Questions your patients may have about Zika virus

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 [1]. This suggestion, that received support in the general press [2], 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 [3]. 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 [4]. 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 [5]. 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 [7].

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 [11]. The maximal concentrations of ivermectin found in human venous plasma after treatment with 150 μg/kg ivermectin ranges from 9 to 75 ng/ml [12]. 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 [13] 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.

REFERENCES
1. Sánchez-Delgado E. Zika virus and Ivermectin to reduce transmision of diseases by mosquitoes. BMJ 2016;352:i467.
2. Szabo L. WHO to hold emergency meeting Monday on Zika virus. USA Today 31/12/2016.
3. Omura S. Ivermectin: 25 years and still going strong. Int J Antimicrob Ag 2008;31:91-8.
4. Foy BD, Kobylinski KC, da Silva IM, et al. Endectocides for malaria control. Trends Parasitol 2011;27:423-8.
5. Slater HC, Walker PG, Bousema T, et al. The potential impact of adding ivermectin to a mass treatment intervention to reduce malaria transmission: a modelling study. J Infect Dis 2014;210:1972-80.
6. Kobylinski KC, Foy BD, Richardson JH. Ivermectin inhibits the sporogony of Plasmodium falciparum in Anopheles gambiae. Malar J 2012;11:381.
7. Meyers JI, Gray M, Foy BD. Mosquitocidal properties of IgG targeting the glutamate-gated chloride channel in three mosquito disease vectors (Diptera: Culicidae). J Exp Biol 2015;218:1487-95.
8. Kobylinski KC, Deus KM, Butters MP, et al. The effect of oral anthelmintics on the survivorship and re-feeding frequency of anthropophilic mosquito disease vectors. Acta Trop 2010;116:119-26.
9. Ouedraogo AL, Bastiaens GJ, Tiono AB, et al. Efficacy and safety of the mosquitocidal drug ivermectin to prevent malaria transmission after treatment: a double-blind, randomized, clinical trial. Clin Infect Dis 2015;60(3):357-65.
10. Deus KM, Saavedra-Rodriguez K, Butters MP, et al. The effect of ivermectin in seven strains of Aedes aegypti (Diptera: Culicidae) including a genetically diverse laboratory strain and three permethrin resistant strains. J Med Entomol 2012;49:356-63.
11. Mectizan Donation Program. http://www.mectizan.org/. Accessed on 4/2/2016.
12. Elkassaby MH. Ivermectin uptake and distribution in the plasma and tissue of Sudanese and Mexican patients infected with Onchocerca volvulus. Trop Med Parasitol 1991;42:79-81.
13. Awadzi K, Opoku NO, Addy ET, et al. The chemotherapy of onchocerciasis. XIX: The clinical and laboratory tolerance of high dose ivermectin. Trop Med Parasitol 1995;46:131-7.