Ivermectin to prevent ZIKV transmission: a word of caution
This week, the World Health Organization announced that the recent cluster of neurological disorders and neonatal malformations that has been associated with Zika virus (ZIKV) disease constitutes a Public Health Emergency of International Concern. Without an available vaccine or efficacious treatment, preventive measures form the only current option to curb the ZIKV epidemic and include personal protection against mosquito bites and vector control measures that target ZIKV transmitting mosquitoes in the genus Aedes, notably Aedes aegypti. Recently, a Rapid Response in The BMJ suggested that the anti-parasitic drug ivermectin may be of great value to reduce ZIKV transmission by targeting these mosquitoes . This suggestion, that received support in the general press , was based on the potency of ivermectin in the fight against another vector-borne disease, malaria. We have serious concerns with this suggestion. Despite the evident promise of ivermectin, caution is warranted when extrapolating promising results for one vector borne disease to another.
Ivermectin is active against a range of malaria-transmitting Anopheles mosquitoes. Its mode of action depends on the activation of glutamate-gated chloride channels (GluCl) in neuronal and neuromuscular tissues of mosquitoes, causing flaccid paralysis and death upon ingestion . Anophelines that feed on humans who have taken ivermectin have a reduced lifespan while sub-lethal concentrations of ivermectin affect the feeding capacity and propagation of surviving mosquitoes . Because of these activities, mass drug administration with ivermectin, often in combination with a curative dose of antimalarials, is considered as a promising component for integrated malaria control . The lethal concentration at which 50% of the mosquitoes die (LC50) is in the range of 5-22 ng/ml [6-9] for anophelines. The LC50 for Aedes aegypti however, is at least 10-fold higher in the range of 180-600 ng/mL [8, 10].These differences may be associated with differences in the expression of GluCl between these mosquito species .
At present, ivermectin is available for use in humans at a concentration of 150-200μg/kg through the Mectizan donation programme and more than 2 billion doses have been administered since 1987 . The maximal concentrations of ivermectin found in human venous plasma after treatment with 150 μg/kg ivermectin ranges from 9 to 75 ng/ml . Whilst the ivermectin plasma concentration declines rapidly in the days following treatment, the achieved plasma levels are sufficient to have an impact on malaria transmission. However, plasma levels fall short of concentrations that are likely to affect the survival of Aedes mosquitoes, even if the highest currently used dose of 800 μg/kg  is administered (see figure). If ivermectin is to be used for control of the transmission of ZIKV, even higher doses of ivermectin are necessary for which the safety profile needs to be determined in long-term pharmacokinetic and safety studies. In addition, the prospect of repeated mass drug administrations over short time-windows in large urban areas poses considerable challenges.
In conclusion, whilst mosquitocidal drugs should be further explored for a potential role in integrated control of vector-borne diseases, the current ZIKV epidemic requires control tools different from the currently available ivermectin regimens.
FIGURE. Ivermectin plasma levels in relation to its mosquitocidal effects. The pharmacokinetic curves for ivermectin are presented, assuming initial doses of 200 µg/kg or 800 µg/kg. In the grey shaded areas are the estimated values for the lethal concentration at which 50% of the mosquitoes die (LC50) for malaria-transmitting Anopheles mosquitoes and ZIKV transmitting Aedes aegypti mosquitoes.
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Competing interests: No competing interests