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Effectiveness of Paxlovid in Reducing Severe Coronavirus Disease 2019 and Mortality in High-Risk Patients
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In this real-world study, we show that treatment with Paxlovid in the first 5 days of SARS-CoV-2 infection is associated with markedly reduced risk of progression to severe COVID-19 or mortality, regardless of vaccination status for SARS-CoV-2. Notably, this study was conducted in Israel when Omicron was the dominant variant, and shows high effectiveness of Paxlovid against infection with the Omicron variant. In addition, this study confirms that having adequate vaccination status against SARS-CoV-2 remains the most effective treatment in preventing severe illness.

Paxlovid was granted an Emergency Use Authorization for the treatment of mild to moderate coronavirus disease 2019 (COVID-19), based on the interim analysis of the Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) trial. Paxlovid effectiveness needs to be assessed in a noncontrolled setting. In this study we used population-based real-world data to evaluate the effectiveness of Paxlovid.
The database of the largest healthcare provider in Israel was used to identify all adults aged 18 years or older with first-ever positive test for severe acute respiratory syndrome coronavirus 2 between January and February 2022, who were at high risk for severe COVID-19 and had no contraindications for Paxlovid use. Patients were included irrespective of their COVID-19 vaccination status. Cox hazard regression was used to estimate the 28-day hazard ratio (HR) for severe COVID-19 or mortality with Paxlovid examined as time-dependent variable.
Overall, 180 351 eligible patients were included; of these, only 4737 (2.6%) were treated with Paxlovid, and 135 482 (75.1%) had adequate COVID-19 vaccination status. Both Paxlovid and adequate COVID-19 vaccination status were associated with significant decrease in the rate of severe COVID-19 or mortality with adjusted HRs of 0.54 (95% confidence interval [CI], .39-.75) and 0.20 (95% CI, .17-.22), respectively. Paxlovid appears to be more effective in older patients, immunosuppressed patients, and patients with underlying neurological or cardiovascular disease (interaction P < .05 for all). No significant interaction was detected between Paxlovid treatment and COVID-19 vaccination status.
This study suggests that in the era of Omicron and in real-life settings, Paxlovid is highly effective in reducing the risk of severe COVID-19 or mortality.
Predictors of Paxlovid Treatment
Multivariable logistic regression models showed that low-middle SES was associated with lower use of Paxlovid, compared to high SES. Belonging to the Arab population sector was also associated with lower use of Paxlovid, compared to the general Jewish sector. Patients with adequate COVID-19 vaccination status were less likely to be treated with Paxlovid in comparison to patients with inadequate COVID-19 vaccination status (Figure 2). Older age, obesity, diabetes, cardiovascular disease, chronic lung disease, malignancy, and immunosuppression were all independent predictor of higher use of Paxlovid, whereas chronic kidney disease and neurological disease were associated with lower likelihood of Paxlovid use (Figure 2).
Effectiveness of Paxlovid
Overall, 942 events occurred in all 180 351 included patients, reflecting a crude incidence rate of 5.6 per 1000 person-months. The crude incidence rate was 3.4 per 1000 person-months in vaccinated patients and 13.4 per 1000 person-months in unvaccinated patients. A total of 39 events occurred in the 4737 patients treated with Paxlovid, reflecting a crude incidence rate of 10.4 per 1000 person-months, whereas 903 events occurred in the 175 614 patients not treated with Paxlovid, reflecting a crude incidence rate of 5.6 per 1000 person-months. The higher crude incidence rate in treated patients is likely attributed to older age and higher frequency of underlying comorbidities (Table 1). Indeed, Paxlovid was independently associated with a significantly decreased risk for the composite of severe COVID-19 or mortality, in a multivariable Cox regression models, with an HR of .54 (95% CI, .39-.75). Adequate COVID-19 vaccination status was also associated with significantly decreased risk for the composite of severe COVID-19 or mortality (HR, 0.20 [95% CI, .17-.22]) (Table 2).
Safety and Tolerability of Paxlovid (Nirmatrelvir/Ritonavir) in High-risk Patients Clinical Infectious Diseases 1 December 2022
To the Editor-We read with great interest the analysis by Saliba and colleagues on the real-world experience with nirmatrelvir/ritonavir (Paxlovid) in reducing severe coronavirus disease 2019 (COVID-19) and mortality in high-risk patients [1]. This is the largest retrospective cohort study to date that demonstrated Paxlovid treatment and vaccination status were associated with significant decrease in the rate of severe COVID-19 or mortality with adjusted hazard ratio (HR) 0.54 (95% confidence interval, 0.39-0.75) and 0.2 (95% confidence interval, 0.17-0.22), respectively. Timely real-world data are important to evaluate the effectiveness of Paxlovid in populations outside of the clinical trial, but the authors were unable to assess medication tolerability and safety. As of 14 May 2022, Assistant Secretary for Preparedness and Response estimated 668 954 Paxlovid courses were given in the United States [2]. In the randomized clinical trial, EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patient), Paxlovid appeared to be well tolerated but real-world data are lacking [3]. At the University of Washington Medicine, we developed a standardized process to prioritize high-risk patients meeting National Institutes of Health Tier 1 and 2 criteria and assessed patient tolerability and safety through telephonic postprescription outreach when supplies were initially limited. Patients who were prescribed Paxlovid were interviewed over the phone using a standardized questionnaire to assess adverse effects and adherence within 1 week of starting therapy.
Between January 5 and 21, 2022, 50 patients were prescribed Paxlovid (Table 1). The median age was 48 years, with 64% of females and 20% of Latino/Hispanic ethnicity. The majority (82%) had immunocompromising conditions with a median of 5 comorbid conditions and 8.5 concomitant medications. Sixteen (32%) patients required chronic medication adjustment while taking Paxlovid. All patients were contacted within 1 week of starting Paxlovid, 19 (38%) and 21 (42%) patients were interviewed during therapy and after completion of therapy, respectively, whereas 9 (18%) patients were lost to follow-up and 1 (2%) patient did not start Paxlovid. Among the 40 respondents, 34 (85%) had experienced at least 1 adverse effect. Twelve (30%) patients reported ≥ 3 adverse effects and all were ≥ 5 concomitant chronic medications. The most frequently reported adverse effect was dysgeusia (57.5%). Most patients reported the onset of 1 to 2 hours after taking Paxlovid and usually subsided within 24 hours after discontinuation of therapy.
We reported a high incidence of adverse effects with 85% of patients reporting at least 1 side effect while taking Paxlovid leading to 17.5% of patients discontinuing therapy prematurely compared with 2% observed in the EPIC-HR trial. Most notably, dysgeusia was reported in 57.5% of patients compared to 5.6% in clinical trial [3]. We used this information to better prepare our patients for anticipated side effects and provided mitigation strategies based on our evaluation. To the best of our knowledge, this is the first report to date evaluating the tolerability and safety of Paxlovid through telephonic postprescription outreach in the real-world setting. This underscores the importance of close monitoring and postmarketing surveillance with medications that are still under investigation.

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