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      In-Hospital Safety in Field Conditions of Nifurtimox Eflornithine Combination Therapy (NECT) for T. b. gambiense Sleeping Sickness

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          Abstract

          Background

          Trypanosoma brucei (T.b.) gambiense Human African trypanosomiasis (HAT; sleeping sickness) is a fatal disease. Until 2009, available treatments for 2 nd stage HAT were complicated to use, expensive (eflornithine monotherapy), or toxic, and insufficiently effective in certain areas (melarsoprol). Recently, nifurtimox-eflornithine combination therapy (NECT) demonstrated good safety and efficacy in a randomised controlled trial (RCT) and was added to the World Health Organisation (WHO) essential medicines list (EML). Documentation of its safety profile in field conditions will support its wider use.

          Methodology

          In a multicentre, open label, single arm, phase IIIb study of the use of NECT for 2 nd stage T.b. gambiense HAT, all patients admitted to the trial centres who fulfilled inclusion criteria were treated with NECT. The primary outcome was the proportion of patients discharged alive from hospital. Safety was further assessed based on treatment emergent adverse events (AEs) occurring during hospitalisation.

          Principal Findings

          629 patients were treated in six HAT treatment facilities in the Democratic Republic of the Congo (DRC), including 100 children under 12, 14 pregnant and 33 breastfeeding women. The proportion of patients discharged alive after treatment completion was 98.4% (619/629; 95%CI [97.1%; 99.1%]). Of the 10 patients who died during hospitalisation, 8 presented in a bad or very bad health condition at baseline; one death was assessed as unlikely related to treatment. No major or unexpected safety concerns arose in any patient group. Most common AEs were gastro-intestinal (61%), general (46%), nervous system (mostly central; 34%) and metabolic disorders (26%). The overall safety profile was similar to previously published findings.

          Conclusions/Significance

          In field conditions and in a wider population, including children, NECT displayed a similar tolerability profile to that described in more stringent clinical trial conditions. The in-hospital safety was comparable to published results, and long term efficacy will be confirmed after 24 months follow-up.

          Registration

          The trial is registered at ClinicalTrials.gov, number NCT00906880.

          Author Summary

          Sleeping sickness is a neglected tropical disease affecting people in Sub-Saharan Africa, most of them in poor, rural settings. If not treated, the disease usually progresses into a serious stage affecting the central nervous system, causing severe sleep disturbances, as well as other neurological and psychiatric disorders, coma, and death. Until recently, the only ways to treat 2 nd stage gambiense sleeping sickness involved drugs that were either toxic (such as the arsenic derivative melarsoprol) or difficult to administer in resource-constrained settings (e.g. eflornithine). A new treatment, nifurtimox-eflornithine combination therapy (NECT), was developed and tested in clinical trials, and is now recommended as the treatment of choice for 2nd stage sleeping sickness. NECT is easier to administer than eflornithine, but more information needs to be gathered for its use in the field: logistical barriers must be overcome, health care staff must be well trained, and, importantly, the safety profile of the treatment in real-life conditions needs to be better evaluated. We report here the results of a study designed to gain better understanding of the clinical tolerability, feasibility and effectiveness of NECT in field conditions, and to gather data on its use in specific populations, such as children and pregnant women.

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          Most cited references 16

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          Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial.

          Human African trypanosomiasis (HAT; sleeping sickness) caused by Trypanosoma brucei gambiense is a fatal disease. Current treatment options for patients with second-stage disease are toxic, ineffective, or impractical. We assessed the efficacy and safety of nifurtimox-eflornithine combination therapy (NECT) for second-stage disease compared with the standard eflornithine regimen. A multicentre, randomised, open-label, active control, phase III, non-inferiority trial was done at four HAT treatment centres in the Republic of the Congo and the Democratic Republic of the Congo. Patients aged 15 years or older with confirmed second-stage T b gambiense infection were randomly assigned by computer-generated randomisation sequence to receive intravenous eflornithine (400 mg/kg per day, every 6 h; n=144) for 14 days or intravenous eflornithine (400 mg/kg per day, every 12 h) for 7 days with oral nifurtimox (15 mg/kg per day, every 8 h) for 10 days (NECT; n=143). The primary endpoint was cure (defined as absence of trypanosomes in body fluids and a leucocyte count
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            The Atlas of human African trypanosomiasis: a contribution to global mapping of neglected tropical diseases

            Background Following World Health Assembly resolutions 50.36 in 1997 and 56.7 in 2003, the World Health Organization (WHO) committed itself to supporting human African trypanosomiasis (HAT)-endemic countries in their efforts to remove the disease as a public health problem. Mapping the distribution of HAT in time and space has a pivotal role to play if this objective is to be met. For this reason WHO launched the HAT Atlas initiative, jointly implemented with the Food and Agriculture Organization of the United Nations, in the framework of the Programme Against African Trypanosomosis. Results The distribution of HAT is presented for 23 out of 25 sub-Saharan countries having reported on the status of sleeping sickness in the period 2000 - 2009. For the two remaining countries, i.e. Angola and the Democratic Republic of the Congo, data processing is ongoing. Reports by National Sleeping Sickness Control Programmes (NSSCPs), Non-Governmental Organizations (NGOs) and Research Institutes were collated and the relevant epidemiological data were entered in a database, thus incorporating (i) the results of active screening of over 2.2 million people, and (ii) cases detected in health care facilities engaged in passive surveillance. A total of over 42 000 cases of HAT and 6 000 different localities were included in the database. Various sources of geographic coordinates were used to locate the villages of epidemiological interest. The resulting average mapping accuracy is estimated at 900 m. Conclusions Full involvement of NSSCPs, NGOs and Research Institutes in building the Atlas of HAT contributes to the efficiency of the mapping process and it assures both the quality of the collated information and the accuracy of the outputs. Although efforts are still needed to reduce the number of undetected and unreported cases, the comprehensive, village-level mapping of HAT control activities over a ten-year period ensures a detailed and reliable representation of the known geographic distribution of the disease. Not only does the Atlas serve research and advocacy, but, more importantly, it provides crucial evidence and a valuable tool for making informed decisions to plan and monitor the control of sleeping sickness.
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              Clinical aspects of 2541 patients with second stage human African trypanosomiasis.

              The clinical symptoms and signs of patients with second stage HAT are described for a large cohort of patients treated in a prospective multicentre, multinational study. Special emphasis is given to the influence of disease stage (duration, number of WBC in CSF) and patient age to the clinical picture. Even though the frequencies of symptoms and signs are highly variable between centres, the clinical picture of the disease is similar for all countries. Headache (78.7%), sleeping disorder (74.4%) and lymphadenopathy (56.1%) are the most frequent symptoms and signs and they are similar for all stages of the disease. Lymphadenopathy tends to be highest in the advanced second stage (59.0%). The neurological and psychiatric symptoms increase significantly with the number of WBC in the CSF indicating the stage of progression of the disease. Pruritus is observed in all stages and increases with the number of WBC in CSF from 30 to 55%. In children younger than 7 years, lymphadenopathy is less frequently reported (11.8-37.3%) than in older children or adults (56.4-61.2%). Fever is most frequently reported in children between 2 and 14 years of age (26.1-28.7%) and malnutrition is significantly more frequently observed in children of all ages (43-56%) than in adults (23.5%).
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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, USA )
                1935-2727
                1935-2735
                November 2012
                29 November 2012
                : 6
                : 11
                Affiliations
                [1 ]Department of Medicines Research, Swiss Tropical and Public Health Institute, Basel, Switzerland
                [2 ]University of Basel, Basel, Switzerland
                [3 ]Consultant, Paris, France
                [4 ]Programme National de Lutte contre la Trypanosomiase Humaine Africaine (PNLTHA), Kinshasa, Democratic Republic of the Congo
                [5 ]Bureau Diocesain d'Oeuvres Médicales (BDOM), Kikwit, Democratic Republic of the Congo
                [6 ]DND i, , Geneva, Switzerland
                Foundation for Innovative New Diagnostics (FIND), Switzerland
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CS AK SG VK WM. Performed the experiments: WM MI IL SM PN DT NM MK. Analyzed the data: CS AK JB SG SB OVM. Wrote the paper: CS AK SG OVM.

                [¤]

                Current address: CRP-SANTE, Centre for Health Studies, Public Research Centre for Health, Strassen, Luxembourg

                Article
                PNTD-D-12-00537
                10.1371/journal.pntd.0001920
                3510081
                23209861

                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
                Pages: 10
                Funding
                The study was funded by the Drugs for Neglected Diseases initiative (DNDi, Geneva, Switzerland), which was involved in the conception of the study, the interpretation of results and in the preparation of this manuscript. DNDi would like to acknowledge the following donors for their support of DNDi's NECT-related activities: the Department for International Development (DFID, UK); the Ministry of Foreign and European Affairs (MAEE, France); Republic and Canton of Geneva, Department International Solidarity (Switzerland); Spanish Agency for International Development Cooperation (AECID, Spain); Swiss Agency for Development and Cooperation (SDC, Switzerland); Médecins Sans Frontières (Doctors Without Borders) International; the Medicor Foundation (Liechtenstein); and others who would like to remain anonymous. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine
                Infectious Diseases
                Neglected Tropical Diseases
                African Trypanosomiasis

                Infectious disease & Microbiology

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