Melarsoprol administration for the treatment of late-stage human African trypanosomiasis (HAT) is associated with the development of an unpredictable and badly characterized encephalopathic syndrome (ES), probably of immune origin, that kills approximately 50% of those affected. We investigated the characteristics and clinical risk factors for ES, as well as the association between the Human Leukocyte Antigen (HLA) complex and the risk for ES in a case-control study. Late-stage Gambiense HAT patients treated with melarsoprol and developing ES (69 cases) were compared to patients not suffering from the syndrome (207 controls). Patients were enrolled in six HAT treatment centres in Angola and in the Democratic Republic of Congo. Standardized clinical data was obtained from all participants before melarsoprol was initiated. Class I (HLA-A, HLA-B, HLA-Cw) and II (HLA-DR) alleles were determined by PCR-SSOP methods in 62 ES cases and 189 controls. The principal ES pattern consisted in convulsions followed by a coma, whereas ES with exclusively mental changes was not observed. Oedema, bone pain, apathy, and a depressed humour were associated with a higher risk of ES, while abdominal pain, coma, respiratory distress, and a Babinski sign were associated with higher ES-associated mortality. Haplotype C*14/B*15 was associated with an elevated risk for ES (OR: 6.64; p-value: 0.008). Haplotypes A*23/C*14, A*23/B*15 and DR*07/B*58 also showed a weaker association with ES. This result supports the hypothesis that a genetically determined peculiar type of immune response confers susceptibility for ES.

BACKGROUND: Socio-cultural and economic factors constitute real barriers for uptake of screening and treatment of Human African Trypanosomiasis (HAT) in the Democratic Republic of Congo (DRC). Better understanding and addressing these barriers may enhance the effectiveness of HAT control.
METHODS: We performed a qualitative study consisting of semi-structured interviews and focus group discussions in the Bandundu and Kasaï Oriental provinces, two provinces lagging behind in the HAT elimination effort. Our study population included current and former HAT patients, as well as healthcare providers and program managers of the national HAT control program. All interviews and discussions were voice recorded on a digital device and data were analysed with the ATLAS.ti software.
RESULTS: Health workers and community members quoted a number of prohibitions that have to be respected for six months after HAT treatment: no work, no sexual intercourse, no hot food, not walking in the sun. Violating these restrictions is believed to cause serious, and sometimes deadly, complications. These strong prohibitions are well-known by the community and lead some people to avoid HAT screening campaigns, for fear of having to observe such taboos in case of diagnosis.
CONCLUSIONS: The restrictions originally aimed to mitigate the severe adverse effects of the melarsoprol regimen, but are not evidence-based and became obsolete with the new safer drugs. Correct health information regarding HAT treatment is essential. Health providers should address the perspective of the community in a constant dialogue to keep abreast of unintended transformations of meaning.

Gambian (Trypanosoma brucei gambiense) human African trypanosomiasis (HAT) evolves from the hemolymphatic stage 1, treated with pentamidine, to the meningoencephalitic stage 2, often treated with melarsoprol. This arseniate may provoke a deadly reactive encephalopathy. It is therefore crucial to diagnose precisely the stages of HAT, especially when clinical and biological examinations are doubtful. We present here the case of a 30-month old girl (E20 KOLNG) diagnosed with stage 1 HAT during a field survey in June 2007 in Congo. She was followed-up every six months for 18 months in a village dispensary facility at Mpouya. Her health status deteriorated in December 2008, although cerebrospinal fluid (CSF) white blood cell (WBC) count was normal. The child was hospitalized at Brazzaville and a daytime polysomnographic recording (electroencephalogram, electrooculogram, and electromyogram) was performed (Temec Vitaport 3® portable recorder) to avoid a new lumbar puncture. The child presented a complete polysomnographic syndrome of HAT with a major disturbance of the distribution of sleep and wake episodes and the occurrence of sleep onset REM periods (SOREMPs). The relapse at stage 2 was confirmed by a new CSF examination that showed an elevated WBC count (23cells·μL(-1)) with the presence of B lymphocytes. Melarsoprol treatment was undertaken. A post-treatment recording was immediately performed, showing the resolution of sleepwake pattern abnormalities. Another polysomnography, taken four months later, confirmed the normalization of sleep-wake patterns indicating healing. We therefore propose that polysomnography, being a non-invasive technique, should be used in children to alleviate burden caused by HAT staging procedures, especially regarding lumbar punctures in remote African villages.

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BACKGROUND: Treatment of second-stage sleeping sickness relies mainly on melarsoprol. Nifurtimox has been successfully used to cure melarsoprol-refractory sleeping sickness caused by Trypanosoma brucei gambiense infection.
METHODS: An open, randomized trial was conducted to test for equivalence between the standard melarsoprol regimen and 3 other regimens, as follows: standard melarsoprol therapy (3 series of 3.6 mg/kg/day intravenously [iv] for 3 days, with 7-day breaks between the series); 10-day incremental-dose melarsoprol therapy (0.6 mg/kg iv on day 1, 1.2 mg/kg iv on day 2, and 1.8 mg/kg iv on days 3-10); nifurtimox monotherapy for 14 days (5 mg/kg orally 3 times per day); and consecutive 10-day melarsoprol-nifurtimox combination therapy (0.6 mg/kg iv melarsoprol on day 1, 1.2 mg/kg iv melarsoprol on day 2, and 1.2 mg/kg/day iv melarsoprol combined with oral 7.5 mg/kg nifurtimox twice a day on days 3-10). Primary outcomes were relapse, severe adverse events, and death attributed to treatment.
RESULTS: A total of 278 patients were randomized. The frequency of adverse events was similar between the standard melarsoprol regimen and the other regimens. Encephalopathic syndromes occurred in all groups and caused all deaths that were likely due to treatment. Relapses (n=48) were observed only with the 3 monotherapy regimens.
CONCLUSIONS: A consecutive 10-day low-dose melarsoprol-nifurtimox combination is more effective than the standard melarsoprol regimen.

A total of 389 patients with late-stage Trypanosoma brucei gambiense trypanosomiasis were enrolled in a randomized controlled trial comparing the efficacy and toxicity of three regimens of melarsoprol: regimen A, 3.6 mg/kg (max. 180 mg) for all i.v. injections, given as three series of three injections separated by 1-week intervals; regimen B, 10 consecutive daily i.v. injections of 2.16 mg/kg; or regimen C, three series of three i.v. injections separated by 1-week intervals, but with graded dosing (1.8, 2.16, 2.52, 2.52, 2.88, 3.24, then 3.6 mg/kg for the last three injections). After treatment, patients were followed with half-yearly lumbar punctures for 2 years. During treatment, convulsions were significantly more common in patients allocated to the graded dosing regimen (7/70 [10.0%] vs. 11/319 [3.4%], P = 0.03). The 2-year probability of relapse was 5.4%, 7.4% and 25.0% for regimens A, B and C respectively (P < 0.001). The new regimen of 10 daily injections of melarsoprol was as effective and had the same toxicity as the traditional regimen of three series of three injections at the full dose. Graded dosing, which was associated with a much lower efficacy and more frequent convulsions, should be abandoned.

BACKGROUND: Treatment of late-stage human African trypanosomiasis (HAT) with melarsoprol can be improved by shortening the regimen. A previous trial demonstrated the safety and efficacy of a 10-day treatment schedule. We demonstrate the effectiveness of this schedule in a noncontrolled, multinational drug-utilization study.
METHODS: A total of 2020 patients with late-stage HAT were treated with the 10-day melarsoprol schedule in 16 centers in 7 African countries. We assessed outcome on the basis of major adverse events and the cure rate after treatment and during 2 years of follow-up.
RESULTS: The cure rate 24 h after treatment was 93.9%; 2 years later, it was 86.2%. However, 49.3% of patients were lost to follow-up. The overall fatality rate was 5.9%. Of treated patients, 8.7% had an encephalopathic syndrome that was fatal 45.5% of the time. The rate of severe bullous and maculopapular eruptions was 0.8% and 6.8%, respectively.
CONCLUSIONS: The 10-day treatment schedule was well implemented in the field and was effective. It reduces treatment duration, drug amount, and hospitalization costs per patient, and it increases treatment-center capacity. The shorter protocol has been recommended by the International Scientific Council for Trypanosomiasis Research and Control for the treatment of late-stage HAT caused by Trypanosoma brucei gambiense.

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