By Lambert Strether of Corrente.
Paxlovid — “Peace and love,” dig? Or even just “Pax,” as
American’s Chief Pharmaceutical Salesman White House Covid response coordinator Ashish Jha dubs it — is the key treatment in the Biden Administration’s “Test to Treat” program. As readers know, I’m all for treatment — indeed, I can’t understand why the White House didn’t intitiate an Operation Warp Speed for treatments when it took office — but with Paxlovid I have some questions. First, I’ll look at the “Test to Treat” program, as it has performed and as the White House Hopes to Improve It. Then, after looking at the FDA EUA for Paxlovid, I’ll raise issues with the drug that might mean uptake is not what the White House expects it to be. I’ll conclude with a few remarks on treatment equity. But before I dive in, here’s the study from the New England Journal of Medicine that’s driving the enthusiasm for Covid: “Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19.” From the Abstract (or, depending, the sales pitch):
Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns.
(Nirmatrelvir plus ritonavir is Paxlovid.) Taking apart a NEJM study is definitely above my paygrade. Two things, however, leap out. First, from Method:
We conducted a phase 2–3 double-blind, randomized, controlled trial [with] symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19)….
So the test population was unvaccinated? Oh. And:
(Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.
Well, alrighty then. On to the “Test to Treat” program.
“Test to Treat”
Up until this point, the Biden Administration’s “Test to Treat” program has been — hold on to your hats, here, folks — an omnishambles. From Kaiser Health News:
The federal “test-to-treat” program, announced in March, is meant to reduce covid hospitalizations and deaths by quickly getting antiviral pills to people who test positive. But even as cases rise again, many Americans don’t have access to the program.
The program allows people with covid symptoms to get tested, be prescribed antiviral pills, and fill the prescription all in one visit. The federal government and many state and local health departments direct residents to an online national map where people can find test-to-treat sites and other pharmacies where they can fill prescriptions.
But large swaths of the country had no test-to-treat pharmacies or health centers listed as of April 14. And the website of the largest participant, CVS, has significant technical issues that make booking an appointment difficult.
Even people who regularly see a doctor may be unable to get a prescription in time, and that’s where the program comes in. Before the pandemic, 28% of Americans didn’t have a regular source of medical care, with rates even higher for Black and Hispanic Americans….
Although the cost of the pills is covered by the federal government, obtaining a prescription at the pharmacies that dominate the program can be expensive. Though CVS does not charge symptomatic uninsured people for on-site covid tests, MinuteClinics charge upwards of $100 for in-person or telehealth appointments to examine patients and prescribe an antiviral, if needed. People without insurance, whose health plans don’t cover visits to the clinics, or who have high-deductible plans must shoulder the full cost of the appointment.
“All of our public health response relies on lowering the barrier to getting treatments to the right people,” said Dr. Kirsten Bibbins-Domingo, chair of the Department of Epidemiology and Biostatistics at the University of California-San Francisco.
She said the fragmented federal, state, and local public health systems, the U.S. Department of Health and Human Services’ reliance on partners that charge high prices for appointments, and the lack of clear information are stymieing the effort. “The best tools that we have are not going to reach the people who most need them,” she said.
Hey, remember when Trump just gave out vaccines for free? What an idea that was. In any case, here’s how the Biden Administration proposes to improve the program. From CNN:
The Biden administration is set to unveil new details and announcements Monday on Paxlovid, Pfizer’s antiviral Covid-19 pill, a White House official tells CNN.
The administration has plans underway to increase the availability and uptake of the drug, White House Covid-19 Response Coordinator Dr. Ashish Jha announced on Twitter.
… According to Jha’s tweets, the administration is working on establishing more places where Paxlovid will be available, including more test-to-treat sites.
The administration’s nationwide test-to-treat initiative involves “one-stop” sites where people are offered free Covid-19 testing and, if they test positive, can be prescribed free antiviral medications on the spot.
Jha tweeted that the Biden administration’s plans include more education for health care providers on how to use Paxlovid “more regularly” for eligible patients.
The administration’s plans signal “some positive changes” with regard to treating Covid-19 infections, and in some ways, the test-to-treat model “transforms medicine,” Dr. Daniel Griffin, an instructor in clinical medicine and associate research scientist in the Department of Biochemistry and Molecular Biophysics at Columbia University, said Monday.
“When you get sick with a viral illness, the last thing you want to do is try to get an appointment at a physician’s office, get out of bed, wait in the waiting room, get seen, then have to drive somewhere else to pick up at your pharmacy,” Griffin said, adding that “being able to get taken care of as soon as possible without all the delays that our system has introduced” is a positive.
On the ground, it appears that the pace of Covid-19 antiviral prescriptions under the test-to-treat program has not reached the level that health officials expected by this point, said Lori Tremmel Freeman, chief executive officer of the National Association of County and City Health Officials.
“The bottom line is, the uptake is very, very low and slow despite there being a lot of these drugs in the market and available,” Freeman said.
So, translating, the Administration sees doctors as the problem, and hopes to work around them by getting pharmacists to prescribe Paxlovid to, well, customers directly. Why would that be a problem, and why have doctors been reluctant to prescribe Paxlovid? To understand that, we need first to look at Paxlovid’s FDA EUA, which describes who is eligible for treatment.
The Paxlovid EUA: Who is Eligible for Treatment?
Yale Medicine describes who is eligible for Paxlovid:
The FDA authorized Paxlovid for people ages 12 and older who weigh at least 88 pounds. But in order to qualify for a prescription, you must also have had a positive COVID-19 test result and be at high risk for developing severe COVID-19.
That means you must either have certain underlying conditions (including cancer, diabetes, obesity, or others) or be an older adult (more than 81% of COVID-19 deaths occur in people over age 65). The more underlying medical conditions a person has, the higher their risk for developing a severe case of COVID-19, according to the CDC.
But what is “high risk”? From the FDA’s FAQ on the EUA, see footnote 1:
Footnote 1 punts the definition of “high risk” to the CDC:
And here are the “medical conditions” listed on that CDC page, in alphabetical (and not risk) order:
Cancer, chronic kidney disease, chronic liver disease, chronic lung diseases, cystic fibrosis, dementia or other neurological conditions, diabetes (type 1 or type 2), disabilities, heart conditions, HIV infection, immunocompromised state (weakened immune system), mental health conditions, overweight and obesity, physical inactivity, pregnancy, sickle cell disease or thalassemia, smoking, current or former, solid organ or blood stem cell transplant, stroke or cerebrovascular disease, substance use disorders, and tuberculosis.
(Note CDC’s caveat: “Because we are learning more about COVID-19 every day, this list does not include all medical conditions that place a person at higher risk of severe illness from COVID-19.” Yes, of course, but that does leave footnote 1 in the EUA just a little bit open-ended, no?) In any case, superficially “high risk” seems like pretty good news from the uptake standpoint: Millions of Americans are obese, have heart conditions, have substance abuse disorders, and so forth. So a pretty big market for Pfizer, this “high risk” market. Not so fast.
Potential Problems with Paxlovid that Could Reduce Uptake
Paradoxically, the very complexity of “high risk” patients makes doctors reluctant to prescribe Paxlovid; these patients are almost certainly taking other drugs already, and a conscientious doctor would want to know about drug interactions. But these are not necessarily known. From the Philadelphia Inquirer, “Paxlovid is an effective COVID-19 drug that may not be safe if you have these common health conditions“:
The FDA has published a fact sheet for health care providers on Paxlovid. Much more than a sheet, it’s actually 29 pages crammed with facts – and 12 of those pages list potential side effects.
Here’s the irony: Some of the preexisting conditions that make a COVID infection especially dangerous — such as high blood pressure, diabetes, heart failure and arrhythmias — often are treated with multiple medicines that could also make Paxlovid dangerous.
Some of the common cardiac medications that you cannot take with Paxlovid include amiodarone, flecainide, Plavix, Brilinta, and some statins. Some of these can be stopped for the five-day course of Paxlovid. But other meds, such as amiodarone, hang around in the body for quite a while, and adding Paxlovid is completely contraindicated.
Paxlovid is a combination drug (nirmatrelvir with ritonavir). It inhibits an enzyme in the body essential to produce cholesterol, steroids, and prostacyclins, and can increase the concentration of many other medications/
What’s more, many people might not even realize that they could be harmed by this new medication. Because at least 40% of American adults are considered obese, 14% smoke, and more than 10% have diabetes, there are a lot of people at high risk even though they may feel well. They are all potential candidates to develop severe COVID and may need therapy, and an unknown number are taking multiple medications that can interact with Paxlovid.
In light of this information, taking Paxlovid is not an easy decision. It is very effective in the studies done so far, especially in the unvaccinated. However, the drug interferes with so many medications that are used for chronic medical conditions that it needs to be used carefully.
I would be very reluctant to recommend its use for patients taking multiple medications, all of which should be checked for interactions before use. It is not a panacea. Getting vaccinated to reduce the risk of life-threatening complications and hospitalization seems a much safer option.
When David Bookstaver tested positive for COVID-19 he happened to have a telehealth consult with his doctor already scheduled that day, to talk about going on medication to moderate his high blood pressure.
On that call Bookstaver, 63, says his doctor mentioned his age and hypertension made him eligible for Paxlovid, Pfizer’s antiviral pill treatment, which has proven highly effective at keeping higher-risk patients out of the hospital, and preventing them from getting even sicker.
Bookstaver is fully vaccinated and boosted and didn’t feel too ill at the time – but warding off a turn for the worse seemed prudent. The doctor sent a prescription for the new medication to the pharmacy and his wife was kind enough to pick up his medicine and bring it home.
But when he read over the drug information, Bookstaver’s eyes caught on some of the fine print: the cholesterol medication he was already on – and the blood pressure medication he had also just been prescribed – were both listed as having potentially harmful interactions with the Paxlovid he had just been given.
“If I was really sick I probably would have gobbled the first dose up and not looked,” Bookstaver said. “I think most people don’t do due diligence. They trust their doctor implicitly. But if people aren’t checking the contraindications labels I think they kind of need to be told.”
(The doctor believed the pharmaceutical salesman and didn’t read the fine print. Holy moley!) The Conversation summarizes:
It’s kind of limited. It could be beneficial for those at high risk of severe disease and possibly death, such as people who are older or who have hypertension, diabetes, obesity, heart disease or who are immunocompromised. And that’s the population that we’re really the most worried about when it comes to COVID-19.
But the more medically complicated a person is – by which I mean the more health conditions they have and medications they take – the more likely it is that Paxlovid will interact with one of their drugs. That means that one drug could alter or interfere with how another drug works, which can be dangerous.
Some of the really important Paxlovid interactions are with anti-rejection medications for people who have transplants. A lot of blood thinners have interactions with it that can be very serious. Medications that treat heart rhythm abnormalities can be a major issue if patients on those medications take Paxlovid. And there’s a whole range of other things that it just doesn’t mix well with in the body.
Some who could most benefit from Paxlovid are also at highest risk for drug interaction with Paxlovid. That makes it somewhat less useful.
The Biden Administration’s solution for this problem is, apparently, to cut the doctor out of the prescription loop entirely, and have
patients customers deal directly with pharmacists, who presumably will use checklists or an app of some sort. What could go wrong?
There is also a second, and to my mind lesser, issue with Paxlovid, called “rebound.” From the Boston Globe, “A puzzling phenomenon: Patients report a rebound of COVID-19 symptoms after taking the antiviral Paxlovid“:
But now some patients are reporting on social media an unusual and unnerving phenomenon: their COVID symptoms appear to rebound after taking [Paxlovid].
And it’s not just their symptoms that reappear. Many report that after finishing their five-day course of treatment, feeling better, and testing negative on an at-home rapid test, they then test positive again a few days later.
The issue has captured the attention of at least two teams of Boston-area scientists, who are trying to understand what might be fueling the problem. Resistance to the drug? Patients being quickly reinfected? Or maybe some people just need to take the medicine longer to mount a more effective immune response.
But some infectious disease specialists, while still extolling Paxlovid’s benefits, have expressed concern that the rebounds they are seeing and hearing about may indicate patients, after completing treatment — and testing negative and then positive, again — may still be infectious and transmitting the virus to others.
“If you have a rebound after 12 days and are back at work and not wearing a mask, are you still contagious?” said Dr. Kathryn Stephenson, an assistant professor at Harvard Medical School and an infectious disease physician at Beth Israel Deaconess Medical Center. “If you are testing positive on a rapid antigen test, then you have a decent amount of virus and likely an infectious amount of virus,” she said.
We absolutely should have been warning patients (and doctors) that rapid improvement, followed by clinical deterioration and, presumably, high risk of contagion, could happen in some 10% of high-risk patients. It’s also quite clear that we need more information about Paxlovid now.
For one: presumably Pfizer and the FDA know what happened to the trial subjects who saw their viral load rebound. Was this a mere annoyance, or did it increase the risk of hospitalization? If most or all of the small group of hospitalized patients who received Paxlovid (i.e., treatment failures) were in this rebound sub-group, it is highly possible that treating them with an additional course might have made the effectiveness of Paxlovid even better. In the FDA’s most recent approval letter to Pfizer, none of this information was requested or even mentioned; most of their emphasis was data on possible SARS-CoV-2 mutations from people treated with Paxlovid.
(Rebound was described in the EUA, but not to the level of detail “Doctor Buzz” rightly demands.)
Both issues, to my mind, will combine to make Paxlovid uptake slower than the Biden Administration expects; so far, at least, “the dogs won’t eat the dog food,” though it’s clearly Ashish Jha’s mission in life to make them do so.
Other problems with “Test to Treat” stem from our Harkonnen-style health care system. I don’t know how on earth it happened that Trump’s Surgeon General becames one of the most level-headed, empathetic voices around, but here we are:
My concerns w/ “test to treat”:
-Many who would benefit from Paxlovid are ineligible due to contraindications
-FDA EUA limits who can prescribe- so marginalized communities less likely to have a pharmacy clinic that can legally prescribe
-Can’t see it “changing the game.”🤷🏽♂️
— Jerome Adams (@JeromeAdamsMD) March 4, 2022
And speaking of “marginalized communities”:
Surprised to learn that Kamala Harris who is asymptomatic, healthy, and quadruple vaccinated is getting Paxlovid, a drug reserved for high-risk patients per the FDA label.
— Marty Makary MD, MPH (@MartyMakary) April 27, 2022
Why is Kamala Harris a “high risk” patient? The CDC (see above) has a list of medical conditions that would make her so. Mental health? Substance use? In fact, probably not. Probably something much more simple and old-fashioned. Jerome Adams once again:
“The people who know about [Paxlovid] are the people who know how to advocate for themselves, so we are seeing inequities actually expand.
Harris, for example. Or all the attendees at the Gridiron Club, who probably dosed themselves to the gills the day after. You’ll notice that the Biden revisions to “Test to Treat” do absolutely nothing to address the structural inequities identified by Kaiser Health News. First we had “shots in arms.” Now we have “pills in mouths.” So, by Betteridge’s Law….
 Health Online describes Paxlovid’s regimen and mechanism of action:
The three-pill regimen contains two different drugs: nirmatrelvir, which disrupts the novel coronavirus’s ability to replicate; and ritonavir, which slows down how quickly the body processes the drug.
The three pills are taken twice daily during a 5-day course.
“Nirmatrelvir works by inhibiting the COVID virus’s protease enzyme that speeds up the replication of the virus in the body,” Dr. David Cutler, a family medicine physician at Providence Saint John’s Health Center in Santa Monica, California, told Healthline. “By inhibiting that enzyme it stops the progression of the disease in its tracks. The second drug inhibits the liver system which is responsible for the breakdown and excretion of nirmatrelvir. Therefore, the second drug, ritonavir, prolongs the ability of the first drug, nirmatrelvir, to work within the body to fight the infection.”
Let’s hope you don’t need an uninhibited liver for any other purpose, I suppose.