Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort study.
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SUBMITTER: Kande Betu Ku Mesu V
PROVIDER: S-EPMC8220131 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
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Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort study.
Kande Betu Ku Mesu Victor V Mutombo Kalonji Wilfried W Bardonneau Clélia C Valverde Mordt Olaf O Ngolo Tete Digas D Blesson Séverine S Simon François F Delhomme Sophie S Bernhard Sonja S Mahenzi Mbembo Hélène H Mpia Moke Christian C Lumeya Vuvu Steven S Mudji E'kitiak Junior J Akwaso Masa Felix F Mukendi Ilunga Melchias M Mpoyi Muamba Nzambi Dieudonné D Mayala Malu Tim T Kapongo Tshilumbwa Serge S Botalema Bolengi Franck F Nkieri Matsho Mathieu M Lumbala Crispin C Scherrer Bruno B Strub-Wourgaft Nathalie N Tarral Antoine A
The Lancet. Global health 20210701 7
<h4>Background</h4>Staging and treatment of human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT) required lumbar puncture to assess cerebrospinal fluid (CSF) and intravenous drugs that cross the blood-brain barrier for late-stage infection. These procedures are inconvenient in rural health systems of disease-endemic countries. A pivotal study established fexinidazole as the first oral monotherapy to be effective against non-severe stage 2 g-HAT. We aimed to assess the saf ...[more]
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Project description:BackgroundFexinidazole has been reported as an effective oral monotherapy against non-severe gambiense human African trypanosomiasis in a recent trial in adults. We aimed to assess the safety and efficacy of fexinidazole in children across all disease stages of gambiense human African trypanosomiasis.MethodsWe did a multicentre, single-arm, open-label, phase 2-3 trial at eight district hospitals in the Democratic Republic of the Congo. We recruited children with a Karnofsky score of more than 50, those aged 6 years to younger than 15 years, weighing 20 kg or more, and with confirmed gambiense human African trypanosomiasis (any stage). Children weighing 20 kg or more and less than 35 kg received oral fexinidazole of 1200 mg (two × 600 mg tablets) once per day for 4 days (days 1-4) followed by 600 mg (one × 600 mg tablet) once per day for 6 days (days 5-10). Children weighing 35 kg or more received oral fexinidazole of 1800 mg (three × 600 mg tablets) once per day for 4 days (days 1-4), followed by 1200 mg (two × 600 mg tablets) once per day for 6 days (days 5-10). The primary endpoint was fexinidazole treatment success rate 12 months after end of treatment. A rate greater than 80% was deemed acceptable and a target value of 92% was aimed for. Safety was assessed through routine monitoring. This study is completed and registered with ClinicalTrials.gov, number NCT02184689.FindingsBetween May 3, 2014, and Nov 22, 2016, we screened a total of 130 paediatric patients, of whom 125 (96%) received at least one dose of fexinidazole. All 125 patients (69 [55%] patients with stage 1, 19 [15%] with early stage 2, and 37 [30%] with late stage 2 gambiense human African trypanosomiasis) completed the 10-day treatment. Treatment success rate at 12 months was 97·6% (95% CI 93·1-99·5; 122 of 125 patients). The primary endpoint was met and the targeted value of 92% was exceeded. Treatment success at 12 months was elevated across all disease stages: 98·6% (95% CI 92·2-99·9; 68 of 69 patients) in stage 1, 94·7% (74·0-99·9; 18 of 19 patients) in early stage 2, and 97·3% (85·8-99·9; 36 of 37 patients) in late stage 2 gambiense human African trypanosomiasis. No new safety issues were observed beyond those found in adult trials. Overall, 116 (93%) of 125 patients reported 586 treatment-emergent adverse events, mainly mild or moderate. The most frequently reported treatment-emergent adverse events of interest during hospital admission were vomiting (86 [69%] of 125) and headache (41 [33%]). Seven (6%) of 125 patients had severe malaria, which was often accompanied by anaemia that was unrelated to fexinidazole. One patient died following dyspnoea and injury due to traumatic aggression 172 days after end of treatment, which was considered unrelated to fexinidazole or gambiense human African trypanosomiasis.InterpretationOral fexinidazole is a safe and effective first-line treatment option across all gambiense human African trypanosomiasis disease stages in paediatric patients.FundingThrough the Drugs for Neglected Diseases initiative: the Bill & Melinda Gates Foundation (USA), the Republic and Canton of Geneva (Switzerland), the Dutch Ministry of Foreign Affairs (Netherlands), the Norwegian Agency for Development Cooperation (Norway), the Federal Ministry of Education and Research through KfW (Germany), the Brian Mercer Charitable Trust (UK), and other private foundations and individuals from the human African trypanosomiasis campaign.TranslationFor the French translation of the abstract see Supplementary Materials section.
| S-EPMC9554014 | biostudies-literature
Project description:BackgroundHuman African trypanosomiasis caused by Trypanosoma brucei gambiense (gambiense HAT) in patients with late-stage disease requires hospital admission to receive nifurtimox-eflornithine combination therapy (NECT). Fexinidazole, the latest treatment that has been recommended by WHO, also requires systematic admission to hospital, which is problematic in areas with few health-care resources. We aim to assess the safety and efficacy of acoziborole in adult and adolescent patients with gambiense HAT.MethodsThis multicentre, prospective, open-label, single-arm, phase 2/3 study recruited patients aged 15 years or older with confirmed gambiense HAT infection from ten hospitals in the Democratic Republic of the Congo and Guinea. Inclusion criteria included a Karnofsky score greater than 50, ability to swallow tablets, a permanent address or traceability, ability to comply with follow-up visits and study requirements, and agreement to hospital admission during treatment. Oral acoziborole was administered as a single 960 mg dose (3 × 320 mg tablets) to fasted patients. Patients were observed in hospital until day 15 after treatment administration then for 18 months as outpatients with visits at 3, 6, 12, and 18 months. The primary efficacy endpoint was the success rate of acoziborole treatment at 18 months in patients with late-stage gambiense HAT (modified intention-to-treat [mITT] population), based on modified WHO criteria. A complementary post-hoc analysis comparing the 18-month success rates for acoziborole and NECT (using historical data) was performed. This study is registered at ClinicalTrials.gov, NCT03087955.FindingsBetween Oct 11, 2016, and March 25, 2019, 260 patients were screened, of whom 52 were ineligible and 208 were enrolled (167 with late-stage and 41 with early-stage or intermediate-stage gambiense HAT; primary efficacy analysis set). All 41 (100%) patients with early-stage or intermediate-stage and 160 (96%) of 167 with late-stage disease completed the last 18-month follow-up visit. The mean age of participants was 34·0 years (SD 12·4), including 117 (56%) men and 91 (44%) women. Treatment success rate at 18 months was 95·2% (95% CI 91·2-97·7) reached in 159 of 167 patients with late-stage gambiense HAT (mITT population) and 98·1% (95·1-99·5) reached in 159 of 162 patients (evaluable population). Overall, 155 (75%) of 208 patients had 600 treatment-emergent adverse events. A total of 38 drug-related treatment-emergent adverse events occurred in 29 (14%) patients; all were mild or moderate and most common were pyrexia and asthenia. Four deaths occurred during the study; none were considered treatment related. The post-hoc analysis showed similar results to the estimated historical success rate for NECT of 94%.InterpretationGiven the high efficacy and favourable safety profile, acoziborole holds promise in the efforts to reach the WHO goal of interrupting HAT transmission by 2030.FundingBill & Melinda Gates Foundation, UK Aid, Federal Ministry of Education and Research, Swiss Agency for Development and Cooperation, Médecins Sans Frontières, Dutch Ministry of Foreign Affairs, Norwegian Agency for Development Cooperation, Norwegian Ministry of Foreign Affairs, the Stavros Niarchos Foundation, Spanish Agency for International Development Cooperation, and the Banco Bilbao Vizcaya Argentaria Foundation.TranslationFor the French translation of the abstract see Supplementary Materials section.
| S-EPMC10033454 | biostudies-literature
Project description:BackgroundTrypanosoma brucei gambiense is the causative agent of chronic Human African Trypanosomiasis or sleeping sickness, a disease endemic across often poor and rural areas of Western and Central Africa. We have previously published the genome sequence of a T. b. brucei isolate, and have now employed a comparative genomics approach to understand the scale of genomic variation between T. b. gambiense and the reference genome. We sought to identify features that were uniquely associated with T. b. gambiense and its ability to infect humans.Methods and findingsAn improved high-quality draft genome sequence for the group 1 T. b. gambiense DAL 972 isolate was produced using a whole-genome shotgun strategy. Comparison with T. b. brucei showed that sequence identity averages 99.2% in coding regions, and gene order is largely collinear. However, variation associated with segmental duplications and tandem gene arrays suggests some reduction of functional repertoire in T. b. gambiense DAL 972. A comparison of the variant surface glycoproteins (VSG) in T. b. brucei with all T. b. gambiense sequence reads showed that the essential structural repertoire of VSG domains is conserved across T. brucei.ConclusionsThis study provides the first estimate of intraspecific genomic variation within T. brucei, and so has important consequences for future population genomics studies. We have shown that the T. b. gambiense genome corresponds closely with the reference, which should therefore be an effective scaffold for any T. brucei genome sequence data. As VSG repertoire is also well conserved, it may be feasible to describe the total diversity of variant antigens. While we describe several as yet uncharacterized gene families with predicted cell surface roles that were expanded in number in T. b. brucei, no T. b. gambiense-specific gene was identified outside of the subtelomeres that could explain the ability to infect humans.
| S-EPMC2854126 | biostudies-literature
Project description:BackgroundWhile the combination of nifurtimox and eflornithine (NECT) is currently recommended for the treatment of the late stage human African trypansomiasis (HAT), single-agent eflornithine was still the treatment of choice when this trial commenced. This study intended to provide supportive evidence to complement previous trials.MethodsA multi-centre randomised, open-label, non-inferiority trial was carried out in the Trypanosoma brucei gambiense endemic districts of North-Western Uganda to compare the efficacy and safety of NECT (200 mg/kg eflornithine infusions every 12 h for 7 days and 8 hourly oral nifurtimox at 5 mg/kg for 10 days) to the standard eflornithine regimen (6 hourly at 100 mg/kg for 14 days). The primary endpoint was the cure rate, determined as the proportion of patients alive and without laboratory signs of infection at 18 months post-treatment, with no demonstrated trypanosomes in the cerebrospinal fluid (CSF), blood or lymph node aspirates, and CSF white blood cell count < 20 /μl. The non-inferiority margin was set at 10%.ResultsOne hundred and nine patients were enrolled; all contributed to the intent-to-treat (ITT), modified intent-to-treat (mITT) and safety populations, while 105 constituted the per-protocol population (PP). The cure rate was 90.9% for NECT and 88.9% for eflornithine in the ITT and mITT populations; the same was 90.6 and 88.5%, respectively in the PP population. Non-inferiority was demonstrated for NECT in all populations: differences in cure rates were 0.02 (95% CI: -0.07-0.11) and 0.02 (95% CI: -0.08-0.12) respectively. Two patients died while on treatment (1 in each arm), and 3 more during follow-up in the NECT arm. No difference was found between the two arms for the secondary efficacy and safety parameters. A meta-analysis involving several studies demonstrated non-inferiority of NECT to eflornithine monotherapy.ConclusionsThese results confirm findings of earlier trials and support implementation of NECT as first-line treatment for late stage T. b. gambiense HAT. The overall risk difference for cure between NECT and eflornithine between this and two previous randomised controlled trials is 0.03 (95% CI: -0.02-0.08). The NECT regimen is simpler, safer, shorter and less expensive than single-agent DFMO.Trial registrationISRCTN ISRCTN03148609 (registered 18 April 2008).
| S-EPMC5824494 | biostudies-literature
Project description:BackgroundThe World Health Organization targeted Trypanosoma brucei gambiense human African trypanosomiasis (gHAT) for elimination as a public health problem and for elimination of transmission. To measure gHAT elimination success with prevalences close to zero, highly specific diagnostics are necessary. Such a test exists in the form of an antibody-mediated complement lysis test, the trypanolysis test, but biosafety issues and technological requirements prevent its large-scale use. We developed an inhibition ELISA with high specificity and sensitivity that is applicable in regional laboratories in gHAT endemic countries.MethodsThe T. b. gambiense inhibition ELISA (g-iELISA) is based on the principle that binding of monoclonal antibodies to specific epitopes of T. b. gambiense surface glycoproteins can be inhibited by circulating antibodies of gHAT patients directed against the same epitopes. Using trypanolysis as reference test, the diagnostic accuracy of the g-iELISA was evaluated on plasma samples from 739 gHAT patients and 619 endemic controls and on dried blood spots prepared with plasma of 95 gHAT and 37 endemic controls.ResultsOverall sensitivity and specificity on plasma were, respectively, 98.0% (95% CI 96.7-98.9) and 99.5% (95% CI 98.6-99.9). With dried blood spots, sensitivity was 92.6% (95% CI 85.4-97.0), and specificity was 100% (95% CI 90.5-100.0). The g-iELISA is stable for at least 8 months when stored at 2-8°C.ConclusionThe g-iELISA might largely replace trypanolysis for monitoring gHAT elimination and for postelimination surveillance. The g-iELISA kit is available for evaluation in reference laboratories in endemic countries.
| S-EPMC8563279 | biostudies-literature
Project description:Human African trypanosomiasis (HAT, also called sleeping sickness), a neglected tropical disease endemic to sub-Saharan Africa, is caused by the parasites Trypanosoma brucei gambiense and T. brucei rhodesiense. Current drugs against this disease have significant limitations, including toxicity, increasing resistance, and/or a complicated parenteral treatment regimen. DB829 is a novel aza-diamidine that demonstrated excellent efficacy in mice infected with T. b. rhodesiense or T. b. brucei parasites. The current study examined the pharmacokinetics, in vitro and in vivo activity against T. b. gambiense, and time of drug action of DB829 in comparison to pentamidine. DB829 showed outstanding in vivo efficacy in mice infected with parasites of T. b. gambiense strains, despite having higher in vitro 50% inhibitory concentrations (IC50s) than against T. b. rhodesiense strain STIB900. A single dose of DB829 administered intraperitoneally (5 mg/kg of body weight) cured all mice infected with different T. b. gambiense strains. No cross-resistance was observed between DB829 and pentamidine in T. b. gambiense strains isolated from melarsoprol-refractory patients. Compared to pentamidine, DB829 showed a greater systemic exposure when administered intraperitoneally, partially contributing to its improved efficacy. Isothermal microcalorimetry and in vivo time-to-kill studies revealed that DB829 is a slower-acting trypanocidal compound than pentamidine. A single dose of DB829 (20 mg/kg) administered intraperitoneally clears parasites from mouse blood within 2 to 5 days. In summary, DB829 is a promising preclinical candidate for the treatment of first- and second-stage HAT caused by both Trypanosoma brucei subspecies.
| S-EPMC3811327 | biostudies-literature
Project description:Gambiense trypanosomiasis is considered an anthroponotic disease. Consequently, control programs are generally aimed at stopping transmission of Trypanosoma brucei gambiense (T. b. gambiense) by detecting and treating human cases. However, the persistence of numerous foci despite efforts to eliminate this disease questions this strategy as unique tool to pursue the eradication. The role of animals as a reservoir of T. b. gambiense is still controversial, but could partly explain maintenance of the infection at hypo-endemic levels. In the present study, we evaluated the presence of T. b. gambiense in wild animals in Equatorial Guinea. The infection rate ranged from 0.8% in the insular focus of Luba to more than 12% in Mbini, a focus with a constant trickle of human cases. The parasite was detected in a wide range of animal species including four species never described previously as putative reservoirs. Our study comes to reinforce the hypothesis that animals may play a role in the persistence of T. b. gambiense transmission, being particularly relevant in low transmission settings. Under these conditions the integration of sustained vector control and medical interventions should be considered to achieve the elimination of gambiense trypanosomiasis.
| S-EPMC4513237 | biostudies-literature
Project description:African trypanosomiasis or sleeping sickness is a zoonotic disease caused by Trypanosoma brucei, a protozoan parasite transmitted by Glossina spp. (tsetse fly). Parasite introduction into mammal hosts triggers a succession of events, involving both innate and adaptive immunity. Macrophages (MΦ) have a key role in innate defence since they are antigen-presenting cells and have a microbicidal function essential for trypanosome clearance. Adaptive immune defence is carried out by lymphocytes, especially by T cells that promote an integrated immune response. Like mammal cells, T. b. brucei parasites release extracellular vesicles (TbEVs), which carry macromolecules that can be transferred to host cells, transmitting biological information able to manipulate cell immune response. However, the exact role of TbEVs in host immune response remains poorly understood. Thus, the current study examined the effect elicited by TbEVs on MΦ and T lymphocytes. A combined approach of microscopy, nanoparticle tracking analysis, multiparametric flow cytometry, colourimetric assays and detailed statistical analyses were used to evaluate the influence of TbEVs in mouse mononuclear cells. It was shown that TbEVs can establish direct communication with cells of innate and adaptative immunity. TbEVs induce the differentiation of both M1- and M2-MΦ and elicit the expansion of MHCI+, MHCII+ and MHCI+MHCII+ MΦ subpopulations. In T lymphocytes, TbEVs drive the overexpression of cell-surface CD3 and the nuclear factor FoxP3, which lead to the differentiation of regulatory CD4+ and CD8+ T cells. Moreover, this study indicates that T. b. brucei and TbEVs seem to display opposite but complementary effects in the host, establishing a balance between parasite growth and controlled immune response, at least during the early phase of infection.
| S-EPMC8394715 | biostudies-literature
Project description:Gambiense human African trypanosomiasis (gHAT), also known as gambiense sleeping sickness, is a parasitic infection caused by Trypanosoma brucei gambiense. During the last decades, gHAT incidence has been brought to an all-time low. Newly developed serological tools and drugs for its diagnosis and treatment put the WHO goal of interruption of transmission by 2030 within reach. However, further research is needed to efficiently adapt these new advances to new control strategies. We assessed the serological evolution of cured gHAT patients over a two-year period using four different tests: the rapid diagnostic test (RDT) HAT Sero K-SeT, ELISA/T.b. gambiense, Trypanosoma brucei gambiense inhibition ELISA (iELISA), and the immune trypanolysis test. High seropositive rates were observed in all the tests, although sero-reversion rates were different in each test: ELISA/T.b. gambiense was the test most likely to become negative two years after treatment, whereas RDT HAT Sero-K-SeT was the least likely. iELISA and trypanolysis showed intermediate and comparable probabilities to become negative. Stage 1 patients were also noted to be more likely to become negative than Stage 2 patients in all four serological tests. Our results confirm previous findings that trypanosome-specific antibody concentrations in blood may persist for up to two years, implying that HAT control programs should continue to take the history of past HAT episodes into consideration.
| S-EPMC8871350 | biostudies-literature
Project description:Trypanosoma brucei gambiense Genome sequencing
| PRJNA272153 | ENA