Early Changes in Plasmodium falciparum Asexual and Sexual Populations in Children with Acute Infections Following Treatment with Artemisinin-Based Combination Drugs

Artemisinin-based combination therapies (ACTs) may influence malaria transmission but the early changes in parasite populations have not been frequently evaluated. The changes in Plasmodium falciparum asexual and sexual populations in the first 16 h following treatment with artemether-lumefantrine (AL) or artesunate-amodiaquine (AA) were evaluated in 443 children with acute infections. The effects of gametocyte density on gametocyte sex ratio (GSR) were characterized in another cohort of 52 children treated with AL and AA. Stages of asexual and sexual parasites in peripheral blood were determined morphologically. In 167 children there were significant increases in peripheral asexual parasitemia at 1 h, and in 15 of these, an insignificant increase in gametocytemia at 1 h, followed thereafter by a precipitous and significant fall in all patients. Time-course of GSR showed a female-male-female-biased cycle at 0 h, 4 h, and 8 h. Pre-treatment GSR and time-course of GSR post-treatment were independent of density in the additional cohort of 52 gametocyte carriers treated with AL or AA. Population changes were similar in AL- and AAtreated children. Treatment with AL or AA is associated with early increases in asexual and sexual parasites and is closely followed by rapid elimination of these parasites

A Simple Dose Regimen of Artesunate and Amodiaquine Based on Age or Body Weight Range for Uncomplicated Falciparum Malaria in Children: Comparison of Therapeutic Efficacy With Standard Dose Regimen of Artesunate and Amodiaquine and Artemether–Lumefantrine

A new dose regimen of artesunate and amodiaquine (NDRAA) based on age or body weight range was compared with standard dose regimen of artesunate and amodiaquine (SDRAA) calculated according to body weight and with fixed-dose artesunate–amodiaquine (FDAA) and artemether–lumefantrine (AL) in 304 children afflicted by malaria aged 15 years or younger. In initial comparison (n = 208), children on NDRAA received 1–3 times amodiaquine per kilogram of body weight and 1–1.5 times of artesunate per kilogram of body weight compared with those receiving SDRAA. Parasite but not fever clearance was significantly faster in children who received NDRAA (19.4 ± 8.4 hours vs. 24.6 ± 15.5 hours, P = 0.003). Polymerase chain reaction–uncorrected cure rates on days 28–42 were also significantly higher in children who received NDRAA (P < 0.02 in all cases). Therapeutic responses in children younger than 5 years (n = 96) treated with NDRAA, FDAA, and AL were similar. Changes in hematocrit values and reported adverse events after commencing therapy were similar in those who received NDRAA and SDRAA. All drug regimens were well tolerated. NDRAA based on age or body weight range is simple, is therapeutically superior to SDRAA calculated according to body weight, and is as efficacious as AL in children younger than 5 years

Fall in Hematocrit per 1000 Parasites Cleared From Peripheral Blood: A Simple Method for Estimating Drug-Related Fall in Hematocrit After Treatment of Malaria Infections

A simple method to estimate antimalarial drug-related fall in hematocrit (FIH) after treatment of Plasmodium falciparum infections in the field is described. The method involves numeric estimation of the relative difference in hematocrit at baseline (pretreatment) and the first 1 or 2 days after treatment begun as numerator and the corresponding relative difference in parasitemia as the denominator, and expressing it per 1000 parasites cleared from peripheral blood. Using the method showed that FIH/1000 parasites cleared from peripheral blood (cpb) at 24 or 48 hours were similar in artemether–lumefantrine and artesunate– amodiaquine-treated children (0.09; 95% confidence interval, 0.052–0.138 vs 0.10; 95% confidence interval, 0.069–0.139%; P = 0.75) FIH/1000 parasites cpb in patients with higher parasitemias were significantly (P < 0.0001) and five- to 10-fold lower than in patients with lower parasitemias suggesting conservation of hematocrit or red cells in patients with higher parasitemias treated with artesunate–amodiaquine or artemether–lumefantrine. FIH/1000 parasites cpb were similar in anemic and nonanemic children. Estimation of FIH/1000 parasites cpb is simple, allows estimation of relatively conserved hematocrit during treatment, and can be used in both observational studies and clinical trials involving antimalarial drugs

Plasmodium falciparum gametocyte carriage, emergence, clearance and population sex ratios in anaemic and non-anaemic malarious children

Anaemia in falciparum malaria is associated with an increased risk of gametocyte carriage, but its effects on transmission have not been extensively evaluated in malarious children. Plasmodium falciparum gametocyte carriage, emergence, clearance, population sex ratios (SR) (defined as the proportion of gametocytes that are male), inbreeding rates and temporal changes in SR were evaluated in 840 malarious children. Gametocyte carriage pre-treatment was at a level of 8.1%. Anaemia at enrolment was an independent risk factor for gametocyte carriage post-treatment. The emergence of gametocytes seven days post-treatment was significantly more frequent in anaemic children (7/106 vs. 10/696, p = 0.002). In the initially detected gametocytes, the proportion of children with a male-biased SR (MBSR) (> 0.5) was significantly higher in anaemic children (6/7 vs. 3/10, p = 0.027). Pre-treatment SR and estimated inbreeding rates (proportion of a mother’s daughters fertilised by her sons) were similar in anaemic and non-anaemic children. Pre-treatment SR became more female-biased in non-anaemic children following treatment. However, in anaemic children, SR became male-biased. Anaemia was shown to significantly increase gametocyte emergence and may significantly alter the SR of emerging gametocytes. If MBSR is more infective to mosquitoes at low gametocytaemia, then these findings may have significant implications for malaria control efforts in endemic settings where malaria-associated anaemia is common

Plasmodium falciparum hyperparasitaemia in Nigerian children: epidemiology, clinical characteristics, and therapeutic responses to oral artemisinin-based combination treatments

To evaluate the epidemiology, clinical characteristics and response to oral artemisininbased combination treatments (ACTs) of children with Plasmodium falciparum hyperparasitaemia (PfHP). Methods All children with febrile or history of febrile illness who were suspected to be malaria were evaluated for the presence of PfHP and their parasitological and clinical characteristics at presentation and follow-up for four weeks were recorded during a 3-year period. Patients were treated with oral artemisinin-baesd combination drugs

Therapeutic Efficacy and Effects of Artemether-Lumefantrine and Artesunate-Amodiaquine Coformulated or Copackaged on Malaria-Associated Anemia in Children with Uncomplicated Plasmodium falciparum Malaria in Southwest Nigeria

The therapeutic efficacy and effects of artemether-lumefantrine (AL) and artesunate-amodiaquine coformulated (AAcf) or co-packaged (AAcp) on malaria-associated anemia (MAA) were evaluated in 285 children < 12 years of age with uncomplicated Plasmodium falciparum malaria randomized to receive one of the three drug combinations. Fever and parasite clearance times were similar in all treatment groups. Mean drug-attributable fall in hematocrit (DAFH), defined as difference between hematocrit values pre- and 3 d post- initiation of treatment, was low (< 4.5%) and rates of recovery from MAA were similar with all treatments. Mean areas under curve (AUCs) of the plot of deficit in hematocrit levels from 30% versus time in anemic children were similar in all groups. All regimens were well tolerated. AL, AAcf and AAcp cleared fever and parasitemia rapidly and had similar rates of resolution of MAA after treatment in malarious Nigerian children. * Address corresp

Recrudescent Plasmodium falciparum infections in children in an endemic area following artemisinin–based combination treatments: Implications for disease control

To evaluate the features and risk factors associated with recrudescent infections that arose following artemisinin-based combination drug treatment of the primary infections. Methods The clinical features and risk factors associated with subsequent recrudescence of primary Plasmodium falciparum infections were evaluated in 37 of 877 children following artesunate or artemisinin-based combination treatments (ACTs). Recrudescence was determined by polymerase chain reaction

Early variations in plasmodium falciparum dynamics in Nigerian children after treatment with two artemisinin-based combinations: implications on delayed parasite clearance

<p>Abstract</p> <p>Background</p> <p>Combination treatments, preferably containing an artemisinin derivative, are recommended to improve efficacy and prevent <it>Plasmodium falciparum </it>drug resistance. Artemether-lumefantrine (AL) and artesunate-amodiaquine (AA) are efficacious regimens that have been widely adopted in sub-Saharan Africa. However, most study designs ignore the effects of these regimens on peripheral parasitaemia in the first 24 hours of therapy. The study protocol was designed to evaluate more closely the early effects and the standard measures of efficacies of these two regimens.</p> <p>Methods</p> <p>In an open label, randomized controlled clinical trial, children aged 12 months to 132 months were randomized to receive AL (5-14 kg, one tablet; 15-24 kg, two tablets and 25-34 kg, three tablets twice daily) or artesunate (4 mg/kg daily) plus amodiaquine (10 mg/kg daily) for three days. Peripheral blood smears were made hourly in the first 4 hours, 8 h, 16 h, 24 h, and daily on days 2-7, and on days 7, 14, 21, 28, 35, and 42 for microscopic identification and quantification of <it>Plasmodium falciparum</it>.</p> <p>Results</p> <p>A total of 193 children were randomized to receive either AL (97) or AA (96). In children that received both medications, early response of peripheral parasitaemia showed that 42% of children who received AL and 36.7% of those who received AA had an immediate rise in peripheral parasitaemia (0-4 h after treatment) followed by a rapid fall. The rise in parasitaemia was significant and seems to suggest a mobilization of asexual parasites from the deep tissues to the periphery. Days 3, 7, 14, 28, and 42 cure rates in the per protocol (PP) population were > 90% in both groups of children. Both drug combinations were well tolerated with minimal side effects.</p> <p>Conclusion</p> <p>The study showed the high efficacy of AL and AA in Nigerian children. In addition the study demonstrated the mobilisation of asexual parasites from the deep to the periphery in the early hours of commencing ACT treatment in a subset of patients in both study groups. It is unclear whether the early parasite dynamics discovered in this study play any role in the development of drug resistance and thus it is important to further evaluate this discovery. It may be useful for studies investigating delay in parasite clearance of artemisinin derivatives as a way of monitoring the development of resistance to artemisinin to assess the early effects of the drugs on the parasites.</p

Therapeutic Efficacy and Effects of Artesunate-Mefloquine and Mefloquine Alone on Malaria-Associated Anemia in Children with Uncomplicated Plasmodium falciparum Malaria in Southwest Nigeria

The treatment efficacy and effects of artesunate-mefloquine (AMQ) and mefloquine (MQ) on malariaassociated anemia (MAA) were evaluated in 342 children ≤ 10 years of age with uncomplicated Plasmodium falciparum malaria randomized to receive either drug/drug combination. All children recovered clinically. Fever clearance times were similar. Parasite clearance was significantly faster with AMQ (mean ± SD = 1.4 ± 0.6 days, 95% confidence interval [CI] = 1.3–1.5, P < 0.0001), but polymerase chain reaction–corrected cure rates were similar (97% versus 94%). Gametocyte carriage rates and the drug-attributable fall in hematocrit were significantly lower with AMQ (mean ± SD = 4.8 ± 3.8%, 95% CI = 3.6–6.0, P = 0.03), but the rates of resolution of MAA were similar. Both regimens were well tolerated. AMQ clears parasitemia and reduces gametocyte carriage more rapidly and causes lesser fall in hematocrit than MQ, but both regimens are effective treatment of uncomplicated P. falciparum malaria in Nigerian children

Use of area under the curve to evaluate the effects of antimalarial drugs on malaria associated anemia after treatment

To evaluate the effects of antimalarial drugs on Plasmodium falciparum malaria associated anemia (MAA), we use the area under curve (AUC) of anemia levels after treatment as an approach to combine their duration and magnitude. The method involves numerical estimation, by trapezoidal rule, of AUC from a plot of deficit in hematocrit levels from 30% (the lower threshold of normal) versus time in anemic children. Using the method, we evaluated, in randomized trials, the effects of artesunate-mefloquine (AMQ) versus mefloquine alone (MQ), and artemether-lumefantrine (AL) versus amodiaquine-artesunate (AA) on the time-course of recovery from MAA in 109 children. Anemia resolution times were similar (10.9 ± 6.2 [SD] vs 13.3 ± 8.9 d, P = 0.2) but mean AUC was significantly lower in AMQ- compared to MQ- treated children (35.5 ± 7.1 [SEM] vs 49.8 ± 11.3 %.h, P = 0.02) indicating larger exposure to anemia in MQ-treated children. In ALand AA- treated children, both anemia resolution times (8.6 ± 5.3 [SD] vs 8.6 ± 4.8 d, P = 0.98) and mean AUC (57.1 ± 12.9 [SEM] vs 46.3 ± 8.7 %.h, P = 0.74) were similar. Estimation of AUC appears more robust than estimation of anemia resolution time in evaluating antimalarial drug effects and can be used in both observational studies and clinical trials assessing the effects of therapies on MAA