Grant Dorsey

The proliferation of antimalarial drug trials in the last ten years provides the opportunity to launch a concerted global surveillance effort to monitor antimalarial drug efficacy. The diversity of clinical study designs and analytical methods undermines the current ability to achieve this. The proposed World Antimalarial Resistance Network (WARN) aims to establish a comprehensive clinical database from which standardised estimates of antimalarial efficacy can be derived and monitored over time from diverse geographical and endemic regions. The emphasis of this initiative is on five key variables which define the therapeutic response. Ensuring that these data are collected at the individual patient level in a consistent format will facilitate better data management and analytical practices, and ensure that clinical data can be readily collated and made amenable for pooled analyses. Such an approach, if widely adopted will permit accurate and timely recognition of trends in drug efficacy. This will guide not only appropriate interventions to deal with established multidrug resistant strains of malaria, but also facilitate prompt action when new strains of drug resistant plasmodia first emerge. A comprehensive global database incorporating the key determinants of the clinical response with in vitro, molecular and pharmacokinetic parameters will bring together relevant data on host, drug and parasite factors that are fundamental contributors to treatment efficacy. This resource will help guide rational drug policies that optimize antimalarial drug use, in the hope that the emergence and spread of resistance to new drugs can be, if not prevented, at least delayed.

Malaria infections in Africa frequently include multiple parasite strains. We examined the relationship between the number of infecting Plasmodium fa

BackgroundRecent clinical trials from Uganda have shown that the risk of failure following antimalarial therapy varies geographically. We tested the hypothesis that geographic differences in the response to therapy could be explained by differences in the prevalence of known molecular markers of drug resistance MethodsSamples from 2084 patients treated with chloroquine (CQ) plus sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) plus SP were tested for the presence of known molecular markers of resistance. Differences in the risk of treatment failure across 6 sites were compared, and age and complexity of infection were controlled for ResultsThe prevalence of molecular markers of drug resistance was high at all of the sites: 61%–91% of patients were infected with parasites containing the pfcrt Thr-76 mutation and dhfr/dhps quintuple mutation. The risk of treatment failure decreased with increasing transmission intensity for both CQ plus SP (73% to 19%) and AQ plus SP (38% to 2%). Restricting the analyses to patients infected with parasites containing all 6 mutations of interest did not affect these trends ConclusionsThe risk of treatment failure was inversely proportional to transmission intensity and was not explained by differences in molecular markers of antimalarial drug resistance. Our findings strongly suggest that geographic differences in response to antimalarial therapy in Uganda are primarily mediated by acquired immunity associated with malaria transmission intensity, rather than by parasite factors

Background: Studies of malaria in well-defined cohorts offer important data about the epidemiology of this complex disease, but few have been done in urban African populations. To generate a sampling frame for a longitudinal study of malaria incidence and treatment in Kampala, Uganda, a census, mapping and survey project was conducted. Methods: All households in a geographically defined area were enumerated and mapped. Probability sampling was used to recruit a representative sample of children and collect baseline descriptive data for future longitudinal studies. Results: 16,172 residents living in 4931 households in a densely-populated community (18,824 persons/km²) were enumerated. A total of 582 households were approached with at least one child less than 10 years of age in order to recruit 601 children living in 322 households. At enrollment, 19% were parasitaemic, 24% were anaemic, 43% used bednets, and 6% used insecticide-treated nets. Low G6PD activity (OR = 0.33, P = 0.009) and bednet use (OR = 0.64, P = 0.045) were associated with a decreased risk of parasitaemia. Increasing age (OR = 0.62 for each year, P < 0.001) and bednet use (OR = 0.58, P = 0.02) were associated with a decreased risk of anaemia Conclusion: Detailed surveys of target populations in urban Africa can provide valuable descriptive data and provide a sampling frame for recruitment of representative cohorts for longitudinal studies. Plans to use a multi-disciplinary approach to improve the understanding of the distribution and determinants of malaria incidence and response to therapy in this population are discussed.

Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination antimalarial therapy including artemisinins has been advocated recently to improve efficacy and limit the spread of resistance, but artemisinins are expensive and relatively untested in highly endemic areas. We compared artemisinin-based and other combination therapies in four districts in Uganda with varying transmission intensity. We enrolled 2,160 patients aged 6 mo or greater with uncomplicated falciparum malaria. Patients were randomized to receive chloroquine (CQ) + sulfadoxine-pyrimethamine (SP); amodiaquine (AQ) + SP; or AQ + artesunate (AS). Primary endpoints were the 28-d risks of parasitological failure either unadjusted or adjusted by genotyping to distinguish recrudescence from new infections. A total of 2,081 patients completed follow-up, of which 1,749 (84%) were under the age of 5 y. The risk of recrudescence after treatment with CQ + SP was high, ranging from 22% to 46% at the four sites. This risk was significantly lower (p < 0.01) after AQ + SP or AQ + AS (7%–18% and 4%–12%, respectively). Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection. The overall risk of repeat therapy due to any recurrent infection (recrudescence or new infection) was similar at two sites and significantly higher for AQ + AS at the two highest transmission sites (risk differences = 15% and 16%, p< 0.003). AQ + AS was the most efficacious regimen for preventing recrudescence, but this benefit was outweighed by an increased risk of new infection. Considering all recurrent infections, the efficacy of AQ + SP was at least as efficacious at all sites and superior to AQ + AS at the highest transmission sites. The high endemicity of malaria in Africa may impact on the efficacy of artemisinin-based combination therapy. The registration number for this trial is ISRCTN67520427 (http://www.controlled-trials.com/isrctn/trial/|/0/67520427.html).

Antimalarial resistance to sulfadoxine-pyrimethamine (SP) is mediated by mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes. However, the relative importance of different mutations is incompletely understood and has not been studied with combination therapy. Samples from 812 patients treated for uncomplicated malaria in Kampala, Uganda were tested for the presence of mutations commonly found in Africa. The dhps Glu-540 mutation was the strongest independent predictor of treatment failure. The dhfr Arg-59 mutation was only predictive of treatment failure in the presence of the dhps Glu-540 mutation. Comparing combination regimens with SP monotherapy, the addition of chloroquine to SP did not improve efficacy, the addition of artesunate lowered the risk of treatment failure only for infections with both the dhfr Arg-59 and dhps Glu-540 mutations, and the addition of amodiaquine lowered this risk for all dhfr/dhps mutation patterns. The dhps Glu-540 mutation played a principal role and the dhfr Arg-59 mutation a secondary role in mediating resistance to SP alone and in combination.

Antimalarial drug treatment policy in sub-Saharan Africa is generally guided by the results of clinical drug efficacy studies in patients with uncomplicated Plasmodium falciparum malaria. The selection criteria used to enroll these patients often vary and may have a significant impact on treatment outcomes. In Kampala, Uganda, we investigated the impact of age, baseline temperature, and pre-treatment parasite density on estimates of treatment efficacy using a statistical modeling approach in 2,138 patients enrolled in six clinical trials involving seven different treatment regimens. Decreasing age, increasing temperature, and increasing parasite density were all independent predictors of an increased risk of treatment failure across all treatment groups. Compared with an unrestrictive approach to subject selection, enrolling only patients fulfilling selection criteria recommended by the World Health Organization (age < 5 years old, documented fever, and parasite density < 200,000/μL) increased the risk of treatment failure by 25–60% for the different treatment regimens. Caution should be taken when comparing results from drug efficacy studies with different subject selection criteria.

Summary: Sulphadoxine/pyrimethamine (SP) has become the first‐line treatment of uncomplicated malaria in a number of African countries. Molecular surveillance of resistance‐mediating mutations in Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) has been proposed as a means of predicting SP treatment outcomes, but optimal methods of surveillance in different populations have not been well established. To investigate the relationship between molecular markers of SP resistance, host immunity, and response to therapy, we evaluated the association between the presence of five key dhfr and dhps mutations at enrollment and clinical outcome in children and adults treated with SP for uncomplicated malaria in Kampala, Uganda. Clinical treatment failure was 11% at 14 days, increasing to 30% at 28 days, after excluding new infections. Outcomes varied markedly based on the number of dhfr and dhps mutations and on the age of treated subjects. All infections with less than two dhfr/dhps mutations were successfully treated. Treatment failure associated with any two, three, or four dhfr/dhps mutations occurred in nine of 24 (38%) children up to 5 years, but not in older patients (0/20). In the presence of all five mutations, treatment failure occurred equally in children aged 5 years or younger [7/16 (44%)] and in older patients [8/16 (50%)]. Our results showed that age, a surrogate marker of antimalarial immunity, had a major impact on the relationship between polymorphisms in SP target enzymes and treatment outcomes. The use of molecular markers of SP resistance to predict treatment failure rates should take age into account.

Combination antimalarial therapy may delay the spread of drug resistance, but clinical data supporting this notion are limited. For 1 year, we studie

Summary: Objectives To assess malaria‐related knowledge, attitude and practices (KAP) among primary caregivers, to identify associations between primary caregivers’ characteristics and positive KAP towards malaria, and to identify independent predictors of childhood malaria incidence in an urban setting.Methods Children aged 6 months to 5 years living in Kampala, Uganda were enrolled as part of a longitudinal study on antimalarial therapy. Primary caregivers of 307 children were interviewed and information was collected on demographics, malaria‐related KAP, environmental and household factors. Malaria incidence was measured prospectively using passive surveillance.Results A total of 90% of respondents reported mosquitoes and/or malaria as the cause of fever. Caregivers reported that if their child had fever, 63% would go to a clinic or hospital as their first action and 97% as their first or second action. Only 38% knew that chloroquine was the recommended first‐line treatment for malaria and 29% knew the correct dose. Preventive measures for malaria were reported in 45% of households but only 25% reported using bednets. Higher levels of education for the caregiver were associated with positive malaria‐related KAP. Malaria incidence varied widely. The following were independent predictors of malaria incidence: (1) Children aged 24–41 months at enrolment had a higher incidence of malaria. (2) Reported bednet or chemoprophylaxis use reduced the incidence of malaria. (3) A child's place of residence was associated with incidence. (4) Children from households using open water sources had a higher incidence than those using closed sources.Conclusion Primary caregivers were knowledgeable about malaria and used modern health care facilities but knew less about the proper administration of antimalarials and had limited use of preventive measures. Malaria incidence was associated with child's age at enrolment, geography, source of water and the use of preventive measures.