Much hype has been made in the media about the current advances in using hydroxychloroquine to treat the new 2019 coronavirus (COVID-19). The media has exaggerated the amount of information we have on the potential of this medication in treating the virus, disregarding the fact that it has not been FDA approved nor adequately tested in human trials. Even Donald Trump, the president of the United States, has claimed it to be the cure while next to nothing is actually known about the drug in vivo for the treatment of COVID-19. In this article, I will discuss hydroxychloroquine and its antiviral activity in vitro as well as touch on the role of adding azithromycin, another mechanism of treating COVID-19 that is being explored.
Hydroxychloroquine was originally an antimalarial medication but has been shown to have some antiviral mechanisms in vitro. According to Fox (1993), who did an in vitro study on hydroxychloroquine, the drug has the following mechanisms of defeating viruses:
· It increases the pH inside the cell vacuole. This alters protein degradation by acid hydrolases in the lysosome, macromolecule assembly in the endosomes, and posttranslational modification in the Golgi apparatus (Fox, 1993)
· It interferes with antigen processing in macrophages and therefore interferes with antigen presentation to other immune cells (Fox, 1993)
· It inhibits nucleic acid replication, glycosylation of viral proteins, viral assembly, and viral release (Yao et al., 2020)
· It decreases the terminal glycosylation of angiotensin-converting enzyme-2 (ACE-2), therefore cellular interactions between viral cells and human airway cells are less efficient (Kearney, 2020).
Although it appears that, in vitro, hydroxychloroquine could be a likely treatment option for COVID-19, it is more complicated to prove efficacy in vivo. Kayaerts et al. (2020) showed in their study that even in vitro the antiviral effect of hydroxychloroquine were minimal compared to its antiparasitic and anti-inflammatory effects. It is also important to note that the in vitro environment is vastly different to that of the body, which is unpredictable and consists of a variety of metabolic processes that influence the action and efficacy of the drug. Even with all this positive in vitro research, hydroxychloroquine has not been used as an antiviral in vivo. The only property that the drug has shown in vivo, besides its antimalarial properties, is an anti-inflammatory effect in the treatment of Rheumatoid Arthritis (Cai et al., 2020). In these patients, it was shown that hydroxychloroquine decreased cytokine production. This may therefore be useful in preventing the cytokine storm seen in some patients with COVID-19 (Cai et al., 2020).
There has been a single, small and unreliable study done in France on hydroxychloroquine in vivo for the treatment of COVID-19. The study had 16 control patients and 26 treatment patients. From those treatment patients, 6 dropped out of the study, 3 went to intensive care units, 1 left due to nausea, 1 left the hospital and 1 died (Lowe, 2020). Therefore the small sample of 26 patients dropped even further to 20 patients. The sample for the investigation of hydroxychloroquine efficacy alone gets worse, as 6 of these patients were given concurrent azithromycin therefore decreasing the sample for hydroxychloroquine treatment alone to 14 patients (Lowe, 2020). The study results showed that after 6 days, the PCR remained positive for COVID-19 for 89% of the control group and 45% for the treatment group (Lowe, 2020), therefore claiming that there is some efficacy in using hydroxychloroquine. This study cannot, however, be used as a stand-alone study due to its significant limitations, namely, it being an open-label small study with a massive drop out number. It is disheartening that this is the study that Donald Trump’s sweeping statement, about hydroxychloroquine being a successful treatment for COVID-19, was based on.
In addition to the previously mentioned constraints of the French study, it was also a very short-term study and the adverse effects of hydroxychloroquine were not investigated in COVID-19 patients. The adverse effects of this drug on the human body are no secret, and many of the effects can be serious. This is especially true for a person with underlying medical conditions, which makes up most of the serious cases of COVID-19 patients. The common, more benign adverse effects of hydroxychloroquine include:
· Nausea
· Vomiting
· Diarrhoea
· Abdominal discomfort (Kearney, 2020).
The main problem comes in with patients with renal dysfunction, as there will be decreased clearance of the drug and therefore increased bioavailability in the body, leading to toxicity (Kearney, 2020). Hydroxychloroquine has also been shown to cause retinopathy, cardiomyopathy and other cardiovascular effects (Kearney, 2020). The cardiac effect that is of most concern is that of prolonged QT intervals. The reason this is a major concern is that the other drugs that have been used in the attempt to treat COVID-19 have the same adverse effect, thus exponentially increasing the cardiovascular risk in patients (Kearney, 2020). The drugs I am alluding to are lopinavir-ritonavir and azithromycin, both of which also cause significant QT prolongation and are contraindicated with other QT prolongation agents – note how in the French study, azithromycin was given with hydroxychloroquine despite this danger.
This brings me to the next, lesser known, treatment option for COVID-19 – azithromycin. Azithromycin is an antibacterial macrolide that binds to the 50s subunit of the ribosome in the cell (Drugbank, 2020). In doing this, it inhibits RNA translation and thus no protein synthesis can occur (Drugbank, 2020). An in vitro study done by Schögler (2020) showed the antiviral mechanisms of azithromycin. These included:
· Stimulating the host’s antiviral response by induction of airway epithelial cells to increase interferons (IFNs) and IFN-stimulated genes (ISGs), which interfere with viral replication (Schögler, 2020).
· Blocking internalization into host cells during the early phase of infection (Tran et al., 2019)
· Targeting newly budded progeny virus from the host cells and inactivating their endocytic activity (Tran et al., 2019).
Again, although the antiviral research on azithromycin looks promising, it is all only done in vitro and in the case of this drug, there have been no in vivo studies for its antiviral effects at all. It is therefore irresponsible to place such heavy value on it as a treatment for COVID-19.
The in vitro studies on both azithromycin and hydroxychloroquine appear to be promising, however there is not enough information yet on their efficacy in vivo. It is therefore not in the best interest of the public to make false promises about the value and potential of these drugs in vivo for the treatment of COVID-19. There is a significant need for large randomized controlled trials for these treatments in order to gain a more reliable understanding on their safety and their capability in treating the COVID-19 virus.
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