The Chloroquine controversy

This is an excerpt from our online coronavirus portal (click here for the hub)

As a reminder of how complex anti-viral development can be, consider this: from 1963 to 2016, of the thousands of anti-viral inhibitors proposed in scientific literature, only 90 were approved for final use. Another reminder: numerous therapies were tested against Ebola, including chloroquine, favipiravir, brincidofovir, monoclonal antibodies, antisense RNA and convalescent plasma. Ultimately, none proved to be effective or safe as proven via randomized clinical trial.

Gilead’s Remdesivir and Bayer AG’s Chloroquine have reportedly shown promise in field tests to treat patients that have already contracted COVID-19, but there are some very important caveats to be aware of. Remdesivir and Chloroquine (a widely-used anti-malarial and autoimmune drug) reduced viral loads in cell cultures with low levels of toxicity to the cell. That’s what is shown in the next chart; but remember, these are cell cultures and not live trials, there are no successful vaccines against any of the coronaviruses, and there are numerous drugs that were promising in vitro for other infectious diseases and which failed in clinical studies.

The controversy on Chloroquine deepened with wiespread media reports of positive results from a March study from France that combined chloroquine and azithromycin (“Z-pack”). The next chart made the rounds on the internet very quickly. However, it is now clear that this French study: was a non-randomized trial with only 36 patients, and had no discussion of outcomes; excluded 6 recipients that were not discussed, some of whom required ventilation and/or died; started out with higher viral loads in the control group than in the infected patients, which could explain why the control group showed higher infected rates at the conclusion of the study; imputed more than 1/3 of the control group virus tests rather than measuring them; and sourced its treatment group (unlike the control group) from a single medical center.

The Chloroquine outlook was muddied further by the Shanghai Public Health Clinical Center which found no benefits at all from Chloroquine when comparing the control group vs the treatment group.

All of these uncertainties led to strongly worded caveats in a paper published on March 30 in the American College of Physicians “Annals of Internal Medicine”, which concluded as follows on the subject of hydroxychloroquine (HCQ):

“There is enough rationale to justify the continued investigation of the efficacy and safety of HCQ in hospitalized COVID-19 patients. It is critical to reiterate that while viral clearance is important, clinical outcomes are much more relevant to patients. There currently are no data to recommend the use of HCQ as a prophylactic for COVID-19, although we eagerly await data from trials underway. Thus, we discourage its off-label use until justified and supply is bolstered. The HCQ shortage will not only limit availability to COVID-19 infected patients if efficacy is truly established, but also represents a real risk to patients with rheumatic diseases who depend on HCQ for their survival"....Alfred Kim (Washington University School of Medicine) and Jeffrey Sparks (Harvard Medical School) in “Rush to Judgment”

All things considered, we should probably all stop flocking to front-line studies of 20-50 patients. Single-group studies without concurrent controls are very unlikely to lead to any definitive conclusions on efficacy or safety; the results from randomized clinical trials are the only viable path to an anti-viral solution.

Note: how might drugs like Chloroloquine work, if it did?

Drugs like Chloroquine may function as an anti-viral medication (which interrupts various steps of the viral lifecycle inside cells), and/or as an immunomodulator. The latter might be very important, since many people that are dying from COVID-19 are suffering from sudden multiple organ failure. Doctors don’t know yet if that’s because of the viral infection itself, or because of immune system damage (via "cytokine storm syndrome"). Some doctors believe that this syndrome is increasing the risk of death above and beyond what would be expected from the viral infection itself. That's why some of the drugs being tested are used for auto immune disorders in order to prevent the cascade of inflammatory damage that accompany them. As a result, it’s possible that some drugs could both inhibit the replication of the virus, and prevent further immune system damage which causes organ failure; only randomized clinical trials will prove either assertion.

Sources

“Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro”, Nature Magazine, Zhihong Hu et al, February 4, 2020

”Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial”, Gautret et al, International Journal of Antimicrobial Agents, March 2020

“A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19”, Chen Jun et al, Shanghai Public Health Clinical Center/Fudan University, March 2020

“A rush to judgment? Rapid reporting and dissemination of results and its consequences regarding the use of hydroxychloroquine for COVID-19”, Alfred Kim (Washington University School of Medicine in St Louis) and Jeff Sparks (Harvard Medical School) in the American College of Physicians’ “Annals of Internal Medicine”, March 30 2020

“Treating COVID-19: Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics”, Andre Kalil, University of Nebraska Medical Center, March 24, 2020

For disclaimer information, click here