Watch Out for Bradycardia in COVID-19 Patients Treated With Lopinavir/Ritonavir

Because it had shown some effect against previous coronaviruses, the combination of the antiretroviral medications lopinavir and ritonavir had been used to treat severe COVID-19 infections at a university hospital in France. Find out why the authors of a new report are cautioning about the risk of bradycardia with the treatment, especially in elderly patients.

AMIENS, FRANCE –  Early in the COVID-19 pandemic, patients with severe infection were treated with specific anti-viral treatments which had shown promise with SARS-COV-1 and MERS-COV and in China where the novel coronavirus first appeared.

Among those was the combination of the antiretroviral medications lopinavir (LPV) and ritonavir (RTV), according to a report in Circulation: Arrhythmia and Electrophysiology, an American Heart Association journal. Now, the authors from University Hospital Amiens are warning that use of those drugs should be closely monitored, especially in elderly patients, because of the possible of increased risk of bradycardia.

“LPV is a protease inhibitor of HIV-1 that is usually combined with RTV, another protease inhibitor that strongly inhibits hepatic cytochrome (CYP) P450 (CYP3A4) activity, in order to increase LPV plasma concentration and efficacy, with limited side effects,” the researchers explain. “Separately, LPV is rapidly metabolized and has very low bioavailability.”

The authors recount how, for HIV-1 patients, a risk of bradycardia was reported possibly due to nodal toxicity of LPV/RTV, although the data on bradycardia related to LPV/RTV treatment for COVID-19 critical ill patients had been limited. They sought to document the risk of bradycardia for COVID-19 patients treated with LPV/RTV.

Bradycardia, defined as a heart rate below 60 beats per minute for a period of more than 24 hours, causes problems if the slow heart rate leads to a decrease in blood flow to the body, which can lead to heart failure, fainting, chest pain and low blood pressure.

Included in this French study were 41 patients with COVID-19 admitted to the intensive care unit at Amiens University Hospital who were treated with 200 mg LPV and 50 mg RTV twice daily for 10 days. All patients received continuous electrocardiogram (ECG) monitoring.

Researchers report that, among the patients who received the LPV/RTV treatment, the following occurred:

  • 22% experienced bradycardia for more than 24 hours;
  • bradycardia occurred at least 48 hours after initiation of treatment, indicating that the medications may have caused bradycardia;
  • a blood test measuring the concentration of ritonavir (RTV plasma concentration) at 72 hours after receiving the treatment showed higher concentrations of RTV in the patients who had bradycardia;
  • no correlation was found between RTV plasma concentration, LPV plasma concentration and mean heart rate at three-days after LPV/RTV treatment began;
  • patients experiencing bradycardia were on average older than patients receiving the treatment who did not experience bradycardia (ages 62-80 vs. 54-68, respectively); and,
  • bradycardia resolved after LPV/RTV were discontinued or doses were reduced.

The authors suggest that bradycardia “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. Intensivists should be aware of this potential side effect in order to closely monitor LPV/RTV plasma levels, notably in elderly patients."

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