Research in context
late-stage disease, neuroencephalitic infection, early-stage disease, pain, early-stage gambiense HAT, pruritus, headache, intermittent fever, painful lumbar puncture, HAT, acoziborole
DISEASE, AFRICAN TRYPANOSOMIASIS, NEGLECTED DISEASES

The choice of treatment for human African trypanosomiasis (HAT) has traditionally depended on the stage of disease. Once parasites proliferate beyond the haemolymphatic system (early-stage disease) and invade the CNS, drugs need to cross the blood–brain barrier to treat neuroencephalitic infection (late-stage disease). Until 2019, patients with early-stage gambiense HAT were given intramuscular pentamidine injections for 7 days, whereas those with late-stage disease received nifurtimox–eflornithine combination therapy (NECT), which requires complex logistics and needs to be administered in hospital. Treatment of gambiense HAT has improved with the development of fexinidazole, the only oral drug available for late-stage disease, and despite its substantial advantages over NECT, disease severity still needs to be assessed (possibly involving a lumbar puncture) and treatment should be taken for 10 days. We searched PubMed for articles published from Sept 25, 2017, to Sept 25, 2022, using the search terms “human African trypanosomiasis”, “treatment”, “NECT”, and “fexinidazole”, with no language restrictions. A disease-stage independent treatment, which would be simpler to administer and as efficacious as NECT, is still needed. To fulfil this unmet need, the Drugs for Neglected Diseases initiative (in collaboration with Anacor Pharmaceuticals and Scynexis) has discovered acoziborole, a new orally active compound with preclinical activity against gambiense HAT parasites, good tolerability, and which reaches the required exposure to the parasite in blood and cerebrospinal fluid after a single dose. This multicentre, prospective, phase 2/3 study was designed to assess the safety and efficacy of a single 960 mg oral dose of acoziborole administered to patients in the fasting state with gambiense HAT.
We showed a positive benefit–risk profile for using a single oral dose of acoziborole to treat gambiense HAT in adults and adolescents, regardless of disease stage. No substantial drug-related safety signals were identified and the primary objective was met, with 159 (95% [95% CI 91·2–97·7]) of 167 patients who had late-stage gambiense HAT in the intention-to-treat population reaching treatment success at 18 months, which was similar to the estimated historical results for NECT with 354 (94% [Jeffreys 95% CI 91·4–96·2]) of 376 patients. In the early-stage and intermediate-stage cohort, all 41 (100%) patients reached treatment success at 18 months. A single oral dose of acoziborole is a clear improvement compared with 10 days of NECT since disease staging by painful lumbar puncture and hospital admission for intravenous treatment are not required, and the treatment duration is shorter.
Due to the substantial decline in incidence, enrolling patients with gambiense HAT into clinical trials is challenging. Following advice from the European Medicines Agency, this study was designed as an open-label, single-arm trial with no comparator or control group. Given high treatment success rates and good safety results in this study, the WHO HAT elimination Technical Advisory Group recommended that a double-blind trial should be conducted to investigate the use of acoziborole versus placebo in seropositive patients with negative parasitological assays to generate further safety data, with an aim of contributing to the WHO target of interrupting HAT transmission by 2030. This randomised study is ongoing (There are two clinical stages of gambiense HAT. In early-stage (haemolymphatic) gambiense HAT, trypanosomes are present in the blood and lymphatic system and symptoms remain non-specific (eg, intermittent fever, headache, joint pain, pruritus, and lymphadenopathy).Therapeutic options depend on disease stage. Patients with early-stage gambiense HAT often receive pentamidine (usually as an intramuscular injection once per day for 7–10 days)Acoziborole, an oral benzoxaborole-6-carboxamide from the Drugs for Neglected Diseases initiative (DNDi) drug discovery programme, showed high activity in vitro in both stages of gambiense HAT in murine models,