What Clinicians Need to Know About Oral Antivirals for COVID-19: An Expert Q&A

In this Q&A, Erica Johnson, MD, provides insight into the new oral antiviral medications that may soon be approved for the treatment of COVID-19.

The Food and Drug Administration (FDA) may soon authorize 2 novel oral antivirals for the treatment of COVID-19. The medications currently under consideration are Merck’s molnupiravir and Pfizer’s paxlovid (PF-07321332/ritonavir). On November 30, 2021, an FDA advisory committee voted narrowly in favor of recommending molnupiravir for emergency use authorization (EUA). The committee is expected to review Pfizer’s paxlovid in the coming weeks. If approved by the FDA for EUA, these oral antivirals would be the first at-home medications for the treatment of COVID-19. In clinical trials that enrolled unvaccinated patients with mild or moderate SARS-CoV-2 infection, molnupiravir decreased the risk for hospitalization by 50% vs 89% for paxlovid.1-2

To gain further insight into the potential impact these oral antivirals will have on the COVID-19 pandemic, we spoke with Erica Johnson, MD. Dr Johnson is an assistant professor of medicine at Johns Hopkins University and the chair of the American Board of Internal Medicine’s Infectious Disease Board.

What role would an oral antiviral COVID treatment have in reshaping acute evaluations in settings such as urgent care centers and emergency departments in the United States?

Dr Johnson: I think what’s really exciting about these oral antivirals is that if they are paired appropriately with rapid testing, then they could become a very effective way to manage the COVID-19 pandemic and help prevent surges that may occur in local areas. I think it really all comes down to the availability of patients with COVID-19 to be evaluated as soon they begin developing symptoms, and the availability of point-of-care testing to produce results quickly enough so that patients receive prescriptions for these oral antivirals as soon as possible. Without that, I think it limits some of the efficacy because these medications only work when they’re given within days of initial onset of SARS-CoV-2 infection, based on what we’ve seen so far.

What lessons can be learned from the implementation of treatment guidelines after the availability of oral antivirals for seasonal influenza?

Dr Johnson: I think that the role of treatment guidelines is standardizing care so that, regardless of where in the US you’re presenting for care, or the circumstances under which you’re presenting for care, you have the same access for testing and the same opportunities for treatment, if indicated. I think it’s also helpful to know for whom treatment may not be indicated. With limited resources, I think we also need to be thinking about the people who may not benefit from care, and the treatment guidelines help us differentiate between individuals with mild cases from those with moderate or severe cases so that we can make the most appropriate treatment decisions.

When these newly developed oral antiviral medications for the treatment of COVID-19 hit the market, such as molnupiravir and paxlovid, what do you expect the response will be among vaccine-hesitant individuals?

Dr Johnson: I’ve thought a lot about this and I’m not sure that the availability of oral medications really factors into people’s decisions about vaccines. I think that people’s decisions about vaccinations are really complicated and nuanced. And honestly, I think the best way to understand them is by asking questions and trying to make sure that information is delivered by people that are trusted by any specific individual so that they can make the best decision. I think there is an expectation that when you are sick and present for care, that you’ll be treated with the standard of care. I think that’s generally a widely held belief here in the United States. If these medications are as promising as they seem based on currently available data, I think that lots of people may feel a sense of hope about the fact that if they do get COVID-19, these medications may be helpful even if they are unvaccinated.      Again, that’s if real-world use of these medications aligns with currently available data. But for those who are vaccine-hesitant, I think that it’s still important to make them aware that we will continue to develop other ways and strategies to combat this pandemic. Ensuring that herd immunity is at as high a level as possible is still going to be the most effective way to return to normal, and vaccination is the most important part. And I don’t think that message is going to get lost even if these oral antivirals become as effective in practice as they seem to be in clinical trials.

Although recent press releases from both Merck and Pfizer show that these COVID antivirals are highly effective in decreasing the risk for hospitalization and severe disease, what level of skepticism do you believe is likely to occur among clinicians regarding the validity of these results, particularly among those whose skepticism stems from discrepancies regarding the efficacy of other antiviral agents that also showed promising results in clinical trials, such as oseltamivir?

Dr Johnson: I think a little skepticism right now is okay, especially since the results from the trials related to paxlovid still need to be fully peer reviewed and published. But if molnupiravir and paxlovid do ultimately receive EUA from the FDA, and if there are clear ways that we can make use of these medications effectively and the results from the clinical trials are replicated with this real-world use, then I think that skepticism may start to melt away. A lot still needs to happen, but I think the bottom line is the healthcare workers will likely continue to recognize that these antivirals are just an additional tool, but not the only tool, that may help, particularly if we find that the real-world data matches what has been reported in the clinical trials.

Is there anything about these clinical trials on COVID antivirals (eg, study design, inclusion/exclusion criteria, patient population, follow-up period, etc) that would help quell concerns of clinicians who may be skeptical of the validity of the results?

Dr Johnson: I think that, as clinicians and scientists, whenever we analyze new data we’re always looking to find out whether the patients included in the clinical trials match the people that we’re trying to treat in front of us. And so, having access to these data, and being able to look at who was included in the trials, how they were managed, how quickly they were able to receive the medication, and the results from both those who received the medication and those who received placebo — I think all of that will go a long way in helping clinicians make decisions about whether or not these medications, if authorized for use, will be effective for the patients that they are treating in front of them.

What effect will the approval of these COVID antivirals have on the management of patients with COVID-19 who are immunocompromised?

Dr Johnson: So, I think the ultimate test is going to be the use of these antivirals in patients who are immunocompromised. There are a variety of different reasons as to why patients may have impairments in their immune system, and it will be important to see what the effect these antivirals have on those patients. I think what’s promising is that we know that patients who are immunocompromised may have less effective immune responses to the COVID-19 vaccine. And so, having treatments that could be helpful if they do develop COVID-19 provides an extra layer of protection, though we definitely need more time and more results to be able to effectively answer that question. Another important point is paxlovid includes the medication ritonavir, which has some drug-drug interactions, interactions broadly, and interactions among patients taking immunosuppressive medications, which may complicate the use of paxlovid. I don’t know to what extent it may impact the use of paxlovid in some situations, because we’re talking about using it for a short period of time and it’s something that does need to be evaluated.

Is there any evidence that these antiviral medications will be as effective against SARS-CoV-2 variants that may develop in the future?

Dr Johnson: Based on the information we have so far, it does seem promising in the sense that, specifically for molnupiravir, it was tested against the Delta variant as well as some of the other SARS-CoV-2 variants of concern that we’ve been monitoring. And early results showed that the drug was effective against the Delta variant. I think that we’ll have to wait and review results of real-world use to see if it continues to be effective as new variants emerge. It will be important to closely monitor patients who do not respond well to treatment and ensure it’s not because of resistance. Based on what we know so far, we expect that these medications actually will hold up against a variety of circulating SARS-CoV-2 variants.

Will these COVID antivirals decrease the risk for SARS-CoV-2 transmission, particularly among those who are unvaccinated? And what role will these medications play in helping to transition COVID-19 from a pandemic to an endemic?

Dr Johnson: So, for the first question, I think that’s definitely an answer that we all want to know. Unfortunately, I don’t think that we have the data to be able to effectively answer that question. But I think that transmission risk is one of the things we’ll be continuing to monitor as we continue to parse out data from the clinical trials, and also as we receive more data from real-world use of these medications, including the real-world use of molnupiravir that’s already happening in the United Kingdom, and then any additional data we may have if the FDA approves it for EUA in the US. As far as the second question, I think that it’s also a little bit too early to tell. But I think that the reason for people’s hope around these oral antivirals is that, although we’ve had some success with monoclonal antibodies and other injectable treatments, there are a lot of issues related to how to effectively distribute these medications broadly, dispense them to centers, and have patients treated within the window of time to make them effective — oral antivirals will help simplify a lot of those issues. And if paired appropriately with rapid testing and early availability of results, I think there’s a great amount of potential for these medications.

Is it possible that these COVID antivirals will be approved for use as a broad-spectrum antiviral agent against other viral infections?

Dr Johnson: I don’t know, but I know that as we’re thinking about opportunities for treatment of a variety of different viral illnesses, we often look to existing viral medications to see whether they would be effective. I can speculate that the same would be true for these oral antivirals. I think it’s a little bit too early to know. For example, ritonavir, which is part of paxlovid, is a commonly used medication in the management of HIV infection, but it’s hard to say for sure whether these medications will have broad-spectrum use.


  1. Mahese E. Covid-19: Molnupiravir reduces risk of hospital admission or death by 50% in patients at risk, MSD reports. BMJ. Published online October 4, 2021. doi:10.1136/bmj.n2422.
  2. Mahese E. COVID-19: Pfizer’s paxlovid is 89% effective in patients at risk of serious illness, company reports. BMJ. Published online November 8, 2021. doi:10.1136/bmj.n2713.

This article originally appeared on Infectious Disease Advisor