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

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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...

Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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

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“…When isolates from the first incident malaria cases were typed, the triple dhfr mutation and the dhps g437 mutation were more frequent in children who received SPAQ than in the malaria cases in the DHAPQ group and in the control group, but the frequencies of pfcrt CVIET T76, pfmdr1 Y86, and pfmdr1 Y184, associated with resistance to AQ, were similar in all three groups. Analysis of molecular markers of resistance in a subset of samples from children in this study taken at enrollment and at the end of the transmission season have been reported separately (28). Among children who received SPAQ who had parasitemia at the end of the transmission season, the frequency of pfcrt 76T, pfdhfr 59R, and pfdhfr 108N was greater than at baseline.…”

Section: Discussionmentioning

confidence: 99%

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

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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...

“…Due to structural similarities between PPQ and CQ, there have been attempts to identify common markers of resistance (9,10). However, the limited number of studies available did not observe selection of Pfcrt single nucleotide polymorphisms (SNPs) (11,12).…”

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In Vivo Selection of Plasmodium falciparum Pfcrt and Pfmdr1 Variants by Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine in Burkina Faso

Baraka

Tinto

Valéa

et al. 2015

g Plasmodium falciparum Pfcrt-76 and Pfmdr1-86 gene polymorphisms were determined during a clinical trial in Burkina Faso comparing the efficacies of dihydroartemisinin-piperaquine (DHA-PPQ) and artemether-lumefantrine (AL). Significant selection of Pfcrt-K76 was observed after exposure to AL and DHA-PPQ, as well as selection of Pfmdr1-N86 after AL but not DHA-PPQ treatment, suggesting reverse selection on the Pfcrt gene by PPQ. These results support the rational use of DHA-PPQ in settings where chloroquine (CQ) resistance is high.