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Does Nirmatrelvir or Molnupiravir Work on Newer COVID-19 Variants?

September 26, 2023

We’re trying something new! Watch quick videos, with my personal take on the articles we cover each week and more! Here’s the JournalFeed YouTube channel link. ~Clay

Written by Clay Smith

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There was a strong association with use of either nirmatrelvir/ritonavir or molnupiravir and lower mortality and hospitalization among high-risk adult outpatients with COVID-19.

Let me get this straight, nirmatrelvir still works and molnupiravir works now too?
Nirmatrelvir/ritonavir (aka Paxlovid, let’s just say nirmatrelvir) was effective in real-world practice at reducing hospitalization and death, even among a largely vaccinated patient population during the early omicron era. However, molnupiravir was not shown to be effective in the PANORAMIC RCT and may even have caused harm. What is the real-world impact of both drugs among patients who were largely vaccinated in the era of subvariants BQ.1.1 and XBB.1.5?

This was a retrospective study from the Cleveland Clinic with 68,867 adult patients at high risk of progression to severe COVID-19. Treatment was at clinician discretion and was initially limited in supply, with nirmatrelvir (Paxlovid) first-line and molnupiravir (Lagevrio) second-line. Cumulative incidence of death at 90-days was 0.13% among those treated with nirmatrelvir and 1.05% among those untreated; 0.6% and 1.57% for molnupiravir, respectively. Adjusted HRs for death were 0.16 (95%CI 0.11-0.23) for nirmatrelvir and 0.23 (95%CI 0.16-0.34) for molnupiravir, and this favorable association remained across most subgroups.

From cited article

There may be systematic differences in patients who received antivirals and those who did not. Only a randomized trial could clear this up. That said, the association of either antiviral agent with reduced 90-day death or hospitalization/death was strong. I was surprised to see the association of molnupiravir with these important outcomes, as it looked no better than placebo in the PANORAMIC RCT.

How will this change my practice?
I will continue to prescribe nirmatrelvir if the patient:

  1. Has a positive COVID test of some kind (in-clinic or home test; PCR or antigen).
  2. Has symptom onset within 5 days.
  3. Meets eligibility criteria: age ≥50 years (especially if ≥65y) OR age ≥12y (or ≥40kg) AND has at least 1 of these conditions associated with higher risk from COVID-19. See also NIH Treatment Guidelines for up to date info.
  4. Does not have drug-drug interactions (use UpToDate drug interaction tool or Liverpool interaction checker).
  5. Does not have other known contraindication. Remember, reduced-dose nirmatrelvir has recently been shown to be safe in CKD, even in patients on dialysis.

I will use molnupiravir as a second-line drug (but not in pregnancy).

Nirmatrelvir or Molnupiravir Use and Severe Outcomes From Omicron Infections. JAMA Netw Open. 2023 Sep 5;6(9):e2335077. doi: 10.1001/jamanetworkopen.2023.35077.

What are your thoughts?