Background:
The world is desperate for treatment options to protect people from COVID-19, a novel viral disease caused by SARS-CoV-19 while it mitigates and minimizes societal and economic pain from the disease. Knowledge of the virus and the spectrum of disease it causes is evolving and data is accumulating from around the world as different countries take different paths in managing the disease, public health measures, and economic impact. As time passes, we will have data on the effects of the various intervention methods. Meanwhile, individuals, health care professionals and leaders, states, and countries are struggling with balancing the micro- and macro effects on individuals, businesses, hospitals, states, etc.
Unfortunately, politics has intruded on science, particularly pertaining to the role of hydroxychloroquine. The goal of this article is to present the state of knowledge at this point in time (August 8, 2020) and to present it without a specific agenda other than explaining the potential role of the drug in treating COVID-19.
The author feels this review is necessary given what she perceives to be a lack of scientific understanding of the role of the drug in ongoing local and national conversations, even among healthcare professionals.
Why was hydroxychloroquine selected as a possible drug for repurposing for COVID-19?
As scientists looked at repurposing existing medications for possible management of COVID-19, one of the medications that was considered was hydroxychloroquine (a safer version of the anti-malarial drug chloroquine). This medication had a documented scientific basis as an anti-viral agent that may work against the novel coronavirus – it has been shown in vitro (in laboratory models) to inhibit viral replication and had been used in the treatment of the original SARS cases. It has also been widely used for treatment of malaria (short-term) and autoimmune conditions (long-term) such as rheumatoid arthritis and lupus and the medical community was well versed in monitoring for the therapeutic benefits and side effects of the drug. There was a potential benefit that its immunomodulatory action may also decrease the “cytokine storm” that leads to respiratory failure in more severe cases of COVID-19.
Importantly, the drug was also widely available in generic form and would be affordable to deploy in large quantities.
Widespread use of hydroxychloroquine was sparked by a small study published in the International Journal of Antimicrobial Agents by Philippe Gautret which demonstrated that hydroxychloroquine (with and without azithromycin) cleared nasopharyngeal carriage of SARS-CoV-2 at 6 days. Criticism of the study appeared almost immediately for failing to demonstrate appropriate evidence of benefit; the methodological flaws included small sample size, lack of control for biases, very short follow up period and failure to capture a clinical outcome. Most damningly, even the board of the journal in which the study was published later wrote that the “article [did] not meet the Society’s expected standard, especially relating to the lack of better explanations of the inclusion criteria and the triage of patients to ensure patient safety”.
What is the risk/benefit analysis and why is it the foundational principle in deciding whether a drug should be used in an individual case?
A decision to use any medication in any given patient rests on a risk/benefit analysis. Does the likely benefit outweigh the likely risk? This is best demonstrated with two extreme examples.
First, is there ever justification for using a very toxic drug that is likely to cause harm to a patient? Yes, toxic drugs like chemotherapy are used every day for treatment of cancer, but only by doctors and ancillary health professionals trained to monitor and handle the adverse effects. The great potential benefit of survival from a lethal condition like cancer justifies the very high risk of side effects from the medication.
Second, why isn’t it ok to use a relatively benign medication like amoxicillin to treat the common cold? Because even a very small risk of a detrimental effect (allergic reaction, diarrhea, yeast infection) is not justified in light of the fact that an antibiotic has zero benefit in treatment of a viral infection.
Important consideration in this analysis is proper patient selection and monitoring, which includes age, organ function, vulnerabilities to side effects and drug-drug interactions, and others. In the case of hydroxychloroquine, it is important to assess the patient risk for cardiovascular side effects.
What are the potential uses of hydroxychloroquine and have they borne out to date?
Pre-exposure prophylaxis
Hypothesis: Presence of a drug in the body will prevent the virus from infecting the cells. This may require lower doses to achieve compared to treatment doses and would thus cause fewer side effects.
Studies:
None to date, but several are underway.
Post-exposure prophylaxis
Hypothesis: Administering the medication in people with high risk exposure to SARS-CoV-19 may lower the risk of developing COVID-19.
Studies:
A recent study published in NEJM did not find benefit for hydroxychloroquine use within 4 days after high-risk or moderate-risk exposure to COVID-19. https://pubmed.ncbi.nlm.nih.gov/32492293/
A July 26th pre-print of a Spanish cluster-randomized trial of around 2,300 patients treated with hydroxychloroquine as prevention of Covid-19 transmission and disease failed to demonstrate benefit. https://www.medrxiv.org/content/10.1101/2020.07.20.20157651v1
Treatment
Hypothesis: Antiviral effects of hydroxychloroquine may decrease viral replication and the immunomodulatory effects may lower severity of COVID-19.
Studies:
Multiple high-quality studies have failed to demonstrate the clinical benefit of hydroxychloroquine. Specific examples:
Hydroxychloroquine with or without azithromycin in mild-to-mild hospitalized COVID-19 cases failed to improve clinical status at 15 days as compared to standard care. https://www.nejm.org/doi/full/10.1056/NEJMoa2019014
Early hydroxychloroquine use (within the first 4 days of symptom onset) in non-hospitalized adults did not demonstrate benefit in symptoms after 14 days compared to placebo. https://www.acpjournals.org/doi/10.7326/M20-4207
The University of Oxford RECOVERY trial of hydroxychloroquine use in hospitalized patients was halted when no benefit on mortality rates after 28 days was noted in the intervention group compared to standard care.
Two additional large studies using the same proprietary Surgisphere database were published in renowned medical journals and were later retracted after the owner of the data refused to release the entire set for analysis and peer review.
Is it OK for government agencies to curtail the right of physicians to use commercially available drugs in the manner they chose?
The FDA regulates drugs, not prescribing. The approval process involves precise dosing and monitoring protocols for very specific indications and very specific patient populations in the moment in time when the drug is approved based on studies of efficacy and safety submitted to the FDA. However, the state of medicine develops outside of this narrow FDA approval process and the drugs are used for “off label” purposes and in “unapproved” patient populations, dosing protocols, or other medical conditions. It is uncommon for manufacturers to go back to the FDA to add these new uses to the “product label” since it is a very expensive and time-consuming process. The evolving state of medical practice, instead, is managed through studies that are published in peer-reviewed journals. Potential new uses of drugs are identified through case studies, hypotheses are developed and are then tested in studies (gold standard of which is the randomized controlled trial) under the strict supervision of Investigational Review Boards that serve to protect the rights of human subjects.
It is the responsibility of the individual physician to practice within the scope of their license and training (i.e. their specialty) and to be well informed and base their treatment choices on firm scientific rationale, sound medical evidence, and also to maintain records on product use and effects. Pharmacists have a corresponding responsibility to ensure that every prescription that they fill and dispense to a patient has conformed to the above standard. Individual practitioners that fail to do so are subject to legal and professional sanctions.
Government public health agencies must ensure that the delicate balance is maintained between regulatory objectives of protecting the patient from unsafe or ineffective drugs and allowing the physicians to use their professional judgement to treat their own patients. Occasionally, they step in to curtail the prescribing privileges of medical practitioners when there is an imperative public health concern.
When does this professional prerogative cross the line from appropriate care into unsafe and unethical territory? The deceptively simple answer is: when standard care within appropriate scope of practice moves into territory of “patient experimentation”. But this moment is difficult to judge and given the bias of the Dunning-Kruger effect, likely impossible to self-identify. That is why professional oversight is essential, particularly in fast evolving conditions like the COVID-19. The medical establishment and regulatory agencies have a duty to protect the public.
Are other treatment modalities available for treatment of COVID-19?
We already know that several treatment modalities have been shown to be beneficial for management of COVID-19, though most of them are only applied in more severe cases in hospitalized patients: remdesivir, dexamethasone, toclizumab, positioning and proning, convalescent plasma, anti-coagulants, statins, and others. Our healthcare practitioners are gaining experience in treating patients with COVID-19 to improve survival, but a lot remains to be learned about the long-term consequences of the disease.
The efforts of clinicians and researchers should be centered around therapies with the greatest promise and should not continue to be mired in treatment modalities that have failed to achieve their early promise.
Final thoughts on the future:
SARS-CoV-2 is likely to be around for good and when herd immunity is achieved (through some combination of natural infection and vaccination efforts) and therapeutic protocols are developed for prophylaxis and/or treatment of the full spectrum of disease presentation, we will be able to go back to “normal”. Luckily, the best minds around the world are working on achieving this goal. Until then, we have to trust and listen to medical and public health experts and understand that their scientific training and rigor keeps them focused on health (and not the politics of the day).