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. 2024 May 15;78(5):1175-1184.
doi: 10.1093/cid/ciad696.

Symptoms, Viral Loads, and Rebound Among COVID-19 Outpatients Treated With Nirmatrelvir/Ritonavir Compared With Propensity Score-Matched Untreated Individuals

Sarah E Smith-Jeffcoat  1 , Jessica E Biddle  2 , H Keipp Talbot  3 , Kerry Grace Morrissey  4 , Melissa S Stockwell  5   6   7 , Yvonne Maldonado  8 , Huong Q McLean  9 , Katherine D Ellingson  10 , Natalie M Bowman  11 , Edwin Asturias  12 , Alexandra M Mellis  2 , Sheroi Johnson  2 , Hannah L Kirking  1 , Melissa A R Rolfes  2 , Vanessa Olivo  4 , Lori Merrill  4 , Steph Battan-Wraith  4 , Ellen Sano  7   13 , Son H McLaren  7   13 , Celibell Y Vargas  5 , Sara Goodman  8 , Clea C Sarnquist  8 , Prasanthi Govindaranjan  8 , Joshua G Petrie  9 , Edward A Belongia  9 , Karla Ledezma  10 , Kathleen Pryor  10 , Karen Lutrick  10 , Ayla Bullock  11 , Amy Yang  11 , Quenla Haehnel  11 , Suchitra Rao  12 , Yuwei Zhu  3 , Jonathan Schmitz  3 , Kimberly Hart  3 , Carlos G Grijalva  3 , Phillip P Salvatore  1
Affiliations

Symptoms, Viral Loads, and Rebound Among COVID-19 Outpatients Treated With Nirmatrelvir/Ritonavir Compared With Propensity Score-Matched Untreated Individuals

Sarah E Smith-Jeffcoat et al. Clin Infect Dis. .

Abstract

Background: Nirmatrelvir/ritonavir (N/R) reduces severe outcomes from coronavirus disease 2019 (COVID-19); however, rebound after treatment has been reported. We compared symptom and viral dynamics in individuals with COVID-19 who completed N/R treatment and similar untreated individuals.

Methods: We identified symptomatic participants who tested severe acute respiratory syndrome coronavirus 2-positive and were N/R eligible from a COVID-19 household transmission study. Index cases from ambulatory settings and their households contacts were enrolled. We collected daily symptoms, medication use, and respiratory specimens for quantitative polymerase chain reaction for 10 days during March 2022-May 2023. Participants who completed N/R treatment (treated) were propensity score matched to untreated participants. We compared symptom rebound, viral load (VL) rebound, average daily symptoms, and average daily VL by treatment status measured after N/R treatment completion or 7 days after symptom onset if untreated.

Results: Treated (n = 130) and untreated participants (n = 241) had similar baseline characteristics. After treatment completion, treated participants had greater occurrence of symptom rebound (32% vs 20%; P = .009) and VL rebound (27% vs 7%; P < .001). Average daily symptoms were lower among treated participants without symptom rebound (1.0 vs 1.6; P < .01) but not statistically lower with symptom rebound (3.0 vs 3.4; P = .5). Treated participants had lower average daily VLs without VL rebound (0.9 vs 2.6; P < .01) but not statistically lower with VL rebound (4.8 vs 5.1; P = .7).

Conclusions: Individuals who completed N/R treatment experienced fewer symptoms and lower VL but rebound occured more often compared with untreated individuals. Providers should prescribe N/R, when indicated, and communicate rebound risk to patients.

Keywords: SARS-CoV-2; antiviral treatment; rebound; symptoms; viral loads.

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Conflict of interest statement

Potential conflicts of interest. S. R. reports grant support from BioFire. H. Q. M. reports grant/research support from CSL Sequiris and CSK. J. G. P. reports serving as a former consultant for CSL Seqirus and receipt of grants from the National Institutes of Health (NIH) and CSL Seqirus. E. A. reports serving as a former consultant for Hillevax and Moderna, presenting a Merck-supported lecture at the Latin American Vaccine Summit, and receipt of grant/research support from Pfizer for pneumococcal pneumonia studies. C. G. G. reports being a former advisor to Merck, participation on a data and safety monitoring board (DSMB) or advisory board for Merck, and receipt of grant/research support from AHRQ, CDC, US Food and Drug Administration, NIH, and Syneos Health. N. M.B. reports grant/contracts from NIH to the University of North Carolina School of Medicine, Doris Duke Charitable Foundation, and North Carolina Collaboratory; participation on a DSMB or advisory board for the Snowball Study Technical Interchange; a leadership or fiduciary role on the American Society of Tropical Medicine and Hygiene Scientific Committee; and other financial or nonfinancial interests with the COVID-19 Equity Evidence Academy (RADx-UP CDCC) Steering Committee and North Carolina Occupational Safety and Health Education Research Center. S. H. M. reports grants/contracts from NIH, the American Academy of Pediatrics, and the Doris Duke Charitable Foundation. E. A. B. reports research support to the Marshfield Clinic Research Institute from the CDC. E. S. reports grants or contracts to institution from Vanderbilt University Medical Center (originating at CDC #75D30121C11656). S. G. reports support for attending meetings and/or travel from the Infectious Diseases Society of America for Infectious Disease Week 2022 and 2023. K. G. M., L. M., S. B.-W., and V. O. report funding to Westat via the CDC (contract 75D30121C11571). M. S. S. reports a leadership role as Associate Director of the American Academy of Pediatrics’ Pediatric Research in Office Settings (PROS), paid to Trustees of Columbia University. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1
Figure 1. Participants eligible for analysis, nirmatrelvir/ritonavir treatment completion, and propensity score matched selection of untreated participants from a larger case-ascertained household transmission study of COVID-19 in the United States
Footnote: Elicited symptoms included fever (including feeling feverish/chills), cough, sore throat, runny nose, nasal congestion, fatigue (including feeling run down), wheezing, trouble breathing (including shortness of breath), chest tightness (including chest pain), loss of smell or taste, headache, abdominal pain, diarrhea, vomiting, and body aches (including muscle aches). Elicited COVID-19 medications included molnupiravir, remdesivir, and nirmatrelvir/ritonavir; other medications were reported in a free-response section of the diary. PS matching was performed using logistic regression with the outcome of N/R treatment completion (N/R treated) versus no COVID-19 treatment (untreated) and covariates included age at enrollment, sex, race/ethnicity, Social Vulnerability Index, prior COVID-19, recruitment method, participant type (index vs. contact), accessed medical care after enrollment, received ≥3 verified COVID-19 vaccine doses, received a verified COVID-19 vaccine dose ≤6 months of index onset, SARS-CoV-2 variant circulating at the time of index onset, number of comorbidities, and whether the participant reported each of asthma or other lung disease, heart disease, diabetes, cancer, liver or kidney disease, immunocompromising condition or taking immunosuppressing medication, or any other chronic health condition. SCV2=SARS-CoV-2; N/R=nirmatrelvir/ritonavir
Figure 2
Figure 2. Symptom dynamics during the first two weeks after symptom onset by nirmatrelvir/ritonavir (N/R) treatment and symptom rebound1 visualized as (A) cumulative probability of symptom resolution2, (B) median number of symptoms each day since symptom onset and proportion of patients experiencing symptom rebound, and (C) average daily symptoms after N/R completion (or seven days since symptom onset for untreated group)
Footnote: Participants reported symptoms daily from a list of 15 symptoms including fever (including feeling feverish/chills), cough, sore throat, runny nose, nasal congestion, fatigue (including feeling run down), wheezing, trouble breathing (including shortness of breath), chest tightness (including chest pain), loss of smell or taste, headache, abdominal pain, diarrhea, vomiting, and body aches (including muscle aches). 1Symptom rebound was defined as an increase of at least two reported symptoms after treatment completion or treatment completion proxy 2Symptom resolution was defined as the first day in which a participant was asymptomatic after which no later symptoms were reported
Figure 3
Figure 3. Viral dynamics during the first two weeks after symptom onset by nirmatrelvir/ritonavir treatment completion and viral load rebound1 visualized by (A) cumulative probability of RT-PCR conversion to negative2, (B) median viral load each day since symptom onset and proportion with viral load rebound, and (C) median of each participant’s average daily viral load after nirmatrelvir/ritonavir completion or seven days since symptom onset
Footnote: N/R=nirmatrelvir/ritonavir; 1VL rebound was defined as an increase of at least 1 log10IU/mL for which the maximum VL exceeded 5 log10IU/mL after treatment completion/proxy; 2PCR conversion was defined as the first day in which a patient had a negative PCR result after which no additional positive results occurred.
Figure 4
Figure 4. Proportion of participants experiencing symptom and viral load rebound outcomes (A) and odds of viral load rebound when symptom rebound experienced (B), overall and stratified by nirmatrelvir/ritonavir treatment completion status
Footnote: VL=viral load; N/R=nirmatrelvir/ritonavir
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