Human African trypanosomiasis – current treatments and the drug pipeline


Human African trypanosomiasis (HAT), commonly referred to as sleeping sickness, is a protozoan parasitic infection transmitted by the tsetse fly. Its two causative agents, Trypansoma brucei gambiense and Trypanosoma brucei rhodesiense, lead to different courses of disease, with T. brucei gambiense (responsible for >98% of reported cases) causing a chronic infection and T. b. rhodesiense a far more acute disease. However, in both cases, once symptoms emerge the patients is often in an advanced stage where the parasite has invaded the central nervous system (CNS), leading to severe physiological outcomes [1].

Sustained control efforts have dramatically reduced the number of HAT cases; for example, between 2000 and 2012 case numbers decreased by 73% [1]. Following this, the WHO has set the target of eliminating this disease as a public health problem by 2020 as part of their Roadmap on neglected tropical diseases. However, approximately 13 million individuals are still considered to be at medium- to high-risk of HAT infection [2], and there are concerns that current diagnostic and treatment methods may present some barriers to the elimination goal.

Here, we discuss the issues around the current guidance and give an overview of the current clinical pipeline being spearheaded by the Drugs for Neglected Diseases initiative (DNDi; Geneva, Switzerland). Read on to find out more.

Current protocols – the issues

At present, the diagnosis of HAT begins with screening for infection – the screening process has been central to the elimination strategy and involves simple serological tests and checks for clinical signs and symptoms. However, if a case is suspected the disease must then be ‘staged’ to determine disease progression and choose appropriate treatment. This process requires a trained healthcare professional as it involves an invasive lumbar puncture to examine the cerebrospinal fluid [1].

HAT is considered to have two stages: during the first stage the parasite replicates in blood, lymph and subcutaneous tissues causing symptoms such as headache, fever and joint pain. In stage two the parasite crosses the blood–brain barrier, infecting the CNS and producing more severe symptoms including confusion, poor coordination, behavior changes and sleep-pattern disturbance [1].

Without treatment, this disease is often fatal [1]; therefore, correct staging and therapy are crucial. There are a total of five compounds currently used for sleeping sickness [2].

Stage one

Suramin is currently the first-line option for treating the initial stage of HAT (before the CNS has been infected), with pentamidine being second choice. However, both drugs are administered via injection, requiring a healthcare professional, and both are ineffective in stage two and have adverse side effects. In the case of suramin, these include nausea, vomiting and allergic reactions [3].

Stage two

Melarsoprol was the first drug to be developed for HAT, having been used medically since 1949. It can treat both gambiense and rhodesiense infections; a clear advantage compared with other treatments as it is the only stage two drug effective against rhodesiense. However, as an arsenic derivative this compound has many undesirable effects including fatal, reactive encephalopathy, which occurs in up to 1 in 20 patients. In addition, resistance to this drug has been observed in several foci [3].

Eflornithine, a less toxic alternative to melarsoprol, can also be used to treat HAT in the second stage. However, not only is this compound ineffective against T.b. rhodesiense, the drug regimen is also extremely complex. The therapy constitutes an extensive 56 intravenous infusions (4-times per day across 14 days) and therefore the attention of medical professionals and an extended hospital stay are necessary requirements. Today eflornithine is rarely used alone [3].

In 2009, the DNDi and its partners launched the first new HAT treatment in 25 years – nifurtimox. Nifurtimox is often used in a combination treatment with eflornithine, which simplifies the regemin of eflornithine alone by introducing this oral compound. The course requires only 14 intravenous infusions (for 2 hours each across 7 days), halving the prior treatment time of eflornithine alone [3]. However, this regimen still requires a hospital stay and trained healthcare professionals in order to be administered.

With the elimination goal in mind, it has been argued that there needs to be a shift in both diagnosis and treatment approaches, moving away from complex medical procedures [2]. Issues with administration and stage-specificity have presented a need for patients to be screened at home, and given safe, effective and easy-to-administer oral treatments. The hope is that simpler regimens would allow more individuals, particularly those in rural areas, to access treatments and screening programs, aiding wider public health goals.

Current clinical candidates

The DNDi, along with partners including the Bill & Melinda Gates Foundation (WA, USA), Sanofi (Paris, France) and Médecins Sans Frontières (Geneva, Switzerland) are attempting to address the deficiency in accessible treatments and currently have two oral candidates in clinical trials [7].

Acoziborole (SCYX-7158)

Acoziborole was selected as a promising candidate in late 2009 following years of compound optimization. When given in a single dose, acoziborole was demonstrated to be safe and effective against the equivalent of HAT stage two in animal models [6]. After successful preclinical trials, the drug entered clinical development in 2012, becoming the first to do so from the DNDi’s lead-optimization program.

A Phase II/III trial was initiated in the last quarter of 2016, which is aiming to enrol 360 participants across seven study sites in the Democratic Republic of Congo. The study is hoping to assess the safety and efficacy of acoziborole when given as a single dose to adult patients with T.b. Gambiense. Participants in a fasting state (to facilitate the oral administration) will be given 960 mg of the drug via a single intake of three tablets. Initial completion of the trial is expected to be completed by April 2020 [5].


Fexinidazole is the result of compound-mining efforts pursued by the DNDi in 2005 and is currently the most advanced candidate being developed for HAT. If successful, fexinidazole will provide a 10-day oral treatment able to be administered at the primary healthcare level for patients to take at home [7].

A pivotal Phase II//III trial was completed in 2016 [8,4], although results are yet to be published, and two additional ‘plug-in’ trials are currently ongoing. These two ongoing investigations are aiming to gather additional information about the drug in special population groups not examined in the initial cohort [7].

The first plug-in study is assessing the efficacy and safety of fexinidazole in adults in HAT stage one and early stage two. Unlike the original study, which only examined stage two, this plug-in is hoping to gather data on earlier phases of the disease [10]. It is aiming to enrol 230 participants. The second trial is investigating the same parameters – safety and efficacy – in children over the age of 6 and at least 20 kg in body weight. This population has not previously been investigated, as the initial trial only assessed adults. Once again the participants enrolled will also be a mixture of both stage one and two [11].

In addition to these, the DNDi are also running a Phase III trial examining the effectiveness of fexinidazole in patients treated on both an out-patient basis and in a clinical hospital setting – depending on status. The trial is currently recruiting participants at all stages of T.b. gambiense infection and hopes to provide information about the drug’s use in settings replicating what the DNDi hope will become standard. The trial is aiming to enrol 170 participants, with an estimated completion date of March 2020 [9].


The 2012 WHO Roadmap calls for sustained HAT case detection and surveillance in addition to close monitoring of elimination activities in order to ensure the elimination goal is achieved. However, the Roadmap states: “it can be expected that new tools, mainly medicines and diagnostic techniques, will become available in the coming years to facilitate the eliminations process” [12]. Therefore the ongoing trials and investment in the pipeline are of the utmost importance until 100% of foci are eliminated, whether this is by 2020 or beyond.

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Want to find out more? Take a look at the global prevalence of Human African trypanosomiasis and the institutions researching it on our Disease Tracker.

  1. World Health Organization, Trypanosomiasis. Human African (sleeping sickness). (Accessed 15th August 2017)
  2. Drugs for Neglected Diseases initiative. HAT, Human African Trypansomiasis. (Accessed 15th August 2017)
  3. Drugs for Neglected Diseases initiative. About sleeping sickness > The current treatments. 15th August 2017)
  4. Drugs for Neglected Diseases initiative. New oral drug candidate for African sleeping sickness. (Accessed 15th August 2017)
  5. Drugs for Neglected Diseases initiative. Prospective study on efficacy and safety of SCYX-7158 in patients infected by human African trypanosomiasis due to b. Gambiense (OXA002). NLM identifier: NCT03087955
  6. Drugs for Neglected Diseases initiative. Portfolio: Acoziborole (SCYX-7158) (Accessed 15th August 2017)
  7. Drugs for Neglected Diseases initiative. Portfolio: Fenindazole. 15th August 2017)
  8. Drugs for Neglected Diseases initiative. Pivotal study of Fexinidazole for human African trypanosomiasis in Stage 2. NLM identifier: NCT01685827
  9. Drugs for Neglected Diseases initiative. Fexinidazole in human African trypanosomiasis due to b. Gambiense at any stage. NLM identifier: NCT03025789
  10. Drugs for Neglected Diseases initiative. Efficacy and safety of fexinidazole in patients with stage 1 or early stage 2 human African trypanosomiasis (HAT) due to b. Gambiense: a prospective, multicentre, open-label cohort study, plug-in to the pivotal study. NLM identifier: NCT02169557
  11. Drugs for Neglected Diseases initiative. Efficacy and safety of Fexinidazole in children at least 6 years old and weighing over 20 kg with human African trypanosomiasis (HAT) due to b. Gambiense: a prospective, multicentre, open study, plug-in to the pivotal study NLM identifier: NCT02184689
  12. World Health Organization. Accelerating work to overcome the global impact of neglected tropical diseases: A roadmap for implementation. (Accessed 15th August 2017)



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