Paxlovid (nirmatrelvir + ritonavir) and Legevrio (molnupiravir) got a green light from the FDA two years ago. Like everything surrounding COVID-19, there is controversy about the benefits and risks of these antiviral drugs. A review in the Cochrane Database of Systematic Reviews (Nov. 30, 2023) is not exactly a ringing endorsement. Here are some of the authors’ conclusions:
Outpatients:
“Based on the current low‐certainty evidence (one trial), in outpatients nirmatrelvir/ritonavir [Paxlovid] may reduce all‐cause mortality and hospital admission or death within 28 days.
“This review only included one trial for the outpatient setting investigating people who were unvaccinated without previous infection who were at high risk of disease progression due to coexisting conditions or other characteristics associated with an increased risk of developing severe illness from COVID‐19. There is currently no evidence for the use of nirmatrelvir/ritonavir in a broader population of vaccinated people, those with previous SARS‐CoV‐2 infection, or those without increased risk for progression to severe disease.”
Inpatients:
“Based on the current low‐certainty evidence (one trial), we are uncertain whether nirmatrelvir/ritonavir reduces all‐cause mortality at 28 days or increases viral clearance at seven or 14 days.
“The study only included mildly to moderately affected participants, which might not resemble the typical hospitalized people with COVID‐19. It only included participants without previous infection and most were unvaccinated who were at high risk of disease progression due to severe comorbidities or a SOFA [Sequential Organ Failure Assessment]/Charlson score of 2 or greater. There is currently no evidence for the use of nirmatrelvir/ritonavir in more severely affected people as well as a broader population of participants with previous SARS‐CoV‐2 infection, or those without increased risk for progression to severe disease.”
That’s a lot of doctorspeak. I interpret that to mean that in nonhospitalized patients, Paxlovid may reduce the risk of serious disease from COVID-19 (less mortality or hospitalization). These were unvaccinated outpatients. The Cochrane experts rate the data from hospitalized patients as “very low-certainty evidence.” That’s not terribly reassuring.
Somewhat more optimistic are results from a small study in China published in Medicine (Baltimore), Dec. 22, 2023. The authors reported:
“Compared to patients with standard treatment, patients with Paxlovid had a significantly shorter nucleic acid shedding time (3.26 vs 7.75), days until negative swab test (1.74 vs 5.33), days of first symptoms resolution (4.86 vs 7.45)…However, there was no significant difference in hospital stay between patients with Paxlovid and standard treatment (7.97 vs 9.08).”
Of course the fact that hospital stays did not improve is disappointing.
Positive News About Paxlovid!
A study published in Nature Communications (Dec. 16, 2023) offers a more optimistic outlook on the combination of nirmatrelvir/ritonavir. In this study from Hong Kong, researchers reviewed electronic health records of more than 87,000 adults who had received Paxlovid. Those who got the drug within 1 day of developing symptoms or a diagnosis of COVID:
“…significantly reduced the incidence of 28-day all-cause mortality and hospitalization compared to delayed initiation (2 or more days) (absolute risk reduction [ARR]:1.5%).
“The observed benefit from administering nirmatrelvir/ritonavir as soon as possible after diagnosis or symptom onset may be attributable to an early suppression of viral replication, which in turn reduced the risk of subsequent deterioration to severe disease and death.
“In conclusion, our results suggest that initiating nirmatrelvir/ritonavir as early as possible after symptom onset or diagnosis better protects against all-cause mortality and hospitalization than initiating therapy with longer delays.”
Pharmacists Can Now Prescribe Paxlovid:
Paxlovid is most effective if the patient takes it shortly after testing positive or developing symptoms. As a result, the FDA updated its Paxlovid rules on July 6, 2022. Dr. Patrizia Cavazzoni, Director of the agency’s Center for Drug Evaluation and Resarch (CDER) announced that state-licensed pharmacists can now prescribe these pills for high-risk patients over 12 years old.
In its statement, FDA officials still advise people to seek attention from their regular healthcare provider or from an established Test-to-Treat site. At these one-stop sites, people can get reliable tests and prescriptions for treatment when appropriate. Allowing pharmacists to prescribe a short course of the medication should help curb infections more quickly.
‘Unfortunately, it does not settle questions about Paxlovid rebound. Moreover, pharmacists may have difficulty determining just who is at high risk. To help the pharmacists decide if a Paxlovid prescription is warranted, patients should provide recent medical records with laboratory blood work results as well as a complete list of prescription and over the counter medicines the person is using. After all, Paxlovid interacts with a number of other drugs.
What Is the Current Status of Anti-COVID Medicine?
With COVID cases rising again, there is a push to make Paxlovid more accessible to patients. This combination drug can reduce the severity of the infection if taken shortly after symptoms appear.
There are two caveats, however. First, it can interact with a great many other medications including statins, which are taken by tens of millions of people. We detail some of the interactions below.
Another possible concern involves the recurrence of symptoms and even positive COVID tests after patients complete their 5-day course of treatment with Paxlovid. So far, there are individual reports of people becoming ill again shortly after finishing the antiviral drug. We don’t yet have an organized study that would explain it. No one yet knows how common this rebound effect may be, but it is worrisome.
How Does Paxlovid Work?
This oral medication works differently from molnupiravir. Paxlovid attacks protease enzymes that are essential for snipping strands of viral protein. That’s how the drug blocks replication of COVID-19.
Molnupiravir works by forcing the virus to scramble its genetic code. By inducing mistakes, the drug forces the virus to mutate. As a result, it can no longer reproduce. Both drugs interfere with the ability of SARS-CoV02 to replicate. They just use different mechanisms.
Paxlovid vs. Molnupiravir:
At first glance, Paxlovid appears to be the hands down winner in the battle of the oral antiviral meds against COVID-19. The interim analysis suggests 89% effectiveness vs. 30% effectiveness for molnupiravir. That’s relative risk reduction.
Let’s compare absolute risk reduction. In the molnupiravir trial 68 out of 699 placebo patients were hospitalized or died (9.7%). The active drug reduced hospitalization or death to 48 out of 708 (6.8%). That is a 3% absolute risk reduction with molnupiravir.
In the Paxlovid trial, 27 out of 385 patients receiving placebo were hospitalized or died (7%). The active drug reduced that to 3 people hospitalized out of 385 (0.8%). That is a 6% absolute risk reduction with the Pfizer drug. Paxlovid seems to be winning big, but there are some disadvantages too.
The Downside of Paxlovid:
Patients will need to take the Pfizer pill with another medication, an HIV/AIDS drug called ritonavir (Norvir). This second pill interferes with the body’s ability to break down (metabolize) Paxlovid. As a result, ritonavir prolongs the activity of the anti-COVID drug.
Sadly, we don’t know a lot about Paxlovid’s side effect profile. However, we do know that ritonavir can cause digestive tract upset (nausea, vomiting, stomach pain, diarrhea), fatigue, cough, dizziness, itching, confusion and fluid retention. That’s just for starters. There are many other potential adverse reactions. Fortunately, the dose of ritonavir is considered low and it is taken for only five days.
According to the FDA,
Possible side effects of Paxlovid include impaired sense of taste, diarrhea, high blood pressure and muscle aches.
Overcoming the Bad Taste of Paxlovid:
A reader of our newspaper column recently shared this experience with cottage cheese and Paxlovid:
Q. Last week my husband and I came down with COVID even though we’d had our shots and boosters. Both of us were given Paxlovid because we are older people. My husband has COPD, so he was also given a steroid pack.
I was told Paxlovid could leave a metallic taste in my mouth. It did for me, but not for my husband. Then I decided to put the pills into cottage cheese. BINGO. The metallic taste was substantially relieved. Others might like this tip.
A. Thank you for sharing your experience with the antiviral drug Paxlovid. We checked to make sure your strategy would not interfere with absorption. The official prescribing information states:
“Take PAXLOVID with or without food.” It also states, however, “Swallow the tablets whole. Do not chew, break, or crush the tablets.”
Paxlovid can increase blood levels of some corticosteroids such as dexamethasone or methylprednisolone. If your husband needs another course of Paxlovid, his doctor should monitor his steroid dose carefully.
Dangerous Drug Interactions:
The real challenge with ritonavir has to do with drug interactions. This medication can interact with hundreds of other drugs. That means doctors and pharmacists will need to be extremely careful if they consider prescribing the Paxlovid/ritonavir combination to patients who are taking any other meds.
For example, ritonavir should not be prescribed to patients taking drugs such as atorvastatin, amiodarone, butalbital, carbamazepine, dronedarone, eletriptan, enzalutamide, lovastatin, metronidazole, midazolam, modafinil, phenobarbital, phenytoin, sildenafil, sirolimus, tacrolimus or triazolam.
That too is just for starters. There are literally hundreds of other drugs that make Pfizer’s antiviral combo problematic. People taking drugs to control cardiac arrhythmias, high blood pressure, elevated cholesterol and HIV infections may have serious complications as a result of drug interactions. Anyone prescribed Paxlovid must ask both the physician and pharmacist to review all other drugs they take to prevent dangerous interactions.
COVID Resistance?
There is one other potential complication. In our conversation with Dr. Ralph Baric about oral antiviral drugs against COVID-19, he raised the possibility that the SARS virus could develop resistance to the antiviral medicine. You can listen to our interview with him in which he discusses the oral meds and the likely future of the COVID pandemic. Here is a link to the podcast:
Show 1281: New Antiviral Pills and the Future of COVID-19
Coronavirus hunter Dr. Ralph Baric helps you understand the future of COVID-19. How can we become better prepared for the next pandemic?
