Hydroxychloroquine, alone or in combination with azithromycin, found ineffective for treating COVID-19 in large clinical trials

Key takeaway

Large-scale clinical trials demonstrate no beneficial effect of hydroxychloroquine in terms of viral shedding, disease severity, or mortality among COVID-19 patients. However, numerous ongoing clinical trials are still evaluating the potential use of hydroxychloroquine to prevent infection in people with a high risk of exposure to COVID-19. Public health institutions caution against unsupervised use of the drug, as it may increase the risk of cardiac toxicity in people with underlying medical conditions. Furthermore, the high demand for hydroxychloroquine is causing a shortage of the drug, which may harm patients who need it to treat chronic diseases like lupus.

Reviewed content

Claim:

“Hydroxychloroquine, azithromycin and zinc cure [COVID-19]”

Verdict detail

Unsupported: Large randomized controlled clinical trials in several countries have found no beneficial effect of hydroxychloroquine in terms of mortality rate or clinical outcomes in COVID-19 patients. Large clinical trials are currently evaluating the effect of zinc supplementation in COVID-19 patients. Until the results from these studies are released, the use of zinc supplementation for treating or preventing COVID-19 is not supported.
Lacks context: Studies suggest that hydroxychloroquine may cause cardiac toxicity in some COVID-19 patients, particularly in those with underlying medical conditions. This evidence advises against a generalized use of the drug, but not against its medically supervised use for treating chronic rheumatic conditions, such as lupus. Furthermore, the doses of hydroxychloroquine used to treat these chronic diseases are lower than those tested in COVID-19 clinical trials and are carefully adjusted for any underlying health conditions.

See our method of evaluation

Full Claim

“Hydroxychloroquine, azithromycin and zinc cure [COVID-19]”

In late July 2020, numerous memes on social media spread the unsupported claim that hydroxychloroquine (HCQ), azithromycin (AZM), and zinc can cure COVID-19. Other versions questioned why the drug is considered unsafe for COVID-19 patients when it is used to safely treat patients with malaria and lupus, and demand over the counter access to it (examples here, here, and here). Recent clinical trials contradict these claims and suggest that HCQ, alone or in combination with AZM, is ineffective for treating COVID-19. The effect of zinc supplementation alone or in combination with HCQ for preventing or treating COVID-19 is currently being evaluated in clinical trials. However, zinc supplementation above the recommended dietary allowance can cause copper deficiency leading to anemia and potential neurological damage, and the U.S National lnstitutes of Health recommends against its use for preventing COVID-19.

As mentioned in previous reviews by Health Feedback, the World Health Organization has stated that no drug is currently effective for preventing or curing COVID-19. Among many potential candidates, the anti-malarial drug HCQ attracted special attention after early studies claimed to show a beneficial effect in treating COVID-19 patients. However, larger, more recent studies have increasingly come to the opposite conclusion.

The first hint that HCQ might be useful for treating COVID-19 were two studies from China published in February and March showing that CQ and its less toxic derivative HCQ effectively blocked viral infection in cell culture^[1,2]. And in March 2020, a group from the University of Aix-Marseille led by Didier Raoult published a small observational study in the International Journal of Antimicrobial Agents, which suggested that HCQ could reduce viral shedding in COVID-19 patients, particularly when combined with the antibiotic AZM^[3].

In observational studies, researchers do not control the treatments or assign subjects to experimental groups. Instead, they observe and measure variables of interest and look for relationships between them. Randomized trials are statistically more robust than observational studies because they contain far fewer confounding variables. However, observational studies are conducted when it is impossible or unethical to randomize study participants into treatment groups, or when results are urgently needed.

Shortly after the Marseille study, a preprint (a study which has not been peer-reviewed by other scientists yet) by another research group in China suggested that HCQ improved some clinical symptoms such as fever and cough in a small randomized controlled study in COVID-19 patients from Wuhan^[4].

The Marseille study popularized the idea that HCQ might be an effective treatment for COVID-19. But as previously reviewed by Health Feedback, these results were heavily criticized by the scientific community for containing significant bias. For example, the researchers excluded from analysis several patients who had bad outcomes or died during the study. This discovery prompted the International Society of Antimicrobial Chemotherapy (ISAC), which publishes the journal, to issue a statement expressing that “the article [did] not meet the Society’s expected standard”. ISAC then published an independent review of the study by epidemiologist Fritz Rosendaal from the Leiden University Medical Center in The Netherlands, who called the study “irresponsible”^[5]. In April, Raoult’s group published the results from two larger observational studies claiming to show significant clinical improvements in patients treated with HCQ and AZM, but these studies were similarly criticized for methodological flaws^[6-7].

The urgent need for an effective COVID-19 treatment prompted researchers to launch more than 200 clinical trials worldwide to evaluate the safety and efficacy of HCQ in reducing COVID-19 severity and mortality. Data from randomized controlled clinical trials were particularly relevant since they are the gold standard for assessing the safety and efficacy of a new treatment. Such studies include a control group, randomly allocate patients to either the control or test group, and ensure that demographics, such as age and gender, are equally represented in both groups. These features of a randomized controlled trial are critical for reducing bias and for accurately estimating the efficacy of a new drug.

As of this review’s publication, eight large randomized controlled clinical trials have concluded in the U.S., Canada, Brazil, Spain, the U.K., and China. None have reported a beneficial effect of HCQ in terms of clinical outcome, mortality, viral shedding, or risk of intubation among COVID-19 patients^[8-13]. The studies include three large clinical trials conducted by the University of Oxford, the U.S. National Institutes of Health, and the World Health Organization. In all three cases, the hydroxychloroquine treatment arms were halted after researchers observed that the drug had no effect on the mortality rate or clinical outcomes of patients. These trials involved patients presenting mild, moderate, and severe forms of the disease, suggesting that HCQ is not effective for treating any severity of COVID-19.

The claim that the combination of HCQ with AZM can cure COVID-19 is similarly not supported by current scientific evidence. The randomized controlled clinical trial conducted in Brazil specifically investigated the effect of this drug combination in 504 patients with mild to moderate COVID-19. The results showed no improvement in the mortality rate or the clinical status of the patients treated with HCQ and AZM after 15 days^[13]. Five additional observational studies comprising a total of 1,820 COVID-19 patients in the U.S., Italy, and Ireland also reported no clinical improvement or reduced mortality in patients treated with that drug combination^[14-18].

Studies that claim to have found a beneficial effect of the HCQ and AZM drug combination contain significant flaws. A large observational study from the Henry Ford Hospital published in July in the International Journal of Infectious Diseases reported that the mortality rate in COVID-19 patients treated with HCQ and AZM was half of that observed in untreated patients^[19]. However, an editorial published in the same journal questioned the results by pointing out several biases and confounding factors^[20], as previously explained by Health Feedback. In another study, a group from China published a preprint showing that treatment with either CQ or HCQ accelerated recovery in a very small group of COVID-19 patients^[21]. However, each treatment group comprised only 18 patients, and the manuscript has not been peer reviewed or published yet.

A search on ClinicalTrials.gov, which is run by the U.S. National Library of Medicine, shows that hundreds of clinical trials are still evaluating the potential of HCQ for treating or preventing COVID-19 infection (prophylaxis), particularly in individuals at high risk of exposure. On 3 June, the University of Minnesota published in the New England Journal of Medicine the first results from a randomized, controlled, double-blind trial testing prophylactic use of HCQ in 821 participants. The study concluded that HCQ did not prevent COVID-19 infection within four days after exposure^[9]. However, data on the prophylactic efficacy of HCQ is still scarce and does not allow us to form definite conclusions.

Despite the lack of compelling scientific evidence regarding HCQ’s efficacy, demands for over-the-counter access to the drug have spread on social media. In April 2020, the U.S. Food and Drug Administration cautioned against the unsupervised use of HCQ due to potential cardiac toxicity. Several studies further indicate that HCQ may increase the risk of disturbances to normal heart rhythms, especially when HCQ is combined with AZM^[22-24]. These disturbances, named QT prolongation, can trigger potentially serious or fatal tachycardias, which is an abnormally rapid heartbeat. The interaction of HCQ with other medications, including those that do not require a prescription, can further increase the risks.

These and other studies strongly suggest that the unsupervised use of HCQ may cause serious adverse events in the general population, even though severe arrhythmias were found to be rare in the context of clinical trials. For instance, some studies recommend extreme caution when using HCQ in older patients and people with underlying health conditions^[25-26]. Some posts on social media misleadingly claim that HCQ is only dangerous for COVID-19 patients, but not for patients who take the drug on a long-term basis to treat lupus or other chronic autoimmune diseases. However, the doses of HCQ used to treat lupus are lower (200-400 mg per day) than those used in the COVID-19 trials (400-800 mg per day). Furthermore, HCQ treatment for autoimmune diseases is continuously supervised and adjusted for any underlying medical conditions.

One of the principal ethical rules in medicine states that it is better to do nothing, rather than risking a larger harm (primum non nocere, “first, do no harm”). The benefits of HCQ treatment in autoimmune diseases largely outweigh any potential harm caused by the drug. This is not the case in COVID-19 patients, for whom treatment with HCQ does not seem to provide any significant benefit. But even beyond safety issues, the high demand for HCQ is causing a shortage of the drug, which can negatively impact the survival of patients with systemic lupus erythematosus^[27].

In summary, the claim that HCQ alone or combined with AZM and zinc can cure COVID-19 is unsupported. Robust clinical trials suggest no beneficial effect of HCQ in COVID-19 patients and, because of the risks associated with the drug, do not support making the drug available over the counter.

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Other fact-checkers including Lead Stories and USA Today have addressed similar claims supporting the efficacy of HCQ for treating COVID-19 and found them false or unsupported.

REFERENCES

• 1 – Wang et al. (2020) Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus. Cell Research.
• 2 – Liu et al. (2020) Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery.
• 3 – Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents.
• 4 – Chen et al. (2020) Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study. MedRxiv [Note: This is a pre-print that has not yet been peer reviewed or been published in a journal at the time of this review’s publication.]
• 5 – Rosendaal. (2020) Review of: “Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Gautret et al 2010. International Journal of Antimicrobial Agents.
• 6 – Gautret et al. (2020) Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Medicine and Infectious Disease.
• 7 – Million et al. (2020) Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France. Travel Medicine and Infectious Disease.
• 8 – Tang et al. (2020) Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. British Medical Journal.
• 9 – Boulware et al. (2020) A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. The New England Journal of Medicine.
• 10 – Horby et al. (2020) Effect of hydroxychloroquine in hospitalized patients with COVID-19: preliminary results from a multi-centre, randomized, controlled trial. MedRxiv [Note: This is a pre-print that has not yet been peer reviewed or been published in a journal at the time of this review’s publication.]
• 11 – Skipper et al. (2020) Hydroxychloroquine in nonhospitalized adults with early COVID-19. Annals of Internal Medicine.
• 12 – Mitjà et al. (2020) Hydroxychloroquine for early treatment of adults with mild Covid-19: a randomized-controlled trial. Clinical Infectious Diseases.
• 13 – Cavalcanti et al. (2020) Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. The New England Journal of Medicine.
• 14 – Kelly et al. (2020) Clinical outcomes and adverse events in patients hospitalised with COVID‐19, treated with off‐label hydroxychloroquine and azithromycin. British Journal of Clinical Pharmacology.
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• 17 – Geleris et al. (2020) Observational study of hydroxychloroquine in hospitalized patients with Covid-19. The New England Journal of Medicine.
• 18 – Rosenberg et al. (2020) Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York state. Journal of American Medical Association.
• 19 – Arshad et al. (2020) Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. International Journal of Infectious Diseases.
• 20 – Lee et al. (2020) An observational cohort study of hydroxychloroquine and azithromycin for COVID-19: (Can’t Get No) Satisfaction. International Journal of Infectious Diseases.
• 21 – Chen et al. (2020) Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study. MedRxiv [Note: This is a pre-print that has not yet been peer reviewed or been published in a journal at the time of this review’s publication.]
• 22 – Moschini et al. (2020) Effects on QT interval of hydroxychloroquine associated with ritonavir/darunavir or azithromycin in patients with SARS-CoV-2 infection. Heart and Vessels.
• 23 – Hsia et al. (2020) QT prolongation in a diverse, urban population of COVID-19 patients treated with hydroxychloroquine, chloroquine, or azithromycin. Journal of Interventional Cardiac Electrophysiology.
• 24 – Lofgren et al. (2020) Safety of hydroxychloroquine among outpatient clinical trial participants for COVID-19. MedRxiv [Note: This is a pre-print that has not yet been peer reviewed or been published in a journal at the time of this review’s publication.]
• 25 – Magagnoli et al. (2020) Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. MedRxiv [Note: This is a pre-print that has not yet been peer reviewed or been published in a journal at the time of this review’s publication.]
• 26 – Rivera et al. (2020) Utilization of COVID-19 treatments and clinical outcomes among patients with cancer: A COVID-19 and Cancer Consortium (CCC19) cohort study. Cancer Discovery.
• 27 – Mehta et al. (2020) Potential shortages of hydroxychloroquine for patients with lupus during the coronavirus disease 2019 pandemic. JAMA Health Forum.

NOTES

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