Uncomplicated Malaria In Children Research Articles

Safety and efficacy of pyronaridine–artesunate paediatric granules in the treatment of uncomplicated malaria in children: insights from randomized clinical trials and a real-world study

BackgroundChildren are particularly at risk of malaria. This analysis consolidates the clinical data for pyronaridine–artesunate (PA) paediatric granules in children from three randomized clinical trials and a real-world study (CANTAM).MethodsAn integrated safety analysis of individual patient data from three randomized clinical trials included patients with microscopically-confirmed Plasmodium falciparum, body weight ≥ 5 kg to < 20 kg, who received at least one dose of study drug (paediatric safety population). PA was administered once daily for 3 days; two trials included the comparator artemether–lumefantrine (AL). PCR-adjusted day 28 adequate clinical and parasitological response (ACPR) was evaluated. Real-world PA granules safety and effectiveness was also considered.ResultsIn the integrated safety analysis, 63.9% (95% CI 60.2, 67.4; 426/667) of patients had adverse events following PA and 62.0% (95% CI 56.9, 66.9; 222/358) with AL. Vomiting was more common with PA (7.8% [95% CI 6.0, 10.1; 52/667]) than AL (3.4% [95% CI 1.9, 5.8; 12/358]), relative risk 2.3 (95% CI 1.3, 4.3; P = 0.004), occurring mainly following the first PA dose (6.7%, 45/667), without affecting re-dosing or adherence. Prolonged QT interval occurred less frequently with PA (3.1% [95% CI 2.1, 4.8; 21/667]) than AL (8.1% [95% CI 5.7, 11.4; 29/358]), relative risk 0.39 (95% CI 0.22, 0.67; P = 0.0007). In CANTAM, adverse events were reported for 17.7% (95% CI 16.3, 19.2; 460/2599) of patients, most commonly vomiting (5.4% [95% CI 4.6, 6.4; 141/2599]), mainly following the first dose, (4.5% [117/2599]), with all patients successfully re-dosed, and pyrexia (5.4% [95% CI 4.6, 6.3; 140/2599]). In the two comparative clinical trials, Day 28 ACPR in the per-protocol population for PA was 97.1% (95% CI 94.6, 98.6; 329/339) and 100% (95% CI 99.3, 100; 514/514) versus 98.8% (95% CI 95.7, 99.9; 165/167) and 98.4% (95% CI 95.5, 99.7; 188/191) for AL, respectively. In CANTAM, PA clinical effectiveness was 98.0% (95% CI 97.3, 98.5; 2273/2320).ConclusionsAnti-malarial treatment with PA paediatric granules administered once daily for 3 days was well tolerated in children and displayed good clinical efficacy in clinical trials, with effectiveness confirmed in a real-world study.Trial registration Clinicaltrials.gov: SP-C-003-05: identifier NCT00331136; SP-C-007-07: identifier NCT0541385; SP-C-021-15: identifier NCT03201770. Pan African Clinical Trials Registry: SP-C-013-11: identifier PACTR201105000286876

Efficacy and safety of pyronaridine–artesunate versus artemether–lumefantrine in the treatment of acute uncomplicated malaria in children in South-West Nigeria: an open-labelled randomized controlled trial

BackgroundIn Nigeria, declining responsiveness to artemether–lumefantrine (AL), the artemisinin-based combination therapy (ACT) of choice since 2005, has been reported. Pyronaridine–artesunate (PA) is a newer fixed-dose ACT recently prequalified by the WHO for the treatment of uncomplicated falciparum malaria. However, PA data from the Nigerian pediatric population is scarce. Therefore, the efficacy and safety of PA and AL using the WHO 28-day anti-malarial therapeutic efficacy study protocol in Ibadan, southwest Nigeria, were compared.MethodsIn an open-labelled, randomized, controlled clinical trial, 172 children aged 3–144 months with a history of fever and microscopically confirmed uncomplicated Plasmodium falciparum malaria were enrolled in southwest Nigeria. Enrollees were randomly assigned to receive PA or AL at standard dosages according to body weight for 3 days. Venous blood was obtained for hematology, blood chemistry, and liver function tests on days 0, 3, 7, and 28 as part of the safety evaluation.Results165 (95.9%) of the enrolled individuals completed the study. About half (52.3%; 90/172) of enrollees were male. Eighty-seven (50.6%) received AL, while 85 (49.4%) received PA. Day 28, adequate clinical and parasitological response for PA was 92.7% [(76/82) 95% CI 83.1, 95.9] and 71.1% [(59/83) 95% CI 60.4, 79.9] for AL (0.001). Fever and parasite clearance were similar in both groups. Two of six and eight of 24 parasite recurrences were observed among PA- and AL-treated children, respectively. PCR-corrected Day-28 cure rates for PA were 97.4% (76/78) and 88.1% (59/67) for AL (= 0.04) in the per-protocol population after new infections were censored. Hematological recovery at day 28 was significantly better among PA-treated patients (34.9% 2.8) compared to those treated with AL (33.1% 3.0) (0.002). Adverse events in both treatment arms were mild and similar to the symptoms of malaria infection. Blood chemistry and liver function tests were mostly within normal limits, with an occasional marginal rise.ConclusionPA and AL were well-tolerated. PA was significantly more efficacious than AL in both the PCR-uncorrected and PCR-corrected per-protocol populations during this study. The results of this study support the inclusion of PA in the anti-malarial treatment guidelines in Nigeria.Retrospective trial registrationClinicaltrials.gov: NCT05192265.

The effect of sickle cell genotype on the pharmacokinetic properties of artemether-lumefantrine in Tanzanian children

Since there are inconsistent data relating to the effect of haemoglobinopathies on disposition of artemisinin antimalarial combination therapy, and none in sickle cell trait (SCT) or sickle cell disease (SCD), the aim of this study was to characterize the pharmacokinetic properties of artemether-lumefantrine (ARM-LUM) in children with SCD/SCT. Thirty-eight Tanzanian children aged 5–10 years with normal (haemoglobin AA; n = 12), heterozygous (haemoglobin AS; n = 14) or homozygous (haemoglobin SS; n = 12) sickle genotypes received six ARM-LUM doses (1.7 mg/kg plus 10 mg/kg, respectively) over 3 days. Sparse venous and mixed-capillary dried blood spot (DBS) samples were taken over 42 days. Plasma and DBS ARM and LUM, and their active metabolites dihydroartemisinin (DHA) and desbutyl-lumefantrine (DBL), were assayed using validated liquid chromatography-mass spectrometry. Multi-compartmental pharmacokinetic models were developed using a population approach. Plasma but not DBS concentrations of ARM/DHA were assessable. The majority (85%) of the 15 measurable values were within 95% prediction intervals from a published population pharmacokinetic ARM/DHA model in Papua New Guinean children of similar age without SCD/SCT who had uncomplicated malaria, and there was no clear sickle genotype clustering. Plasma (n = 38) and corrected DBS (n = 222) LUM concentrations were analysed using a two-compartment model. The median [inter-quartile range] LUM AUC0–∞ was 607,296 [426,480–860,773] μg.h/L, within the range in published studies involving different populations, age-groups and malaria status. DBS and plasma DBL concentrations correlated poorly and were not modelled. These data support use of the conventional ARM-LUM treatment regimen for uncomplicated malaria in children with SCT/SCD.

Exploring Barriers and Facilitators of Adherence to Artemisinin-Based Combination Therapies for the Treatment of Uncomplicated Malaria in Children in Freetown, Sierra Leone.

Medication adherence is an essential step in the malaria treatment cascade. We conducted a qualitative study embedded within a randomized controlled trial comparing the adherence to the recommended dosing of two artemisinin-based combination therapies (ACT) to treat uncomplicated malaria in Freetown, Sierra Leone. This study explored the circumstances and factors that influenced caregiver adherence to the ACT prescribed for their child in the trial. In-depth interviews were conducted with 49 caregivers; all interviews were recorded, transcribed, and translated. Transcripts were coded and aggregated into themes, applying a thematic content approach. We identified four key factors that influenced optimal treatment adherence: (1) health system influences, (2) health services, (3) caregivers’ experiences with malaria illness and treatment, and (4) medication characteristics. Specifically, caregivers reported confidence in the health system as facilities were well maintained and care was free. They also felt that health workers provided quality care, leading them to trust the health workers and believe the test results. Ease of medication administration and perceived risk of side effects coupled with caregivers’ prior experience treating malaria influenced how medications were administered. To ensure ACTs achieve maximum effectiveness, consideration of these contextual factors and further development of child-friendly antimalarials are needed.

Paediatric formulations of artemisinin-based combination therapies for treating uncomplicated malaria in children.

BackgroundIn endemic malarial areas, young children have high levels of malaria morbidity and mortality. The World Health Organization recommends oral artemisinin‐based combination therapy (ACT) for treating uncomplicated malaria. Paediatric formulations of ACT have been developed to make it easier to treat children.ObjectivesTo evaluate evidence from trials on the efficacy, safety, tolerability, and acceptability of paediatric ACT formulations compared to tablet ACT formulations for uncomplicated P falciparum malaria in children up to 14 years old.Search methodsWe searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; the Latin American and Caribbean Health Science Information database (LILACS); ISI Web of Science; Google Scholar; Scopus; and the metaRegister of Controlled Trials (mRCT) to 11 December 2019.Selection criteriaWe included randomised controlled clinical trials (RCTs) of paediatric versus non‐paediatric formulated ACT in children aged 14 years or younger with acute uncomplicated malaria.Data collection and analysisTwo authors independently assessed eligibility and risk of bias, and carried out data extraction. We analyzed the primary outcomes of efficacy, safety and tolerability of paediatric versus non‐paediatric ACT using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were: treatment failure on the last day of observation (day 42), fever clearance time, parasite clearance time, pharmacokinetics, and acceptability.Main resultsThree trials met the inclusion criteria. Two compared a paediatric dispersible tablet formulation against crushed tablets of artemether‐lumefantrine (AL) and dihydroartemisinin‐piperaquine (DHA‐PQ), and one trial assessed artemether‐lumefantrine formulated as powder for suspension compared with crushed tablets. The trials were carried out between 2006 and 2015 in sub‐Saharan Africa (Benin, Mali, Mozambique, Tanzania, Kenya, Democratic Republic of the Congo, Burkina Faso, and The Gambia).In all three trials, the paediatric and control ACT achieved polymerase chain reaction (PCR)‐adjusted treatment failure rates of < 10% on day 28 in the per‐protocol (PP) population.For the comparison of dispersible versus crushed tablets, the two trials did not detect a difference for treatment failure by day 28 (PCR‐adjusted PP population: RR 1.35, 95% CI 0.49 to 3.72; 1061 participants, 2 studies, low‐certainty evidence). Similarly, for the comparison of suspension versus crushed tablet ACT, we did not detect any difference in treatment failure at day 28 (PCR‐adjusted PP population: RR 1.64, 95% CI 0.55 to 4.87; 245 participants, 1 study).We did not detect any difference in serious adverse events for the comparison of dispersible versus crushed tablets (RR 1.05, 95% CI 0.38 to 2.88; 1197 participants, 2 studies, low‐certainty evidence), or for the comparison of suspension versus crushed tablet ACT (RR 0.74, 95% CI 0.17 to 3.26; 267 participants, 1 study).In the dispersible ACT arms, drug‐related adverse events occurred in 9% of children in the AL study and 34% of children in the DHA‐PQ study. In the control arms, drug‐related adverse events occurred in 12% of children in the AL study and in 42% of children in the DHA‐PQ study. Drug‐related adverse events were lower in the dispersible ACT arms (RR 0.78, 95% CI 0.62 to 0.99; 1197 participants, 2 studies, moderate‐certainty evidence).There was no detected difference in the rate of drug‐related adverse events for suspension ACT versus crushed tablet ACT (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study).Drug‐related vomiting appeared to be less common in the dispersible ACT arms (RR 0.75, 95% CI 0.56 to 1.01; 1197 participants, 2 studies, low‐certainty evidence) and in the suspension ACT arm (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study), but both analyses were underpowered.No study assessed acceptability.Authors' conclusionsTrials did not demonstrate a difference in efficacy between paediatric dispersible or suspension ACT when compared with the respective crushed tablet ACT for treating uncomplicated P falciparum malaria in children. However, the evidence is of low to moderate certainty due to limited power. There appeared to be fewer drug‐related adverse events with dispersible ACT compared to crushed tablet ACT. None of the included studies assessed acceptability of paediatric ACT formulation.

Haptoglobin gene diversity and incidence of uncomplicated malaria among children in Iganga, Uganda

BackgroundHaptoglobin (Hp) is an acute phase protein that takes part in systemic regulation of haem during Plasmodium falciparum infections. Numerous genotypes of haptoglobin have been reported in malaria endemic populations. In this study, the relationship between haptoglobin genotypes and incidence of uncomplicated malaria in a cohort of children living in a malaria-endemic area of Uganda was determined.MethodsThis is an extension of a longitudinal study comprising of 423 children aged between six months and nine years, who were actively followed up for one year. Malaria episodes occurring in the cohort children were detected and the affected children treated with national policy drug regimen. Haptoglobin genotypes were determined by an allele-specific PCR method and their frequencies were calculated. A multivariate negative binomial regression model was used to estimate the impact of haptoglobin genotypes on incidence of uncomplicated malaria in the children’s cohort. In all statistical tests, a P–value of < 0.05 was considered as significant.ResultsThe prevalence of the Hp 1–1, Hp 2–1 and Hp 2–2 genotypes in the children’s cohort was 41%, 36.2% and 22.9%, respectively. The overall frequency for the Hp 1 allele was 59%, while Hp 2 allele occurred at a frequency of 41%. After adjustment of incidence rates for age, insecticide treated bed net (ITN) use and malaria history, the incidence of uncomplicated malaria for children carrying the Hp 2–2 genotype and those with the Hp 2–1 genotype was statistically similar (P = 0.41). Also, no difference in the incidence of uncomplicated malaria was observed between children carrying the Hp 1–1 genotype and those having the Hp 2–1 genotype (P = 0.84) or between Hp 2–2 Vs Hp 1–1 genotypes (P = 0.50).ConclusionsThis study showed that the Hp 1–1 and Hp 2–1 genotypes each occur in nearly 4 in 10 children and the Hp 2–2 genotype occurs in 2 of every 10 children. No association with incidence of uncomplicated malaria was found. Additional studies of influence of haptoglobin genotypes on P. falciparum malaria severity are needed to understand the role of these genotypes in malarial protection.

Reticulocyte count changes in paediatric patients with uncomplicated malaria treated with artemisinin combination therapy

Background: Acute malaria is associated with reticulocyte count depression, and artemisinin derivatives have also been shown to cause reversible count changesin patients with severe malaria. However, there has been no report on the effect of artemisinin on reticulocytecountwhen used in combination with other antimalarials, or the effect of artemisinin-based treatment on reticulocyte count changes in patients with uncomplicated malaria. Objective: This study reports the effects of artemisinin-based antimalarial treatments on reticulocytes among paediatric patients with uncomplicated malaria. Methods: The reticulocyte counts, haemoglobin, and platelet counts of children with uncomplicated malaria treated with artesunate-amodiaquine (116), artemether-lumefantrine (90), or amodiaquine (17) were measured before treatment (day 0) and then on days 3, 7, 14, and 28. Results: The fractional changes in reticulocyte counts were higher in the artesunate-amodiaquine and artemether-lumefantrine groups during the initial stages of treatment. However, the overall fractional reticulocyte change between acute illness and pre-illness levels was higher in the amodiaquine treated group. There was a negative correlation between haemoglobin and reticulocyte counts before treatment (day 0 ) and on all the follow up days. Conclusion: Treatment of uncomplicated malaria in children with artesunate-amodiaquine or artemether-lumefantrine was associated with less profound reticulocyte count changes compared with children treated with amodiaquine alone. These changes were most likely due to the rapid parasite clearance by the two artemisinin-based combination treatment regimens.

Reticulocyte count changes in paediatric patients with uncomplicated malaria treated with artemisinin combination therapy

Background: Acute malaria is associated with reticulocyte count depression, and artemisinin derivatives have also been shown to cause reversible count changes in patients with severe malaria. However, there has been no report on the effect of artemisinin on reticulocyte count when used in combination with other antimalarials, or the effect of artemisinin-based treatment on reticulocyte count changes in patients with uncomplicated malaria. Objective:This study reports the effects of artemisinin-based antimalarial treatments on reticulocytes among paediatric patients with uncomplicated malaria. Methods: The reticulocyte counts, haemoglobin, and platelet counts of children with uncomplicated malaria treated with artesunate-amodiaquine (116), artemether-lumefantrine (90), or amodiaquine (17) were measured before treatment (day 0) and then on days 3, 7, 14, and 28. Results: The fractional changes in reticulocyte counts were higher in the artesunate-amodiaquine and artemether-lumefantrine groups during the initial stages of treatment. However, the overall fractional reticulocyte change between acute illness and pre-illness levels was higher in the amodiaquine treated group. There was a negative correlation between haemoglobin and reticulocyte counts before treatment (day0) and on all the follow up days. Conclusion: Treatment of uncomplicated malaria in children with artesunate-amodiaquine or artemether-lumefantrine was associated with less profound reticulocyte count changes compared with children treated with amodiaquine alone. These changes were most likely due to the rapid parasite clearance by the two artemisinin-based combination treatment regimens

In vivo/ex vivo efficacy of artemether\u2013lumefantrine and artesunate\u2013amodiaquine as first-line treatment for uncomplicated falciparum malaria in children: an open label randomized controlled trial in Burkina Faso

BackgroundArtemisinin-based combination therapy (ACT) is recommended to improve malaria treatment efficacy and limit drug-resistant parasites selection in malaria endemic areas. 5 years after they were adopted, the efficacy and safety of artemether–lumefantrine (AL) and artesunate–amodiaquine (ASAQ), the first-line treatments for uncomplicated malaria were assessed in Burkina Faso.MethodsIn total, 440 children with uncomplicated Plasmodium falciparum malaria were randomized to receive either AL or ASAQ for 3 days and were followed up weekly for 42 days. Blood samples were collected to investigate the ex vivo susceptibility of P. falciparum isolates to lumefantrine, dihydroartemisinin (the active metabolite of artemisinin derivatives) and monodesethylamodiaquine (the active metabolite of amodiaquine). The modified isotopic micro test technique was used to determine the 50% inhibitory concentration (IC50) values. Primary endpoints were the risks of treatment failure at days 42.ResultsOut of the 440 patients enrolled, 420 (95.5%) completed the 42 days follow up. The results showed a significantly higher PCR unadjusted cure rate in ASAQ arm (71.0%) than that in the AL arm (49.8%) on day 42, and this trend was similar after correction by PCR, with ASAQ performing better (98.1%) than AL (91.1%). Overall adverse events incidence was low and not significantly different between the two treatment arms. Ex vivo results showed that 6.4% P. falciparum isolates were resistant to monodesthylamodiaquine. The coupled in vivo/ex vivo analysis showed increased IC50 values for lumefantrine and monodesethylamodiaquine at day of recurrent parasitaemia compared to baseline values while for artesunate, IC50 values remained stable at baseline and after treatment failure (p > 0.05).ConclusionThese findings provide substantial evidence that AL and ASAQ are highly efficacious for the treatment of uncomplicated malaria in children in Burkina Faso. However, the result of P. falciparum susceptibility to the partner drugs advocates the need to regularly replicate such surveillance studies. This would be particularly indicated when amodiaquine is associated in seasonal malaria chemoprophylaxis (SMC) mass drug administration in children under 5 years in Burkina Faso.Trial registration clinicaltrials, NCT00808951. Registered 05 December 2008,https://clinicaltrials.gov/ct2/show/NCT00808951?cond=NCT00808951&rank=1

Monitoring of efficacy, tolerability and safety of artemether\u2013lumefantrine and artesunate\u2013amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Lambar\xe9n\xe9, Gabon: an open-label clinical trial

BackgroundMalaria remains a major public health problem, affecting mainly low-and middle-income countries. The management of this parasitic disease is challenged by ever increasing drug resistance. This study, investigated the therapeutic efficacy, tolerability and safety of artemether–lumefantrine (AL) and artesunate–amodiaquine (AS–AQ), used as first-line drugs to treat uncomplicated malaria in Lambaréné, Gabon.MethodsA non-randomized clinical trial was conducted between October 2017 and March 2018 to assess safety, clinical and parasitological efficacy of fixed-doses of AL and AS–AQ administered to treat uncomplicated Plasmodium falciparum malaria in children aged from 6 months to 12 years. After 50 children were treated with AL, another 50 children received ASAQ. The 2009 World Health Organization protocol for monitoring of the efficacy of anti‑malarial drugs was followed. Molecular markers msp1 and msp2 were used to differentiate recrudescence and reinfection. For the investigation of artemisinin resistant markers, gene mutations in Pfk13 were screened.ResultsPer-protocol analysis on day 28 showed a PCR corrected cure rate of 97% (95% CI 86–100) and 95% (95% CI 84–99) for AL and AS–AQ, respectively. The most frequent adverse event in both groups was asthenia. No mutations in the kelch-13 gene associated with artemisinin resistance were identified. All participants had completed microscopic parasite clearance by day 3 post-treatment.ConclusionThis study showed that AL and AS–AQ remain efficacious, well-tolerated, and are safe to treat uncomplicated malaria in children from Lambaréné. However, a regular monitoring of efficacy and a study of molecular markers of drug resistance to artemisinin in field isolates is essential.Trial registration ANZCTR, ACTRN12616001600437. Registered 18 November, http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=ACTRN12616001600437p&isBasic=True

Failures in the case management of children with uncomplicated malaria in Bata district of Equatorial Guinea and associated factors.

BackgroundIn Equatorial Guinea, malaria continues to be one of the main causes of morbidity and mortality among children. The National Therapeutic Guide established artesunate-amodiaquine (ASAQ) as first-line treatment for uncomplicated malaria, but compliance with this treatment is low. The aim of this study was to assess, for the first time, the performance of public healthcare workers in the diagnosis and treatment of uncomplicated malaria, their compliance with first-line Malaria National Therapeutic Guide and the associated factors.MethodsA cross-sectional survey was conducted at the nine public health facilities in the Bata District of Equatorial Guinea to assess the management of uncomplicated malaria in children < 15 years of age. Bivariate and multivariate statistical analyses were used to determine the recommended treatment compliance and related factors.ResultsA total of 227 children with uncomplicated malaria were recorded from 9 public health facilities. Most of the treatments prescribed (83.3%) did not follow the first-line treatment recommended for uncomplicated malaria. The diagnosis was established with parasite confirmation in 182 cases (80.2%). After adjustment for other variables, children under 2 months of age, the use of parasite confirmation to the diagnosis of malaria and being familiar with the national therapeutic guide were significantly associated with the prescription of the first-line recommended treatment. Cases attended at the hospital or in a health facility with ASAQ in the pharmacy at the time of the study were also more likely to be prescribed with the recommended treatment, but with non-significant association after adjustment for other variables.ConclusionsThis study identified the factors associated with the low compliance with the first-line treatment by the public healthcare facilities of Bata District of Equatorial Guinea. It seems necessary to improve case management of children with uncomplicated malaria; to reinforce the use of Malaria National Therapeutic Guide and to inform about the danger of using artemisinin monotherapy. Furthermore, it is crucial to provide recommended first-line treatment to the pharmacies of all public health facilities to ensure access to this treatment.

The Advanced Development Pathway of the RTS,S/AS01 Vaccine.

Following successful phase 1 and 2 trials, RTS,S/AS01 was evaluated in a large phase 3 trial in 7 African countries in which 8922 young children and 6537 infants were enrolled and followed for a median of 48 and 38months, respectively. The vaccine efficacy against uncomplicated malaria in children was 28% without booster and 36% with booster. The vaccine received the approval of the European Medical Agency in 2015, but two WHO expert committees requested more data before the programmatic use of RTS,S/AS01 in African children can be recommended. To provide such data, a very large, cluster randomized trial is currently in progress in three African countries. The integration of RTS,S/AS01 in national childhood vaccination programs will benefit the individual vaccinated child but is unlikely to make an impact on malaria transmission. Mass vaccination campaigns that include all age groups over short periods are more likely to harness the short but high protection afforded by RTS,S/AS01.

Uncomplicated Malaria in Children under 6 Months or Less than 5 Kg; How Prescribers in Ghana Manage it in the Absence of a National Policy

Uncomplicated Malaria in Children under 6 Months or Less than 5 Kg; How Prescribers in Ghana Manage it in the Absence of a National Policy

Adherence to treatment with artemether\u2013lumefantrine or amodiaquine\u2013artesunate for uncomplicated malaria in children in Sierra Leone: a randomized trial

BackgroundPrompt, effective treatment of confirmed malaria cases with artemisinin-based combination therapy (ACT) is a cornerstone of malaria control. Maximizing adherence to ACT medicines is key to ensuring treatment effectiveness.MethodsThis open-label, randomized trial evaluated caregiver adherence to co-formulated artemether–lumefantrine (AL) and fixed-dose amodiaquine–artesunate (AQAS) in Sierra Leone. Children aged 6–59 months diagnosed with malaria were recruited from two public clinics, randomized to receive AL or AQAS, and visited at home the day after completing treatment. Analyses were stratified by site, due to differences in participant characteristics and outcomes.ResultsOf the 784 randomized children, 680 (85.6%) were included in the final per-protocol analysis (340 AL, 340 AQAS). Definite adherence (self-reported adherence plus empty package) was higher for AL than AQAS at both sites (Site 1: 79.4% AL vs 63.4% AQAS, odds ratio [OR] 2.16, compared to probable adherence plus probable or definite non-adherence, 95% confidence interval [CI] 1.34–3.49; p = 0.001; Site 2: 52.1% AL vs 37.5% AQAS, OR 1.53, 95% CI 1.00–2.33, p = 0.049). However, self-reported adherence (ignoring drug package inspection) was higher for both regimens at both sites and there was no strong evidence of variation by treatment (Site 1: 96.6% AL vs 95.9% AQAS, OR 1.19, 95% CI 0.39–3.63, p = 0.753; Site 2: 91.5% AL vs 96.4% AQAS, OR 0.40, 95% CI 0.15–1.07, p = 0.067). In Site 2, correct treatment (correct dose + timing + duration) was lower for AL than AQAS (75.8% vs 88.1%, OR 0.42, 95% CI 0.23–0.76, p = 0.004). In both sites, more caregivers in the AQAS arm reported adverse events (Site 1: 3.4% AL vs 15.7% AQAS, p < 0.001; Site 2: 15.2% AL vs 24.4% AQAS, p = 0.039).ConclusionsSelf-reported adherence was high for both AL and AQAS, but varied by site. These results suggest that each regimen has potential disadvantages that might affect adherence; AL was less likely to be taken correctly at one site, but was better tolerated than AQAS at both sites. Measuring adherence to anti-malarials remains challenging, but important. Future research should focus on comparative studies of new drug regimens, and improving the methodology of measuring adherence.Trial registration: Clinicaltrials.gov, NCT01967472. Retrospectively registered 18 October 2013, https://clinicaltrials.gov/ct2/show/NCT01967472

Artemisinin based combination therapy for uncomplicated malaria management among children under five in Cameroon: a best practice implementation project.

The aim of this evidence implementation project is to promote evidence-based practice in artemisinin-based combination therapy for managing uncomplicated malaria in children under five, thereby improving patient outcomes and resource utilization in the Bali Health District, Cameroon. The burden of disease attributable to malaria has significantly improved in the last three years, however morbidity and mortality risks are still present, especially for children under five. In children with uncomplicated P. falciparum malaria, there is strong evidence to suggest that artemisinin-based combination therapy (ACT) is effective in treating malaria. The World Health Organization has strong recommendations with high-quality evidence guiding practice in the "test, treat and track" approach using microscopy, rapid diagnostics tests and ACTs. This evidence implementation project used the Joanna Briggs Institute Practical Application of Clinical Evidence System (JBI PACES) and Getting Research into Practice (GRiP) audit and feedback tool for promoting evidence-based healthcare involving three phases of activity. We compared compliance with best practice recommendations at baseline against a follow-up compliance at four months, following implementation of strategies identified. Compliance rates improved overall by 31% (R: 20-42) for all criteria and sites, with differences noticed between sites. Nineteen barriers were identified, stratified into clinician, community health worker, patient and policy maker related barriers. Despite existing barriers to evidence implementation, getting research into practice is possible and does improve quality of care.

Comparative Efficacy of Artemether-lumefantrin and Dihydroartemisinin-piperaquine in the Treatment of Uncomplicated Malaria in Children Under 5 years in Two Primary Health Care Centres in Port Harcourt, Rivers State, Nigeria

Comparative Efficacy of Artemether-lumefantrin and Dihydroartemisinin-piperaquine in the Treatment of Uncomplicated Malaria in Children Under 5 years in Two Primary Health Care Centres in Port Harcourt, Rivers State, Nigeria

Cost-effectiveness of artemisinin\u2013naphthoquine versus artemether\u2013lumefantrine for the treatment of uncomplicated malaria in Papua New Guinean children

BackgroundA recent randomized trial showed that artemisinin–naphthoquine (AN) was non-inferior to artemether–lumefantrine (AL) for falciparum malaria and superior for vivax malaria in young Papua New Guinean children. The aim of this study was to compare the cost-effectiveness of these two regimens.MethodsAn incremental cost-effectiveness analysis was performed using data from 231 children with Plasmodium falciparum and/or Plasmodium vivax infections in an open-label, randomized, parallel-group trial. Recruited children were randomized 1:1 to receive once daily AN for 3 days with water or twice daily AL for 3 days given with fat. World Health Organisation (WHO) definitions were used to determine clinical/parasitological outcomes. The cost of transport between the home and clinic, plus direct health-care costs, served as a basis for determining each regimen’s incremental cost per incremental treatment success relative to AL by Day 42 and its cost per life year saved.ResultsIn the usual care setting, AN was more effective for the treatment of uncomplicated malaria in children aged 0.5–5.9 years. AL and AN were equally efficacious for the treatment of falciparum malaria, however AN had increased anti-malarial treatment costs per patient of $10.46, compared with AL. AN was the most effective regimen for treatment of vivax malaria, but had increased treatment costs of $14.83 per treatment success compared with AL.ConclusionsWhilst AN has superior overall efficacy for the treatment of uncomplicated malaria in PNG children, AL was the less costly regimen. An indicative extrapolation estimated the cost per life year saved by using AN instead of AL to treat uncomplicated malaria to be $12,165 for girls and $12,469 for boys (discounted), which means AN may not be cost-effective and affordable for PNG at current cost. However, AN may become acceptable should it become WHO prequalified and/or should donated/subsidized drug supply become available.

Network meta-analysis including treatment by covariate interactions: Consistency can vary across covariate values.

BackgroundMany reviews aim to compare numerous treatments and report results stratified by subgroups (eg, by disease severity). In such cases, a network meta‐analysis model including treatment by covariate interactions can estimate the relative effects of all treatment pairings for each subgroup of patients. Two key assumptions underlie such models: consistency of treatment effects and consistency of the regression coefficients for the interactions. Consistency may differ depending on the covariate value at which consistency is assessed. For valid inference, we need to be confident of consistency for the relevant range of covariate values. In this paper, we demonstrate how to assess consistency of treatment effects from direct and indirect evidence at various covariate values.MethodsConsistency is assessed using visual inspection, inconsistency estimates, and probabilities. The method is applied to an individual patient dataset comparing artemisinin combination therapies for treating uncomplicated malaria in children using the covariate age.ResultsThe magnitude of the inconsistency appears to be decreasing with increasing age for each comparison. For one comparison, direct and indirect evidence differ for age 1 (P = .05), and this brings results for age 1 for all comparisons into question.ConclusionWhen fitting models including interactions, the consistency of direct and indirect evidence must be assessed across the range of covariates included in the trials. Clinical inferences are only valid for covariate values for which results are consistent.

Comparison of anti-malarial drug efficacy in the treatment of uncomplicated malaria in African children and adults using network meta-analysis

BackgroundArtemisinin-based combination therapy (ACT) and novel drug combinations are available and used in African countries to treat uncomplicated malaria. Network meta-analysis methods are rarely and poorly applied for the comparison of their efficacies. This method was applied on a set of randomized controlled trials to illustrate its usefulness.MethodsA literature review available in Pubmed was conducted in July 2016. Eligible studies, conducted in sub-Saharan Africa, published between 2002 and 2016, focused on randomized controlled trials of at least two artemisinin-based combinations to treat uncomplicated malaria in children and adults. Agglomerate data were: the number of PCR-corrected adequate clinical and parasitological response (ACPR) on day 28, used as the primary endpoint in all interventions, the number of participants and the list of treatments. A Bayesian random effect meta-analysis using a binary outcome was the method to compare the efficacy. Ranking measure was used to obtain a hierarchy of the competing interventions.ResultsIn total, 76 articles were included; 13 treatment regimens were involved and tested in 36,001 patients. Using artemether–lumefantrine (AL) as the common comparator for the entire network, 12 relative treatment effects were estimated and indirect comparisons were obtained. Dihydroartemisinin–piperaquine (DHAP) was shown to be more effective than AL (odds ratio [OR] = 1.92; 95% CI 1.30–2.82; 19,163 patients), ASAQ (OR = 1.70; 95% CI 1.10–2.64; 14,433 patients), and amodiaquine–sulfadoxine–pyrimethamine (AQSP): OR = 2.20; 95% CI 1.21–3.96; 8863 patients. Artesunate–amodiaquine (ASAQ) was comparable to AL (OR = 1.11; 95% CI 0.84–1.45; 21,235 patients). No significant difference was found between artesunate and mefloquine (ASMQ) and AL (OR = 1.20; 95% CI = 0.52-2.8; 13,824 participants). According to treatment ranking, among the WHO-recommended ACT medicines, DHAP was shown to be the most efficacious.ConclusionsBased on the available evidence, this study demonstrated the superiority of DHAP among currently recommended artemisinin-based combinations. The application of the methods described here may be helpful to gain better understanding of treatment efficacy and improve future decisions. However, more data are needed to allow robust conclusions about the results in comparison with novel drugs. Further surveillance of the efficacy of anti-malarial drugs and clinical trials are needed to closely follow the evolution of the epidemiology of drug-resistant malaria in Africa.

Cost-Effectiveness Analysis of Test-Based versus Presumptive Treatment of Uncomplicated Malaria in Children under Five Years in an Area of High Transmission in Central Ghana.

BackgroundThe presumptive approach of confirming malaria in health facilities leads to over-diagnosis of malaria, over use of anti-malaria drugs and the risk of drug resistance development. WHO recommends parasitological confirmation before treatment with artemisinin-based combination therapy (ACT) in all suspected malaria patients. The use of malaria rapid diagnostic tests (mRDTs) would make it possible for prescribers to diagnose malaria at point-of-care and better target the use of antimalarials. Therefore, a cost-effectiveness analysis was performed on the introduction of mRDTs for management of malaria in under-five children in a high transmission area in Ghana where presumptive diagnosis was the norm in public health centres.MethodsA cluster-randomised controlled trial where thirty-two health centres were randomised into test-based diagnosis of malaria using mRDTs (intervention) or clinical judgement (control) was used to measure the effect of mRDTs on appropriate treatment: ‘a child with a positive reference diagnosis prescribed a course of ACT or a child with a negative reference diagnosis not given an ACT’. Cost data was collected from five purposively selected health centres and used to estimate the health sector costs of performing an mRDT and treat children for malaria and other common febrile illnesses. Costs of training healthcare personnel and supervision in the study period were also collected. A sample of caregivers to children participating in the trial was interviewed about household cost incurred on transport, drugs, fees, and special food during a period of one week after the health centre visit as well as days unable to work. A decision model approach was used to calculate the incremental cost-effectiveness ratios (ICERs). Univariate and multivariate sensitivity analyses were applied to assess the robustness of ICERs.ResultsThe availability of mRDTs for malaria diagnosis resulted in fewer ACT treatments compared to the clinical judgement approach (73% versus 81%) and more children appropriately treated (70% versus 57%). The introduction of mRDT-based diagnosis would cost the Ministry of Health US$18.6 per extra appropriately treated child under five compared to clinical judgement while the ICER from a societal perspective was lower at US$11.0 per appropriately treated child. ICERs were sensitive to a decrease in adherence to negative mRDTs, malaria positivity rate and specificity of the mRDT.ConclusionThe introduction of mRDTs is likely to be considered cost-effective in this high transmission setting as this intervention increased the number of appropriately treated children at low cost.Trial RegistrationClinicalTrials.gov NCT00832754