Because of intense interest in finding immediate therapeutics for the COVID-19 illness, a number of small trials have been quickly initiated around the globe to determine whether chloroquine (CQ) and hydroxychloroquine (HCQ, sold under the brand name Plaquenil [Novartis], among others) can be of value in minimizing the effects of this rampant disease. These antiviral drugs are primarily used to treat malaria but are also used for systemic lupus erythematosus (SLE) and other rheumatoid diseases. Although the FDA has now approved the antivirals for emergency use, and Novartis has donated 30 million doses of hydroxychloroquine, questions have been raised by ophthalmologists as to possible retinal toxicity associated with these drugs.

As Michael F. Marmor, MD, of the Byers Eye Institute, Stanford University, pointed out in an article published in Science Direct, CQ and HCQ are familiar to ophthalmologists because of retinal toxicity after long-term usage for SLE and rheumatoid diseases. Dr. Marmor noted that even very high CQ/HCQ doses do not cause retinal toxicity if they are used for a short period of time. Although the doses reported to have been used in Chinese COVID-19 cases are extremely high, the drug is used for a very brief period of time. He also reports “that some rheumatologists had been giving 1200 mg/day for 6 weeks as a loading dose when starting HCQ for SLE, and no visual loss was seen, although detailed ophthalmologic exams were not performed.^1,2 Similar outcomes were seen in trials for myeloma^3,4 and small-cell lung cancer.⁵

“Evidence to date indicates that extreme doses do accelerate retinal toxicity, but with a probable time course of many months rather than days,” Dr. Marmor asserts.

Dr. Marmor also cited a recent small French trial of 22 COVID-19 positive patients using 600 mg/day of HCQ for 10 days to reduce the viral load.⁶ “The number of polymerase chain reaction (PCR)-positive cases fell nearly 50% relative to controls, and it dropped to nearly zero if azithromycin was added. This dose is only about 2 times AAO recommended levels on average and should have no risk of retinopathy in this time frame,” he wrote.

Dr. Marmor concluded that ophthalmic screening is not necessary for COVID-19 patients who take CQ or HCQ for less than 2 weeks as antiviral therapy, because the likelihood of retinal damage is exceedingly low even with high doses.

References

1. Furst DE, Lindsley H, Baethge B, et al. Dose-loading with hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: a randomized, double-blind six-week trial with eighteen-week extension. Arthritis Rheum. 1999;42(2):357-365.
2. Munster T, Gibbs JP, Shen D, et al. Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis. Arthritis Rheum. 2002;46(6):1460-1469.
3. Vogl DT, Stadtmauer EA, Tan KS, et al. Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy. 2014;10(8):1380-1390.
4. Rangwala R, Chang YC, Hu J, et al. Combined MTOR and autophagy Inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy. 2014;10(8):1391-1402.
5. Leung LS, Neal JW, Wakelee HA, Sequist LV, Marmor MF. Rapid onset of retinal toxicity from high-dose hydroxychloroquine given for cancer therapy. Am J Ophthalmol. 2015;160(4):799-805.
6. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of anopen-label non-randomized clinical trial. Int J Antimicrob Agents. 2020. [Epub ahead of print]

Editor's note: For the latest American Academy of Ophthalmology recommendations to ophthalmologists on the novel coronavirus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), please visit aao.org/coronavirus.