Pharmacometric evaluation of amodiaquine-sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine seasonal malaria chemoprevention in northern Uganda

Abstract Background Seasonal malaria chemoprevention (SMC) using monthly amodiaquine-sulfadoxine-pyrimethamine (SPAQ) is being deployed East Africa, where antimalarial drug resistance levels are high. Dihydroartemisinin-piperaquine (DP) is a potential alternative. Methods A 28 day pharmacometric assessment of SMC was conducted in Karamoja, Northern Uganda. In two villages children received SPAQ and in one, either DP or no SMC. The primary outcome was malaria infection (all species) defined by capillary blood sample qPCR positivity on day 28, or new slide or rapid diagnostic test positivity after day 2. Results Baseline qPCR malaria parasitemia prevalence among 1250 enrolled children was 46% (575/1250); P. falciparum 85%, other malarias (mainly P. ovale ) 25%. Breakthrough parasitemias occurred in 7% (33/496) of DP, 31% (158/504) of SPAQ, and 39% (98/250) of no drug recipients. Clinical malaria (all P. falciparum ) developed in 17% of no drug (42/250; 1 severe), 8% of SPAQ (38/504; 2 severe) and 2% of DP (13/496) recipients. Adjusted protective efficacies against all malaria, all clinical malaria and all falciparum malaria were SPAQ; 56% (95%CI 35-70%), 60% (27-78%), and 46% (11-68%), and for DP; 84% (77-89%), 86% (74-92%) and 86% (75-92%) respectively. Some asymptomatic P. falciparum infections were not cleared by SPAQ. All 260 P. falciparum isolates genotyped were Pfcrt K76 (haplotype CVMNK, a marker of 4-aminoquinoline susceptibility) and most were quintuple Pf dhfr/dhps mutants (i.e. relatively SP resistant). The chemoprevention drug exposure-response relationship was strong for desethylamodiaquine, but weak for sulfadoxine. Conclusions SPAQ SMC had low clinical and parasitological chemopreventive efficacy in Northern Uganda whereas dihydroartemisinin-piperaquine was effective. Funding Bill & Melinda Gates Foundation; GiveWell; Wellcome. The Infectious Diseases Research Collaboration (IDRC) and Malaria consortium received funds from grant Investment IDs INV-043830 and INV-039889 - Uganda SMC and CPES Phase 2 from the Gates Foundation. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Gates Foundation. NJW is a Principal Research Fellow funded by the Wellcome Trust (093956/Z/10/C). JAW is a Sir Henry Dale Fellow funded by the Wellcome Trust (223253/Z/21/Z). Clinical Trials registration NCT05323721