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OBJECTIVE: To evaluate the therapeutic efficacy of sulfadoxine-pyrimethamine, amodiaquine, and the sulfadoxine-pyrimethamine-amodiaquine combination for the treatment of uncomplicated Plasmodium falciparum malaria in young children in Cameroon. METHODS: In a randomized study we evaluated the effectiveness and tolerance of (i) sulfadoxine-pyrimethamine (SP) (25 mg/kg body weight of sulfadoxine and 1.25 mg/kg of pyrimethamine in a single oral dose), (ii) amodiaquine (AQ) (30 mg/kg body weight in three divided daily doses), and (iii) the sulfadoxine-pyrimethamine-amodiaquine combination (SP+AQ) (same doses as in the other two treatment groups, given simultaneously on day 0) in young children in southern Cameroon. The parasitological and clinical responses were studied until day 28 in accordance with the modified 1996 WHO protocol for the evaluation of the therapeutic efficacy of antimalarial drugs. FINDINGS: Of 191 enrolled patients, 6 and 8 were excluded or lost to follow-up before day 14 and between day 14 and day 28, respectively. For the AQ-treated patients, parasitological and clinical evaluation on day 14 showed late treatment failure in 2 of 61 (3.3%) and adequate clinical response with parasitological failure in one (1.6%). There was an adequate clinical response in all patients treated with SP or SP+AQ. Therapeutic failure rates on day 28 were 13.6%, 10.2% and 0% in the SP, AQ, and SP+AQ groups, respectively. Anaemia improved in all three regimens. AQ produced faster fever clearance but was associated with more transient minor side-effects than SP. SP+AQ reduced the risk of recrudescence between day 14 and day 28 but increased the incidence of minor side-effects. CONCLUSION: SP+AQ can be recommended as a temporary means of slowing the spread of multidrug resistance in Plasmodium falciparum in Africa while the introduction of other combinations, including artemisinin derivatives, is awaited.

Abstract Background Congo-Brazzaville adopted artemisinin-based combination therapy (ACT) in 2006. Artesunate-amodiaquine (AS + AQ) and artemether-lumefantrine are the first-line and second-line anti-malarial drugs to treat uncomplicated Plasmodium falciparum malaria, respectively. The baseline efficacy of AS + AQ was evaluated from February to August 2005 in patients living in Brazzaville, the capital city of the Republic of Congo. Methods One hundred and ninety-seven patients (96 ≤5 years old and 101 >5 years old, including adults) were recruited in a non-randomized study, treated under supervision with AS + AQ, and were followed up for 28 days in accordance with the 2003 World Health Organization protocol. Plasmodium falciparum recrudescent isolates from day 7 to day 28 were compared to pretreatment isolates by polymerase chain reaction (PCR) to distinguish between re-infection and recrudescence. Results The overall efficacy of AS + AQ after PCR correction on day 28 was 94.4%. An adequate clinical and parasitological response was observed in 94.3% and 94.4% of children aged ≤5 years old and those aged >5 years old (including adults), respectively. The main reported adverse events were dizziness, vomiting, diarrhoea, pruritus, headache, anorexia, and abdominal pain. Conclusion This study has shown the high efficacy of AS + AQ in Congolese patients of all ages with acute uncomplicated falciparum malaria and serves as the baseline efficacy and tolerance of this ACT in Brazzaville.

Abstract Background Regulatory T cells (Tregs) are a subset of T cells that play an important role in modulating T effector responses during infectious challenges. The aim of this study was to evaluate possible associations between regulatory gene polymorphisms and the risk of uncomplicated malaria and the control of Plasmodium falciparum parasite density levels. Methods Twelve regulatory single nucleotide polymorphisms (SNPs) in the promoter regions of FOXP3 (ss270137548, rs11091253), IL10RA (rs56356146, rs7925112), IL10RB (rs8178433, rs8178435, rs999788), STAT6 (rs3024941, rs3024943, rs3024944) and TNFRSF18 (ss2080581728, rs3753344) were genotyped in a cohort of Congolese children. Studied subjects were followed up (passively) during one year. The children who experienced one or several clinical episodes were genotyped as “uncomplicated malaria” group (n=179) and those children who did not experience any episode were genotyped as “asymptomatic children” group (n=138). Results The prevalence of rs3024944CC genotype of STAT6 was significantly higher in the group of asymptomatic children compared to that of uncomplicated malaria (P=0.003). Similarly, the minor allele rs3024944C was more prevalent in the group of asymptomatic children (P=0.019). Two novel SNPs were observed including -163T/G (ss491228441) in IL10RA gene and -163C/T (ss491228440) in TNFRSF18 gene. The genotype ss491228441TT and the minor allele ss491228441G of the IL10RA were more frequent in the group of asymptomatic children (P=0.006 and P=0.007, respectively). The genotype rs11091253CT of the FOXP3 was associated with high parasite density levels. In addition, a new promoter IL10RA variant (ss491228441) contributes to shield against mild malaria. Conclusion The study indicated that the STAT6 promoter polymorphism rs3024944 was associated with uncomplicated malaria, whereas the FOXP3 promoter variant rs11091253 was associated with significant P. falciparum parasitaemia levels. These genetic data may contribute to the understanding of molecular mechanisms that regulate immune response to P. falciparum infections.

Abstract Background In this first study conducted after the introduction of artemisinin-combination therapy (ACT), the major objective was to evaluate Plasmodium falciparum genetic diversity and multiplicity of infection in isolates from Congolese children between one and nine years of age enrolled and followed up for one year. The secondary objective was to characterize the msp2 profiles of P. falciparum isolates collected from successive malaria episodes in ten children who had four or more clinical episodes during the follow up. Methods Three-hundred and thirteen children residing in southern part of Brazzaville participated in this study. Blood samples were obtained from all children at enrollment and checked for P. falciparum infection. Based on the one year follow-up data, two clinical groups were considered according to the number of malaria episodes presented over the follow up period: “protected”(children who did not experience any episode) and “unprotected” (those who experienced more that two episodes). Therefore, the msp2 genetic diversity of P. falciparum isolates collected at enrollment in the two groups was characterized by allele-specific nested PCR and compared. The msp2 profiles of P. falciparum isolates collected from successive malaria episodes was also characterized by allele-specific nested PCR. Results Forty-three percent of FC27 and fifty-seven percent of 3D7 in protected vs fifty-six percent of FC27 and forty-four percent of 3D7 in isolates from unprotected children were detected. Seven and two alleles belonging to the FC27, and six and three alleles belonging to 3D7 families were distinguished in isolates from protected and unprotected children respectively. The mean multiplicity of infection (MOI) values at inclusion for the msp2 locus was 1.29 and 1.43 for protected and unprotected children respectively. 43 isolates were obtained from the ten children who had four or more clinical episodes during the follow up. A total of 63 alleles or fragments corresponding to 57% (36/63) FC27 and 43% (27/63) 3D7 were detected. The variant 400bp of FC27 was the most prevalent. 46% (20/43), 42% (18/43), 2% (1/43) and 2% (1/43) of isolates were found to have 1, 2, 3 and 4 parasite genotypes respectively and the mean MOI was 1.78. Conclusion This study shows that the introduction of ACT in the Republic of Congo has reduced the MOI but not the genetic diversity of P. falciparum isolates from children living in Southern districts of Brazzaville.

Abstract Background In order to prepare the field site for future interventions, the prevalence of asymptomatic Plasmodium falciparum infection was evaluated in a cohort of children living in Brazzaville. Plasmodium falciparum merozoite surface protein 2 gene (msp2) was used to characterize the genetic diversity and the multiplicity of infection. The prevalence of mutant P. falciparum chloroquine resistance transporter (pfcrt) allele in isolates was also determined. Methods Between April and June 2010, 313 children below 10 years of age enrolled in the cohort for malaria surveillance were screened for P. falciparum infection using microscopy and polymerase chain reaction (PCR). The children were selected on the basis of being asymptomatic. Plasmodium falciparum msp2 gene was genotyped by allele-specific nested PCR and the pfcrt K76T mutation was detected using nested PCR followed by restriction endonuclease digestion. Results The prevalence of asymptomatic P. falciparum infections was 8.6% and 16% by microscopy and by PCR respectively. Allele typing of the msp2 gene detected 55% and 45% of 3D7 and FC27 allelic families respectively. The overall multiplicity of infections (MOI) was 1.3. A positive correlation between parasite density and multiplicity of infection was found. The prevalence of the mutant pfcrt allele (T76) in the isolates was 92%. Conclusion This is the first molecular characterization of P. falciparum field isolates in Congolese children, four years after changing the malaria treatment policy from chloroquine (CQ) to artemisinin-based combination therapy (ACT). The low prevalence of asymptomatic infections and MOI is discussed in the light of similar studies conducted in Central Africa.

Abstract Background The characterization of malaria parasite populations circulating in an area is part of site characterization, as a basis for evaluating the impact of malaria interventions on genetic diversity, parasite species, and multiplicity of infection. The present study was aimed at analysing genetic diversity of Plasmodium falciparum merozoite surface proteins 1 and 2 (MSP-1 and MSP-2) and to determine the multiplicity of infection in clinical isolates collected from children living in the Southern district of Brazzaville in the Republic of Congo. Methods A total of 125 isolates from patients with uncomplicated malaria attending Terinkyo and Madibou health centres were collected between January and June 2005 while evaluating the therapeutic efficacy of amodiaquine-artesunate combination. DNA was extracted and msp-1 and msp-2 genes were genotyped using allele-specific nested-PCR. Results Out of 468 distinct fragments detected, 15 msp-1 and 20 msp-2 genotypes were identified. For the msp-1 gene, K1 family was the predominant allelic type carried alone or in association with RO33 and Mad20 types, whereas the 3D7 family was the most prevalent in the msp-2 gene. Overall, the mean multiplicity of infection was 2.2. Out of 125 samples, 104 (83%) harboured more than one parasite genotype. There was no statistical significant difference in the multiplicity of infection by either sex or age of patients. However, a statistically significant correlation was found between parasite densities and the number of genotypes. Conclusion Polymorphism in P. falciparum clinical isolates from Brazzaville was high and mainly of multiple clones. The basis for the positive association between parasite densities and multiplicity of infection is discussed.

Abstract Background European and Developing Countries Clinical Trials Partnership (EDCTP) was founded in 2003 by the European Parliament and Council. It is a partnership of 14 European Union (EU) member states, Norway, Switzerland, and Developing Countries, formed to fund acceleration of new clinical trial interventions to fight the human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS), malaria and tuberculosis (TB) in the sub-Saharan African region. EDCTP seeks to be synergistic with other funding bodies supporting research on these diseases. Methods EDCTP promotes collaborative research supported by multiple funding agencies and harnesses networking expertise across different African and European countries. EDCTP is different from other similar initiatives. The organisation of EDCTP blends important aspects of partnership that includes ownership, sustainability and responds to demand-driven research. The Developing Countries Coordinating Committee (DCCC); a team of independent scientists and representatives of regional health bodies from sub-Saharan Africa provides advice to the partnership. Thus EDCTP reflects a true partnership and the active involvement and contribution of these African scientists ensures joint ownership of the EDCTP programme with European counterparts. Results The following have been the major achievements of the EDCTP initiative since its formation in 2003; i) increase in the number of participating African countries from two to 26 in 2008 ii) the cumulative amount of funds spent on EDCTP projects has reached € 150 m, iii) the cumulative number of clinical trials approved has reached 40 and iv) there has been a significant increase number and diversity in capacity building activities. Conclusion While we recognise that EDCTP faced enormous challenges in its first few years of existence, the strong involvement of African scientists and its new initiatives such as unconditional funding to regional networks of excellence in sub-Saharan Africa is envisaged to lead to a sustainable programme. Current data shows that the number of projects supported by EDCTP is increasing. DCCC proposes that this success story of true partnership should be used as model by partners involved in the fight against other infectious diseases of public health importance in the region.

Abstract Background Plasmodium vivax is estimated to affect 75 million people annually. It is reportedly absent, however, from west and central Africa due to the high prevalence of the Duffy negative phenotype in the indigenous populations. Despite this, non-African travellers consistently return to their own countries with P. vivax malaria after visiting this region. An attempt was made, therefore, to detect the presence of P. vivax parasites in blood samples collected from the indigenous populations of west and central Africa. Methods Parasite species typing (for all four human malaria parasites) was carried out by PCR on 2,588 blood samples collected from individuals from nine African malaria-endemic countries. Results Most infections (98.5%) were Plasmodium falciparum, Plasmodium malariae was identified in 8.5% of all infections, and Plasmodium ovale in 3.9%. The prevalence of both parasites varied greatly by country. Only one case of P. vivax was detected from Sao Tome, an island off the west coast of Africa, confirming the scarcity of this parasite in Africa. Conclusion The prevalence of P. vivax in local populations in sub-Saharan Africa is very low, despite the frequent identification of this parasite in non-African travellers.

Background: The Republic of Congo adopted a new anti-malarial treatment policy in 2006, with artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) as the first- and second-line anti-malarial drugs, respectively. Only three clinical studies had been conducted before the policy change. A randomized study on these two artemisininbased combinations was conducted, and the effect that sickle cell trait may have on treatment outcomes was evaluated in children under 10 years old followed during 12 months in Brazzaville in 2010–2011. Methods: A cohort of 330 children under 10 years of age living in a suburban area in the south of Brazzaville were passively followed for registration of malaria episodes. Uncomplicated Plasmodium falciparum episodes were randomly treated with co-formulated ASAQ (Coarsucam®) or AL (Coartem®). Patients were followed according to the 2009 World Health Organization protocol for the evaluation of anti-malarial drug efficacy. Plasmodium falciparum recrudescent isolates were compared to pre-treatment isolates by polymerase chain reaction (PCR) to distinguish between re-infection and recrudescence. PCR-uncorrected and PCR-corrected responses to treatment were determined using per protocol analysis. Haemoglobin type (AA, AS, SS) was determined by PCR. Results: Of 282 clinical malaria episodes registered during 1-year follow-up period, 262 children with uncomplicated malaria were treated with ASAQ (129 patients) or AL (133 patients). The PCR-corrected efficacy, expressed as the percentage of adequate clinical and parasitological response, was 97.0 % for ASAQ and 96.4 % for AL. Among ASAQtreated patients, 112 (86.8 %) carried AA genotype and 17 (13.2 %) were AS carriers. The PCR-corrected efficacy was 96.4 % for AA-carriers and 100 % for AS-carriers treated with ASAQ [relative risk (RR) = 0.96; 95 % confidence interval, 0.93–1.00, p = 0.5]. Among 133 AL-treated children, 109 (82 %) carried AA, and 24 (18 %) AS genotypes. The PCR-corrected efficacy was 96.7 % among AA-carriers and 95.2 % among AS-carriers [RR = 1.01 (0.92–1.12), p = 0.6]. Nausea, jaundice, headache, dizziness, vomiting, pruritus, abdominal pain, and diarrhoea were registered as adverse events in both groups. ASAQ was associated with significantly more frequent adverse events (P < 0.05). Conclusion: This first randomized study in Brazzaville confirmed the excellent efficacy of these co-formulated antimalarial drugs in children. Sickle cell genotype did not influence the treatment efficacy of artemisinin-based combination therapy. [ABSTRACT FROM AUTHOR]

Background: European and Developing Countries Clinical Trials Partnership (EDCTP) was founded in 2003 by the European Parliament and Council. It is a partnership of 14 European Union (EU) member states, Norway, Switzerland, and Developing Countries, formed to fund acceleration of new clinical trial interventions to fight the human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS), malaria and tuberculosis (TB) in the sub-Saharan African region. EDCTP seeks to be synergistic with other funding bodies supporting research on these diseases. Methods: EDCTP promotes collaborative research supported by multiple funding agencies and harnesses networking expertise across different African and European countries. EDCTP is different from other similar initiatives. The organisation of EDCTP blends important aspects of partnership that includes ownership, sustainability and responds to demand-driven research. The Developing Countries Coordinating Committee (DCCC); a team of independent scientists and representatives of regional health bodies from sub-Saharan Africa provides advice to the partnership. Thus EDCTP reflects a true partnership and the active involvement and contribution of these African scientists ensures joint ownership of the EDCTP programme with European counterparts. Results: The following have been the major achievements of the EDCTP initiative since its formation in 2003; i) increase in the number of participating African countries from two to 26 in 2008 ii) the cumulative amount of funds spent on EDCTP projects has reached € 150 m, iii) the cumulative number of clinical trials approved has reached 40 and iv) there has been a significant increase number and diversity in capacity building activities. Conclusion: While we recognise that EDCTP faced enormous challenges in its first few years of existence, the strong involvement of African scientists and its new initiatives such as unconditional funding to regional networks of excellence in sub-Saharan Africa is envisaged to lead to a sustainable programme. Current data shows that the number of projects supported by EDCTP is increasing. DCCC proposes that this success story of true partnership should be used as model by partners involved in the fight against other infectious diseases of public health importance in the region. [ABSTRACT FROM AUTHOR]

Introduction: Molecular characterization of malaria parasites from different localities is important to improve understanding of acquisition of natural immunity to Plasmodium falciparum, to assist in identifying the most appropriate strategies for control and to evaluate the impact of control interventions. This study aimed to determine the genetic diversity and the multiplicity of infection in Plasmodium falciparum isolates from Pointe- Noire, Republic of Congo. Methods: Plasmodium falciparum isolates were collected from 71 children with uncomplicated malaria; enrolled into the study for evaluating the therapeutic efficacy of artemether-lumefantrine combination. Both msp-1 and msp-2 genes were genotyped. Results: From 296 distinct fragments detected, 13 msp-1 and 27 msp-2 different alleles were identified. For msp-1, RO33 family was poorly polymorphic. The K1 family has shown the trend of predominance (41%), followed by Mad20 (35%). Comparatively to msp-2, 49.6% and 48.8% fragments belonged to 3D7 and FC27 respectively. Taking together msp-1 and msp-2 genes, the overall multiplicity of infection has been increased to 2.64 and 86% harbored more than one parasite genotype. Parasite density was not influenced by age as well as the multiplicity of infection which was not influenced neither by age nor by parasite density. Conclusion: Genetic diversity of Plasmodium falciparum in isolates from patients with uncomplicated malaria in Pointe-Noire is high and consisted mainly of multiple clones. The overall multiplicity of infection has been largely increased when considering msp-1 and msp-2 genes together. With the changes in malaria epidemiology, the use of both msp-1 and msp-2 genes in the characterization of Plasmodium falciparum infection is recommended. [ABSTRACT FROM AUTHOR]

Evaluates the therapeutic efficacy of sulfadoxine-pyrimethamine, combination sulfadoxine-pyrimethamine-amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in young children in Cameroon. Dosage; Treatment failure rate; Incidence of side effects.