. 2021 Apr 26:373:n949.

doi: 10.1136/bmj.n949.

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

Jessica J Bartoszko^#¹, Reed A C Siemieniuk^#¹, Elena Kum^#¹, Anila Qasim^#¹, Dena Zeraatkar^#¹, Juan Pablo Diaz Martinez¹, Maria Azab¹, Sara Ibrahim¹, Ariel Izcovich², Gonzalo Bravo Soto¹, Yetiani Roldan¹, Arnav Agarwal^{1

3}, Thomas Agoritsas^{1

4}, Derek K Chu^{1

5}, Rachel Couban⁶, Tahira Devji¹, Farid Foroutan¹, Maryam Ghadimi¹, Kimia Honarmand⁷, Assem Khamis⁸, Francois Lamontagne⁹, Mark Loeb^{1

5}, Shelley L McLeod^{10

11}, Sharhzad Motaghi¹, Srinivas Murthy¹², Reem A Mustafa^{1

13}, Bram Rochwerg^{1

5}, Charlotte Switzer¹, Lehana Thabane¹, Per O Vandvik¹⁴, Robin W M Vernooij^{15

16}, Ying Wang¹, Liang Yao¹, Gordon H Guyatt^{1

5}, Romina Brignardello-Petersen¹

Affiliations

¹ Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
² Servicio de Clinica Médica del Hospital Alemán, Buenos Aires, Argentina.
³ Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁴ Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland.
⁵ Department of Medicine, McMaster University, Hamilton, ON, Canada.
⁶ Department of Anesthesia, McMaster University, Hamilton, ON, Canada.
⁷ Department of Medicine, Western University, London, ON, Canada.
⁸ Wolfson Palliative Care Research Centre, Hull York Medical School, Hull, UK.
⁹ Department of Medicine and Centre de recherche du CHU de Sherbrooke, Sherbrooke, Quebec, Canada.
¹⁰ Schwartz/Reisman Emergency Medicine Institute, Sinai Health, Toronto, ON, Canada.
¹¹ Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada.
¹² Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
¹³ Department of Medicine, University of Kansas Medical Center, Kansas City, MO, USA.
¹⁴ Institute of Health and Society, University of Oslo, Oslo, Norway.
¹⁵ Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands.
¹⁶ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

^# Contributed equally.

PMID: 33903131
PMCID: PMC8073806
DOI: 10.1136/bmj.n949

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

Jessica J Bartoszko et al. BMJ. 2021.

. 2021 Apr 26:373:n949.

doi: 10.1136/bmj.n949.

Authors

Affiliations

¹ Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8, Canada.
² Servicio de Clinica Médica del Hospital Alemán, Buenos Aires, Argentina.
³ Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁴ Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland.
⁵ Department of Medicine, McMaster University, Hamilton, ON, Canada.
⁶ Department of Anesthesia, McMaster University, Hamilton, ON, Canada.
⁷ Department of Medicine, Western University, London, ON, Canada.
⁸ Wolfson Palliative Care Research Centre, Hull York Medical School, Hull, UK.
⁹ Department of Medicine and Centre de recherche du CHU de Sherbrooke, Sherbrooke, Quebec, Canada.
¹⁰ Schwartz/Reisman Emergency Medicine Institute, Sinai Health, Toronto, ON, Canada.
¹¹ Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada.
¹² Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
¹³ Department of Medicine, University of Kansas Medical Center, Kansas City, MO, USA.
¹⁴ Institute of Health and Society, University of Oslo, Oslo, Norway.
¹⁵ Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, Netherlands.
¹⁶ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

^# Contributed equally.

PMID: 33903131
PMCID: PMC8073806
DOI: 10.1136/bmj.n949

Abstract

Updates: This is the second version (first update) of the living systematic review, replacing the previous version (available as a data supplement). When citing this paper please consider adding the version number and date of access for clarity.

Objective: To determine and compare the effects of drug prophylaxis on severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (covid-19).

Design: Living systematic review and network meta-analysis (NMA).

Data sources: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 4 March 2022.

Study selection: Randomised trials in which people at risk of covid-19 were allocated to prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles.

Methods: After duplicate data abstraction, we conducted random-effects bayesian network meta-analysis. We assessed risk of bias of the included studies using a modification of the Cochrane risk of bias 2.0 tool and assessed the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach.

Results: The second iteration of this living NMA includes 32 randomised trials which enrolled 25 147 participants and addressed 21 different prophylactic drugs; adding 21 trials (66%), 18 162 participants (75%) and 16 (76%) prophylactic drugs. Of the 16 prophylactic drugs analysed, none provided convincing evidence of a reduction in the risk of laboratory confirmed SARS-CoV-2 infection. For admission to hospital and mortality outcomes, no prophylactic drug proved different than standard care or placebo. Hydroxychloroquine and vitamin C combined with zinc probably increase the risk of adverse effects leading to drug discontinuation—risk difference for hydroxychloroquine (RD) 6 more per 1000 (95% credible interval (CrI) 2 more to 10 more); for vitamin C combined with zinc, RD 69 more per 1000 (47 more to 90 more), moderate certainty evidence.

Conclusions: Much of the evidence remains very low certainty and we therefore anticipate future studies evaluating drugs for prophylaxis may change the results for SARS-CoV-2 infection, admission to hospital and mortality outcomes. Both hydroxychloroquine and vitamin C combined with zinc probably increase adverse effects.

Systematic review registration: This review was not registered. The protocol established a priori is included as a supplement.

Funding: This study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321).

PubMed Disclaimer

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: BS reports receiving funding from PIPRA AG (www.pipra.ch) to conduct a systematic review and individual patient data meta-analysis on predictors of postoperative delirium in elderly people in 2020-21; funding from Mitacs Canada, Accelerate internship in partnership with Nestlé Canada to support his graduate student stipend from 2016 to 2018. Mitacs is a national, not-for-profit organisation that has designed and delivered research and training programmes in Canada, working with universities, companies, and both federal and provincial governments; and funding from the International Life Sciences Institute (ILSI)-North America to support his graduate work for his 2015 academic year. In 2016-17, BS worked part-time for the Cornerstone Research Group (CRG), a contract research organisation. The ILSI funding and being employed by CRG are outside the required three year period requested on the ICJME form. ML reports personal fees and non-financial support from Sanofi, grants and personal fees from Seqirus, and personal fees from Pfizer and Medicago outside the submitted work; and is co-investigator on an Anti-Coronavirus Therapies (ACT) randomised trial of covid-19 treatment. LG reports grants from the Ministry of Science and Technology of China, outside the submitted work. All other authors report no financial relationships with any organisations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work.

Figures

**Fig 3**
Summary of effects of interventions compared with standard care

See this image and copyright information in PMC

Comment in

Update to living systematic review on prophylaxis against covid-19.
[No authors listed] [No authors listed] BMJ. 2023 Mar 23;380:688. doi: 10.1136/bmj.p688. BMJ. 2023. PMID: 36958734 No abstract available.

References

1. Johns Hopkins University. Coronavirus Resource Center. 2020 https://coronavirus.jhu.edu/map.html.
1. Centers for Disease Control and Prevention. SARS-CoV-2 Variant Classifications and Definitions. 2021. www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/var....
1. Krakower DS, Jain S, Mayer KH. Antiretrovirals for primary HIV prevention: the current status of pre- and post-exposure prophylaxis. Curr HIV/AIDS Rep 2015;12:127-38. . 10.1007/s11904-014-0253-5 - DOI - PMC - PubMed
1. Vandvik PO, Brignardello-Petersen R, Guyatt GH. Living cumulative network meta-analysis to reduce waste in research: A paradigmatic shift for systematic reviews? BMC Med 2016;14:59. . 10.1186/s12916-016-0596-4 - DOI - PMC - PubMed
1. Lamontagne F, Agoritsas T, Siemieniuk R, et al. A living WHO guideline on drugs to prevent covid-19. BMJ 2021;372:n526. 10.1136/bmj.n526 - DOI - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous