Prophylaxis against covid-19: living systematic review and network meta-analysis
Authors: Bartoszko Jessica J , Siemieniuk Reed AC , Kum Elena , Qasim Anila , Zeraatkar Dena , Martinez Juan Pablo Diaz , Azab Maria , Ibrahim Sara , Izcovich Ariel , Soto Gonzalo Bravo , Roldan Yetiani , Agarwal Arnav , Agoritsas Thomas , Chu Derek K , Couban Rachel , Devji Tahira , Foroutan Farid , Ghadimi Maryam , Honarmand Kimia , Khamis Assem , Lamontagne Francois , Loeb Mark , McLeod Shelley L , Motaghi Sharhzad , Murthy Srinivas , Mustafa Reem A , Rochwerg Bram , Switzer Charlotte , Thabane Lehana , Vandvik Per O , Vernooij Robin WM , Wang Ying , Yao Liang , Guyatt Gordon H , Brignardello-Petersen Romina 
Published: April 2021

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
WHO 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.

Conclusion
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).