COVID-19 Resource Center
COVID-19 Resource Center
Source/Disclosures
Disclosures: Balevic reports support from the FDA, NIH, the Patient-Centered Outcomes Research Institute, the Rheumatology Research Foundation’s Scientist Development Award, the Thrasher Research Fund and the Childhood Arthritis and Rheumatology Research Alliance/Arthritis Foundation, as well as consulting fees from UCB. Please see the full study for all other authors’ relevant financial disclosures.
June 03, 2020
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Long-term hydroxychloroquine use for rheumatic disease unlikely to prevent COVID-19

Source/Disclosures
Disclosures: Balevic reports support from the FDA, NIH, the Patient-Centered Outcomes Research Institute, the Rheumatology Research Foundation’s Scientist Development Award, the Thrasher Research Fund and the Childhood Arthritis and Rheumatology Research Alliance/Arthritis Foundation, as well as consulting fees from UCB. Please see the full study for all other authors’ relevant financial disclosures.
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The average patient who received hydroxychloroquine for a rheumatic disease was unlikely to achieve the total serum or plasma concentration necessary to inhibit the coronavirus in vitro, particularly at dosages of less than 400 mg per day, according to data published in The Journal of Rheumatology.

“In vitro studies suggest that hydroxychloroquine can inhibit replication of the novel coronavirus SARS-CoV-2,” Stephen J. Balevic, MD, MHS, of the Duke University School of Medicine, told Healio Rheumatology. “However, medications can only be effective if the right amount of the drug reaches the target tissue. Because HCQ accumulates in the body over several months, it is possible that patients taking the drug long-term may obtain higher levels.”

The average patient who received hydroxychloroquine for a rheumatic disease was unlikely to achieve the total serum or plasma concentration necessary to inhibit the coronavirus in vitro, according to data.

He added, “Our study addressed the important and unanswered question: Do patients with rheumatic disease already taking HCQ long-term achieve levels of the medication that have been shown to inhibit SARS-CoV-2 in vitro?”

To analyze exposure among patients treated with long-term hydroxychloroquine for rheumatic diseases, and compare it with target concentrations reportedly associated with antiviral activity against COVID-19, Balevic and colleagues studied serum and plasma from three sources. These included published literature values, frozen serum samples from a pediatric lupus trial, and simulated concentrations using a published pharmacokinetic model during pregnancy.

The researchers collected published data from 90 patients with rheumatic diseases from Japan, for a total of 270 plasma concentrations, who had been enrolled in a clinical trial for hydroxychloroquine, as well as from 276 patients with systematic lupus erythematosus from China. Using the pediatric study, Balevic and colleagues conducted a secondary analysis of frozen serum samples from 131 children in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial. Lastly, from the adult pregnancy study, the researchers extracted the mean hydroxychloroquine concentrations collectively for all doses, and separately for the 400 mg dose, for 45 patients with 135 concentrations.

Data from all the studies showed the average total serum and plasma concentrations for hydroxychloroquine were below the lowest COVID-19 target — 0.48 mg/L. All studies also demonstrated concentrations that were approximately one-tenth of what is necessary for in vitro coronavirus inhibition, assuming the highest antiviral target exposure of 4.1 mg/L.

Further, pharmacokinetic model simulations confirmed that pregnant adults treated with common doses for rheumatic diseases failed to achieve target exposures. However, the models suggested that a dosage of 600 mg once a day during pregnancy would result in the lowest median target exposure for most patients after the first dose, the researchers wrote.

“Our data suggest that patients with rheumatic disease are unable to safely obtain the plasma HCQ levels needed to completely inhibit SARS-CoV-2 based on the in vitro studies, indicating that HCQ is unlikely to be effective in the setting of SARS-CoV-2 viremia,” Balevic said. “While it is possible that patients achieve significantly higher HCQ levels in the lung tissue, animal studies suggest several months of treatment is necessary to reach peak tissue concentrations.”

“Therefore, we should interpret the results of current clinical trials for HCQ and COVID-19 separately in the context of whether dosing was short term vs. long-term,” he added. “Ultimately, we highlight the need for high-quality clinical trial data to clarify HCQ's effectiveness, safety, and goal concentrations in the target tissue for SARS-CoV-2 before any specific dosage adjustments can be recommended.”