever or rigors (in 40%) and increased anemia or thrombocytopenia (in 2%); such events in the conventional-therapy group were fever or rigors (in 64%), increased anemia (in 19%), and hypokalemia (in 2%). Nephrotoxicity or hepatotoxicity developed in no more than 1% of patients in each group. A single infusion of liposomal amphotericin B was not inferior to and was less expensive than conventional therapy with amphotericin B deoxycholate. (ClinicalTrials.gov number, NCT00628719.) 2010 Massachusetts Medical Society
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                Author and article information

                Contributors
                opbhu07@gmail.com
                bhavanasonali9@gmail.com
                tapadar@gmail.com
                drshyamsundar@hotmail.com
                Journal
                Infect Dis Poverty
                Infect Dis Poverty
                Infectious Diseases of Poverty
                BioMed Central (London )
                2049-9957
                8 March 2016
                8 March 2016
                2016
                : 5
                : 19
                Affiliations
                Infectious Disease Research Laboratory, Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
                Article
                112
                10.1186/s40249-016-0112-2
                4782357
                26951132
                c8730914-3aed-426f-916f-f3aff580d779
                © Singh et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 2 November 2015
                : 2 March 2016
                Funding
                Funded by: National Institute of Allergy and Infectious Disease (NIAID), National Institute of Health
                Award ID: P50AI074321
                Award Recipient :
                Categories
                Scoping Review
                Custom metadata
                © The Author(s) 2016

                visceral leishmaniasis,treatment,drug resistance,multidrug therapy

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