Artemisinin-based Combination Therapy Research Articles

Targeted deep amplicon sequencing of antimalarial resistance markers in Plasmodium falciparum isolates from Cameroon

BackgroundRecent studies showed the first emergence of the R561H artemisinin-associated resistance marker in Africa, which highlights the importance of continued molecular surveillance to assess the selection and spread of this and other drug resistance markers in the region. MethodIn this study, we used targeted amplicon deep sequencing of 116 isolates collected in two areas of Cameroon to genotype the major drug resistance genes, k13, crt, mdr1, dhfr, and dhps, and the cytochrome b gene (cytb) in Plasmodium falciparum. ResultsNo confirmed or associated artemisinin resistance markers were observed in Pfk13. In comparison, both major and minor alleles associated with drug resistance were found in Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps. Notably, a high frequency of other nonsynonymous mutations was observed across all the genes, except for Pfcytb, suggesting continued selection pressure. ConclusionsThe results from this study supported the continued use of artemisinin-based combination therapy and administration of sulfadoxine-pyrimethamine for intermittent preventive therapy in pregnant women, and for seasonal chemoprevention in these study sites in Cameroon.

Characterization of pfmdr1, pfcrt, pfK13, pfubp1, and pfap2mu in Travelers Returning from Africa with Plasmodium falciparum Infections Reported in China from 2014 to 2018.

The artemisinin-based combination therapies (ACTs) used to treat Plasmodium falciparum in Africa are threatened by the emergence of parasites in Asia that carry variants of the Kelch 13 (K13) locus with delayed clearance in response to ACTs. Single nucleotide polymorphisms (SNPs) in other molecular markers, such as ap2mu and ubp1, were associated with artemisinin resistance in rodent malaria and clinical failure in African malaria patients. Here, we characterized the polymorphisms in pfmdr1, pfcrt, pfK13, pfubp1, and pfap2mu among African isolates reported in Shandong and Guangxi provinces in China. Among 144 patients with P. falciparum returning from Africa from 2014 to 2018, pfmdr1 N86Y (8.3%) and pfcrt K76T (2.1%) were the major mutant alleles. The most common genotype for pfcrt was I74E75T76 (8.3%), followed by E75T76 (2.1%). For K13 polymorphisms, a limited number of mutated alleles were observed, and A578S was the most frequently detected allele in 3 isolates (2.1%). A total of 27.1% (20/144) of the isolates were found to contain pfubp1 mutations, including 6 nonsynonymous and 2 synonymous mutations. The pfubp1 genotypes associated with artemisinin resistance were D1525E (10.4%) and E1528D (8.3%). Furthermore, 11 SNPs were identified in pfap2mu, and S160N was the major polymorphism (4.2%). Additionally, 4 different types of insertions were found in pfap2mu, and the codon AAT, encoding aspartic acid, was more frequently observed at codons 226 (18.8%) and 326 (10.7%). Moreover, 4 different types of insertions were observed in pfubp1 at codon 1520, which was the most common (6.3%). These findings indicate a certain degree of variation in other potential molecular markers, such as pfubp1 and pfap2mu, and their roles in either the parasite's mechanism of resistance or the mode of action should be evaluated or elucidated further.

Combating multi-drug resistant malaria parasite by inhibiting falcipain-2 and heme-polymerization: Artemisinin-peptidyl vinyl phosphonate hybrid molecules as new antimalarials.

Artemisinin-based combination therapies (ACTs) have been able to reduce the clinical and pathological malaria cases in endemic areas around the globe. However, recent reports have shown a progressive decline in malaria parasite clearance in South-east Asia after ACT treatment, thus envisaging a need for new artemisinin (ART) derivatives and combinations. To address the emergence of drug resistance to current antimalarials, here we report the synthesis of artemisinin-peptidyl vinyl phosphonate hybrid molecules that show superior efficacy than artemisinin alone against chloroquine-resistant as well as multidrug-resistant Plasmodium falciparum strains with EC50 in pico-molar ranges. Further, the compounds effectively inhibited the survival of ring-stage parasite for laboratory-adapted artemisinin-resistant parasite lines as compared to artemisinin. These hybrid molecules showed complete parasite clearance invivo using P.berghei mouse malaria model in comparison to artemisinin alone. Studies on the mode of action of hybrid molecules suggested that these artemisinin-peptidyl vinyl phosphonate hybrid molecules possessed dual activities: inhibited falcipain-2 (FP-2) activity, a P.falciparum cysteine protease involved in hemoglobin degradation, and also blocked the hemozoin formation in the food-vacuole, a step earlier shown to be blocked by artemisinin. Since these hybrid molecules blocked multiple steps of a pathway and showed synergistic efficacies, we believe that these lead compounds can be developed as effective antimalarials to prevent the spread of resistance to current antimalarials.

Has artemisinin resistance emerged in Africa?

Earlier this century, Plasmodium falciparum malaria parasites developed the ability to evade the action of artemisinin antimalarials. This delayed clearance phenotype, referred to as artemisinin resistance, is widespread in the Greater Mekong Subregion of southeast Asia, where it is associated with treatment failures for some artemisinin-based combination therapies (ACTs), the drugs of choice to treat P falciparum malaria.1 However, there is little evidence of artemisinin resistance beyond southeast Asia.

Efficacy and safety of artemisinin-based combination therapies for the treatment of uncomplicated malaria in pediatrics: a systematic review and meta-analysis

BackgroundMalaria is a major cause of morbidity and mortality in pediatrics in malaria endemic areas. Artemisinin-based combination therapies (ACTs) are the drugs of choice for malaria management particularly across malaria-endemic countries. This systematic review and meta-analysis was performed to assess efficacy and safety of ACTs for uncomplicated malaria in pediatric populations.MethodsA body of evidence was searched for published ACT trials until March 06, 2020. The search was focused on efficacy and safety studies of ACTs for uncomplicated malaria in pediatrics. PubMed library was searched using best adapted search terms after multiple trials. References were exported to the endnote library and then to Covidence for screening. Data was extracted using the Covidence platform. The per-protocol analysis report for the efficacy and the intention-to-treat analysis for the safety were synthesized. Met-analysis was carried using Open Meta-Analyst software. Random effects model was applied and the heterogeneity of studies was evaluated using I2 statistic.ResultsNineteen studies were included in the final analysis. Overall, crude, PCR-corrected P. falciparum malaria treatment success rate was 96.3 and 93.9% for day 28 and 42, respectively. In the subgroup analysis, PCR-corrected adequate clinical and parasitological response (ACPR) of dihydroartemisinin-piperaquine (DP) was 99.6% (95% CI: 99.1 to 100%, I2 = 0%; 4 studies) at day 28 and 99.6% (95% CI of 99 to 100%, I2 = 0%; 3 studies) at day 42. Nine studies reported ACT related adverse drug reactions (ADR) (8.3%, 356/4304). The reported drug related adverse reactions ranged from 1.8% in DP (two studies) to 23.3% in artesunate-pyronaridine (AP). Gastrointestinal symptoms were the most common ACT related adverse effects, and all ADRs were reported to resolve spontaneously.ConclusionACTs demonstrated a high crude efficacy and tolerability against P. falciparum. The high treatment success and tolerability with low heterogeneity conferred by DP has implication for policy makers who plan the use of ACTs for uncomplicated falciparum malaria treatment in pediatrics.

Molecular surveillance of drug resistance: Plasmodium falciparum artemisinin resistance single nucleotide polymorphisms in Kelch protein propeller (K13) domain from Southern Pakistan

BackgroundK13 propeller (k13) polymorphism are useful molecular markers for tracking the emergence and spread of artemisinin resistance in Plasmodium falciparum. Polymorphisms are reported from Cambodia with rapid invasion of the population and almost near fixation in south East Asia. The study describes single nucleotide polymorphisms in Kelch protein propeller domain of P. falciparum associated with artemisinin resistance from Southern Pakistan.MethodsTwo hundred and forty-nine samples were collected from patients with microscopy confirmed P. falciparum malaria attending Aga Khan University Hospital during September 2015-April 2018. DNA was isolated using the whole blood protocol for the QIAmp DNA Blood Kit. The k13 propeller gene (k13) was amplified using nested PCR. Double-strand sequencing of PCR products was performed using Sanger sequencing methodology. Sequences were analysed with MEGA 6 and Bio edit software to identify specific SNP combinations.ResultsAll isolates analysed for k13 propeller allele were observed as wild-type in samples collected post implementation of ACT in Pakistan. C580Y, A675V, Y493H and R539T variants associated with reduced susceptibility to artemisinin-based combination therapy (ACT) were not found. Low frequency of M476I and C469Y polymorphisms was found, which is significantly associated with artemisinin resistance.ConclusionLow frequencies of both nonsynonymous and synonymous polymorphisms were observed in P. falciparum isolates circulating in Southern Pakistan. The absence of known molecular markers of artemisinin resistance in this region is favourable for anti-malarial efficacy of ACT. Surveillance of anti-malarial drug resistance to detect its emergence and spread need to be strengthened in Pakistan.

Historical trends and new surveillance of Plasmodium falciparum drug resistance markers in Angola

BackgroundPlasmodium falciparum resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) has historically posed a major threat to malaria control throughout the world. The country of Angola officially replaced CQ with artemisinin-based combination therapy (ACT) as a first-line treatment in 2006, but malaria cases and deaths have recently been rising. Many classic resistance mutations are relevant for the efficacy of currently available drugs, making it important to continue monitoring their frequency in Angola.MethodsPlasmodium falciparum DNA was sampled from the blood of 50 hospital patients in Cabinda, Angola from October-December of 2018. Each infection was genotyped for 13 alleles in the genes crt, mdr1, dhps, dhfr, and kelch13, which are collectively involved in resistance to six common anti-malarials. To compare frequency patterns over time, P. falciparum genotype data were also collated from studies published from across Angola in the last two decades.ResultsThe two most important alleles for CQ resistance, crt 76T and mdr1 86Y, were found at respective frequencies of 71.4% and 6.5%. Historical data suggest that mdr1 N86 has been steadily replacing 86Y throughout Angola in the last decade, while the frequency of crt 76T has been more variable across studies. Over a third of new samples from Cabinda were ‘quintuple mutants’ for SP resistance in dhfr/dhps, with a sixth mutation at dhps A581G present at 9.6% frequency. The markers dhfr 51I, dhfr 108N, and dhps 437G have been nearly fixed in Angola since the early 2000s, whereas dhfr 59R may have risen to high frequency more recently. Finally, no non-synonymous polymorphisms were detected in kelch13, which is involved in artemisinin resistance in Southeast Asia.ConclusionsGenetic markers of P. falciparum resistance to CQ are likely declining in frequency in Angola, consistent with the official discontinuation of CQ in 2006. The high frequency of multiple genetic markers of SP resistance is consistent with the continued public and private use of SP. In the future, more complete haplotype data from mdr1, dhfr, and dhps will be critical for understanding the changing efficacy of multiple anti-malarial drugs. These data can be used to support effective drug policy decisions in Angola.

Ethical, Regulatory and Market related aspects of Deploying Triple Artemisinin-Based Combination Therapies for Malaria treatment in Africa: A study protocol.

Introduction:According to the World Malaria Report 2019, Africa accounts for 94% of the global malaria deaths. While malaria prevalence and mortality have declined over the years, recent reports suggest that these gains may stand the risk of being reversed if resistance to Artemisinin Combination Therapies (ACTs) spreads from Southeast Asia to Africa. Efforts are being made to develop new treatments that will address the looming threat of ACT resistance, including the development of triple artemisinin combination therapies (TACTs). The proposed study seeks to explore the views of stakeholders on the key ethical, regulatory and market-related issues that should be considered in the potential introduction of triple artemisinin combination therapies (TACTs) in Africa. Methods:The study employed qualitative research methods involving in-depth interviews and focus group discussions (FGDs) with stakeholders, who will be directly affected by the potential deployment of triple artemisinin combination treatments, as regulators, suppliers and end-users. Participants will be purposively selected and will include national regulatory authorities, national malaria control programs, clinicians, distributors and retailers as well as community members in selected districts in Burkina Faso and Nigeria. Discussion:The proposed study is unique in being one of the first studies that seeks to understand the ethical, social, regulatory and market position issues prior to the development of a prospectiveantimalarial medicine.

Advancement of chimeric hybrid drugs to cure malaria infection: An overview with special emphasis on endoperoxide pharmacophores.

Emergence and spread of Plasmodium falciparum resistant to artemisinin-based combination therapy has led to a situation of haste in the scientific and pharmaceutical communities. Sincere efforts are redirected towards finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. Extensive research yielded the concept of "Chimeric Bitherapy (CB)" which involves the linking of two molecules with individual pharmacological activity and exhibit dual mode of action into a single hybrid molecule. Current research in this field seems to endorse hybrid molecules as the next-generation antimalarial drugs and are more effective compared to the multi-component drugs because of the lower occurrence of drug-drug adverse effects. This review is an attempt to congregate complete survey on endoperoxide based hybrid antiplasmodial molecules that will give glimpse on the future directions for successful development and discovery of useful antimalarial hybrid drugs.

Efficacy and safety of dihydroartemisinin\u2013piperaquine versus artemether\u2013lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Ugandan children: a systematic review and meta-analysis of randomized control trials

BackgroundThe emergence of artemisinin resistance in Southeast Asia and Plasmodium falciparum kelch13 propeller gene mutations in sub-Saharan African pose the greatest threat to global efforts to control malaria. This is a critical concern in Uganda, where artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated falciparum. The objective of this study was to compare the efficacy and safety of dihydroartemisinin–piperaquine (DHA–PQ) and artemether–lumefantrine (AL) for the treatment of uncomplicated falciparum malaria in Ugandan children.MethodsA search of PubMed and the Cochrane Central Register of Controlled Trials for retrieving randomized controlled trials comparing the efficacy and safety of DHA–PQ and AL for treatment of uncomplicated falciparum malaria in Ugandan children was done. The search was performed up to 31 August 2020. The data extracted from eligible studies and pooled as risk ratio (RR) with a 95% confidence interval (CI), using Rev Man Software (5.4). The protocol was registered in PROSPERO, ID: CRD42020182354.ResultsEleven trials were included in this review and two of them only included under safety outcome. Total 3798 participants were enrolled. The PCR unadjusted treatment failure was significantly lower with DHA–PQ at day 28 (RR 0.30, 95% CI 0.19–0.49; participants = 7863; studies = 5; I2 = 93%, low quality evidence) and at day 42 (RR 0.53, 95% CI 0.38–0.76; participants = 1618; studies = 4; I2 = 79%, moderate quality of evidence). The PCR adjusted treatment failure at day 42 was significantly lower with DHA–PQ treatment group (RR 0.45, 95% CI 0.28 to 0.72; participants = 1370; studies = 5, high quality of evidence), and it was below 5% in both arms at day 28 (moderate quality of evidence). AL showed a longer prophylactic effect on new infections which may last for up to 63 days (PCR-adjusted treatment failure: RR 2.04, 95% CI 1.13–3.70; participants = 1311; studies = 2, moderate quality of evidence). Compared to AL, DHA–PQ was associated with a slightly higher frequency of cough (RR 1.07, 95% CI 1.01 to 1.13; 2575 participants; six studies; high quality of evidence). In both treatment groups, the risk of recurrent parasitaemia due to possible recrudescence was less than 5% at day 28. The appearance of gametocyte between 29 and 42 days was also significantly lower in DHA–PQ than AL (RR 0.26, 95% CI 0.12 to 0.56; participants = 623; studies = 2; I2 = 0%).ConclusionCompared to AL, DHA–PQ appeared to reduce treatment failure and gametocyte carriage in Ugandan children. This may trigger DHA–PQ to become the first-line treatment option. Both treatments were safe and well-tolerated.

Evaluation of the Pediatric Antimalarial Prescriptions in a Teaching Hospital in Southeastern Nigeria

Background: Malaria in Nigeria with the highest morbidity and mortality in children between 6 months and 5 years continues to be a disease burden. In line with the World Health Organization recommendation of diagnosis in all ages before treatment, Nigeria provided guidelines on parasite-based diagnosis. Therefore, in order to achieve its preelimination and the reduction of mortality caused by it to zero by 2020, it is necessary to assess the compliance of the prescribers to the guidelines. Objectives: The objectives of this study were to determine the cases who were diagnosed based on positive malaria parasite test and the level of compliance of the prescribers to the National Malaria Treatment Guidelines. Methods: A total of 3034 prescriptions of antimalarial drugs were collected between 2003 and 2011 in the Outpatient Department of the Pediatric Clinic. Data were analyzed using Microsoft Excel and SPSS V.20.0 and grouped into two: prepolicy (2003–2005) and postpolicy (2006–2011) periods. Descriptive and inferential statistics were used at P < 0.05 level of significance. Results: The study revealed that diagnosis based on positive malaria parasite test was 4.8% of 2765 patients. There was a noticeable increase in the prescription of artemisinin combination therapy in the postpolicy period (32.6%), but the compliance to the Antimalarial Treatment Guideline was low (23.8%). Conclusion: There was a high incidence of empirical diagnoses of malaria and treatment. Many of the artemisinin-based combination therapies prescribed were not recommended.

Drug resistance profile and clonality of Plasmodium falciparum parasites in Cape Verde: the 2017 malaria outbreak

BackgroundCape Verde is an archipelago located off the West African coast and is in a pre-elimination phase of malaria control. Since 2010, fewer than 20 Plasmodium falciparum malaria cases have been reported annually, except in 2017, when an outbreak in Praia before the rainy season led to 423 autochthonous cases. It is important to understand the genetic diversity of circulating P. falciparum to inform on drug resistance, potential transmission networks and sources of infection, including parasite importation.MethodsEnrolled subjects involved malaria patients admitted to Dr Agostinho Neto Hospital at Praia city, Santiago island, Cape Verde, between July and October 2017. Neighbours and family members of enrolled cases were assessed for the presence of anti-P. falciparum antibodies. Sanger sequencing and real-time PCR was used to identify SNPs in genes associated with drug resistance (e.g., pfdhfr, pfdhps, pfmdr1, pfk13, pfcrt), and whole genome sequencing data were generated to investigate the population structure of P. falciparum parasites.ResultsThe study analysed 190 parasite samples, 187 indigenous and 3 from imported infections. Malaria cases were distributed throughout Praia city. There were no cases of severe malaria and all patients had an adequate clinical and parasitological response after treatment. Anti-P. falciparum antibodies were not detected in the 137 neighbours and family members tested. No mutations were detected in pfdhps. The triple mutation S108N/N51I/C59R in pfdhfr and the chloroquine-resistant CVIET haplotype in the pfcrt gene were detected in almost all samples. Variations in pfk13 were identified in only one sample (R645T, E668K). The haplotype NFD for pfmdr1 was detected in the majority of samples (89.7%).ConclusionsPolymorphisms in pfk13 associated with artemisinin-based combination therapy (ACT) tolerance in Southeast Asia were not detected, but the majority of the tested samples carried the pfmdr1 haplotype NFD and anti-malarial-associated mutations in the the pfcrt and pfdhfr genes. The first whole genome sequencing (WGS) was performed for Cape Verdean parasites that showed that the samples cluster together, have a very high level of similarity and are close to other parasites populations from West Africa.

Malaria prevention and treatment awareness and practice among patent medicine vendors (PMVs) in Gombe Metropolis, Nigeria

The ravaging consequences of Malaria in Sub-Saharan Africa (SSA) have been a subject of serious concern to every stakeholder. Literature and anecdotal evidence shows that around 60% of Nigerians seek fever treatment from Patent Medicine Vendors (PMVs) despite the limited formal dispensing knowledge most possess. This study attempts to establish a base line of knowledge, attitude and practices of Malaria control among PMVs in Gombe Metropolis, North Eastern Nigeria. The study was a descriptive cross sectional survey based on structured questionnaires used to collect relevant information from 109 PMVs selected by purposive sampling technique. The result show that 85.3% of the participants in this study correctly identified fever or high body temperature as the common sign of uncomplicated (UC) Malaria, while 70.6% recognized convulsion as one of the main symptoms of severe Malaria. Furthermore, 86.2% of the PMVs also knew that sleeping inside treated nets constitute one of the best ways to prevent Malaria. In the same vein, awareness of change in Malaria treatment policy from monotherapy to Artemisinin based combination therapy (ACT) was high (73.3%) among them. However, those PMVs that had ever undergone some degree of drug dispensing training exhibited a significantly higher level of awareness of change in malaria treatment policy (X2 =17.903, P = 0.000). Although 85.3% of PMVs frequently recommend Arthemeter Lumefantrine (AL) as treatment of uncomplicated Malaria, only 39.4% of the participants would refer severe malaria cases. Even though most Malaria control awareness and practice variables were found to be fairly good among the participants, it is clear from the study that there is the need for enhanced training, monitoring and supervision by the relevant authorities so as to fully harness the vast potential in PMVs.

The Epidemiology of Plasmodium falciparum Malaria in the Bijagos Islands of Guinea-Bissau.

.Distribution of long-lasting insecticide-treated nets (LLINs), passive detection and treatment with artemisinin-based combination therapy (ACT), and intermittent preventive treatment in pregnancy (IPTp) are the mainstay malaria control measures of Guinea-Bissau’s national control programme. This study aimed to estimate the prevalence of Plasmodium falciparum on Bubaque, the most populous island of the country’s remote Bijagos archipelago. A cross-sectional survey was performed at the start of the rainy season in August 2017. Participants were recruited using systematic random sampling in a two-stage stratified cluster design. Malaria parasitemia was detected using rapid diagnostic tests (RDTs) and quantitative PCR (qPCR). Data on housing, education, larval source management, socioeconomic status, anemia, and malaria preventive measures were collected. Multivariable logistic regression models were constructed to identify associations with P. falciparum infection. Four hundred four persons (aged 6 months–79 years, median 17 years) were enrolled in the study. The prevalence of P. falciparum parasitemia was 5.8% by RDT (95% CI: 3.55–9.33) and 16.9% by qPCR (95% CI: 13.09–21.71). The prevalence of anemia was 74.3% (95% CI: 69.04–78.85) as defined by the WHO criteria. All sampled houses were found to have open eaves; 99.5% of the surveyed population reported sleeping under a bednet (95% CI: 97.8–99.9). Although reported LLIN use is high, there remains an appreciable prevalence of malaria, suggesting that transmission is ongoing and further tools are required to reduce the burden of the disease.

Knowledge and attitude of primary healthcare workers towards rational prescription of Artemisinin-based combination therapy in the treatment of uncomplicated malaria in Ondo State, southwestern Nigeria

1. World Health Organization. World Malaria Report 2019. Geneva. WHO Regional Office for Africa. 2019. 1–232 p. Google Scholar

Pattern of Prescription of Anti-malarial Drugs in the Primary Health Care Facilities in Sokoto State Nigeria

Introduction: Prescription practices for malaria have been shown to influence the emergence of resistance to antimalarial drugs. Appropriate antimalarial drug use contributes to reductions in morbidity and mortality due to malaria with a consequent socioeconomic benefit, thus the success of a new malaria treatment policy would depend on the adherence of health care providers and patients to treatment recommendations. This study aimed to determine the prescribing pattern of anti-malaria in primary health care facilities in Sokoto State.
 Methods: A cross sectional study was carried-out in the Primary Health Care facilities in Sokoto State. Screening of prescription forms from the patients who presented at the outpatient clinic during the period of the study in the selected health facilities was done at the point of exit, and only those with antimalarial prescription were consecutively selected. An interviewer administered questionnaire was used to obtained brief history of the illness among 276 respondents who were enrolled in to the study. Record of Rapid Diagnostic Test (mRDT) for the diagnosis of the malaria was obtained from the patients and or their caregivers. Data were analyzed using IBM® SPSS version 20 statistical packages.
 Results: Majority 85 (30.8%) of the respondents were aged ≤ 1-10 years followed by 21-30 years 81 (29.3) Of the 276 antimalarial prescription forms obtained from the respondents, artemisinin- based combination therapy (ACT) was 166 (60.1%) and monotherapy was 110 (39.9%). The commonest artemisinin-based combination therapy prescribed for the respondents was Artemether-Lumefantrine 141 (84.9%) followed by Artesunate- Amodiaquine 16 (9.6%). The commonest oral mono-therapy prescribed was Sulphadoxine-pyrimethamine 28 (75.7%) while the most prescribed injectable monotherapy was artemether 59 (80.8%). Rapid Diagnostic Test for malaria (mRDT) was done for 274 (99.3%) respondents; those with mRDT positive were 238 (86.9%). The commonest presenting symptoms was fever 274 (99.3%) flowed by headache 225 (80.7%) and loss of appetite 215 (77.9%). 
 Conclusion: The pattern of antimalarial prescription observed in this study was mainly artemisinin-based combination therapy. However, antimalarial monotherapy is still being prescribed. There is need for regular training of the health care workers on the appropriate treatment of malaria using the national guideline for treatment of malaria. Regular supply and availability of ACTs in all health facilities across the state will ensure full compliance with national guideline for malaria treatment using ACTs.

Variation in Calculating and Reporting Antimalarial Efficacy against Plasmodium falciparum in Sub-Saharan Africa: A Systematic Review of Published Reports.

Antimalarials, in particular artemisinin-based combination therapies (ACTs), are critical tools in reducing the global burden of malaria, which is concentrated in sub-Saharan Africa. Performing and reporting antimalarial efficacy studies in a transparent and standardized fashion permit comparison of efficacy outcomes across countries and time periods. This systematic review summarizes study compliance with WHO laboratory and reporting guidance pertaining to antimalarial therapeutic efficacy studies and evaluates how well studies from sub-Saharan Africa adhered to these guidelines. We included all published studies (January 2020 or before) performed in sub-Saharan Africa where ACT efficacy for treatment of uncomplicated Plasmodium falciparum infection was reported. The primary outcome was a composite indicator for study methodology consistent with WHO guidelines for statistical analysis of corrected efficacy, defined as an article presenting a Kaplan-Meier survival analysis of corrected efficacy or reporting a per-protocol analysis where new infections were excluded from the numerator and denominator. Of 581 articles screened, we identified 279 for the review. Molecular correction was used in 83% (232/279) to distinguish new infections from recrudescences in subjects experiencing recurrent parasitemia. Only 45% (99/221) of articles with therapeutic efficacy as a primary outcome and performing molecular correction reported corrected efficacy outcomes calculated in a way consistent with WHO recommendations. These results indicate a widespread lack of compliance with WHO-recommended methods of analysis, which may result in biases in how antimalarial effectiveness is being measured and reported from sub-Saharan Africa.

Assessment of Plasmodium falciparum anti-malarial drug resistance markers in pfk13-propeller, pfcrt and pfmdr1 genes in isolates from treatment failure patients in Democratic Republic of Congo, 2018\u20132019

BackgroundThe national policy for malaria treatment of the Democratic Republic of Congo recommends two first-line artemisinin-based combinations for the treatment of uncomplicated malaria: artesunate-amodiaquine and artemether-lumefantrine. This study investigated the presence of markers associated with resistance to the current first-line artemisinin-based combination therapy (ACT) in isolates of Plasmodium falciparum from treatment failure patients in the Democratic Republic of Congo.MethodsFrom November 2018 to November 2019, dried blood spots were taken from patients returning to health centres for fever within 28 days after an initial malaria treatment in six sentinel sites of the National Malaria Control Programme across Democratic Republic of Congo. The new episode of malaria was first detected by a rapid diagnostic test and then confirmed by a real-time PCR assay to define treatment failure. Fragments of interest in pfk13 and pfcrt genes were amplified by conventional PCR before sequencing and the Pfmdr1 gene copy number was determined by a TaqMan real-time PCR assay.ResultsOut of 474 enrolled patients, 364 (76.8%) were confirmed positive by PCR for a new episode of P. falciparum malaria, thus considered as treatment failure. Of the 325 P. falciparum isolates obtained from 364 P. falciparum-positive patients and successfully sequenced in the pfk13-propeller gene, 7 (2.2%) isolates carried non-synonymous mutations, among which 3 have been previously reported (N498I, N554K and A557S) and 4 had not yet been reported (F506L, E507V, D516E and G538S). Of the 335 isolates successfully sequenced in the pfcrt gene, 139 (41.5%) harboured the K76T mutation known to be associated with chloroquine resistance. The SVMNT haplotype associated with resistance to amodiaquine was not found. None of the isolates carried an increased copy number of the pfmdr1 gene among the 322 P. falciparum isolates successfully analysed.ConclusionNo molecular markers currently known to be associated with resistance to the first-line ACT in use were detected in isolates of P. falciparum from treatment failure patients. Regular monitoring through in vivo drug efficacy and molecular studies must continue to ensure the effectiveness of malaria treatment in Democratic Republic of Congo.

Trends in access to anti\u2010malarial treatment in the formal private sector in Uganda: an assessment of availability and affordability of first\u2010line anti\u2010malarials and diagnostics between 2007 and 2018

BackgroundMalaria is the single largest cause of illness in Uganda. Since the year 2008, the Global Fund has rolled out several funding streams for malaria control in Uganda. Among these are mechanisms aimed at increasing the availability and affordability of artemisinin-based combination therapy (ACT). This paper examines the availability and affordability of first-line malaria treatment and diagnostics in the private sector, which is the preferred first point of contact for 61% of households in Uganda between 2007 and 2018.MethodsCross-sectional surveys were conducted between 2007 and 2018, based on a standardized World Health Organization/Health Action International (WHO/HAI) methodology adapted to assess availability, patient prices, and affordability of ACT medicines in private retail outlets. A minimum of 30 outlets were surveyed per year as prescribed by the standardized methodology co-developed by the WHO and Health Action International. Availability, patient prices, and affordability of malaria rapid diagnostic tests (RDTs) was also tracked from 2012 following the rollout of the test and treat policy in 2010. The median patient prices for the artemisinin-based combinations and RDTs was calculated in US dollars (USD). Affordability was assessed by computing the number of days’ wages the lowest-paid government worker (LPGW) had to pay to purchase a treatment course for acute malaria.ResultsAvailability of artemether/lumefantrine (A/L), the first-line ACT medicine, increased from 85 to100% in the private sector facilities during the study period. However, there was low availability of diagnostic tests in private sector facilities ranging between 13% (2012) and 37% (2018). There was a large reduction in patient prices for an adult treatment course of A/L from USD 8.8 in 2007 to USD 1.1 in 2018, while the price of diagnostics remained mostly stagnant at USD 0.5. The affordability of ACT medicines and RDTs was below one day’s wages for LPGW.ConclusionsAvailability of ACT medicines in the private sector medicines retail outlets increased to 100% while the availability of diagnostics remained low. Although malaria treatment was affordable, the price of diagnostics remained stagnant and increased the cumulative cost of malaria management. Malaria stakeholders should consolidate the gains made and consider the inclusion of diagnostic kits in the subsidy programme.

Seeking research questions from implementers: considerations for leveraging ground actors research needs in the fight against malaria in West Africa

BackgroundTo strengthen the fight against malaria, it is imperative to identify weaknesses and possible solutions in order to improve programmes implementation. This study reports experiences gained from collaboration between decision-makers and researchers from a World Bank project (Malaria and Neglected Tropical Diseases in the Sahel, SM/NTD). The objectives of this paper were to identify bottlenecks in malaria programme implementation as well as related research questions they bring up.MethodsQuestionnaire addressed to National Malaria Control Programme managers and prioritization workshops were used as a medium to identify research questions. The bottlenecks in malaria programme implementation were identified in seven thematic areas namely governance, human resources, drugs, service provision, use of prevention methods, monitoring and evaluation (M and E), and public support or buy-in. The first five priority questions were: (1) compliance with drug doses on the second and third days during the seasonal chemoprevention (SMC) campaigns, (2) the contribution of community-based distributors to the management of severe cases of malaria in children under 5 years, (3) the SMC efficacy, (4) artemisinin-based combination therapy (ACT) tolerance and efficacy according to existing guidelines, and (5) the quality of malaria control at all levels of the health system.Results and conclusionThis work showed the effectiveness of collaboration between implementers, programmes managers, and researchers in identifying research questions. The responses to these identified research questions of this study may contribute to improving the implementation of malaria control programmes across African countries.