• Jessica J Bartoszko, SiemieniukReed A CRAC0000-0002-3725-3031Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada reed.siemieniuk@medportal.ca.Joint first authors., Elena Kum, Anila Qasim, Dena Zeraatkar, Long Ge, Mi Ah Han, Behnam Sadeghirad, Arnav Agarwal, Thomas Agoritsas, Derek K Chu, Rachel Couban, Andrea J Darzi, Tahira Devji, Maryam Ghadimi, Kimia Honarmand, Ariel Izcovich, Assem Khamis, Francois Lamontagne, Mark Loeb, Maura Marcucci, Shelley L McLeod, Sharhzad Motaghi, Srinivas Murthy, Reem A Mustafa, John D Neary, Hector Pardo-Hernandez, Gabriel Rada, Bram Rochwerg, Charlotte Switzer, Britta Tendal, Lehana Thabane, Per O Vandvik, Robin W M Vernooij, Andrés Viteri-García, Ying Wang, Liang Yao, Zhikang Ye, Gordon H Guyatt, and Romina Brignardello-Petersen.
• Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
• BMJ. 2021 Apr 26; 373: n949.

ObjectiveTo determine and compare the effects of drug prophylaxis on SARS-CoV-2 infection and covid-19.DesignLiving systematic review and network meta-analysis.Data SourcesWorld Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 25 March 2021, and six additional Chinese databases to 20 February 2021.Study SelectionRandomised trials of people at risk of covid-19 who were assigned to receive prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles.MethodsRandom effects bayesian network meta-analysis was performed after duplicate data abstraction. Included studies were assessed for risk of bias using a modification of the Cochrane risk of bias 2.0 tool, and certainty of evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach.ResultsThe first iteration of this living network meta-analysis includes nine randomised trials-six of hydroxychloroquine (n=6059 participants), one of ivermectin combined with iota-carrageenan (n=234), and two of ivermectin alone (n=540), all compared with standard care or placebo. Two trials (one of ramipril and one of bromhexine hydrochloride) did not meet the sample size requirements for network meta-analysis. Hydroxychloroquine has trivial to no effect on admission to hospital (risk difference 1 fewer per 1000 participants, 95% credible interval 3 fewer to 4 more; high certainty evidence) or mortality (1 fewer per 1000, 2 fewer to 3 more; high certainty). Hydroxychloroquine probably does not reduce the risk of laboratory confirmed SARS-CoV-2 infection (2 more per 1000, 18 fewer to 28 more; moderate certainty), probably increases adverse effects leading to drug discontinuation (19 more per 1000, 1 fewer to 70 more; moderate certainty), and may have trivial to no effect on suspected, probable, or laboratory confirmed SARS-CoV-2 infection (15 fewer per 1000, 64 fewer to 41 more; low certainty). Owing to serious risk of bias and very serious imprecision, and thus very low certainty of evidence, the effects of ivermectin combined with iota-carrageenan on laboratory confirmed covid-19 (52 fewer per 1000, 58 fewer to 37 fewer), ivermectin alone on laboratory confirmed infection (50 fewer per 1000, 59 fewer to 16 fewer) and suspected, probable, or laboratory confirmed infection (159 fewer per 1000, 165 fewer to 144 fewer) remain very uncertain.ConclusionsHydroxychloroquine prophylaxis has trivial to no effect on hospital admission and mortality, probably increases adverse effects, and probably does not reduce the risk of SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, it is highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection.Systematic Review RegistrationThis review was not registered. The protocol established a priori is included as a supplement.Readers' NoteThis article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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