scholarly journals Identifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Erika Wallender ◽  
Ali Mohamed Ali ◽  
Emma Hughes ◽  
Abel Kakuru ◽  
Prasanna Jagannathan ◽  
...  

AbstractIntermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries. Optimal DP dosing regimens will maximize efficacy and reduce toxicity and resistance selection. We analyze piperaquine (PPQ) concentrations (n = 4573), malaria incidence data (n = 326), and P. falciparum drug resistance markers from a trial of children randomized to IPT with DP every 12 weeks (n = 184) or every 4 weeks (n = 96) from 2 to 24 months of age (NCT02163447). We use nonlinear mixed effects modeling to establish malaria protective PPQ levels and risk factors for suboptimal protection. Compared to DP every 12 weeks, DP every 4 weeks is associated with 95% protective efficacy (95% CI: 84–99%). A PPQ level of 15.4 ng/mL reduces the malaria hazard by 95%. Malnutrition reduces PPQ exposure. In simulations, we show that DP every 4 weeks is optimal across a range of transmission intensities, and age-based dosing improves malaria protection in young or malnourished children.

2009 ◽  
Vol 53 (5) ◽  
pp. 1753-1759 ◽  
Author(s):  
Ina Danquah ◽  
Ekkehart Dietz ◽  
Philipp Zanger ◽  
Klaus Reither ◽  
Peter Ziniel ◽  
...  

ABSTRACT Intermittent preventive treatment in infants with sulfadoxine-pyrimethamine (IPTi-SP) reduces malaria episodes by 20 to 59% across Africa. This protective efficacy, however, may be affected by the high frequency of malnutrition in African infants. We analyzed the impact of malnutrition as defined by anthropometry on the incidence of malaria and on the protective efficacy of IPTi in a cohort of 1,200 children in northern Ghana, where malaria is hyperendemic. These children received IPTi-SP or placebo at 3, 9, and 15 months of age and were monitored until 24 months of age. Malnutrition was present in 32, 40, and 50% of children at ages 3, 9, and 15 months, respectively. It was associated with increased risks of severe anemia and death but not an increased risk of malaria. Although malaria slightly contributed to chronic malnutrition, IPTi did not substantially improve child growth. Importantly, the protective efficacies of IPTi in malnourished children were roughly half or even less of those observed in nonmalnourished children. In the first year of life, IPTi reduced the incidence of malaria to a significantly lesser extent in infants who received both doses in a malnourished condition (25%; 95% confidence interval [CI], −7 to 48%) compared to that of nonmalnourished children (46%; 95% CI, 30 to 58%; P = 0.049). Moreover, in contrast to nutritionally advantaged children, the rate of severe malaria appeared to be increased in malnourished children who took IPTi. IPTi might exhibit reduced efficacy in regions of abundant malnutrition. Concomitant nutrition programs may be needed in these places to achieve the desired impact.


2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Jesmin Permala ◽  
Joel Tarning ◽  
François Nosten ◽  
Nicholas J. White ◽  
Mats O. Karlsson ◽  
...  

ABSTRACT Intermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women. IPT with the fixed dose combination of piperaquine (PQ) and dihydroartemisinin (DHA) is being evaluated as a potential mass treatment to control and eliminate artemisinin-resistant falciparum malaria. This study explored alternative DHA-PQ adult dosing regimens compared to the monthly adult dosing regimen currently being studied in clinical trials. A time-to-event model describing the concentration-effect relationship of preventive DHA-PQ administration was used to explore the potential clinical efficacy of once-weekly adult dosing regimens. Loading dose strategies were evaluated and the advantage of weekly dosing regimen was tested against different degrees of adherence. Assuming perfect adherence, three tablets weekly dosing regimen scenarios maintained malaria incidence of 0.2 to 0.3% per year compared to 2.1 to 2.6% for all monthly dosing regimen scenarios and 52% for the placebo. The three tablets weekly dosing regimen was also more forgiving (i.e., less sensitive to poor adherence), resulting in a predicted ∼4% malaria incidence per year compared to ∼8% for dosing regimen of two tablets weekly and ∼10% for monthly regimens (assuming 60% adherence and 35% interindividual variability). These results suggest that weekly dosing of DHA-PQ for malaria chemoprevention would improve treatment outcomes compared to monthly administration by lowering the incidence of malaria infections, reducing safety concerns about high PQ peak plasma concentrations and being more forgiving. In addition, weekly dosing is expected to reduce the selection pressure for PQ resistance.


Author(s):  
Clara Pons-Duran ◽  
Mireia Llach ◽  
Charfudin Sacoor ◽  
Sergi Sanz ◽  
Eusebio Macete ◽  
...  

Abstract Background Intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) is a key malaria prevention strategy in areas with moderate to high transmission. As part of the TIPTOP (Transforming IPT for Optimal Pregnancy) project, baseline information about IPTp coverage was collected in eight districts from four sub-Saharan countries: Democratic Republic of Congo (DRC), Madagascar, Mozambique and Nigeria. Methods Cross-sectional household surveys were conducted using a multistage cluster sampling design to estimate the coverage of IPTp and antenatal care attendance. Eligible participants were women of reproductive age who had ended a pregnancy in the 12 months preceding the interview and who had resided in the selected household during at least the past 4 months of pregnancy. Coverage was calculated using percentages and 95% confidence intervals. Results A total of 3911 women were interviewed from March to October 2018. Coverage of at least three doses of IPTp (IPTp3+) was 22% and 24% in DRC project districts; 23% and 12% in Madagascar districts; 11% and 16% in Nigeria local government areas; and 63% and 34% in Mozambique districts. In DRC, Madagascar and Nigeria, more than two-thirds of women attending at least four antenatal care visits during pregnancy received less than three doses of IPTp. Conclusions The IPTp3+ uptake in the survey districts was far from the universal coverage. However, one of the study districts in Mozambique showed a much higher coverage of IPTp3+ than the other areas, which was also higher than the 2018 average national coverage of 41%. The reasons for the high IPTp3+ coverage in this Mozambican district are unclear and require further study.


2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Abel Kakuru ◽  
Michelle E. Roh ◽  
Richard Kajubi ◽  
Teddy Ochieng ◽  
John Ategeka ◽  
...  

Abstract Background Placental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM. Methods Data from a birth cohort of 656 infants born to HIV-uninfected mothers randomised to IPTp with dihydroartemisinin–piperaquine (DP) or Sulfadoxine–pyrimethamine (SP) was analysed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (> 0–20% high powered fields [HPFs] with pigment), or severe past PM (> 20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM. Results There were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00–1.71, p = 0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89–1.83, p = 0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45–3.25, p < 0.001), but not female infants (aIRR 0.74, 95% CI 0.46–1.20, p = 0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM. Conclusion PM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk. Trial registration ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622


2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Patience Nayebare ◽  
Victor Asua ◽  
Melissa D. Conrad ◽  
Richard Kajubi ◽  
Abel Kakuru ◽  
...  

ABSTRACT Intermittent preventive treatment in pregnancy (IPTp) with monthly sulfadoxine-pyrimethamine (SP) is recommended for malaria-endemic parts of Africa, but efficacy is compromised by resistance, and, in recent trials, dihydroartemisinin-piperaquine (DP) has shown better antimalarial protective efficacy. We utilized blood samples from a recent trial to evaluate selection by IPTp with DP or SP of Plasmodium falciparum genetic polymorphisms that alter susceptibility to these drugs. The prevalence of known genetic polymorphisms associated with altered drug susceptibility was determined in parasitemic samples, including 375 collected before IPTp drugs were administered, 125 randomly selected from those receiving SP, and 80 from those receiving DP. For women receiving DP, the prevalence of mixed/mutant sequences was greater in samples collected during IPTp than that in samples collected prior to the intervention for PfMDR1 N86Y (20.3% versus 3.9%; P < 0.001), PfMDR1 Y184F (73.0% versus 53.0%; P < 0.001), and PfCRT K76T (46.4% versus 24.0%; P < 0.001). Considering SP, prior to IPTp, the prevalence of all 5 common antifolate mutations was over 92%, and this prevalence increased following exposure to SP, although none of these changes were statistically significant. For two additional mutations associated with high-level SP resistance, the prevalence of PfDHFR 164L (13.7% versus 4.0%; P = 0.004), but not PfDHPS 581G (1.9% versus 3.0%; P = 0.74), was greater in samples collected during IPTp compared to those collected before the intervention. Use of IPTp in Uganda selected for parasites with mutations associated with decreased susceptibility to IPTp regimens. Thus, a potential drawback of IPTp is selection of parasites with decreased drug susceptibility.


Author(s):  
Bénédicte Apouey ◽  
Gabriel Picone ◽  
Joshua Wilde

Malaria is a potentially life-threatening disease transmitted through the bites of female anopheline mosquitos infected with protozoan parasites. Malaria remains one of the major causes of mortality by infectious disease: in 2015, there were an estimated 212 million cases and 429,000 deaths globally, according to the 2016 World Malaria Report. Children under 5 years in sub-Saharan Africa bear the greatest burden of the disease worldwide. However, most of these cases could be prevented or treated. Several methods are highly effective in preventing malaria: in particular, sleeping under an insecticide-treated mosquito net (ITN), indoor residual spraying (IRS), and taking intermittent preventive treatment for pregnant women (IPTp). Regarding treatment, artesiminin-based combination therapy (ACT) is recommended as first-line treatment in many countries. Compared with other actions, malaria prevention behaviors have some specific features. In particular, they produce public health externalities. For example, bed net usage creates positive externalities since bed nets not only directly protect the user, but also reduce transmission probabilities through reduction in the number of disease hosts, and in the case of ITNs, reduction of the vector itself. In contrast, ACT uptake creates both positive externalities when individuals with malaria are treated, and negative externalities in the case of overtreatment that speeds up the spread of long-run parasite resistance. Moreover, ITNs, IPTp, and ACTs are experience goods (meaning individuals only ascertain their benefits upon usage), which implies that current preventive actions are linked to past preventive behaviors. Malaria prevention and eradication produce unambiguous benefits across various domains: economic conditions, educational outcomes, survival, fertility, and health. However, despite the high private returns to prevention, the adoption of antimalarial products and behaviors remains relatively low in malaria-affected areas. A variety of explanations have been proposed for low adoption rates, including financial constraints, high prices, and absence of information. While recent studies highlight that all of these factors play a role, the main barrier to adoption is probably financial constraints. This finding has implications regarding the appropriate pricing policy for these health products. In addition, there is a shortage of causally identified research on the effect of cultural and psychological barriers to the adoption of preventive behaviors. The literature which does exist is from a few randomized control trials of few individuals in very specific geographic and cultural contexts, and may not be generalizable. As a result, there are still ample opportunities for research on applying the insights of behavioral economics to malaria-preventive behavior in particular. Moreover, little research has been done on the supply side, such as whether free or heavily subsidized distribution of prevention technologies is fiscally sustainable; finding effective methods to solve logistical problems which lead to shortages and ineffective alternative treatments to fill the gap; or training sufficient healthcare workers to ensure smooth and effective delivery. Given these gaps in the literature, there are still multiple fruitful avenues for research which may have a first-order effect on reducing the prevalence of malaria in the developing world.


2021 ◽  
Author(s):  
Lydia Burgert ◽  
Theresa Reiker ◽  
Monica Golumbeanu ◽  
Joerg J. Moehrle ◽  
Melissa A. Penny

Seasonal malaria chemoprevention (SMC) has proven highly efficacious in reducing malaria incidence. However, the continued success of SMC is threatened by the spread of resistance against one of its main preventive ingredients, Sulfadoxine-Pyrimethamine(SP), operational challenges in delivery, and incomplete adherence to the regimens. Via a simulation study with an individual-based model of malaria dynamics, we provide quantitative evidence to assess long-acting injectables (LAIs) as potential alternatives to SMC. We explored the predicted impact of a range of novel preventive LAIs as a seasonal prevention tool in children aged three months to five years old during late-stage clinical trials and at implementation. LAIs were co-administered with a blood-stage clearing drug once at the beginning of the transmission season. We found the establishment of non-inferiority of LAIs to standard 3 or 4 rounds of SMC with SP-amodiaquine was challenging in clinical trial stages due to high intervention deployment coverage. However, our analysis of implementation settings where the achievable SMC coverage was much lower, LAIs with fewer visits per season are potential suitable replacements to SMC. Suitability as a replacement with higher impact is possible if the duration of protection of LAIs covered the duration of the transmission season. Furthermore, optimizing LAIs coverage and protective efficacy half-life via simulation analysis in settings with an SMC coverage of 60% revealed important trade-offs between protective efficacy decay and deployment coverage. Our analysis additionally highlights that for seasonal deployment for LAIs, it will be necessary to investigate the protective efficacy decay as early as possible during clinical development to ensure a well-informed candidate selection process.


2020 ◽  
Author(s):  
Abel Kakuru ◽  
Michelle E. Roh ◽  
Richard Kajubi ◽  
Teddy Ochieng ◽  
John Ategeka ◽  
...  

Abstract BackgroundPlacental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM. MethodsData from a birth cohort of 656 infants born to HIV-uninfected mothers randomized to IPTp with dihydroartemisinin-piperaquine (DP) or sulfadoxine-pyrimethamine (SP) was analyzed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (>0-20% high powered fields [HPFs] with pigment), or severe past PM (>20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM. ResultsThere were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00-1.71, p=0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89-1.83, p=0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45-3.25, p<0.001), but not female infants (aIRR 0.74, 95% CI 0.46-1.20, p=0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM.ConclusionPM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk.Trial registrationTrial registration: ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622


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