Journal Article > ResearchFull Text
Trans R Soc Trop Med Hyg. 21 October 2008; Volume 103 (Issue 3); DOI:10.1016/j.trstmh.2008.09.005
Balasegaram M, Young H, Chappuis F, Priotto G, Raguenaud ME, et al.
Trans R Soc Trop Med Hyg. 21 October 2008; Volume 103 (Issue 3); DOI:10.1016/j.trstmh.2008.09.005
This paper describes the effectiveness of first-line regimens for stage 2 human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense infection in nine Médecins Sans Frontières HAT treatment programmes in Angola, Republic of Congo, Sudan and Uganda. Regimens included eflornithine and standard- and short-course melarsoprol. Outcomes for 10461 naïve 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.
Journal Article > ResearchFull Text
Trop Med Int Health. 1 April 2004; Volume 9 (Issue 4); DOI:10.1111/j.1365-3156.2004.01217.x
Checchi F, Piola P, Kosack CS, Ardizzoni E, Klarkowski DB, et al.
Trop Med Int Health. 1 April 2004; Volume 9 (Issue 4); DOI:10.1111/j.1365-3156.2004.01217.x
We report below an in vivo antimalarial efficacy study conducted in 2002 in Bundi Bugyo, a district of western Uganda housing a large displaced population. We tested sulfadoxine-pyrimethamine (SP), amodiaquine (AQ) and the combination chloroquine plus SP (CQ + SP). A total of 268 children with uncomplicated Plasmodium falciparum malaria were followed-up for 28 days according to WHO recommendations, with PCR genotyping to distinguish late recrudescences from re-infections. PCR-adjusted failure proportions at day 28 were 37.0% (34/92, 95% CI 27.1-47.7) in the SP group, 20.6% (14/68, 95% CI 11.7-32.1) in the AQ group and 22.8% (18/79, 95% CI 14.1-33.6) in the CQ + SP group. Early failures were particularly frequent in the SP group (15.2%). Clearance of gametocytes was slower in the SP and CQ + SP groups than in the AQ group. This study suggests that, in Bundi Bugyo, CQ + SP (Uganda's first-line regimen) will need to be replaced by a more efficacious regimen. Across Uganda, the deployment of SP containing combinations may not be a feasible long-term strategy. For Bundi Bugyo, we recommend a combination of artesunate and AQ. Our study also confirms previous findings that resistance is considerably underestimated by 14-day follow-ups. Antimalarial policy decisions should therefore be based on 28-day studies, with PCR adjustment to distinguish re-infections.
Journal Article > CommentaryFull Text
PLoS Negl Trop Dis. 25 May 2010; Volume 4 (Issue 5); DOI:10.1371/journal.pntd.0000720
Yun O, Priotto G, Tong J, Flevaud L, Chappuis F
PLoS Negl Trop Dis. 25 May 2010; Volume 4 (Issue 5); DOI:10.1371/journal.pntd.0000720
Journal Article > ResearchFull Text
Clin Infect Dis. 1 December 2007; Volume 45 (Issue 11); DOI:10.1086/522982
Priotto G, Kasparian S, Ngouama D, Ghorashian S, Arnold U, et al.
Clin Infect Dis. 1 December 2007; Volume 45 (Issue 11); DOI:10.1086/522982
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.
Journal Article > ResearchFull Text
Trop Med Int Health. 1 February 2007; Volume 12 (Issue 2); DOI:10.1111/j.1365-3156.2007.01813.x
Mugittu K, Priotto G, Guthmann JP, Kiguli J, Adjuik M, et al.
Trop Med Int Health. 1 February 2007; Volume 12 (Issue 2); DOI:10.1111/j.1365-3156.2007.01813.x
Polymerase chain reaction (PCR) genotyping of malaria parasites in drug efficacy trials helps differentiate reinfections from recrudescences. A combination therapy trial of one (n = 115) or three (n = 117) days artesunate (1AS, 3AS 4 mg/kg/day) plus sulphadoxine-pyrimethamine (SP) vs. SP alone (n = 153) was conducted in Mbarara, a mesoendemic area of western Uganda. All paired recurrent Plasmodium falciparum parasitaemias on days 7, 14, 21 and 28 post-treatment were genotyped by PCR amplification and analysis of glutamate-rich protein (glurp) and merozoite surface proteins (msp) 1 and 2 genes to distinguish recrudescent from new infections. A total of 156 (1AS = 61, 3AS = 35, SP alone = 60) of 199 paired recurrent samples were successfully analysed and were resolved as 79 recrudescences (1AS = 32, 3AS = 8, SP = 39) and 77 as new infections (1AS = 29, 3AS = 27, SP = 21). The ratios of proportions of new to recrudescent infections were 0.2, 0.9, 1.4 and 1.9 on days 7, 14, 21 and 28, respectively (P < 0.001, chi(2) test for linear trend). Unexpected high new infection rates were observed early in follow-up on days 7 [5/26 (19.2%)] and 14 [24/51 (47.1%)]. These results impact significantly on resistance monitoring and point to the value of genotyping all recurrent infections in antimalarial trials.
Journal Article > ResearchFull Text
Trans R Soc Trop Med Hyg. 14 February 2008
Guthmann JP, Ruiz A, Priotto G, Kiguli J, Bonte L, et al.
Trans R Soc Trop Med Hyg. 14 February 2008
A study was conducted to measure the overall performance of several rapid diagnostic tests for Plasmodium falciparum infection, in order to select the most appropriate test to be used in the field. A total of 742 patients attending the out-patient department of Mbarara Hospital with a clinical suspicion of malaria were included in the study. For each patient, a thick/thin film and 5 rapid tests based on the detection of histidine-rich protein II (HRP-II) (Paracheck Pf dipstick and device, ParaHIT f, Malaria Rapid and BIO P.F.) were performed. Outcomes were validity, inter-reader reliability and 'ease of use in the field', measured by both the general characteristics of the test and by the opinion of the readers. About half (57%) of the patients were positive for P. falciparum. The Paracheck Pf (dipstick and device) was considered as the most appropriate for the use in the field, being sensitive (97%), moderately specific (88%), reliable (kappa coefficient = 0.97), easy to use and cheap (about US$ 0.5/test). The ParaHIT f represented a good alternative.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 5 July 2011; Volume 5 (Issue 7); DOI:10.1371/journal.pntd.0001233
Checchi F, Chappuis F, Karunakara U, Priotto G, Chandramohan D
PLoS Negl Trop Dis. 5 July 2011; Volume 5 (Issue 7); DOI:10.1371/journal.pntd.0001233
Algorithms to diagnose gambiense human African trypanosomiasis (HAT, sleeping sickness) are often complex due to the unsatisfactory sensitivity and/or specificity of available tests, and typically include a screening (serological), confirmation (parasitological) and staging component. There is insufficient evidence on the relative accuracy of these algorithms. This paper presents estimates of the accuracy of five algorithms used by past Médecins Sans Frontières programmes in the Republic of Congo, Southern Sudan and Uganda.
Journal Article > ResearchFull Text
Trans R Soc Trop Med Hyg. 25 January 2008
Priotto G, Kabakyenga JK, Pinoges LLP, Ruiz A, Eriksson T, et al.
Trans R Soc Trop Med Hyg. 25 January 2008
Drug-resistant malaria is spreading in Africa. The few available drugs might be safeguarded if combined with an artemisinin derivative. We investigated the efficacy, safety, and tolerability of 2 combinations of artesunate with sulfadoxine-pyrimethamine (SP) in a mesoendemic region in Uganda with SP resistance, from September 1999 to June 2000. In a randomized, double-blind, placebo-controlled trial, 420 children aged 6-59 months with uncomplicated Plasmodium falciparum malaria were assigned SP alone (25 mg/kg sulfadoxine, 1.25 mg/kg pyrimethamine) or combined with artesunate (AS; 4 mg/kg/d) for either 1 d (SPAS1) or 3 d (SPAS3). Children were followed-up for 28 d. Day 14 cure rates were 84.6% (99/117) with SPAS3 and 61.9% (73/118) with SPAS1 compared with 55.8% (86/154) with SP. Corresponding day 28 results were 74.4% (87/117) and 45.2% (52/115) compared with 40.5% (62/153). A significant improvement was obtained with the addition of 3 d, but not 1 d, of artesunate (risk ratio [RR] = 1.5, 95% CI 1.3-1.8 at 14 d and RR = 1.8, 95% CI 1.5-2.3 at 28 d). Both AS regimens achieved significantly faster parasite clearance and lower gametocyte carriage. All drug regimens were well tolerated, but SP alone was ineffective. Treatment efficacy improved with SPAS3 but the cure rate at day 28 was modest. The combinations were well tolerated and safe. In areas where SP resistance is prevalent other combinations should be considered.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 5 June 2012; Volume 6 (Issue 6); DOI:10.1371/journal.pntd.0001662
Priotto G, Chappuis F, Bastard M, Flevaud L, Etard JF
PLoS Negl Trop Dis. 5 June 2012; Volume 6 (Issue 6); DOI:10.1371/journal.pntd.0001662
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.
Journal Article > ResearchFull Text
BMJ. 5 March 2008; Volume 336 (Issue 7646); DOI:10.1136/bmj.39485.592674.BE
Priotto G, Pinoges LLP, Fursa IB, Burke B, Nicolay N, et al.
BMJ. 5 March 2008; Volume 336 (Issue 7646); DOI:10.1136/bmj.39485.592674.BE
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 ≥100x109/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: 20-99x109/l (2.35, 1.36 to 4.06); ≥100x109/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.