Artesunate-amodiaquine Research Articles

Efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in mainland Tanzania, 2018

BackgroundThe use of artemisinin-based combination therapy (ACT) is recommended by the World Health Organization for the treatment of uncomplicated falciparum malaria. Artemether-lumefantrine (AL) is the most widely adopted first-line ACT for uncomplicated malaria in sub-Saharan Africa (SSA), including mainland Tanzania, where it was introduced in December 2006. The WHO recommends regular assessment to monitor the efficacy of the first-line treatment specifically considering that artemisinin partial resistance was reported in Greater Mekong sub-region and has been confirmed in East Africa (Rwanda and Uganda). The main aim of this study was to assess the efficacy and safety of AL for the treatment of uncomplicated falciparum malaria in mainland Tanzania.MethodsA single-arm prospective anti-malarial drug efficacy trial was conducted in Kibaha, Mlimba, Mkuzi, and Ujiji (in Pwani, Morogoro, Tanga, and Kigoma regions, respectively) in 2018. The sample size of 88 patients per site was determined based on WHO 2009 standard protocol. Participants were febrile patients (documented axillary temperature ≥ 37.5 °C and/or history of fever during the past 24 h) aged 6 months to 10 years. Patients received a 6-dose AL regimen by weight twice a day for 3 days. Clinical and parasitological parameters were monitored during 28 days of follow-up to evaluate the drug efficacy and safety.ResultsA total of 653 children were screened for uncomplicated malaria and 349 (53.7%) were enrolled between April and August 2018. Of the enrolled children, 345 (98.9%) completed the 28 days of follow-up or attained the treatment outcomes. There were no early treatment failures, but recurrent infections were higher in Mkuzi (35.2%) and Ujiji (23%). By Kaplan–Meier analysis of polymerase chain reaction (PCR) uncorrected adequate clinical and parasitological response (ACPR) ranged from 63.4% in Mkuzi to 85.9% in Mlimba, while PCR-corrected ACPR on day 28 varied from 97.6% in Ujiji to 100% in Mlimba. The drug was well tolerated; the commonly reported adverse events were cough, runny nose, and abdominal pain. No serious adverse event was reported.ConclusionThis study showed that AL had adequate efficacy and safety for the treatment of uncomplicated falciparum malaria. The high number of recurrent infections were mainly due to new infections, indicating the necessity of utilizing alternative artemisinin-based combinations, such as artesunate amodiaquine, which provide a significantly longer post-treatment prophylactic effect.

Copayment mechanism in selected districts of Uganda: Availability, market share and price of quality assured artemisinin-based combination therapies in private drug outlets.

Malaria remains one of the leading causes of morbidity, and mortality in Uganda. A large proportion of malaria symptomatic patients seek healthcare in private sector. However, availability and affordability are major barriers to access to effective treatment. The private sector copayment mechanism in Uganda aims to increase availability and affordability of antimalarial agents. Our study assessed availability, price, and market share of quality assured artemisinin-based combination therapies (QAACTs) in private drug outlets in selected districts during the implementation of copayment mechanism. This was a cross-sectional survey of anti-malarial agents in private drug outlets in in selected moderate-to-high (Tororo, and Apac districts) and low (Kabale and Mbarara districts) malaria transmission settings. Following the World Health Organization/Health Action International (WHO/HAI) criteria, an audit of the antimalarial agents was done using a checklist to determine availability, price, and market share of QAACTs. Data were entered in Epi-data and analyzed in STATA ver 14.0 at 95% confidence level. A total of twenty-eight (28) private drug outlets (pharmacies and drug shops) were included in the survey. One in seven (20/144: 95%CI: 9.1, 20.6) of the antimalarial agents in private drug outlets were quality assured artemisinin-based combination therapies (QAACT). Artemether-lumefantrine (AL), 8.9% (11/124) and Artesunate-Amodiaquine (AQ), 7.3% (9/124) were the only QAACTs present in the drug outlets at the time of the survey. The majority, 86.1%% (124/144) of antimalarial agents present in stock in the drug outlets were artemisinin based. The most common, 38.9% (56/144) ACT in the drug outlets was Dihydroartemisinin-Piperaquine (DHP). Most, 69.4% (100/144) of the antimalarial agents were in high malaria transmission settings. The cost of ACT antimalarial agents is high in the country, USD 1.4 (Artemether-Lumefantrine, AL), USD 2.4 (Dihydroartemisinin-Piperaquine, DP), the first line and second-line agents respectively for treatment of uncomplicated malaria in Uganda. There was a statistically significant difference between the dispensing price of 'Green leaf' ACTs (QAACT) and the recommended price (p<0.001). Predictors of availability of QAACT in private drug outlets include pharmacy drug outlet (aPR:0.4; 95%CI: 0.2, 0.9) and dispensing price more than 3000UGX (USD 0.83) (aPR: 0.4, 95%CI: 0.1, 0.51). Quality assured artemisinin-based combination therapies (QAACTs) are not common in private drug outlets in selected districts in Uganda. All the drug outlets had at least one ACT antimalarial agent present on the day of the survey. The dispensing price of QAACTs was significantly higher than the recommended markup price. There is need for awareness creation, surveillance, and monitoring of the implementation of Copayment mechanism in the country.

Variation in neutrophil levels and artemisinin-based combination therapy efficacy in West-Africa.

Polymorphonuclear neutrophils (PMN) are involved in pathogen clearance by phagocytosis. However, the role of PMNs in the efficacy of artemisinin-based combination therapy (ACT) is poorly understood. In a prospective longitudinal in vivo study, neutrophil rates were compared with malaria carriage after treatment with different ACTs: Artemether - lumefantrine (AL), Artesunate - amodiaquine (ASAQ), Dihydroartemisinin - piperaquine (DP) or Pyronaridine artesunate (PA). The study cases were classified as having neutropenia, normal neutrophil levels or neutrophilia depending on the level of neutrophils in the blood. This study included 3148 patients and was analyzed using R. On day 7, only four patients in the neutropenia group and treated with AL had a malaria positive blood smear based on microscopy. On day 28, the rate of recurrent parasitemia in the AL arm was significantly higher in neutropenia patients (50.9%) than in patients with normal rates of neutrophils (43.1%) or in those with neutrophilia (6.0%) (p < 0.001). In ASAQ arm, the rate of recurrent Plasmodium falciparum parasitemia was 58.8% in the neutropenia group versus 29.4% in patients with normal rates of neutrophils and 11.8% in patients with neutrophilia (p < 0.001). No patient treated with DP with normal neutrophil counts or neutrophilia was carrying malaria parasites on day 28. Among the 15 patients with parasitemia on day 28 in the PA arm, 11 (73.33%) had neutropenia while 4 (26.67%) had a normal neutrophil count (p < 0.001). Patients with neutropenia had higher rates of recurrent P. falciparum parasitemia after ACT.

Increasing Prevalence of Artemisinin-Resistant HRP2-Negative Malaria in Eritrea

BackgroundAlthough the clinical efficacy of antimalarial artemisinin-based combination therapies in Africa remains high, the recent emergence of partial resistance to artemisinin in Plasmodium falciparum on the continent is troubling, given the lack of alternative treatments.MethodsIn this study, we used data from drug-efficacy studies conducted between 2016 and 2019 that evaluated 3-day courses of artemisinin-based combination therapy (artesunate–amodiaquine or artemether–lumefantrine) for uncomplicated malaria in Eritrea to estimate the percentage of patients with day-3 positivity (i.e., persistent P. falciparum parasitemia 3 days after the initiation of therapy). We also assayed parasites for mutations in Pfkelch13 as predictive markers of partial resistance to artemisinin and screened for deletions in hrp2 and hrp3 that result in variable performance of histidine rich protein 2 (HRP2)–based rapid diagnostic tests for malaria.ResultsWe noted an increase in the percentage of patients with day-3 positivity from 0.4% (1 of 273) in 2016 to 1.9% (4 of 209) in 2017 and 4.2% (15 of 359) in 2019. An increase was also noted in the prevalence of the Pfkelch13 R622I mutation, which was detected in 109 of 818 isolates before treatment, from 8.6% (24 of 278) in 2016 to 21.0% (69 of 329) in 2019. The odds of day-3 positivity increased by a factor of 6.2 (95% confidence interval, 2.5 to 15.5) among the patients with Pfkelch13 622I variant parasites. Partial resistance to artemisinin, as defined by the World Health Organization, was observed in Eritrea. More than 5% of the patients younger than 15 years of age with day-3 positivity also had parasites that carried Pfkelch13 R622I. In vitro, the R622I mutation conferred a low level of resistance to artemisinin when edited into NF54 and Dd2 parasite lines. Deletions in both hrp2 and hrp3 were identified in 16.9% of the parasites that carried the Pfkelch13 R622I mutation, which made them potentially undetectable by HRP2-based rapid diagnostic tests.ConclusionsThe emergence and spread of P. falciparum lineages with both Pfkelch13-mediated partial resistance to artemisinin and deletions in hrp2 and hrp3 in Eritrea threaten to compromise regional malaria control and elimination campaigns. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry numbers, ACTRN12618001223224, ACTRN12618000353291, and ACTRN12619000859189.)

Therapeutic efficacy of artesunate–amodiaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Chad: clinical and genetic surveillance

BackgroundArtesunate–amodiaquine (AS–AQ) and artemether–lumefantrine (AL) are the currently recommended first-and second-line therapies for uncomplicated Plasmodium falciparum infections in Chad. This study assessed the efficacy of these artemisinin-based combinations, proportion of day 3 positive patients, proportions of molecular markers associated with P. falciparum resistance to anti-malarial drugs and variable performance of HRP2-based malaria rapid diagnostic tests (RDTs).MethodsA single-arm prospective study assessing the efficacy of AS–AQ and AL at three sites (Doba, Kelo and Koyom) was conducted between November 2020 to January 2021. Febrile children aged 6 to 59 months with confirmed uncomplicated P. falciparum infection were enrolled sequentially first to AS–AQ and then AL at each site and followed up for 28 days. The primary endpoint was PCR-adjusted adequate clinical and parasitological response (ACPR). Samples collected on day 0 were analysed for mutations in pfkelch13, pfcrt, pfmdr-1, pfdhfr, pfdhps genes and deletions in pfhrp2/pfhrp3 genes.ResultsBy the end of 28-day follow-up, per-protocol PCR corrected ACPR of 97.8% (CI 95% 88.2–100) in Kelo and 100% in Doba and Kayoma were observed among AL treated patients. For ASAQ, 100% ACPR was found in all sites. All, but one patient, did not have parasites detected on day 3. Out of the 215 day 0 samples, 96.7% showed pfkelch13 wild type allele. Seven isolates carried nonsynonymous mutations not known to be associated artemisinin partial resistance (ART-R). Most of samples had a pfcrt wild type allele (79% to 89%). The most prevalent pfmdr-1 allele detected was the single mutant 184F (51.2%). For pfdhfr and pfdhps mutations, the quintuple mutant allele N51I/C59R/S108N + G437A/540E responsible for SP treatment failures in adults and children was not detected. Single deletion in the pfhrp2 and pfhrp3 gene were detected in 10/215 (4.7%) and 2/215 (0.9%), respectively. Dual pfhrp2/pfhrp3 deletions, potentially threatening the efficacy of HRP2-based RDTs, were observed in 5/215 (2.3%) isolates.ConclusionThe results of this study confirm that AS–AQ and AL treatments are highly efficacious in study areas in Chad. The absence of known pfkelch13 mutations in the study sites and the high parasite clearance rate at day 3 suggest the absence of ART-R. The absence of pfdhfr/pfdhps quintuple or sextuple (quintuple + 581G) mutant supports the continued use of SP for IPTp during pregnancy. The presence of parasites with dual pfhrp2/pfhrp3 deletions, potentially threatening the efficacy of HRP2-based RDTs, warrants the continued surveillance.Trial registration ACTRN12622001476729

Hepatoprotective effect of Vernonia amygdalina and Ocimum gratissimum on Wistar rats exposed to long-term administration of artemisinin-based combination therapies

In this study the protective effect of Vernonia amygdalina (VA) and Ocimum gratissimum (OG) on rats exposed to long term oral administration of artesunate-amodiaquine and arthemeter-lumefantrine were investigated. Forty-two albino rats were divided into seven groups. They were given the drugs, artesunate amodiaquine (AA) and artemether lumefantrine (AL) base on their body weight. Group 1: Control, received distilled water, group 2, received of 2.86 mg/7.7 mg AA, group 3, received of 1.14 mg/6.86 mg AL, group 4 received of 2.86 mg/7.7 mg AA + 200 mg VA, group 5 received of 1.14 mg/6.86 mg AL + 200 mg VA, group 6 received of 2.86 mg/7.7 mg AA + 200 mg OG and group 7 received of 1.14 mg/6.86 mg AL + 200 mg OG. The animals were sacrificed and blood samples obtained through cardiac puncture for biochemical investigations. Biochemical assay for total protein, albumin, total bilirubin, direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyltransferase (γ-GT) were done. Co-administration of artesunate-amodiaquine and arthemeter-lumefantrine significantly decreased (P&lt; 0.05) total protein and albumin while there was significant increase (P&lt; 0.05) in total bilirubin, direct bilirubin, AST, ALT, ALP and γ-GT when compared with control group. The administration of VA and OG significantly increased the total protein and albumin and significantly decreased (P&lt; 0.05) total bilirubin and liver enzymes when compared with control group. The results indicate hepatic injury in the rats exposed to long term administration of artemisinin-based combination therapies (ACTs) which was reversed by the administration of VA and OG. There is need for caution while taking ACTs as malaria chemotherapy.

Effectiveness and safety of intermittent preventive treatment with dihydroartemisinin–piperaquine or artesunate–amodiaquine for reducing malaria and related morbidities in schoolchildren in Tanzania: a randomised controlled trial

In high transmission settings, most school-aged children harbour malaria parasites without showing symptoms, often leading to anaemia and possibly impaired psychomotor and cognitive abilities. We aimed to assess the effectiveness and safety of intermittent preventive treatment for malaria in school-aged children (IPTsc) living in highly endemic areas. We did an open-label randomised controlled trial in seven primary schools in northeastern Tanzania. Schoolchildren aged 5-15 years were individually randomly assigned (1:1:1) to receive dihydroartemisinin-piperaquine, artesunate-amodiaquine, or standard of care (control) using a balanced block design. Drugs were administered by schoolteachers, with supervision from study nurses, at months 0 (baseline), 4, and 8, and were given in line with manufacturer's recommendations with dose based on the child's bodyweight. The primary endpoints were change from baseline in mean haemoglobin concentration at months 12 and 20, and clinical incidence of malaria and prevalence of parasitaemia at months 12 and 20 in the intervention groups versus the control group. The outcome data were collected through longitudinal surveys conducted every 4 months. Data were analysed on the basis of intention to treat (including all randomised participants) and per protocol (comprising children who completed the full 3-day regimen of all three IPTsc treatment rounds as assigned). This study is registered with ClinicalTrials.gov (NCT03640403). Of the 1797 children scheduled for clinical screening, 1566 were enrolled and randomly allocated (526 to receive dihydroartemisinin-piperaquine, 527 to receive artesunate-amodiaquine, and 513 to receive standard of care). Due to COVID-19-related school closures, only two schools were visited at month 12 (135 children in the dihydroartemisinin-piperaquine group, 131 in the artesunate-amodiaquine group, and 118 in the control group). At month 12, compared with the control group, the change from baseline in mean haemoglobin concentration was increased by 0·5 g/dL (95% CI 0·2 to 0·8; p<0·0001) in the dihydroartemisinin-piperaquine group and 0·5 g/dL (0·2 to 0·7; p=0·0020) in the artesunate-amodiaquine group in the intention-to-treat analysis (with similar findings in the per protocol analysis). In the same period, in the intention-to-treat analysis, the prevalence of malaria parasitaemia increased from 28·5% (138 of 485 participants) to 33·6% (39 of 116) in the control group, but decreased from 28·0% (139 of 497) to 12·0% (15 of 125) in the dihydroartemisinin-piperaquine group (-21·6 percentage points [95% CI -31·9 to -11·3], p=0·0001 vs control at month 12) and from 24·7% (124 of 502) to 16·0% (20 of 125) in the artesunate-amodiaquine group (-17·6 percentage points [-28·4 to -6·9], p=0·0015). The decrease for artesunate-amodiaquine was larger in the per protocol analysis (-25·3 percentage points [-36·3 to -14·2], p<0·0001). The protective effect of IPTsc against malaria parasitaemia was 64% (95% CI 39 to 79; p<0·0001) for dihydroartemisinin-piperaquine and 52% (23 to 70; p=0·0015) for artesunate-amodiaquine in the intention-to-treat analysis, and was slightly higher on per protocol analysis. The protective effect against clinical malaria at month 12 was 20% (95% CI 9 to 29; p=0·0002) for dihydroartemisinin-piperaquine and 19% (8 to 28; p=0·0004) for artesunate-amodiaquine. No significant differences in any primary outcomes between the intervention and control groups were noted at month 20. Dihydroartemisinin-piperaquine and artesunate-amodiaquine were associated with a small number of mild adverse events, and there were no treatment-related serious adverse events or deaths. IPTsc with dihydroartemisinin-piperaquine or artesunate-amodiaquine is a safe and effective approach to reducing malaria parasitaemia, clinical malaria, and related morbidities, and is feasible to implement through programmes delivered by schoolteachers. Flemish Interuniversity Council (VLIRUOS), EU EDCTP2 programme (MaReCa project), and Global Minds 2019. For the Swahili translation of the abstract see Supplementary Materials section.

Effect of Vernonia amygdalina and Ocimum gratissimum on Antioxidant Status and Lipid Profile of Wistar Rats Exposed to Long-Term Administration of Artemisinin-based Combination Therapies

In this study the effect of Vernonia amygdalina and Ocimum gratissimum on antioxidant status and lipid profile of Wistar rats exposed to long-term administration of artemisinin-based combination therapies were investigated. Forty-two albino rats were divided into seven groups. The rats were given two different types of drugs, artesunate amodiaquine (AA) and artemether lumefantrine (AL) base on their body weight. Group 1: Control, received distilled water, group 2, received of 2.86mg/7.7mg AA, group 3, received of 1.14mg/6.86mg AL, group 4 received of 2.86mg/7.7mg AA + 200mg VA, group 5 received of 1.14mg/6.86mg AL + 200mg VA, group 6 received of 2.86mg/7.7mg AA + 200mg OG and group 7 received of 1.14mg/6.86mg AL + 200mg OG. The animals were sacrificed under chloroform anaesthesia and blood samples obtained through cardiac puncture for biochemical investigations. Artesunate-amodiaquine and arthemeter-lumefantrine and plant extracts were administered once daily for 21 days after which the total cholesterol, triacylglycerol, high density and low-density lipoprotein, superoxide dismutase (SOD), catalase (CAT) and gluthatione (GSH) and malondialdehyde (MDA) were determined. Co-administration of artesunate/amodiaquine and arthemeter/lumefantrine significantly increased (P&lt; 0.05) total cholesterol, triacylglycerol and low-density lipoprotein. The SOD and CAT activities and GSH concentration significantly decreased (P&lt; 0.05) with an increase in the MDA concentration in treated groups when compared with the normal control. The results obtained suggest that long term co-administration of artesunate/amodiaquine and arthemeter/lumefantrine could result to coronary heart disease and depletion of antioxidant capacity and should be given with caution.

Pre-existing partner-drug resistance to artemisinin combination therapies facilitates the emergence and spread of artemisinin resistance: a consensus modelling study

SummaryBackgroundArtemisinin-resistant genotypes of Plasmodium falciparum have now emerged a minimum of six times on three continents despite recommendations that all artemisinins be deployed as artemisinin combination therapies (ACTs). Widespread resistance to the non-artemisinin partner drugs in ACTs has the potential to limit the clinical and resistance benefits provided by combination therapy. We aimed to model and evaluate the long-term effects of high levels of partner-drug resistance on the early emergence of artemisinin-resistant genotypes.MethodsUsing a consensus modelling approach, we used three individual-based mathematical models of Plasmodium falciparum transmission to evaluate the effects of pre-existing partner-drug resistance and ACT deployment on the evolution of artemisinin resistance. Each model simulates 100 000 individuals in a particular transmission setting (malaria prevalence of 1%, 5%, 10%, or 20%) with a daily time step that updates individuals' infection status, treatment status, immunity, genotype-specific parasite densities, and clinical state. We modelled varying access to antimalarial drugs if febrile (coverage of 20%, 40%, or 60%) with one primary ACT used as first-line therapy: dihydroartemisinin–piperaquine (DHA-PPQ), artesunate–amodiaquine (ASAQ), or artemether–lumefantrine (AL). The primary outcome was time until 0·25 580Y allele frequency for artemisinin resistance (the establishment time).FindingsHigher frequencies of pre-existing partner-drug resistant genotypes lead to earlier establishment of artemisinin resistance. Across all models, a 10-fold increase in the frequency of partner-drug resistance genotypes on average corresponded to loss of artemisinin efficacy 2–12 years earlier. Most reductions in time to artemisinin resistance establishment were observed after an increase in frequency of the partner-drug resistance genotype from 0·0 to 0·10.InterpretationPartner-drug resistance in ACTs facilitates the early emergence of artemisinin resistance and is a major public health concern. Higher-grade partner-drug resistance has the largest effect, with piperaquine resistance accelerating the early emergence of artemisinin-resistant alleles the most. Continued investment in molecular surveillance of partner-drug resistant genotypes to guide choice of first-line ACT is paramount.FundingSchmidt Science Fellowship in partnership with the Rhodes Trust; Bill & Melinda Gates Foundation; Wellcome Trust.

Determinants of Patients' Adherence to Malaria Treatment in the Democratic Republic of the Congo.

(1) Background: Malaria heavily affects the Democratic Republic of the Congo (DRC) despite the use of effective drugs. Poor adherence to malaria treatment may contribute to this problem. (2) Methods: In one rural and one urban health area in each of the 11 former provinces of the DRC, all households with a case of malaria in the 15 days preceding the survey were selected and the patients or caregivers were interviewed. Adherence to malaria treatment was assessed by self-declaration about its completion. Logistic regression was used to assess predictors. (3) Results: 1732 households participated. Quinine was the most used drug; adherence to artesunate–amodiaquine was the lowest and the main reason for treatment discontinuation was adverse reactions. Predictors of adherence were residence in an urban area, university education, catholic religion, and adoption of recommended behaviour towards a malaria case. Adherence was significantly lower for responders who obtained information on antimalarials from Community Health Workers (CHW). (4) Conclusions: Usage of recommended drugs and adherence to malaria treatment need to be promoted, especially in rural areas, and CHW involvement needs to be improved. Awareness messages need to be made accessible and comprehensible to poorly educated populations and churches need to be involved.

Pcr-rflp genotyping of pfcrt and pfmdr1 in plasmodium falciparum isolates from children in Vatomandry, Madagascar

RésuméContexteLa surveillance de l'efficacité thérapeutique et des marqueurs génétiques de la résistance aux antipaludiques est primordiale afin de détecter le plus tôt possible l’émergence des parasites potentiellement résistants. Dans ce contexte, notre étude a pour objectif de réaliser le typage du gène Plasmodium falciparum chloroquine resistance transporter ou Pfcrt et Plasmodium falciparum multidrug resistant gene 1 ou Pfmdr1 sur des isolats provenant des enfants du district de Vatomandry.MéthodologiesAu total, 142 isolats de P. falciparum collectés lors d'un dépistage actif du paludisme chez des enfants âgés de moins de 15 ans, entre février et mars des années 2016 et 2017 à Vatomandry, ont été analysés. Le typage du codon K76T du gène Pfcrt et du codon N86Y du gène Pfmdr1 a été ensuite effectué par la technique de polymérisation en chaîne suivie de digestion enzymatique (restriction fragment length polymorphism) ou PCR-RFLP.RésultatsLe taux de succès d'amplification des gènes Pfcrt et Pfmdr1 était faible, de l'ordre de 27 % et 39 % respectivement. La prévalence des isolats mutants pour le codon K76T de Pfcrt était de 2,6 % [intervalle de confiance à 95 % (IC95%) : 0,1 - 15,0 %] et de 36 % [IC95% : 23,7 - 49,7 %] pour le codon N86Y du gène Pfmdr1.ConclusionNotre étude a mis en évidence la présence d'isolats portant à la fois la mutation au niveau du codon K76T de Pfcrt et N86Y de Pfmdr1. Bien que le taux de mutation que nous avons observé soit faible, d'autres études méritent d’être effectuées afin de suivre l’évolution de ces marqueurs dans le temps et dans l'espace à Madagascar.

Cost-Utility Analysis of Community Case Management for Malaria Control in Burundi.

The community case management (CCM) program for malaria control is a community-based strategy implemented to regulate malaria in children in Burundi. This study compared the cost and utility of implementing the CCM program combined with health facility management (HFM) versus HFM alone for malaria control in children under five in Burundi. This study constructed a five-year Markov model with one-week cycles to estimate cost-utility and budget impact analysis (BIA). The model defined 10 health states, simulating the progression of the disease and the risk of recurrent malaria in children under five years of age. Cost data were empirically collected and presented for 2019. Incremental cost per disability-adjusted life year (DALY) averted, and a five-year budget was estimated. One-way and probabilistic sensitivity analyses (PSAs) were then performed. From provider and societal perspectives, combining the CCM program with HFM for malaria control in Burundi was more cost-effective than implementing HFM alone. The addition of CCM, using artesunate amodiaquine (ASAQ) as the first-line treatment, increased by US$1.70, and US$ 1.67 per DALY averted from the provider and societal perspectives, respectively. Using Artemether Lumefantrine (AL) as the first-line treatment, adding the CCM program to HFM increased by US$ 1.92, and US$ 1.87 per DALY averted from the provider and societal perspectives. At a willingness-to-pay of one GDP/capita, the CCM program remained a 100% chance of being cost-effective. In addition, implementing the program for five years requires a budget of US$ 15 800 486-19 765 117. Implementing the CCM program and HFM is value for money for malaria control in Burundi. The findings can support decision-makers in Burundi in deciding on resource allocation, especially during the program's scale up.

Artesunate\u2013amodiaquine and artemether\u2013lumefantrine for the treatment of uncomplicated falciparum malaria in Liberia: in vivo efficacy and frequency of molecular markers

BackgroundArtesunate–amodiaquine (ASAQ) and Artemether–lumefantrine (AL) are the recommended treatment for uncomplicated Plasmodium falciparum malaria in Liberia. Intermittent preventive treatment with sulfadoxine/pyrimethamine is also recommended for pregnant women. The therapeutic efficacy of Artesunate–amodiaquine and Artemether–lumefantrine, and the frequency of molecular markers associated with anti-malarial drug resistance were investigated.MethodsThe therapeutic efficacy of ASAQ and AL was evaluated using the standard World Health Organization protocol (WHO. Methods for Surveillance of Antimalarial Drug Efficacy. Geneva: World Health Organization; 2009. https://www.who.int/malaria/publications/atoz/9789241597531/en/). Eligible children were recruited and monitored clinically and parasitologically for 28 days. Polymorphisms in the Pfkelch 13, chloroquine resistance transporter (Pfcrt), multidrug resistance 1 (Pfmdr-1), dihydrofolate reductase (Pfdhfr), and dihydropteroate synthase (Pfdhps) genes and copy number variations in the plasmepsin-2 (Pfpm2) gene were assessed in pretreatment samples.ResultsOf the 359 children enrolled, 180 were treated with ASAQ (89 in Saclepea and 91 in Bensonville) and 179 with AL (90 in Sinje and 89 in Kakata). Of the recruited children, 332 (92.5%) reached study endpoints. PCR-corrected per-protocol analysis showed ACPR of 90.2% (95% CI: 78.6–96.7%) in Bensonville and 92.7% (95% CI: 83.4.8–96.5%) in Saclepea for ASAQ, while ACPR of 100% was observed in Kakata and Sinje for AL. In both treatment groups, only two patients had parasites on day 3. No artemisinin resistance associated Pfkelch13 mutations or multiple copies of Pfpm2 were found. Most samples tested had the Pfcrt 76 T mutation (80/91, 87.9%), while the Pfmdr-1 86Y (40/91, 44%) and 184F (47/91, 51.6%) mutations were less frequent. The Pfdhfr triple mutant (51I/59R/108 N) was the predominant allele (49.2%). For the Pfdhps gene, it was the 540E mutant (16.0%), and the 436A mutant (14.3%). The quintuple allele (51I/59R/108 N-437G/540E) was detected in only one isolate (1/357).ConclusionThis study reports a decline in the efficacy of ASAQ treatment, while AL remained highly effective, supporting the recent decision by NMCP to replace ASAQ with AL as first-line treatment for uncomplicated falciparum malaria. No association between the presence of the mutations in Pfcrt and Pfmdr-1 and the risk of parasite recrudescence in patients treated with ASAQ was observed. Parasites with signatures known to be associated with artemisinin and piperaquine resistance were not detected. The very low frequency of the quintuple Pfdhfr/Pfdhps mutant haplotype supports the continued use of SP for IPTp. Monitoring of efficacy and resistance markers of routinely used anti-malarials is necessary to inform malaria treatment policy.Trial registration ACTRN12617001064392.

Therapeutic efficacy of artemether-lumefantrine, artesunate-amodiaquine and dihydroartemisinin-piperaquine in the treatment of uncomplicated Plasmodium falciparum malaria in Sub-Saharan Africa: A systematic review and meta-analysis.

Sub-Saharan Africa has the highest burden of malaria in the world. Artemisinin-based combination therapies (ACTs) have been the cornerstone in the efforts to reduce the global burden of malaria. In the effort to facilitate early detection of resistance for artemisinin derivatives and partner drugs, WHO recommends monitoring of ACT's efficacy in the malaria endemic countries. The present systematic meta-analysis study summarises the evidence of therapeutic efficacy of the commonly used artemisinin-based combinations for the treatment of uncomplicated P. falciparum malaria in Sub-Saharan Africa after more than a decade since the introduction of the drugs. Fifty two studies carried out from 2010 to 2020 on the efficacy of artemether-lumefantrine or dihydro-artemisinin piperaquine or artesunate amodiaquine in patients with uncomplicated P. falciparum malaria in Sub-Saharan Africa were searched for using the Google Scholar, Cochrane Central Register of controlled trials (CENTRAL), PubMed, Medline, LILACS, and EMBASE online data bases. Data was extracted by two independent reviewers. Random analysis effect was performed in STATA 13. Heterogeneity was established using I2 statistics. Based on per protocol analysis, unadjusted cure rates in malaria infected patients treated with artemether-lumefantrine (ALU), artesunate-amodiaquine (ASAQ) and dihydroartemisinin-piperaquine (DHP) were 89%, 94% and 91% respectively. However, the cure rates after PCR correction were 98% for ALU, 99% for ASAQ and 99% for DHP. The present meta-analysis reports the overall high malaria treatment success for artemether-lumefantrine, artesunate-amodiaquine and dihydroartemisinin-piperaquine above the WHO threshold value in Sub-Saharan Africa.

Perceived Adverse Drug reactions to Artemether Lumefantrine and Artesunate Amodiaquine in Lagos, Nigeria

Introduction: Medications produce a therapeutic effect that modulates a disorder and unwarranted effects that may be intrinsically harmful. Adverse drug reactions (ADRs) are undesirable effects that results from drug administration at usual doses and are the primary focus of regulatory agencies and post-marketing surveillance. Aim and objectives: To evaluate ADRs to Artemisinin-based Combination Therapies (ACTs) such as Artemether-Lumefantrine (AL) and Artesunate-Amodiaquine (AA) among adults with the objectives of (i) estimating and comparing the frequency of ADRs associated with AL and AA and (ii) developing a list of classical adverse drug reactions to both antimalarials. Materials and Methods: This cross-sectional, quantitative study was conducted from March to May 2013 at Ikorodu, a peri-urban settlement in Lagos State of Nigeria among 252 patients diagnosed with malaria and randomized into Artemether Lumefantrine (AL) arm and Artesunate Amodiaquine (AA) arm. Results: The mean age (years) of all the study subjects was 34.4 (10.6) with 58% of them who attained secondary level education. About 50% of them took other non-antimalarial medication together with prescribed ACT during their illness. Overall mean duration of illness (days) before taking ACT was 2.8 (1.14) which was significantly longer (t-est=-3.57, P-value=0.0002) in AA arm (3.1 ± 1.2) than in AL arm (2.6 ± 1.0). In all, 234 (96.4%) and 169 (67.1%) severally completed the full dose of treatment and ate pre-medication fatty meal. Overall prevalence of ADRs was 47.6% - 27.8% in the AL arm and 69.8% in the AA arm. Among those who did not take fatty meal, the risk of ADRs was higher (χ²=0.69, P-value=0.40, RR=1.26, 95% CI=0.72, 2.21) in the AA arm compared to the AL arm. Weakness, dizziness and headache were the most prevalent ADRs reported in both AL (25.9%, 13.8%, 15.5% respectively) and AA (50.0%, 10.0%, 16.4% respectively) arms. Conclusion: In general, the frequency of ADRs, though mild or moderate in severity, was significantly higher in the AA arm than in the AL arm and the frequency of serious ADR was very low. The most prevalent ADRs reported were weakness/fatigue, headache and dizziness. Pre-medication consumption of fatty meal reduced the frequency of ADRs in both arms of the study. Programmes on the management of malaria with ACT should consider this baseline information for active surveillance for ADRs in Nigeria.

Ascorbic acid coadministration with artesunate\u2013amodiaquine, up-regulated antioxidant enzymes gene expression in bone marrow cells and elicited biochemical changes in Plasmodium berghei-infected mice

One of the hallmarks of malaria infection is oxidative stress. This study was aimed at investigating the potential effects of coadministering a therapeutic dose of artesunate–amodiaquine (AS/AQ) with Vitamin C (Vit C) orally on some biochemical parameters and antioxidant enzymes gene expression in bone marrow cells of Plasmodium berghei-infected mice. Thirty male Swiss albino mice were divided into five groups of six mice each as follows: Basal control (not infected with P. berghei), Untreated (P. berghei-infected without treatment), Vit C, AS/AQ and AS/AQ + Vit C combination treated mice. Treatment was done twice daily for three consecutive days. Complete parasite clearance was observed on the second day of treatment in AS/AQ and AS/AQ + Vit C combination treated P. berghei-infected mice. Serum albumin and bilirubin levels were higher in the AS/AQ + Vit C combination treated P. berghei-infected mice compared with those treated with AS/AQ only. Artesunate–amodiaquine + Vit C combination increased superoxide dismutase activity and reduced hydrogen peroxide and malondialdehyde levels in P. berghei-infected mice when compared with the mice treated with only AS/AQ. Furthermore, AS/AQ + Vit C combination significantly up-regulated catalase and glutathione peroxidase-1 (GPx-1) mRNA expression compared with the mice treated with only AS/AQ. This is the first report linking AS/AQ to antioxidant enzyme gene expression in bone marrow cells. Our findings showed that AS/AQ and Vit C coadministration may be beneficial as it ameliorated oxidative stress and up-regulated antioxidant enzyme gene expression in P. berghei-infected mice.

Artemisinin derivative-containing therapies and abnormal hemoglobin: Do we need to adapt the treatment?

Background: Artemisinin-based treatment in malaria patients with abnormal hemoglobin may be ineffective because of their genetic particularity, which could lead to resistance. The main purpose of this study was to assess the effect of artemisinin derivatives on in vivo parasite clearance according to erythrocyte variants. In vivo response was investigated through retrospective data obtained over a 42-day artemether-lumefantrine/artesunate amodiaquine efficacy protocol conducted from 2012 to 2016. Results: A total of 770 patients in Côte d’Ivoire attending the hospitals of Anonkoua-koute (Abidjan), Petit Paris (Korhogo), Libreville (Man), Dar es salam (Bouaké), Ayamé and Yamoussoukro with acute uncomplicated falciparum malaria were selected for successful hemoglobin typing. HbAS, HbSS, HbAC, and HbSC genotypes were found. Parasite clearance time was obtained for 414 patients. In the population with abnormal hemoglobin, parasite densities on admission and parasite clearance rates were significantly lower in the HbSC group compared to HbAA (p = 0.02 and p = 0.007, respectively). After PCR correction on day 42, the acute treatment rate was 100% for each group. Parasite half-life and time for initial parasitaemia to decline by 50 and 99% were longer for the HbSC group (p < 0.05). The study also investigated the prevalence of K13-propeller polymorphisms across different hemoglobin genotype groups. A total of 185 and 63 samples were sequenced in the HbAA group and patients with abnormal Hb, respectively. Only two nonsynonymous mutations D559N and V510M were found in the HbAA group. Conclusion: Although this study proved good efficacy of artemether-lumefantrine and artesunate amodiaquine in the treatment of uncomplicated Plasmodium falciparum malaria in patients with abnormal hemoglobin, the increased delay of parasite clearance may represent a threat to health in these patients in relation with sickle cell crisis, which could support selection of parasites resistant to artemisinin.

Concurrent process validation: A case study for Artesunate and Amodiaquine tablets

Process validation is a requirement of Current Good Manufacturing Practices (cGMP). The essence of process validation is to ascertain the quality of a product throughout its production life cycle. The various steps in manufacturing processes must be validated as it is essential for quality to be built into the manufacturing processes of drugs. In this study, we discuss the Process validation of Artesunate (Art) tablets and Amodiaquine (Amod) tablets. The following critical tests were performed on the blend; Assay, blend uniformity studies, blend characteristics and flowability properties (Bulk Density, Tap Density, Compressibility Index, Hausner Ratio), resistance to Segregation studies, Loss on Drying and Blend hold-time studies. The following analytical tests were performed on the compressed tablets; Identification, weight variation, Disintegration, Hardness, Average weight, Loss on Drying, Friability, Assay, Dissolution, Thickness and Uniformity of Dosage Unit. The following were performed on the packaged finished products; leak test, Print quality, carton seal integrity. Percentage yield was also determined. The following statistical tools were used in the data evaluation; F-test, Shapiro-Wilk test, Kurtosis, Skewness, T-test emanating from regression analysis, Tests for Normality and Tests for Significant differences. Results indicated an acceptable level of homogeneity within a batch and a high level of consistencies between batches. The manufacturing process was concluded to be capable and stable to assure quality and safe products.

Markhamia tomentosa enhanced the antimalarial activity of chloroquine and amodiaquine in chloroquine resistant P. berghei infected mice

The prevalence of malaria is on a steady increase in Nigeria. However, people residing in the areas of high malaria transmission use medicinal plants in combination with standard antimalarial drugs. This study aimed to investigate the effect of aqueous leaf extract of Markhamia tomentosa (Benth.) K. Schum. Ex Engl. (Bignoniaceae) on the antimalarial activity of standard antimalarial drugs using Peter’s 4-day suppressive test. Also, identify the chemical constituents of n- hexane fraction of the plant using GC-MS spectrometry was identified. Standard antimalarial drugs [chloroquine, amodiaquine (10 mg/kg/day) and artesunate/amodiaquine (4/10 mg/kg)] were combined with 100, 250 and 500 mg/kg/day extract of M. tomentosa once daily for 3 days using a 4-day suppressive test. Survival of animals were assessed till day 21 (D 21). Combination of amodiaquine (AQ) and M. tomentosa or artesunate amodiaquine (AS/AQ) and M. tomentosa (100-500 mg/kg) significantly reduced chemosuppression of parasite growth. On D 14 p.i. chemosuppression of parasite growth in infected mice treated with the combination of amodiaquine (AQ) and M. tomentosa group was significantly (p &lt; 0.05) higher (78-88%) than mice treated with AQ alone (67%). In addition, combination of chloroquine and MT at 200 or 500 mg/kg (71.09 - 91.66%) produced significant chemosuppression of parasite growth than chloroquine (CQ) alone (0.0 – 19.06%) on day 12 and 14. Likewise higher survival of experimental mice was observed in CQ + 500 mg/kg MT than animals treated with CQ alone. Analysis of the n-hexane fraction with GC-MS revealed fifteen constituents, Heptadecane and Hexadecane were the most prominent (20.49% and 35.55%) respectively. M. tomentosa augments the antimalarial activity of chloroquine and amodiaquine in mice infected with chloroquineresistant P. berghei ANKA strain.

Investigating the Comparative Effects of Six Artemisinin-based Combination Therapies on Plasmodium-induced Hepatorenal Toxicity.

Background:Too many artemisinin-based combination therapies (ACTs) are available, thus creating a dilemma on the most preferred for the treatment of malaria.Aim:We compared the effect of six ACTs in mitigating Plasmodium-induced hepatorenal toxicity in experimental malaria.Materials and Methods:Forty adult male Swiss mice allotted into eight groups: Group 1 (normal control [NC] uninfected and untreated), Group 2 (parasitized nontreated – [PNT]), and Groups 3–8 received Plasmodium berghei inoculum. After 72 h, the initial parasitemia was established. Groups 3–8 were administered oral therapeutic doses of artesunate-amodiaquine (AA), artesunate-mefloquine (AM), artesunate-sulfadoxine-pyrimethamine (ASP), artemisinin-piperaquine (AP), dihydroartemisinin-piperaquine (DP), and artemether-lumefantrine (AL) per kg bodyweight, respectively, as standard regimen, and final parasitemia determined. Animals were euthanized via chloroform inhalation and blood collected for hepatorenal analysis. Liver and kidney were dissected out for histology.Results:Parasitemia was significantly (P < 0.05) decreased in tests compared to PNT, except in ASP group. Liver enzymes were significantly (P < 0.05) increased in PNT compared to tests and NC. Hyperplastic cells and portal tract inflammation were prominent in ASP group, but mild to moderate in other treated groups. Urea-creatinine were significantly (P < 0.05) increased in PNT compared to treated groups. The Na+ and Cl− were significantly (P < 0.05) reduced in PNT, with significantly (P < 0.05) increased K+ compared to NC and treated groups. Glomerulonephritis and glomerulus splitting was observed in PNT, while moderate distortions were observed in treated groups. The AA and AM groups had good kidney histoarchitecture.Conclusion:Parasitemia decreased in all the treatment groups except in PNT and ASP groups which had severe hepatorenal distortions. Hepatorenal histoarchitecture were mildly distorted in the AA, AM and AL-administered groups with lower hepatorenal indices comparable to NC. The least elevated liver enzymes were in AA and AM. In decreasing order ASP > DP > AL > AP > AM > AA.