Malaria Transmission Dynamics in a High-Transmission Setting of Western Kenya and the Inadequate Treatment Response to Artemether-Lumefantrine in an Asymptomatic Population

Abstract

Background: Assessing the infectious reservoir is critical in malaria control and elimination strategies. We conducted a longitudinal epidemiological study in a high-malaria-burden region in Kenya to characterize transmission in an asymptomatic population.

Methods: 488 study participants encompassing all ages in 120 households within 30 clusters were followed for 1 year with monthly sampling. Malaria was diagnosed by microscopy and molecular methods. Transmission potential in gametocytemic participants was assessed using direct skin and/or membrane mosquito feeding assays, then treated with artemether-lumefantrine. Study variables were assessed using mixed-effects generalized linear models.

Results: Asexual and sexual parasite data were collected from 3792 participant visits, with 903 linked with feeding assays. Univariate analysis revealed that the 6-11-year-old age group was at higher risk of harboring asexual and sexual infections than those <6 years old (odds ratio [OR] 1.68, P < .001; and OR 1.81, P < .001), respectively. Participants with submicroscopic parasitemia were at a lower risk of gametocytemia compared with microscopic parasitemia (OR 0.04, P < .001), but they transmitted at a significantly higher rate (OR 2.00, P = .002). A large proportion of the study population who were infected at least once remained infected (despite treatment) with asexual (71.7%, 291/406) or sexual (37.4%, 152/406) parasites. 88.6% (365/412) of feeding assays conducted in individuals who failed treatment the previous month resulted in transmissions.

Conclusions: Individuals with asymptomatic infection sustain the transmission cycle, with the 6-11-year age group serving as an important reservoir. The high rates of artemether-lumefantrine treatment failures suggest surveillance programs using molecular methods need to be expanded for accurate monitoring and evaluation of treatment outcomes.

Keywords: Plasmodium falciparum; artemether/lumefantrine; drug resistance; malaria control and elimination; malaria surveillance and transmission dynnamics.

Figure 1.

Study site locations. Map showing the study area in western Kenya, which has been cartographically mapped by the HDSS using GPS, located on the northeastern shores of Lake Victoria. Each grid is 1 km². The gray dots represent all the households on HDSS, and the blue triangle represent the households enrolled in the study. Abbreviations: GPS, Global Positioning System; HDDS, Health and Demographic Surveillance System; mtrs, meters.

Figure 2.

Risk factors associated with asexual and sexual stage infections. The aOR for (A) asexual and (B) sexual stage infection for each predictor assessed is shown, with 95% CIs as whiskers surrounding each point. Abbreviations: aOR, adjusted odds ratio; CI, confidence interval.

Figure 3.

Relationship and predictors of oocyst density and prevalence. The relationship between oocyst density (the average number of oocysts per feeding assay) and (A) Pfs16 and (B) Pfs25 RT-qPCR Ct is shown for both DFA and MFA. A linear relationship was found to best explain the relationship in both panels A and B, although this was within 2 AIC differences compared with a power law relationship. A significant correlation is observed between oocyst density and Ct in MFA but not DFA (Pfs16 Ct [MFA: P = .002; DFA: P = .509] and Pfs25 Ct [MFA: P = .040; DFA: P = .262]). In panel C, a significant logistic relationship observed between oocyst prevalence (proportion of mosquitoes with at least 1 oocyst per feeding assay) is shown to be positively correlated against oocyst density (P < .001). In panel D, factors significantly associated (P < .05) with oocyst prevalence are shown in red, indicating oocyst prevalence is significantly higher during months with higher parasite prevalence and from submicroscopic sexual infections. The aORs and 95% CIs are shown on the right. Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; Ct, cycle threshold; DFA, direct skin feeding assay; MFA, membrane feeding assay; RT-qPCR, reverse transcriptasereal-time quantitative polymerase chain reaction.

Figure 4.

Characterization of asexual infection treatment failures. Individuals who were treated with artemether-lumefantrine but remained infected the following month were regarded as treatment failures. A mixed-effects logistic regression model with random intercepts at the household level (effect size and 95% CI) shown in panel A was used to identify that (B) cluster-level monthly malaria prevalence and (C) age were significant predictors of treatment failure. The parasite profiles of all individuals in the 3 households with a significantly increased risk of treatment failure identified in panel A are shown in panel D. For each individual, the RT-qPCR Ct for asexual parasite stages is plotted over time. Gametocyte status and feeding assay outcome are indicated by the color of the point, and the shape of the point indicates whether the individual was microscopy positive for asexual parasites. Continual observation (ie, observations the following month) are indicated by points connected by lines. Abbreviations: CI, confidence interval; Ct, cycle threshold; RT-qPCR, reverse transcriptase–real-time quantitative polymerase chain reaction; +ve, positive; –ve, negative.