Impact of Intermittent Preventive Treatment With Dihydroartemisinin-Piperaquine on Malaria in Ugandan Schoolchildren: A Randomized, Placebo-Controlled Trial

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...

Section: Discussionsupporting

confidence: 92%

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

“…Study samples were from a randomized, double-blinded, placebo-controlled trial conducted in Tororo, Uganda, from 2011 to 2012 (6,39). In brief, 740 schoolchildren aged 6 to 14 years from one primary school in Mulanda subcounty, Tororo District, were enrolled and randomized 1:1:1 to one of three study arms: DP monthly, DP once per school term (four treatments over 12 months), or placebo.…”

Section: Methodsmentioning

confidence: 99%

“…Compared to IPTp with SP, IPTp with DP was associated with lower risks of P. falciparum infection and symptomatic malaria during pregnancy in Kenya (14) and Uganda (15). 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).…”

mentioning

confidence: 94%

“…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

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...

“…In Senegalese children, the incidences of malaria were the same with monthly DP and monthly AQ/SP, although protective efficacies could not be measured due to the lack of a control group (13). In Uganda, monthly DP administered without directly observed therapy to children 6 to 24 months of age had a protective efficacy against malaria of 58%, significantly greater than that of monthly SP or daily trimethoprim-sulfamethoxazole (14), and monthly DP administered to school children 6 to 14 years of age for 1 year had a protective efficacy of 96% (15). In Burkina Faso, intermittent preventive therapy with DP in children aged 3 to 59 months showed 77% protective efficacy compared to 83% for AQ/SP (I. Zongo, unpublished data).…”

mentioning

confidence: 99%

Selection of Drug Resistance-Mediating Plasmodium falciparum Genetic Polymorphisms by Seasonal Malaria Chemoprevention in Burkina Faso

Somé

Zongo

Compaoré

et al. 2014

e Seasonal malaria chemoprevention (SMC), with regular use of amodiaquine plus sulfadoxine-pyrimethamine (AQ/SP) during the transmission season, is now a standard malaria control measure in the Sahel subregion of Africa. Another strategy under study is SMC with dihydroartemisinin plus piperaquine (DP). Plasmodium falciparum single nucleotide polymorphisms (SNPs) in P. falciparum crt (pfcrt), pfmdr1, pfdhfr, and pfdhps are associated with decreased response to aminoquinoline and antifolate antimalarials and are selected by use of these drugs. To characterize selection by SMC of key polymorphisms, we assessed 13 SNPs in P. falciparum isolated from children aged 3 to 59 months living in southwestern Burkina Faso and randomized to receive monthly DP or AQ/SP for 3 months in 2009. We compared SNP prevalence before the onset of SMC and 1 month after the third treatment in P. falciparum PCR-positive samples from 120 randomly selected children from each treatment arm and an additional 120 randomly selected children from a control group that did not receive SMC. The prevalence of relevant mutations was increased after SMC with AQ/SP. Significant selection was seen for pfcrt 76T (68.5% to 83.0%, P ‫؍‬ 0.04), pfdhfr 59R (54.8% to 83.3%, P ‫؍‬ 0.0002), and pfdhfr 108N (55.0% to 87.2%, P ‫؍‬ 0.0001), with trends toward selection of pfmdr1 86Y, pfdhfr 51I, and pfdhps 437G. After SMC with DP, only borderline selection of wild-type pfmdr1 D1246 (mutant; 7.7% to 0%, P ‫؍‬ 0.05) was seen. In contrast to AQ/SP, SMC with DP did not clearly select for known resistance-mediating polymorphisms. SMC with AQ/ SP, but not DP, may hasten the development of resistance to components of this regimen. (This study has been registered at ClinicalTrials.gov under registration no. NCT00941785.)