Investigating Challenges to Effective Malaria Case Management in Kinshasa Province, Democratic Republic of the Congo

Malaria still causes significant morbidity and mortality worldwide, despite being preventable and treatable. Variable performance of diagnostic tools, non-adherence to test-and-treat guidelines, and the emergence of resistance to current first-line treatments impede effective case management and should be better understood to inform control strategies.In this dissertation, we used data from a seven-year longitudinal cohort study in Kinshasa Province, Democratic Republic of the Congo to investigate challenges to malaria diagnosis and treatment and characterize molecular markers associated with decreased susceptibility to amodiaquine and lumefantrine — two partner drugs included in first-line artemisinin-based combination therapies. First, we quantified malaria misdiagnosis and inappropriate treatment and assessed adherence to treatment guidelines. The seven-year cumulative incidences of a first Plasmodium falciparum infection by qPCR, false-positive and false-negative rapid diagnostic test (RDT) were 99.2%, 77.7%, and 83.4%, respectively. False-positive RDTs were more common in clinics, and false-negatives in the community. Misdiagnosis was associated with age, recent antimalarial treatment, transmission intensity, and parasite density – factors that could inform refinements to test-and-treat guidelines. About 58% of RDT-negative participants received antimalarial treatment, while 4% of RDT-positive participants did not. Fever significantly reduced adherence to test-and-treat guidelines.Next, we estimated trends in partner drug resistance markers (mdr1 86Y and crt 76T), assessed their within-host dominance and clinical presentation, and identified associated individual- and community-level factors. The prevalence of mdr1 86Y declined from 33.0% in 2015 to 16.4% in 2021-2022 at rural and peri-urban sites, consistent with negative selection s = -0.19 (95% Bayesian Credible Interval, BCrI: -0.08, -0.29). The prevalence of crt 76T decreased from 74.0% in 2015 to 43.2% in 2021-2022 across all sites, with stronger negative selection s = -0.31 (95% BCrI: -0.36, -0.27). In mixed infections, mdr1 86Y and crt 76T were often minor alleles. Although not statistically significant, higher parasite densities and more symptomatic infections were observed with mdr1 86Y. While a similar effect of crt 76T on parasite density was observed, the presence of crt 76T resulted in more asymptomatic infections Odds ratio of fever = 0.83 (95% CI: 0.72, 0.96). The prevalence of infections carrying these markers decreased with age and urbanicity.