Date Published: November 7, 2007
Publisher: Public Library of Science
Author(s): Francesco Checchi, Patrice Piola, Harriet Ayikoru, Florence Thomas, Dominique Legros, Gerardo Priotto, Photini Sinnis
Abstract: BackgroundWe 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 findingsEligible 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/SignificanceCombined 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.
Partial Text: 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 injectable, which in certain transmission foci is <70% effective due to parasite resistance ; (ii) eflornithine, a safer, and efficacious, drug (if given in a 14-day standard regimen) 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. Since no new drugs are expected on the market for at least eight years, 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. In mid-2002, the centre of HAT screening activities shifted from Omugo, Arua district, to Yumbe District hospital, about 40 Km northeast. Accordingly, the NECS study recruited patients presenting to Yumbe hospital, on a sequential basis. Yumbe district (pop. 253 000, 2002 census) borders Sudan. Most of the district's villages (rural communities scattered over thinly forested savannah) reported HAT cases in the decade prior to the study (MSF, unpublished observations). The BTT and NECS studies represent the first experience with a nifurtimox and eflornithine combination within a research context. Though small and inconclusive, we believe these studies represent a ‘proof of concept’ justifying further N+E experimentation. Altogether, our group of 48 patients shows very promising results: a favourable safety profile within the context of HAT, only one temporary regimen interruption (in the BTT), no treatment- or HAT-associated deaths, and no relapses in a setting where melarsoprol failures exceed 30%. By comparison, case-fatality rates among non-relapsing patients treated with melarsoprol were 4% (66/1596) in Omugo during 1996–2002, and 1% (1/93) in Yumbe during 2000–2002 (MSF unpublished data). Among adverse events, the high frequency of neutropaenia, already highlighted during the BTT, was confirmed as a safety concern in the NECS, although only one of the nine episodes was considered major. In the two weeks following treatment, this could lead to opportunistic infections that might not receive appropriate treatment in remote HAT foci, especially among very advanced stage 2 patients, who may already be immuno-compromised, and among HIV-positives. Haematological and post-discharge monitoring of future N+E cohorts is thus warranted. Because the N+E regimen we applied reduces the eflornithine dose by half, it might nonetheless carry a lower risk of neutropaenia than eflornithine monotherapy, unless a drug interaction exists. Neutropenia as well as other bone marrow toxic effects affect 25–50% of patients receiving eflornithine monotherapy, but the numbers followed to date are small, and the clinical significance of such adverse events has not been studied in the context of HAT. Source: http://doi.org/10.1371/journal.pntd.0000064