Coronavirus updates June 2024

[missy]

I am hoping soon we will not need these threads and I thought we were almost finished but as any news pops up I will try sharing it here

Opinion | Paxlovid Trial Flops for COVID Pneumonia

Small study found no decrease in mortality among inpatients in three countries

www.medpagetoday.com

Paxlovid Trial Flops for COVID Pneumonia​

— Small study found no decrease in mortality among inpatients in three countries​

by Jeremy Faust, MD, MS, MA, Editor-in-Chief, MedPage TodayJune 6, 2024

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Starting point: nirmatrelvir/ritonavir (Paxlovid) used to work very well.

In 2021, nirmatrelvir/ritonavir clearly decreased hospitalization and deathopens in a new tab or window among COVID-19 patients who had high risks of severe disease and who had not been vaccinated or previously infected. It's a drug that saved lives -- and would have saved many more if the vaccines had not beaten it to the punch.

The key thing to know is that nirmatrelvir/ritonavir's blockbuster effect was found in people who had neither been infected with SARS-CoV-2 nor vaccinated. But by the time it actually reached the open market, the vast majority of the high-risk U.S. population had already been infected or vaccinated. That immunity provides substantial long-term protection from severe COVID-19 when future infections occur, a fact which should not be minimized.



So, we've never really had the whole story on how well this drug works during its life in the real world. Observational studies (including work by my colleagues and meopens in a new tab or window, and countless other studies) have helped, but we've been waiting for far more valuable trial data. In the last few months, we've gotten some news, finally.

It's good news or bad news, depending on how you see things.

It's 2024: Where Do We Stand?

Well, we already found out this spring that nirmatrelvir/ritonavir is not as useful as it once was. Pfizer finally released resultsopens in a new tab or window from its 2021-2022 trial showing that nirmatrelvir/ritonavir had no influence on symptoms among vaccinated patients with high risks or unvaccinated standard-risk patients. That study also found that hospitalizations were not statistically different across the nirmatrelvir/ritonavir and placebo groups but the study was not specifically designed to be definitive on that question.



But, we've been awaiting the results from a randomized controlled trial from the U.K. (the PANORAMIC studyopens in a new tab or window), which are expected to give key results on hospitalization and mortality for thousands of study participants.

New Trial Data: Nirmatrelvir/Ritonavir Does Not Improve Mortality in Hospitalized Patients

In the meantime, we got some other data that is important. In late May, another U.K.-based study quietly preprinted findingsopens in a new tab or window from its randomized controlled trial of nirmatrelvir/ritonavir (conducted in 2022-2023 in the U.K., Indonesia, and Nepal). In this study, patients who were being hospitalized with COVID-related pneumonia were randomized to either receive nirmatrelvir/ritonavir or not. The patients' mortality rates were compared after 28 days. There was absolutely no difference.

This figure is pretty jarring. If the study had looked at 14-day outcomes, there would have been more deaths in the nirmatrelvir/ritonavir recipients. By day 28, things were equal. In any case, not a win for nirmatrelvir/ritonavir.



I ran some math known as power calculations -- albeit informally -- that I want to share with you. As it stands, nirmatrelvir/ritonavir was 0% effective in preventing death among patients hospitalized for COVID in the new RECOVERY study.

But let's imagine that we somehow knew for sure that the drug is effective, but that due to random chance, the study was "unlucky" and found that the death rate in the drug and control groups were equal.

In this table I made for us, the left column represents the "ground truth" hypothetical. That is, if nirmatrelvir/ritonavir were really 1%, 5%, 10%, 25%, 50%, or 75% effective in decreasing mortality, how likely would the 50-50 result (or worse) that was seen in the RECOVERY trial be (right column)? Here's the approximate readout:

In other words, if nirmatrelvir/ritonavir is actually 75% effective, the odds of a study like RECOVERY finding a 50-50 death rate (or worse) in the control and drug recipients just due to chance/bad luck is zero. If nirmatrelvir/ritonavir is actually 25% effective, the odds are just 18%. There's a reasonable chance (40-48%) that nirmatrelvir/ritonavir could be 5-10% effective against death, despite the 50-50 mortality findings in this study.



Folks, that is not good news for this drug. Remember: Pfizer's initial study found an 88% decrease in hospitalizations or deaths, and literally 100% of the deaths were among placebo recipients.

While the numbers in this newer study are on the smaller side, the researchers who did the study are highly respected and used good methods. For context, the parent study (RECOVERYopens in a new tab or window) has randomized over 49,000 COVID-19 patients since 2020 to see which drugs work and which ones don't. (It was this study, for example, that found that the inexpensive steroid dexamethasone had a massive benefitopens in a new tab or window for COVID patients in 2020.)

In short, this study was small, but meaningful.

Is This the End for Paxlovid?

While this is a pretty hefty blow to nirmatrelvir/ritonavir, it is not the end of the story for this drug, for two reasons. First, the RECOVERY trial results looked at patients already being hospitalized. So, we do not know if nirmatrelvir/ritonavir might still decrease hospitalizations and death in patients who are earlier in their illness. That is what Pfizer's 2021 blockbuster study found. The question is whether it remains true in 2024. The eagerly awaited PANORAMIC study will likely answer this question, as it is much larger and designed specifically to answeropens in a new tab or window that question.



We should brace for the possibility that the PANORAMIC trial will either show nirmatrelvir/ritonavir is now completely unable to decrease hospitalizations or deaths, or that at best, it does so modestly for a narrow group of very high-risk patients. Results are anticipated this year.

Remember when I said, "It's good news or bad news, depending on how you see things." What did I mean by that? Well, the bad news is that the drug doesn't seem to work as well as it once did. The good news is the reason for this: Collectively, we have far more immunity to severe consequences of COVID than we did back in 2020-2021.

So, here's the best way I can summarize things: It isn't that nirmatrelvir/ritonavir no longer works; rather, it's that in 2024, there are relatively few people who still seem to really need it to stay alive or out of the hospital.

This piece originally appeared in Inside Medicineopen
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[missy]

National Academies Issue New Broad Definition of Long COVID

The condition can exacerbate preexisting health conditions or present as new ones.

ma1.mdedge.com

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National Academies Issue New Broad Definition of Long COVID​

A new broadly inclusive definition of long COVID from the National Academies of Sciences, Engineering, and Medicine (NASEM) has been developed with the aim of improving consistency, documentation, and treatment for both adults and children.
According to the 2024 NASEM definition of long COVID issued on June 11, 2024, “Long COVID is an infection-associated chronic condition that occurs after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.”
People with long COVID may present with one or more of a long list of symptoms, such as shortness of breath, rapid heartbeat, extreme fatigue, post-exertional malaise, or sleep disturbance and with single or multiple diagnosable conditions, including interstitial lung disease, arrhythmias, postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), diabetes, or autoimmune disorders. The condition can exacerbate preexisting health conditions or present as new ones.
The definition does not require laboratory confirmation or other proof of initial infection. Long COVID can follow SARS-CoV-2 infection of any severity, including asymptomatic infections, whether or not they were initially recognized.
Several working definitions and terms for long COVID had previously been proposed, including those from the World Health Organization (WHO) and the US Centers for Disease Control and Prevention, but no common definition or terminology had been established.
The new definition was developed at the request of the Administration for Strategic Preparedness and Response and the Office of the Assistant Secretary for Health (OASH). It was written by a multi-stakeholder panel convened by NASEM, which recommended that the new definition be universally adopted by the federal government, clinical societies and associations, public health practitioners, clinicians, payers, the drug industry, and others using the term long COVID.
Recent surveys suggest that approximately 7% of Americans have experienced or are experiencing long COVID. “It’s millions of people,” panel chair Harvey V. Fineberg, MD, president of the Gordon and Betty Moore Foundation, told this news organization.
The new definition “does not erase the problem of clinical judgment ... But we think this definition has the real advantage of elevating to the clinician’s mind the real likelihood in the current environment of prevalence of this virus that a presenting patient’s strange symptoms are both real and maybe related as an expression of long COVID,” Dr. Fineberg noted.
One way this new definition differs from previous ones such as WHO’s, he said, is “they talk about a diagnosis of exclusion. One of the important points in our definition is that other diagnosable conditions like ME/CFS or POTS can be part of the picture of long COVID. They are not alternative. They are, in fact, an expression of long COVID.”
Indeed, the NASEM report also introduces the term infection-associated chronic condition (IACC). This was important, Dr. Fineberg said, “because it’s the larger family of conditions of which long COVID is a part. It emphasizes a relatedness of long COVID to other conditions that can follow from a variety of infections. We also adopted the term ‘disease state’ to convey the seriousness and reality of this condition in the lives of patients.”

Comments on New Definition​

In a statement provided to this news organization, Lucinda Bateman, MD, and Brayden Yellman, MD, co-medical directors of the Bateman-Horne Center in Salt Lake City, said that “describing long COVID as an IACC ... not only meets the NASEM goal of allowing clinicians, researchers, and public health officials to meaningfully identify and serve all persons who suffer illness or disability in the wake of a SARS-CoV-2 infection, but also draws direct comparison to other known IACC’s (such as ME/CFS, post-treatment Lyme, POTS) that have been plaguing many for decades.”

Dr. Fineberg noted another important aspect of the NASEM report: “Our definition includes an explicit statement on equity, explaining that long COVID can affect anyone, young and old, different races, different ages, different sexes, different genders, different orientations, different socioeconomic conditions ... This does not mean that every single person is at equal risk. There are risk factors, but the important point is the universal nature of this as a condition.”

Two clinical directors of long COVID programs who were contacted by this news organization praised the new definition. Zijian Chen, MD, director of Mount Sinai’s Center for Post-COVID Care, New York, said that it’s “very similar to the definition that we have used for our clinical practice since 2020. It is very important that the broad definition helps to be inclusive of all patients that may be affected. The inclusion of children as a consideration is important as well, since there is routinely less focus on children because they tend to have less disease frequency ... The creation of a unified definition helps both with clinical practice and research.”


Nisha Viswanathan, MD, director of the long COVID program at the University of California, Los Angeles, said: “I think they left it intentionally broad for the medical practitioner to not necessarily use the definition to rule out individuals, but to perhaps use more of a clinical gestalt to help rule in this diagnosis ... I think this definition is providing clarity to health care providers on what exactly would be falling under the long-COVID diagnosis header.”

Dr. Viswanathan also said that she anticipates this definition to help patients make their case in filing disability claims. “Because long COVID has not previously had a good fleshed-out definition, it was very easy for disability providers to reject claims for patients who continue to have symptoms ... I actually think this might help our patients ultimately in their attempt to be able to have the ability to care for themselves when they’re disabled enough to not be able to work.”

Written into the report is the expectation that the definition “will evolve as new evidence emerges and the understanding of long COVID matures.” The writing committee calls for reexamination in “no more than 3 years.” Factors that would prompt a reevaluation could include improved testing methods, discovery of medical factors and/or biomarkers that distinguish long COVID from other conditions, and new treatments.

Meanwhile, Dr. Fineberg told this news organization, “If this definition adds to the readiness, awareness, openness, and response to the patient with long COVID, it will have done its job.”

Dr. Fineberg, Dr. Bateman, Dr. Yellman, Dr. Viswanathan, and Dr. Chen have no relevant disclosures.

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[missy]

"

Dueling theories​

The origin of the Covid virus remains the pandemic’s biggest mystery. Did the virus jump to human beings from animals being sold at a food market in Wuhan, China? Or did the virus leak from a laboratory in Wuhan?

U.S. officials remain divided. The F.B.I. and the Department of Energy each concluded that a lab leak was the more likely cause. The National Intelligence Council and some other agencies believe that animal-to-human transmission is more likely. The C.I.A. has not taken a position. The question remains important partly because it can inform the strategies to reduce the chances of another horrific pandemic.

A recent Times Opinion essay — by Alina Chan, a biologist — refocused attention on the issue by making the case for the lab-leak theory. In today’s newsletter, I’ll try to lay out the clearest arguments for each side to help you decide which you consider more likely.

The case for natural transmission​

1. It’s the norm.

Covid is part of the coronavirus family, so named because the virus contains a protein shaped like a spike. (Corona is the Latin word for crown.) In recent decades, the main way that coronaviruses have infected people is through animal-to-human transmission, which is also known as natural transmission.

The SARS virus, for example, appears to have jumped from civet cats, a relative of the mongoose, to humans in Asia in 2002. MERS seems to have jumped from camels to people in the Middle East around 2012. There is no previous example of a major coronavirus escaping a lab.

When you’re trying to choose between a historically common explanation for a phenomenon and an unusual explanation, the common one is usually the better bet.

2. Look around the market.

Two scientific papers have pointed out that a suspiciously large number of early confirmed Covid cases had connections to the Huanan Seafood Wholesale Market in Wuhan. Many of these cases, in late 2019, occurred in people who lived near the market. This map comes from a Times story about the research:

Source: Michael Worobey et al., preprint via Zenodo | By The New York Times​

Importantly, the market also sold live animals, including raccoon dogs, that scientists previously found to be susceptible to coronaviruses.

3. Look inside the market.

Shortly after Covid began spreading, Chinese scientists swabbed walls, floors and other surfaces inside the Huanan market for the virus. They found a cluster of positive samples in the market’s southwest corner, where 10 stalls sold live animals.

“Strikingly, five of the samples came from a single stall,” my colleagues Carl Zimmer and Benjamin Mueller wrote. That stall appears to have had a history of selling raccoon dogs.

The case for a lab leak​

1. Follow the lab.

If historical logic points to natural transmission, a different concept arguably points to a lab leak: Occam’s razor. It’s a philosophical principle holding that the simplest explanation for a phenomenon is usually the correct one. In this case, a new SARS-like virus started in a city with one of the world’s leading labs for researching SARS-like viruses. Many Chinese cities have markets selling live animals; only one is home to the Wuhan Institute of Virology.

The Wuhan lab maintained “one of the world’s largest repositories of bat samples, which has enabled its coronavirus research,” U.S. intelligence officials have written. Before the pandemic, the lab’s scientists traveled to faraway caves to collect virus samples. And bats, like raccoon dogs, can carry coronaviruses.

One possibility is that a virus that would otherwise have remained in the caves infected a lab employee. Another possibility is that scientists in Wuhan engineered a contagious new virus while researching cures and that the virus accidentally escaped.

Notably, there is no evidence of any infected animals, dead or alive, from the Huanan market. Consider this table, from Chan’s Opinion essay:

By The New York Times​

2. Leaks happen.

In recent decades, reports suggests that laboratory employees working on a variety of diseases have been accidentally infected in the United States, Britain, China, Germany, Russia, South Korea and elsewhere.

Even before the pandemic, the Wuhan lab seemed to present a safety risk. When one outside expert heard that the lab planned to research coronaviruses without using state-of-the-art precautions, he wrote in 2018 that “U.S. researchers will likely freak out.”

3. China controls the evidence.

It’s worth asking which of the two stories China would rather the world believe. Either would be damaging, but a lab leak seems significantly more so. It would mean that China’s scientific incompetence killed millions of people — which could explain why Chinese officials have worked so hard to restrict outside research and scrutiny about the virus’s origins.

The bottom line​

Do you find both explanations plausible? I do.

As I’ve followed this debate over the past few years, I have gone back and forth about which is more likely. Today, I’m close to 50-50. I have heard similar sentiments from some experts.

“No one has proof,” Julian Barnes, who covers intelligence agencies for The Times, told me. “Everyone is using logic.” Julian’s advice to the rest of us: “Be wary, keep an open mind, rule nothing out.”

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