Antivirals

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Antivirals

Last reviewed: January 20, 2022

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The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.

Overview

Antivirals are a class of drug that inhibit viral replication and are commonly used against influenza. According to NIH, antivirals’ role in COVID-19 treatment is to “inhibit viral entry via the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane serine protease 2 (TMPRSS2); viral membrane fusion and endocytosis; or the activity of the SARS-CoV-2 3-chymotrypsin-like protease (3CLpro) and the RNA-dependent RNA polymerase. Because viral replication may be particularly active early in the course of COVID-19, antiviral therapy may have the greatest impact before the illness progresses to the hyperinflammatory state that can characterize the later stages of disease, including critical illness.”

Remdesivir (administered intravenously) was the first antiviral to be FDA-approved for the treatment of COVID-19 in October 2020. In December 2021, FDA granted the first emergency use authorization for an oral antiviral protease inhibitor for COVID-19, ritonavir-boosted nirmatrelvir (brand name Paxlovid), which was followed closely by EUA approval for molnupiravir. Both have been studied in a variety of clinical trials.

The table below compares efficacy measures for antivirals among a variety of outpatient therapeutics for COVID-19.

Comparison of Outpatient Therapeutics for COVID-19: Prevention of Hospitalization or Death

 

BAM/

ETESIV

CAS/

IMDEV

SOTROVIMAB

NIRMATRELVIR/ RITONAVIR

MOLNUPIRAVIR

[REMDESIVIR] x 3 days (PINE-TREE Study)

Time from Symptom Onset (days)

3

10

5

5

5

7

~Cost for a course

$2400

$2100

$2100

$529

$700

$1872

Incidence (drug)

11/518 (2.1%)

18/1355 (1.3%)

6/529 (1.1%)

8/1039 (0.77%)

48/709 (6.77%)

 2/279 (0.7%)

 

Incidence (placebo)

36/517 (7%)

62/1341 (4.6%)

 

30/529 (5.7%)

 

66/1046 (6.3%)

 

68/699 (9.72%)

 

15/283 (5.3%)

 

Absolute RR (Risk difference)

4.9%

 

3.3%

 

4.6%

 

5.5%

(p<0.0001)

 

2.95%

(-5.9 to -0.1)

 

4.6%

 

Relative RR (RRR)

70%

 

71%

 

79% (50 to 91%)

 

88%

 

30.3%

 

87%

 

Hazard Ratio (95% CI)

0.30

P<0.001

 

0.29

p<0.0001

 

0.21 (0.09-0.50)

P=0.002

 

0.12

 

0.69 (0.48-1.01)

 

0.13 (0.03-0.59)

P=0.008

 

Number Needed to Treat (NNT)

20.4

 

30.3

 

21.7

 

18

 

33.8

 

21.7

 


Molnupiravir

Overview

Molnupiravir (brand name Lagevrio; formerly called EIDD-2801 and MK-4482) has been FDA-authorized for emergency use to treat mild-to-moderate COVID-19 since December 2021 (FDA Fact Sheet for Health Care Providers, December 2021). It is a readily bioavailable prodrug of a ribonucleoside analogue that interferes with multiple SARS-CoV-2 viral processes, including replication. It also acts potently against several other RNA viruses, including Ebola, influenza, MERS-CoV and Venezuelan equine encephalitis virus.

In human airway epithelial cells, molnupiravir has potent effect against SARS-CoV-2,  reducing viral production with an in vitro IC50 of 0.024 µM, without observed cytotoxicity (Sheahan, April 2020). In mice and ferret models of SARS-CoV-2, molnupiravir has shown efficacy in prevention and treatment of infection, laying a strong foundation and rationale for clinical studies (Cox, January 2021; Wahl, March 2021).

Quick-reference guide from IDSA for clinicians with guidance on eligibility, dosing, clinical decision-making, and supply and access information.

Clinical Studies

In a Phase 1 randomized controlled single and multiple ascending dose pharmacokinetic study, molnupiravir had rapid appearance in plasma of ß-d-N4-hydroxycytidine (NHC, also called EIDD-1931) with a time of peak concentrations 1 to 1.75 hours after the dose and plasma concentrations which exceeded those expected to be efficacious based on preclinical data (Holman, August 2021; Painter, March 2021).

Phase 2 studies to examine safety, tolerability and antiviral effect followed, in both outpatients with COVID-19 (Study MK-4482-006, also known as EIDD-2801-2003) and inpatients (the ongoing END-COVID study):

  • Study MK-4482-006 assessed safety, tolerability and antiviral effect of molnupiravir given within 7 days of symptom onset in nonhospitalized adults with confirmed COVID-19. A total of 202 participants were randomized to receive molnupiravir (200 mg, 400 mg or 800 mg twice daily for 5 days) versus placebo (N=23, 62, 55 and 62 in the respective groups). Endpoints included the time to undetectable levels of nasopharyngeal viral RNA (by RT-PCR) and time to elimination of replication-competent (i.e., infectious) virus from nasopharyngeal secretions. The drug was well tolerated; rates of any adverse event were 48% in the molnupiravir 200 mg recipients, 32.3% in the 400 mg recipients, 20% in the 800 mg recipients and 29% in placebo recipients, with similar very low rates of drug discontinuation across the groups. At day 3 after treatment initiation, there was lower recovery of virus from recipients of molnupiravir 800 mg (1.9%) versus placebo (16.7%) (p=0.02). This effect was also seen at day 5 (0% virus recovery in 400 mg or 800 mg recipients; 11.1% in placebo recipients; p=0.03). The time it took to clear viral RNA was also shorter in participants who got 800 mg of molnupiravir as compared to placebo (p=0.01). The END-COVID study in hospitalized patients with COVID-19 is still enrolling participants, with results anticipated soon (Fischer, June 2021 – preprint, not peer-reviewed).

Several Phase 3 trials of molnupiravir have been initiated for COVID-19:

  • MOVe-AHEAD, an ongoing Phase 3 trial of molnupiravir for prevention of COVID-19, MOVe-OUT (also called MK-4482-002), a Phase 2/3 randomized, placebo-controlled trial of efficacy, safety and PK of molnupiravir among outpatients with PCR-confirmed COVID-19.
  • MOVe-IN, a phase 2/3 randomized, placebo-controlled study of safety, efficacy and PK of molnupiravir among hospitalized patients with COVID-19. Notably, there was a slight imbalance in mortality between the study groups in the MOVe-IN study: the number of deaths in groups assigned molnupiravir 200mg, 400mg, and 800mg were 4 (5.5%), 8  (11%), and 3 (4.2%), as compared to 2 (2.7%) in the placebo group.  An interim analysis of the MOVe-IN study data concluded that there was no meaningful benefit of molnupiravir in hospitalized patients, and at that time, the study was stopped.

In October 2021, Merck and Ridgeback announced submission of an FDA EUA application for oral molnupiravir based on preliminary MOVe-OUT trial data. In November 2021, the companies announced by press release further analyses from the entire cohort of 1,433 enrolled participants indicating that the rate of hospitalization or death was 68/699 (9.7%) in the placebo group and dropped to 6.8% (48/709) in the molnupiravir group. The absolute risk reduction was 3.0% (95% CI: 0.1, 5.9; nominal p-value=0.0218) and the relative risk was 0.70 (95% CI: 0.49, 0.99), so the relative risk reduction was revised from 50% to 30%. Overall, there were 9/699 (1.2%) deaths in the placebo group and 1/709 (0.14%) in the group given molnupiravir (FDA Briefing Document, November 2021). In November 2021, the FDA Advisory Committee voted narrowly (with 13 in favor and 10 opposed) that the benefits of the drug outweigh its risks when used for the treatment of mild to moderate COVID-19 in non-pregnant, non-hospitalized people within five days of the onset of symptoms

Efforts are underway to supply molnupiravir (once approved for emergency use) to governments of high-income countries as well as low- and middle-income countries. The manufacturer (in North America, Merck & Co., Inc. holds the rights to the trademark "Merck," but globally the company trades under the name MSD) has committed to nonexclusive voluntary licensing agreements with eight generic manufacturers, with a goal of distributing molnupiravir to 100 low- and middle-income countries. Notably, the same week that the MOVe-OUT trial results were announced, two Indian generic manufacturers (Aurobindo Pharma Ltd. and MSN Laboratories) announced that they would end trials of a generic version of molnupiravir in patients with moderate COVID-19 (defined as COVID-positive with oxygen saturation of >90%), due to a lack of efficacy. The MOVe-OUT trial, however, had specified that patients with oxygen saturation lower than 93% should be excluded, so there were probably slightly sicker participants in the Indian trials, and it is not known at this time whether some were hospitalized. At this time, the two generic manufacturers are continuing Phase 3 trials of generic molnupiravir in patients with mild disease.

Safety

Clinical Safety

There is accumulating human safety data for molnupiravir, though as yet no long-term safety data, which may be more relevant for genetic or reproductive toxicities. In Phase 1 single-dose and multiple ascending dose studies, more participants in the placebo arm experienced adverse events than in the molnupiravir arm (43.8% versus 35.4%, respectively, for the single-dose study, and 50% versus 42.9%, respectively, for the multiple-dose study) (Painter, May 2021). These AEs were mostly mild; the only grade 2 AEs in the molnupiravir group were headache and oropharyngeal pain. The only AE deemed potentially treatment related by the investigator was a pruritic rash, which resolved after discontinuation of the study drug. No concerning trends in clinical laboratory abnormalities were observed. In the Phase 2 and 3 studies, the participants who received molnupiravir had similar rates of AEs to placebo recipients (Fischer, June 2021 – preprint, not peer-reviewed).

Mutagenesis

Theoretical safety concerns have arisen from the drug’s mechanism. The prodrug molnupiravir is quickly converted into NHC. NHC in turn gets converted by intracellular kinases/phosphatases into the triphosphorylated active drug, NHC-TP (or EIDD-2061). NHC-TP is recognized by the RNA-dependent RNA polymerase of the coronavirus, which confuses it with cytidine, in a manner that is not detected and corrected by the proofreading exonuclease enzyme of coronavirus (an advantage in preventing the acquisition of drug resistance). NHC-monophosphate gets incorporated into the coronavirus genome and causes lethal mutagenesis (an accumulation of detrimental mutations resulting in viral error catastrophe) in the nascent strand of viral RNA, interfering further with viral functioning.

As the presumed mechanism of action of molnupiravir is to induce lethal mutagenesis in the nascent SARS-CoV-2 viral strand, questions have previously arisen about the potential for an NHC metabolite to be incorporated into human DNA and induce mutagenesis in human cells (Stuyver, January 2003). The basis for this concern is that a common ribonucleoside diphosphate form of NHC can be transformed into ribonucleoside triphosphates (causing damage to viral RNA) or be recognized by the host ribonucleotide reductase enzyme and transformed into 2′-deoxyribonucleoside triphosphates (which are potentially incorporated into and cause damage to host cell DNA in actively dividing cells). One study examined this potential using a hypoxanthine phosphoribosyltransferase gene mutation assay in cells derived from hamster ovaries and exposed the cells to high doses of molnupiravir for 32 days. The study found that 3 µM concentrations of NHC were associated with mutagenesis in cell culture (Zhou, August 2021). It is worth noting that the maximum course being studied in clinical trials is 5 days of twice daily molnupiravir, and that the positive control, 1 minute of UV light, caused a higher mutation rate than any of the drug concentrations.

As in vitro Ames testing for NHC did show positive results with mutagenicity for two of six bacterial strains, likely on the basis of the incorporation of the molecule into bacterial DNA, the manufacturer of molnupiravir has followed that with extensive in vivo preclinical toxicology studies to assess whether molnupiravir has toxicities in small mammals. This testing included the Big Blue assay, which uses transgenic rodents carrying a mutation (lacI) that allows for detection of small mutations and deletions in tissues, to test whether high doses of molnupiravir induced mutagenesis within the animals. It also included the PIG-a assay, which uses flow cytometry to detect mutations in a reporter gene to see whether a drug causes mutations in vivo. The totality of the mutational toxicology assays performed for molnupiravir were reportedly reassuring that the drug was found to be neither mutagenic nor genotoxic in mammals (Painter, October 2021).

FDA’s Antimicrobial Drugs Advisory Committee held a hearing on molnupiravir on Nov. 30, 2021, to make further regulatory decisions regarding the drug. Other approved antivirals such as ribavirin and favipiravir have similar (less potently) mutagenic mechanisms (Crotty, June 2001), and favipiravir has restrictions placed on its use by Japan’s regulatory body for that reason (Nagata, February 2015).

 

Nirmatrelvir/Ritonavir (Paxlovid)

Overview

Nirmatrelvir/ritonavir (brand name Paxlovid) has been FDA-authorized for emergency use to treat mild-to-moderate COVID-19 since December 2021 (FDA Fact Sheet for Health Care Providers, December 2021). The novel protease inhibitor combination is administered as two separate tablets of 150 mg each of nirmatrelvir, formerly known as PF-07321332, and one individual tablet of 100 mg of ritonavir has been developed to block the 3C-like protease of SARS-COV-2, which cleaves the large polyproteins produced from viral RNA into essential functional proteins. Notably, this protease is fairly conserved across coronaviruses and across described variants of SARS-COV-2 (He, August 2020). 

Clinical Trials

The drug has been studied in Phase 2/3 trials, including in unvaccinated high-risk participants in the EPIC-HR trial, which used a primary endpoint of 28-day all-cause mortality or COVID-related hospitalization. According to a Pfizer press release describing final results, nirmatrelvir/ritonavir significantly reduced the risk of hospitalization or death by 88% (p<0.0001) when administered to nonhospitalized, high-risk adults with COVID-19 within 5 days of symptom onset and by 89% when administered within 3 days of symptom onset. The study included 2,246 individuals with confirmed COVID-19 and was stopped early by the Data and Safety Monitoring Board in consultation with FDA due to overwhelming efficacy results. In the study drug group, 5/697 (0.7%) were hospitalized; in the placebo group 44/682 (6.5%) were hospitalized, 9 of whom (1.3%) died. Rates of treatment-related adverse events were similar between the two arms; there were fewer serious treatment-related adverse effects in the treatment arm (1.6%) than in the placebo arm (6.6%).

Another study, the EPIC-SR study, evaluated Paxlovid in unvaccinated nonhospitalized adults with COVID-19 and low risk of progression to severe disease, as well as vaccinated adults with at least one risk factor for progression to severe disease. It showed in an interim analysis a marked (70%) reduction in hospitalizations in the study drug group: 2/333 (0.6%) in the group treated with nirmatrelvir/ritonavir compared with 8/329 (2.4%) in the group treated with placebo. This study did not meet the primary endpoint of 4 consecutive symptom-free days.  In both the high-risk study and the standard risk study, the study drug was found to reduce SARS-CoV-2 viral load about a log more at day 5 than did placebo.

Dosing & Safety

The inclusion in Paxlovid of ritonavir, a protease inhibitor used to boost levels of companion drugs via its inhibition of cytochrome P450 metabolizing enzymes, may in some cases have important implications for other therapeutics used to treat COVID-19. Below is a table of expected effect (in most cases theoretical, as PK DDI studies are not yet available).

Therapeutic

Expected Effect of Ritonavir

Dexamethasone

Increased serum concentrations of dexamethasone1

Methylprednisolone

Increased serum concentrations of methylprednisolone 1

Remdesivir

No effect expected2

Anti-SARS-COV2 Monoclonal Antibodies

No effect expected

Convalescent Plasma

No effect expected

Molnupiravir

No effect expected

Tocilizumab

No effect expected

Baricitinib

No significant effect expected

Favipiravir

No effect expected

1Combination has been associated with elevated steroid levels and development of Cushing’s syndrome as early as 14 days from the start of coadministration. Given the low doses of dexamethasone used in COVID-19 treatment, this increase in steroid levels may not be clinically significant (University of Liverpool COVID-19 Drug Interactions).
2 Note that less than 10% of baricitinib's metabolism is via CYP enzymes (Yang, May 2020).

It is important to note that this drug is dispensed as a blister pack containing two 150 mg tablets of nirmatrelvir; this contains more tablets than are needed for patients with mild renal impairment (see chart below). Another important consideration is that in individuals with undiagnosed or uncontrolled HIV, administration of this drug could lead to resistance of the HIV to protease inhibitors. Screening for HIV should be considered in all hospitalized patients with COVID-19 and as part of routine care.

The dosing for nirmatrelvir/ritonavir is as follows:

EGFR (CKD-EPI formula)

Dose of nirmatrelvir/ritonavir

> 60 mL/min

300 mg nirmatrelvir + 100 mg ritonavir, twice daily for 5 days

30-<60 mL/min

150 mg nirmatrelvir + 100 mg ritonavir, twice daily for 5 days

<30 mL/min

Not recommended: appropriate dosing has not been determined

Guidelines

IDSA Guidelines on Nirmatrelvir/Ritonavir

In ambulatory patients with mild-to-moderate COVID-19 at high risk for progression to severe disease, IDSA guidelines suggest nirmatrelvir/ritonavir initiated within 5 days of symptom onset rather than no nirmatrelvir/ritonavir (conditional recommendation, low certainty of evidence).

 


Remdesivir

Overview

Remdesivir is an intravenous nucleotide prodrug of an adenosine analog that was initially developed during the 2013 Ebola epidemic (Weston, March 2020Brown, September 2019). When converted to its active form (largely by plasma carboxylesterases; its further metabolism is largely mediated by hydrolases), remdesivir interferes with RNA polymerase and is thought to lead to premature termination of RNA transcription (Yang, September 2020). It is also able to evade viral exonuclease proofreading, which is an advantage, as the ability of the coronavirus to detect and remove any incompatible nucleotides during its replication and transcription can block the efficacy of drugs that work by altering coronavirus nucleotide sequence.  

Early in the pandemic, remdesivir was found to have antiviral effects against SARS-CoV-2 in both in vitro studies and in vivo studies with rhesus macaques (Wang, February 2020Williamson, June 2020). In May 2020, FDA approved an Emergency Use Authorization for remdesivir in adults and children hospitalized with severe COVID-19. FDA approval for use in hospitalized adults and children over age 12 followed in October 2020. FDA approval for the use of remdesivir in hospitalized and high-risk, non-hospitalized children under 12 years and over 28 days of age, weighing less than 40 kg and down to 3 kg, followed in April of 2022. 

Hospitalized patients

Several large, randomized trials have been published on the use of remdesivir in hospitalized patients with COVID-19. The largest so far, the ACTT-1 and SOLIDARITY trials, have found varying results: 

  • ACTT-1 showed a reduction in time to clinical improvement and, in subgroup analysis, a mortality benefit in patients requiring supplemental oxygen but not ventilation.
  • Conversely, SOLIDARITY showed no mortality benefit with the use of remdesivir.
  • Notably, the trials had different primary endpoints, and thus varied in design and what they were powered to examine.
  • ACTT-1’s primary endpoint was time to clinical improvement — it was not powered for mortality.
  • SOLIDARITY was powered for mortality but was not designed to examine subgroups by time to clinical improvement or based on clinical status other than ventilated versus non-ventilated.
  • A quarter of patients in ACTT-1 were ventilated upon enrollment, as opposed to 8% in SOLIDARITY. Approximately a quarter of patients in ACTT-1 received concomitant glucocorticoids, while nearly half did in SOLIDARITY. Time from symptom onset to randomization was examined in ACTT-1, but similar data was not available for SOLIDARITY. The majority of patients in ACTT-1 lived in North America, while the majority in SOLIDARITY lived in Asia, Africa or Latin America.

Further clinical outcomes data on remdesivir are being collected in the large platform trial RECOVERY, and data is forthcoming. Inserm’s Phase 3 DisCoVeRy trial (conducted at 48 sites in Europe as an add-on to the WHO Solidarity trial) was stopped in January 2021 after a Data and Safety Monitoring Board review evaluated participants on remdesivir (200 mg IV on day 1 followed by 100 mg IV thereafter for 9 more days) and on standard of care and found no evidence of efficacy in clinical outcomes or viral clearance at 15 or 29 days after initiation of remdesivir. However, looking at the subset of patients who were not on mechanical ventilation or ECMO at study entry, remdesivir did significantly delay progression to mechanical ventilation or death, which is in line with the findings of the ACTT-1 trial. There were important differences between the study populations in ACTT-1 and DisCoVeRy, that might partially explain the discrepant findings. Fewer ACTT-1 participants were on oxygen at baseline than DisCoVeRy participants (87% vs. 99%) and fewer received steroids (23% vs. 40%, respectively).  

More recently, there have been efforts to capture large-scale observational data on remdesivir outcomes. An observational analysis of a large real-world database (N= 28,855 remdesivir patients and 16,687 propensity-matched non-remdesivir patients) compared mortality between hospitalized COVID-19 patients who did and did not get remdesivir (Mozaffari, October 2021). During the study period (between August and November 2020), patients on remdesivir had a significantly lower risk of death at day 14 than patients not on remdesivir (for both those on low-flow and high-flow oxygen at baseline, aHR 0.76 [0.68-0.83]). A mortality difference was also seen on day 28 (aHR 0.89 [0.82-0.96]). These findings accord with the ACTT-1 trial and trends seen in the Solidarity trial.

Another retrospective observational study conducted at five hospitals in the Baltimore and Washington DC area (N=358 remdesivir; 1,957 controls) looked at whether remdesivir with or without corticosteroids hastened clinical improvement among hospitalized patients with confirmed COVID-19 (Garibaldi, March 2021).  This study used propensity-score matching to pair each remdesivir recipient with a patient who did not receive remdesivir, on the basis of age, severity of illness, sex and other clinical parameters, and examined a primary outcome of rate of clinical improvement (hospital discharge or decrease of two points on a clinical severity scale). The study found that remdesivir recipients had a faster time to clinical improvement than controls (median [IQR] of 5 days [4-8] vs. 7 days [4-10], respectively). The mortality rate was 7.7% and 14% in the remdesivir and control groups, respectively (aHR non-significant at 0.70; 95% CI, 0.38-1.28). Furthermore, the study did not find an additive benefit in time to clinical improvement when corticosteroids were added to remdesivir. This study was followed by another, larger retrospective study by the same authors of 96,859 individuals hospitalized with COVID-19 (42,474 of whom received remdesivir), which showed a significantly greater likelihood of clinical improvement at 28 days among remdesivir recipients, particularly among those participants on no oxygen or low-flow oxygen (aHR 1.30 [95% CI 1.22-1.38] and aHR 1.23 [95% CI 1.19-1.27], respectively). The same study also found that remdesivir recipients on low-flow oxygen were significantly less likely to die than those who did not receive remdesivir (aHR 0.85 [95% CI 0.77-0.92]).  In terms of antiviral effect, an independent add-on randomized controlled study (N=185) to the WHO Solidarity trial, NOR-Solidarity, found that remdesivir did not affect viral clearance of SARS-CoV-2 among hospitalized people with COVID-19 (Barratt-Due, September 2021). A meta-analysis of four randomized trials of remdesivir (7,333 total patients across studies) found uncertain impact of remdesivir on death or progression to mechanical ventilation, with an odds ratio for mortality with remdesivir of 0.9 (95% CI, 0.7-1.12) and for mechanical ventilation of 0.9 (95% CI, 0.76-1.03) as compared to placebo or usual care (Siemieniuk, July 2020). Subgroup analyses on patients with lesser degrees of illness were absent, which may have occluded a benefit in a certain subgroup (i.e., the subgroup shown to benefit in the ACTT-1 trial, those requiring low-flow supplemental oxygen).

Non-hospitalized patients

A single Phase 3 randomized placebo-controlled trial called the PINE-TREE study examined the impact of 3 days of remdesivir (a 200 mg IV load followed by 100 mg IV infusions on the two subsequent days) on the endpoint of COVID-related hospitalization or death among high-risk outpatients. The study, which had to stop enrollment early due to enrollment feasibility concerns relating to scarce patients, found that 2/279 (0.7%) remdesivir recipients met the primary endpoint, as compared to 15/283 (5.3%) placebo recipients, for a significant 87% relative risk reduction (HR 0.13 [0.03-0.59]; p=0.008) and number needed to treat of 21 to prevent one hospitalization or death. 

Guidelines

There is a lack of consensus among society and organizational guidelines on whether remdesivir should be used in the management of COVID-19, given the varying results in existing clinical trial data. 

Hospitalized Patients

In hospitalized patients with severe COVID-19, IDSA guidelines suggest remdesivir over no antiviral treatment (conditional recommendation, moderate certainty of evidence). Severe illness is defined as patients with SpO2 ≤94% on room air.

In patients with COVID-19 on invasive ventilation and/or ECMO, the IDSA panel recommends against the routine initiation of remdesivir (conditional recommendation, very low certainty of evidence).

In patients on supplemental oxygen but not on mechanical ventilation or ECMO, the IDSA panel suggests treatment with five days of remdesivir rather than 10 days of remdesivir (conditional recommendation, low certainty of evidence).

In patients with COVID-19 admitted to the hospital without the need for supplemental oxygen and oxygen saturation >94% on room air, the IDSA panel suggests against the routine use of remdesivir (conditional recommendation, very low certainty of evidence).

Ambulatory Patients

Among ambulatory patients with mild-to-moderate COVID-19 at high risk for progression to severe disease, IDSA guidelines suggest remdesivir initiated within 7 days of symptom onset rather than no remdesivir (conditional recommendation, low certainty of evidence).

NIH guidelines recommend use of remdesivir in hospitalized COVID-19 patients requiring supplemental oxygen through nasal cannula. 

  • For patients who require oxygen through a high-flow device or noninvasive ventilation, remdesivir plus dexamethasone may be used. 

WHO guidelines conditionally recommend against remdesivir outside of clinical trials for COVID-19, regardless of disease severity. 

Key Literature

In summary: Overall, there is conflicting data, but it appears based on randomized trials that remdesivir does not provide an overall mortality benefit to the aggregated group of patients hospitalized with COVID-19, but that it does reduce time to clinical improvement when given early in the course of illness and/or to patients with mild hypoxia but less severe disease. While observational trials are more vulnerable to confounding, there is some suggestion from large-scale comparative efficacy studies of observational cohorts that remdesivir may confer a modest mortality benefit.  

Repurposed antiviral drugs for COVID-19 — Interim WHO SOLIDARITY trial results (WHO Solidarity Trial Consortium, October 2020).

Overall, in this large multinational open-label non-placebo controlled randomized trial, remdesivir was not associated with reduced mortality compared to standard of care.  

Study population: 

  • 11,266 hospitalized adult patients with COVID-19, representing 405 hospitals and 30 countries.
  • Patients were equally randomized between whichever study drugs were locally available and standard of care (open-label, local standard-of-care vs. remdesivir or hydroxychloroquine or interferon beta-1a or lopinavir/ritonavir).
  • 2,750 patients were randomized to receive 10 days of remdesivir.
  • Of those allocated remdesivir, 98.5% began treatment. The intent-to-treat (ITT) analysis included 2,743 remdesivir vs. 2,708 control.
  • 35% of patients were younger than 50 years of age, 45% were 50-69 years of age, and 19% were 70 years of age or older. 62% were male.
  • 25% of patients had diabetes and 21% had heart disease.
  • 63% of patients were on oxygen at entry, and 8% were ventilated upon study enrollment.
  • 62% of patients were randomized between days 0-1 of hospitalization.

Primary endpoint: 

  • In-hospital mortality of remdesivir vs. control.
  • Secondary endpoints included ventilation and time to discharge.

Key findings: 

  • Overall mortality was 11.8%.
  • There was no difference in mortality between patients receiving standard of care and remdesivir (RR=0.95 [0.81-1.11, p=0.50; 301/2743 vs. 303/2708]).
  • There was no difference in initiation of ventilation or time to discharge between patients receiving standard of care and remdesivir.
  • The proportion of individuals still hospitalized at day 7 for remdesivir versus control was 69% versus 59%.
  • The use of other agents in the remdesivir group and controls were: corticosteroids (47.8% vs. 47.6%, respectively); convalescent plasma (1.9% vs. 2.1%, respectively); anti-IL-6 therapy (4.9% vs. 5.3%, respectively); non-trial interferon (0.1% vs. 0.9%, respectively); and non-trial antiviral (2.4% vs. 5.6%, respectively).

Limitations: 

  • Open-label design.
  • Time from symptom onset to randomization was not included. If there was a delay between symptom onset and presenting for care, the benefit of remdesivir (an antiviral) may have been lost.
  • Time to recovery in the remdesivir group may have been artificially extended due to a planned 10-day course.
  • Subgroup analyses were not done other than in patients who were already ventilated upon study entry.
  • The patient's provider could choose to deviate from protocol and stop/change therapy; further details have not been shared.
  • There were variable numbers of patients in the remdesivir and interferon arms, despite the trial being randomized. This could reflect different drugs being available at different sites, but the difference is not explained.
  • An intention to treat analysis was done for the primary endpoint, despite patients not necessarily receiving the drug they were initially randomized to. An analysis was not performed based on the drugs patients were actually randomized to.

Remdesivir for the Treatment of Covid-19 — Final Report (Beigel, November 2020). 

Overall, in this randomized-placebo controlled trial, remdesivir shortened time to recovery by 5 days and was safe. Patients who were randomized after 10 days of symptoms did not experience this effect. In subgroup analysis, remdesivir was associated with lower mortality in patients requiring supplemental oxygen but not ventilation.

Study population:   

  • 1,062 hospitalized adult patients (79.8% located in North America) with COVID-19.
  • 541 patients were randomized to remdesivir and 52 to placebo. 
  • Median 6 days from symptom onset to starting remdesivir.  
  • The mean age of patients was 58.9 years; 64.4% were male.
  • 3% of patients were white.
  • 2% had hypertension, 44.8% had obesity and 30.3% had diabetes.
  • 15% of patients had mild-moderate disease, and 85% had severe disease.
  • The median number of days between symptom onset and randomization was 9 (IQR 6-12).

Primary endpoint:   

  • Time to clinical recovery (defined as discharge from the hospital or hospitalization for infection control purposes only) during 28 days postenrollment, as measured by an eight-point ordinal scale.
  • Secondary outcomes included clinical status at day 15 using the ordinal scale.

Key findings:  

  • Patients who received remdesivir had a median recovery time of 10 days, as compared with 15 days among those who received placebo (RR for recovery, 1.29; p<0.001).
  • Kaplan–Meier estimates of mortality by day 15 were 6.7% in the remdesivir group and 11.9% in the placebo group (hazard ratio, 0.55; 95% CI, 0.36 to 0.83).
  • There was no difference in 28-day mortality between patients who received remdesivir (6.7%) or placebo by day 15 (11.4%; HR 0.73; 95% CI, 0.52 to 1.03).
  • On subgroup analysis of patients at ordinal scale 5 (requiring supplemental oxygen but not ventilation), mortality in the remdesivir arm was 4%, versus 12.7% in the placebo arm (HR 0.30, 95% 0.14-0.64).
  • The rate ratio for recovery was largest among patients with a baseline ordinal score of 5 (RR for recovery, 1.45; 95% CI, 1.18 to 1.79).
  • Patients who underwent randomization during the first 10 days after symptom onset had a rate ratio for recovery of 1.37 (95% CI, 1.14 to 1.64), whereas patients who underwent randomization more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.20 (95% CI, 0.94 to 1.52).
  • Adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and 163 of the 516 patients who received placebo (31.6%).
  • 6% of patients received hydroxychloroquine and 23% received a glucocorticoid.

Limitations:   

  • The original primary endpoint was ordinal endpoint after 14 days, but this was changed to a time-to-recovery endpoint based on researchers’ realization that the clinical course of COVID-19 could be longer than initially thought. 
  • The trial was not powered for mortality.
  • The clinical relevance of the ordinal scale is not clear.
  • Patients generally received remdesivir around 9 days after symptom onset; this may have been too late to see a mortality benefit.

Effect of Remdesivir vs. Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial (Spinner, August 2020)

Overall, in this open-label randomized controlled trial, 5 days of remdesivir was associated with a higher odds of a better clinical status distribution than those receiving standard care. The clinical significance of this finding is unclear.

Study population:

  • 584 patients at 105 hospitals in the United States, Europe and Asia, hospitalized with moderate COVID-19 (defined as pulmonary infiltrates and room-air oxygen saturation >94%).
  • Patients were randomized to either a 5-day course of remdesivir, a 10-day course or standard of care.
  • The median age was 57 (IQR 46-66) and 227 (39%) of the patients were women.
  • 56% had cardiovascular disease, 42% had hypertension and 40% had diabetes.
  • Patients were enrolled if they had a positive SARS-CoV-2 PCR within 4 days of randomization.

Primary endpoint:

  • Day 11 clinical status based on a 7-point ordinal scale; category 1 was death, category 7 was discharged.

Key findings:

  • 533 (91%) of the participants completed the trial, including 76% of the 5-day remdesivir group and 38% of the 10-day group.
  • Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group.
  • On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; p = .02).
  • The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (p = .18 by Wilcoxon rank sum test).
  • There was no difference in 28-day all-cause mortality.

Limitations:

  • Open-label design, which could have led to selection bias.
  • No virologic data was collected.
  • An important number of patients did not complete their assigned treatment duration, primarily due to hospital discharge; this occurred more frequently in the 10-day group and could have affected the results.
  • The median duration of symptoms prior to randomization over a week in all groups. This could have affected the study results.
  • The initial endpoint was proportion of patients discharged by day 14; this was changed the day study enrollment began.
  • Other therapies used for SARS-CoV-2 as part of local standard of care were initially allowed.
  • The 10-day group actually received a median of 6 days of remdesivir; the effect of 5 days of treatment compared to 10 days of treatment is not adequately answered in this study.
  • All participants had moderate disease with low risk of mortality or clinical progression. It is unclear whether differences in outcomes would be observed by duration of remdesivir treatment with a population that was more ill.

SIMPLE-Severe Trial: Gilead-sponsored multinational, open-label trial of remdesivir in patients with severe COVID-19 (Goldman, May 2020).   

Overall, in hospitalized patients with COVID-19 who are not on mechanical ventilation or extracorporeal mechanical oxygenation, 5 days of remdesivir shows similar clinical benefit to 10 days.

Study population:  

  • Patients in this study had either SpO2 ≤94% on room air or were receiving supplemental oxygen.
  • 397 patients received remdesivir for 5 days; 197 received remdesivir for 10 days.

Primary endpoint

  • Clinical status at day 14.

Key findings:

  • After adjusting for imbalances in the baseline clinical status, the day 14 distribution in clinical status on the ordinal scale was similar in the 5-day and 10-day groups (p=0.14).

Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial (Wang, May 2020).  

Overall, in this under-powered study, remdesivir did not show a benefit in time to clinical improvement, 28-day mortality or rate of viral clearance in patients with severe COVID-19 compared to placebo.

Study population:

  • 237 patients received IV remdesivir for 10 days; concomitant use of lopinavir/ritonavir, corticosteroids and interferons was permitted.
  • The median time from symptom onset to starting remdesivir was 10 days.

 

Primary endpoint

  • Time to clinical improvement, defined as improvement on an ordinal scale or discharged alive from the hospital, whichever came first.

 

Key findings:

  • There was no difference in the time to clinical improvement between the groups (median 21 days vs. 23 days).
  • For those who started remdesivir within 10 days of symptom onset, a faster time to clinical improvement was seen in the remdesivir arm (median 18 days vs. 23 days); this was not statistically significant.
  • There was no mortality benefit at 28 days.

 

Limitations:

  • Due to underenrollment, the trial was stopped early and was likely underpowered.   

 

Safety

Although a full understanding of remdesivir’s safety profile remains incomplete, notable considerations include:   

Hepatotoxicity 

  • Remdesivir should not be used in combination with other hepatotoxic drugs, and clinicians should monitor hepatic function throughout treatment (FDA EUA, July 2020).  

Nephrotoxicity 

  • Clinicians should monitor kidney function of all patients on remdesivir, particularly those with pre-existing renal impairments and those receiving other nephrotoxins.  
  • Avoid use for patients with eGFR <30 ML/min or full-term neonates with SCr >1 mg/dL (FDA EUA, July 2020).

Bradycardia 

  • There have been reports of bradycardia in patients receiving remdesivir, and an analysis of the WHO safety reports found an increased likelihood of bradycardia among remdesivir recipients, compared to other agents, with a reporting OR of 1.65 (95% CI, 1.23-2.22) (Touafchia, February 2021; Barkas, February 2021; Gubitosa, November 2020).

 


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