While heading the Food & Drug Administration, Dr. Frank Young believes that regulation sometimes needs to be tempered with common sense. Regulators would do well to implement that advice, as the Agency questions whether additional steps are needed to guide Paxlovid users.
As we have been reading for days as background, Paxlovid is a true breakthrough drug with over 90% efficacy in treating mild to moderate COVID-19 and preventing hospitalization and death. It is an oral combination regimen of two drugs – one drug is nirmatrelvir, an antiviral agent, while the second, ritonavir, inhibits the metabolism of nirmatrelvir, preserving therapeutic levels.
But as with the president and a small number of other cases, doctors sometimes see an unexpected phenomenon — an improvement in symptoms, only to have them (and test positivity) return within days of completing the five-day course. It is known as the Paxlovid rebound.
There is not much data on how often this occurs, but a recent article in Clinical Infectious Diseases reported an incidence of 0.8%. Whatever the frequency, there are several possible mechanisms to explain such a phenomenon. The most likely is that the dose of Paxlovid is too low or the treatment time is too short to prevent the rebound, because the drug breaks down the amount of virus present so quickly that the immune system doesn’t have enough time to eradicate it, and the virus kicks in. to replicate again.
A pertinent question then is, how long does it take for the immune system to clear SARS-CoV-2 from an infected patient? Ironically, the best answer to this question comes from the TOGETHER randomized controlled trial who examined the effect of ivermectin versus placebo on multiple parameters of COVID-19, including the number of days it took to clear the virus. (TOGETHER is a private sector funded international collaboration to identify existing drugs that can be reused to prevent or treat COVID-19)
In the study, only a quarter of the study participants were able to clear the virus within seven days without treatment, so the time to achieve complete viral clearance should be significantly longer for most patients, perhaps two or three weeks. maybe more. So how long does it take for patients treated with Paxlovid to clear the virus?
While this precise information is not available from Pfizer’s clinical trials (which were conducted prior to Omicron), the company does provide this information:
An approximately 10-fold reduction in viral load at day 5, compared to placebo, was observed in both EPIC-HR and EPIC-SR [trials]indicating robust activity against SARS-CoV-2 and the strongest reduction in viral load reported to date for an oral antiviral agent against COVID-19.
This provides a solid clue as to what is happening. While a five-day course of Paxlovid is enough to keep about 90% of Covid victims out of the hospital and reduce their viral load tenfold, there appears to be a subpopulation of people who either did not respond as well as others to Paxlovid or, perhaps, had a higher viral load to begin with.
That corresponds to the findings from researchers at the University of California, San Diego, who concluded that Paxlovid rebound occurs when infected cells are not sufficiently exposed to the drug to stop all viral replication, either because the drug was metabolized too quickly in some patients or the drug has to be given for a longer period of time.
White House Covid Adviser Dr. Anthony Fauci seems to have experienced one of those phenomena, leading to a bounce back of his Covid-19 infection after taking Paxlovid.
After five days on the drug, he tested negative, then had negative tests for three consecutive days, but on the fourth day, he tested positive again. Fauci said his symptoms were worse when they came back after treatment, so — and here’s the interesting part — his doctors prescribed another course of Paxlovid and his symptoms improved.
The FDA’s Emergency Use Authorization (EUA) for Paxlovid, in April 2022 from the Agency letter to Pfizerthe manufacturer of the drug, contains this statement:
pAXLOVID should not be used for more than 5 consecutive days
So, strictly speaking, that second course was not allowed under the EUA…which brings us back to FDA Commissioner Frank Young’s admonition about the use of common sense by regulators.
Even in the absence of definitive data, which would currently be time-consuming and expensive to collect, it would be prudent for the FDA to extend the approved treatment with Paxlovid to, say, eight or ten days. It could spare Paxlovid recipients the rebound from Covid symptoms and additional virus-induced damage.
Good medicine, like good regulations, sometimes requires common sense in addition to hard data.
dr. Henry I. Miller, a physician and molecular biologist, is a senior fellow at the Pacific Research Institute. He was the founder and director of the Office of Biotechnology at the FDA. Find Henry on Twitter @henryimiller
Josh Bloom, ACSH’s Director of Chemical and Pharmaceutical Sciences, received his Ph.D. in organic chemistry from the University of Virginia, followed by a postgraduate degree from the University of Pennsylvania. His career 20+ year first career was researching drug discovery at Wyeth. (Disclosure: He has a small amount of Pfizer stock in his IRA.) Find Dr. Bloom on Twitter @JoshBloomACSH