Kinetoplastid parasites have caused human disease for millennia. Significant achievements have been made toward developing new treatments for leishmaniasis (particularly on the Indian subcontinent) and for human African trypanosomiasis (HAT). Moreover, the sustained decrease in the incidence of HAT... has made the prospect of elimination a tantalizing reality. Despite the gains, no new chemical or biological entities to treat kinetoplastid diseases have been registered in more than three decades, and more work is needed to discover safe and effective therapies for patients with Chagas disease and leishmaniasis. Advances in tools for drug discovery and novel insights into the biology of the host−parasite interaction may provide opportunities for accelerated progress. Here, we summarize the output from a gathering of scientists and physicians who met to discuss the current status and future directions in drug discovery for kinetoplastid diseases.
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Background: East African trypanosomiasis is an uncommon, potentially lethal disease if not diagnosed and treated in a timely manner. South Africa, as a centre for emergency medical evacuations from much of sub-Saharan Africa, receives a high proportion of these patients, mostly tourists and expatria...te residents.
Methods: The cases of East African trypanosomiasis patients evacuated to South Africa, for whom diagnostic and clinical management advice was provided over the years 2004–2018, were reviewed, using the authors’ own records and those of collaborating clinicians.
Results: Twenty-one cases were identified. These originated in Zambia, Malawi, Zimbabwe, Tanzania, and Uganda. Nineteen cases (90%) had stage 1 (haemolymphatic) disease; one of these patients had fatal myocarditis. Of the two patients with stage 2 (meningoencephalitic) disease, one died of melarsoprol encephalopathy. Common problems were delayed diagnosis, erroneous assessment of severity, and limited access to treatment.
Conclusions: The key to early diagnosis is recognition of the triad of geographic exposure, tsetse fly bites, and trypanosomal chancre, plus good microscopy. Elements for successful management are rapid access to specific drug treatment, skilled intensive care, and good laboratory facilities. Clinical experience and the local stock of antitrypanosomal drugs from the World Health Organization have improved the chance of a successful outcome in the management of East African trypanosomiasis in South Africa; the survival rate over the period was 90.5%.
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In support of the London Declaration goals, PATH aims to catalyze engagement of the diagnostics industry and product development efforts. As part of this work, PATH conducted a diagnostic landscape analysis to identify gaps and evaluated current and nascent HAT diagnostics that may provide solutions....
We conducted literature reviews and interviews with key stakeholders to identify use cases for HAT diagnostics, understand current practices, and analyze progress toward more robust diagnostics across
different biomarkers.
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Full Perscribing information on Fexinidazole Tablet for oral use
INDICATIONS AND USAGE
Fexinidazole Tablets are indicated for the treatment of both the first-stage (hemolymphatic) and second-stage (meningoencephalitic) human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense in pati...ents 6 years of age and older and weighing at least 20 kg.
Limitations of Use
Due to the decreased efficacy observed in patients with severe second stage HAT (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/μL) due to T. brucei gambiense disease, Fexinidazole Tablets should only be used in these patients if there are no other available treatment options [see Warnings and Precautions (5.1)]
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Les progrès remarquables réalisés dans la lutte contre la forme à T. b. gambiense reposent sur le dépistage et le traitement curatif, une stratégie qui interrompt la transmission en réduisant le réservoir de parasites chez l’être humain. Parfois, cette
approche a été combinée avec des... activités de lutte antivectorielle. L’objet de ces lignes directrices est donc de la plus haute importance pour la poursuite des progrès en vue de l’élimination de la THA.
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This document focuses on the management of patients affected by gambiense HAT and
constitutes an update to the WHO therapeutic guidance issued in 2013. The main changes in recommendations concern the criteria and methods for deciding the treatment among the new set of therapeutic options and the pa...rticular conditions that apply to treatment with fexinidazole, as outlined below. Because HAT is a serious, life-threatening disease and because the efficacy of fexinidazole depends on swallowing the medicine after an appropriate intake of food as well as on completing the full 10-day
treatment schedule, the recommendations regarding fexinidazole administration are considered key elements that must be carefully followed. When the conditions listed in these guidelines are not met for any individual patient, the alternative available treatments should be prescribed.
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FIND and Standard Diagnostics (SD) have developed a lateral flow rapid diagnostic test (RDT) to screen for
T.b. gambiense HAT that is cheap and easy to use. The tests are packed individually and are stable at 40°C for
up to 25 months; they are performed on fresh blood obtained from a finger prick..., and no instrument or electricity is required. The RDT detects host antibodies to infection in populations that are at risk, or in suspect individuals. Positive cases are subjected to further confirmatory methods to identify HAT patients.
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Sleeping sickness is a neglected tropical disease affecting rural communities in sub-Saharan Africa. The reduction in the number of reported cases in recent years indicates that disease transmission is under control. However, many aspects of patient management still need to be improved. Undiagnosed ...patients or inappropriate treatment due to an incorrect determination of the disease stage could in fact lead to its re-emergence. There is thus a strong need for new diagnostic and staging tools to keep the disease under control and to improve the clinical care of patients. This review describes the most promising biomarkers proposed so far for the diagnosis and stage determination of patients suffering from sleeping sickness, with a particular emphasis on their translation into diagnostic tools for field applications.
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A wide spectrum of disease severity has been described for Human African Trypanosomiasis (HAT) due to
Trypanosoma brucei rhodesiense (T.b. rhodesiense), ranging from chronic disease patterns in southern countries of East Africa to an increase in virulence towards the north. However, only limited d...ata on the clinical presentation of T.b. rhodesiense HAT is available. From 2006-2009 we conducted the first clinical trial program (I MPAMEL III) in T.b. rhodesiense endemic areas of
Tanzania and Uganda in accordance with international standards (ICH-GCP). The primary and secondary outcome measures were safety and efficacy of an abridged melarsoprol schedule for treatment of second stage disease. Based on diagnostic findings and clinical examinations at baseline we describe the clinical presentation of T.b. rhodesiense HAT in second stage patients from two distinct geographical settings in East Africa.
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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 associat...ed 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.
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Treatment of second-stage gambiense human African trypanosomiasis relied on toxicarsenic-based derivatives for over 50 years. The availability and subsequent use of eflornithine,initially in monotherapy and more recently in combination with nifurtimox (NECT), has drasticallyimproved the pro...gnosis of treated patients. However, NECT logistic and nursing requirementsremain obstacles to its deployment and use in peripheral health structures in rural sub-SaharanAfrica. Two oral compounds, fexinidazole and SCYX-7158, are currently in clinical development.The main scope of this article is to discuss the potential impact of new oral therapies to improvediagnosis-treatment algorithms and patients’access to treatment, and to contribute to reach theobjectives of the recently launched gambiense humanAfrican trypanosomiasis elimination program
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Arsenical monotherapies were previously very successful for treating human African trypanosomiasis (HAT).
Melarsoprol resistance emerged as early as the 1970s and was widespread by the late 1990s.
Melarsoprol resistance represents the only example of widespread drug resistance in HAT patients wher...e the genetic mechanism has been established.
The current goal of elimination of HAT as a public health problem by 2020 may be undermined by the emergence and spread of resistance to current or new drugs.
Insights into potential resistance mechanisms for current and new drugs will facilitate predictions of the likelihood of resistance and will also facilitate rational approaches to minimizing, monitoring, and tackling the future emergence of resistance.
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The development of this target product profile (TPP) was led by the WHO Department of Control of Ne-
glected Tropical Diseases (NTD) following standard WHO guidance for TPP development. In order to
identify and prioritize diagnostic needs, a WHO NTD Diagnostics Technical Advisory Group (DTAG)
was... formed, and different subgroups were created to advise on specific NTDs, including a subgroup
working on the human African trypanosomiasis (HAT) diagnostic innovation needs. This group of in-
dependent experts included leading scientists, public health officials and endemic-country end-user rep-
resentatives. Standard WHO Declaration of Interest procedures were followed. A landscape analysis of
the available products and of the development pipeline was conducted, and the salient areas with unmet
needs were identified
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DNDi is now striving to make fexinidazole available to the majority of people who have T.b. gambiense sleeping sickness. We are supporting a three-year access and pharmacovigilance study that began in 2020 and have so far carried out in-country training of relevant staff in 250 hospitals and... health centres in T.b. gambiense-endemic countries; and updated national treatment and pharmacovigilance guidelines in Angola, Central African Republic, the Democratic Republic of Congo, Equatorial Guinea, Guinea, and Chad.
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This was a Phase 3, multi-center, randomized, open-label, parallel-group, active control study where 273 male and female patients with first stage Trypanosoma brucei gambiense HAT were treated at six sites: one trypanosomiasis reference center in Angola, one hospital in South Sudan, and four hospita...ls in the Democratic Republic of the Congo between August 2005 and September 2009 to support the registration of pafuramidine for treatment of first stage HAT in collaboration with the United States Food and Drug Administration. Patients were treated with either 100 mg of pafuramidine orally twice a day for 10 days or 4 mg/kg pentamidine intramuscularly once daily for 7 days to assess the efficacy and safety of pafuramidine versus pentamidine. Pregnant and lactating women as well as adolescents were included.
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At the forefront of DNDi’s efforts to develop new treatments is the need to understand the realities and treatment needs of patients and health care staff in the field. The ultimate goal for human African trypanosomiasis (HAT) is a truly simplified
treatment which can be orally administered, impl...emented at the primary health care level, and effective against both stages of the disease.
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After 100 years of chemotherapy with impractical and toxic drugs, an oral cure for human African trypanosomiasis (HAT) is available: Fexinidazole. In this case, we review the history of drug discovery for HAT with special emphasis on the discovery, pre-clinical development, and operational challenge...s of the clinical trials of fexinidazole. The screening of the Drugs for Neglected Diseases initiative (DNDi) HAT-library by the Swiss TPH had singled out fexinidazole, originally developed by Hoechst (now Sanofi), as the most promising of a series of over 800 nitroimidazoles and related molecules. In cell culture, fexinidazole has an IC50 of around 1 µM against Trypanosoma brucei and is more than 100-fold less toxic to mammalian cells. In the mouse model, fexinidazole cures both the first, haemolymphatic, and the second, meningoencephalitic stage of the infection, the latter at 100 mg/kg twice daily for 5 days. In patients, the clinical trials managed by DNDi and supported by Swiss TPH mainly conducted in the Democratic Republic of the Congo demonstrated that oral fexinidazole is safe and effective for use against first- and early second-stage sleeping sickness. Based on the positive opinion issued by the European Medicines Agency in 2018, the WHO has released new interim guidelines for the treatment of HAT including fexinidazole as the new therapy for first-stage and non-severe second-stage sleeping sickness caused by Trypanosoma brucei gambiense (gHAT). This greatly facilitates the diagnosis and treatment algorithm for gHAT, increasing the attainable coverage and paving the way towards the envisaged goal of zero transmission by 2030.
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Human African trypanosomiasis (HAT), or sleeping sickness, is a painful and protracted disease transmitted through the bite of infected tsetse flies and it is found in rural parts of sub-Saharan Africa. Sleeping sickness has two clinical phases but this review focuses only on treatment of the second...-stage, which is characterized by neurological changes and almost invariably fatal without treatment. There are only a few drugs currently available for second-stage sleeping sickness, all with considerable adverse events and variable efficacy.
The review includes nine trials with 2577 participants. Each trial reported different comparisons of the drugs currently available to treat second stage HAT (melarsoprol, eflornithine, nifurtimox) so no meta-analysis was possible.
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