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Tratamento farmacológico de COVID-19 e risco de óbito em pacientes hospitalizados no Brasil: estudo retrospectivo de dados secundários
COVID-19 drug treatment and risk of death in hospitalized patients in Brazil: a retrospective study of secondary data
Tratamiento farmacológico de la COVID-19 y riesgo de muerte en pacientes hospitalizados en Brasil: un estudio retrospectivo de datos secundarios

Gbènankpon Mathias Houvessou1*, Gary Joseph2, Manuel Mahoche,3

1Gertrude H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, USA, E-mail: gbemathg@gmail.com, https://orcid.org/0000-0003-3401-2547.
2Department of Environmental Medicine and Public Health, Icahn School of Medicine, New York, USA. E-mail: garyjoseph056@gmail.com, https://orcid.org/0000-0002-9300-2069.
3Departamento de Epidemiologia, Escola de Saúde Pública, Universidade de São Paulo, SP, Brasil. E-mail: manuelmahoche@gmail.com, https://orcid.org/0000-0002-9784-6402.

* Corespondence:
E-mail: gbemathg@gmail.com

Resumo
Introdução: A pandemia de COVID-19 impôs desafios sem precedentes aos sistemas de saúde em nível global, com altas taxas de hospitalização e mortalidade, justificando a adoção emergencial de intervenções farmacológicas em vários países, incluindo o Brasil. Objetivo: Descrever os tratamentos administrados e avaliar o risco de mortalidade entre pacientes hospitalizados com COVID-19 no Brasil. Métodos: Estudo retrospectivo foi baseado em dados secundários do Sivep-Gripe disponíveis no período de janeiro de 2022 a agosto de 2024. Para a análise dos dados foi usada a regressão de Poisson para estimar o risco relativo de mortalidade, considerando variáveis demográficas, clínicas e tratamentos administrados. Resultados: Foram analisados 1.721 casos. Pacientes tratados com Nirmatrelvir-Ritonavir, Molnupiravir ou Baricitinibe apresentaram 2,52 (IC 95%: 1,76 – 3,62), 4,02 (IC 95%: 2,77 – 5,82) e 3,96 (IC 95%: 2,93 – 5,36) vezes mais risco de mortalidade, respectivamente, em comparação aos tratados com Remdesivir. A análise sugere que o Remdesivir mais eficaz para pacientes graves, reduzindo a mortalidade. Conclusão: Os resultados reforçam que Remdesivir deve ser considerado uma opção preferencial no tratamento de casos graves de COVID-19 no Brasil, apoiando a formulação de políticas públicas de saúde.
Palavras-chave: COVID-19, Mortalidade, Tratamento Farmacológico, Brasil.

Abstract
Introduction: The COVID-19 pandemic has imposed unprecedented challenges on health systems globally, with high hospitalization and mortality rates, justifying the emergency adoption of pharmacological interventions in several countries, including Brazil. Objective: To describe the treatments administered and assess the risk of mortality among hospitalized patients with COVID-19 in Brazil. Methods: A retrospective cohort study was based on secondary data from Sivep-Gripe available from January 2022 through August 2024. Poisson regression was used to estimate the relative risk of mortality, considering demographic and clinical variables, and treatments administered. Results: A total of 1,721 cases were analyzed. Patients treated with Nirmatrelvir-Ritonavir, Molnupiravir, or Baricitinib had a 2.52 (95% CI: 1.76–3.62), 4.02 (95% CI: 2.77–5.82), and 3.96 (95% CI: 2.93–5.36) times greater risk of mortality, respectively, compared to those treated with Remdesivir. The analysis indicated that Remdesivir was more effective for severe patients, possibly reducing mortality. Conclusion: The results suggest that Remdesivir should be considered a preferred option in the treatment of severe cases of COVID-19 in Brazil, supporting the formulation of public health policies.
Keywords: COVID-19, Mortality, Pharmacological Treatment, Brazil.

Resumen
Introducción: La pandemia de COVID-19 ha impuesto desafíos sin precedentes a los sistemas de salud a nivel mundial, con altas tasas de hospitalización y mortalidad, lo que justifica la adopción urgente de intervenciones farmacológicas en varios países, incluido Brasil. Objetivo: Describir los tratamientos administrados y evaluar el riesgo de mortalidad en pacientes hospitalizados con COVID-19 en Brasil. Métodos: Este estudio retrospectivo utilizó datos secundarios de Sivep-Gripe disponibles entre enero de 2022 y agosto de 2024. Se utilizó la regresión de Poisson para estimar el riesgo relativo de mortalidad, considerando variables demográficas y clínicas, y los tratamientos administrados. Resultados: Se analizaron 1721 casos. Los pacientes tratados con Nirmatrelvir-Ritonavir, Molnupiravir o Baricitinib presentaron un riesgo de mortalidad de 2,52 (IC 95 %: 1,76-3,62), 4,02 (IC 95 %: 2,77-5,82) y 3,96 (IC 95 %: 2,93-5,36) veces mayor, respectivamente, en comparación con los tratados con Remdesivir. El análisis sugiere que Remdesivir es más eficaz en pacientes graves, reduciendo la mortalidad. Conclusiones: Los resultados refuerzan la idea de que Remdesivir debe considerarse una opción preferente en el tratamiento de casos graves de COVID-19 en Brasil, lo que respalda la formulación de políticas de salud pública.
Palabras claves: COVID-19, Mortalidad, Tratamiento Farmacológico, Brasil

Introduction
Described as the first major global pandemic in the digital era, COVID-19 has posed several challenges to global health systems1. As of March 3, 2024, the World Health Organization (WHO) recorded 774,834,251 cases of COVID-19 and 7,037,007 deaths2. In Brazil, the Ministry of Health reported 38,729,836 cases and 711,249 deaths3, being the second country in absolute mortality in the Americas, behind the United States.
The initial responses to the pandemic, including social distancing, the use of personal protective equipment, and lockdowns, demonstrated effectiveness in controlling the transmission of the disease4-6. Studies from Aquino et al.5 and Cowling et al.7 highlighted the importance of these interventions in reducing infection rates in several regions. From a pathophysiological perspective, SARS-CoV-2 infects lung epithelial cells via the ACE2 receptor, triggering a systemic inflammatory response (cytokine storm) that can progress to acute respiratory distress syndrome in severe cases⁸. This mechanism justifies the use of antivirals such as remdesivir to mitigate viral replication and reduce disease severity, as demonstrated in clinical trials⁹.
Globally, mass testing, contact tracing, prevention education campaigns, and international cooperation have strengthened the response to the pandemic10. The WHO has highlighted the importance of these strategies in its reports, citing successful examples from countries that implemented mass testing and education campaigns10. Vaccination has emerged as a central pillar with evidence indicating a reduction in severe cases and deaths11. However, it does not guarantee complete immunity due to the high transmissibility of the virus11, as detailed in the WHO reports on vaccines10.
In Brazil, COVID-19 treatment is stratified by disease severity. Palliative care and monitoring are recommended for mild to moderate cases. In contrast, severe or critical cases often require hospitalization and necessitate more intensive interventions12. Medications such as remdesivir, dexamethasone, lopinavir/ritonavir, and, in some cases, tocilizumab are used, in addition to supportive measures like mechanical ventilation in accordance with the guidelines of the National Institutes of Health and the Brazilian Medical Association13-16. The controversy surrounding medications such as hydroxychloroquine, initially promoted by the government, was expressive among experts, but studies advised against its use due to a lack of evidence17,18.
The situation in Brazil reflects the heterogeneity of the global crisis, with local structural characteristics shaping the impacts. Factors such as the large population, socioeconomic inequalities, and limitations in the health system19 have intensified the challenges.
This study aims to describe the treatment administered and assess the risk of mortality due to COVID-19 among hospitalized patients with COVID-19 in Brazil, focusing on the use of antiviral drugs such as Remdesivir, Nirmatrelvir-Ritonavir, and Molnupiravir, in a context of limited resources and high disease burden.
Methods
Participants and data sources
A retrospective cohort assessed severe COVID-19 cases in hospitalized Brazilian patients, using data from the Influenza Epidemiological Surveillance Information System (SIVEP-Gripe - Sistema de Informação de Vigilância Epidemiológica da Gripe), a public database maintained by the Ministry of Health that records cases of severe acute respiratory syndrome20.
The period from January 2022 to August 2024 was selected to reflect the availability of data in SIVEP-Gripe and the incorporation of antivirals such as nirmatrelvir-ritonavir (Paxlovid), molnupiravir, baricitinib (Olumiant), remdesivir, azithromycin (or in combination with other drugs), and other drugs in Brazil. Patients with a confirmed diagnosis of COVID-19, hospitalized for at least 24 hours, and with available treatment information were included in the study. Of the 304,664 registered cases, 1,721 were analyzed after excluding incomplete records (Figure 1). Data available for hospitalized patients from January 2022 to August 5, 2024, included information on treatments with Nirmatrelvir-Ritonavir, Molnupiravir, Baricitinib, Remdesivir, azithromycin, and other medications. Cases with recorded outcomes (discharge or death) were considered. After obtaining the data, it was cleaned and prepared for statistical analysis.
Data were collected using the mandatory notification form for severe COVID-19 hospitalizations within the SIVEP-Gripe system, completed by hospital teams. Patients with acute respiratory illness symptoms exhibiting two or more symptoms such as fever, chills, sore throat, headache, cough, runny nose, loss of smell or taste, as well as signs such as dyspnea, respiratory distress, chest tightness, oxygen saturation below 95% on room air, or cyanosis, were classified as severe cases of COVID-19.
Exposures and outcome
Exposures were defined as the types of administered treatment for COVID-19, categorized into six groups: (1) Nirmatrelvir combined with ritonavir (Paxlovid); (2) Molnupiravir (Lagevrio); (3) Baricitinib (Olumiant); (4) Remdesivir; (5) Azithromycin or in combination with other drugs; and (6) Other drugs. The outcome was death from COVID-19, which was identified based on the patient\'s clinical evolution. It was recorded in a pre-existing variable with four categories: cure/recovery, death, death from other causes, and unknown. For this analysis, the categories "death from other causes" and "unknown" were excluded, restricting the event of interest to deaths caused by COVID-19.
Covariates
Covariates were grouped into three main categories: (i) Demographic and Clinical: sex (female/male), age in years (0-20/21-50/51-60/61-70/71 or older), and the presence of specific comorbidities such as obesity, heart disease, hematologic disease, asthma, diabetes mellitus, neurological disease, lung disease, immunodeficiency disorders, and kidney disease. All comorbidity variables were categorized as yes/no; (ii) ICU admission, and it was classified into three groups (yes, no, unknown). Individuals in the "unknown" category were excluded from the analysis.
Hospital teams identified comorbidities through analysis of patient charts. The Sivep-Gripe notification form, in field 35, reports about the presence of risk factors or comorbidities, followed by a list of 12 comorbidities to be marked21. After filing the form, the data was entered into an online information system. Individuals who checked "Yes" were considered to have comorbidities, while those who checked "No" or left the field blank were considered to have no comorbidities. For each assessed comorbidity, individuals in the "Unknown" category were excluded from the analyses.
Statistical analysis
The independent variables and the outcome were initially explored through descriptive analyses. Subsequently, bivariate analyses were performed to investigate the relationship between the independent variables and the outcome, considering 95% confidence intervals (95% CI).
Poisson regression with robust standard error estimation was used to estimate the relative risk (RR) for death from COVID-19 in both unadjusted and adjusted models, with a statistical significance level of p < 0.05. A collinearity test was conducted between the independent variables, and an assessment of model fit was made by comparing the pseudo-R² and log pseudolikelihood. This assessment was performed by comparing models that varied in complexity, ranging from those that only considered the outcome and treatment to more comprehensive models that included sex and age. In cases where information for the variables was missing, a variable incompleteness analysis was performed. Among the 3,464 cases marked "Yes" as having received treatment for COVID-19, a complementary analysis was performed comparing, according to the variables, those included in the analyses with information on the type of treatment received and those excluded. Furthermore, a sensitivity analysis was performed, including the 67 deaths from other causes, to determine whether they affected the estimates.
Statistical calculations were performed using Stata 15.0 software (Stata Corp., College Station, Texas, USA). The study complied with the ethical guidelines established by Resolution No. 466 of the National Health Council.
Results
During the evaluation period, 304,664 hospitalizations for COVID-19 were recorded, of which 66,045 had information on the treatment. Of these, 4,059 answered "Yes" and received treatment for COVID-19. Of those who responded “Yes”, 2,160 patients had detailed data on the type of treatment, and 1,721 had information on outcome and covariates, and were included in the analysis (Figure 1).
Of the patients analyzed, 50.8% (875) were male and 73.7% (1,267) were 61 years or older. Furthermore, 42.3% (728) had cardiac disease, and 42.8% (736) were admitted to an ICU (Table 1). In the complementary analysis, no differences were observed between those included in the analyses and those lacking information on the type of treatment received for the variables sex (p = 0.506), age (p = 0.054), death from COVID-19 (p = 0.487), and the specific comorbidities studied. However, there was a difference in the proportion of ICU admissions, with 42.8% and 33.2% of those included and excluded, respectively. Regarding the administered treatments, 217 patients (12.6%) received Nirmatrelvir/ritonavir, 83 (4.8%) were treated with Molnupiravir, 373 (21.7%) with Baricitinib, 420 (24.4%) with Remdesivir, and 183 (10.6%) were treated with Azithromycin or in combination with other drugs. Other types of drugs were administered to 446 patients (25.9%).
The distribution of hospitalized COVID-19 cases, with information on received treatment, varied by the federation unit and region (Table 2). Table 3 shows that patients aged 71 years and older received a higher proportion of all medications, especially remdesivir (342; 69.9%) and azithromycin or combination with other drugs (181; 63.7%). Individuals without heart disease received a higher proportion of all medicines, except remdesivir, which was more frequently administered to patients with heart disease (251; 51.3% versus 238; 48.7%, p<0.001). Obese patients showed a higher use of remdesivir and other medications (38; 7.8% and 40; 7.5%, respectively, p = 0.034). Furthermore, patients with immunodeficiency disorders represented a high proportion in receiving treatment with Remdesivir (80; 16.4%) and Nirmatrelvir/ritonavir (34; 12.9%). Among treatment groups, ICU admission was frequent in patients treated with Remdesivir (326; 66.9%) and Molnupiravir (47; 49.5%).
The association between type of received treatment and death from COVID-19 indicated that, compared to patients treated with Remdesivir, those who received Nirmatrelvir/Ritonavir, Molnupiravir or Baricitinib had a significantly higher relative risk of death, of 2.52 (95% CI: 1.76–3.62), 4.02 (95% CI: 2.77–5.82) and 3.96 (95% CI: 2.93–5.36), respectively (Table 4).
Discussion
This study shows the complexity of managing hospitalized COVID-19 patients in Brazil, highlighting the differential performance of the antivirals remdesivir, nirmatrelvir-ritonavir, and molnupiravir. The predominance of male and elderly patients in the sample reflects global trends that indicate greater severity of COVID-19 in these groups. For instance, a randomized study conducted in 2020 with 397 patients22 that investigated the impact of remdesivir treatment duration on critically ill patients, suggested that more extended regimens may be beneficial for specific patient subgroups.
The efficacy of antiviral treatments, especially remdesivir, is a key issue in this study. A final report conducted in 2020, with hospitalized COVID-19 patients23, indicated that remdesivir was associated with improved recovery time, which is consistent with our study\'s findings regarding the association between remdesivir use and lower mortality rates23. Furthermore, previous research has highlighted remdesivir\'s ability to promote accelerated recovery from COVID-1923,24. An in-silico study conducted in 2023 suggests that remdesivir may act to block SARS-CoV-2 by modulating the immune response25. SARS-CoV-2 infects lung epithelial cells via the ACE2 receptor. Remdesivir, a nucleotide analog, interacts with ACE2 and concomitantly modulates the coagulation cascade, preventing hypercoagulability25. Thus, the drug inhibits the dependent RNA polymerase of SARS-CoV-2 RNA, blocking viral replication26,27. When administered intravenously, the drug reaches rapid therapeutic concentrations in critically ill patients, reducing viral load and the associated inflammatory response, according to a study by Pagliarin et al.25
There is controversy regarding the benefits of molnupiravir in the treatment of COVID-19. Some studies suggest its efficacy in mild cases of COVID-1928-30, while others emphasize its lower efficacy compared to nirmatrelvir/ritonavir31 or standard medical care32. On the other hand, treatment guidelines suggest molnupiravir as an alternative when other options are inappropriate or unavailable33.
In addition to antivirals, research on treatments for COVID-19 has explored a range of therapies. The monoclonal antibodies bamlanivimab and etesevimab, used alone or in combination, can reduce viral load in patients with COVID-1934. This is a therapeutic approach that may complement the use of antivirals. These findings align with a review study by Mahase35 that examined several therapeutic strategies under investigation for COVID-19, including antivirals, anti-inflammatories, and supportive care, reflecting the current state of research into treatments for the disease. Meanwhile, other studies offer a global view on the efficacy of antiviral drugs, highlighting the importance of robust clinical trials in validating treatment options36.
Dexamethasone, a corticosteroid, has been shown to reduce mortality in COVID-19 patients requiring respiratory support, underscoring the importance of anti-inflammatory therapies in the treatment of the disease, especially in severe cases36. Therefore, this study highlights the need for a multifaceted treatment approach for COVID-19 in Brazil, considering both antiviral therapies and anti-inflammatory and supportive care options. Also, it emphasizes the importance of continuous clinical evaluation and adaptation of therapeutic strategies in emerging evidence.
A regional analysis of data on treatment revealed variations that may be related to differences in pandemic management, access to medications, and treatment protocols across states. These regional differences are crucial to understanding the dynamics of the pandemic in the country and may help identify areas for improvement in resource allocation and implementation of treatment strategies.
The absence of details regarding the timing of treatment initiation following hospitalization precludes a precise analysis of the optimal therapeutic window and its association with mortality outcomes. It was not possible to establish direct causal relationships between the treatments administered and the outcome. The possibility of selection bias cannot be discarded, where patients received specific treatments based on their clinical status rather than being randomly assigned. Additionally, we cannot rule out the presence of residual confounding in the relative risk estimates due to a lack of adjustment for socioeconomic variables. Furthermore, the variable "skin color" was not included in the adjustment due to missing data. In this context, generalization of the results to other populations may be limited, given Brazil\'s specific context with its regional, social, and economic nuances, in addition to the limited available information on COVID-19 treatment.
Conclusion
The results reinforce the relevance of remdesivir as a preferred treatment for severe COVID-19 cases in hospitalized patients in Brazil, demonstrating an association with lower mortality compared to other evaluated antivirals. The findings highlight the need for differentiated therapeutic strategies for advanced stages of the disease, suggesting that remdesivir could potentially be prioritized in clinical protocols, especially in contexts of high demand and limited resources. Furthermore, the observed regional variations in access to treatments point to inequalities in the implementation of health policies, which require targeted actions to ensure equity. Thus, these findings may contribute to the development of policies aimed at managing severe COVID-19 cases in Brazil
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