Modeling suggests SARS-CoV-2 rebound after nirmatrelvir-ritonavir treatment is driven by target cell preservation coupled with incomplete viral clearance
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- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Harvard Medical School, Boston, MA (United States)
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA (United States)
- Harvard Medical School, Boston, MA (United States); Univ. of Pittsburgh, PA (United States). Medical Center
- Harvard Medical School, Boston, MA (United States); Africa Health Research Institute (South Africa)
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA (United States); Harvard Medical School, Boston, MA (United States)
- Harvard Medical School, Boston, MA (United States); Broad Inst., Cambridge, MA (United States)
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); Santa Fe Inst. (SFI), Santa Fe, NM (United States)
In a subset of SARS-CoV-2-infected individuals treated with the antiviral nirmatrelvir-ritonavir, the virus rebounds following treatment. The mechanisms driving this rebound are not well understood. We used a mathematical model to describe the longitudinal viral load dynamics of 51 individuals treated with nirmatrelvir-ritonavir, 20 of whom rebounded. Target cell preservation, either by a robust innate immune response or initiation of N-R near the time of symptom onset, coupled with incomplete viral clearance, appears to be the main factor leading to viral rebound. Moreover, the occurrence of viral rebound is likely influenced by the time of treatment initiation relative to the progression of the infection, with earlier treatments leading to a higher chance of rebound. A comparison with an untreated cohort suggests that early treatments with nirmatrelvir-ritonavir may be associated with a delay in the onset of an adaptive immune response. Nevertheless, our model demonstrates that extending the course of nirmatrelvir-ritonavir treatment to a 10-day regimen may greatly diminish the chance of rebound in people with mild-to-moderate COVID-19 and who are at high risk of progression to severe disease. Altogether, our results suggest that in some individuals, a standard 5-day course of nirmatrelvir-ritonavir starting around the time of symptom onset may not completely eliminate the virus. Thus, after treatment ends, the virus can rebound if an effective adaptive immune response has not fully developed. These findings on the role of target cell preservation and incomplete viral clearance also offer a possible explanation for viral rebounds following other antiviral treatments for SARS-CoV-2.
- Research Organization:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Organization:
- USDOE National Nuclear Security Administration (NNSA); USDOE Laboratory Directed Research and Development (LDRD) Program; National Institutes of Health (NIH)
- Grant/Contract Number:
- 89233218CNA000001
- OSTI ID:
- 2570787
- Alternate ID(s):
- OSTI ID: 3005605
- Report Number(s):
- LA-UR--24-31531; 10.1128/jvi.01623-24; 1098-5514
- Journal Information:
- Journal of Virology, Journal Name: Journal of Virology Journal Issue: 3 Vol. 99; ISSN 0022-538X; ISSN 1098-5514
- Publisher:
- American Society for MicrobiologyCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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