Impact of population based indoor residual spraying with and without mass drug administration with dihydroartemisinin-piperaquine on malaria prevalence in a high transmission setting: a quasi-experimental controlled before-and-after trial in northeastern Uganda

Abstract

Background: Declines in malaria burden in Uganda have slowed. Modelling predicts that indoor residual spraying (IRS) and mass drug administration (MDA), when co-timed, have synergistic impact. This study investigated additional protective impact of population-based MDA on malaria prevalence, if any, when added to IRS, as compared with IRS alone and with standard of care (SOC).

Methods: The 32-month quasi-experimental controlled before-and-after trial enrolled an open cohort of residents (46,765 individuals, 1st enumeration and 52,133, 4th enumeration) of Katakwi District in northeastern Uganda. Consented participants were assigned to three arms based on residential subcounty at study start: MDA+IRS, IRS, SOC. IRS with pirimiphos methyl and MDA with dihydroartemisinin- piperaquine were delivered in 4 co-timed campaign-style rounds 8 months apart. The primary endpoint was population prevalence of malaria, estimated by 6 cross-sectional surveys, starting at baseline and preceding each subsequent round.

Results: Comparing malaria prevalence in MDA+IRS and IRS only arms over all 6 surveys (intention-to-treat analysis), roughly every 6 months post-interventions, a geostatistical model found a significant additional 15.5% (95% confidence interval (CI): [13.7%, 17.5%], Z = 9.6, p = 5e-20) decrease in the adjusted odds ratio (aOR) due to MDA for all ages, a 13.3% reduction in under 5's (95% CI: [10.5%, 16.8%], Z = 4.02, p = 5e-5), and a 10.1% reduction in children 5-15 (95% CI: [8.5%, 11.8%], Z = 4.7, p = 2e-5). All ages residents of the MDA + IRS arm enjoyed an overall 80.1% reduction (95% CI: [80.0%, 83.0%], p = 0.0001) in odds of qPCR confirmed malaria compared with SOC residents. Secondary difference-in-difference analyses comparing surveys at different timepoints to baseline showed aOR (MDA + IRS vs IRS) of qPCR positivity between 0.28 and 0.66 (p < 0.001). Of three serious adverse events, one (nonfatal) was considered related to study medications. Limitations include the initial non-random assignment of study arms, the single large cluster per arm, and the lack of an MDA-only arm, considered to violate equipoise.

Conclusions: Despite being assessed at long time points 5-7 months post-round, MDA plus IRS provided significant additional protection from malaria infection over IRS alone. Randomized trials of MDA in large areas undergoing IRS recommended as well as cohort studies of impact on incidence.

Trial registration: This trial was retrospectively registered 11/07/2018 with the Pan African Clinical Trials Registry (PACTR201807166695568).

Keywords: Controlled trial; Dihydroartemisinin; High burden; IRS; MDA; Malaria; Pirimiphos; Uganda.

Fig. 1

The study site with mapped households and arm assignments. Katakwi district on a map of Uganda, with an inset map showing the study area bordering Lake Bisina. The points on the inset map show geolocated households in 85 villages, color coded by adjacent intervention arms: green for Arm A with MDA + IRS, blue for Arm B with IRS, red for Arm C, standard of care. All sites have ITNs, case management, and IPTp which constitutes standard of care

Fig. 2

Flow chart of study intervention implementation

Fig. 3

Chronology of the study interventions and monitoring activities. The bottom six green diamonds represent the six cross-sectional surveys in November 2016, June 2017, November 2017, March 2018, November 2018 and April 2019. The four top blue diamonds represent the co-timed intervention rounds (Arms A B) in late November/ early December 2016, August 2017, April 2018, and late November/early December 2018. The top yellow diamond shows the universal ITN coverage campaign conducted in April 2017 by MOH. The bottom two orange diamonds show ongoing entomological and health facility epidemiological surveillance

Fig. 4

Cross-sectional malaria prevalence by arm, at six time points (all ages, under 5, and children 5–15). The vertical dashed red lines show the co-timed IRS + MDA and IRS only intervention rounds in the IRS arms, while the vertical grey dashed line shows the universal ITN coverage campaign in all three arms. The points show the cross-sectional survey sample percent qPCR positivity at the times of the surveys, while the bars represent the associated 95% confidence intervals for population prevalence

Fig. 5

Adjusted odds of being found infected if resident in IRS + MDA or IRS arm relative to resident in standard care (children under 5, children 5–15, and all ages in panels left to right)

Fig. 6

Heat maps of predicted spatial heterogeneity in malaria prevalence in children under 5 in surveys 1–6

Fig. 7

DiD adjusted odds ratio of qPCR confirmed malaria (all ages), MDA + IRS vs IRS, by survey timing compared to baseline