Protective Efficacy and Safety of Three Antimalarial Regimens for the Prevention of Malaria in Young Ugandan Children: A Randomized Controlled Trial

Bigira, Victor; Kapisi, James; Clark, Tamara D.; Kinara, Stephen; Mwangwa, Florence; Muhindo, Mary; Osterbauer, Beth; Aweeka, Francesca; Huang, Liusheng; Achan, Jane; Havlir, Diane V.; Rosenthal, Philip J.; Kamya, Moses R.; Dorsey, Grant

doi:10.1371/journal.pmed.1001689

Cited by 93 publications

(137 citation statements)

References 27 publications

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“…In Ugandan schoolchildren, monthly IPT with DP was associated with a reduced incidence of malaria and reduced prevalence of parasitemia and anemia compared to DP given approximately once every 3 months or placebo (6,16). Similar results were observed in Ugandan infants when monthly IPT with DP was compared with daily trimethoprim-sulfamethoxazole or monthly SP (7). Thus, DP is a promising alternative to SP or SP-AQ for IPT, but its benefits may be undone by the emergence of P. falciparum resistance to either component of the combination.…”

supporting

confidence: 55%

“…Among key tools in the control of malaria is intermittent preventive treatment (IPT), the provision of full treatment courses at regular intervals to high-risk populations (4). IPT is standard practice during pregnancy (IPTp), is recommended for children living in seasonal malaria transmission settings as seasonal malaria chemoprevention (5), and is being investigated in other populations (6)(7)(8)(9). However, currently IPT is advocated only with sulfadoxine-pyrimethamine (SP) or a combination of SP and amodiaquine (SP-AQ) (5,10), regimens that are severely compromised by drug resistance in much of Africa (11)(12)(13).…”

mentioning

confidence: 99%

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Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity

Nankabirwa

Conrad

Legac

et al. 2016

Antimicrob Agents Chemother

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e Dihydroartemisinin-piperaquine (DP) offers prolonged protection against malaria, but its impact on Plasmodium falciparum drug sensitivity is uncertain. In a trial of intermittent preventive treatment in schoolchildren in Tororo, Uganda, in 2011 to 2012, monthly DP for 1 year decreased the incidence of malaria by 96% compared to placebo; DP once per school term offered protection primarily during the first month after therapy. To assess the impact of DP on selection of drug resistance, we compared the prevalence of key polymorphisms in isolates that emerged at different intervals after treatment with DP. Blood obtained monthly and at each episode of fever was assessed for P. falciparum parasitemia by microscopy. Samples from 160 symptomatic and 650 asymptomatic episodes of parasitemia were assessed at 4 loci (N86Y, Y184F, and D1246Y in pfmdr1 and K76T in pfcrt) that modulate sensitivity to aminoquinoline antimalarials, utilizing a ligase detection reaction-fluorescent microsphere assay. For pfmdr1 N86Y and pfcrt K76T, but not the other studied polymorphisms, the prevalences of mutant genotypes were significantly greater in children who had received DP within the past 30 days than in those not treated within 60 days (86Y, 18.0% versus 8.3% [P ‫؍‬ 0.03]; 76T, 96.0% versus 86.1% [P ‫؍‬ 0.05]), suggesting selective pressure of DP. Full sequencing of pfcrt in a subset of samples did not identify additional polymorphisms selected by DP. In summary, parasites that emerged soon after treatment with DP were more likely than parasites not under drug pressure to harbor pfmdr1 and pfcrt polymorphisms associated with decreased sensitivity to aminoquinoline antimalarials. (This study has been registered at ClinicalTrials.gov under no. NCT01231880.) M alaria, in particular infection with Plasmodium falciparum, remains a huge public health problem, with the highest disease burden in sub-Saharan Africa (1, 2). Important advances have been made in malaria control recently, with a significant decrease in malaria burden and progress toward elimination noted in some areas (3). Among key tools in the control of malaria is intermittent preventive treatment (IPT), the provision of full treatment courses at regular intervals to high-risk populations (4). IPT is standard practice during pregnancy (IPTp), is recommended for children living in seasonal malaria transmission settings as seasonal malaria chemoprevention (5), and is being investigated in other populations (6-9). However, currently IPT is advocated only with sulfadoxine-pyrimethamine (SP) or a combination of SP and amodiaquine (SP-AQ) (5, 10), regimens that are severely compromised by drug resistance in much of Africa (11-13). For malaria treatment, older regimens have been replaced by artemisinin-based combination therapies (ACTs), and a similar change may be warranted for IPT.Dihydroartemisinin-piperaquine (DP), which provides rapid killing of most parasites by dihydroartemisinin, prolonged action against any remaining parasites by piperaquine, and protection for weeks after...

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supporting

confidence: 55%

mentioning

confidence: 99%

Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity

Nankabirwa

Conrad

Legac

et al. 2016

Antimicrob Agents Chemother

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“…These results are consistent with those of previous studies in children (8,9) and a study in adults in Thailand (11), which showed that DHAPQ was well tolerated and highly effective when used for monthly prophylaxis, and with a study in schoolchildren in Uganda, which showed that monthly DHPAQ was well tolerated and reduced malaria incidence by 96% and the prevalence of anemia by 40% (23). In another study in Uganda in younger children, the efficacy of monthly DHAPQ was only 58%, possibly due to poor adherence and underdosing (24). In our study, the efficacy of DHAPQ was related to the circulating concentration of piperaquine; there was a steady reduction in incidence of malaria with increasing day 7 concentration.…”

Section: Discussionmentioning

confidence: 82%

Randomized Noninferiority Trial of Dihydroartemisinin-Piperaquine Compared with Sulfadoxine-Pyrimethamine plus Amodiaquine for Seasonal Malaria Chemoprevention in Burkina Faso

Zongo

Milligan

Compaoré

et al. 2015

Antimicrob Agents Chemother

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fThe WHO recommends that children living in areas of highly seasonal malaria transmission in the Sahel subregion should receive seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ). We evaluated the use of dihydroartemisinin-piperaquine (DHAPQ) as an alternative drug that could be used if SPAQ starts to lose efficacy. A total of 1,499 children 3 to 59 months old were randomized to receive SMC with SPAQ or DHAPQ over 3 months. The primary outcome measure was the risk of clinical malaria (fever or a history of fever with a parasite density of at least 3,000/l). A cohort of 250 children outside the trial was followed up as a control group. Molecular markers of drug resistance were assessed. The risk of a malaria attack was 0.19 in the DHAPQ group and 0.15 in the SPAQ group, an odds ratio of 1.33 (95% confidence interval [CI], 1.02 to 1.72). Efficacy of SMC compared to the control group was 77% (67% to 84%) for DHAPQ and 83% (74% to 89%) for SPAQ. pfdhfr and pfdhps mutations associated with antifolate resistance were more prevalent in parasites from children who received SPAQ than in children who received DHAPQ. Both regimens were highly efficacious and well tolerated. DHAPQ is a potential alternative drug for SMC. (This trial is registered at ClinicalTrials.gov under registration no. NCT00941785.) S ubstantial progress has been made in the control of malaria (1), but in most of sub-Saharan Africa, the disease remains a major public health problem. In Burkina Faso, malaria is still a leading cause of severe illness and mortality, accounting for 63% of hospital admissions and 71% of all deaths in hospital among children under 5 years of age in 2011 (2). Results from research studies indicate that the burden remains very high. In Boussé, in the Sahelian zone of the country, in 2011, 1,232 episodes of malaria were recorded over one transmission season in 1,500 children under 5 years of age who were using an insecticide-treated net (3). In such areas, new strategies for malaria control are needed. The WHO now recommends seasonal malaria chemoprevention (SMC) with sulfadoxine pyrimethamine plus amodiaquine (SPAQ) as a new strategy for malaria control in children in areas of highly seasonal transmission (4, 5), defined as areas where at least 60% of malaria cases occur during 4 months of the year and where SP and AQ retain good efficacy. Most parts of Burkina Faso fit these criteria, and implementation of SMC in Burkina Faso started in 2014 in seven districts.Resistance to both SP and AQ is common in much of Africa, but in most areas of seasonal transmission in the Sahel these drugs retain their antimalarial efficacy (5). However, alternative drug regimens may be needed in these areas in the future, and they are needed now if SMC is to be deployed in areas of eastern or southern Africa where antifolate resistance makes SP an unsuitable drug for SMC. Dihydroartemisinin-piperaquine (DHAPQ) is a potential alternative. Piperaquine (PQ) is a long-acting antimalarial; administration dail...

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“…The study was conducted in Tororo District, a rural area in eastern Uganda characterized by subsistence farming, relatively high rates of poverty, intense year-round malaria transmission, and an entomological inoculation rate (EIR) estimated at 125 infectious bites per person-year in 2011-2012. 14 This sub-study was conducted within the context of a larger randomized control trial evaluating three regimens for the prevention of malaria, the details of which have been described previously in other studies. 15,16 In brief, between June 2010 and July 2011, 400 human immunodeficiency virus (HIV)-unexposed and 200 HIV-exposed children of age 4-6 months were recruited using convenience sampling at a dedicated study clinic located at Tororo District Hospital. Potential study subjects were recruited from an adjacent antenatal clinic and surrounding government health centers.…”

Section: Methodsmentioning

confidence: 99%

Poor Housing Construction Associated with Increased Malaria Incidence in a Cohort of Young Ugandan Children

Snyman¹,

Mwangwa²,

Bigira³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. Despite the use of accepted interventions to combat malaria, such as insecticide-treated bed nets and artemisinin-based combination therapy, malaria remains a leading cause of morbidity and mortality in Uganda. We investigated associations between household factors and malaria incidence in a cohort of children living in a highly endemic region of Uganda. Living in a modern house, defined as the use of non-earth floors, non-thatched roofs, and non-mud walls, was associated with approximately half malaria incidence compared with living in a traditional home (incidence rate ratio [IRR] = 0.54, P = 0.001). Other factors found to be associated with a lower incidence of malaria included living in town versus rural setting; sleeping in a room with openings to the outside (windows, eaves, and airbricks); and having an older and more educated primary caregiver. This study adds to the growing body of evidence that improved house construction may be associated with a lower risk of malaria.

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Protective Efficacy and Safety of Three Antimalarial Regimens for the Prevention of Malaria in Young Ugandan Children: A Randomized Controlled Trial

Abstract: Grant Dorsey and colleagues investigate the efficacy of three antimalarial drugs for preventing malaria in children living in Uganda, an area of high transmission intensity. Please see later in the article for the Editors' Summary

Cited by 93 publications

References 27 publications

Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity

Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity

Randomized Noninferiority Trial of Dihydroartemisinin-Piperaquine Compared with Sulfadoxine-Pyrimethamine plus Amodiaquine for Seasonal Malaria Chemoprevention in Burkina Faso

Poor Housing Construction Associated with Increased Malaria Incidence in a Cohort of Young Ugandan Children

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