Virus World

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.

There's been a surge of about 900,000 people with disabilities in the U.S. workforce since 2020, likely because of the increase in Americans with long COVID, according to new research published by the Federal Reserve Bank of New York.

Why it matters: It's an encouraging sign, in one sense. Disabled Americans face enormous obstacles in the job market; if folks with long COVID can keep working, that means some employers are accommodating their needs.

• But as the economy cools, employers could become less willing on that front — and it's an open question as to whether these folks stay employed.
• "I hope that isn't true, but it's something I would certainly keep an eye on," says Katie Bach, a nonresident senior fellow at Brookings who has been studying long COVID's impact on the workforce, and recently found the condition is keeping as many as 4 million people out of work.

State of play: The pandemic led to an increase in the number of Americans who say they're disabled. (See the chart below.)

• There were 1.05 million more disabled working-age Americans in August 2022 compared to January 2020, according to data compiled by Richard Deitz, an economist at the NY Fed.
• "The majority [of the newly disabled] deal with fatigue and brain fog, the hallmarks of long COVID," he writes.

The intrigue: Economists are still nailing down why so many more disabled people, who traditionally have very low labor force participation, are working now.

• Deitz's paper is among the first to pinpoint long COVID as a possible factor; others attribute the surge to the tight labor market and the rise of remote work — which can make it easier for disabled workers to remain employed or get a job.
• There's likely an interplay between the two. Some disabled people can now more easily work remotely and may have entered the job market; and the ability to work from home is also helping many of those with long COVID — a cohort that didn't exist before 2020 — keep their jobs.

What they're saying: "I would bet that the majority of the [increase in disabled workers] is people with long COVID who are still working," Bach says. She's currently researching the newly disabled population to better understand these numbers.

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 

The companies hope to earn the trust of the public and of scientists who have clamored for details of the studies.  Two drug companies that are leading the race to develop coronavirus vaccines bowed to public pressure on Thursday, abandoning their traditional secrecy and releasing comprehensive road maps of how they are evaluating their vaccines. The companies, Moderna and Pfizer, revealed details about how participants are being selected and monitored, the conditions under which the trials could be stopped early if there were problems, and the evidence researchers will use to determine whether people who got the vaccines were protected from Covid-1. Moderna’s study will involve 30,000 participants, and Pfizer’s 44,000.  Companies typically share these documents after their studies are complete. The disclosures while the trials are still underway, a rare move, are aimed at addressing growing suspicion among Americans that President Trump’s drive to produce a vaccine before the election on Nov. 3 could result in a product that was unsafe.  The plan released by Moderna on Thursday morning included a likely timetable that could reach into next year for determining whether its vaccine works. It does not jibe with the president’s optimistic predictions of a vaccine widely available to the public in October.

Pfizer’s plan does not appear to estimate when its results could be available. Its chief executive has said repeatedly that the company hopes to have an answer as early as October. Moderna has said only that it could have a result before the end of the year. Moderna’s 135-page plan, or protocol, indicated that the company’s first analysis of early trial data might not be conducted until late December, though company officials now say they expect the initial analysis in November. In any case, there may not be enough information then to determine whether the vaccine works, and the final analysis might not take place until months later, heading into the spring of next year. Moderna’s timeline meshes with the cautionary estimates from many researchers, including Dr. Robert R. Redfield, the director of the Centers for Disease Control and Prevention, who told senators on Wednesday that a vaccine would not be widely available until the middle of next year. Hours later, Mr. Trump sharply contradicted him, making unsubstantiated projections that a vaccine could become widely available weeks from now. On Wednesday, Joseph R. Biden Jr., the Democratic presidential nominee, said in Wilmington, Del., that the process used to evaluate and approve a vaccine would have to be “totally transparent” to win public confidence. He has said that Mr. Trump’s calls for companies and regulators to speed the process have shaken the public’s faith in vaccines and that politics has no place in vaccine development. Researchers in particular have been urging vaccine makers to share the detailed blueprints of their studies so that outside experts can evaluate them. At least one expert, after reading the plans, has already raised questions about the way the trials were designed. “I want to acknowledge a good deed done,” said Peter Doshi, who is on the faculty at the University of Maryland School of Pharmacy in Baltimore and an editor with The BMJ, a medical journal. He previously requested the plans from Moderna and Pfizer. “They have opened up, for the first time, the ability for researchers not involved in the trial to form their own independent judgment about the design of this study.”

Until now, none of the nine companies that are testing vaccines in large clinical trials had released this level of detail. Moderna, AstraZeneca and Pfizer, which is collaborating with the German company BioNTech, are among the front-runners in the global race to produce a vaccine to fight the pandemic. A spokeswoman for AstraZeneca said the company intended to publish its protocol shortly. Novavax, which is expected to start a large, advanced clinical trial later this year, also did not comment. Johnson & Johnson, which has said it plans to begin a large trial this month, said it would have “more information to share” when the trial starts.AstraZeneca’s trial was stopped temporarily because of serious illness in a participant. It has resumed in Britain and Brazil, but not in the United States. Earlier studies of both vaccines in small numbers of people found that after the second shot, they developed so-called neutralizing antibodies, which can inactivate the virus in lab tests. The vaccines also produced a favorable response involving T-cells, another part of the immune system...