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      Drug resistance and treatment failure in leishmaniasis: A 21st century challenge

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          Abstract

          Reevaluation of treatment guidelines for Old and New World leishmaniasis is urgently needed on a global basis because treatment failure is an increasing problem. Drug resistance is a fundamental determinant of treatment failure, although other factors also contribute to this phenomenon, including the global HIV/AIDS epidemic with its accompanying impact on the immune system. Pentavalent antimonials have been used successfully worldwide for the treatment of leishmaniasis since the first half of the 20th century, but the last 10 to 20 years have witnessed an increase in clinical resistance, e.g., in North Bihar in India. In this review, we discuss the meaning of “resistance” related to leishmaniasis and discuss its molecular epidemiology, particularly for Leishmania donovani that causes visceral leishmaniasis. We also discuss how resistance can affect drug combination therapies. Molecular mechanisms known to contribute to resistance to antimonials, amphotericin B, and miltefosine are also outlined.

          Author summary

          Chemotherapy is central to the control and management of leishmaniasis. Antimonials remain the primary drugs against different forms of leishmaniasis in several regions. However, resistance to antimony has necessitated the use of alternative medications, especially in the Indian subcontinent (ISC). Compounds, notably the orally available miltefosine (MIL), parenteral paromomycin, and amphotericin B (AmB), are increasingly used to treat leishmaniasis. Although treatment failure (TF) has been observed in patients treated with most anti-leishmanials, its frequency of appearance may be important in patients treated with MIL, which has replaced antimonials within the kala-azar elimination program in the ISC. AmB is highly efficacious, and the associated toxic effects—when administered in its free deoxycholate form—are somewhat ameliorated in its liposomal formulation. Regrettably, laboratory experimentation has demonstrated a risk of resistance towards AmB as well. The rise of drug resistance impacts treatment outcome, and understanding its causes, spread, and impact will help us manage the risks it imposes. Here, we review the problem of TF in leishmaniasis and the contribution of drug resistance to the problem. Molecular mechanisms causing resistance to anti-leishmanials are discussed along with the appropriate use of additional available drugs, as well as the urgent need to consolidate strategies to monitor drug efficacy, epidemiological surveillance, and local policies. Coordination of these activities in national and international programs against leishmaniasis might represent a successful guide to further research and prevention activities.

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          Most cited references 124

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          The relationship between leishmaniasis and AIDS: the second 10 years.

          To date, most Leishmania and human immunodeficiency virus (HIV) coinfection cases reported to WHO come from Southern Europe. Up to the year 2001, nearly 2,000 cases of coinfection were identified, of which 90% were from Spain, Italy, France, and Portugal. However, these figures are misleading because they do not account for the large proportion of cases in many African and Asian countries that are missed due to a lack of diagnostic facilities and poor reporting systems. Most cases of coinfection in the Americas are reported in Brazil, where the incidence of leishmaniasis has spread in recent years due to overlap with major areas of HIV transmission. In some areas of Africa, the number of coinfection cases has increased dramatically due to social phenomena such as mass migration and wars. In northwest Ethiopia, up to 30% of all visceral leishmaniasis patients are also infected with HIV. In Asia, coinfections are increasingly being reported in India, which also has the highest global burden of leishmaniasis and a high rate of resistance to antimonial drugs. Based on the previous experience of 20 years of coinfection in Europe, this review focuses on the management of Leishmania-HIV-coinfected patients in low-income countries where leishmaniasis is endemic.
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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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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                14 December 2017
                December 2017
                : 11
                : 12
                Affiliations
                [1 ] Department of Physiological Sciences, Laboratory of Molecular Physiology, Institute of Experimental Medicine, Luis Razetti School of Medicine, Universidad Central de Venezuela, Caracas, Venezuela
                [2 ] Department of Biochemistry and Molecular Pharmacology, Instituto de Parasitología y Biomedicina López-Neyra, Spanish National Research Council (IPBLN-CSIC), Granada, Spain
                [3 ] Molecular Parasitology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
                [4 ] Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
                [5 ] Department of Infectious Diseases, National Referral Unit for Tropical Diseases, Ramón y Cajal University Hospital, Madrid, Spain
                [6 ] Department of Biomedical Sciences, School of Veterinary Medicine, University of Zambia, Lusaka, Zambia
                [7 ] Research Center in Infectious Diseases, CHU de Quebec Research Center and Department of Microbiology-Infectious Disease and Immunology, University Laval, Quebec, Canada
                University of Antwerp, BELGIUM
                Author notes

                The authors have declared that no competing interests exist.

                Article
                PNTD-D-17-01203
                10.1371/journal.pntd.0006052
                5730103
                29240765
                © 2017 Ponte-Sucre et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 2, Tables: 0, Pages: 24
                Product
                Funding
                Research reported in this publication was supported by the Canadian Institutes of Health Research operating grant MOP-12182 awarded to BP; the Spanish Grant Proyecto de Excelencia, Junta de Andalucía Ref. CTS-7282 awarded to FG; the Spanish Grant SAF2015-68042-R awarded to FG; the Wellcome Trust (104111/Z/14/Z) awarded to MPB; and the Alexander von Humboldt Foundation, Germany awarded to APS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Review
                Biology and Life Sciences
                Organisms
                Eukaryota
                Protozoans
                Parasitic Protozoans
                Leishmania
                Medicine and Health Sciences
                Tropical Diseases
                Neglected Tropical Diseases
                Leishmaniasis
                Medicine and Health Sciences
                Parasitic Diseases
                Protozoan Infections
                Leishmaniasis
                Medicine and Health Sciences
                Infectious Diseases
                Zoonoses
                Leishmaniasis
                Medicine and Health Sciences
                Parasitic Diseases
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Biology and Life Sciences
                Organisms
                Eukaryota
                Protozoans
                Parasitic Protozoans
                Leishmania
                Leishmania Donovani
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobial Resistance
                Medicine and Health Sciences
                Pharmacology
                Antimicrobial Resistance
                Physical Sciences
                Chemistry
                Chemical Elements
                Antimony
                Medicine and Health Sciences
                Epidemiology
                Molecular Epidemiology

                Infectious disease & Microbiology

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