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Background Nifurtimox-eflornithine combination therapy (NECT) for the treatment of second stage gambiense human African trypanosomiasis (HAT) was added to the World Health Organization’s Essential Medicines List in 2009 after demonstration of its non-inferior efficacy compared to eflornithine therapy. A study of NECT use in the field showed acceptable safety and high efficacy until hospital discharge in a wide population, including children, pregnant and breastfeeding women, and patients with a HAT treatment history. We present here the effectiveness results after the 24-month follow-up visit. Methodology/Principal findings In a multicenter, open label, single arm phase IIIb study, second stage gambiense HAT patients were treated with NECT in the Democratic Republic of Congo. Clinical cure was defined 24 months after treatment as survival without clinical and/or parasitological signs of HAT. Of the 629 included patients, 619 (98.4%) were discharged alive after treatment and were examined for the presence of trypanosomes, white blood cell count in cerebro-spinal fluid, and disease symptoms. The clinical cure rate of 94.1% was comparable for all subpopulations analyzed at the 24-month follow-up visit. Self-reported adverse events during follow-up were few and concerned mainly nervous system disorders, infections, and gastro-intestinal disorders. Overall, 28 patients (4.3%) died during the course of the trial. The death of 16 of the 18 patients who died during the follow-up period was assessed as unlikely or not related to NECT. Within 24 months, eight patients (1.3%) relapsed and received rescue treatment. Sixteen patients were completely lost to follow-up. Conclusions/Significance NECT treatment administered under field conditions was effective and sufficiently well tolerated, no major concern arose for children or pregnant or breastfeeding women. Patients with a previous HAT treatment history had the same response as those who were naïve. In conclusion, NECT was confirmed as effective and appropriate for use in a broad population, including vulnerable subpopulations. Trial registration The trial is registered at ClinicalTrials.gov, number NCT00906880., Author summary The advanced stage of the neglected tropical disease human African trypanosomiasis was, until relatively recently, treated with an old toxic arsenical drug and there was little investment in an improved treatment option. Eflornithine alone was efficacious, but difficult to administer as it required four two-hour infusions a day for 14 days. Nifurtimox-eflornithine combination therapy (NECT) was developed as a simplified and easier to use treatment and was shown to be effective and sufficiently well tolerated in a randomized clinical trial. The present study was conducted to assess the overall effectiveness, including the feasibility of implementation of NECT under field conditions in a wider population than in the randomized clinical trial. We found that NECT can be implemented under field conditions and in remote areas, with the necessary logistical support and staff training for treatment administration. Adverse events, although very frequent, were considered acceptable given the severity of the disease. Less than 10% of patients showed severe adverse events. Over 24 months, the case fatality rate was 4.5% and relapses were rare (1.3%). The effectiveness of NECT was confirmed in a broad spectrum of second stage gambiense HAT patients, including children, pregnant and breastfeeding women, and patients who had been previously treated for HAT.

Background Spliced Leader (SL) trypanosome RNA is detectable only in the presence of live trypanosomes, is abundant and the Trypanozoon subgenus has a unique sequence. As previously shown in blood from Guinean human African trypanosomiasis (HAT) patients, SL-RNA is an accurate target for diagnosis. Detection of SL-RNA in the cerebrospinal fluid (CSF) has never been attempted. In a large group of Congolese gambiense HAT patients, the present study aims i) to confirm the sensitivity of SL-RNA detection in the blood and; ii) to assess the diagnostic performance of SL-RNA compared to trypanosome detection in CSF. Methodology/Principal findings Blood and CSF from 97 confirmed gambiense HAT patients from the Democratic Republic of Congo were collected using PAXgene blood RNA Tubes. Before RNA extraction, specimens were supplemented with internal extraction control RNA to monitor the extraction, which was performed with a PAXgene Blood RNA Kit. SL-RNA qPCR was carried out with and without reverse transcriptase to monitor DNA contamination. In blood, 92/97 (94.8%) HAT patients tested SL-RNA positive, which was significantly more than combined trypanosome detection in lymph and blood (78/97 positive, 80.4%, p = 0.001). Of 96 CSF RNA specimens, 65 (67.7%) were SL-RNA positive, but there was no significant difference between sensitivity of SL-RNA and trypanosome detection in CSF. The contribution of DNA to the Cq values was negligible. In CSF with normal cell counts, a fraction of SL-RNA might have been lost during extraction as indicated by higher internal extraction control Cq values. Conclusions/Significance Detection of SL-RNA in blood and CSF allows sensitive demonstration of active gambiense HAT infection, even if trypanosomes remain undetectable in blood or lymph. As this condition often occurs in treatment failures, SL-RNA detection in blood and CSF for early detection of relapses after treatment deserves further investigation. Trial registration This study was an integral part of the diagnostic trial "New Diagnostic Tools for Elimination of Sleeping Sickness and Clinical Trials: Early tests of Cure" (DiTECT-HAT-WP4, ClinicalTrials.gov Identifier: NCT03112655)., Author summary Human African trypanosomiasis is a parasitic infection occurring in sub-Saharan Africa, which is fatal if left untreated. Diagnosis relies on demonstration of trypanosomes, which may occur at such low concentrations that they remain microscopically undetectable. Nucleic acid detection offers an alternative, in particular RNA, which is unstable and a better marker for live organisms than DNA. Trypanosomal SL-RNA detection in blood by reverse transcriptase quantitative PCR has hitherto only been tested twice. Although in cerebrospinal fluid, trypanosome presence indicates brain infection, SL-RNA detection has never been attempted. We evaluated sensitivity of SL-RNA detection in blood and cerebrospinal fluid. For each specimen, 2 controls were included: presence of genomic DNA contamination and efficacy of RNA extraction. Sensitivity of SL-RNA detection in blood was higher than of combined blood and lymph microscopy. In cerebrospinal fluid, SL-RNA and trypanosome detection had similar sensitivity. In a few specimens, traces of DNA were amplified. In some cerebrospinal fluids, some RNA was lost during extraction. Performing both internal controls is crucial, to ensure that negative SL-RNA cerebrospinal fluid findings are not due to a failed extraction and, in particular when testing treated patients, to differentiate live parasite RNA from reminiscent DNA.

Background Nifurtimox eflornithine combination therapy (NECT) to treat human African trypanosomiasis (HAT), commonly called sleeping sickness, was added to the World Health Organisation’s (WHO) Essential Medicines List in 2009 and to the Paediatric List in 2012. NECT was further tested and documented in a phase IIIb clinical trial in the Democratic Republic of Congo (DRC) assessing the safety, effectiveness, and feasibility of implementation under field conditions (NECT-FIELD study). This trial brought a unique possibility to examine concomitant drug management. Methodology/Principal findings This is a secondary analysis of the NECT-FIELD study where 629 second stage gambiense HAT patients were treated with NECT, including children and pregnant and breastfeeding women in six general reference hospitals located in two provinces. Concomitant drugs were prescribed by the local investigators as needed. Patients underwent daily evaluations, including vital signs, physical examination, and adverse event monitoring. Concomitant medication was documented from admission to discharge. Patients’ clinical profiles on admission and safety profile during specific HAT treatment were similar to previously published reports. Prescribed concomitant medications administered during the hospitalization period, before, during, and immediately after NECT treatment, were mainly analgesics/antipyretics, anthelmintics, antimalarials, antiemetics, and sedatives. Use of antibiotics was reasonable and antibiotics were often prescribed to treat cellulitis and respiratory tract infections. Prevention and treatment of neurological conditions such as convulsions, loss of consciousness, and coma was used in approximately 5% of patients. Conclusions/Significance The prescription of concomitant treatments was coherent with the clinical and safety profile of the patients. However, some prescription habits would need to be adapted in the future to the evolving available pharmacopoeia. A list of minimal essential medication that should be available at no cost to patients in treatment wards is proposed to help the different actors to plan, manage, and adequately fund drug supplies for advanced HAT infected patients. Trial registration number The initial study was registered at ClinicalTrials.gov, number NCT00906880., Author summary Sleeping sickness is a neglected tropical disease caused by a parasite, the trypanosome, transmitted by the tse-tse fly. It affects people in Sub-Saharan Africa, most of them living in poor rural settings with limited access to healthcare. If the disease remains untreated, it usually progresses from a haemo-lymphatic invasion into a second stage or neuro-encephalitic infection evolving into coma and death. When these second stage patients are referred to treatment centres, the disease is often advanced. Therefore, on top of sleeping sickness treatment, additional care and medications are regularly required. We report here the concomitant medications that were prescribed to second stage sleeping sickness patients, including vulnerable populations such as children, and pregnant and breastfeeding women, in the context of a phase IIIb trial assessing the safety, effectiveness, and feasibility of implementation of the Nifurtimox Eflornithine Combination Therapy (NECT) in field conditions. Our objective is to provide evidence to national health systems or private actors to plan and fund their essential medicine supplies adapted to second stage sleeping sickness patients.