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      Potential of Artesunate in the treatment of visceral leishmaniasis in dogs naturally infected by Leishmania infantum: Efficacy evidence from a randomized field trial

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          Abstract

          Leishmaniasis is among the world’s most neglected diseases. Dogs are the main reservoirs/hosts of Leishmania infantum, causative agent of both canine and human visceral leishmaniosis. Canine leishmaniasis (CanL) represents a public health problem as one of the most prevalent zoonotic diseases worldwide. Current therapeutics present drawbacks; thus, there is a need for more effective, safer, and cheaper drugs. The aim of this study was to evaluate and to compare the efficacy of oral administration of artesunate or meglumine antimoniate/allopurinol in dogs with clinical leishmaniasis. Forty-two dogs with naturally occurring clinical leishmaniasis were included in this open-label, simple randomized positive-control clinical field trial with 6 months of follow-up. Dogs received meglumine antimoniate 100 mg/kg/day and allopurinol 30 mg/kg/day for 28 days (control group, n = 26) or artesunate 25 mg/kg/day for 6 days (test group, n = 16). The animals were evaluated for their clinical evolution, parasite load (by qPCR) and humoral response at different time points: 0, 30, 90, and 180 days after treatment. Data analyses showed a significant improvement in both groups in clinical scores, parasitemia and antibody titers after treatment. Compared to the control group, the artesunate group showed significantly lower clinical score (P = 0.0001), lower parasitemia (P = 0.0001) and antibody titers after 6 months of follow-up. Compared to baseline values, a rapid, significant reduction (P < 0.012) in antibody levels, 2.28- versus 3.04-fold for the control versus artesunate groups, respectively, was observed 30 days after treatment. Antibody levels continued to decrease further in the artesunate group, where 58% of cases became seronegative at the 6-month follow-up. All qPCR-positive dogs were negative after treatment with artesunate, while 14.3% remained positive with the appearance of two new cases in the control group. Artesunate was well tolerated, and no side effects were recorded. Treatment failures were similar in both groups with 27.27% (6/22), including 18.18% (4/22) mortality in the control group, versus 26.66% (4/15), including 13.33% (2/15) mortality in the artesunate group. This is the first report showing the potential of artesunate in the treatment of dogs with clinical leishmaniasis. Artesunate showed higher efficacy than the current first-line treatment for CanL without any adverse effects. It could be a good alternative chemotherapy for CanL, and may be considered for further studies in human leishmaniases. Further clinical trials are needed to confirm these findings, to determine if there are relapses after treatment and if dogs remain infective to sandflies, to define the ideal therapeutic dosage and duration of treatment with artesunate.

          Author summary

          Canine leishmaniasis (CanL) is a fatal, zoonotic vector-borne disease caused by Leishmania infantum, a common pathogen for both humans and dogs. Most CanL therapeutics are toxic, expensive, or ineffective. Artemisinin and derivatives have recently demonstrated potent antileishmanial activity in vitro and in experimental models. In this study, dogs with clinical leishmaniasis were randomly included in one of the treatment groups: meglumine antimoniate/allopurinol (control) or artesunate (alternative). Dogs were followed up for 6 months for their clinical score, parasitemia and Leishmania antibody levels. Both groups showed improved clinical scores, parasitemia and antibody titers after treatment. After six months of follow-up, treatment success was very similar in both groups, and 72.73% (16/22) of the controls versus 73.34% (11/15) in the artesunate group had clinical improvement. All dogs initially seropositive by PCR became negative after artesunate treatment, while 14.3% remained positive with the appearance of new cases in the control group. Antibody titers decreased rapidly (from day 30) from baseline especially in the artesunate group, where 58% of the dogs converted to seronegative after 6 months. Artesunate could be a good alternative for treatment of leishmaniasis. Additional clinical trials are needed to obtain more data on this drug.

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          Most cited references68

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          Leishmaniasis Worldwide and Global Estimates of Its Incidence

          As part of a World Health Organization-led effort to update the empirical evidence base for the leishmaniases, national experts provided leishmaniasis case data for the last 5 years and information regarding treatment and control in their respective countries and a comprehensive literature review was conducted covering publications on leishmaniasis in 98 countries and three territories (see ‘Leishmaniasis Country Profiles Text S1, S2, S3, S4, S5, S6, S7, S8, S9, S10, S11, S12, S13, S14, S15, S16, S17, S18, S19, S20, S21, S22, S23, S24, S25, S26, S27, S28, S29, S30, S31, S32, S33, S34, S35, S36, S37, S38, S39, S40, S41, S42, S43, S44, S45, S46, S47, S48, S49, S50, S51, S52, S53, S54, S55, S56, S57, S58, S59, S60, S61, S62, S63, S64, S65, S66, S67, S68, S69, S70, S71, S72, S73, S74, S75, S76, S77, S78, S79, S80, S81, S82, S83, S84, S85, S86, S87, S88, S89, S90, S91, S92, S93, S94, S95, S96, S97, S98, S99, S100, S101’). Additional information was collated during meetings conducted at WHO regional level between 2007 and 2011. Two questionnaires regarding epidemiology and drug access were completed by experts and national program managers. Visceral and cutaneous leishmaniasis incidence ranges were estimated by country and epidemiological region based on reported incidence, underreporting rates if available, and the judgment of national and international experts. Based on these estimates, approximately 0.2 to 0.4 cases and 0.7 to 1.2 million VL and CL cases, respectively, occur each year. More than 90% of global VL cases occur in six countries: India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil. Cutaneous leishmaniasis is more widely distributed, with about one-third of cases occurring in each of three epidemiological regions, the Americas, the Mediterranean basin, and western Asia from the Middle East to Central Asia. The ten countries with the highest estimated case counts, Afghanistan, Algeria, Colombia, Brazil, Iran, Syria, Ethiopia, North Sudan, Costa Rica and Peru, together account for 70 to 75% of global estimated CL incidence. Mortality data were extremely sparse and generally represent hospital-based deaths only. Using an overall case-fatality rate of 10%, we reach a tentative estimate of 20,000 to 40,000 leishmaniasis deaths per year. Although the information is very poor in a number of countries, this is the first in-depth exercise to better estimate the real impact of leishmaniasis. These data should help to define control strategies and reinforce leishmaniasis advocacy.
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            LeishVet guidelines for the practical management of canine leishmaniosis

            The LeishVet group has formed recommendations designed primarily to help the veterinary clinician in the management of canine leishmaniosis. The complexity of this zoonotic infection and the wide range of its clinical manifestations, from inapparent infection to severe disease, make the management of canine leishmaniosis challenging. The recommendations were constructed by combining a comprehensive review of evidence-based studies, extensive clinical experience and critical consensus opinion discussions. The guidelines presented here in a short version with graphical topic displays suggest standardized and rational approaches to the diagnosis, treatment, follow-up, control and prevention of canine leishmaniosis. A staging system that divides the disease into four stages is aimed at assisting the clinician in determining the appropriate therapy, forecasting prognosis, and implementing follow-up steps required for the management of the leishmaniosis patient.
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              Directions for the diagnosis, clinical staging, treatment and prevention of canine leishmaniosis.

              Canine leishmaniosis (CanL) due to Leishmania infantum is a life threatening zoonotic disease with a wide distribution in four continents and importance also in non-endemic regions. The purpose of this report is to present a consensus of opinions on the diagnosis, treatment, prognosis and prevention of CanL in order to standardize the management of this infection. CanL is a disease in which infection does not equal clinical illness due to the high prevalence of subclinical infection among endemic canine populations. The most useful diagnostic approaches include serology by quantitative techniques and PCR. High antibody levels are associated with severe parasitism and disease and are diagnostic of clinical leishmaniosis. However, the presence of lower antibody levels is not necessarily indicative of disease and further work-up is necessary to confirm CanL by other diagnostic methods such as cytology, histopathology and PCR. We propose a system of four clinical stages, based on clinical signs, clinicopathological abnormalities and serological status. Suitable therapy and expected prognosis are presented for each of the stages. The combination of meglumine antimoniate and allopurinol constitutes the first line pharmaceutical protocol. However, although most dogs recover clinically after therapy, complete elimination of the parasite is usually not achieved and infected dogs may eventually relapse. Follow-up of treated dogs with blood counts, serum biochemistry, urinalysis, serology and PCR is essential for prevention of relapses. Protection against sand fly bites by topical insecticides is effective in reducing infection, and recent development of vaccines has indicated that prevention by vaccination is feasible.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – original draft
                Role: Project administrationRole: Writing – review & editing
                Role: Investigation
                Role: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: Investigation
                Role: Project administrationRole: Supervision
                Role: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                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
                18 December 2020
                December 2020
                : 14
                : 12
                : e0008947
                Affiliations
                [1 ] IHU-Méditerranée Infection, Marseille, France
                [2 ] Aix Marseille Univ., IRD, AP-HM, MEPHI, Marseille, France
                [3 ] PADESCA Laboratory, Veterinary Science Institute, University Constantine 1, El Khroub, Algeria
                [4 ] Aix-Marseille Univ, IRD, AP-HM, SSA, VITROME, Marseille, France
                [5 ] Superior School of Food Sciences and Food Industries of Algiers, Algeria
                [6 ] Institute of Veterinary Sciences, University of Blida 1, Algeria
                [7 ] Laboratory of Biotechnology related to Animal Reproduction (LBRA), University of Blida, Blida, Algeria
                [8 ] Department of Biology, Faculty of Sciences, University of Boumerdes, Algeria
                [9 ] Ceva Santé Animale, Libourne, France
                KU Leuven, BELGIUM
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0002-5208-2576
                https://orcid.org/0000-0003-1176-5802
                https://orcid.org/0000-0002-7836-6809
                https://orcid.org/0000-0001-6039-2008
                Article
                PNTD-D-20-01418
                10.1371/journal.pntd.0008947
                7781483
                33338041
                a1b7cd8d-f88d-4f36-891e-01abd0c4ebd1
                © 2020 Medkour 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.

                History
                : 6 August 2020
                : 3 November 2020
                Page count
                Figures: 4, Tables: 4, Pages: 18
                Funding
                Funded by: Institut Hospitalo-Universitaire (IHU) Méditerranée Infection
                Funded by: National Research Agency
                Award ID: ANR-10-IAHU-03
                Funded by: Région Provence-Alpes-Côte d’Azur
                Funded by: European funding FEDER PRIMI
                This study was supported by the Institut Hospitalo-Universitaire (IHU) Méditerraneé Infection, the National Research Agency under the program « Investissements d’avenir », reference ANR-10-IAHU-03, the Région Provence-Alpes-Cote d’Azur and European funding FEDER PRIMI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Mammals
                Dogs
                Biology and Life Sciences
                Zoology
                Animals
                Vertebrates
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                Mammals
                Dogs
                Medicine and Health Sciences
                Pharmacology
                Drugs
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                Artesunate
                Medicine and Health Sciences
                Medical Conditions
                Tropical Diseases
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                Parasitic Diseases
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                Biology and Life Sciences
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                Anatomy
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                Biology and Life Sciences
                Physiology
                Body Fluids
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                Biology and Life Sciences
                Organisms
                Eukaryota
                Protozoans
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                Leishmania
                Leishmania Infantum
                Biology and Life Sciences
                Parasitology
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                Parasitemia
                Custom metadata
                vor-update-to-uncorrected-proof
                2021-01-04
                All relevant data are within the manuscript and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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