Conference Material > Abstract
Signorell A, Hetzel M, Tshefu AK, Omoluabi E, Awor P, et al.
MSF Scientific Days International 2022. 11 May 2022; DOI:10.57740/16vw-z635
INTRODUCTION
In sub-Saharan Africa, over 400,000 children die annually from malaria and other preventable illnesses. Little is known about where these children die, from which causes, and under which circumstances. A better understanding of these factors is crucial to effectively address the remaining burden of preventable childhood diseases and mortality. Rectal artesunate (RAS) is a potentially life-saving pre-referral treatment for children with severe malaria. However, limited evidence is available regarding the operational feasibility of incorporating RAS into the continuum of care for severe malaria, and the unanticipated consequences, like inappropriate use as artemisinin monotherapy or treatment of uncomplicated malaria, this could have on overall case management.
METHODS
The Community Access to Rectal Artesunate for Malaria (CARAMAL) study accompanied the implementation of RAS as a pre-referral treatment in DRC, Nigeria and Uganda. 8,563 children aged <5 years with severe febrile illnesses were detected and enrolled at primary care level, and 6,348 at referral health facilities. The children were followed up during admission and after 28 days to assess healthcare-seeking patterns, RAS use and acceptance, anti-malarial treatment received at the various points of contact with the health system, and health outcomes at day 28.
ETHICS
This study was approved by the World Health Organization’s Research Ethics Review Committee; the University of Kinshasa School of Public Health Ethics Committee; the Health Research Ethics Committee of the Adamawa State Ministry of Health and the National Health Research Ethics Committee, Nigeria; the Research and Ethics Committee of the Makerere University School of Public Health and the Uganda National Council for Science and Technology; and CHAI’s Scientific and Ethical Review Committee.
RESULTS
Post-RAS introduction, RAS was administered to 88% of eligible patients in DRC, 52% in Nigeria, and 70% in Uganda. We followed up 93% of enrolled children (13,870/14,911) 28 days after enrolment at home to determine status and healthcare trajectory. After roll-out, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase in DRC (adjusted odds ratio, aOR: 0.48) and Uganda (aOR: 0.72). Postreferral treatment with parenteral artesunate was high (above 80%), but the administration of a full course of artemisinin-based combination therapy to complete treatment as per WHO guidelines was variable (from virtually zero in Nigeria to 65% in DRC). Hence, many children were in fact treated with artemisinin monotherapy. Case fatality rates (CFR) varied largely by country and place of initial presentation (range: 0.3% to 15%). RAS was associated with reduced likelihood of being dead or sick on day 28 only in Uganda (aOR: 0.61, p<0.05) where overall CFR was lowest. No protective effect was found in DRC and Nigeria. Most children were considered healthy on day 28, but over 60% had detectable malaria antigenaemia.
CONCLUSION
For RAS to be an effective pre-referral treatment for children with severe malaria in hard-to-reach locations, underlying health system factors need to be addressed to ensure a functional continuum of care.
CONFLICTS OF INTEREST
None declared
In sub-Saharan Africa, over 400,000 children die annually from malaria and other preventable illnesses. Little is known about where these children die, from which causes, and under which circumstances. A better understanding of these factors is crucial to effectively address the remaining burden of preventable childhood diseases and mortality. Rectal artesunate (RAS) is a potentially life-saving pre-referral treatment for children with severe malaria. However, limited evidence is available regarding the operational feasibility of incorporating RAS into the continuum of care for severe malaria, and the unanticipated consequences, like inappropriate use as artemisinin monotherapy or treatment of uncomplicated malaria, this could have on overall case management.
METHODS
The Community Access to Rectal Artesunate for Malaria (CARAMAL) study accompanied the implementation of RAS as a pre-referral treatment in DRC, Nigeria and Uganda. 8,563 children aged <5 years with severe febrile illnesses were detected and enrolled at primary care level, and 6,348 at referral health facilities. The children were followed up during admission and after 28 days to assess healthcare-seeking patterns, RAS use and acceptance, anti-malarial treatment received at the various points of contact with the health system, and health outcomes at day 28.
ETHICS
This study was approved by the World Health Organization’s Research Ethics Review Committee; the University of Kinshasa School of Public Health Ethics Committee; the Health Research Ethics Committee of the Adamawa State Ministry of Health and the National Health Research Ethics Committee, Nigeria; the Research and Ethics Committee of the Makerere University School of Public Health and the Uganda National Council for Science and Technology; and CHAI’s Scientific and Ethical Review Committee.
RESULTS
Post-RAS introduction, RAS was administered to 88% of eligible patients in DRC, 52% in Nigeria, and 70% in Uganda. We followed up 93% of enrolled children (13,870/14,911) 28 days after enrolment at home to determine status and healthcare trajectory. After roll-out, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase in DRC (adjusted odds ratio, aOR: 0.48) and Uganda (aOR: 0.72). Postreferral treatment with parenteral artesunate was high (above 80%), but the administration of a full course of artemisinin-based combination therapy to complete treatment as per WHO guidelines was variable (from virtually zero in Nigeria to 65% in DRC). Hence, many children were in fact treated with artemisinin monotherapy. Case fatality rates (CFR) varied largely by country and place of initial presentation (range: 0.3% to 15%). RAS was associated with reduced likelihood of being dead or sick on day 28 only in Uganda (aOR: 0.61, p<0.05) where overall CFR was lowest. No protective effect was found in DRC and Nigeria. Most children were considered healthy on day 28, but over 60% had detectable malaria antigenaemia.
CONCLUSION
For RAS to be an effective pre-referral treatment for children with severe malaria in hard-to-reach locations, underlying health system factors need to be addressed to ensure a functional continuum of care.
CONFLICTS OF INTEREST
None declared
Conference Material > Slide Presentation
Signorell A, Hetzel M, Tshefu AK, Omoluabi E, Awor P, et al.
MSF Scientific Days International 2022. 11 May 2022; DOI:10.57740/3jc0-8f15
Journal Article > ResearchFull Text
J Infect Dis. 1 June 2005; Volume 191 (Issue 11); DOI:10.1086/429929
Schmid C, Richer M, Bilenge CM, Josenando T, Chappuis F, et al.
J Infect Dis. 1 June 2005; Volume 191 (Issue 11); DOI:10.1086/429929
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.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 16 February 2016; 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. 16 February 2016; 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 > ResearchFull Text
Treatment of human African trypanosomiasis--present situation and needs for research and development
Lancet Infect Dis. 1 July 2002
Legros D, Ollivier G, Gastellu-Etchegorry M, Paquet C, Burri C, et al.
Lancet Infect Dis. 1 July 2002
Human African trypanosomiasis re-emerged in the 1980s. However, little progress has been made in the treatment of this disease over the past decades. The first-line treatment for second-stage cases is melarsoprol, a toxic drug in use since 1949. High therapeutic failure rates have been reported recently in several foci. The alternative, eflornithine, is better tolerated but difficult to administer. A third drug, nifurtimox, is a cheap, orally administered drug not yet fully validated for use in human African trypanosomiasis. No new drugs for second-stage cases are expected in the near future. Because of resistance to and limited number of current treatments, there may soon be no effective drugs available to treat trypanosomiasis patients, especially second-stage cases. Additional research and development efforts must be made for the development of new compounds, including: testing combinations of current trypanocidal drugs, completing the clinical development of nifurtimox and registering it for trypanosomiasis, completing the clinical development of an oral form of eflornithine, pursuing the development of DB 289 and its derivatives, and advancing the pre-clinical development of megazol, eventually engaging firmly in its clinical development. Partners from the public and private sector are already engaged in joint initiatives to maintain the production of current drugs. This network should go further and be responsible for assigning selected teams to urgently needed research projects with funds provided by industry and governments. At the same time, on a long term basis, ambitious research programmes for new compounds must be supported to ensure the sustainable development of new drugs.
Journal Article > CommentaryFull Text
Lancet. 14 October 2009; Volume 375 (Issue 9709); 148-159.; DOI:10.1016/S0140-6736(09)60829-1
Brun R, Blum J, Chappuis F, Burri C
Lancet. 14 October 2009; 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.
Journal Article > CommentaryAbstract
Lancet. 9 January 2010; Volume 375 (Issue 9709); DOI:10.1016/S0140-6736(09)60829-1
Brun R, Blum J, Chappuis F, Burri C
Lancet. 9 January 2010; Volume 375 (Issue 9709); DOI:10.1016/S0140-6736(09)60829-1