This is a scientific review, published to inform health care professionals and public officials, and for an open peer review. It is not medical advice.
Hydroxycholoroquine (HCQ) is effective against COVID-19 in a variety of roles – the main two being antiviral and immunomodulator. This “silver bullet” effect may have caused confusion between different effects. It is better to start HCQ-based treatment as early as possible.
Hydroxycholoroquine (HCQ) has many mechanisms against COVID-19. This diversity of mechanisms may have created confusion, even among medical professionals. Most importantly, HCQ and its combinations are effective antivirals against SARS-CoV-2, the coronavirus causing COVID-19. As all antivirals, HCQ combinations should be taken early, before the virus overwhelms the body. Therefore, and because current COVID-19 tests have a large rate of false negatives, Dr. Zelenko recommends starting an HCQ-based treatment immediately upon suspicion of COVID-19 : “Given the urgency of the situation, I recommend initiating treatment based on clinical suspicion as soon as possible, even without confirmatory testing.”
I can understand the theoretical basis for starting immediately. If common flu is treated with antivirals, the CDC recommends starting within 48 hours of symptoms onset : “treatment is most effective when given as early as possible after symptoms develop, and its effectiveness diminishes markedly after 48 hours.” Those antivirals, like oseltamivir, begin acting immediately upon entering the bloodstream . HCQ, however, is different. It needs to accumulate in the tissues, and that takes time. Thus, there seems to be no 48 hours window. HCQ’s anti-viral effect diminishes with every day that treatment is delayed.
HCQ as anti-viral
The most tested HCQ-based treatment for COVID-19 is HCQ+AZ (Azithromycin). This drug combination treatment is associated with Didier Raoult, head of the Institut Hospitalo-Universitaire Méditerranée Infection (IHU) , . He and his colleagues cited earlier experience of doctors in China.
The two drugs, HCQ+AZ, are considered synergetic in suppressing the SARS-CoV-2 spike — ACE2 interaction, which the coronavirus uses to enter the cell , . These “spikes” make up the crown, or “corona”, which gives this type of virus its name. AZ is also an antibiotic, necessary to protect the body from any opportunistic bacterial infection during treatment.
To suppress the SARS-CoV-2 spike – ACE2 interaction, HCQ must accumulate in the lungs. This process begins when HCQ enters the bloodstream and proceeds slowly from there. This is explained in  (on chloroquine):
Drug disposition proceeds in three phases—distribution from blood to tissues, equilibration between blood and tissues, and release from tissues back into blood. These phases have half-lives of 3–8, 40–216 h, and 30–60 days, respectively
The times vary by tissue.
Zinc (Zn) prevents viruses from multiplying within cells, however, little Zn is found within cells. Zn ions cannot cross cell membranes. HCQ is known as Zn ionophore – it crosses cell membranes and carries Zinc with it . This antiviral mechanism is entirely distinct from HCQ+AZ ability to suppress the SARS-CoV-2 spike – ACE2 interaction.
Unfortunately, HCQ does not shuttle back and forth through cell membranes carrying Zn but tends to enter the cells and stay there. Some level of tissue saturation is needed for HCQ to be effective as an ionophore.
I am not aware of any reported results on HCQ + Zn + (non-AZ antibiotic) treatment for COVID-19. Dr. Vladimir Zelenko and Dr. Anthony Cardillo (Thousand Oaks, CA) give their patients HCQ + Zn + AZ, so it is hard to say whether HCQ + Zn works. Dr. Zelenko has just registered a clinical trial , in which he will compare HCQ + Zn + AZ vs. HCQ + Zn + Doxycycline. Doxycycline is a milder antibiotic with no known activity against the coronavirus.
When used on its own, HCQ does exhibit antiviral effect against COVID-19, but not strong enough .
HCQ as an Immunosuppressant
HCQ is most known as an immunomodulator (mild immunosuppressant). Hence, its use against auto-immune diseases like lupus and rheumatoid arthritis. The main direct cause of death from COVID-19, like many other pulmonary diseases, is a cytokinetic storm and related acute respiratory distress syndrome (ADRS). This is caused by excessive immune reaction to the infection, which leads to multiple organ failure and death. HCQ decreases this excessive reaction and can do so at any time in the development of COVID-19. Apparently, early attempts to use HCQ against COVID-19 were done in the late stages of the disease.
HCQ combinations are being used for COVID-19 treatment all over the world, from India to Czechia, with excellent results. Random population sampling is needed to evaluate the spread of the coronavirus infection and immunity to it.
Chloroquine was noticed for its antiviral and immunomodulatory effects in context of SARS epidemic in 2003 :
Chloroquine exerts direct antiviral effects, inhibiting pH-dependent steps of the replication of several viruses including members of the flaviviruses, retroviruses, and coronaviruses.
… chloroquine has immunomodulatory effects … which mediate the inflammatory complications of several viral diseases.
… the tolerability, low cost, and immunomodulatory properties of chloroquine/hydroxychloroquine are associated with biochemical effects that suggest a potential use in viral infections, some of whose symptoms may result from the inflammatory response.
As regards viral diseases, what is clear is that the drug has antiviral and immunomodulatory effects that warrant particular consideration.
|||V. Zelenko, “To all medical professionals around the world,” 2020.|
|||Centers for Disease Control and Prevention (CDC), “What are Flu Antiviral Drugs,” 2019.|
|||B. Davies, “Article Navigation Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations,” Journal of Antimicrobial Chemotherapy, 2010.|
|||P. Gautret and D. e. a. Raoult, “Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study,” Travel Medicine and Infectious Disease, 4 April 2020.|
|||G. Hache and D. e. a. Raoult, “Combination of hydroxychloroquine plus azithromycin as potential treatment for COVID 19 patients: pharmacology, safety profile, drug interactions and management of toxicity.,” Mediterranee Infection, 22 April 2020.|
|||G. Sakoulas, “ACE2 Is the SARS-CoV-2 Receptor Required for Cell Entry,” NEJM Journal Watch, 18 March 2020.|
|||D. J. Browning, “Pharmacology of Chloroquine and Hydroxychloroquine,” in Hydroxychloroquine and Chloroquine Retinopathy, Springer, 2014.|
|||J. e. a. Xue, “Chloroquine Is a Zinc Ionophore,” PLOS ONE, 2014.|
|||A. Thakore, “Hydroxychloroquine and Zinc With Either Azithromycin or Doxycycline for Treatment of COVID-19 in Outpatient Setting,” clinicaltrials.gov, 1 May 2020.|
|||C. e. a. A. Devaux, “New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?,” International Journal of Antimicrobial Agents, 12 March 2020.|
|||A. Savarino and et al., “Effects of chloroquine on viral infections: an old drug against today’s diseases,” The Lancet, November 2003.|