Rebound of COVID-19 After Treatment With Paxlovid

The recurrence of COVID-19 clinical symptoms after completing treatment is a cause for concern. Rebound COVID-19 infection after nirmatrelvir–ritonavir (Paxlovid) therapy famously occurred in President Joe Biden, bringing national attention to the Pfizer treatment.

According to a recent study, published in the New England Journal of Medicine, “The frequency and clinical implications of potential recurrence of coronavirus disease 2019 (COVID-19) are unknown.” The phase 2-3, double-blind, randomized, controlled trial EPIC-HR reviewed data on the frequency of COVID-19 viral load rebound.

EPIC-HR included 2246 unvaccinated adults who developed symptomatic COVID-19 infection. The study participants were at high risk of severe disease progression. Every 12 hours, for 5 days, the participants received either 300 mg nirmatrelvir and 100 mg ritonavir or placebo.

After an average of 27 days, the nirmatrelvir-ritonavir cohort had an 88% reduced risk of COVID-19-induced hospitalization or death, compared to the placebo recipients. By day 34, there were no deaths in the nirmatrelvir-ritonavir group and 13 deaths in the placebo group.

The investigators collected nasopharyngeal swab samples at baseline (day 1 of enrollment), and subsequently on days 3, 5, 10, and 14 of the trial. Patients were enrolled and sampled from July-December 2021.

COVID-19 recurrence was defined by a half-log increase in viral load on day 10 or on day 14, a definition developed to determine patient resistance to nirmatrelvir.

By the data cutoff in December 2021, there were 990 nirmatrelvir–ritonavir recipients and 980 placebo recipients with viral load measurement data from day 5 and the rebound period. From baseline through day 14, viral load rebound occurred in 2.3% of the nirmatrelvir–ritonavir cohort (n = 23) and 1.7% of the placebo group (n = 17).

Viral load rebound rates were similar between the 2 cohorts, when comparing by coexisting illnesses, nirmatrelvir exposure, nirmatrelvir resistance, recurrence of moderate-to-severe COVID-19 symptoms, baseline COVID-19 serologic status, and occurrence of hospitalization or death. No hospitalizations occurred in the placebo patients with viral load rebound, and no deaths occurred in either group with rebound.

The study authors found COVID-19 viral load rebound was similar between the nirmatrelvir–ritonavir and placebo cohorts. A potential limitation may be that the EPIC-HR study was conducted while Delta was the predominant COVID-19 variant, whereas now Omicron and its subvariants are responsible for the vast majority of infections. However, nirmatrelvir–ritonavir is also believed to effectively neutralize Omicron.

The investigators concluded that viral load rebound may be a facet of some COVID-19 infections, recommending further study into this evasive virus.