Artemisinin-based combination therapy has been adopted as first-line anti-malarials for case management by most malaria-endemic countries. The change to ACT in most cases was prompted by the development of resistance to conventional anti-malarial monotherapies creating the need to implement a clinically efficacious drug and supported by the potential for reduced transmission and delayed development or spread of anti-malarial drug resistance. However, little is still known about the impact of introducing ACT on malaria endemicity as measured by asexual parasitaemia prevalence, especially in settings of high malaria transmission. The results of this large observational study document that implementation of AS + SP was associated with a modest decrease in the population asexual parasitaemia prevalence.
This evaluation design with a contemporaneous comparison group, allows adjustment for potential confounders, such as untreated net and ITN use, rainfall, and other factors that are associated with parasitaemia, such as age and socioeconomic status. Prior studies have demonstrated individual level clinical efficacy of ACT and some studies have suggested reduced malaria burden with ACT implementation
[10–14], but to date there has been little evidence for the independent contribution of ACT-based case management over and above vector control interventions. This study is the first to show an independent association between ACT implementation and malaria endemicity after controlling for other malaria interventions such as ITN use, environmental factors such as rainfall, and other secular trends.
These findings suggest it is plausible that the introduction of AS + SP contributed to the reduction in asexual parasitaemia prevalence is based on an ecological association between the introduction of AS + SP and decreased asexual parasitaemia prevalence. After implementation of AS + SP, 20 to 87 AS + SP treatments per 100 persons per year were delivered through fixed health facilities. Although this number varied substantially during the study time period and is based on individual recall and an underlying assumption that AS + SP use was constant throughout the year, it still represents substantial drug pressure on the population and could plausibly account for the decrease in parasitaemia prevalence. Indeed, the introduction of SP monotherapy at fixed health facilities in these sites between 2001 and 2002 exerted enough drug pressure to select for genotypes associated with clinical drug resistance
. A more detailed analysis of dispensing patterns in Rufiji, Kilombero and Ulanga Districts documenting over 271,953 clinician-patient encounters at health facilities supports the widespread use of AS + SP in our intervention site throughout the year
. In addition, AS + SP is likely more efficacious at clearing parasitaemia than SP alone based on in vivo results collected from these sites over the same time period as well as published reports from elsewhere in Tanzania
A modest absolute reduction in asexual parasitaemia prevalence of 5 percentage-points or a relative decrease of 23% occurred following the introduction of ACT in Rufiji. Since asexual parasitaemia prevalence was observed in all ages and the majority of parasitaemic persons were asymptomatic adults, this finding reflects the effect of ACT on asymptomatic carriage of parasites mostly in adults. The relationship between asexual parasitaemia prevalence and other disease burden estimates, such as uncomplicated or severe malaria incidence and mortality, is not addressed in this study. Previous mathematical models suggest an appreciable reduction in uncomplicated malaria incidence with the introduction of ACT, thus although the true magnitude of the reduction in malaria morbidity and mortality that might have been associated with this intervention cannot be quantified, the modest reduction in malaria endemicity noted in this study does not undermine the large public health impact of ACT.
Although a modest reduction in malaria endemicity was demonstrated, several mechanisms by which the introduction of ACT might reduce population level asexual parasitaemia prevalence are possible. The effect on population level parasitaemia prevalence might be related to the ACT’s superior efficacy at the individual level alone. In addition, the gametocytocidal effects of artemisinins could contribute, as has been suggested by individual-level studies
[3–8, 47, 48]. It was not possible to support this claim with the population-level gametocytaemia prevalence reported here, as the data were limited by sample size and the low prevalence (~1%) of gametocytaemia among asymptomatic community members. Moreover, in this area of high transmission intensity and frequent AS + SP use, the decrease in population level parasitaemia might be due to the post-treatment prophylactic effect of SP. However, since both sites used SP, it is unlikely that the prophylactic effect would contribute to reduced parasitaemia prevalence differentially in Rufiji versus Kilombero-Ulanga. Lastly, mathematical models suggest that the introduction of even highly gametocytocidal ACT for case management of symptomatic patients with uncomplicated malaria will have only a modest impact on malaria endemicity, because of the presence of a large reservoir of asymptomatic patients who can sustain high levels of transmission and the rapid re-infection of patients who had been recently treated with ACT. In addition, the gametocytocidal properties of artemisinin drugs appear limited to immature sexual stages and mature gametocytes present at the time of treatment may persist and perpetuate transmission even after successfully completing an ACT regimen
. In sum, although one or more of several possible mechanisms may contribute, the modest reduction in parasitaemia prevalence found in this study is in line with reductions predicted by mathematical models of case management using effective artemisinins with rapid schizonticidal activity, gametocytocidal properties and post-treatment prophylactic effect
This study had a number of limitations. The observational nature of this study leaves the analysis unable to control or even measure all potential confounders. On the other hand, the presence of a contemporaneous comparison area did allow consideration of known environmental factors such as rainfall and the use of malaria control interventions such as ITNs. Although randomization and blinding were not practical, the sites are ecologically similar and were observed over a period of several years. Prior research in both sites suggests similar malaria transmission intensity, although differences in malaria intervention coverage were present as noted. In addition, the quantification of SP monotherapy and AS + SP drug pressure may be imprecise as it relied on individual recall and the assumption that anti-malarial access, uptake and use were constant throughout the year while the survey was conducted following peak malaria transmission season each year. In particular, AS + SP use was likely underestimated for Rufiji in 2006 since the site experienced a localized stockout of AS at the time of the survey, following delayed implementation of the National Malaria Control Programme’s plans to transition to artemether-lumefantrine as a first-line anti-malarial. However, even rough estimates suggest substantial AS + SP drug pressure on the population and suggest it is plausible that the implementation of AS + SP contributed to the reduction in parasitaemia prevalence. Lastly, we relied solely on light microscopy to measure gametocytaemia, which most likely yields lower prevalence than could be detected via newer means such as molecular assays
. This robust data set with observations over five years using a pre-post evaluation design with a non-randomized contemporaneous comparison design may offer one of the best opportunities to observe the impact of ACT policy in a real-world context. Given the increased use of ACT worldwide it is unlikely that there will be another such opportunity to compare ACT and non-ACT case management policies on such a scale.