Browsing by Author "Akano, Kazeem"

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    Clinical Illness and Outcomes in Nigerian Children with Persistent Early-appearing Anaemia following Initiation of Artemisinin-Based Combination Treatments of Uncomplicated Falciparum Malaria
    (EDP Sciences, 2019-09-13) Akano, Kazeem
    – In non-anaemic children with malaria, early-appearing anaemia (EAA) is common following artemisininbased combination treatments (ACTs) and it may become persistent (PEAA). The factors contributing to and kinetics of resolution of the deficit in haematocrit from baseline (DIHFB) characteristic of ACTs-related PEAA were evaluated in 540 consecutive children with malaria treated with artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine. Asymptomatic PEAA occurred in 62 children. In a multiple logistic regression model, a duration of illness 3 days before presentation, haematocrit <35% before and <25% one day after treatment initiation, drug attributable fall in haematocrit 6%, and treatment with dihydroartemisinin-piperaquine independently predicted PEAA. Overall, mean DIHFB was 5.7% (95% CI 4.8–6.6) 7 days after treatment initiation and was similar for all treatments. Time to 90% reduction in DIHFB was significantly longer in artemether-lumefantrine-treated children compared with other treatments. In a one compartment model, declines in DIHFB were monoexponential with overall mean estimated half-time of 3.9 days (95% CI 2.6–5.1), Cmax of 7.6% (95% CI 6.7–8.4), and Vd of 0.17 L/kg (95% CI 0.04–0.95). In Bland-Altman analyses, overall mean anaemia recovery time (AnRT) of 17.4 days (95% CI 15.5–19.4) showed insignificant bias with 4, 5 or 6 multiples of half-time of DIHFB. Ten children after recovery from PEAA progressed to late-appearing anaemia (LAA). Progression was associated with female gender and artesunateamodiaquine treatment. Asymptomatic PEAA is common following ACTs. PEAA or its progression to LAA may have implications for case and community management of anaemia and for anaemia control efforts in sub-Saharan Africa where ACTs have become first-line antimalarials.
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    Declining Responsiveness of Childhood Plasmodium Falciparum Infections To Artemisinin-Based Combination Treatments Ten Years following Deployment as First-Line Antimalarials in Nigeria
    (BMC: Infectious Diseases of Poverty, 2019-08-06) Akano, Kazeem
    The development and spread of artemisinin-resistant Plasmodium falciparum malaria in Greater Mekong Subregion has created impetus for continuing global monitoring of efficacy of artemisinin-based combination therapies (ACTs). This post analyses is aimed to evaluate changes in early treatment response markers 10 years after the adoption of ACTs as first-line treatments of uncomplicated falciparum malaria in Nigeria. Methods: At 14 sentinel sites in six geographical areas of Nigeria, we evaluated treatment responses in 1341 children under 5 years and in additional 360 children under 16 years with uncomplicated malaria enrolled in randomized trials of artemether-lumefantrine versus artesunate-amodiaquine at 5-year interval in 2009–2010 and 2014–2015 and at 2-year interval in 2009–2010 and 2012–2015, respectively after deployment in 2005. Asexual parasite positivity 1 day after treatment initiation (APPD1) rose from 54 to 62% and 2 days after treatment initiation from 5 to 26% in 2009–2010 to 2014–2015 (P = 0.002 and P < 0.0001, respectively). Parasite clearance time increased significantly from 1.6 days (95% confidence interval [CI]: 1.55–1.64) to 1.9 days (95% CI, 1.9–2.0) and geometric mean parasite reduction ratio 2 days after treatment initiation decreased significantly from 11 000 to 4700 within the same time period (P < 0.0001 for each). Enrolment parasitaemia > 75 000 μl − 1 , haematocrit > 27% 1 day post-treatment initiation, treatment with artemether-lumefantrine and enrolment in 2014–2015 independently predicted APPD1. In parallel, KaplanMeier estimated risk of recurrent infections by day 28 rose from 8 to 14% (P = 0.005) and from 9 to 15% (P = 0.02) with artemether-lumefantrine and artesunate-amodiaquine, respectively. Mean asexual parasitaemia half-life increased significantly from 1.1 h to 1.3 h within 2 years (P < 0.0001). Conclusions: These data indicate declining parasitological responses through time to the two ACTs may be due to emergence of parasites with reduced susceptibility or decrease in immunity to the infections in these children.
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    Genetic Diversity and Population Structure of Plasmodium Falciparum in Nigeria: insights from Microsatellite Loci Analysis
    (BMC: Malaria Journal, 2021-05-26) Akano, Kazeem
    Malaria remains a public health burden especially in Nigeria. To develop new malaria control and elimination strategies or refne existing ones, understanding parasite population diversity and transmission patterns is crucial. Methods: In this study, characterization of the parasite diversity and structure of Plasmodium falciparum isolates from 633 dried blood spot samples in Nigeria was carried out using 12 microsatellite loci of P. falciparum. These microsatellite loci were amplifed via semi-nested polymerase chain reaction (PCR) and fragments were analysed using population genetic tools. Estimates of parasite genetic diversity, such as mean number of diferent alleles (13.52), efective alleles (7.13), allelic richness (11.15) and expected heterozygosity (0.804), were high. Overall linkage disequilibrium was weak The high level of parasite genetic diversity and low population structuring in this study suggests that parasite populations circulating in Nigeria are homogenous. However, higher resolution methods, such as the 24 SNP barcode and whole genome sequencing, may capture more specifc parasite genetic signatures circulating in the country. The results obtained can be used as a baseline for parasite genetic diversity and structure, aiding in the formulation of appropriate therapeutic and control strategies in Nigeria.
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    A One-compartment Constant Rate Intravascular Infusion Model for the Evaluation of Increases in Hematocrit after Artemisinin-based Combination Treatments of Acute Falciparum Malaria in Children
    (Biomed Research International, USA, 2015) Akano, Kazeem
    Increases in hematocrit frequently follow successful treatment of uncomplicated Plasmodium falciparum infections in children, but there is no pharmacokinetic model for the analyses of the increases in hematocrit following artemisininbased combination treatments (ACTs) in malarious children. A one-compartment constant rate intravascular infusion model (CRIVIM), which employed the principles of constant rate intravenous infusion of drugs (CRIVID), was used to evaluate the kinetics of the increases in hematocrit after artesunate-amodiaquine (AA) or artemether-lumefantrine (AL) treatments in 112 malarious children. The model assumed baseline hematocrit was zero, a constant rate increase in hematocrit from baseline following treatment, and it involved semi-logarithm plots of the difference between hematocrit at plateau and that at earlier times, against the corresponding times. Hematocrit reached a plateau in a median time of 28 days after treatment started. Mean plateau hematocrit was 6.7% (95%CI 5.9.-7.5) and was similar in AA- and AL- treated children [6.8% (95%CI 6-7.7), n = 81 v 6.3% (95%CI 4.9-7.7), n = 31, P = 0.56]. Times to plateau were significantly shorter and plateau hematocrit significantly lower in non-anemic compared to anemic children. Overall, declines from semi-logarithm plots were monoexponential with mean half-time of hematocrit of 2.5 days (95%CI 2.2-2.8). Half-times were similar in AA and AL-treated children [2.4 days (95%CI 2.1-2.8) v 2.7 days (95%CI 2-3.3), P = 0.46], and were significantly shorter in anemic compared to non-anemic children [2.1 days (95%CI 1.8-2.4, n = 57) v 2.9 days (95%CI 2.4-3.5, n = 55), P = 0.01). Mean anemia recovery time was 13.8 days (95%CI 11.9 – 15.7). Bland-Altman analysis of 7 or 8 multiples of anaemia half-time and anaemia recovery times showed narrow limit of agreement with insignificant biases (P = 0.17 or 0.68, respectively). Steady state parameters were independent of baseline parasitemias. The one-compartment CRIVIM permits evaluation of increases in hematocrit following ACTs and may be used in observational and clinical studies in uncomplicated falciparum malaria.
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    Polymorphisms in Plasmodium Falciparum Dihydropteroate Synthetase and Dihydrofolate Reductase Genes in Nigerian Children with Uncomplicated Malaria using High‑Resolution Melting Technique
    (Scientifc Reports, 2021-01-12) Akano, Kazeem
    In 2005, the Nigerian Federal Ministry of Health revised the treatment policy for uncomplicated malaria with the introduction of artemisinin-based combination therapies (ACTs). This policy change discouraged the use of Sulphadoxine-pyrimethamine (SP) as the second-line treatment of uncomplicated falciparum malaria. However, SP is used as an intermittent preventive treatment of malaria in pregnancy (IPTp) and seasonal malaria chemoprevention (SMC) in children aged 3–59 months. There have been increasing reports of SP resistance especially in the non-pregnant population in Nigeria, thus, the need to continually monitor the efcacy of SP as IPTp and SMC by estimating polymorphisms in dihydropteroate synthetase (dhps) and dihydrofolate reductase (dhfr) genes associated with SP resistance. The high resolution-melting (HRM) assay was used to investigate polymorphisms in codons 51, 59, 108 and 164 of the dhfr gene and codons 437, 540, 581 and 613 of the dhps gene. DNA was extracted from 271 dried bloodspot flter paper samples obtained from children (<5 years old) with uncomplicated malaria. The dhfr triple mutant I51R59N108, dhps double mutant G437G581 and quadruple dhfr I51R59N108 +dhpsG437 mutant haplotypes were observed in 80.8%, 13.7% and 52.8% parasites, respectively. Although the quintuple dhfr I51R59N108 +dhpsG437E540 and sextuple dhfr I51R59N108 +dhpsG437E540G581 mutant haplotypes linked with in-vivo and in-vitro SP resistance were not detected, constant surveillance of these haplotypes should be done in the country to detect any change in prevalence.
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    Polymorphisms in Plasmodium Falciparum Chloroquine Resistance Transporter (Pfcrt) and Multidrug-Resistant Gene 1 (Pfmdr-1) in Nigerian children 10 years Post-Adoption Of Artemisinin-Based Combination Treatments
    (Elsevier: International Journal for Parasitology, 2020-12-24) Akano, Kazeem
    The emergence and spread of Plasmodium falciparum parasites resistant to artemisinin derivatives and their partners in southeastern Asia threatens malaria control and elimination efforts, and heightens the need for an alternative therapy. We have explored the distribution of P. falciparum chloroquine resistance transporter (Pfcrt) and multidrug-resistant gene 1 (Pfmdr-1) haplotypes 10 years following adoption of artemisinin-based combination therapies in a bid to investigate the possible re-emergence of Chloroquine-sensitive parasites in Nigeria, and investigated the effect of these P. falciparum haplotypes on treatment outcomes of patients treated with artemisinin-based combination therapies. A total of 271 children aged <5 years with uncomplicated falciparum malaria were included in this study. Polymorphisms on codons 72–76 of the Pfcrt gene and codon 86 and 184 of Pfmdr-1 were determined using the high resolution melting assay. Of 240 (88.6%) samples successfully genotyped with HRM for Pfcrt, wildtype C72M74N75K76 (42.9%) and mutant C72I74E75T76 (53.8%) were observed. Also, wildtype N86Y184 (62.9%) and mutant N86F184 (21.1%), Y86Y184 (6.4%), and Y86F184 (0.4%) haplotypes of Pfmdr-1 were observed. Measures of responsiveness to ACTs were similar in children infected with P. falciparum crt haplotypes (C72I74E75T76 and C72M74N75K76) and major mdr-1 haplotypes (N86Y184, N86F184 and Y86Y184). Despite a 10 year gap since the malaria treatment policy changed to ACTs, over 50% of the P. falciparum parasites investigated in this study harboured the Chloroquine-resistant C72I74E75T76 haplotype, however this did not compromise the efficacy of artemisinin-based combination therapies. Should complete artemisinin resistance emerge from or spread to Nigeria, chloroquine might not be a good alternative therapy
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    Tempora Changes in Haematocrit following Artemisinin-Based Combination Treatments of Uncomplicated Falciparum Malaria in Children
    (Springer Nature, 2015-10-26) Akano, Kazeem
    Artemisinin-based combination treatments (ACTs) or intravenous artesunate are used in over 100 countries for uncomplicated or severe falciparum malaria. Although intravenous artesunate may cause delayed haemolytic anaemia, there is little evaluation of the temporal changes in haematocrit following ACTs. Methods: Clinical and parasitological parameters were measured before and following treatment of uncomplicated falciparum malaria in children with artesunate-amodiaquine (AA) or artemether-lumefantrine (AL) over 6-weeks. Changes in haematocrit were characterized in individual patients based on a haematocrit <30 % or ≥30 % before and following treatment. Kinetics of the deficit in haematocrit from <30 % until attainment of ≥30 % were estimated by a non-compartment model. Results: In 248 of 1180 children eligible for evaluation, common temporal patterns were: no change or increase in haematocrit from ≥ 30 % [50 % of patients], haematocrit >30 % at presentation declining to <30 % within 2 weeks (early monophasic fall) [19 % of patients], and haematocrit <30 % at presentation increasing to ≥ 30 % [23 % of patients]. Haematocrit >30 % at presentation declining to <30 %, 3–5 weeks later (late monophasic fall) occurred in 7 children (3 %). Fall in haematocrit ≥5 units following treatment occurred in 57 children [23 %] between 14 and 28 days after treatment began. Baseline parasitaemia and proportion with > 100,000μL-1 asexual forms were significantly higher in children with ≥5 units compared to <5 units fall in haematocrit 21 or 28 days after treatment began. Irrespective of pattern, declines in haematocrit deficit from <30 % were mono-exponential, with similar half-times for AA- and AL-treated children (1.32 d versus 1.14 d). Anaemia halftime correlated significantly positively with anaemia recovery time in the same patients (r = 0.55, P < 0.0001). Bland-Altman analysis of 9 or 10 multiples of anaemia half-time and anaemia recovery times showed narrow limit of agreement with insignificant biases (P = 0.19 or 0.63, respectively). Conclusions: In uncomplicated falciparum malaria, increases or falls in haematocrit are common following ACTs. Falls in haematocrit ≥ 5 units are common and may or may not result in early or late anaemia. In children who recovered from acute falciparum malaria-associated anaemia following ACTs, decline in haematocrit deficit is mono-exponential.