Use of hydroxychloroquine to prevent SARS-CoV-2 infection and treat mild COVID-19: a systematic review and meta-analysis

Tanni, Suzana E; Bacha, Hélio A; Naime, Alexandre; Bernardo, Wanderley M

doi:10.36416/1806-3756/e20210236

Acessibilidade / Reportar erro

Brasil

Jornal Brasileiro de Pneumologia

Español English

Brasil

Español English

sumário « anterior atual seguinte »

Sumário

SYSTEMATIC REVIEW AND META-ANALYSIS • J. bras. pneumol. 47 (05) • 2021 • https://doi.org/10.36416/1806-3756/e20210236 copy

Use of hydroxychloroquine to prevent SARS-CoV-2 infection and treat mild COVID-19: a systematic review and meta-analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective:

Chloroquine or hydroxychloroquine has demonstrated no effect on the treatment of hospitalized COVID-19 patients. This study aimed to answer questions related to the use of hydroxychloroquine for pre-exposure or post-exposure prophylaxis of SARS-CoV-2 infection and in the treatment of patients with mild COVID-19 in terms of hospitalization, adverse events, and mortality.

Methods:

This was a systematic review and meta-analysis of phase 3 randomized clinical trials, selected from various databases, which compared patients who received hydroxychloroquine for SARS-CoV-2 prophylaxis or treatment of mild COVID-19 cases with controls.

Results:

A total number of 1,376 studies were retrieved. Of those, 9 met the eligibility criteria and were included in the study. No statistically significant differences were found between the hydroxychloroquine and control groups in terms of pre- or post-exposure prophylaxis of SARS-CoV-2 infection. The use of hydroxychloroquine increased the risk of adverse 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 control groups regarding hospitalization (risk difference [RD] = −0.02; 95% CI, −0.04 to 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

Study/country	Participants (N)	Type/identifier	Context	Eligibility criterion	Group	Outcome	Follow-up period
Abella et al.⁸8 Abella BS, Jolkovsky EL, Biney BT, Uspal JE, Hyman MC, Frank I, et al. Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial. JAMA Intern Med. 2021;181(2):195-202. https://doi.org/10.1001/jamainternmed.2020.6319 https://doi.org/10.1001/jamainternmed.20... United States of America	132	Parallel RCT NCT04329923	Post-exposure prophylaxis	Health care workers at COVID-19 units and no previous SARS-CoV-2 infection within the last 2 weeks	Placebo vs. Hydroxychloroquine, 600 mg/day for 8 weeks	- Positive test for SARS-CoV-2 during 8 weeks - Adverse events	8 weeks
Mitjà et al.¹⁰10 Mitjà O, Corbacho-Monné M, Ubals M, Alemany A, Suñer C, Tebé C, et al. A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19. N Engl J Med. 2021;384(5):417-427. https://doi.org/10.1056/NEJMoa2021801 https://doi.org/10.1056/NEJMoa2021801... Spain	2,485	Cluster RCT NCT04304053	Post-exposure prophylaxis	Health care workers, household contacts, and nursing home workers or residents with no previous SARS-CoV-2 infection within the last 2 weeks	Usual care vs. Hydroxychloroquine, 800 mg on day 1, followed by 600 mg/day for 6 days	- Symptoms and positive test for SARS-CoV-2 - Hospitalization - Adverse events - Death	4 weeks
Boulware et al.¹²12 Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020;383(6):517-525. https://doi.org/10.1056/NEJMoa2016638 https://doi.org/10.1056/NEJMoa2016638... Unites States of America and Canada	821	Parallel RCT NCT04308668	Post-exposure prophylaxis	Household or occupational exposure to individuals with confirmed COVID-19 (distance ≤ 6 ft for >10 min with an infected subject or no use of face mask or eye shield)	Placebo vs. Hydroxychloroquine, 800 mg on day 1 and 600 mg within 6-8 h after the first dose, followed by 600 mg/day for 4 days	- Positive test for SARS-CoV-2 - Hospitalization - Adverse events - Deaths	2 weeks
Rajasingham et al.¹¹11 Rajasingham R, Bangdiwala AS, Nicol MR, Skipper CP, Pastick KA, Axelrod ML, et al. Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial. Clin Infect Dis. 2021;72(11):e835-e843. https://doi.org/10.1093/cid/ciaa1571 https://doi.org/10.1093/cid/ciaa1571... United States of America and Canada	1,483	Parallel RCT NCT04328467	Pre-exposure prophylaxis	Health care workers with high risk for SARS-CoV-2 exposure (ICU, ER, COVID-19 units)	Placebo (folic acid) vs. Hydroxychloroquine, 400 mg on day 1 and 400 mg 6-8 h later, followed by 400 mg once a week for 12 weeks vs. Hydroxychloroquine, 400 mg on day 1 and 400 mg 6-8 h later, followed by 400 mg twice a week for 12 weeks	- COVID-19 free (no symptoms or negative RT-PCR result) - Hospitalization - Adverse events - Death	12 weeks
Barnabas et al.⁹9 Barnabas RV, Brown ER, Bershteyn A, Stankiewicz Karita HC, Johnston C, Thorpe LE, et al. Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial [published correction appears in Ann Intern Med. 2021 Mar;174(3):435]. Ann Intern Med. 2021;174(3):344-352. https://doi.org/10.7326/M20-6519 https://doi.org/10.7326/M20-6519... United States of America	689	Parallel RCT NCT04328961	Post-exposure prophylaxis	Contact with an index case diagnosed SARS-CoV-2 infection within 96 h	Placebo vs. Hydroxychloroquine, 400 mg for 3 days, followed by 200 mg/day for 11 days	- Positive test for SARS-CoV-2 - Adverse events	14 days
Omrani et al.¹⁴14 Omrani AS, Pathan SA, Thomas SA, Harris TRE, Coyle PV, Thomas CE, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19. EClinicalMedicine. 2020;29:100645. https://doi.org/10.1016/j.eclinm.2020.100645 https://doi.org/10.1016/j.eclinm.2020.10... Qatar	456	Triple parallel RCT NCT04349592	Outpatients with mild COVID-19	Mild disease or no symptoms, outpatients	Placebo vs. Hydroxychloroquine, 600 mg/day for 1 week vs. Hydroxychloroquine, 600 mg/day for 1 week + azithromycin	- Viral load - Hospitalization - Severe adverse events - Death	14 days
Reis et al.¹³13 Reis G, Moreira Silva EADS, Medeiros Silva DC, Thabane L, Singh G, Park JJH, et al. Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial. JAMA Netw Open. 2021;4(4):e216468. https://doi.org/10.1001/jamanetworkopen.2021.6468 https://doi.org/10.1001/jamanetworkopen.... Brazil	685	Triple parallel RCT NCT04403100	Mild COVID-19	Outpatients reporting less than 8 days since onset of flu-like symptoms or chest CT consistent with COVID-19	Placebo vs. Hydroxychloroquine, 800 mg as a loading dose, followed by 400 mg daily for 9 days vs. Lopinavir-ritonavir loading dose of 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	- Adverse events - Severe adverse events - Hospitalization - Deaths	90 days
Mitjà et al.¹⁵15 Mitjà O, Corbacho-Monné M, Ubals M, Tebe C, Peñafiel J, Tobias A, et al. Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial. Clin Infect Dis. 2020;ciaa1009. https://doi.org/10.1093/cid/ciaa1009 https://doi.org/10.1093/cid/ciaa1009... Spain	293	Parallel RCT NCT04304053	Mild symptoms of COVID-19	Outpatients; symptoms for less than 5 days prior to enrollment	Usual care vs. Hydroxychloroquine, 800 mg on day 1, followed by 400 mg/day for 6 days	- Viral load - WHO progression scale - Hospitalization - Severe adverse events - Deaths	28 days
Skipper et al.¹⁶16 Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial [published correction appears in Ann Intern Med. 2021 Mar;174(3):435]. Ann Intern Med. 2020;173(8):623-631. https://doi.org/10.7326/M20-4207 https://doi.org/10.7326/M20-4207... United States of America and Canada	491	Parallel RCT NCT04308668	Mild COVID-19	Outpatients, positive SARS-CoV-2 test and symptoms for ≤ 4 days or compatible symptoms after high-risk exposure to a contact with PCR-confirmed SARS-CoV-2 within the last 14 days	Placebo vs. Hydroxychloroquine, 800 mg once and 600 mg in 6-8 h, followed by 600 mg daily for another 4 more days	- Hospitalization - Adverse events - Deaths	14 days

Study	Year	Randomization	Blinding/Allocation concealment	Double blinding	Blinding of outcome assessors	Loss	Prognostic characteristic	Appropriate outcome	Intention-to-treat analysis	Sample size calculation	Early interruption
Abella et al.⁸8 Abella BS, Jolkovsky EL, Biney BT, Uspal JE, Hyman MC, Frank I, et al. Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial. JAMA Intern Med. 2021;181(2):195-202. https://doi.org/10.1001/jamainternmed.2020.6319 https://doi.org/10.1001/jamainternmed.20...	2021	Low	Low	Low	Uncertain	Low	High	Low	High	Low	Low
Barnabas et al.⁹9 Barnabas RV, Brown ER, Bershteyn A, Stankiewicz Karita HC, Johnston C, Thorpe LE, et al. Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial [published correction appears in Ann Intern Med. 2021 Mar;174(3):435]. Ann Intern Med. 2021;174(3):344-352. https://doi.org/10.7326/M20-6519 https://doi.org/10.7326/M20-6519...	2021	Low	Low	Low	Uncertain	High	Uncertain	Low	High	Low	Low
Mitjà et al.¹⁰10 Mitjà O, Corbacho-Monné M, Ubals M, Alemany A, Suñer C, Tebé C, et al. A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19. N Engl J Med. 2021;384(5):417-427. https://doi.org/10.1056/NEJMoa2021801 https://doi.org/10.1056/NEJMoa2021801...	2021	Low	Low	High	Uncertain	Low	Low	Low	High	Low	Low
Rajasingham et al.¹¹11 Rajasingham R, Bangdiwala AS, Nicol MR, Skipper CP, Pastick KA, Axelrod ML, et al. Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial. Clin Infect Dis. 2021;72(11):e835-e843. https://doi.org/10.1093/cid/ciaa1571 https://doi.org/10.1093/cid/ciaa1571...	2020	Low	Low	Low	Uncertain	Low	Low	Low	High	Low	Low
Boulware et al.¹²12 Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020;383(6):517-525. https://doi.org/10.1056/NEJMoa2016638 https://doi.org/10.1056/NEJMoa2016638...	2020	Low	Low	Low	Uncertain	Uncertain	High	Low	Uncertain	High	Low

Study	Year	Randomization	Blinding/Allocation concealment	Double blinding	Blinding of outcome assessors	Loss	Prognostic characteristic	Appropriate outcome	Intention-to-treat analysis	Sample size calculation	Early interruption
Reis et al.¹³13 Reis G, Moreira Silva EADS, Medeiros Silva DC, Thabane L, Singh G, Park JJH, et al. Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial. JAMA Netw Open. 2021;4(4):e216468. https://doi.org/10.1001/jamanetworkopen.2021.6468 https://doi.org/10.1001/jamanetworkopen....	2021	Low	Low	Low	Uncertain	Low	Low	Low	Low	Low	Low
Omrani et al.¹⁴14 Omrani AS, Pathan SA, Thomas SA, Harris TRE, Coyle PV, Thomas CE, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19. EClinicalMedicine. 2020;29:100645. https://doi.org/10.1016/j.eclinm.2020.100645 https://doi.org/10.1016/j.eclinm.2020.10...	2020	Low	Low	Low	Uncertain	Low	Low	Low	Low	Low	Low
Mitjà et al.¹⁵15 Mitjà O, Corbacho-Monné M, Ubals M, Tebe C, Peñafiel J, Tobias A, et al. Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial. Clin Infect Dis. 2020;ciaa1009. https://doi.org/10.1093/cid/ciaa1009 https://doi.org/10.1093/cid/ciaa1009...	2020	Low	Low	High	Uncertain	Low	Low	Low	Low	Low	Low
Skipper et al.¹⁶16 Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial [published correction appears in Ann Intern Med. 2021 Mar;174(3):435]. Ann Intern Med. 2020;173(8):623-631. https://doi.org/10.7326/M20-4207 https://doi.org/10.7326/M20-4207...	2020	Low	Low	Low	Uncertain	Low	Low	Low	Low	Low	Low

Certainty assessment							Patient (n)		Effect		Certainty
Studies (n)	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	HCQ	CONTROL	Relative (95% CI)	Absolute (95% CI)
POSITIVE RT-PCR
6	randomized trials	serious^a,b,c,d,e	not serious	not serious	not serious	none	148/3026 (4.9%)	124/3071 (4.0%)	RR 1.19 (0.95 to 1.50)	8 more per 1,000 (from 2 fewer to 20 more)	⨁⨁⨁ MODERATE
HOSPITALIZATION
4	randomized trials	serious^a,b,c,d,e	not serious	not serious	not serious	none	24/2609 (0.9%)	33/2674 (1.2%)	RR 0.74 (0.44 to 1.25)	3 fewer per 1,000 (from 7 fewer to 3 more)	⨁⨁⨁ MODERATE
ADVERSE EFFECTS
4	randomized trials	serious^a,b,c,d,e	very serious ^f	not serious	not serious	publication bias strongly suspected ^g	522/1756 (29.7%)	305/1731 (17.6%)	RR 1.69 (1.36 to 2.09)	122 more per 1,000 (from 63 more to 192 more)	⨁ VERY LOW
SERIOUS ADVERSE EFFECTS
4	randomized trials	serious^a,b,c,d,e	very serious ^f	not serious	not serious	publication bias strongly suspected ^g	26/2548 (1.0%)	16/2603 (0.6%)	RR 1.70 (0.91 to 3.17)	4 more per 1,000 (from 1 fewer to 13 more)	⨁ VERY LOW
DEATHS
4	randomized trials	serious^a,b,c,d,e	not serious	not serious	not serious	none	5/2609 (0.2%)	8/2674 (0.3%)	RR 0.66 (0.22 to 2.02)	1 fewer per 1,000 (from 2 fewer to 3 more)	⨁⨁⨁ MODERATE

Certainty assessment							Patient (n)s		Effect		Certainty
Studies (n)	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	HCQ	CONTROL	Relative (95% CI)	Absolute (95% CI)
HOSPITALIZATION
4	randomized trials	not serious	not serious	not serious	not serious	none	23/714 (3.2%)	36/747 (4.8%)	RR 0.68 (0.41 to 1.14)	15 fewer per 1,000 (from 28 fewer to 7 more)	⨁⨁⨁⨁ HIGH
ADVERSE EFFECTS
2	randomized trials	not serious	very serious ^a	not serious	serious ^b	publication bias strongly suspected ^c	138/426 (32.4%)	92/438 (21.0%)	RR 1.47 (0.79 to 2.72)	99 more per 1,000 (from 44 fewer to 361 more)	⨁ VERY LOW
SERIOUS ADVERSE EFFECTS
3	randomized trials	not serious	not serious	not serious	not serious	none	11/502 (2.2%)	12/536 (2.2%)	RR 0.97 (0.44 to 2.16)	1 fewer per 1,000 (from 13 fewer to 26 more)	⨁⨁⨁⨁ HIGH
DEATHS
4	randomized trials	not serious	not serious	not serious	not serious	none	1/714 (0.1%)	1/747 (0.1%)	RR 1.07 (0.15 to 7.86)	0 fewer per 1,000 (from 1 fewer to 9 more)	⨁⨁⨁⨁ HIGH

Sociedade Brasileira de Pneumologia e Tisiologia SCS Quadra 1, Bl. K salas 203/204, 70398-900 - Brasília - DF - Brasil, Fone/Fax: 0800 61 6218 ramal 211, (55 61)3245-1030/6218 ramal 211 - São Paulo - SP - Brazil
E-mail: jbp@sbpt.org.br

Acompanhe os números deste periódico no seu leitor de RSS

[1] 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