Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial
Authors: Risa Hoffman
William Paarz
Matthew Ikuma
Megan Connolly
Jairam R Lingappa
Ameila Weldon
Mueenah Anibaba
Florice Numbi
Ruanne V Barnabas
Ricardo Cruz
Samantha N Fagan
Hanna LeBuhn
Alyssa Braun
Aira L Contreras
Lori Henault
Lara Kidoguchi
Jacqueline Connery
Clare E Brown
Maxwell Brown
Jane Coates
Elle Anastasiou
Sandra India Aldana
Ryan Kofron
Angelica Kottkamp
Ethan Valinetz
Michelle Blyth
Sarah Kimball
Jared M Baeten
Michelle Bulterys
Margot Rogers
Maja Fadzan
Timothy Endy
Stephen Eustace
Thepthara Pholsena
Prabhu Sasankan
April McDougal
Jay Stadelman
Juan Gago
Andrea Rodriguez
Amy Shire
Gentry Wilkerson
Diana Buist
Sydney Sauter
Matthew S Dreier
Gabriela Were
Alicia Pettit
Jake Hall
Akash Gujral
Rodrigo Arce Cardozo
Abir Hussein
Margaret Huntwork
Patricia J Kissinger
Danielle Escobedo
Kaicy Gabriela Naranjo
Cherie Blair
Ashita Ganguly
Ivayla Geneva
Patrick Mehlek
Sarina Gupta
Madelaine Humphreys
Jared Castor
Xiaolei Hao
Mark D Schwartz
Lucy Zhao
Myriam Yepez
Daphne Hamilton
Anna Bershteyn
Azra J Bhimani
Helen C Stankiewicz Karita
Saydee McQuay
Julien Dedier
Selorm Tamakole
Nathaniel Davenport
Ben R Spoer
Scott Miller
Vaidehi Agrawal
Mariel McConville
Savannah Lawton
Daniel Triggs
Elizabeth Brandstetter
Stela Sota
Karla Largaespada
Jackie Yang
Matthew Seymour
Urvashi Pandey
Shirley Chen
Rubi Arias
Peter Dull
Luisa Arroyave
Lev Paasche‚ÄêOrlow
Amanda Gonzalez
Kathleen Salerno
Katherine Perdomo
Jeff Purcell
Thy Pham
Stefanie E Bendik
Michelle Klick
Jessica C Moreno
Sneha R Sharma
Michelle Chang
Priscilla M Lopez
Robert T James
Kamilla Bakirova
Katie Wicklander
Hydroxychloroquine COVID-19 PEP Study Team
Marie Bauer
Sean Galagan
Florian Hladik
Michael Massaro
Christopher Balthazar
Peter Greco
Tiara Towner
Justice Quame‚ÄêAmaglo
Melissa Reale
Cheryl Greenstein
Qausarat Ogunneye
Nadia Gakou
Meighan L Krows
Shannon Watson
Hamada Rady
Sadia Mohaimin
Anna Wald
Hannah Mansky
Marissa Alsaloum
Torin T Schaafsma
Leslie Anna Greene
Rachel Johnson
Crystal Ng
Meng Cao
Amena Tungara
Gregory Pepper
DeAnna Friedman‚ÄêKlabanoff
Harald S Haugen
Elliott Sanger
Meilani Cayabyab
Michael Camuso
Alfred Luk
Raphael J Landovitz
Alice Li Juan Liang
Zohdi Young
Anne Jarris
Jamie Fried
Sukhleen K Bedi
Rachel Martin‚ÄêBlais
Ashley Peltekci
Heather Larkin
Alexander Shercliffe
Lillianna Carsch
Jenell C Stewart
Lorna E Thorpe
Norine Schmidt
Rafael Corona
Melissa Billington
Sean Kim
Meagan Welsh
Caroline H Liou
Elsa Hay
Biraj Shrestha
Carlo Foppinao Palacios
Christopher Miller
Yulun Wei
Erika Feutz
Maria Ribando
Omar Gambito
Mary Lou Pompeii
Katherine Waite
Meagan Deming
Marianne Cloeren
Ivy Doan
Andrea Shaw
Brian R Wood
Meei-Li Huang
Penina Krieger
Colleen Mullenix
Gregory C Morlin
Jina M Taub
Deidra Montoya
Susan N Landon
Miriam K Laufer
Crystal Zheng
Keely Terrillion
Terrell Johnson
Rebecca Letterer
Evan Atkinson
Helen Y Chu
Kate Caiello
Griffin Popp
Faith Pa&#x27;ahana‚ÄêBrown
Maianna Dematteis
Valentine Wanga
Mark Drummond
Esther Liu
Robert A Pitts
Carl Streed
Kirsten Hauge
Krissy Nguyen‚ÄêStone
Rodal Issema
Jack Knauer
Jennifer Baugh
Christina B Wysota
Michelle Palomares
Katherine K Thomas
Azaad Zimmermann
Elizabeth R Brown
Dia B Beggs
Emily Gill
Christina Shin
Kianna Ripich
Tran T Tran
Dana L Varon
Caroline Barnes
Cara Bayer
Anna Cheng
Nathan Alidina
Susan Morrison
Zulfiya Bakirova
Christine Johnston
Bethany Springer
Michael Smithline
Alyson Kwon
Beita Badiei
Mark Wener
Meredith Lu
Sarah Conderino
Melissa Myers
Mari Metter
Mary Kirk
Deborah J Brown
Elizabeth Harausz
Stephen Thomas
Sybil Hosek
Andrea Pe√±a
Kathleen Mandziuk
Katie Lund
Cedrick Ntambwe
Demetrius Plaxico
Toni Maddox
Samuel Arnold
Viany Vazquez
Husam Dennaoui
Christina Hughes
Zoe Thuesmunn
Erin Martinez
Lia Mamistvalova
Toze Reichard
Wei William Miao
Stella K Chong
Marian Poley
Steven R Kuntz
Reigran Sampoleo
Mark Abbott
Elizabeth Asiago‚ÄêReddy
Chloe D Waters
Nisha Verma
Eveline Teresa Hidalgo
Leticia Cardoso
Michael K Paasche-Orlow
Doug Houston
Lindsey Quintana
Alexander L Greninger
Xuanlin Hou
Megan Birkhold
Emily Duan
Melissa McDiarmid
Mary Beth Campbell
Neha Upadhyay
Anya Mathur
Carlie Martinez
Grant Young
Pablo Buitron
Kathleen M Neuzil
Lindsey McClellan
Bao‚ÄêChau Vo
Shabir Somani
Kristen Baxter
Medhavi Bole
Anna Goldman
John Huntwork
Colleen Boyce
Catie Cambou
Elina Lingappa
Connie Celum
Daisuke Furukawa
Antonia Petreuse
Heather Karpf
Kristopher Paolino
Amanda J Reynolds
Nancy Lopez
Jonathan Berz
Keith R Jerome
Danielle Cram
Journal: Annals of Internal Medicine (2021)
Discipline: CLINICAL MEDICINE
Keywords: COVID-19; SARS-CoV-2; hydroxychloroquine; postexposure prophylaxis; randomized controlled trial
Affiliations: University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington (R.V.B., E.R.B., C.J., A.L.G., K.R.J., A.W.), New York University Grossman School of Medicine, New York, New York (A.B., L.E.T., A.K.), University of Washington, Seattle, Washington (H.C.S., T.T.S., M.L.K., K.K.T., S.M., H.S.H., L.K., M.W., C.C., H.Y.C., J.M.B.), University of Maryland School of Medicine, Baltimore, Maryland (K.M.N., M.K.L., M.D.), Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts (M.K.P.), School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana (P.J.K.), School of Medicine, Tulane University, New Orleans, Louisiana (A.L.), State University of New York Upstate Medical University, Syracuse, New York (K.P.), University of California, Los Angeles, California (R.J.L., R.H.), Fred Hutchinson Cancer Research Center, Seattle, Washington (M.H.).

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 (&lt;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 &gt; 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 &amp; Melinda Gates Foundation. 

Retracted: No

PubPeer comments:
 # Vitamin C is not a placebo equivalent In their RCT to test hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2, Barnabas et al. used vitamin C as a placebo [1]: *u201cHouseholds were randomly assigned in a 1:1 ratio to receive either hydroxychloroquine (400 mg d orally for 3 days, then 200 mg d orally for an additional 11 days) or **ascorbic acid (500 mg d orally for 3 days, then 250 mg d orally for 11 days) as a placebo equivalent.**u201d* [bold added] Vitamin C is not a physiologically inactive substance. Cochrane review on vitamin C for respiratory virus infections reported that 31 comparisons examined the effect of regular vitamin C on the duration of 9745 episodes. In adults the duration of respiratory virus infections was reduced by 7.7% (95% CI 3.7% to 11.8%, P = 0.00018) and in children by 14.2% (95% CI 7.3% to 21.1%, P = 0.000053) [2: Analysis 2.1]. In another meta-analysis of 12 controlled trials, vitamin C shortened the duration of ICU stay on average by 7.8% (95% CI: 4.2% to 11.2%; P = 0.00003) [3]. In a third meta-analysis, vitamin C was most beneficial for critical care patients with the longest mechanical ventilation, corresponding to the most severely ill patients. In 5 controlled trials including 471 patients requiring ventilation for over 10u2009h, a dosage of 1u20136u2009g day of vitamin C shortened ventilation time on average by 25% (Pu2009 u20090.0001) [4]. A recent RCT observed that vitamin C increased the recovery rate of outpatient cases of SARS-CoV-2 infection by 70% [5,6]. Another recent RCT found that vitamin C decreased mortality of sepsis patients in the period up to day 4 with RR = 0.19 (95% CI 0.06-0.55), but had no effect from day 5 onwards. Compared to the statistical model with no vitamin C effect over the 28-day period, the two-period model improved the Cox regression with P = 0.002 [7,8]. Hydroxychloroquine may be ineffective as a prophylaxis to prevent SARS-CoV-2. However, vitamin C is not a valid placebo. Using vitamin C as a placebo might lead to a false negative conclusions about hydroxychloroquine. **References** 1. Barnabas RV, Brown ER, Bershteyn A, Stankiewicz Karita HC, 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. Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial. Ann Intern Med. 2020 Dec 8:M20-6519. https: doi.org 10.7326 m20-6519 http: www.ncbi.nlm.nih.gov pmc articles pmc7732017 2. https: doi.org 10.1002 14651858.CD000980.pub4 https: helda.helsinki.fi handle 10138 225864 3. https: doi.org 10.3390 nu11040708 https: www.ncbi.nlm.nih.gov pmc articles PMC6521194 4. https: doi.org 10.1186 s40560-020-0432-y https: www.ncbi.nlm.nih.gov pmc articles PMC7006137 5. https: doi.org 10.1001 jamanetworkopen.2021.0369 6. https: www.researchsquare.com article rs-289381 v1 7. https: doi.org 10.1001 jama.2019.11825 8. https: doi.org 10.3389 fmed.2020.590853 , 
 It s worth noting that many more patients tested positive at baseline (and were consequently excluded from the analysis) in the control group vs. HCQ group:  How this may have affected the results is unclear, but it suggests the randomisation was not optimal. ,