Effectiveness of sulfadoxine–pyrimethamine plus amodiaquine and dihydroartemisinin–piperaquine for seasonal malaria chemoprevention in Uganda

Authors: Anthony Nuwa, Kevin Baker, Richard Kajubi, Chukwudi A Nnaji, Katherine Theiss-Nyland, Musa Odongo, Tonny Kyagulanyi, Jane Nabakooza, David Salandini, Victor Asua, Maureen Nakirunda, Christian Rassi, Damian Rutazaana, Richard Achuma, Patrick Sagaki, John Baptist Bwanika, Godfrey Magumba, Adoke Yeka, Sam Nsobya, Moses R Kamya, James Tibenderana, Jimmy Opigo

No evidence for selection of antimalarial drug resistance was found in this cluster-randomised controlled trial to assess the effectiveness of a standard and alternative drug regimen for seasonal malaria chemoprevention in under-fives.

Background

Seasonal malaria chemoprevention (SMC) with sulfadoxine–pyrimethamine combined with amodiaquine (SPAQ) effectively protects eligible children from malaria in areas of high and seasonal transmission. However, concerns about parasite resistance to sulfadoxine–pyrimethamine in East and southern Africa necessitate evaluating alternative drug regimens. This study assessed the effectiveness of SPAQ and dihydroartemisinin–piperaquine for SMC in Uganda.

Methods

This three-arm, open-label, non-inferiority and superiority, cluster-randomised, controlled trial was conducted in Karamoja subregion, Uganda, among children aged 3–59 months and 6–59 months for SPAQ and dihydroartemisinin–piperaquine, respectively. Of 427 villages, 380 were randomly assigned (1:1) to the SPAQ group and dihydroartemisinin–piperaquine group, and 47 were assigned to the control group (no SMC). The superiority component compared the SPAQ and dihydroartemisinin–piperaquine groups with the control group, whereas the non-inferiority component compared the dihydroartemisinin–piperaquine group with the SPAQ group. The primary endpoint was confirmed malaria incidence using rapid diagnostic tests or microscopy. Survival analyses were done on an intention-to-treat basis (in all randomised participants), with adjustments made for covariate imbalances at baseline. Additionally, molecular markers associated with resistance to sulfadoxine–pyrimethamine and amodiaquine were analysed on 750 malaria-positive blood samples from children younger than five years before and after five SMC cycles. This trial was registered with ClinicalTrials.gov, NCT05323721, and has been completed.

Findings

During June 18–30, 2022, 3,881 children were enrolled; 1,755 in SPAQ, 1,736 in dihydroartemisinin–piperaquine, and 390 in control villages. Of these children, 3,629 were analysed. Incidence rates were 0.90 cases per 100 person-months in the SPAQ group, 0.80 cases per 100 person-months in the dihydroartemisinin–piperaquine group, and 18.26 cases per 100 person-months in the control group. SPAQ and dihydroartemisinin–piperaquine reduced malaria risk by 94 percent (hazard ratio [HR] 0.06 [95 percent CI 0.04–0.08]; p<0.001) and 96 percent (0.04 [0.03–0.06]; p<0.001), respectively. Based on the prespecified non-inferiority margin of 1.4, there was non-inferiority between the protective effectiveness of dihydroartemisinin–piperaquine and that of SPAQ (HR 0.90 [95 percent CI 0.58–1.39]). Prevalence of mutations linked to moderate (Plasmodium falciparum dihydrofolate reductase [PfDHFR] and P. falciparum dihydropteroate synthetase reductase [PfDHPS]) and high (PfDHFR Ile164Leu and PfDHPS Ala581Gly) sulfadoxine–pyrimethamine resistance were more than 88 percent and less than 5 percent, respectively. Mutations associated with 4-aminoquinolone resistance (P. falciparum multidrug resistance protein-1 [PfMDR1] Asp1246Tyr and PfMDR1 Asn86Tyr) were less than 1 percent. There was no significant increase in the prevalence of antifolate and artemisinin partial resistance-associated mutations, but a decrease was observed for key aminoquinoline resistance-associated alleles: P. falciparum chloroquine resistance transporter protein Lys76Thr, P. falciparum multidrug resistance protein Asn86Tyr, and PfMDR1 Asp1246Tyr (p<0.001). No serious or fatal adverse events were reported.

Interpretation

SPAQ and dihydroartemisinin–piperaquine effectively reduced malaria in children younger than five years, with no safety concerns. There was no evidence of resistance selection by SMC. Although these findings support SPAQ-based SMC in Eastern and southern Africa, ongoing resistance surveillance and efficacy monitoring are essential for sustained impact.

Citation: The Lancet Infectious Diseases, 2025; online first. DOI: 10.1016/S1473-3099(24)00746-1