Claim that hydroxychloroquine is an effective early treatment for COVID-19 isn’t supported by evidence from clinical trials

As of 22 September 2022, the U.S. Food and Drug Administration (FDA) has approved two treatments for patients with COVID-19, the antiviral remdesivir and the immune modulator baricitimib. The FDA has also given Emergency Use Authorization (EUA) to other treatments, including several monoclonal antibody treatments and two oral antiviral pills (Paxlovid and molnupiravir). There are also four COVID-19 vaccines approved or authorized in the US.

This is a far cry from early 2020, when the pandemic began. COVID-19 is caused by the novel coronavirus SARS-CoV-2, meaning this virus hadn’t been previously identified. This novelty meant that when COVID-19 appeared, there were no approved treatments or vaccines, leaving scientists and doctors scrambling to find already approved drugs that might work to treat patients with COVID-19.

The process of taking a drug previously approved for one condition and seeing whether it works for a second condition is called drug repurposing. There are many advantages to drug repurposing, such as lower costs and a quicker path to approval. By May 2020, over 100 different drugs had been tested as potential treatments for COVID-19. Two of these were the antimalarial medications chloroquine and hydroxychloroquine.

Hydroxychloroquine (HCQ) and chloroquine (CQ) are two FDA-approved drugs that can prevent and treat certain types of malaria; HCQ is also approved for rheumatoid arthritis and lupus. Though the drugs are well-tolerated at the doses used for malaria, the U.S. Centers for Disease Control and Prevention (CDC) cautions that both drugs can cause side effects and that fatal overdoses have been reported.

Following promising results from laboratory experiments and small human trials done in China, a number of clinical trials evaluating HCQ and/or CQ were conducted, with some studies receiving outsized media attention despite the limitations of these studies. On 28 March 2020, the FDA issued an EUA allowing HCQ and CQ to be used by certain hospitalized patients with COVID-19.

Less than three months later, on 15 June 2020, the FDA revoked the EUA for HCQ and CQ in light of reports of serious adverse reactions and data from other studies demonstrating that the drugs were “unlikely to be effective in treating COVID-19”. Data from two large trials, RECOVERY (4,716 participants) and SOLIDARITY (5,042 participants), further provided strong evidence of HCQ/CQ’s lack of efficacy in treating COVID-19^[1].

Despite the evidence of these drugs’ lack of benefits for COVID-19 patients, HCQ and CQ have continued to be promoted by some commentators. Health Feedback reviewed numerous inaccurate claims about HCQ; an investigation by The Intercept found that America’s Frontline Doctors, a network of U.S. health care providers whose claim about HCQ that Health Feedback previously reviewed, had made millions of dollars selling HCQ and other ineffective treatments.

On 17 September 2022, the Gateway Pundit published a piece in which they claimed that “the FDA hid the evidence that HCQ was effective in the early treatment of the disease” and this resulted in “hundreds of thousands of people” dying. The claim comes from Harvey Risch, a cancer epidemiologist and professor emeritus at Yale University. On 15 September 2022, Risch claimed on an episode of the Steve Deace Show that the FDA suppressed the use of HCQ on the basis that it was “unsafe to be used in outpatients”.

He added that “had this medication been used at the outset of this pandemic it would have saved hundreds of thousands of lives”. In that same episode, Risch also claimed that the “pandemic was used to sell vaccines and patent medications at tremendous, tremendous profit to the pharma industry with collusion from the FDA and the CDC”.

To evaluate these claims, we’ll break them into two parts.

Several health bodies have warned against the use of hydroxychloroquine

First, there is no proof that the FDA hid evidence that HCQ was effective or that the FDA and the CDC colluded with the pharma industry to sell vaccines and patent medications. No evidence of such collusion or suppression was provided by the Gateway Pundit, Risch, or the Steve Deace Show.

Similar to the U.S., a number of countries don’t recommend HCQ as a treatment for COVID-19. In their 2 August 2021 “Guía clínico para el tratamiento de la COVID-19 en México”, the Mexican government included HCQ in a list of “medications that SHOULD NOT BE USED against COVID-19”, adding that there are no proven benefits of HCQ. On 26 August 2020, Australia’s Therapeutic Goods Administration (TGA) reiterated in a safety alert that it “strongly discourages the use of hydroxychloroquine to treat COVID-19 (including in hospitalised patients)”.

The World Health Organization also doesn’t recommend HCQ as a treatment for COVID-19, explaining that this “recommendation is based on 30 trials with more than 10 000 COVID-19 patients” and that “taking hydroxychloroquine to treat COVID-19 may increase the risk of heart rhythm problems, blood and lymph disorders, kidney injury, liver problems and failure”.

There is no reliable evidence for hydroxychloroquine’s effectiveness as an early treatment for COVID-19

Second, the claim that “HCQ [is] effective in the early treatment” of COVID-19 is unsupported by current evidence. While there are large clinical trials such as RECOVERY and SOLIDARITY providing strong evidence that HCQ isn’t beneficial for hospitalized COVID-19 patients, there are no trials with thousands of participants evaluating the effect of HCQ on outpatients with mild COVID-19. According to Bhagteshwar Singh, the lead author of a Cochrane Review of HCQ and CQ for prevention and treatment of COVID-19, “the evidence is less clear for prevention of COVID-19 and for people being treated as outpatients. However, with no benefit when used for treatment of severe COVID-19, a benefit in these situations is unlikely”.

To assess the current evidence that is available, Health Feedback evaluated peer-reviewed and published clinical trials that assessed early treatment of COVID-19 with HCQ/CQ. The U.S. National Institutes of Health define clinical trials as “a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes”.

On PubMed, a digital repository of articles published in biomedical and life sciences journal maintained by the U.S. National Center for Biotechnology Information, we searched for “COVID-19 Early Treatment + Hydroxychloroquine” and “COVID-19 Early Treatment + Chloroquine”, filtering for “Clinical Trials”.

The PubMed search generated 19 results, 14 of which were not clinical trials evaluating early treatment with HCQ in outpatients and/or patients with mild COVID-19

• Five of these were not clinical trials. Four were protocols for future clinical trials and one was a commentary on whether it was possible to conduct clinical trials during a pandemic^[2-6].
• Another four were clinical trials that evaluated other potential COVID-19 treatments (interferon β-1a, ivermectin and an anti-inflammatory treatment) or the heart safety in infants of mothers who used HCQ while pregnant^[7-10].
• Two clinical trials studied whether HCQ could help prevent COVID-19 infection; both studies found that HCQ didn’t prevent infection^[11,12].
• One clinical trial investigated CQ as a nasal spray, but found it had no impact on clinical outcomes for participants with mild illness, while two other studies investigated the effect of HCQ in patients with severe COVID, including systemic inflammation, and hospitalized patients^[13-15]. The last study mentioned received substantiated criticism, as acknowledged by the International Journal of Antimicrobial Agents in an editorial, and the last author, Didier Raoult is under criminal investigation for serious malfunctions^[15].

Of the 19 search results, only five evaluated early treatment in outpatients and/or patients with mild COVID-19^[16-20]. All five were randomized controlled trials, which are the gold standard for studying whether a medical intervention is effective, and the trials ranged from 70 to 685 enrolled study participants^[19,17].

All five studies found that, compared to the placebo, HCQ provided no significant benefits for these patients: HCQ didn’t decrease symptom severity^[16] or duration^[18,20], didn’t decrease COVID-19-associated hospitalization^[17,18], and didn’t lower viral loads^[19]. In short, all five of the clinical trials evaluating early treatment with HCQ in outpatients and/or patients with mild COVID-19 found that the antimalarial drug provided no significant benefits for these patients.

Health Feedback made a second search on PubMed, using a modified search query–COVID-19[Title] AND (early[Title/Abstract] OR outpatient[Title/Abstract] OR mild[Title]) AND (Hydroxychloroquine[Title] OR chloroquine[Title]) AND trial[Title/Abstract]–to identify additional papers that evaluated HCQ in outpatients and/or patients with mild COVID-19 but didn’t use the term “early treatment”. This generated 14 search results and of these nine were studies already identified in the first search^{[2,5,12,13,15,16,17,18,19]}.

Two search results included a trial evaluating COVID-19 prevention and another was a protocol for a future clinical trial^[21,22]. Of the three remaining search results, two were for clinical trials with patients with mild or moderate COVID-19 admitted to hospitals, and both found that HCQ provided no significant benefits for patients^[23,24]. The last trial evaluated HCQ or the antiviral favipiravir compared to standard of care (SOC) in 150 patients with mild or moderate COVID-19 and found that neither HCQ nor favipiravir provided significant benefits for COVID-19 patients compared to the SOC^[25].

As such, all three of the new trials identified with the second search query  evaluated HCQ treatment in patients with mild or moderate COVID-19, some of which were hospitalized, but none found that HCQ provided significant benefits to these patients.

Lastly, Health Feedback also searched for completed trials that evaluated HCQ or CQ in “outpatients OR early OR mild” on ClinicalTrails.gov, a database of clinical trials conducted around the world that’s maintained by the US National Institutes of Health. This search generated 36 clinical trials, the majority without published results, or with published papers we’d already previously reviewed^[16]. We identified one new study that evaluated HCQ in outpatients with mild-to-moderate COVID-19, finding that HCQ did not significantly reduce the risk of hospitalization due to COVID-19 compared to the placebo^[26].

It’s important to note that a handful of studies evaluating the effectiveness of HCQ have been withdrawn or retracted since publication; the blog Retraction Watch maintains a running list of retracted papers about COVID-19. A randomized clinical trial comparing the effectiveness of HCQ with the antiviral favipiravir in treating mild and moderate COVID-19 was retracted after concerns about the raw data underlying the results, with the Nature Scientific Reports editors concluding that they “no longer have confidence in the results and conclusions presented”.

A retrospective study–retrospective studies evaluate an intervention after it’s been made and are considered weaker than prospective clinical trials–that looked at the effectiveness of early therapy with HCQ combined with the antibiotic azithromycin was withdrawn. The retrospective study was eventually republished in another journal, though serious questions about the study’s methodology and conclusion remain.

Considering both the lack of large clinical trials in the vein of RECOVERY and SOLIDARITY evaluating early treatment of COVID-19 with HCQ, and the existing evidence from published clinical trials identified in PubMed and ClinicalTrials.gov showing a lack of benefits, the claim that “HCQ [is] effective in the early treatment of the disease” is unsupported. As such, there is no basis for the allegation that “hundreds of thousands of people died’ because the FDA didn’t promote HCQ as an early treatment. Health organizations like the WHO and federal agencies like the CDC in the U.S. and the TGA in Australia do not recommend individuals treat COVID-19 with HCQ.

REFERENCES

• 1 – Wüstner et al. (2022) Clinical Evidence Informing Treatment Guidelines on Repurposed Drugs for Hospitalized Patients During the Early COVID-19 Pandemic: Corticosteroids, Anticoagulants, (Hydroxy)chloroquine. Frontiers in Public Health.
• 2 – Niriella et al. (2020) Hydroxychloroquine for post-exposure prophylaxis of COVID-19 among naval personnel in Sri Lanka: study protocol for a randomized, controlled trial. Trials.
• 3 – Ader (2020) Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults. BMJ Open.
• 4 – Granados-Montiel et al. (2021) New prophylaxis regimen for SARS-CoV-2 infection in health professionals with low doses of hydroxychloroquine and bromhexine: a randomised, double-blind placebo clinical trial (ELEVATE Trial). BMJ Open.
• 5 – Oliveira Junior et al. (2022) Rationale and Design of the COVID-19 Outpatient Prevention Evaluation (COPE – Coalition V) Randomized Clinical Trial: Hydroxychloroquine vs. Placebo in Non-Hospitalized Patients. Arquivos Brasileiros de Cardiologia.
• 6 – Lilli et al. (2021) Is it possible to conduct clinical trials during a pandemic? The example of a trial of hydroxychloroquine. Epidemiologia & Prevenzione.
• 7 – Davoudi-Monfared et al. (2020) A Randomized Clinical Trial of the Efficacy and Safety of Interferon β-1a in Treatment of Severe COVID-19. Antimicrobial Agents and Chemotherapy.
• 8 – Buonfrate et al. (2022) High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. International Journal of Antimicrobial Agents
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• 10 – Friedman et al. (2020) Electrocardiographic QT Intervals in Infants Exposed to Hydroxychloroquine Throughout Gestation. Circulation: Arrhythmia and Electrophysiology.
• 11 – Abella et al. (2020) Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial. JAMA Internal Medicine.
• 12 – Vijayaraghavan et al. (2022) Hydroxychloroquine plus personal protective equipment versus personal protective equipment alone for the prevention of laboratory-confirmed COVID-19 infections among healthcare workers: a multicentre, parallel-group randomised controlled trial from India. BMJ Open.
• 13 – Thakar et al. (2021) Chloroquine nasal drops in asymptomatic & mild COVID-19: An exploratory randomized clinical trial. Indian Journal of Medical Research.
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• 17 – Reis et al. (2021) Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial. JAMA Open
• 18 – Schwartz et al. (2021) Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial. Canadian Medical Association Journal.
• 19 – Rodrigues et al. (2021) Hydroxychloroquine plus azithromycin early treatment of mild COVID-19 in an outpatient setting: a randomized, double-blinded, placebo-controlled clinical trial evaluating viral clearance. International Journal of Antimicrobial Agents.
• 20 – Mitjà et al. (2021) Hydroxychloroquine for Early Treatment of Adults With Mild Coronavirus Disease 2019: A Randomized, Controlled Trial. Clinical Infectious Diseases.
• 21 – McKinnon et al. (2021) Safety and tolerability of hydroxychloroquine in health care workers and first responders for the prevention of COVID-19: WHIP COVID-19 Study. International Journal of Infectious Diseases.
• 22 – Liu et al. (2020) Efficacy of chloroquine versus lopinavir/ritonavir in mild/general COVID-19 infection: a prospective, open-label, multicenter, randomized controlled clinical study. Trails
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