Effectiveness of Nifurtimox Eflornithine Combination Therapy (NECT) in T. b. gambiense second stage sleeping sickness patients in the Democratic Republic of Congo: Report from a field study.

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.

Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial.

BACKGROUND: Human African trypanosomiasis (HAT; sleeping sickness) caused by Trypanosoma brucei gambiense is a fatal disease. Current treatment options for patients with second-stage disease are toxic, ineffective, or impractical. We assessed the efficacy and safety of nifurtimox-eflornithine combination therapy (NECT) for second-stage disease compared with the standard eflornithine regimen. METHODS: A multicentre, randomised, open-label, active control, phase III, non-inferiority trial was done at four HAT treatment centres in the Republic of the Congo and the Democratic Republic of the Congo. Patients aged 15 years or older with confirmed second-stage T b gambiense infection were randomly assigned by computer-generated randomisation sequence to receive intravenous eflornithine (400 mg/kg per day, every 6 h; n=144) for 14 days or intravenous eflornithine (400 mg/kg per day, every 12 h) for 7 days with oral nifurtimox (15 mg/kg per day, every 8 h) for 10 days (NECT; n=143). The primary endpoint was cure (defined as absence of trypanosomes in body fluids and a leucocyte count

Prescription of concomitant medications in patients treated with Nifurtimox Eflornithine Combination Therapy (NECT) for T.b. gambiense second stage sleeping sickness in the Democratic Republic of the Congo.

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.

High failure rates of melarsoprol for sleeping sickness, Democratic Republic of Congo.

A retrospective chart review of 4,925 human African trypanosomiasis patients treated with melarsoprol in 2001-2003 in Equateur Nord Province of the Democratic Republic of Congo showed a treatment failure rate of 19.5%. This rate increased over the 3 years. Relapse rates were highest in the central part of the province.

Cost-effectiveness of algorithms for confirmation test of human African trypanosomiasis.

The control of Trypanosoma brucei gambiense human African trypanosomiasis (HAT) is compromised by low sensitivity of the routinely used parasitologic confirmation tests. More sensitive alternatives, such as mini-anion exchange centrifugation technique (mAECT) or capillary tube centrifugation (CTC), are more expensive. We used formal decision analysis to assess the cost-effectiveness of alternative HAT confirmation algorithms in terms of cost per life saved. The effectiveness of the standard method, a combination of lymph node puncture (LNP), fresh blood examination (FBE), and thick blood film (TBF), was 36.8%; the LNP-FBE-CTC-mAECT sequence reached almost 80%. The cost per person examined ranged from euro1.56 for LNP-FBE-TBF to euro2.99 for LNP-TBF-CTC-mAECT-CATT (card agglutination test for trypanosomiasis) titration. LNP-TBF-CTC-mAECT was the most cost-effective in terms of cost per life saved. HAT confirmation algorithms that incorporate concentration techniques are more effective and efficient than the algorithms that are currently and routinely used by several T.b. gambiense control programs.

Sensitivity and Specificity of a Prototype Rapid Diagnostic Test for the Detection of Trypanosoma brucei gambiense Infection: A Multi-centric Prospective Study.

BACKGROUND: A major challenge in the control of human African trypanosomiasis (HAT) is lack of reliable diagnostic tests that are rapid and easy to use in remote areas where the disease occurs. In Trypanosoma brucei gambiense HAT, the Card Agglutination Test for Trypanosomiasis (CATT) has been the reference screening test since 1978, usually on whole blood, but also in a 1/8 dilution (CATT 1/8) to enhance specificity. However, the CATT is not available in a single format, requires a cold chain for storage, and uses equipment that requires electricity. A solution to these challenges has been provided by rapid diagnostic tests (RDT), which have recently become available. A prototype immunochromatographic test, the SD BIOLINE HAT, based on two native trypanosomal antigens (VSG LiTat 1.3 and VSG LiTat 1.5) has been developed. We carried out a non-inferiority study comparing this prototype to the CATT 1/8 in field settings. METHODOLOGY/PRINCIPAL FINDINGS: The prototype SD BIOLINE HAT, the CATT Whole Blood and CATT 1/8 were systematically applied on fresh blood samples obtained from 14,818 subjects, who were prospectively enrolled through active and passive screening in clinical studies in three endemic countries of central Africa: Angola, the Democratic Republic of the Congo and the Central African Republic. One hundred and forty nine HAT cases were confirmed by parasitology. The sensitivity and specificity of the prototype SD BIOLINE HAT was 89.26% (95% confidence interval (CI) = 83.27-93.28) and 94.58% (95% CI = 94.20-94.94) respectively. The sensitivity and specificity of the CATT on whole blood were 93.96% (95% CI = 88.92-96.79) and 95.91% (95% CI = 95.58-96.22), and of the CATT 1/8 were 89.26% (95% CI = 83.27-93.28) and 98.88% (95% CI = 98.70-99.04) respectively. CONCLUSION/SIGNIFICANCE: After further optimization, the prototype SD BIOLINE HAT could become an alternative to current screening methods in primary healthcare settings in remote, resource-limited regions where HAT typically occurs.

Human african trypanosomiasis diagnosis in first-line health services of endemic countries, a systematic review.

While the incidence of Human African Trypanosomiasis (HAT) is decreasing, the control approach is shifting from active population screening by mobile teams to passive case detection in primary care centers. We conducted a systematic review of the literature between 1970 and 2011 to assess which diagnostic tools are most suitable for use in first-line health facilities in endemic countries. Our search retrieved 16 different screening and confirmation tests for HAT. The thermostable format of the Card Agglutination Test for Trypanosomiasis (CATT test) was the most appropriate screening test. Lateral flow antibody detection tests could become alternative screening tests in the near future. Confirmation of HAT diagnosis still depends on visualizing the parasite in direct microscopy. All other currently available confirmation tests are either technically too demanding and/or lack sensitivity and thus rather inappropriate for use at health center level. Novel applications of molecular tests may have potential for use at district hospital level.

Should I get screened for sleeping sickness? A qualitative study in Kasai province, Democratic Republic of Congo.

BACKGROUND: Control of human African trypanosomiasis (sleeping sickness) in the Democratic Republic of Congo is based on mass population active screening by mobile teams. Although generally considered a successful strategy, the community participation rates in these screening activities and ensuing treatment remain low in the Kasai-Oriental province. A better understanding of the reasons behind this observation is necessary to improve regional control activities. METHODS: Thirteen focus group discussions were held in five health zones of the Kasai-Oriental province to gain insights in the regional perceptions regarding sleeping sickness and the national control programme's activities. PRINCIPAL FINDINGS: Sleeping sickness is well known among the population and is considered a serious and life-threatening disease. The disease is acknowledged to have severe implications for the individual (e.g., persistence of manic periods and trembling hands, even after treatment), at the family level (e.g., income loss, conflicts, separations) and for communities (e.g., disruption of community life and activities). Several important barriers to screening and treatment were identified. Fear of drug toxicity, lack of confidentiality during screening procedures, financial barriers and a lack of communication between the mobile teams and local communities were described. Additionally, a number of regionally accepted prohibitions related to sleeping sickness treatment were described that were found to be a strong impediment to disease screening and treatment. These prohibitions, which do not seem to have a rational basis, have far-reaching socio-economic repercussions and severely restrict the participation in day-to-day life. CONCLUSIONS/SIGNIFICANCE: A mobile screening calendar more adapted to the local conditions with more respect for privacy, the use of less toxic drugs, and a better understanding of the origin as well as better communication about the prohibitions related to treatment would facilitate higher participation rates among the Kasai-Oriental population in sleeping sickness screening and treatment activities organized by the national HAT control programme.

In-hospital safety in field conditions of nifurtimox eflornithine combination therapy (NECT) for T. b. gambiense sleeping sickness.

BACKGROUND: Trypanosoma brucei (T.b.) gambiense Human African trypanosomiasis (HAT; sleeping sickness) is a fatal disease. Until 2009, available treatments for 2(nd) stage HAT were complicated to use, expensive (eflornithine monotherapy), or toxic, and insufficiently effective in certain areas (melarsoprol). Recently, nifurtimox-eflornithine combination therapy (NECT) demonstrated good safety and efficacy in a randomised controlled trial (RCT) and was added to the World Health Organisation (WHO) essential medicines list (EML). Documentation of its safety profile in field conditions will support its wider use. METHODOLOGY: In a multicentre, open label, single arm, phase IIIb study of the use of NECT for 2(nd) stage T.b. gambiense HAT, all patients admitted to the trial centres who fulfilled inclusion criteria were treated with NECT. The primary outcome was the proportion of patients discharged alive from hospital. Safety was further assessed based on treatment emergent adverse events (AEs) occurring during hospitalisation. PRINCIPAL FINDINGS: 629 patients were treated in six HAT treatment facilities in the Democratic Republic of the Congo (DRC), including 100 children under 12, 14 pregnant and 33 breastfeeding women. The proportion of patients discharged alive after treatment completion was 98.4% (619/629; 95%CI [97.1%; 99.1%]). Of the 10 patients who died during hospitalisation, 8 presented in a bad or very bad health condition at baseline; one death was assessed as unlikely related to treatment. No major or unexpected safety concerns arose in any patient group. Most common AEs were gastro-intestinal (61%), general (46%), nervous system (mostly central; 34%) and metabolic disorders (26%). The overall safety profile was similar to previously published findings. CONCLUSIONS/SIGNIFICANCE: In field conditions and in a wider population, including children, NECT displayed a similar tolerability profile to that described in more stringent clinical trial conditions. The in-hospital safety was comparable to published results, and long term efficacy will be confirmed after 24 months follow-up. REGISTRATION: The trial is registered at ClinicalTrials.gov, number NCT00906880.

Prevalence of human African trypanosomiasis in the Democratic Republic of the Congo.

Human African Trypanosomiasis (HAT) is a major public health problem in the Democratic Republic of the Congo (DRC). Active and passive surveillance for HAT is conducted but may underestimate the true prevalence of the disease. We used ELISA to screen 7,769 leftover dried blood spots from a nationally representative population-based survey, the 2007 Demographic and Health Survey. 26 samples were positive by ELISA. Three of these were also positive by trypanolysis and/or PCR. From these data, we estimate that there were 18,592 people with HAT (95% confidence interval, 4,883-32,302) in the DRC in 2007, slightly more than twice as many as were reported.

Diagnostic accuracy and feasibility of serological tests on filter paper samples for outbreak detection of T.b. gambiense human African trypanosomiasis.

Control of human African trypanosomiasis (HAT) in the Democratic Republic of Congo is based on mass population screening by mobile teams; a costly and labor-intensive approach. We hypothesized that blood samples collected on filter paper by village health workers and processed in a central laboratory might be a cost-effective alternative. We estimated sensitivity and specificity of micro-card agglutination test for trypanosomiasis (micro-CATT) and enzyme-linked immunosorbent assay (ELISA)/T.b. gambiense on filter paper samples compared with parasitology-based case classification and used the results in a Monte Carlo simulation of a lot quality assurance sampling (LQAS) approach. Micro-CATT and ELISA/T.b. gambiense showed acceptable sensitivity (92.7% [95% CI 87.4-98.0%] and 82.2% [95% CI 75.3-90.4%]) and very high specificity (99.4% [95% CI 99.0-99.9%] and 99.8% [95% CI 99.5-100%]), respectively. Conditional on high sample size per lot (> or = 60%), both tests could reliably distinguish a 2% from a zero prevalence at village level. Alternatively, these tests could be used to identify individual HAT suspects for subsequent confirmation.

[The efficiency of different detection strategies of human African trypanosomiasis by T. b. gambiense]. / Efficience de differentes strategies de detection de la Trypanosomiase Humaine Africaine aT. b. gambiense.

INTRODUCTION: Population screening for human African trypanosomiasis (HAT) is often based on a combination of two screening tests: lymph node palpation (LN) and card agglutination test for trypanosomiasis (CATT). This decision analysis compared the efficiency of three alternative detection strategies: screening by LN only, CATT only and their combination (LN and CATT). METHOD: An HAT detection strategy was defined as the sequence of screening and confirmation. Efficacy was evaluated in terms of lives saved. The cost of screening and confirmation tests was estimated in US$. The different parameters in the decision tree were based on published literature and observations of the HAT control programme in the Democratic Republic of Congo. A sensitivity analysis was carried out on those parameters subject to uncertainty. RESULTS: The cost-effectiveness of a detection strategy based on CATT was US $125 per life saved, compared with US $517 for LN and US $452 for the combined. Marginal cost to add LN to CATT only was between US $1225 and US $5000 per life saved. Sensitivity analysis shows that these results are robust to variation. DISCUSSION: The CATT strategy was the most efficient. None of the strategies was able to avoid more than 60% of HAT deaths. This moderate efficacy is due to the low sensitivity of the confirmatory (diagnostic) tests. Substantial efficiency gains can be obtained by adopting a CATT only strategy and resources can be better allocated to more sensitive confirmatory tests or to increasing the coverage of populations at risk.