Sax, Paul E.

Abstract Background With progressive accumulation of knowledge on SARS-CoV-2 infection clinical management, treatment guidelines recommended several options including remdesivir, a broad-spectrum antiviral. Given the evolving nature of coronavirus disease 2019, capturing the totality of scientific evidence from clinical trials and observational studies is critical to inform clinical decision making. We conducted a systematic literature review with meta-analysis to summarize the effectiveness of remdesivir among hospitalized adults. Methods We systematically searched MEDLINE, Embase and Cochrane Library databases for interventional and observational studies examining remdesivir efficacy. A rigorous double-reviewer approach was used for source identification, screening, data extraction and risk of bias assessment. A hierarchical random-effects model meta-analysis was used, with subgroup analyses for randomized controlled trials (RCTs) and real-world (RW) studies. Results From January 2019 to December 2023 >18 000 sources were screened, and 122 unique studies were identified, reporting on 25 174 participants in RCTs and 1 279 859 in RW studies. Remdesivir significantly increased survival in the overall population (odds ratio, 0.69 [95% confidence interval, .55–.86]; P = .001] across SARS-CoV-2 variants and disease severity levels: no supplemental oxygen (0.81 [.75–.88]), low-flow oxygen (0.71 [.64–.79]), high-flow oxygen (0.87 [.83–.91]), and invasive mechanical ventilation (0.78 [.68–.90]). Rehospitalization risk was significantly reduced in patients receiving remdesivir (odds ratio, 0.72 [95% confidence interval, .64–.81]). Conclusions Our comprehensive systematic literature review, capturing the totality of evidence, showed a significant survival benefit among patients hospitalized for SARS-CoV-2 infection and receiving remdesivir, across all disease severity levels. To assure that healthcare providers are aware of and deploy evidence-based optimal care, recommendations should rely on both RCT and RW data.

Abstract Background With progressive understanding of the natural history of COVID-19 and accumulation of knowledge on clinical management, treatment guidelines recommended several options including remdesivir (RDV), a broad-spectrum antiviral. Given the evolving nature of COVID-19, it is critical to capture the totality of scientific evidence to inform clinical decision making. We conducted a systematic literature review (SLR) to summarize the mortality endpoint for RDV among hospitalized adults throughout COVID-19 eras and contrasted with evidence informing treatment recommendations in clinical guidelines. Methods We systematically searched MEDLINE, Embase and Cochrane Library databases for interventional and observational studies examining RDV efficacy. Clinical trial registries, Cochrane COVID-19 Study Register, and conference abstracts were hand-searched (Fig1). Case reports and case studies were excluded. A review of most recent RDV recommendations across guidelines was conducted. Results From Dec ’19 to Dec ’22, 123 relevant publications were identified. In ’23, the evidence grew significantly, with 70 new publications. In total, 193 publications were evaluated, and 122 unique studies were included. While early randomized clinical trials (RCT) and small sample size observational studies did not universally demonstrate a significant difference in mortality in all severity groups of RDV-treated patients, real-world studies with larger sample sizes showed a significant impact across disease severity levels, regardless of COVID-19 era (Table1). Guideline recommendations for COVID-19 treatment with RDV are based on early RCTs (Table2) and most have not been updated (Fig2). Conclusion Our comprehensive evaluation of scientific literature indicates that evidence of RDV impact on mortality in hospitalized COVID-19 patients continued to grow and cover full range of disease severity. Guideline recommendations have not evolved in parallel which may explain differing recommendations in certain subgroups (e.g. IMV/ECMO). To assure that providers in the hospital setting are aware of and deploy evidence-based optimal care for patients with COVID-19, recommendations should rely on current evidence, including real-world data. Disclosures Essy Mozaffari, PharmD, MPH, MBA, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Michele Bartoletti, MD, PhD, Advan pharma: Advisor/Consultant|Advan pharma: Honoraria|Biomereux: Honoraria|Gilead: Advisor/Consultant|Gilead: Honoraria|Infectopharma: Advisor/Consultant|Msd: Advisor/Consultant|Msd: Grant/Research Support|Msd: Honoraria|Pfizer: Honoraria Alpesh N. Amin, MD, MBA, Alexion: Advisor/Consultant|Aseptiscope: Advisor/Consultant|AstraZeneca: Advisor/Consultant|Bayer: Advisor/Consultant|Dexcom: Advisor/Consultant|Eli Lilly: Advisor/Consultant|Ferring: Advisor/Consultant|Gilead: Advisor/Consultant|GSK: Advisor/Consultant|Heartrite: Advisor/Consultant|Nova Nordisk: Advisor/Consultant|Pfizer: Advisor/Consultant|Renibus: Advisor/Consultant|Reprieve: Advisor/Consultant|Salix: Advisor/Consultant|Seres: Advisor/Consultant|Spero: Advisor/Consultant Yohei Doi, MD, PhD, bioMerieux: Lecture fees|Entasis: Grant/Research Support|Fujifilm: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|GSK: Advisor/Consultant|KANTO CHEMICAL CO.,INC.: Grant/Research Support|KANTO CHEMICAL CO.,INC.: Patent for genotyping kit|MeijiSeika Pharma: Advisor/Consultant|Moderna: Advisor/Consultant|MSD: Lecture fees|Pfizer: Advisor/Consultant|Shionogi & Co., Ltd.: Grant/Research Support|Shionogi & Co., Ltd.: Lecture fees Paul LOUBET, MD, PhD, Astrazeneca: Advisor/Consultant|Gilead: Advisor/Consultant|Moderna: Advisor/Consultant|Pfizer: Advisor/Consultant Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Board Member Michael Roshon, MD/PhD, MD/PhD, Gilead: Honoraria Thomas F. Oppelt, PharmD, BCPS, Gilead Sciences, Inc: I am an employee of Gilead Sciences, Inc|Gilead Sciences, Inc: Stocks/Bonds (Public Company) Mel Chiang, Ph.D., Gilead Sciences: I am an employee of Gilead Sciences|Gilead Sciences: Stocks/Bonds (Public Company)

Background: Patients with immunocompromising conditions, including those affected by hematologic malignancies, have a disproportionately high burden of morbidity and mortality related to COVID-19 compared to individuals without such conditions.Clinical practice guidelines (CPGs) recommend the use of remdesivir, a broad-spectrum antiviral, for treatment of mild to severeCOVID-19 in immunocompetent patients not requiring invasive mechanical ventilation. While the CPGs issued by the World Health Organization (WHO, 2023), National Institutes of Health (NIH, 2023) and the Infectious Diseases Society of America (IDSA, 2022) also recommended the use of remdesivir in patients with immunocompromising conditions at high risk for severe disease, there was limited evidence available at the time the recommendations were communicated, more than two years after the start of the pandemic. The European Conference on Infections in Leukemia (ECIL, 2022) guidelines include remdesivir among the treatment options for mild to moderate COVID-19 patients with hematologic malignancies. The lack of evidence for treatment efficacy and safety in patients with immunocompromising conditions, a population underrepresented or excluded from clinical trials, was mentioned in CPGs as a knowledge gap and as need for further research. In this research, we summarize the evidence for remdesivir efficacy and safety for treatment of COVID-19 in hospitalized patients with hematologic malignancies accumulated since the start of the pandemic. Methods: We systematically searched MEDLINE, Embase and Cochrane Library databases from January 2019 through December 2023 for interventional and observational studies examining remdesivir efficacy and safety. Case reports and case studies were excluded. A dual-reviewer approach was used for screening and data extraction. Results: Of the 7,654 references retrieved through the implementation of the extensive search strategy 59 (0.8%) reporting on patients with hematologic malignancies, unspecified cancers, or immunodeficiencies were identified and reviewed in full text. Only eight unique studies (8 of 59) were conducted in patients with hematologic malignancies, of which two reported remdesivir use in a minority of participants (n<5) and were excluded from further analyses. The remaining six studies, of which four were peer-reviewed original articles, one was a letter to editor and the last was a conference abstract, used a retrospective cohort design and reported efficacy outcomes for a combined total of 1,579 individuals across the studies. Three of the six studies were conducted during the pre-Omicron variant era (November 2021) while the remaining three started data collection in December 2021. There were four studies reporting number of deaths or the mortality rate, while a fifth study based on medical chart reviews of 313 patients in Israel found a significantly reduced risk of mortality among remdesivir recipients compared to patients not receiving remdesivir (OR: 0.297; 95% CI: 0.105, 0.834). In addition, a study including 466 patients from the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Registry reported mortality among remdesivir treated group related to baseline disease progression, use of corticosteroids for COVID-19 therapy and the presence of coinfections while B-cell malignancy as underlying disease, severe COVID-19, late antiviral initiation (≥5 days after first positive PCR) and longer treatment duration (≥5 days) were factors significantly associated with prolonged viral shedding. The same Spanish study reported safety outcomes indicating that adverse events of grade 3 or above were rare, occurring in 0.5% of remdesivir treated patients. Conclusion: Despite the call for research to fill the knowledge gap signaled by the CPGs, our comprehensive systematic literature review identified only a few publications conducted since the start of the pandemic in patients with hematological malignancies. In the current endemic era, these patients are among the most at risk for severe outcomes and COVID-19 related hospitalizations. While the limited evidence suggests that remdesivir use can reduce mortality in patients with hematologic malignancies, additional research will be instrumental to inform development and updating of evidence-based recommendations to support and guide clinical management of oncology patients.