key: cord-0765446-g96n11vj
authors: Cardwell, Karen; O Murchu, Eamon; Byrne, Paula; Broderick, Natasha; Walsh, Kieran A.; O'Neill, Sinéad M.; Smith, Susan M.; Harrington, Patricia; Ryan, Máirín; O'Neill, Michelle
title: Pharmacological interventions to prevent Covid‐19 disease: A rapid review
date: 2021-09-28
journal: Rev Med Virol
DOI: 10.1002/rmv.2299
sha: 042d6951728dd67c8ffe19d565ec3636c59748af
doc_id: 765446
cord_uid: g96n11vj

The aim of this rapid review was to determine the effectiveness of pharmacological interventions (excluding vaccines) to prevent coronavirus disease 2019 (Covid‐19) or reduce the severity of disease. A systematic search of published peer‐reviewed articles and non‐peer‐reviewed pre‐prints was undertaken from 1 January 2020 to 17 August 2021. Four randomised controlled trials (RCTs) and one non‐RCT were included; three trials (two RCTs and one non‐RCT) tested ivermectin with or without carrageenan. While all reported some potential protective effect of ivermectin, these trials had a high risk of bias and the certainty of evidence was deemed to be ‘very low’. One RCT tested bamlanivimab compared to placebo and reported a significantly reduced incidence of Covid‐19 in the intervention group; this trial had a low risk of bias however the certainty of evidence was deemed ‘very low’. The fifth RCT tested casirivimab plus imdevimab versus placebo and reported that the combination of monoclonal antibodies significantly reduced the incidence of symptomatic and asymptomatic SARS‐CoV‐2 infection, viral load, duration of symptomatic disease and the duration of a high viral load; this trial was deemed to have a low risk of bias, and the certainty of evidence was ‘low’. The designations ‘low' and ‘very low’ regarding the certainty of evidence indicate that the estimate of effect is uncertain and therefore is unsuitable for informing decision‐making. At the time of writing, there is insufficient high quality evidence to support the use of pharmacological interventions to prevent Covid‐19.

March 2020, the World Health Organization (WHO) declared the coronavirus (Covid-19) outbreak a pandemic. 1 Pharmacological prevention of Covid-19 (i.e., prior to infection with severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], not treatment of Covid-19 following infection with SARS-CoV-2) could be an important intervention, especially in the context of vaccine hesitancy, inequitable access to such and variants of concern. However, the risk-benefit of such interventions must be evaluated. 2 On 2 March 2021, the WHO published a recommendation against the use of hydroxychloroquine for individuals who do not have Covid- 19 . The panel acknowledged that in light of this recommendation, this area is no longer a research priority and that resources devoted to clinical research should be oriented to evaluate other more promising interventions. 3 As such, the aim of this rapid review was to determine the effectiveness of pharmacological interventions (excluding hydroxychloroquine and vaccines) in the community, prior to a diagnosis of Covid-19, to prevent Covid-19 disease.

A detailed report of the methods is provided in the protocol. 4 In summary, a systematic search of published peer-reviewed articles and non-peer-reviewed pre-prints was undertaken from 1 January 2020 to 17 August 2021; no language restrictions were applied.

Titles, abstracts and full texts of potentially eligible papers were single screened based on the inclusion and exclusion criteria. 4 Eligible study designs were randomised controlled trials (RCTs) and non-RCTs; outcomes of interest were laboratory-confirmed diagnosis of Covid-19 or symptomatic infection. Data extraction and quality appraisal of included studies were completed by a single reviewer and checked by a second reviewer. Data extraction was completed using a standardised data extraction form. Quality appraisal of RCTs was completed using the Cochrane risk of bias tool version 2, 5 while ROBINS-I tool 6 (Risk of bias in nonrandomised studies of interventions) was used for non-RCTs. A modified version of Grading of Recommendations Assessment, Development and Evaluation (GRADE), that is, using GRADE in situations of emergencies and urgencies during the Covid-19 pandemic, was used to evaluate the certainty of evidence by outcomes. 7

Five controlled trials (four RCTs [8] [9] [10] [11] and one non-RCT 12 ), were included; see Figure 1 for a preferred reporting items for systematic reviews and meta-analyses flow diagram of included studies.

Two RCTs and one non-RCT tested oral ivermectin, alone or in combination with a barrier nasal spray, using different dosing schedules. One RCT tested bamlanivimab, and another RCT tested REGEN-COV (casirivimab and imdevimab). p < 0.001) 8 ; see Table 1 .

The non-RCT of ivermectin, by Hector et al., 12 Disaggregated results (for residents and staff separately) showed that the reduction in incidence was statistically significant in residents only. The incidence of Covid-19 was 8.8% in the intervention group versus 22.5% in the control group (OR 0.20, 95% CI 0.08-0.49; p < 0.001), compared with 8.4% versus 12.2% in the intervention and control groups, respectively for staff (OR 0.58, 95% CI 0.33-1.02; p = 0.6) 10 ; see Table 1 . Table 1 .

The quality of the RCTs was appraised using the Cochrane Collaboration's tool for assessing risk of bias in randomised trials. 5 One RCT 8 of ivermectin was deemed to be at high overall risk of bias, while some concerns were identified for the other RCT. 9 Specific domains of concern were potential bias in the measure of outcomes and bias arising from the randomisation process. 

This rapid review identified five controlled trials of pharmacological interventions to prevent Covid-19; additionally, 60 ongoing trials were identified, and the results of which are yet to be published.

Three trials tested ivermectin for the prevention of Covid-19, either used alone or in combination with (iota) carrageenan nasal spray.

Carrageenans have displayed viricidal effects in vitro against a range of different viruses including human rhinoviruses and the influenza virus. 9 In the US and EU, ivermectin is approved in humans for treatment of some parasitic worm infestations and skin conditions such as rosacea. While ivermectin has been shown to inhibit SARS-CoV-2 in vitro, the dose required to achieve adequate concentrations in the lungs to be effective against SARS-CoV-2, is much higher than currently authorised for use in other conditions. 13 16 However, in light of emerging variants of concern, this emergency use authorisation for bamlanivimab monotherapy was revoked (on 16 April 2021), due to concerns that these variants may be resistant to bamlanivimab monotherapy. 16 In addition to the controlled trials included in this rapid review, phase I RCT data were identified with respect to the safety of another monoclonal antibody, meplazumab. However, no Covid-19 outcomes were included, and it is unclear if it is intended that this agent would be used for the prevention of Covid-19. 20

Rapid reviews have methodological limitations due to the time constraints involved. The included evidence for ivermectin, bamlanivimab and REGEN-COV was deemed to be of 'low' or 'very low' certainty, thus not suitable for informing changes in policy. Moreover, one trial was a pre-print and had not been formally peer-reviewed. This raises additional concerns about the overall quality and the potential for results to change prior to formal publication of these studies. 

WHO Director-General's opening remarks at the media briefing on COVID-19. World Health Organization

Prophylaxis against Covid-19: living systematic review and network meta-analysis

WHO Living guideline: Drugs to prevent Covid-19. World Health Organization

Protocol: interventions in the community setting, prior to diagnosis of Covid-19, to prevent or minimise progression to severe disease. Health Information and Quality Authority

The Cochrane Collaboration's tool for assessing risk of bias in randomised trials

ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions

Using GRADE in situations of emergencies and urgencies: certainty in evidence and recommendations matters during the Covid-19 pandemic, now more than ever and no matter what

Use of ivermectin as a potential chemoprophylaxis for Covid-19 in Egypt: a randomised clinical trial

A randomised trialintensive treatment based in ivermectin and iota-carrageenan as pre-exposure prophylaxis for Covid-19 in healthcare agents

Effect of bamlanivimab vs placebo on incidence of Covid-19 among residents and staff of skilled nursing and assisted living facilities: a randomized clinical trial

Subcutaneous REGEN-COV antibody combination to prevent Covid-19

Study of the efficacy and safety of topical ivermectin + iota-carrageenan in the prophylaxis against Covid-19 in health personnel

Why you should not use ivermectin to treat or prevent Covid-19

Flawed ivermectin preprint highlights challenges of Covid drug studies

EMA advises against use of ivermectin for the prevention or treatment of Covid-19 outside randomised clinical trials

Covid-19) update: FDA revokes emergency use authorization for monoclonal antibody bamlanivimab

Covid-19) update: FDA authorizes monoclonal antibodies for treatment of Covid-19

FDA authorizes REGEN-COV monoclonal antibody therapy for post-exposure prophylaxis (prevention) for COVID-19

Covid-19: UK approves first monoclonal antibody treatment

Safety and efficacy of meplazumab in healthy volunteers and Covid-19 patients: a randomized phase 1 and an exploratory phase 2 trial

The authors would like to thank the Library and Information Services 

No conflict of interest declared.

Ethics approval was not required for this study as it involved a review of the published literature. 

No patients were involved in this study.

Not applicable.

Data sharing is not applicable to this article as no new data were created or analysed in this study.

https://orcid.org/0000-0002-5909-7439Kieran A. Walsh https://orcid.org/0000-0002-4386-3012