Résistance de la Tique Invasive Rhipicephalus (Boophilus) Microplus à la Nouvelle Gamme d’Acaricides Distribués en Côte d’Ivoire

Ce travail avait pour objectif d’améliorer la lutte contre la tique Rhipicephalus (Boophilus) microplus en Côte d’Ivoire en apportant une assistance aux éleveurs dans le choix des acaricides qui leur sont proposés. Pour ce faire, il a été question de répertorier les spécialités d’acaricides distribuées en Côte d’Ivoire pour le détiquage des bovins et par la suite, évaluer le niveau de résistance-sensibilité des tiques R. (B.) microplus à ces acaricides dans les élevages péri-urbains de bovins au sud de la Côte d’Ivoire, précisément dans la zone d’Azaguié où la tique exotique R. (B.) microplus a été découverte pour la première fois en Afrique de l’Ouest. Il ressort de l’étude que six (6) molécules acaricides sont officiellement distribuées en Côte d’Ivoire (Alphacyperméthrine, Cyperméthrine, Amitraz, Fluméthrine, Deltaméthrine et Fipronil) sous diverses appellations commerciales. Face aux échecs thérapeutiques recurents et aux plaintes des éleveurs, une nouvelle gamme d’acaricides est actuellement proposée aux éleveurs. Elle est essentiellement constituée de produits à base de fluméthrine, de fipronil, de deltaméthrine ou de cyperméthrine associée au chlorpyriphos, au butoxide de pipéronyl et à la citronnelle. La méthode de référence LPT (Larval Packet Test) standardisée par la FAO a été utilisée pour évaluer le niveau de résistance de cette tique invasive R. (B.) microplus à trois (3) molécules acaricides de cette gamme à savoir la deltaméthrine, la fluméthrine et la nouvelle spécialité de molécules associées (cyperméthrine-chlorpyriphos-citronnelle-butoxide de pipéronyl). Une variation du niveau de résistance a été signalée d’un acaricide à l’autre vis-à-vis des populations de tiques R. (B.) microplus testées. L’étude a montré une résistance des populations de tiques R. (B.) microplus à la deltaméthrine et à la fluméthrine. Quant à la nouvelle spécialité de molécules associées, elle a présenté un niveau de sensibilité acceptable exprimé par les populations de tiques R. (B.) microplus.   This work aimed to improve the fight against the tick Rhipicephalus (Boophilus) microplus in Côte d'Ivoire by providing assistance to breeders in the choice of acaricides marketed. To do this, the acaricides distributed in Côte d'Ivoire for cattle treatment was inventoried and then, the level of resistance- susceptibility of R. (B.) microplus to these acaricides was estimated in peri-urban cattle farms in southern Côte d'Ivoire, precisely in the area of Azaguié where the exotic tick R. (B.) microplus was discovered for the first time in West Africa. It appears from the study that six (6) acaricidal molecules are officially distributed in Côte d'Ivoire (Alphacypermethrin, Cypermethrin, Amitraz, Flumethrin, Deltamethrin and Fipronil) under various trade names. Faced with recurrent treatment failures and complaints from breeders, a new range of acaricides is currently being offered to breeders. It essentially consists of products based on flumethrin, fipronil, deltamethrin or cypermethrin associated with chlorpyrifos, piperonyl butoxid and citronella. The reference method LPT (Larval Packet Test) standardized by the FAO was used to estimate the level of resistance of the invasive tick R. (B.) microplus to three (3) acaricides, namely deltamethrin, flumethrin and the new product of associated acaricides (cypermethrin-chlorpyrifos-piperonyl butoxid- citronella). A variation of the resistance of R. (B.) microplus has been reported from one acaricide to another. The study showed a resistance of R. (B.) microplus tick populations to deltamethrin and flumethrin. However, an acceptable level of susceptibility expressed by the population ticks of R. (B.) microplus to the association of acaricides (cypermethrin-chlorpyrifos-piperonyl butoxid-citronella) was reported

Résistance de la Tique Invasive Rhipicephalus (Boophilus) Microplus à la Nouvelle Gamme d’Acaricides Distribués en Côte d’Ivoire

Ce travail avait pour objectif d’améliorer la lutte contre la tique Rhipicephalus (Boophilus) microplus en Côte d’Ivoire en apportant une assistance aux éleveurs dans le choix des acaricides qui leur sont proposés. Pour ce faire, il a été question de répertorier les spécialités d’acaricides distribuées en Côte d’Ivoire pour le détiquage des bovins et par la suite, évaluer le niveau de résistance-sensibilité des tiques R. (B.) microplus à ces acaricides dans les élevages péri-urbains de bovins au sud de la Côte d’Ivoire, précisément dans la zone d’Azaguié où la tique exotique R. (B.) microplus a été découverte pour la première fois en Afrique de l’Ouest. Il ressort de l’étude que six (6) molécules acaricides sont officiellement distribuées en Côte d’Ivoire (Alphacyperméthrine, Cyperméthrine, Amitraz, Fluméthrine, Deltaméthrine et Fipronil) sous diverses appellations commerciales. Face aux échecs thérapeutiques recurents et aux plaintes des éleveurs, une nouvelle gamme d’acaricides est actuellement proposée aux éleveurs. Elle est essentiellement constituée de produits à base de fluméthrine, de fipronil, de deltaméthrine ou de cyperméthrine associée au chlorpyriphos, au butoxide de pipéronyl et à la citronnelle. La méthode de référence LPT (Larval Packet Test) standardisée par la FAO a été utilisée pour évaluer le niveau de résistance de cette tique invasive R. (B.) microplus à trois (3) molécules acaricides de cette gamme à savoir la deltaméthrine, la fluméthrine et la nouvelle spécialité de molécules associées (cyperméthrine-chlorpyriphos-citronnelle-butoxide de pipéronyl). Une variation du niveau de résistance a été signalée d’un acaricide à l’autre vis-à-vis des populations de tiques R. (B.) microplus testées. L’étude a montré une résistance des populations de tiques R. (B.) microplus à la deltaméthrine et à la fluméthrine. Quant à la nouvelle spécialité de molécules associées, elle a présenté un niveau de sensibilité acceptable exprimé par les populations de tiques R. (B.) microplus.   This work aimed to improve the fight against the tick Rhipicephalus (Boophilus) microplus in Côte d'Ivoire by providing assistance to breeders in the choice of acaricides marketed. To do this, the acaricides distributed in Côte d'Ivoire for cattle treatment was inventoried and then, the level of resistance- susceptibility of R. (B.) microplus to these acaricides was estimated in peri-urban cattle farms in southern Côte d'Ivoire, precisely in the area of Azaguié where the exotic tick R. (B.) microplus was discovered for the first time in West Africa. It appears from the study that six (6) acaricidal molecules are officially distributed in Côte d'Ivoire (Alphacypermethrin, Cypermethrin, Amitraz, Flumethrin, Deltamethrin and Fipronil) under various trade names. Faced with recurrent treatment failures and complaints from breeders, a new range of acaricides is currently being offered to breeders. It essentially consists of products based on flumethrin, fipronil, deltamethrin or cypermethrin associated with chlorpyrifos, piperonyl butoxid and citronella. The reference method LPT (Larval Packet Test) standardized by the FAO was used to estimate the level of resistance of the invasive tick R. (B.) microplus to three (3) acaricides, namely deltamethrin, flumethrin and the new product of associated acaricides (cypermethrin-chlorpyrifos-piperonyl butoxid- citronella). A variation of the resistance of R. (B.) microplus has been reported from one acaricide to another. The study showed a resistance of R. (B.) microplus tick populations to deltamethrin and flumethrin. However, an acceptable level of susceptibility expressed by the population ticks of R. (B.) microplus to the association of acaricides (cypermethrin-chlorpyrifos-piperonyl butoxid-citronella) was reported

Efficacy, safety, and dose of Pafuramidine, a new oral drug for treatment of first stage sleeping sickness, in a phase 2a clinical study and phase 2b randomized clinical studies

Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT.; The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent.; Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3

Should I Get Screened for Sleeping Sickness? A Qualitative Study in Kasai Province, Democratic Republic of Congo

Active screening strategies are common disease control interventions in the context of poor and remote rural communities with no direct access to healthcare facilities. For such activities to be as effective as possible, it is necessary that they are well adapted to local socio-economic and cultural settings. Our aim was to gain insight into the barriers communities in the Kasai-Oriental province of the Democratic Republic of Congo experience in relation to their participation in active screening activities for African sleeping sickness. Participation rates seem to be especially low in this province compared to other endemic regions in the country. We found several important factors to be in play, a number of which could be addressed by adapting the operational procedures of the mobile teams that perform the active screening activities (e.g., improved confidentiality during the screening procedure). However, more profound considerations were found in the form of regional beliefs related to the treatment of the disease. Although not based on rational grounds, these prohibitions seem to pose a significant barrier in a person's decision to seek diagnosis and treatment. A better understanding of these prohibitions and their origin could lead to improved participation rates for sleeping sickness screening in Kasai-Oriental

Safety and efficacy of oral fexinidazole in children with gambiense human African trypanosomiasis: a multicentre, single-arm, open-label, phase 2-3 trial

BACKGROUND: Fexinidazole 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. METHODS: We 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 x 600 mg tablets) once per day for 4 days (days 1-4) followed by 600 mg (one x 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 x 600 mg tablets) once per day for 4 days (days 1-4), followed by 1200 mg (two x 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. FINDINGS: Between 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. INTERPRETATION: Oral fexinidazole is a safe and effective first-line treatment option across all gambiense human African trypanosomiasis disease stages in paediatric patients. FUNDING: Through 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. TRANSLATION: For the French translation of the abstract see Supplementary Materials section

Anopheles bionomics, insecticide resistance mechanisms, and malaria transmission in the Korhogo area, northern Cote d'Ivoire : a pre-intervention study

A better understanding of malaria transmission at a local scale is essential for developing and implementing effective control strategies. In the framework of a randomized controlled trial (RCT), we aimed to provide an updated description of malaria transmission in the Korhogo area, northern Cote d'Ivoire, and to obtain baseline data for the trial. We performed human landing collections (HLCs) in 26 villages in the Korhogo area during the rainy season (September-October 2016, April-May 2017) and the dry season (November-December 2016, February-March 2017). We used PCR techniques to ascertain the species of the Anopheles gambiae complex, Plasmodium falciparum sporozoite infection, and insecticide resistance mechanisms in a subset of Anopheles vectors. Anopheles gambiae s.l. was the predominant malaria vector in the Korhogo area. Overall, more vectors were collected outdoors than indoors (p < 0.001). Of the 774 An. gambiae s.l. tested in the laboratory, 89.65% were An. gambiae s.s. and 10.35% were An. coluzzii. The frequencies of the kdr allele were very high in An. gambiae s.s. but the ace-1 allele was found at moderate frequencies. An unprotected individual living in the Korhogo area received an average of 9.04, 0.63, 0.06 and 0.12 infected bites per night in September-October, November-December, February-March, and April-May, respectively. These results demonstrate that the intensity of malaria transmission is extremely high in the Korhogo area, especially during the rainy season. Malaria control in highly endemic areas such as Korhogo needs to be strengthened with complementary tools in order to reduce the burden of the disease

Efficacy and safety of pafuramidine versus pentamidine maleate for treatment of first stage sleeping sickness in a randomized, comparator-controlled, international phase 3 clinical trial

Sleeping sickness (human African trypanosomiasis [HAT]) is a neglected tropical disease with limited treatment options that currently require parenteral administration. In previous studies, orally administered pafuramidine was well tolerated in healthy patients (for up to 21 days) and stage 1 HAT patients (for up to 10 days), and demonstrated efficacy comparable to pentamidine.; 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 hospitals 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. The primary efficacy endpoint was the combined rate of clinical and parasitological cure at 12 months. The primary safety outcome was the frequency and severity of adverse events. The study was registered on the International Clinical Trials Registry Platform at www.clinicaltrials.gov with the number ISRCTN85534673.; The overall cure rate at 12 months was 89% in the pafuramidine group and 95% in the pentamidine group; pafuramidine was non-inferior to pentamidine as the upper bound of the 95% confidence interval did not exceed 15%. The safety profile of pafuramidine was superior to pentamidine; however, 3 patients in the pafuramidine group had glomerulonephritis or nephropathy approximately 8 weeks post-treatment. Two of these events were judged as possibly related to pafuramidine. Despite good tolerability observed in preceding studies, the development program for pafuramidine was discontinued due to delayed post-treatment toxicity