Did scientists’ political leanings affect clinical research on hydroxychloroquine?

From a well-known commonly used antimalarial drug to a promising star drug against the new coronavirus, during the epidemic, the clinical research of hydroxychloroquine has experienced many heart-wrenching twists and turns, including the president's endorsement, data falsification, clinical trials being suspended and restarted, etc. How many of these twists and turns are related to data, and how many are related to things other than science?

Written by | Ji Zhi

On June 4, 2020, a major research paper on hydroxychloroquine published by The Lancet was retracted on the grounds that the original case data could not be provided. Major media outlets revealed that the data provider, Surgisphere, was likely suspected of falsifying data. The WHO's hydroxychloroquine clinical trial was suspended at the end of May and restarted a week later, and hydroxychloroquine was once again pushed to the forefront.

Major events in hydroxychloroquine clinical research in 2020

Old drugs are used in new ways: Hydroxychloroquine (HCQ) shines again. Among the many star drugs currently undergoing clinical trials, a large part are innovative drugs under development, such as the famous remdesivir. Hydroxychloroquine (HCQ) is not a new drug that has not been launched on the market. On the contrary, it has a very long history. Chloroquine is a traditional antimalarial drug in the early days, and hydroxychloroquine is its improved version. It is based on the structure of chloroquine, using hydroxyethyl to replace an ethyl group. Its therapeutic effect is similar to that of chloroquine, but its toxic side effects are significantly reduced.

Figure 1 Molecular structures of chloroquine and hydroxychloroquine

In 1955, the United States approved the medical use of hydroxychloroquine[1] and included it in the World Health Organization's list of essential medicines. Hydroxychloroquine has become the safest and most effective drug in the medical system. From 2007 to 2017, it has consistently ranked among the top 200 most commonly prescribed drugs in the United States, with an average annual prescription volume of more than 5 million[2].

Although hydroxychloroquine is an antimalarial drug, it can also treat autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. In recent years, as people have a deeper understanding of its mechanism of action, more and more literature reports that hydroxychloroquine has new therapeutic uses: it can be anti-inflammatory and is a potential drug for systemic vasculitis[3]; combined with traditional anti-tumor drugs, it can increase the sensitivity of tumor cells to multiple drugs[4].

The antiviral potential of hydroxychloroquine is not a recent discovery. Long before the outbreak of the COVID-19 pandemic, researchers had already discovered the potential antiviral properties of chloroquine-based drugs. In in vitro experiments, hydroxychloroquine was found to effectively inhibit HIV activity[5], so researchers had already tested the potential of hydroxychloroquine to treat HIV patients in 2012[6].

The confusing journey of COVID-19 • Early small clinical trials bring encouraging results

https://www.thepaper.cn/newsDetail_forward_6040864

After the outbreak of the COVID-19 pandemic, hydroxychloroquine first showed its effectiveness in some small clinical trials in China. On February 18, 2020, The Paper published a report titled "Small-scale clinical trial at Wuhan University People's Hospital: Hydroxychloroquine has short-term efficacy in treating COVID-19". The report said that none of the 80 patients with systemic lupus erythematosus treated by the Department of Dermatology at Wuhan University People's Hospital were infected with the COVID-19. Considering that it may be the effect of hydroxychloroquine, the research team conducted a clinical trial of hydroxychloroquine in treating patients with COVID-19. The report pointed out that as of February 17, the hospital's "Hydroxychloroquine + Basic Treatment Group (Azithromycin)" had enrolled 20 patients with COVID-19. After treatment with hydroxychloroquine, the patients' clinical symptoms improved significantly in 1 to 2 days. However, the number of cases in this study was small and the therapeutic effect of hydroxychloroquine could not be confirmed, but it made everyone look forward to the follow-up research on hydroxychloroquine.

On March 18, WHO announced the launch of several large-scale international collaborative clinical trials, called "Solidarity", aimed at finding effective treatments for Covid-2019. This also includes clinical research on hydroxychloroquine. [7]

Figure 2 The results of French researchers were published in the International Journal of Antimicrobial Research

Subsequently, French researchers also conducted a clinical trial with a similar number of patients. 42 patients who met the criteria were included in the experiment, of which 26 were treated with hydroxychloroquine as the experimental group and 16 were treated as the control group. The results showed that the viral load of the patients in the experimental group was significantly reduced compared with the control group (Figure 3). This shows that hydroxychloroquine can effectively resist the infection of the new coronavirus (SARS-CoV-2), especially when used in combination with the antibiotic azithromycin. The results were published in the International Journal of Antimicrobial Agents on March 20 [8]. Although the results of the study are encouraging, the scale of the trial is too small to prove the effectiveness of hydroxychloroquine for the general public.

Figure 3 A small clinical trial in France showed the therapeutic effect of hydroxychloroquine

• Trump becomes the king of sales

After the French paper was published, on March 21, US President Trump tweeted that he recommended the use of the "hydroxychloroquine + azithromycin" therapy, believing that it could effectively inhibit the new coronavirus. He even named hydroxychloroquine "a gift from God." Trump said in his tweet that this was the FDA's recommendation, but it was officially denied by the FDA that night. The FDA said that it should be treated with caution.

Under Trump's relentless propaganda, hydroxychloroquine was sold out in the US market, and other countries quickly ran out of hydroxychloroquine. Although the medical community has never stopped experimental research on hydroxychloroquine during this period, there are also negative results showing that hydroxychloroquine not only has no preventive effect, but can even bring fatal side effects.

The consequence of the president's endorsement is that the public blindly follows suit. A couple in their 60s in Phoenix, Arizona, heard Trump say at a press conference on March 21 that hydroxychloroquine is very effective against COVID-19, so they decided to take some to prevent infection. But what they took was not the drug itself, but an additive commonly used to clean fish tanks. This additive contained another chemical form of chloroquine: chloroquine phosphate. 30 minutes after taking it, the couple felt very uncomfortable. After being sent to the hospital, the husband died and the wife was critically ill. (See "Anti-epidemic Diary of a New Drug Development Expert: I Hope Clinical Data Will No Longer Cause Tragedy | 117 Three People")

In the absence of sufficient clinical evidence, Trump's push for hydroxychloroquine triggered a surge of public opinion. Although subsequent research results have shown that hydroxychloroquine is "negative" in preventing and treating Covid-19, Trump has not given up his promotion. On May 18, Trump revealed to the public that because White House staff had been infected with the new coronavirus, he had been taking hydroxychloroquine and zinc supplements regularly to prevent the new coronavirus on the advice of his doctor (Figure 5).

Figure 5 White House memo: Trump and White House staff regularly take hydroxychloroquine and zinc supplements to prevent the new coronavirus

• Two top journals published: Hydroxychloroquine is "ineffective" and even dangerous

On May 1, 2020, NEJM (New England Journal of Medicine) published an important retrospective study online, "Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19" (Figure 6). This study was not a randomized double-blind clinical trial specifically for hydroxychloroquine, but rather reviewed patients infected with the new coronavirus during previous treatments and calculated the relationship between the use of hydroxychloroquine and the patient's endotracheal intubation and mortality rate, in order to evaluate the clinical efficacy of hydroxychloroquine in the treatment of COVID-19. This retrospective study included 1,376 COVID-19 patients and used Cox regression analysis.

The study found that the use of hydroxychloroquine did not increase or decrease the final intubation rate and mortality rate of patients, which indirectly shows that hydroxychloroquine has no clear clinical efficacy [9]. Unfortunately, the study was not a strict double-blind experiment with randomized patients. The biggest difference between the test group and the control group was whether or not hydroxychloroquine was taken. There may be many differences between patients that would affect the efficacy, but they were not included in the study. Therefore, the conclusions of this retrospective study need to be further verified by randomized double-blind trials.

Figure 6. Retrospective study published in NEJM

The results of the retrospective study published by NEJM poured cold water on people’s hopes, but worse was to come: On May 22, The Lancet published a sensational study [10], which found that hydroxychloroquine may be associated with higher mortality and increased incidence of heart disease in Covid-19 patients (Figure 7). This study analyzed data from nearly 96,000 Covid-19 patients who were treated with hydroxychloroquine alone or with a combination of hydroxychloroquine and antibiotics. The analysis showed that whether hydroxychloroquine was used alone or in combination with macrolide antibiotics, patients had a higher mortality rate and an increased frequency of arrhythmias.

The Lancet article "Hydroxychloroquine may increase the risk of death in COVID-19 patients" has attracted global attention. Due to concerns about the adverse effects of hydroxychloroquine, on May 25, the WHO announced the suspension of clinical trials of hydroxychloroquine as a potential treatment for the new coronavirus. The executive team of the "Solidarity" trial decided to suspend the use of hydroxychloroquine in the trial while reviewing the safety data.

Figure 7 Large peer-reviewed study published in The Lancet

• Reversal: Large-scale research data was exposed as fake

The study published in The Lancet has sparked controversy in the scientific community, and the source of its data has also been questioned. Faced with a third-party independent review, the three authors of this article (a total of four authors) requested to withdraw their research on June 4, 2020 because they were unable to provide the original case data (Figure 7).

According to an investigation by the British newspaper The Guardian, the data of 96,000 Covid-19 patients used in this study all came from a little-known health data analysis company, Surgiphere, and the company's president, Sapan Desai, was one of the authors of the paper - the only author who did not request the retraction of the paper. Surgiphere claims to run the world's largest and fastest hospital database, but the Guardian's investigation showed that the company's formal employees had almost no scientific research background. One of the employees was a science fiction writer, and another was an adult model. The president, Sapan Desai, was also involved in three medical malpractice lawsuits[11].

Just days after the Lancet paper went online, Guardian Australia uncovered an obvious error in the paper's Australian data. The paper said that researchers collected data from five Australian hospitals from the Surgisphere database, collecting 600 Australian Covid-19 patients and 73 Australian deaths as of April 21. Data from Johns Hopkins University showed that as of that day, Australia had recorded only 67 Covid-19 deaths, and it was not until April 23 that the number rose to 73.

Desai explained that the Australian data in the Surgisphere database accidentally included an Asian hospital, leading to the wrong number of cases. Following the Guardian Australia report, The Lancet published a short retraction related to the Australian findings, the only correction to the study so far.

The Guardian has since contacted five hospitals in Melbourne and two in Sydney - without whose cooperation the Surgisphere database would not have contained as much Australian data. However, all seven hospitals denied any connection to the Surgisphere database and said they had never heard of Surgisphere. Desai did not respond to requests for comment.

• WHO announces restart of global trial of hydroxychloroquine

On June 3, World Health Organization Director-General Tedros Adhanom Ghebreyesus said that after evaluating the mortality data collected in the hydroxychloroquine trial, the Data Safety and Monitoring Committee of the Solidarity Trial recommended that the hydroxychloroquine treatment trial should continue without modifying the trial protocol. Previously, its Data Safety Monitoring Committee found that the risk of death in COVID-19 patients taking hydroxychloroquine did not increase.

Peter Horby, professor of emerging infectious diseases and global health at the Nuffield Department of Medicine, University of Oxford, said: "We should seriously reflect on the quality of editorial and peer review during the COVID-19 pandemic. Scientific publishing must first and foremost be rigorous and honest. Emergencies require these values ​​more than ever."

• New study reveals hydroxychloroquine has no effect in preventing infection

Also on June 3, NEJM published a new study showing that hydroxychloroquine has no effect in preventing COVID-19 infection after exposure [12].

Figure 8. Latest research published by NEJM

This is a randomized, double-blind, placebo-controlled trial conducted in parts of the United States and Canada. Volunteers signed up online and accepted online follow-up surveys. The participants finally selected had experience of exposure to the new coronavirus environment. Participants were randomly assigned to take a placebo or hydroxychloroquine, followed for 14 consecutive days, and laboratory tests were performed to confirm whether the participants were eventually infected with Covid-19, in order to verify whether hydroxychloroquine has the effect of preventing infection.

The study included 821 participants, of which 87.6% (719 people) had a history of high-risk contact with confirmed Covid-19 patients. Follow-up results showed that there was no significant difference in the final diagnosis rate of patients in the hydroxychloroquine and placebo groups, and the side effects of hydroxychloroquine were more common than placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported. The results showed that high-dose hydroxychloroquine started within 4 days of high-risk or moderate-risk exposure did not prevent Covid-19-related illness.

Figure 9 Results of the experimental and control groups High doses of hydroxychloroquine do not prevent Covid-19-related illnesses

Return to science, maintain skepticism After the scandal of Surgisphere's alleged data falsification was exposed, the scientific community was in an uproar. Dr. Carlos Chaccour, chief scientific officer of the US BOHEMIA project and ivermectin researcher, said in an interview with The Guardian [13]:

"There is a serious political polarization around hydroxychloroquine, and too many political factors are mixed in the decision-making. Some people defend hydroxychloroquine because they support Trump; some people hate Trump, so they resist hydroxychloroquine. But the research on hydroxychloroquine should only be about data, not opinions, and even less about politics. The world is crazy."

This should be about data, not opinions, and absolutely not about politics. The world had gone crazy.

by Dr. Carlos Chaccour

Humans are still in a protracted battle against the novel coronavirus. Based on existing research, the effectiveness and safety of hydroxychloroquine, whether as a preventive or therapeutic drug, need further investigation. In addition to the above-mentioned trials of using hydroxychloroquine to prevent infection after exposure to the virus, there are many other randomized double-blind trials underway or already in data analysis to see what effect hydroxychloroquine can have on Covid-19.

At present, scientific research and reports related to the new crown are emerging in an endless stream. From this data fraud and retraction incident, we may be able to get more inspiration: the more critical the moment, the more we must emphasize the rigor of science. The development of science will affect policy changes and even affect the lives of patients. We must be vigilant and not blindly follow the conclusions of authoritative journals, while ignoring the attitude of thinking and questioning that science requires. There are still well-designed clinical trials testing the effectiveness of hydroxychloroquine in treating COVID-19. Let us wait and see how things will develop.

In the absence of sufficient evidence, rashly exaggerating the effects of hydroxychloroquine could have disastrous consequences. However, exaggerating its side effects without basis will also delay medication at a critical moment of the epidemic, sacrificing many lives in vain. The more critical the moment when drugs are urgently needed, the more we should emphasize scientific rigor, abandon subjective positions, respect data, remain skeptical, and not blindly follow authoritative magazines and conclusions. If science is linked to political positions - whether intentionally or unintentionally - it is like examining experimental results with tinted glasses. Such scientific research will only deviate from the truth and the original intention of the researchers.

Let science be science and politics be politics.

References

[1] https://web.archive.org/web/20200320234847/https://www.drugs.com/monograph/hydroxychloroquine-sulfate.html

[2] https://clincalc.com/DrugStats/Drugs/HydroxychloroquineSulfate

[3] Casian A, Shirish R Sangle, D'Cruz D P. New use for an old treatment: Hydroxychloroquine as a potential treatment for systemic vasculitis[J]. Autoimmunity Reviews, 2018, 17(7)

[4] Verbaanderd C, Maes H, Schaaf MB, et al. Repurposing Drugs in Oncology (ReDO)—chloroquine and hydroxychloroquine as anti-cancer agents[J]. ecancermedicalscience, 2017, 11.

[5] Chiang, G et al. “Inhibition of HIV-1 replication by hydroxychloroquine: mechanism of action and comparison with zidovudine.” Clinical therapeutics vol. 18,6 (1996): 1080-92. doi:10.1016/s0149-2918(96)80063-4

[6] Paton, Nicholas I et al. “Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antiretroviral therapy: a randomized controlled trial.” JAMA vol. 308,4 (2012): 353-61. doi:10.1001/jama.2012.6936

[7] https://www.who.int/en/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments

[8] https://www.sciencedirect.com/science/article/pii/S0924857920300996

[9] https://www.nejm.org/doi/full/10.1056/NEJMoa2012410

[10] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31180-6/fulltext

[11] https://amp.theguardian.com/world/2020/jun/03/covid-19-surgisphere-who-world-health-organization-hydroxychloroquine

[12] https://www.nejm.org/doi/full/10.1056/NEJMoa2016638

[13] https://www.theguardian.com/world/2020/jun/04/unreliable-data-doubt-snowballed-covid-19-drug-research-surgisphere-coronavirus-hydroxychloroquine?page=with%3Aimg-8