The Future of Paxlovid for COVID-19

As of December 2022, about 6 million Americans had taken Paxlovid free of charge, courtesy of the US federal government. Paxlovid — the trademarked name for the nirmatrelvir/ritonavir pill produced by Pfizer — helped prevent hospitalization and death in patients with COVID-19 during the pandemic and may also help prevent long-term COVID-19.¹ 

Now, patients’ ability to access this drug in the future is uncertain: When the COVID-19 Public Health Emergency Declaration ended on May 11, 2023, the federal government’s free coverage of Paxlovid also ended.¹ Although the US Food and Drug Administration subsequently approved Paxlovid on May 25, 2023, there has been no additional insight on the coverage of Paxlovid through private insurances and Medicare and Medicaid.²

At this point, there is a great deal of uncertainty about the future access, availability, and price of Paxlovid. The switch from government-purchased to insured Paxlovid may prove jarring for patients and clinicians. Although the price of Paxlovid will likely rise, experts demur on predicting exact numbers.¹ The US government had previously purchased 20 million courses of Paxlovid to secure a bulk rate of $530 a dose. Moving forward, the drug will no longer be priced in bulk.¹ 

Paxlovid: a pandemic success story

Throughout the pandemic, different drugmakers took their shot at developing treatments for mitigating the clinical course of COVID-19, with little success. Various antiviral drugs, monoclonal antibodies, and immunomodulatory drugs have been proposed as possible treatments for SARS-CoV-2 infection. However, most of these interventions failed to decrease the risk of progression to severe COVID-19 or are too expensive or hard to secure from a logistics perspective.³

Then came Paxlovid. In 2021, researchers for the EPIC-HR trial (ClinicalTrials.gov Identifier: NCT04960202) found that nirmatrelvir/ritonavir decreased the risk for severe COVID-19 by nearly 90% in unvaccinated people.^4,5 This study was done during the Delta-variant period and prior to widespread vaccination for COVID-19.

Subsequently, Dryden-Peterson et al conducted a large, retrospective study (n=44,551) of the effects of nirmatrelvir/ritonavir in mostly-vaccinated nonhospitalized patients aged 50 and older with COVID-19 in early 2022. Although the overall rates of hospitalization and death from COVID-19 were less than 1% during the period studied — much lower than when the EPIC-HR trial was conducted — Dryden-Peterson et al nevertheless found that nirmatrelvir/ritonavir reduced the risk of hospitalization and death from COVID-19 by 44% in the overall study population and by 81% among those who were unvaccinated.^4,6

Another large Israeli study (n=180,351) conducted in the Omicron era likewise found nirmatrelvir/ritonavir effective in mitigating the severity of COVID-19 and reducing mortality in a population that was mostly vaccinated.  The researchers suggested that Paxlovid appeared more effective in the elderly, immunosuppressed patients, or those with a history of neurological/cardiovascular disease.³

The efficacy of Paxlovid could be due to the nature of its target, said Ryan Maves, MD, Professor of Infectious Diseases at Wake Forest School of Medicine and Chair of the COVID-19 Task Force with the American College of Chest Physicians, in an exclusive interview. “The molecular target of nirmatrelvir (the active component of Paxlovid) is the SARS-CoV-2 viral protease. This enzyme is highly conserved across different variants. As a result, we have not seen any decrease in effectiveness with the newer variants. A mutation in the protease gene could lead to decreased effectiveness in the future, but that would likely come at some cost to the virus as well, such as a decreased capacity to replicate,” he said.

Alternative Therapies and How They Compare

With AstraZeneca’s Evusheld (tixagevimab/cilgavimab) no longer on the US market, Merck’s Lagevrio (molnupiravir) is another agent that can help with treating COVID-19. Molnupiravir, however, is a far cry from Paxlovid. 

“Molnupiravir is a viral RNA polymerase inhibitor, blocking a different enzyme than nirmatrelvir in Paxlovid. Molnupiravir prevents the virus from replicating its genetic material in a human cell, while nirmatrelvir prevents the protein products of those viral genes from being cleaved and subsequently assembled into a mature virion,” said Dr Maves.

He added, “Molnupiravir does not appear to have a large impact on hospitalization or death in fully vaccinated patients, but it probably reduces overall risk in unvaccinated or under-vaccinated patients by about 40%.”

In addition to being less effective than Paxlovid, molnupiravir could also be teratogenic.

“Molnupiravir seems to be less effective than Paxlovid in high-risk patients, although it does have some benefit in reducing severe disease and is likely better than no therapy at all. There does appear to be some risk of teratogenicity with molnupiravir, so women of child-bearing potential need testing for pregnancy and careful counseling if they receive it,” stated Dr Maves.

Future Access: What Can Be Done

Dr Maves noted that the use of Paxlovid by the general public has been underwhelming.

“Paxlovid is a great drug for individual patients, to be sure,” he said. “Paxlovid uptake has never been as high as we would have liked it to be in patients with COVID-19 at high risk for severe illness, such as older adults or those with significant chronic health conditions. Those patients with good access to Paxlovid have tended to be the usual groups: well-insured, with good access to care.”

When asked whether individual specialists can assist patients who may be unable to afford Paxlovid treatment, Dr Maves had some ideas.

“For those who work in large health systems, we need to figure out our local policies for Paxlovid prescribing and access, as well as establish what sort of financial support we can offer to uninsured and under-insured patients. There are some patients for whom medication interactions with Paxlovid will be prohibitive; in them, molnupiravir might be an acceptable alternative. The same applies to independent physicians working in the community. The best thing we can do, of course, is to prevent the need for Paxlovid in the first place, by advocating for vaccination for eligible patients,” he said.