USE OF HYDROXYCHLOROQUINE TO PREVENT SARS-COV-2 INFECTION AND TREAT MILD COVID-19: A SYSTEMATIC REVIEW AND META-ANALYSIS
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J Bras Pneumol. 2021;47(5):e20210236 SYSTEMATIC REVIEW AND
https://dx.doi.org/10.36416/1806-3756/e20210236 META-ANALYSIS
Use of hydroxychloroquine to prevent
SARS-CoV-2 infection and treat mild
COVID-19: a systematic review and
meta-analysis
Suzana E Tanni1a, Hélio A Bacha2a, Alexandre Naime3a, Wanderley M Bernardo4a
ABSTRACT
1. Disciplina de Pneumologia,
Objective: Chloroquine or hydroxychloroquine has demonstrated no effect on the
Departamento de Clínica Médica,
Faculdade de Medicina de Botucatu, treatment of hospitalized COVID-19 patients. This study aimed to answer questions
Universidade Estadual Paulista, related to the use of hydroxychloroquine for pre-exposure or post-exposure prophylaxis
Botucatu (SP) Brasil. of SARS-CoV-2 infection and in the treatment of patients with mild COVID-19 in terms
2. Hospital Israelita Albert Einstein, of hospitalization, adverse events, and mortality. Methods: This was a systematic
São Paulo (SP) Brasil.
review and meta-analysis of phase 3 randomized clinical trials, selected from various
3. Disciplina de Doenças Infecciosas,
Faculdade de Medicina de Botucatu, databases, which compared patients who received hydroxychloroquine for SARS-
Universidade Estadual Paulista, CoV-2 prophylaxis or treatment of mild COVID-19 cases with controls. Results: A total
Botucatu (SP) Brasil. number of 1,376 studies were retrieved. Of those, 9 met the eligibility criteria and were
4. Faculdade de Medicina, Universidade de included in the study. No statistically significant differences were found between the
São Paulo, São Paulo (SP) Brasil. hydroxychloroquine and control groups in terms of pre- or post-exposure prophylaxis
Submitted: 10 June 2021. of SARS-CoV-2 infection. The use of hydroxychloroquine increased the risk of adverse
Accepted: 15 July 2021. events by 12% (95% CI, 6-18%; p < 0.001), and the number needed to harm was 9.
In addition, no significant differences were found between the hydroxychloroquine and
Study carried out at the Faculdade de
Medicina de Botucatu, Universidade control groups regarding hospitalization (risk difference [RD] = −0.02; 95% CI, −0.04 to
Estadual Paulista, Botucatu (SP) Brasil. 0.00; p = 0.14) or mortality (RD = 0.00; 95% CI, −0.01 to 0.02; p = 0.98) in the treatment
of mild COVID-19. Conclusions: The use of hydroxychloroquine for prophylaxis of
SARS-CoV-2 infection or treatment of patients with mild COVID-19 is not recommended.
Keywords: Hydroxychloroquine; COVID-19; SARS-CoV-2.
INTRODUCTION is none to support the use of hydroxychloroquine to
COVID-19 is caused by SARS-CoV-2, which emerged reduce the need for mechanical ventilation or all-cause
in China in December of 2019, and has been declared a mortality rate.(5) Conversely, there are places where
pandemic by the World Health Organization. The economy the routine use of hydroxychloroquine is still being
of each country is represented by the impairment in the recommended as an optimal intervention to prevent
rate of infected cases and mortality in the population, infection in subjects with a high risk of contamination
along with access to vaccines against SARS-CoV-2, and (pre-exposure prophylaxis or post-exposure prophylaxis)
the national policies implemented to reduce airborne or to control severity progression of COVID-19 after an
transmission are represented by the load on the health infection. Moreover, there are no systematic reviews
care system.(1) In this context, empiric pharmacological assessing the use of hydroxychloroquine in patients with
treatment strategies to prevent or control the progression mild COVID-19. Therefore, there is a lack of knowledge
of COVID-19 have been debated in different scenarios to determine whether chloroquine or hydroxychloroquine
and discussed in the scientific literature.(2,3) can prevent SARS-CoV-2 infection or control COVID-19
COVID-19 is a novel disease that required implementing severity in non-hospitalized patients. The objective of
rapid treatment proposals to reduce transmission, the present study was to collect and evaluate evidence
protecting exposed subjects, and decreasing mortality. from the literature regarding these topics and to provide
The use of chloroquine or hydroxychloroquine has been treatment recommendations. To that end, we addressed
suggested for reducing viral load and controlling disease the following clinical questions: “Does hydroxychloroquine
severity.(4) However, after over a year of living with the prevent illness in individuals who have not been diagnosed
COVID-19 pandemic, we have accumulated scientific with COVID-19 but have had contact with an infected
evidence stating that the use of hydroxychloroquine individual?” and “Does hydroxychloroquine reduce the
is futile for treating hospitalized COVID-19 patients. chances of hospitalization, the development of adverse
Indeed, the actual treatment guidelines are supported events, or the risk of mortality in patients with mild
by the premise of the best medical evidence, and there COVID-19?”
Correspondence to:
Suzana E Tanni. Disciplina de Pneumologia, Departamento de Clínica Médica, Faculdade de Medicina de Botucatu, Distrito de Rubião Junior, s/n, CEP 18618-
970, Botucatu, SP, Brasil.
Tel.: 55 14 3811-1171. E-mail: suzanapneumo@gmail.com
Financial support: None.
© 2021 Sociedade Brasileira de Pneumologia e Tisiologia ISSN 1806-3756 1/11Use of hydroxychloroquine to prevent SARS-CoV-2 infection and treat mild COVID-19: a systematic review and meta-analysis
METHODS Regarding prophylaxis with hydroxychloroquine,
the results (outcomes) collected were positive
This systematic review was conducted in accordance
RT-PCR (longer follow-up), hospitalization, adverse
with the Preferred Reporting Items for Systematic Reviews
events, severe adverse events, and mortality.
and Meta-Analyses (PRISMA) recommendations.(6)
Regarding treatment of mild COVID-19 cases with
hydroxychloroquine, the outcomes were hospitalization,
Eligibility criteria
adverse events, severe adverse events, and mortality.
The protocol of this study was based on the Patients
Control groups varied among the studies.
of interest, Intervention to be studied, Comparison
of intervention, and Outcome of interest (PICO) Risk of bias and quality of evidence
methodology. Regarding the prophylactic use of
The risk of bias was assessed using the Cochrane
hydroxychloroquine, the PICO framework was as
risk-of-bias (RoB 2)(7) tool as were other fundamental
follows: Patients: pre-exposure (not diagnosed
elements, being expressed as very serious, serious,
with COVID-19) or post-exposure (positive RT-PCR
or non-serious. The quality of the evidence was
for SARS-CoV-2) patients; Intervention: use of
extrapolated from the risk of bias and was described
hydroxychloroquine; Comparison: standard treatment
by the Grading of Recommendations Assessment,
or placebo; and Outcome: individuals with positive Development and Evaluation (GRADE) terminology as
RT-PCR tests, hospitalization (ward or ICU admission), very low, low, or high, and, for meta-analyses, it was
mortality, and adverse events. We also investigated described by the GRADEpro Guideline Development Tool
beneficial or harmful outcomes due to the use of (GDT; McMaster University, Hamilton, ON, Canada),
hydroxychloroquine in adults at risk for SARS-CoV-2 as very low, low, moderate, or high.
infection. Health care workers at hospital-based units
were considered at risk for being infected. Regarding Synthesis of results and analysis
patients with mild COVID-19, the PICO framework was Categorical outcomes were expressed by group
as follows: Patients: patients with a confirmed positive (hydroxychloroquine and control), number of events,
RT-PCR test who had not been hospitalized prior to and calculated risk (in %) for each group (by dividing
randomization; Intervention: use of hydroxychloroquine; the number of events by the total number of patients in
and Comparison: standard treatment or placebo; and each group). If the risk difference between the groups
Outcome: hospitalization (ward or ICU admission), was significant, a 95% CI was expressed on the basis
mortality, and adverse events. of the number needed to treat or the number needed
The eligibility criteria for the inclusion of studies were to harm (NNH). We used fixed-effect meta-analysis to
phase 3 randomized controlled trials (RCTs) and phase evaluate the effect of hydroxychloroquine vs. control
3 RCTs systematically reviewing the PICO questions. We on the outcomes when those data were available in
imposed no restrictions regarding date of publication, at least two RCTs considered to have homogeneous
language, or full-text availability. study characteristics. Effects of meta-analyses were
reported as risk differences (RD) and corresponding
Information sources and search strategy 95% CIs; a 95% CI including the number 0 in its range
Two of the authors developed the search strategy, meant that there was no difference in the outcome
which was revised and approved by the team, effect between the hydroxychloroquine and control
selected information sources, and systematically arms. The use of RD shows the absolute effect size
searched the following databases: MEDLINE, EMBASE, in the meta-analysis when compared with relative
Central Cochrane, and ClinicalTrials.gov. Specific risk (RR) or odds ratio, and this technique can be
search strategies were used for each database: 1: used when the binary outcome is zero in both study
(“COVID” OR “COV” OR “coronavirus” OR “SARS”); 2: arms. Heterogeneity of effects among studies was
quantified with the I2 statistic (an I2 > 50% means
(“chloroquine” OR “chlorochin” OR “hydroxychloroquine”
high heterogeneity). For the meta-analysis, we used
OR “oxychloroquine” OR “hydroxychlorochin”) 3: 1
the Review Manager software, version 5.4 (RevMan
AND 2; and 4: 3 AND (Random*).
5; Cochrane Collaboration, Oxford, United Kingdom).
Study selection
RESULTS
Two independent researchers selected and extracted
the data from the included studies. First, the articles A total of 1,376 studies were retrieved from the
were selected based on the title and abstract. Second, selected databases (Figure 1). After eliminating
full texts were evaluated in order to include or exclude duplicates and including studies that met the eligibility
the studies; disagreements were resolved by consensus. criteria, 58 studies were selected for the assessment
of their full texts (MEDLINE: 51; EMBASE: 4; and
Data collection and investigated outcomes ClinicalTrials.gov: 3). Of those, 49 studies were
Data regarding authorship, year of publication, excluded. Therefore, 9 RCTs(8-16) were selected, whose
patient description, interventions (hydroxychloroquine characteristics (Table 1), results, risk of bias, quality
and control), outcomes, and follow-up period were of evidence, and synthesis of evidence are described
extracted from the studies. below (Tables 2-5).
2/11 J Bras Pneumol. 2021;47(5):e20210236Tanni SE, Bacha HA, Naime A, Bernardo WM
We assumed that the risk of bias in the studies NNH = 9) when compared with the control group (RR
selected to support the conclusions on the treatment = 1.69 [95% CI, 1.36-2.09]; Figure 2C). However, the
was not serious. The quality of evidence in the analysis quality of evidence was very low (Table 4).
of prophylaxis varied according to the analyzed outcome: In terms of the incidence of serious adverse events,
diagnosis of COVID-19 (moderate), hospitalization no statistically significant difference was found between
(moderate), adverse events (very low), serious adverse the hydroxychloroquine and control groups (RD =
events (very low), and mortality (moderate). The 0.00 [95% CI, −0.01 to 0.01]; p = 0.77; Figure 2D;
quality of evidence in the analysis of mild COVID-19 and RR = 1.70 [95% CI, 0.91-3.17]). The quality
treatment varied according to the analyzed outcome: of evidence was very low (Table 4). Likewise, no
hospitalization (high), adverse events (very low), statistically significant difference was found regarding
serious adverse events (high), and mortality (high). the incidence of mortality between the groups (RD:
−0.00 [95% CI, −0.00 to 0.00]; p = 0.51; Figure 2E;
Hydroxychloroquine for pre- or post- and RR = 0.66 [95% CI, 0.22-2.02]). The quality of
exposure prophylaxis of SARS-CoV-2 infection evidence was moderate (Table 4).
The follow-up period ranged from 2 to 8 weeks in the
studies selected. No statistically significant difference Hydroxychloroquine for treating mild COVID-19
was found regarding the incidence of positive COVID-19 When we compared the hydroxychloroquine and
results (RT-PCR) between the hydroxychloroquine and control groups that included patients with mild
control groups for pre- or post-exposure prophylaxis of COVID‑19, no statistical differences (Figure 3) were
SARS-CoV-2 infection during the follow-up period (RD found regarding hospitalizations (RD = −0.02 [95% CI,
= 0.01; 95% CI, −0.01 to 0.02; p = 0.13; Figure 2A). −0.04 to 0.00]; p = 0.14; Figure 3A; and RR = 0.68
The RR was 1.19 (95% CI, 0.95-1.50). The quality of [95% CI, 0.41-1.14]), with high quality of evidence
evidence was moderate (Table 4). (Table 5); adverse events (RD = 0.11 [95% CI: −0.09
There was no significant difference between the to 0.31]; p = 0.27; Figure 3B; and RR = 1.47 [95%
hydroxychloroquine and control groups regarding the CI, 0.79-2.72]), with very low quality of evidence
incidence of hospitalization during the follow-up period (Table 5); serious adverse events (RD = −0.00 [95% CI,
(RD = −0.00 [95% CI, −0.01 to −0.00]; p = 0.26; −0.04 to 0.04]; p = 0.95); Figure 3C; and RR = 0.97
Figure 2B; and RR = 0.74 [95% CI, 0.44-1.25]). The [95% CI, 0.44-2.16]); and mortality (RD = 0.00 [95%
quality of evidence was moderate (Table 4). The use CI, −0.01 to 0.01]; p = 0.98; Figure 3D; and RR =
of prophylactic hydroxychloroquine increased the risk 1.07 [95% CI, 0.15-7.86]), both with high quality of
of adverse events by 12% (95% CI, 6-8%; p < 0.001; evidence (Table 5).
Medline EMBASE Cochrane ClinicalTrials.gov
(n = 422) (n = 117) (n = 561) (n = 276)
Duplicates or incomplete studies
(n = 0)
Total screened Excluded by title and abstract
(n = 1,376) (n = 1,318)
Full texts assessed for eligibilty Excluded (n = 49)
(n = 58) Different outcome (n = 5)
Different intervention (n = 5)
Different population (n = 15)
Duplicate of population (n = 6)
Study other than RCT (n = 12)
Study protocol (n = 5)
Included in quantitative synthesis Comment (n = 1)
(n = 9)
Figure 1. Flow chart of the selection process in accordance with Preferred Reporting Items for Systematic Reviews and
Meta-Analyses recommendations. RCT: randomized clinical trial.
J Bras Pneumol. 2021;47(5):e20210236 3/114/11
Table 1. Description of the studies included. (Continue...)
Study/ Participants Type/ Context Eligibility criterion Group Outcome Follow-up
country (N) identifier period
Abella Placebo
Health care workers at COVID-19 - Positive test for SARS-CoV-2
et al.(8) Parallel RCT Post-exposure vs.
132 units and no previous SARS-CoV-2 during 8 weeks 8 weeks
United States NCT04329923 prophylaxis Hydroxychloroquine, 600 mg/day for
infection within the last 2 weeks - Adverse events
of America 8 weeks
Health care workers, household - Symptoms and positive test for
Usual care
contacts, and nursing home workers SARS-CoV-2
Mitjà et al.(10) Cluster RCT Post-exposure vs.
2,485 or residents with no previous - Hospitalization 4 weeks
Spain NCT04304053 prophylaxis Hydroxychloroquine, 800 mg on day
SARS-CoV-2 infection within the last - Adverse events
1, followed by 600 mg/day for 6 days
2 weeks - Death
J Bras Pneumol. 2021;47(5):e20210236
Placebo
Boulware Household or occupational exposure
vs. - Positive test for SARS-CoV-2
et al.(12) to individuals with confirmed
Parallel RCT Post-exposure Hydroxychloroquine, 800 mg on day - Hospitalization
Unites States 821 COVID-19 (distance ≤ 6 ft for >10 2 weeks
NCT04308668 prophylaxis 1 and 600 mg within 6-8 h after the - Adverse events
of America min with an infected subject or no
first dose, followed by 600 mg/day - Deaths
and Canada use of face mask or eye shield)
for 4 days
Placebo (folic acid)
vs.
Rajasingham Hydroxychloroquine, 400 mg on day - COVID-19 free (no symptoms or
et al.(11) Health care workers with high risk 1 and 400 mg 6-8 h later, followed by negative RT-PCR result)
Parallel RCT Pre-exposure
United States 1,483 for SARS-CoV-2 exposure (ICU, ER, 400 mg once a week for 12 weeks - Hospitalization 12 weeks
NCT04328467 prophylaxis
of America COVID-19 units) vs. - Adverse events
and Canada Hydroxychloroquine, 400 mg on day - Death
1 and 400 mg 6-8 h later, followed by
400 mg twice a week for 12 weeks
Placebo
Barnabas
Contact with an index case vs.
et al.(9) Parallel RCT Post-exposure - Positive test for SARS-CoV-2
689 diagnosed SARS-CoV-2 infection Hydroxychloroquine, 400 mg for 3 14 days
United States NCT04328961 prophylaxis - Adverse events
within 96 h days, followed by 200 mg/day for
of America
11 days
Placebo
vs.
- Viral load
Omrani Triple Outpatients Hydroxychloroquine, 600 mg/day for
Mild disease or no symptoms, - Hospitalization
et al.(14) 456 parallel RCT with mild 1 week 14 days
outpatients - Severe adverse events
Qatar NCT04349592 COVID-19 vs.
- Death
Hydroxychloroquine, 600 mg/day for
1 week + azithromycin
Use of hydroxychloroquine to prevent SARS-CoV-2 infection and treat mild COVID-19: a systematic review and meta-analysis
Continue ▶Table 1. Description of the studies included. (Continuation...)
Study/ Participants Type/ Context Eligibility criterion Group Outcome Follow-up
country (N) identifier period
Placebo
vs.
Hydroxychloroquine, 800 mg as a
loading dose, followed by 400 mg
Outpatients reporting less than - Adverse events
Triple daily for 9 days
Reis et al.(13) Mild 8 days since onset of flu-like - Severe adverse events
685 parallel RCT vs. 90 days
Brazil COVID-19 symptoms or chest CT consistent - Hospitalization
NCT04403100 Lopinavir-ritonavir loading dose of
with COVID-19 - Deaths
800 mg and 200 mg, respectively,
every 12 h, followed by 400 mg and
100 mg, respectively, every 12 h for
the following 9 days
- Viral load
Usual care - WHO progression scale
Mild
Mitjà et al.(15) Parallel RCT Outpatients; symptoms for less than vs. - Hospitalization
293 symptoms of 28 days
Spain NCT04304053 5 days prior to enrollment Hydroxychloroquine, 800 mg on day - Severe adverse events
COVID-19
1, followed by 400 mg/day for 6 days - Deaths
Outpatients, positive SARS-CoV-2
Skipper Placebo
test and symptoms for ≤ 4 days or
et al.(16) vs. - Hospitalization
Parallel RCT Mild compatible symptoms after high-
United States 491 Hydroxychloroquine, 800 mg once - Adverse events 14 days
NCT04308668 COVID-19 risk exposure to a contact with
of America and 600 mg in 6-8 h, followed by 600 - Deaths
PCR-confirmed SARS-CoV-2 within
and Canada mg daily for another 4 more days
the last 14 days
RCT: randomized controlled trial.
J Bras Pneumol. 2021;47(5):e20210236
Tanni SE, Bacha HA, Naime A, Bernardo WM
5/11Use of hydroxychloroquine to prevent SARS-CoV-2 infection and treat mild COVID-19: a systematic review and meta-analysis
DISCUSSION
interruption
interruption
The main results of this systematic review showed
Early
Early
Low
Low
Low
Low
Low
Low
Low
Low
Low
that the use of hydroxychloroquine for pre- or post-
exposure prophylaxis of SARS-CoV-2 had no effect on
the incidence rate of confirmed SARS-CoV-2 positivity
and that its use increased the risk of adverse events
Appropriate Intention-to- Sample size
Sample size
outcome treat analysis calculation
calculation
by 12%. In addition, the use of hydroxychloroquine
High
Low
Low
Low
Low
Low
Low
Low
Low
in mild COVID-19 patients caused no significant
differences in the rates of hospitalization, adverse
events, and mortality.
Intention- The choice of relevant clinical outcomes is fundamental
Uncertain
analysis
to-treat in defining the effectiveness of a medical treatment,
High
High
High
High
Low
Low
Low
Low
and this is also true for COVID-19. treatment. For
potential COVID-19 patients, prophylaxis is essential
to prevent disease, and the treatment of patients with
mild COVID-19 is necessary to prevent hospitalization
Appropriate
outcome
(ward or ICU admission) and disease progression.
Low
Low
Low
Low
Low
Low
Low
Low
Low
Our results are similar to those of a previous systematic
Table 2. Risk of bias of the individual studies included on the use of hydroxychloroquine for prophylaxis of SARS-CoV-2 infection.
review comprising two RCTs that studied the use of
Table 3. Risk of bias of the individual studies included on the treatment of mild COVID-19 patients with hydroxychloroquine.
hydroxychloroquine for pre- or post-exposure prophylaxis
characteristic
characteristic
against SARS-CoV-2 infectio.(17-19) However, this is the
Prognostic
Prognostic
Uncertain
first review that studied the use of hydroxychloroquine
High
High
Low
Low
Low
Low
Low
Low
only in patients with mild COVID-19 to assess disease
progression. Our systematic review included one more
RCT than did a study by Lewis et al.(19) to evaluate the
efficacy of pre-exposure or post-exposure prophylaxis
Uncertain
with hydroxychloroquine. By adding that RCT to the
Loss
Loss
High
Low
Low
Low
Low
Low
Low
Low
analysis, we obtained results that were similar to
those reported by Lewis et al.,(19) but we identified a
decrease in the 95% CI related to risk. In other words,
we reduced the uncertainty of pre- or post-exposure
Blinding of
Blinding of
assessors
assessors
Uncertain
Uncertain
Uncertain
Uncertain
Uncertain
outcome
Uncertain
Uncertain
Uncertain
Uncertain
outcome
prophylaxis with hydroxychloroquine, and we reinforce
the recommendation of not using hydroxychloroquine
for that. Likewise, Hernandez et al.(18) described cohort
studies and RCTs on the use of hydroxychloroquine as
an intervention.
blinding
blinding
Double
Double
High
High
Low
Low
Low
Low
Low
Low
Low
When we analyzed the results regarding the use of
hydroxychloroquine in patients with mild COVID-19,
most of the RoB 2 table items presented with a low risk
of bias, and, concomitantly, the quality of evidence in
concealment
concealment
Allocation
Allocation
Blinding/
Blinding/
most of the outcomes was high, which reinforces our
Low
Low
Low
Low
Low
Low
Low
Low
Low
final recommendation of not using hydroxychloroquine
for the treatment of mild COVID-19 patients.
Phase 3 RCTs have several fundamental characteristics
Year Randomization
Year Randomization
that guarantee the lowest degree of uncertainty when
two forms of treatment or prophylaxis are compared:
Low
Low
Low
Low
Low
Low
Low
Low
Low
a. homogeneous samples in both groups are compared
(patients with similar characteristics); b. allocation of
patients to groups has no influence or interference by
using random methods (unpredictability guarantees the
2021
2021
2021
2020
2020
2021
2020
2020
2020
same chance for any individual to be allocated to any of
the groups); c. the population is represented (sample
Rajasingham et al.(11)
size estimation and power analysis that guarantees
Boulware et al.(12)
applicability and reproduction of results in practice);
Barnabas et al.(9)
Skipper et al.(16)
Omrani et al.(14)
d. interventions are blinded (avoiding interference in
Study
Study
Abella et al.(8)
Mitjà et al.(10)
Mitjà et al.(15)
Reis et al.(13)
the application of interventions); e. there is loss of
control (avoiding manipulation in patient selection); f.
procedures and interventions are standardized (avoiding
variations in processes, doses, co-interventions, etc.);
6/11 J Bras Pneumol. 2021;47(5):e20210236Table 4. Table of evidence of the use of hydroxychloroquine for prophylaxis of SARS-CoV-2 infection.
Question: Should hydroxychloroquine, when compared with controls, be used for pre-exposure or post-exposure prophylaxis of SARS-CoV-2 infection?
Certainty assessment Patient (n) Effect Certainty Importance
Studies (n) Study Risk of bias Inconsistency Indirectness Imprecision Other HCQ CONTROL Relative Absolute
design considerations (95% CI) (95% CI)
POSITIVE RT-PCR
6 randomized seriousa,b,c,d,e not serious not serious not serious none 148/3026 124/3071 RR 1.19 8 more per
trials (4.9%) (4.0%) (0.95 to 1,000 MODERATE
⨁⨁⨁¡
1.50) (from 2 fewer
to 20 more)
HOSPITALIZATION
4 randomized seriousa,b,c,d,e not serious not serious not serious none 24/2609 33/2674 RR 0.74 3 fewer per
trials (0.9%) (1.2%) (0.44 to 1,000 MODERATE
⨁⨁⨁¡
1.25) (from 7 fewer
to 3 more)
ADVERSE EFFECTS
4 randomized seriousa,b,c,d,e very serious f not serious not serious publication 522/1756 305/1731 RR 1.69 122 more per
trials bias strongly (29.7%) (17.6%) (1.36 to 1,000 VERY LOW
⨁¡¡¡
suspected g 2.09) (from 63 more
to 192 more)
SERIOUS ADVERSE EFFECTS
4 randomized seriousa,b,c,d,e very serious f not serious not serious publication 26/2548 16/2603 RR 1.70 4 more per
trials bias strongly (1.0%) (0.6%) (0.91 to 1,000 VERY LOW
⨁¡¡¡
suspected g 3.17) (from 1 fewer
to 13 more)
DEATHS
4 randomized seriousa,b,c,d,e not serious not serious not serious none 5/2609 8/2674 RR 0.66 1 fewer per
trials (0.2%) (0.3%) (0.22 to 1,000 MODERATE
⨁⨁⨁¡
2.02) (from 2 fewer
to 3 more)
HCQ: hydroxychloroquine; and RR: Risk ratio.
Explanations
a. ABSENCE OF INTENTION-TO-TREAT ANALYSIS
b. UNBALANCED PROGNOSTIC CHARACTERISTICS BETWEEN THE GROUPS
c. ABSENCE OF SAMPLE CALCULATION
d. ABSENCE OF DOUBLE BLINDING
e. LOSSES OVER 20%
f. HETEROGENEITY GREATER THAN 75%
g. OUTLIER
J Bras Pneumol. 2021;47(5):e20210236
Tanni SE, Bacha HA, Naime A, Bernardo WM
7/118/11
Table 5. Table of evidence of the use of hydroxychloroquine for the treatment of mild COVID-19.
Question: Should hydroxychloroquine, compared with controls, be used for the treatment of mild COVID-19?
Certainty assessment Patient (n)s Effect Certainty Importance
Studies Study Risk of Inconsistency Indirectness Imprecision Other HCQ CONTROL Relative Absolute
(n) design bias considerations (95% CI) (95% CI)
HOSPITALIZATION
4 randomized not serious not serious not serious not serious none 23/714 36/747 RR 0.68 15 fewer per
trials (3.2%) (4.8%) (0.41 to 1,000 HIGH
⨁⨁⨁⨁
1.14) (from 28 fewer
to 7 more)
ADVERSE EFFECTS
2 randomized not serious very serious a not serious serious b publication 138/426 92/438 RR 1.47 99 more per
J Bras Pneumol. 2021;47(5):e20210236
trials bias strongly (32.4%) (21.0%) (0.79 to 1,000 VERY LOW
⨁¡¡¡
suspected c 2.72) (from 44 fewer
to 361 more)
SERIOUS ADVERSE EFFECTS
3 randomized not serious not serious not serious not serious none 11/502 12/536 RR 0.97 1 fewer per
trials (2.2%) (2.2%) (0.44 to 1,000 HIGH
⨁⨁⨁⨁
2.16) (from 13 fewer
to 26 more)
DEATHS
4 randomized not serious not serious not serious not serious none 1/714 1/747 (0.1%) RR 1.07 0 fewer per
trials (0.1%) (0.15 to 1,000 HIGH
⨁⨁⨁⨁
7.86) (from 1 fewer
to 9 more)
HCQ: hydroxychloroquine; and RR: Risk ratio.
Explanations
a. HETEROGENEITY GREATER THAN 75%
b. WIDE CI
c. OUTLIER
Use of hydroxychloroquine to prevent SARS-CoV-2 infection and treat mild COVID-19: a systematic review and meta-analysisTanni SE, Bacha HA, Naime A, Bernardo WM
A
HCQ Control Risk Difference Risk Difference
Study or Subgroup Events Total Events Total Weight M–H, Fixed, 95% Cl M–H, Fixed, 95% Cl
Abella BS 2021 4 64 8 61 2.0% –0.07 [–0.17, 0.03]
Barnabas RV 2021 58 353 48 336 11.3% 0.02 [–0.03, 0.08]
Boulware DR 2020 11 414 9 407 13.5% 0.00 [–0.02, 0.03]
Mitjà O 2021 65 1206 47 1279 40.7% 0.02 [–0.00, 0.03]
Rajasingham R (a) 2020 4 494 6 494 16.2% –0.00 [–0.02, 0.01]
Rajasingham R (b) 2020 7 495 6 494 16.2% 0.00 [–0.01, 0.02]
Total (95% Cl) 3026 3071 100.0% 0.01 [–0.00, 0.02]
Total events 148 124
Heterogenelty: Chi = 7.68, df = 5 (P = 0.17); i = 35%
2 2
–0.2 –0.1 0 0.1 0.2
Test for overall effect: Z = 1.53 (P = 0.13) Favours [HCQ] Favours [Control]
B
HCQ Control Risk Difference Risk Difference
Study or Subgroup Events Total Events Total Weight M–H, Fixed, 95% Cl M–H, Fixed, 95% Cl
Boulware DR 2020 1 414 1 407 15.5% –0.00 [–0.01, 0.01]
Mitjà O 2021 11 1206 12 1279 47.0% –0.02 [–0.01, 0.01]
Rajasingham R (a) 2020 4 494 10 494 18.7% –0.01 [–0.03, 0.00]
Rajasingham R (b) 2020 8 495 10 494 18.7% –0.00 [–0.02, 0.01]
Total (95% Cl) 2609 2674 100.0% –0.00 [–0.01, 0.00]
Total events 24 33
Heterogenelty: Chi2 = 2.84, df = 3 (P = 0.42); i2 = 0% –0.2 –0.1 0 0.1 0.2
Test for overall effect: Z = 1.12 (P = 0.26) Favours [HCQ] Favours [Control]
C
HCQ Control Risk Difference Risk Difference
Study or Subgroup Events Total Events Total Weight M–H, Random, 95% Cl M–H, Random, 95% Cl
Barnabas RV 2021 66 353 46 336 25.0% 0.05 [–0.00, 0.10]
Boulware DR 2020 140 414 59 407 24.6% 0.19 [0.14, 0.25]
Rajasingham R (a) 2020 148 494 100 494 25.3% 0.10 [0.04, 0.15]
Rajasingham R (b) 2020 168 495 100 494 25.1% 0.14 [0.08, 0.19]
Total (95% Cl) 1756 1731 100.0% 0.12 [0.06, 0.18]
Total events 522 305
Heterogenelty: Tau = 0.00; Chi = 13.71, df = 3 (P = 0.003); i = 78%
2 2 2
-1 –0.5 0 0.5 1
Test for overall effect: Z = 3.96 (P < 0.0001) Favours [HCQ] Favours [Control]
D HCQ Control Risk Difference Risk Difference
Study or Subgroup Events Total Events Total Weight M–H, Random, 95% Cl M–H, Random, 95% Cl
Barnabas RV 2021 2 353 2 336 19.3% –0.00 [–0.01, 0.01]
Mitjà O 2021 24 1206 12 1279 22.3% 0.01 [0.00, 0.02]
Rajasingham R (a) 2020 0 494 1 494 29.2% –0.00 [–0.01, 0.00]
Rajasingham R (b) 2020 0 495 1 494 29.2% –0.00 [–0.01, 0.00]
Total (95% Cl) 2548 2603 100.0% 0.12 [–0.01, 0.01]
Total events 26 16
Heterogenelty: Tau2 = 0.00; Chi2 = 11.98, df = 3 (P = 0.007); i2 = 75% -0.1 –0.05 0 0.05 0.1
Test for overall effect: Z = 0.29 (P = 0.77) Favours [HCQ] Favours [Control]
E HCQ Control Risk Difference Risk Difference
Study or Subgroup Events Total Events Total Weight M–H, Fixed, 95% Cl M–H, Fixed, 95% Cl
Boulware DR 2020 0 414 0 407 15.5% 0.00 [–0.00, 0.00]
Mitjà O 2021 5 1206 8 1279 47.0% –0.00 [–0.01, 0.00]
Rajasingham R (a) 2020 0 494 0 494 18.7% 0.00 [–0.00, 0.00]
Rajasingham R (b) 2020 0 495 0 494 18.7% 0.00 [–0.00, 0.00]
Total (95% Cl) 2609 2674 100.0% –0.00 [–0.00, 0.00]
Total events 8
Heterogenelty: Chi2 =0.80, df = 3 (P = 0.85); i2 = 0% –0.02 –0.01 0 0.01 0.02
Test for overall effect: Z = 0.66 (P = 0.51) Favours [HCQ] Favours [Control]
Figure 2. Comparison between hydroxychloroquine and control groups for prophylaxis of SARS-CoV-2 infection regarding
the incidence of positive RT-PCR results (in A); hospitalization (in B); adverse events (in C); serious adverse events
(in D); and deaths (in E). HCQ: hydroxychloroquine; M-H: Mantel-Haenszel (method); and df: degrees of freedom.
and g. statistical analyses are performed directly using Several barriers can hamper the performance of RCTs,
the number of events and averages, with no need including three major barriers: 1. lack of patients (rare
for corrections. These characteristics are absent in diseases); 2. technologies that are difficult to implement
comparative observational studies (cohort studies). (incomparable, expensive, or complex); and 3. a long
J Bras Pneumol. 2021;47(5):e20210236 9/11Use of hydroxychloroquine to prevent SARS-CoV-2 infection and treat mild COVID-19: a systematic review and meta-analysis
A
HCQ Control Risk Difference Risk Difference
Study or Subgroup Events Total Events Total Weight M–H, Fixed, 95% Cl M–H, Fixed, 95% Cl
Mitjà O 2021 8 136 11 157 20.0% –0.01 [–0.07, 0.04]
Omrani AS 2020 3 152 4 152 20.8% –0.01 [–0.04, 0.03]
Rels G 2021 8 214 11 227 30.2% –0.01 [–0.05, 0.03]
Skipper CP 2020 4 212 10 211 29.0% –0.03 [–0.06, 0.01]
Total (95% Cl) 714 747 100.0% –0.02 [–0.04, 0.00]
Total events 23 36
Heterogenelty: Chi = 0.91, df = 3 (P = 0.82); i = 0%
2 2
–0.1 –0.05 0 0.05 0.1
Test for overall effect: Z = 1.49 (P = 0.14)
Favours [HCQ] Favours [Control]
B
HCQ Control Risk Difference Risk Difference
Study or Subgroup Events Total Events Total Weight M–H, Random, 95% Cl M–H, Random, 95% Cl
Rels G 2021 46 214 46 227 50.6% 0.01 [–0.06, 0.09]
Skipper CP 2020 92 212 46 211 49.4% 0.22 [0.13, 0.30]
Total (95% Cl) 426 438 100.0% 0.11 [–0.09, 0.31]
Total events 138 92
Heterogenelty: Tau2 = 0.02; Chi2 = 12.12, df = 1 (P = 0.0005); i2 = 92%
Test for overall effect: Z = 1.10 (P = 0.27) –1 –0.5 0 0.5 1
Favours [HCQ] Favours [Control]
C
HCQ Control Risk Difference Risk Difference
Study or Subgroup Events Total Events Total Weight M–H, Fixed, 95% Cl M–H, Fixed, 95% Cl
Mitjà O 2021 0 136 0 157 28.1% 0.00 [–0.01, 0.01]
Omrani AS 2020 0 152 0 152 29.3% 0.00 [–0.01, 0.01]
Rels G 2021 11 214 12 227 42.5% –0.00 [–0.04, 0.04]
Total (95% Cl) 502 536 100.0% –0.00 [–0.02, 0.02]
Total events 11 12
Heterogenelty: Chi2 = 0.02, df = 2 (P = 0.99); i2 = 0%
Test for overall effect: Z = 0.07 (P = 0.95) –0.1 –0.05 0 0.05 0.1
Favours [HCQ] Favours [Control]
D
HCQ Control Risk Difference Risk Difference
Study or Subgroup Events Total Events Total Weight M–H, Fixed, 95% Cl M–H, Fixed, 95% Cl
Mitjà O 2021 0 214 0 227 30.2% 0.00 [–0.01, 0.01]
Omrani AS 2020 0 152 0 152 20.8% 0.00 [–0.01, 0.01]
Rels G 2021 0 136 1 157 20.0% –0.01 [–0.02, 0.01]
Skipper CP 2020 1 212 0 211 29.0% 0.00 [–0.01, 0.02]
Total (95% Cl) 714 747 100.0% 0.00 [–0.01, 0.01]
Total events 1 1
Heterogenelty: Chi2 = 0.97, df = 3 (P = 0.81); i2 = 0%
–0.02 –0.01 0 0.01 0.01
Test for overall effect: Z = 0.03 (P = 0.98)
Favours [HCQ] Favours [Control]
Figure 3. Comparison between hydroxychloroquine and control groups for the treatment of mild COVID-19 regarding
the incidence of hospitalizations (in A); adverse events (in B); serious adverse events (in C);.and deaths (in D). HCQ:
hydroxychloroquine; M-H: Mantel-Haenszel (method); and df: degrees of freedom.
time for outcomes to occur (requiring a long follow-up The number of patients included in the present
period). However, this is not the case with COVID-19. systematic review and meta-analysis is adequate, and
the results are reproducible and can be applied in the
The available evidence can change over time. However,
management and care of patients.
there is a considerable degree of certainty that can be
This systematic review has limitations that need to
conferred by individual RCTs or meta-analyses using
be elucidated. First, we were unable to examine funnel
such studies, which greatly reduces the likelihood that
plots to detect publication bias, given the small number
new studies will emerge and modify the conclusions.
of RCTs. However, we used a comprehensive search
Therefore, the use of hydroxychloroquine for prophylaxis
strategy. Second, we did not register or publish our
of SARS-CoV-2 infection or for treatment of mild protocol before, given the urgency to demonstrate the
COVID-19 patients is unjustifiable and is currently best evidence to be implemented in the local clinical
contraindicated in order to avoid uncertainties and practice. Nevertheless, all outcomes for this systematic
difficulties in making decisions. review were defined a priori.
10/11 J Bras Pneumol. 2021;47(5):e20210236Tanni SE, Bacha HA, Naime A, Bernardo WM
FINAL CONSIDERATIONS hydroxychloroquine and control groups in patients with
mild COVID-19, and the quality of evidence was high.
Regarding the use of hydroxychloroquine for
The same result was found regarding the incidence of
prophylaxis of SARS-CoV-2 infection, there were no
adverse events, but the quality of evidence was very
significant differences in the incidence of infected cases
low. Therefore, the use of hydroxychloroquine in the
(positive RT-PCR), hospitalization, serious adverse
prophylaxis of SARS-CoV-2 infection or treatment of
events, and mortality between the groups during
patients with mild COVID-19 is not recommended.
the follow-up period. In addition, the use of pre- or
post-exposure prophylaxis with hydroxychloroquine
increased the risk of adverse events by 12% (95% CI, AUTHOR CONTRIBUTIONS
6-8%; NNH = 9) when compared with controls during SET, HAB, AN, and WMB: study concept and design.
the follow-up period. The quality of evidence varied WMB and SET: data collection. WMB and SET: statistical
from very low to moderate. Likewise, no significant analyses and interpretation of data. WMB and SET:
differences in the number of hospitalizations, serious drafting of the manuscript. SET, HAB, AN, and WMB:
adverse events, and deaths were found between the critical review and approval of the final version.
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