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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 ≤20 cells per μL) 18 months after treatment. Efficacy analyses were done in the intention-to-treat (ITT), modified ITT, and per-protocol (PP) populations. The non-inferiority margin for the difference in cure rates was defined as 10%. This study is registered with ClinicalTrials.gov, number NCT00146627. One patient from the eflornithine group absconded after receiving the first dose, without any type of assessment done, and was excluded from all analyses. In the ITT population, 131 (91·6%) of 143 patients assigned to eflornithine and 138 (96·5%) of 143 patients assigned to NECT were cured at 18 months (difference −4·9%, one-sided 95% CI −0·3; p<0·0001). In the PP population, 122 (91·7%) of 133 patients in the eflornithine group and 129 (97·7%) of 132 in the NECT group were cured at 18 months (difference −6·0%, one-sided 95% CI −1·5; p<0·0001). Drug-related adverse events were frequent in both groups; 41 (28·7%) patients in the eflornithine group and 20 (14·0%) in the NECT group had major (grade 3 or 4) reactions, which resulted in temporary treatment interruption in nine and one patients, respectively. The most common major adverse events were fever (n=18), seizures (n=6), and infections (n=5) in the eflornithine group, and fever (n=7), seizures (n=6), and confusion (n=2) in the NECT group. There were four deaths, which were regarded as related to study drug (eflornithine, n=3; NECT, n=1). The efficacy of NECT is non-inferior to that of eflornithine monotherapy. Since this combination treatment also presents safety advantages, is easier to administer (ie, infusion every 12 h for 7 days vs every 6 h for 14 days), and potentially protective against the emergence of resistant parasites, it is suitable for first-line use in HAT control programmes. Médecins Sans Frontières (Dutch section), Médecins Sans Frontières International, and the Drugs for Neglected Diseases Initiative.

In 1994, combined active and passive screening reported 1469 cases from the historic Gambian Human African Trypanosomiasis (gHAT) foci of West Nile, Uganda. Since 2011 systematic active screening has stopped and there has been reliance on passive screening. During 2014, passive screening alone detected just nine cases. In the same year a tsetse control intervention was expanded to cover the main gHAT foci in West Nile to curtail transmission of gHAT contributing to the elimination of gHAT as a public health problem in the area. It is known that sole reliance on passive screening is slow to detect cases and can underestimate the actual true number. We therefore undertook an active screening programme designed to test the efficacy of these interventions against gHAT transmission and clarify disease status. Screening was conducted in 28 randomly selected villages throughout the study area, aiming to sample all residents. Whole blood from 10,963 participants was analysed using CATT and 97 CATT suspects (0.9%) were evaluated with microscopy and trypanolysis. No confirmed cases were found providing evidence that the gHAT prevention programmes in West Nile have been effective. Results confirm gHAT prevalence in the study area of West Nile is below the elimination threshold (1 new case / 10,000 population), making elimination on course across this study area if status is maintained. The findings of this study can be used to guide future HAT and tsetse management in other gHAT foci, where reduced caseloads necessitate a shift from active to passive screening.

Human African trypanosomiasis (sleeping sickness) is a parasitic infection that almost invariably progresses to death unless treated. Human African trypanosomiasis caused devastating epidemics during the 20th century. Thanks to sustained and coordinated efforts over the past 15 years, the number of reported cases has fallen to an historically low level. Fewer than 3000 cases were reported in 2015, and the disease is targeted for elimination by WHO. Despite these recent successes, the disease is still endemic in parts of sub-Saharan Africa, where it is a considerable burden on rural communities, most notably in central Africa. Since patients are also reported from non-endemic countries, human African trypanosomiasis should be considered in differential diagnosis for travellers, tourists, migrants, and expatriates who have visited or lived in endemic areas. In the absence of a vaccine, disease control relies on case detection and treatment, and vector control. Available drugs are suboptimal, but ongoing clinical trials provide hope for safer and simpler treatments.

In the 1960s, it appeared that human African trypanosomiasis (HAT) could be effectively controlled, but by the beginning of the twenty-first century several decades of neglect had led to alarming numbers of reported new cases, with an estimated 300 000 people infected. The World Health Organization (WHO) responded with a series of initiatives aimed at bringing HAT under control again. Since 2001, the pharmaceutical companies that produce drugs for HAT have committed themselves to providing them free of charge to WHO for distribution for the treatment of patients. In addition, funds have been provided to WHO to support national sleeping sickness control programmes to boost control and surveillance of the disease. That, coupled with bilateral cooperation and the work of nongovernmental organizations, helped reverse the upward trend in HAT prevalence. By 2012, the number of reported cases was fewer than 8000. This success in bringing HAT under control led to its inclusion in the WHO Roadmap for eradication, elimination and control of neglected tropical diseases, with a target set to eliminate the disease as a public health problem by 2020. A further target has been set, by countries in which HAT is endemic, to eliminate gambiense HAT by reducing the incidence of infection to zero in a defined geographical area. This report provides information about new diagnostic approaches, new therapeutic regimens and better understanding of the distribution of the disease with high-quality mapping. The roles of human and animal reservoirs and the tsetse fly vectors that transmit the parasites are emphasized. The new information has formed the basis for an integrated strategy with which it is hoped that elimination of gambiense HAT will be achieved. The report also contains recommendations on the approaches that will lead to elimination of the disease.

Few therapeutic options are available to treat the late-stage of human African trypanosomiasis, a neglected tropical disease, caused by Trypanosoma brucei gambiense (g-HAT). The firstline treatment is a combination therapy of oral nifurtimox and intravenous eflornithine that needs to be administered in a hospital setting by trained personnel, which is not optimal given that patients often live in remote areas with few health resources. Therefore, we aimed to assess the safety and efficacy of an oral regimen of fexinidazole (a 2-substituted 5-nitroimidazole with proven trypanocidal activity) versus nifurtimox eflornithine combination therapy in patients with late-stage g-HAT. In this randomised, phase 2/3, open-label, non-inferiority trial, we recruited patients aged 15 years and older with late-stage g-HAT from g-HAT treatment centres in the Democratic Republic of the Congo (n=9) and the Central African Republic (n=1). Patients were randomly assigned (2:1) to receive either fexinidazole or nifurtimox eflornithine combination therapy according to a predefined randomisation list (block size six). The funder, data management personnel, and study statisticians were masked to treatment. Oral fexinidazole was given once a day (days 1–4: 1800 mg, days 5–10: 1200 mg). Oral nifurtimox was given three times a day (days 1–10: 15 mg/kg per day) with eflornithine twice a day as 2 h infusions (days 1–7: 400 mg/kg per day). The primary endpoint was success at 18 months (ie, deemed as patients being alive, having no evidence of trypanosomes in any body fluid, not requiring rescue medication, and having a cerebrospinal fluid white blood cell count ≤20 cells per μL). Safety was assessed through routine monitoring. Primary efficacy analysis was done in the modified intention-to-treat population and safety analyses in the intention-to-treat population. The acceptable margin for the difference in success rates was defined as 13%. This study has been completed and is registered with ClinicalTrials.gov, number NCT01685827. Between October, 2012, and November, 2016, 419 patients were pre-screened. Of the 409 eligible patients, 14 were not included because they did not meet all inclusion criteria (n=12) or for another reason (n=2). Therefore, 394 patients were randomly assigned, 264 to receive fexinidazole and 130 to receive nifurtimox eflornithine combination therapy. Success at 18 months was recorded in 239 (91%) patients given fexinidazole and 124 (98%) patients given nifurtimox eflornithine combination therapy, within the margin of acceptable difference of −6·4% (97·06% CI −11·2 to −1·6; p=0·0029). We noted no difference in the proportion of patients who experienced treatment-related adverse events (215 [81%] in the fexinidazole group vs 102 [79%] in the nifurtimox eflornithine combination therapy group). Treatment discontinuations were unrelated to treatment (n=2 [1%] in the fexinidazole group). Temporary nifurtimox eflornithine combination therapy interruption occurred in three (2%) patients. 11 patients died during the study (nine [3%] in the fexinidazole group vs two [2%] in the nifurtimox eflornithine combination therapy group). Our findings show that oral fexinidazole is effective and safe for the treatment of T b gambiense infection compared with nifurtimox eflornithine combination therapy in late-stage HAT patients. Fexinidazole could be a key asset in the elimination of this fatal neglected disease. Drugs for Neglected Diseases initiative.

Human African trypanosomiasis, or sleeping sickness, is caused by infection with parasites of the genus Trypanosoma, transmitted by the tsetse fly. The disease has two forms, Trypanosoma brucei (T b) rhodesiense and T b gambiense; and is almost always fatal if untreated. Despite a recent reduction in the number of reported cases, patients with African trypanosomiasis continue to present major challenges to clinicians. Because treatment for CNS-stage disease can be very toxic, diagnostic staging to distinguish early-stage from late-stage disease when the CNS in invaded is crucial but remains problematic. Melarsoprol is the only available treatment for late-stage T b rhodesiense infection, but can be lethal to 5% of patients owing to post-treatment reactive encephalopathy. Eflornithine combined with nifurtimox is the first-line treatment for late-stage T b gambiense. New drugs are in the pipeline for treatment of CNS human African trypanosomiasis, giving rise to cautious optimism.

Trypanosomiasis has been recognized as a scourge in sub-Saharan Africa for centuries. The disease, caused by protozoan parasites of the genus, is a major cause of mortality and morbidity in animals and man. Human African trypanosomiasis (HAT), or sleeping sickness, results from infections with or with accounting for over 95% of infections. Historically there have been major epidemics of the infection, followed by periods of relative disease control. As a result of concerted disease surveillance and treatment programmes, implemented over the last two decades, there has been a significant reduction in the number of cases of human disease reported. However, the recent identification of asymptomatic disease carriers gives cause for some concern. The parasites evade the host immune system by switching their surface coat, comprised of variable surface glycoprotein (VSG). In addition, they have evolved a variety of strategies, including the production of serum resistance associated protein (SRA) and -specific glycoprotein (TgsGP) to counter host defense molecules. Infection with either disease variant results in an early haemolymphatic-stage followed by a late encephalitic-stage when the parasites migrate into the CNS. The clinical features of HAT are diverse and non-specific with early-stage symptoms common to several infections endemic within sub-Saharan Africa which may result in a delayed or mistaken diagnosis. Migration of the parasites into the CNS marks the onset of late-stage disease. Diverse neurological manifestations can develop accompanied by a neuroinflammatory response, comprised of astrocyte activation, and inflammatory cell infiltration. However, the transition between the early and late-stage is insidious and accurate disease staging, although crucial to optimize chemotherapy, remains problematic with neurological symptoms and neuroinflammatory changes recorded in early-stage infections. Further research is required to develop better diagnostic and staging techniques as well as safer more efficacious drug regimens. Clearer information is also required concerning disease pathogenesis, specifically regarding asymptomatic carriers and the mechanisms employed by the trypanosomes to facilitate progression to the CNS and precipitate late-stage disease. Without progress in these areas it may prove difficult to maintain current control over this historically episodic disease.

Human African trypanosomiasis or sleeping sickness is caused by infection with Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense parasites, which are transmitted by tsetse flies in sub-Saharan Africa. Control of human African trypanosomiasis is based on case detection, treatment, and vector control. In the past decade, simple rapid diagnostic tests were introduced for gambiense human African trypanosomiasis, facilitating screening in primary health-care facilities. A new oral drug, fexinidazole, became the first-line treatment for gambiense human African trypanosomiasis without severe meningo-encephalitic disease, as well as for rhodesiense human African trypanosomiasis. Medical interventions, in some areas combined with tiny target-based vector control, have substantially reduced human African trypanosomiasis incidence, despite temporary disruptions to health-care systems. The elimination of human African trypanosomiasis as a public health problem has been achieved, and elimination of gambiense human African trypanosomiasis transmission is now targeted for 2030. Improved diagnostics and drugs, continued involvement of populations at risk of disease, health staff, national authorities, and partners and donors all contribute to achieve this goal.

Human African trypanosomiasis (HAT), also known as sleeping sickness, is one of the Africa's 'neglected diseases' and is caused by infection with protozoan parasites of the Trypanosoma genus. Transmitted by the bite of the tsetse fly, it puts 70 million people at risk throughout sub-Saharan Africa and is usually fatal if untreated or inadequately treated. In this brief overview, some important recent developments in this disease are outlined. These cover various aspects including a reduction in disease incidence, newly recognised parasite reservoir sites in humans, disease outcome, novel diagnostic methods, new and improved treatment, and disease neuropathogenesis.

We report 4 cases of human African trypanosomiasis that occurred in Ethiopia in 2022, thirty years after the last previously reported case in the country. Two of 4 patients died before medicine became available. We identified the infecting parasite as Trypanosoma brucei rhodesiense. Those cases imply human African trypanosomiasis has reemerged.