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Department of Medicine
Harvard Medical School
Director, Viral Hepatitis Clinic
Division of Infectious Diseases
Massachusetts General Hospital
Arthur Kim, MD: advisor: Kintor and research: NIH-funded site investigator for casirivimab/imdevimab prevention trial.
The Rise and Fall of Monoclonal Antibodies
The primary goal of treatment for patients with mild to moderate COVID-19 is to prevent clinical progression to hospitalization and/or death. For most of 2021, when patients with the highest risk of hospitalization with COVID-19 were prioritized, monoclonal antibodies (mAbs) were a mainstay of outpatient treatment. As omicron became the predominant circulating strain of SARS-CoV-2, mutations in its spike protein resulted in immediate loss of in vitro activity of several mAbs and their subsequent withdrawal from our armamentarium. By February 2022, a single mAb—bebtelovimab—was left standing because it was the only one that retained activity against the predominant emerging strains at that time.
On November 4, 2022, the FDA updated the fact sheet for bebtelovimab, heralding the rising prevalence of omicron subvariants with spike mutations that confirmed resistance to bebtelovimab in vitro. Weekly updates from the CDC variant surveillance tool Nowcast have chronicled their steady takeover, driven predominantly by BQ.1 and BQ.1.1.
As these subvariants now constitute the majority of circulating sequences in virtually all regions of the United States, on November 30, 2022, the FDA withdrew the authorization for bebtelovimab, and it will no longer be available for use. On December 6, 2022, the National Institutes of Health (NIH) updated their COVID-19 treatment guideline to recommend against the use of bebtelovimab for treatment of ambulatory patients with COVID-19. What are the implications of the loss of bebtelovimab for our COVID-19 treatment paradigms?
Fortunately, other antivirals—oral nirmatrelvir plus ritonavir, IV remdesivir, and oral molnupiravir—are available via Emergency Use Authorization. Of importance, they retain activity against omicron and its subvariants.
The Role of Nirmatrelvir Plus Ritonavir
A 5-day course of nirmatrelvir plus ritonavir now has become the predominant COVID-19 outpatient treatment in the United States, despite the need for evaluation of drug–drug interactions, dose adjustment for moderate renal insufficiency, and concerns about symptom recrudescence.
Randomized, controlled trials that support the use of antivirals for early treatment of COVID-19 generally occurred in the prevaccine era. Omicron may be less likely to cause hospitalization than delta, and a significant proportion of the population now has protective immunity from vaccination and/or prior COVID-19 infection. The generalizability of trials conducted pre omicron to the current era cannot be automatically inferred.
Emerging reports regarding the real-world use of nirmatrelvir plus ritonavir indicate that receipt still is associated with reduced hospitalization rates. One of the larger datasets included 699,848 adult patients diagnosed with COVID-19 and eligible for nirmatrelvir plus ritonavir and compared 198,927 people who received nirmatrelvir plus ritonavir within 5 days after diagnosis with 500,921 people who did not. This analysis found that receipt of nirmatrelvir plus ritonavir was associated with protection against hospitalization (adjusted HR: 0.49; 95% CI: 0.46-0.53). This reduction in hospitalization was preserved among persons who received 2 or more mRNA COVID-19 vaccine doses and across other important subgroups, including people with immunocompromise. These observational data suggest that nirmatrelvir plus ritonavir has retained efficacy in reducing hospitalization in the omicron era, even among vaccinated people.
Remdesivir to the Rescue
Remdesivir is an IV inhibitor of the polymerase of SARS-COV-2 and is approved by the FDA for the treatment of COVID-19. In ambulatory people with mild to moderate COVID-19, remdesivir was associated with an 87% reduction in the rate of hospitalization. Because of its single-dose administration, bebtelovimab was preferred over a 3-day infusion of outpatient remdesivir by many health systems in the United States. Because our health systems have withdrawn bebtelovimab from clinical use, we now turn to remdesivir, as it retains activity against omicron subvariants.
Options for remdesivir deployment include repurposing the infusion capacity of mAb programs, home infusion services, and administration in long-term care facilities. Infusion therapies are significantly more inconvenient than oral options and cannot be delivered to all patients at risk for hospitalization. Remdesivir therefore is reserved for the same patients who were receiving bebtelovimab. Such patients fall primarily within 2 groups: (1) those with certain drug–drug interactions precluding nirmatrelvir plus ritonavir use or (2) those with significantly impaired renal function.
What About Molnupiravir?
Molnupiravir is an oral antiviral that introduces mutations into the viral genome and a phenomenon known as “error catastrophe.” The authorization for molnupiravir was based on the MOVe-OUT trial, which demonstrated a 30% reduction in risk of hospitalization for patients with mild to moderate COVID-19. Because of concerns regarding mutagenicity, molnupiravir should be used with caution in patients of reproductive potential.
Molnupiravir has no significant drug–drug interactions and does not require renal dose adjustment—2 factors that would make it an excellent alternative to other antivirals. However, remdesivir and nirmatrelvir plus ritonavir each were substantially more effective in preventing hospitalization in their pivotal trials. A pragmatic open-label trial conducted in the United Kingdom was unable to demonstrate that molnupiravir reduced the risk of hospitalization, but overall rates of hospitalization were very low (0.8%) in the population tested. Molnupiravir was associated with a 4-day benefit in time to first recovery.
Molnupiravir may have a role when treatment with nirmatrelvir plus ritonavir or remdesivir is not possible, but healthcare professionals and patients should be aware that the efficacy of molnupiravir is unclear.
Where Do We Go From Here?
Several murky areas remain in outpatient antiviral therapy for COVID-19, such as the role of combination antiviral therapy, extended courses, and/or convalescent plasma (currently authorized only for people with immunocompromise). Our antiviral armamentarium could be augmented by development of new mAbs that maintain activity against past and current SARS-CoV-2 variants, as well as new medications with fewer drug–drug interactions than nirmatrelvir plus ritonavir, greater ease of administration than remdesivir, and greater efficacy than molnupiravir.
With the loss of bebtelovimab from our COVID-19 treatment armamentarium for outpatient treatment, do you agree with the NIH COVID-19 treatment guideline ranking of nirmatrelvir plus ritonavir as the preferred option, preserving remdesivir for people who cannot take nirmatrelvir plus ritonavir, and prescribing molnupiravir only if the other two are not available or feasible? Join the conversation by leaving a comment below.