Artemisinin-Based Combination Therapy

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Stabilizing supply of artemisinin and artemisinin based combination therapy in an era of wide spread scale up

Stabilizing supply of artemisinin and artemisinin based combination therapy in an era of wide spread scale up

The global demand for artemisinin-based combination therapy (ACT) has grown sharply since its recommendation by the World Health Organization in 2002. However, a combination of financing and programmatic uncertainties, limited suppliers of finished products, information opacity across the different tiers in the supply chain, and widespread fluctuations in raw material prices have together contributed to a market fraught with demand and supply uncertainties and price volatility. Various short-term solutions have been deployed to alleviate supply shortages caused by these challenges; however, new mechanisms are required to build resilience into the supply chain. This review concludes that a mix of strategies is required to stabilize the artemisinin and ACT market. First, better and more effective pooling of demand and supply risks and better contracting to allow risk sharing among the stakeholders are needed. Physical and financial buffer stocks will enable better matching of demand and supply in the short and medium term. Secondly, physical buffers will allow stable supplies when there are procurement and supply management challenges while financial buffer funds will address issues around funding disruptions. Finally, in the medium to long term, significant investments in country level system strengthening will be required to minimize national level demand uncertainties. In addition a voluntary standard for extractors to ensure
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Brazilian Plasmodium falciparum isolates: investigation of candidate polymorphisms for artemisinin resistance before introduction of artemisinin based combination therapy

Brazilian Plasmodium falciparum isolates: investigation of candidate polymorphisms for artemisinin resistance before introduction of artemisinin based combination therapy

Resistance to anti-malarial drugs is one of the major obstacles to effective malaria treatment and control. Due to the worldwide spread of Plasmodium falciparum resistant to chloroquine and sulphadoxine-pyrimetha- mine, the World Health Organization (WHO) recom- mends the use of artemisinin-based combination therapy (ACT) as first-line malaria treatment. Artemisi- nin and its derivatives rapidly reduce clinical symptoms and parasite burden. Combination with a second agent improves treatment outcomes and minimizes the possi- bility of selecting artemisinin-resistant parasites [1].
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Artemisinin-based combination therapy for treating uncomplicated malaria (Review)

Artemisinin-based combination therapy for treating uncomplicated malaria (Review)

Artemisinin derivatives have been shown to produce faster re- lief of clinical symptoms and faster clearance of parasites from the blood than other antimalarial drugs (McIntosh 1999; Adjuik 2004; WHO 2006). When used as monotherapy, the short half- life of the artemisinin derivatives (and rapid elimination from the blood) means that patients must take the drug for at least seven days (Meshnick 1996; Adjuik 2004). Failure to complete the course, due to the rapid improvement in clinical symptoms, can lead to high levels of treatment failure even in the absence of drug resistance. Artemisinin derivatives are therefore usually given with another longer-acting drug, with a different mode of action, in a combination known as artemisinin-based combination therapy or ACT. These combinations can then be taken for shorter durations than artemisinin alone (White 1999; WHO 2006).
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Adherence to artemisinin based combination therapy for the treatment of malaria: a systematic review of the evidence

Adherence to artemisinin based combination therapy for the treatment of malaria: a systematic review of the evidence

ACT: Artemisinin-based combination therapy; AL: Artemether-lumefantrine; AMFm: Affordable Medicines Facility – malaria; AQAS: Amodiaquine-artesunate co-formulated; AQ + AS: Amodiaquine plus artesunate co-packaged; ASMQ: Artesunate-mefloquine co-formulated; AS + AS: Artesunate plus mefloquine co-packaged; AS + SP: Artesunate plus sulfadoxine-pymetheramine; BMQ: Brief medical questionnaire; CASP: Critical Appraisal Skills Programme; CONSORT: Consolidated Standards for Reporting Trials; CPD: Chlorproguanil- dapsone; DHA-PQ: Dihydroartemisinin-piperaquine; DOT: Directly observed therapy; GFATM: The global fund to fight AIDS, tuberculosis and malaria; MEMS: Medical event monitory services; MIS: Malaria indicator survey; NDOT: Non-directly observed treatment; PMI: The President ’ s Malaria Initiative; OR: Odds ratio; RBM: Roll Back Malaria; RR: Relative risk; RCT: Randomized Controlled Trial; STROBE: The strengthening the reporting of observational studies in epidemiology; WHO: World Health Organization.
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Efficacy and safety of artemether lumefantrine for the treatment of uncomplicated malaria and prevalence of Pfk13 and Pfmdr1 polymorphisms after a decade of using artemisinin based combination therapy in mainland Tanzania

Efficacy and safety of artemether lumefantrine for the treatment of uncomplicated malaria and prevalence of Pfk13 and Pfmdr1 polymorphisms after a decade of using artemisinin based combination therapy in mainland Tanzania

ACPR: adequate clinical and parasitological response; ACT : artemisinin-based combination therapy; AL: artemether-lumefantrine; ASAQ: artesunate + amo- diaquine; AS + SP: artesunate + sulfadoxine/pyrimethamine; CDC: Centers for Disease Control and Prevention; DBS: dried blood spot; DNA: deoxyribonucleic acid; DP: Dihydroartemisinin–Piperaquine; ETF: early treatment failure; LCF: late clinical failure; LPF: late parasitological failure; MRCC : Medical Research Coordinating Committee; PARMA: US PMI-supported Antimalarial Resistance Monitoring in Africa Network; Pfk13: Plasmodium falciparum Kelch 13 gene; Pfmdr1: Plasmodium falciparum multi-drug resistance 1 gene; PMI: US Presi- dent’s Malaria Initiative; NIMR: National Institute for Medical Research; NMCP: National Malaria Control Programme; PCR: polymerase chain reaction; SNP: single nucleotide polymorphism; TES: therapeutic efficacy study; USA: United States of America; WHO: World Health Organization.
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Artemisinin based combination therapy for uncomplicated Plasmodium falciparum malaria in Colombia

Artemisinin based combination therapy for uncomplicated Plasmodium falciparum malaria in Colombia

Since mid 2006, Colombia is the only country in South America that has not yet introduced artemisinin-based combination therapy (ACT) into its national malaria drug policy for uncomplicated Plasmodium falciparum malaria. Colombia accounted for 13.2% (116,872) of the 886,102 malaria cases reported in the Americas in 2004; of these, 44,437 (10.2%) were due to P. falciparum [1]. The Colom- bian Ministry of Social Protection (formerly the Ministry of Health) currently recommends amodiaquine (AQ) at a dose of 25 mg/Kg over 48 h plus a single dose of sulfadox- ine/pyrimethamine (SP) and primaquine (PQ, as a game- tocytocidal drug) for the treatment for uncomplicated falciparum malaria [2]. Malaria treatment is provided free-of-charge to all microscopically-confirmed cases. Combination therapy for P. falciparum malaria is not new in Colombia. It was first used in the early 1980's when the combination of chloroquine (CQ) plus SP was recom- mended for all areas where CQ resistance had not been reported and AQ plus SP for areas with known CQ resist- ance. The combination of AQ plus SP was adopted for the entire country in 1999, after reports of widespread CQ resistance. The most recent clinical studies show that P. falciparum therapeutic failure to CQ ranges from 67% to 97% in Antioquia (in the north), and from 44% to 70% in the Pacific Coast region [3,4].
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From chloroquine to artemisinin based combination therapy: the Sudanese experience

From chloroquine to artemisinin based combination therapy: the Sudanese experience

In Sudan, malaria control was based for decades on vector control, through spraying with insecticides. In the late 1990s, great efforts were directed to improve malaria case management and this was included in the development of the Roll Back Malaria (RBM) strategic plan in 2001. Case management requires the provision of prompt, effective and safe treatment to malaria cases [6]. Using the results of research on resistance to CQ, Sudanese policy-makers updated their national malaria treatment guidelines in 2004 to artemisinin-based combination therapy (ACTs), both as first- and second-line treatment for the manage- ment of uncomplicated falciparum malaria. This case study aims to provide the evidence-basis and to describe the process for change and the experience of one year implementation.
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Willingness and ability to pay for artemisinin based combination therapy in rural Tanzania

Willingness and ability to pay for artemisinin based combination therapy in rural Tanzania

Malaria constitutes a major burden on individuals and on the community in low-income countries. In Tanzania, it has been estimated that 1% of GDP is spent on the dis- ease. For comparison, total health expenditure in Tanza- nia constitutes about 4% of GDP. 71% of the total expenditure on malaria is from private sources [1]. In sub-Saharan Africa, the utilization of ineffective drugs in recent years has led to treatment failures and elevated rates of mortality, particularly among young children [2,3]. Artemisinin-based combination therapy (ACT) is, therefore, recommended as the first-line anti-malarial treatment strategy in most parts of sub-Saharan Africa [4]. Efficacy and effectiveness studies have shown that ACT provides cure rates of over 90% [5-7] and generally, it is also well tolerated [8,9]. However, good quality of health care is critical to ensure efficacy and prevent parasitic resistance to the anti-malarial drugs, by limiting over- treatment and unnecessary drug exposure, as well as ensuring compliance to standard treatment doses. The cost of artemisinin derivatives is a limiting factor for the affordability and optimal use of ACT. Various forms of ACT are 5–10-fold more costly compared with the previ- ously recommended treatments, chloroquine or sul- phadoxine/pyrimethamine (SP). Coartem ® (artemether-
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Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin based combination therapy with primaquine

Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin based combination therapy with primaquine

ACT : artemisinin-based combination therapy; AE: adverse events; AL: fixed dose combination of 20 + 120 mg artemether and lumefantrine with con- comitant use of primaquine; ANVISA: National Regulatory Agency; AS: CYP2D6 activity score; ASMQ: fixed dose combination of 100 + 200 mg artesunate and mefloquine with concomitant use of primaquine; AUC : area-under-the-curve; CQ: chloroquine; CI: confidence interval; CQ: chloroquine with concomitant use of primaquine; G6PD: glucose-6-phosphate dehydrogenase; GEE: general- ized estimation equation; GLM: generalized linear models; Hb: haemoglobin; HPLC-MS/MS: high performance liquid chromatography-tandem mass spec- trometry; LMF: lumefantrine; MQ: mefloquine; OR: odds ratio; PCR: polymerase chain reaction; RR: relative risks; SD: standard deviations; SEFAR: Equivalence and Pharmacokinetics Service; t 1/2 : half-life; WHO: World Health Organization.
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Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin based combination therapy with primaquine

Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin based combination therapy with primaquine

ACT: Artemisinin-based combination therapy; AE: Adverse events; AL: Fixed dose combination of 20 + 120 mg artemether and lumefantrine with concomitant use of primaquine; ANVISA: National Regulatory Agency; ASMQ: Fixed dose combination of 100 + 200 mg artesunate and mefloquine with concomitant use of primaquine; CI: Confidence interval; CNS: Brazilian National Health Council; CQ: chloroquine with concomitant use of primaquine; G6PD: Glucose-6-phosphate dehydrogenase; HPLC- MS/MS: High performance liquid chromatography-tandem mass spectrometry; PCR: Polymerase chain reaction; SD: Standard deviations; SEFAR: Equivalence and Pharmacokinetics Service; WHO: World Health Organization.
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Efficacy and safety of artemisinin based combination therapy and chloroquine with concomitant primaquine to treat Plasmodium vivax malaria in Brazil: an open label randomized clinical trial

Efficacy and safety of artemisinin based combination therapy and chloroquine with concomitant primaquine to treat Plasmodium vivax malaria in Brazil: an open label randomized clinical trial

Results: A total of 264 patients were followed up to day 63. The cure rate of all three treatment arms was greater than 90% at 28 and 42 days. Cure rates were below 90% in all three treatment groups at day 63, although the 95% confi- dence interval included 90% for all three treatments. Most of the adverse events were mild in all treatment arms. Only one of the three serious adverse events was related to the treatment and significant drops in haemoglobin were rare. Conclusion: This study demonstrated the efficacy and safety of all three regimens that were tested with 42-day cure rates that meet World Health Organization criteria. The efficacy and safety of artemisinin-based combination therapy regimens in this population offers the opportunity to treat all species of malaria with the same regimen, simplifying pro- tocols for malaria control programmes and potentially contributing to elimination of both vivax and falciparum malaria. Trial registration RBR-79s56s
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Efficacy and safety of artemisinin based combination therapy, and molecular markers for artemisinin and piperaquine resistance in Mainland Tanzania

Efficacy and safety of artemisinin based combination therapy, and molecular markers for artemisinin and piperaquine resistance in Mainland Tanzania

ACT : artemisinin-based combination therapy; ACPR: adequate clinical and parasitological response; AL: artemether/lumefantrine; ASAQ: artesunate/amo- diaquine; DHAPQ: dihydroartemisinin/piperaquine; DNA: deoxyribonucleic acid; ETF: early treatment failure; IHI: Ifakara Health Institute; LCF: late clinical failure; LPF: late parasitological failure; mdr1: Plasmodium falciparum multi drug resistance1; MRCC : Medical Research Coordinating Committee; NMCP: National Malaria Control Programme; PCR: polymerase chain reaction; SNP: single- nucleotide polymorphism; WHO: World Health Organization.
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Priority setting for the implementation of artemisinin-based combination therapy policy in Tanzania: evaluation against the accountability for reasonableness framework

Priority setting for the implementation of artemisinin-based combination therapy policy in Tanzania: evaluation against the accountability for reasonableness framework

One participant was concerned about the urban-poor populations who have to make a choice between long waiting times and unreliable public health services ver- sus reliable but unaffordable services in the private sec- tor. Participants from National Malaria Control Program (NMCP) said that other strategies were being considered to make sure ALu was also available at a subsidized price in the private-for-profit healthcare facilities. Effectiveness and cost-effectiveness Participants said that fixed-combination antimalarial drugs have better compliance, hence are more effective compared to non- fixed combinations. However, artemether-lumefantrine’s six-dose regimen of four tablets to be taken twice a day with a fatty meal for three successive days was a major concern.
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Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria

Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria

Artemisinin and its derivatives (artesunate, artemether, and di- hydroartemisinin) are short-acting antimalarial drugs which have been shown to produce rapid relief from clinical symptoms and rapid clearance of the parasite from the peripheral blood (Pukrittayakamee 2000; WHO 2010). They are usually combined with a longer-acting partner drug to produce ACTs. Until recently there was no known resistance to the artemisinin derivatives but some resistance among P. falciparum species has now been reported in southeast Asia and is being investigated (Dondorp 2009). Artemisinin derivatives are generally reported as being well-toler- ated, and the safety profile of ACTs may be largely determined by the partner drug (Taylor 2004). Studies of artemisinin derivatives in animals have reported significant neurotoxicity (brain damage), but this has not been seen in human studies (Price 1999). Animal studies have also shown adverse effects on the early development of the foetus, but the artemisinin derivatives have not been fully evaluated during early pregnancy in humans. Other reported ad- verse events include gastrointestinal disturbance (stomach upset), dizziness, tinnitus (ringing in the ears), neutropenia (low levels of white blood cells), elevated liver enzymes (a marker for liver damage), and electrocardiographic (ECG) abnormalities (changes in cardiac conduction). Most studies, however, have found no ev- idence of ECG changes, and only non-significant changes in liver enzymes (Nosten 2007; WHO 2010). The incidence of type 1 hypersensitivity (allergic) reactions is reported to be approximately 1 in 3000 patients (Nosten 2007).
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Subsidising artemisinin-based combination therapy in the private retail sector

Subsidising artemisinin-based combination therapy in the private retail sector

Decisions to incorporate retail sector ACT subsidies into national malaria control programmes need to involve consideration of in- dividual country contexts (which could include local malaria epi- demiology, public sector to private sector antimalarial market ra- tio, diagnostic and distributional capacity of retail outlets, access to rapid malaria diagnostics and treatment seeking behaviours). In addition malaria subsidy policies need to balance the benefits of retail sector ACT subsidies and potential unintended adverse effects (for example, delaying the formal treatment-seeking that is needed for correct diagnosis and treatment of malaria and non- malarial fevers; under-treatment of malaria (under-dosing); failing to diagnose and treat co-morbid non-malarial fevers such as pneu- monia; and over-treatment of malaria resulting from inappropriate use of subsidised ACTs in individuals with non-malarial fevers). Such use of ACTs may increase the likelihood of emergence of artemisinin resistance.
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Adherence to prescribed artemisinin based combination therapy in Garissa and Bunyala districts, Kenya

Adherence to prescribed artemisinin based combination therapy in Garissa and Bunyala districts, Kenya

Disadvantages of AL include the large number of tablets that need to be taken to complete the full course of therapy. This is further complicated by the fact that the first two doses of AL need to be taken 8 hours apart, and the remaining doses taken twice a day in the morning and evening. In this study, patients reporting dislikes to AL, such as taste and smell, were less likely to be fully adherent (OR = 0.62). Increasing the accept- ability of AL is very important in Kenya, where it was found 36% of people are non-compliant. Other studies have focussed on addressing dislikes to AL in children, with a recent study in collaboration with Novartis ® eval- uating a novel dispersible tablet of Coartem ® in different flavours. These are specifically designed with clear instructions to promote adherence and the sweeter fla- vour encourages children to take their medication [37]. Increased use of dispersible AL may reduce difficulties administering medication to children, and therefore positively improve adherence in the future. Manufac- turers of other formulations of ACT have addressed acceptability and adherence issues by significantly redu- cing the daily number of tablets required [38].
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Who continues to stock oral artemisinin monotherapy? Results of a provider survey in Myanmar

Who continues to stock oral artemisinin monotherapy? Results of a provider survey in Myanmar

Background: Artemisinin-based combination therapy (ACT) is a key strategy for global malaria elimination efforts. However, the development of artemisinin-resistant malaria parasites threatens progress and continued usage of oral artemisinin monotherapies (AMT) predisposes the selection of drug resistant strains. This is particularly a problem along the Myanmar/Thailand border. The artemisinin monotherapy replacement programme (AMTR) was established in 2012 to remove oral AMT from stocks in Myanmar, specifically by replacing oral AMT with quality-assured ACT and conducting behavioural change communication activities to the outlets dispensing anti-malarial medications. This study attempts to quantify the characteristics of outlet providers who continue to stock oral AMT despite these concerted efforts.
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Anti malarial prescription practices among outpatients with laboratory confirmed malaria in the setting of a health facility based sentinel site surveillance system in Uganda

Anti malarial prescription practices among outpatients with laboratory confirmed malaria in the setting of a health facility based sentinel site surveillance system in Uganda

In 2001 the World Health Organization (WHO) recom- mended artemisinin-based combination therapy (ACT) for the treatment of uncomplicated Plasmodium falcip- arum malaria in countries with resistance to older mo- notherapies [1]. At the time ACT was neither widely available nor affordable in many countries with limited re- sources. Five years later, 41 African countries (and 65 worldwide) had adopted ACT as first-line therapy and 21 were deploying ACT at public health facilities [2]. In 2010, WHO expanded its recommendations to include labora- tory confirmation with microscopy or a rapid diagnostic test (RDT) before initiating anti-malarial therapy [3]. The use of ACT based on laboratory confirmation represents a dramatic shift in malaria case management in Africa fol- lowing decades of largely empiric therapy with inexpen- sive, older monotherapies. Currently, limited data exist on recent anti-malarial prescription practices in Africa fol- lowing these changes. In Kenya, where case management practices have been published following a policy change promoting universal parasitological diagnosis before treat- ment, a majority of patients were not getting diagnostic testing or treatment according to test result, although those with positive tests and uncomplicated malaria did receive recommended treatment with artemether-lume- fantrine (AL) in 90% of cases when AL was available [4].
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Anti malarial landscape in Myanmar: results from a nationally representative survey among community health workers and the private sector outlets in 2015/2016

Anti malarial landscape in Myanmar: results from a nationally representative survey among community health workers and the private sector outlets in 2015/2016

Methods: This was a cross-sectional survey, which employed stratified cluster-random sampling across four regions in Myanmar. A census of community health workers (CHWs) and private outlets with potential to distribute malaria testing and/or treatment was conducted. An audit was completed for all anti-malarials, malaria rapid diagnostic tests. Results: A total of 28,664 outlets were approached and 4416 met the screening criteria. The anti-malarial market composition comprised CHWs (41.5%), general retailers (27.9%), itinerant drug vendors (11.8%), pharmacies (10.9%), and private for-profit facilities (7.9%). Availability of different anti-malarials and diagnostic testing among anti-malarial- stocking CHWs was as follows: artemisinin-based combination therapy (ACT) (81.3%), chloroquine (67.0%), confirma- tory malaria test (77.7%). Less than half of the anti-malarial-stocking private sector had first-line treatment in stock: ACT (41.7%) chloroquine (41.8%), and malaria diagnostic testing was rare (15.4%). Oral artemisinin monotherapy (AMT) was available in 27.7% of private sector outlets (Western, 54.1%; Central, 31.4%; Eastern; 25.0%, Coastal; 15.4%). The private-sector anti-malarial market share comprised ACT (44.0%), chloroquine (26.6%), and oral AMT (19.6%). Among CHW the market share was ACT (71.6%), chloroquine (22.3%); oral AMT (3.8%). More than half of CHWs could correctly state the national first-line treatment for uncomplicated falciparum and vivax malaria (59.2 and 56.9%, respectively) compared to the private sector (15.8 and 13.2%, respectively). Indicators on support and engagement were as follows for CHWs: reportedly received training on malaria diagnosis (60.7%) or national malaria treatment guidelines (59.6%), received a supervisory or regulatory visit within 12 months (39.1%), kept records on number of patients tested or treated for malaria (77.3%). These indicators were less than 20% across the private sector.
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Malaria: Knowledge, Attitudes and Acceptances of Rapid Diagnostic Test amongst Primary Healthcare Workers in Some Selected Local Government Areas, Lagos State, Nigeria

Malaria: Knowledge, Attitudes and Acceptances of Rapid Diagnostic Test amongst Primary Healthcare Workers in Some Selected Local Government Areas, Lagos State, Nigeria

Universal access to parasite-based diagnosis of malaria-like febrile illness is the current global policy recommendation due to the use of Artemisinin - based Combination Therapy (ACT), as the first line anti- malaria treatment for Plasmodium falciparum infection in most endemic Countries. [3] However ACT is expensive and relies on an insecure supply of raw materials. Therefore, RDT is important in the diagnosis of malaria by differentiating malarial cases from non-malarial cases to ensure that ACTs are used for malaria cases only. Factors reported to have reduced the appeal of RDTs included the cost of the test and the extra time required to be tested. [4] Studies have also shown that utilisation of RDT is high and its introduction has led to judicious use of antimalarial drugs, including ACTs. [5, 6] However, some other previous studies reported under-utilisation of RDT. [7, 8]
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