-By Dr. Shruti Maroo Rathi
(Article Last Updated on 7th June, 2020)
1. What is hydroxychloroquine ?
2. How corona virus attacks cell and what is the proposed mechanism of action of hydroxychloroquine?
3. What is the recommended Prophylactic dose?
5. Side effects?
4. Is it safe to take hydroxychloroquine for prophylaxis against COVID-19? What are the latest guidelines by various research bodies around the world
What is hydroxychloroquine?
Hydroxychloroquine is an antimalarial which is also used in the treatment of lupus and rheumatoid arthritis. In last 2 months it has gained an outsized stature for treating COVID-19 due to some early reports from Chinese researchers  who showed the efficacy of chloroquine in treating COVID-19 in humans. Another small non-randomized trial in France  also found similar promising results. These findings prompted many, including US President Donald Trump, to tout hydroxychloroquine as a gamechanger in the fight against COVID-19. The US Food and Drug Administration has also designated hydroxychloroquine for off-label, compassionate use for treating COVID-19, and WHO had added the drug to its large global SOLIDARITY trial to test a variety of potential treatments.
However, on May 22, the Lancet published the largest study to date about treating coronavirus patients with hydroxychloroquine and chloroquine. Researchers in that study concluded that patients who were treated with an antimalarial were more likely to develop a heart arrhythmia, which can lead to cardiac death. Consequently, on 25th May WHO temporarily suspended the hydroxychloroquine arm within the Solidarity Trial to review the safety data by the Data Safety Monitoring Board
Before going into details of whether it is safe to take or not, let’s have a look at its mechanism of action.
How Corono virus enters the host cell and what is the proposed mechanism of action of hydroxychloroquine?
Corona virus attacks Type 2 pnueomocytes which are responsible for production of surfactant. It enters the cell by binding to the surface receptor (ACE-2) via its spike protein. ACE2 receptos is also abundantly expressed in the epithelial cells of the oral mucosa, with higher expression in the tongue, in comparison to the buccal and gingival tissues. These findings suggest that the oral cavity has high susceptibility to COVID-19 infection.
As it enters the cell, it is endocytosed forming an endosome. Lysosomes fuse with endosome forming endo-lyosome releasing lyosomal proteases which activates the spikes of corona virus. This causes release of ss- RNA of virus inside the cell that goes and fuses with the nuclear genome of the host cell, multiplies and are then released from the cell.
ACE2 receptos are also abundantly expressed in the epithelial cells of the oral mucosa, with higher expression in the tongue, in comparison to the buccal and gingival tissues. These findings suggest that the oral cavity has high susceptibility to COVID-19 infection.
Proposed Mechanism of Action against Corona Virus:
1. Hydroxychloroquine, or chloroquine, prevents binding of spike protein on ACE-2 Inhibitor.
2.It also inactivates lysosomal proteases by increasing the pH.
3.Increases the influx of Zn ions in host cell inactivating RNA – dependent RNA polymerase and prevents viral RNA from being formed. The mechanism of action is extended to Azithromycin as a drug delivery vector that helps in binding of hydroxychloroquine to RNA necleotides and results in inhibition of the replication of the corona virus 
Therefore, hydroxychloroquine could theoretically be used not only as treatment, but as prevention also.
What is the recommended dose for prophylactic use of hydroxychloroquine ?
400 mg twice a day on day 1, followed by 400 mg once weekly for 7 weeks, to be taken with meals . The drug is contraindicated in persons with known case of retinopathy, hypersensitivity to hydroxychloroquine and cardiac rhythm disorders and is not recommended for prophylaxis in children under 15 years of age and in pregnancy and lactation, the advisory said.
What are the side effects of the drug?
Nausea, vomiting, diarrhea, and abdominal pain, mood changes (such as anxiety, depression, hallucinations), auditory changes (such as ringing in the ears, hearing loss), easy bruising/bleeding, signs of liver disease (such as severe stomach/abdominal pain, yellowing eyes/skin, dark urine), muscle weakness, unwanted/uncontrolled movements (including tongue/face twitching), hair loss, hair/skin color changes, low blood sugar level, irregular heart rhythm, etc. A study conducted in 2015 also highlighted that toxicity due to this drug is not as rare as once believed, but depends critically on daily dosage and duration of use, as well as other risk factors. 
Now the question arises …Is it Safe to Take? Latest Guidelines by Various Authorities
On May 22, the Lancet published a study based on the data procured from Surgisphere (a data analytics company) and concluded that COVID-19 patients taking chloroquine or hydroxychloroquine were more likely to show an irregular heart rhythm 
Reason Cited: Increase in QT interval (defined as the time taken for ventricular depolarization and repolarization) by blocking hERG potassium channel. 
Based on this WHO had, temporarily, suspended the hydroxychloroquine arm within the Solidarity Trial to review the safety data by the Data Safety Monitoring Board (25th May).
But soon the Lancet study came under withering online scrutiny from researchers all over the world as the huge number of patients and details about their demographics and dosing seemed implausible. This led authors to retract the study as they could not provide the data for an independent third party review. Therefore, WHO resumed the trial on hydroxychloroquine on June 3.
Meanwhile, India’s apex medical research agency, the Indian Council of Medical Research (ICMR), has been recommending the prophylactic use of hydroxychloroquine not only for healthcare workers involved in taking care of COVID-19 patients but also for asymptomatic healthcare workers working in non-COVID-19 hospitals, front line staff on surveillance duty in containment zones, paramilitary/police personnel involved in corona virus infection related activities and household contacts of COVID-19 patients (March 23). Even after the WHO halted the trail, ICMR, continued to advocate prohpylactic use of hydroxychloroquine based on studies conducted in India and also recommends that at-least one ECG should be done during the treatment. (26th May) ICMR also published a case control study on 31 May, 2020 to compare the risks of and protective factors against SARS-CoV-2 infection among health care workers in India. This study concluded that consumption of four or more maintenance doses of hydroxychloroquine was associated with a significant decline in the odds of getting infected. 
However, a recent Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19, published on June 3 in NEJM showed that here is not much benefit in “post-exposure prophylaxis”. At the same time, hydroxychlorouine showed only minor Gastro-Intestinal disturbance as side effects.  This as well as recent deaths of a 36-year-old dentist and a 44-year-old anesthesiologist , both allegedly taking hydroxychloroquine, have raised questions about the benefits of using hydroxychloroquine as an off-label drug for prophylaxis of COVID-19. FDA also has issued a caution against its widespread use in the past ,. The evidence in the favor of prophylactic use of hydroxychloroquine is still scant.
The intake of the medicine should not instill a sense of false security among doctors. We should, diligently, follow the recommended infection control practices to prevent transmission of infection. There is so much research going on and articles coming out every day providing new and often valuable information about this virus making it necessary for us to stay updated on the changing guidelines.
At Wikidentz, we take constant efforts in providing the latest information on COVID-19 & Dentistry. We would be regularly updating this article and to ensure that it reflects the current situation, any corrections made will also be footnoted.
Last Update made on 7 June, 2020 11:40AM, includes the retraction of lancet study  and new NEJM randomized study showed that here is not much benefit in “post-exposure prophylaxis”
Previous Updates: 1/6/2020;1:45 PM: Included latest ICMR Case Control Study results (Refernce 9)
 Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial [published online ahead of print, 2020 Mar 20]. Int J Antimicrob Agents. 2020;105949. doi:10.1016/j.ijantimicag.2020.105949.
 Vinayachandran D, Saravanakarthikeyan B. Salivary diagnostics in COVID-19: Future research implications [published online ahead of print, 2020 Apr 23]. J Dent Sci. 2020;10.1016/j.jds.2020.04.006. doi:10.1016/j.jds.2020.04.006
 Costedoat-Chalumeau N, Dunogué B, Leroux G, et al. A Critical Review of the Effects of Hydroxychloroquine and Chloroquine on the Eye. Clin Rev Allergy Immunol. 2015;49(3):317‐326. doi:10.1007/s12016-015-8469-8
 Mehra Madeep, Desai S, Ruschitzka F, Patel A et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. The Lancet. Pulished :May 22, 2020DOI: https://doi.org/10.1016/S0140-6736(20)31180-6
 David R. Boulware. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. NEJM June 3, 2020