THE United States Strategic National Stockpile is laden with 63 million doses of hydroxychloroquine (HCQ) that have no clinical use in coronavirus disease 2019 (COVID-19). This has occurred as the US Food and Drug Administration (FDA) has revoked the emergency use authorisation for the use of HCQ in patients with COVID-19 admitted to hospital for whom a clinical trial is unavailable or not feasible. It is worth reflecting how things ever got to this situation.

Developing drugs for clinical use is expensive and time consuming, and the costs and time are opportunity costs for other areas of clinical service and research in COVID-19. Thus, following the removal of HCQ from large randomised clinical trials and from the FDA emergency register, it is time to question the assumptions and decisions that were made in selecting HCQ for repurposing in COVID-19, such as the use of non-standard methods to the standard physiological, pharmacological and regulatory processes for taking repurposed drugs at appropriate dose and timing into clinical trials.

Specific questions should be asked regarding how HCQ was chosen for clinical trials, what the biological rationale was, and how the choice was made to study antiviral therapy over “treating the host” response – the factor that causes morbidity and mortality in humans in COVID-19. Were there adequate pre-clinical in vitro studies showing efficacy? Were target concentrations of HCQ even achievable in relevant human compartments, and was posology optimisation considered to ensure appropriate dosing and timing of therapy prior to human trials? Importantly, was the drug concentration required for efficacy in COVID-19 likely to cause unacceptable toxicity?

It seems that these questions were not adequately answered prior to the commencement of clinical trials. What followed was an example of the piecemeal and fragmented approach to a global therapeutics research platform, including studying HCQ, which, based on pharmacology and physiology, was not only unlikely to be effective but also had complicated pharmacology and significant toxicities. It has meant an opportunity cost for clinical research using other biologically plausible research platforms and obviously also a cost to patients, who at this point still have no therapeutic options. We consider these aspects and suggest for future pandemic planning a national research group spanning all relevant disciplines, including clinical drug and therapeutics experts, be convened to develop a research platform.

Biological plausibility and in vitro studies

Results from in vitro studies for a potential repurposed drug play a critical role for the “go/no-go” decision to commence follow-on clinical trials. Following the initial outbreak of COVID-19, in vitro antiviral studies of chloroquine and HCQ were undertaken; however, there were significant limitations with these. For example, the in vitro HCQ EC50 (the drug concentration required to obtain a 50% effect) should be compared with in vivo HCQ concentration within an appropriate dosing regimen for COVID-19, as opposed to using doses effective for other diseases. Specifically, if the in vivo concentration is larger or much larger than the in vitro EC50, those doses of HCQ might be effective for patients with COVID-19. The in vitro HCQ EC50 is effectively extracellular drug concentration and it should be compared with the in vivo HCQ concentration (free plasma HCQ concentration). This comparison seems obvious, but a number of recent studies (here, here, here, here, here and here) compared the in vitro EC50 not with the free plasma HCQ concentration, but with the intracellular HCQ concentrations. This turns out to be an important error, because with HCQ, the intracellular HCQ concentrations are significantly higher (about 1000-fold) than the corresponding extracellular or free plasma HCQ concentration, due to the entrapment of HCQ in the cell as a consequence of the intracellular acidic environment (here and here). Once intracellular HCQ concentration is compared with the determined in vitro EC50, it is clear that the intracellular concentration is larger than the in vitro EC50 — this is certain because the in vivo HCQ concentration was “artificially” made about 1000-fold larger from its corresponding free plasma HCQ concentration. Consequently, clinical investigators starting studies may have received incorrect information that HCQ might be effective at standard doses and moved to the clinical trial phase. This error was actually described and presented by the FDA before removing the emergency use of HCQ. As well as HCQ, these errors in pre-clinical trialling of a repurposed drug for COVID-19 were seen with other drugs studied for this disease.

Enough efficacy to start a clinical trial?

On 15 February 2020, a Chinese news briefing claimed chloroquine had been used successfully to enhance viral clearance and reduce disease progression in an unpublished case series of 100 patients followed by the development of Chinese treatment guidelines. Subsequently, a small (20 cases treated with HCQ), open label, non-randomised trial, with a high proportion of loss to follow-up in the treatment group (six of the initial 26 enrolled) emerged, reporting induction of viral clearance with HCQ but published before peer review. The US president infamously promoted HCQ during a media briefing based on this report, labelling HCQ as “a powerful drug” and later on Twitter as a “game-changer”. Later, on 28 March, the US FDA provided emergency use authorisation for HCQ, allowing its use in patients with COVID-19 admitted to hospital.

Cognitive dissonance – additional trials are subsequently ethically approved

A significant quantity of poor quality trials then followed during April and May 2020, often published prior to peer review, with predominantly negative or equivocal results. A second observational, non-comparative trial evaluated a group of 80 cases who received HCQ and azithromycin with relatively mild COVID-19. The researchers reported only one death during the study period, lower than the death rate France was experiencing at that time. This group also published a retrospective descriptive analysis of 1061 cases of COVID-19 treated with HCQ and azithromycin suggesting that the therapeutic combination appeared safe and associated with a low mortality rate. A small, prospective trial conducted in Wuhan randomised 62 admitted patients with COVID-19 to receive HCQ in addition to standard treatment (therapies such as other antiviral agents, immunoglobulin and corticosteroids at the discretion of the treating physician) or standard treatment alone. The non-validated end point chosen in this trial was “time to clinical recovery”, defined as the return of body temperature to normal range and relief of cough for more than 72 hours. The HCQ group had a shorter “time to clinical recovery” – 3.2 days in the control and 2.2. days in the HCQ group. Another retrospective Chinese trial concluded that HCQ use was associated with decreased mortality in critically ill patients. In observational case reports of 568 patients in Wuhan who presented with severe COVID-19, 48 received HCQ. Although there was a significant difference in mortality between the two groups, favouring HCQ, as with the many other studies quoted above, the patients who received HCQ were likely to be the less unwell patients.

But there’s more

Multiple negative higher quality trials were subsequently published. Jun et al conducted a small prospective trial in which 30 patients with moderate COVID-19 were randomised to receive either HCQ plus supportive treatment or supportive treatment alone. There was no difference between the groups in the primary outcome of negative conversion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid detection in nasopharyngeal swab after 7 days, nor in another small, retrospective study with SARS-CoV-2 pneumonia. Additionally, a retrospective analysis of data from patients with COVID-19 admitted to hospital in all US Veterans Health Administration medical centres categorised patients based on their exposure to HCQ and azithromycin. The use of HCQ did not reduce the risk of the primary outcome of death and need for mechanical ventilation. In fact, the authors reported an association with increased mortality in patients treated with HCQ. Similarly, an observational study in New York analysing COVID-19 cases admitted to hospital also failed to show a reduction in risk of intubation or death. An observational study in France showed no survival benefit of HCQ use in COVID-19 pneumonia requiring oxygen.

Furthermore, a large, multinational registry analysis did not show benefit of HCQ or chloroquine on in-hospital outcomes for COVID-19, yet an association with decreased in-hospital survival. However, the article was later infamously retracted, not because the conclusions were incorrect (nevertheless, concerns had been raised with respect to the veracity of the data and analyses, prompting the attempt at an independent third-party peer review), but because the company with the database refused auditing.

Although large, randomised clinical trial data from groups around the world are still pending publication (eg, SOLIDARITY and RECOVERY), trial investigators have now removed the HCQ arm of these trials based on preliminary data.

How did we get here? The HCQ journey timeline

Overall, there have been several great collaborations and excellent public health leadership in many areas of the world during the COVID-19 pandemic. What we lacked was a cohesive vision and strategy for drug development in the repurposing area and implementation in the therapeutics area. The choice of HCQ and then the dose for COVID-19 treatment were areas that experts skilled in pharmacology, clinical pharmacology, pharmacokinetic/pharmacodynamic modelling and pre-clinical drug development could have provided guidance on. A global drug coordination by means of the World Health Organization would have enabled local experts to contribute knowledge to a more streamlined program; a program that could have given advice at each one of the steps in the HCQ journey. Also important to note is that additional HCQ trials continued despite equipoise being less likely as time went on.

What can we do better next time?

As previously noted, an international approach to rapidly identify drugs that treat the host to permit time for vaccine and antiviral development is needed. Importantly, coordination of the repurposing of existing drugs based on the principles of Fedson’s “treating the host” and repurposing existing drugs for new indications using existing pharmacology and physiology knowledge and observational administrative data are important to ensure time is not wasted, and that the most likely therapeutic targets based on physiology and pharmacology are chosen for clinical trials. Lastly, as we have seen, the work of epidemiology and public health staff is key to our broader response to worldwide pandemics.

Jennifer Martin is a physician and clinical pharmacologist co-directing the national Centre for Drug Repurposing and Medicines Research. Together with colleagues Nikola Bowden and Richard Head she has proposed a platform for repurposing drugs for COVID-19 which includes an international approach to rapidly identify drugs that treat the host in a pandemic.

Dr Zheng Liu received his PhD in Process Modeling in Chemical Engineering. He is now focusing on pharmacokinetic and pharmacodynamic modeling and simulation, and clinical trial design as a pharmacometrician.

Dr Steven Bollipo is the Director of Gastroenterology at John Hunter Hospital in Newcastle. He has authored the GESA statement on management of liver disease during the COVID-19 pandemic in Australia.

Dr Joshua McCarthy is a medical registrar in the John Hunter Hospital in Newcastle. He is currently studying a Master of Public Health and Tropical Medicine through James Cook University.

 

 

 

The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.

10 thoughts on “COVID-19: the rise and fall of hydroxychloroquine

  1. Andrew F says:

    These authors should hang their respective heads in abject shame.

    What a lot of mindless spin. Would be a good case study for propaganda in a university course.

    The data and the studies really are crystal clear:

    1. Use HCQ with zinc et al. EARLY in a person’s illness, you get invariably 100% efficacy.

    2. Treat it late in an illness, very little effect (and no one ever disputed that fact).

    Who would have that thought that’s the best time to administer an anti viral?

    Not the authors clearly.

    After all, who treats illnesses early, right?

    c19study.com

  2. Anonymous says:

    Doctors on the front lines know better, HQC works as an early intervention.

  3. Thabisa Sibanda says:

    I appreciate that the use of HCQ in Covid-19 is a controversial subject but my understanding of this article is that it dealt with a much broader subject of clinical evaluation of repurposed medications. I agree with the authors that there were many missed opportunities to pause and evaluate existing evidence before commencing a lot of Covid-19 related studies including HCQ studies. I am not sure that the authors adequately covered the most important challenges faced by clinical trial professionals with regards to Covid-19. I would have liked some suggestions on how the following challenges could have been addressed in a better way:
    1. Appropriate clinical trial methodologies during an epidemic.
    2. Evidence based decision making for emergency use authorizations.
    3. Building effective collaborations at a time when National and even state borders are closed.

    We definitely have a lot of lessons learned from many of the Covid-19 related studies but I suggests we start focusing on these challenges that I believe where blown up by this crisis.

  4. Anonymous says:

    The authors have published a biased paper. They should not have brought up the US President in an academic paper as it brings a political bias.
    There are two major flaws in the Solidarity and Recovery trials.
    1) The doses used were about 4 times higher than the recommended upper level for clinical use. This means the cost (adverse effects) of this treatment was raised for these trials.
    2) The treatment was given to patients who were already hospitalised and some on ventilation. Thus this was the wrong population to test this treatment on. The excessive inflammatory response cannot be prevented if it has already occurred. Thus any potential benefit from the treatment was reduced in the study design.

    So, if you want a treatment to fail, increasing the cost-benefit ratio is the way to do it.

    Further, the comments made about EC50 appears to have little relevance in a clinical situation for a drug that has a long history of use in multiple settings. On the contrary, the relevant evidence from basic science is that physiological effects of HCQ has impact on various points of viral action including the cytokine storm. When purporting to write to an audience of clinicians one has to be mindful of “not teaching your grandmother how to suck eggs”.

    The trials that are positive, all involved early treatment and non toxic (conventional) doses.

  5. Joe Kosterich says:

    If only Donald Trump had not spoken in support go HCQ, then a rational evaluation could occur. Maybe it helps a bit (especially with zinc) – maybe it does not. Giving people who have more severe symptoms the option is hardly unreasonable. The zeal of its opponents is fascinating.

  6. Anonymous says:

    Re the comment by Sue Ieraci: I am one of (the ) anonymous commenters here..I am definitely not an anti-vaccination type..to the contrary, I cannot conceive of being one. I am only interested in having the best available therapy for this virus. I think Dr David Katz provides the balance and analysis everyone should be aware of. He is an authentic sensible qualified voice to be discussing this issue and having weighed the evidence he says that he would treat his loved ones in a high risk group in the early viral replication phase with proven covid with HCQ +azithramycin (or doxycyclin) +zinc (he states 30mg) and he would do so on the balance of the evidence available even though it is not proven yet by randomised trials. He says that because it is a pandemic, treatment should be offerred such high risk cases as the risk of a bad outcome from the viral disease outweighs other risks…the evidence from randomised trials can be established one way or the other at a later stage. From my own point of view, given that HCQ, the antibiotic and the zinc are readily available and cheap, there should be no arbitrary obstruction to the prescription of this treatment provided it is for the right type of case– high risk, early with symptoms, virus positive. Dr Katz talk is 13 minutes and 7 seconds, he speaks calmly, analytically, quotes sources and background and has no bias. Listen to the whole talk: covexit.com/the-esteemed-david-katz-weighs-in-on-hydroxychloroquine/

  7. Sue Ieraci says:

    It’s fascinating to watch how many on-line discussions about drug treatment of COVID-19 get swamped with comments – often anonymous – wanting to promote hydroxychloroquine, with or without other drugs. The irony is that many of these comments are motivated by anti-vaccination sentiments – if they can argue that there is effective medical treatment, they can extrapolate that to arguing that there is no “need for a vaccine” (even though prevention is better than cure – that argument gets conveniently forgotten).

    In the case of this article, it’s interesting to see that the comments seem to completely ignore the discussion in the article (other than to accuse the authors of ‘bias’) and none provide valid evidence for their assertions.

    Some anti-vaxxers have been more honest in declaring their motivation for promoting a “Big Pharm” drug.

    “Anonymous” asserts that “The proposition, apparently supported by studies not mentioned here, is that it is the zinc that is essential with the HCQ being necessary to facilitate the entry of the zinc into cells containing the virus and in which the zinc proves toxic to the virus”. No such papers are cited, and the assertion ignores the article’s paragraph about biological plausibility and intra-cellular vs serum concentrations.

    If commenters proposing to disagree with the article seek any credibility, comments addressing the points (and evidence) in the article, written without the cloak of anonymity, and citing valid sources for the assertions made would be a good start. Medical policy needs to be based on an accumulation of valid evidence, not social media wars.

  8. Anon says:

    This appears a biased assessment against HCQ. There is more than enough data in the peer reviewed journals to suggest combinations of hcq with zinc and other drugs including azithro and doxy works As occupiers of authoritarian positions we have to understand what we publish gets Read and can be criticised for not being up to standard. As humans and as professionals we cannot allow personal bias to reflect in our disseminations.

  9. Anonymous says:

    This revioew seemingly ignores studies that include zinc with (or maybe without) azithramycin or doxycyclin. The proposition, apparently supported by studies not mentioned here, is that it is the zinc that is essential with the HCQ being necessary to facilitate the entry of the zinc into cells containing the virus and in which the zinc proves toxic to the virus…. when the combination is given in early, positive, non-hospital cases. At least that is the suggestion. It would be helpful for this review to have included an analysis of the studies of the use of HCQ with zinc +/- azithramycin/doxycyclin in such early cases.

  10. M Robertson says:

    HCQ combo works extremely well. Hundreds if not thousands of USA patients been treated & no side effects.
    Ohio Gov lifted restrictions off use of combo so more can be treated.
    African countries using combo have decreased mortality by 79%
    75 articles (41 peer reviews) out there on how well combo works.
    Increasingly calls to stop politicization of this drug & combo.
    Class actions being formulated from USA (& possibly into Oz) regarding the negativity against this combo when it works so well.
    WHO trial was flawed from beginning. Lancet realized their printed study was also flawed

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