Frequent, Repeated Mass Ivermectin Administration Reduces Malaria Transmission

Frequently repeated mass administration of ivermectin during transmission season may reduce the incidence of uncomplicated malaria episodes in children living in endemic regions, according to study results published in the Lancet.¹

Since 2017, when researchers at the World Health Organization suggested that the global fight against malaria had stalled,² novel ways to prevent the transmission of malaria parasites have been needed. Ivermectin has emerged as a possible new and effective malaria control tool, not only because of its mosquitocidal effects, but also because of its ability to reduce residual transmission of malaria.^3-6

Therefore, researchers in the study enrolled 2712 participants from 8 village clusters from Burkina Faso, which is hyperendemic for malaria, during the 2015 rainy season. (ClinicalTrials.gov identifier: NCT02509481).¹ The villages were randomly assigned on a 1:1 ratio to either a control or intervention group. Both groups received a single 150 to 200 μg/kg oral dose of ivermectin plus 400 mg of albendazole, but patients in the intervention group received 5 further doses of ivermectin alone at 3-week intervals over the 18-week treatment period.

The primary outcome was the cumulative incidence of uncomplicated malaria episodes over the 18-week intervention period in children aged ≤5 years. The study was blinded to the outcomes assessor. Malaria incidence was monitored by nurses a minimum of 3 times every 2 weeks over the treatment phase.

In the final model, which was adjusted for sex and clustering effects of village and household, the cumulative malaria incidence was reduced in the intervention group (648 cases in 327 children; 2.00 episodes per child) compared with the control group (647 cases in 263 children; 2.49 episodes per child). The risk ratio was 0.81 (95% CI, 0.72-0.90) and the risk difference was −0.49 (95% CI, −0.79 to −0.21; P =.0009).

As a result of the unexpected large percentage of children aged 4 to 5 years in the study cohort who were at least 90 cm in height and thus eligible to receive ivermectin treatment, researchers conducted a post hoc, subgroup analysis. Of the 327 children in the intervention group, 69 were treatment with ivermectin 4 to 6 times. In the control group, 52 of 263 children were treated once with ivermectin. When accounting for this confounder, there was a 44% lower incidence in the intervention group. The percentage of children with no malaria episodes in the intervention group was more than twice that in the control group (20% vs 9%, respectively). Moreover, the median time to first malaria episode was longer in the intervention group than in the control group.

“Supporting these data, ivermectin-treated children from the intervention group had a significantly reduced molecular force of infection compared with those from the control group, indicating that such repeated treatments affect malaria incidence connected to P falciparum clonal exposure or development,” noted the researchers. Future research will need to verify the observations made in this study, as well as the safety and efficacy of higher dose⁷ or slow-release formulations.

“Beyond the generation of evidence regarding safety and efficacy of ivermectin, the crucial next steps are [the] determination of the best distribution approaches, identification of synergies in alliance with neglected tropical disease programmes, and ensuring a supply of the drug for campaigns at an affordable cost,” concluded Drs Carlos Chaccour and N. Regina Rabinovich, from the ISGlobal, Hospital Clínic, Universitat de Barcelona, Spain in an editorial commentary.⁸

References

1. Foy BD, Alout H, Seaman JA, et al. Efficacy and risk of harms of repeat ivermectin mass drug administrations for control of malaria (RIMDAMAL): a cluster-randomised trial [published online March 13, 2019]. Lancet. doi:10.1016/S0140-6736(18)32321-3
2. World malaria report 2018. World Health Organization. www.who.int/malaria/publications/world-malaria-report-2018/en/.  Published November 19, 2018. Accessed April 1, 2019.
3. Chaccour CJ, Kobylinski KC, Bassat Q, et al. Ivermectin to reduce malaria transmission: a research agenda for a promising new tool for elimination. Malar J. 2013;12:153.
4. Kobylinski KC, Sylla M, Chapman PL, Sarr MD, Foy BD. Ivermectin mass drug administration to humans disrupts malaria parasite transmission in Senegalese villages. Am J Trop Med Hyg. 2011;85(1):3-5.
5. Alout H, Krajacich BJ, Meyers JI, et al. Evaluation of ivermectin mass drug administration for malaria transmission control across different West African environments. Malar J. 2014;13:417.
6. Kobylinski KC, Foy BD, Richardson JH. Ivermectin inhibits the sporogony of Plasmodium falciparum in Anopheles gambiae. Malar J. 2012;11:381.
7. Smit MR, Ochomo EO, Aljayyoussi G, et al. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018;18(6):615-626.
8. Chaccour C, Rabinovich NR. Advancing the repurposing of ivermectin for malaria [published online March 13, 2019]. Lancet. doi:10.1016/S0140-6736(18)32613-8