An ongoing dialogue on HIV/AIDS, infectious diseases,
May 4th, 2022
More on Relapses after Paxlovid Treatment for COVID-19
Unless you’ve been hiding under a rock, you’ve heard that some people treated for COVID-19 with nirmatrelvir/ritonavir (Paxlovid) experience a relapse in illness shortly after stopping treatment.
It’s both a recurrence of symptoms and a positive antigen test — sometimes after the test became negative. One case report published as a pre-print shows that a relapse can have a very low cycle threshold, meaning a high viral load:
Relapses vary in severity, from very mild and brief to worse than the initial illness. Check out the comments in my previous post for a sampling.
Some posit that the immune system doesn’t get a chance to mount a full response since the drug quickly reduces exposure to viral antigens. Others note that certain individuals experience prolonged viral replication, symptoms, and antigen test positivity, and perhaps it’s this group that’s destined to rebound after the 5 days of Paxlovid use. The drug knocks down replication for a while, but not long enough, so it rebounds.
Maybe it’s both — these aren’t mutually exclusive hypotheses. Regardless, as noted in my prior post, there’s still plenty we don’t know. But given the rapidly increasing use of Paxlovid nationally, I thought it worth this brief update about two important things we’ve learned since then, plus my opinion on a commonly asked question about contagiousness.
First, Pfizer offered additional details from their EPIC-HR study, citing that late viral rebounds occurred in roughly the same proportion of treated and untreated participants in their trial — around 2%:
UPDATE: Pfizer gave me the figures regarding the proportion of people who had Covid rebound in the Paxlovid clinical trial: About 2% of participants who got the drug experienced rebound, compared with ~1.5% of those who received the placebo rebounding within the same time frame.
— Benjamin Ryan (@benryanwriter) April 28, 2022
Whether the rate of relapse is higher than this 2% in clinical practice is unknown. Certainly, it seems that way — it even happened to a famous virologist! — but without knowing the denominator of total treated patients, we can only speculate.
And remember, clinicians have noted biphasic illness patterns since the start of the pandemic, and continue to do so. We’ve attributed that second period of worsening mostly to a robust (and sometimes hyperactive) immune response, but potentially there could be a component of concomitant heightened viral replication.
Second, in communications with clinicians, the FDA and Pfizer have made it clear that the people who relapse are in fact eligible for re-treatment under the Emergency Use Authorization (EUA). In other words, the within-5-day symptom clock starts over with the relapse. This would be justified clinically for our highest-risk patients (severely immunocompromised, medically fragile, or with severe recurrent symptoms), and favored over other outpatient treatments (all of which have logistical or efficacy issues) until we know more. So far, viral resistance has not been identified.
So where does that leave us with regard to infection control issues? In my opinion, we should assume that people who experience a symptomatic relapse with a positive antigen test could transmit the virus to others. Until data prove otherwise — meaning studies show these late relapsers have defective virions that are not replication-competent — this should be the recommended approach for work, school, and socializing. Symptoms plus positive antigen test equals potentially contagious.
In the meantime, I completely agree with this editorialist that we should be doing more to monitor how Paxlovid is doing since the EUA launched. I’m hoping large healthcare systems can quickly assemble observational studies evaluating how often this relapse phenomenon occurs out there in what is often called “the real world” — which means, in this context, “not in a clinical trial”. Prospective studies collecting virologic and immunologic data would also provide great value, especially given the theoretical concern that treatment blunts a favorable immune response.
So let’s keep learning.
You know, baby steps.