Management of moderate severity outpatients with COVID‐19 disease: Proposed criteria and algorithm for initiation of antiviral treatment

Key points.

• Early treatment of high‐risk patients with COVID‐19 could significantly decrease hospitalizations, intubations and deaths.

• Nirmatrelvir/ritonavir is the treatment of choice in patients with normal renal functions and who do not take other medication with significant drug interactions.

• Treatment with Remdesivir, as a 3‐day intravenous course, is in the majority of cases, the alternative choice.

• Molnupiravir is reserved for patients with severe renal impairment.

Recently ERS, WHO and NIH have updated the extensive living guidelines for the treatment of adults with COVID‐19 disease, ¹ , ² , ³ concerning both hospitalized and non‐hospitalized patients. In this paper, we propose a simplified algorithm for the management of COVID‐19 infection in outpatients, to achieve early treatment initiation to reduce hospitalizations, intubations and deaths.

According to the aforementioned algorithm, infected patients are categorized according to oxygen saturation while breathing room air (i.e., FiO₂: 21%) and the presence of risk factors for deterioration. These risk factors include: age >65 years, history of cancer under treatment during the past year, history of solid organ transplantation, primary and secondary immunodeficiencies, obesity [Body Mass Index >35], haemodialysis for end stage renal disease, chronic heart disease, chronic respiratory insufficiency, interstitial lung disease, diabetes mellitus and hemoglobinopathies. If the patient's oxygen saturation is greater than 94% and no risk factors exist, then the patient is defined as low risk and no specific treatment is indicated. On the other hand, patients with oxygen saturation greater than 94% and at least one risk factor are considered as moderate risk and specific antiviral treatment is recommended to prevent progression to severe disease. Options of early treatment include: orally administrated molnupiravir (with conditional recommendation since the drug has not been officially approved), orally administrated nirmatrelvir/ritonavir and intravenously administrated remdesivir (Figure 1).

FIGURE 1.

Treatment algorithm for patients at risk for developing severe COVID‐19.

Molnupiravir is a small‐molecule ribonucleoside prodrug of N‐hydroxycytidine (NCH), with activity against SARS‐CoV‐2 and other RNA viruses. ⁴ The MOVe‐OUT study was a phase 3, double‐blind, randomized, placebo‐controlled trial conducted to evaluate efficacy and safety of treatment with molnupiravir initiated within 5 days from the onset of symptoms or signs in non‐hospitalized, unvaccinated adults with mild–moderate, laboratory‐confirmed COVID‐19 and at least one risk factor for severe COVID‐19. ⁵ The study concluded that the treatment group which received 800 mg molnupiravir twice daily for 5 days had lower risk of hospitalization for any case or death compared to placebo. ⁵ The drug was well tolerated, and few adverse events were reported, with the commonest being diarrhoea, nausea and dizziness. ⁵

Nirmatrelvir is an antiviral agent targeting SARS‐CoV‐2 3‐chymotrypsin‐like cysteine protease enzyme (M^pro) which is essential in replication cycle of the virus. ⁶ When nirmatrelvir is administered in combination with ritonavir, a CYP3A4 inhibitor, pharmacokinetics of nirmatrelvir is enhanced. ⁶ The EPIC‐HR trial was a 2–3 phase double‐blind, randomized, controlled trial, conducted to evaluate safety and efficacy of nirmatrelvir/ritonavir treatment initiated within 3 days from the onset of symptoms in adult outpatients with mild‐to‐moderate COVID‐19 being at high risk of progression to severe disease. ⁷ The authors concluded that the treatment group receiving 300 mg of nirmatrelvir plus 100 mg ritonavir twice daily, for 5 days had 89% lower risk of progression to severe COVID‐19 compared to placebo, without evident safety concerns. ⁷ Treatment with nirmatrelvir/ritonavir has some limitations including interactions with many commonly used drugs while it cannot be administered to patients with estimated glomerular filtration rate (eGFR) <30 ml/min. Moreover, a recent study has shown that healthy adults <65 years of age, do not seem to benefit from the treatment, ⁸ and so this option should be reserved only for patients with underlying comorbidities who are at risk to develop severe disease.

Remdesivir is a direct‐acting nucleotide prodrug inhibitor of the SARS‐CoV‐2 RNA‐dependent RNA polymerase. ⁹ The PINETREE study was a randomized, double‐blind, placebo‐controlled trial which was conducted to evaluate safety and efficacy of treatment with remdesivir initiated within 7 days from symptoms onset in COVID‐19 outpatients at high risk for disease progression. ¹⁰ The study group received remdesivir intravenously (200 mg on day 1 and 100 mg on days 2 and 3) and was found to have 87% lower risk of hospitalization or death versus placebo. ¹⁰ The commonest reported adverse events were nausea and elevation of ALT and AST. ¹⁰ Remdesivir is not recommended in patients with eGFR <30 ml/h and/or hepatic impairment (transaminase levels >10 times of normal), ¹¹ while further studies are needed to evaluate its safety during pregnancy. ¹²

To sum up, in patients with normal renal function not receiving concomitant medication which interact with the drug, nirmatrelvir/ritonavir is the first choice of treatment. On the other hand, in patients with eGFR <30 ml/min oral molnupiravir would be the most appropriate treatment. In patients receiving medications which might interact with nirmatrelvir/ritonavir, oral molnupiravir or intravenous remdesivir administered in an outpatient basis (Figure 1) could be the treatment of choice. Further real‐life studies must be conducted to better evaluate the importance of these medications in the management of the pandemic.

CONFLICTS OF INTEREST

Stelios Loukides has received honoraria from Gilead and Pfizer, as well as support for attending meetings and/or travel from Pfizer. The other authors have nothing to disclose.

Apollonatou V, Papaioannou AI, Loukides S. Management of moderate severity outpatients with COVID‐19 disease: Proposed criteria and algorithm for initiation of antiviral treatment. Respirology. 2023;28(2):107–109. 10.1111/resp.14441