Artemisinin-based Combination Therapy Research Articles

Effectiveness of artemether-lumefantrine for treating uncomplicated malaria in low- and high-transmission areas of Ghana.

Artemisinin-based combination therapy (ACT) has been effective in the supervised treatment of uncomplicated malaria in Ghana. Since ACT usage is primarily unsupervised, this study aimed to determine the effectiveness of artemether-lumefantrine (AL) for treating malaria patients in two transmission settings in Ghana. Eighty-four individuals with uncomplicated Plasmodium falciparum malaria were recruited from Lekma Hospital (LH) in Accra (low-transmission area; N = 28), southern Ghana, and King's Medical Centre (KMC) in Kumbungu (high-transmission area; N = 56), northern Ghana. Participants were followed up for 28days after unsupervised treatment with AL. The presence of asexual parasites was determined by microscopic examination of Giemsa-stained blood smears. Plasmodium species identification was confirmed using species-specific primers targeting the 18S rRNA gene. Parasite recrudescence or reinfection was determined by genotyping the Pfmsp 1 and Pfmsp 2 genes. After AL treatment, 3.6% (2/56) of the patients from KMC were parasitaemic on day 3 compared to none from the LH patients. One patient from KMC with delayed parasite clearance on day 3 remained parasite-positive by microscopy on day 7 but was parasite-free by day 14. While none of the patients from LH experienced parasite recurrence during the 28-day follow-up, three and two patients from KMC had recurrent parasitaemia on days 21 and 28, respectively. Percentage reduction in parasite densities from day 1, 2, and 3 for participants from the KMC was 63.2%, 89.5%, and 84.5%. Parasite densities for participants from the LH reduced from 98.2%, 99.8% on day 1, and 2 to 100% on day 3. The 28-day cumulative incidence rate of treatment failure for KMC was 12.8% (95% confidence interval: 1.9-23.7%), while the per-protocol effectiveness of AL in KMC was 89.47%. All recurrent cases were assigned to recrudescence after parasite genotyping by Pfmsp 1 and Pfmsp 2. While AL is efficacious in treating uncomplicated malaria in Ghana, when taken under unsupervised conditions, it showed an 89.4% PCR-corrected cure rate in northern Ghana, which is slightly below the WHO-defined threshold.

Single - nucleotide polymorphisms of artemisinin resistance - related Pfubp1 and Pfap2mu genes in Bioko Island, Equatorial Guinea from 2018 to 2020

To investigate the prevalence of single nucleotide polymorphisms (SNPs) of artemisinin resistance-related Pfubp1 and Pfap2mu genes in Plasmodium falciparum isolates from Bioko Island, Equatorial Guinea, so as to to provide baseline data for the formulation of malaria control strategies in Bioko Island. A total of 184 clinical blood samples were collected from patients with P. falciparum malaria in Bioko Island, Equatorial Guinea from 2018 to 2020, and genomic DNA was extracted. The Pfubp1 and Pfap2mu gene SNPs of P. falciparum were determined using a nested PCR assay and Sanger sequencing, and the gene sequences were aligned. There were 159 wild-type P. falciparum isolates (88.83%) from Bioko Island, Equatorial Guinea, and 6 SNPs were identified in 20 Pfubp1-mutant P. falciparum isolates (11.17%), in which 4 non-synonymous mutations were detected, including E1516G, K1520E, D1525E, E1528D. There was only one Pfubp1gene mutation site in 19 Pfubp1-mutant P. falciparum isolates (95.00%), in which non-synonymous mutations accounted for 68.42% (13/19). D1525E and E1528D were identified as major known epidemic mutation sites in the Pfubp1 gene associated with resistance to artemisinin-based combination therapies (ACTs). At amino acid position 1525, there were 178 wild-type P. falciparum isolates (99.44%) and 1 mutant isolate (0.56%), with such a mutation site identified in blood samples in 2018, and at amino acid position 1528, there were 167 wild-type P. falciparum isolates (93.30%) and 12 mutant isolates (6.70%). The proportions of wild-type P. falciparum isolates were 95.72% (134/140), 79.25% (126/159) and 95.83% (161/168) in the target amplification fragments of the three regions in the Pfap2mu gene (Pfap2mu-inner1, Pfap2mu-inner2, Pfap2mu-inner3), respectively. There were 16 different SNPs identified in all successfully sequenced P. falciparum isolates, in which 7 non-synonymous mutations were detected, including S160N, K199T, A475V, S508G, I511M, L595F, and Y603H. There were 7 out of 43 Pfap2mu-mutant P. falciparum isolates (16.28%) that harbored only one gene mutation site, in which non-synonymous mutations accounted for 28.57% (2/7). For the known delayed clearance locus S160N associated with ACTs, there were 143 wild-type (89.94%) and 16 Pfap2mu-mutant P. falciparum isolates (10.06%). Both Pfubp1 and Pfap2mu gene mutations were detected in P. falciparum isolates from Bioko Island, Equatorial Guinea from 2018 to 2020, with a low prevalence rate of Pfubp1 gene mutation and a high prevalence rate of Pfap2mu gene mutation. In addition, new mutation sites were identified in the Pfubp1 (E1504E and K1520E) and Pfap2mu genes (A475V and S508G).

Two decades of malaria control in Malawi: Geostatistical Analysis of the changing malaria prevalence from 2000-2022.

Malaria remains a public health problem in Malawi and has a serious socio-economic impact on the population. In the past two decades, available malaria control measures have been substantially scaled up, such as insecticide-treated bed nets, artemisinin-based combination therapies, and, more recently, the introduction of the malaria vaccine, the RTS,S/AS01. In this paper, we describe the epidemiology of malaria for the last two decades to understand the past transmission and set the scene for the elimination agenda. A collation of parasite prevalence surveys conducted between the years 2000 and 2022 was done. A spatio-temporal geostatistical model was fitted to predict the yearly malaria risk for children aged 2-10 years (PfPR 2-10) at 1×1 km spatial resolutions. Parameter estimation was done using the Monte Carlo maximum likelihood method. District-level prevalence estimates adjusted for population are calculated for the years 2000 to 2022. A total of 2,595 sampled unique locations from 2000 to 2022 were identified through the data collation exercise. This represents 70,565 individuals that were sampled in the period. In general, the PfPR2_10 declined over the 22 years. The mean modelled national PfPR2_10 in 2000 was 43.93 % (95% CI:17.9 to 73.8%) and declined to 19.2% (95%CI 7.49 to 37.0%) in 2022. The smoothened estimates of PfPR2_10 indicate that malaria prevalence is very heterogeneous with hotspot areas concentrated on the southern shores of Lake Malawi and the country's central region. The last two decades are associated with a decline in malaria prevalence, highly likely associated with the scale-up of control interventions. The country should move towards targeted malaria control approaches informed by surveillance data.

In vitro delayed response to dihydroartemisinin of malaria parasites infecting sickle cell erythocytes

BackgroundDecreased efficacy of artemisinin-based combination therapy (ACT) for Plasmodium falciparum malaria has been previously reported in patients with sickle cell disease (SCD). The main purpose of this study was to investigate the in vitro susceptibility of isolates to dihydro-artemisinin (DHA) to provide a hypothesis to explain this treatment failure.MethodsIsolates were collected from patients attending health centres in Abidjan with uncomplicated P. falciparum malaria. The haemoglobin type has been identified and in vitro drug sensitivity tests were conducted with the ring stage assay and maturation inhibition assay.Results134 isolates were obtained. Parasitaemia and haemoglobin levels at inclusion were lower in patients with haemoglobin HbSS and HbSC than in patients with normal HbAA. After ex vivo RSA and drug inhibition assays, the lowest rate of parasitic growth was found with isolates from HbAS red cells. Conversely, a significantly higher survival rate of parasites ranging from 15 to 34% were observed in isolates from HbSS. Isolates with in vitro reduced DHA sensitivity correlate with lower RBC count and haematocrit and higher parasitaemia at inclusion compared to those with isolates with normal DHA sensitivity. However, this decrease of in vitro sensitivity to DHA was not associated with Kelch 13-Propeller gene polymorphism.ConclusionThis study highlights an in vitro decreased sensitivity to DHA, for isolates collected from HbSS patients, not related to the Pfkelch13 gene mutations. These results are in line with recent studies pointing out the role of the redox context in the efficacy of the drug. Indeed, SCD red cells harbour a highly different ionic and redox context in comparison with normal red cells. This study offers new insights into the understanding of artemisinin selective pressure on the malaria parasite in the context of haemoglobinopathies in Africa.

Factors influencing patients' adherence to malaria artemisinin-based combination therapy in Kamuli District, Uganda.

Patients' adherence to artemisinin-based combination therapy (ACT) is a malaria control strategy. Studies report varied experiences regarding patients' adherence to ACT. The study aimed at determining factors influencing patients' adherence to ACT for malaria in Kamuli, Uganda. In a longitudinal study, 1266 participants at 8 public health facilities were enrolled. Equal numbers (422) were assigned to the three arms (no follow-up, day 2 and day 4). To establish the mean difference between groups, Student t-test was used and a chi-square test was used for proportionality. A multivariate logistic regression analysis was used to establish the influence of predictor variables on the dependent variable. Statistical significance was established at p < 0.05. A total of 844 patients were analysed. The median age was 20 years, majority (64.3%) were females. Overall patients' adherence was 588/844 (69.7%). At bivariate level, age (t-test = 2.258, p = 0.024), household head (χ2 = 14.484, p = 0.002), employment status (χ2 = 35.886, p < 0.0001), patients' preference of ACT to other anti-malarials (χ2 = 15.981, p < 0.0001), giving a patient/caregiver instructions on how to take the medication (χ2 = 7.134, p = 0.011), being satisfied with getting ACT at facility (χ2 = 48.261, p < 0.0001), patient/caregiver knowing the drug prescribed (χ2 = 5.483, p = 0.019), patient history of saving ACT medicines (χ2 = 39.242, p < 0.0001), and patient ever shared ACT medicines (χ2 = 30.893, p < 0.0001) were all associated with patients' adherence to ACT. Multivariate analysis demonstrated that adhering to ACT is 3.063 times higher for someone satisfied with getting ACT at the facility (OR = 3.063; p < 0.0001), 4.088 times for someone with history of saving ACT medicines (OR = 4.088; p < 0.0001), 2.134 times for someone who shared ACT (OR = 2.134; p = 0.03), and 2.817 times for someone with a household head (OR = 2.817; p = 0.008). Patients' adherence to ACT is generally good in the studied population. However, patients' tendencies to save ACT for future use and sharing among family members is a threat, amidst the benefits associated with adherence. There is a need to educate all about adherence to medicines as prescribed, and tighten government medicine supply chain to avoid stock-outs.

Improving malaria case management with artemisinin-based combination therapies and malaria rapid diagnostic tests in private medicine retail outlets in sub-Saharan Africa: A systematic review.

Private medicine retailers (PMRs) such as pharmacies and drug stores account for a substantial share of treatment-seeking for fever and malaria, but there are widespread concerns about quality of care, including inadequate access to malaria rapid diagnostic tests (RDTs) and artemisinin-based combination therapies (ACTs). This review synthesizes evidence on the effectiveness of interventions to improve malaria case management in PMRs in sub-Saharan Africa (PROSPERO #2021:CRD42021253564). We included quantitative studies evaluating interventions supporting RDT and/or ACT sales by PMR staff, with a historical or contemporaneous control group, and outcomes related to care received. We searched Medline Ovid, Embase Ovid, Global Health Ovid, Econlit Ovid and the Cochrane Library; unpublished studies were identified by contacting key informants. We conducted a narrative synthesis by intervention category. We included 41 papers, relating to 34 studies. There was strong evidence that small and large-scale ACT subsidy programmes (without RDTs) increased the market share of quality-assured ACT in PMRs, including among rural and poorer groups, with increases of over 30 percentage points in most settings. Interventions to introduce or enhance RDT use in PMRs led to RDT uptake among febrile clients of over two-thirds and dispensing according to RDT result of over three quarters, though some studies had much poorer results. Introducing Integrated Community Case Management (iCCM) was also effective in improving malaria case management. However, there were no eligible studies on RDT or iCCM implementation at large scale. There was limited evidence that PMR accreditation (without RDTs) increased ACT uptake. Key evidence gaps include evaluations of RDTs and iCCM at large scale, evaluations of interventions including use of digital technologies, and robust studies of accreditation and other broader PMR interventions.

Alternative first-line malaria treatment.

Malaria is a disease affecting millions of people, especially in Africa, Asia, and South America, and has become a substantial economic burden. Because malaria is contracted through the bite of a mosquito vector, it is very challenging to prevent. Bed nets and insect repellents are used in some homes; others do not have or use them even when available. Thus, treatment measures are crucial to controlling this disease. Artemisinin-based combination therapy (ACT) is currently the first-line treatment for malaria. ACT has been used for decades, but recently, there has been evidence of potential resistance. This threat of resistance has led to the search for possible alternatives to ACT. In sub-Saharan Africa, Azadirachta indica, or simply neem, is a plant used to treat a variety of ailments, including malaria. Neem is effective against one of the more deadly malaria parasites Plasmodium falciparum. Reports show that neem inhibits microgametogenesis of P. falciparum and interferes with the parasite's ookinete development. Although there is substantial in vitro research on the biological activity of A. indica (neem), there is limited in vivo research. Herein, we discuss the in vivo effects of neem on malaria parasites. With A. indica, the future of malaria treatment is promising, especially for high-risk patients, but further research and clinical trials are required to confirm its biological activity.

Efficacy and safety of Artemisinin Combination Therapy for the treatment of uncomplicated Plasmodium falciparum malaria across international borders of India

Background &amp; objectives: Malaria due to Plasmodium falciparum (Pf) remains a major public threat in India. Artemisinin-based combination therapy (ACT) has been the country’s first-line drug for uncomplicated Pf malaria. In 2013-2014, Artesunate plus sulfadoxine (AS+SP) was replaced by Artemether Lumefantrine (AL) as the first- line antimalarial in North East (NE) states of the country which are endemic for Pf malaria. Regular monitoring of antimalarial drugs is of utmost importance to achieve the goal of elimination. This study aimed to assess the efficacy and safety of ACT for treating uncomplicated Pf malaria in the NE states of India. Methods: A prospective study of 28-day follow-up was conducted to monitor the efficacy and safety of AL from 2018-2019 in four districts, Udalgiri, Meghalaya, Lawngtlai, and Dhalai of NE, India. The clinical and parasitological response and the polymorphism analysis of the Pfdhps, P/dhfr, and Pfkelch 13 gene were evaluated. Results: A total of 234 patients were enrolled in the study out of 216 patients who completed the follow-up to 28 days. One-hundred percent adequate clinical and parasitological responses (ACPR) were observed with polymerase chain reaction (PCR) correction. The genotype results suggest no recrudescence in the treatment-failure patients. The classical single nucleotide polymorphisms (SNP) in the Pfdhfr gene was S108N (94.9%), followed by C59R (91.5%), whereas, in the Pfdhps gene, the common SNP was A437G (79.6%), followed by S3436A. No associated or validated mutations were found in the propeller region of the PfKelch13 gene. Interpretation &amp; conclusion: AL was efficacious and safe in uncomplicated P. falciparum malaria in North East India. In contrast, mutations in the genes responsible for sulfadoxine and pyrimethamine resistance have been fixed in northeast India’s population.

Infections in Pregnancy

Abstract Infections in pregnant women tend to be more severe and pose unique treatment challenges. After all, the well-being of two individuals is at stake. Screening all pregnant women in early pregnancy for bacteriuria is recommended. Pyelonephritis and puerperal sepsis should be managed aggressively with appropriate empiric antibiotic choices. Increasing resistance in Enterobacterales is the complicating treatment of both these illnesses in the Indian setting. Influenza can lead to serious maternal and fetal outcomes; early empiric antiviral therapy and universal maternal vaccination are important. Dengue is an important cause of fever in pregnant women and can complicate vaginal and operative delivery due to thrombocytopenia. Falciparum malaria can now be treated with artemisinin-based combination therapy (ACT) in all trimesters. The drug of choice for scrub typhus is azithromycin; a combination of doxycycline and azithromycin can be considered in very severe disease. Treatment of both drug-sensitive and drug-resistant tuberculosis in pregnancy is similar to the nonpregnant. Safety data relating to bedaquiline and delamanid from animal models and cohort studies are reassuring.

Increased sensitivity of malaria parasites to common antimalaria drugs after the introduction of artemether-lumefantrine: Implication of policy change and implementation of more effective drugs in fight against malaria.

Single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum multi-drug resistance protein 1 (Pfmrp1) gene have previously been reported to confer resistance to Artemisinin-based Combination Therapies (ACTs) in Southeast Asia. A total of 300 samples collected from six sites between 2008 and 2019 under an ongoing malaria drug sensitivity patterns in Kenya study were evaluated for the presence of SNPs at Pfmrp1 gene codons: H191Y, S437A, I876V, and F1390I using the Agena MassARRAY® platform. Each isolate was further tested against artemisinin (ART), lumefantrine (LU), amodiaquine (AQ), mefloquine (MQ), quinine (QN), and chloroquine (CQ) using malaria the SYBR Green I-based method to determine their in vitro drug sensitivity. Of the samples genotyped, polymorphism at Pfmrp1 codon I876V was the most frequent, with 59.3% (163/275) mutants, followed by F1390I, 7.2% (20/278), H191Y, 4.0% (6/151), and S437A, 3.3% (9/274). A significant decrease in median 50% inhibition concentrations (IC50s) and interquartile range (IQR) was noted; AQ from 2.996 ng/ml [IQR = 2.604-4.747, n = 51] in 2008 to 1.495 ng/ml [IQR = 0.7134-3.318, n = 40] (P<0.001) in 2019, QN from 59.64 ng/ml [IQR = 29.88-80.89, n = 51] in 2008 to 18.10 ng/ml [IQR = 11.81-26.92, n = 42] (P<0.001) in 2019, CQ from 35.19 ng/ml [IQR = 16.99-71.20, n = 30] in 2008 to 6.699 ng/ml [IQR = 4.976-9.875, n = 37] (P<0.001) in 2019, and ART from 2.680 ng/ml [IQR = 1.608-4.857, n = 57] in 2008 to 2.105 ng/ml [IQR = 1.266-3.267, n = 47] (P = 0.0012) in 2019, implying increasing parasite sensitivity to the drugs over time. However, no significant variations were observed in LU (P = 0.2692) and MQ (P = 0.0939) respectively, suggesting stable parasite responses over time. There was no statistical significance between the mutation at 876 and parasite sensitivity to selected antimalarials tested, suggesting stable sensitivity for the parasites with 876V mutations. These findings show that Kenyan parasite strains are still sensitive to AQ, QN, CQ, ART, LU, and MQ. Despite the presence of Pfmrp1 mutations in parasites among the population.

Reinvestigation of diphenylmethylpiperazine analogues of pyrazine as new class of Plasmodial cysteine protease inhibitors for the treatment of malaria.

Malaria eradication is still a global challenge due to the lack of a broadly effective vaccine and the emergence of drug resistance to most of the currently available drugs as part of the mainline artemisinin-based combination therapy. A variety of experimental approaches are quite successful in identifying and synthesizing new promising pharmacophore hybrids with distinct mechanisms of action. Based on our recent findings, the current study demonstrates the reinvestigation of a series of diphenylmethylpiperazine and pyrazine-derived molecular hybrids. Pyrazine-derived molecular hybrids were screened to investigate the antiplasmodial activity on drug-susceptible Pf3D7 and drug-resistant PfW2 strains. The selected compounds were shown to be potent dual inhibitors of cysteine protease PfFP2 and PfFP3. Time-course parasitic development study demonstrated that compounds were able to arrest the growth of the parasite at the early trophozoite stage. The compounds did not show hemolysis of red blood cells and showed selectivity to the parasite compared with the mammalian Vero and A5489 cell lines. The study underlined HR5 and HR15 as a new class of Plasmodial falcipain inhibitors with an IC50 of 6.2 μM and 5.9 μM for PfFP2 and 6.8 μM and 6.4 μM for PfFP3, respectively. Both compounds have antimalarial efficacy with IC50 values of 3.05 μM and 2.80 μM for the Pf3D7 strain, and 4.35 μM and 3.39 μM for the PfW2 strain, respectively. Further structural optimization may turn them into potential Plasmodial falcipain inhibitors for malaria therapeutics.

Critical Analysis of the Literature Comparing Artemisinin-Based Combination Therapy and Quinine Treatments for Uncomplicated Malaria in Pregnancy

Critical Analysis of the Literature Comparing Artemisinin-Based Combination Therapy and Quinine Treatments for Uncomplicated Malaria in Pregnancy

Prevalence of polymorphisms in marker genes associated with antimalarial drug resistance in Plasmodium falciparum following 10 years of artemisinin-based combination therapy implementation in urban Kolkata.

Resistance to antimalarial drugs is one of the major challenges for malaria elimination. In India, artemisinin combination therapy (artesunate-sulfadoxin pyrimethamine) was introduced in place of chloroquine (CQ) for the treatment of uncomplicated falciparum malaria in 2010. Periodical monitoring of polymorphisms in antimalarial drug resistance marker genes will be useful for assessing drug pressure, mapping and monitoring of drug resistance status; and will be helpful for searching alternative treatments. This study was conducted to study the polymorphisms in antimalarial drug resistance marker genes among clinical Plasmodium falciparum isolates collected from Kolkata after 10 years of artemisinin-based combination therapie (ACT) implementation. Blood samples were collected from P. falciparum mono-infected patients and polymorphisms in P. falciparum CQ resistance transporter (pfcrt), P. falciparum multidrug resistance (pfmdr-1), P. falciparum dihydrofolate reductase (pfdhfr), P. falciparum dihydropteroate synthetase (pfdhps), pfATPase6 and pfK-13 propeller genes were analysed by polymerase chain reaction and DNA sequencing. In pfcrt gene, C72S, and K76T mutation was recorded in 100% isolates and no mutations was detected in any of the targeted codons of pfmdr-1 gene. A double mutant pfcrt haplotype SVMNT and wildtype haplotype NYD in pfmdr-1 were prevalent in 100% of study isolates. Triple mutant pfdhfr-pfdhps haplotype ANRNI-SGKAA was recorded. No polymorphism in pfK13 gene was documented in any of the isolates. Observed wild codon N86 along with Y184 and D1246 of pfmdr-1 gene might be an indication of the reappearance of CQ sensitivity. The absence of quadruple and quintuple haplotypes in pfdhfr-pfdhps gene along with the wild haplotype of pfK13 is evidence of ACT effectivity. Hence, similar studies with large sample size are highly suggested for monitoring the drug resistance status of P. falciparum.

Meta-Analysis of Data from Four Clinical Trials in the Ivory Coast Assessing the Efficacy of Two Artemisinin-Based Combination Therapies (Artesunate-Amodiaquine and Artemether-Lumefantrine) between 2009 and 2016.

The combinations of artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) are used as first-line treatments for uncomplicated malaria in the Ivory Coast. Different studies document the efficacy of two artemisinin-based combination therapies (ACTs) (AL and ASAQ) in the Ivory Coast. However, there is no meta-analysis examining the data set of these studies. The purpose of this work was to determine the prevalence of malaria treatment failure cases in randomized control trials with two artemisinin-based combination therapies (AL versus ASAQ) in the Ivory Coast between 2009 to 2016. This study is a meta-analysis of data from the results of four previous multicenter, open-label, randomized clinical trial studies evaluating the clinical and parasitological efficacy of artemether-lumefantrine and artesunate-amodiaquine conducted between 2009 and 2016 following World Health Organization (WHO) protocol at sentinel sites in the Ivory Coast. These drug efficacy data collected between 2009 and 2016 were analyzed. During these studies, to distinguish between recrudescence and new infection, molecular genotyping of genes encoding merozoite surface protein 1 and 2 was carried out using nested polymerase chain reaction (PCR). A total of 1575 patients enrolled in the four studies, including 768 in the AL arm and 762 in the ASAQ arm, which were fully followed either for 28 days or 42 days according to WHO protocol. The adequate clinical and parasitological response (ACPR) was higher than 95% in the two groups (intention to treat (ITT): AL = 96.59% and ASAQ = 96.81; Per Protocol (PP): AL = 99.48% and ASAQ = 99.61%) after PCR correction at day 28. Aggregate data analysis (2009-2016) showed that at day 28, the proportions of patients with recurrent infection was higher in the AL group (ITT: 3.79%, PP: 3.9%) than in the ASAQ group (ITT: 2.17%, PP: 2.23%). After PCR correction, most treatment failures were classified as new infections (AL group (ITT: 0.13%, PP: 0.13%); ASAQ group (ITT: 0.39%, PP: 0.39%). The recrudescent infections rate was high, at 0.39% compared to 0.13% for ASAQ and AL, respectively, for both ITT and PP, no significant difference. However, the Kaplan-Meier curve of cumulative treatment success showed a significant difference between the two groups after PCR from 2012-2013 (p = 0.032). Overall, ASAQ and AL have been shown to be effective drugs for the treatment of uncomplicated P. falciparum malaria in the study areas, 14 years after deployment of these drugs.

Primaquine Reduces P vivax Parasitemia Risk

In areas where both P falciparum and P vivax are co-endemic, and a patient is diagnosed with P falciparum malaria, the standard practice is to treat the acute infection with an appropriate antimalarial, often an Artemisinin-based combination therapy (ACT). Primaquine is not typically used for treating the acute P falciparum infection. However, adding primaquine to ACT could help reduce their risk of subsequent P vivax parasitemia. Thriemer and colleagues performed a multicenter clinical trial across Bangladesh, Indonesia, and Ethiopia. The primary endpoint was the incidence risk of P vivax parasitemia on day 63. This trial was registered at ClinicalTrials.gov, NCT03916003. The trial recruited 500 patients and the results suggest that there were very few serious adverse effects while 143 mild adverse effects were also reported. The incidence risk of P vivax parasitemia at day 63 was 11·0% (95% CI 7·5–15·9) in the standard care arm (low dose primaquine) compared with 2·5% (1·0–5·9) in the intervention (high dose primaquine) arm (hazard ratio 0·20, 95% CI 0·08–0·51; p=0·0009). These results suggest that high-dose short-course primaquine can reduce P vivax parasitemia risk within 63 days by fivefold. Lancet. 2023 Dec 2;402(10417):2101-2110. doi: 10.1016/S0140-6736(23)01553-2.

Artemisinin resistance-associated gene mutations in Plasmodium falciparum: A case study of severe malaria from Mozambique

BackgroundThe effectiveness of artemisinin-based combination therapies (ACT) in treating Plasmodium falciparum, is vital for global malaria control efforts, particularly in sub-Saharan Africa. The examination of imported cases from endemic areas holds implications for malaria chemotherapy on a global scale. MethodA 45-year-old male presented with high fever, dry cough, diarrhoea and generalized muscle pain, following a two-week trip to Mozambique. P. falciparum infection with hiperparasitemia was confirmed and the patient was treated initially with quinine and doxycycline, then intravenous artesunate. To assess drug susceptibility, ex vivo half-maximal inhibitory concentration assays were conducted, and the isolated P. falciparum genome was deep sequenced. ResultsThe clinical isolate exhibited elevated ex vivo half-maximal inhibitory concentration values to dihydroartemisinin, lumefantrine, mefloquine and piperaquine. Genomic analysis identified a I416V mutation in the P. falciparum Kelch13 (PF3D7_1343700) gene, and several mutations at the Kelch13 interaction candidate genes, pfkics (PF3D7_0813000, PF3D7_1138700, PF3D7_1246300), including the ubiquitin carboxyl-terminal hydrolase 1, pfubp1 (PF3D7_0104300). Mutations at the drug transporters and genes linked to next-generation antimalarial drug resistance were also present. ConclusionsThis case highlights the emergence of P. falciparum strains carrying mutations in artemisinin resistance-associated genes in Mozambique, couple with a reduction in ex vivo susceptibility to ACT drugs. Continuous surveillance of mutations linked to drug resistance and regular monitoring of drug susceptibility are imperative to anticipate the spread of potential resistant strains emerging in Mozambique and to maintain effective malaria control strategies.

Case Report: Entamoeba Histolytica and Candida Impair Artemisinin-Based Combination Therapy Effect in Malaria Patient

Malaria is an endemic disease in Sudan, and the emergence of antimalarial drugs resistance represent a serious problem affecting the Sudanese population. Acidity reduces absorption of antimalarial drugs and allows for malaria parasites to survive and multiply. Enteric pathogens such as Entamoeba histolytica, candida and Helicobacter pylori may support the growth of Plasmodium falciparum, through inhibition of the absorption of antimalarial agent, such as artemisinin-based combination therapy (ACT).

Private sector availability and affordability of under 5 malaria health commodities in selected states in Nigeria and the Federal Capital Territory.

To guarantee uninterrupted service delivery, quality-assured products must be affordable and continuously available across all sectors, including the private sector, which provides more than 60% of healthcare services in Nigeria. We investigated the private sector availability and affordability of under 5 malaria commodities to establish the level of access in this sector. We surveyed patent medicine and pharmacy stores across seven states in Nigeria and the Federal Capital Territory to establish the availability and affordability of selected malaria commodities for children under 5 years. Availability was measured as the percentage of visited outlets with the product of interest on the day of visit, while affordability was assessed by establishing if it cost more than a day's wage for the least-paid government worker to purchase a full course of malaria diagnostic test and/or medication. Artemisinin-based antimalarials for uncomplicated and severe malaria were the most available commodities. SPAQ1 and SPAQ2 used for seasonal malaria chemoprevention campaign were surprisingly also available in some outlets. However, only about half (48.3% and 53.3%) of the surveyed outlets had stock of artemether/lumefantrine (AL1) and artesunate injection, respectively. The median price of surveyed products ranged from USD (United States Dollars) 0.38 to USD 2.17 per treatment/test. Except for amodiaquine tablet and artemether injection, which cost less, all other originator brands cost the same or more than the lowest-priced generic. Antimalarial products were affordable as their median prices were not more than a day's wage for the least-paid government worker. However, when the cost of testing and treatment with artemisinin-based combination therapies (ACTs) was assessed, testing and treatment with dihydroartemisinin/piperaquine were unaffordable as the they cost more than 1.5 times the daily wage of the least-paid government worker. The overall private sector availability of under-five malaria commodities in surveyed locations was suboptimal. Also, testing and treatment with recommended ACTs were not affordable for all surveyed products. These findings suggest the need for interventions to improve access to affordable under-five malaria commodities.

Evaluation of Stability and TLC Fingerprinting of the Artemether Component in Artemether-Lumefantrine Combination Suspension Formulations Available in Nigeria Pharmaceutical Market

Aim: Artemether is the main component of the artemisinin-based combination therapy (ACT), used in the management of malaria infection caused by Plasmodium falciparum. Hence, its stability and conformation to pharmacopeia standards are necessary for use. The study aimed to review the first-order derivative spectrophotometric method for simultaneous estimation of artemether and its derivatives in pure and combined formulations, and their stability profiles, then develop a simple, precise, and fast technique for their rapid physicochemical analysis.&#x0D; Methodology: Thin-layer chromatographic (TLC) Fingerprinting principles were used in the analysis. Artemether and its derivatives were spotted on the TLC chromatograms after adding 25 mL of the suspension to a mixture of 100 mL of distilled water and 4 mL of NaOH, extracting the mixture with 60 mL of dichloromethane (DCM), drying, and sonicating the residue with 20 mL of the solvent. It was centrifuged, and the clear supernatant was spotted on the TLC plates.&#x0D; Results: The color test results revealed the presence of the artemether compound in the reference standard as well as the six brands of suspensions (A, B, C, D, E, and F) utilized in the study. Artemether melting point was obtained between 86 - 89 °C; within the International Pharmacopeia specified range. The chromatograms of Artemether and derivatives showed Rf values of 0.25 (impurity A), 0.3 (artenimol impurity B), 0.35 (impurity C), 0.4 (α-artemether: impurity D), and 0.55 (artemether).&#x0D; Conclusion: The devised method can be applied to the routine quality control analysis of artemether-lumefantrine suspension in addition to existing analytical techniques.

Metabolic engineering of microbial and plant chasses to optimize artemisinin production

Abstract Artemisinin, a sesquiterpene lactone extracted from the sweet wormwood plant ( Artemisia annua ), is a crucial component in the production of artemisinin-based combination therapies (ACTs), the most effective treatment for malaria. In recent years, metabolic engineering has emerged as a powerful tool to enhance the production of artemisinin, both in microbial and plant chasses. This review article provides an overview of the recent literature on the metabolic engineering strategies employed to optimize artemisinin production, highlighting breakthroughs, challenges, and future directions.