The entire world, since the end of 2019, has been facing one of the longest-running pandemics caused by the SARS-CoV-2 virus. Originated from South East Asian countries, it spread across the rest of the world in no time. Symptoms of the Covid virus start with flu-like symptoms and progress to severe conditions such as pneumonia, prophylactic shock and multiple organ failure. Until today, approx 5 billion people have been hit by the pandemic, with 2 million mortality cases.
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The tiles above show the situation in Australia from 2020 to the total number of cases currently in one day. Treatment options and even vaccines have been introduced. But there are a few downsides to vaccines that put a damp on their popularity.
What are the downsides to Covid vaccines?
– They are eliminated quickly
– Side effects show up within weeks of vaccine administration
– The unavailability of the vaccines because of their high demand
In short, other options have to be considered and weighed on as alternate treatment regimens in case of unavailability or adverse reactions with vaccine intake- Hydroxychloroquine is one of such options.
A word about Hydroxychloroquine
Hydroxychloroquine dispensed under the brand name Plaquenil is primarily an antimalarial drug by nature. It works on the growth and replication of the malarial parasite to prevent the spread of and work on the treatment of symptoms caused by the malarial parasite. Apart from malaria, it is a DMARD by nature. The activation of Toll-like receptors that play a role in immune response and autoimmune disease is suppressed by Hydroxychloroquine for the treatment of autoimmune disorders like arthritis and lupus erythematosus. Hydroxychloroquine is FDA approved for all of the above mentioned treatment measures and even listed by WHO as an Essential Medication.
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There have been a lot of speculations and trials of Hydroxychloroquine regarding its possible role in the treatment of the Covid virus. To understand the effectiveness of Hydroxychloroquine on Covid, it is first imperative to have an idea of how Covid enters and affects our system.
Mechanism of Covid infection
Sars Covid 2 is regarded as the 7th member of the Covid family affecting humans. While NL63-Cov, HKU1- Cov and 229E-COv are among the less serious ones resulting in common flu symptoms, SARS- Cov, MERS-COV and SARS- Cov is strained that invade in a deeper manner and cause intensive damage to the system.
The human body contains ACE-2 receptors scattered throughout the heart, lungs, connective tissue and gastrointestinal tract of the body. To enter the human body, the virus binds to the ACE-2 receptors through a membrane fusion mechanism. Studies have shown that the binding capacity of Sars-Covid 2 is 10-20 fold higher than the SARS Covid virus. Once the virus gets inside pf your body, it starts replicating at a 100 fold rate and spreading to other parts of the body.
Its invasion of the lower respiratory tract results in irritation and dry cough. If left untreated, it passes further into the lungs and starts causing inflammatory reactions like pneumonia and SARD (Severe Acute Respiratory Distress). The lung’s unable to absorb oxygen properly leads to breathing difficulties and other complications. In people with other systemic conditions, the virus at times creates a cytokinetic storm (overactive immune system harming the body in the process of fighting the virus), resulting in multiple organ failures and finally death.
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How does Hydroxychloroquine work on the Covid virus?
Researchers have postulated a number of ways through which Hydroxychloroquine can work against the Covid virus. Some of them are
1) Inhibition of blockage of Sialic Acid Receptors
2) Inhibition through restriction of pH mediated S protein cleavage at the ACE 2 binding site
3) Inhibition through prevention of Cytokine storm
Let’s understand them one by one.
Inhibition of blockage of Sialic Acid Receptors
The S protein is the main antigen component in structural proteins of SARS Covid 2 that plays an important role in virus attachment, fusion and entry into the host cells. The surface location of the S protein also makes it a direct target for host-mediated immune response as well as a target for vaccine and antiviral therapies. Researchers have postulated that the N terminal of these S proteins is similar to Sialic Acid binding in MERS-Covid, and there is a chance SARS COVID virus enters the human body through Sialic Acid Receptors present in the upper respiratory tract. Hydroxychloroquine inhibits this entry of the virus through blockage of the Sialic Receptors and prevents the risk of inflammation to a great extent.
Inhibition through restriction of pH mediated S Protein Cleavage at ACE-2 binding site.
Studies have found that the above mentioned S protein of the virus has two subunits, S1 and S2. The S1 subunit facilitates the entry of the virus into the host cells through the ACE 2 receptor. Following the entry, the TMPRSS2 enzymes in the human body help in S priming and cleavage of the S1 and S2 units for the better fusion of the virus with the ACE-2 cells. This leads to them getting glycolysis and speaking the immunity of the human body. Hydroxychloroquine prevents this glycosylation from occurring, which in turn strengthens the ACE-2 receptors and prevents the intensity of virus attack.
Inhibition through prevention of Cytokine storm
Cytokines are small glycoproteins produced by human cells that play an important role in regulating the immune and inflammatory responses in the human body. Excessive production of these inflammatory cytokines during Covid virus invasion in the human body results in ARDS ( Acute Respiratory Distress Syndrome) and widespread tissue damage, which culminates in multiple organ failures and death. HCQ works on the T cells of the body responsible for Cytokine production and wards off the possibility of Cytokine storm.
In short, it is postulated to prevent the entry of the virus, spreading of the virus and works on minimising/ repairing the damage caused by the virus on the human body.
What do clinical trials say?
In a study conducted to evaluate the efficacy of Hydroxychloroquine as a postexposure prophylactic measure for Covid, adults with household or occupational exposure to Covid positive patients were enrolled. People with less than 6 feet of exposure to Covid positive patients for more than 10 minutes without any protective measures (mask, facial shield) were preferred as subjects. Within four days of exposure, these participants were randomly assigned a placebo or Hydroxychloroquine. Out of the 821 asymptomatic participants, 87.6% reported high-risk exposure to Covid -19 contact that did not differ significantly between participants receiving Hydroxychloroquine or Placebo. Side effects were more common with Hydroxychloroquine than with placebo, but no serious adverse reactions were observed.
The study proved that post-high-risk or moderate risk exposure to Covid-19, Hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as post-exposure prophylaxis within four days after exposure.
In another study conducted to compare the efficiency of Hydroxychloroquine against Lopinavir-Ritonavir in Covid-19 patients, 685 high-risk Covid positive patients were enrolled in the study. In total, 214 participants were administered Hydroxychloroquine, 244 patients administered Lopinavir-Ritonavir and 227 administered placebo. Neither Hydroxychloroquine nor Lopinavir-Ritonavir showed significant benefit for decreasing Covid-19 associated hospitalisation or secondary clinical outcomes.
Other sides aimed at evaluating the efficacy of Hydroxychloroquine in comparison to placebo did not produce any conclusive results either. All of these findings led the NIH to conclude that Hydroxychloroquine does not provide clinical benefit to Covid positive patients hospitalised due to the infection.
In a State of the art review of Hydroxychloroquine conducted by Italian based researchers, all the literature-based data and published clinical data on the medication and the clinical trials involving it were examined. The search found a substantial amount of preclinical data but a lack of clinical data to back the claims. The study highlighted the need to further access the translational impact of in vitro data in a clinical setting and expostulated that further trials were required in a standard manner to reach a concrete conclusion.
The final say of FDA / WHO on Hydroquinone for use in Covid positive patients
Based on scientific analysis and lack of satisfactory data, the FDA has revoked the emergency use authorisation to use Hydroxychloroquine for Covid 19 hospitalised patients outside of clinical trials. It has further issued reports of complications like heart rhythm problems, kidney injuries and liver problems associated with the use of Hydroxychloroquine outside of its intended destination.
WHO has strongly advised against the use of Hydroxychloroquine for Covid-19 prevention based on current clinical trials evaluation. The most important concern of WHO is regarding the dose of Hydroquinone required for successfully fighting Covid symptoms. As per WHO, it is beyond safety limits and post-use, the complications arising as a result of overdose of the medication risk surpassing its beneficial effect on the virus and mode of action. Subjects are strongly recommended to use the medication only for its approved purpose and abide by their health care providers for medical guidance regarding dealing with Covid symptoms.