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Clinical and Translational Science Apr 2024Drug resistance to sulfadoxine-pyrimethamine and amodiaquine threatens the efficacy of malaria chemoprevention interventions in children and pregnant women. Combining... (Randomized Controlled Trial)
Randomized Controlled Trial
Drug resistance to sulfadoxine-pyrimethamine and amodiaquine threatens the efficacy of malaria chemoprevention interventions in children and pregnant women. Combining pyronaridine (PYR) and piperaquine (PQP), both components of approved antimalarial therapies, has the potential to protect vulnerable populations from severe malaria. This randomized, double-blind, placebo-controlled (double-dummy), parallel-group, single site phase I study in healthy adult males or females of Black sub-Saharan African ancestry investigated the safety, tolerability, and pharmacokinetics of PYR + PQP (n = 15), PYR + placebo (n = 8), PQP + placebo (n = 8), and double placebo (n = 6) administered orally once daily for 3 days at the registered dose for the treatment of uncomplicated malaria. All participants completed the study. Forty-five adverse events were reported in 26 participants, most (41/45) were mild/moderate in severity, with no serious adverse events, deaths, or study withdrawals. Adverse events were reported in 66.7% (10/15) of participants administered PYR + PQP, 87.5% (7/8) with PYR + placebo, 50.0% (4/8) with PQP + placebo, and 83.3% (5/6) with placebo. For PYR containing regimens, five of 23 participants had asymptomatic transient increases in alanine and/or aspartate aminotransferase. With PQP containing regimens, four of 23 participants had mild Fridericia-corrected QT interval prolongation. Liver enzyme elevations and prolonged QTc interval were consistent with observations for PYR-artesunate and dihydroartemisinin-PQP, respectively, administered to healthy adults and malaria patients. Increases in PYR and PQP exposures were observed following co-administration versus placebo, with substantial interparticipant variability. The findings suggest that PYR + PQP may have potential in chemoprevention strategies. Further studies are needed in the target populations to assess chemoprotective efficacy and define the benefit-risk profile, with special considerations regarding hepatic and cardiac safety.
Topics: Adult; Child; Male; Humans; Female; Pregnancy; Malaria, Falciparum; Malaria; Double-Blind Method; Africa South of the Sahara; Naphthyridines; Piperazines; Quinolines
PubMed: 38594824
DOI: 10.1111/cts.13738 -
Open Forum Infectious Diseases Apr 2024Trials evaluating antimalarials for intermittent preventive treatment in pregnancy (IPTp) have shown that dihydroartemisinin-piperaquine (DP) is a more efficacious...
BACKGROUND
Trials evaluating antimalarials for intermittent preventive treatment in pregnancy (IPTp) have shown that dihydroartemisinin-piperaquine (DP) is a more efficacious antimalarial than sulfadoxine-pyrimethamine (SP); however, SP is associated with higher birthweight, suggesting that SP demonstrates "nonmalarial" effects. Chemoprevention of nonmalarial febrile illnesses (NMFIs) was explored as a possible mechanism.
METHODS
In this secondary analysis, we leveraged data from 654 pregnant Ugandan women without HIV infection who participated in a randomized controlled trial comparing monthly IPTp-SP with IPTp-DP. Women were enrolled between 12 and 20 gestational weeks and followed through delivery. NMFIs were measured by active and passive surveillance and defined by the absence of malaria parasitemia. We quantified associations among IPTp regimens, incident NMFIs, antibiotic prescriptions, and birthweight.
RESULTS
Mean "birthweight for gestational age" scores were 0.189 points (95% CI, .045-.333) higher in women randomized to IPTp-SP vs IPTp-DP. Women randomized to IPTp-SP had fewer incident NMFIs (incidence rate ratio, 0.74; 95% CI, .58-.95), mainly respiratory NMFIs (incidence rate ratio, 0.69; 95% CI, .48-1.00), vs IPTp-DP. Counterintuitively, respiratory NMFI incidence was positively correlated with birthweight in multigravidae. In total 75% of respiratory NMFIs were treated with antibiotics. Although overall antibiotic prescriptions were similar between arms, for each antibiotic prescribed, "birthweight for gestational age" scores increased by 0.038 points (95% CI, .001-.074).
CONCLUSIONS
Monthly IPTp-SP was associated with reduced respiratory NMFI incidence, revealing a potential nonmalarial mechanism of SP and supporting current World Health Organization recommendations for IPTp-SP, even in areas with high-grade SP resistance. While maternal respiratory NMFIs are known risk factors of lower birthweight, most women in our study were presumptively treated with antibiotics, masking the potential benefit of SP on birthweight mediated through preventing respiratory NMFIs.
PubMed: 38585183
DOI: 10.1093/ofid/ofae143 -
Communications Medicine Apr 2024Genomic surveillance is crucial for monitoring malaria transmission and understanding parasite adaptation to interventions. Zambia lacks prior nationwide efforts in...
BACKGROUND
Genomic surveillance is crucial for monitoring malaria transmission and understanding parasite adaptation to interventions. Zambia lacks prior nationwide efforts in malaria genomic surveillance among African countries.
METHODS
We conducted genomic surveillance of Plasmodium falciparum parasites from the 2018 Malaria Indicator Survey in Zambia, a nationally representative household survey of children under five years of age. We whole-genome sequenced and analyzed 241 P. falciparum genomes from regions with varying levels of malaria transmission across Zambia and estimated genetic metrics that are informative about transmission intensity, genetic relatedness between parasites, and selection.
RESULTS
We provide genomic evidence of widespread within-host polygenomic infections, regardless of epidemiological characteristics, underscoring the extensive and ongoing endemic malaria transmission in Zambia. Our analysis reveals country-level clustering of parasites from Zambia and neighboring regions, with distinct separation in West Africa. Within Zambia, identity by descent (IBD) relatedness analysis uncovers local spatial clustering and rare cases of long-distance sharing of closely related parasite pairs. Genomic regions with large shared IBD segments and strong positive selection signatures implicate genes involved in sulfadoxine-pyrimethamine and artemisinin combination therapies drug resistance, but no signature related to chloroquine resistance. Furthermore, differences in selection signatures, including drug resistance loci, are observed between eastern and western Zambian parasite populations, suggesting variable transmission intensity and ongoing drug pressure.
CONCLUSIONS
Our findings enhance our understanding of nationwide P. falciparum transmission in Zambia, establishing a baseline for analyzing parasite genetic metrics as they vary over time and space. These insights highlight the urgency of strengthening malaria control programs and surveillance of antimalarial drug resistance.
PubMed: 38582941
DOI: 10.1038/s43856-024-00498-8 -
The Journal of Infection May 2024The effectiveness of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) is threatened by increasing SP-resistance in...
OBJECTIVE
The effectiveness of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) is threatened by increasing SP-resistance in Africa. We assessed the level of SP-resistance markers, and the clinical and parasitological effectiveness of IPTp-SP in southern Mozambique.
METHODS
P. falciparum infection, antimalarial antibodies and dhfr/dhps SP-resistance mutants were detected by quantitative polymerase chain reaction (qPCR), suspension array technology and targeted deep sequencing, respectively, among 4016 HIV-negative women in Maputo province (2016-2019). Univariate and multivariate regression models were used to assess the association between taking the recommended three or more IPTp-SP doses (IPTp3+) and parasitological and clinical outcomes.
RESULTS
84.3% (3385/4016) women received three or more IPTp-SP doses. The prevalence of quintuple mutants at first antenatal care (ANC) visit was 94.2%. IPTp3+ was associated with a higher clearance rate of qPCR-detected infections from first ANC visit to delivery (adjusted odds ratio [aOR]=5.9, 95% CI: 1.5-33.3; p = 0.012), lower seroprevalence at delivery of antibodies against the pregnancy-specific antigen VAR2CSA (aOR=0.72, 95% CI: 0.54-0.95; p = 0.022), and lower prevalence of low birth weight deliveries (aOR: 0.61, 95% CI: 0.41-0.90; p = 0.013).
CONCLUSION
A sustained parasitological effect of IPTp-SP contributes to the clinical effectiveness of IPTp3+ in areas with high prevalence of SP-resistance markers.
Topics: Humans; Female; Sulfadoxine; Pyrimethamine; Pregnancy; Drug Combinations; Antimalarials; Adult; Drug Resistance; Malaria, Falciparum; Plasmodium falciparum; Mozambique; Young Adult; Pregnancy Complications, Parasitic; Adolescent; Chemoprevention
PubMed: 38574776
DOI: 10.1016/j.jinf.2024.106144 -
The American Journal of Tropical... May 2024Surveillance for genetic markers of resistance can provide valuable information on the likely efficacy of antimalarials but needs to be targeted to ensure optimal use of...
Surveillance for genetic markers of resistance can provide valuable information on the likely efficacy of antimalarials but needs to be targeted to ensure optimal use of resources. We conducted a systematic search and review of publications in seven databases to compile resistance marker data from studies in India. The sample collection from the studies identified from this search was conducted between 1994 and 2020, and these studies were published between 1994 and 2022. In all, Plasmodium falciparum Kelch13 (PfK13), P. falciparum dihydropteroate synthase, and P. falciparum dihydrofolate reductase (PfDHPS) genotype data from 2,953, 4,148, and 4,222 blood samples from patients with laboratory-confirmed malaria, respectively, were extracted from these publications and uploaded onto the WorldWide Antimalarial Resistance Network molecular surveyors. These data were fed into hierarchical geostatistical models to produce maps with a predicted prevalence of the PfK13 and PfDHPS markers, and of the associated uncertainty. Zones with a predicted PfDHPS 540E prevalence of >15% were identified in central, eastern, and northeastern India. The predicted prevalence of PfK13 mutants was nonzero at only a few locations, but were within or adjacent to the zones with >15% prevalence of PfDHPS 540E. There may be a greater probability of artesunate-sulfadoxine-pyrimethamine failures in these regions, but these predictions need confirmation. This work can be applied in India and elsewhere to help identify the treatments most likely to be effective for malaria elimination.
Topics: Plasmodium falciparum; Pyrimethamine; Sulfadoxine; India; Drug Resistance; Antimalarials; Drug Combinations; Humans; Malaria, Falciparum; Artemisinins; Tetrahydrofolate Dehydrogenase; Genetic Markers; Dihydropteroate Synthase; Protozoan Proteins
PubMed: 38574550
DOI: 10.4269/ajtmh.23-0631 -
Malaria Journal Mar 2024A Stakeholder engagement meeting on the implementation of post-discharge malaria chemoprevention (PDMC) in Benin, Kenya, Malawi, and Uganda was held in Nairobi, Kenya,... (Meta-Analysis)
Meta-Analysis
A Stakeholder engagement meeting on the implementation of post-discharge malaria chemoprevention (PDMC) in Benin, Kenya, Malawi, and Uganda was held in Nairobi, Kenya, on 27 September 2023. Representatives from the respective National Malaria Control Programmes, the World Health Organization (WHO) Geneva, Africa Regional and Kenya offices, research partners, non-governmental organizations, and the Medicines for Malaria Venture participated. PDMC was recommended by the WHO in June 2022 and involves provision of a full anti-malarial treatment course at regular intervals during the post-discharge period in children hospitalized with severe anaemia in areas of moderate-to-high malaria transmission. The WHO recommendation followed evidence from a meta-analysis of three clinical trials and from acceptability, delivery, cost-effectiveness, and modelling studies. The trials were conducted in The Gambia using monthly sulfadoxine-pyrimethamine during the transmission season, in Malawi using monthly artemether-lumefantrine, and in Kenya and Uganda using monthly dihydroartemisinin-piperaquine, showing a significant reduction in all-cause mortality by 77% (95% CI 30-98) and a 55% (95% CI 44-64) reduction in all-cause hospital readmissions 6 months post-discharge. The recommendation has not yet been implemented in sub-Saharan Africa. There is no established platform for PDMC delivery. The objectives of the meeting were for the participating countries to share country contexts, plans and experiences regarding the adoption and implementation of PDMC and to explore potential delivery platforms in each setting. The meeting served as the beginning of stakeholder engagement within the PDMC Saves Lives project and will be followed by formative and implementation research to evaluate alternative delivery strategies in selected countries. Meeting highlights included country consensus on use of dihydroartemisinin-piperaquine for PDMC and expansion of the target group to "severe anaemia or severe malaria", in addition to identifying country-specific options for PDMC delivery for evaluation in implementation research. Further exploration is needed on whether the age group should be extended to school-age children.
Topics: Child; Humans; Antimalarials; Kenya; Uganda; Aftercare; Malawi; Benin; Patient Discharge; Stakeholder Participation; Artemether; Artemether, Lumefantrine Drug Combination; Malaria; Pyrimethamine; Drug Combinations; Chemoprevention; Anemia; Artemisinins
PubMed: 38539181
DOI: 10.1186/s12936-023-04810-0 -
PLOS Global Public Health 2024Malaria in pregnancy is a major public health concern that contributes to a significant increase in maternal and child mortality and morbidity. Intermittent preventive...
Factors associated with the uptake of intermittent preventive treatment for malaria during pregnancy in Cameroon: An analysis of data from the 2018 Cameroon Demographic and Health Survey.
Malaria in pregnancy is a major public health concern that contributes to a significant increase in maternal and child mortality and morbidity. Intermittent preventive treatment of malaria during pregnancy using sulfadoxine-pyrimethamine (IPTp-SP) is a key intervention recommended by the World Health Organization (WHO) and implemented in Cameroon to reduce the morbidity associated with malaria during pregnancy. This study aimed to assess the distribution of the poor uptake of IPTp-SP (i.e. fewer than three doses) in Cameroon and the factors associated. We conducted a secondary analysis of data extracted from the 2018 Cameroon Demographic and Health Survey. Data was collected using a face-to-face questionnaire administered to mothers with at least one child under the age of five. The participants were selected using a two-stage stratified sampling process. We estimated the frequencies of mothers receiving fewer than three doses of IPTp-SP. Multilevel logistic regression modeling was used to assess the associations between key suspected determinants and uptake of fewer than three doses of IPTp-SP. Crude and adjusted Odds-Ratio (ORs) were estimated. A total of 13,527 women of childbearing age were interviewed, of whom 5,528 (40.9%) met our selection criteria. Among them, 845 (15.3%) women had no antenatal consultation (ANC) visit, 1,109 (20%) had 1-3 visits, 3,379 (61.1%) had 4-7 visits, and only 195 (3.5%) had at least eight visits. Moreover, 3,398 (61.5%, CI: 60.2-62.8) had received fewer than three doses of IPTp-SP. Our findings show that the predictors of poor uptake of IPTp-SP include attending the first ANC visit after the third month of pregnancy (aOR = 1.52, CI: 1.30-1.77), attending fewer than four ANC visits (aOR = 1.29, CI: 1.06-1.56), and not being attended to by a healthcare professional during the prenatal period (aOR = 4.63, CI: 2.81-7.64). Residing in the Sahelian regions was not increasing the risk of poor IPTp-SP uptake on its own but was positively modifying the effect of not being attended by a healthcare professional (p < 0.001). We did not find a significant association between a higher level of education and the uptake of IPTp-SP (aOR = 1.10, CI: 0.90-1.32). Nearly two third of the pregnant women in Cameroon have a poor uptake of IPTp-SP. Interventions focused on ANC provision ought to be explored and tested to address this gap, with priority assigned to the Sahelian region.
PubMed: 38536856
DOI: 10.1371/journal.pgph.0001245 -
Oncoscience 2024This short note presents the data and rationale for adding five generic non-oncology drugs from general medical practice to gemcitabine, nab-paclitaxel, a current...
IPIAD- an augmentation regimen added to standard treatment of pancreatic ductal adenocarcinoma using already-marketed repurposed drugs irbesartan, pyrimethamine, itraconazole, azithromycin, and dapsone.
This short note presents the data and rationale for adding five generic non-oncology drugs from general medical practice to gemcitabine, nab-paclitaxel, a current standard cytotoxic chemotherapy of pancreatic ductal adenocarcinoma. The regimen, called IPIAD, uses an angiotensin receptor blocker (ARB) irbesartan indicated for treating hypertension, an old antimicrobial drug pyrimethamine indicated for treating toxoplasmosis or malaria, an old antifungal drug itraconazole, an old broad spectrum antibiotic azithromycin and an old antibiotic dapsone. In reviewing selected growth driving systems active in pancreatic ductal adenocarcinoma then comparing these with detailed data on ancillary attributes of the IPIAD drugs, one can predict clinical benefit and slowing growth of pancreatic ductal adenocarcinoma by this augmentation regimen.
PubMed: 38524376
DOI: 10.18632/oncoscience.594 -
Acta Tropica Jun 2024Over the past year, P. falciparum infections have declined in Thailand, yet nonhuman primate malaria infections have correspondingly increased, including Plasmodium...
Over the past year, P. falciparum infections have declined in Thailand, yet nonhuman primate malaria infections have correspondingly increased, including Plasmodium knowlesi and P. cynomolgi. Nevertheless, little is known about simian malaria in its natural macaque hosts, Macaca mulatta and Macaca fascicularis. This study aims to address several research questions, including the prevalence and distribution of simian malaria in these two Thai wild macaque species, variations in infection between different macaque species and between M. fascicularis subspecies, and the genetic composition of these pathogens. Blood samples were collected from 82 M. mulatta and 690 M. fascicularis across 15 locations in Thailand, as well as two locations in Vietnam and Myanmar. We employed quantitative real-time PCR targeting the Plasmodium genus-specific 18S ribosomal RNA (rRNA) gene to detect malaria infection, with a limit of detection set at 1,215.98 parasites per mL. We genotyped eight microsatellite markers, and the P. cynomolgi dihydrofolate reductase gene (DHFR) was sequenced (N = 29). In total, 100 of 772 samples (13 %) tested positive for malaria, including 45 (13 %) for P. cynomolgi, 37 (13 %) for P. inui, 16 (5 %) for P. coatneyi, and 2 (0.25 %) for Hepatocystis sp. in Saraburi, central and Ranong, southern Thailand. Notably, simian malaria infection was observed exclusively in M. fascicularis and not in M. mulatta (P = 0.0002). Particularly, P. cynomolgi was detected in 21.7 % (45/207) of M. f. fascicularis living in Wat Tham Phrapothisat, Saraburi Province. The infection with simian malaria was statistically different between M. fascicularis and M. mulatta (P = 0.0002) but not within M. fascicularis subspecies (P = 0.78). A haplotype network analysis revealed that P. cynomolgi shares a lineage with reference strains obtained from macaques. No mutation in the predicted binding pocket of PcyDHFR to pyrimethamine was observed. This study reveals a significant prevalence of simian malaria infection in M. fascicularis. The clonal genotypes of P. cynomolgi suggest in-reservoir breeding. These findings raise concerns about the potential spread of nonhuman primate malaria to humans and underscore the need for preventive measures.
Topics: Animals; Thailand; Malaria; Macaca fascicularis; Prevalence; RNA, Ribosomal, 18S; Genetic Variation; Macaca mulatta; Genotype; Microsatellite Repeats; Monkey Diseases; Humans; Myanmar; Tetrahydrofolate Dehydrogenase; Plasmodium knowlesi; Plasmodium; Vietnam; DNA, Protozoan; Plasmodium cynomolgi; Real-Time Polymerase Chain Reaction
PubMed: 38518834
DOI: 10.1016/j.actatropica.2024.107187 -
BMJ Open Mar 2024Seasonal malaria chemoprevention (SMC) involves repeated administrations of sulfadoxine-pyrimethamine plus amodiaquine to children below the age of 5 years during the...
Understanding and maximising the community impact of seasonal malaria chemoprevention in Burkina Faso (INDIE-SMC): study protocol for a cluster randomised evaluation trial.
INTRODUCTION
Seasonal malaria chemoprevention (SMC) involves repeated administrations of sulfadoxine-pyrimethamine plus amodiaquine to children below the age of 5 years during the peak transmission season in areas of seasonal malaria transmission. While highly impactful in reducing malaria burden in controlled research settings, the impact of SMC on infection prevalence is moderate in real-life settings. It remains unclear what drives this efficacy decay. Recently, the WHO widened the scope for SMC to target all vulnerable populations. The Ministry of Health (MoH) in Burkina Faso is considering extending SMC to children below 10 years old. We aim to assess the impact of SMC on clinical incidence and parasite prevalence and quantify the human infectious reservoir for malaria in this population.
METHODS AND ANALYSIS
We will perform a cluster randomised trial in Saponé Health District, Burkina Faso, with three study arms comprising 62 clusters of three compounds: arm 1 (control): SMC in under 5-year-old children, implemented by the MoH without directly observed treatment (DOT) for the full course of SMC; arm 2 (intervention): SMC in under 5-year-old children, with DOT for the full course of SMC; arm 3 (intervention): SMC in under 10-year-old children, with DOT for the full course of SMC. The primary endpoint is parasite prevalence at the end of the malaria transmission season. Secondary endpoints include the impact of SMC on clinical incidence. Factors affecting SMC uptake, treatment adherence, drug concentrations, parasite resistance markers and transmission of parasites will be determined.
ETHICS AND DISSEMINATION
The London School of Hygiene & Tropical Medicine's Ethics Committee (29193) and the Burkina Faso National Medical Ethics Committee (Deliberation No 2023-05-104) approved this study. The findings will be presented to the community; disease occurrence data and study outcomes will also be shared with the Burkina Faso MoH. Findings will be published irrespective of their results.
TRIAL REGISTRATION NUMBER
NCT05878366.
Topics: Child, Preschool; Humans; Infant; Antimalarials; Burkina Faso; Chemoprevention; Drug Combinations; Malaria; Randomized Controlled Trials as Topic; Seasons; Child
PubMed: 38479748
DOI: 10.1136/bmjopen-2023-081682