Carlos Chaccour

Ivermectin to reduce malaria transmission: a research agenda for a promising new tool for elimination

BackgroundThe heterogeneity of malaria transmission makes widespread elimination a difficult goal to achieve. Most of the current vector control measures insufficiently target outdoor transmission. Also, insecticide resistance threatens to diminish the efficacy of the most prevalent measures, indoor residual spray and insecticide treated nets. Innovative approaches are needed. The use of endectocides, such as ivermectin, could be an important new addition to the toolbox of anti-malarial measures. Ivermectin effectively targets outdoor transmission, has a novel mechanism of action that could circumvent resistance and might be distributed over the channels already in place for the control of onchocerciasis and lymphatic filariasis.MethodsThe previous works involving ivermectin and Anopheles vectors are reviewed and summarized. A review of ivermectin’s safety profile is also provided. Finally three definitive clinical trials are described in detail and proposed as the evidence needed for implementation. Several smaller and specific supportive studies are also proposed.ConclusionsThe use of ivermectin solves many challenges identified for future vector control strategies. It is an effective and safe endectocide that was approved for human use more than 25 years ago. Recent studies suggest it might become an effective and complementary strategy in malaria elimination and eradication efforts; however, intensive research will be needed to make this a reality.

Establishment of the Ivermectin Research for Malaria Elimination Network: updating the research agenda

The potential use of ivermectin as an additional vector control tool is receiving increased attention from the malaria elimination community, driven by the increased importance of outdoor/residual malaria transmission and the threat of insecticide resistance where vector tools have been scaled-up. This report summarizes the emerging evidence presented at a side meeting on “Ivermectin for malaria elimination: current status and future directions” at the annual meeting of the American Society of Tropical Medicine and Hygiene in New Orleans on November 4, 2014. One outcome was the creation of the “Ivermectin Research for Malaria Elimination Network” whose main goal is to establish a common research agenda to generate the evidence base on whether ivermectin-based strategies should be added to the emerging arsenal to interrupt malaria transmission.

Mind the gap: residual malaria transmission, veterinary endectocides and livestock as targets for malaria vector control

The work of Pooda et al. published in Malaria Journal [1] provides encouraging evidence of the potential use of systemic insecticides in cattle as a complementary means to further reduce residual malaria transmission that persists despite high coverage of current front-line vector measures, namely long-lasting insecticidal nets (LLINs) and indoor residual sprays (IRS). LLINs and IRS interventions are responsible for most of the remarkable reductions in malaria burden achieved in this century [2], but even more ambitious new vector control measures will be required to achieve elimination of transmission from most endemic areas in the years ahead [3–5]. This is because LLINs and IRS leave two obvious spatial and temporal gaps wherever vector mosquitoes attack people outdoors, especially in the evenings and mornings, or rest outdoors before and after feeding [3–5]. There is, however, a third gap that does not usually receive as much attention, specifically their failure to kill mosquitoes that feed on animals rather than humans. Zoophagic vectors that feed predominantly on animals can sustain malaria transmission even if they only bite humans infrequently [6]. Even with near-complete coverage of human sleeping spaces and houses, LLINs and IRS cannot be reasonably expected to have any meaningful impact upon the density or longevity of zoophagic vector populations, because they achieve no insecticidal coverage of the animals that constitute their main source of protein [4, 6]. Fortunately, by far the most common source of blood for most zoophagic malaria vectors are domesticated livestock, cattle in particular [7], so it is also possible to control the malaria transmission they mediate through veterinary applications of insecticides [8], the most exciting of which may be the systemic insecticides which the mosquito actually ingests along with its blood meal. Fritz et al. first described increased mortality of Anopheles gambiae feeding on ivermectin-treated cattle and suggested a potential role of this strategy for integrated vector management [9]. These findings have since been extended to Anopheles culicifacies and Anopheles stephensi, the main malaria vectors of Pakistan [10], and more recently to an important African vector of residual transmission, Anopheles arabiensis [11]. This latest report by Pooda et al. [1] now demonstrates similar increased mortality and reduced fertility of Anopheles coluzzii, a widely distributed vector species which maintains robust malaria transmission all across west and central Africa [12]. Interestingly, the lethal effect of ivermectin was seen even when the colony used had high prevalence of the kdr mutation which contributes to pyrethroid resistance in many parts of Africa. Although the evidence base is growing fast, the full potential of ivermectin for malaria vector and transmission control remains to be established, but most discourse thus far has focused on medical delivery to human beings [13]. However, the alternative strategy of veterinary delivery to livestock has several advantages: Long-lasting injectable veterinary formulations of ivermectin already exist that can dramatically increase the effectiveness of this approach, by not only targeting a more important blood source for vector populations than humans, but also by achieving far longer duration of efficacy than is possible with the oral formulations available for human pharmaceutical delivery. A much greater diversity of different endectocides are available for cattle and other livestock, which offers an opportunity to combine drugs with different mechanisms of action, especially if ivermectin is to be used for mass drug administration to humans. Integrating an endectocide into traditional zooprophylaxis strategies [14] removes potential risks of accidentally increasing malaria transmission by increasing vector survival and reproduction [15], because mosquitoes attracted to feeding on animals could be killed rather than merely diverted away from humans. Endectocides can contribute to an overall One Health strategy by simultaneously improving livestock and human health. Nonzoonotic livestock parasites pose an important burden on human health by reducing economic output and nutrient availability. In addition to preventing malaria transmission, broadening the use of veterinary endectocides also offers an excellent opportunity to alleviate poverty and malnutrition by reducing the burden of livestock parasites on the health and economic resilience of their human owners [16]. Plasmodium falciparum and Plasmodium vivax are both strict anthroponoses, so it is understandable that ivermectin mass drug administration for malaria control and elimination is usually viewed primarily as an intervention for human populations. However, the use of veterinary antiparasitic drugs with insecticidal proprieties in domesticated livestock could perhaps achieve greater impact in many settings where persisting transmission is mediated by zoophagic vectors, and contribute to human health in previously unforeseen ways.

Developing an expanded vector control toolbox for malaria elimination

Vector control using long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) accounts for most of the malaria burden reductions achieved recently in low and middle-income countries (LMICs). LLINs and IRS are highly effective, but are insufficient to eliminate malaria transmission in many settings because of operational constraints, growing resistance to available insecticides and mosquitoes that behaviourally avoid contact with these interventions. However, a number of substantive opportunities now exist for rapidly developing and implementing more diverse, effective and sustainable malaria vector control strategies for LMICs. For example, mosquito control in high-income countries is predominantly achieved with a combination of mosquito-proofed housing and environmental management, supplemented with large-scale insecticide applications to larval habitats and outdoor spaces that kill off vector populations en masse, but all these interventions remain underused in LMICs. Programmatic development and evaluation of decentralised, locally managed systems for delivering these proactive mosquito population abatement practices in LMICs could therefore enable broader scale-up. Furthermore, a diverse range of emerging or repurposed technologies are becoming available for targeting mosquitoes when they enter houses, feed outdoors, attack livestock, feed on sugar or aggregate into mating swarms. Global policy must now be realigned to mobilise the political and financial support necessary to exploit these opportunities over the decade ahead, so that national malaria control and elimination programmes can access a much broader, more effective set of vector control interventions.

Going beyond personal protection against mosquito bites to eliminate malaria transmission: Population suppression of malaria vectors that exploit both human and animal blood

Protecting individuals and households against mosquito bites with long-lasting insecticidal nets (LLINs) or indoor residual spraying (IRS) can suppress entire populations of unusually efficient malaria vector species that predominantly feed indoors on humans. Mosquitoes which usually feed on animals are less reliant on human blood, so they are far less vulnerable to population suppression effects of such human-targeted insecticidal measures. Fortunately, the dozens of mosquito species which primarily feed on animals are also relatively inefficient vectors of malaria, so personal protection against mosquito bites may be sufficient to eliminate transmission. However, a handful of mosquito species are particularly problematic vectors of residual malaria transmission, because they feed readily on both humans and animals. These unusual vectors feed often enough on humans to be potent malaria vectors, but also often enough on animals to evade population control with LLINs, IRS or any other insecticidal personal protection measure targeted only to humans. Anopheles arabiensis and A. coluzzii in Africa, A. darlingi in South America and A. farauti in Oceania, as well as A. culicifacies species E, A. fluviatilis species S, A. lesteri and A. minimus in Asia, all feed readily on either humans or animals and collectively mediate residual malaria transmission across most of the tropics. Eliminating malaria transmission by vectors exhibiting such dual host preferences will require aggressive mosquito population abatement, rather than just personal protection of humans. Population suppression of even these particularly troublesome vectors is achievable with a variety of existing vector control technologies that remain underdeveloped or underexploited.

Ivermectin to reduce malaria transmission II. Considerations regarding clinical development pathway

The development of ivermectin as a complementary vector control tool will require good quality evidence. This paper reviews the different eco-epidemiological contexts in which mass drug administration with ivermectin could be useful. Potential scenarios and pharmacological strategies are compared in order to help guide trial design. The rationale for a particular timing of an ivermectin-based tool and some potentially useful outcome measures are suggested.

Travel and fake artesunate: a risky business

Division of Internal Medicine (C J Chaccour MD), and Division of Infectious Diseases, Department of Medicine (C J Chaccour, J L Del Pozo MD), and Division of Clinical Microbiology and Parasitology (J L Del Pozo), Clinica Universidad de Navarra, Pamplona, Spain; and Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK (Prof D Mabey PhD, H Kaur PhD)

Ivermectin to reduce malaria transmission III. Considerations regarding regulatory and policy pathways

Vector control is a task previously relegated to products that (a) kill the mosquitoes directly at different stages (insecticides, larvicides, baited traps), or (b) avoid/reduce human-mosquito contact (bed nets, repellents, house screening), thereby reducing transmission. The potential community-based administration of the endectocide ivermectin with the intent to kill mosquitoes that bite humans, and thus reduce malaria transmission, offers a novel approach using a well-known drug, but additional steps are required to address technical, regulatory and policy gaps. The proposed community administration of this drug presents dual novel paradigms; first, indirect impact on the community rather than on individuals, and second, the use of a drug for vector control. In this paper, the main questions related to the regulatory and policy pathways for such an application are identified. Succinct answers are proposed for how the efficacy, safety, acceptability, cost-effectiveness and programmatic suitability could result in regulatory approval and ultimately policy recommendations on the use of ivermectin as a complementary vector control tool.

Falsified antimalarials: a minireview

Malaria is a curable disease, provided timely access to efficacious drugs is sought. Poor quality and, in particular, falsified antimalarial drugs harm the population of malaria endemic areas; they put lives in peril, cause economic losses to patients, families, industry, and generally undermine the trust in health systems. The extent of the problem is not easily assessed, and although a prevalence of up to 35% of poor-quality antimalarials has been reported, this number should be interpreted with caution given the heterogeneity of methods used to measure it. The trade in falsified antimalarials can be curtailed by putting in place drug quality surveillance, better legislation and improving the access and affordability of these essential drugs.

Slow Release Ivermectin Formulation for Malaria Control: a Pilot Study in 80-kg Pigs

Carlos Chaccour,a,b Gloria Abizanda,c Ángel Irigoyen,d José Luis Del Pozoe Instituto de Salud Tropical, Universidad de Navarra, Pamplona, Spaina; ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clínic—Universitat de Barcelona, Barcelona, Spainb; Centro de Investigación Médica Aplicada, Pamplona, Spainc; Drug Developing Unit, Universidad de Navarra, Pamplona, Spaind; Infectious Diseases Division and Clinical Microbiology, Clínica Universidad de Navarra, Pamplona, SpaineSlow Release Ivermectin Formulation for Malaria Control: a Pilot Study in 80-kg Pigs 1 2 3 Carlos Chaccour,# Gloria Abizanda, Ángel Irigoyen, José Luis Del Pozo 4 5 Instituto de Salud Tropical, Universidad de Navarra, Pamplona, Spain; ISGlobal, Barcelona 6 Ctr. Int. Health Res. (CRESIB), Hospital Clínic Universitat de Barcelona, Barcelona, Spain; 7 Centro de Investigación Médica Aplicada, Pamplona, Spain; Drug Developing Unit, 8 Universidad de Navarra, Pamplona, Spain; Infectious Diseases Division and Clinical 9 Microbiology, Clínica Universidad de Navarra, Pamplona, Spain 10 11 # Address correspondence to: carlos.chaccour@isglobal.org 12 13 Vector control with long-lasting insecticidal nets (LLINs) and indoor residual spraying are 14 responsible for more than two thirds of the reduction seen in malaria prevalence in Africa 15 over the last 15 years (1). Yet the behavioral plasticity of mosquito vectors can lead to 16 residual transmission and possibly hamper elimination efforts (2, 3). 17 One identified source of residual transmission is partial zoophagy. Mosquitoes that feed on 18 peridomestic livestock can avoid contact with insecticides and survive to continue 19 transmission once human blood is available again (3). This behavioral pattern could be seen 20 after the scale-up of LLINs that put selective pressure on vectors that bite predominantly 21 humans indoors (4), either by allowing a shift to a vector species with different behavior (5) 22 or by selecting members of the same species that circumvent LLINs by biting outdoors (6) or 23 outside sleeping hours (7). 24 AAC Accepted Manuscript Posted Online 28 December 2016 Antimicrob. Agents Chemother. doi:10.1128/AAC.02104-16 Copyright