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Gerardo Priotto - One of the best experts on this subject based on the ideXlab platform.
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NECT Is Next: Implementing the New Drug Combination Therapy for Trypanosoma brucei gambiense Sleeping Sickness
PLOS Neglected Tropical Diseases, 2010Co-Authors: Gerardo Priotto, Jacqueline Tong, Laurence Flevaud, Francois ChappuisAbstract:Fatal if untreated, human African trypanosomiasis (HAT; sleeping sickness) afflicts an estimated 50,000–70,000 people each year [1], all in sub-Saharan Africa, with only a minority of cases (nearly 12,000 in 2008) being reported [2]. HAT is one of four neglected tropical diseases (NTDs) identified by the World Health Organization (WHO) as requiring Innovative and Intensified Disease Management (IDM), along with Chagas disease, leishmaniasis, and Buruli ulcer [3]. These particular NTDs have poorly understood burdens, lack optimal control tools, receive insufficient research and development (R&D) investment, and affect people who often live in remote or insecure areas with limited access to health care. Excluding Buruli ulcer, these IDM diseases have the highest death rates of all NTDs [4]. HAT in west and central Africa is caused by the protozoan parasite Trypanosoma brucei gambiense, transmitted through tsetse flies. The disease progresses from first stage (infecting blood and lymph) to second stage (infecting the central nervous system), which can lead to severe sleep disturbances, neurological and psychiatric disorders, coma, and death. Primary elements of HAT management are surveillance, diagnosis, treatment, and vector control. Drug treatments for T. b. gambiense HAT have been limited: pentamidine for first-stage disease, and melarsoprol or Eflornithine for second-stage disease. Eflornithine is safer and often more effective than melarsoprol, which is associated with high toxicity, even fatal at times, and exhibits high rates of treatment failure in numerous HAT-endemic foci. However, despite an increasing proportion of second-stage HAT treated with Eflornithine during recent years [5], melarsoprol remains in use in many treatment centers due to Eflornithine's long, burdensome treatment administration requirements, which are difficult to implement in resource-constrained settings. In April 2009, a new treatment option, nifurtimox-Eflornithine combination therapy (NECT), was added to the WHO Essential Medicines List (EML) for the treatment of second-stage T. b. gambiense HAT [6]. NECT was added to the EML based on the high efficacy and good safety profile observed in all studies done to date, against a background of recognized severity of stage 2 disease and toxicity of existing treatments. Surveillance of adverse events was strongly recommended [7]. Compared with Eflornithine monotherapy, NECT is easier to administer and requires fewer human and material resources. In the current context, NECT stands as the most promising first-line treatment for second-stage T. b. gambiense HAT. Here we describe the developments and challenges in rolling out and implementing NECT in HAT-endemic areas.
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nifurtimox Eflornithine combination therapy for second stage african trypanosoma brucei gambiense trypanosomiasis a multicentre randomised phase iii non inferiority trial
The Lancet, 2009Co-Authors: Gerardo Priotto, S Kasparian, D Ngouama, Sara Ghorashian, U Arnold, Salah Ghabri, Wilfried Mutombo, Elisabeth Baudin, Vincent Buard, Serge KazadikyanzaAbstract:Summary 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 ≤20 cells per μL) 18 months after treatment. Efficacy analyses were done in the intention-to-treat (ITT), modified ITT, and per-protocol (PP) populations. The non-inferiority margin for the difference in cure rates was defined as 10%. This study is registered with ClinicalTrials.gov, number NCT00146627. Findings One patient from the Eflornithine group absconded after receiving the first dose, without any type of assessment done, and was excluded from all analyses. In the ITT population, 131 (91·6%) of 143 patients assigned to Eflornithine and 138 (96·5%) of 143 patients assigned to NECT were cured at 18 months (difference −4·9%, one-sided 95% CI −0·3; p Interpretation The efficacy of NECT is non-inferior to that of Eflornithine monotherapy. Since this combination treatment also presents safety advantages, is easier to administer (ie, infusion every 12 h for 7 days vs every 6 h for 14 days), and potentially protective against the emergence of resistant parasites, it is suitable for first-line use in HAT control programmes. Funding Medecins Sans Frontieres (Dutch section), Medecins Sans Frontieres International, and the Drugs for Neglected Diseases Initiative.
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effectiveness of melarsoprol and Eflornithine as first line regimens for gambiense sleeping sickness in nine medecins sans frontieres programmes
Transactions of The Royal Society of Tropical Medicine and Hygiene, 2009Co-Authors: Manica Balasegaram, Gerardo Priotto, Heather Young, Francois Chappuis, Marieeve Raguenaud, Francesco ChecchiAbstract:This paper describes the effectiveness of first-line regimens for stage 2 human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense infection in nine Medecins Sans Frontieres HAT treatment programmes in Angola, Republic of Congo, Sudan and Uganda. Regimens included Eflornithine and standard- and short-course melarsoprol. Outcomes for 10461 naive stage 2 patients fitting a standardised case definition and allocated to one of the above regimens were analysed by intention-to-treat analysis. Effectiveness was quantified by the case fatality rate (CFR) during treatment, the proportion probably and definitely cured and the Kaplan-Meier probability of relapse-free survival at 12 months and 24 months post admission. The CFR was similar for the standard- and short-course melarsoprol regimens (4.9% and 4.2%, respectively). The CFR for Eflornithine was 1.2%. Kaplan-Meier survival probabilities varied from 71.4-91.8% at 1 year and 56.5-87.9% at 2 years for standard-course melarsoprol, to 73.0-91.1% at 1 year for short-course melarsoprol, and 79.9-97.4% at 1 year and 68.6-93.7% at 2 years for Eflornithine. With the exception of one programme, survival at 12 months was >90% for Eflornithine, whilst for melarsoprol it was <90% except in two sites. Eflornithine is recommended where feasible, especially in areas with low melarsoprol effectiveness.
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Effectiveness of melarsoprol and Eflornithine as first-line regimens for gambiense sleeping sickness in nine Médecins Sans Frontières programmes
Transactions of The Royal Society of Tropical Medicine and Hygiene, 2008Co-Authors: Manica Balasegaram, Gerardo Priotto, Heather Young, Francois Chappuis, Marieeve Raguenaud, Francesco ChecchiAbstract:This paper describes the effectiveness of first-line regimens for stage 2 human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense infection in nine Medecins Sans Frontieres HAT treatment programmes in Angola, Republic of Congo, Sudan and Uganda. Regimens included Eflornithine and standard- and short-course melarsoprol. Outcomes for 10 461 naive stage 2 patients fitting a standardised case definition and allocated to one of the above regimens were analysed by intention-to-treat analysis. Effectiveness was quantified by the case fatality rate (CFR) during treatment, the proportion probably and definitely cured and the Kaplan–Meier probability of relapse-free survival at 12 months and 24 months post admission. The CFR was similar for the standard- and short-course melarsoprol regimens (4.9% and 4.2%, respectively). The CFR for Eflornithine was 1.2%. Kaplan–Meier survival probabilities varied from 71.4–91.8% at 1 year and 56.5–87.9% at 2 years for standard-course melarsoprol, to 73.0–91.1% at 1 year for short-course melarsoprol, and 79.9–97.4% at 1 year and 68.6–93.7% at 2 years for Eflornithine. With the exception of one programme, survival at 12 months was >90% for Eflornithine, whilst for melarsoprol it was
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safety and effectiveness of first line Eflornithine for trypanosoma brucei gambiense sleeping sickness in sudan cohort study
BMJ, 2008Co-Authors: Gerardo Priotto, Loretxu Pinoges, Isaac Badi Fursa, Barbara Burke, Nathalie Nicolay, Guillaume Grillet, Cathy Hewison, Manica BalasegaramAbstract:OBJECTIVE: To assess the safety and effectiveness of Eflornithine as first line treatment for human African trypanosomiasis. DESIGN: Cohort study. SETTING: Control programme in Ibba, southern Sudan. PARTICIPANTS: 1055 adults and children newly diagnosed with second stage disease in a 16 month period. MAIN OUTCOME MEASURES: Deaths, severe drug reactions, and cure at 24 months. RESULTS: 1055 patients received Eflornithine for 14 days (400 mg/kg/day in adults and 600 mg/kg/day in a subgroup of 96 children). Overall, 2824 drug reactions (2.7 per patient) occurred during hospital stay, 1219 (43.2%) after the first week. Severe reactions affected 138 (13.1%) patients (mainly seizures, fever, diarrhoea, and bacterial infections), leading to 15 deaths. Risk factors for severe reactions included cerebrospinal fluid leucocyte counts > or =100x10(9)/l (adults: odds ratio 2.6, 95% confidence interval 1.5 to 4.6), seizures (adults: 5.9, 2.0 to 13.3), and stupor (children: 9.3, 2.5 to 34.2). Children receiving higher doses did not experience increased toxicity. Follow-up data were obtained for 924 (87.6%) patients at any follow-up but for only 533 (50.5%) at 24 months. Of 924 cases followed, 16 (1.7%) died during treatment, 70 (7.6%) relapsed, 15 (1.6%) died of disease, 403 (43.6%) were confirmed cured, and 420 (45.5%) were probably cured. The probability of event free survival at 24 months was 0.88 (0.86 to 0.91). Most (65.8%, 52/79) relapses and disease related deaths occurred after 12 months. Risk factors for relapse included being male (incidence rate ratio 2.42, 1.47 to 3.97) and cerebrospinal fluid leucocytosis: 20-99x10(9)/l (2.35, 1.36 to 4.06); > or =100x10(9)/l (1.87, 1.07 to 3.27). Higher doses did not yield better effectiveness among children (0.87 v 0.85, P=0.981). Conclusions Eflornithine shows acceptable safety and effectiveness as first line treatment for human African trypanosomiasis. Relapses did occur more than 12 months after treatment. Higher doses in children were well tolerated but showed no advantage in effectiveness.
Unni Karunakara - One of the best experts on this subject based on the ideXlab platform.
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nifurtimox Eflornithine combination therapy for second stage trypanosoma brucei gambiense sleeping sickness a randomized clinical trial in congo
Clinical Infectious Diseases, 2007Co-Authors: Gerardo Priotto, S Kasparian, D Ngouama, Sara Ghorashian, U Arnold, Salah Ghabri, Unni KarunakaraAbstract: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. Human African trypanosomiasis (HAT), or sleeping sickness, remains a public health challenge in sub-Saharan Africa, with an estimated 50,000-70,000 new cases per year, of which ∼20,000 are detected and reported (1). The disease is caused by the protozoan parasite Trypanosoma brucei gambiense, which is transmitted by the tsetse fly (Glossina species), and it pro- gresses from the hemolymphatic first stage to the meningo- encephalitic second stage. It is invariably fatal without appro- priate treatment. Since 1949, melarsoprol is the most commonly used treatment for second-stage HAT. This arsenical derivative is associated with severe toxic effects—in particular, reactive encephalopathy, which is fatal in 10%-70% of cases and affects 5%-10% of treated patients (2, 3). Moreover, in-
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melarsoprol versus Eflornithine for treating late stage gambian trypanosomiasis in the republic of the congo
Bulletin of The World Health Organization, 2006Co-Authors: Manica Balasegaram, Sara Ghorashian, Steve Harris, Francesco Checchi, Catherine Hamel, Unni KarunakaraAbstract: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.
Francois Chappuis - One of the best experts on this subject based on the ideXlab platform.
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nifurtimox Eflornithine combination therapy for second stage gambiense human african trypanosomiasis medecins sans frontieres experience in the democratic republic of the congo
Clinical Infectious Diseases, 2013Co-Authors: Emilie Alirol, David Schrumpf, Josue Amici Heradi, Andrea Riedel, Catherine De Patoul, Michel Quere, Francois ChappuisAbstract:Existing diagnostic and treatment tools for human African trypanosomiasis (HAT) are limited. The recent development of nifurtimox-Eflornithine combination therapy (NECT) has brought new hopes for patients in the second stage. While NECT has been rolled out in most endemic countries, safety data are scarce and derive only from clinical trials. The World Health Organization (WHO) coordinates a pharmacovigilance program to collect additional data on NECT safety and efficacy. We report here the results of 18 months of experience of NECT use in treatment centers run by Medecins Sans Frontieres in the Democratic Republic of the Congo (DRC).
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NECT Is Next: Implementing the New Drug Combination Therapy for Trypanosoma brucei gambiense Sleeping Sickness
PLOS Neglected Tropical Diseases, 2010Co-Authors: Gerardo Priotto, Jacqueline Tong, Laurence Flevaud, Francois ChappuisAbstract:Fatal if untreated, human African trypanosomiasis (HAT; sleeping sickness) afflicts an estimated 50,000–70,000 people each year [1], all in sub-Saharan Africa, with only a minority of cases (nearly 12,000 in 2008) being reported [2]. HAT is one of four neglected tropical diseases (NTDs) identified by the World Health Organization (WHO) as requiring Innovative and Intensified Disease Management (IDM), along with Chagas disease, leishmaniasis, and Buruli ulcer [3]. These particular NTDs have poorly understood burdens, lack optimal control tools, receive insufficient research and development (R&D) investment, and affect people who often live in remote or insecure areas with limited access to health care. Excluding Buruli ulcer, these IDM diseases have the highest death rates of all NTDs [4]. HAT in west and central Africa is caused by the protozoan parasite Trypanosoma brucei gambiense, transmitted through tsetse flies. The disease progresses from first stage (infecting blood and lymph) to second stage (infecting the central nervous system), which can lead to severe sleep disturbances, neurological and psychiatric disorders, coma, and death. Primary elements of HAT management are surveillance, diagnosis, treatment, and vector control. Drug treatments for T. b. gambiense HAT have been limited: pentamidine for first-stage disease, and melarsoprol or Eflornithine for second-stage disease. Eflornithine is safer and often more effective than melarsoprol, which is associated with high toxicity, even fatal at times, and exhibits high rates of treatment failure in numerous HAT-endemic foci. However, despite an increasing proportion of second-stage HAT treated with Eflornithine during recent years [5], melarsoprol remains in use in many treatment centers due to Eflornithine's long, burdensome treatment administration requirements, which are difficult to implement in resource-constrained settings. In April 2009, a new treatment option, nifurtimox-Eflornithine combination therapy (NECT), was added to the WHO Essential Medicines List (EML) for the treatment of second-stage T. b. gambiense HAT [6]. NECT was added to the EML based on the high efficacy and good safety profile observed in all studies done to date, against a background of recognized severity of stage 2 disease and toxicity of existing treatments. Surveillance of adverse events was strongly recommended [7]. Compared with Eflornithine monotherapy, NECT is easier to administer and requires fewer human and material resources. In the current context, NECT stands as the most promising first-line treatment for second-stage T. b. gambiense HAT. Here we describe the developments and challenges in rolling out and implementing NECT in HAT-endemic areas.
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effectiveness of melarsoprol and Eflornithine as first line regimens for gambiense sleeping sickness in nine medecins sans frontieres programmes
Transactions of The Royal Society of Tropical Medicine and Hygiene, 2009Co-Authors: Manica Balasegaram, Gerardo Priotto, Heather Young, Francois Chappuis, Marieeve Raguenaud, Francesco ChecchiAbstract:This paper describes the effectiveness of first-line regimens for stage 2 human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense infection in nine Medecins Sans Frontieres HAT treatment programmes in Angola, Republic of Congo, Sudan and Uganda. Regimens included Eflornithine and standard- and short-course melarsoprol. Outcomes for 10461 naive stage 2 patients fitting a standardised case definition and allocated to one of the above regimens were analysed by intention-to-treat analysis. Effectiveness was quantified by the case fatality rate (CFR) during treatment, the proportion probably and definitely cured and the Kaplan-Meier probability of relapse-free survival at 12 months and 24 months post admission. The CFR was similar for the standard- and short-course melarsoprol regimens (4.9% and 4.2%, respectively). The CFR for Eflornithine was 1.2%. Kaplan-Meier survival probabilities varied from 71.4-91.8% at 1 year and 56.5-87.9% at 2 years for standard-course melarsoprol, to 73.0-91.1% at 1 year for short-course melarsoprol, and 79.9-97.4% at 1 year and 68.6-93.7% at 2 years for Eflornithine. With the exception of one programme, survival at 12 months was >90% for Eflornithine, whilst for melarsoprol it was <90% except in two sites. Eflornithine is recommended where feasible, especially in areas with low melarsoprol effectiveness.
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Effectiveness of melarsoprol and Eflornithine as first-line regimens for gambiense sleeping sickness in nine Médecins Sans Frontières programmes
Transactions of The Royal Society of Tropical Medicine and Hygiene, 2008Co-Authors: Manica Balasegaram, Gerardo Priotto, Heather Young, Francois Chappuis, Marieeve Raguenaud, Francesco ChecchiAbstract:This paper describes the effectiveness of first-line regimens for stage 2 human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense infection in nine Medecins Sans Frontieres HAT treatment programmes in Angola, Republic of Congo, Sudan and Uganda. Regimens included Eflornithine and standard- and short-course melarsoprol. Outcomes for 10 461 naive stage 2 patients fitting a standardised case definition and allocated to one of the above regimens were analysed by intention-to-treat analysis. Effectiveness was quantified by the case fatality rate (CFR) during treatment, the proportion probably and definitely cured and the Kaplan–Meier probability of relapse-free survival at 12 months and 24 months post admission. The CFR was similar for the standard- and short-course melarsoprol regimens (4.9% and 4.2%, respectively). The CFR for Eflornithine was 1.2%. Kaplan–Meier survival probabilities varied from 71.4–91.8% at 1 year and 56.5–87.9% at 2 years for standard-course melarsoprol, to 73.0–91.1% at 1 year for short-course melarsoprol, and 79.9–97.4% at 1 year and 68.6–93.7% at 2 years for Eflornithine. With the exception of one programme, survival at 12 months was >90% for Eflornithine, whilst for melarsoprol it was
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Eflornithine is safer than melarsoprol for the treatment of second stage trypanosoma brucei gambiense human african trypanosomiasis
Clinical Infectious Diseases, 2005Co-Authors: Francois Chappuis, Nitya Udayraj, Kai Stietenroth, Ann Meussen, Patrick A BovierAbstract: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).
Jacques Pepin - One of the best experts on this subject based on the ideXlab platform.
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combination of Eflornithine and melarsoprol for melarsoprol resistant gambian trypanosomiasis
Tropical Medicine & International Health, 2002Co-Authors: Bokelo Mpia, Jacques PepinAbstract:Summary Objective To evaluate the efficacy and toxicity of a combination of Eflornithine and melarsoprol among relapsing cases of Gambian trypanosomiasis. Methods Forty-two late-stage Trypanosoma brucei gambiense trypanosomiasis patients relapsing after initial treatment with melarsoprol were treated with a sequential combination of intravenous Eflornithine (100 mg/kg every 6 h for 4 days) followed by three daily injections of melarsoprol (3.6 mg/kg, up to 180 mg). They were then followed-up for 24 months. Results Two (4.8%) patients died during treatment. Of the 40 surviving patients, two had a treatment failure, 13 and 19 months after having received the combination therapy. By Kaplan–Meier analysis, the 2-year probability of cure was 93.3% (95% confidence interval: 84.3–100%). Conclusion This sequential combination has an efficacy and a toxicity similar to a 7-day course of Eflornithine monotherapy, but is easier to administer. Whether such therapeutic success corresponds tosynergism between Eflornithine and melarsoprol, or merely means that 4 days of Eflornithine monotherapy suffices for such patients, will need to be determined in a comparative trial.
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short course Eflornithine in gambian trypanosomiasis a multicentre randomized controlled trial
Bulletin of The World Health Organization, 2000Co-Authors: Jacques Pepin, Bokelo Mpia, Nzambi Khonde, Faustine Maiso, Felix Doua, Shabbar Jaffar, Stephane Ngampo, Dawson Mbulamberi, Felix KuzoeAbstract:Objective A randomized controlled trial was conducted to determine whether 7 days of intravenous Eflornithine (100 mg/kg every 6 h) was as effective as the standard 14-day regimen in the treatment of late-stage Trypanosoma brucei gambiense trypanosomiasis. Methods A total of 321 patients (274 new cases, 47 relapsing cases) were randomized at four participating centres in Congo, Cote d'Ivoire, the Democratic Republic of the Congo, and Uganda to one of these treatment regimens and followed up for 2 years. Results Six patients died during treatment, one of whom was on the 7-day regimen, whereas the other five had been on the 14-day regimen (P = 0.2). The response to Eflornithine differed markedly between Uganda and other countries. Among new cases in Uganda, the 2-year probability of cure was 73% on the 14-day course compared with 62% on the 7-day regimen (hazard ratio (HR) for treatment failure, 7-day versus 14-day regimen: 1.45, 95% CI: 0.7, 3.1, P = 0.3). Among new cases in Cote d'Ivoire, Congo, and the Democratic Republic of the Congo combined, the 2-year probability of cure was 97% on the 14-day course compared with 86.5% on the 7-day regimen (HR for treatment failure, 7-day vs 14-day: 6.72, 95% confidence interval (CI): 1.5, 31.0, P = 0.003). Among relapsing cases in all four countries, the 2-year probability of cure was 94% with 7 days and 100% with 14 days of treatment. Factors associated with a higher risk of treatment failure were: a positive lymph node aspirate (HR 4.1; 95% CI: 1.8-9.4), a cerebrospinal fluid (CSF) white cell count 5100/mm 3 (HR 3.5; 95% CI: 1.1-10.9), being treated in Uganda (HR 2.9; 95% CI: 1.4-5.9), and CSF trypanosomes (HR 1.9; 95% CI : 0.9-4.1). Being stuporous on admission was associated with a lower risk of treatment failure (HR 0.18; 95% CI: 0.02-1.4) as was increasing age (HR 0.977; 95% CI: 0.95-1.0, for each additional year of age). Discussion The 7-day course of Eflornithine is an effective treatment of relapsing cases of Gambian trypanosomiasis. For new cases, a 7-day course is inferior to the standard 14-day regimen and cannot be recommended.
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a seven days course of Eflornithine for relapsing trypanosoma brucei gambiense sleeping sickness
Transactions of The Royal Society of Tropical Medicine and Hygiene, 1997Co-Authors: Nzambi Khonde, Jacques Pepin, Bokelo MpiaAbstract:Abstract Forty-seven patients with a relapse following a first treatment of Trypanosoma brucei gambiense trypanosomiasis were treated with a 7 d course of intravenous Eflornithine (100 mg/kg every 6 h) and followed for 2 years. Four patients died after treatment, 2 of them possibly due to trypanosomiasis. One patient was completely lost to follow-up, 36 were followed for at least one year, and 25 have completed the 2 years' follow-up. Only one patient, a 5 years old child, subsequently relapsed. Considering this child and 2 of the fatalities as treatment failures, the rate of failure was 6·5%. A 7 d course of intravenous Eflornithine is an adequate treatment for cases of Gambian trypanosomiasis relapsing after treatment with another drug.
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Eflornithine concentrations in serum and cerebrospinal fluid of 63 patients treated for trypanosoma brucei gambiense sleeping sickness
Transactions of The Royal Society of Tropical Medicine and Hygiene, 1993Co-Authors: F Milord, Bokelo Mpia, Lutete Loko, L Ethier, Jacques PepinAbstract:Abstract Eflornithine (difluoromethylornithine, DFMO) has recently been approved for the treatment of Trypanosoma brucei gambiense trypanosomiasis. Treatment failures have been infrequent but have occurred among patients treated with oral DFMO only, and among children. To investigate the higher frequency of failures observed in young patients, DFMO trough concentrations in serum and cerebrospinal fluid (CSF) were measured at the end of treatment in 13 children and 50 adults who had received 200 mg/kg intravenously every 12 h for 14 d. Mean DFMO concentration in CSF was significantly lower among children aged less than 12 years when compared to older patients (25·1 vs 68·9 nmol/mL, P P = 0·03). Among patients who received DFMO as initial therapy for sleeping sickness, the mean CSF/serum ratio was lower in children (0·41 vs 0·91, P
Sara Ghorashian - One of the best experts on this subject based on the ideXlab platform.
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nifurtimox Eflornithine combination therapy for second stage african trypanosoma brucei gambiense trypanosomiasis a multicentre randomised phase iii non inferiority trial
The Lancet, 2009Co-Authors: Gerardo Priotto, S Kasparian, D Ngouama, Sara Ghorashian, U Arnold, Salah Ghabri, Wilfried Mutombo, Elisabeth Baudin, Vincent Buard, Serge KazadikyanzaAbstract:Summary 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 ≤20 cells per μL) 18 months after treatment. Efficacy analyses were done in the intention-to-treat (ITT), modified ITT, and per-protocol (PP) populations. The non-inferiority margin for the difference in cure rates was defined as 10%. This study is registered with ClinicalTrials.gov, number NCT00146627. Findings One patient from the Eflornithine group absconded after receiving the first dose, without any type of assessment done, and was excluded from all analyses. In the ITT population, 131 (91·6%) of 143 patients assigned to Eflornithine and 138 (96·5%) of 143 patients assigned to NECT were cured at 18 months (difference −4·9%, one-sided 95% CI −0·3; p Interpretation The efficacy of NECT is non-inferior to that of Eflornithine monotherapy. Since this combination treatment also presents safety advantages, is easier to administer (ie, infusion every 12 h for 7 days vs every 6 h for 14 days), and potentially protective against the emergence of resistant parasites, it is suitable for first-line use in HAT control programmes. Funding Medecins Sans Frontieres (Dutch section), Medecins Sans Frontieres International, and the Drugs for Neglected Diseases Initiative.
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nifurtimox Eflornithine combination therapy for second stage trypanosoma brucei gambiense sleeping sickness a randomized clinical trial in congo
Clinical Infectious Diseases, 2007Co-Authors: Gerardo Priotto, S Kasparian, D Ngouama, Sara Ghorashian, U Arnold, Salah Ghabri, Unni KarunakaraAbstract: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. Human African trypanosomiasis (HAT), or sleeping sickness, remains a public health challenge in sub-Saharan Africa, with an estimated 50,000-70,000 new cases per year, of which ∼20,000 are detected and reported (1). The disease is caused by the protozoan parasite Trypanosoma brucei gambiense, which is transmitted by the tsetse fly (Glossina species), and it pro- gresses from the hemolymphatic first stage to the meningo- encephalitic second stage. It is invariably fatal without appro- priate treatment. Since 1949, melarsoprol is the most commonly used treatment for second-stage HAT. This arsenical derivative is associated with severe toxic effects—in particular, reactive encephalopathy, which is fatal in 10%-70% of cases and affects 5%-10% of treated patients (2, 3). Moreover, in-
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melarsoprol versus Eflornithine for treating late stage gambian trypanosomiasis in the republic of the congo
Bulletin of The World Health Organization, 2006Co-Authors: Manica Balasegaram, Sara Ghorashian, Steve Harris, Francesco Checchi, Catherine Hamel, Unni KarunakaraAbstract: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.