Hydroxychloroquine as postexposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 infection a randomized trial

Ruanne V. Barnabas; Elizabeth R. Brown; Anna Bershteyn; Helen C.Stankiewicz Karita; Christine Johnston; Lorna E. Thorpe; Angelica Kottkamp; Kathleen M. Neuzil; Miriam K. Laufer; Meagan Deming; Michael K. Paasche-Orlow; Patricia J. Kissinger; Alfred Luk; Kristopher Paolino; Raphael J. Landovitz; Risa Hoffman; Torin T. Schaafsma; Meighan L. Krows; Katherine K. Thomas; Susan Morrison; Harald S. Haugen; Lara Kidoguchi; Mark Wener; Alexander L. Greninger; Meei Li Huang; Keith R. Jerome; Anna Wald; Connie Celum; Helen Y. Chu; Jared M. Baeten

doi:10.7326/M20-6519

Hydroxychloroquine as postexposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 infection a randomized trial

Ruanne V. Barnabas, Elizabeth R. Brown, Anna Bershteyn, Helen C.Stankiewicz Karita, Christine Johnston, Lorna E. Thorpe, Angelica Kottkamp, Kathleen M. Neuzil, Miriam K. Laufer, Meagan Deming, Michael K. Paasche-Orlow, Patricia J. Kissinger, Alfred Luk, Kristopher Paolino, Raphael J. Landovitz, Risa Hoffman, Torin T. Schaafsma, Meighan L. Krows, Katherine K. Thomas, Susan MorrisonHarald S. Haugen, Lara Kidoguchi, Mark Wener, Alexander L. Greninger, Meei Li Huang, Keith R. Jerome, Anna Wald, Connie Celum, Helen Y. Chu, Jared M. Baeten

Urban Initiative

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Effective prevention against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently limited to nonpharmaceutical strategies. Laboratory and observational data suggested that hydroxychloroquine had biological activity against SARS-CoV-2, potentially permitting its use for prevention.

OBJECTIVE: To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection.

DESIGN: Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961).

SETTING: National U.S. multicenter study.

PARTICIPANTS: Close contacts recently exposed (<96 hours) to persons with diagnosed SARS-CoV-2 infection.

INTERVENTION: Hydroxychloroquine (400 mg/d for 3 days followed by 200 mg/d for 11 days) or ascorbic acid (500 mg/d followed by 250 mg/d) as a placebo-equivalent control.

MEASUREMENTS: Participants self-collected mid-turbinate swabs daily (days 1 to 14) for SARS-CoV-2 polymerase chain reaction (PCR) testing. The primary outcome was PCR-confirmed incident SARS-CoV-2 infection among persons who were SARS-CoV-2 negative at enrollment.

RESULTS: Between March and August 2020, 671 households were randomly assigned: 337 (407 participants) to the hydroxychloroquine group and 334 (422 participants) to the control group. Retention at day 14 was 91%, and 10 724 of 11 606 (92%) expected swabs were tested. Among the 689 (89%) participants who were SARS-CoV-2 negative at baseline, there was no difference between the hydroxychloroquine and control groups in SARS-CoV-2 acquisition by day 14 (53 versus 45 events; adjusted hazard ratio, 1.10 [95% CI, 0.73 to 1.66]; P > 0.20). The frequency of participants experiencing adverse events was higher in the hydroxychloroquine group than the control group (66 [16.2%] versus 46 [10.9%], respectively; P = 0.026).

LIMITATION: The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days.

CONCLUSION: This rigorous randomized controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection.

PRIMARY FUNDING SOURCE: Bill & Melinda Gates Foundation.

Original language	English (US)
Pages (from-to)	344-352
Number of pages	9
Journal	Annals of internal medicine
Volume	174
Issue number	3
DOIs	https://doi.org/10.7326/M20-6519
State	Published - Mar 1 2021

Keywords

Adolescent
Adult
Aged
Aged, 80 and over
Antiviral Agents/adverse effects
COVID-19/diagnosis
COVID-19 Nucleic Acid Testing
Double-Blind Method
Female
Humans
Hydroxychloroquine/adverse effects
Male
Middle Aged
Post-Exposure Prophylaxis
SARS-CoV-2
Time Factors
Treatment Outcome
United States
Young Adult

ASJC Scopus subject areas

Internal Medicine

Access to Document

10.7326/M20-6519

Cite this

Barnabas, R. V., Brown, E. R., Bershteyn, A., Karita, H. C. S., Johnston, C., Thorpe, L. E., Kottkamp, A., Neuzil, K. M., Laufer, M. K., Deming, M., Paasche-Orlow, M. K., Kissinger, P. J., Luk, A., Paolino, K., Landovitz, R. J., Hoffman, R., Schaafsma, T. T., Krows, M. L., Thomas, K. K., ... Baeten, J. M. (2021). Hydroxychloroquine as postexposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 infection a randomized trial. Annals of internal medicine, 174(3), 344-352. https://doi.org/10.7326/M20-6519

Barnabas, RV, Brown, ER, Bershteyn, A, Karita, HCS, Johnston, C, Thorpe, LE, Kottkamp, A, Neuzil, KM, Laufer, MK, Deming, M, Paasche-Orlow, MK, Kissinger, PJ, Luk, A, Paolino, K, Landovitz, RJ, Hoffman, R, Schaafsma, TT, Krows, ML, Thomas, KK, Morrison, S, Haugen, HS, Kidoguchi, L, Wener, M, Greninger, AL, Huang, ML, Jerome, KR, Wald, A, Celum, C, Chu, HY & Baeten, JM 2021, 'Hydroxychloroquine as postexposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 infection a randomized trial', Annals of internal medicine, vol. 174, no. 3, pp. 344-352. https://doi.org/10.7326/M20-6519

@article{f77f1dd8b59f4581b30f5ecd0992d2a1,

title = "Hydroxychloroquine as postexposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 infection a randomized trial",

abstract = "BACKGROUND: Effective prevention against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently limited to nonpharmaceutical strategies. Laboratory and observational data suggested that hydroxychloroquine had biological activity against SARS-CoV-2, potentially permitting its use for prevention.OBJECTIVE: To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection.DESIGN: Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961).SETTING: National U.S. multicenter study.PARTICIPANTS: Close contacts recently exposed (<96 hours) to persons with diagnosed SARS-CoV-2 infection.INTERVENTION: Hydroxychloroquine (400 mg/d for 3 days followed by 200 mg/d for 11 days) or ascorbic acid (500 mg/d followed by 250 mg/d) as a placebo-equivalent control.MEASUREMENTS: Participants self-collected mid-turbinate swabs daily (days 1 to 14) for SARS-CoV-2 polymerase chain reaction (PCR) testing. The primary outcome was PCR-confirmed incident SARS-CoV-2 infection among persons who were SARS-CoV-2 negative at enrollment.RESULTS: Between March and August 2020, 671 households were randomly assigned: 337 (407 participants) to the hydroxychloroquine group and 334 (422 participants) to the control group. Retention at day 14 was 91%, and 10 724 of 11 606 (92%) expected swabs were tested. Among the 689 (89%) participants who were SARS-CoV-2 negative at baseline, there was no difference between the hydroxychloroquine and control groups in SARS-CoV-2 acquisition by day 14 (53 versus 45 events; adjusted hazard ratio, 1.10 [95% CI, 0.73 to 1.66]; P > 0.20). The frequency of participants experiencing adverse events was higher in the hydroxychloroquine group than the control group (66 [16.2%] versus 46 [10.9%], respectively; P = 0.026). LIMITATION: The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days.CONCLUSION: This rigorous randomized controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection.PRIMARY FUNDING SOURCE: Bill & Melinda Gates Foundation.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Antiviral Agents/adverse effects, COVID-19/diagnosis, COVID-19 Nucleic Acid Testing, Double-Blind Method, Female, Humans, Hydroxychloroquine/adverse effects, Male, Middle Aged, Post-Exposure Prophylaxis, SARS-CoV-2, Time Factors, Treatment Outcome, United States, Young Adult",

author = "Barnabas, {Ruanne V.} and Brown, {Elizabeth R.} and Anna Bershteyn and Karita, {Helen C.Stankiewicz} and Christine Johnston and Thorpe, {Lorna E.} and Angelica Kottkamp and Neuzil, {Kathleen M.} and Laufer, {Miriam K.} and Meagan Deming and Paasche-Orlow, {Michael K.} and Kissinger, {Patricia J.} and Alfred Luk and Kristopher Paolino and Landovitz, {Raphael J.} and Risa Hoffman and Schaafsma, {Torin T.} and Krows, {Meighan L.} and Thomas, {Katherine K.} and Susan Morrison and Haugen, {Harald S.} and Lara Kidoguchi and Mark Wener and Greninger, {Alexander L.} and Huang, {Meei Li} and Jerome, {Keith R.} and Anna Wald and Connie Celum and Chu, {Helen Y.} and Baeten, {Jared M.}",

note = "Funding Information: The study was funded by the Bill & Melinda Gates Foundation through the COVID-19 Therapeutics Accelerator and the University of Washington King K. Holmes Endowed Professorship in STDs and AIDS. Hydroxychloroquine for the study was donated by Sandoz. The funders had no role in study design; data collection, analysis, and interpretation; writing of the report; or in the decision to submit for publication. The corresponding author had full access to all study data and had final responsibility for the decision to submit for publication. Funding Information: Financial Support: The HCQ COVID-19 PEP Study was funded by the Bill & Melinda Gates Foundation (INV-016204) through the COVID-19 Therapeutics Accelerator and the University of Washington King K. Holmes Endowed Professorship in STDs and AIDS. Hydroxychloroquine for the study was donated by Sandoz. Publisher Copyright: {\textcopyright} 2021 American College of Physicians. All rights reserved.",

year = "2021",

month = mar,

day = "1",

doi = "10.7326/M20-6519",

language = "English (US)",

volume = "174",

pages = "344--352",

journal = "Annals of internal medicine",

issn = "0003-4819",

publisher = "American College of Physicians",

number = "3",

}

TY - JOUR

T1 - Hydroxychloroquine as postexposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 infection a randomized trial

AU - Barnabas, Ruanne V.

AU - Brown, Elizabeth R.

AU - Bershteyn, Anna

AU - Karita, Helen C.Stankiewicz

AU - Johnston, Christine

AU - Thorpe, Lorna E.

AU - Kottkamp, Angelica

AU - Neuzil, Kathleen M.

AU - Laufer, Miriam K.

AU - Deming, Meagan

AU - Paasche-Orlow, Michael K.

AU - Kissinger, Patricia J.

AU - Luk, Alfred

AU - Paolino, Kristopher

AU - Landovitz, Raphael J.

AU - Hoffman, Risa

AU - Schaafsma, Torin T.

AU - Krows, Meighan L.

AU - Thomas, Katherine K.

AU - Morrison, Susan

AU - Haugen, Harald S.

AU - Kidoguchi, Lara

AU - Wener, Mark

AU - Greninger, Alexander L.

AU - Huang, Meei Li

AU - Jerome, Keith R.

AU - Wald, Anna

AU - Celum, Connie

AU - Chu, Helen Y.

AU - Baeten, Jared M.

N1 - Funding Information: The study was funded by the Bill & Melinda Gates Foundation through the COVID-19 Therapeutics Accelerator and the University of Washington King K. Holmes Endowed Professorship in STDs and AIDS. Hydroxychloroquine for the study was donated by Sandoz. The funders had no role in study design; data collection, analysis, and interpretation; writing of the report; or in the decision to submit for publication. The corresponding author had full access to all study data and had final responsibility for the decision to submit for publication. Funding Information: Financial Support: The HCQ COVID-19 PEP Study was funded by the Bill & Melinda Gates Foundation (INV-016204) through the COVID-19 Therapeutics Accelerator and the University of Washington King K. Holmes Endowed Professorship in STDs and AIDS. Hydroxychloroquine for the study was donated by Sandoz. Publisher Copyright: © 2021 American College of Physicians. All rights reserved.

PY - 2021/3/1

Y1 - 2021/3/1

N2 - BACKGROUND: Effective prevention against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently limited to nonpharmaceutical strategies. Laboratory and observational data suggested that hydroxychloroquine had biological activity against SARS-CoV-2, potentially permitting its use for prevention.OBJECTIVE: To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection.DESIGN: Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961).SETTING: National U.S. multicenter study.PARTICIPANTS: Close contacts recently exposed (<96 hours) to persons with diagnosed SARS-CoV-2 infection.INTERVENTION: Hydroxychloroquine (400 mg/d for 3 days followed by 200 mg/d for 11 days) or ascorbic acid (500 mg/d followed by 250 mg/d) as a placebo-equivalent control.MEASUREMENTS: Participants self-collected mid-turbinate swabs daily (days 1 to 14) for SARS-CoV-2 polymerase chain reaction (PCR) testing. The primary outcome was PCR-confirmed incident SARS-CoV-2 infection among persons who were SARS-CoV-2 negative at enrollment.RESULTS: Between March and August 2020, 671 households were randomly assigned: 337 (407 participants) to the hydroxychloroquine group and 334 (422 participants) to the control group. Retention at day 14 was 91%, and 10 724 of 11 606 (92%) expected swabs were tested. Among the 689 (89%) participants who were SARS-CoV-2 negative at baseline, there was no difference between the hydroxychloroquine and control groups in SARS-CoV-2 acquisition by day 14 (53 versus 45 events; adjusted hazard ratio, 1.10 [95% CI, 0.73 to 1.66]; P > 0.20). The frequency of participants experiencing adverse events was higher in the hydroxychloroquine group than the control group (66 [16.2%] versus 46 [10.9%], respectively; P = 0.026). LIMITATION: The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days.CONCLUSION: This rigorous randomized controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection.PRIMARY FUNDING SOURCE: Bill & Melinda Gates Foundation.

AB - BACKGROUND: Effective prevention against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently limited to nonpharmaceutical strategies. Laboratory and observational data suggested that hydroxychloroquine had biological activity against SARS-CoV-2, potentially permitting its use for prevention.OBJECTIVE: To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection.DESIGN: Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961).SETTING: National U.S. multicenter study.PARTICIPANTS: Close contacts recently exposed (<96 hours) to persons with diagnosed SARS-CoV-2 infection.INTERVENTION: Hydroxychloroquine (400 mg/d for 3 days followed by 200 mg/d for 11 days) or ascorbic acid (500 mg/d followed by 250 mg/d) as a placebo-equivalent control.MEASUREMENTS: Participants self-collected mid-turbinate swabs daily (days 1 to 14) for SARS-CoV-2 polymerase chain reaction (PCR) testing. The primary outcome was PCR-confirmed incident SARS-CoV-2 infection among persons who were SARS-CoV-2 negative at enrollment.RESULTS: Between March and August 2020, 671 households were randomly assigned: 337 (407 participants) to the hydroxychloroquine group and 334 (422 participants) to the control group. Retention at day 14 was 91%, and 10 724 of 11 606 (92%) expected swabs were tested. Among the 689 (89%) participants who were SARS-CoV-2 negative at baseline, there was no difference between the hydroxychloroquine and control groups in SARS-CoV-2 acquisition by day 14 (53 versus 45 events; adjusted hazard ratio, 1.10 [95% CI, 0.73 to 1.66]; P > 0.20). The frequency of participants experiencing adverse events was higher in the hydroxychloroquine group than the control group (66 [16.2%] versus 46 [10.9%], respectively; P = 0.026). LIMITATION: The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days.CONCLUSION: This rigorous randomized controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection.PRIMARY FUNDING SOURCE: Bill & Melinda Gates Foundation.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antiviral Agents/adverse effects

KW - COVID-19/diagnosis

KW - COVID-19 Nucleic Acid Testing

KW - Double-Blind Method

KW - Female

KW - Humans

KW - Hydroxychloroquine/adverse effects

KW - Male

KW - Middle Aged

KW - Post-Exposure Prophylaxis

KW - SARS-CoV-2

KW - Time Factors

KW - Treatment Outcome

KW - United States

KW - Young Adult

UR - http://www.scopus.com/inward/record.url?scp=85100688269&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85100688269&partnerID=8YFLogxK

U2 - 10.7326/M20-6519

DO - 10.7326/M20-6519

M3 - Article

C2 - 33284679

AN - SCOPUS:85100688269

SN - 0003-4819

VL - 174

SP - 344

EP - 352

JO - Annals of internal medicine

JF - Annals of internal medicine

IS - 3

ER -

Hydroxychloroquine as postexposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 infection a randomized trial

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