ADVANCES IN EM

Oral medicine for Covid 19
– Are they the Game Changer?

wongkb

Dr WONG Kwun Bun
Associate Consultant, PWH, A&E

Emergency Medicine Department is under tremendous stress due the latest wave of COVID-19 infections. Many patients presented to A&E with fever, influenza like illness, dyspnoea or even with respiratory failure, shock, or multi-organ dysfunction. With the arrival and approval of oral antiviral in March 2022, will the management protocol be revised in future? This article will review the indications and contradictions, evidence and common side effects of the oral antiviral. 

Nirmatrelvir-ritonavir (Paxlovid) (Pifizer) 

The dose is 300 mg nirmatrelvir (two 150 mg tablets) with one 100 mg ritonavir tablet taken together orally twice daily for 5 days. Nirmatrelvir is an orally bioavailable protease inhibitor that is active against MPRO, a viral protease that plays an essential role in viral replication by cleaving the 2 viral polyproteins. (1)  Co-administration of ritonavir is required to increase nirmatrelvir concentrations to the target therapeutic range.

Current Evidence

The EPIC-HR trial with 2246 patients demonstrated that starting ritonavir-boosted nirmatrelvir treatment in nonhospitalized adults with mild to moderate COVID-19 within 5 days of symptom onset reduced the risk of hospitalization or death through Day 28 by 89% compared to placebo (2)

Efficacy Results in Non-Hospitalized Adults with COVID-19 Dosed within 5 Days of Symptom Onset who Did Not Receive COVID-19 mAb Treatment at Baseline

Molnupiravir (MSD)


Molnupiravir is the oral prodrug of beta-D-N4-hydroxycytidine (NHC), a ribonucleoside that has broad antiviral activity against RNA viruses. NHC uptake by viral RNA-dependent RNA-polymerases results in viral mutations and lethal mutagenesis (3,4) It is the first approved oral antiviral agent for treating COVID-19


Current Evidence 
 

In the MOVe-OUT trial with 1433 patients, molnupiravir reduced the rate of hospitalization or death by 30% compared to placebo (5)

Adjusted relative risk reduction of molnupiravir compared to placebo for all randomized participants was 30% (95% CI: 1%, 51%).

Omicron Variants

Currently, there is lack of data on the clinical efficacy of ritonavir-boosted nirmatrelvir and Molnupiravir against this VOC. There were some studies demonstrate that nirmatrelvir, molnupiravir, and remdesivir retain their antiviral activity against all tested SARS-CoV-2 variants in vito. (6,7)

Comparison of oral antivirals

Summary of treatment options for high-risk non-hospitalized patients with mild to moderate COVID-19

Hong Kong Situation 


Molnupiravir and Paxlovid were delivered to Hong Kong in March year. (8). The clinical criteria in Hong Kong are the following:  Within 5 days of symptom onset, AND Test positive (RAT/PCR), AND SpO2 > 94% (room air), AND With or without early pneumonic changes (9) Due to the limit supply of early stage, the oral antiviral should be prioritized for immunocompromised individuals expected to have a suboptimal vaccine response and unvaccinated or incompletely vaccinated individuals at highest risk for severe disease. We need to beware the definitions of complete vaccination and the host criteria of using the oral medicine in the coming weeks. 

Reference 

  1. Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH. An overview of severe acute respiratory syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule chemotherapy. J Med Chem. 2016;59(14):6595-6628. Available at:

  2. Hammond J, Leister-Tebbe H et al, Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19.N Engl J Med. 2022; 

  3. Zhou S, Hill CS, Sarkar S, et al. Beta-d-N4-hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis but is also mutagenic to mammalian cells. J Infect Dis. 2021;224(3):415-419. 

  4. Kabinger F, Stiller C, Schmitzova J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol. 2021;28(9):740-746. 

  5. Jayk Bernal A, Gomes da Silva MM,etc al Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022;386(6):509. Epub 2021 Dec 16.

  6. Laura Vangeel 1Winston Chiu 1, Steven De Jonghe et al Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern Antiviral Res . 2022 Feb;198:105252

  7. Pengfei Li, Yining Wang, Marla Lavrijsen, et al  SARS-CoV-2 Omicron variant is highly sensitive to molnupiravir, nirmatrelvir, and the combination Cell Research volume 32, pages322–324 (2022)

  8. https://www.info.gov.hk/gia/general/202202/23/P2022022300303.htm

  9. Interim Recommendation on Clinical Management of Adult Cases with Coronavirus Disease 2019 (COVID19)