By March 29, 2020, Covid-19 had afflicted more than one hundred thousand people and killed more than three thousand in the United States alone.1 On that same day, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases and spokesman for the White House Coronavirus Task Force, predicted that the pandemic would kill two hundred thousand Americans.2 By this time, states had instituted lockdowns; major events were postponed or canceled, including the 2020 Summer Olympics; schools were closed or moved online; and businesses were shuttered.3 People prepared to shelter in place, sparking shortages of common goods such as toilet paper. Doctors sought to discover the best options to diagnose and treat patients infected with the virus. In the face of widespread shortages, hospitals scrambled to buy gowns, masks, gloves, and hand sanitizer.4
As a physician, I worried for my own safety and that of my patients. I spent almost every free moment reading about, thinking about, and communicating with other medical professionals about treating patients infected with the virus. I joined Facebook groups in which physicians from North and South America, Europe, Asia, and Australia posted new information day and night. I spoke with colleagues in the first two hot spots in America, Washington State and New York City, to learn from their experiences. I read old publications on SARS and MERS and new ones on Covid-19 from China and Italy.
Early in the pandemic, physicians tried many treatments. One such treatment, a now infamous and controversial drug, was known to have some antiviral properties from decades-old studies.5 This drug, hydroxychloroquine (HCQ), was and still is used by physicians worldwide to treat Covid-19. On March 20, French researchers and physicians published data suggesting that HCQ could reduce the virus’s ability to replicate.6 Graphs from this paper immediately circulated among physicians, bolstering excitement for the drug, which led to increased use. . . .
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2. Lisette Voytko, “Fauci Predicts up to 200,000 Deaths and ‘Millions’ Infected in U.S.,” Forbes, March 29, 2020, https://www.forbes.com/sites/lisettevoytko/2020/03/29/fauci-predicts-up-to-200000-deaths-and-millions-infected-in-us/ (accessed October 2, 2020).
3. “Timeline of the COVID-19 Pandemic in the United States,” https://en.wikipedia.org/wiki/Timeline_of_the_Covid-19_pandemic_in_the_United_States (accessed September 14, 2020).
4. “Sourcing Personal Protective Equipment during the COVID-19 Pandemic,” JAMA Network, March 28, 2020, https://jamanetwork.com/journals/jama/fullarticle/2764031 (accessed October 6, 2020).
5. Matthew H. Ornstein and Kirk Sperber, “The Antiinflammatory and Antiviral Effects of Hydroxychloroquine in Two Patients with Acquired Immunodeficiency Syndrome and Active Inflammatory Arthritis,” Arthritis & Rheumatology, January 1996, https://onlinelibrary.wiley.com/doi/abs/10.1002/art.1780390122 (accessed September 26, 2020).
6. Philippe Gautret et al., “Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-randomized Clinical Trial,” International Journal of Antimicrobial Agents 56, no. 1 (March 2020), https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102549/ (accessed September 14, 2020).
7. Donald J. Trump, “Hydroxychloroquine & Azithromycin, Taken Together, Have a Real Chance to Be One of the Biggest Game Changers in the History of Medicine,” Twitter, March 21, 2020, https://twitter.com/realdonaldtrump/status/1241367239900778501 (accessed September 14, 2020).
8. “Hydroxychloroquine Sulfate Must Be Administered Orally,” FDA, April 27, 2020, https://www.fda.gov/media/136537/download (accessed September 14, 2020); “HHS Accepts Donations of Medicine to Strategic National Stockpile as Possible Treatments for COVID-19 Patients,” U.S. Department of Health and Human Services, March 29, 2020, https://www.hhs.gov/about/news/2020/03/29/hhs-accepts-donations-of-medicine-to-strategic-national-stockpile-as-possible-treatments-for-covid-19-patients.html (accessed September 26, 2020).
9. Emily Kopp, “States Weigh What to Do with Millions of Malaria Pills,” Roll Call, May 7, 2020, https://www.rollcall.com/2020/05/07/states-weigh-what-to-do-with-millions-of-malaria-pills/ (accessed September 26, 2020); “State Action on Hydroxychloroquine and Chloroquine Access,” Lupus Foundation of America, https://www.lupus.org/advocate/state-action-on-hydroxychloroquine-and-chloroquine-access (accessed September 26, 2020).
10. Lisette Voytko, “New York to Begin Clinical Trials for Coronavirus Treatment Tuesday, Cuomo Says,” Forbes, March 22, 2020, https://www.forbes.com/sites/lisettevoytko/2020/03/22/new-york-to-begin-clinical-trials-for-coronavirus-treatment-tuesday-cuomo-says/ (accessed September 14, 2020).
11. Joseph Magagnoli et al., “Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized with COVID-19,” MedRxiv, April 21, 2020, https://www.medrxiv.org/content/10.1101/2020.04.16.20065920v1.full.pdf (accessed September 14, 2020).
12. Maria Anderson, “A Timeline on the Malaria Drug That Became a Front-Running COVID-19 Treatment,” Becker’s Hospital Review, April 30, 2020, https://www.beckershospitalreview.com/pharmacy/a-timeline-on-the-malaria-drug-that-became-a-front-running-Covid-19-treatment.html (accessed September 14, 2020); “FDA Cautions against Use of Hydroxychloroquine or Chloroquine for COVID-19 outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems,” U.S. Food and Drug Administration, July 1, 2020, https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-Covid-19-outside-hospital-setting-or (accessed September 14, 2020).
13. Joshua Geleris et al., “Observational Study of Hydroxychloroquine in Hospitalized Patients with COVID-19,” New England Journal of Medicine, June 18, 2020, https://www.nejm.org/doi/full/10.1056/nejmoa2012410 (accessed September 14, 2020).
14. Annie Karni and Katie Thomas,” Trump Says He’s Taking Hydroxychloroquine, Prompting Warning from Health Experts,” New York Times, May 18, 2020, https://www.nytimes.com/2020/05/18/us/politics/trump-hydroxychloroquine-Covid-coronavirus.html (accessed September 14, 2020).
15. Mandeep R. Mehra et al., “Retracted: Hydroxychloroquine or Chloroquine with or without a Macrolide for Treatment of COVID-19: A Multinational Registry Analysis,” The Lancet, May 22, 2020, https://www.thelancet.com/lancet/article/s0140673620311806 (accessed September 14, 2020).
16. Charles Piller, “Who’s to Blame? These Three Scientists Are at the Heart of the Surgisphere COVID-19 Scandal,” Science, June 8, 2020, https://www.sciencemag.org/news/2020/06/whos-blame-these-three-scientists-are-heart-surgisphere-Covid-19-scandal (accessed September 14, 2020).
17. “Coronavirus (Covid-19) Update: FDA Revokes Emergency Use Authorization for Chloroquine and Hydroxychloroquine,” U.S. Food and Drug Administration, https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine-and (accessed October 6, 2020).
18. Maria Anderson, “Ohio’s Board of Pharmacy Bans Hydroxychloroquine for Use in COVID-19 Patients,” Becker’s Hospital Review, July 30, 2020, https://www.beckershospitalreview.com/pharmacy/ohio-s-board-of-pharmacy-bans-hydroxychloroquine-for-use-in-Covid-19-patients.html (accessed September 14, 2020); “Hydroxychloroquine Politicization Continues as Ohio Board of Pharmacy Bans Drug & Then Rescinds,” TrialSite News, August 1, 2020, https://www.trialsitenews.com/hydroxychloroquine-politicization-continues-as-ohio-board-of-pharmacy-bans-drug/ (accessed September 15, 2020).
19. “Boards of Pharmacy and Other Actions Relating to COVID-19 Prescribing,” American Medical Association, April 27, 2020, https://www.ama-assn.org/system/files/2020-04/board-of-pharmacy-covid-19-prescribing.pdf (accessed September 21, 2020).
20. “FDA Cautions against Use of Hydroxychloroquine or Chloroquine for COVID-19 outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems,” U.S. Food and Drug Administration.
21. Leocadia Bongben, “Dr Stella Immanuel Doctor: Houston Texas Physician Family in Cameroon Wash Hand off Hydroxychloroquine Video Deleted by Facebook, Twitter and YouTube,” BBC News, July 29, 2020, https://www.bbc.com/pidgin/tori-53585731 (accessed September 26, 2020); a transcript of the video is available at “America’s Frontline Doctors SCOTUS Press Conference Transcript,” July 28, 2020, http://archive.vn/U1qcE; the video, with some cuts, is available at GAGmen, “White Paper on Hydroxychloroquine of America’s Frontline Doctors,” USA GAG, July 29, 2020, https://usagag.com/2020/07/29/white-paper-on-hydroxychloroquine-of-americas-frontline-doctors/.
23. Giles et al., “Hydroxychloroquine: Why a Video Promoted by Trump Was Pulled on Social Media.”
24. “Harvey Risch, MD, PhD,” Yale School of Medicine, https://medicine.yale.edu/profile/harvey_risch/ (accessed September 26, 2020); Harvey A. Risch, “The Key to Defeating COVID-19 Already Exists. We Need to Start Using It,” Newsweek, July 23, 2020, https://www.newsweek.com/key-defeating-covid-19-already-exists-we-need-start-using-it-opinion-1519535 (accessed September 21, 2020).
25. Risch, “The Key to Defeating COVID-19 Already Exists.”
26. I also have reviewed the arguments of other prominent HCQ advocates, including Dr. Zelenko, whose data is cited by Dr. Risch; and I have read the white paper written by America’s Frontline Doctors and the white paper published in the Economic Standard. Their arguments are similar to those of Dr. Risch, but Risch is more specific in his treatment protocol and more rigorous in his analysis and handling of methodology and data. For this reason, I have focused on Dr. Risch’s analysis and evidence base; Simone Gold, “White Paper on Hydroxychloroquine,” http://www.americasfrontlinedoctors.com/ (accessed October 19, 2020); Erik Sass, “Hydroxychloroquine and the Burden of Proof,” Economic Standard, https://hcqwhitepaper.com/ (accessed October 19, 2020).
27. Harvey A. Risch, “Early Outpatient Treatment of Symptomatic, High-Risk Coronavirus Disease 2019 Patients That Should Be Ramped up Immediately as Key to the Pandemic Crisis,” American Journal of Epidemiology, May 27, 2020, https://academic.oup.com/aje/advance-article/doi/10.1093/aje/kwaa093/5847586 (accessed September 15, 2020); Tony M. Korman, “Re: ‘Early Outpatient Treatment of Symptomatic, High-Risk Coronavirus Disease 2019 Patients That Should Be Ramped up Immediately as Key to the Pandemic Crisis,’” American Journal of Epidemiology, July 20, 2020, https://academic.oup.com/aje/advance-article/doi/10.1093/aje/kwaa154/5873639 (accessed September 15, 2020).
28. “The Ingraham Angle Interview with Dr. Harvey Risch—Hydroxychloroquine Use by Front Line Doctors,” YouTube, Fox News, July 21, 2020, https://www.youtube.com/watch?v=vfF4_peyG1I (accessed September 15, 2020).
32.I would like to express my sincere thanks to Dr. Risch for his time and openness in our personal communications. I have the utmost respect for his domain expertise and experience.
33. Tran Duc Anh Ly et al., “Pattern of Sars-Cov-2 Infection among Dependent Elderly Residents Living in Retirement Homes in Marseille, France, March–June 2020”; “COVID-19 Treatment Analysis,” https://c19study.com/ (accessed September 26, 2020); Eva Heras et al., “COVID-19 Mortality Risk Factors in Older People in a Long-Term Care Center,” https://doi.org/10.21203/rs.3.rs-70219/v2; Andrew Ip et al., “Hydroxychloroquine in the Treatment of Outpatients with Mildly Symptomatic COVID-19: A Multi-Center Observational Study,” MedRxiv, https://www.medrxiv.org/content/10.1101/2020.08.20.20178772v1 (accessed September 26, 2020); Jean-Christophe Lagier et al., “Early Treatment of COVID-19 Patients with Hydroxychloroquine and Azithromycin: A Retrospective Analysis of 1061 Cases in Marseille, France,” Travel Medicine and Infectious Disease, 35, May–June 2020, https://doi.org/10.1016/j.tmaid.2020.101738; Gautret et al., “Hydroxychloroquine and Azithromycin as a Treatment of COVID-19”; Rodrigo B. Esper et al., “Empirical Treatment with Hydroxychloroquine and Azithromycin for Suspected Cases of COVID-19 Followed-up by Telemedicine,” (accessed August 12, 2020); Celia M. Lombardi and Stuart H. Hurlbert, “Misprescription and Misuse of One‐Tailed Tests,” Austral Ecology, May 28, 2009, https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1442-9993.2009.01946.x; Peter A. McCullough et al., “Pathophysiological Basis and Rationale for Early Outpatient Treatment of Sars-Cov-2 (Covid-19) Infection,” American Journal of Medicine, August 6, 2020, https://www.amjmed.com/article/S0002-9343(20)30673-2/fulltext; Oriol Mitja et al., “A Cluster-Randomized Trial of Hydroxychloroquine as Prevention of COVID-19 Transmission and Disease,” MedRxiv, July 26, 2020, https://www.medrxiv.org/content/10.1101/2020.07.20.20157651v1; Tarek Sulaiman et al., “The Effect of Early Hydroxychloroquine-Based Therapy in COVID-19 Patients in Ambulatory Care Settings: A Nationwide Prospective Cohort Study,” MedRxiv, September 13, 2020, https://www.medrxiv.org/content/10.1101/2020.09.09.20184143v1 (accessed September 26, 2020).
34. “Coronavirus News: Long Island Doctors Embrace Combination Drug Therapy in Fighting COVID-19,” Eyewitness News, April 13, 2020, https://abc7ny.com/coronavirus-treatment-long-island-news-nassau-county/6093072/ (accessed August 13, 2020).
35. Rodrigo B. Esper et al., “Empirical Treatment with Hydroxychloroquine and Azithromycin for Suspected Cases of COVID-19 Followed-up by Telemedicine.”
36. Those who couldn’t be treated because they had a preexisting condition or a conflicting prescription were excluded from the study.
37. Joshua P. Metlay et al., “Diagnosis and Treatment of Adults with Community-Acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America,” ATSJournals 56, no. 1, https://www.atsjournals.org/doi/full/10.1164/rccm.201908-1581ST (accessed October 9, 2020); “Azithromycin (Rx),” Medscape, https://reference.medscape.com/drug/zithromax-zmax-azithromycin-342523 (accessed October 9, 2020).
38. The shortcomings of this study could easily have affected its outcome. The authors report that 1.9 percent of the 412 patients in the treatment group were hospitalized, as were 5.4 percent of the 224 patients in the “refusal” group. The study does not report absolute numbers, but calculation yields that eight patients (412*0.019 = 8) in the treatment group and twelve (224*0.054 = 12) in the refusal group required hospitalization. So, if, for example, five more patients from the treatment group had been hospitalized and five fewer from the “refusal” group, due to differences in the treatment of bacterial infections with azithromycin or any similar problem, the hospitalization rate between the groups would be equal (13/412 = 0.032) and (7/224 = 0.031). Unfortunately, we have no way of knowing how many patients subsequently were diagnosed with and treated for such conditions given that the manuscript is missing these details.
39. Personal communication with Dr. Harvey Risch, September 14, 2020.
40. Sulaiman et al., MedRxiv.
41. Heras et al., “COVID-19 Mortality Risk Factors in Older People in a Long-Term Care Center.”
43. Wilson, “Hydroxychloroquine RCTs.”
44. Gregg Gonsalves, “Statement from Yale Faculty on Hydroxychloroquine and Its Use in COVID-19,” Medium, August 4, 2020, https://medium.com/@gregggonsalves/statement-from-yale-faculty-on-hydroxychloroquine-and-its-use-in-covid-19-47d0dee7b2b0 (accessed October 9, 2020).
45. “CNN Host John Berman vs Yale’s Dr. Harvey Risch,” YouTube; Update—On September 29, 2020, Dr. Risch released a new meta-analysis in preprint that reviews five RCTs on HCQ, that in combination contain 5,577 patients. The meta-analysis concludes that “HCQ was associated with a 24% reduction in COVID-19 infection, hospitalization, or death.” This analysis combined RCTs with different methodologies, different patient populations, and different treatment regimens, and draws conclusions on the effect of HCQ across studies; Joseph A. Ladapo et al., “Randomized Controlled Trials of Early Ambulatory Hydroxychloroquine in the Prevention of COVID-19 Infection, Hospitalization, and Death: Meta-Analysis,” MedRxiv, September 30, 2020, https://www.medrxiv.org/content/10.1101/2020.09.30.20204693v1.full.pdf (accessed October 9, 2020)..
46. “Top Sepsis Studies,” Critical Care Reviews, https://criticalcarereviews.com/index.php/majorstudies/landmark-studies/336-by-system/1145-top-sepsis-studies (accessed September 16, 2020); Andrea Morelli et al., “Phenylephrine versus Norepinephrine for Initial Hemodynamic Support of Patients with Septic Shock: A Randomized, Controlled Trial,” Critical Care, May 3, 2015, https://www.atsjournals.org/doi/abs/10.1164/rccm.201505-0857OC (accessed September 16, 2020).
47. David R. Boulware et al., “A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for COVID-19,” New England Journal of Medicine, June 3, 2020, https://www.nejm.org/doi/full/10.1056/NEJMoa2016638 (accessed October 9, 2020).
48. “COVID-19 Treatment Analysis.”
49. As of September 14, 2020, I could not find a single case in the FDA Adverse Event Reporting System (FAERS) documenting a case of ventricular arrhythmia in a patient who died after receiving HCQ for Covid-19; https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4-0135608ddc13/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysis.
50. Harvey Risch, “Hydroxychloroquine Works in High-Risk Patients, and Saying Otherwise Is Dangerous,” Washington Examiner, August 12, 2020, https://www.washingtonexaminer.com/opinion/hydroxychloroquine-works-in-high-risk-patients-and-saying-otherwise-is-dangerous (accessed October 6, 2020).