Numerous medications are now available for individuals with mild to moderate COVID-19 who are not hospitalised but are at high risk of disease progression. Here we put together a quick summary of the recent NIH guideline update that will prove useful in planning treatment.

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Before mid-December 2021, the COVID-19 Treatment Guidelines NIH Panel recommended only the anti-SARS-CoV-2 monoclonal antibodies (mAbs) bamlanivimab plus etesevimab, casirivimab plus imdevimab, and sotrovimab for non-hospitalised patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease. In many regions of the world, the B.1.1.529 (Omicron) variation of concern (VOC) has now become the dominant version.

The Omicron variation, which has multiple spike protein mutations, is anticipated to have a significantly decreased sensitivity to bamlanivimab plus etesevimab and casirivimab plus imdevimab.

Due to the fact that sotrovimab is the only existing anti-SARS-CoV-2 monoclonal antibody (mAb) that is expected to have efficacy against the Omicron VOC, the panel recently included a 3-day course of intravenous (IV) remdesivir as an alternative therapeutic option for this group of patients.

The COVID-19 Treatment Guidelines NIH Panel recommends that most high-risk, non-hospitalised individuals with mild to moderate COVID-19 get ritonavir-boosted nirmatrelvir (Paxlovid).

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Emergency use authorised antiviral medicines by FDA

The Food and Drug Administration (FDA) has granted Emergency Use Authorisations (EUAs) for two novel oral antiviral medicines in this patient population: Nirmatrelvir (Paxlovid) enhanced with ritonavir and molnupiravir.

Ritonavir-boosted nirmatrelvir (paxlovid)

Nirmatrelvir (PF-07321332) is an orally available protease inhibitor that inhibits MPRO, a viral protease that is required for viral replication since it cleaves the two viral polyproteins. It has been shown to be antiviral against all coronaviruses known to infect people.

Molnupiravir

Molnupiravir is an oral prodrug of beta-D-N4-hydroxycytidine (NHC), a ribonucleoside with antiviral efficacy against a wide variety of RNA viruses. The binding of NHC to viral RNA-dependent RNA polymerases leads to viral mutations and fatal mutagenesis.

One investigation provided ambiguous findings; the other found no indication of mutagenicity. The FDA assessed that molnupiravir has a modest risk of genotoxicity based on existing evidence and the 5-day length of therapy. Additionally, there have been worries regarding molnupiravir's possible influence on SARS-CoV-2 mutation rates The FDA has mandated that the company build a mechanism for monitoring genomic databases for the introduction of SARS-CoV-2 variants.

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The recommendation's objective

The goal of this statement is to offer doctors guidelines on the use of nirmatrelvir (Paxlovid) boosted with ritonavir, sotrovimab, remdesivir, and molnupiravir in non-hospitalised patients with COVID-19 who are at high risk of developing severe illness.

These recommendations are based on the results of clinical trials involving ritonavir-boosted nirmatrelvir (Paxlovid), remdesivir, and molnupiravir, as well as the results of clinical trials and laboratory evaluations of the anti-SARS-CoV-2 monoclonal antibodies currently available via EUAs for COVID-19 treatment.

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Guidelines

The Panel advises the use of one of the following medications (listed in order of preference) for non-hospitalised individuals with mild to moderate COVID-19 who are at high risk of disease progression:

1. Nirmatrelvir 300 mg in combination with ritonavir 100 mg (Paxlovid) orally twice daily for 5 days, starting as soon as feasible and within 5 days after symptom onset in children aged 12 years and weighing 40 kilogrammes (AIIa).
   1. Nirmatrelvir (Paxlovid) with ritonavir boost has considerable and complicated drug-drug interactions, particularly owing to the ritonavir component of the combo.
   2. Prior to prescription nirmatrelvir (Paxlovid) with ritonavir, doctors should carefully check the patient's concomitant medicines, including over-the-counter drugs and herbal supplements, to rule out possible drug-drug interactions.
2. Sotrovimab 500 mg given as a single IV infusion as soon as feasible and within 10 days of symptom start in children aged 12 years and weighing 40 kg who reside in locations with a high incidence of the Omicron VOC (AIIa).
   1. If the Delta VOC continues to account for a significant proportion of infections in the region and other options are unavailable or contraindicated, patients may be offered bamlanivimab plus etesevimab or casirivimab plus imdevimab, with the understanding that this treatment will be ineffective if they are infected with the Omicron VOC.
   2. Sotrovimab should be delivered in a facility that is capable of managing severe hypersensitivity responses, such as anaphylaxis. Patients should be watched during the infusion and for at least one hour thereafter.
3. Remdesivir 200 mg IV on day 1, followed by remdesivir 100 mg IV daily on Days 2 and 3 in individuals aged 12 years and weighing 40 kg, began as soon as practicable and within 7 days after symptom onset (BIIa).
   1. Because remdesivir needs three consecutive days of IV infusion, it may provide logistical challenges in many situations.
   2. Remdesivir is presently authorised by the FDA for use in hospitalised patients, and its usage in outpatient settings would be considered off-label.
   3. Remdesivir should be provided in a facility that is capable of managing severe hypersensitivity responses, such as anaphylaxis. Patients should be watched during the infusion and for at least one hour thereafter.
4. Molnupiravir 800 mg orally twice daily for 5 days, starting as soon as feasible and within 5 days after symptom onset in individuals aged 18 years ONLY when none of the preceding choices are available (CIIa).

The prescribing doctor should record that the patient and prescribing clinician discussed the risks and benefits and that the patient selected this treatment. There is no evidence on the use of molnupiravir in patients who have received COVID-19 vaccinations, and the risk-to-benefit ratio is anticipated to be lower due to this drug's decreased effectiveness.

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Rationalisation

If nirmatrelvir (Paxlovid) with ritonavir is not available or cannot be used due to medication interactions, the panel recommends sotrovimab. In the absence of sotrovimab, the panel suggests using remdesivir.

Molnupiravir should be used only if the other three alternatives are unavailable or ineffective.

There are presently no clinical trial data comparing the clinical effectiveness of these four medications, and no evidence on the use of antiviral medicines and/or anti-SARS-CoV-2 monoclonal antibodies in the treatment of COVID-19.

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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a practising super specialist from New Delhi.