• Artesunate and sulfadoxine-pyrimethamine combinations for the treatment of uncomplicated Plasmodium falciparum malaria in Uganda: a randomized, double-blind, placebo-controlled trial.

      Priotto, G; Kabakyenga, J K; Pinoges, L; Ruiz, A; Eriksson, T; Coussement, F; Ngambe, T; Taylor, W R J; Perea, W; Guthmann, J P; Olliaro, P; Legros, D; Epicentre, 8 rue Saint Sabin, 75011 Paris, France. gpriotto@epicentre.msf.org (Elsevier, 2008-01-25)
      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.
    • Clinical efficacy of chloroquine or sulfadoxine-pyrimethamine in children under five from south-western Uganda with uncomplicated falciparum malaria.

      Legros, D; Johnson, K; Houpikian, P; Makanga, M; Kabakyenga, J K; Talisuna, A O; Taylor, W R J; Epicentre, P.O. Box 2362, Kampala, Uganda. (2002)
      We conducted a 14-day study (during March-May 1998) to assess the efficacy of chloroquine and sulfadoxine-pyrimethamine (SP) for treating uncomplicated Plasmodium falciparum malaria in Uganda. Overall treatment failure rates were 43 (81.1%) of 53 chloroquine recipients and 16 (25.0%) of 64 SP patients. Strategies to improve the life-span of standard and affordable anti-malarial drugs are needed.
    • Different methodological approaches to the assessment of in vivo efficacy of three artemisinin-based combination antimalarial treatments for the treatment of uncomplicated falciparum malaria in African children.

      Ashley, E A; Pinoges, L; Turyakira, E; Dorsey, G; Checchi, F; Bukirwa, H; van den Broek, I; Zongo, I; Urruta, P P P; van Herp, M; Balkan, S; Taylor, W R J; Olliaro, P; Guthmann, J P; Epicentre, Paris, France. elizabeth.ashley@epicentre.msf.org (2008-08-09)
      BACKGROUND: Use of different methods for assessing the efficacy of artemisinin-based combination antimalarial treatments (ACTs) will result in different estimates being reported, with implications for changes in treatment policy. METHODS: Data from different in vivo studies of ACT treatment of uncomplicated falciparum malaria were combined in a single database. Efficacy at day 28 corrected by PCR genotyping was estimated using four methods. In the first two methods, failure rates were calculated as proportions with either (1a) reinfections excluded from the analysis (standard WHO per-protocol analysis) or (1b) reinfections considered as treatment successes. In the second two methods, failure rates were estimated using the Kaplan-Meier product limit formula using either (2a) WHO (2001) definitions of failure, or (2b) failure defined using parasitological criteria only. RESULTS: Data analysed represented 2926 patients from 17 studies in nine African countries. Three ACTs were studied: artesunate-amodiaquine (AS+AQ, N = 1702), artesunate-sulphadoxine-pyrimethamine (AS+SP, N = 706) and artemether-lumefantrine (AL, N = 518).Using method (1a), the day 28 failure rates ranged from 0% to 39.3% for AS+AQ treatment, from 1.0% to 33.3% for AS+SP treatment and from 0% to 3.3% for AL treatment. The median [range] difference in point estimates between method 1a (reference) and the others were: (i) method 1b = 1.3% [0 to 24.8], (ii) method 2a = 1.1% [0 to 21.5], and (iii) method 2b = 0% [-38 to 19.3].The standard per-protocol method (1a) tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a). It either overestimated or underestimated the risk when endpoints based on parasitological rather than clinical criteria were applied. The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled. Only 2% of the sample size was lost when failures were classified on the first day of parasite recurrence and survival analytical methods were used. CONCLUSION: The primary purpose of an in vivo study should be to provide a precise estimate of the risk of antimalarial treatment failure due to drug resistance. Use of survival analysis is the most appropriate way to estimate failure rates with parasitological recurrence classified as treatment failure on the day it occurs.
    • In vivo assessment of drug efficacy against Plasmodium falciparum malaria: duration of follow-up.

      Stepniewska, K; Taylor, W R J; Mayxay, M; Price, R; Smithuis, F; Guthmann, J P; Barnes, K; Myint, H Y; Adjuik, M; Olliaro, P; Pukrittayakamee, S; Looareesuwan, S; Hien, T T; Farrar, J; Nosten, F; Day, N P J; White, N J; Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd., Bangkok 10400, Thailand. (2004-11)
      To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years; 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in individual trials) but could be used to predict the true failure rate if either parasite genotyping was performed (r(2) = 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up.
    • Molecular genotyping in a malaria treatment trial in Uganda - unexpected high rate of new infections within 2 weeks after treatment.

      Mugittu, K; Priotto, G; Guthmann, J P; Kiguli, J; Adjuik, M; Snounou, G; Beck, H P; Mshinda, H; Olliaro, P; Taylor, W R J; Ifakara Health Research and Development Centre, Ifakara, Tanzania. (2007-02)
      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.
    • Supervised versus unsupervised antimalarial treatment with six-dose artemether-lumefantrine: pharmacokinetic and dosage-related findings from a clinical trial in Uganda.

      Checchi, F; Piola, P; Fogg, C; Bajunirwe, F; Biraro, S; Grandesso, F; Ruzagira, E; Babigumira, J; Kigozi, I; Kiguli, J; Kyomuhendo, J; Ferradini, L; Taylor, W R J; Guthmann, J P; Epicentre, Paris, France. francesco.checchi@lshtm.ac.uk (BioMed Central, 2006)
      BACKGROUND: A six-dose antimalarial regimen of artemether-lumefantrine (A/L) may soon become one of the most widely used drug combination in Africa, despite possible constraints with adherence and poor absorption due to inadequate nutrition, and a lack of pharmacokinetic and effectiveness data. METHODS: Within a trial of supervised versus unsupervised A/L treatment in a stable Ugandan Plasmodium falciparum transmission setting, plasma lumefantrine concentrations were measured in a subset of patients on day 3 (C [lum]day3) and day 7 (C [lum]day7) post-inclusion. Predictors of lumefantrine concentrations were analysed to show how both C [lum]day7 and the weight-adjusted lumefantrine dose affect 28-day recrudescence and re-infection risks. The implications of these novel findings are discussed in terms of the emergence of lumefantrine-resistant strains in Africa. RESULTS: C [lum]day3 and C [lum]day7 distributions among 241 supervised and 238 unsupervised patients were positively skewed. Unsupervised treatment and decreasing weight-adjusted lumefantrine dose were negatively associated with C [lum]day3. Unsupervised treatment and decreasing age showed strong negative associations with C [lum]day7. Both models were poorly predictive (R-squared < 0.25). There were no recrudescences in either arm, but decreasing lumefantrine dose per Kg resulted in up to 13-fold higher adjusted risks of re-infection. Re-infections occurred only among patients with C [lum]day7 below 400 ng/mL (p < 0.001). CONCLUSION: Maintaining the present six-dose regimen and ensuring high adherence and intake are essential to maximize the public health benefits of this valuable drug combination.