Oral Antiviral Treatment for COVID-19: A Comprehensive Review on Nirmatrelvir/Ritonavir

Abstract

Despite the rapid development of efficient and safe vaccines against COVID-19, the need to confine the pandemic and treat infected individuals on an outpatient basis has led to the approval of oral antiviral agents. Taking into account the viral kinetic pattern of SARS-CoV-2, it is of high importance to intervene at the early stages of the disease. A protease inhibitor called nirmatrelvir coupled with ritonavir (NMV/r), which acts as a CYP3A inhibitor, delivered as an oral formulation, has shown much promise in preventing disease progression in high-risk patients with no need for supplemental oxygen administration. Real-world data seem to confirm the drug combination’s efficacy and safety against all viral variants of concern in adult populations. Although, not fully clarified, viral rebound and recurrence of COVID-19 symptoms have been described following treatment; however, more data on potential resistance issues concerning the Mpro gene, which acts as the drug’s therapeutic target, are needed. NMV/r has been a gamechanger in the fight against the pandemic by preventing hospitalizations and halting disease severity; therefore, more research on future development and greater awareness on its use are warranted.

Comparative effectiveness of Paxlovid versus sotrovimab and molnupiravir for preventing severe COVID-19 outcomes in non-hospitalised patients: observational cohort study using the OpenSAFELY platform

“…A recent literature review shows that a growing body of real-world evidence supports the efficacy of Paxlovid among vaccinated adult patients in the Omicron era [18], though most of those observational studies were conducted during the BA.1/BA.2 wave. A large-scale cohort study in Israel showed that among high-risk outpatients with COVID-19 aged ≥65 years, Paxlovid users had substantially lower risks of hospitalisation due to COVID-19 (adjusted hazard ratio=0.27, 95% CI: 0.15 to 0.49) and death due to COVID-19 (adjusted hazard ratio=0.21, 95% CI: 0.05 to 0.82) than untreated patients; whereas no association was observed in patients aged <65 years [5].…”

“…Another cohort study in the US population showed that non-hospitalised adult patients who were prescribed Paxlovid had a lower risk of all-cause hospitalisation or death than non-users (adjusted risk ratio=0.56, 95% CI: 0.42 to 0.75) [19]. The evidence for the safety of Paxovid in routine clinical use, however, is still limited, and the concerns of viral rebound and recurrence of COVID-19 symptoms following Paxlovid treatment need further investigation [18].…”

The Use of Nirmatrelvir-ritonavir in a Case of Breakthrough Long COVID

“…Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease that prevents viral replication, and ritonavir acts as a CYP3A4 inhibitor that enhances the bioavailability of nirmatrelvir. 8 The present emergency use authorization for nirmatrelvirritonavir is indicated for individuals with mild or moderate acute COVID-19, and high risk of severe infection. 9 However, it remains unclear whether the patient had COVID-19 re-infection with falsenegative testing, or whether the patient acquired a different viral infection that caused similar symptoms, and how this may have impacted the chronic PASC symptoms.…”

Design and statistical optimisation of emulsomal nanoparticles for improved anti-SARS-CoV-2 activity of N -(5-nitrothiazol-2-yl)-carboxamido candidates: in vitro and in silico studies

“…Recently, the orally active nirmatrelvir (PF-07321332) in combination with ritonavir, was granted emergency use by the FDA in December 2021 for COVID-19 treatment under the trade name Paxlovid ® 10 . The combination elicited an efficacy of about 88% against hospitalisation or mortality in adult outpatients after its administration within five days of the onset of symptoms 11 . Nirmatrelvir is a peptidomimetic inhibitor of the main protease Mpro that acts via a reversible covalent interaction with its key Cys-145 residue 12 .…”