Remdesivir (Veklury)

Number: 0982

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

1. Criteria for Initial Approval

   1. Treatment of COVID-19 in non-hospitalized, high-risk members

      Aetna considers remdesivir (Veklury) medically necessary for treatment of COVID-19 in non-hospitalized, high-risk members when all of the following criteria are met:
      

      1. Member has a confirmed active infection with COVID-19; and
      2. Member is 28 days of age and older and weighs at least 3 kg; and
      3. Member has eGFR greater than or equal to 30 mL/min; and
      4. Member will have at least one ongoing symptom consistent with COVID-19 within 7 days before treatment (e.g., fever, cough, fatigue, shortness of breath, sore throat, headache, myalgia/arthralgia); and
      5. Member is non-hospitalized and is at risk for progression to severe COVID-19 (e.g., chronic lung disease, diabetes mellitus, obesity (BMI greater than 30), heart condition), including hospitalization or death; and
      6. Renal function, hepatic function, and prothrombin time have been taken prior to starting remdesivir and will be monitored while receiving therapy as clinically appropriate; and
      7. Member will not receive a total duration of therapy greater than 3 days for an individual infection; and
      8. Remdesivir will not be administered in combination with chloroquine or hydroxychloroquine; and
      9. Remdesivir will be administered in a setting where severe hypersensitivity reactions, such as anaphylaxis, can be managed.

   Note: The criteria outlined in this policy is only applicable to coverage in the outpatient setting. Hospitalized members receiving Veklury for the treatment of COVID-19 will be managed according to the member’s inpatient benefit.

   Aetna considers all other indications for remdesivir (Veklury) experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   See Dosage and Administration and Background sections for additional information. 

Note: See MCG Guidelines, Viral Illness, Acute (M-280), for clinical indications for hospitalization. See also, "The COVID-19 Treatment Guidelines Panel's Statement on Therapies for High-Risk, Nonhospitalized Patients With Mild to Moderate COVID-19" (NIH, 2021).

Dosage and Administration

Below includes dosing recommendations as per the FDA-approved prescribing information.

Veklury is available in two different formulations:

• Veklury for injection (supplied as 100 mg of remdesivir as lyophilized powder in vial) which must be reconstituted with Sterile Water for Injection prior to diluting in a 100 mL or 250 mL 0.9% sodium chloride infusion bag. Note: This is the only approved dosage form of Veklury for pediatrics weighing 3 kg to less than 40 kg; and
• Veklury injection (supplied as 100 mg/20 mL [5 mg/mL] remdesivir solution in vial) which must be diluted in a 250 mL 0.9% sodium chloride infusion bag.

Veklury may only be administered in settings in which healthcare providers have immediate access to medications to treat a severe infusion or hypersensitivity reaction, such as anaphylaxis, and the ability to activate the emergency medical system (EMS), as necessary.

COVID-19 (SARS-CoV-2)

• Testing:

  In all individuals, before starting Veklury and during treatment as clinically appropriate, perform renal and hepatic laboratory testing. Assess prothrombin time before starting Veklury and monitor as clinically appropriate.

• Recommended dosage:

  • Adults and pediatric persons weighing at least 40 kg is a single loading dose of Veklury 200 mg on Day 1 via intravenous infusion followed by once-daily maintenance doses of Veklury 100 mg from Day 2 via intravenous infusion. 
  • Pediatric persons 28 days of age and older and weighing 3 kg to less than 40 kg is a single loading dose of Veklury 5 mg/kg on Day 1 via intravenous infusion followed by once-daily maintenance doses of Veklury 2.5 mg/kg from Day 2 via intravenous infusion.

• Hospitalized Persons:

  • The treatment course of Veklury should be initiated as soon as possible after diagnosis of symptomatic COVID-19 has been made.
  • The recommended total treatment duration for hospitalized persons requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO) is 10 days;
  • The recommended treatment duration for hospitalized persons not requiring invasive mechanical ventilation and/or ECMO is 5 days. If an individual does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days for a total treatment duration of up to 10 days.
    
    

• Non-Hospitalized Persons:

  • The treatment course of Veklury should be initiated as soon as possible after diagnosis of symptomatic COVID-19 has been made and within 7 days of symptom onset.
  • The recommended total treatment duration for non-hospitalized persons diagnosed with mild-tomoderate COVID-19 who are at high risk for progression to severe COVID-19, including hospitalization or death, is 3 days.
    
    
• Administer Veklury via intravenous (IV) infusion over 30 to 120 minutes.
• Renal impairment: Veklury is not recommended in persons with eGFR less than 30 mL/min.

Dose preparation and administration: Refer to the full prescribing information for further details for both formulations.

Source: Gilead Sciences, 2022a

Experimental and Investigational

Aetna considers the combined use of remdesivir and human monoclonal antibodies as experimental and investigational for the treatment of COVID-19.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
HCPCS codes covered if selection criteria are met:
J0248	Injection, remdesivir, 1 mg
Other HCPCS codes related to the CPB:
J0390	Injection, chloroquine hydrochloride, up to 250 mg
ICD-10 codes covered if selection criteria are met:
J12.82	Pneumonia due to coronavirus disease 2019
U07.1	COVID-19

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Treatment of coronavirus disease 2019 (COVID-19) in adults and pediatric patients (28 days of age and older and weighing at least 3 kg) with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, who are:

  • Hospitalized, or
  • Not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death.

Remdesivir is available as Veklury (Gilead Sciences, Inc), a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor. Remdesivir is an antiviral drug with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The prescribed label for Veklury carries the following warnings and precautions:

• Hypersensitivity including infusion-related and anaphylactic reactions: Hypersensitivity reactions have been observed during and following administration of Veklury. Slower infusion rates, with a maximum infusion time of up to 120 minutes, can be considered to potentially prevent signs and symptoms of hypersensitivity. If signs and symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue administration of VEKLURY and initiate appropriate treatment. 
• Increased risk of transaminase elevations: Transaminase elevations have been observed in healthy volunteers and have also been reported in patients with COVID-19 who received Veklury. Perform hepatic laboratory testing in all patients before starting Veklury and while receiving Veklury as clinically appropriate. Consider discontinuing Veklury if ALT levels increase to greater than 10 times the upper limit of normal. Discontinue Veklury if ALT elevation is accompanied by signs or symptoms of liver inflammation.
• Risk of reduced antiviral activity when coadministered with chloroquine phosphate or hydroxychloroquine sulfate: Coadministration of Veklury and chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on cell culture data demonstrating an antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of Veklury. 

The most common adverse reactions (incidence greater than or equal to 5%, all grades) observed with treatment with Veklury are nausea, ALT increased, and AST increased.

COVID-19 (SARS-CoV-2)

For Persons Requiring Hospitalization

On May 1, 2020, after review of unpublished data from available clinical trials, the US Food and Drug Administration (FDA) issued an emergency use authorization (EUA) to permit the use of remdesivir, a nucleotide analog that inhibits viral RNA-dependent RNA polymerase (RDRP), for treatment of adults and children hospitalized with severe coronavirus disease 2019 (COVID-19). EUA was granted after an interim analysis of 606 recoveries in the randomized, placebo-controlled National Institute of Allergy and Infectious Diseases Adaptive Covid-19 Treatment Trial (n=1063 participants from 47 United States sites and 21 international sites). Remdesivir reduced the median time to recovery (11 versus 15 days; hazard ratio, 1.31; 95% confidence interval, 1.12 to 1.54; P<0.001) compared with placebo, and overall mortality among patients treated with remdesivir was 8.0% compared with 11.6% among those treated with placebo (P=0.59). However, patients with severe acute kidney injury and end-stage kidney disease were excluded from this and all other remdesivir trials on the basis of eGFR cutoffs (either 50 or 30 ml/min per 1.73 m²). As a result, the EUA fact sheet for health care providers states that “The pharmacokinetics of remdesivir have not been evaluated in patients with renal impairment. Adult and pediatric patients (>28 days old) must have creatinine clearance determined and full-term neonates (≥7 days to ≤28 days old) must have serum creatinine determined before dosing. Remdesivir is not recommended in adults and pediatric patients (>28 days old) with eGFR less than 30 mL per minute or in full-term neonates (≥7 days and ≤28 days old) with serum creatinine ≥1 mg/dL, unless the potential benefit outweighs the potential risk. (emphasis added)” (Adamsick 2020).  

On October 22, 2020, the FDA approved Gilead’s antiviral drug Veklury (remdesivir) injection for adults and pediatric patients (12 years of age and older and weighing at least 40 kg) for the treatment of coronavirus disease 2019 (COVID-19) requiring hospitalization. Veklury is a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor and is the first and only FDA-approved drug in the United States for treating the coronavirus. Veklury was initially given Emergency Use Authorization (EUA) on May 1, 2020. Veklury should only be administered in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care.  Although the FDA approval is limited to patients 12 years and older, the FDA has also issued an emergency use authorization (EUA) to ensure access to treatment for hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg or pediatric patients with suspected or laboratory confirmed COVID-19 who weigh 3.5 kg to less than 40 kg. Clinical trials assessing the safety and efficacy of Veklury in this pediatric patient population are ongoing.

The FDA approval is based on results from three randomized, controlled clinical trials that included patients hospitalized with mild, moderate, and severe COVID-19. The first trial, NIAID ACTT-1, was a randomized, double-blind, placebo-controlled clinical trial in hospitalized adults with mild, moderate, or severe SARS-CoV-2 infection and had evidence of lower respiratory tract infection (Beigel 2020; NCT04280705). A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Patients were randomly assigned to receive either intravenous remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. At baseline, mean age was 59 years (with 36% of subjects aged 65 or older); 64% of subjects were male, 53% were White, 21% were Black, and 13% were Asian; 24% were Hispanic or Latino; 105 subjects had mild/moderate disease (10% in both treatment groups); 957 subjects had severe disease (90% in both treatment groups). A total of 285 subjects (27%) (n=131 received remdesivir) were on invasive mechanical ventilation or ECMO. The most common comorbidities were hypertension (51%), obesity (45%), and type 2 diabetes mellitus (31%); the distribution of comorbidities was similar between the two treatment groups. 

The primary clinical endpoint was time to recovery within 29 days after randomization. Recovery was defined as discharged from the hospital without limitations on activities, discharged from the hospital with limitations on activities and/or requiring home oxygen, or hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care. A key secondary endpoint was clinical status on Day 15 assessed on an 8-point ordinal scale consisting of the following categories:

1. not hospitalized, no limitations on activities;
2. not hospitalized, limitation on activities and/or requiring home oxygen;
3. hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care;
4. hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise);
5. hospitalized, requiring supplemental oxygen;
6. hospitalized, on noninvasive ventilation or high-flow oxygen devices; 
7. hospitalized, on invasive mechanical ventilation or ECMO; and
8. death.

The median time to recovery was 10 days in the remdesivir group compared to 15 days in the placebo group (recovery rate ratio 1.29 [95% CI 1.12 to 1.49], p<0.001). Among subjects with mild/moderate disease at enrollment (n=105), the median time to recovery was 5 days in both the remdesivir and placebo groups (recovery rate ratio 1.22 [95% CI 0.82 to 1.81]). Among subjects with severe disease at enrollment (n=957), the median time to recovery was 11 days in the remdesivir group compared to 18 days in the placebo group (recovery rate ratio 1.31 [95% CI 1.12 to 1.52]). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%). The authors concluded that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Beigel 2020). 

A second study, Study GS-US-540-5773, was a randomized, open-label multi-center clinical trial in adult subjects with confirmed severe SARS-CoV-2 infection, an oxygen saturation (SpO2) of  less than or equal to 94% on room air, and radiological evidence of pneumonia (Goldman 2020; NCT04292899). In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). Treatment with remdesivir was stopped in subjects who were discharged from the hospital prior to completion of their protocol-defined duration of treatment. Subjects on mechanical ventilation at screening were excluded. All subjects received 200 mg of remdesivir on Day 1 and 100 mg once daily on subsequent days via intravenous infusion, plus standard of care. At baseline, the median age of subjects was 61 years (range, 20 to 98 years); 64% were male, 75% were White, 12% were Black, and 12% were Asian; 22% were Hispanic or Latino. More subjects in the 10-day group than the 5-day group required invasive mechanical ventilation or ECMO (5% vs 2%), or high-flow oxygen support (30% vs 25%), at baseline. Median duration of symptoms and hospitalization prior to first dose of remdesivir were similar across treatment groups. The primary endpoint was clinical status on Day 14 assessed on a 7-point ordinal scale consisting of the following categories:

1. death;
2. hospitalized, receiving invasive mechanical ventilation or ECMO;
3. hospitalized, receiving noninvasive ventilation or high-flow oxygen devices;
4. hospitalized, requiring low-flow supplemental oxygen;
5. hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or not related to COVID-19);
6. hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that specified in the protocol for remdesivir administration); and
7. not hospitalized.

Overall, after adjusting for between-group differences at baseline, subjects receiving a 5-day course of remdesivir had similar clinical status at Day 14 as those receiving a 10-day course (odds ratio for improvement 0.75 [95% CI 0.51 to 1.12]). There were no statistically significant differences in recovery rates or mortality rates in the 5-day and 10-day groups once adjusted for between-group differences at baseline. All-cause mortality at Day 28 was 12% vs 14% in the 5- and 10-day treatment groups, respectively. The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).  

The third study, Study GS-US-540-5774, was a randomized, open-label multi-center clinical of hospitalized adult subjects with a confirmed moderate SARS-CoV-2 infection, SpO2 greater than 94% and radiological evidence of pneumonia (Spinner 2020; NCT04292730). This study compared treatment with remdesivir for 5 days (n=191) and treatment with remdesivir for 10 days (n=193) with standard of care (n=200). Treatment with remdesivir was stopped in subjects who were discharged from the hospital prior to completion of their protocol-defined duration of treatment. Subjects treated with remdesivir received 200 mg on Day 1 and 100 mg once daily on subsequent days via intravenous infusion. At baseline, the median age of subjects was 57 years (range, 12 to 95 years); 61% were male, 61% were White, 19% were Black, and 19% were Asian; 18% were Hispanic or Latino. Baseline clinical status, oxygen support status, and median duration of symptoms and hospitalization prior to first dose of remdesivir were similar across treatment groups.  

The primary endpoint was clinical status on Day 11 assessed on a 7-point ordinal scale consisting of the following categories: 

1. death;
2. hospitalized, receiving invasive mechanical ventilation or ECMO;
3. hospitalized, receiving noninvasive ventilation or high-flow oxygen devices;
4. hospitalized, requiring low-flow supplemental oxygen;
5. hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or not related to COVID-19);
6. hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that specified in the protocol for remdesivir administration); and
7. not hospitalized. 

Overall, the odds of improvement in the ordinal scale were higher in the 5-day remdesivir group at Day 11 when compared to those receiving only standard of care (odds ratio 1.65 [95% CI 1.09 to 2.48], p=0.017). The odds of improvement in clinical status with the 10-day treatment group when compared to those receiving only standard of care were not statistically significant (odds ratio 1.31 [95% CI 0.88 to 1.95]). All-cause mortality at Day 28 was ≤2% in all treatment groups.

Rochwerg and colleagues (2020) noted that remdesivir has received worldwide attention as a potentially effective treatment for severe COVID-19.  After rapid market approval in the United States, remdesivir is already being used in clinical practice.  The guideline panel made a weak recommendation for the use of remdesivir in severe COVID-19 while recommending continuation of active enrollment of patients into ongoing randomized controlled trials (RCTs) examining remdesivir.  An international panel of patients, clinicians, and methodologists produced these recommendations in adherence with standards for trustworthy guidelines using the GRADE approach.  The recommendations were based on a linked systematic review and network meta-analysis.  The panel considered an individual patient perspective and allowed contextual factors (such as resources) to be taken into account for countries and healthcare systems. The linked systematic review (published July 31, 2020) identified 2 randomized trials with 1300 subjects, showing low certainty evidence that remdesivir may be effective in reducing time to clinical improvement and may decrease mortality in patients with severe COVID-19.  Remdesivir probably has no important effect on need for invasive mechanical ventilation; it may have little or no effect on hospital length of stay (LOS).  The authors concluded that most patients with severe COVID-19 would likely choose treatment with remdesivir given the potential reduction in time to clinical improvement; however, given the low certainty evidence for critical outcomes and the fact that different perspectives, values, and preferences may alter decisions regarding remdesivir, the panel issued a weak recommendation with strong support for continued recruitment in randomized trials. 

Piscoya and associates (2020) stated that the safety and effectiveness of treatments for hospitalized COVID-19 are uncertain. These researchers examined the safety and effectiveness of remdesivir for the treatment of COVID-19.  Studies evaluating remdesivir in adults with hospitalized COVID-19 were searched in several engines until August 21, 2020.  Primary outcomes included all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAEs).  Inverse variance random effects meta-analyses were carried out.  These investigators included 4 RCTs (n = 2,296) [2 versus placebo (n = 1,299) and 2 comparing 5-day versus 10-day regimens (n = 997)], and 2 case-series studies (n = 88).  Studies used intravenous remdesivir 200-mg the 1st day and 100-mg for 4 or 9 more days.  One RCT (n = 236) was stopped early due to AEs; the other 3 RCTs reported outcomes between 11 and 15 days.  Time to recovery was decreased by 4 days with remdesivir versus placebo in 1 RCT (n = 1,063), and by 0.8 days with 5-days versus 10-days of therapy in another RCT (n = 397).  Clinical improvement was better for 5-days regimen versus standard of care in 1 RCT (n = 600).  Remdesivir did not decrease all-cause mortality (relative risk [RR] 0.71, 95 % confidence interval [CI] 0.39 to 1.28, I2 = 43 %) and need for invasive ventilation (RR 0.57, 95 % CI: 0.23 to 1.42, I2 = 60 %) versus placebo at 14 days but had fewer SAEs; 5-day decreased need for invasive ventilation and SAEs versus 10-day in 1 RCT (n = 397).  No differences in all-cause mortality or SAEs were observed among 5-day, 10-day and standard of care.  There were some concerns of bias to high risk of bias in RCTs.  Heterogeneity between studies could be due to different severities of disease, days of therapy before outcome determination, and how ordinal data were analyzed.  The authors concluded that there is paucity of adequately powered and fully reported RCTs examining effects of remdesivir in hospitalized COVID-19 patients.  These researchers stated that until stronger evidence emerges, they could not conclude that remdesivir is effective for the treatment of patients with COVID-19. 

In a systematic review for the American College of Physicians (ACP)’s practice points, Wilt and co-workers (2020) examined the effectiveness and harms of remdesivir for the treatment of patients with COVID-19.  Several databases, tables of contents of journals, as well as FDA and company websites were searched from January 1 through August 31, 2020.  English-language, randomized trials of remdesivir treatments for adults with suspected or confirmed COVID-19 were selected for analysis; and new evidence will be incorporated using living review methods.  Data extraction entailed single-reviewer abstraction and risk-of-bias assessment verified by a 2nd reviewer; GRADE (Grading of Recommendations Assessment, Development and Evaluation) methods used for certainty-of-evidence assessments.  A total of 4 randomized trials were included.  In adults with severe COVID-19, remdesivir compared with placebo probably improved recovery by a large amount (absolute risk difference [ARD] range, 7 % to 10 %) and may result in a small reduction in mortality (ARD range, -4 % to 1 %) and a shorter time to recovery or clinical improvement.  Remdesivir may have little to no effect on hospital LOS.  Remdesivir probably reduced SAEs by a moderate amount (ARD range, -6 % to -8 %).  Compared with a 10-day remdesivir course, a 5-day course may reduce mortality, increase recovery or clinical improvement by small-to-moderate amounts, reduce time to recovery, and reduce SAEs among hospitalized patients not requiring MV.  Recovery due to remdesivir may not vary by age, sex, symptom duration, or disease severity.  The authors concluded that in hospitalized adults with COVID-19, remdesivir probably improved recovery and reduced SAEs and may reduce mortality and time to clinical improvement.  For adults not receiving MV or ECMO, a 5-day course of remdesivir may provide similar benefits to and fewer harms than a 10-day course.  These researchers stated that the drawbacks of this study were low-certainty evidence with few published trials, including 1 preliminary report and 2 open-label trials.  Furthermore, trials excluded pregnant women and adults with severe kidney or liver disease. 

These investigators stated that current research has drawbacks.  Few studies exist, some information is based on preliminary findings of published results, and 2 of the 4 studies were open-label.  Most studies used time to recovery or improvement as their primary outcome; however, in comparative clinical studies of COVID-19, patients may die before recovery or improvement occurs, which can bias treatment effect estimates.  This, combined with other issues relevant to short-term studies in critical care, has led to recommendations for how such studies should quantify and interpret treatment effects.  Disease severity definitions varied slightly across studies and did not fully align with those provided by the NIH, WHO, or FDA.  Changing definitions of disease severity may alter the benefit-risk profile of remdesivir from that currently reported.  The ACTT-1 study enrolled hospitalized patients with mild-to-moderate disease but did not provide a definition or outcomes separately for those with mild versus moderate disease; therefore, making interpretation of these findings difficult.  Pregnant women and patients with severe renal and hepatic dysfunction were excluded from trials; thus, results may not apply to these individuals, including the finding of lack of serious harms.  The FDA advised caution in the use of remdesivir among pregnant women and recommended against use in patients with an eGFR of less than 30 ml/min/1.73 m2, unless the potential benefits outweigh the potential risks.  Additional harms reported to the FDA from clinical studies of remdesivir, which were not identified in the current studies, included infusion-related allergic reactions and elevated liver transferase levels.  The FDA recommended that clinicians evaluate hepatic and renal functions at baseline and during treatment.  Remdesivir should be withdrawn if alanine aminotransferase levels increase to 5 or more times the upper limit (UL) of normal or if any alanine aminotransferase elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin levels, alkaline phosphatase levels, or international normalized ratio.  The FDA has also recommended against the co-administration of chloroquine or hydroxychloroquine because of the potential for reduced anti-viral activity of remdesivir. 

Vegivinti and associates (2021) carried out a systematic review and meta-analysis of RCTs that evaluated remdesivir for the treatment of patients with COVID-19.  These researchers carried out a systematic literature search using PubMed, Embase, and ClinicalTrials.gov to identify studies published up to October 25, 2020 that examined COVID-19 treatment with remdesivir.  A total of 3 RCTs (n = 1,691 patients) were included in the meta-analysis.  The odds for mechanical ventilation (MV) or extracorporeal membrane oxygenation (ECMO) following treatment was significantly lower in the remdesivir-treated group compared to the control group (odds ratio [OR] = 0.48 [95 % CI: 0.34 to 0.69], p < 0.001).  The odds of early (at day 14/15; OR = 1.42 [95 % CI: 1.16 to 1.74], p < 0.001) and late (at day 28/29; OR = 1.44 [95 % CI: 1.16 to 1.79], p = 0.001) hospital discharge were significantly higher in the remdesivir-treated group compared to the control group.  There was no difference in the odds for mortality in patients treated with remdesivir (OR = 0.77 [95 % CI: 0.56 to 1.06], p = 0.108).  The authors concluded that remdesivir attenuated disease progression, resulting in lower odds of MV/ECMO, and greater odds of hospital discharge for COVID-19 patients; however, remdesivir did not affect odds of mortality. 

Rezagholizadeh and colleagues (2021) noted that the COVID-19 pandemic has become a global health crisis.  Considering the recent FDA approval of remdesivir as the first officially approved agent for COVID-19 treatment, these researchers carried out a systematic review and meta-analysis to examine the safety and effectiveness of remdesivir in COVID-19 patients.  They performed a systematic literature search via Medline, Google Scholar, Web of Science, Scopus, Science Direct, Cochrane Library, medRxiv, and bioRxiv from their inception to December 22, 2020.  A total of 5 RCTs and 5 non-randomized studies of intervention (NRSI) were entered into the meta-analysis.  The results showed that remdesivir use was associated with a significant improvement in the 28-day recovery (RR = 1.09, 95 % CI: 1.04 to 1.15), low flow oxygen support through days 1 to 14 (RR = 2.88, 95 % CI: 1.80 to 4.60), and invasive MV or ECMO requirement through days 14 to 28 of the follow-up time (RR = 5.34, 95 % CI: 2.37 to 12.05).  The risk of experiencing serious adverse drug reactions (ADRs) was significantly lower (RR = 0.75, 95 % CI: 0.63 to 0.90) in the remdesivir-treated group than the comparison/control group.  The pooled median difference of the time to clinical improvement was 2.99 days (95 % CI: 2.71 to 3.28), which did not remain significant during the sensitivity analysis.  The clinical output comparison of the 5-day and 10-day remdesivir courses revealed that the 5-day regimen might provide similar benefits while causing fewer serious ADRs than 10-day.  The authors concluded that the current meta-analysis provided an updated evaluation of scientific evidence on the use of remdesivir in COVID-19 patients.  These researchers stated that performing adequate well-designed RCTs are needed to demonstrate more accurate results.

For Non-Hospitalized, High-Risk Persons

On December 30, 2021, the National Institutes of Health (NIH) released "The COVID-19 Treatment Guidelines Panel's Statement on Therapies for High-Risk, Nonhospitalized Patients with Mild to moderate COVID-19" which includes use of remdesivir as a treatment option for non-hospitalized patients with COVID-19 who are at high risk of progressing to severe disease. Treatment options had included bamlanivimab plus etesevimab, casirivimab plus imdevimab, and sotrovimab; however, "the B.1.1.529 (Omicron) variant of concern (VOC) has become the dominant variant in many parts of the United States. This variant, which has numerous mutations in the spike protein, is predicted to have markedly reduced susceptibility to bamlanivimab plus etesevimab and casirivimab plus imdevimab. Because sotrovimab is the only available anti-SARS-CoV-2 mAb that is anticipated to have activity against the Omicron VOC, the Panel recently added a 3-day course of intravenous (IV) remdesivir as another treatment option for this group of patients". The Panel's recommendations are based on results of clinical trials and laboratory assessments of the activity of the anti-SARS-CoV-2 mAb products that are available through Emergency Use Authorizations (EUAs) for COVID-19 treatment. 

The Panel's recommendation for remdesivir include the following: "remdesivir 200 mg IV on Day 1, followed by remdesivir 100 mg IV daily on Days 2 and 3, initiated as soon as possible and within 7 days of symptom onset in those aged ≥12 years and weighing ≥40 kg. Because remdesivir requires IV infusion for 3 consecutive days, there may be logistical constraints to administering remdesivir in many settings. Remdesivir is currently approved by the FDA for use in hospitalized individuals, and outpatient treatment would be an off-label indication. Remdesivir should be administered in a setting where severe hypersensitivity reactions, such as anaphylaxis, can be managed. Patients should be monitored during the infusion and observed for at least 1 hour after infusion".

Remdesivir is not the Panel's first treatment choice. "The Panel favors the use of ritonavir-boosted nirmatrelvir (Paxlovid) in most high-risk, nonhospitalized patients with mild to moderate COVID-19. If ritonavir-boosted nirmatrelvir (Paxlovid) is not available or cannot be used because of drug interactions, then the Panel recommends using sotrovimab. If sotrovimab is not available, then the Panel recommends using remdesivir. Molnupiravir should only be administered when the other 3 options are either not available or cannot be used. There are currently no clinical trial data that compare the clinical efficacy of these 4 therapies, and there are no data on the use of combinations of antiviral agents and/or anti-SARS-CoV-2 mAbs for the treatment of COVID-19" (NIH, 2021).

Remdesivir has been studied in non-hospitalized patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease. The PINETREE trial showed that 3 consecutive days of IV remdesivir resulted in an 87% relative reduction in the risk of hospitalization or death compared to placebo (NIH, 2021). The PINETREE trial  (ClinicalTrials.gov NCT04501952) was a randomized, double-blind, placebo-controlled trial involving non-hospitalized patients with lab-confirmed COVID-19 who had symptom onset within the previous 7 days. Eligible patients were required to be 12 years of age or older and had at least one preexisting risk factor for progression to severe COVID-19 or were 60 years of age or older, regardless of whether they had other risk factors. Risk factors included hypertension, cardiovascular or cerebrovascular disease, diabetes mellitus, obesity (a body-mass index (BMI) of ≥30), immune compromise, chronic mild or moderate kidney disease, chronic liver disease, chronic lung disease, current cancer, or sickle cell disease. Patients (n=562) were randomly assigned to receive intravenous remdesivir (n=279; 200 mg on day 1 and 100 mg on days 2 and 3) or placebo (n=283). The primary efficacy end point was a composite of COVID-19–related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a COVID-19–related medically attended visit or death from any cause by day 28. Results from the trial found that COVID-19–related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (p=0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a COVID-19–related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. The conclusion of this study found that among non-hospitalized patients who were at high risk for COVID-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. This trial excluded patients who had received SARS-CoV-2 vaccines; thus, it is difficult to generalize these data to the vaccinated population. This trial was also conducted before the emergence of the B.1.617.2 (delta) variant of SARS-CoV-2 as the dominant circulating strain. Finally, the trial was stopped for administrative reasons, and less than half of the planned enrollment was achieved (Gottlieb et al, 2022).

"Remdesivir is expected to be active against the Omicron VOC, although in vitro and in vivo data are currently limited. Because remdesivir requires IV infusion for 3 consecutive days, there may be logistical constraints to administering remdesivir in many settings, but it is an option if ritonavir-boosted nirmatrelvir (Paxlovid) and sotrovimab are not available" (NIH, 2021).

FDA-approval of Veklury (remdesivir) had been limited to hospitalized patients for the treatment of COVID-19. However, on January 21, 2022, the FDA expanded the approval to include use in adults and pediatric patients (12 years of age and older who weigh at least 40 kilograms, which is about 88 pounds) with positive results of direct SARS-CoV-2 viral testing, and who are not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization or death. In addition, the FDA revised the Emergency Use Authorization (EUA) for Veklury to authorize the drug for treatment of pediatric patients weighing 3.5 kilograms (kg) to less than 40 kg or pediatric patients less than 12 years of age weighing at least 3.5 kg, with positive results of direct SARS-CoV-2 viral testing, and who are not hospitalized and have mild-to-moderate COVID-19, and are at high risk for progression to severe COVID-19, including hospitalization of death. These high-risk non-hospitalized patients may receive Veklury via intravenous infusion for a total of three days for the treatment of mild-to-moderate COVID-19 disease. FDA approval was based on outcomes from the PINETREE trial (ClinicalTrials.gov NCT04501952). Per the FDA, "Pediatric patients for whom Veklury is authorized will receive doses adjusted for their body weight in order to achieve comparable exposures to adults and pediatric patients receiving the approved dose. Given the similar course of COVID-19 disease, the authorization of Veklury in certain pediatric patients is based on extrapolation of efficacy from adequate and well-controlled studies in adults".

Combined Use of Remdesivir and Human Monoclonal Antibodies

Martinez and colleagues (2021) stated that improving the standard of clinical care for COVID-19 is a global health priority.  Small molecule antivirals like remdesivir (RDV) and biologics such as human monoclonal antibodies (mAb) have demonstrated therapeutic efficacy against SARS-CoV-2, the causative agent of COVID-19.  However, the efficacy of single agent therapies has not been comprehensively defined over the time course of infection and it is unclear if combination RDV/mAb will improve outcomes over single agent therapies.  In kinetic studies in a mouse-adapted SARS-CoV-2 pathogenesis model, these researchers demonstrated that single-agent therapies exerted potent antiviral effects even when initiated relatively late after infection; however, heir efficacy was diminished as a function of time.  RDV and a cocktail of 2 mAbs in combination provided improved outcomes compared to single agents alone extending the therapeutic window of intervention with less weight loss, decreased virus lung titers, reduced acute lung injury, and improved pulmonary function.  The authors demonstrate that direct-acting antivirals combined with potent mAb could improve outcomes over single agents alone in animal models of COVID-19; thereby providing a rationale for the coupling of therapies with disparate modalities to extend the therapeutic window of treatment. 

The authors stated that although this study showed that the combination of RDV and mAbs led to more rapid recovery from disease in mice, a clear downside was that both RDV and mAbs are generally given as IV treatments, which is not a practical method for broad human distribution.  Potential strategies to allow the wider dissemination of treatment may include subcutaneous (SC) or intramuscular (IM) administration of mAbs, which may aid in the more rapid distribution of antiviral treatments in an outpatient setting that can protect against SARS-CoV-2 acquisition.  Given the improved efficacy of RDV/mAb combination therapy, it will also be critical to develop next-generation antivirals that can be administered orally, which could be more easily combined with mAbs in an outpatient setting, potentially to complement other oral direct-acting antivirals.  As coronaviruses have consistently emerged in the past 20 years, and genetically distinct and pathogenic coronaviruses are likely to continue to emerge, refining combination therapies, such as oral antivirals and combinations of mAbs, will better prepare clinicians to combat future coronavirus outbreaks.  These findings provided the rationale that the combination of broadly neutralizing mAbs against Sarbecoviruses in combination with broad-acting antivirals may be a useful strategy to mitigate future outbreaks with emerging coronaviruses.  The findings of this study showed that RDV and neutralizing mAb treatments late in infection offered little benefit in the SARS-CoV-2 mouse model and with regard to therapeutic use in humans raise the hypotheses that early treatment with direct antivirals; and combination therapy with direct-acting antivirals in the early course of COVID-19 will improve outcomes in humans.

Treatment for Pediatrics with COVID-19

In April 2022, the FDA approved a supplemental new drug application (sNDA) for Veklury for the treatment of pediatric patients who are older than 28 days, weighing at least 3 kg, and are either hospitalized with COVID-19 or have mild-to-moderate COVID-19 and are considered high risk for progression to severe COVID-19, including hospitalization or death. This approval follows the recent sNDA approval for Veklury for the treatment of non-hospitalized adult and adolescent patients who are at high risk of progression to severe COVID-19. FDA approval was based on outcomes from the  CARAVAN Phase 2/3 single arm, open-label study, which demonstrated that Veklury was generally well-tolerated among pediatric patients hospitalized with COVID-19 with a high proportion of participants showing clinical improvement and recovery, as well as data from trials in adults. Of the 53 pediatric patients enrolled in the CARAVAN study, no new safety signals were apparent for patients treated with Veklury. Overall, 75% and 85% showed clinical improvement (greater than or equal to 2 point increase on the ordinal scale) at Day 10 and last assessment, respectively, while 60% and 83% were discharged by Day 10 and Day 30, respectively. In the study, 38 patients (72%) experienced adverse events (AEs), with 11 patients (21%) experiencing serious adverse events (SAEs) that were determined not to be study-drug related, including three participant deaths, which were consistent with the patients’ underlying medical conditions prior to study entry or with COVID-19 disease during hospitalization (Gilead, 2022b).

Under the expanded indication, a three-day Veklury treatment regimen is recommended to help prevent hospitalization in non-hospitalized COVID-19 pediatric patients who are at high risk for COVID-19 disease progression. For hospitalized pediatric patients who do not require invasive mechanical ventilation and/or ECMO, a 5-day treatment course is recommended (Gilead, 2022b.

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