A combination of antiretroviral medications might increase the risk of bradycardia in elderly patients with severe COVID-19, according to a small study that was published Thursday.
Christophe Beyls, MD, and colleagues, of University Hospital Amiens, France, reported these results in a manuscript published online in Circulation: Arrythmia and Electrophysiology.
One treatment that showed promise early in the COVID-19 outbreak was the combination of lopinavir (LPV) and ritonavir (RTV). This was based on previous experience of the treatment with the severe acute respiratory coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). COVID-19 is caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2).
The LPV-RTV combination is typically used to treat HIV, and a risk of bradycardia was known in these patients. Beyls and colleagues aimed to determine the risk of bradycardia with the use of these antiretroviral protease inhibitors in critically ill COVID-19 patients.
During the first month of the outbreak in Europe, 41 COVID-19 patients in University Hospital Amiens’s intensive care unit (ICU) received 200 mg of LPV and 50 mg of RTV twice daily for 10 days. Nine of these patients (22%) developed bradycardia; of the nine, eight (89%) had sinus bradycardia and one (11%) had third-degree atrioventricular block. The authors attributed this to the LPV/RTV combination because bradycardia began at least 48 hours after the drug treatment started and was resolved after the dosage was discontinued or reduced, and no alternative cause was found.
Patients who presented with bradycardia were older (mean age 73 years vs. 62 years; p=0.009) had a higher RTV plasma concentration at 72 hours, and a lower lymphocyte count. The investigators found no correlation between RTV plasma concentration, LPV plasma concentration and mean heart rate on the third day of treatment. None of these patients developed bradycardia within the first 48 hours of LPV-RTV treatment.
Beyls and colleagues contrasted their results with those from a recent Chinese study, which reported no cases of bradycardia from the LPV/RTV combination. Beyls and colleagues noted that compared to their study in France, the Chinese study patients had less severe COVID-19 (only 15% were on mechanical ventilation and none required extracorporeal membrane oxygenation) and were younger (mean age 58 years vs. 73 years for the French study patients). Also, the Chinese patients’ heart rates were not continuously monitored, whereas the French patients’ heart rates were.
Beyls and colleagues posited that COVID-19’s inflammation might increase the intestinal absorption of LPV/RTV in elderly patients. The authors added that bradycardia in these patients could be a sign of severe cardiological or neurological impairment “since it is associated with lymphopenia that seems to reflect the severity of COVID-19 infection.”
The World Health Organization announced Saturday that it discontinued the hydroxychloroquine and LPV/RTV arms of its Solidarity Trial, an international trial that is aiming to find an effective treatment for hospitalized COVID-19 patients. The U.S. Food and Drug Administration recommended in April that hydroxychloroquine and chloroquine not be used to treat COVID-19 outside hospital settings or clinical trials.
Beyls C, Martin N, Hermida A, et al. Lopinavir-ritonavir Treatment for COVID-19 Infection in Intensive Care Unit: Risk of Bradycardia. Circ Arrhythm Electrophysiol 2020 Jul 9. https://www.ahajournals.org/doi/10.1161/CIRCEP.120.008798