RESUMEN
Background: A 5-day course of nirmatrelvir-ritonavir (N/R) can significantly reduce the hospitalization and death rates and the duration of infectiousness in high-risk SARS-CoV-2 patients. However, in a fraction of treated individuals virus rebounds following an initial recovery after treatment. The mechanism driving rebound is not well understood. We hypothesize that treatment with N/R near the time of symptom onset halts the depletion of target cells, but does not fully eliminate the virus, and thus can lead to viral rebound. Method(s): Previously, we and others have developed viral dynamic models and successfully used them to fit data on SARS-CoV-2 infection. Here we expand these models and incorporate N/R pharmacokinetic and pharmacodynamic effects and an adaptive immune response. Result(s): We fit this model to the data presented in Charness et al., NEJM (2022) where longitudinal quantitative PCR data is available for 3 individuals who experienced viral rebounds after taking N/R. We found that the model fit the data well. By varying model parameters from their best-fit values, we show the occurrence of viral rebound is sensitive to model parameters, and the time treatment is initiated, which may explain why only a fraction of individuals rebound. Finally, the model with its best-fit parameter values was used to test the therapeutic effects of treatment extended to 10 days or a second 5-day course of N/R initiated one day after symptoms reoccur. Conclusion(s): Our model fits predicted that virus is not fully eliminated during N/R treatment and supported our initial hypothesis that at the end of treatment target cells are available to allow viral resurgence. Simulating the effect of starting treatment later, we find the probability of viral rebound occurring decreases, suggesting that delaying treatment may be a strategy to reduce viral rebound. However, N/R treatment accelerates viral clearance and hence potentially can reduce viral transmission. Thus, delaying treatment may have a detrimental effect on public health and could also have impact on the severity of disease in the high-risk patients for whom N/R is recommended. Increasing treatment from 5 to 10 days continues to preserve target cells and thus may still allow viral rebound if viable virus is present at the end of treatment and sufficient adaptive immunity has not developed. Simulating giving a second course of treatment one day after symptoms reappear, did not prevent rebound.
RESUMEN
Background: The within-host reproductive number R0 is an important parameter to predict the minimum antiviral efficacy needed to suppress viral infection. However, this parameter has not been well quantified for SARS-CoV-2. This is because accurate estimation of this quantity requires longitudinal viral load measurements during the initial phase of infection, when the virus population expands before the viral load peak;yet, most available measurements are made after the viral load peak. Methods: We constructed viral dynamic models to describe a set of longitudinal viral load data from a study where individuals were tested frequently such that viral loads during the viral expansion phase were measured. We fit multiple models to data from a total of 42 infected individuals (14 symptomatic and 28 asymptomatic) to estimate R0 and used a model linking within-host viral load to the infectiousness of a person to evaluate the infectiousness of asymptomatic individuals compared to symptomatic individuals. Results: We estimated that the within-host R0 is between 8-16 across the 48 individuals. This suggests that antiviral efficacy has to be greater than 95% to suppress virus infection in a majority of individuals. The estimated R0 in asymptomatic individuals is lower than in symptomatic individuals (mean 10.0 vs. 13.8;p-value<0.0001). Our model suggests there exists large heterogeneity in infectiousness among individuals, and asymptomatic individuals may be on average 15% less infectious than symptomatic individuals (p-value=0.02), not considering isolation measures. Conclusion: An antiviral efficacy of 95% or more is needed to suppress viral infection in most infected individuals. Asymptomatic individuals may be slightly less infectious than symptomatic individuals.