COVID-19: A Cautionary Tale about Hydroxychloroquine

Photo by Michał Parzuchowski on Unsplash


The world has seen over 7.4 million confirmed cases of COVID-19 and approximately 418k deaths. The pandemic has catalyzed the development of vaccine and commencement of clinical trials for treatment options at an unprecedented speed.

As of May 24th, 10 candidate vaccines are undergoing human clinical trials and over 100 candidate vaccines are in preclinical evaluation. Similarly, there are ongoing development and testing of potential treatments for COVID-19. Among them, Remdesivir (developed by Gilead Sciences) and Hydroxychloroquine (HCQ) have made headlines in recent months.

In particular, HCQ has been touted by US President Donald Trump as the ‘miracle’ drug, which he took as prevention of COVID-19. Here we discuss the facts regarding HCQ and why when it comes to drug treatment, we should tread carefully.

What are chloroquine and hydroxychloroquine?

First developed in the 1940s, Chloroquine (US brand name: Aralen) is a compound with antimalarial properties. The drug has been shown to inhibit parasitic enzymes resulting in the accumulation of toxic heme within the parasite. Therefore, it has been used for the prevention and treatment of malaria, a disease caused by plasmodium parasites, transmitted through infected mosquitoes. 

Chloroquine has also been described as anti-inflammatory and anti-autophagy agents (note: autophagy is a cellular mechanism of the degradation and recycling cellular components). Besides malaria, chloroquine is also used for treating extraintestinal amebiasis and as an off-label treatment for rheumatoid arthritis and lupus (an autoimmune disease).

Hydroxychloroquine (US brand name: Plaquenil) is a derivative from chloroquine. They share structural similarities. Similarly, HCQ is shown to have antimalarial, anti-inflammatory, anti-autophagy properties. It is also prescribed as prophylaxis of malaria, treatment of uncomplicated malaria, lupus, and rheumatoid arthritis.

Both chloroquine and HCQ are can be taken orally in a tablet or solution. In a nutshell, although these two compounds share similarities in their structures and properties, they are not exactly the same. These days, HCQ is typically preferred over chloroquine as it has fewer side effects.

Hydroxychloroquine side effects

Some of the common side effects of HCQ include headache, dizziness, stomach cramps, diarrhea, and vomiting. These symptoms are considered minor and may persist for a few days to a few weeks.

However, when taken at higher doses (> 5 mg/kg) over a long term (> 5 years), both chloroquine and HCQ can cause more severe adverse effects such as retinopathy, cardiac toxicity, neuromyopathy, severe hypoglycemia, etc. Prolonged exposure to both drugs can cause irreversible visual changes and may lead to blindness. As for their cardiac effects, the overdose of these drugs may cause cardiovascular collapse, abnormal heart rhythm, and sometimes fatal cardiac arrest.

Interactions with other drugs?

HCQ is known to interact with certain medications. Some of these medications include digoxin (medications for treating various heart conditions), antidiabetic drugs, arrhythmogenic drugs, cyclosporin (immunosuppressant medication), etc.

In particular, HCQ is shown to prolong QT intervals (a measurement indicating heart rhythm). HCQ increases the risk of cardiac arrhythmia.

Hydroxychloroquine and COVID-19, what’s the connection?

Early preliminary studies (such as #1 and #2) have indicated that chloroquine and HCQ have antiviral properties that may be effective against SARS-CoV-2 infections.

Photo by Martin Sanchez on Unsplash

In these studies, drug treatment affected the uptake and release of SARS-CoV-2 virions, disrupting the viral life cycles. Besides, HCQ has been shown to reduce overactivation of immune response and inflammation in other diseases, hence it may attenuate “cytokine storm”, a known complication of COVID-19.

However, it is important to note that the antiviral properties of HCQ and chloroquine were only studied in cultured cells and were not verified in living animals or human studies. Nonetheless, due to the widespread publicity of these small and uncontrolled studies, more observational and interventional studies have been reported.

On March 28th, the FDA issued a EUA (Emergency Use Authorization) for health providers to request a supply of HCQ and chloroquine and increase access for COVID-19 patients. (NOTE: this does not mean that the FDA has approved these medications for COVID-19 treatment)

Does hydroxychloroquine treat or prevent COVID-19? What do research studies say?

Both chloroquine and HCQ are being studied for the treatment of COVID-19 patients and as prophylaxis against COVID-19. However, there are still very limited convincing data available on the efficacy of these drugs. Some of the findings from the past few months are summarized below.

March reports

In a communication letter to BioScience Trends journal, researchers from China reported that chloroquine was effective in treating COVID-19 associated pneumonia in over 100 patients. However, the study findings have not been published. There is also a lack of information regarding the parameters (dosage, duration, age, indications, etc.) of the cohort. Another study consists of 62 patients who investigated the efficacy of HCQ in treating mild COVID-19. This small, randomized study in Wuhan, China reported improvements in symptoms such as cough, fever, and pneumonia. Interestingly, another study of 30 COVID-19 cases from Shanghai reported no difference in recovery between untreated patients and patients receiving HCQ for 5 days. 

In France, a small study reported that treatment with HCQ was associated with an overall reduction or disappearance of the SARS-CoV-2 viral load. The anti-viral effect of HCQ was reportedly reinforced by combination treatment with azithromycin. Although the report has been peer-reviewed, it is still under further investigation. The study itself has a few major limitations such as small sample size (only 20 out of 26 COVID-19 patients treated with HCQ were included in final findings) and the lack of untreated control patients from the same hospital.

Following the initial report, the authors published another observational study on the combination of HCQ and azithromycin treatment on 80 COVID-19 patients. The researchers reported that 93% of the patients had cleared the virus (measured by qPCR) after 8 days of the treatment. However, this study lacked a control group. Hence, we don’t know whether a similar result can be achieved regardless of the treatment.  

Set out to verify the findings above, another research team in France conducted another study on 11 COVID-19 patients. In this study, the patients were given the same combination of HCQ and azithromycin. The researchers reported no evidence of clinical benefits with the combination treatment. By day 6 of the treatment, one patient had died and two were transferred to ICU followed by an early cessation of treatment for one of the ICU patients due to cardiac side effects. 8 out of 10 patients still showed positive virologic results after 6 days of treatment. However, this study was small and lack a proper control group. Besides, the majority of the patients had significant comorbidities such as obesity and cancer, which might affect the outcomes of the study. 

April reports

In the U.S., HCQ is being used for COVID-19 treatment despite the lack of efficacy and safety evidence from clinical trials. A retrospective study analyzed data from veterans hospitalized with COVID-19 in all U.S. Veterans Health Administration medical centers. The patients were grouped based on their treatments: (1) HCQ alone + standard care (SC) ; (2) HCQ+ azithromycin + SC; (3) SC only.

Out of the three groups, the mortality rate was the highest in the group that received HCQ alone, at 28%. The group that received combination administration of HCQ and azithromycin had a mortality rate of 22%. Interestingly, the group receiving normal SOC had the lowest death rate, at 11%. 

Note that the study was published as a preprint and has not been peer-reviewed (a process where scientific studies are assessed by experts in the field prior to publishing in scientific journals).

May reports

In May, several major studies on HCQ and COVID-19 were published and had made headlines.

large observational study published in the New England Journal of Medicine (NEJM) had looked at HCQ use in 1376 hospitalized COVID-19 patients at a large medical center in New York City. The authors concluded that there were no noteworthy differences in the risk of intubation or death among patients who received the drug than those who did not. Although the results could not confidently suggest any benefits or harm of HCQ use, the medical center has removed the suggestion that COVID-19 patients be treated with HCQ.

Around the same time as the above study, a retrospective study of 1438 COVID-19 patients in New York state was published in the Journal of the American Medical Association. This study examined the association between HCQ use, with or without azithromycin, and in-hospital mortality among the patients. Similar to other studies, this study did not report observe any differences in mortality rates between patients who received HCQ (with or without azithromycin) and patients who received neither drugs. Once again, this is an observational study using existing data collected outside controlled clinical trial settings. Therefore, there may be variables that were not accounted for which could affect the results.

Two independent studies were published in the British Medical Journal in May. Both studies concluded that HCQ administration did not provide additional clinical benefits over standard hospital care. The first study used data from 181 COVID-19 patients, collected across 4 French medical centers. All patients had documented for SARS-CoV-2-positive pneumonia and required oxygen but were not under intensive care. The clinical responses of patients who received HCQ and those who did not were about the same. Again, the interpretation of the results is limited by the observational design of this study. 

The second study was conducted in China on 150 hospitalized COVID-19 patients. In the study, patients were randomly selected to either receive standard care alone or together with HCQ. The study found that the administration of HCQ did not lead to a significantly higher clearance rate of the virus. Besides, 30% of the patients receiving HCQ experienced mild side effects. The authors also discussed the limitations of their study including the underpowered sample size and the risk of bias assessment due to study design. 

The Lancet incident

large study was published on the Lancet, one of the world’s top medical journals on the 22nd of May. The paper was subsequently retracted on 4th June. In this study, the authors analyzed data of 96,032 hospitalized patients collected across 671 hospitals in 6 countries. The analysis showed that HCQ use was associated with an increased risk of cardiac side effects and death.

This study has gained considerable attention in the media and even led to the temporary suspension of one of the world’s largest clinical trial (the Solidarity Trial). The Solidarity trial by WHO is being conducted worldwide. Over 400 hospitals in 35 countries are participating in the trial. The Solidarity trial is investigating the efficacy of four treatment options including HCQ compared to standard hospital care for COVID-19 treatment.

The study published in Lancet had raised safety concerns of HCQ and led to the suspension of the HCQ investigation in the Solidarity trial. No doubt, the publication and media attention also impacted other clinical trials on HCQ.

The subsequent retraction of the paper has prompted the WHO to resume its investigation on HCQ use. Following comments and scrutiny from other scientists on the inconsistencies in the data, an independent audit of the provenance and data validity was prompted by some of the study’s authors. The authors sought access to the raw data of the registry used in the study, which was managed by the Surgisphere Corporation, a healthcare analytics company in the U.S.

There was also a major conflict of interest as one of the authors, Dr. Sapan Desai is the founder of Surgisphere Corporation. Desai also supervised the acquisition and performed statistical analysis of the data for the Lancet paper while the other two authors conceived the study and written the manuscripts. The other authors of the paper had claimed they never had access to or witnessed the primary data source.

When Surgisphere failed to provide the other authors and independent reviewers access to the company’s database, the authors requested a retraction of the paper as they claimed they could not vouch for the veracity of the data.

Subsequently, another large study published on NEJM regarding the use of anti-angiotensin therapies on COVID-19 patients was also retracted. The NEJM study used the same healthcare data from Surgisphere and was co-authored by Desai too.

Latest reports

On 3rd June, a publication in NEJM indicated that HCQ was not effective when used as postexposure prophylaxis. The new double-blinded, randomized, placebo-controlled trial recruited 821 patients. Within 4 days of exposure to someone with confirmed COVID-19, asymptomatic patients were randomly assigned to either receive given HCQ or vitamin folate as a placebo.

The primary outcome of this study was either laboratory confirmation of COVID-19 or symptoms compatible with the disease within 14 days. Overall, there were no significant differences between placebo and HCQ groups. However, patients who received HCQ reported more gastrointestinal side effects than those who received a placebo. Although the trial followed the gold-standard methodology, there were some unusual limitations. For example, patients were enrolled remotely over the internet and self-reported their data. The sample size of the study is inadequate for ruling out potential disease preventative effect of HCQ.  

The latest press release (on 5th June) regarding the RECOVERY trial further strengthens the notion that HCQ may not be an effective treatment option for COVID-19 after all. The RECOVERY trial was established in March as a randomized clinical trial examining a range of treatment options for COVID-19 including HCQ.

The trial was conducted in the UK and had recruited over 11,000 patients from 175 NHS hospitals. The study compared the mortality rate of 1542 patients who received HCQ compared to 3132 patients who received standard care alone. At the end of the endpoint (28 days), the mortality rate was 26% in the HCQ group compared to 24% in the control group. The difference was not statistically significant and there was also no indication of benefits on hospital stay duration or other clinical outcomes. As a result, the RECOVERY trial has stopped recruitment for the HCQ arm of the study.  

Is this end of the Hydroxychloroquine?

Photo by Jon Tyson on Unsplash

Well, the answer is no. Lack of evidence is simply not the same as evidence of absence. Although most studies indicate that HCQ is not an effective treatment for COVID-19, they were not short of their own limitations and design flaws. And as always, only more studies and data can shed more light on this matter. Currently, there are still clinical trials being conducted worldwide on HCQ use for COVID-19, examining various clinical outcomes including its use as a pre-exposure prophylactic.

The rapid pace of the COVID-19 pandemic had brought tremendous pressure on the researchers. Government and institutions expect credible evidence and advice from the researchers for rapid decision making. Research studies are being conducted at an unprecedented pace with undue attention from the media. Sped-up science may not be good science.

The HCQ fiasco in this pandemic has caused great confusion and loss of public confidence in science. There are flaws in the current system such as inadequate governance of scientific bodies, research integrity issues, conflict of interests, lack of accountability to the public, and lack of data transparency. The Lancet paper retraction also reviewed flaws in the existing peer-review process.

It is more critical than ever for the scientific community to remain vigilant and ensure data transparency. It is also an opportunity for the community to reflect and work together in improving the system.

IMPORTANT:
Do not self-medicate to prevent or treat COVID-19. Seek medical advice if you have any health concerns.

Resources:
Chloroquine drug information
Hydroxychloroquine drug information
WHO SOLIDARITY trial information
RECOVERY trial information
Real-time COVID-19 trial tracker and its LANCET publication

About the Author

Ameline Lim, Ph.D.
Ameline Lim, Ph.D., is a research scientist and biologist. She received her PhD from the University of New South Wales at Sydney, Australia. She has broad interests in medicine, history of science, and behavioural science. She is particularly interested in science education and the public understanding of scientific research. Her blog 'Science with Amy' celebrates the pleasures of finding things out and general curiosity.

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