Malaria Chemoprevention Research Articles

An observational analysis of the impact of indoor residual spraying in two distinct contexts of Burkina Faso

BackgroundIndoor residual spraying (IRS) is a cornerstone malaria control intervention in Burkina Faso. From 2018 to 2021, non-pyrethroid IRS was implemented annually in two regions of Burkina Faso with distinct malaria transmission patterns, concurrently with annual seasonal malaria chemoprevention (SMC), and a mass insecticide-treated net (ITN) distribution in 2019.MethodsA retrospective quasi-experimental approach was used to evaluate the impact of the 2018, 2020, and 2021 IRS campaigns on routinely reported confirmed malaria case incidence at health facilities. The 2019 campaign was excluded due to lack of data reporting during a health sector strike. Controlled interrupted time series models were fit to detect changes in level and trend in malaria case incidence rates following each IRS campaign when compared to the baseline period 24-months before IRS. IRS districts Solenzo (Sudano-Sahelien climate), and Kampti (tropical climate) were compared with neighbouring control districts and the analyses were stratified by region. Modelled health facility catchment population estimates based on travel time to health facilities and weighted by non-malaria outpatient visits were used as an offset. The study period encompassed July 2016 through June 2022, excluding July 2018 to June 2019.ResultsDistrict-level population and structure coverage achieved by IRS campaigns was greater than 85% in 2018, 2020, and 2021 in Solenzo and Kampti. In Solenzo a significant difference in malaria case incidence rates was detected after the 2018 campaign (IRR = 0.683; 95% CI 0.564–0.827) when compared to the control district. The effect was not detected following the 2020 or 2021 IRS campaigns. In Kampti, estimated malaria incidence rates were between 36 and 38% lower than in the control district following all three IRS campaigns compared to the baseline period.ConclusionsImplementation of IRS in Kampti, a tropical region of Burkina Faso, appeared to have a consistent significant beneficial impact on malaria case rates. An initial positive impact in Solenzo after the first IRS campaign was not sustained in the successive evaluated IRS campaigns. This study points to a differential effect of IRS in different malaria transmission settings and in combination with ITN and SMC implementation.

Measuring changes in Plasmodium falciparum census population size in response to sequential malaria control interventions.

Here we introduce a new endpoint ″census population size″ to evaluate the epidemiology and control of Plasmodium falciparum infections, where the parasite, rather than the infected human host, is the unit of measurement. To calculate census population size, we rely on a definition of parasite variation known as multiplicity of infection (MOI var ), based on the hyper-diversity of the var multigene family. We present a Bayesian approach to estimate MOI var from sequencing and counting the number of unique DBLα tags (or DBLα types) of var genes, and derive from it census population size by summation of MOI var in the human population. We track changes in this parasite population size and structure through sequential malaria interventions by indoor residual spraying (IRS) and seasonal malaria chemoprevention (SMC) from 2012 to 2017 in an area of high-seasonal malaria transmission in northern Ghana. Following IRS, which reduced transmission intensity by > 90% and decreased parasite prevalence by ~40-50%, significant reductions in var diversity, MOI var , and population size were observed in ~2,000 humans across all ages. These changes, consistent with the loss of diverse parasite genomes, were short lived and 32-months after IRS was discontinued and SMC was introduced, var diversity and population size rebounded in all age groups except for the younger children (1-5 years) targeted by SMC. Despite major perturbations from IRS and SMC interventions, the parasite population remained very large and retained the var population genetic characteristics of a high-transmission system (high var diversity; low var repertoire similarity) demonstrating the resilience of P. falciparum to short-term interventions in high-burden countries of sub-Saharan Africa.

Barriers to the quality delivery of seasonal malaria chemoprevention in Chad and Burkina Faso: a qualitative exploration of caregivers and community distributors’ perspectives

BackgroundRecommended since 2012 by the World Health Organization (WHO), seasonal malaria chemoprevention (SMC) is a community-based intervention to prevent malaria in children in African regions where malaria transmission follows a seasonal pattern. Following the publication of consolidated WHO guidelines for malaria, SMC is expected to reach more children in new geographies in future years. Though SMC has been shown to reduce malaria-related morbidity and mortality, there is potential for quality improvement of the intervention implementation. Assisted by ten quality standards from a framework developed by Malaria Consortium, this paper aims to better understand the quality of SMC implementation and identify potential barriers to quality delivery of SMC.MethodsA qualitative thematic analysis on data collected after the annual SMC rounds implemented in Burkina Faso and Chad in 2019 was conducted. Sixteen focus group discussions conducted with caregivers and community distributors were analysed. Three selected quality standards for SMC delivery; planning and enumeration; community engagement; and administration of SMC medicines provided overarching quality themes under which subthemes were identified.ResultsEight subthemes relating to the three quality standards were identified. Although SMC was well accepted by communities in both settings, common barriers to the quality delivery of SMC were identified including difficulty ensuring adherence to the SMC administration protocol; difficulties reaching mobile populations; concerns around adverse drug reactions; rumours, and concerns about SMC safety; and community distributors’ working conditions. Context-specific barriers included: the suboptimal timeliness of the SMC round in Burkina Faso, and the lack of involvement of female caregivers in mobilization activities in Chad.ConclusionIn the context of increased adoption of SMC, this paper provides relevant insights and recommendations for the improved implementation of SMC programmes. These include the integration of strategies addressing communities’ concerns around adverse drug reactions, gender-specific mobilization strategies, and attention to community distributors’ working conditions. It also highlights the importance and utility of further, robust research on the quality of SMC delivery.

Plasmodium falciparum infection status in children less than 10 years old under seasonal malaria chemoprevention and risk of clinical malaria in the Koulikoro health district, Mali.

Seasonal malaria chemoprevention (SMC) with Sulfadoxine pyrimethamine plus amodiaquine (SP + AQ) consist of a monthly administration of therapeutic dose to children under five years of age during the high risk of malaria in area where malaria is highly seasonal. According to SMC recommendation, both non-infected and asymptomatic Plasmodium falciparum infected children will receive similar treatment. The gap in our knowledge is how the effect of asymptomatic infection on the efficacy of SMC in preventing clinical malaria over a four-week period. Thus, this study aimed to assess the risk of clinical malaria and its association with children's infection status when SMC treatment is given. The study was carried out in the Koulikoro health district in Mali and concerned children under 10 years of age. A total of 726 and 1452 children were randomly selected and followed over the SMC campaign in the years 2019 and 2020 respectively. Prevalence of asymptomatic P. falciparum infection was determined each round by microscopy before SMC drugs intake. Children were passively followed over a four-week period to determine incidence of clinical malaria. R-Studio software was used for analysis. The risk of clinical malaria by infection status was estimated using a logistic regression. A Kaplan-Meier curve was used to determine the survival time between infected and uninfected children. The Pearson Chi-square test was used to compare proportions with the significant level at p< 0.05. The average prevalence of asymptomatic infection was 11.0% both years, and it was higher among children aged 5 to 9 years old in 2019 (p<0.001) and 2020 (p=0.016). The risk of clinical malaria was significantly higher among asymptomatic infected children 2019: (RR=3.05, CI [2.04-4.72]) and 2020 (RR=1.43, CI [1.04-1.97]) transmission seasons. Likewise, the time of the first malaria occurrence was statistically lower among infected children regardless the year (p<0.001 in 2019 and p=0.01 in 2020). Results show a high risk of clinical malaria in asymptomatic infected children during SMC delivery. Screening for P. falciparum infection before the SMC treatment could significantly enhance the impact of the strategy on malaria morbidity in endemic areas.

Mass drug administration to reduce malaria incidence in a low-to-moderate endemic setting: short-term impact results from a cluster randomised controlled trial in Senegal.

In Africa, the scale-up of malaria control interventions, including seasonal malaria chemoprevention (SMC), has dramatically reduced malaria burden, but progress toward malaria elimination has stalled. We evaluated mass drug administration (MDA) as a strategy to accelerate reductions in malaria incidence in Senegal. We conducted an open-label, cluster-randomised controlled trial in a low-to-moderate transmission setting of Tambacounda, Senegal. Eligible villages had a population size between 200-800. All villages received pyrethroid-piperonyl butoxide bednets and proactive community case management of malaria at baseline. Sixty villages were randomised 1:1 to either three cycles of MDA with dihydroartemisinin-piperaquine+single-low dose primaquine administered to individuals aged ≥3 months, six-weeks apart starting the third week of June (intervention), or standard-of-care, which included three monthly cycles of SMC with sulfadoxine-pyrimethamine+amodiaquine administered to children aged 3-120 months starting end of July (control). MDA and SMC were delivered door-to-door. The primary outcome was clinical malaria incidence in all ages assessed during the peak transmission season (July-December), the year after intervention. Here, we report safety, coverage, and impact outcomes during the intervention year. The trial is registered at ClinicalTrials.Gov (NCT04864444). Between June 21, 2021 and October 3, 2021, 6505, 7125, and 7250 participants were administered MDA and 3202, 3174, and 3146 participants were administered SMC across cycles. Coverage of ≥1 dose of MDA drugs was 79%, 82%, and 83% across cycles. During the transmission season of the intervention year, MDA was associated with a 55% [95% CI: 28%-72%] lower incidence of malaria compared to control (MDA: 93 cases/1000 population; control: 173 cases/1000 population). No serious adverse events were reported in either arm. In low-to-moderate malaria transmission settings with scaled-up malaria control interventions, MDA with dihydroartemisinin-piperaquine+single-low dose primaquine is effective and well-tolerated for reducing malaria incidence. Further analyses will focus on the sustainability of this reduction. United States President's Malaria Initiative.

Two decades of molecular surveillance in Senegal reveal rapid changes in known drug resistance mutations over time

BackgroundDrug resistance in Plasmodium falciparum is a major threat to malaria control efforts. Pathogen genomic surveillance could be invaluable for monitoring current and emerging parasite drug resistance.MethodsData from two decades (2000–2020) of continuous molecular surveillance of P. falciparum parasites from Senegal were retrospectively examined to assess historical changes in malaria drug resistance mutations. Several known drug resistance markers and their surrounding haplotypes were profiled using a combination of single nucleotide polymorphism (SNP) molecular surveillance and whole genome sequence based population genomics.ResultsThis dataset was used to track temporal changes in drug resistance markers whose timing correspond to historically significant events such as the withdrawal of chloroquine (CQ) and the introduction of sulfadoxine-pyrimethamine (SP) in 2003. Changes in the mutation frequency at Pfcrt K76T and Pfdhps A437G coinciding with the 2014 introduction of seasonal malaria chemoprevention (SMC) in Senegal were observed. In 2014, the frequency of Pfcrt K76T increased while the frequency of Pfdhps A437G declined. Haplotype-based analyses of Pfcrt K76T showed that this rapid increase was due to a recent selective sweep that started after 2014.Discussion (Conclusion)The rapid increase in Pfcrt K76T is troubling and could be a sign of emerging amodiaquine (AQ) resistance in Senegal. Emerging AQ resistance may threaten the future clinical efficacy of artesunate-amodiaquine (ASAQ) and AQ-dependent SMC chemoprevention. These results highlight the potential of molecular surveillance for detecting rapid changes in parasite populations and stress the need to monitor the effectiveness of AQ as a partner drug for artemisinin-based combination therapy (ACT) and for chemoprevention.

Seasonal malaria chemoprevention and the spread of Plasmodium falciparum quintuple-mutant parasites resistant to sulfadoxine–pyrimethamine: a modelling study

Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine prevents millions of clinical malaria cases in children younger than 5years in Africa's Sahel region. However, Plasmodium falciparum parasites partially resistant to sulfadoxine-pyrimethamine (with quintuple mutations) potentially threaten the protective effectiveness of SMC. We evaluated the spread of quintuple-mutant parasites and the clinical consequences. We used an individual-based malaria transmission model with explicit parasite dynamics and drug pharmacological models to identify and quantify the influence of factors driving quintuple-mutant spread and predict the time needed for the mutant to spread from 1% to 50% of inoculations for several SMC deployment strategies. We estimated the impact of this spread on SMC effectiveness against clinical malaria. Higher transmission intensity, SMC coverage, and expanded age range of chemoprevention promoted mutant spread. When SMC was implemented in a high-transmission setting (40% parasite prevalence in children aged 2-10years) with four monthly cycles to children aged 3months to 5years (with 95% initial coverage declining each cycle), the quintuple mutant required 53·1years (95% CI 50·5-56·0) to spread from 1% to 50% of inoculations. This time increased in lower-transmission settings and reduced by half when SMC was extended to children aged 3months to 10years, or reduced by 10-13years when an additional monthly cycle of SMC was deployed. For the same setting, the effective reduction in clinical cases in children receiving SMC was 79·0% (95%CI 77·8-80·8) and 60·4% (58·6-62·3) during the months of SMC implementation when the quintuple mutant was absent or fixed in the population, respectively. SMC with sulfadoxine-pyrimethamine plus amodiaquine leads to a relatively slow spread of sulfadoxine-pyrimethamine-resistant quintuple mutants and remains effective at preventing clinical malaria despite the mutant spread. SMC with sulfadoxine-pyrimethamine plus amodiaquine should be considered in seasonal settings where this mutant is already prevalent. Swiss National Science Foundation and Marie Curie Individual Fellowship.

Plasmodium falciparum dhps and dhfr markers of resistance to sulfadoxine–pyrimethamine five years (2016–2020) after the implementation of seasonal malaria chemoprevention in Cameroon

Background Antimalarial drug resistance is a major challenge in the fight against malaria. Cameroon implemented seasonal malaria chemoprevention (SMC) with sulfadoxine–pyrimethamine and amodiaquine (SPAQ) to over 1.5 million children aged 3–59 months from 2016, raising concerns whether drug pressure may lead to a selection of known parasite resistance mutations. This study aimed at assessing the profiles of plasmodium falciparum dihydrofolate reductase (DHFR) and plasmodium falciparum dihydropteroate synthase (DHPS) gene mutations that encode enzyme targeting SP before and 5 years after the introduction of SMC in the northern part of Cameroon. Methods Dried blood spots were prepared from symptomatic P. falciparum-positive children prior to SPAQ administration in 2016 and after the SMC round of 2020. DNA was extracted using the Chelex-100 method, and dhfr and dhps mutations were determined after a nested polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) technique and agarose gel electrophoresis. Results 405 children with acute uncomplicated malaria were recruited. Of 405 samples, 201/405 (49.63%) were collected in 2016 and 204/405 (50.37%) were collected in 2020. High levels of mutant alleles S108N, C59R, N51I of dhfr were obtained both in 2016 and 2020 (174 (100%), 166 (95.4%), 131 (75.3%)); (140 (99.4%), 131 (92.2%), 114 (80.3%)) while the frequency of dhps mutant alleles in the A437G and K540E loci stood at 93 (51.9%) and 6 (3.4%) in 2016 and 73 (52.5%) and 4 (2.8%) in 2020, respectively. The quintuple resistant haplotype IRNGE was found in two (1.1%) and one (0.7%) in 2016 and 2020, respectively. No significant difference was observed in the frequency of the studied mutations between the two time points, although we noted a rise in the resistance conferring haplotype IRNG in 2020. Conclusions Continuous monitoring is recommended to preempt the widespread occurrence of high-grade resistance bearing parasites in the northern regions of Cameroon.

Evaluation of practices and attitudes of caregivers influencing adherence to seasonal malaria chemoprevention in children under five years of age: the case of Rural Embangweni, Mzimba District, Malawi

Evaluation of practices and attitudes of caregivers influencing adherence to seasonal malaria chemoprevention in children under five years of age: the case of Rural Embangweni, Mzimba District, Malawi

Assessment of added protection conferred by combined use of indoor residual spraying (IRS) and seasonal malaria chemoprevention (SMC) for malaria prevention in Benin

Assessment of added protection conferred by combined use of indoor residual spraying (IRS) and seasonal malaria chemoprevention (SMC) for malaria prevention in Benin

Impact of seasonal malaria chemoprevention based on the number of medicines doses received on malaria burden among children aged 3-59 months in Nigeria: A propensity score-matched analysis.

Seasonal malaria chemoprevention using sulfadoxine-pyrimethamine plus amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine on Day 1 and amodiaquine on both Day 2 and Day 3) is delivered to children aged 3-59 months in areas of highly season malaria transmission. While the overall population-level impact of seasonal malaria chemoprevention on malaria control has been documented in various countries and time periods, there is no clear evidence regarding seasonal malaria chemoprevention impact based on the number of medicine doses children receive in one cycle in routine programmatic conditions. Data were extracted from Nigeria's routinely collected seasonal malaria chemoprevention end-of-round coverage surveys (2021, 2022). We matched seasonal malaria chemoprevention-targeted children who received specific numbers of seasonal malaria chemoprevention medicines with those who did not receive any doses of seasonal malaria chemoprevention medicines (non-sulfadoxine-pyrimethamine plus amodiaquine) using multiple sets of propensity score matches. We performed multilevel logistic regression for each matched group to evaluate the association between the number of doses of seasonal malaria chemoprevention medicines and monthly confirmed malaria cases (caregiver-reported malaria infection diagnosed by rapid diagnostic test at a health facility following the penultimate cycle of seasonal malaria chemoprevention). Among 21,621 SMC-targeted children, 9.7% received non-sulfadoxine-pyrimethamine plus amodiaquine, 0.5% received only Day 1 sulfadoxine-pyrimethamine plus amodiaquine, 1.0% received Day 1 sulfadoxine-pyrimethamine plus amodiaquine and either Day 2 amodiaquine or Day 3 amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine), and 88.8% received Day 1 sulfadoxine-pyrimethamine plus amodiaquine and both Day 2 and Day 3 amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine + amodiaquine). Children receiving only Day 1 sulfadoxine-pyrimethamine plus amodiaquine did not have significant lower odds of rapid diagnostic tests-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.77, 0.42-1.42). However, children receiving sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine had significantly lower odds of rapid diagnostic tests-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.42, 95% CI 0.28-0.63). Similarly, children receiving sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine + amodiaquine also had significantly lower odds of rapid diagnostic test-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.54, 95% CI 0.47-0.62). Adherence to at least one daily dose of amodiaquine administration following receipt of Day 1 sulfadoxine-pyrimethamine plus amodiaquine by eligible children is crucial to ensure the effectiveness of seasonal malaria chemoprevention. This demonstrates the importance of enhancing caregiver awareness regarding the importance of amodiaquine and identifying barriers toward amodiaquine administration at the community level.

Household-level effects of seasonal malaria chemoprevention in the Gambia.

In 2022 the WHO recommended the discretionary expansion of the eligible age range for seasonal malaria chemoprevention (SMC) to children older than 4 years. Older children are at lower risk of clinical disease and severe malaria so there has been uncertainty about the cost-benefit for national control programmes. However, emerging evidence from laboratory studies suggests protecting school-age children reduces the infectious reservoir for malaria and may significantly impact on transmission. This study aimed to assess whether these effects were detectable in the context of a routinely delivered SMC programme. In 2021 the Gambia extended the maximum eligible age for SMC from 4 to 9 years. We conducted a prospective population cohort study over the 2021 malaria transmission season covering 2210 inhabitants of 10 communities in the Upper River Region, and used a household-level mixed modelling approach to quantify impacts of SMC on malaria transmission. We demonstrate that the hazard of clinical malaria in older participants aged 10+ years ineligible for SMC decreases by 20% for each additional SMC round per child 0-9 years in the same household. Older inhabitants also benefit from reduced risk of asymptomatic infections in high SMC coverage households. Spatial autoregression tests show impacts are highly localised, with no detectable spillover from nearby households. Evidence for the transmission-reducing effects of extended-age SMC from routine programmes implemented at scale has been previously limited. Here we demonstrate benefits to the entire household, indicating such programmes may be more cost-effective than previously estimated.

Field testing of user-friendly perennial malaria chemoprevention packaging in Benin, Côte d’Ivoire and Mozambique

BackgroundPerennial malaria chemoprevention (PMC) aims to protect children at risk from severe malaria by the administration of anti-malarial drugs to children of defined ages throughout the year. Sulfadoxine-pyrimethamine (SP) has been widely used for chemoprevention in Africa and a child-friendly dispersible tablet formulation has recently become available.MethodsThis qualitative non-interventional observational study was conducted in Benin, Côte d’Ivoire, and Mozambique between February and June 2022. Prototype blister packs, dispensing boxes and job aids designed to support dispersible SP deployment for PMC were evaluated using focus group discussions (FGD) and semi-structured in-depth individual interviews (IDI) with health authorities, health personnel, community health workers (CHWs) and caregivers. The aim was to evaluate knowledge and perceptions of malaria and chemoprevention, test understanding of the tools and identify gaps in understanding, satisfaction, user-friendliness and acceptability, and assess the potential role of CHWs in PMC implementation. Interviews were transcribed and imported to ATLAS.ti for encoding and categorization. Thematic content analysis used deductive and inductive coding with cross-referencing of findings between countries and participants to enrich data interpretation. Continuous comparison across the IDI and FGD permitted iterative, collaborative development of materials.ResultsOverall, 106 participants completed IDIs and 70 contributed to FGDs. Malaria was widely recognised as the most common disease affecting children, and PMC was viewed as a positive intervention to support child health. The role of CHWs was perceived differently by the target groups, with caregivers appreciating their trusted status in the community, whereas health authorities preferred clinic-based deployment of PMC by health professionals. Empirical testing of the prototype blister packs, dispensing boxes and job aids highlighted the context-specific expectations of respondents, such as familiar situations and equipment, and identified areas of confusion or low acceptance. A key finding was the need for a clear product identity reflecting malaria.ConclusionSimple modifications profoundly affected the perception of PMC and influenced acceptability. Iterative quantitative investigation resulted in PMC-specific materials suited to the local context and socio-cultural norms of the target population with the aim of increasing access to chemoprevention in children most at risk of severe malaria.

Plasmodium ovale spp dhfr mutations associated with reduced susceptibility to pyrimethamine in sub-Saharan Africa: a retrospective genetic epidemiology and functional study

Mutations in the Plasmodium falciparum dhfr gene confer resistance to pyrimethamine, which is widely used for malaria chemoprevention in Africa. We aimed to evaluate the frequency and evolution of dhfr mutations in Plasmodium ovale spp in Africa and their functional consequences, which are incompletely characterised. We analysed dhfr mutations and their frequencies in P ovale spp isolates collected between Feb 1, 2004, and Aug31, 2023, from the French National Malaria Reference Centre collection and from field studies in Benin, Gabon, and Kenya. Genetic patterns of positive selection were investigated. Full-length recombinant wild-type and mutant DHFR enzymes from both P ovale curtisi and P ovale wallikeri were expressed in bacteria to test whether the most common mutations reduced pyrimethamine susceptibility. We included 518 P ovale spp samples (314 P ovale curtisi and 204 P ovale wallikeri). In P ovale curtisi, Ala15Ser-Ser58Arg was the most common dhfr mutation (39%; 124 of 314 samples). In P ovale wallikeri, dhfr mutations were less frequent, with Phe57Leu-Ser58Arg reaching 17% (34 of 204 samples). These two mutants were the most prevalent in central and east Africa and were fixed in Kenyan isolates. We detected six and four other non-synonymous mutations, representing 8% (24 isolates) and 2% (five isolates) of the P ovale curtisi and Povale wallikeri isolates, respectively. Whole-genome sequencing and microsatellite analyses revealed reduced genetic diversity around themutant pocdhfr and powdhfr genes. The mutant DHFR proteins showed structural changes at the pyrimethamine binding site in-silico, confirmed by a 4-times increase in pyrimethamine half-maximal inhibitory concentration in an Escherichia coli growth assay for the Phe57Leu-Ser58Arg mutant and 50-times increase for the Ala15Ser-Ser58Arg mutant, compared with the wild-type counterparts. The widespread use of sulfadoxine-pyrimethamine for malaria chemoprevention might have exerted fortuitous selection pressure for dhfr mutations in P ovale spp. This calls for closer monitoring of dhfr and dhps mutations in P ovale spp. French Ministry of Health, Agence Nationale de la Recherche, and Global Emerging Infections Surveillance branch of the Armed Forces Health Surveillance Division.

Measuring protective efficacy and quantifying the impact of drug resistance: A novel malaria chemoprevention trial design and methodology.

Recently revised WHO guidelines on malaria chemoprevention have opened the door to more tailored implementation. Countries face choices on whether to replace old drugs, target additional age groups, and adapt delivery schedules according to local drug resistance levels and malaria transmission patterns. Regular routine assessment of protective efficacy of chemoprevention is key. Here, we apply a novel modelling approach to aid the design and analysis of chemoprevention trials and generate measures of protection that can be applied across a range of transmission settings. We developed a model of genotype-specific drug protection, which accounts for underlying risk of infection and circulating genotypes. Using a Bayesian framework, we fitted the model to multiple simulated scenarios to explore variations in study design, setting, and participant characteristics. We find that a placebo or control group with no drug protection is valuable but not always feasible. An alternative approach is a single-arm trial with an extended follow-up (>42 days), which allows measurement of the underlying infection risk after drug protection wanes, as long as transmission is relatively constant. We show that the currently recommended 28-day follow-up in a single-arm trial results in low precision of estimated 30-day chemoprevention efficacy and low power in determining genotype differences of 12 days in the duration of protection (power = 1.4%). Extending follow-up to 42 days increased precision and power (71.5%) in settings with constant transmission over this time period. However, in settings of unstable transmission, protective efficacy in a single-arm trial was overestimated by 24.3% if recruitment occurred during increasing transmission and underestimated by 15.8% when recruitment occurred during declining transmission. Protective efficacy was estimated with greater precision in high transmission settings, and power to detect differences by resistance genotype was lower in scenarios where the resistant genotype was either rare or too common. These findings have important implications for the current guidelines on chemoprevention efficacy studies and will be valuable for informing where these studies should be optimally placed. The results underscore the need for a comparator group in seasonal settings and provide evidence that the extension of follow-up in single-arm trials improves the accuracy of measures of protective efficacy in settings with more stable transmission. Extension of follow-up may pose logistical challenges to trial feasibility and associated costs. However, these studies may not need to be repeated multiple times, as the estimates of drug protection against different genotypes can be applied to different settings by adjusting for transmission intensity and frequency of resistance.

Implementation of perennial malaria chemoprevention in infants at district-level in Togo: mixed methods assessment of health system readiness

IntroductionIn June 2022, WHO recommended the administration of Perennial Malaria Chemoprevention (PMC) alongside Expanded Immunization Programmes for children under two years. We investigated the health systems readiness for PMC implementation in Togo. MethodAs part of the multi-country MULTIPLY project, we conducted a mixed methods implementation research study in the 27 health facilities of Haho district in Togo. All district health care providers (n=188) and a sample of community health workers (n=43) were invited to respond to a self-administered Knowledge-Attitudes-Practices questionnaire. Structured observations in 4 health facilities and 19 semi-structured interviews were conducted. Descriptive analysis was conducted on quantitative data. Qualitative data was analysed thematically, using an inductive approach. We report here on the implementation context for PMC, its infrastructural feasibility and its acceptability among health care workers (HCWs). ResultsOverall, respondents perceived PMC as relevant in the context of high malaria burden and had a good knowledge about malaria and its prevention. HCWs foresaw good community acceptability of PMC. Although some HCWs did not understand the rationale of PMC if children are not sick, they also believed PMC would be effective, in line with their perceptions of preventive malaria treatment during pregnancy. Several challenges were foreseen such as distance barriers for accessing health facilities, difficulties in accessing drinking water, supplies for PMC administration, or lack of dedicated health workforce and area for PMC administration. ConclusionAt district-level in Togo, overall pre-intervention acceptability of PMC was encouraging. Structural and operational challenges were identified as possible barriers to implementation feasibility.

Predictors of accessing seasonal malaria chemoprevention medicines through non-door-to-door distribution in Nigeria

BackgroundIn Nigeria, seasonal malaria chemoprevention (SMC) is typically administered door-to-door to children under five by community medicine distributors during high transmission seasons. While door-to-door distribution (DDD) is exclusively employed in Nigeria as part of standard operating procedures of SMC programmes, some households access SMC through non-DDD channels, such as fixed-point distributions, health facilities, and private purchase. However, analysis of access to SMC medicines through non-DDD has been limited, with little evidence of its outcomes on adherence to the three-day complete course of SMC medicines and caregiver actions in the event of adverse reactions to SMC medicines.MethodsData were obtained from SMC end-of-round coverage surveys conducted in Nigeria in 2021 and 2022, including 25,278 households for the analysis. The proportion of households accessing SMC medicine through non-DDD and the distribution of various non-DDD sources of SMC medicines were described. Multivariate random-effects logistic regression models were performed to identify predictors of accessing SMC medicines through non-DDD. The associations between non-DDD, and caregiver-reporting of adherence to complete administration of SMC medicines and caregiver actions in the event of adverse reactions to SMC medicines were also assessed.ResultsLess than 2% (314/24003) of households accessed SMC medicines through non-DDD in the states surveyed. Over 60% of non-DDD access was via health facility personnel and community medicine distributors from different locations. Variables associated with non-DDD access included heads of household being born in the local state (OR = 0.68, 95% CI 0.47 to 0.90), households residing in the study state since the first cycle of the SMC round (OR = 0.39, 95% CI 0.17 to 0.88), households with high wealth index (OR = 1.36, 95% CI 1.01 to 1.82), and caregivers hearing about date of SMC delivery in the previous cycle (OR = 0.18, 95%CI 0.14 to 0.24). Furthermore, non-DDD was associated with reduced SMC adherence and higher caregiver non-reporting of adverse reactions to SMC medicines in children compared with DDD.ConclusionThis study provides evidence on the characteristics of households accessing SMC medicines through non-DDD and its potential negative outcomes on adherence to SMC medicine and adverse reaction reporting, underscoring potential implementation issues that may arise if non-DDD delivery models are adopted in SMC, particularly in places where DDD had been firstly used.

Artemether–lumefantrine with or without single-dose primaquine and sulfadoxine–pyrimethamine plus amodiaquine with or without single-dose tafenoquine to reduce Plasmodium falciparum transmission: a phase 2, single-blind, randomised clinical trial in Ouelessebougou, Mali

Artemether-lumefantrine is widely used for uncomplicated Plasmodium falciparum malaria; sulfadoxine-pyrimethamine plus amodiaquine is used for seasonal malaria chemoprevention. We aimed to determine the efficacy of artemether-lumefantrine with and without primaquine and sulfadoxine-pyrimethamine plus amodiaquine with and without tafenoquine for reducing gametocyte carriage and transmission to mosquitoes. In this phase 2, single-blind, randomised clinical trial conducted in Ouelessebougou, Mali, asymptomatic individuals aged 10-50 years with P falciparum gametocytaemia were recruited from the community and randomly assigned (1:1:1:1) to receive either artemether-lumefantrine, artemether-lumefantrine with a single dose of 0·25mg/kg primaquine, sulfadoxine-pyrimethamine plus amodiaquine, or sulfadoxine-pyrimethamine plus amodiaquine with a single dose of 1·66 mg/kg tafenoquine. All trial staff other than the pharmacist were masked to group allocation. Participants were not masked to group allocation. Randomisation was done with a computer-generated randomisation list and concealed with sealed, opaque envelopes. The primary outcome was the median within-person percent change in mosquito infection rate in infectious individuals from baseline to day 2 (artemether-lumefantrine groups) or day 7 (sulfadoxine-pyrimethamine plus amodiaquine groups) after treatment, assessed by direct membrane feeding assay. All participants who received any trial drug were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT05081089. Between Oct 13 and Dec 16, 2021, 1290 individuals were screened and 80 were enrolled and randomly assigned to one of the four treatment groups (20 per group). The median age of participants was 13 (IQR 11-20); 37(46%) of 80 participants were female and 43 (54%) were male. In individuals who were infectious before treatment, the median percentage reduction in mosquito infection rate 2 days after treatment was 100·0% (IQR 100·0-100·0; n=19; p=0·0011) with artemether-lumefantrine and 100·0% (100·0-100·0; n=19; p=0·0001) with artemether-lumefantrine with primaquine. Only two individuals who were infectious at baseline infected mosquitoes on day 2 after artemether-lumefantrine and none at day 5. By contrast, the median percentage reduction in mosquito infection rate 7 days after treatment was 63·6% (IQR 0·0-100·0; n=20; p=0·013) with sulfadoxine-pyrimethamine plus amodiaquine and 100% (100·0-100·0; n=19; p<0·0001) with sulfadoxine-pyrimethamine plus amodiaquine with tafenoquine. No grade 3-4 or serious adverse events occurred. These data support the effectiveness of artemether-lumefantrine alone for preventing nearly all mosquito infections. By contrast, there was considerable post-treatment transmission after sulfadoxine-pyrimethamine plus amodiaquine; therefore, the addition of a transmission-blocking drug might be beneficial in maximising its community impact. Bill & Melinda Gates Foundation.

Sustained clinical benefit of malaria chemoprevention with sulfadoxine-pyrimethamine (SP) in pregnant women in a region with high SP resistance markers

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. 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. 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 VAR2CSADBL34 (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). A sustained parasitological effect of IPTp-SP contributes to the clinical effectiveness of IPTp3+ in areas with high prevalence of SP-resistance markers.

Receipt of seasonal malaria chemoprevention by age-ineligible children and associated factors in nine implementation states in Nigeria

BackgroundAs part of implementation quality standards, community distributors are expected to ensure that only age-eligible children (aged 3–59 months) receive seasonal malaria chemoprevention (SMC) medicines during monthly campaigns. There is uncertainty about the extent to which SMC medicines are administered to ineligible children. This study aimed to assess the magnitude of this occurrence, while exploring the factors associated with it across nine states where SMC was delivered in Nigeria during the 2022 round.MethodsThis analysis was based on data from representative end-of-round SMC household surveys conducted in nine SMC-implementing states in Nigeria. Data of 3299 age-ineligible children aged > 5 years and their caregivers were extracted from the survey dataset. Prevalence of receipt of SMC medicines by ineligible children was described by child-, caregiver- and SMC-related factors. Mixed-effects multivariable logistic regression models were fitted to explore the factors associated with ineligible receipt of SMC medicines.Results30.30% (95% CI 27.80–32.90) of ineligible children sampled received at least one dose of SMC medicines in 2022, the majority (60.60%) of whom were aged 5–6 years while the rest were aged 7–10 years. There were lower odds of an age-ineligible child receiving SMC medicines among caregivers who were knowledgeable of SMC age eligibility (OR: 0.53, 95% CI 0.37–0.77, p < 0.001), compared with those who were not knowledgeable of age eligibility. Higher odds of receipt of SMC were found among age-ineligible children whose caregivers had higher confidence in the protective effect of SMC against malaria (OR: 2.01, 95% CI 1.07–3.72, p = 0.030), compared with those whose caregivers were less confident. Compared with ineligible children of younger caregivers (aged < 20 years), those whose caregivers were older had lower odds of receiving SMC than those whose caregivers were younger; with lower odds among children of caregivers aged 20–39 years (OR: 0.50, 95% CI 0.30–0.82, p = 0.006).ConclusionsThis study contributes important evidence on the magnitude of the receipt of SMC medicines by age-ineligible children, while identifying individual and contextual factors associated with it. The findings provide potentially useful insights that can help inform and guide context-specific SMC implementation quality improvement efforts.