What is Plaquenil (Hydroxychloroquine)?
Hydroxychloroquine (brand name Plaquenil) is a drug developed from Quinine, which is isolated from the bark of Cinchona trees in Peru. Over the years, quinine has been used in folk medicines in the southern states of America. By the 1940s, it was recognized and used by the United States government as an anti-malarial for troops fighting in the Pacific during WW2. At that time, the compound was very toxic. In 1945, it was modified by hydroxylation to be less toxic. We use this form today. The drug is an anti-parasitic and immunosuppressive FDA-approved drug to treat or prevent malaria, lupus, and arthritis.
Several days ago, it was announced by the US President that Hydroxychloroquine has shown promising results in other countries for treating patients affected by COVID-19. More specifically, Chinese researchers have reported that “two drugs, Remdesivir (GS-5734) and Chloroquine (CQ) phosphate, efficiently inhibited SARS-CoV-2 infection in vitro.”
Hydroxychloroquine is thought to have both antiviral and anti-inflammatory properties. High concentrations of cytokines were found in the plasma of very ill patients. Chloroquine is an effective anti-inflammatory agent, which may reduce the cytokine storm thought to be associated with disease severity. Additionally, Chloroquine appears to be the best choice for use due to availability, proven safety record, and low cost.
However, even a proven safety record does not mean that Chloroquine is without risks. As Liu et al. noted in their report, an overdose of CQ can be fatal, as in the recent tragic case of an Arizona couple who attempted to self-medicate with chloroquine phosphate. The woman is in critical condition; her husband has died.
Editor's Note: As of June 15, 2020, the FDA has revoked the Emergency Use Authorization of Plaquenil (hydroxychloroquine) for the treatment of COVID-19. The FDA has determined that despite early indications, the drug is "unlikely to be effective in treating COVID-19" and bears serious ongoing adverse effects, both known and unknown.
Although recent reports have shown it may be an effective treatment for the Novel Coronavirus, no clinical trials have been completed. Trials are now underway in China, the US, UK, and Spain.
How does it work?
Chloroquine and Hydroxychloroquine increase pH within intracellular vacuoles and alter cellular processes. According to Robert I. Fox, MD, PhD, “Protein degradation by acidic hydrolyses in the lysosome, assembly of macromolecules in the endosomes, and post translation modification of proteins in the Golgi apparatus” may all be altered by the drug. It is thought that the anti-rheumatic properties result from their interfering with the “antigen processing” in macrophages and other antigen- presenting cells. Antimalarials decrease the formation of peptide-MHC protein complexes required to CD4+ T cells and down-regulate the immune response.
How should it be dosed?
The mechanism for toxicity is poorly understood, but directly affected by high dose and long duration. Studies show retinal toxicity is not rare among long-term users of the drug. Lower risk was achieved with 5 mg/kg real weight.
A Hydroxychloroquine calculator is available as a resource to check appropriate dosage for the patient’s weight.
Check out this article from ophthalmologist Yuna Rapoport, MD, MPH on the dose-related response and what it means for eyecare practitioners during the Coronavirus pandemic!
What should optometrists consider when encountering patients on Plaquenil (Hydroxychloroquine)?
Patients may present with or without symptoms. Vague symptoms upon presentation may include difficulty with reading, decrease in vision, missing central vision, glare, light flashes, and metamorphopsia. A careful history should be conducted including duration of treatment and dosage.
Hydroxychloroquine’s effects on the eye have long been monitored by optometrists. Ocular toxicity may include keratopathy, ciliary body involvement, lens opacity, and retinopathy. The macula has a bull’s eye appearance.
However, the risk of retinopathy is very low; less than 20 cases have been reported in the literature. Additional risk factors for toxicity may include: daily dosage, cumulative dosage, duration of treatment, coexisting renal or liver disease, patient age, and presence of other retinal disease.
While the exact mechanism for toxicity is unknown, it is thought that perhaps Hydroxychloroquine binding to the melanin in the RPE layer of the retina may prolong the toxic effect. Both inner and outer retina are damaged in prolonged exposure. Clinically, the damage is in photoreceptors and disruption of the RPE. However, doctors should know, “No anatomic features of the retina and RPE are known to correlate specifically with the parafoveal or extramacular patterns of damage” as toxicity develops.” According to the AAO, light absorption or cone metabolism could also play a role.
As of 2016, the American Academy of Ophthalmology recommends a baseline fundus exam upon initiating treatment and 5 years after. Patients on higher doses with risk factors should be screened more often. Visual fields and SD OCT should be performed.
As standard dosage as well as duration of treatment is unknown at this time, it is yet to be determined whether ocular side effects will be seen in COVID-19 treated patients, and if follow-up will be required by optometrists. However, the American Academy of Ophthalmology has stated that "the need for baseline fundus examination and/or imaging is also unknown in cases with high doses over a relatively short duration," and additional testing is likely unnecessary.
Is Plaquenil (Hydroxychloroquine) now approved for the treatment of COVID-19 by the FDA?
As of publication, Hydroxychloroquine has not been approved by the FDA for the treatment of COVID-19. The FDA has clinical trials underway as to its efficacy in the treatment of the virus. FDA Commissioner Stephen Hahn and President Trump said the drug could be used for treatment of patients under “compassionate use,” which means the FDA could authorize doctors to use experimental drugs to treat seriously ill patients only if no other treatment is available. According to Modern Healthcare’s article debunking the President’s claims that Hydroxychloroquine is approved by the FDA for the treatment of Coronavirus, "While there are no FDA-approved therapeutics or drugs to treat, cure or prevent COVID-19, there are several FDA-approved treatments that may help ease the symptoms from a supportive care perspective.”
What other treatments are being considered for the treatment of COVID-19?
Remdesivir is an antiviral treatment given intravenously that has been present for years, but never approved by the FDA. It was previously studied as a possible treatment for Ebola. Lab studies were also performed for its treatment for the viruses behind SARS and MERS with success. Remdesivir interferes with the action of viral RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production.
It is currently in 3 clinical trial studies for COVID-19 and should be completed around May 2020. The handful of patients who have been given the drug through the compassionate use program seemed to get better, raising hope that Remdesivir may be effective. We do not know about its effects on the eye. It is also not expected to be available for a large number of patients.
Azithromycin + Hydroxychloroquine
A French study found that a combination treatment of Azithromycin and Hydroxychloroquine may be effective in treating and reducing the COVID-19 virus. The study was conducted on 30 confirmed COVID-19 patients, treating each with either hydroxychloroquine, a combination of the medicine with the antibiotic, as well as a control group that received neither.
Hydroxychloroquine was found to be effective, but when combined with Azithromycin was even more effective after 5 days of treatment. We currently use both of these medications, and are familiar with their effects on the eye.
Favipiravir is a Japanese antiviral medication for the flu, which has proven effective by the Chinese in treating COVID-19. Patients given the medication had a negative COVID-19 test after 4 days vs 11 days if not treated. It doesn’t seem to be effective if the virus has already multiplied. The medication was supplied as a possible treatment of Ebola in 2016. We do not know about its effects on the eye.
In hospitalized adult patients with severe Covid-19, no benefit was observed with Lopinavir–Ritonavir treatment beyond standard care. Future trials in patients with illness may help to confirm or exclude the possibility of a treatment benefit.
Toclizumab or Actemra is a Rheumatoid Arthritis drug in testing for its efficacy for treating the Pneumonia associated with COVID-19. Actemra is an IL-6 inhibitor. The IL-6 protein triggers the body’s immune and inflammatory response to fight infections. If the immune system overreacts, the drug could keep the body from attacking itself. Reports show some physicians in China have been using Actemra in a number of patients who are showing overactive immune responses to COVID-19.
One study was available showing this medication may cause inflammatory eye disease. Uveitis, Keratitis and Scleritis could be possible side effects of this injection.
ODs: pay attention as the situation changes
As the COVID-19 situation evolves and changes at a rapid rate, our role in the care and management of these patients may change. Eye doctors have years of experience in identifying and managing patients on Plaquenil (Hydroxychloroquine). It is a common and well-known drug by the optometric community, and may be the best treatment for the virus due to its availability, proven safety record, and low cost, but clinical trials are yet to be completed.
CovalentCareers is committed to supporting optometrists and optometry students during the Coronavirus pandemic. For more optometry-specific resources and information, visit our Optometry COVID-19 Resource Center.