Assessment of α-Cypermethrin Pour-On Application and Diminazene Aceturate for Treating Trypanosome-Related Diseases Caused by Tsetse Flies on Cattle in Mô, Togo.

The effects of tsetse-transmitted trypanosomosis control in high tsetse flies (Glossina spp.) challenge and trypanocidal drug resistance settings remain poorly understood in Togo owing to poor data coverage on the current disease impact. From March 2014 to November 2017, a database of zoo-sanitary surveys integrating the evolution of disease incidence and intervention coverage made it possible to quantify the apparent effects attributable to the control effort, focused on all sedentary cattle breeds in the 1,000 km² area of Mô in Togo. The strategy involved an initial phase with cross-sectional entomological and parasitological. Then, three times a year, 20% of the bovine animals of the study area received α-cypermethrin pour-on, and infected cattle with poor health (798 cattle in 2014 and 358 in 2017) were individually given diminazene aceturate at 7 mg/kg of body weight. The tsetse density in the area decreased significantly, from 1.78 ± 0.37 in March 2014 before the α-cypermethrin application to 0.48 ± 0.07 in February 2017. The α-cypermethrin pour-on application and diminazene aceturate treatment of cattle led to the largest reduction in disease incidence, from 28.1% in 2014 to 7.8% in 2017, an improvement in hematocrit from 24.27 ± 4.9% to 27.5 ± 4.6%, and a reduction in calf mortality from 15.9 ± 11% to 5.9%. Improved access to these interventions for different types of livestock and maintaining their effectiveness, despite high tsetse (Diptera: Glossinidae) challenges, should be the primary focus of control strategies in many areas of Togo.

The complex health seeking pathway of a human African trypanosomiasis patient in Côte d'Ivoire underlines the need of setting up passive surveillance systems.

BACKGROUND: Significant efforts to control human African trypanosomiasis (HAT) over the two past decades have resulted in drastic decrease of its prevalence in Côte d'Ivoire. In this context, passive surveillance, integrated in the national health system and based on clinical suspicion, was reinforced. We describe here the health-seeking pathway of a girl who was the first HAT patient diagnosed through this strategy in August 2017. METHODS: After definitive diagnosis of this patient, epidemiological investigations were carried out into the clinical evolution and the health and therapeutic itinerary of the patient before diagnosis. RESULTS: At the time of diagnosis, the patient was positive in both serological and molecular tests and trypanosomes were detected in blood and cerebrospinal fluid. She suffered from important neurological disorders. The first disease symptoms had appeared three years earlier, and the patient had visited several public and private peripheral health care centres and hospitals in different cities. The failure to diagnose HAT for such a long time caused significant health deterioration and was an important financial burden for the family. CONCLUSION: This description illustrates the complexity of detecting the last HAT cases due to complex diagnosis and the progressive disinterest and unawareness by both health professionals and the population. It confirms the need of implementing passive surveillance in combination with continued sensitization and health staff training.

Human African Trypanosomiasis: Progress and Stagnation.

Control efforts have considerably reduced the prevalence of human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense in West/Central Africa and to Trypanosoma brucei rhodesiense in East Africa. Management of T brucei gambiense HAT has recently improved, with new antibody-based rapid diagnostic tests suited for mass screening and clinical care, and simpler treatments, including the nifurtimox-eflornithine combination therapy and the new oral drug fexinidazole to treat the second stage of the disease. In contrast, no major advance has been achieved for the treatment of T brucei rhodesiense HAT, a zoonosis that occasionally affects short-term travelers to endemic areas.

Integration of Human African Trypanosomiasis Control Activities into Primary Health Services in the Democratic Republic of the Congo: A Qualitative Study of Stakeholder Perceptions.

Human African trypanosomiasis is close to elimination in several countries in sub-Saharan Africa. The diagnosis and treatment is currently rapidly being integrated into first-line health services. We aimed to document the perspective of stakeholders on this integration process. We conducted 12 focus groups with communities in three health zones of the Democratic Republic of the Congo and held 32 interviews with health-care providers, managers, policy makers, and public health experts. The topic guide focused on enabling and blocking factors related to the integrated diagnosis and treatment approach. The data were analyzed with NVivo (QSR International, Melbourne, Australia) using a thematic analysis process. The results showed that the community mostly welcomed integrated care for diagnosis and treatment of sleeping sickness, as they value the proximity of first-line health services, but feared possible financial barriers. Health-care professionals thought integration contributed to the elimination goal but identified several implementation challenges, such as the lack of skills, equipment, motivation and financial resources in these basic health services. Patients often use multiple therapeutic itineraries that do not necessarily lead them to health centers where screening is available. Financial barriers are important, as health care is not free in first-line health centers, in contrast to the population screening campaigns. Communities and providers signal several challenges regarding the integration process. To succeed, the required training of health professionals, as well as staff deployment and remuneration policy and the financial barriers in the primary care system need to be addressed, to ensure coverage for those most in need.

Pharmacokinetic-Pharmacodynamic Assessment of the Hepatic and Bone Marrow Toxicities of the New Trypanoside Fexinidazole.

Fexinidazole is a novel oral treatment for human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT). Fexinidazole also has activity against T. cruzi, the causative agent of Chagas disease. During the course of a dose ranging assessment in patients with chronic indeterminate Chagas disease, delayed neutropenia and significant increases in hepatic transaminases were observed and clinical investigations were suspended. We retrospectively analyzed all available pharmacokinetic and pharmacodynamic data on fexinidazole in normal healthy volunteers and in patients with Chagas disease and g-HAT to assess the determinants of toxicity. A population pharmacokinetic model was fitted to plasma concentrations (n = 4,549) of the bioactive fexinidazole sulfone metabolite, accounting for the majority of the bioactive exposure, from three phase 1 studies, two g-HAT phase 2/3 field trials, and one Chagas disease phase 2 field trial (n = 462 individuals in total). Bayesian exposure-response models were then fitted to hematological and liver-related pharmacodynamic outcomes in Chagas disease patients. Neutropenia, reductions in platelet counts, and elevations in liver transaminases were all found to be exposure dependent and, thus, dose dependent in patients with Chagas disease. Clinically insignificant transient reductions in neutrophil and platelet counts consistent with these exposure-response relationships were observed in patients with g-HAT. In contrast, no evidence of hepatotoxicity was observed in patients with g-HAT. Fexinidazole treatment results in a dose-dependent liver toxicity and transient bone marrow suppression in Chagas disease patients. Regimens of shorter duration should be evaluated in clinical trials with patients with Chagas disease. The currently recommended regimen for sleeping sickness provides exposures within a satisfactory safety margin for bone marrow suppression and does not cause hepatotoxicity.

The Long Wait for a New Drug for Human African Trypanosomiasis.

Human African trypanosomiasis (HAT) is responsible for around 3000 reported cases each year. Treatments for HAT are expensive and problematic to administer, and available drugs are old and less than ideal, some with high levels of toxicity that result in debilitating and, in some cases, fatal side effects. Treatment options are limited, with only one drug, eflornithine, introduced in the last 28 years. Here we examine the limitations of current chemotherapeutic approaches to manage HAT, the constraints to new drug development exploring drug failures and new drugs on the horizon, and consider the epidemiological, political, social, and economic factors influencing drug development.

Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides.

A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.

Cost analysis of options for management of African Animal Trypanosomiasis using interventions targeted at cattle in Tororo District; south-eastern Uganda.

BACKGROUND: Tsetse-transmitted African trypanosomes cause both nagana (African animal Trypanosomiasis-AAT) and sleeping sickness (human African Trypanosomiasis - HAT) across Sub-Saharan Africa. Vector control and chemotherapy are the contemporary methods of tsetse and trypanosomiasis control in this region. In most African countries, including Uganda, veterinary services have been decentralised and privatised. As a result, livestock keepers meet the costs of most of these services. To be sustainable, AAT control programs need to tailor tsetse control to the inelastic budgets of resource-poor small scale farmers. To guide the process of tsetse and AAT control toolkit selection, that now, more than ever before, needs to optimise resources, the costs of different tsetse and trypanosomiasis control options need to be determined. METHODS: A detailed costing of the restricted application protocol (RAP) for African trypanosomiasis control in Tororo District was undertaken between June 2012 and December 2013. A full cost calculation approach was used; including all overheads, delivery costs, depreciation and netting out transfer payments to calculate the economic (societal) cost of the intervention. Calculations were undertaken in Microsoft Excel without incorporating probabilistic elements. RESULTS: The cost of delivering RAP to the project was US$ 6.89 per animal per year while that of 4 doses of a curative trypanocide per animal per year was US$ 5.69. However, effective tsetse control does not require the application of RAP to all animals. Protecting cattle from trypanosome infections by spraying 25%, 50% or 75% of all cattle in a village costs US$ 1.72, 3.45 and 5.17 per animal per year respectively. Alternatively, a year of a single dose of curative or prophylactic trypanocide treatment plus 50% RAP would cost US$ 4.87 and US$ 5.23 per animal per year. Pyrethroid insecticides and trypanocides cost 22.4 and 39.1% of the cost of RAP and chemotherapy respectively. CONCLUSIONS: Cost analyses of low cost tsetse control options should include full delivery costs since they constitute 77.6% of all project costs. The relatively low cost of RAP for AAT control and its collateral impact on tick control make it an attractive option for livestock management by smallholder livestock keepers.

Human African trypanosomiasis prevention, treatment and control costs: a systematic review.

The control and eventual elimination of human African trypanosomiasis (HAT) requires the expansion of current control and surveillance activities. A systematic review of the published literature on the costs of HAT prevention, treatment, and control, in addition to the economic burden, was conducted. All studies that contained primary or secondary data on costs of prevention, treatment and control were considered, resulting in the inclusion of 42 papers. The geographically focal nature of the disease and a lack of standardization in the cost data limit the usefulness of the available information for making generalizations across diverse settings. More recent information on the costs of treatment and control interventions for HAT is needed to provide accurate information for analyses and planning. The cost information contained herein can be used to inform rational decision making in control and elimination programs, and to assess potential synergies with existing vector-borne disease control programs, but programs would benefit significantly from new cost data collection.

Development and evaluation of an ITS1 "Touchdown" PCR for assessment of drug efficacy against animal African trypanosomosis.

Animal African trypanosomoses (AAT) are caused by flagellated protozoa of the Trypanosoma genus and contribute to considerable losses in animal production in Africa, Latin America and South East Asia. Trypanosoma congolense is considered the economically most important species. Drug resistant T. congolense strains present a threat to the control of AAT and have triggered research into discovery of novel trypanocides. In vivo assessment of trypanocidal efficacy relies on monitoring of treated animals with microscopic parasite detection methods. Since these methods have poor sensitivity, follow-up for up to 100 days after treatment is recommended to increase the chance of detecting recurrent parasitaemia waves. Molecular techniques are more amendable to high throughput processing and are generally more sensitive than microscopic detection, thus bearing the potential of shortening the 100-day follow up period. The study presents a "Touchdown" PCR targeting the internal transcribed spacer 1 of the ribosomal DNA (ITS1 TD PCR) that enables detection and discrimination of different Trypanosoma taxa in a single run due to variations in PCR product sizes. The assay achieves analytical sensitivity of 10 parasites per ml of blood for detection of T. congolense savannah type and T. brucei, and 100 parasites per ml of blood for detection of T. vivax in infected mouse blood. The ITS1 TD PCR was evaluated on cattle experimentally infected with T. congolense during an investigational new veterinary trypanocide drug efficacy study. ITS1 TD PCR demonstrated comparable performance to microscopy in verifying trypanocide treatment success, in which parasite DNA became undetectable in cured animals within two days post-treatment. ITS1 TD PCR detected parasite recrudescence three days earlier than microscopy and had a higher positivity rate than microscopy (84.85% versus 57.58%) in 66 specimens of relapsing animals collected after treatments. Therefore, ITS1 TD PCR provides a useful tool in assessment of drug efficacy against T. congolense infection in cattle. As the assay bears the potential for detection of mixed infections, it may be applicable for drug efficacy studies and diagnostic discrimination of T. vivax and T. congolense against other pathogenic trypanosomes, including T. brucei, T. evansi and T. equiperdum.

Synthesis and assessment of catechol diether compounds as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1).

Human African trypanosomiasis (HAT) is a parasitic neglected tropical disease that affects 10,000 patients each year. Current treatments are sub-optimal, and the disease is fatal if not treated. Herein, we report our continuing efforts to repurpose the human phosphodiesterase 4 (hPDE4) inhibitor piclamilast to target trypanosomal phosphodiesterase TbrPDEB1. We prepared a range of substituted heterocyclic replacements for the 4-amino-3,5-dichloro-pyridine headgroup of piclamilast, and found that these compounds exhibited weak inhibitory activity of TbrPDEB1.

Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis.

Despite the fact that eflornithine was considered as the safer drug to treat human African trypanosomiasis (HAT) and has been freely available since 2001, the difficulties in logistics and cost burden associated with this drug meant that the toxic melarsoprol remained the drug of choice. The World Health Organization responded to the situation by designing a medical kit containing all the materials needed to use eflornithine, and by implementing a training and drugs distribution programme which has allowed a transition to this much safer treatment. The introduction of the combination of nifurtimox and eflornithine (NECT) has accelerated the shift from melarsoprol to the best treatment available, due to reduced dosage and treatment time for eflornithine that has significantly lessened the cost and improved the burden of logistics encountered during treatment and distribution. The decrease in the use of more dangerous but cheaper melarsoprol has meant a rise in the per patient cost of treating HAT. Although NECT is cheaper than eflornithine monotherapy, an unexpected consequence has been a continuing rise in the per patient cost of treating HAT. The ethical decision of shifting to the best available treatment imposes a financial burden on HAT control programmes that might render long-term application unsustainable. These factors call for continuing research to provide new safer and more effective drugs that are simple to administer and cheaper when compared to current drugs.

Research priorities for Chagas disease, human African trypanosomiasis and leishmaniasis.

This report provides a review and analysis of the research landscape for three diseases - Chagas disease, human African trypanosomiasis and leishmaniasis - that disproportionately afflict poor and remote populations with limited access to health services. It represents the work of the disease reference group on Chagas Disease, Human African Trypanosomiasis and Leishmaniasis (DRG3) which was established to identify key research priorities through review of research evidence and input from stakeholders' consultations. The diseases, which are caused by related protozoan parasites, are described in terms of their epidemiology and diseases burden, clinical forms and pathogenesis, HIV coinfection, diagnosis, drugs and drug resistance, vaccines, vector control, and health-care interventions. Priority areas for research are identified based on criteria such as public health relevance, benefit and impact on poor populations and equity, and feasibility. The priorities are found in the areas of diagnostics, drugs, vector control, asymptomatic infection, economic analysis of treatment and vector control methods, and in some specific issues such as surveillance methods or transmission-blocking vaccines for particular diseases. This report will be useful to researchers, policy and decision-makers, funding bodies, implementation organizations, and civil society. This is one of ten disease and thematic reference group reports that have come out of the TDR Think Tank, all of which have contributed to the development of the Global Report for Research on Infectious Diseases of Poverty, available at: www.who.int/tdr/stewardship/global_report/en/index.html.

Antiprotozoal compounds: state of the art and new developments.

Protozoa can cause severe diseases, including malaria, leishmaniasis, Chagas disease, sleeping sickness and amoebiasis, all being responsible for morbidity and mortality particularly in tropical countries. To date there are no protective vaccines against any of these diseases, and many of the available drugs are old or elicit serious adverse reactions. Moreover, parasite resistance to existing drugs has become a serious problem. Owing to lack of financial returns, research in this field is of limited interest to pharmaceutical companies and largely depends on funding by public authorities. This article aims to provide a concise overview of the state-of-the-art treatment for the most important tropical protozoal infections as well as new approaches.

Collaborative actions in anti-trypanosomatid chemotherapy with partners from disease endemic areas.

The protozoan diseases leishmaniasis, human African trypanosomiasis and Chagas disease are responsible for substantial global morbidity, mortality and economic adversity in tropical and subtropical regions. In most countries, existing strategies for control and treatment are either failing or under serious threat. Environmental changes, drug resistance and immunosuppression contribute to the emergence and spread of these diseases. In the absence of safe and efficient vaccines, chemotherapy, together with vector control, remains the most important measures to control trypanosomatid diseases. Here, we review current limitations of anti-trypanosomatid chemotherapy and describe new efforts to safeguard existing treatments and to identify novel drug leads through the three multinational and interdisciplinary European Union Framework Programmes for Research and Technological Development (FP7) funded consortia KALADRUG-R, TRYPOBASE, and LEISHDRUG.

Eflornithine is a cost-effective alternative to melarsoprol for the treatment of second-stage human West African trypanosomiasis in Caxito, Angola.

OBJECTIVE: To compare the cost-effectiveness of eflornithine and melarsoprol in the treatment of human African trypanosomiasis. METHOD: We used data from a Médecins Sans Frontières treatment project in Caxito, Angola to do a formal cost-effectiveness analysis, comparing the efficiency of an eflornithine-based approach with melarsoprol. Endpoints calculated were: cost per death avoided; incremental cost per additional life saved; cost per years of life lost (YLL) averted; incremental cost per YLL averted. Sensitivity analysis was done for all parameters for which uncertainty existed over the plausible range. We did an analysis with and without cost of trypanocidal drugs included. RESULTS: Effectiveness was 95.6% for melarsoprol and 98.7% for eflornithine. Cost/patient was 504.6 for melarsoprol and 552.3 for eflornithine, cost per life saved was 527.5 USD for melarsoprol and 559.8 USD for eflornithine without cost of trypanocidal drugs but it increases to 600.4 USD and 844.6 USD per patient saved and 627.6 USD and 856.1 USD per life saved when cost of trypanocidal drugs are included. Incremental cost-effectiveness ratio is 1596 USD per additional life saved and 58 USD per additional life year saved in the baseline scenario without cost of trypanocidal drugs but it increases to 8169 USD per additional life saved and 299 USD per additional life year saved if costs of trypanocidal drugs are included. CONCLUSION: Eflornithine saves more lives than melarsoprol, but melarsoprol is slightly more cost-effective. Switching from melarsoprol to eflornithine can be considered as a cost-effective option according to the WHO choice criteria.

Human African trypanosomiasis: pharmacological re-engagement with a neglected disease.

This review discusses the challenges of chemotherapy for human African trypanosomiasis (HAT). The few drugs registered for use against the disease are unsatisfactory for a number of reasons. HAT has two stages. In stage 1 the parasites proliferate in the haemolymphatic system. In stage 2 they invade the central nervous system and brain provoking progressive neurological dysfunction leading to symptoms that include the disrupted sleep wake patterns that give HAT its more common name of sleeping sickness. Targeting drugs to the central nervous system offers many challenges. However, it is the cost of drug development for diseases like HAT, that afflict exclusively people of the world's poorest populations, that has been the principal barrier to new drug development and has led to them becoming neglected. Here we review drugs currently registered for HAT, and also discuss the few compounds progressing through clinical trials. Finally we report on new initiatives that might allow progress to be made in developing new and satisfactory drugs for this terrible disease.

Drug toxicity and cost as barriers to community participation in HAT control in the Democratic Republic of Congo.

INTRODUCTION: Active case-finding programmes by mobile teams are the cornerstone of West African Human African Trypanosomiasis (HAT) control. Low attendance rates of screening and low uptake of treatment after diagnosis are major problems. The objectives of this survey were to explore community perception of HAT, to assess acceptability of control activities and to identify barriers amenable to intervention. METHODS: In September 2004, we conducted 33 focus group discussions with beneficiaries of the HAT control programme among various ethnic groups in two ecological settings (savannah and fluvial) of the Democratic Republic of Congo. RESULTS: The population had a very detailed knowledge and understanding of HAT transmission, utility of screening, symptoms and treatment. Melarsoprol treatment was feared for its side effects. The sudden death of previously asymptomatic people during treatment was attributed to witchcraft, to which one becomes more vulnerable when the diagnosis is disclosed in public. Lack of confidentiality was also a problem because HAT carries a stigma as a mental disease. Lumbar punctures, especially when performed in public, were disliked but less feared. Financial barriers were a major obstacle for many patients. CONCLUSION: Less toxic drugs, lowering financial barriers and improving confidentiality would have considerable impact on the participation in population screening for HAT.