Do you know when Paxlovid should be used to treat COVID-19? Are you aware of the reasons for the mixed results of its phase two and phase three clinical trial data compared with its real-life studies? Do you know what the most significant concern about Paxlovid is for its future application in treating COVID-19?
Reputed as a so-called “game-changer” oral antiviral pill to treat COVID-19, Paxlovid can prevent hospitalization and death in people who are at high risk of severe COVID-19. However, you should know that the research findings on Paxlovid are not always what they seem to be.
Summary of Key Facts
- Paxlovid is not yet approved by the FDA.
- The drug should be used soon after viral infection.
- Its clinical trial reported 89 percent efficacy with side effects of dysgeusia and diarrhea.
- Paxlovid doesn’t work in younger patients.
- In a real-world study, the drug showed limited effectiveness.
- Finding “treatable” patients has proven challenging.
- Drug resistance is a major concern.
- Another major concern is Paxlovid’s interaction with other drugs.
- Natural immunity influences the success of Paxlovid and other antivirals.
1. Paxlovid Is Not Yet Approved by the FDA
On Dec. 22, 2021, the FDA issued an emergency use authorization (EUA) for Paxlovid (nirmatrelvir tablets co-packaged with ritonavir tablets) to treat mild-to-moderate COVID-19.2. Paxlovid Should Be Used Soon After Virus Infection
A group of researchers, mainly from Pfizer Worldwide Research, published an article in Science on Nov. 2, 2021, about the discovery and characterization of Paxlovid. In vitro antiviral activity of Paxlovid has been evaluated in multiple cellular models. In vitro testing showed that Paxlovid demonstrated potent antiviral activity against SARS-CoV-2, MERS-CoV, and other similar coronaviruses.However, the researchers noted that Paxlovid should be given very soon after a subject is infected with COVID-19.
When given to mice as early as four hours after infection with SARS-CoV-2, a 300 or 1,000 mg/kg treatment of Paxlovid was effective in reducing the SARS-CoV-2 viral load in the lungs.
This means Paxlovid should be taken as early as possible after infection with the virus. That is also the rationale for the inclusion criteria: Only patients within five days of symptom onset were recruited in phase two and phase three clinical trials. If the viral infection is in a late stage and the illness is more severe, Paxlovid may not be as helpful.
3. Clinical Trial: 89 Percent Efficacy With Side Effects of Dysgeusia and Diarrhea
The findings of a phase two/phase three double-blind, randomized, controlled trial supported by Pfizer were published on Feb. 16, 2022, in the New England Journal of Medicine.The trial involved 2,246 symptomatic, unvaccinated, non-hospitalized adult patients who were at high risk for developing severe COVID-19 symptoms, and symptom onset was no more than five days. They were randomly selected to receive either Paxlovid (300 mg nirmatrelvir and 100 mg ritonavir) with other standard care or a placebo with other traditional medicine twice a day for five days.
The final analysis, involving 1,379 patients, showed that when administered less than five days after symptom onset, Paxlovid reduced the risk of COVID-19-related hospitalization or death by 89 percent compared with the placebo group.
The main side effects observed with Paxlovid were dysgeusia (a taste disorder, 5.6 percent versus 0.3 percent in the control group) and diarrhea (3.1 percent versus 1.6 percent). This indicates potential side effects on the neurological and gastroenterological systems.
Again, consistent with the development concept of this drug and aligned with its animal data, the drug has to be taken at an early stage of infection. Most patients (66.3 percent) received the first dose of the trial drug or placebo within three days of the onset of symptoms.
4. Paxlovid Doesn’t Work in Younger Patients
A large-scale observational, retrospective cohort study involving more than 100,000 subjects conducted in Israel during the Omicron-surge phase was published in the New England Journal of Medicine on Sept. 1, 2022.This study was based on data obtained from a large health care organization covering approximately 52 percent of the Israeli population.
5. Finding ‘Treatable’ Patients Has Proven Challenging
We may wonder why Paxlovid works in elderly patients but not in the younger group of people in the Israel study.First, the drug has to be taken by a patient as early as possible after SARS-CoV-2 infection. This is evident from the administration timings in the studies of the drug, and it makes sense because of the drug’s mechanism of action. It’s also common sense that earlier treatment produces a better outcome.
This causes an issue: On the one hand, we have to start treatment; on the other, the high false-negative rate hampers early Paxlovid application in the maximal patient population.
Paxlovid is not indicated for treating COVID-19 patients who require hospitalization due to severe or critical COVID-19 diseases. Based on previous clinical trial data, none of those trials were conducted in severe COVID-19 patients, so it’s essential to bear this point in mind.
6. In a Real-World Study, Paxlovid Has Shown Limited Effectiveness
In October 2022, Hong Kong University researchers compared the clinical effectiveness of two oral antiviral drugs, Paxlovid and molnupiravir, among Hong Kong residents. The researchers’ observational study was published in The Lancet.Between Feb. 26 and Jun. 26, 2022, among the 1,074,856 non-hospitalized patients infected with Omicron, 6,464 were treated with Paxlovid and 5,383 with molnupiravir. The molnupiravir group older patients, and more unvaccinated ones, than the Paxlovid group.
It’s worth noting that these two antivirals were not compared directly in this study, but each was compared with its control group with matching patient conditions.
Paxlovid reduced the mortality rate by 66 percent versus the control, while molnupiravir lowered the mortality rate by 24 percent versus its own control.
Molnupiravir did not lower hospitalization rate; Paxlovid lowered the hospitalization rate by 24 percent.
Both drugs lowered in-hospital disease progression by 43 percent.
These rates don’t look as good as Paxlovid’s phase two and phase three clinical trial data. One of the most likely reasons is how well the narrow treatment window of the drug has been followed.
7. Drug Resistance Is a Major Concern
Antiviral treatments are often associated with the development of drug-resistant viruses. There is a well-known saying in the antiviral community: “No antiviral, no resistance.”A virus is a cunning microorganism. When you add pressure to its replication cycle, a virus will typically find a way to detour by mutating and will manage to survive. This is the primary mechanism of antiviral resistance.
In this sense, Paxlovid is no different from other antivirals.
Two research groups have independently shown that SARS-CoV-2 quickly gains the ability to avoid nirmatrelvir’s attack.
8. Another Major Concern Is Paxlovid’s Interaction With Other Drugs
CYP3A breaks down Paxlovid. CYP3A is one of the most important enzymes in our liver and digestive tract, and it plays a significant role in breaking down the drug.Potent CYP3A inducers will reduce the drug exposure of Paxlovid, resulting in loss of response to Paxlovid treatment and increased risks of drug resistance.
9. Natural Immunity Influences the Success of Paxlovid and Other Antivirals
The main merit of antiviral drugs is that when the body’s immune system is not strong enough, external drugs can temporarily inhibit the replication of the virus, giving our natural defense system some time to recover to its full strength.
Meanwhile, we shouldn’t neglect the ability of our bodies to produce antiviral substances. Interferon, for example, is produced by many immune cells (white blood cells, NK, NKT, and T cells). As the name implies, through “interference,” it achieves antiviral effects. Interferon is like a commander, giving instructions to coordinate various cells and signaling pathways to work together to fight a virus.
Natural immunity is an endogenous antiviral force in our body, like a joint force ready to fight against invading pathogens. If we are mindful enough to nourish our immunity in peaceful times, the defense mechanisms will work well when “war” breaks out.
In summary, we should calmly view the strengths and limitations of antiviral drugs. On the one hand, we expect antiviral drugs to work well; on the other hand, we must enhance our immune system’s power to resist the virus in a more natural, systematic, dynamic, and resourceful manner.