Should All Adults 65 Years and Older With Early COVID-19 Receive Antivirals?

Key Takeaways

• Efficacy of molnupiravir, nirmatrelvir plus ritonavir, and remdesivir in early COVID-19 is preserved in the setting of new SARS-CoV-2 variants of concern
• Patients with previous COVID-19 immunity due to immunization, infection, or both may still benefit from nirmatrelvir plus ritonavir or molnupiravir use
• The largest reductions in hospitalization and death with the use of nirmatrelvir plus ritonavir or molnupiravir are seen in older patients (older than 65 years)

Studies of oral antiviral agent use in older adults with early COVID-19 indicate a consistent benefit in reducing progression to severe disease, hospitalization, and death. Recently published studies of nirmatrelvir plus ritonavir and molnupiravir have demonstrated efficacy in people aged 65 years or older, whereas there is not the same benefit demonstrated in younger patients.

Antiviral Use in High-Risk and Standard-Risk Patients
In the EPIC-HR trial of symptomatic, nonhospitalized, unvaccinated adults at high risk for progression, nirmatrelvir, an orally administered ritonavir-boosted SARS-CoV-2 protease inhibitor, was superior to placebo in reducing progression to severe COVID-19 (relative risk reduction [RRR] 88.9%; P <.001). Of note, the RRR for patients 65 years of age or older was 94%. These results led to the FDA granting Emergency Use Authorization (EUA) of this drug in December 2021.

The MOVe-OUT trial of oral molnupiravir use in nonhospitalized, at-risk patients with mild to moderate COVID-19 reduced the risk of hospitalization or death by 30% when started within 5 days of symptom onset. Based on these data, the FDA issued an EUA for the use of molnupiravir when alternative authorized COVID-19 treatment options are not accessible or clinically appropriate.

In vitro, nirmatrelvir, along with remdesivir and molnupiravir, exhibits strong pan-human coronavirus activity unaffected by novel variants or omicron subvariants. This is different from all monoclonal antibodies (except bebtelovimab), which have lost activity against the omicron subvariants. Nirmatrelvir has a good safety profile (dysgeusia and diarrhea are the main noted adverse events), but drug–drug interactions must be systematically checked due to the ritonavir component.

Vaccinated patients were excluded from the EPIC-HR and MOVe-OUT studies. Because the proportion of the US population that was fully vaccinated reached 90% by April 2022 for people 65 years of age or older, the beneficial effects of oral antivirals in vaccinated people is unknown.

A separate ongoing trial (EPIC-SR) has enrolled vaccinated, standard-risk people with COVID-19 and found a low rate of hospitalization or death with a nonsignificant 57% reduction in hospitalizations and death in nirmatrelvir plus ritonavir-treated patients with at least 1 risk factor for severe COVID-19. Enrollment has been completed but the final results have not yet been published.

Antivirals: Place in Therapy
Nirmatrelvir plus ritonavir has been the preferred option in all treatment guidelines for nonhospitalized patients at high risk for progression to severe COVID-19 when started within 5 days of symptom onset. Treatment guidelines for nonhospitalized patients list remdesivir (started within 7 days of symptom onset) as the second preferred agent based on efficacy data, followed by bebtelovimab and molnupiravir as alternative treatment options when neither of the preferred therapies are available, clinically appropriate, or feasible to administer.

Personally, my order of treatment preference after nirmatrelvir plus ritonavir is slightly different based on efficacy and ease of administration: I believe the second agent used should be bebtelovimab because it is available as a single-dose IV push, followed by remdesivir because it requires 3 consecutive days of IV infusion at an outpatient infusion center, and finally, molnupiravir due to its lower efficacy compared with the other agents.

Who are these nonhospitalized persons with a “high risk for progression to severe COVID-19?” They are defined as unvaccinated individuals older than 80 years, or individuals older than 60 or older than 65 years of age (based on clinical trial inclusion criteria) with at least 1 disease causing severe immune suppression, a chronic disease (eg, diabetes, hypertension), or obesity.

Should Age Determine Oral Antiviral Use?
New research continues to offer insight about the efficacy of antivirals in younger and/or vaccinated people. Although the risk of death from COVID-19 is more pronounced in people older than 80 years, it increases continuously from 50 years old onwards. In fact, treating individuals with early COVID-19 who are at high risk for progression to severe disease contributes to reduced hospital collapses when new SARS-CoV-2 variants escape vaccine-induced protection; therefore, leveraging this strategy is of utmost importance. Finally, the virologic response to drug treatment could lessen the likelihood of onward transmission, although its effects could be relatively minor. The potential impact of drug treatment on long COVID or other prolonged postinfectious symptoms is unknown.

A retrospective cohort study of 1130 subjects assessed nirmatrelvir plus ritonavir administration within 5 days of a COVID-19 diagnosis in nonhospitalized, vaccinated patients at high risk for COVID-19–related complications. The mean age of patients who received drug therapy was older than those who did not (57.6 vs 49.3 years). After 1:1 propensity score matching with untreated subjects, there was a reduced likelihood of a composite endpoint including emergency department visits, hospitalization, or death (odds ratio: 0.5; 95% CI: 0.39-0.67; P <.005). Complications and overall resource use were also decreased, with a significant reduction in multisystem symptom burden and subsequent complications such as lower respiratory tract infection, cardiac arrhythmia, and diagnostic radiology testing. With cases of COVID-19 continuing to occur despite widespread vaccination, these data support administering nirmatrelvir plus ritonavir to this vulnerable group, vaccination status notwithstanding, while ongoing clinical trials confirm these data.

A retrospective cohort analysis of 890 nirmatrelvir plus ritonavir recipients and 1856 molnupiravir recipients (and equal numbers of propensity score–matched controls) in Hong Kong during the omicron BA.2 subvariant surge confirmed that both oral antivirals were associated with a low risk of all-cause mortality (HR: 0.34, 95% CI: 0.23-0.50, P <.0001 for nirmatrelvir plus ritonavir; HR: 0.48, 95% CI: 0.40-0.59, P <.0001 for molnupiravir), a low risk of a composite disease progression outcome (HR: 0.57, 95% CI: 0.45-0.72, P <.0001 for nirmatrelvir plus ritonavir; HR: 0.60, 95% CI 0.52-0.69, P <.0001 for molnupiravir), and a shorter time to achieving a low viral burden. The mortality benefit of each antiviral was driven by patients older than 65 years (HR: 0.34, 95% CI: 0.22-0.52, P <.0001 for nirmatrelvir plus ritonavir; HR: 0.49, 95% CI: 0.40-0.59, P <.0001 for molnupiravir) because the mortality benefit in patients 65 years of age or younger was not statistically significant (HR: 1.13, 95% CI: 0.28-4.59, P = .86 for nirmatrelvir plus ritonavir; HR: 1.28, 95% CI: 0.56-2.96, P = .56 for molnupiravir). Of note, this study included individuals hospitalized with SARS-CoV-2 infection not requiring oxygen therapy on admission.

Finally, a retrospective cohort study in Israel during the omicron surge found significantly lower rates of hospitalization and death due to COVID-19 among adults 65 years of age and older at high risk for progression who received nirmatrelvir plus ritonavir, regardless of previous SARS-CoV-2 immunity induced by infection, vaccination, or both compared with those who did not receive drug therapy (adjusted HR for hospitalization: 0.27, 95% CI: 0.15-0.49; adjusted HR for death: 0.21, 95% CI: 0.05-0.82). No evidence of a treatment benefit was found in adults younger than 65 years.

Together, these new data suggest the preservation of the efficacy of oral antivirals against new variants of concern or in subjects with previous immunity due to immunity from a previous infection, vaccination, or both, including hard endpoints such as hospitalization or death.

Your Thoughts?
Would you support expanding the prescription of antivirals in early COVID-19 to all patients 65 years and older regardless of their previous SARS-COV-2 immunity and risk status?