Nirmatrelvir plus ritonavir reduces COVID-19 hospitalization and prevents long COVID in adult outpatients – Scientific Reports

Study design

In this study, we analyzed administrative data from the SALAMA healthcare system in Dubai. SALAMA is the unified electronic medical record system used by Dubai Health Authority (DHA) hospitals and clinics, which work under a unified admissions and treatment system¹⁹. The study included data from patients who received oral antiviral nirmatrelvir-ritonavir (nirmatrelvir 300 mg plus ritonavir 100 mg orally twice daily for 5 days), and those who did not receive any antiviral treatment for COVID-19 between May 22, 2022, and April 30, 2023, at any of these DHA-affiliated hospitals and clinics. The retrieved data for each patient included demographics (age, gender, and ethnicity/race); dates of SARS-CoV-2 positive and negative reverse transcriptase–polymerase chain reaction (RT-PCR) results; COVID-19-related symptoms and oxygen saturation level (SpO2) at the time of diagnosis; date of prescription of nirmatrelvir-ritonavir; dates of the various doses of the COVID-19 vaccine; medical history at the patient level; details of the next visit, including the date, location (name of hospital or clinic), department (emergency department and/or family medicine), and the reported symptoms—pneumonia-related for emergency visits and long COVID symptoms for family medicine visits; survival status (alive or dead), and if deceased, the cause and date of death.

Ethical approval and consent to participation

This study received ethical approval from the Dubai Scientific Research Ethics Committee (DSREC) at Rashid Hospital (DSREC-12/2020_02). All patients’ records were analyzed in a fully anonymized and de-identified manner, and researchers had no access to patients’ personal information; hence, no written consent was required. This waiver of informed consent was approved by the Dubai Scientific Research Ethics Committee. Furthermore, all methods were performed in accordance with the relevant guidelines (Declaration of Helsinki and the Belmont Report) and regulations (DSREC rules).

Patients and treatment selection

The study included participants aged 18 years or older who tested positive for SARS-CoV-2 via RT-PCR and had mild to moderate COVID-19-related symptoms with SpO2 of ≥ 94% on room air, without requiring hospitalization²⁰. Hospitalized patients with SpO2 levels below 94% or those needing supplemental oxygen were excluded.

The selection of patients for treatment with nirmatrelvir-ritonavir or no-treatment was based on the published national protocol for managing adult patients with COVID-19²¹, and it also involved physician decision-making. The national protocol recommended administering nirmatrelvir-ritonavir within 5 days of symptom onset to high-risk individuals to prevent progression to severe COVID-19 and hospitalization²¹. This high-risk group included individuals aged ≥ 65 years, those with obesity (≥ 25 kg/m²), diabetes mellitus, cardiovascular disease or hypertension, chronic lung disease, individuals with immunocompromising conditions or on immunosuppressive treatment, chronic kidney disease, pregnant individuals, those with sickle cell anemia, neurodevelopmental disorders, and individuals dependent on medical-related technology such as tracheostomy²¹. Based on the protocol, patients with severe chronic kidney disease, defined as an eGFR of less than 30 mL/min, and those with severe liver disease were not recommended to receive nirmatrelvir-ritonavir²¹. Instead, they received other COVID-19 treatments, such as remdesivir or sotrovimab. These patients were also excluded from the no-treatment (control) group to avoid confounding factors. Moreover, all included patients did not receive molnupiravir, remdesivir, or sotrovimab, which were recommended for non-hospitalized patients at risk of COVID-19 progression.

Outcomes

In this study, the index date was defined as the date of a positive SARS-CoV-2 RT-PCR test result, which indicated an acute COVID-19 diagnosis and prescription of nirmatrelvir-ritonavir. The primary outcome assessed was the risk of COVID-19-related hospitalization up to day 28, with both the nirmatrelvir-ritonavir treated group and the no-treatment group followed for 28 days post-acute COVID-19 diagnosis (Fig. 1). During the emergency department visit, patients were evaluated for COVID-19 pneumonia as the primary diagnosis, and hospitalization lasting more than 24 h was considered. The secondary outcome was evaluated as a patient visit to the family medicine department due to the symptom(s) of long COVID, defined as continuous or new symptom(s) present 28 days or more following acute COVID-19 infection^9,22,23. The physician notes were evaluated for the presence of these symptoms (as shown in Fig. 2A and B) reported by the patients. Both the nirmatrelvir-ritonavir treated group and the no-treatment group were followed for 90 days post-acute COVID-19 diagnosis for this secondary outcome.

The effect of nirmatrelvir-ritonavir on long COVID symptoms reported within 90 days of treatment initiation. (A) Frequency of each reported symptom (B) Time of each reported symptom within 90 days from the acute COVID infection. (C) Kaplan-Meier plot comparing individuals not treated and those treated with nirmatrelvir-ritonavir. A cumulative hazard value of 5 for no antiviral treatment indicates that the risk of developing long COVID over 90 days is five times the baseline risk, while a value of 2 for nirmatrelvir-ritonavir indicates a risk that is twice the baseline over the same period. Abbreviations: HR, Hazard ratio.

Statistical analysis

For descriptive analysis, means and standard deviations or medians and interquartile ranges were used for continuous data, as appropriate. Chi-square tests were used to compare percentages across treatment groups for categorical variables.

To determine the risk of COVID-19-related hospitalizations and the risk of developing long COVID symptoms, we developed Cox proportional hazards models adjusted for patients’ demographics (age, gender, ethnicity/race), pre-existing conditions (diabetes mellitus, overweight, cardiovascular disease, hypertension, autoimmune disorder, malignancy), and vaccination status. Kaplan-Meier survival curves were constructed to show cumulative survival. We tested all variables for multicollinearity to avoid strong correlations. Standard errors and variance inflation factors were evaluated for collinearity.

We analyzed the data using SPSS software (version 26.0), R software (version 3.6.1), and PRISM software (version 8).