Cardiovascular risks of COVID-19 antivirals

Several antivirals, including remdesivir, Paxlovid, molnupiravir, and monoclonal antibodies like tixagevimab and cilgavimab, have been repurposed to treat the coronavirus disease 2019 (COVID-19) or received emergency use authorization (EUA). Antimalarial and antiparasitic drugs like ivermectin, hydroxychloroquine, and chloroquine have also been investigated for their potential activity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

A recent review published in the journal Acta Pharmacologica Sinica discusses the cardiovascular adverse effects associated with antiviral drugs used to treat COVID-19.

About the virus

SARS-CoV-2 is a single-stranded ribonucleic acid (RNA) virus enclosed in a protein envelope comprising the membrane, spike, and envelope proteins. Viral RNA is stored within the nucleocapsid, comprised of the nucleocapsid protein.

The SARS-CoV-2 spike protein recognizes and subsequently binds to the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of the host cell. The S1 subunit of the spike protein consists of an N-terminal domain (NTD) and receptor-binding domain (RBD).

RBD-ACE2 binding causes the S2 subunit to dissociate from the ACE2 molecule, which subsequently causes the virus to transition from a pre to post-fusion state. Thereafter, the virus and host cell membranes fuse together, thereby allowing viral entry into the cell.

ACE2 and cardiovascular adverse effects

ACE2 regulates the vasoactive effects of ACE, which converts angiotensin I to angiotensin II, a potent vasoconstrictor and pro-inflammatory agent. Angiotensin II induces hyperinflammation due to the dysregulated release of cytokines, leading to severe tissue damage and multi-organ failure, which is often characteristic of severe COVID-19.

Pre-pandemic antivirals and cardiovascular effects

Idoxuridine was the first antiviral approved in 1963 for feline herpesvirus-1 eye infections; since then, 37 antivirals have been approved to treat a wide range of infections caused by the human immunodeficiency virus (HIV), hepatitis B virus (HBV), cytomegalovirus (CMV), influenza virus, respiratory syncytial virus (RSV), and hepatitis C virus (HCV).

Among the drugs used to treat HIV include protease inhibitors like lopinavir/ritonavir, which increase lipid levels in the blood, liver, and heart, in addition to weakening heart pumping activity. Endothelial damage has also been observed, which may cause atherosclerosis with its cardiovascular sequelae. Interferon-α, which is used in the treatment of multiple viral infections and cancers, has also been associated with adverse cardiac effects.

Remdesivir

Remdesivir is a prodrug that converts to an analog of the nucleotide adenosine, thereby disrupting viral replication. The vasodilation activity of adenosine can induce the release of catecholamines like epinephrine, thereby increasing the risk of ventricular tachycardia, ventricular fibrillation, and atrial fibrillation.

When administered intravenously, remdesivir can trigger QT prolongation and the potentially deadly arrhythmia torsade de pointes. Thus, continuous heart monitoring is essential for COVID-19 patients being treated with remdesivir, especially those with pre-existing cardiac disease or electrolyte abnormalities.

Paxlovid

Paxlovid, which consists of nirmatrelvir and ritonavir, may cause bradycardia and sinus dysfunction. However, it remains unclear which component of Paxlovid is responsible and what mechanisms are involved in this adverse side effect.

The toxicity of Paxlovid, when combined with tacrolimus, an immunosuppressant, has been reported in several cases. Paxlovid may also increase the risk of bleeding when used in combination with ticagrelor, warfarin, or rivaroxaban.

Paxlovid may also interact with other drugs to cause skeletal muscle breakdown and myopathy.

Molnupiravir

Esterases in host plasma activate molnupiravir to its active antiviral nucleoside analog EIDD-1931. Molnupiravir can increase oxidant stress, which may cause tissue damage. However, like Paxlovid, the use of molnupiravir can reduce the risk of severe COVID-19, particularly among those with diabetes and patients 65 years of age and older.

Other drugs

Hydroxychloroquine (HCQ) acidifies intracellular endosomes and affects the viral life cycle at multiple stages. Its therapeutic effects may be synergistic with those of azithromycin.

Nevertheless, both HCQ and azithromycin can cause prolonged QTc or cardiac arrhythmias. Thus, the combination of these drugs may not be ideal for severe COVID-19 or patients at an increased risk of QT prolongation.

Ivermectin

Ivermectin inhibits interactions between the virus and host cell, thereby preventing nuclear transport of viral proteins. However, preclinical data suggests the accumulation of ivermectin in the heart and inhibition of potassium currents. Patients with COVID-19 who are treated with ivermectin should be monitored for arrhythmias or QT prolongation.

Antibodies

Both monoclonal antibodies (mAbs) and plasma have been used to treat COVID-19. Cardiac arrhythmias have been reported with mAb, particularly following treatment with tixagevimab or cilgavimab.

The combination of cilgavimab and tocilizumab may cause thromboembolic events. Hypertension is most commonly reported with mAbs like casirivimab and imdevimab, bamlanivimab alone or with etesevimab, and sotrovimab.

Conclusions

The potential cardiovascular side effects of COVID-19 therapeutics must be carefully considered before prescribing these agents to high-risk patients. Despite reported observations of cardiotoxicity, additional studies are needed to differentiate the cardiovascular effects of SARS-CoV-2 infection from those of antivirals.

Future antiviral drug development assisted with the newest artificial intelligence platform may improve the accuracy to predict the structures of biomolecules of antivirals and therefore to mitigate their associated cardiovascular adversities.”