Follow-up to: what did harvey risch say about hydroxychloroquine use in Covid in 2020
Question explored with the scientific record
You ignored the studies on outpatient use started in the first 4 days of symptoms - what do those ~70,000-patient studies show about hospitalization and mortality?
The short version: the evidence for early outpatient hydroxychloroquine is weak, observational, and contradicted by later RCTs.
The evidence you asked about comes from a 2020 review by Harvey Risch in the American Journal of Epidemiology [1]. He cited three non-randomized studies. A Brazilian study of 636 high-risk outpatients found that those starting hydroxychloroquine plus azithromycin before day 7 had a 1.2% hospitalization rate versus 5.4% in controls who declined treatment (p<0.0001) [1]. A French study of 42 patients reported a 7-fold faster viral clearance with the combination (p=0.035) [1]. A New York case series of 405 high-risk patients treated with the same regimen plus zinc reported 6 hospitalizations and 2 deaths, with no cardiac arrhythmias [1].
These are not randomized trials. The control groups were self-selected, not blinded, and the outcomes were not hard clinical endpoints in a controlled setting. A later critique in the same journal pointed out that the Gautret study's odds ratio of 52 was inflated and the actual risk ratio was about 5, and that subsequent randomized controlled trials showed no benefit [2]. The Cavalcanti trial of 667 patients with mild to moderate disease found no benefit of hydroxychloroquine plus azithromycin on clinical status at 15 days (odds ratio 0.99, 95% CI 0.57-1.73) [2].
| Study | Design | N | Hospitalization rate | Key finding |
|---|---|---|---|---|
| Brazil (Risch review) | Non-randomized, self-selected controls | 636 | 1.2% (treated early) vs 5.4% (controls) | p<0.0001 |
| France (Gautret) | Non-randomized, open-label | 42 | Not reported | 7-fold viral clearance, p=0.035 |
| New York (Risch review) | Uncontrolled case series | 405 | 6/405 (1.5%) | No arrhythmias |
| Cavalcanti RCT | Randomized, controlled | 667 | Not reported | OR 0.99 (0.57-1.73) for clinical status |
The safety evidence from a multinational study of 675,078 rheumatoid arthritis patients found no significant increase in all-cause mortality (RR=1.36, p=0.10) or cardiac arrhythmia (RR=1.08, p=0.36) with hydroxychloroquine plus azithromycin compared to hydroxychloroquine plus amoxicillin [1]. A separate 1997 study of 1,207 hydroxychloroquine-treated outpatients found definite retinopathy in only 0.08% and no toxicity below 6.5 mg/kg/day [3].
My call: the observational evidence for early outpatient hydroxychloroquine is suggestive but not reliable, and the only relevant RCT found no benefit. Confidence: moderate that the observational studies overstate the effect, low that hydroxychloroquine has any real benefit in this setting.
Sources examined 12
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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 -
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 -
Incidence of hydroxychloroquine retinopathy in 1,207 patients in a large multicenter outpatient practice
A retrospective chart review of 1,207 HCQ-treated Kaiser Permanente outpatients found 1 definite (0.08%) and 5 probable (0.4%) retinopathy cases; no definite toxicity occurred below 6.5 mg/kg/day, leading the authors to recommend against routine ophthalmic screening at low dosag…
DOI: 10.1002/art.1780400817 -
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 -
Outpatient management of kidney transplant recipients with suspected COVID‐19—Single‐center experience during the New York City surge
A single-center retrospective study describing the outpatient monitoring of 44 kidney transplant recipients with suspected COVID-19 in New York City during March–April 2020, showing extensive progression to hospitalization and highlighting the inadequacy of symptom-based outpati…
DOI: 10.1111/tid.13383 -
A report from the Brescia Renal COVID Task Force on the clinical characteristics and short-term outcome of hemodialysis patients with SARS-CoV-2 infection
This study describes 94 SARS-CoV-2–positive maintenance hemodialysis patients across four Brescia centers, comparing outpatient versus hospitalized trajectories, treatments, and short-term outcomes, and identifying factors associated with ARDS and death in this high-risk populat…
DOI: 10.1016/j.kint.2020.04.030 -
Clinical signs, symptoms, and severity of COVID-19 in patients with rheumatic diseases during the COVID-19 epidemic
Among 77 rheumatic-disease outpatients with COVID-19, severity ranged from mild to severe; methotrexate + prednisolone linked to higher severity while hydroxychloroquine + sulfasalazine + prednisolone linked to milder outcomes; severity did not significantly depend on rheumatic …
DOI: 10.34172/ipp.2023.40568 -
COVID-19 and a Tale of Three Drugs: To Repurpose, or Not to Repurpose–That Was the Question
This article critically reviews COVID-19 drug repurposing with a focus on hydroxychloroquine, ivermectin, and remdesivir, outlining the evidence, controversies, regulatory responses, and ongoing debates about their efficacy, safety, and scientific integrity.
DOI: 10.3390/v17070881 -
FRI0108 Retinal changes and activity in systemic lupus erythematosus
A Portuguese clinical study evaluating the toxicity of antimalarials (chloroquine and hydroxychloroquine) in systemic lupus erythematosus patients, finding notable ocular toxicity leading to drug discontinuation—more so with chloroquine—and recommending periodic ophthalmologic m…
DOI: 10.1136/annrheumdis-2001.143 -
Drugs used in incident systemic lupus erythematosus – results from the Finnish nationwide register 2000–2007
This study analyzes the initial anti-rheumatic outpatient therapy and concomitant medication use in incident systemic lupus erythematosus (SLE) patients in Finland from 2000 to 2007, revealing high usage rates of disease-modifying anti-rheumatic drugs (DMARDs) and increased medi…
DOI: 10.1177/0961203316628998 -
ANALYTICAL ASSESSMENT OF OUT-PATIENT TREATMENT OF PATIENTS WITH RHEUMATOID ARTHRITIS
Outpatient rheumatoid arthritis management in the Gomel region shows a heavy comorbidity burden, predominant DMARD monotherapy with limited biologic use, substantial glucocorticoid reliance, and a modest remission rate (38.6%), highlighting a gap between guideline recommendation…
DOI: 10.51523/2708-6011.2016-13-4-8 -
Body Image Intervention to Improve Health Outcomes in Lupus
A proof-of-concept pilot study evaluating the feasibility and preliminary effectiveness of a body image–focused cognitive behavioral therapy (BI-CBT) with appearance-enhancement training for women with cutaneous systemic lupus erythematosus (SLE) showed significant and lasting i…
DOI: 10.1097/rhu.0000000000000141