Nirmatrelvir treatment duration and frequency of COVID-19 rebound

Abstract

Background

Nirmatrelvir has been shown to reduce morbidity and mortality associated with COVID-19. However, it is underutilized due to concerns regarding COVID-19 symptom rebound following nirmatrelvir’s standard 5-day course. This study aims to identify and evaluate a nirmatrelvir dosage regimen that lowers symptom rebound.

Methods

Based on nirmatrelvir pharmacokinetics, we propose a novel 8-day regimen: two doses twice-daily followed by six doses once-daily to reduce rebound frequency. We then carried out a retrospective case series study of clinical outcomes among our patients to investigate their frequency of COVID-19 symptom rebound following nirmatrelvir usage.

Results

Among the 58 prescribed case patients, 49 filled and initiated the prescription. Of those 49 patients, four took the medication for fewer than 5 days, 24 for 5 days (standard regimen), and 21 for 7 or 8 days (extended regimen). Among 5-day treatment cases (n = 24), 8 (33%) experienced clinical rebound, whereas among the 7-day or 8-day treatment cases (n = 21), 2 (9.5%) experienced rebound.

Conclusions

These findings suggest that a longer nirmatrelvir/ritonavir course might reduce rebound symptoms compared to the standard 5-day regimen.

Introduction

The National Institutes of Health (NIH) COVID-19 Treatment Guidelines recommend a twice-daily treatment of nirmatrelvir/ritonavir for 5 days, [1] which has been shown to reduce the frequency of hospitalization and death among people with COVID-19. [2] Despite a good safety profile and proven effectiveness, nirmatrelvir/ritonavir remains highly underused by patients and under prescribed by clinicians. [3] One cause of this underutilization can be attributed to concerns of COVID-19 rebound occurring following the completion of the recommended nirmatrelvir/ritonavir course. [3] Although a US Centers for Disease Control and Prevention (CDC) report concluded that there was no association between nirmatrelvir/ritonavir treatment and COVID-19 rebound, [4] patients and providers remain concerned about rebound as a clinical indicator of treatment failure and the prolongation in the duration of symptoms. [3] To reduce the frequency of symptom recurrence based on the pharmacokinetics of nirmatrelvir/ritonavir, we prescribed a novel extended regimen prescribing twice-daily dosing the first 2 days with subsequent daily dosing for the next 6 days, resulting in 8 days duration of treatment. This dosing regimen was selected to provide a 2-day loading dose and the longest duration of additional days of dosing available with a standard 10-dose pack of nirmatrelvir/ritonavir.

Methods

To investigate the potential efficacy of this new treatment course, a pharmacokinetic model using a Monte Carlo simulation was conducted where nirmatrelvir boosted with ritonavir was administered at a 300/100 mg twice-daily dosing for 2 days, followed by 300/100 mg daily dosing for 6 days. The simulation takes advantage of Pfizer’s population pharmacokinetic model, which included over 5000 measurements in 1237 participants. [5] That study population comprised non-hospitalized individuals with COVID-19, aged under 65 years, and having normal kidney function. Our model predicted the median nirmatrelvir concentrations with a 90% Prediction Interval (5th–95th), comparing these values to the concentration of nirmatrelvir required to inhibit 90% of in vitro viral replication (IC₉₀) of 0.292 mcg/ml. [6] According to our model, the median trough in individuals with COVID-19 on the 8-day nirmatrelvir/ritonavir regimen was 0.58 mcg/ml, with 79% troughs above the IC₉₀ value (Figure 1). These pharmacokinetic data suggest that the 8-day regimen is capable of inhibiting SARS-CoV-2 viral growth by at least 90% over the course of the treatment period. To further study the clinical validity of this theoretical model, we assessed differences between the 5-day regimen and our longer-duration regimen through a retrospective case series study of clinical outcomes among our patients.

Figure 1.

Monte Carlo simulation with a 90% PI where nirmatrelvir/ritonavir was administered at 300/100 mg twice-daily for 2 days, followed by 300/100 mg once-daily for an additional 6 days. *Based on PopPK Model by Chan et al, CPT 2023 [5].

Through a retrospective review of patient medical records, we assessed the duration of reported nirmatrelvir/ritonavir treatment and the frequency of self-reported rebound symptoms. Selected records included those of any patient prescribed nirmatrelvir/ritonavir seen in our telehealth practice since the initial authorization of nirmatrelvir/ritonavir in December 2021 until December 2023. Patients were prescribed an 8-day nirmatrelvir/ritonavir course, two doses in the first 2 days, followed by daily doses for the next 6 days. Some still opted to take the dosage over 5 days. All patients were evaluated by their provider during routine clinical follow-up and asked about ongoing symptoms. We defined clinical rebound as the worsening of clinical symptoms following a period of clinical improvement while taking nirmatrelvir/ritonavir.

Results

Of the 63 case patients prescribed nirmatrelvir from December 2021 to December 2023, 58 completed routine clinical follow-up, where 49 confirmed that they had initiated the nirmatrelvir prescription. Of those 49 patients, four took the medication for fewer than 5 days, 24 took the medication for 5 days (standard regimen), and 21 took the medication for 7 or 8 days (extended regimen).

To ensure valid comparison of treatment effects, demographic characteristics of each group were analysed. The 5-day treatment group comprised 46% females, whereas the 7- to 8-day treatment group comprised 62% females. A chi-square test was performed to assess whether sex distribution differed significantly between groups, yielding a χ² value of 1.16 with a p-value of 0.28. This indicates no statistically significant difference in sex distribution, suggesting that sex was unlikely to confound the comparison of rebound rates. Both groups also had the same median age of 53 years, with an interquartile range of 20 for the 5-day group and 24 for the 7- to 8-day group, demonstrating comparable demographic characteristics.

Among the 5-day treatment group (n = 24), 8 cases (33%) experienced clinical rebound, whereas among the 7- to 8-day treatment group (n = 21), only 2 cases (9.5%) experienced rebound. No case patients experienced severe disease, hospitalization, or death. A comparison of these rebound rates yielded a Fisher’s exact test p-value of 0.08, indicating a trend toward fewer rebounds in the extended treatment group, though it did not meet the conventional threshold for statistical significance (p < .05). A larger sample size may help clarify whether this observed difference is statistically meaningful.

Discussion

Our theoretical model and clinical outcome data suggest that a longer course of nirmatrelvir/ritonavir might result in a lower frequency of clinical rebound. Although the standard 5-day regimen has demonstrated effectiveness in reducing hospitalizations and mortality in high-risk patients, concerns about post-treatment rebound have contributed to hesitancy in its use. Prior studies have reported symptom rebound rates ranging from 2.31% to 5.87% within 7 to 30 days after treatment completion. [7] Our observed rebound rate of 33% in the standard treatment group and 9.5% in the extended treatment group suggests that modifying treatment duration may influence symptom recurrence.

The potential benefit of an extended regimen aligns with existing research demonstrating the effectiveness of Paxlovid in preventing severe outcomes. [8] By extending treatment with a 2-day loading dose followed by a 6-day daily dose, our approach may sustain viral suppression for a longer period, potentially reducing the risk of symptom recurrence. However, additional prospective studies are needed to determine the optimal duration of nirmatrelvir/ritonavir treatment that maximizes its clinical benefits while minimizing the risk of rebound.

One of the primary limitations of our study is the small sample size, which limits statistical power. A power analysis suggests that a sample size of 98 with a 1:1 enrolment ratio would be required to detect a statistically significant difference in rebound rates, based on an alpha of 0.05 and a beta of 0.8. Furthermore, although demographic characteristics were comparable between groups, potential confounders such as comorbidities and concurrent medications were not fully controlled. Additionally, our study was conducted between December 2021 and December 2023, a period dominated by the Omicron variant. Future SARS-CoV-2 variants may exhibit different rebound patterns, potentially affecting treatment outcomes.

Despite these limitations, our study provides preliminary evidence that extending nirmatrelvir/ritonavir treatment may reduce symptom rebound without compromising safety. Future clinical trials with larger, more diverse patient populations will be essential in determining the optimal treatment duration to maximize benefits while minimizing risks. These findings contribute to the ongoing discussion on how best to optimize antiviral strategies for COVID-19 treatment and post-treatment symptom management.