A non-randomized controlled trial to assess the protective effect of SMC in the context of high parasite resistance in Uganda

Abstract

Background Until recently, due to widespread prevalence of molecular markers associated with sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) resistance in east and southern Africa, seasonal malaria chemoprevention (SMC) has not been used at scale in this region. This study assessed the protective effectiveness of monthly administration of SP + AQ (SPAQ) to children aged 3–59 months in Karamoja sub-region, Uganda, where parasite resistance is assumed to be high and malaria transmission is seasonal. Methods A two-arm quasi-experimental, open-label prospective non-randomized control trial (nRCT) was conducted in three districts. In two intervention districts, 85,000 children aged 3–59 months were targeted to receive monthly courses of SMC using SPAQ during the peak transmission season (May to September) 2021. A third district served as a control, where SMC was not implemented. Communities with comparable malaria attack rates were selected from the three districts, and households with at least one SMC-eligible child were purposively selected. A total cohort of 600 children (200 children per district) were selected and followed using passive surveillance for breakthrough confirmed malaria episodes during the five-month peak transmission season. Malaria incidence rate per person-months and number of malaria episodes among children in the two arms were compared. Kaplan–Meier failure estimates were used to compare the probability of a positive malaria test. Other factors that may influence malaria transmission and infection among children in the two arms were also assessed using multivariable cox proportional hazards regression model. Results The malaria incidence rate was 3.0 and 38.8 per 100 person-months in the intervention and control groups, respectively. In the intervention areas 90.0% (361/400) of children did not experience any malaria episodes during the study period, compared to 15% (29/200) in the control area. The incidence rate ratio was 0.078 (95% CI 0.063–0.096), which corresponds to a protective effectiveness of 92% (95% CI 90.0–94.0) among children in the intervention area. Conclusion SMC using SPAQ provided high protective effect against malaria during the peak transmission season in children aged 3–59 months in the Karamoja sub-region of Uganda.

Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study

“…33 In particular, recent evidence indicates that SP-AQ retains its effectiveness for chemoprevention within regions with moderate prevalence of the dhfr/dhps quadruple mutant associated with SP treatment failure. 9,10 Yet, our lack of understanding of SP-AQ’s liver stage actionmeans that the reasons for SP-AQ’s continued effectiveness remains unclear. Furthermore, it is posited that part of SP’s effectiveness in other chemoprevention programs, such as intermittent preventative therapy in pregnancy (IPTp), may be due to non-malarial pathways.…”

“…6–8 SMC appears to be maintaining its effectiveness as a public health control measure. 9,10 However, this may not continue if the frequency of resistant mutations increases. More evidence is needed to assess this risk.…”

Malaria prevention in children: an update

“…Recent studies disagree on SMC's effects on resistance, with some showing an increase in molecular resistance markers and others showing that resistance markers remained rare [22 ▪▪ ,25–27]. Also, in an area with previously documented high levels of molecular resistance markers, SMC with SP+AQ remained highly effective, so the clinical relevance of molecular resistance markers is not always clear [14 ▪ ]. Another research gap is the potential for rebound, i.e., increased risk of clinical malaria, in older children as they age out of SMC.…”

“…Recent postimplementation studies report a 17–75% reduction in RDT-positive malaria cases in children under five, demonstrating a range of measured efficacy influenced by transmission, uptake, compliance, and drug resistance, although most centered around 60–75% [10–13]. In a highly endemic area in Uganda, comparison of two districts implementing SP+AQ SMC versus a control district documented 92% efficacy against clinical malaria [14 ▪ ]. The new WHO guideline flexibility will allow for more tailored responses between countries and even subnational areas within countries.…”

Malaria trends in districts that were targeted and not-targeted for seasonal malaria chemoprevention in children under five years of age in Guinea, 2014–2021

“…Because SMC is consistently proving to be a high-coverage and effective intervention, several countries with seasonal malaria transmission outside of the Sahel are now piloting SMC to be included in their malaria intervention package (e.g., Uganda 44 and Mozambique 45 ). WHO recently amended the SMC guidelines to give countries flexibility to change the SMC regimen (e.g., by adding additional SMC cycles to cover longer peak transmission seasons, or by including older age groups).…”