The development of an oral anti-viral medication that could reduce COVID-19 hospitalizations and deaths in unvaccinated high-risk individuals was nothing short of game-changing and something that clinicians like me were clamoring for. This milestone was achieved with the FDA’s granting of emergency use authorization (EUA) to Pfizer’s nirmatrelvir/ritonavir (Paxlovid) in December 2021.
The active ingredient in the combination is nirmatrelvir, a molecule that blocks the protease enzyme of SARS-CoV-2. Ritonavir, which also happens to be a protease inhibitor, is used in this combination not for any antiviral effect but for pharmacological boosting of nirmatrelvir levels in the body. As this drug targets the virus and its “life-cycle,” the earlier it is taken the more impactful it will be. Thus, the drug is indicated within a 5-day window following symptom onset.
But with some anecdotal reports of young, healthy people taking nirmatrelvir/ritonavir, the question at hand is: Should healthcare professionals be prescribing the antiviral to these patients?
The primary aim in developing a drug like nirmatrelvir/ritonavir was to decrease the likelihood of an individual developing severe COVID-19. As such, it is not surprising that the benefits are most pronounced and evident in those who have a substantial risk for severe disease and much less so in lower-risk groups. Indeed, there was debate about its impact in vaccinated individuals given that vaccination significantly drives down the risk of severe disease. However, recent studies have shown a benefit does exist in older high-risk vaccinated individuals.
As the drug is indicated for reducing the risk of severe disease, it is targeted exclusively toward those who have a risk for severe disease and are symptomatic. This is explicit in the EUA. For example, the risk of severe disease in a healthy 29-year-old is exceedingly low and nirmatrelvir/ritonavir is not going to appreciably reduce the occurrence of something already so rare. Accordingly and unsurprisingly, a recent study found that the antiviral failed to show significant benefit in lower-risk individuals.
In my practice, I do not prescribe nirmatrelvir/ritonavir to those who are at low risk for severe disease, but I unhesitatingly prescribe it to higher-risk individuals and those over the age of 60. This is not because younger, healthy people accrue some benefit from battling the virus without the aid of an antiviral; rather, it’s because the drug has not been shown to be valuable in this population. It is important to explain to low-risk individuals, no matter how adamant they may be about receiving the antiviral, that they will not benefit from a drug aimed at reducing the risk of death and hospitalization if they have a negligible risk for death and hospitalization. Discussing how the data currently only support use of the drug in high-risk, but not low-risk, individuals is usually sufficient. Though there are no major side effects (drug-drug interactions are usually not an issue in healthy populations who are not prescribed any other medications) to worry about except an alteration in taste and diarrhea, the drug simply has not been shown to be beneficial outside of high-risk groups.
In the future, data may emerge for nirmatrelvir/ritonavir or some other antiviral that show a benefit in reducing symptom duration, contagiousness, and/or long-term symptom risk, but that data do not yet exist for nirmatrelvir/ritonavir. Studies whose outcomes are targeted to these secondary benefits are of great interest, and would be a major step forward in taming the virus and make COVID-19 all the more manageable.
Amesh Adalja, MD, is a senior scholar at the Johns Hopkins Center for Health Security and a practicing infectious disease, critical care, and emergency physician in Pittsburgh. He has no relevant disclosures.