Preventive Treatment Of Malaria Research Articles

Implementation of a Mobile Health Approach to a Long-Lasting Insecticidal Net Uptake Intervention for Malaria Prevention Among Pregnant Women in Tanzania: Process Evaluation of the Hati Salama (HASA) Randomized Controlled Trial Study.

Malaria infection is associated with many adverse outcomes for pregnant women and neonates, yet pregnant women in East and Southern Africa remain frequently exposed to malaria. Long-lasting insecticidal nets (LLINs) can help prevent malarial infections and the associated adverse events. The Hati Salama (HASA) study was a cluster-randomized controlled trial implemented in 100 antenatal health facilities in urban and rural settings of Tanzania that provided pregnant women in both intervention and control groups with e-vouchers to redeem for LLINs for malaria prevention. The intervention group received behavior change communication mobile messages across a 14-day period while the e-voucher was active, and no significant difference between the rates of e-voucher redemption was found across the two groups. This study was a process evaluation of the HASA randomized controlled trial to determine barriers and facilitators to e-voucher reception and LLIN acquisition for pregnant women enrolled in the trial, as well as challenges and lessons learned by nurses who worked at the antenatal health facilities supporting the trial. Following the e-voucher's expiration at 14 days, voluntary phone follow-up surveys were conducted for nurses who supported the trial, as well as participants in both intervention and control groups of the trial who did not redeem their e-vouchers. Survey questions asked nurses about workflow, training sessions, network connectivity, proxy phone use, and more. Surveys asked participants about reasons for not redeeming e-vouchers. Both surveys provided lists of preset answers to questions, as well as the option to provide open-ended responses. Nurses and trial participants were contacted between January and June 2016 on up to three occasions. While nurses who supported the HASA trial seemed to recognize the value of the program in their communities, some barriers identified by nurses included network connectivity, workload increase, inadequate training and on-the-ground support, and difficulty following the workflow. Several barriers identified by trial participants included personal obligations preventing them from redeeming the e-voucher on time, network connectivity issues, losing the e-voucher number, no stock of LLINs at retailers when attended, inadequate explanation of where or how to redeem the e-voucher, or not receiving an SMS text message with the e-voucher number promptly or at all. Large-scale e-voucher platforms for health-related commodity interventions, such as LLIN distribution in sub-Saharan Africa, are feasible, but challenges, including network connectivity, must be addressed. Nurses identified issues to be considered in a future scale-up, such that the number of nurses trained should be increased and the e-voucher issuance workflow should be simplified. To address some of the key barriers impacting e-voucher redemption for trial participants, the network of retailers could be expanded and the e-voucher expiration period should be extended. ClinicalTrials.gov NCT02561624; https://clinicaltrials.gov/ct2/show/NCT02561624.

The effect of intermittent preventive treatment for malaria with dihydroartemisinin–piperaquine on vaccine-specific responses among schoolchildren in rural Uganda (POPVAC B): a double-blind, randomised controlled trial

Several important vaccines differ in immunogenicity and efficacy between populations. We hypothesised that malaria suppresses responses to unrelated vaccines and that this effect can be reversed-at least partially-by monthly malaria intermittent preventive treatment (IPT) in high-transmission settings. We conducted an individually randomised, double-blind, placebo-controlled trial of the effect of malaria IPT with dihydroartemisinin-piperaquine on vaccine responses among schoolchildren aged 9-17 years in Jinja district, Uganda. Participants were recruited from two schools and did not have exposure to vaccines of interest after the age of 5 years, with the exception of human papillomavirus (HPV). Computer-generated 1:1 randomisation was implemented in REDCap. 3-day courses of dihydroartemisinin-piperaquine (dosage by weight) or placebo were administered monthly, including twice before the first vaccination. Trial participants were vaccinated with the live parenteral BCG vaccine (Serum Institute of India, Pune, India) at week 0; yellow fever vaccine (YF-17D; Sanofi Pasteur, Lyon, France); live oral typhoid vaccine (Ty21a; PaxVax, London, UK), and quadrivalent virus-like particle HPV vaccine (Merck, Rahway, NJ, USA) at week 4; and toxoid vaccines (tetanus-diphtheria; Serum Institute of India) and an HPV booster at week 28. An additional HPV vaccination at week 8 was provided to female participants older than 14 years who had not previously been vaccinated, and a tetanus-diphtheria booster was given after completion of the trial at week 52. Primary outcomes were vaccine responses at week 8 and, for tetanus-diphtheria, at week 52, and analysis was done in the intention-to-treat population. Malaria parasite prevalence at enrolment and during follow-up was determined retrospectively by PCR. The safety population comprised all randomly allocated participants. The trial was registered at the ISRCTN Registry (ISRCTN62041885) and is complete. Between May 25 and July 14, 2021, we assessed 388 potential participants for eligibility. We enrolled and randomly allocated 341 participants to the two groups (170 [50%] to dihydroartemisinin-piperaquine and 171 [50%] to placebo); 192 (56%) were female and 149 (44%) participants were male. 145 (85%) participants in the dihydroartemisinin-piperaquine group and 140 participants (82%) in the placebo group were followed up until the week 52 endpoint. At enrolment, 109 (64%) of all participants in the dihydroartemisinin-piperaquine group and 99 (58%) of 170 participants in the placebo group had malaria; this reduced to 6% or lower at all follow-up visits in the dihydroartemisinin-piperaquine group. There was no effect of dihydroartemisinin-piperaquine versus placebo on primary outcomes: BCG-specific IFNγ ELISpot response had a geometric mean ratio (GMR) of 1·09 (95% CI 0·93-1·29), p=0·28; yellow fever neutralising antibody was 1·19 (0·91-1·54), p=0·20 for plaque reduction neutralising reference tests (PRNT50) titres (the reciprocal of the last plasma dilution that reduced by 50%) and 1·24 (0·97-1·58), p=0·09 for PRNT90 titres (reciprocal of the last plasma dilution that reduced by 90%); and IgG to Salmonella enterica serovar Typhi O-lipopolysaccharide was 1·09 (0·81-1·46), p=0·58, HPV-16 was 0·72 (0·44-1·77), p=0·19, HPV-18 was 0·71 (0·47-1·09), p=0·11; tetanus toxoid was 1·22 (0·91-1·62), p=0·18, and diphtheria toxoid was 0·97 (0·83-1·13), p=0·72. There was some evidence that dihydroartemisinin-piperaquine reduced waning of the yellow fever response. IPT for malaria with dihydroartemisinin-piperaquine did not improve peak vaccine responses, despite reducing malaria prevalence. Possible longer-term effects on response waning should be further explored. UK Medical Research Council. For the Luganda translation of the abstract see Supplementary Materials section.

Intermittent preventive treatment for malaria in pregnancy and infant growth: a mediation analysis of a randomised trial

Intermittent preventive treatment for malaria in pregnancy (IPTp) can improve birth outcomes, but whether it confers benefits to postnatal growth is unclear. We investigated the effect of IPTp on infant growth in Uganda and its pathways of effects using causal mediation analyses. We analysed data from 633 infants born to mothers enrolled in a randomised trial of monthly IPTp with dihydroartemisinin-piperaquine (DP) vs. sulfadoxine-pyrimethamine (SP) (NCT02793622). Weight and length were measured from 0 to 12 months of age. Using generalised linear models, we estimated effects of DP vs. SP on gravidity-stratified mean length-for-age (LAZ) and weight-for-length Z-scores (WLZ). We investigated mediation by placental malaria, gestational weight change, maternal anaemia, maternal inflammation-related proteins, preterm birth, birth length, and birth weight. Mediation models adjusted for infant sex, gravidity, gestational age at enrolment, maternal age, maternal parasitaemia at enrolment, education, and wealth. SP increased mean LAZ by 0.18-0.28 Z from birth through age 4 months compared to DP, while DP increased mean WLZ by 0.11-0.28 Z from 2 to 8 months compared to SP among infants of multigravidae; at these ages, confidence intervals for mean differences excluded 0. We did not observe differences among primigravida. Mediators of SP included birth weight, birth length, maternal stem cell factor, and DNER. Mediators of DP included placental malaria and birth length, maternal IL-18, CDCP1, and CD6 at delivery. In high malaria transmission settings, this exploratory study suggests different IPTp regimens may influence infant growth among multigravidae, potentially through distinct pathways, in the exclusive breastfeeding period, when few other interventions are available. Stanford Center for Innovation in Global Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation.

Intermittent Preventive Treatment of Malaria in Pregnancy and the Impact on Neonates in African Countries as Assessed by Entropy Weight and TOPSIS Methods.

Background/Objectives: In regions of Africa with a high prevalence of malaria, pregnant women in their first or second trimester should be administered intermittent preventive treatment in pregnancy (IPTp). However, infants may contract malaria despite the IPTp therapy that their mothers have received. The objective of the present investigation was to assess the symptoms and various treatments for neonatal malaria. Methods: Entropy weight and TOPSIS were used to achieve the study goal. The TOPSIS multi-attribute decision-making system was used to assess newborn malaria symptoms and select the optimal treatment, even for mothers receiving IPTp medication during pregnancy. The entropy weight approach calculated TOPSIS attribute weights. The present research used UNICEF data for 14 African nations in 2023. Results: The results indicated that neonates whose mothers received IPTp therapy ultimately contracted malaria, with diarrhea being the primary symptom. It is important to note that health providers administer a combination of zinc and oral rehydration solution (ORS) to infants as the most effective treatment for malaria symptoms, thereby abandoning the first-line treatment for malaria, artemisinin-based combination therapy (ACT). Conclusions: The most effective treatment for neonatal malaria is a combination of zinc and ORS, although less than half of children in Africa have access to ORS. Therefore, the findings of this study may encourage African countries to prioritize co-pack therapy in their procurement and supply, healthcare provider training, and expenditures. This therapy will also help alleviate the symptoms of malaria in neonates.

New Strides in Prevention of Malaria during Pregnancy Present Multitudinous Opportunities.

Pregnant women are at a higher risk of developing complications from malaria, a mosquito-borne disease caused by Plasmodium parasites, resulting in considerable maternal and infant morbidity and mortality. Malaria in pregnancy causes unfavorable and life-threatening outcomes for both the mother and fetus not limited to maternal anemia, hypoglycaemia, cerebral malaria, pulmonary edema, and puerperal sepsis. WHO recommends wide-ranging strategies for this detrimental but preventable disease; however, numerous challenges persist in ensuring high uptake of preventive therapies, effective usage of insecticide-treated bed nets, and early initiation and optimal antenatal care coverage for pregnant women. This work distils recent global advances in preventive strategies for malaria in pregnancy. We discuss three mainstay interventions by WHO, viz. intermittent preventive treatment of malaria in pregnancy (IPTp), utilization and outcomes of insecticide-treated bed nets (ITNs), and headways in malaria case management using therapeutic drugs. We cover multitudinous facets of antenatal care, WHO-advised community-based delivery of IPTp (c-IPTp), intermittent screening and treatment for malaria in pregnancy (ISTp), a malaria vaccine for pregnant women, and auxiliary factors that are crucial for improving prevention outcomes. Despite the reduction in malaria globally, malaria in pregnancy remains a prevalent issue in endemic areas, which warrants strengthening of preventative strategies. This work attempts to consolidate pivotal observations of the prevention of malaria during pregnancy by highlighting key advances, priority areas, new opportunities, research gaps, and challenges that need to be addressed to ensure improved outcomes in pregnant women infected with malaria.

Drug-Drug Interaction Between Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine During Malaria Chemoprevention in Pregnant Women.

Co-administration of dihydroartemisinin-piperaquine (DP) and sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) may be superior in preventing adverse birth outcomes compared with either therapy alone, but potential drug-drug interactions require investigation. We conducted intensive and sparse pharmacokinetic (PK) studies in a subset of Ugandan women participating in a randomized controlled trial of monthly IPTp with SP vs. DP vs. DP + SP. Intensive PK sampling was performed from day 0 to 23 after dosing at 28 weeks gestation in 87 participants across treatment arms. Sparse sampling was performed on day 28 (trough) after dosing at 20 and 28 gestational weeks in additional 196 participants receiving SP vs. DP + SP. Intensive PK analysis demonstrated that compared with SP alone, co-administration of DP + SP was associated with lower maximal concentrations, the area under the concentration-time curves (AUC), and day 23 concentrations of sulfadoxine (25%, 25%, and 27%) and pyrimethamine (26%, 34%, and 32%) (P < 0.05 for all comparisons). Sparse PK results demonstrated participants co-administered DP + SP had lower trough concentrations after dosing at 20 and 28 gestational weeks for sulfadoxine (6%, P = 0.68 and 31%, P = 0.023, respectively) and pyrimethamine (18%, P = 0.032 and 33%, P < 0.001, respectively) compared with SP alone. Co-administration of DP + SP was associated with a 19% reduction in piperaquine AUC (P = 0.046), but no significant difference in other PK parameters compared with DP alone. In summary, co-administration of DP + SP was associated with significantly reduced SP exposure, with a greater magnitude during the third vs. second trimester. The clinical consequences of this interaction are yet unknown.

Enhancing preventive treatment for malaria in pregnancy: insights from a trial on targeted information transfer

Enhancing preventive treatment for malaria in pregnancy: insights from a trial on targeted information transfer

Delivery effectiveness of and adherence to intermittent preventive treatment for malaria in pregnancy with dihydroartemisinin–piperaquine with or without targeted information transfer or sulfadoxine–pyrimethamine in western Kenya: a three-armed, pragmatic, open-label, cluster-randomised trial

Delivery effectiveness of and adherence to intermittent preventive treatment for malaria in pregnancy with dihydroartemisinin–piperaquine with or without targeted information transfer or sulfadoxine–pyrimethamine in western Kenya: a three-armed, pragmatic, open-label, cluster-randomised trial

Protecting maternal health: Strategies against HIV and malaria in pregnancy.

Maternal health remains a global priority, with particular emphasis on combating infectious diseases such as HIV and malaria during pregnancy. Despite significant progress in prevention and treatment efforts, both HIV and malaria continue to pose significant risks to maternal and fetal well-being, particularly in resource-limited settings. The prevention of mother-to-child transmission (PMTCT) programs for HIV and intermittent preventive treatment (IPTp) for malaria represent cornerstone strategies in mitigating the impact of these infections on pregnancy outcomes. PMTCT programs focus on early HIV diagnosis, antiretroviral therapy initiation, and promoting safe infant feeding practices to reduce the risk of mother-to-child transmission. Similarly, IPTp involves the administration of antimalarial medication to pregnant women in malaria-endemic regions to prevent maternal and fetal complications associated with malaria infection. Integration of HIV and malaria prevention and treatment services within existing maternal and child health programs is crucial for maximizing impact and minimizing healthcare system strain. Strengthening health systems, improving access to antenatal care services, and enhancing community engagement are essential components of comprehensive maternal health strategies. Furthermore, promoting awareness, education, and empowerment of pregnant women and communities are vital in fostering health-seeking behaviors and adherence to preventive measures against HIV and malaria. In conclusion, protecting maternal health from the dual threat of HIV and malaria requires a multifaceted approach that encompasses prevention, screening, treatment, and community engagement.

Uptake and Effectiveness of Intermittent Preventive Treatment with Sulfadoxine-Pyrimethamine during Pregnancy in Africa: A Scoping Review.

Malaria poses a significant threat to pregnant women in sub-Saharan Africa, necessitating effective interventions like the intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). However, challenges persist in the uptake and effectiveness of this intervention. This scoping review aims to explore IPTp-SP uptake in African countries, identify influencing factors, and assess its effectiveness in preventing malaria and adverse outcomes in pregnancy. This scoping review follows Arksey and O'Malley's framework, employing the PRISMA-ScR guidelines for reporting. Searches were conducted in PubMed, Embase, Scopus, JSTOR, Web of Science, Google Scholar, and ProQuest, focusing on studies post-2000 published in the English language. The search produced 15,153 records, of which 104 full-text records were eligible and 101 papers were included in this review. The findings suggest varying IPTp-SP uptake rates, spanning from 5.3% to 98.9%, with their effectiveness supported by longitudinal studies, randomised controlled-trials (RCTs), cross-sectional surveys, and mixed-method studies. IPTp-SP demonstrates efficacy in reducing malaria during pregnancy, placental parasitaemia, and anaemia episodes, alongside improved birth outcomes. Common adverse effects of IPTp-SP include prematurity and low birth weight. Facilitators of IPTp-SP uptake include education and ANC attendance, while commonly reported barriers included inadequate knowledge and healthcare system challenges. The findings also suggest adverse effects such as prematurity, low birth weight, and maternal and perinatal mortality associated with IPTp-SP uptake. It is vital to strengthen antenatal care services by integrating comprehensive counselling on IPTp-SP and address healthcare system challenges. Community engagement, women's empowerment, and context-specific interventions are necessary for promoting IPTp-SP uptake and improving maternal and neonatal health outcomes in Africa.

Community-based strategies to increase coverage of intermittent preventive treatment of malaria in pregnancy with sulfadoxine–pyrimethamine in sub-Saharan Africa: a systematic review, meta-analysis, meta-ethnography, and economic assessment

Community-based approaches might increase uptake of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). We assessed the effects of community-based approaches on IPTp-SP and antenatal care coverage, and barriers and facilitators to implementation in sub-Saharan Africa. We did a systematic review, meta-analysis, meta-ethnography, and economic assessment. We searched the WHO International Clinical Trials Registry Platform, PubMed, the Malaria in Pregnancy Library database, Medline, Global Health and Global Health Archives, and the Cochrane Library for trials, mixed-methods, qualitative, and cost-effectiveness studies of community health worker promotion of antenatal care, IPTp-SP delivery, or both, with no language restrictions, published before March 21, 2024. Information on interventions, number of IPTp-SP doses, antenatal care visits, and barriers and facilitators were extracted. We did a meta-analysis (random effects) comparing effects on two or more or three or more IPTp-SP doses and one or more or four or more antenatal care visits. We followed Noblit and Hare's method of meta-ethnography to synthesise qualitative findings, using reciprocal translation and line-of-argument synthesis. We developed a theory for increased community IPTp-SP uptake. We also summarised cost and cost-effectiveness studies. This study is registered with PROSPERO, CRD42022364114. Of 4753 records screened, we included 23 (0·5%) reporting on 15 studies. Community health worker involvement was associated with an increase in two or more IPTp-SP doses (pooled risk ratio 1·48, [95% CI 1·24-1·75]; 12 sub-studies; I2 94·7%) and three or more IPTp-SP doses (1·73 [1·19-2·50]; ten sub-studies, I2 97·5%), with no decrease in four or more antenatal care visits (1·17 [1·00-1·36]; 13 sub-studies; I2 90·3%). Cluster-randomised controlled trials showed a lower increase in coverage of three or more IPTp-SP doses (1·08 [1·00-1·16]; I2 0·0%; six studies) compared with before-and-after studies (2·86 [1·29-6·33]; I2 98·9%; four studies; subgroup analysis p=0·019). Barriers to community health worker delivery of IPTp-SP included women's fear of side-effects, lack of knowledge, lack of trust in community health workers, and sociocultural factors. Community sensitisation, engagement of husbands, pre-established community health worker networks, and trained and supported community health workers facilitated IPTp-SP delivery by community health workers. Incremental cost-effectiveness ratios ranged from $1·1 to $543 per disability-adjusted life-year averted. Community-based approaches increased IPTp-SP coverage and might have a positive effect on the number of antenatal care visits in addition to being cost-effective, although we found high heterogeneity among studies. Community sensitisation and engagement in addition to established, trained, and supported community health workers can facilitate acceptability, delivery, and uptake of IPTp-SP delivered by community health workers. EDCTP-2 supported by the European Union. For the French translation of the abstract see Supplementary Materials section.

Epidemiological characteristics and strategies for prevention and elimination of malaria in Qingdao, Shandong Province, China from 1949 to 2021.

Malaria is an insect-borne disease transmitted by Anopheles mosquitoes or the importation of Plasmodium-infected blood, posing a serious threat to human health and life safety. This study aims to analyze the incidence of malaria in Qingdao at various stages from 1949 to 2021, to collate the control measures taken at different epidemic stages to assess the effectiveness of malaria control, and to identify a set of malaria control strategies suitable for Qingdao, while providing Chinese experience for other countries or cities in their malaria elimination efforts. A retrospective survey was used to collect information on malaria cases, control measures and prevention and control effects in Qingdao from 1949 to 2021, and to evaluate malaria control strategies and measures in Qingdao. 704 155 cases have been reported from 1949 to 2021, with three epidemic peaks: the incidence rate was 1715.9/100 000 in 1961, 1409.7/100 000 in 1965, and the most severe case occurred in 1972, with an incidence rate of 1635.6/100 000 and a case count exceeding 90 000. Throughout the various stages of malaria epidemics, Qingdao has effectively eliminated indigenous malaria by implementing diverse preventive and control measures. Since the last indigenous case of Plasmodium vivax was reported in 2002, all locally reported cases have been imported, mainly by returning migrant workers from Africa. This study examines a range of malaria prevention and control strategies and interventions that are appropriate for Qingdao. These measures have enabled Qingdao to successfully eliminate malaria and maintain malaria-free status for more than 20 years. These measures can also serve as a reference for similarly situated cities in Africa and Southeast Asia.

Cost-effectiveness of interventions for HIV/AIDS, malaria, syphilis, and tuberculosis in 128 countries: a meta-regression analysis

Cost-effectiveness analyses have been conducted for many interventions for HIV/AIDS, malaria, syphilis, and tuberculosis, but they have not been conducted for all interventions that are currently recommended in all countries. To support national decision makers in the effective allocation of resources, we conducted a meta-regression analysis of published incremental cost-effectiveness ratios (ICERs) for interventions for these causes, and predicted ICERs for 14 recommended interventions for Global Fund-eligible countries. In the meta-regression analysis, we used data from the Tufts University Center for the Evaluation of Value and Risk in Health (Boston, MA, USA) Cost-Effectiveness Registries (the CEA Registry beginning in 1976 and the Global Health CEA registry beginning in 1995) up to Jan 1, 2018. To create analysis files, we standardised and mapped the data, extracted additional data from published articles, and added variables from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Then we selected ratios for interventions with a minimum of two published articles and three published ICERs that mapped to one of five GBD causes (HIV/AIDS, malaria, syphilis, drug-susceptible tuberculosis, or multi-drug resistant tuberculosis), and to a GBD country; reported a currency year during or after 1990; and for which the comparator intervention was defined as no intervention, standard of care, or placebo. Our meta-regression analysis used all available data on 25 eligible interventions, and quantified the association between ICERs and factors at country level and intervention level. We used a five-stage statistical model that was developed to synthesise evidence on cost-effectiveness analyses, and we adapted it for smaller sample sizes by grouping interventions by cause and type (ie, prevention, diagnostics, and treatment). Using the meta-regression parameters we predicted country-specific median ICERs, IQRs, and 95% uncertainty intervals in 2019 US$ per disability-adjusted life-year (DALY) for 14 currently recommended interventions. We report ICERs in league tables with gross domestic product (GDP) per capita and country-specific thresholds. The sample for the analysis was 1273 ratios from 144 articles, of which we included 612 ICERs from 106 articles in our meta-regression analysis. We predicted ICERs for antiretroviral therapy for prevention for two age groups and pregnant women, pre-exposure prophylaxis against HIV for two risk groups, four malaria prevention interventions, antenatal syphilis screening, two tuberculosis prevention interventions, the Xpert tuberculosis test, and chemotherapy for drug-sensitive tuberculosis. At the country level, ranking of interventions and number of interventions with a predicted median ICER below the country-specific threshold varied greatly. For instance, median ICERs for six of 14 interventions were below the country-specific threshold in Sudan, whereas 12 of 14 were below the country-specific threshold in Peru. Antenatal syphilis screening had the lowest median ICER among all 14 interventions in 81 (63%) of 128 countries, ranging from $3 (IQR 2-4) per DALY averted in Equatorial Guinea to $3473 (2244-5222) in Ukraine. Pre-exposure prophylaxis for HIV/AIDS for men who have sex with men had the highest median ICER among all interventions in 116 (91%) countries, ranging from $2326 (1077-4567) per DALY averted in Lesotho to $53 559 (23 841-108 534) in Maldives. Country-specific league tables highlight the interventions that offer better value per DALY averted, and can support decision making at a country level that is more tailored to available resources than GDP per capita and country-specific thresholds. Meta-regression is a promising method to synthesise cost-effectiveness analysis results and transfer them across settings. Bill & Melinda Gates Foundation.

Use of population pharmacokinetic‐pharmacodynamic modelling to inform antimalarial dose optimization in infants

Infants bear a significant malaria burden but are usually excluded from participating in early dose optimization studies that inform dosing regimens of antimalarial therapy. Unlike older children, infants' exclusion from early‐phase trials has resulted in limited evidence to guide accurate dosing of antimalarial treatment for uncomplicated malaria or malaria‐preventive treatment in this vulnerable population. Subsequently, doses used in infants are often extrapolated from older children or adults, with the potential for under‐ or overdosing. Population pharmacokinetic‐pharmacodynamic (PK‐PD) modelling, a quantitative methodology that applies mathematical and statistical techniques, can aid the design of clinical studies in infants that collect sparse pharmacokinetic data as well as support the analysis of such data to derive optimized antimalarial dosing in this complex and at‐risk yet understudied subpopulation. In this review, we reflect on what PK‐PD modelling can do in programmatic settings of most malaria‐endemic areas and how it can be used to inform antimalarial dose optimization for preventive and curative treatment of uncomplicated malaria in infants. We outline key developmental physiological changes that affect drug exposure in early life, the challenges of conducting dose optimization studies in infants, and examples of how PK‐PD modelling has previously informed antimalarial dose optimization in this subgroup. Additionally, we discuss the limitations and gaps of PK‐PD modelling when used for dose optimization in infants. To utilize modelling well, there is a need to generate useful, sparse, PK and PD data in this subpopulation to inform antimalarial optimal dosing in infancy.

Pathways through which intermittent preventive treatment for malaria in pregnancy influences child growth faltering: a mediation analysis.

Intermittent preventive treatment for malaria in pregnancy (IPTp) can improve birth outcomes, but whether it confers benefits to postnatal growth is unclear. We investigated the effect of IPTp on infant growth in Uganda and its pathways of effects using causal mediation analyses. We analyzed data from 633 infants born to mothers enrolled in a randomized trial of monthly IPTp with dihydroartemisinin-piperaquine (DP) vs sulfadoxine-pyrimethamine (SP) (NCT02793622). Weight and length were measured from 0-12 months of age. Using generalized linear models, we estimated effects of DP vs. SP on gravidity-stratified mean length-for-age (LAZ) and weight-for-length Z-scores (WLZ). We investigated mediation by placental malaria, gestational weight change, maternal anemia, maternal inflammation-related proteins, preterm birth, birth length, and birth weight. Mediation models adjusted for infant sex, gravidity, gestational age at enrollment, maternal age, maternal parasitemia at enrollment, education, and wealth. SP increased LAZ by 0.18-0.28 Z from birth through age 4 months compared to DP, while DP increased WLZ by 0.11-0.28 Z from 2-8 months compared to SP among infants of multigravidae. We did not observe these differences among primigravida. Mediators of SP included increased birth weight and length and maternal stem cell factor at delivery. Mediators of DP included placental malaria and birth length, maternal IL-18, CDCP1, and CD6 at delivery. In high malaria transmission settings, different IPTp regimens influenced infant growth among multigravidae through distinct pathways in the period of exclusive breastfeeding, when few other interventions are available. Stanford Center for Innovation and Global Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bill & Melinda Gates Foundation.

A pharmacokinetic randomised interventional study to optimise dihydroartemisinin-piperaquine dosing for malaria preventive treatment in Malawian infants: A protocol for the OPTIMAL study

Background A newer malaria preventive treatment, dihydroartemisinin-piperaquine (DP), has been identified as an effective alternative to sulfadoxine-pyrimethamine, to which malaria parasites are increasingly becoming resistant. However, how best to dose DP to safely prevent malaria in infants when aligned with routine health facility visits remains unresolved. As infants are usually excluded from participating in early dose optimisation clinical trials, the present study seeks to shift the paradigm and develop optimised DP dosing strategies for malaria preventive treatment in infants. Methods A randomised, single-blind, placebo-controlled, two-arm, interventional study will be conducted in southern Malawi. At 10 weeks (2.5 months) of age, 220 eligible infants will be randomised to receive DP (intervention group, n=110) or placebo (control group, n=110) with routine vaccines. They will be followed until 12 months of age and receive three further DP or placebo treatment courses at 14 weeks, six- and nine months. Infants in the intervention group will contribute capillary samples for piperaquine concentrations pre-dose and at three-, seven-, 14- and 28-days post-DP dosing as well as capillary samples pre-dose and on day 28 post-DP to quantify malaria parasitaemia using microscopy and quantitative PCR. In the control group, infants will contribute capillary blood samples for malaria parasitaemia at the same time points as the intervention group. Malaria incidence and adverse events will be compared between the two groups. Population pharmacokinetic-pharmacodynamic modelling techniques will be applied to derive feasible, optimised, efficacious, and safe DP dosing strategies for malaria preventive treatment in infancy. Conclusions The findings will provide the much-needed evidence to inform DP dosing for malaria preventive treatment in infants when administered with routine health facility visits. Additionally, they will help inform optimal DP dosing for malaria treatment in infants. The trial was registered with the Pan African Clinical Trials Registry; (PACTR202211575727659) on 8 November 2022. Protocol version 3.1, dated 29 September 2022.

Spatial distribution and determinants of intermittent preventive treatment for malaria during pregnancy: a secondary data analysis of the 2019 Ghana malaria indicators survey

BackgroundMalaria during pregnancy is associated with poor maternal, foetal, and neonatal outcomes. To prevent malaria infection during pregnancy, the World Health Organization recommended the use of intermittent preventive therapy with sulfadoxine-pyrimethamine (IPTp-SP) in addition to vector control strategies. Although Ghana’s target is to ensure that all pregnant women receive at least three (optimal) doses of SP, the uptake of SP has remained low; between 2020 and 2022, only 60% of pregnant women received optimal SP during their most recent pregnancy. This study sought to map the geospatial distribution and identify factors associated with SP uptake during pregnancy in Ghana.MethodsSecondary data analysis was conducted using the 2019 Ghana Malaria Indicator Survey dataset. The data analysed were restricted to women aged 15–49 years who reported having a live birth within the two years preceding the survey. A modified Poisson regression model was used to determine factors associated with SP uptake during pregnancy. Geospatial analysis was employed to map the spatial distribution of optimal SP uptake across the ten regions of Ghana using R software.ResultsThe likelihood that pregnant women received optimal SP correlated with early initiation of first antenatal care (ANC), number of ANC contacts, woman’s age, region of residence, and family size. Overall, the greater the number of ANC contacts, the more likely for pregnant women to receive optimal SP. Women with four or more ANC contacts were 2 times (aPR: 2.16; 95% CI: [1.34–3.25]) more likely to receive optimal SP than pregnant women with fewer than four ANC contacts. In addition, early initiation and a high number of ANC contacts were associated with a high number of times a pregnant woman received SP. Regarding spatial distribution, a high uptake of optimal SP was significantly observed in the Upper East and Upper West Regions, whereas the lowest was observed in the Eastern Region of Ghana.ConclusionsIn Ghana, there were regional disparities in the uptake of SP during pregnancy, with the uptake mainly correlated with the provision of ANC services. To achieve the country’s target for malaria control during pregnancy, there is a need to strengthen intermittent preventive treatment for malaria during pregnancy by prioritizing comprehensive ANC services.

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.

Level of and factors associated with optimal uptake of intermittent preventive treatment for malaria in pregnancy at private-not-for-profit health facilities in Kasese district.

Malaria in pregnancy poses a high risk of poor maternal and neonatal outcomes and WHO recommends IPTp. However, its uptake has remained sub-optimal among mothers who attend antenatal care at private-not-for-profit health facilities. This study determined the level of and factors associated with uptake Intermittent preventive treatment of malaria for pregnant women (IPTp) at private-not-for-profit (PNFP) health facilities in Kasese District, Uganda. This was a cross-sectional study involving 396 postpartum mothers in the postnatal wards of 8 PNFP health facilities in Kasese district was conducted in September 2022. One hospital and 2 Health Centre IVs were purposively selected and 5 Health Centre IIIs selected randomly. Mothers were consecutively selected and interviewer administered semi-structured questionnaires were used to collect the data. Data were entered in epi-data version 3.1, cleaned and analyzed using STATA version 14. Data were adjusted for clustering & modified poison regression was used to determine associations of the factors and the outcome. From the analysis, level of optimal uptake of IPTp was 51.5% CI = (46.6-56.4). Being married (aPR = 1.35, 95% CI = 1.06-1.7, p = 0.014), attending ANC more than 4 Visits (aPR = 1.29, 95%CI = 1.09-1.54, p<0.001) positively influence optimal uptake while not taking IPTp at recommended time intervals (aPR = 0.49, 95%CI = 0.39-0.62 p<0.001) and mothers paying for IPTp drugs themselves (aPR = 0.74, 95%CI = 0.57-0.97, p = 0.031) negatively influence optimal uptake. This moderate uptake of IPTp among pregnant mothers suggests insufficient protection of pregnant mothers against malaria. Efforts to improve Antenatal care attendance, taking IPTp at recommended time intervals, not paying for ITPp drugs and encouraging marriages should be intensified.

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.