As another COVID-19 summer surge hit the US this year, many infected people likely were prescribed the antivirals nirmatrelvir and ritonavir, better known as Paxlovid, for the first time. Or for the fourth time. Or somewhere in between.

 

 

Nirmatrelvir-ritonavir, the only approved oral therapy for COVID-19, is recommended for treating mild to moderate SARS-CoV-2 infections among people who are at high risk of progression to severe disease. This includes people aged 50 years or older, especially those 65 years or older, as well as younger individuals who have any of a long list of comorbidities that increase the risk of severe COVID-19.

 

The clinical trials leading to the US Food and Drug Administration (FDA) authorizing emergency use of nirmatrelvir-ritonavir in December 2021 and approving it in May 2023 were conducted with unvaccinated people who were infected with the now long-gone SARS-CoV-2 Delta variant. This has led to questions about its effectiveness for people who have been vaccinated or have been infected with subvariants of Delta’s successor Omicron, which have been circulating for nearly 3 years.

 

But recent observational studies suggest nirmatrelvir-ritonavir still protects people at high risk against hospitalization and death from COVID-19. That is if they’re able to get a prescription for it—research has uncovered racial and ethnic disparities in which eligible patients get a prescription for the treatment.

 

And as the number of people with postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, grows, scientists have been investigating whether nirmatrelvir-ritonavir might be useful in protecting against or treating the condition.

 

 

Because the nirmatrelvir-ritonavir phase 2 and 3 trial involved unvaccinated adults without prior COVID-19 infection when the Delta variant dominated, questions have remained about its relevance today.

 

Scientists from Pfizer, which markets nirmatrelvir-ritonavir, and coauthors recently published a systematic literature review examining that question. They searched for real-world studies reported from December 2021 through March 2023 and identified 18 that met their final selection criteria.

 

The evidence showed that nirmatrelvir-ritonavir was effective regardless of age, underlying high-risk conditions, or vaccination status. The treatment significantly reduced the postinfection risk of all-cause and COVID-19–related mortality both within the first 30 days and in the long-term. Treatment started within 5 days of symptom onset, as recommended on the label, was associated with the greatest reduction in postinfection risk.

 

“We remain very confident in Paxlovid’s clinical effectiveness at preventing severe outcomes, including hospitalization and death, from COVID-19 in patients at high risk of severe disease,” Pfizer spokesperson Kit Longley said in an early August email.

 

Another recently published study reached a somewhat different conclusion. That study, conducted by University of Manitoba researchers, analyzed results from 4 randomized trials and 16 real-world studies, some of which had not yet been peer-reviewed, with a total of nearly 2 million adults aged 18 years or older.

 

The evidence suggested nirmatrelvir-ritonavir has a small but significant efficacy in reducing COVID-19 hospitalization and all-cause mortality among people with laboratory-confirmed mild to moderate infections, but the evidence is weak, so more studies are needed, the authors concluded.

 

 

COVID-19 laid bare health disparities in the US, and nirmatrelvir-ritonavir has been no exception, according to a study published in August.

 

Using National COVID Cohort Collaborative (N3C) data, researchers studied individuals 18 years of age or older who were diagnosed with COVID-19 between January 2022 and December 2023; up until the end of that period, the US government covered the cost of nirmatrelvir-ritonavir for everyone who needed it.

 

About 1.26 million people in the N3C cohort were at high risk of progressing to severe disease, making them eligible for nirmatrelvir-ritonavir treatment. But overall, nearly two-thirds of those who were eligible weren’t prescribed the treatment, the authors observed. After accounting for age, sex, and clinical characteristics, the researchers found that non-Hispanic Black and Latino individuals were nearly a third less likely to have used nirmatrelvir-ritonavir than non-Hispanic White individuals.

 

Patients may not seek care or may not seek it out early enough for the treatment to be effective, coauthor Hemalkumar Mehta, PhD, a core member of the N3C, speculated in an interview with JAMA Medical News.

 

Another reason could be that patients don’t have a regular source of primary care whom they could ask for a prescription, noted Mehta, a pharmacist and epidemiologist at the Johns Hopkins Bloomberg School of Public Health. They likely don’t know that the FDA has authorized state-licensed pharmacists to prescribe nirmatrelvir-ritonavir, he said.

 

Mehta acknowledged that until he conducted his study, even he didn’t realize that pharmacists could prescribe the COVID-19 treatment. Publicizing that fact by simply hanging a sign in pharmacies would help, he pointed out.

 

However, the FDA created an obstacle to quick prescribing of nirmatrelvir-ritonavir by pharmacists, a 2023 article noted. Prior to prescribing, pharmacists must assess patients’ liver and kidney function through health records from the previous 12 months or consultation with their clinician. Other prescribers can simply ask patients about their liver and kidney function and take their word for it, the authors explained. In addition, there is no standardized pathway for pharmacists to bill payors for assessing patients to see if they’re eligible for nirmatrelvir-ritonavir, which typically takes 15 to 30 minutes, according to the American Pharmacists Association.

 

When people do get a prescription for nirmatrelvir-ritonavir, most get it filled, a recently published study of Walgreens pharmacies nationwide data found. The retrospective study included people 12 years of age or older for whom a nirmatrelvir-ritonavir prescription was ordered from Walgreens pharmacies between December 2021 and August 2023.

 

A total of about 2.1 million nirmatrelvir-ritonavir prescriptions were ordered for about 2 million individuals. Among the 95% of people who were prescribed only 1 course of the treatment, 88% filled their prescription. Improving uptake of nirmatrelvir-ritonavir requires increasing patient and prescriber awareness, reducing prescribing disparities, and ensuring treatment initiation within 5 days of symptom onset, the authors concluded.

 

 

Taking nirmatrelvir-ritonavir for acute COVID-19 might protect against long COVID, although research into that topic has had mixed results.

 

For example, 2 recent studies, neither of which had yet been peer-reviewed, reached different conclusions.

 

A preprint posted in June reported observational study results from the Researching COVID to Enhance Recovery (RECOVER) initiative funded by the US National Institutes of Health (NIH). The study population included nearly 500 000 people who tested positive for SARS-CoV-2 between March 2022 and February 2023. Of those, about 165 000 were treated with nirmatrelvir-ritonavir within 5 days after becoming infected.

 

Compared with no treatment, nirmatrelvir-ritonavir therapy was associated with a 12% lower risk of developing long COVID within 180 days of infection, or an absolute risk reduction of about 3 cases per 100 people. However, no such risk reduction was seen in people at low risk of severe COVID-19 infection who received nirmatrelvir-ritonavir.

 

“There are quite a few patients who are not at risk but who received a Paxlovid prescription,” first author Fei Wang, PhD, explained in an interview with JAMA Medical News. “This provides us an opportunity to evaluate a low-risk population that got COVID.”

 

Another preprint, posted this summer, used N3C electronic health records. It found that nirmatrelvir-ritonavir treatment of acute COVID-19 was not significantly associated with reducing long COVID overall, although it was linked to fewer cognitive and fatigue symptoms.

 

The mixed findings between the 2 studies aren’t surprising, said Wang, an assistant professor of health care policy and research at Weill Cornell Medicine.

 

Some information, such as COVID-19 vaccination history and nirmatrelvir-ritonavir use, isn’t always encoded in electronic health records, Wang pointed out. Although he and his colleagues “spend a lot of effort” to make sure they have complete patient information, Wang explained, “there’s no way we can evaluate how complete that is.”

 

He added that not having a consensus definition of long COVID is another critical issue. The N3C’s definition isn’t the same as RECOVER’s, and the 2 cohorts have different patient populations. “All these can lead to different results,” he said.

 

For Wang, it makes sense that taking nirmatrelvir-ritonavir, an antiviral, for acute COVID-19 would protect against long COVID. The severity of acute SARS-CoV-2 infections is correlated with the risk of long COVID, he said, and one theory about the cause of PASC is the persistence of SARS-CoV-2 in the body.

 

However, Yale cardiologist Harlan Krumholz, MD, SM, pointed out that unidentified confounders, not nirmatrelvir-ritonavir itself, might be at play in the relationship between treating acute SARS-CoV-2 infection and long COVID risk. “People who take Paxlovid might be different in many other ways,” he noted.

 

 

Many individuals with long COVID didn’t have the opportunity to take nirmatrelvir-ritonavir when they first became ill with acute COVID-19. They might have been infected before the treatment became available, or they weren’t considered to be at high risk for severe disease, so they weren’t eligible for it.

 

Some case reports have suggested that it might not be too late for people who’ve had long COVID for months to benefit from nirmatrelvir-ritonavir. For example, in early 2023 internist Linda Geng, MD, PhD, codirector of Stanford’s PASC clinic, and coauthors reported the case of a patient who’d had long COVID for 7 months, around which time the symptoms of acute COVID-19 returned. Although rapid antigen test results were negative, the patient had been exposed to multiple people with COVID-19, so a primary care physician prescribed nirmatrelvir-ritonavir. Not only did the acute flu-like symptoms resolve, but so did the long COVID symptoms, which included severe fatigue and cognitive difficulties.

 

That patient spurred Geng and her colleagues to conduct what they say is the first published randomized trial of nirmatrelvir-ritonavir to treat PASC, which appeared in June in JAMA Internal Medicine. The trial enrolled 155 participants with long COVID, all but 2 of whom had received the primary COVID-19 vaccination series. On average, the time between their initial SARS-CoV-2 infection and randomization into the trial was about a year and a half.

 

The trial found that the longer 15-day course of nirmatrelvir-ritonavir it used was generally safe. However, the treatment didn’t significantly improve long COVID symptoms compared with the control group.

 

It’s far from the final answer about nirmatrelvir-ritonavir’s effectiveness against long COVID, though, Geng noted. “This is just the first step in many investigations that need to be done.”

 

The NIH is funding several clinical trials targeting long COVID under the RECOVER initiative umbrella. One, the Platform Protocol to Measure the Effects of Antiviral Therapies on Long COVID Symptoms (RECOVER-VITAL), is testing an even longer course of nirmatrelvir-ritonavir among an estimated 900 participants at centers throughout the US.

 

And Krumholz and colleagues at Yale University are in the process of analyzing data from their placebo-controlled randomized trial of nirmatrelvir-ritonavir in 100 patients with long COVID. (The trial received funding and design input from Pfizer.)

 

“We’re not sure it works,” said Krumholz, founder and director of the Yale New Haven Hospital Center for Outcomes Research and Evaluation. “What I think we need are a lot more studies of 100 people or 200 people, trying a lot more things” to treat long COVID.

 

Participants in the Yale trial were all highly symptomatic and lived throughout the contiguous US. Instead of having them go to participating centers, the trial came to them. “Setting up centers is expensive,” Krumholz explained, noting that the trial’s decentralized design could help cut costs and could work for a variety of conditions and treatments.

 

Participants were shipped the medication. They gave blood and saliva samples at a local laboratory or at home and answered questions about their symptoms in a digital diary. Yale colleague Akiko Iwasaki, PhD, who studies antiviral immunity and viral disease pathogenesis, is looking at the blood and saliva samples for differences between people who appeared to respond to nirmatrelvir-ritonavir and those who didn’t.

 

 

Meanwhile, Pfizer is working to eliminate what one recent publication referred to as nirmatrelvir-ritonavir’s Achilles’ heel: the limited metabolic stability of nirmatrelvir, a protease inhibitor that requires ritonavir to boost it to the target therapeutic range.

 

The problem is that ritonavir boosts the plasma levels of a long list of other medications beyond the therapeutic range, so nirmatrelvir-ritonavir is contraindicated for people taking them, unless they can temporarily stop or reduce the dose of the concomitant drugs while taking the COVID-19 treatment. Ritonavir is also the source of the metallic taste many individuals who take Paxlovid experience.

 

Pfizer’s second-generation protease inhibitor for treating COVID-19 is called ibuzatrelvir. Although it’s structurally related to nirmatrelvir, ibuzatrelvir has greater bioavailability when taken orally, so it doesn’t require a ritonavir boost.

 

Pfizer has completed a phase 2B trial testing the safety and efficacy of a 5-day course of ibuzatrelvir treatment. Participants were nonhospitalized individuals aged 18 to 65 years with confirmed COVID-19 whose symptoms began within 5 days of randomization. Ibuzatrelvir showed robust antiviral activity in the trial, with statistically significant, dose-dependent decreases in viral load at days 3 and 5 compared with placebo, Pfizer researchers reported in April at the European Congress of Clinical Microbiology and Infectious Diseases.

 

“It is premature to speculate on potential timing of phase 3, but we are considering next steps and plan to share updates as they are available,” Pfizer spokesperson Longley said.

 

Meanwhile, SARS-CoV-2 continues to evolve along with attitudes toward COVID-19, Krumholz said. Many people “are treating it like a head cold,” he explained. “They’ve obviously made the determination that it’s not dangerous, but it is dangerous.”

 

Published Online: September 6, 2024. doi:10.1001/jama.2024.16432

Conflict of Interest Disclosures: Dr Geng reported grants from Pfizer during the conduct of her nirmatrelvir-ritonavir study; personal fees from UnitedHealth Group; and grants from the NIH and the Agency for Healthcare Research and Quality. Dr Krumholz reported receiving stock options for Element Science and Identifeye and payments from F-Prime for advisory roles; he is a cofounder of and holds equity in Hugo Health, Refactor Health, and ENSIGHT-AI; and, through Yale University, he is associated with research contracts from Janssen, Kenvue, Novartis, and Pfizer. No other disclosures were reported.