Journal Article > Short ReportFull Text
BMC Research Notes. 2015 July 4; Volume 8 (Issue 292); DOI:10.1186/s13104-015-1244-3
Checchi F, Funk S, Chandramohan D, Haydon DT, Chappuis F
BMC Research Notes. 2015 July 4; Volume 8 (Issue 292); DOI:10.1186/s13104-015-1244-3
BACKGROUND
The duration of the stages of HAT is an important factor in epidemiological studies and intervention planning. Previously, we published estimates of the duration of the haemo-lymphatic stage 1 and meningo-encephalitic stage 2 of the gambiense form of human African trypanosomiasis (HAT), in the absence of treatment. Here we revise the estimate of stage 2 duration, computed based on data from Uganda and South Sudan, by adjusting observed infection prevalence for incomplete case detection coverage and diagnostic inaccuracy.
FINDINGS
The revised best estimate for the mean duration of stage 2 is 252 days (95% CI 171-399), about half of our initial best estimate, giving a total mean duration of untreated gambiense HAT infection of approximately 2 years and 2 months.
CONCLUSIONS
Our new estimate provides improved information on the transmission dynamics of this neglected tropical disease in Uganda and South Sudan. We stress that there remains considerable variability around the estimated mean values, and that one must be cautious in applying these results to other foci.
The duration of the stages of HAT is an important factor in epidemiological studies and intervention planning. Previously, we published estimates of the duration of the haemo-lymphatic stage 1 and meningo-encephalitic stage 2 of the gambiense form of human African trypanosomiasis (HAT), in the absence of treatment. Here we revise the estimate of stage 2 duration, computed based on data from Uganda and South Sudan, by adjusting observed infection prevalence for incomplete case detection coverage and diagnostic inaccuracy.
FINDINGS
The revised best estimate for the mean duration of stage 2 is 252 days (95% CI 171-399), about half of our initial best estimate, giving a total mean duration of untreated gambiense HAT infection of approximately 2 years and 2 months.
CONCLUSIONS
Our new estimate provides improved information on the transmission dynamics of this neglected tropical disease in Uganda and South Sudan. We stress that there remains considerable variability around the estimated mean values, and that one must be cautious in applying these results to other foci.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 2012 November 29; Volume 6 (Issue 11); DOI:10.1371/journal.pntd.0001920
Schmid C, Kuemmerle A, Blum J, Ghabri S, Kande V, et al.
PLoS Negl Trop Dis. 2012 November 29; Volume 6 (Issue 11); DOI:10.1371/journal.pntd.0001920
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.
Journal Article > CommentaryFull Text
PLoS Negl Trop Dis. 2012 December 13; Volume 6 (Issue 12); DOI:10.1371/journal.pntd.0001950
Hasker E, Lutumba P, Chappuis F, Kande V, Potet J, et al.
PLoS Negl Trop Dis. 2012 December 13; Volume 6 (Issue 12); DOI:10.1371/journal.pntd.0001950
Conference Material > Video (talk)
Beko P, Woudenberg T
MSF Scientific Days International 2020: Research. 2020 May 26
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 2016 February 16; Volume 10 (Issue 2); e0004362.; DOI:10.1371/journal.pntd.0004362
Burri C, Yeramian PD, Allen JL, Merolle A, Serge KK, et al.
PLoS Negl Trop Dis. 2016 February 16; Volume 10 (Issue 2); e0004362.; DOI:10.1371/journal.pntd.0004362
BACKGROUND
Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT.
METHODS
The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent.
FINDINGS/CONCLUSION
Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3.
AUTHOR SUMMARY
Sleeping sickness (human African trypanosomiasis [HAT]) is caused by parasites, and has a chronic progressive course that may last from several months to several years before death occurs. The present studies were done to assess the effectiveness and safety of oral pafuramidine versus intramuscular pentamidine (the standard treatment), in patients with first stage HAT. The results indicated that, several months after treatment, pafuramidine administered for 10 days was as effective as pentamidine administered for 7 days, and it had a better safety profile than pentamidine. With further study, pafuramidine could be a promising alternative for patients with first stage HAT. In addition, the design of the studies can be used a guide for future studies for identification and delivery of treatment to affected individuals in rural Africa.
Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT.
METHODS
The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent.
FINDINGS/CONCLUSION
Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3.
AUTHOR SUMMARY
Sleeping sickness (human African trypanosomiasis [HAT]) is caused by parasites, and has a chronic progressive course that may last from several months to several years before death occurs. The present studies were done to assess the effectiveness and safety of oral pafuramidine versus intramuscular pentamidine (the standard treatment), in patients with first stage HAT. The results indicated that, several months after treatment, pafuramidine administered for 10 days was as effective as pentamidine administered for 7 days, and it had a better safety profile than pentamidine. With further study, pafuramidine could be a promising alternative for patients with first stage HAT. In addition, the design of the studies can be used a guide for future studies for identification and delivery of treatment to affected individuals in rural Africa.
Journal Article > CommentaryFull Text
PLoS Negl Trop Dis. 2010 May 25; Volume 4 (Issue 5); DOI:10.1371/journal.pntd.0000720
Yun O, Priotto G, Tong J, Flevaud L, Chappuis F
PLoS Negl Trop Dis. 2010 May 25; Volume 4 (Issue 5); DOI:10.1371/journal.pntd.0000720
Journal Article > Meta-AnalysisFull Text
Confl Health. 2011 May 26; Volume 5 (Issue 1); DOI:10.1186/1752-1505-5-7
Tong J, Valverde O, Mahoudeau C, Yun O, Chappuis F
Confl Health. 2011 May 26; Volume 5 (Issue 1); DOI:10.1186/1752-1505-5-7
Human African trypanosomiasis (HAT), or sleeping sickness, is a fatal neglected tropical disease if left untreated. HAT primarily affects people living in rural sub-Saharan Africa, often in regions afflicted by violent conflict. Screening and treatment of HAT is complex and resource-intensive, and especially difficult in insecure, resource-constrained settings. The country with the highest endemicity of HAT is the Democratic Republic of Congo (DRC), which has a number of foci of high disease prevalence. We present here the challenges of carrying out HAT control programmes in general and in a conflict-affected region of DRC. We discuss the difficulties of measuring disease burden, medical care complexities, waning international support, and research and development barriers for HAT.
Conference Material > Abstract
Baudin E, Mordt OV, Alves D, Seixas J, Lemerani M, et al.
MSF Scientific Day International 2024. 2024 May 16; DOI:10.57740/6ss9-0934
INTRODUCTION
Trypanosoma brucei rhodesiense human African trypanosomiasis (r-HAT), the zoonotic, acute form of sleeping sickness in eastern Africa, is lethal if untreated. Today, only one arsenic- based, neurotoxic drug, melarsoprol, is available for treatment of the advanced meningo-encephalitic stage. A new oral treatment would simplify HAT elimination as proposed by WHO. Fexinidazole was recommended by the European Medicines Agency (EMA) in 2018 as the first oral treatment for Trypanosoma brucei gambiense HAT, but it was not yet evaluated for r-HAT.
METHODS
This single-arm clinical trial, sponsored by DNDi, began in October 2019 and tested fexinidazole treatment in patients with r-HAT as an alternative to existing treatment in Malawi and Uganda. Patients (aged ≥6 years) with both stages of the disease were recruited up to the target of 34 patients with stage 2 disease evaluable at the end of hospitalization. Patients were hospitalised during the 10 days of treatment and followed up to 12 months after hospital discharge. The primary outcome was r-HAT-related or treatment-related fatality at the end of hospitalisation in patients with stage 2 disease and was compared with an unacceptable fatality rate of 8.5%, a threshold defined according to results from a previous clinical trial with melarsoprol. This trial is registered with ClinicalTrials.gov, NCT03974178.
RESULTS
45 patients received treatment between 1 October 2019 and 28 November 2021 (35 [78%] had stage 2 disease and ten [22%] stage 1, 31 [69%] were male and 14 [31%] female, with median age of 24 years). The primary efficacy result of the clinical trial, analysed among the 34 evaluable patients, was achieved, with no r-HAT-related or treatment-related deaths during hospitalisation (0.0%, 95% CI 0.0–8.4), compared with a benchmark of 8.5% lethality attributable to melarsoprol. Safety was acceptable, with no severe adverse events related to fexinidazole; and one patient relapsed.
CONCLUSION
Fexinidazole, an oral treatment, was shown to be a good alternative to existing injectable and toxic drugs. Results were submitted for EMA regulatory review in preparation for use in endemic countries, and a positive scientific opinion was received in December 2023 to extend the indication of fexinidazole for the treatment of r-HAT. Fexinidazole is expected to be deployed in 2024 as a new r-HAT therapeutic.
Trypanosoma brucei rhodesiense human African trypanosomiasis (r-HAT), the zoonotic, acute form of sleeping sickness in eastern Africa, is lethal if untreated. Today, only one arsenic- based, neurotoxic drug, melarsoprol, is available for treatment of the advanced meningo-encephalitic stage. A new oral treatment would simplify HAT elimination as proposed by WHO. Fexinidazole was recommended by the European Medicines Agency (EMA) in 2018 as the first oral treatment for Trypanosoma brucei gambiense HAT, but it was not yet evaluated for r-HAT.
METHODS
This single-arm clinical trial, sponsored by DNDi, began in October 2019 and tested fexinidazole treatment in patients with r-HAT as an alternative to existing treatment in Malawi and Uganda. Patients (aged ≥6 years) with both stages of the disease were recruited up to the target of 34 patients with stage 2 disease evaluable at the end of hospitalization. Patients were hospitalised during the 10 days of treatment and followed up to 12 months after hospital discharge. The primary outcome was r-HAT-related or treatment-related fatality at the end of hospitalisation in patients with stage 2 disease and was compared with an unacceptable fatality rate of 8.5%, a threshold defined according to results from a previous clinical trial with melarsoprol. This trial is registered with ClinicalTrials.gov, NCT03974178.
RESULTS
45 patients received treatment between 1 October 2019 and 28 November 2021 (35 [78%] had stage 2 disease and ten [22%] stage 1, 31 [69%] were male and 14 [31%] female, with median age of 24 years). The primary efficacy result of the clinical trial, analysed among the 34 evaluable patients, was achieved, with no r-HAT-related or treatment-related deaths during hospitalisation (0.0%, 95% CI 0.0–8.4), compared with a benchmark of 8.5% lethality attributable to melarsoprol. Safety was acceptable, with no severe adverse events related to fexinidazole; and one patient relapsed.
CONCLUSION
Fexinidazole, an oral treatment, was shown to be a good alternative to existing injectable and toxic drugs. Results were submitted for EMA regulatory review in preparation for use in endemic countries, and a positive scientific opinion was received in December 2023 to extend the indication of fexinidazole for the treatment of r-HAT. Fexinidazole is expected to be deployed in 2024 as a new r-HAT therapeutic.
Journal Article > Short ReportFull Text
Emerg Infect Dis. 2010 February 1; Volume 16; DOI:10.3201/eid1602.090967
Chappuis F, Lima MA, Flevaud L, Ritmeijer KKD
Emerg Infect Dis. 2010 February 1; Volume 16; DOI:10.3201/eid1602.090967
Journal Article > CommentaryFull Text
Lancet. 2009 October 14; Volume 375 (Issue 9709); 148-159.; DOI:10.1016/S0140-6736(09)60829-1
Brun R, Blum J, Chappuis F, Burri C
Lancet. 2009 October 14; Volume 375 (Issue 9709); 148-159.; DOI:10.1016/S0140-6736(09)60829-1
Human African trypanosomiasis (sleeping sickness) occurs in sub-Saharan Africa. It is caused by the protozoan parasite Trypanosoma brucei, transmitted by tsetse flies. Almost all cases are due to Trypanosoma brucei gambiense, which is indigenous to west and central Africa. Prevalence is strongly dependent on control measures, which are often neglected during periods of political instability, thus leading to resurgence. With fewer than 12 000 cases of this disabling and fatal disease reported per year, trypanosomiasis belongs to the most neglected tropical diseases. The clinical presentation is complex, and diagnosis and treatment difficult. The available drugs are old, complicated to administer, and can cause severe adverse reactions. New diagnostic methods and safe and effective drugs are urgently needed. Vector control, to reduce the number of flies in existing foci, needs to be organised on a pan-African basis. WHO has stated that if national control programmes, international organisations, research institutes, and philanthropic partners engage in concerted action, elimination of this disease might even be possible.