The severe and devastating impact of the global Covid-19 pandemic has set off a frenzy of worldwide laboratory and clinical testing. This concerted international effort is aimed at countering the many undesirable effects of the virus, by either reliably protecting against infection, or by effectively treating those infected anyway. While vaccines take time to develop, and new drugs even longer, several established drugs, already in use for other conditions, are now being tested as potential treatments for the new coronavirus. Since we already know a lot about the safety, efficacy, side effects and interactions of such medications, it becomes easier to justify the testing of certain selected drugs in people with Covid-19 infection.
The drugs currently being tested include some that have already been tried out in other viral infections. They include oral medications, such as hydroxychloroquine (HCQ), which may be used by itself or combined with an antibiotic known as azithromycin, and intravenous drugs, such as remdesivir, a “broad-spectrum” anti-viral agent that was used during the previous Ebola virus outbreak. The drugs under study may either prevent entry of the virus into the human host cell, or inhibit continued viral replication or multiplication upon entering the cell. Specifically, HCQ blocks the binding of Covid-19’s “spike protein” to a host human cell surface receptor, known as ACE2, and thereby protect the host cell from becoming infected. HCQ is also believed to have other effects, thereby conferring “broad-spectrum” antiviral activity.
The relentless spread of Covid-19 has created an imperative to act quickly, bypassing existing “gold standard” procedures and protocols for drug testing whenever safely possible. In “wartime” situations, there is often not much time for thoughtful deliberation and protracted decision- making. The first “trials” of penicillin did indeed take place on the battlefields of the Second World War. Similarly, HCQ has been rapidly thrust into the limelight as a possible defence against the latest global enemy. The “off-label” use of HCQ for Covid-19, for which there is no drug licence at present, has been guided by the use of chloroquine during a previous coronavirus outbreak, that of SARS in 2003. Seldom, if ever, has a generic, and already widely used, drug received such repeated and enthusiastic endorsement from the leader of the free world, in the person of President Trump himself.
A paper appeared online, on 20 March 2020, in the International Journal of Antimicrobial Agents, a joint project of the International Society of Antimicrobial Therapy and the Dutch publisher Elsevier. The study, titled “Hydroxychloroquine and azithromycin as a treatment of Covid-19: results of an open-label non-randomised clinical trial”, looked at 36 patients admitted to hospital with Covid-19 infection. All of them were tested daily for six days, using nasopharyngeal swabs, for excreted “viral load”, using the PCR (polymerase chain reaction) technique. Of the six patients who received a combination of HCQ and azithromycin, all tested negative for Covid-19 on Day Six. Fourteen patients received HCQ alone. Six in the HCQ-treated group were lost to followup, six still tested positive after six days, while three were moved to the intensive care unit (one died). Sixteen patients, for the sake of comparison, did not receive either drug.
The paper is the work of a team, at the University of Aix-Marseille in the south of France, that is headed by Professor Didier Raoult, an infectious diseases specialist with a somewhat controversial reputation, extending to severe areas beyond mere matters of infection. Raoult’s paper was soon to be spotted by Dr Mehmet Oz, celebrity doctor and New York City heart surgeon. Oz endorsed the study findings on Fox News and on his own show,. Fox News star presenter Sean Hannity picked up on the story with great vigour. Once it came to President Trump’s attention, there was no looking back. With Trump’s personal recommendation, the drug has rapidly gained cult status, not only among his followers within the US, but right across the globe. There are many reports of stockpiling, leading to shortages for those in continued need of the drug, such as people with malaria as well as those with chronic inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus. India, which is a leading manufacturer and user of the drug, actually banned all export “without any exception” on April 4.
Much has happened in a relatively short time, ever since the first positive reports about HCQ. On 28 March, the US Food and Drug Administration (FDA) issued an Emergency Use Authorisation for HCQ in hospitals, in selected situations. Some US hospitals are engaged in clinical trials of the drug, while others have already incorporated HCQ into treatment protocols for Covid-19. Some people have started buying the drug online, many doctors are prescribing the drug, and many other members of the public are self-medicating, including a couple in Phoenix, Arizona, who ingested a chloroquine phosphate preparation meant for cleaning fish tanks, with predictably disastrous consequences.
The opinions of doctors whose opinions have been sought seem to vary from optimistic, through “guarded” or undecided, to those frankly dismissive of what is perceived to be “anecdotal” evidence. Further studies have been published, and many more are expected as the number of trials continues to steadily increase. The results seem to differ between studies. For example, a study of 30 patients in Shanghai did not demonstrate any benefit from HCQ treatment. On the other hand, on 27 March, the original team from Marseille published a study of a further 80 Covid-19 patients, in whom a combination of HCQ and azithromycin reduced excreted viral load in 93 per cent of patients by Day 8.
Recommendations for HCQ use have yet to become part of mainstream medical practice, despite the original French researchers advocating liberal and widespread use of their “cost-effective therapeutic strategy”. On 7 April, the FDA thus issued a statement reiterating that “There are no drugs or other therapeutics approved by the US Food or Drug Administration to prevent or treat COVID-19”. Furthermore, the editorial board of the International Society of Antimicrobial Therapy, which publishes the journal in which the original report appeared, distanced itself from the report’s conclusions on the grounds of deficient study design.
The controversy over HCQ will undoubtedly be resolved one way or the other. But this will take time. In the meantime, many people will be treated with HCQ, in many countries, irrespective of any benefit or otherwise. It is just as well that the drug’s side effects are mostly only annoying and self-limiting, although HCQ can rarely damage the retina of the eyes, especially when used for longer periods of time and at higher doses. HCQ can also affect the electrical activity of the heart, lengthening the QT interval of the ECG (electrocardiogram), which can lead to life-threatening abnormalities of heart rhythm.
For reasons of safety, any treatment with HCQ should always be prescribed by qualified medical professionals, who are able to adequately supervise treatment as well as recognise and deal with any side effects. There is no denying, however, in the words of Sean Hannity, on 7 April: “The president (Trump) has changed the rules forever on how we will fight pandemics here and worldwide”.
Ashis Banerjee (retired consultant in emergency medicine)