Medical News & Perspectives
January 31, 2024
Paxlovid Is Effective but Underused—Here’s What the Latest Research Says About Rebound and More
Rita Rubin
JAMA. Published online January 31, 2024. doi:10.1001/jama.2023.28254
Anyone who watches television has probably seen the Pfizer commercial with the tagline, “If it’s COVID, Paxlovid.”
That might be a catchy slogan, but, apparently, a lot of people aren’t getting the message.
The US Food and Drug Administration (FDA) approved Paxlovid last May for the treatment of mild to moderate COVID-19 in adults who are at risk of progression to severe disease. But it has been available since early 2022 under Emergency Use Authorization (EUA) from the FDA for treating COVID-19 in people 12 years or older. A dose of Paxlovid consists of 2 pills of the protease inhibitor nirmatrelvir and 1 pill of ritonavir, which boosts nirmatrelvir’s concentration in plasma to the target therapeutic range by slowing its metabolism in the liver.
Thanks in a large part to vaccines and treatments such as nirmatrelvir-ritonavir, hospitalizations and deaths from COVID-19 have plummeted since the early months of the pandemic. Still, approximately 33 000 patients were hospitalized for COVID-19 in the US during the week ending January 13, a period in which 1 in 25 US deaths were due to the disease, according to the Centers for Disease Control and Prevention (CDC).
“The number of hospitalizations for COVID right now are much higher than for flu,” Pragna Patel, MD, MPH, chief medical officer in the Coronavirus and Other Respiratory Viruses Division of the CDC’s National Center for Immunization and Respiratory Diseases, pointed out in an interview with JAMA.
One likely reason: relatively few eligible patients are getting nirmatrelvir-ritonavir, the preferred treatment for keeping mild to moderate COVID-19 from progressing to severe disease.
A retrospective study published in January of this year found that only 12.2% of 309 755 eligible adult outpatients received nirmatrelvir-ritonavir. The patients, seen from January 2022 through December 2022, received care from the National Veterans Affairs Healthcare System. The proportion of eligible patients prescribed the treatment did increase over the course of the study, the authors noted, but by December still had only reached 23.2%.
And a study of a million patients diagnosed with COVID-19 between December 2021 and February 2023, selected from the National COVID Cohort Collaborative database, found that just under 10% of eligible patients received nirmatrelvir-ritonavir. That research, published last June and not yet peer reviewed, found that treatment within 5 days after a COVID-19 diagnosis reduced 28-day hospitalization and mortality.
Concerns about the widely reported “rebound” phenomenon linked with nirmatrelvir-ritonavir, unfamiliarity with the treatment, and cost might all be contributing to underuse, Patel and other experts say. “I have heard from a lot of clinicians there’s some confusion around who’s at high risk for severe disease,” Patel added.
Here are answers to that question and others that both prescribers and patients might have about nirmatrelvir-ritonavir and other treatments designed to reduce the risk of severe COVID-19.
Is Nirmatrelvir-Ritonavir Treatment Still Free?
Myron Cohen, MD, director of the University of North Carolina Institute for Global Health and Infectious Diseases in Chapel Hill, expressed concern in an interview that use of nirmatrelvir-ritonavir might slide now that it’s on the commercial market. According to manufacturer Pfizer, it has a list price of $1390 per 5-day course of treatment.
However, “no one should be paying full price for Paxlovid” unless they choose to, Meghan Pennini, PhD, chief vaccines and therapeutics officer at the Administration for Strategic Preparedness and Response (ASPR) said at a January 11 webinar on COVID-19 antivirals sponsored by the National Press Foundation.
From December 2021 to December 15, 2023, the ASPR, part of the US Department of Health and Human Services, worked with health departments, pharmacies, long-term care facilities, and other relevant parties to support the distribution of free nirmatrelvir-ritonavir.
Under the US government’s Patient Assistance Program, the treatment will remain free through the end of this year for Medicare or Medicaid beneficiaries and for those who are uninsured.
Insured individuals can enroll in the Paxcess program, which can cover their out-of-pocket costs, Pennini noted at the webinar, adding that physicians and pharmacists can also enroll patients in the program. “We want providers to be aware of that,” she emphasized. “We want the public to be aware of that.”
Who’s a Candidate for Treatment to Prevent Severe COVID-19?
Everyone aged 50 years or older, to begin with.
Being in that age group is the most important risk factor for severe COVID-19, and the risk increases substantially starting at age 65 years, according to the CDC’s Interim Clinical Considerations for COVID-19 Treatment in Outpatients webpage, updated on January 17 of this year.
Other risk factors for severe disease include being unvaccinated or not being up to date with COVID-19 vaccinations, as well as specific medical conditions, such as diabetes, cancer, coronary artery disease, chronic lung diseases, pregnancy or recent pregnancy, or the use of immunosuppressant drugs.
The CDC has also noted that members of racial and ethnic minority groups are not only more likely to become infected than non-Hispanic White people but are also “more likely to be hospitalized, be admitted to the ICU [intensive care unit], and die from COVID-19 at younger ages.”
Pfizer had conducted a trial of nirmatrelvir-ritonavir among people with COVID-19 who weren’t at high risk for progression to severe disease, but the primary end point of self-reported, sustained alleviation of all symptoms for 4 consecutive days was not met; the company announced in June 2022 that it was going to halt enrollment in the trial due to the low rate of hospitalization and death in standard-risk patients.
Are There Other Treatments to Prevent Severe COVID-19?
In the US, 3 other treatments are available for people with mild to moderate COVID-19 who are at high risk of progression to severe disease, although nirmatrelvir-ritonavir is preferred for most.
However, the treatment is contraindicated for some patients because ritonavir slows the metabolism of a variety of medications, leading to excessively high concentrations. (The University of Liverpool Drug Interaction Group has created a free online tool to check for drug interactions with nirmatrelvir-ritonavir and other COVID-19 drugs, Patel noted.)
The antiviral remdesivir (Veklury) is recommended for patients who can’t take nirmatrelvir-ritonavir, according to the CDC’s Interim Clinical Considerations webpage. Unlike nirmatrelvir-ritonavir, which has an EUA for patients 12 years through 17 years of age, remdesivir is approved for pediatric patients as young as 28 days.
Compared with placebos, both treatments were shown to be highly effective in clinical trials for reducing the risk of hospitalization and death—efficacy was 86% for nirmatrelvir-ritonavir and 87% for remdesivir. However, patients must go to an infusion center for 3 consecutive days to receive remdesivir intravenously.
For those who can’t access either of those treatments or have a contraindication to them, the antiviral pill molnupiravir (Lagevrio), which wasn’t as effective in clinical trials as the other 2 antivirals, can be used, according to the CDC.
Under an EUA, COVID-19 convalescent plasma with high titers of anti–SARS-CoV-2 antibodies is available to treat COVID-19 in patients who are immunocompromised, but the National Institutes of Health (NIH) COVID-19 Treatment Guidelines note that there is insufficient evidence to recommend for or against its use.
Does Nirmatrelvir-Ritonavir Cause Rebound?
Maybe, but it appears that untreated COVID-19 can too.
Perhaps the main reason nirmatrelvir-ritonavir has been underused is the rebound phenomenon, usually described as the return of symptoms and test positivity a few days after completing treatment and appearing to have recovered.
Research findings have been mixed about whether rebound is linked to nirmatrelvir-ritonavir or COVID-19 itself, but the consensus is that when it occurs, it is brief and mild and shouldn’t be a reason not to treat eligible patients.
An observational study published in November 2023 compared rebound rates of 130 treated and 241 untreated patients who were eligible for treatment. The treated and untreated groups had similar baseline characteristics. Researchers collected daily reports for 10 days from each patient about symptoms and medication use as well as respiratory specimens for polymerase chain reaction (PCR) testing from March 2022 to May 2023.
Patients who completed treatment reported experiencing fewer symptoms and had a lower viral load than those who weren’t treated, the authors found. However, those who were treated had a greater occurrence of symptom rebound compared with untreated participants (32% vs 20%) and viral load rebound (27% vs 7%).
The study had several limitations. The authors noted that some patients might not have reported using COVID-19 medication and that the 10-day follow-up might not have been long enough to detect all cases of rebound. Clinicians should prescribe nirmatrelvir-ritonavir to eligible patients and explain the possibility of rebound, the authors concluded.
Another small observational study, also published last November, found that virological rebound occurred in about 20% of 72 patients who took nirmatrelvir-ritonavir, compared with only 1 of 55 people who did not receive the treatment after being diagnosed with COVID-19. Only half of the people who experienced virological rebound also reported that their symptoms had returned.
The authors pointed out that other differences between the treated and untreated groups could have contributed to the variation in virological rebound. The treated patients were older, more commonly had immunosuppression, and had received more COVID-19 vaccinations, the researchers noted.
People who are at risk of severe COVID-19 due to older age or immunosuppression or both may be more likely to experience rebound, explained Cohen, who coauthored an editorial accompanying the second research article. And it’s not that being vaccinated increases the risk of rebound, he said. It’s that people who are at risk of severe COVID-19 are more likely to be up to date with their vaccinations.
In contrast to the studies published in November, 2 papers that appeared a month later in Morbidity and Mortality Weekly Report (MMWR), one by Patel and CDC colleagues and the other by FDA scientists, both concluded that among patients with COVID-19, virological rebound rates were similar between patients treated with nirmatrelvir-ritonavir and those who were not.
There were reports of COVID-19 rebound even before nirmatrelvir-ritonavir became available to treat the disease, Patel pointed out. Rebound has also been seen in patients who received corticosteroids or monoclonal antibodies to treat COVID-19, she added.
For the MMWR article, Patel’s team reviewed 23 SARS-CoV-2 rebound-related studies published from February 1, 2020, to November 29, 2023. Seven of the studies—1 randomized trial and 6 observational studies—met inclusion criteria. In the trial and 3 of the observational studies, no statistically significant difference in rebound rates was identified between patients treated with an antiviral such as nirmatrelvir-ritonavir and those who weren’t treated. Rebound signs and symptoms were mild, and no hospitalizations or deaths were reported among those who experienced it.
“We were worried that rebound got linked to Paxlovid, and folks might be hesitant to take it because of rebound,” Patel said in explaining why she and her colleagues conducted their study. The benefits of treatment outweigh the risks of rebound, she emphasized, especially among people at high risk of severe disease.
To minimize confounding, the FDA researchers analyzed data that Pfizer had submitted to the agency from 2 randomized double-blind, placebo-controlled clinical trials, one conducted with high-risk individuals and one with standard-risk patients. In the trials, viral RNA levels were evaluated with nasopharyngeal specimens from day 5, the end of treatment, to day 10 or day 14. The data showed that SARS-CoV-2 rebound can occur with or without antiviral treatment, the FDA scientists concluded.
When Is the Best Time to Begin Treatment?
Treatment is supposed to begin as soon as possible after a COVID-19 diagnosis and within 5 days of symptom onset, according to the nirmatrelvir-ritonavir label.
A recent retrospective study by researchers at the University of Hong Kong suggested that within those 5 days, the sooner treatment begins, the better.
The authors used real-world electronic medical record data from all 87 070 adult nirmatrelvir-ritonavir users in Hong Kong between March 16, 2022, and January 15, 2023. They compared patients who started treatment on the same day as symptom onset or diagnosis or the next day with those who started treatment 2 or more days afterward. (According to the authors, about 4% of users in the late initiation group started treatment after the recommended limit of 5 days after symptom onset or diagnosis, but a sensitivity analysis that excluded them showed consistent results from the main analysis.)
Early treatment was associated with a significantly reduced incidence of 28-day all-cause mortality and hospitalization, which may be due to early suppression of viral replication, the researchers noted.
That said, starting treatment within a day of symptom onset might be tricky for some people because rapid antigen tests can yield false-negatives. These results should be confirmed right away with a PCR test if possible or another antigen test in 48 hours, according to the CDC.
“False-negatives could lead to delayed confirmation of illness and…a delay in antiviral treatment,” 3 of the University of Hong Kong researchers, Joseph Wu, PhD, Carlos Wong, PhD, and Jonathan Lau, MPH, acknowledged in a joint email to JAMA. (In February 2023, the FDA removed the requirement that patients test for COVID-19 before being prescribed nirmatrelvir-ritonavir “to provide flexibility in making a clinical diagnosis of COVID-19” but still recommended testing to diagnose the disease.)
During the period of their study, prescribing nirmatrelvir-ritonavir or, if contraindicated, molnupiravir to eligible patients was the default practice in Hong Kong’s public health sector, the researchers wrote in their email.
Their study also found that early treatment may be associated with a significantly higher risk of viral burden rebound, although the number of late-treated patients who experienced rebound was too low to be certain.
“We recommend clinicians and patients should not be overly worried about the risk of rebound, as there was no association between rebound and adverse clinical outcomes in our earlier study,” the researchers noted in their email, referring to a comparison of patients hospitalized with COVID-19 who received either nirmatrelvir-ritonavir or molnupiravir or no antiviral. That study found no difference in rebound rates among the 3 groups of patients.
Should Patients Resume Treatment If They Experience Rebound?
Anthony Fauci, MD, former director of the National Institute of Allergy and Infectious Diseases, noted in June 2022 that he took a second course of nirmatrelvir-ritonavir after experiencing a rebound in symptoms and test positivity a few days after finishing his first course of treatment.
However, no data have yet been reported either to support that decision or to invalidate it.
Pfizer is currently analyzing the results of a trial designed to answer this question. The double-blind trial involved people 12 years of age or older who’d experienced a rebound in symptoms and test positivity after a 5-day treatment course. Study participants were randomly assigned either to a repeat 5-day course of nirmatrelvir-ritonavir or a 5-day course of a nirmatrelvir placebo and ritonavir.
Some have speculated that rebound occurs because 5 days of treatment is inadequate to clear SARS-CoV-2. However, Pfizer compared 5-day and 10-day treatment courses in a trial of nirmatrelvir-ritonavir for postexposure prophylaxis and did not find a statistically significant advantage to the longer treatment.
The NIH COVID-19 treatment guidelines suggest that clinicians could prescribe patients who are immunocompromised a longer or repeat course of treatment if symptoms persist and there is evidence of ongoing SARS-CoV-2 replication. However, definitive data to support doing so are lacking, the guidelines note.
Does Treatment Reduce the Risk of Long COVID?
Again, the findings have been mixed.
Higher acute viral load or prolonged shedding may be associated with post–COVID-19 condition (PCC), commonly known as long COVID, so scientists have speculated that nirmatrelvir-ritonavir might help minimize the risk.
A study published in March 2023 in JAMA Internal Medicine found that among people with SARS-CoV-2 infection who had at least 1 risk factor for progression to severe disease, treatment with nirmatrelvir-ritonavir was associated with a reduced risk of PCC. Researchers used the Veterans Affairs health care databases to identify high-risk patients with a positive SARS-CoV-2 test result in 2022. Their cohort included approximately 282 000 patients, of whom about 36 000 were treated with nirmatrelvir-ritonavir.
And a study of approximately 2.3 million Medicare enrollees diagnosed with COVID-19 in 2022 found that nirmatrelvir-ritonavir and molnupiravir were associated with a small reduction in PCC incidence. The findings were reported in October 2023 in JAMA Internal Medicine.
But an observational cohort study published in January of this year found no difference in the development of PCC in treated and untreated patients. The study included 4684 vaccinated individuals diagnosed with COVID-19 who were part of the COVID-19 Citizen Science study, an online cohort study with more than 100 000 participants.
Of the cohort of 4684, about 1 in 5 received nirmatrelvir-ritonavir for acute SARS-SoV-2 infection. About a third of both the treated and the untreated patients responded to surveys at least 3 months after SARS-CoV-2 infection. The surveys asked about PCC symptoms and rebound in symptom or test positivity.
The study found that nirmatrelvir-ritonavir use was not associated with a lower prevalence of PCC. And among the treated participants who answered rebound questions, neither test-positivity rebound nor symptom rebound was associated with higher prevalence of PCC.
“It really was surprising to us,” lead author Matthew Durstenfeld, MD, MAS, said of the lack of an association between treatment and PCC. After all, he told JAMA in an interview, even people with mild COVID-19 can develop PCC, and data show that nirmatrelvir-ritonavir decreases viral load.
However, “we were pleasantly surprised” to find that rebound wasn’t linked to a greater risk of PCC, said Durstenfeld, a cardiologist and clinical researcher at the University of California, San Francisco. “We were wondering if rebound was kind of an early warning sign of long COVID.”
Are More COVID-19 Antivirals on the Way?
Nirmatrelvir-ritonavir may soon have more competition in the US and already does in at least a couple of countries.
Simnotrelvir is an antiviral pill that is also boosted by ritonavir. It received emergency conditional authorization a year ago in China, where it’s sold as Xiannuoxin, for the treatment of mild to moderate COVID-19.
A phase 2 and 3 trial in China, funded by developer Jiangsu Simcere Pharmaceutical based in Nanjing, compared simnotrelvir with a placebo in 1208 patients with COVID-19, only half of whom had risk factors for progression to severe disease. Compared with placebo, simnotrelvir treatment initiated within 3 days after symptom onset shortened the time to sustained resolution of COVID-19 symptoms by a day and a half, researchers reported January 18 in the New England Journal of Medicine.
Shionogi, a pharmaceutical company headquartered in Osaka, Japan, announced last April that the FDA had granted “fast track” designation—reserved for drugs that treat serious conditions and fill an unmet medical need—to its antiviral pill ensitrelvir.
In November 2022, ensitrelvir received emergency regulatory approval in Japan, where it’s sold as Xocova, for the treatment of mild to moderate COVID-19 in anyone, whether at high risk of progression to severe disease or not. It remains an investigational drug elsewhere.
Like nirmatrelvir-ritonavir, ensitrelvir is taken for 5 days. A phase 2B Shionogi-sponsored trial reported in December 2022 concluded that the difference from placebo in the reduction of SARS-CoV-2 RNA from baseline to day 4 appeared to be greater than that observed in clinical trials of nirmatrelvir-ritonavir and molnupiravir. The study didn’t find a significant difference overall when it assessed the difference in a dozen symptoms from baseline to day 4, which the researchers attributed to the low occurrence of some at baseline. However, ensitrelvir did improve respiratory symptoms and fever compared with placebo.
Ensitrelvir doesn’t require boosting with ritonavir, but that doesn’t mean it’s free of interactions with other drugs. In this case, though, drug-drug interactions can lead to a marked decrease in concentrations of the COVID-19 drug “and the loss of virological response and possible resistance,” according to the University of Liverpool’s COVID-19 Drug Interactions website.
Ongoing postmarketing surveillance in Japan found that ensitrelvir was safe and effective in real-world patients no matter their age or other risk factors for severe disease, according to data Shionogi presented in October at IDWeek (Infectious Disease Week). No deaths due to COVID-19 were reported, and no new concerns about tolerability or effectiveness were identified, according to the company.
At least 1 other antiviral pill for treating COVID-19 has received the US FDA’s fast track designation. Atea Pharmaceuticals, a Boston-based company, announced in April 2023 that its investigational drug bemnifosbuvir had been fast-tracked. Atea is now recruiting high-risk patients for a phase 3, double-blind, placebo-controlled trialof its antiviral pill.
But for now, Cohen said that patients who could benefit from nirmatrelvir-ritonavir should be prescribed it: “[M]y personal belief is that Paxlovid is a valuable drug. It’s really important that the drug be used.”
