Hydroxychloroquine (Plaquenil) & Coronoavirus (COVID-19)
Hydroxychloroquine (Plaquenil) is in clinical trials for the treatment and management of coronavirus (COVID-19). Currently, it is not confirmed to be a cure or effective treatment option. And, the premature announcement is leading to shortages.
Recently, President Donald Trump announced that the important lupus medication hydroxychloroquine (Plaquenil) was a “cure” for Coronavirus Disease 2019 (COVID-19). This has led to increased demand for the drug.
The President's assertion was not confirmed by Dr. Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases and member of the White House Coronavirus Task Force. Dr. Fauci noted that the available data comes primarily from anecdotal reports and that controlled clinical trials are needed to evaluate the medication's effectiveness.
Many experts are calling the rush to use the drugs unwise. “In times of epidemic, you want to prioritize manufacturing things that have been proven to work," said Dr. Vinay Prasad, a hematologist and oncologist at Oregon Health and Science University.
“I have the experience of seeing promising drugs that look really good, that don’t really work," said Dr. Joan Merrill of the Oklahoma Medical Research Foundation. "It might be interacting in ways we aren't familiar with."
Currently unanswered questions for Lupus Warriors
Are people with lupus who are taking hydroxychloroquine more/less likely to contract COVID-19?
Does taking hydroxychloroquine improve your ability to fight off coronavirus?
Will medication prices change dramatically? Will hydroxychloroquine be available?
Mylan has announced that the factory in India will ramp up production of the medication. They are still operating in India as this production is deemed essential. Impacts on pricing and/or availability are unknown.
People with lupus are at a higher risk of COVID-19. It is not known how much more likely immunocompromised individuals are to contract it.
The theory behind using hydroxychloroquine COVID-19?
Hydroxychloroquine is an antimalarial medication that is important to people with rheumatic diseases because it modulates the immune system and prevents flares. However, it does not suppress the immune system completely. So, it does not leave the body vulnerable to infection and disease like other immunosuppressant medications would.
It works by preventing plasmacytoid dendritic cells from activating and producing interferon, a part of the immune system virus response. Interferon, a type of cytokine or cell messenger, is produced by an activated cell and spread to other surrounding cells. These cells then produce a series of enzymes that block protein synthesis and attack any RNA molecules in the cells.
Because viruses (including COVID-19) use RNA as their blueprint and take advantage of the mechanisms of the cell to produce more virus, interferon may help stop infection in its tracks. The virus cannot replicate or spread, and can then be targeted and destroyed by the body.
However, RNA is also the blueprint for protein synthesis in general. The cell needs to produce proteins of its own. If the body is overproducing interferon, it can damage the cells, leaving them less able to function. Because people with lupus have over-active immune systems that attack their own cells, interferon production can lead to flares. Plaquenil turns down this reaction and reduces the symptoms of lupus.
Since interferon is so important for fighting viruses, especially viruses in the coronavirus family which are RNA-based, scientists looked at Plaquenil as a potential treatment
Some initial observations and studies seem to imply that there is an antiviral effect. The mechanism of action is unknown, but modulating the immune response against viruses could prevent an overreaction from the immune system and lower the risks of life-threatening symptoms. It could also allow the body to make a more fine-tuned response against the virus.
According to the CDC, part of the reason why they were looking into the use of the antimalarials hydroxychloroquine and chloroquine for COVID-19 was because they were safe to use in people with liver or kidney dysfunction or suppressed immune systems. Chloroquine is currently being evaluated in the SOLIDARITY Global Trial. Hydroxychloroquine, under the brand name Plaquenil, is more available in the US than chloroquine. Because of this, it is being researched separately.
Both are still currently under investigation, and the results of the study were inconclusive.
Evaluating the efficacy in clinical studies
The most discussed study to date was performed in France. The study was:
non-blinded (also known as open-label)
Clinicians and participants knew what treatment arm they were in.
non-randomized
Patients were asked if they wanted to have the treatment. If they refused, they were put into the "negative control" group with other people who were not offered the treatment.
36 patients with a confirmed COVID-19 diagnosis participated. Participants received 600mg of hydroxychloroquine daily. Azithromycin, an antibiotic, was added to the treatment for several patients. This is used to prevent severe respiratory tract infections such as pneumonia. It prevents the weakened lungs of people with COVID-19 from being infected and helps them conserve their strength to fight off the disease.
All participants were tested daily in a hospital setting for "virus load" (the amount of virus present in their upper respiratory tract). Virus load was measured using real-time reverse transcription PCR. This testing method looks for the "RNA blueprint" of the virus.
Real-time reverse transcription PCR is the current reliable test for COVID-19. But, in an article in Nature, researchers note that the test's accuracy can vary. Results can change based on the:
location that the sample was taken from
timing of the test
lab technician variability
possible false-positive from other coronaviruses (including the common cold)
Results of the French study
The endpoint of the study was presence/absence of the virus 6 days after participants were included. Of the 36 treated, 20 people showed "significant reduction of the viral carriage... compared to controls, and a much lower average carrying duration."
Other research
Additionally, Chinese researchers reported treating over 100 coronavirus patients with chloroquine, and praised its effectiveness. However, the data supporting this claim have not been published. There have been over 20 COVID-19 trials in China using chloroquine and hydroxychloroquine, but those results have also been difficult to find. “WHO is engaging with Chinese colleagues at the mission in Geneva and have received assurances of improved collaboration; however, no data has been shared regarding the chloroquine studies.”
"In guidance published on Friday, the U.S. Society of Critical Care Medicine said 'there is insufficient evidence to issue a recommendation on the use of chloroquine or hydroxychloroquine in critically ill adults with COVID-19.'"
Kaletra, a combination of chloroquine and AbbVie's HIV drug, and an influenza medication called Arbidol are also top candidates to be repurposed for COVID-19 treatment. However, even with the backing of top officials the drugs have all had disappointing results in two Chinese clinical trials of mild COVID-19 patients. Kaletra has had more than one trial disappointment, as physicians in Wuhan, China, recently tested the drug and found no additional benefits over standard medical care in severe COVID-19 cases.
What do these outcomes mean?
Setting aside the concerns about the methodologies used in these studies, these results are a step towards identifying possible treatments. The research community works in concert to test and further hypotheses while identifying issues in studies. Pandemics and major health crises, like Ebola, have provided opportunities for alternative study designs that ensure at-risk patients have access to potential treatments.
The results do not offer insight into changes in symptoms or survivability. “Viral load,” a measure of how much virus could be detected in the nasal region of the body, was used in the French study.
While the World Health Organization (the WHO) a major player in the response to the pandemic, considers this a good enough result to explore the possibilities in further research, it does not recommend it as a treatment for people with COVID-19. Plaquenil is also not approved by the FDA for treatment of this virus.
Hydroxychloroquine is also not without risks and side effects, including increased risk of heart disease, stomach pain, and headache.
Other potential COVID-19 treatments
Remdesivir is an antiviral currently under trial for treating the virus itself. It mimics adenosine, an essential component of RNA, and makes itself available to be used by the virus when it builds more blueprints of itself. However, it is a trap. It either prevents the construction of the blueprints from continuing or makes the virus' proofreading mechanism less effective, causing the virus to experience fatal "bugs" in its programming. It may act through both mechanisms and, in either case, Remdesivir makes the viruses less effective at producing more virus and spreading to other cells, hindering the course of disease.
Remdesivir is still in the trial phase.