Remdesivir Treatment Research Articles

Safety and Efficacy of Remdesivir for the Treatment of COVID-19: A Systematic Review and Meta-Analysis.

To evaluate the safety and efficacy of remdesivir in adult patients with COVID-19. PubMed, Embase, Scopus, Web of Science, Cochrane Library, ClinicalTrials.gov, and medRxiv databases were searched using a search strategy tailored to each database. The Consolidated Standards of Reporting Trials (CONSORT) and Strengthening the reporting of observational studies in epidemiology (STROBE) checklists were used for the studies' qualitative assessment. The outcomes studied were mortality, all adverse events, serious adverse events, and clinical improvement. The quantitative synthesis was conducted using fixed and random effects models in the CMA 2.2. Heterogeneity was tested using the I-squared (I2) measure. In general, six studies, including five randomized controlled trials and one cohort study were found eligible. Comparison of the findings related to both groups receiving remdesivir (10-day remdesivir group) and placebo/control group showed that remdesivir treatment had no significant effect on mortality at day 14 of the treatment (RR=0.769; 95% CI :0.563-1.050; p=0.098), and all adverse events (RR= 1.078; 95% CI: 0.908-1.279; p= 0.392). However, remdesivir had a significant effect on clinical improvement at day 14 compared to placebo/control (OR= 1.447; 95% CI: 1.005-2.085; p= 0.047) and reduced serious adverse events (RR= 0.736; 95% CI: 0.611-0.887; p= 0.001). Remdesivir has positive effects on clinical improvement, and reduction of the risk of serious adverse events. However, it does not influence the mortality at day 14 of treatment.

Economic evaluation of remdesivir for the treatment of severe COVID-19 patients in China under different scenarios.

AimsThe present study aimed to evaluate the cost‐effectiveness of the 5‐day remdesivir regimen compared with standard of care among severe COVID‐19 patients in China, the evidence on which is essential to inform the necessity of securing access to remdesivir.MethodsA dynamic transmission model that extended the susceptible–exposed–infected–recovered framework by incorporating asymptomatic, presymptomatic and waiting‐to‐be‐diagnosed patients was constructed to conduct the cost‐effectiveness analysis from the healthcare system perspective. To estimate epidemic parameters, the model was first calibrated to the observed epidemic curve in Wuhan from 23 January to 19 March 2020. Following the calibration, the infected compartment was replaced by 3 severity‐defined health states to reflect differential costs and quality of life associated with disease gravity. Costs and quality‐adjusted life year (QALY) outcomes of 9 million simulated people were accrued across time to evaluate the incremental cost‐effectiveness ratio of remdesivir. As robustness checks, an alternative modelling technique using decision tree, additional epidemic scenarios representing different epidemic intensities, and 1‐way parameter variations were also analysed.ResultsRemdesivir treatment cost CN¥97.93 million more than standard of care. Also, the net QALY gain from 5‐day remdesivir treatment was 6947 QALYs. As such, the incremental cost‐effectiveness ratio was CN¥14 098/QALY, substantially lower than the gross domestic product per capita threshold. The peak daily number of severe cases was 19% lower in the remdesivir treatment strategy. Overall, results were robust in alternative scenarios and sensitivity analyses.ConclusionGiven the cost‐effectiveness profile, access to remdesivir for severe COVID‐19 patients in China should be considered.

Liver and kidney function in patients with Covid-19 treated with remdesivir.

For the treatment of Covid‐19 patients with remdesivir, poor renal and liver function were both exclusion criteria in randomized clinical trials and contraindication for treatment. Also, nephrotoxicity and hepatotoxicity are reported as adverse events. We retrospectively reviewed renal and liver functions of Covid‐19 103 patients who received remdesivir in the 15 days after treatment initiation. Approximately 20% of the patient population met randomized clinical trial exclusion criteria. In total, 11% of the patients had a decrease in estimated glomerular filtration rate >10 mL/min/1.73m2. Also, 25 and 35% had increased alanine transaminase and aspartate transaminase levels, respectively. However, serious adverse events were limited. Therefore, based on these preliminary results, contraindications based on kidney and liver function should not be absolute for remdesivir treatment in patients with Covid‐19 if these functions are monitored regularly. A larger patient cohort is warranted to confirm our results.

Annals for Hospitalists - May 2021.

Annals for Hospitalists - May 2021.

Compassionate Use of Remdesivir in Children With Severe COVID-19.

Remdesivir shortens time to recovery in adults with severe coronavirus disease 2019 (COVID-19), but its efficacy and safety in children are unknown. We describe outcomes in children with severe COVID-19 treated with remdesivir. Seventy-seven hospitalized patients <18 years old with confirmed severe acute respiratory syndrome coronavirus 2 infection received remdesivir through a compassionate-use program between March 21 and April 22, 2020. The intended remdesivir treatment course was 10 days (200 mg on day 1 and 100 mg daily subsequently for children ≥40 kg and 5 mg/kg on day 1 and 2.5 mg/kg daily subsequently for children <40 kg, given intravenously). Clinical data through 28 days of follow-up were collected. Median age was 14 years (interquartile range 7-16, range <2 months to 17 years). Seventy-nine percent of patients had ≥1 comorbid condition. At baseline, 90% of children required supplemental oxygen and 51% required invasive ventilation. By day 28 of follow-up, 88% of patients had a decreased oxygen-support requirement, 83% recovered, and 73% were discharged. Among children requiring invasive ventilation at baseline, 90% were extubated, 80% recovered, and 67% were discharged. There were 4 deaths, of which 3 were attributed to COVID-19. Remdesivir was well tolerated, with a low incidence of serious adverse events (16%). Most adverse events were related to COVID-19 or comorbid conditions. Laboratory abnormalities, including elevations in transaminase levels, were common; 61% were grades 1 or 2. Among 77 children treated with remdesivir for severe COVID-19, most recovered and the rate of serious adverse events was low.

The Longest Persistence of Viable SARS-CoV-2 With Recurrence of Viremia and Relapsing Symptomatic COVID-19 in an Immunocompromised Patient-A Case Study.

BackgroundImmunocompromised patients show prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal swabs. We report a case of prolonged persistence of viable SARS-CoV-2 associated with clinical relapses of coronavirus disease 2019 (COVID-19) in a patient with mantle cell lymphoma who underwent treatment with rituximab, bendamustine, cytarabine with consequent lymphopenia and hypogammaglobulinemia.MethodsNasopharyngeal swabs and blood samples were tested for SARS-CoV-2 by real-time polymerase chain reaction (RT-PCR). On 5 positive nasopharyngeal swabs, we performed viral culture and next-generation sequencing. We analyzed the patient’s adaptive and innate immunity to characterize T- and NK-cell subsets.ResultsSARS-CoV-2 RT-PCR on nasopharyngeal swabs samples remained positive for 268 days. All 5 performed viral cultures were positive, and genomic analysis confirmed a persistent infection with the same strain. Viremia resulted positive in 3 out of 4 COVID-19 clinical relapses and cleared each time after remdesivir treatment. The T- and NK-cell dynamic was different in aviremic and viremic samples, and no SARS-CoV-2-specific antibodies were detected throughout the disease course.ConclusionsIn our patient, SARS-CoV-2 persisted with proven infectivity for >8 months. Viremia was associated with COVID-19 relapses, and remdesivir treatment was effective in viremia clearance and symptom remission, although it was unable to clear the virus from the upper respiratory airways. During the viremic phase, we observed a low frequency of terminal effector CD8+ T lymphocytes in peripheral blood; these are probably recruited in inflammatory tissue for viral eradication. In addition, we found a high level of NK-cell repertoire perturbation with relevant involvement during SARS-CoV-2 viremia.

Viral Load Kinetics of Severe Acute Respiratory Syndrome Coronavirus 2 in Hospitalized Individuals With Coronavirus Disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) kinetics remain understudied, including the impact of remdesivir. In hospitalized individuals, peak sputum viral load occurred in week 2 of symptoms, whereas viremia peaked within 1 week of symptom-onset, suggesting early systemic seeding of SARS-CoV-2. Remdesivir treatment was associated with faster viral decay.

Pharmacological treatment in pregnant women with moderate symptoms of coronavirus disease 2019 (COVID-19) pneumonia

Objective Pregnant women with moderate symptoms of COVID-19 are at risk for progressing to severe or critical illness. While there are limited data on the management of severe COVID-19 during pregnancy, information on pharmacological treatments of moderate COVID-19 is lacking. We report clinical outcomes of pregnant women hospitalized due to moderate COVID-19 illness treated with a 5-day course of remdesivir, antibiotics, and/or glucocorticoids. Materials and methods Case series of pregnant women hospitalized with moderate symptoms of COVID −19 pneumonia at two INOVA Health System hospitals from April 1 to December 31, 2020. Primary outcome was clinical recovery (breathing on ambient air and/or hospital discharge) on hospital day 7 (HD7). Cox regression analysis was performed to evaluate which variables were associated with the primary outcome. Results Out of 748 pregnant women with confirmed infection by reverse transcriptase polymerase chain reaction, 35 were hospitalized due to moderate symptoms of COVID-19 pneumonia (median gestational age 29 weeks). There was no maternal death. Seventeen patients received remdesivir within 48 hours of hospitalization: 15 remained with moderate symptoms and 2 (who also received glucocorticoids) had progressed to critical COVID-19 at remdesivir initiation; all 17 women in this group achieved clinical recovery on HD7. Seven women received remdesivir >48 hours following admission after they began treatment with glucocorticoids ± antibiotics and worsened to severe or critical disease; they all required supplemental oxygen on HD7. Eleven women were treated with antibiotics ± glucocorticoids but no remdesivir; on HD7, 3/11 achieved clinical recovery. Clinical recovery was significantly different among treatment groups; p < 0.001. When analyzing only women who remained with moderate symptoms at pharmacological treatments initiation, all 15 on remdesivir and only 3 of 11 on antibiotics achieved clinical recovery on HD7; p < 0.001. Delaying remdesivir for >48 hours after admission (HR 2.32, 95% CI 1.45–4.16) and >4-day duration of symptoms prior to hospitalization (HR 1.65, 95% CI 1.27–3.50) had an inverse association with clinical recovery. Incidental oligohydramnios was seen in 3/24 (12.5%) of women within 5 days of completing remdesivir treatment. Elevated transaminases was prevalent in women treated with remdesivir (8/24, 33.3%). Conclusion In our cohort, prompt initiation of remdesivir in pregnant women hospitalized with moderate symptoms of COVID-19 pneumonia within 48 hours of admission prevented worsening and allowed a fast clinical recovery by HD7. Deferring remdesivir for >48 hours after hospitalization and duration of symptoms >4 days before admission were independently associated with delayed clinical recovery and longer hospital admission. Ultrasound evaluation of the amniotic fluid in patients recovering from COVID-19 hospitalization should be considered.

Comparison of Time to Clinical Improvement With vs Without Remdesivir Treatment in Hospitalized Patients With COVID-19

Clinical effectiveness data on remdesivir are urgently needed, especially among diverse populations and in combination with other therapies. To examine whether remdesivir administered with or without corticosteroids for treatment of coronavirus disease 2019 (COVID-19) is associated with more rapid clinical improvement in a racially/ethnically diverse population. This retrospective comparative effectiveness research study was conducted from March 4 to August 29, 2020, in a 5-hospital health system in the Baltimore, Maryland, and Washington, DC, area. Of 2483 individuals with confirmed severe acute respiratory syndrome coronavirus 2 infection assessed by polymerase chain reaction, those who received remdesivir were matched to infected individuals who did not receive remdesivir using time-invariant covariates (age, sex, race/ethnicity, Charlson Comorbidity Index, body mass index, and do-not-resuscitate or do-not-intubate orders) and time-dependent covariates (ratio of peripheral blood oxygen saturation to fraction of inspired oxygen, blood pressure, pulse, temperature, respiratory rate, C-reactive protein level, complete white blood cell count, lymphocyte count, albumin level, alanine aminotransferase level, glomerular filtration rate, dimerized plasmin fragment D [D-dimer] level, and oxygen device). An individual in the remdesivir group with k days of treatment was matched to a control patient who stayed in the hospital at least k days (5 days maximum) beyond the matching day. Remdesivir treatment with or without corticosteroid administration. The primary outcome was rate of clinical improvement (hospital discharge or decrease of 2 points on the World Health Organization severity score), and the secondary outcome, mortality at 28 days. An additional outcome was clinical improvement and time to death associated with combined remdesivir and corticosteroid treatment. Of 2483 consecutive admissions, 342 individuals received remdesivir, 184 of whom also received corticosteroids and 158 of whom received remdesivir alone. For these 342 patients, the median age was 60 years (interquartile range, 46-69 years), 189 (55.3%) were men, and 276 (80.7%) self-identified as non-White race/ethnicity. Remdesivir recipients had a shorter time to clinical improvement than matched controls without remdesivir treatment (median, 5.0 days [interquartile range, 4.0-8.0 days] vs 7.0 days [interquartile range, 4.0-10.0 days]; adjusted hazard ratio, 1.47 [95% CI, 1.22-1.79]). Remdesivir recipients had a 28-day mortality rate of 7.7% (22 deaths) compared with 14.0% (40 deaths) among matched controls, but this difference was not statistically significant in the time-to-death analysis (adjusted hazard ratio, 0.70; 95% CI, 0.38-1.28). The addition of corticosteroids to remdesivir was not associated with a reduced hazard of death at 28 days (adjusted hazard ratio, 1.94; 95% CI, 0.67-5.57). In this comparative effectiveness research study of adults hospitalized with COVID-19, receipt of remdesivir was associated with faster clinical improvement in a cohort of predominantly non-White patients. Remdesivir plus corticosteroid administration did not reduce the time to death compared with remdesivir administered alone.

Clinical efficacy and safety of remdesivir in patients with COVID-19: a systematic review and network meta-analysis of randomized controlled trials.

ObjectivesWe performed a systematic review and network meta-analysis of randomized controlled trials (RCTs) to provide updated information regarding the clinical efficacy of remdesivir in treating coronavirus disease 2019 (COVID-19).MethodsPubMed, Embase, Cochrane Library, clinical trial registries of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched for relevant articles published up to 18 November 2020.ResultsFive RCTs, including 13 544 patients, were included in this meta-analysis. Among them, 3839 and 391 patients were assigned to the 10 day and 5 day remdesivir regimens, respectively. Patients receiving 5 day remdesivir therapy presented greater clinical improvement than those in the control group [OR = 1.68 (95% CI 1.18–2.40)], with no significant difference observed between the 10 day and placebo groups [OR = 1.23 (95% CI 0.90–1.68)]. Patients receiving remdesivir revealed a greater likelihood of discharge [10 day remdesivir versus control: OR = 1.32 (95% CI 1.09–1.60); 5 day remdesivir versus control: OR = 1.73 (95% CI 1.28–2.35)] and recovery [10 day remdesivir versus control: OR = 1.29 (95% CI 1.03–1.60); 5 day remdesivir versus control: OR = 1.80 (95% CI 1.31–2.48)] than those in the control group. In contrast, no mortality benefit was observed following remdesivir therapy. Furthermore, no significant association was observed between remdesivir treatment and an increased risk of adverse events.ConclusionsRemdesivir can help improve the clinical outcome of hospitalized patients with COVID-19 and a 5 day regimen, instead of a 10 day regimen, may be sufficient for treatment. Moreover, remdesivir appears as tolerable as other comparators or placebo.

Clinical Efficacy and Adverse Event of Remdesivir Treatment in Seven COVID-19 Cases with Respiratory Failure

A preliminary report from a global study showed that remdesivir, a nucleoside analog pro-drug that was originally developed as a therapeutic drug against Ebola virus, may exert clinical efficacy in cases of COVID-19, by shortening the time to recovery. We had the opportunity to use this new drug in the treatment of 7 COVID-19 patients with respiratory failure.

Evaluating Clinical Efficacy of Antiviral Therapy for COVID-19: A Surrogate Endpoint Approach.

IntroductionEfficient evaluation with an early surrogate endpoint, taking into account the process of disease evolution, may not only clarify inconsistent or underpowered results but also provide a new insight into the exploration of a new antiviral therapy for treating COVID-19 patients.MethodsWe assessed the dynamics of COVID-19 disease spectrum, commencing from low-risk (no or low oxygen supplement), medium-risk (non-invasive ventilator or high oxygen supplement), and high-risk (extracorporeal membrane oxygenation or invasive ventilator) risk state on enrollment, and then the subsequent progression and regression of risk states until discharge or death. The efficacy of antiviral therapy in altering the dynamics was assessed by using the high-risk state as a surrogate endpoint based on the data retrieved from the two-arm Adaptive Covid-19 Treatment Trial.ResultsUsing the high-risk state as a surrogate endpoint, remdesivir treatment led to a decrease in the high-risk COVID-19 state by 34.8% (95% CI 26.7–42.0%) for a 14-day period and 29.3% (95% CI 28.8–29.8%) up to 28 days, which were consistent with a statistically significant reduction of death by 30.5% (95% CI 6.6, 50.9%) up to a 28-day period. The estimates of numbers needed to be treated were 100.9 (95% CI 88.1, 115.7) for using the high-risk COVID-19 state as a surrogate endpoint for a 14-day period and 133.3 (95% CI 112.5, 158.0) were required for averting one death from COVID-19 up to 28 days.ConclusionsWe demonstrate the expedient use of the high-risk COVID-19 disease status as a surrogate endpoint for evaluating the primary outcome of the earliest death.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00431-9.

A real-life setting evaluation of the effect of remdesivir on viral load in COVID-19 patients admitted to a large tertiary centre in Israel

ObjectivesThe effectiveness of remdesivir, a Food and Drug Administration-approved drug for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been repeatedly questioned during the current coronavirus disease 2019 (COVID-19) pandemic. Most of the recently reported studies were randomized controlled multicentre clinical trials. Our goal was to test the efficiency of remdesivir in reducing nasopharyngeal viral load and hospitalization length in a real-life setting in patients admitted to a large tertiary centre in Israel. MethodsA total of 142 COVID-19 patients found to have at least three reported SARS-CoV-2 quantitative RT-PCR tests during hospitalization were selected for this study. Of these, 29 patients received remdesivir, while the remaining non-treated 113 patients served as controls. ResultsAmong the tested parameters, the control and remdesivir groups differed significantly only in the intubation rates. Remdesivir treatment did not significantly affect nasopharyngeal viral load, as determined by comparing the differences between the first and last cycle threshold values of the SARS-CoV-2 quantitative RT-PCR tests performed during hospitalization (cycle threshold 7.07 ± 6.85 vs. 7.08 ± 7.27, p 0.977 in the control and treated groups, respectively). Remdesivir treatment shortened hospitalization length by less than a day compared with non-treated controls and by 3.1 days when non-intubated patients from both groups were compared. These differences, however, were not statistically significant, possibly because of the small size of the remdesivir group. DiscussionRemdesivir was not associated with nasopharyngeal viral load changes, but our study had a significant disease severity baseline imbalance and was not powered to detect viral load or clinical differences.

Length of remdesivir treatment in patients with severe COVID-19.

In severe COVID-19, a 5-day remdesivir regimen seems as effective as a 10-day course of treatment and it may be safer. To date, the drug has no clearly proven efficacy over time. https://bit.ly/3tKOuvt

Clinical outcomes of using remdesivir in patients with moderate to severe COVID-19: A prospective randomised study.

Background and Aims:When the world was frantically searching for a drug effective against the coronavirus disease (COVID)-19, remdesivir, a broad-spectrum anti-viral medication, became a part of the COVID treatment. We planned a study to evaluate improvement in clinical outcomes with remdesivir treatment for five days.Methods:Participants more than 40-years old and with moderate to severe COVID-19 but not on mechanical ventilation were randomly assigned into two groups-remdesivir group (34 cases) to receive the study drug intravenous (IV) remdesivir for five days plus the standard care (SC) and non-remdesivir group (36 cases) to receive the SC but not to receive the study drug. Follow-up was continued for 12 days after the beginning of treatment or until discharge/death. Patient's clinical status was assessed by laboratory investigations and physical examination (from day 1 to day 12 on a 4-point ordinal scale and from day 12 to 24 on a 6-point ordinal scale). Oxygen support requirements and adverse events were recorded. The data were entered and analysed using Statistical Package for the Social Sciences (SPSS) version 22.0.Results:High-flow oxygen support and non-invasive ventilation was required at baseline by lesser patients in the remdesivir group. In the end, both groups had similar outcomes after adjustment for baseline clinical status. There was no statistical difference in mortality between the two groups (p = 0.749). Patients in both groups had an equal time to recovery. There was no difference in the occurrence of adverse effects of remdesivir between the two groups.Conclusion:Remdesivir therapy for five days did not produce improvement in clinical outcomes in moderate to severe COVID-19 cases.

The FDA and the COVID-19: A political economy perspective.

This article utilizes a political economy framework to examine how FDA regulations impacted the U.S. healthcare sector's ability to address COVID‐19. I specifically examine the developing COVID‐19 testing, the approval of the medication remdesivir, and COVID‐19 vaccines. By examining periods before and after the FDA issued Emergency Use Authorizations (EUAs), my analysis finds that the FDA's regulations enacted before the COVID‐19 pandemic began strongly restricted clinician and patient access to COVID‐19 testing, remdesivir treatment, and approving vaccines. After the FDA issued EUAs, the healthcare sector quickly adopted COVID‐19 testing and remdesivir with little evidence of negative consequences. These findings contribute to the economics literature examining the FDA and contemporary COVID‐19 policy research.

A shorter symptom onset to remdesivir treatment (SORT) interval is associated with a lower mortality in moderate-to-severe COVID-19: A real-world analysis

ObjectivesRemdesivir is the current recommended anti-viral treatment in moderate-to-severe COVID-19. However, data on impact of timing of therapy, efficacy, and safety are limited. We evaluated the impact of timing of remdesivir initiation (symptom onset to remdesivir treatment [SORT] interval) on in-hospital all-cause mortality in patients with moderate-to-severe COVID-19. MethodsThis retrospective study was conducted between June 25 and October 3, 2020, at a tertiary care dedicated COVID center in India. Patients with moderate-to-severe COVID-19 (moderate: SpO2 <94%; severe: SpO2 <90%) were included. The main outcome was impact of SORT interval on in-hospital all-cause mortality. Subgroups were formed and analyzed based on SORT interval. ResultsOf 350 patients treated with remdesivir, 346 were included in the final analysis. Overall, 76 (22.0%) patients died (moderate: 3 [2.8%], severe: 73 [30.8%]). All-cause mortality was significantly lower in patients with SORT interval ≤9 days (n = 260) vs SORT interval >9 days (n = 86; 18.1% vs 33.7%; p = 0.004). The odds of death were significantly lower in patients with SORT interval ≤9 days vs >9 days (odds ratio = 0.43; 95% CI, 0.25–0.75; p = 0.003). ConclusionRemdesivir initiation ≤9 days from symptom onset was associated with mortality benefit, defining a treatment window and reinforcing the need for appropriately-timed remdesivir in moderate-to-severe COVID-19.

Effectiveness of Antiviral and Immunomodulatory Agents in the Treatment of COVID-19: A Systematic Review

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) posed a severe threat to global health. Therefore, new findings on effective treatment for symptomatic patients with COVID-19 are considered among emergency issues. This systematic review investigated the effectiveness of pharmacologic interventions in the management of patients with COVID-19. All the articles published in three electronic databases, including Google Scholar, PubMed, and Web of Science, were searched from September 15 to September 30, 2020. Eventually, 24 papers published till September 30 remained to be included in this review. The effectiveness of immunomodulatory and antiviral agents in the treatment of patients with COVID-19 was assessed in this review. The obtained results of the current review rejected the potential of HCQ for the treatment of COVID; however, there was a clinical improvement in patients treated with ruxolitinib in comparison to that reported for the control group. Methylprednisolone, dexamethasone, and calcifediol were suggested as beneficial treatments for patients with COVID-19. The potential efficacy of these antiviral drugs against the SARS-CoV-2 virus is controversial; nevertheless, the triple combination of antiviral and immunomodulatory agents is effective in suppressing the shedding of SARS-CoV-2. There have been no supportive data on the superiority of favipiravir and LPV/r to standard care in the treatment of COVID-19. In addition, no difference was observed between favipiravir and arbidol for the treatment of these patients. There was an association between remdesivir treatment and a reduction of 5 days in clinical improvement among COVID-19 patients. It is required to carry out further RCTs with an in-depth research basis on COVID-19.

Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium.

The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of epithelial cell types are susceptible to infection, ciliated cells are the predominant cell target of SARS-CoV-2. The host protease TMPRSS2 was required for infection of these cells. Importantly, remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. Induction of interferon responses within infected cells was rare and there was significant heterogeneity in the antiviral gene signatures, varying with the burden of infection in each cell. We also found that heavily infected secretory cells expressed abundant IL-6, a potential mediator of COVID-19 pathogenesis.

Remdesivir in COVID-19 Patients with Impaired Renal Function.

In their perspective, Adamsick et al.1 argue that, on the basis of its known pharmacokinetics, a 5-day course of remdesivir in patients with an eGFR of <30 ml/min per 1.73 m2 should be considered safe. Therefore, in their opinion, patients with coronavirus disease 2019 (COVID-19) who have impaired renal function should be offered remdesivir treatment, because this is a potentially life-saving treatment for such a vulnerable population. We agree with the authors that accumulation of the carrier sulfobutylether-β-cyclodextrin is likely to be of no concern because there is clinical experience with other agents, such as voriconazole. However, with respect to remdesivir and its metabolite GS-441524, to our knowledge, there are no human data to claim its safety in people with impaired renal function because they were excluded from the clinical trials.2 It should be emphasized that, in repeat-dose toxicity studies in rats and monkeys, the kidney (i.e., tubular epithelium) was identified as the primary target organ of remdesivir toxicity.3 Furthermore, although remdesivir exhibits low renal excretion as an intact drug (<10% of the administered dose), 49% was recovered as GS-441524, and a total of 74% of a radiolabeled dose was recovered in urine.3,4 Not surprisingly, a recent pharmacokinetic study showed higher GS-441524 levels in a patient with renal dysfunction.5 Apparently, because GS-441524 will be removed by hemodialysis, toxicity of remdesivir or its metabolite will not be an issue in patients who are already on hemodialysis.6 In contrast, in patients with COVID-19 and CKD, it cannot be excluded that remdesivir treatment might lead to an urgent need for RRT, and that remdesivir in this patient population might even have a negative risk-benefit ratio. The recent signal on potential renal side effects of remdesivir also holds concern about its use in patients with CKD.7 Therefore, we would like to discourage remdesivir as routine treatment in patients with COVID-19 and CKD (eGFR of <30 ml/min per 1.73 m3). Its use should be reserved to the context of clinical trials to improve our knowledge on safety and efficacy. Disclosures All authors have nothing to disclose. Funding None.