• 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.
    • Drug resistance in Plasmodium falciparum from the Chittagong Hill Tracts, Bangladesh.

      van den Broek, I; van der Wardt, S; Talukder, L; Chakma, S; Brockman, A; Nair, S; Anderson, T C; Médecins sans Frontières-Holland, Gulshan, Dhaka, Bangladesh. ingrid.van.den.braek@london.msf.org (Wiley-Blackwell, 2004-06)
      OBJECTIVE: To assess the efficacy of antimalarial treatment and molecular markers of Plasmodium falciparum resistance in the Chittagong Hill Tracts of Bangladesh. METHODS: A total of 203 patients infected with P. falciparum were treated with quinine 3 days plus sulphadoxine/pyrimethamine (SP) combination therapy, and followed up during a 4-week period. Blood samples collected before treatment were genotyped for parasite mutations related to chloroquine (pfcrt and pfmdr1 genes) or SP resistance (dhfr and dhps). RESULTS: Of 186 patients who completed follow-up, 32 patients (17.2%) failed to clear parasitaemia or became positive again within 28 days after treatment. Recurring parasitaemia was related to age (chi(2) = 4.8, P < 0.05) and parasite rates on admission (t = 3.1, P < 0.01). PCR analysis showed that some of these cases were novel infections. The adjusted recrudescence rate was 12.9% (95% CI 8.1-17.7) overall, and 16.6% (95% CI 3.5-29.7), 15.5% (95% CI 8.3-22.7) and 6.9% (95% CI 0.4-13.4) in three age groups (<5 years, 5-14, > or =15). The majority of infections carried mutations associated with chloroquine resistance: 94% at pfcrt and 70% at pfmdr. Sp-resistant genotypes were also frequent: 99% and 73% of parasites carried two or more mutations at dhfr and dhps, respectively. The frequency of alleles at dhfr, dhps and pfmdr was similar in cases that were successfully treated and those that recrudesced. CONCLUSIONS: The clinical trial showed that quinine 3-days combined to SP is still relatively effective in the Chittagong Hill Tracts. However, if this regimen is continued to be widely used, further development of SP resistance and reduced quinine sensitivity are to be expected. The genotyping results suggest that neither chloroquine nor SP can be considered a reliable treatment for P. falciparum malaria any longer in this area of Bangladesh.
    • Efficacy of amodiaquine in uncomplicated falciparum malaria in Nigeria in an area with high-level resistance to chloroquine and sulphadoxine/pyrimethamine.

      Graupner, J; Göbels, K; Grobusch, M P; Lund, A; Richter, J; Häussinger, D; Medecins sans Frontières (MSF), Max Euweplein 40, 1001, EA, Amsterdam, The Netherlands. (2005-06)
      Falciparum Malaria is hyperendemic in southern Nigeria and chloroquine resistance is an increasing problem. Therefore, the parasitological and haematological response to treatment with amodiaquine was studied in children under 5 years during a 14-day follow-up. Of 105 children who accomplished the study (out of 114 who were enrolled), 95.3% were parasite-negative on thick blood film on day 7, which decreased to 89.5% on day 14. The haemoglobin levels increased on average by 1.3% on day 14 (+/-1.9) and more pronounced in children with anaemia<10 g/dl on enrollment. The number of patients with adverse events (mainly pruritus and nausea) was few. This study shows that amodiaquine is effective, safe and affordable in an area with high resistance to chloroquine.
    • In vivo parasitological measures of artemisinin susceptibility

      Stepniewska, Kasia; Ashley, Elizabeth; Lee, Sue J; Anstey, Nicholas; Barnes, Karen I; Binh, Tran Quang; D'Alessandro, Umberto; Day, Nicholas P J; de Vries, Peter J; Dorsey, Grant; Guthmann, Jean-Paul; Mayxay, Mayfong; Newton, Paul N; Olliaro, Piero; Osorio, Lyda; Price, Ric N; Rowland, Mark; Smithuis, Frank; Taylor, Walter R J; Nosten, François; White, Nicholas J; Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand; Shoklo Malaria Research Unit, Mae Sot, Thailand; Menzies School of Health Research and Royal Darwin Hospital, Darwin, Australia; Division of Clinical Pharmacology, Department of Medicine, University (2010-01-19)
      Parasite clearance data from 18,699 patients with falciparum malaria treated with an artemisinin derivative in areas of low (n=14,539), moderate (n=2077), and high (n=2083) levels of malaria transmission across the world were analyzed to determine the factors that affect clearance rates and identify a simple in vivo screening measure for artemisinin resistance. The main factor affecting parasite clearance time was parasite density on admission. Clearance rates were faster in high-transmission settings and with more effective partner drugs in artemisinin-based combination treatments (ACTs). The result of the malaria blood smear on day 3 (72 h) was a good predictor of subsequent treatment failure and provides a simple screening measure for artemisinin resistance. Artemisinin resistance is highly unlikely if the proportion of patients with parasite densities of <100,000 parasites/microL given the currently recommended 3-day ACT who have a positive smear result on day 3 is <3%; that is, for n patients the observed number with a positive smear result on day 3 does not exceed (n + 60)/24.
    • Low efficacy of the combination artesunate plus amodiaquine for uncomplicated falciparum malaria among children under 5 years in Kailahun, Sierra Leone.

      Grandesso, F; Hagerman, A; Kamara, S; Lam, E; Checchi, F; Balkan, S; Scollo, G; Durand, R; Guthmann, J P; Epicentre, Paris, France. (Wiley-Blackwell, 2006-07)
      OBJECTIVE: In 2004, Sierra Leone adopted artesunate plus amodiaquine as first-line antimalarial treatment. We evaluated the efficacy of this combination in Kailahun, where a previous study had shown 70.2% efficacy of amodiaquine in monotherapy. METHODS: Method and outcome classification of the study complied with WHO guidelines. Children 6-59 months with uncomplicated malaria were followed-up for 28 days. PCR genotyping was used to distinguish recrudescence from reinfection. Reinfections were reclassified as cured. RESULTS: Of 172 children who were referred to the study clinic, 126 satisfied inclusion criteria and were enrolled. No early treatment failures were reported. The day 14, efficacy was 98.2% (95% CI: 93.8-99.8). Of 65 recurrent parasitaemias analysed by PCR, 17 were recrudescences. The PCR-adjusted day 28 efficacy was 84.5% (95% CI: 76.4-90.7). All true failures occurred in the last 8 days of follow-up. Of 110 children who completed the 28-day follow-up, 54 (49.1%) experienced a novel infection. CONCLUSION: The efficacy of this combination was disappointing. The high reinfection rate suggested little prophylactic effect. In Kailahun a more efficacious combination might be necessary in the future. The efficacy of AS + AQ needs to be monitored in Kailahun and in the other regions of Sierra Leone.
    • Malaria in camps for internally-displaced persons in Uganda: evaluation of an insecticide-treated bednet distribution programme.

      Spencer, S; Grant, A D; Piola, P; Tukpo, K; Okia, M; Garcia, M; Salignon, P; Genevier, C; Kiguli, J; Guthmann, J P; Médecins Sans Frontières, 4 rue Saint Sabin, 75011 Paris, France. (ElsevierWiley-Blackwell, 2004-12)
      Malaria is a key health problem among displaced populations in malaria-endemic areas. Mass distribution of insecticide-treated bednets (ITN) to prevent malaria is often carried out in complex emergencies, but there are few data on the outcome or operational effectiveness of such programmes. In June 2001, Medecins Sans Frontieres completed a mass distribution of ITNs (Permanet) to internally displaced persons in Bundibugyo, southwest Uganda, distributing one to four nets per household, and aiming to provide coverage for all residents. In July 2002, we did a cross-sectional survey using three-stage cluster sampling to evaluate the programme. A total of 1245 individuals from 835 households were interviewed. An ITN was present in 75.6% (95% CI 72.7-78.5) of the households, but only 56.5% (95% CI 52.3-60.4) of individuals were sleeping under an ITN, and nets were often damaged. The prevalence of malarial parasitaemia was 11.2% (95% CI 9.4-13.0), and was significantly lower in ITN users compared to non-users (9.2% vs. 13.8%, relative risk [RR] 0.63, 95% CI 0.46-0.87); ITNs with severe damage remained effective (RR for severely damaged net 0.58, 95% CI 0.35-0.98). There was no significant difference in haemoglobin concentration between ITN users and non-users.
    • 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.
    • Plasmodium vivax resistance to chloroquine in Dawei, southern Myanmar.

      Guthmann, J P; Pittet, A; Lesage, A; Imwong, M; Lindegardh, N; Min Lwin, M; Zaw, T; Annerberg, A; de Radiguès, X; Nosten, F; Epicentre, Paris, France. (Wiley-Blackwell, 2008-01)
      OBJECTIVE: To assess the efficacy of chloroquine in the treatment of Plasmodium vivax malaria in in Dawei District, southern Myanmar. METHODS: Enrolled patients at Sonsinphya clinic >6 months of age were assessed clinically and parasitologically every week for 28 days. To differentiate new infections from recrudescence, we genotyped pre- and post-treatment parasitaemia. Blood chloroquine was measured to confirm resistant strains. RESULTS: Between December 2002 and April 2003, 2661 patients were screened, of whom 252 were included and 235 analysed. Thirty-four per cent (95% CI: 28.1-40.6) of patients had recurrent parasitaemia and were considered treatment failures. 59.4% of these recurrences were with a different parasite strain. Two (0.8%) patients with recurrences on day 14 had chloroquine concentrations above the threshold of 100 ng/ml and were considered infected with chloroquine resistant parasites. 21% of failures occurred during the first 3 weeks of follow-up: early recurrence and median levels of blood chloroquine comparable to those of controls suggested P. vivax resistance. CONCLUSIONS: Plasmodium vivax resistance to chloroquine seems to be emerging in Dawei, near the Thai-Burmese border. While chloroquine remains the first-line drug for P. vivax infections in this area of Myanmar, regular monitoring is needed to detect further development of parasite resistance.
    • Risk associated with asymptomatic parasitaemia occurring post-antimalarial treatment

      Olliaro, P; Pinoges, L; Checchi, F; Vaillant, M; Guthmann, J P; UNICEF/UNDP/World Bank/WHO Special Programme on Research and Training in Tropical Diseases (TDR), Geneva, Switzerland. Centre for Tropical Medicine and Vaccinology, University of Oxford, Oxford, UK. Epicentre, Paris, France. Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK. Centre de Recherches Publiques (CRP)-Santé, Luxembourg. (2008-01)
      OBJECTIVE: Parasites may recur asymptomatically after initial clearance by antimalarial treatment. Current guidelines recommend treatment only when patients develop symptoms or at the end of follow-up. We wanted to assess prospectively the probability of becoming symptomatic and the risks of this practice. METHODS: We analysed data collected in 13 trials of uncomplicated paediatric malaria conducted in eight sub-Saharan African countries. These studies followed all cases of post-treatment asymptomatic parasitaemia until they developed symptoms or to the end of the 28-day follow-up period, at which time parasite genotypes were compared to pre-treatment isolates to distinguish between recrudescences and new infections. RESULTS: There were 425 asymptomatic recurrences after 2576 treatments with either chloroquine, sulfadoxine/pyrimethamine or amodiaquine, of which 225 occurred by day 14 and 200 between day 15 and day 28. By day 28, 42% developed fever (median time to fever = 5 days) and 30% remained parasitaemic but afebrile, while 23% cleared their parasites (outcome unknown in 4%). Young age, parasitaemia >/=500 parasites/microl; onset of parasitaemia after day 14, and treatment with amodiaquine were the main variables associated with higher risk of developing fever. CONCLUSION: In areas of moderate to intense transmission, asymptomatic recurrences of malaria after treatment carry a substantial risk of becoming ill within a few days and should be treated as discovered. Young children are at higher risk. The higher risk carried by cases occurring in the second half of follow-up may be explained by falling residual drug levels.