Question explored with the scientific record
What did Harvey Risch say about hydroxychloroquine for treating Covid outpatients in 2020?
The short version: Harvey Risch argued for early HCQ+AZ in outpatients based on weak, non-randomized evidence that later RCTs did not confirm.
Harvey Risch published an opinion piece in the American Journal of Epidemiology in 2020 arguing that hydroxychloroquine plus azithromycin, preferably with zinc, was safe and effective as early outpatient treatment for high-risk COVID-19 patients [2]. He cited several non-randomized and observational studies, including a small French study of 42 patients and a Brazilian study of 636 patients where treatment was offered, not randomized [2]. The evidence he presented was weak at best and contained factual errors, according to a subsequent critique in the same journal [4].
The key problem: the studies Risch relied on were not randomized controlled trials. The French study had only 42 patients and compared treated patients to other treated patients, not to a true control [2, 4]. The Brazilian study compared patients who chose treatment to those who declined it, which introduces self-selection bias [2]. Later, properly randomized trials found no benefit. The Cavalcanti trial randomized 667 patients and found no effect of HCQ+AZ on clinical status at 15 days (odds ratio 0.99) [4]. The evidence has moved on, and the RCTs do not support Risch's early claims.
| Study type | Key finding | What it means |
|---|---|---|
| Non-randomized (Risch's evidence) | 1.2% hospitalization in treated vs 5.4% in controls [2] | Looks promising but confounded by self-selection |
| Randomized (Cavalcanti et al.) | Odds ratio 0.99 for clinical improvement [4] | No benefit over standard care |
| Critique of Risch's piece | Factual errors, weak evidence [4] | The original argument was not sound |
My call: the evidence for HCQ+AZ as early outpatient treatment was never strong, and later randomized trials showed no benefit.
Sources examined 4
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Controversy over smoking in COVID‐19—A real world experience in New York city
A large retrospective cohort study from the Mount Sinai Health System in New York City evaluating whether current or former smoking influences hospitalization, in-hospital mortality, ICU admission, and mechanical ventilation among COVID-19 patients, finding no statistically sign…
DOI: 10.1002/jmv.26738 -
Early Outpatient Treatment of Symptomatic, High-Risk COVID-19 Patients That Should Be Ramped Up Immediately as Key to the Pandemic Crisis
This review argues that hydroxychloroquine plus azithromycin or doxycycline, preferably with zinc, is safe and effective as early outpatient treatment for high-risk COVID-19 patients, citing non-randomized and observational evidence to prevent hospitalization.
DOI: 10.1093/aje/kwaa093 -
Evidence-based approach to early outpatient treatment of SARS-CoV-2 (COVID-19) infection
A CME-style, evidence-based guide to early outpatient treatment of COVID-19, outlining infection-control measures, EUA outpatient therapies (notably monoclonal antibodies) when appropriate, and safe supportive options while noting the limitations of the available evidence.
DOI: 10.1080/08998280.2021.1925049 -
Concerns About the Special Article on Hydroxychloroquine and Azithromycin in High-Risk Outpatients With COVID-19
This commentary critiques Dr. Risch's opinion piece on hydroxychloroquine plus azithromycin for early outpatient COVID-19, highlighting factual errors, weak studies, confounding, and subsequent RCTs showing no benefit.
DOI: 10.1093/aje/kwaa189