Virus World

BACKGROUND

METHODS

Paxlovid does not reduce the risk of long COVID for vaccinated people who’ve tested positive for the first time, according to a new study by UCSF researchers. The COVID-19 treatment Paxlovid does not reduce the risk of long COVID for vaccinated people who’ve tested positive for the virus for the first time, according to a new study by UCSF researchers. The study, published Thursday in the Journal of Medical Virology, also found that a higher share than previously reported experienced rebound symptoms and tested positive for COVID after taking the antiviral medication.  The new study suggests that other COVID-19 prevention strategies, like vaccination, masking and social distancing, “are still relevant,” said one study author, Dr. Matthew Durstenfeld, a cardiologist and UCSF assistant professor of medicine.

TUESDAY, Nov. 14, 2023 (HealthDay News) — For patients receiving nirmatrelvir-ritonavir (N-R) for acute COVID-19, virologic rebound (VR) occurs in about one in five, according to a study published online Nov. 14 in the Annals of Internal Medicine. Gregory E. Edelstein, from Brigham and Women’s Hospital in Boston, and colleagues conducted an observational study to compare the frequency of VR in 72 patients receiving and 55 not receiving N-R treatment for acute COVID-19. The intervention was five days of N-R treatment versus no COVID-19 treatment. The researchers found that VR occurred in 20.8 and 1.8 percent of those taking N-R versus untreated persons. All participants with VR had a positive viral culture result after a previous negative result. Only N-R use was associated with VR in multivariable models (adjusted odds ratio, 10.02).

Compared with those who started therapy two or more days after symptom onset, those who started therapy within two days of symptom onset more often had VR (26.3 versus 0 percent). Among participants receiving N-R, shedding of replication-competent virus was prolonged in those who had versus did not have VR (median, 14 versus three days). Symptom rebound occurred in eight of the 16 patients with VR; two patients were completely asymptomatic. There were no post-VR resistance mutations noted. “These data support the possibility of an N-R-specific VR phenomenon, which substantially increases the duration of shedding of replication-competent virus and has implications for post-N-R monitoring and isolation recommendations,” the authors write.

Study published in Annals of Int. Medicine:

https://doi.org/10.7326/M23-1756 

On May 25, the FDA approvedopens in a new tab or window nirmatrelvir-ritonavir (Paxlovid) for treating adult outpatients with mild to moderate COVID-19 who are at risk for severe disease. Until then, nirmatrelvir-ritonavir had only received emergency use authorizationopens in a new tab or window. Upon approval, the Center for Drug Evaluation and Research director Patrizia Cavazzoni, MD, proclaimedopens in a new tab or window, "Today's approval demonstrates that Paxlovid has met the agency's rigorous standards for safety and effectiveness." But, just how rigorous were the standards? This question matters in terms of the risk-benefit analysis for prescribing nirmatrelvir-ritonavir to patients, as well as for the standard it sets for approval of other drugs. 

The approval was based on two studies. Published in February 2022, the EPIC-HR (HR is for High Risk) randomized trial reportedopens in a new tab or window that nirmatrelvir-ritonavir reduces the risk of hospitalization and death at 28 days by 86% compared to placebo. The 86% relative risk was calculated from hospitalizations and deaths among those taking nirmatrelvir-ritonavir in relation to the rate for those randomly assigned to placebo. Eight of 1,039 (0.77%) patients who started nirmatrelvir-ritonavir within the first 5 days of COVID symptom onset were hospitalized within 28 days. None died. In contrast, 66 out of 1,046 (6.3%) people who took the placebo were hospitalized and 7 died.

Notably, this study was completed during the dangerous Delta waveopens in a new tab or window -- and it was against this backdrop that the 6.3% hospitalization rate in the control group resulted. Times have now changed, with cases at a significantly lower level than pandemic peaks. During the EPIC-HR study in fall 2021, hospitalizations peaked at 25.4/100,000. For the week ending June 3, 2023, CDC reportedopens in a new tab or window 2.17/100,000 hospitalizations -- a rate approximately 12 times lower than during the EPIC-HR study. Furthermore, EPIC-HR exclusion criterionopens in a new tab or window turned away people who had been vaccinated or previously infected. According to CDC estimates, 96% of the U.S. populationopens in a new tab or window now meet these exclusion criteria. In 2023, it is difficult to find people like the participants in the EPIC-HR study....

(Bloomberg) -- In a real-world study of people with Covid-19, Pfizer Inc.’s antiviral Paxlovid was less effective at preventing the infection’s most serious cases than it was in initial trials.  The pill was just 37% effective at preventing hospitalization or death in high-risk patients when compared to no Covid treatment at all, according to an observational study published Thursday in JAMA Network Open. In earlier studies, it cut the risk of hospitalization or death by as much as 89%.  Paxlovid is still an important drug for Covid’s worst outcome: The new study showed it was 84% effective against death alone. The study published Thursday measures how the drug is performing in the real world, rather than carefully designed and monitored clinical trials. Both the earlier trial and the newer study measured people at high risk of developing Covid complications. Pfizer’s initial Paxlovid studies were conducted in unvaccinated people, which could explain some of the differences in outcomes. The coronavirus has also evolved since the studies that provided more positive results.

Despite the lower efficacy against hospitalization and death in the new study, the antiviral is still “definitely recommended for high-risk patients,” says Danyu Lin, a biostatistics professor at the University of North Carolina at Chapel Hill and lead author of the study. The study also found that another therapy — Merck & Co.’s Lagevrio — had similar efficacy to Paxlovid. Merck’s drug works through a genetic mechanism and isn’t recommended for use in pregnant women. Sill, it should be considered when patients can’t take Pfizer’s, which sometimes interacts with other medications, Lin said. High-risk patients who took Lagevrio saw a 41% reduction in hospitalizations and deaths in the observational study compared to those who took no treatment, while earlier studies showed reductions of only about 30%. The Merck drug was also 77% effective against death in the JAMA study. The study looked at electronic health records of 68,867 patients at several hospitals in Cleveland and Florida.

Cited study published in JAMA Network Open (Sept. 21, 2023):

https://doi.org/10.1001/jamanetworkopen.2023.35077 

The Food and Drug Administration (FDA) on Thursday granted full approval to Pfizer’s COVID-19 oral antiviral pill Paxlovid for use in adults who are at high risk for progression to severe disease. The agency’s approval comes nearly a year and a half after the drug received an emergency use authorization, and as hospitalization and deaths from the virus continue to decline. The agency’s approval comes nearly a year and a half after the drug received an emergency use authorization, and as hospitalization and deaths from the virus continue to decline. Paxlovid is given as a 5-day treatment course, and FDA said it should be initiated as soon as possible after a diagnosis of COVID-19 has been made, but no more than five days after symptom onset.  The drug is specifically advised for use in people aged 50 and older as well as those who suffer from certain medical conditions that put them at high risk of developing complications, including hospitalization and severe disease from COVID-19. In March, an FDA independent advisory committee recommended the agency fully approved Paxlovid, finding the medicine was safe and effective for treating COVID-19 in high-risk adults based on three of Pfizer’s clinical trials.  The agency further said Paxlovid does not cause “rebound” COVID-19 infection. 

Paxlovid has been shown to be most effective among patients who have not received a COVID-19 vaccine and those who have not been previously infected. One of Pfizer’s clinical trials showed Paxlovid significantly reduced the proportion of people with COVID-19 related hospitalization or death by 86 percent compared to placebo among patients treated within five days of symptom onset, and 89 percent in those treated within three days, “Today’s approval demonstrates that Paxlovid has met the agency’s rigorous standards for safety and effectiveness, and that it remains an important treatment option for people at high risk for progression to severe COVID-19, including those with prior immunity,” said Patrizia Cavazzoni, director for the FDA’s Center for Drug Evaluation and Research. “The FDA remains committed to working with sponsors to facilitate the development of new prevention and treatment options for COVID-19,” she said. The federal government owns 1.1 million doses of Paxlovid that it already purchased, that are available at pharmacies nationwide. Once that stockpile is used up, distribution will shift to the private sector, and Pfizer will sell directly to health providers. The company sells to the government for about $530 for a 5-day course of treatment, but has not said what it will charge commercially.

FDA Press Release (May 25, 2023):

https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-antiviral-treatment-covid-19-adults 

People who are vaccinated or who take Paxlovid during a Covid-19 infection have a lower risk of developing long Covid, new research shows. The US Centers for Disease Control and Prevention defines long Covid as new, returning or ongoing health issues more than four weeks after an initial infection. According to the CDC, 1 in 5 Covid-19 survivors ages 18 to 64 and 1 in 4 survivors 65 or older have an ongoing health issue that might be attributable to Covid-19 infection. A study published Thursday in JAMA Internal Medicine analyzed data from 41 studies, including more 860,000 people around the world. Of the four studies with vaccination information of nearly 250,000 people, those who had been vaccinated against Covid-19 had almost half the risk of long Covid than people who weren’t vaccinated. “These findings are important because they enable us to better understand who may develop long Covid and also advocate for the benefit of vaccination,” said Dr. Eleana Ntatsaki, a rheumatologist at Ipswich Hospital in England and co-author of the study. Dr. Linda Geng, co-director of Stanford University’s Post-Acute Covid-19 Syndrome Clinic, says the findings are encouraging and add to mounting evidence that vaccines can reduce the risk of long Covid. “That is probably one of the best tools that we have, to get vaccinated to help reduce severe acute illness but helping hopefully also to prevent and protect against developing long Covid,” said Geng, who was not involved in the research. Women, people who smoke, those who are overweight and adults over 40 are more likely to have long Covid, the study found.

Hospitalization during a Covid-19 infection as well as underlying health problems including asthma, COPD, diabetes, coronary heart disease, a weakened immune system, anxiety and depression are also associated with increased risk of the condition. Previous research has found that long Covid is associated with nearly twice the risk of heart and lung problems or death. The study authors say these findings will help providers better understand long Covid and serve those living with the condition. “We can have a better strategy for optimizing any modifiable risk factors, with public health promotion campaigns, encouraging smoking cessation, vaccination and healthy weight management in the target population,” Ntatsaki said. Another study published Thursday in JAMA Internal Medicine found that using the antiviral medication Paxlovid within five days of a positive Covid-19 test was associated with a lower risk of long Covid in all age groups, regardless of vaccination status or history of infection. Paxlovid was linked with a 26% lower risk of long Covid, a 47% lower risk of death and a 24% lower risk of hospitalization 30 days after an initial infection.

Could taking Paxlovid reduce the risk of getting long COVID? Preliminary data suggests it might, but experts say there’s much more to learn. Long COVID, a wide-ranging set of sometimes debilitating symptomsfollowing a COVID infection, is a pressing and worrisome challenge for both patients and medical researchers, who are racing to figure out how to both prevent and treat the disease. Some evidence has emerged that Paxlovid, an oral antiviral medication used to treat COVID-19, can help reduce the risk of ending up with long COVID, experts said — and it’s one more reason to seek the treatment. Dr. Bob Wachter, UCSF’s chair of medicine, said in an email that the evidence, which comes from a study out of the Department of Veterans Affairs, isn’t huge, but shows Paxlovid can make “a meaningful difference” in warding off long COVID. It’s one of the reasons he’d take Paxlovid if he had COVID, he said. The November 2022 study of 56,000 people with COVID found that the more than 9,000 who took Paxlovid in the first five days of their infection had a 25% lower risk of long COVID symptoms, including heart disease, blood disorders, fatigue, liver disease, kidney disease, muscle pain, neurocognitive impairment and shortness of breath. In an interview with Wachter live streamed Thursday for the UCSF medical school’s grand rounds series, Dr. Eric Topol, director of the Scripps Research Translational Institute and a leading voice on COVID, agreed with Wachter, saying even the chance that Paxlovid helps prevent long COVID or reduce its severity is one of the main reasons to take the drug early.

Background

Methods

Findings

Interpretation

Protease inhibitors are among the most powerful antiviral drugs. Nirmatrelvir is the first protease inhibitor specifically developed against the SARS-CoV-2 protease 3CLpro that has been licensed for clinical use. To identify mutations that confer resistance to this protease inhibitor, we engineered a chimeric vesicular stomatitis virus (VSV) that expressed a polyprotein composed of the VSV glycoprotein (G), the SARS-CoV-2 3CLpro, and the VSV polymerase (L). Viral replication was thus dependent on the autocatalytic processing of this precursor protein by 3CLpro and release of the functional viral proteins G and L, and replication of this chimeric VSV was effectively inhibited by nirmatrelvir.

Using this system, we applied nirmatrelvir to select for resistance mutations. Resistance was confirmed by retesting nirmatrelvir against the selected mutations in additional VSV-based systems, in an independently developed cellular system, in a biochemical assay, and in a recombinant SARS-CoV-2 system. We demonstrate that some mutants are cross-resistant to ensitrelvir and GC376, whereas others are less resistant to these compounds. Furthermore, we found that most of these resistance mutations already existed in SARS-CoV-2 sequences that have been deposited in the NCBI and GISAID databases, indicating that these mutations were present in circulating SARS-CoV-2 strains.

Published in Science Translational Medicine:

https://doi.org/10.1126/scitranslmed.abq7360 

A trial of a Chinese-developed derivative of remdesevir showed comparable efficacy to Paxlovid in a study published in NEJM. When H. Eric Xu fell sick and tested positive with Covid this month, he took pills of his own invention. Paxlovid, the primary oral antiviral available in the U.S., is in short supply in China. But Xu, a prominent biochemist at the Chinese Academy of Sciences, had helped devise his own in 2021 and, as the drug’s inventor, could legally take it even as it went through clinical trials.  His symptoms were alleviated, and he wasn’t alone. In an 822-patient clinical trial published Wednesday in the New England Journal of Medicine, Xu’s antiviral, VV116, appeared just as effective as Paxlovid at easing patient’s symptoms. Newly diagnosed patients who took VV116 recovered after a median of 4 days, compared with 5 days for Paxlovid, though experts caution that the study was not large enough to say one was better than the other. The drug is being developed by Chinese drugmakers Junshi Biosciences and Vigonvita Life Science. The results could lend Chinese authorities and physicians a new tool as they try to keep a burgeoning outbreak at bay, while eventually adding another antiviral to the world’s arsenal. “I hope the publication of these results will get approval much quicker,” Xu said in an interview. Quicker, however, may not be quick enough. The virus has spread rapidly in China since authorities lifted many of the country’s strict mitigation measures in response to protests over its zero-Covid policies. “It will take time to manufacture,” he added. “I think the pandemic will pass.” Although promising, the data may not in fact be enough to win over regulators and other researchers, particularly in countries where alternatives are available.  Part of the problem is the study’s main metric.

While the FDA has previously approved antivirals, such as the flu drugs Xofluza and Tamiflu, that are shown to alleviate symptoms faster than alternatives, the primary endpoint of U.S. trials of antivirals to treat Covid has been their effectiveness in preventing hospitalization or death. It isn’t actually clear how quickly Paxlovid — the drug VV116 was compared to — alleviates symptoms in all patients.  Pfizer presented data at ID Week, an annual infectious disease conference, this year showing high-risk unvaccinated patients who took Paxlovid recovered faster than patients on placebo, said Davey Smith, an infectious disease physician at University of California-San Diego. But the company acknowledged this year that vaccinated, standard-risk patients who received Paxlovid didn’t recover significantly faster than placebo in a separate trial.  The VV116 study contained a mix of vaccinated and unvaccinated patients, randomized to receive VV116 or Paxlovid. The majority — around 75% — had received at least a primary vaccine course. It was also smaller than typical non-inferiority studies, in which  researchers try to show a new drug is just as good as an existing one, said Smith. Usually, these studies have thousands of patients.  "Our FDA would probably not go for this being an approved drug, based on this endpoint,” Smith said. David Perlin, who develops new anti-infectives as chief scientist at the Center of Discovery and Innovation in New Jersey, said VV116 appeared to be a “good addition” and little different than the approved antiviral molnupiravir, which has a similar mechanism of action.  But he agreed there wasn’t enough data for U.S. authorities.  “With 800 participants, I’m not sure the FDA is going to extract enough of the adverse events you would want to look for,” he said. 

The drug itself has attracted broad interest. It is a derivative of Gilead’s remdesivir, the first antiviral authorized for Covid-19 in May, 2020. Xu said he and a team of researchers, including collaborators at the Wuhan Institute of Virology, took remdesivir’s “parent” molecule, called GS-441524, and spent six months modifying it, until they struck upon a version that could neutralize the virus throughout the body, without causing toxicity.  In early 2020, a pair of researchers called on Gilead to develop GS-441524 itself as a pill for Covid. In public statements and emails to the researchers, Gilead claimed it wouldn’t be effective or safe. And it would take longer to develop, because, unlike remdesivir, it had never been tested in humans. But the researchers argued that Gilead preferred remdesivir because it had a longer patent life.  Those scientists now see VV116’s results as vindication. “As for whether an effective pill could have been available far earlier in the pandemic if Gilead did develop GS-441524: The answer is yes” said Victoria Yan, one of the researchers and a graduate student at MD Anderson Cancer Center, in an email.  Xu argued it’s likely GS-441524 would have worked to some degree, but that changes his team made ensured it was potent in the body. Yan agreed that one of the changes did help.  Gilead reiterated in an email that the company didn’t develop GS-441524 because of concerns about “technical feasibility.” The company announced in January it is working on an oral antiviral, based off of GS-441524, which is now in Phase 3. It’s among a small handful of efforts, including VV116, to develop antiviral pills that are as effective as Paxlovid but don’t come with the same drug-to-drug interactions that prevent some of the highest risk patients from taking Pfizer’s drug.  These efforts could also make antivirals more available across the globe. Although molnupiravir, a less effective drug, is now widely available, access to Paxlovid has been “pretty limited,” said Julien Potet, a policy advisor to Doctors Without Borders.  That could be because Pfizer started striking agreements with generic manufacturers later than Merck, molnupiravir’s developer, and Paxlovid is more complex to make, Potet said.    “If reasonably priced, [VV116] could make a major difference,” he added in an email.

The trials to make these new drugs available in the U.S. will have to look different than the one Junshi ran. Currently, U.S. researchers can’t easily run non-inferiority studies against Paxlovid. Because the drug is under emergency use authorization, researchers can only get it from Pfizer, but academics have so far struggled to access the drug for outside trials. As part of the team of researchers working on National Institutes of Health trials for Covid, Smith said he tried and failed to get Paxlovid for a non-inferiority study. “You could not run this non-inferiority trial here,” he said.  Companies developing new Covid antivirals have complained to federal officials that it has become impossible to run studies, said one government scientist involved in such talks, who spoke on condition of anonymity to discuss confidential deliberations. The FDA has asked them to compare their experimental drug to standard-of-care, but Pfizer refused to provide Paxlovid for the studies. “I’ve heard multiple times from multiple drug companies,” the researcher said. Drugmakers have had to go to other countries where regulations or the standard-of-care are different, the scientist said, and then hope they can convince the FDA to accept the data. Gilead, for example, currently lists three study sites for its Phase 3 trial. Two are in Canada. One is in Romania.  Pfizer, in a statement, said it “is prioritizing”  Paxlovid for “patients at high risk for severe COVID-19 through governments and government-funded research organizations” and that, while it has received many research requests, “unfortunately, it is impossible to support them all.” “We evaluate each proposal, selecting those with strongest scientific basis, the greatest likelihood of generating data important to patients and physicians, the intention to generate new data that is not already being collected through different means, and the ability of the requesting organization to protect the welfare of patients participating in research studies,” they said. 

The story has been updated to correct a name and to include a comment from Gilead. 

Nearly 6 million Americans have taken Paxlovid for free, courtesy of the federal government. But the government plans to stop footing the bill within months, and millions of people who are at the highest risk of severe illness and are least able to afford the drug may have to pay the full price. And that means fewer people will get the potentially lifesaving treatments, experts said. “I think the numbers will go way down,” said Jill Rosenthal, director of public health policy at the Center for American Progress, a left-leaning think tank. A bill for several hundred dollars or more would lead many people to decide the medication isn’t worth the price, she said. In response to the unprecedented public health crisis caused by COVID, the federal government spent billions of dollars on developing new vaccines and treatments, to swift success: Less than a year after the pandemic was declared, medical workers got their first vaccines. But as many people have refused the shots and stopped wearing masks, the virus still rages and mutates. In 2022 alone, 250,000 Americans have died from COVID, more than from strokes or diabetes. But soon the Department of Health and Human Services will stop supplying COVID treatments, and pharmacies will purchase and bill for them the same way they do for antibiotic pills or asthma inhalers. Paxlovid is expected to hit the private market in mid-2023, according to HHS plans shared in an October meeting with state health officials and clinicians. Merck’s Lagevrio, a less-effective COVID treatment pill, and AstraZeneca’s Evusheld, a preventive therapy for the immunocompromised, are on track to be commercialized sooner, sometime in the winter.

The U.S. government has so far purchased 20 million courses of Paxlovid, priced at about $530 each, a discount for buying in bulk that Pfizer CEO Albert Bourla called “really very attractive” to the federal government in a July earnings call. The drug will cost far more on the private market, although in a statement to KHN, Pfizer declined to share the planned price. The government will also stop paying for the company’s COVID vaccine next year — those shots will quadruple in price, from the discount rate the government pays of $30 to about $120. Bourla told investors in November that he expects the move will make Paxlovid and its COVID vaccine “a multibillion-dollars franchise.” Nearly 9 in 10 people dying from the virus now are 65 or older. Yet federal law restricts Medicare Part D — the prescription drug program that covers nearly 50 million seniors — from covering the COVID treatment pills. The medications are meant for those most at risk of serious illness, including seniors. Paxlovid and the other treatments are currently available under an emergency use authorization from the FDA, a fast-track review used in extraordinary situations. Although Pfizer applied for full approval in June, the process can take anywhere from several months to years. And Medicare Part D can’t cover any medications without that full stamp of approval. Paying out-of-pocket would be “a substantial barrier” for seniors on Medicare — the very people who would benefit most from the drug, wrote federal health experts. “From a public health perspective, and even from a health care capacity and cost perspective, it would just defy reason to not continue to make these drugs readily available,” said Dr. Larry Madoff, medical director of Massachusetts’ Bureau of Infectious Disease and Laboratory Sciences. He’s hopeful that the federal health agency will find a way to set aside unused doses for seniors and people without insurance.

In mid-November, the White House requested that Congress approve an additional $2.5 billion for COVID therapeutics and vaccines to make sure people can afford the medications when they’re no longer free. But there’s little hope it will be approved — the Senate voted that same day to end the public health emergency and denied similar requests in recent months. Many Americans have already faced hurdles just getting a prescription for COVID treatment. Although the federal government doesn’t track who’s gotten the drug, a Centers for Disease Control and Prevention study using data from 30 medical centers found that Black and Hispanic patients with COVID were much less likely to receive Paxlovid than white patients. (Hispanic people can be of any race or combination of races.) And when the government is no longer picking up the tab, experts predict that these gaps by race, income, and geography will widen. People in Northeastern states used the drug far more often than those in the rest of the country, according to a KHN analysis of Paxlovid use in September and October. But it wasn’t because people in the region were getting sick from COVID at much higher rates — instead, many of those states offered better access to health care to begin with and created special programs to get Paxlovid to their residents. About 10 mostly Democratic states and several large counties in the Northeast and elsewhere created free “test-to-treat” programs that allow their residents to get an immediate doctor visit and prescription for treatment after testing positive for COVID. In Massachusetts, more than 20,000 residents have used the state’s video and phone hotline, which is available seven days a week in 13 languages. Massachusetts, which has the highest insurance rate in the country and relatively low travel times to pharmacies, had the second-highest Paxlovid usage rate among states this fall.

States with higher COVID death rates, like Florida and Kentucky, where residents must travel farther for health care and are more likely to be uninsured, used the drug less often. Without no-cost test-to-treat options, residents have struggled to get prescriptions even though the drug itself is still free. “If you look at access to medications for people who are uninsured, I think that there’s no question that will widen those disparities,” Rosenthal said. People who get insurance through their jobs could face high copays at the register, too, just as they do for insulin and other expensive or brand-name drugs. Most private insurance companies will end up covering COVID therapeutics to some extent, said Sabrina Corlette, a research professor at Georgetown University’s Center on Health Insurance Reforms. After all, the pills are cheaper than a hospital stay. But for most people who get insurance through their jobs, there are “really no rules at all,” she said. Some insurers could take months to add the drugs to their plans or decide not to pay for them. And the additional cost means many people will go without the medication. “We know from lots of research that when people face cost sharing for these drugs that they need to take, they will often forgo or cut back,” Corlette said. One group doesn’t need to worry about sticker shock. Medicaid, the public insurance program for low-income adults and children, will cover the treatments in full until at least early 2024. HHS officials could set aside any leftover taxpayer-funded medication for people who can’t afford to pay the full cost, but they haven’t shared any concrete plans to do so. The government purchased 20 million courses of Paxlovid and 3 million of Lagevrio. Fewer than a third have been used, and usage has fallen in recent months, according to KHN’s analysis of the data from HHS. Sixty percent of the government’s supply of Evusheld is also still available, although the COVID prevention therapy is less effective against new strains of the virus. The health department in one state, New Mexico, has recommended against using it. HHS did not make officials available for an interview or answer written questions about the commercialization plans. The government created a potential workaround when they moved bebtelovimab, another COVID treatment, to the private market this summer. It now retails for $2,100 per patient. The agency set aside the remaining 60,000 government-purchased doses that hospitals could use to treat uninsured patients in a convoluted dose-replacement process. But it’s hard to tell how well that setup would work for Paxlovid: Bebtelovimab was already much less popular, and the FDA halted its use on Nov. 30 because it’s less effective against current strains of the virus. Federal officials and insurance companies would have good reason to make sure patients can continue to afford COVID drugs: They’re far cheaper than if patients land in the emergency room. “The medications are so worthwhile,” said Madoff, the Massachusetts health official. “They’re not expensive in the grand scheme of health care costs.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Paxlovid, the antiviral pill that reduces the risk of hospitalization and death from Covid-19, also reduces the risk of long Covid, according to a new study by researchers at the US Department of Veterans Affairs. The study, posted online as a preprint on Saturday, analyzed electronic records for more than 56,000 veterans with Covid-19, including more than 9,000 who were treated with Paxlovid within the first five days of their infection. The analysis showed people treated with Paxlovid had a 26% reduced risk of developing several long Covid conditions, including heart disease, blood disorders, fatigue, liver disease, kidney disease, muscle pain, neurocognitive impairment and shortness of breath. That corresponded to 2.3 fewer cases of long Covid conditions per 100 people three months after their diagnosis. Paxlovid also reduced the risk of hospitalization or death following acute Covid-19.  In the analysis, there wasn’t a statistically significant link between taking Paxlovid and risk of two long Covid conditions: cough and new diabetes diagnosis. The study was posted to the preprint server medRxiv and hasn’t been peer-reviewed or published in a medical journal. Patients included in the study had an average age of 65 and were diagnosed with Covid-19 between March 1 and June 30, 2022. They all had at least one risk factor for progression to severe Covid-19, such as older age, diabetes or being a current smoker. Paxlovid reduced the risk of long Covid in people who were unvaccinated, vaccinated and boosted, and in people experiencing their first Covid-19 infection or a reinfection, the study said.

“Paxlovid reduces the risk of severe COVID-19 in the acute phase, and now, we have evidence that it can help reduce the risk of long COVID,” Dr. Ziyad Al-Aly, chief of research and development at the VA St. Louis Health Care System and leader of the study, said in a news release. “This treatment could be an important asset to address the serious issue of long COVID.” The study has several limitations, including that the majority of people included were White and male, which might limit its relevance more generally. The analysis captured Paxlovid use only through the VA system and considered only 12 long Covid conditions, although many people with long Covid describe a wide variety of symptoms.

Millions of people who had Covid-19 face a range of lasting symptoms since their initial illness, but there is no specific treatment for long Covid. Paxlovid is an antiviral treatment for Covid-19 that combines a newer antiviral, nirmatrelvir, with an older drug, ritonavir. It’s available for people as young as 12 and has been shown to sharply reduce risk of hospitalization and death in people at risk of severe Covid-19.   The drug is made by Pfizer and comes as pills taken over five days. It works best if started within five days of symptom onset; researchers noted it’s not clear whether longer duration or higher dose or both might reduce risk of long Covid conditions even more, or whether starting Paxlovid after acute illness from Covid-19 would reduce risk of long Covid. The National Institutes of Health said last month it would launch a study of Paxlovid as a treatment for patients already experiencing long Covid. “The totality of evidence suggests the need to improve uptake and utilization of nirmatrelvir in the acute phase as a means of not only preventing progression to severe acute disease, but to also reduce the risk of post-acute adverse health outcomes,” authors of the VA study wrote.

Study cited in medRxiv (Nov. 5, 2022):

https://doi.org/10.1101/2022.11.03.22281783 

Reports have described SARS-CoV-2 rebound in COVID-19 patients treated with nirmatrelvir, a 3CL protease inhibitor. The cause remains a mystery, although drug resistance, re-infection, and lack of adequate immune responses have been excluded. We now present virologic findings that provide a clue to the cause of viral rebound, which occurs in ∼20% of the treated cases. The persistence of an intermediary form of infectious SARS-CoV-2 was experimentally documented in vitro after treatment with nirmatrelvir or another 3CL protease inhibitor, but not with a polymerase inhibitor, remdesivir.

This infectious intermediate decayed slowly with a half-life of ∼1 day, suggesting that its persistence could outlive the treatment course to re-ignited SARS-CoV-2 infection as the drug is eliminated. Additional studies are needed to define the nature of this viral intermediate, but our findings point to a particular direction for future investigation and offer a specific treatment recommendation that should be tested clinically.

Available in bioRxiV (Dec. 21, 2023):

 https://doi.org/10.1101/2023.12.20.572655 

Background

Methods

Findings

Interpretation

Why can Covid symptoms sometimes return after treatment? And what should you do about it? As Covid cases crept up over the summer and new variants have emerged, the basics of preventing and managing the virus have come back into focus — including a critical tool for warding off severe disease and death: the antiviral treatment Paxlovid. The therapy, which consists of two medications, is intended for people who are at high risk for developing severe disease. According to the Centers for Disease Control and Prevention, this is a fairly broad category, including people with mood disorders like depression, current and former smokers and those with obesity. Experts stress that Paxlovid is an effective, lifesaving treatment that helps to keep people out of the hospital. It may even lower the risk of developing long Covid. But the medication has gotten a bad reputation from high-profile instances of “Paxlovid rebound,” or testing positive days after recovering from the virus, said Dr. Peter Chin-Hong, an infectious disease specialist at the University of California, San Francisco.

The clinical trials are designed to evaluate multiple treatments simultaneously to identify more swiftly those that are effective....

Vaccines and drugs have helped reduce disease severity and blunt the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, ongoing virus transmission, continuous evolution, and increasing selective pressures have the potential to yield viral variants capable of resisting these interventions. Here, we investigate the susceptibility of natural variants of the main protease [Mpro; 3C-like protease (3CLpro)] of SARS-CoV-2 to protease inhibitors. Multiple single amino acid changes in Mpro confer resistance to nirmatrelvir (the active component of Paxlovid). An additional clinical-stage inhibitor, ensitrelvir (Xocova), shows a different resistance mutation profile.

Importantly, phylogenetic analyses indicate that several of these resistant variants have pre-existed the introduction of these drugs into the human population and are capable of spreading. These results encourage the monitoring of resistance variants and the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles for combinatorial therapy.

Published in Science Advances (March 29, 2023)

Advisers to the US Food and Drug Administration voted 16-1 on Thursday in support of approval of Paxlovid, stating that the benefits outweigh the risks of the drug for treatment of mild-to-moderate Covid-19 in adult high risk for progression to severe disease, including hospitalization and death. Before the antiviral medication is fully approved, the FDA – which typically follows the recommendations of the independent advisory committee – must conduct its own review. That’s expected to wrap up in May. Over 8 million people in the US have received Paxlovid, a combination of the drugsnirmatrelvir and ritonavir, since it became available under emergency use authorization in December 2021. “I’d say besides oxygen, Paxlovid has probably been the single most important tool in this epidemic, and it continues to be,” said Dr. Richard Murphy, chief of infectious diseases with the Veterans Affairs White River Junction Medical Center and a member of the FDA’s Antimicrobial Drugs Advisory Committee who voted in support of approval at the meeting. “We still have many groups that stand to benefit from the use of Paxlovid, including unvaccinated persons, undervaccinated persons, elderly, immunocompromised, and the other treatment options that we have have significant disadvantages,” he said. Data from phase 2 and 3 clinical trials supports the efficacy of Paxlovid regardless of Covid vaccination status or prior infection, the FDA said in documents released ahead of Thursday’s meeting. The agency also said it is reasonable to conclude, despite limited data, that Paxlovid is “likely to retain clinical efficacy” in high-risk adults with Covid infection caused by the Omicron variant of the coronavirus, as with earlier variants. “I thought that the efficacy data were clear and convincing,” said Dr. Shankar Swaminathan, chief of infectious diseases at the University of Utah School of Medicine, who voted in support of approval Thursday. “I think that the fact that the drug has retained activity against various evolutionary strains of the virus is also reassuring and gives hope that this will continue to be the case going forward.”

Not linked to Covid rebound

The FDA also concluded that Paxlovid is not associated with Covid-19 rebound, in which people test positive or see their symptoms return after they finish the five-day course of the drug. The agency said it has reviewed data regarding rebound cases, which some users have reported since Paxlovid was authorized in 2021. Last year, both President Biden and his former chief medical adviser, Dr. Anthony Fauci, reported rebound symptoms after taking Paxlovid. However, based on clinical trial data, the FDA “did not identify a clear association between Paxlovid treatment and Covid-19 rebound.” Covid rebound rates ranged from 10% to 16%, with no difference between people who took Paxlovid and those who got a placebo. This was also regardless of a person’s risk of severe disease with the Omicron variant compared with the Delta variant, according to clinical trial data reviewed by the FDA. Overall, the agency said, the findings indicate that Covid-19 rebound may occur in a subset of infections as part of the natural progression and resolution of the disease.

Monitoring drug-drug interactions

No major safety concerns were identified in the clinical trial data, the FDA said. However, the agency has flagged 137 medications with Paxlovid drug-drug interactions (DDIs) that may lead to serious adverse reactions. Paxlovid may keep the body from metabolizing certain drugs, leading to higher drug concentrations that can lead to serious or life-threatening reactions, according to an FDA Emergency Use Authorization Fact Sheet. Drugs that should not be taken with Paxlovid include some medications to treat conditions such as high cholesterol, gout, migraine, irregular heartbeat and benign prostatic hyperplasia. According to the agency, over 50% of Paxlovid-eligible patients may be on medication with a DDI at the time of Covid diagnosis. “I would just emphasize that we underscore the importance of risk-mitigation to the prescriber, primary care physicians and other prescribers in terms of drug-drug interactions,” said FDA committee member Dr. David Hardy, an adjunct clinical professor at the Keck School of Medicine at the University of Southern California, who voted in support of approval. “That’s where I think we may get into trouble – or I can say where they can get into trouble – prescribing this medication without a good knowledge of what ritonavir does to other medications.” The committee said the benefits of Paxlovid may not outweigh the risk of adverse drug reactions in all patients. For those at high risk of severe Covid-19, DDIs can be managed by holding the drug, adjusting the dose or increasing monitoring. Clinical trials on the safety and efficacy of Paxlovid in children, people who are pregnant and those with weakened immune systems are ongoing.

The antiviral ensitrelvir, which is not approved in the United States, shortens symptoms in people with mild COVID and might reduce risk of long COVID — but more data are needed. COVID-19 can inflict days of misery, even on people who do not develop serious illness. Now, trial data show that an antiviral called ensitrelvir shortens symptoms of mild to moderate COVID-19 by about a day — and is the first drug to make a statistically significant cut in the number of days people test positive for SARS-CoV-2. The drug’s manufacturer, Shionogi in Osaka, Japan, says the data also show that ensitrelvir has the potential to prevent long COVID. But scientists are sceptical about that claim and critical of the design of the clinical trial. The research was presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Washington, on 21 February, and has not yet been peer reviewed. Two oral antivirals are already widely used to treat COVID-19: Paxlovid (nirmatrelvir/ritonavir) and molnupiravir. Both target people who are at high risk of severe disease. But ensitrelvir was tested on people irrespective of their risk, which could have implications for its use in individuals at low risk. No drug has been conclusively shown to reduce the risk of long COVID, although preliminary evidence hints that Paxlovid might have this effect.

A pill for COVID cough

Organizers of the ensitrelvir trial investigated roughly 1,200 people, with the main goal of determining whether the drug could accelerate recovery. The results showed that participants who took 125-milligram ensitrelvir pills recovered from five specific symptoms — stuffy or runny nose, sore throat, cough, feeling hot or feverish and low energy or tiredness — about 24 hours earlier than did those in the control group. Participants who took the 125-milligram dose also tested negative for SARS-CoV-2 about 29 hours earlier than did those who took a placebo. According to Shionogi, the study was the first to show a statistically significant reduction in the time to a negative test result. A subset of participants were asked about their COVID-19 symptoms three and six months after trial enrolment as well as during their acute infection period. Those who reported two or more of the same symptoms at least twice in a row over this period were defined as having developed long COVID. Participants who had a relatively high number of symptoms during the illness's early stages had a 14% risk of developing long COVID if they took the antiviral, compared with a 26% risk for similar participants in the placebo group. This led Shionogi to conclude that participants who received ensitrelvir had a reduced risk of developing long COVID.

Doubts about design

But scientists who were not involved with the study point out that the trial was not specifically intended to investigate the risk of long COVID. That means that the pre-trial research plan didn’t describe any methods for analysing long COVID data. This means, for example, that it’s unclear whether Shionogi’s definition of long COVID was determined before the trial began, notes physician Eric Topol, director of the Scripps Research Translational Institute in San Diego, California. Because this was an exploratory phase of the study, it’s not possible to make any strong conclusions, he adds. Simon Portsmouth, head of clinical development at Shionogi in Florham Park, New Jersey, says that the company could not specify the plan for analysing long COVID data ahead of time because long COVID was less clearly defined in the past than now. He says that these results, although not definitive, will shape an ongoing trial evaluating ensitrelvir’s effect on COVID-19 symptoms. Scientists say it’s plausible that antivirals could prevent long COVID. One recent analysis found that people who took Paxlovid had a reduced risk of developing long COVID compared with those who took no antiviral drugs1. The study, published as a preprint, has not yet been peer reviewed. Study co-author Ziyad Al-Aly, chief of research and development at the VA St Louis Health Care System, in Missouri, says the ensitrelvir data make him more optimistic that attacking the virus early during an infection “seems to hold the key to reducing the risk of long COVID.” Topol agrees that the data that Shionogi have made public support the idea that antivirals protect against long COVID, at least when residual virus is involved in causing prolonged symptoms.

Published in Nature March 3, 2023:

https://doi.org/10.1038/d41586-023-00548-6