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.