Chaccour et al discuss the ivermectin, a widely used drug for the treatment and control of several neglected tropical diseases, and COVID-19. Caly et al recently reported that ivermectin is a potent ...inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in vitro. Given the coronavirus disease-19 (COVID-19) pandemic, this has understandably resonated widely in the global press. They believe the recent findings regarding ivermectin warrant rapidly implemented controlled clinical trials to assess its efficacy against SARS-CoV-2. These trials may open a new field of research on the potential use of avermectin antiparasitic drugs, including compounds with an improved pharmacokinetic profile, as antivirals.
Ivermectin is an endectocide that has been used broadly in single dose community campaigns for the control of onchocerciasis and lymphatic filariasis for more than 30 years. There is now interest in ...the potential use of ivermectin regimens to reduce malaria transmission, envisaged as community-wide campaigns tailored to transmission patterns and as complement of the local vector control programme. The development of new ivermectin regimens or other novel endectocides will require integrated development of the drug in the context of traditional entomological tools and endpoints. This document examines the main pharmacokinetic and pharmacodynamic parameters of the medicine and their potential influence on its vector control efficacy and safety at population level. This information could be valuable for trial design and clinical development into regulatory and policy pathways.
Achieving a malaria-free world presents exciting scientific challenges as well as overwhelming health, equity, and economic benefits. WHO and countries are setting ambitious goals for reducing the ...burden and eliminating malaria through the "Global Technical Strategy" and 21 countries are aiming to eliminate malaria by 2020. The commitment to achieve these targets should be celebrated. However, the need for innovation to achieve these goals, sustain elimination, and free the world of malaria is greater than ever. Over 180 experts across multiple disciplines are engaged in the Malaria Eradication Research Agenda (malERA) Refresh process to address problems that need to be solved. The result is a research and development agenda to accelerate malaria elimination and, in the longer term, transform the malaria community's ability to eradicate it globally.
There is ever-increasing anticipation for the potential of mass drug administration of endectocides (also known as systemic insecticides) to reduce malaria transmission, with ivermectin emerging as ...the most likely first-in-class endectocide.1 More than half of the 46 papers published on this subject in the past decade appeared in the past 2 years. 23 projects are registered in the MESA Track database, of which seven are active today; and, more importantly, trial mapping by the Malaria Ivermectin Roadmap2 shows that abundant new evidence on the topic will be available by 2020. After achieving remarkable advances from 2000 to 2015, the global fight against malaria has stalled.3 Beyond funding and access gaps, residual transmission—driven by mosquito behavioural adaptations that allow avoidance of home-based insecticides—has become a key liability for vector control, and challenges achievement of the global goals set forth by WHO.4 Ivermectin lays the path for a whole new concept: drug-based vector control.5,6 Ivermectin, or indeed any effective endectocide, could be administered to eligible members of the at-risk community as a complementary tool for vector control. Eligible village residents in the control and intervention groups received a single 150–200 μg/kg dose of ivermectin plus 400 mg of albendazole, but those in the intervention group received five additional 3-weekly doses of ivermectin alone, with mass drug administration coverage of 70–75% across the 18-week intervention period.
When ivermectin's ability to kill the microfilaria of onchocerciasis was recognised it was developed for use in human beings, and through an ambitious donation programme launched by Ray Vagelos at ...Merck with the World Bank, more than 2·5 billion doses have been distributed in mass drug administration campaigns over the past 30 years. Repurposing a drug for a novel indication—in this case, as a complementary vector control tool to decrease malaria transmission—is not a minor endeavour in the context of modern requirements for efficacy, effectiveness, and safety. The WHO World Malaria Report released in 20178 shows the global effort is increasingly resource constrained, and that although there are 21 countries targeting malaria elimination by 2020 with current tools, another group of highly endemic countries have evidence that the advance against malaria has stalled, and in several cases is worsening.
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.
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.
Malaria programmes use Plasmodium falciparum histidine-rich protein-2 (PfHRP2) based rapid diagnostic tests (RDTs) for malaria diagnosis. The deletion of this target antigen could potentially lead to ...misdiagnosis, delayed treatment and continuation of active transmission.
Plasmodium falciparum isolates (n = 1162) collected in Southern Mozambique were assessed by RDTs, microscopy and/or 18SrRNA qPCR. pfhrp2 and pfhrp3 deletions were investigated in isolates from individuals who were negative by RDT but positive by microscopy and/or qPCR (n = 69) using gene-specific PCRs, with kelch13 PCR as the parasite DNA control.
Lack of pfhrp2 PCR amplification was observed in one of the 69 isolates subjected to molecular analysis 1.45% (95% CI 0.3-7.8%).
The low prevalence of pfhrp2 deletions suggests that RDTs will detect the vast majority of the P. falciparum infections. Nevertheless, active surveillance for changing deletion frequencies is required.
About 3·7 billion doses of ivermectin have been distributed in mass drug administration (MDA) campaigns globally over the past 30 years. At 10–100 times higher than current human doses, ivermectin is ...a known teratogen in mammals. During these campaigns with recommended doses, pregnant women might be inadvertently exposed. We therefore aimed to evaluate the existing evidence for serious and non-serious adverse events after ivermectin exposure in pregnant women.
For this systematic review and meta-analysis, we searched relevant databases and trial registry platforms on July 15, 2018, for randomised controlled trials (RCTs) and observational studies that reported adverse events in pregnant women. We did not use language or date restrictions. Outcomes of interest were spontaneous abortions, stillbirths, congenital anomalies, and neonatal death (serious adverse events), as well as maternal morbidity, preterm births, and low birthweight (adverse events). The risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias Tool for RCTs. We did the meta-analysis of observational studies and RCTs separately. The quality of evidence was assessed using the GRADE approach. The study protocol is registered with PROSPERO, protocol CRD42016046914.
We identified 147 records, of which only five observational studies and one RCT were included for quantitative analysis; these studies were published between 1990 and 2008, and were done in six African countries. 893 women with 899 pregancy outcomes were included, of whom 496 pregnant women (500 pregnancy outcomes) received ivermectin inadvertently during MDA campaigns in the observational studies and 397 pregnant women (399 pregnancy outcomes) purposely received ivermectin as part of the open-label RCT. No study reported neonatal deaths, maternal morbidity, preterm births, or low birthweight. It is unclear whether exposure to ivermectin during pregnancy increases the risk of spontaneous abortions and stillbirths (odds ratio OR 1·15 95% CI 0·75–1·78 with very low certainty of evidence for the four observational studies and 0·62 0·18–2·14 with very low certainty of evidence for the RCT) or congenital anomalies (OR 1·69 95% CI 0·83–3·41 with very low certainty of evidence for the five observational studies and 1·10 0·07–17·65 with very low certainty of evidence for the RCT).
There is insufficient evidence to conclude on the safety profile of ivermectin during pregnancy. Treatment campaigns should focus additional efforts on preventing inadvertent treatment of pregnant women.
Unitaid.
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