27 abril, 2021

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


Objective To determine and compare the effects of drug prophylaxis on SARS-CoV-2 infection and covid-19.

Design Living systematic review and network meta-analysis.

Data sources World 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 selection Randomised 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.

Methods Random 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.

Results The 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.

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

Readers’ note This 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.


As of 30 March 2021, more than 127 million people have been infected with SARS-CoV-2, the virus responsible for covid-19; of these, more than 2.7 million have died.1 Cases and deaths continue to rise as SARS-CoV-2 variants of concern become increasingly widespread. Because of vaccine hesitancy, contraindications to receiving the vaccine, and potential reduced vaccine effectiveness against these variants of concern, drug and antibody prophylaxis, if effective, will be an important intervention against covid-19.2 Drugs used as pre-exposure prophylaxis in a high risk population and post-exposure prophylaxis are effective and commonly used for other viruses, including HIV and hepatitis B.3 If effective against covid-19, these drugs could also have a monumental impact worldwide to prevent SARS-CoV-2 infection and attenuate disease, especially in those at high risk of death. Researchers around the world are therefore enrolling participants in randomised trials of drugs and antiviral antibodies for prophylaxis against covid-19.

Clinicians, patients, guideline bodies, and government agencies face challenges in interpreting the results from trials that are being published at a rate never encountered previously. This environment necessitates well developed summaries that can distinguish between trustworthy and untrustworthy evidence.

Living systematic reviews and network meta-analyses resolve an important limitation of traditional systematic reviews, which provide an overview of the relevant evidence only at a specific time.4 The ability of a living network meta-analysis to present a complete, broad, and up-to-date view of the evidence makes it ideal to inform the development of practice recommendations, ideally in the form of living clinical practice guidelines.456 Network meta-analysis, rather than pairwise meta-analysis, provides useful information about the comparative effectiveness of interventions that have not been tested head to head. The lack of such direct comparisons is certain to limit inferences in the covid-19 setting; therefore, network meta-analysis is critical to inform the selection of the best drug among all alternative options. Moreover, the incorporation of indirect evidence can strengthen evidence from comparisons that were tested head to head.7

In this living systematic review and network meta-analysis, we compare the effects of drug prophylaxis for covid-19. This living network meta-analysis will, similar to our established living network meta-analysis on covid-19 treatment,8 directly inform living World Health Organization guidelines on drugs for covid-19,56 a collaborative effort between WHO and the MAGIC Evidence Ecosystem Foundation (, inspired by BMJ Rapid Recommendations.9 This review will inform trustworthy, actionable, and living guidance to clinicians caring for patients with covid-19 (also see box 1).

Créditos: Comité científico Covid

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