Targeted Testing and Treatment To Reduce Human Malaria Transmission in High-Risk Populations: A Systematic Review

ABSTRACT. As countries approach elimination of malaria, groups with increased exposure to malaria vectors or poor access to health services may serve as important human reservoirs of infection that help maintain transmission in the community. Parasitological testing and treatment targeted to these groups may reduce malaria transmission overall. This systematic review assessed the effectiveness of targeted testing and treatment (TTaT) to reduce malaria transmission, the contextual factors, and the results of modeling studies that estimated the intervention’s potential impact. Bibliographic searches were conducted in March 2021 and updated in April 2022, and a total of 1,210 articles were identified. Three studies were included for outcome data: one factorial cluster randomized controlled trial (cRCT) in Kenya (5,233 participants), one cRCT in Ghana (3,046 participants), and one controlled before-and-after cohort study in schoolchildren in Malawi (786 participants). Nine reports were included for contextual factors, and two were included for mathematical modeling. Data on outcomes from the three studies suggested that at the community level, TTaT would result in little to no difference in the incidence of malaria infection (measured via active surveillance), adverse events, and severe AEs. In contrast, the effects of TTaT on prevalence (malaria parasitemia) among those targeted by the intervention were found to include a short-term impact on reducing transmission but little to no impact on transmission for extended periods. Future iterations of this review should ensure consideration for populations proven to host the vast majority of the reservoir of infection in lower-transmission settings to determine the effectiveness of the intervention.


Supplementary Table 1: Search Strategy
("Forest-goers " or Forests/ or Vulnerable or Worksites or Farm* OR plantation* or mining or miner* or Miners/ or laborers or cultivators or military or "armed forces" or Military Personnel/ or "peace-keepers" or agricultural ) "high risk population*".mp.or Risk Factors/ "special populations".tw"high exposure".twor "highly exposed".twor "high transmission".tw or hotspot*.tw

Study
Reference Reason for exclusion Amboko (2022) Population -all outpatient population were targeted

39.
Anon.Malaria Consortium -Expanding the health system into the forest: Analysis of and response to the challenge of providing malaria services inside forest areas within the Greater Mekong Subregion in the context of malaria elimination.Available at: https://www.malariaconsortium.org/resources/publications/1182/expanding-the-health-systeminto-the-forest-analysis-of-and-response-to-the-challenge-of-providing-malaria-services-insideforest-areas-within-the-greater-mekong-subregion-in-the-context-of-malaria-elimination.Accessed 40.
Lopes SC, Mugizi R, Pires JE, David F, Martins J, Dimbu PR, Fortes F, Rosário J, Allan R., 2020.Malaria Test, Treat and Track policy implementation in Angola: A retrospective study to assess the progress achieved after 4 years of programme implementation.Malar J The geographical heterogeneity observed in the prevalence of P. falciparum infection is likely to reflect a complexity of factors that influence vector distribution and density as well as vector-human contact and human infection.D1b: Timing of identification or recruitment of participants

Low risk
No randomization occurred at the school level and students were given the assigned intervention of their school.

Low risk
The study was not blinded.
No indication of deviation from intended intervention 1. it was not possible to blind the parents, participants, or field officers delivering the IST intervention to experimental assignment, which could have led to a possible ''John Henry'' effect whereby children in the control group adjust their behavior as they know they are not receiving the intervention, for example in risk aversion and treatment seeking 2) Second, study children's access to alternative malaria treatments outside of the schoolbased IST rounds was not monitored during the two years of the trial.3) the lack of multiple testing adjustments may have increased the possibility of type 1 error, and results should be interpreted in light of this possible error, but it is unlikely to have masked a beneficial effect of IST.D3: Missing outcome data

Low risk
Of the 5,233 children enrolled initially, 4,446 (85.0%) were included in the 12-month follow-up health survey and 4,201 (80.3%) were included in the 24month health survey.At 12 and 24 months, children lost to follow-up across both study arms were largely similar to children followed up.
Lowest cluster range was 26 at any timepoint (figure 3) D4: Measurement of the outcome

Low risk
The analyses described here correspond to a prespecified statistical analysis plan, approved by both the data monitoring committee and trial steering committee before any data were examined.D5: Selection of the reported result

Low risk
Reported primary and secondary outcomes are the same as reported on clinicaltrials.gov.
The primary pre-specified analysis adjusted for age (as a continuous variable), sex, and the baseline measure of the outcome, except for baseline P. falciparum, which was not measured in the control schools.The IST intervention was randomly allocated at the level of the school, with the 101 schools re-stratified by (i) literacy intervention group assignment and (ii) quintiles of average school exam scores.)."

Risk of bias
The geographical heterogeneity observed in the prevalence of P. falciparum infection is likely to reflect a complexity of factors that influence vector distribution and density as well as vector-human contact and human infection.D1b: Timing of identification or recruitment of participants

Low risk
No randomization occurred at the school level and students were given the assigned intervention of their school.

Low risk
The study was not blinded.
No indication of deviation from intended intervention D3: Missing outcome data Some Concerns Adverse events were monitored by the study team for 24 hours after each treatment, and a further 28 days thereafter using a passive surveillance system in schools.
Adverse events not monitored in control arm D4: Measurement of the outcome

Low risk
Adverse events were monitored using passive surveillance in the schools for up to 24 months followup period.D5: Selection of the reported result

Low risk
Adverse events were monitored by the study team for 24 hours after each treatment, and a further 28 days thereafter using a passive surveillance system in schools.Travel costs were reimbursed, and treatment charges waived.Adverse experiences were monitored until the event was cured or had stabilised.

Risk of bias Outcome: Incidence of malaria infection Domain
Author's judgement Justification D1a: Randomization process Low risk "Thirty-two health centers were stratified by districts, ranked by the number of Diptheria-Pertussis-Tetanus1 (DPT1) vaccinations given in the facility in the preceding year and paired according to the rank within each district.Within each pair of health facilities, one was allocated randomly to implement test-based (RDT-arm) management of malaria, while the other health facility within the pair was allocated to implement the clinical judgement (CJ arm) approach."No significant differences in the characteristics and comparability of children enrolled into the two arms of the study.D1b: Timing of identification or recruitment of participants

Low risk
Investigators enumerated all households that were located within 2km radius of the selected health centers and enrolled one hundred children per health facility who met the inclusion criteria; they enrolled children living closest to the selected health centers and extended outwards circumferentially until the target of 100 children was achieved.No significant differences in the characteristics and comparability of children enrolled into the two arms of the study.D2: Deviations from the intended interventions

Low risk
Caregivers had to provide consent to participation and received assistance for enrollment in the national insurance scheme as well home visits from field workers.
All children received clinical assessment for malaria appropriately that was not obviously linked to the intervention assignment from a service delivery standpoint.Children in the RDT group were tested using RDTs from the NMCP and were also treated for any concurrent illnesses according to IMCI guidelines.
In the control group children who presented with fever were not tested for malaria.The treatment for malaria in these facilities was presumptive and based on presenting clinical symptoms and signs.The treatment of all other ailments were based on the IMCI guidelines.The fieldworkers stationed in each (intervention and control) health facility helped to ensure compliance with the protocol by reminding attending clinicians about the protocol of the study, as applicable to the particular health centre.This was reinforced during the 4-6 monthly training sessions that were held for health workers in both intervention and control facilities. A

Low risk
Caregivers had to provide consent to participation and received assistance for enrollment in the national insurance scheme as well home visits from field workers.All children received clinical assessment for malaria appropriately that was not obviously linked to the intervention assignment from a service delivery standpoint.Children in the RDT group were tested using RDTs from the NMCP and were also treated for any concurrent illnesses according to IMCI guidelines.
In the control group children who presented with fever were not tested for malaria.The treatment for malaria in these facilities was presumptive and based on presenting clinical symptoms and signs.The treatment of all other ailments were based on the IMCI guidelines.The fieldworkers stationed in each (intervention and control) health facility helped to ensure compliance with the protocol by reminding attending clinicians about the protocol of the study, as applicable to the particular health centre.This was reinforced during the 4-6 monthly training sessions that were held for health workers in both intervention and control facilities.
A multilevel Poisson model assuming unstructured covariance was used to estimate the incidence of malaria over the 24-month period to account for repeat episodes of malaria within a child, and clustering by health facility.D3: Missing outcome data

Low risk
In control and intervention group 405 and 355 individuals were not seen at least every 100 days post follow-up initiation.Deaths were recorded in both the clinical judgement and intervention arms D4: Measurement of the outcome

Low risk
Data were double-entered using FoxPro version 9. The analysis was conducted using STATA version 12. D5: Selection of the reported result

High risk
Although mortality was measured in the study, it was assumed a priori that the number of deaths would not be sufficient to detect any significant difference between the two arms.

Study 3 .
Cohee et al. (2021) April-May) and Dry season (September-October) Baseline transmission intensity Moderate Maseya and Makjuwira: >40% parasite prevalence in school children Bvumbwe and Ngowe : lower, seasonally varied transmission (> two-fold seasonal prevalence difference) At 12-months follow-up, 2,148 children in the control schools and 2,298 in the intervention schools provided a finger-prick blood sample for Hb assessment, and at 24 months 2,027 and 2,174 children provided fingerprick samples in the control and intervention groups, respectively.
Saad NJ, et al., 2018.Pro-active case detection in an area of artemisinin resistance: identifying asymptomatic carriers and accelerating elimination efforts.AJTMH 46.Anon.Correction: Cost-Effectiveness Analysis of Test-Based versus Presumptive Treatment of Uncomplicated Malaria in Children under Five Years in an Area of High Transmission in Central Ghana -PubMed.Available at: https://pubmed.ncbi.nlm.nih.gov/28107534/.Accessed 47.Wijesinghe RS, Atkinson JAM, Bobogare A, Wini L, Whittaker M., 2011.Exploring provider and community responses to the new malaria diagnostic and treatment regime in Solomon Islands.Malar J 10: 1-12 48.Zurovac D, Githinji S, Memusi D, Kigen S, Machini B, Muturi A, Otieno G, Snow RW, Nyandigisi A., 2014.Major Improvements in the Quality of Malaria Case-Management under the "Test and Treat" 34.9 kg, and 35 kg).AL was given at a dose of 20/120 mg to children ,15 kg, 40/240 mg to children 15-24.9kg, 60/360 mg to children 25-34.9kg, and 80/480 mg to those who weighed >35 kg.quintiles of average school exam scores.)." (iv) control group where neither intervention was implemented…,The 101 schools were randomized in two stages with each stage conducted during a public ceremony.Schools are aggregated into sets of between three and six closely located schools, which regularly meet and share information, supported by a Ministry of Education Teacher Advisory Centre tutor.
"Schools were randomised to one of four groups, receiving either: (i) IST alone; (ii) the literacy intervention alone; (iii) both interventions combined; or