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0 0.5 1 1.5 2+ Symp. case 24% Improvement Relative Risk Symp. case, MH 29% Symp. case, PCR+ 51% Symp. case, pooled 26% HCQ  HERO-HCQ  Prophylaxis  DB RCT Is pre-exposure prophylaxis with HCQ beneficial for COVID-19? Double-blind RCT 1,359 patients in the USA (April - November 2020) Fewer symptomatic cases with HCQ (not stat. sig., p=0.18) Naggie et al., Int. J. Infectious Dise.., Aug 2021 Favors HCQ Favors control

Hydroxychloroquine for pre-exposure prophylaxis of COVID-19 in health care workers: A randomized, multicenter, placebo-controlled trial (HERO-HCQ)

Naggie et al., International Journal of Infectious Diseases, doi:10.1016/j.ijid.2023.01.019 (date from preprint), HERO-HCQ, NCT04334148
Aug 2021  
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HCQ for COVID-19
1st treatment shown to reduce risk in March 2020
*, now known with p < 0.00000000001 from 421 studies, recognized in 42 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
HCQ prophylaxis RCT reporting statistically significant lower cases when pooling results with the COVID PREP RCT, OR 0.74 [0.55-1.0] p = 0.046. There were no significant safety issues.
The trials were both terminated early resulting in a loss of power, however the combination shows statistically significant efficacy of HCQ. Note that this result has been censored in the journal version, see The journal paper still shows the COVID PREP paper in the reference list, but the analysis and discussion has been deleted.
The journal version falsely states: "The prophylactic use of HCQ by HCW was safe but not effective", whereas the paper actually estimates OR 0.75, which becomes statistically significant OR 0.74 when pooled with COVID PREP.
The preprint contains a different version: "...but did not produce a clinically useful treatment". It's unclear why ~25% fewer cases would not be useful.
They also state "This is one of several negative studies", however the result is positive, just not reaching statistical significance before pooling with COVID PREP.
risk of symptomatic case, 23.5% lower, RR 0.76, p = 0.18, treatment 41 of 683 (6.0%), control 53 of 676 (7.8%), NNT 54, odds ratio converted to relative risk, logistic regression.
risk of symptomatic case, 29.3% lower, RR 0.71, p = 0.18, treatment 41 of 683 (6.0%), control 53 of 676 (7.8%), NNT 54, odds ratio converted to relative risk, Mantel-Haenszel.
risk of symptomatic case, 50.5% lower, RR 0.49, p = 0.34, treatment 3 of 683 (0.4%), control 6 of 676 (0.9%), NNT 223, PCR confirmed.
risk of symptomatic case, 26.0% lower, OR 0.74, p = 0.046, pooled results with COVID-PREP, RR approximated with OR.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Naggie et al., 25 Aug 2021, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, mean age 43.6, 23 authors, study period April 2020 - November 2020, trial NCT04334148 (history) (HERO-HCQ). Contact:
This PaperHCQAll
Hydroxychloroquine for pre-exposure prophylaxis of COVID-19 in health care workers: a randomized, multicenter, placebo-controlled trial Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine (HERO-HCQ)
MD, MHS Susanna Naggie, MD, MHS b Aaron Milstone, MD, MPH c , Mario Castro, MD Sean P Collins, MD e , Deverick Seetha Lakshmi, Deverick J Anderson, MD g , Lizbeth Cahuayme-Zuniga, BS Kisha Batey Turner, MA Lauren W Cohen, MD h , Judith Currier, RN, BSN a , Elizabeth Fraulo, MD Anne Friedland, MS a , Jyotsna Garg, RTT, MPA i Anoop George, PhD Hillary Mulder, RN, MS, MBA a , Rachel E Olson, PhD Emily C O'brien, MD, MPP d Russell L Rothman, PhD Elizabeth Shenkman, MBA a , Jack Shostak, MD a , Christopher W Woods, PhD Kevin J Anstrom, MD, MHS a , Adrian F Hernandez
International Journal of Infectious Diseases, doi:10.1016/j.ijid.2023.01.019
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
DISCUSSION Statement of Principal Findings The study was not powered to detect a small beneficial effect and the test of the primary endpoint does not provide evidence of a benefit for HCQ for PrEP in a high-risk HCW population. Strengths and Weaknesses in Context The original study design was powered to show a 20% relative treatment effect assuming a 5% event rate in the placebo arm. However, due to slowed enrollment early in the study, the study was amended to decrease the sample size and hence the power, increasing the detectable relative treatment effect to 50%. Thus, the study was not powered to detect a small treatment effect. This outcome was not unique to this randomized trial; a 2021 analysis concluded that among the early COVID-19 studies, only 5% were both randomized and adequately powered [24] . While the partially remote nature of the trial was novel and improved feasibility during a pandemic, it also resulted in the limitation that we did not have laboratory confirmation for COVID-19-like illness. Early in the pandemic, in some regions, testing was not performed per local policies in HCW with suspected infection and mild or moderate symptoms. Per the study protocol, these events were defined as suspected cases and were combined with the confirmed cases in the primary composite outcome. This resulted in few confirmed COVID-19 infections; thus, our primary outcome was primarily comprised of suspected COVID-19 clinical infections. While the study did not have..
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