Follow-up to: what did harvey risch say about hydroxychloroquine use in Covid in 2020
Question explored with the scientific record
You ignored the subsequent studies of outpatient use started in the first 4 days of symptoms - what do those ~70,000-patient studies show about hospitalization and mortality?
The outpatient early-treatment studies you ask about are not in the evidence retrieved here. Not one of the 12 records reports a ~70,000-patient trial of hydroxychloroquine started within 4 days of symptoms, with hospitalization or mortality as the endpoint. The closest match is a 636-patient non-randomized Brazilian study cited in a 2020 review [4], which found 1.2% hospitalization in those treated before day 7 versus 5.4% in untreated controls. That is a 4.2 percentage-point absolute reduction, but the study was not randomized, the control group was self-selected (patients who declined treatment), and the treated group had greater baseline severity, which should bias against the treatment, not for it. The same review cites a 405-patient uncontrolled case series with 6 hospitalizations and 2 deaths, but there is no concurrent control group at all [4].
The evidence that does exist on hydroxychloroquine for COVID-19 comes from larger, randomized trials in hospitalized patients, which found no benefit and signals of harm. The RECOVERY and SOLIDARITY trials, cited in a 2025 review [9], showed hydroxychloroquine associated with increased mortality in pooled analyses and QT prolongation risks. Those trials studied hospitalized patients, not early outpatients, so they do not answer your question directly. But they do show that when you test the drug in a well-designed trial, the benefit disappears and the harm appears.
The gap in the evidence is the gap itself. No large, randomized, placebo-controlled trial of early outpatient hydroxychloroquine with hard clinical endpoints was ever completed and published in a form that settles the question. The 636-patient Brazilian study is the largest outpatient study cited here, and it is non-randomized. The 70,000-patient studies you refer to are not in the retrieved evidence. If they exist, they were not retrieved here.
My call: the evidence retrieved does not answer the question. Confidence: not clear.
Sources examined 12
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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 -
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 -
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 -
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 -
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