Treatment of asymptomatic carriers with artemether-lumefantrine: an opportunity to reduce the burden of malaria?

Background: Increased investment and commitment to malaria prevention and treatment strategies across Africa has produced impressive reductions in the incidence of this disease. Nevertheless, it is clear that further interventions will be necessary to meet the international target of a reversal in the incidence of malaria by 2015. This article discusses the prospective role of an innovative malaria control strategy - the community-based treatment of asymptomatic carriers of Plasmodium falciparum, with artemisinin-based combination therapy (ACT). The potential of this intervention was considered by key scientists in the field at an Advisory Board meeting held in Basel, in April 2009. This article summarizes the discussions that took place among the participants. Presentation of the hypothesis: Asymptomatic carriers do not seek treatment for their infection and, therefore, constitute a reservoir of parasites and thus a real public-health risk. The systematic identification and treatment of individuals with asymptomatic P. falciparum as part of a surveillance intervention strategy should reduce the parasite reservoir, and if this pool is greatly reduced, it will impact disease transmission. Testing the hypothesis: This article considers the populations that could benefit from such a strategy and examines the ethical issues associated with the treatment of apparently healthy individuals, who represent a neglected public health risk. The potential for the treatment of asymptomatic carriers to impair the development of protective immunity, resulting in a \u27rebound\u27 and age escalation of malaria incidence, is also discussed. For policymakers to consider the treatment of asymptomatic carriers with ACT as a new tool in their malaria control programmes, it will be important to demonstrate that such a strategy can produce significant benefits, without having a negative impact on the efficacy of ACT and the health of the target population. Implications of the hypothesis: The treatment of asymptomatic carriers with ACT is an innovative and essential tool for breaking the cycle of infection in some transmission settings. Safe and effective medicines can save the lives of children, but the reprieve is only temporary so long as the mosquitoes can become re-infected from the asymptomatic carriers. With improvements in rapid diagnostic tests that allow easier identification of asymptomatic carriers, the elimination of the pool of parasites is within reach. © 2010 Ogutu et al; licensee BioMed Central Ltd

Community screening and treatment of asymptomatic carriers of Plasmodium falciparum with artemether-lumefantrine to reduce malaria disease burden: a modelling and simulation analysis

<p>Abstract</p> <p>Background</p> <p>Asymptomatic carriers of <it>Plasmodium falciparum </it>serve as a reservoir of parasites for malaria transmission. Identification and treatment of asymptomatic carriers within a region may reduce the parasite reservoir and influence malaria transmission in that area.</p> <p>Methods</p> <p>Using computer simulation, this analysis explored the impact of community screening campaigns (CSC) followed by systematic treatment of <it>P. falciparum </it>asymptomatic carriers (AC) with artemether-lumefantrine (AL) on disease transmission. The model created by Okell <it>et al </it>(originally designed to explore the impact of the introduction of treatment with artemisinin-based combination therapy on malaria endemicity) was modified to represent CSC and treatment of AC with AL, with the addition of malaria vector seasonality. The age grouping, relative distribution of age in a region, and degree of heterogeneity in disease transmission were maintained. The number and frequency of CSC and their relative timing were explored in terms of their effect on malaria incidence. A sensitivity analysis was conducted to determine the factors with the greatest impact on the model predictions.</p> <p>Results</p> <p>The simulation showed that the intervention that had the largest effect was performed in an area with high endemicity (entomological inoculation rate, EIR > 200); however, the rate of infection returned to its normal level in the subsequent year, unless the intervention was repeated. In areas with low disease burden (EIR < 10), the reduction was sustained for over three years after a single intervention. Three CSC scheduled in close succession (monthly intervals) at the start of the dry season had the greatest impact on the success of the intervention.</p> <p>Conclusions</p> <p>Community screening and treatment of asymptomatic carriers with AL may reduce malaria transmission significantly. The initial level of disease intensity has the greatest impact on the potential magnitude and duration of malaria reduction. When combined with other interventions (e.g. long-lasting insecticide-treated nets, rapid diagnostic tests, prompt diagnosis and treatment, and, where appropriate, indoor residual spraying) the effect of this intervention can be sustained for many years, and it could become a tool to accelerate the reduction in transmission intensity to pre-elimination levels. Repeated interventions at least every other year may help to prolong the effect. The use of an effective diagnostic tool and a highly effective ACT, such as AL, is also vital. The modelling supports the evaluation of this approach in a prospective clinical trial to reduce the pool of infective vectors for malaria transmission in an area with marked seasonality.</p

Similar efficacy and safety of artemether-lumefantrine (Coartem®) in African infants and children with uncomplicated falciparum malaria across different body weight ranges

<p>Abstract</p> <p>Background</p> <p>Artemisinin-based combination therapy, including artemether-lumefantrine (AL), is currently recommended for the treatment of uncomplicated <it>Plasmodium falciparum </it>malaria. The objectives of the current analysis were to compare the efficacy and safety of AL across different body weight ranges in African children, and to examine the age and body weight relationship in this population.</p> <p>Methods</p> <p>Efficacy, safety and pharmacokinetic data from a randomized, investigator-blinded, multicentre trial of AL for treatment of acute uncomplicated <it>P. falciparum </it>malaria in infants and children in Africa were analysed according to body weight group.</p> <p>Results</p> <p>The trial included 899 patients (intent-to-treat population 886). The modified intent-to-treat (ITT) population (n = 812) comprised 143 children 5 to < 10 kg, 334 children 10 to < 15 kg, 277 children 15 to < 25 kg, and 58 children 25 to < 35 kg. The 28-day PCR cure rate, the primary endpoint, was comparable across all four body weight groups (97.2%, 98.9%, 97.8% and 98.3%, respectively). There were no clinically relevant differences in safety or tolerability between body weight groups. In the three AL body weight dosing groups (5 to < 15 kg, 15 to < 25 kg and 25 to < 35 kg), 80% of patients were aged 10-50 months, 46-100 months and 90-147 months, respectively.</p> <p>Conclusion</p> <p>Efficacy of AL in uncomplicated falciparum malaria is similar across body weight dosing groups as currently recommended in the label with no clinically relevant differences in safety or tolerability. AL dosing based on body weight remains advisable.</p

Dihydroartemisinin-Piperaquine and Artemether-Lumefantrine for Treating Uncomplicated Malaria in African Children: A Randomised, Non-Inferiority Trial

BACKGROUND: Artemisinin combination therapies (ACTs) are currently the preferred option for treating uncomplicated malaria. Dihydroartemisinin-piperaquine (DHA-PQP) is a promising fixed-dose ACT with limited information on its safety and efficacy in African children. METHODOLOGY/PRINCIPAL FINDINGS: The non-inferiority of DHA-PQP versus artemether-lumefantrine (AL) in children 6-59 months old with uncomplicated P. falciparum malaria was tested in five African countries (Burkina Faso, Kenya, Mozambique, Uganda and Zambia). Patients were randomised (2:1) to receive either DHA-PQP or AL. Non-inferiority was assessed using a margin of -5% for the lower limit of the one-sided 97.5% confidence interval on the treatment difference (DHA-PQP vs. AL) of the day 28 polymerase chain reaction (PCR) corrected cure rate. Efficacy analysis was performed in several populations, and two of them are presented here: intention-to-treat (ITT) and enlarged per-protocol (ePP). 1553 children were randomised, 1039 receiving DHA-PQP and 514 AL. The PCR-corrected day 28 cure rate was 90.4% (ITT) and 94.7% (ePP) in the DHA-PQP group, and 90.0% (ITT) and 95.3% (ePP) in the AL group. The lower limits of the one-sided 97.5% CI of the difference between the two treatments were -2.80% and -2.96%, in the ITT and ePP populations, respectively. In the ITT population, the Kaplan-Meier estimate of the proportion of new infections up to Day 42 was 13.55% (95% CI: 11.35%-15.76%) for DHA-PQP vs 24.00% (95% CI: 20.11%-27.88%) for AL (p<0.0001). CONCLUSIONS/SIGNIFICANCE: DHA-PQP is as efficacious as AL in treating uncomplicated malaria in African children from different endemicity settings, and shows a comparable safety profile. The occurrence of new infections within the 42-day follow up was significantly lower in the DHA-PQP group, indicating a longer post-treatment prophylactic effect. TRIAL REGISTRATION: Controlled-trials.com ISRCTN16263443

Safety and efficacy of dihydroartemisinin-piperaquine versus artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Zambian children

<p>Abstract</p> <p>Background</p> <p>Malaria in Zambia remains a public health and developmental challenge, affecting mostly children under five and pregnant women. In 2002, the first-line treatment for uncomplicated malaria was changed to artemether-lumefantrine (AL) that has proved to be highly efficacious against multidrug resistant <it>Plasmodium falciparum</it>.</p> <p>Objective</p> <p>The study objective was to determine whether dihydroartemisinin-piperaquine (DHA/PQP) had similar efficacy, safety and tolerability as AL for the treatment of children with uncomplicated <it>P. falciparum </it>malaria in Ndola, Zambia.</p> <p>Methods</p> <p>Between 2005 and 2006, 304 children (6-59 months old) with uncomplicated <it>P. falciparum </it>were enrolled, randomized to AL (101) or DHA/PQP (203) and followed up for 42 days. Outcome of treatment was defined according to the standard WHO classification, i.e. early treatment failure (ETF), late clinical failure (LCF, late parasitological failure (LPF) and adequate clinical and parasitological response (ACPR). Recurrent infections were genotyped to distinguish between recrudescence and new infection.</p> <p>Results</p> <p>No ETF was observed. At day 28, PCR-uncorrected ACPR was 92% in the DHA/PQP and 74% in the AL arm (OR: 4.05; 95%CI: 1.89-8.74; p < 0.001). Most failure were new infections and PCR-corrected ACPR was similar in the two study arms (OR: 0.69; 95%CI: 0.22-2.26; p = 0.33). Similar results were observed for day 42, i.e. higher PCR-uncorrected ACPR for DHA/PQP, mainly due to the difference observed up to day 28, while the PCR-corrected ACPR was similar: DHA/PQP: 93% (179/192), AL: 93% (84/90), (OR: 0.92; 95%CI: 0.30-2.64; p = 0.85). Except for cough, more frequent in the DHA/PQP arm (p = 0.04), there were no differences between treatment arms in the occurrence of adverse events. Two serious adverse events were probably associated to AL treatment.</p> <p>Conclusion</p> <p>DHA/PQP was as efficacious, safe and well tolerated in treatment of uncomplicated malaria as AL, though in the latter group more new infections during the follow up were observed. DHA/PQP seems a potential candidate to be used as an alternative first-line or rescue treatment in Zambia.</p> <p>Trial Registration</p> <p><a href="http://www.controlled-trials.com/ISRCTN16263443">ISRCTN16263443</a>, at <url>http://www.controlled-trials.com/isrctn</url></p

Early clinical development of artemether-lumefantrine dispersible tablet: palatability of three flavours and bioavailability in healthy subjects

BACKGROUND\ud \ud Efforts to ease administration and enhance acceptability of the oral anti-malarial artemether-lumefantrine (A-L) crushed tablet to infants and children triggered the development of a novel dispersible tablet of A-L. During early development of this new formulation, two studies were performed in healthy subjects, one to evaluate the palatability of three flavours of A-L, and a second one to compare the bioavailability of active principles between the dispersible tablet and the tablet (administered crushed and intact).\ud \ud METHODS\ud \ud Study 1 was performed in 48 healthy schoolchildren in Tanzania. Within 1 day, all subjects tasted a strawberry-, orange- and cherry-flavoured oral A-L suspension for 10 seconds (without swallowing) in a randomized, single-blind, crossover fashion. The palatability of each formulation was rated using a visual analogue scale (VAS). Study 2 was an open, randomized crossover trial in 48 healthy adults given single doses of A-L (80 mg artemether + 480 mg lumefantrine) with food. The objectives were to compare the bioavailability of artemether, dihydroartemisinin (DHA) and lumefantrine between the dispersible tablet and the tablet administered crushed (primary objective) and intact (secondary objective).\ud \ud RESULTS\ud \ud Study 1 showed no statistically significant difference in VAS scores between the three flavours but cherry had the highest score in several ratings (particularly for overall liking). Study 2 demonstrated that the dispersible and crushed tablets delivered bioequivalent artemether, DHA and lumefantrine systemic exposure (area under the curve [AUC]); mean ± SD AUC0-tlast were 208 ± 113 vs 195 ± 93 h.ng/ml for artemether, 206 ± 81 vs 199 ± 84 h.ng/ml for DHA and 262 ± 107 vs 291 ± 106 h x μg/ml for lumefantrine. Bioequivalence was also shown for peak plasma concentrations (Cmax) of DHA and lumefantrine. Compared with the intact tablet, the dispersible tablet resulted in bioequivalent lumefantrine exposure, but AUC and Cmax values of artemether and DHA were 20-35% lower.\ud \ud CONCLUSIONS\ud \ud Considering that cherry was the preferred flavour, and that the novel A-L dispersible tablet demonstrated similar pharmacokinetic performances to the tablet administered crushed, a cherry-flavoured A-L dispersible tablet formulation was selected for further development and testing in a large efficacy and safety study in African children with malaria

Malaria Prevalence among Young Infants in Different Transmission Settings, Africa.

The prevalence and consequences of malaria among infants are not well characterized and may be underestimated. A better understanding of the risk for malaria in early infancy is critical for drug development and informed decision making. In a cross-sectional survey in Guinea, The Gambia, and Benin, countries with different malaria transmission intensities, the overall prevalence of malaria among infants <6 months of age was 11.8% (Guinea, 21.7%; The Gambia, 3.7%; and Benin, 10.2%). Seroprevalence ranged from 5.7% in The Gambia to 41.6% in Guinea. Mean parasite densities in infants were significantly lower than those in children 1-9 years of age in The Gambia (p<0.0001) and Benin (p = 0.0021). Malaria in infants was significantly associated with fever or recent history of fever (p = 0.007) and anemia (p = 0.001). Targeted preventive interventions, adequate drug formulations, and treatment guidelines are needed to address the sizeable prevalence of malaria among young infants in malaria-endemic countries