SARS-CoV-2 Virologic Rebound With Nirmatrelvir-Ritonavir Therapy : An Observational Study

Abstract

Background: Data are conflicting regarding an association between treatment of acute COVID-19 with nirmatrelvir-ritonavir (N-R) and virologic rebound (VR).

Objective: To compare the frequency of VR in patients with and without N-R treatment for acute COVID-19.

Design: Observational cohort study.

Setting: Multicenter health care system in Boston, Massachusetts.

Participants: Ambulatory adults with acute COVID-19 with and without use of N-R.

Intervention: Receipt of 5 days of N-R treatment versus no COVID-19 therapy.

Measurements: The primary outcome was VR, defined as either a positive SARS-CoV-2 viral culture result after a prior negative result or 2 consecutive viral loads above 4.0 log₁₀ copies/mL that were also at least 1.0 log₁₀ copies/mL higher than a prior viral load below 4.0 log₁₀ copies/mL.

Results: Compared with untreated persons (n = 55), those taking N-R (n = 72) were older, received more COVID-19 vaccinations, and more commonly had immunosuppression. Fifteen participants (20.8%) taking N-R had VR versus 1 (1.8%) who was untreated (absolute difference, 19.0 percentage points [95% CI, 9.0 to 29.0 percentage points]; P = 0.001). All persons with VR had a positive viral culture result after a prior negative result. In multivariable models, only N-R use was associated with VR (adjusted odds ratio, 10.02 [CI, 1.13 to 88.74]; P = 0.038). Virologic rebound was more common among those who started therapy within 2 days of symptom onset (26.3%) than among those who started 2 or more days after symptom onset (0%) (P = 0.030). Among participants receiving N-R, those who had VR had prolonged shedding of replication-competent virus compared with those who did not have VR (median, 14 vs. 3 days). Eight of 16 participants (50% [CI, 25% to 75%]) with VR also reported symptom rebound; 2 were completely asymptomatic. No post-VR resistance mutations were detected.

Limitations: Observational study design with differences between the treated and untreated groups; positive viral culture result was used as a surrogate marker for risk for ongoing viral transmission.

Conclusion: Virologic rebound occurred in approximately 1 in 5 people taking N-R, often without symptom rebound, and was associated with shedding of replication-competent virus.

Primary funding source: National Institutes of Health.

Visual Abstract.. SARS-CoV-2 Virologic Rebound With Nirmatrelvir–Ritonavir Therapy

Whether virologic rebound in SARS-CoV-2 infection occurs with greater frequency in patients treated with nirmatrelvir–ritonavir than in untreated patients is currently a question of clinical interest. This observational study in a multicenter health care system compared the occurrence of virologic rebound in treated patients versus untreated patients. Differences in symptoms, viral shedding, and occurrence of viral resistance mutations between the groups were also assessed.

Appendix Figure.. Study flow diagram.

N-R = nirmatrelvir–ritonavir.

Figure 1.. Virologic decay curves with semiquantitative viral cultures and quantitative viral load among persons with acute COVID-19 taking no therapy or N-R.

Black circles and dotted lines indicate persons without rebound, and green squares and dashed lines indicate persons with virologic rebound. Panels A (viral load) and B (viral culture) depict decay curves for those not receiving therapy. Panels C (viral load) and D (viral culture) depict persons who received N-R. Panels E and F are restricted to the 16 persons who had the primary outcome. Panel E shows viral load results with all available study time points, whereas panel F is restricted to viral load results at days 5, 10, and 14, as was done in prior studies (9). Using only these 3 time points to detect rebound resulted in detection of only 3 of 16 (19% [green squares]) of the total primary virologic rebound events with replication-competent virus. N-R = nirmatrelvir–ritonavir; TCID₅₀ = median (50%) tissue culture infectious dose.

Figure 2.. Comparative frequency of virologic rebound by N-R use, stratified by demographic and clinical characteristics (A), the number of days between the first positive SARS-CoV-2 test result and N-R initiation (B), and the number of days between symptom onset and N-R initiation (C).

For the subgroup comparisons, the bottom P values represent Fisher exact tests comparing rebound rates between those taking N-R versus no therapy. The upper P values represent Fisher exact tests comparing rebound rates among those taking N-R across the subgroups (e.g., those with immunosuppression who were taking N-R vs. those without immunosuppression who were taking N-R). N-R = nirmatrelvir–ritonavir.

Figure 3.. Kaplan–Meier survival curves showing time from initial positive SARS-CoV-2 test result until initial negative viral culture result (panels A to C) and final negative culture result (panels D to F).

Panel A shows that there is a shorter time to the first negative culture result in those receiving N-R versus no therapy. Panels B and C show similar patterns in time to the initial negative culture result with the N-R group divided into those who had rebound (panel B) and those who did not (panel C). However, as shown in panel D, there was no difference in time to the final negative culture result between the N-R and no-therapy groups. This seems to be due to the prolonged time to the final negative culture result among N-R users who had rebound (panel E) because the time to the final negative culture result remained shorter in N-R users who did not have rebound compared with the no-therapy group (panel F). N-R = nirmatrelvir–ritonavir.