Association médicamenteuse prometteuse contre la maladie du sommeil

We report efficacy and safety outcomes from a prospective case series of 31 late-stage T.b. gambiense sleeping sickness (Human African Trypanosomiasis, HAT) patients treated with a combination of nifurtimox and eflornithine (N+E) in Yumbe, northwest Uganda in 2002–2003, following on a previously reported terminated trial in nearby Omugo, in which 17 patients received the combination under the same conditions. Methodology/Principal findings Eligible sequential late-stage patients received 400 mg/Kg/day eflornithine (Ornidyl, Sanofi-Aventis) for seven days plus 15 mg/Kg/day (20 mg for children <15 years old) nifurtimox (Lampit, Bayer AG) for ten days. Efficacy (primary outcome) was monitored for 24 months post discharge. Clinical and laboratory adverse events (secondary outcome) were monitored during treatment. All 31 patients were discharged alive, but two died post-discharge of non-HAT and non-treatment causes, and one was lost to follow-up. Efficacy ranged from 90.3% to 100.0% according to analysis approach. Five patients experienced major adverse events during treatment, and neutropenia was common (9/31 patients). Conclusions/Significance Combined with the previous group of 17 trial patients, this case series yields a group of 48 patients treated with N+E, among whom no deaths judged to be treatment- or HAT-related, no treatment terminations and no relapses have been noted, a very favourable outcome in the context of late-stage disease. N+E could be the most promising combination regimen available for sleeping sickness, and deserves further evaluation. Author Summary African sleeping sickness (Human African Trypanosomiasis, or HAT), due to the parasite Trypanosoma brucei gambiense, threatens millions across remote and conflict-affected regions of sub-Saharan Africa, and causes about 15 000 reported cases every year. Untreated HAT progresses from stage 1 (infection of the blood and lymph) to stage 2 (invasion of the central nervous system), and ultimately death. Drugs for stage 2 are few. The historical mainstay, melarsoprol, is highly toxic and inefficacious in some areas due to parasite resistance. Eflornithine is the only viable alternative, already established as safe and efficacious, but difficult to administer and at risk of resistance if used in monotherapy. This paper reports on a series of 48 Ugandan patients treated with a novel combination of nifurtimox (a drug registered for Chagas disease) and eflornithine, 17 as part of a terminated trial, and 31 in a subsequent case series study. Despite the low sample size, findings are promising: no cases of treatment failure, no treatment terminations, and no HAT- or treatment-related deaths. Nifurtimox plus eflornithine may be the best treatment hope for stage 2 HAT patients in the next decade, while new drugs are developed. A larger, multi-centric trial of the combination is ongoing. Citation: Checchi F, Piola P, Ayikoru H, Thomas F, Legros D, et al. (2007) Nifurtimox plus Eflornithine for Late-Stage Sleeping Sickness in Uganda: A Case Series. PLoS Negl Trop Dis 1(2): e64. doi:10.1371/journal.pntd.0000064 Academic Editor: Photini Sinnis, New York University School of Medicine, United States of America Received: April 23, 2007; Accepted: July 11, 2007; Published: November 7, 2007 Copyright: © 2007 Checchi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Médecins Sans Frontières funded the study, was involved in study conception through its Uganda HAT treatment programme, and in preparation of this manuscript through one of its staff (HA). Competing interests: The authors have declared that no competing interests exist. * E-mail: gerardo.priotto@epicentre.msf.org Introduction Treatment of late-stage (meningo-encephalitic, stage 2) human African trypanosomiasis (sleeping sickness, HAT) due to Trypanosoma brucei gambiense currently relies on a meagre and very problematic drug armamentarium, consisting of; (i) melarsoprol, an old, extremely toxic[1] injectable, which in certain transmission foci is <70% effective[2] due to parasite resistance [3]; (ii) eflornithine, a safer[4],[5] and efficacious[4],[6] drug (if given in a 14-day standard regimen[7]) that must however be administered intravenously with 24 hour nursing care, placing an additional workload on the already fragile health systems in HAT-endemic areas; and (iii) nifurtimox, an oral drug originally intended for Chagas disease that is used on an off-label basis in HAT, but has shown disappointing cure rates as a monotherapy[8]. Since no new drugs are expected on the market for at least eight years[9], combinations of these three drugs have long been considered the way forward to maximise cure rates, lengthen the drugs' lifespan by preventing further parasite resistance, and possibly improve safety and tolerability by reducing dosages of each partner drug, which would also result in easier administration. We previously reported[10] on a trial of the three possible combinations, melarsoprol-nifurtimox, melarsoprol-eflornithine, and nifurtimox-eflornithine (N+E), initiated in 2001 in Omugo, Arua district, northwest Uganda, a historical HAT focus with high rates of melarsoprol failure[11]. The trial (known as the Bi-Therapy Trial or BTT) was interrupted on ethical grounds after 54 inclusions due to unacceptable death and severe adverse event rates in the melarsoprol-containing arms, and authorisation from the Uganda National Sleeping Sickness Control Programme to switch to eflornithine as first-line gambiense HAT therapy in Omugo, replacing melarsoprol. In this trial, the 17 patients randomised to N+E experienced significantly better outcomes: no fatalities or relapses, less frequent treatment interruptions, and fewer, milder adverse events[10], clearly delineating a promising new therapeutic avenue. The trial was conducted within a long-established Médecins

Voir : http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0000064

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