4. Discussion
RDV was the first antiviral drug evidenced to inhibit SARS-CoV-2 replication and receive an emergency use authorization, followed by registration for the treatment of patients with COVID-19. Its use was supported by the results of randomized clinical trials proving the clinical improvement, shortening the recovery time and mortality rate in patients with mild to moderate course of infection26,27. Identifying highly infectious Omicron in late 2021 raised concerns about its impact on the pandemic dynamics and the effectiveness of the vaccines and COVID-19-approved therapies28,29,30. Based on literature reports of reduced activity of some monoclonal antibodies against this new lineage, some regulatory institutions, e.g., U.S. FDA, limited their distribution 31. At the same time, the available data indicated that antiviral drugs used in previous waves of the pandemic, including RDV, shall remain active against the new SARS-CoV-2 variant32. However, such assumptions require direct evidence from clinical practice. Therefore, this real-world (RWE) study aimed to assess the effectiveness of RDV in a large cohort of Polish patients hospitalized with COVID-19 during the surges of two SARS-CoV-2 VOC, Delta, and Omicron.
As shown, under the dominance of both viral variants, RDV-treated patients were characterized by lower mortality than a group not treated with any antivirals – despite that these groups were comparable by demographical and clinical parameters. During the Delta wave, the RDV-treated group revealed two-fold lower mortality. This finding clearly shows the benefits of RDV use during the dominance of this highly pathogenic SARS-CoV-2 variant 33. However, the mortality in RDV-treated patients was also reduced, approximately 1.5-fold, in the Omicron wave, which was generally characterized by a milder course of infections 21,22,34–36.
These observations are consistent with the results from clinical trials and RWE studies conducted in the early phases of the COVID-19 pandemic27,37–39. A retrospective analysis of a large U.S. patient cohort of nearly 100,000 patients hospitalized till February 2021 also confirmed a reduction in mortality in the overall population treated with RDV in absolute numbers (15.7 vs. 19.6%), but highlighted a significant difference only in patients who required low-flow oxygen therapy 40. Another study, encompassing patients hospitalized till March 2021, indicated a statistically reduced mortality in women 41. The study conducted in the Netherlands indicated that RDV use was associated with better outcomes during four pandemic waves, but the analysis did not cover the dominance of the Omicron variant 42. To our knowledge, the present investigation is the first to address it in a real-world clinical setting.
Although the RDV-treated group was characterized by a lower percentage of patients requiring mechanical ventilation during both pandemic waves, the difference with a group not receiving any antiviral therapy was statistically insignificant. Nevertheless, the demonstration of a favorable trend in this regard is in line with reports by other authors43,44. Even the Solidarity trial, the initial results of which were the basis for not recommending RDV in the WHO guidelines, in the final report published in 2022 documented a significant beneficial effect on reducing mortality and disease progression requiring mechanical ventilation 45.
This analysis also shows that patients hospitalized due to COVID-19 during the Omicron wave were significantly older and more burdened with comorbidities, especially hypertension, ischemic heart disease, stroke, and neoplastic diseases. The clinical condition of those admitted to the hospital during the Delta wave was more severe, as expressed in a significantly higher percentage of clinically unstable patients with oxygen saturation ≤95%. However, surprisingly, despite the more severe clinical condition, patients infected with Delta started antiviral therapy with RDV statistically later than patients infected with the Omicron variant. This could be due to the healthcare system being more overwhelmed during the Delta-dominated wave, delayed admission of patients to the hospital, and shortages of medicines, including RDV. The other possible explanation is related to the older age and higher comorbidity burden of patients infected with the Omicron variant. Some of these patients could be admitted to the hospital for reasons other than COVID-19, underwent a routine SARS-CoV-2 diagnostics during admission, tested positive on PCR or antigen test, and were immediately treated with RDV. Such phenomenon during the dominance of the Omicron variant has already been noticed in the United States46. In the current study, more than half of the Omicron-infected patients received RDV therapy within 3 days of the onset of symptoms, compared to nearly 28% in the Delta wave, and initiation of therapy within the first 5 days was documented in 87% and 57% of patients, respectively. Early drug administration has an impact on its effectiveness, which has been documented in clinical trials and numerous RWE analyses 27,37,41,47,48. According to national recommendations, the optimal time to start RDV therapy is the first 5 days; however, data from clinical trials indicate the effectiveness of treatment started up to 10 days from the onset of symptoms 20,27. In this study, several patients started treatment with RDV even later than 5 days after the first symptoms. These were immunocompromised patients and those burdened with many risk factors for severe COVID-19, which justified such a decision by the attending physician 49.
Study limitations should be stressed. Firstly, the viral sequencing in hospitalized patients was not performed. However, the subdivision of Delta and Omicron-dominated periods was conducted based on reliable data deposited in GISAID. Secondly, the study did not include the immunization status of patients due to the unavailability of such data. Since the immunization status is the result of both COVID-19 and vaccination, the history of infection, serological markers indicating previous contact with the virus, as well as the number of vaccine doses would need to be taken into account, introducing further challenges to the analysis. With so many confounding factors, a simple distinction between vaccinated and unvaccinated individuals would not be reliable. Thirdly, in some patients, especially during the Omicron wave, the diagnosis of COVID-19 could have been accidental due to the routine testing procedures of all patients admitted to the hospital. Fourth, the impact of other variables, such as the effectiveness of the health care system and environmental factors, including air pollution, which may have influenced patient mortality, was not analyzed50. Lastly, the potential bias resulting from retrospective data collection based on medical records should be highlighted.
The main strength of this study is including and analyzing the data from a large real-world population from many different centers in our country, which ensures nationwide coverage and allows the generalization of conclusions. Patients were managed according to the same national recommendations, and detailed medical records were available for each patient and information up to 28 days after admission unless death occurred earlier. In addition, to our knowledge, this is the first study that documents the effectiveness of RDV against the Omicron variant in a clinical setting and compares it with the period dominated by Delta SARS-CoV-2.