Chloroquine and viral infections: what you need to know

Yesterday unknown to most, thehydroxychloroquine (trade name Plaquenil) is today at the heart of a medical, scientific and ethical matter. Due to the progression of the pandemic, these debates which started in France now know various developments abroad, especially in the USA where President Donald Trump and Professor Anthony Fauci, director of the National Institute of Allergies and Infectious Diseases, are openly opposed.

Tout started on February 19, 2020 with a communication of the Department of Pharmacology of the Chinese University of Qingdao mentioning the antiviral activity of chloroquine phosphate vitro. On March XNUMX, a Chinese team from Guandong Province released a second article reporting the results of treating a small cohort of 30 patients with a daily dose of 400 mg hydroxychloroquine for 5 days. The primary endpoint was the negativation of the Covid-19 viral load at the pharyngeal level after 7 days. This study did not mention any significant difference between the treated group and the control group.

While there is currently no consensus data concerning Covid-19, the history of a potential inhibitory activity of chloroquine (and its derivative, hydroxychloroquine) against coronaviruses is not new. It dates back to the SARS-CoV epidemic in the early 2000s. At the time, several teams described its antiviral activity by investigations vitro. Back to molecules that have caused a lot of ink to flow.

What is Chloroquine

Chloroquine is made by chemical synthesis. It is a derivative of quinine, an alkaloid isolated in 1820 by two French pharmacist-chemists, Pierre Joseph Pelletier and Joseph Bienaimé Caventou, from the bark of cinchona, a shrub native to Ecuador and known under the name of "fever tree" by the Indians of the Andean plateaus.

Chloroquine, initially marketed as Nivaquine, was a central drug in the fight against malaria. It was widely used during the three or four decades following the Second World War, but its interest in this indication has now become anecdotal. Indeed, Plasmodium falciparum, the most common (and potentially deadly) species of the malaria-causing parasite has developed resistance to chloroquine on an almost global scale.

Like any drug, however, this therapy is not without risk: a dose of 2 grams of chloroquine is toxic, while 4 grams is a lethal dose. The development of hydroxychloroquine sulphate, better tolerated by the body, constituted an alternative, which remains however subject to medical prescription because of its narrow therapeutic margin. This drug is not used as an antimalarial, but it is widely prescribed in certain autoimmune diseases such as lupus disease and rheumatoid arthritis, due to its anti-inflammatory properties. Usually prescribed doses are 600 mg / day for several months.

How do these substances work?

Chloroquine and hydroxychloroquine have numerous and complex therapeutic effects. Their major action is linked to an inhibition of lysosomal functions. Lysosomes are vesicles found in cells that contain enzymes. Active when the pH is acidic, the latter are capable of digesting most of the components of the cell: proteins, sugars, lipids, nucleic acids, etc.

What are Lysosomes

Chloroquine was shown very early on to have a remarkable affinity for lysosomes. Once concentrated inside, it increases the pH and thus disrupts their enzymatic functions. Scientists have also discovered that chloroquine and hydroxychloroquine stabilize the membranes of endosomes, another kind of vesicle present in the cell and involved in the transit and sorting of molecules.

This property of chloroquine explains its antimalarial effect. In fact, during their life cycle, the parasites responsible for malaria enter the red blood cells from which they cut the hemoglobin to make their own proteins. For this, they use enzymes contained in a digestive vacuole. By accumulating in the latter, chloroquine disrupts enzymatic functioning, just like what happens in lysosomes.

In addition to these effects, chloroquine influences other levels of the body, by inhibiting the functions of innate (monocytes / macrophages) and specific immunity effectors (lymphocyte activation), or by interfering with certain cellular signaling pathways. These properties are the source of its anti-inflammatory effects, which are used to treat autoimmune diseases such as rheumatoid arthritis.

Finally, it has been proven that chloroquine interferes with the DNA double helix. It is therefore a relatively toxic compound, presenting a risk of genotoxicity which is expressed mainly during its use in long-term therapy.

The most common side effects during treatment are gastrointestinal symptoms, such as vomiting and diarrhea. However, other more serious problems, such as damage to the retina (retinopathy) or the heart (cardiomyopathy) can occur with long-term exposure to chloroquine. In addition, as with many drugs with a narrow therapeutic window, it is also imperative to monitor renal function in the elderly to avoid overdoses.

Chloroquine interferes with certain microorganisms

Chloroquine and hydroxychloroquine are therefore potentially capable of interfering with the development of microorganisms which infect cells and divert their lysosomes or their endosomes for their benefit.

The effectiveness of chloroquine has thus been proven in the treatment of Q fever, caused by the highly infectious bacteria Coxiella burnetii, which enters cells and can cause serious heart problems, or the Whipple's disease, due to another intracellular bacteria, which requires lifelong treatment.

When it comes to viruses, things are less clear. In 2005, work carried out on primate cells revealed a activity vitro on the SARS-CoV-1 virus, responsible for the SARS epidemic of 2003. The SARS-CoV-1 responsible for the disease, having disappeared, the researchers continued to test the activity of chloroquine, in particular on MERS-CoV, with encouraging results vitro.

On the other hand, other studies had shown a lack of efficacy in vivo on other viruses, such as chikungunya, the dengueOr influenza.

To infect a cell, viruses first attach themselves to its surface. In the case of enveloped viruses, that is, viruses surrounded by a membrane, such as SARS-CoV-2, the next step is to fuse said membrane with that of the cell. Depending on the virus, this fusion can take place on the cell surface or in endosomes after internalization of the viral particle.

The SARS-CoV or MERS-CoV type coronavirus life cycle. The release of genetic material from the virus depends on the pH of the endosome that contains it (after Wit E et al., (2016) Nature Reviews Microbiology, doi: 10.1038 / nrmicro.2016.81)
Vega Asensio/Wikimedia Commons

In the case of the SARS-CoV-2 coronavirus, chloroquine could inhibit the fusion of the viral membrane with the cell membrane, thus preventing the passage of the virus in the cytoplasmic compartment. Hydroxychloroquine also inhibits the in vitro replication of SARS-CoV-2 in cell cultures.

Covid-19: is hydroxychloroquine effective?

At this stage of knowledge, it should be noted that it is considered that the passage of the first symptoms of the disease to the acute respiratory distress syndrome (ARDS) is very probably due to an uncontrolled release of molecules promoting the infection, which would trigger an "inflammatory storm".

Testing the pharmacological relevance of hydroxychloroquine is therefore not illogical: it could be due to its ability to block the coronavirus and its anti-inflammatory properties. It is in this spirit that, on March 8, 2020, researchers from the Drug Clinical Trial Center in Beijing expressed their interest in the treatment of patients with Covid-19. by hydroxychloroquine rather than chloroquine.

Didier Raoult and his team, at the IHU Méditerranée-infection in Marseille, therefore decided to conduct two preliminary tests. The results of the first of these tests, published on March 20, 2020, would indicate that an eight-day treatment, combining hydroxychloroquine with a macrolide antibiotic, azithromycin, would result in "viral clearance" (the virus is no longer detected in patients or in cell cultures). ). This antibiotic is used because it has been shown that in the case of infection with the influenza A (H1N1) virus, it interferes with the virus internalization process. Other studies mention a antiviral action on viruses belonging to genus Enterovirus.

This work has been the subject of various criticisms and discussions. as to their methodology : small number of patients, non-randomized trial, absence of a control group, etc. In addition, a team from Saint-Louis hospital is failed to reproduce viral clearance results.

It will therefore be necessary to further clinical trials on large cohorts to determine whether the results observed vitro translate well into interesting effects in vivo, and, if so, to assess the risks associated with side effects, determine the optimal dosage, the indications for this potential drug, etc.

Launched on March 22, the Discovery trial plans to include 3 European patients. While hydroxychloroquine was initially excluded, one arm of the trial will now focus on its evaluation, but without combining it with azithromycin. For its part, the Angers University Hospital has launched the Hycovid trial, which aims to test the effectiveness of this molecule on 1300 patients. Finally, WHO is considering holding a placebo-controlled trial to assess the long-term chloroquine prophylaxis. The study would involve 20 healthcare workers, with chloroquine being tested daily with the doses used for rheumatoid arthritis.

Unless there is a huge surprise, it will probably be necessary to wait several more weeks before knowing with certainty whether the results of the first Chinese and French communications, which concerned small numbers of patients, will be confirmed (or not) on larger series.The Conversation

Emmanuel Drouet, Pharmacist, doctor in human virology, Grenoble Alpes University

This article is republished from The Conversation under Creative Commons license. Read theoriginal article.

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