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Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements...
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Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges

A special issue of Tropical Medicine and Infectious Disease (ISSN 2414-6366). This special issue belongs to the section "Neglected and Emerging Tropical Diseases".

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 72446

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Christian Burri

E-Mail Website
Guest Editor
Department of Medicine, Swiss Tropical & Public Health Institute, Kreuzstrasse, 4123 Allschwil, Switzerland
Interests: sleeping sickness (human African trypanosomiasis); drug and vaccine development against neglected tropical diseases; clinical trials in low resource settings; implementation research; public health

Special Issue Information

Dear Colleagues,

The positive opinion expressed on 16 November 2018 by the European Medicines Agency on the use of the oral drug fexinidazole against human African trypanosomiasis (HAT) caused by T.b. gambiense may be considered a milestone in the treatment of the disease and contributes an essential component towards its elimination. With tremendous efforts, the treatment could be improved, with respect to the past almost 30 years, from a 35-days treatment with the injectable organoarsenic drug melarsoprol with a drug-attributable fatality rate of 5% down to the 10 days oral fexinidazole treatment with a mortality rate of 0.5%. However, this is only one of the many pieces we need to combine in the puzzle of a successful battle against this disease. While the number of T.b. gambiense HAT cases is decreasing, and the dreadful melarsoprol has been replaced by the new treatment, many other issues still need to be addressed to reach the goal of sustainable disease elimination by 2030. Case identification and diagnosis remain complicated and require substantial screening efforts and specific skills (such as case confirmation by microscopy). Contrary to an old dogma, recent evidence shows that not all patients die from the disease, but some may remain infective over many years; in addition, the relevance and nature of the animal reservoir for T.b. gambiense HAT are still not conclusively resolved. Enough questions for a disease marked for elimination, but, eventually, the human factor will be decisive in the “end game”, where decentralized disease recognition and management in lower level health structures and communities, disease awareness and stigma, unrelenting disease surveillance in known foci, as well as oblivion in areas where HAT has not occurred may play a determining role but have not been studied in depth yet. All these unresolved questions gain a significant importance in the light of the known threat of recurrence at large scale of this disease.

As if HAT caused by T.b. gambiense were not a very neglected disease and all this not enough for a considerable challenge, the other form of the disease caused by T.b. rhodesiense is an even more neglected and much more fulminant illness targeted for elimination, with a clear zoonotic reservoir and still only treatable with the old drugs pentamidine and suramin in the first stage and melarsoprol in the late stage, with stage determination requiring a lumbar puncture.

Given where we stand regarding both diseases, it seems now a close-to-perfect time for an overview, status check, and collection of new ideas and innovative approaches to reach the goal of elimination of these debilitating diseases and prepare against their recurrence.

Prof. Christian Burri
Guest Editor

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Keywords

  • sleeping sickness
  • human African trypanosomiasis
  • T. b. gambiense
  • g-HAT
  • T. b. rhodesiense
  • r-HAT
  • elimination
  • neglected tropical diseases

Published Papers (19 papers)

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Editorial

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11 pages, 263 KiB  
Editorial
Sleeping Sickness at the Crossroads
by Christian Burri
Trop. Med. Infect. Dis. 2020, 5(2), 57; https://doi.org/10.3390/tropicalmed5020057 - 08 Apr 2020
Cited by 6 | Viewed by 3273
Abstract
Human African trypanosomiasis (HAT; sleeping sickness) is a disease with truly historic dimensions [...] Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)

Research

Jump to: Editorial, Review, Other

10 pages, 616 KiB  
Article
An Active Follow-up Strategy for Serological Suspects of Human African Trypanosomiasis with Negative Parasitology Set up by a Health Zone Team in the Democratic Republic of Congo
by Matthieu Nkieri, Florent Mbo, Papy Kavunga, Pathou Nganzobo, Titus Mafolo, Chalet Selego and Eric Mwamba Miaka
Trop. Med. Infect. Dis. 2020, 5(2), 53; https://doi.org/10.3390/tropicalmed5020053 - 04 Apr 2020
Cited by 2 | Viewed by 2033
Abstract
Background: The World Health Organization aims for the elimination of Human African Trypanosomiasis (HAT) as a public health problem by 2020 and for full elimination (absence of new cases) by 2030. One of strategies to achieve this is the active follow-up of all [...] Read more.
Background: The World Health Organization aims for the elimination of Human African Trypanosomiasis (HAT) as a public health problem by 2020 and for full elimination (absence of new cases) by 2030. One of strategies to achieve this is the active follow-up of all HAT serological suspects found during passive screening who have never been re-tested for parasitology. This is important because these cases can maintain HAT transmission and may be responsible for reemergence of the disease. Methods: In order to improve case finding at low cost in the targeted population, a general recall was transmitted to aparasitemic serological suspects about the availability of confirmation services at the general referral hospital. Transport was facilitated for re-testing. The initial examinations were carried out in Health Centers from Bagata Health Zone (HZ) in the Democratic Republic of the Congo between January 2017 and April 2019. This strategy of using a HZ team has not been previously documented. Results: From a total sample of 74 serological suspects listed by the health centers, 36 cases were re-examined at the general reference hospital; 19% (7/36) self-presented and 81% (29/36) were actively followed up by HZ personnel. Of those re-examined at the general reference hospital, 39% (14/36) resulted in a parasitologically confirmed case. Of the 14 people diagnosed with HAT, 14% (2/14) self-presented and the remaining 86% (12/14) were diagnosed in suspects who were actively followed up. This new strategy of facilitating transport from the villages added value by contributing to the detection of 12 HAT cases, compared to the passive approach, waiting for self-reference, which resulted in the detection of 2 new HAT cases. The cost per detected patient was 70 USD from the group of 7 suspects who self-presented for testing at the hospital and 346 USD per detected case for the group of 29 patients who were actively followed up by health zone staff. Conclusion: Targeted active follow-up of aparasitemic serological suspects by HZ teams is a cost-effective and promising approach to identifying additional cases of HAT in areas of very low prevalence, which would contribute to the HAT elimination goal set by the World Health Organization. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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18 pages, 500 KiB  
Article
Understanding the Role of the Diagnostic ‘Reflex’ in the Elimination of Human African Trypanosomiasis
by Jennifer J. Palmer, Caroline Jones, Elizeous I. Surur and Ann H. Kelly
Trop. Med. Infect. Dis. 2020, 5(2), 52; https://doi.org/10.3390/tropicalmed5020052 - 01 Apr 2020
Cited by 4 | Viewed by 3402
Abstract
To successfully eliminate human African trypanosomiasis (HAT), healthcare workers (HCWs) must maintain their diagnostic acuity to identify cases as the disease becomes rarer. HAT experts refer to this concept as a ‘reflex’ which incorporates the idea that diagnostic expertise, particularly skills involved in [...] Read more.
To successfully eliminate human African trypanosomiasis (HAT), healthcare workers (HCWs) must maintain their diagnostic acuity to identify cases as the disease becomes rarer. HAT experts refer to this concept as a ‘reflex’ which incorporates the idea that diagnostic expertise, particularly skills involved in recognising which patients should be tested, comes from embodied knowledge, accrued through practice. We investigated diagnostic pathways in the detection of 32 symptomatic HAT patients in South Sudan and found that this ‘reflex’ was not confined to HCWs. Indeed, lay people suggested patients test for HAT in more than half of cases using similar practices to HCWs, highlighting the importance of the expertise present in disease-affected communities. Three typologies of diagnostic practice characterised patients’ detection: ‘syndromic suspicion’, which closely resembled the idea of an expert diagnostic reflex, as well as ‘pragmatic testing’ and ‘serendipitous detection’, which depended on diagnostic expertise embedded in hospital and lay social structures when HAT-specific suspicion was ambivalent or even absent. As we approach elimination, health systems should embrace both expert and non-expert forms of diagnostic practice that can lead to detection. Supporting multidimensional access to HAT tests will be vital for HCWs and lay people to practice diagnosis and develop their expertise. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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9 pages, 1037 KiB  
Article
How Clinical Research Can Contribute to Strengthening Health Systems in Low Resource Countries
by Florent Mbo, Wilfried Mutombo, Digas Ngolo, Patrice Kabangu, Olaf Valverde Mordt, Nathalie Strub Wourgaft and Erick Mwamba
Trop. Med. Infect. Dis. 2020, 5(2), 48; https://doi.org/10.3390/tropicalmed5020048 - 29 Mar 2020
Cited by 5 | Viewed by 2811
Abstract
Clinical research on neglected tropical diseases is a challenge in low-resource countries, and the contribution of clinical and operational research to health system strengthening is poorly documented. Developing new, simple, safe, and effective treatments may improve the effectiveness of health systems, and conducting [...] Read more.
Clinical research on neglected tropical diseases is a challenge in low-resource countries, and the contribution of clinical and operational research to health system strengthening is poorly documented. Developing new, simple, safe, and effective treatments may improve the effectiveness of health systems, and conducting research directly in health structures may have an additional impact. This study describes the process of conducting clinical trials in the Democratic Republic of Congo (DRC) in compliance with international standards, and the role of the trials in strengthening health system functions, including governance, human resources, health information, provision of care, and the equipping of health services with the necessary supplies and infrastructure. We conclude that conducting clinical trials in endemic areas has not only reinforced and supported the aim of conducting high-level clinical research in endemic countries, but has also brought lasting benefits to researchers, staff, and hospitals, as well as to broader health systems, which have positive knock-on effect on patients outside of the clinical trials and their communities. Sustainability, however, remains a challenge in an underfunded health system, especially with respect to specialized equipment. Clinical research in most of sub-Saharan Africa is highly dependent on international input and external technical support; there are areas of weaknesses in trial design and documentation, as well as in data management and analysis. Financing remains a critical issue, as African investigators have difficulties in directly accessing sources of international research funding. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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14 pages, 3019 KiB  
Article
Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis
by Srinivasa P S Rao, Suresh B Lakshminarayana, Jan Jiricek, Marcel Kaiser, Ryan Ritchie, Elmarie Myburgh, Frantisek Supek, Tove Tuntland, Advait Nagle, Valentina Molteni, Pascal Mäser, Jeremy C Mottram, Michael P Barrett and Thierry T Diagana
Trop. Med. Infect. Dis. 2020, 5(1), 28; https://doi.org/10.3390/tropicalmed5010028 - 17 Feb 2020
Cited by 11 | Viewed by 4129
Abstract
Current anti-trypanosomal therapies suffer from problems of longer treatment duration, toxicity and inadequate efficacy, hence there is a need for safer, more efficacious and ‘easy to use’ oral drugs. Previously, we reported the discovery of the triazolopyrimidine (TP) class as selective kinetoplastid proteasome [...] Read more.
Current anti-trypanosomal therapies suffer from problems of longer treatment duration, toxicity and inadequate efficacy, hence there is a need for safer, more efficacious and ‘easy to use’ oral drugs. Previously, we reported the discovery of the triazolopyrimidine (TP) class as selective kinetoplastid proteasome inhibitors with in vivo efficacy in mouse models of leishmaniasis, Chagas Disease and African trypanosomiasis (HAT). For the treatment of HAT, development compounds need to have excellent penetration to the brain to cure the meningoencephalic stage of the disease. Here we describe detailed biological and pharmacological characterization of triazolopyrimidine compounds in HAT specific assays. The TP class of compounds showed single digit nanomolar potency against Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense strains. These compounds are trypanocidal with concentration-time dependent kill and achieved relapse-free cure in vitro. Two compounds, GNF6702 and a new analog NITD689, showed favorable in vivo pharmacokinetics and significant brain penetration, which enabled oral dosing. They also achieved complete cure in both hemolymphatic (blood) and meningoencephalic (brain) infection of human African trypanosomiasis mouse models. Mode of action studies on this series confirmed the 20S proteasome as the target in T. brucei. These proteasome inhibitors have the potential for further development into promising new treatment for human African trypanosomiasis. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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10 pages, 447 KiB  
Article
Haemoparasitic Infections in Cattle from a Trypanosoma brucei Rhodesiense Sleeping Sickness Endemic District of Eastern Uganda
by Enock Matovu, Claire Mack Mugasa, Peter Waiswa, Annah Kitibwa, Alex Boobo and Joseph Mathu Ndung’u
Trop. Med. Infect. Dis. 2020, 5(1), 24; https://doi.org/10.3390/tropicalmed5010024 - 07 Feb 2020
Cited by 9 | Viewed by 3409
Abstract
We carried out a baseline survey of cattle in Kaberamaido district, in the context of controlling the domestic animal reservoir of Trypanosoma brucei rhodesiense human African trypanosomiasis (rHAT) towards elimination. Cattle blood was subjected to capillary tube centrifugation followed by measurement of the [...] Read more.
We carried out a baseline survey of cattle in Kaberamaido district, in the context of controlling the domestic animal reservoir of Trypanosoma brucei rhodesiense human African trypanosomiasis (rHAT) towards elimination. Cattle blood was subjected to capillary tube centrifugation followed by measurement of the packed cell volume (PCV) and examination of the buffy coat area for motile trypanosomes. Trypanosomes were detected in 561 (21.4%) out of 2621 cattle screened by microscopy. These 561 in addition to 724 apparently trypanosome negative samples with low PCVs (≤25%) were transported to the laboratory and tested by PCR targeting the trypanosomal Internal Transcribed Spacer (ITS-1) as well as suspect Tick-Borne Diseases (TBDs) including Anaplasmamosis, Babesiosis, and Theileriosis. PCR for Anaplasma sp yielded the highest number of positive animals (45.2%), followed by Trypanosoma sp (44%), Theileria sp (42.4%) and Babesia (26.3%); multiple infections were a common occurrence. Interestingly, 373 (29%) of these cattle with low PCVs were negative by PCR, pointing to other possible causes of aneamia, such as helminthiasis. Among the trypanosome infections classified as T. brucei by ITS-PCR, 5.5% were positive by SRA PCR, and were, therefore, confirmed as T. b. rhodesiense. Efforts against HAT should therefore consider packages that address a range of conditions. This may enhance acceptability and participation of livestock keepers in programs to eliminate this important but neglected tropical disease. In addition, we demonstrated that cattle remain an eminent reservoir for T. b. rhodesiense in eastern Uganda, which must be addressed to sustain HAT elimination. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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18 pages, 3961 KiB  
Article
Phenotypic Drug Discovery for Human African Trypanosomiasis: A Powerful Approach
by Frederick S. Buckner, Andriy Buchynskyy, Pendem Nagendar, Donald A. Patrick, J. Robert Gillespie, Zackary Herbst, Richard R. Tidwell and Michael H. Gelb
Trop. Med. Infect. Dis. 2020, 5(1), 23; https://doi.org/10.3390/tropicalmed5010023 - 05 Feb 2020
Cited by 5 | Viewed by 3190
Abstract
The work began with the screening of a library of 700,000 small molecules for inhibitors of Trypanosoma brucei growth (a phenotypic screen). The resulting set of 1035 hit compounds was reviewed by a team of medicinal chemists, leading to the nomination of 17 [...] Read more.
The work began with the screening of a library of 700,000 small molecules for inhibitors of Trypanosoma brucei growth (a phenotypic screen). The resulting set of 1035 hit compounds was reviewed by a team of medicinal chemists, leading to the nomination of 17 chemically distinct scaffolds for further investigation. The first triage step was the assessment for brain permeability (looking for brain levels at least 20% of plasma levels) in order to optimize the chances of developing candidates for treating late-stage human African trypanosomiasis. Eleven scaffolds subsequently underwent hit-to-lead optimization using standard medicinal chemistry approaches. Over a period of six years in an academic setting, 1539 analogs to the 11 scaffolds were synthesized. Eight scaffolds were discontinued either due to insufficient improvement in antiparasitic activity (5), poor pharmacokinetic properties (2), or a slow (static) antiparasitic activity (1). Three scaffolds were optimized to the point of curing the acute and/or chronic T. brucei infection model in mice. The progress was accomplished without knowledge of the mechanism of action (MOA) for the compounds, although the MOA has been discovered in the interim for one compound series. Studies on the safety and toxicity of the compounds are planned to help select candidates for potential clinical development. This research demonstrates the power of the phenotypic drug discovery approach for neglected tropical diseases. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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13 pages, 271 KiB  
Article
Centering Patient Expectations of a Novel Home-Based Oral Drug Treatment among T. b. rhodesiense Human African Trypanosomiasis Patients in Uganda
by Shona J Lee, Renah J Apio and Jennifer J Palmer
Trop. Med. Infect. Dis. 2020, 5(1), 16; https://doi.org/10.3390/tropicalmed5010016 - 21 Jan 2020
Cited by 4 | Viewed by 2350
Abstract
The recent approval of fexinidazole for human African trypanosomiasis (HAT) caused by T. b. gambiense enables improved patient management that is pivotal to elimination. Effective in both the early and late stages of the disease, it obviates the need for invasive lumbar punctures [...] Read more.
The recent approval of fexinidazole for human African trypanosomiasis (HAT) caused by T. b. gambiense enables improved patient management that is pivotal to elimination. Effective in both the early and late stages of the disease, it obviates the need for invasive lumbar punctures which guide therapy, in some patients. Unlike existing injectable treatments requiring systematic hospitalisation, fexinidazole’s oral administration will allow many patients to be treated in an outpatient or home-based setting. Drawing on interviews with 25 T. b. rhodesiense HAT patients managed under existing protocols in Uganda where trials of fexinidazole will begin shortly, this article explores patient expectations of the new protocol to help HAT programmes anticipate patient concerns. Alongside frightening symptoms of this life-threatening illness, the pain and anxiety associated with lumbar punctures and intravenous injections of melarsoprol contributed to a perception of HAT as a serious illness requiring expert medical care. While preferring a new protocol that would avoid these uncomfortable procedures, patients’ trust in the care they received meant that nearly half were hesitant towards shifting care out of the hospital setting. Clinical observation is an important aspect of existing HAT care for patients. Programmes may need to offer extensive counselling and monitoring support before patients are comfortable accepting care outside of hospitals. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
18 pages, 444 KiB  
Article
Product Development Partnerships: Delivering Innovation for the Elimination of African Trypanosomiasis?
by Emma Michelle Taylor and James Smith
Trop. Med. Infect. Dis. 2020, 5(1), 11; https://doi.org/10.3390/tropicalmed5010011 - 15 Jan 2020
Cited by 5 | Viewed by 2759
Abstract
African trypanosomiasis has been labelled as a ‘tool-deficient’ disease. This article reflects on the role that Product Development Partnerships (PDPs) have played in delivering new tools and innovations for the control and elimination of the African trypanosomiases. We analysed three product development partnerships—DNDi, [...] Read more.
African trypanosomiasis has been labelled as a ‘tool-deficient’ disease. This article reflects on the role that Product Development Partnerships (PDPs) have played in delivering new tools and innovations for the control and elimination of the African trypanosomiases. We analysed three product development partnerships—DNDi, FIND and GALVmed—that focus on delivering new drugs, diagnostic tests, and animal health innovations, respectively. We interviewed key informants within each of the organisations to understand how they delivered new innovations. While it is too early (and beyond the scope of this article) to assess the role of these three organisations in accelerating the elimination of the African trypanosomiases, all three organisations have been responsible for delivering new innovations for diagnosis and treatment through brokering and incentivising innovation and private sector involvement. It is doubtful that these innovations would have been delivered without them. To varying degrees, all three organisations are evolving towards a greater brokering role, away from only product development, prompted by donors. On balance, PDPs have an important role to play in delivering health innovations, and donors need to reflect on how best to incentivise them to focus and continue to deliver new products. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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15 pages, 1726 KiB  
Article
Gambiense Human African Trypanosomiasis Sequelae after Treatment: A Follow-Up Study 12 Years after Treatment
by Junior Mudji, Anna Blum, Leticia Grize, Rahel Wampfler, Marie-Thérèse Ruf, Lieselotte Cnops, Beatrice Nickel, Christian Burri and Johannes Blum
Trop. Med. Infect. Dis. 2020, 5(1), 10; https://doi.org/10.3390/tropicalmed5010010 - 11 Jan 2020
Cited by 7 | Viewed by 3067
Abstract
The clinical presentation of Human African Trypanosomiasis (HAT) due to Trypanosoma brucei gambiense is well known, but knowledge on long-term sequelae is limited. In the frame of studies conducted between 2004 and 2005 in the Democratic Republic of the Congo (DRC), the prevalence [...] Read more.
The clinical presentation of Human African Trypanosomiasis (HAT) due to Trypanosoma brucei gambiense is well known, but knowledge on long-term sequelae is limited. In the frame of studies conducted between 2004 and 2005 in the Democratic Republic of the Congo (DRC), the prevalence of HAT related signs and symptoms were evaluated before the start of treatment and at the end of treatment. To explore possible long-term sequelae, the same clinical parameters were assessed in 2017 in 51 first stage and 18 second stage HAT patients. Signs and symptoms 12–13 years after treatment were compared to before and immediately after treatment and to controls matched for sex and age (±5 years). In first stage HAT patients, the prevalence of all signs and symptoms decreased compared to before treatment but were still higher after 12–13 years than immediately at the end of treatment and in the control group. In second stage HAT patients, all HAT-specific findings had continuously decreased to the point where they were in the range of the healthy control group. In a selection of oligosymptomatic first stage HAT patients, no trypanosomes were detected in the blood by microscopic examination or PCR. An oligosymptomatic presentation of HAT due to the persistence of parasites in compartments, where first stage HAT medications do not penetrate, could not be ruled out. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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16 pages, 266 KiB  
Article
Whose Elimination? Frontline Workers’ Perspectives on the Elimination of the Human African Trypanosomiasis and Its Anticipated Consequences
by Jean-Benoît Falisse, Erick Mwamba-Miaka and Alain Mpanya
Trop. Med. Infect. Dis. 2020, 5(1), 6; https://doi.org/10.3390/tropicalmed5010006 - 01 Jan 2020
Cited by 6 | Viewed by 2688
Abstract
While academic literature has paid careful attention to the technological efforts―drugs, tests, and tools for vector control―deployed to eliminate Gambiense Human African Trypanosomiasis (HAT), the human resources and health systems dimensions of elimination are less documented. This paper analyses the perspectives and experiences [...] Read more.
While academic literature has paid careful attention to the technological efforts―drugs, tests, and tools for vector control―deployed to eliminate Gambiense Human African Trypanosomiasis (HAT), the human resources and health systems dimensions of elimination are less documented. This paper analyses the perspectives and experiences of frontline nurses, technicians, and coordinators who work for the HAT programme in the former province of Bandundu in the Democratic Republic of the Congo, at the epidemic’s very heart. The research is based on 21 semi-structured interviews conducted with frontline workers in February 2018. The results highlight distinctive HAT careers as well as social elevation through specialised work. Frontline workers are concerned about changes in active screening strategies and the continued existence of the vector, which lead them to question the possibility of imminent elimination. Managers seem to anticipate a post-HAT situation and prepare for the employment of their staff; most workers see their future relatively confidently, as re-allocated to non-vertical units. The findings suggest concrete pathways for improving the effectiveness of elimination efforts: improving active screening through renewed engagements with local leaders, conceptualising horizontal integration in terms of human resources mobility, and investing more in detection and treatment activities (besides innovation). Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
16 pages, 466 KiB  
Article
Clinical Study on the Melarsoprol-Related Encephalopathic Syndrome: Risk Factors and HLA Association
by Jorge Seixas, Jorge Atouguia, Teófilo Josenando, Gedeão Vatunga, Constantin Miaka Mia Bilenge, Pascal Lutumba and Christian Burri
Trop. Med. Infect. Dis. 2020, 5(1), 5; https://doi.org/10.3390/tropicalmed5010005 - 01 Jan 2020
Cited by 8 | Viewed by 2327
Abstract
Melarsoprol administration for the treatment of late-stage human African trypanosomiasis (HAT) is associated with the development of an unpredictable and badly characterized encephalopathic syndrome (ES), probably of immune origin, that kills approximately 50% of those affected. We investigated the characteristics and clinical risk [...] Read more.
Melarsoprol administration for the treatment of late-stage human African trypanosomiasis (HAT) is associated with the development of an unpredictable and badly characterized encephalopathic syndrome (ES), probably of immune origin, that kills approximately 50% of those affected. We investigated the characteristics and clinical risk factors for ES, as well as the association between the Human Leukocyte Antigen (HLA) complex and the risk for ES in a case-control study. Late-stage Gambiense HAT patients treated with melarsoprol and developing ES (69 cases) were compared to patients not suffering from the syndrome (207 controls). Patients were enrolled in six HAT treatment centres in Angola and in the Democratic Republic of Congo. Standardized clinical data was obtained from all participants before melarsoprol was initiated. Class I (HLA-A, HLA-B, HLA-Cw) and II (HLA-DR) alleles were determined by PCR-SSOP methods in 62 ES cases and 189 controls. The principal ES pattern consisted in convulsions followed by a coma, whereas ES with exclusively mental changes was not observed. Oedema, bone pain, apathy, and a depressed humour were associated with a higher risk of ES, while abdominal pain, coma, respiratory distress, and a Babinski sign were associated with higher ES-associated mortality. Haplotype C*14/B*15 was associated with an elevated risk for ES (OR: 6.64; p-value: 0.008). Haplotypes A*23/C*14, A*23/B*15 and DR*07/B*58 also showed a weaker association with ES. This result supports the hypothesis that a genetically determined peculiar type of immune response confers susceptibility for ES. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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10 pages, 2508 KiB  
Article
(+)-Spectaline and Iso-6-Spectaline Induce a Possible Cross-Talk between Autophagy and Apoptosis in Trypanosoma brucei rhodesiense
by Kah Tee Lim, Chiann Ying Yeoh, Zafarina Zainuddin and Mohd. Ilham Adenan
Trop. Med. Infect. Dis. 2019, 4(3), 98; https://doi.org/10.3390/tropicalmed4030098 - 01 Jul 2019
Cited by 1 | Viewed by 2860
Abstract
In our previous study, two known piperidine alkaloids (+)-spectaline (1) and iso-6-spectaline (2) were isolated from the leaves of Senna spectabilis and showed no toxic effect on L6 cells. In view of the potential use of piperidine alkaloids in [...] Read more.
In our previous study, two known piperidine alkaloids (+)-spectaline (1) and iso-6-spectaline (2) were isolated from the leaves of Senna spectabilis and showed no toxic effect on L6 cells. In view of the potential use of piperidine alkaloids in S. spectabilis for the treatment of sleeping sickness, further investigation on the cell death actions of the parasite after treatment with compound 1 and 2 suggested that the treated parasites died by a process of autophagy based on the characteristic morphological alterations observed in intracellular T. b. rhodesiense. In search for apoptosis, interestingly, trypanosomes treated with high concentration of compound 1 and 2 after 72 h significantly induced an early apoptosis-like programmed cell death (PCD) such as phosphatidylserine (PS) exposure, loss of mitochondrial membrane potential and caspases activation. No DNA laddering discriminated late apoptosis event. Taken together, these findings demonstrated the potential of compound 1 and 2 as a natural chemotherapeutic capable of inducing a possible cross-talk between autophagy and apoptosis in T. b. rhodesiense. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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Review

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15 pages, 1047 KiB  
Review
New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story
by Emily A. Dickie, Federica Giordani, Matthew K. Gould, Pascal Mäser, Christian Burri, Jeremy C. Mottram, Srinivasa P. S. Rao and Michael P. Barrett
Trop. Med. Infect. Dis. 2020, 5(1), 29; https://doi.org/10.3390/tropicalmed5010029 - 19 Feb 2020
Cited by 87 | Viewed by 7509
Abstract
The twentieth century ended with human African trypanosomiasis (HAT) epidemics raging across many parts of Africa. Resistance to existing drugs was emerging, and many programs aiming to contain the disease had ground to a halt, given previous success against HAT and the competing [...] Read more.
The twentieth century ended with human African trypanosomiasis (HAT) epidemics raging across many parts of Africa. Resistance to existing drugs was emerging, and many programs aiming to contain the disease had ground to a halt, given previous success against HAT and the competing priorities associated with other medical crises ravaging the continent. A series of dedicated interventions and the introduction of innovative routes to develop drugs, involving Product Development Partnerships, has led to a dramatic turnaround in the fight against HAT caused by Trypanosoma brucei gambiense. The World Health Organization have been able to optimize the use of existing tools to monitor and intervene in the disease. A promising new oral medication for stage 1 HAT, pafuramidine maleate, ultimately failed due to unforeseen toxicity issues. However, the clinical trials for this compound demonstrated the possibility of conducting such trials in the resource-poor settings of rural Africa. The Drugs for Neglected Disease initiative (DNDi), founded in 2003, has developed the first all oral therapy for both stage 1 and stage 2 HAT in fexinidazole. DNDi has also brought forward another oral therapy, acoziborole, potentially capable of curing both stage 1 and stage 2 disease in a single dosing. In this review article, we describe the remarkable successes in combating HAT through the twenty first century, bringing the prospect of the elimination of this disease into sight. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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14 pages, 1479 KiB  
Review
Innovative Partnerships for the Elimination of Human African Trypanosomiasis and the Development of Fexinidazole
by Philippe Neau, Heinz Hänel, Valérie Lameyre, Nathalie Strub-Wourgaft and Luc Kuykens
Trop. Med. Infect. Dis. 2020, 5(1), 17; https://doi.org/10.3390/tropicalmed5010017 - 27 Jan 2020
Cited by 26 | Viewed by 5133
Abstract
Human African Trypanosomiasis (HAT or sleeping sickness) is a life-threatening neglected tropical disease that is endemic in 36 sub-Saharan African countries. Until recently, treatment options were limited and hampered by unsatisfactory efficacy, toxicity, and long and cumbersome administration regimens, compounded by infrastructure inadequacies [...] Read more.
Human African Trypanosomiasis (HAT or sleeping sickness) is a life-threatening neglected tropical disease that is endemic in 36 sub-Saharan African countries. Until recently, treatment options were limited and hampered by unsatisfactory efficacy, toxicity, and long and cumbersome administration regimens, compounded by infrastructure inadequacies in the remote rural regions worst affected by the disease. Increased funding and awareness of HAT over the past two decades has led to a steady decline in reported cases (<1000 in 2018). Recent drug development strategies have resulted in development of the first all-oral treatment for HAT, fexinidazole. Fexinidazole received European Medicines Agency positive scientific opinion in 2018 and is now incorporated into the WHO interim guidelines as one of the first-line treatments for HAT, allowing lumbar puncture to become non-systematic. Here, we highlight the role of global collaborations in the effort to control HAT and develop new treatments. The long-standing collaboration between the WHO, Sanofi and the Drugs for Neglected Diseases initiative (Geneva, Switzerland) was instrumental for achieving the control and treatment development goals in HAT, whilst at the same time ensuring that efforts were led by national authorities and control programs to leave a legacy of highly trained healthcare workers and improved research and health infrastructure. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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23 pages, 1099 KiB  
Review
The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History
by Harry P. De Koning
Trop. Med. Infect. Dis. 2020, 5(1), 14; https://doi.org/10.3390/tropicalmed5010014 - 19 Jan 2020
Cited by 74 | Viewed by 7115
Abstract
With the incidence of sleeping sickness in decline and genuine progress being made towards the WHO goal of eliminating sleeping sickness as a major public health concern, this is a good moment to evaluate the drugs that ‘got the job done’: their development, [...] Read more.
With the incidence of sleeping sickness in decline and genuine progress being made towards the WHO goal of eliminating sleeping sickness as a major public health concern, this is a good moment to evaluate the drugs that ‘got the job done’: their development, their limitations and the resistance that the parasites developed against them. This retrospective looks back on the remarkable story of chemotherapy against trypanosomiasis, a story that goes back to the very origins and conception of chemotherapy in the first years of the 20 century and is still not finished today. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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18 pages, 2054 KiB  
Review
The Trypanosomal Transferrin Receptor of Trypanosoma Brucei—A Review
by Christopher K. Kariuki, Benoit Stijlemans and Stefan Magez
Trop. Med. Infect. Dis. 2019, 4(4), 126; https://doi.org/10.3390/tropicalmed4040126 - 01 Oct 2019
Cited by 16 | Viewed by 5089
Abstract
Iron is an essential element for life. Its uptake and utility requires a careful balancing with its toxic capacity, with mammals evolving a safe and bio-viable means of its transport and storage. This transport and storage is also utilized as part of the [...] Read more.
Iron is an essential element for life. Its uptake and utility requires a careful balancing with its toxic capacity, with mammals evolving a safe and bio-viable means of its transport and storage. This transport and storage is also utilized as part of the iron-sequestration arsenal employed by the mammalian hosts’ ‘nutritional immunity’ against parasites. Interestingly, a key element of iron transport, i.e., serum transferrin (Tf), is an essential growth factor for parasitic haemo-protozoans of the genus Trypanosoma. These are major mammalian parasites causing the diseases human African trypanosomosis (HAT) and animal trypanosomosis (AT). Using components of their well-characterized immune evasion system, bloodstream Trypanosoma brucei parasites adapt and scavenge for the mammalian host serum transferrin within their broad host range. The expression site associated genes (ESAG6 and 7) are utilized to construct a heterodimeric serum Tf binding complex which, within its niche in the flagellar pocket, and coupled to the trypanosomes’ fast endocytic rate, allows receptor-mediated acquisition of essential iron from their environment. This review summarizes current knowledge of the trypanosomal transferrin receptor (TfR), with emphasis on the structure and function of the receptor, both in physiological conditions as well as in conditions where the iron supply to parasites is being limited. Potential applications using current knowledge of the parasite receptor are also briefly discussed, primarily focused on potential therapeutic interventions. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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Other

7 pages, 2892 KiB  
Opinion
From Colonial Research Spirit to Global Commitment: Bayer and African Sleeping Sickness in the Mirror of History
by Ulrich-Dietmar Madeja and Ulrike Schroeder
Trop. Med. Infect. Dis. 2020, 5(1), 42; https://doi.org/10.3390/tropicalmed5010042 - 10 Mar 2020
Cited by 6 | Viewed by 5067
Abstract
In the early 20th century, a series of epidemics across equatorial Africa brought African sleeping sickness (human African trypanosomiasis, HAT) to the attention of the European colonial administrations. This disease presented an exciting challenge for microbiologists across Europe to study the disease, discover [...] Read more.
In the early 20th century, a series of epidemics across equatorial Africa brought African sleeping sickness (human African trypanosomiasis, HAT) to the attention of the European colonial administrations. This disease presented an exciting challenge for microbiologists across Europe to study the disease, discover the pathogen and search for an effective treatment. In 1923, the first “remedy for tropical diseases”—Suramin—manufactured by Bayer AG came onto the market under the brand name “Germanin.” The development and life cycle of this product—which today is still the medicine of choice for Trypanosoma brucei (T.b), hodesiense infections—reflect medical progress as well as the successes and failures in fighting the disease in the context of historic political changes over the last 100 years. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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5 pages, 2302 KiB  
Case Report
The Flipside of Eradicating a Disease; Human African Trypanosomiasis in a Woman in Rural Democratic Republic of Congo: A Case Report
by Junior Mudji, Jonathan Benhamou, Erick Mwamba-Miaka, Christian Burri and Johannes Blum
Trop. Med. Infect. Dis. 2019, 4(4), 142; https://doi.org/10.3390/tropicalmed4040142 - 11 Dec 2019
Cited by 5 | Viewed by 2869
Abstract
Human African Trypanosomiasis (HAT) is a neglected disease caused by the protozoan parasites Trypanosoma brucei and transmitted by tsetse flies that progresses in two phases. Symptoms in the first phase include fever, headaches, pruritus, lymphadenopathy, and in certain cases, hepato- and splenomegaly. Neurological [...] Read more.
Human African Trypanosomiasis (HAT) is a neglected disease caused by the protozoan parasites Trypanosoma brucei and transmitted by tsetse flies that progresses in two phases. Symptoms in the first phase include fever, headaches, pruritus, lymphadenopathy, and in certain cases, hepato- and splenomegaly. Neurological disorders such as sleep disorder, aggressive behavior, logorrhea, psychotic reactions, and mood changes are signs of the second stage of the disease. Diagnosis follows complex algorithms, including serological testing and microscopy. Our case report illustrates the course of events of a 41-year old woman with sleep disorder, among other neurological symptoms, whose diagnosis was made seven months after the onset of symptoms. The patient had consulted two different hospitals in Kinshasa and was on the verge of being discharged from a third due to negative laboratory test results. This case report highlights the challenges that may arise when a disease is on the verge of eradication. Full article
(This article belongs to the Special Issue Human African Trypanosomiasis (Sleeping Sickness): The Road to Elimination Revisited—Achievements and Remaining Challenges)
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