Is the confidence in hydroxychloroquine for the management of COVID-19 justified?

By Dr. Liji Thomas, MDApr 23 2020

A new review paper published in the preprint open-access journal medRxiv in April 2020 reports that there is not enough evidence to justify the widespread use of the drug hydroxychloroquine (HCQ) in the treatment or prophylaxis of the current COVID-19 illness.

Why was HCQ considered at all?

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has brought widespread disease and hundreds of thousands of deaths upon the world. As scientists chase each other towards rolling out a successful vaccine or therapeutic drug, claims of miraculous recoveries using this or that drug are bound to take center stage.

On the other hand, the common-sense route of repurposing already approved drugs for this novel indication seems to be among the more viable alternatives at present. This is because the earliest vaccine approval may lie a year or more in the future, while novel drugs initially designed to work against earlier epidemic viruses such as Ebola and MERS-CoV are only entering phase I trials at present.

A host of drugs such as chloroquine, HCQ, lopinavir, ritonavir, oseltamivir, corticosteroids, interferons, and traditional Chinese medicines have been examined for their potential use to counter this pandemic.

The current review aims to summarize the evidence in favor of and against the utility of the anti-inflammatory drug hydroxychloroquine in the treatment of COVID-19.

Novel Coronavirus SARS-CoV-2 Colorized scanning electron micrograph of a VERO E6 cell (blue) heavily infected with SARS-COV-2 virus particles (orange), isolated from a patient sample. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

What is HCQ?

HCQ is a 4-aminoquinoline derivative which has shown an impressive spectrum of activity against viruses in cultured cells. The drug was earlier approved for use in conditions like rheumatoid arthritis and has been widely used. This means its safety, tolerability, pricing and bulk availability are all factors in its favor.

HCQ is synthesized by substituting a side chain of the parent drug chloroquine, thus increasing its solubility and, therefore possibly less toxic. However, both chloroquine and HCQ have antiviral activity by raising the pH. Both have similar activity against chloroquine, but HCQ is less toxic to ocular tissues.

Other indications for HCQ include rheumatoid arthritis, systemic lupus erythematosus, and similar autoimmune conditions.

How does HCQ act against viruses?

Many different mechanisms have been attributed to this drug, including its inhibition of the viral fusion process by raising the local pH, increasing the pH within the endosomes of the host cells and so preventing the fusion of auto-lysosomes, which in turn interferes with the activity of the viral replication enzymes.

HCQ is also thought to inhibit the addition of a terminal glucose residue to the ACE2 receptor, which is responsible for binding the SARS-CoV-2 and virus entry into the host cell. The non-glycosylated receptor may fail to provide an efficient virus binding site, preventing infection.

The in vitro evidence of the antiviral activity of HCQ coupled with its favorable safety and tolerability profile, has raised hopes among health professionals and laypeople that this may be the answer to COVID-19. The hyped reporting by several media sources and political figures has not helped to evolve a balanced view of the drug. The current study is motivated by the need to identify the actual value of the drug in this situation from a critical analysis of the evidence.

How was the study done?

The authors screened all available articles and found 21 that were eligible, in addition to 88 ongoing trials and 27 randomized trials that are recruiting participants.

What do in vitro studies of HCQ show concerning anti-coronavirus activity?

During the earlier outbreak of SARS (severe acute respiratory syndrome), HCQ was reported to be active against the SARS virus. A newer study found increased potency relative to chloroquine against the SARS-CoV-2 virus, and the researchers recommended a dosage protocol as well. This comprises a loading dose of 400 mg twice daily as the sulfate, followed by 200 mg twice daily for four days.

Another report of an in vitro study showed that it could efficiently inhibit the SARS-CoV-2 virus with a higher 50% maximal effective concentration (EC50) than chloroquine. A 2006 trial also showed effective inhibition of cat and dog coronavirus in cell culture, again with a higher EC50.

What do clinical studies show?

Following the promising in vitro results, a small Chinese randomized controlled trial on 30 patients with COVID-19 was held. The drug did not show any difference between the treatment and control group for the primary outcome, that is, negative nasopharyngeal swab on day 7.

A French non-randomized trial of HCQ with azithromycin on 36 patients showed a virological cure in 70% of patients in the treated group compared to 12.5% in the control group.

From preprint databases, this favorable effect could not be replicated in all studies. While one uncontrolled observational study showed impressive clearance of viral load by day 8, another French study modeled on the earlier trial failed to show clinical benefit or antiviral activity of the HCQ-azithromycin combination. However, this trial included only 11 severely ill COVID-19 patients.

A retrospective study also reported a prolonged QT interval with this combination of drugs and commented that this could be preceded by the warning sign of acute renal failure.

Several clinical trials are still ongoing, and a few registered earlier in China are expected to publish their final results within a few weeks. Other well-designed RCTs will probably come out with their preliminary findings soon.

Is there evidence that HCQ can help COVID-19 patients?

Despite the desire to find a drug that can hopefully overcome the coronavirus, the initial consensus statements that triggered interest in HCQ were indeed the result of in vitro studies in various cell lines rather than clinical testing. The first letter of opinion reporting clinical improvement with chloroquine administration was, in fact, just a mention of many trials going on in various centers in China. There was no mention of the specific protocols being followed, the study designs or the patient characteristics, or the primary outcomes.

Well-designed and properly reported human trials are rare indeed, as many authors have rightly stated. None of the published trials have described the adverse effects or toxicity profiles. The authors of the current study say, “Small but absolute risk of cardiovascular death is seen to be associated significantly with azithromycin as compared to fluoroquinolones.”

HCQ is linked to cardiac conduction abnormalities and ventricular arrhythmias, while the addition of azithromycin can cause prolonged QT intervals. HCQ poisoning is difficult to reverse, and the drug can cause an overdose in patients with liver or kidney dysfunction. It should, therefore, be used with care. The researchers comment, “Irrational use in the general population without credible evidence, may pose a greater risk than benefit.”

What is the take-home?

In this situation, prophylactic use of HCQ in either the general population or the frontline healthcare workers appears to be unjustified by the current state of knowledge. The study concludes, “We believe that expert opinions and clinical consensus statements given by various international authorities for the use of HCQ either as prophylaxis to high-risk individuals and healthcare professionals or as emergency treatment of COVID-19 patients lack a strong evidence base.”

Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.