• Early prediction of treatment efficacy in Second-Stage Gambiense Human African Trypanosomiasis

      Priotto, G; Chappuis, F; Bastard, M; Flevaud, L; Etard, J-F; Epicentre, Paris, France. gpriotto@neuf.fr (2012-06-05)
      Human African trypanosomiasis is fatal without treatment. The long post-treatment follow-up (24 months) required to assess cure complicates patient management and is a major obstacle in the development of new therapies. We analyzed individual patient data from 12 programs conducted by Médecins Sans Frontières in Uganda, Sudan, Angola, Central African Republic, Republic of Congo and Democratic Republic of Congo searching for early efficacy indicators.
    • Effectiveness of a 10-day melarsoprol schedule for the treatment of late-stage human African trypanosomiasis: confirmation from a multinational study (IMPAMEL II).

      Schmid, C; Richer, M; Bilenge, C M M; Josenando, T; Chappuis, F; Manthelot, C R; Nangouma, A; Doua, F; Asumu, P; Simarro, P; et al. (Infectious Diseases Society of America and University of Chicago Press, 2005-06-01)
      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.
    • Eflornithine is Safer Than Melarsoprol for the Treatment of Second-Stage Trypanosoma Brucei Gambiense Human African Trypanosomiasis.

      Chappuis, F; Udayraj, N; Stietenroth, K; Meussen, A; Bovier, P A; Médecins Sans Frontières, Geneva University Hospitals, Geneva, Switzerland. francois.chappuis@hcuge.ch (Published by: Infectious Diseases Society of America, 2005-09-01)
      Patients with second-stage human African trypanosomiasis treated with eflornithine (n = 251) in 2003 in Kiri, southern Sudan, had an adjusted relative risk of death of 0.2 and experienced significantly fewer cutaneous and neurological adverse effects than did patients who were treated with melarsoprol in 2001 and 2002 (n = 708).
    • Estimates of the duration of the early and late stage of gambiense sleeping sickness.

      Checchi, F; Filipe, J A N; Haydon, D T; Chandramohan, D; Chappuis, F; Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E7HT, UK. francesco.checchi@lshtm.ac.uk (BioMed Central, 2008-02-08)
      BACKGROUND: The durations of untreated stage 1 (early stage, haemo-lymphatic) and stage 2 (late stage, meningo-encephalitic) human African trypanosomiasis (sleeping sickness) due to Trypanosoma brucei gambiense are poorly quantified, but key to predicting the impact of screening on transmission. Here, we outline a method to estimate these parameters. METHODS: We first model the duration of stage 1 through survival analysis of untreated serological suspects detected during Médecins Sans Frontières interventions in Uganda and Sudan. We then deduce the duration of stage 2 based on the stage 1 to stage 2 ratio observed during active case detection in villages within the same sites. RESULTS: Survival in stage 1 appears to decay exponentially (daily rate = 0.0019; mean stage 1 duration = 526 days [95%CI 357 to 833]), possibly explaining past reports of abnormally long duration. Assuming epidemiological equilibrium, we estimate a similar duration of stage 2 (500 days [95%CI 345 to 769]), for a total of nearly three years in the absence of treatment. CONCLUSION: Robust estimates of these basic epidemiological parameters are essential to formulating a quantitative understanding of sleeping sickness dynamics, and will facilitate the evaluation of different possible control strategies.
    • Human African trypanosomiasis amongst urban residents in Kinshasa: a case-control study.

      Robays, J; Ebeja, A; Lutumba, P; Miaka mia Bilenge, C; Kande Betu Ku Mesu, V; De Deken, R; Makabuza, J; Deguerry, M; Van der Stuyft, P; Boelaert, M; et al. (2004-08)
      BACKGROUND: Increasing numbers of human African trypanosomiasis (HAT) cases have been reported in urban residents of Kinshasa, Democratic Republic Congo since 1996. We set up a case-control study to identify risk factors for the disease. METHODS: All residents of the urban part of Kinshasa with parasitologically confirmed HAT and presenting for treatment to the city's specialized HAT clinics between 1 August, 2002 and 28 February, 2003 were included as cases. We defined the urban part as the area with contiguous habitation and a population density >5000 inhabitants per square kilometre. A digital map of the area was drawn based on a satellite image. For each case, two serologically negative controls were selected, matched on age, sex and neighbourhood. Logistic regression models were fitted to control for confounding. RESULTS: The following risk factors were independently associated with HAT: travel, commerce and cultivating fields in Bandundu, and commerce and cultivating fields in the rural part of Kinshasa. No association with activities in the city itself was found. DISCUSSION: In 2002, the emergence of HAT in urban residents of Kinshasa appears mainly linked to disease transmission in Bandundu and rural Kinshasa. We recommend to intensify control of these foci, to target HAT screening in urban residents to people with contact with these foci, to increase awareness of HAT amongst health workers in the urban health structures and to strengthen disease surveillance.
    • Melarsoprol Versus Eflornithine for Treating Late-stage Gambian Trypanosomiasis in the Republic of the Congo.

      Balasegaram, M; Harris, S; Checchi, F; Ghorashian, S; Hamel, C; Karunakara, U; Medecins Sans Frontieres, London, England. manica.balasigaram@london.msf.org (Published by WHO, 2006-10)
      OBJECTIVE: To compare the effectiveness of melarsoprol and eflornithine in treating late-stage Gambian trypanosomiasis in the Republic of the Congo. METHODS: We analysed the outcomes of death during treatment and relapse within 1 year of discharge for 288 patients treated with eflornithine, 311 patients treated with the standard melarsoprol regimen and 62 patients treated with a short-course (10-day) melarsoprol regimen between April 2001 and April 2005. FINDINGS: A total of 1.7% (5/288) of patients treated with eflornithine died compared with 4.8% (15/311) of those treated with standard melarsoprol and 6.5% (4/62) of those treated with short-course melarsoprol. Patients treated with eflornithine tended to be younger and were more likely to have trypanosomes or higher white blood cell counts in their cerebrospinal fluid. The cumulated incidence of relapse among patients who attended at least one follow-up visit 1 year after discharge was 8.1% (11/136) for those treated with eflornithine, 14% (36/258) for those treated with standard melarsoprol and 15.5% (9/58) for those treated with shortcourse melarsoprol. In a multivariate analysis, when compared with eflornithine, standard melarsoprol was found to be a risk factor for both death (odds ratio (OR) = 2.87; 95% confidence interval (CI) = 1.03-8.00) and relapse (hazard ratio (HR) = 2.47; 95% CI = 1.22-5.03); when compared with eflornithine, short-course melarsoprol was also found to be a risk factor for death (OR = 3.90; 95% CI = 1.02-14.98) and relapse (HR = 6.65; 95% CI = 2.61-16.94). CONCLUSION: The effectiveness of melarsoprol treatment appears to have diminished. Eflornithine seems to be a better first-line therapy for treating late-stage Gambian trypanosomiasis in the Republic of the Congo.
    • Nifurtimox-eflornithine Combination Therapy for Second-Stage Trypanosoma Brucei Gambiense Sleeping Sickness: A Randomized Clinical Trial in Congo.

      Priotto, G; Kasparian, S; Ngouama, D; Ghorashian, S; Arnold, U; Ghabri, S; Karunakara, U; Epicentre, Paris, France. gpriotto@epicentre.msf.org (Published by: Infectious Diseases Society of America, 2007-12-01)
      BACKGROUND: Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a fatal disease. Current treatment options for patients with second-stage disease are either highly toxic or impracticable in field conditions. We compared the efficacy and safety of the nifurtimox-eflornithine drug combination with the standard eflornithine regimen for the treatment of second-stage disease. METHODS: A randomized, open-label, active-control, phase III clinical trial comparing 2 arms was conducted at the Sleeping Sickness Treatment Center, which was run by Medecins Sans Frontieres, in Nkayi, Bouenza Province, Republic of Congo. Patients were screened for inclusion and randomly assigned to receive eflornithine alone (400 mg/kg per day given intravenously every 6 h for 14 days) or eflornithine (400 mg/kg per day given intravenously every 12 h for 7 days) plus nifurtimox (15 mg/kg per day given orally every 8 h for 10 days). Patients were observed for 18 months. The study's outcomes were cure and adverse events attributable to treatment. RESULTS: A total of 103 patients with second-stage disease were enrolled. Cure rates were 94.1% for the eflornithine group and 96.2% for the nifurtimox-eflornithine group. Drug reactions were frequent in both arms, and severe reactions affected 25.5% of patients in the eflornithine group and 9.6% of those in the nifurtimox-eflornithine group, resulting in 2 and 1 treatment suspensions, respectively. There was 1 death in the eflornithine arm and no deaths in the nifurtimox-eflornithine arm. CONCLUSIONS: The nifurtimox-eflornithine combination appears to be a promising first-line therapy for second-stage sleeping sickness. If our findings are corroborated by ongoing findings from additional sites (a multicenter extension of this study), the new nifurtimox-eflornithine combination therapy will mark a major and multifaceted advance over current therapies.
    • Risk factors for treatment failure after melarsoprol for Trypanosoma brucei gambiense trypanosomiasis in Uganda.

      Legros, D; Evans, S; Maiso, F; Enyaru, J C; Mbulamberi, D; Epicentre, Kampala, Uganda. epicentre@imul.com (1999)
      We evaluated the treatment failure rate among late-stage human African trypanosomiasis (HAT) patients treated with melarsoprol in Arua, northern Uganda, between September 1995 and August 1996, and identified the risk factors for treatment failure. We conducted a retrospective cohort study in October 1998, and performed a survival analysis. A treatment failure was defined as a late-stage HAT patient fully treated with melarsoprol and classified as an HAT case at any follow-up visit within 2 years after treatment. Among 428 patients treated in the study period, 130 (30.4%) were identified as treatment failure within 2 years after discharge. The multivariate analysis showed that patients who experienced treatment failure after melarsoprol were more likely to have been admitted as a relapsing case (relative hazard, RH = 11.15 [6.34-19.61]), and to have been diagnosed with trypanosomes in the lymph nodes (RH = 3.19 [2.10-4.83]) or in the cerebrospinal fluid (CSF) (RH = 1.66 [1.09-2.53]). The risk of treatment failure also increased with the number of cells in the CSF. The treatment failure rate after melarsoprol observed in Arua is greatly above the expected figures of 3-9%. More research is needed to confirm whether it is related to the variation of melarsoprol pharmacokinetics between individuals, or if it is associated with a reduced susceptibility of the trypanosomes to melarsoprol. The study emphasizes the need for second-line drugs to treat patients that have already received one or several full course(s) of melarsoprol.
    • Sleeping sickness in the region of the town of Kinshasa: a retrospective analysis during the surveillance period 1996-2000.

      Ebeja, A; Lutumba, P; Molisho, D; Kegels, G; Miaka mia Bilenge, C; Boelaert, M; Médecins sans Frontières, Kinshasa, République Démocratique du Congo. kadima_ebeja@hotmail.com (Wiley-Blackwell, 2003-10)
      In the Democratic Republic of Congo, the re-emergence of sleeping sickness is no longer limited to rural areas. Over the course of the past decade, more and more cases have been reported from urban centres such as Kinshasa, Mbuji-mayi, Matadi and Boma. This paper presents a retrospective analysis on the region of Kinshasa over the period 1996-2000, using epidemiological surveillance, individual case files and available entomological data. There are 22 health districts in total; they were classified as urban when the population exceeded 5000 per square kilometre. The Human African Trypanosomiasis (HAT) control programme reported 2451 parasitologically confirmed new cases between 1996 and 2000, in the entire region of Kinshasa. Affected people (66%) were aged 15-49 years. Cases occurred in every health district, and 956 (39%) occurred in urban residents. Glossina captures in 1999 established the presence of Trypanosoma spp. Local HAT transmission is plausible but not proven. The high number of urban cases necessitates development of control strategies adapted to cities.
    • Treatment Outcomes and Risk Factors for Relapse in Patients with Early-stage Human African Trypanosomiasis (HAT) in the Republic of the Congo.

      Balasegaram, M; Harris, S; Checchi, F; Hamel, C; Karunakara, U; Medecins Sans Frontieres, London, England. manica.balasigaram@london.msf.org (Published by WHO, 2006-10)
      OBJECTIVE: In 2002-03, the Republic of the Congo increased the threshold separating stage 1 and 2 cases of human African trypanosomiasis (HAT) from a cerebrospinal fluid (CSF) white cell count of 5 cells/mm(3) to 10 cells/mm(3). We aimed to assess whether the increased threshold of 10 cells/mm(3) is a safe indicator of stage 2 disease. METHODS: We assessed patients treated for stage 1 HAT caused by Trypanosoma brucei gambiense in the Republic of the Congo between April 2001 and April 2005. Patients with 0-10 cells/mm(3) in CSF were classed as stage 1 and treated with pentamidine. Patients with CSF of > 10 cells/mm(3) were classed as stage 2 and treated with either melarsoprol or eflornithine. We did a retrospective analysis of all patients treated after the September 2002 increase in threshold for classification of HAT disease stage 2, and who were eligible for at least 1 year of follow-up. Primary outcome was survival without death or relapse within 1 year of discharge. Risk factors for treatment failure, in particular CSF white cell count on diagnosis, were assessed. FINDINGS: Between September 2002 to April 2004, 692 patients eligible for our analysis were treated with pentamidine. All were discharged alive. Relapse rate was 5% (n = 33). The only identified risk factor for relapse was a CSF white cell count of 6-10 cells/mm(3) rather than 0-5 cells/mm(3) (adjusted hazard ratio 3.27 (95% confidence interval, 1.52-7.01); P = 0.002). CONCLUSION: A threshold of 5 white cells/mm(3) in CSF is safer than 10 cells/mm(3) to determine stage 2 HAT and reduce risk of relapse.
    • Trypanosoma Brucei Gambiense Trypanosomiasis in Terego County, Northern Uganda, 1996: A Lot Quality Assurance Sampling Survey.

      Hutin, Y; Legros, D; Owini, V; Brown, V; Lee, E; Mbulamberi, D; Paquet, C; Epicentre Office in Uganda, Kampala, Uganda. (Published by: American Society of Tropical Medicine and Hygiene, 2004-04)
      We estimated the pre-intervention prevalence of Trypanosoma brucei gambiense (Tbg) trypanosomiasis using the lot quality assurance sampling (LQAS) methods in 14 parishes of Terego County in northern Uganda. A total of 826 participants were included in the survey sample in 1996. The prevalence of laboratory confirmed Tbg trypanosomiasis adjusted for parish population sizes was 2.2% (95% confidence interval =1.1-3.2). This estimate was consistent with the 1.1% period prevalence calculated on the basis of cases identified through passive and active screening in 1996-1999. Ranking of parishes in four categories according to LQAS analysis of the 1996 survey predicted the prevalences observed during the first round of active screening in the population in 1997-1998 (P < 0.0001, by chi-square test). Overall prevalence and ranking of parishes obtained with LQAS were validated by the results of the population screening, suggesting that these survey methods may be useful in the pre-intervention phase of sleeping sickness control programs.