Reduction of transmission from malaria patients by artemisinin combination therapies: a pooled analysis of six randomized trials

Abstract

Background: Artemisinin combination therapies (ACT), which are increasingly being introduced for treatment of Plasmodium falciparum malaria, are more effective against sexual stage parasites (gametocytes) than previous first-line antimalarials and therefore have the potential to reduce parasite transmission. The size of this effect is estimated in symptomatic P. falciparum infections.

Methods: Data on 3,174 patients were pooled from six antimalarial trials conducted in The Gambia and Kenya. Multivariable regression was used to investigate the role of ACT versus non-artemisinin antimalarial treatment, treatment failure, presence of pre-treatment gametocytes and submicroscopic gametocytaemia on transmission to mosquitoes and the area under the curve (AUC) of gametocyte density during the 28 days of follow up.

Results: ACT treatment was associated with a significant reduction in the probability of being gametocytaemic on the day of transmission experiments (OR 0.20 95% CI 0.16-0.26), transmission to mosquitoes by slide-positive gametocyte carriers (OR mosquito infection 0.49 95% CI 0.33-0.73) and AUC of gametocyte density (ratio of means 0.35 95% CI 0.31-0.41). Parasitological treatment failure did not account for the difference between ACT and non-artemisinin impact. The presence of slide-positive gametocytaemia prior to treatment significantly reduced ACT impact on gametocytaemia (p < 0.001). Taking account of submicroscopic gametocytaemia reduced estimates of ACT impact in a high transmission setting in Kenya, but not in a lower transmission setting in the Gambia.

Conclusion: Treatment with ACT significantly reduces infectiousness of individual patients with uncomplicated falciparum malaria compared to previous first line treatments. Rapid treatment of cases before gametocytaemia is well developed may enhance the impact of ACT on transmission.

Figure 1

Overview of trial process and pooled data from the six studies.

Figure 2

Mean gametocyte density/μl during follow up in ACT (black, circles) and non-artemisinin (grey, triangles) antimalarial treatment groups, pooled results from the six trials (a) overall (b) stratified by parasitological treatment failure (c) stratified by presence of pre-treatment gametocytes. Error bars show 95% confidence intervals. Lines drawn in between data points are theoretical only. Below: ratios showing ACT impact on gametocyte prevalence and density on each follow up day, allowing for random study effects.

Figure 3

Box plots showing oocyst densities by ACT and (a) parasitological treatment failure and (b) pre-treatment gametocytes.