Innovative Partnerships for the Elimination of Human African Trypanosomiasis and the Development of Fexinidazole

Abstract

Human African Trypanosomiasis (HAT or sleeping sickness) is a life-threatening neglected tropical disease that is endemic in 36 sub-Saharan African countries. Until recently, treatment options were limited and hampered by unsatisfactory efficacy, toxicity, and long and cumbersome administration regimens, compounded by infrastructure inadequacies in the remote rural regions worst affected by the disease. Increased funding and awareness of HAT over the past two decades has led to a steady decline in reported cases (<1000 in 2018). Recent drug development strategies have resulted in development of the first all-oral treatment for HAT, fexinidazole. Fexinidazole received European Medicines Agency positive scientific opinion in 2018 and is now incorporated into the WHO interim guidelines as one of the first-line treatments for HAT, allowing lumbar puncture to become non-systematic. Here, we highlight the role of global collaborations in the effort to control HAT and develop new treatments. The long-standing collaboration between the WHO, Sanofi and the Drugs for Neglected Diseases initiative (Geneva, Switzerland) was instrumental for achieving the control and treatment development goals in HAT, whilst at the same time ensuring that efforts were led by national authorities and control programs to leave a legacy of highly trained healthcare workers and improved research and health infrastructure.

Keywords: T. b. gambiense; T. b. rhodesiense; elimination; fexinidazole; g-HAT; human African trypanosomiasis; neglected tropical diseases; r-HAT; sleeping sickness.

Figure 1

Total number of Human African Trypanosomiasis (HAT) cases reported per year (2000–2018) using data provided by national sleeping sickness control programs, non-governmental organizations, and research institutions, and assembled in the Atlas of HAT published in [2,15].

Figure 2

Latest treatment options for Human African Trypanosomiasis (HAT). (a) Heath workers transporting a Nifurtimox–Eflornithine Combination Therapy (NECT) kit in a remote region of the Democratic Republic of the Congo. The package contains four treatments and weighs approximately 36 kg [23]. (b) NECT required for the treatment of one patient. Nifurtimox is supplied in glass bottles, each containing 100 tablets of 120 mg and is given orally at a dose of 15 mg/kg/day, every 8 h for 10 days. Eflornithine is supplied in glass bottles (200 mg/mL in 100 mL bottles), is given by intravenous infusion 400 mg/kg/day every 12 h for 7 days, and once opened must be stored in the fridge (for up to 24 h) [23]. (c) and (d) Fexinidazole treatment for children (aged ≥ 6 years and weighing ≥ 20 and <35 kg): each wallet contains 14 tablets (1 aluminum foil blister of 6 tablets and 1 aluminum foil blister of 8 tablets) to be taken once daily with food as 2 tablets (1200 mg) once a day for the first 4 days of treatment, and 1 tablet (600 mg) once a day for the remaining 6 days. (e) and (f) Fexinidazole treatment for adults (weighing ≥ 35 kg): each wallet contains 24 tablets (2 aluminum foil blisters of 12 tablets) to be taken once daily with food with 3 tablets (1800 mg) once a day for the first 4 days of treatment, and 2 tablets (1200 mg) once a day for the remaining 6 days [24].

Figure 3

Timeline of the fexinidazole development project. DNDi, Drugs for Neglected Diseases initiative; EMA, European Medicines Agency; FDA, Food and Drug Administration; DRC, Democratic Republic of Congo; CAR, Central African Republic; NSSCP, National Sleeping Sickness Control Program; WHO, World Health Organization; HAT, Human African Trypanosomiasis.

Figure 4

Locations of the 10 sites involved in the phase II/III clinical trials of fexinidazole led by the director of Le Programme National de Lutte contre la Trypanosomiase Humaine Africaine (PNLTHA). Inset: the Isangi clinical site along the Congo river in Democratic Republic of Congo.

Figure 5

Estimated cost and funding of the fexinidazole development project. (a) Estimated allocation of funds per phase of development: 55 million Euros from 2005–2019. (b) Estimated allocation per donor. Donors: the Bill & Melinda Gates Foundation (BMGF, Seattle, WA, USA), the UK Department for International Development (DFID, London, UK), the Dutch Ministry of Foreign Affairs, the German Federal Ministry of Education and Research, the German Development Agency, the French Development Agency, the French Ministry of Foreign and European Affairs, the Norwegian Agency for Development Cooperation, the Spanish Agency for International Development Cooperation, the Republic and Canton of Geneva, Switzerland, the Swiss Agency for Development and Cooperation, Médecins Sans Frontières (MSF)/Doctors without Borders, Brian Mercer Charitable Trust, and other donors from the HAT campaign.