Preventing mosquitoes from biting by the existing tools (e.g. ITNs and IRS) and blocking the transmission of Plasmodium parasites from patients to mosquitoes using agents (vaccine or drugs) may substantially improve public health through reducing the burden of malaria . In areas of stable malaria, a meta-analysis of ITNs on malaria transmission revealed a reduction by 50% . However, a meta-analysis on existing antimalarials to block the transmission of the parasite from patients to mosquitoes has not yet been done to the author’s knowledge.
The current meta-analysis re-affirmed the advantage of ACTs in reducing transmission of Plasmodium to the mosquitoes. In the overall analysis, the odds of transmission of malaria in artesunate-based combination treatment group was 2.78 times less than the odds of transmission of malaria in antimalarials without artesunate (Figure 2). Similarly, the odds of malaria transmission to mosquitoes in artemether-lumefantrine treated group was 2 times less than the odds on other antimalarials used in the studies (Figure 3). Exceptionally, in one trial , the odds of parasite transmission was higher in artesunate-based combination therapy than the standard therapy without artesunate. This difference might be attributed to the use of only one dose of artesunate in the trial.
From the current analysis of the published articles, artesunate- and artemether-based therapy could reduce the transmission of the parasite to the mosquitoes. Thus, these medications, in addition to their role in the clinical case management of malaria, can have an impact on the overall transmission rate of malaria and play a role in controlling malaria.
Primaquine, the old antimalarial drug mainly used in terminal cure of P. vivax infection, was also tested for its impact on the transmission of Plasmodium to mosquitoes. Trials compared the transmission blocking effect of single-dose primaquine with the conventional antimalarials: sulfadoxine-pyrimethamine and pyrimethamine. The current analysis showed that odds of mosquito infection rate was 11 times less for single-dose primaquine relative to the comparative medicine (Figure 4).
In non-comparative longitudinal trials of single-dose primaquine, the current systematic review presented the trends of mosquito infection rate across successive post-treatment days (Figure 5). There was a rapid drop in mosquito infection rate as illustrated in those mosquitoes feeding on the first and second days post-treatment. However, the effect was maintained only for a short period as evidenced by the positivity of mosquitoes biting on some patients after the 10 days of single-dose primaquine therapy. As the trials employed single-dose primaquine therapy, which might target only the mature gametocyte , the continuity of transmission blockade by a single dose of primaquine fails against the new wave of mature gametocytes that appear after primaquine has been washed out .
The use of single-dose primaquine blocks the transmission of malaria temporarily (Figure 5). However, combining it with effective antimalarials - like mefloquine used in the trial conducted by Chen and his colleague - results in a disruption of Plasmodium transmission to the vector for a longer period (Figure 6). This might be explained by the fact that the effective schizonticide (mefloquine), by clearing the parasite, dries out the potential source for a new wave of gametocytes.
Following the introduction of ACTs in malaria case management, many researchers report the additional benefit of ACTs on the partial gametocytocidal effect compared with the non-ACTs regimens [30–34]. Recently, there is also interest of combining ACTs with single-dose primaquine, particularly in areas with a resistant Plasmodium to ACTs or in the phase of malaria elimination. The addition of primaquine to ACTs results in a further reduction in gametocyte carriage rate that can have implications on the extent of malaria transmission [35–39]. However, the optimal time of administration, treatment duration and dose of primaquine needs to be understood for improved outcomes. Further studies are also required to understand the transmission blocking effect upon the addition of primaquine to ACT regimens at the mosquito level, which is a gold standard approach to evaluate malaria transmission.
The present paper analysed the transmission blocking activity of artemisinin derivatives and primaquine. The clinical trials of artemisinin derivatives and primaquine focused on An. gambiae and An. stephensi; respectively. None of the identified literatures pertained to other dominant malaria vectors such as An. funestus and An. arabiensis[40–42]. In all of the trials included for meta-analysis, similar colonies of mosquitoes in both intervention and control groups were used. By so doing, confounding bias related to the variable infection success in the different species of vectors could be avoided. Of course, if the variability in susceptibility of the vectors to P. falciparum infection modified the transmission blocking activity of drugs, trials with different species of malaria vectors having a range of infection success would be required; then systematic reviews should consider subgroup analysis.
Like any retrospective study, this systematic review has a number of limitations. The literature search might have missed some trials. The author assumed that missing reports is unlikely for two reasons. Firstly, a proper search strategy was followed to identify literatures. Secondly, the research groups working on transmission blocking trials at the level of mosquitoes are few. Another concern is the comparison of the reference drugs (artemisinin derivatives and primaquine) with a heterogeneous array of antimalarials probably with different gametocytocidal activity, which in turn might obscure some systematic differences between drugs. To minimize these risk, random analytic method was followed in all data analysis, including in those with little heterogeneity.