Remdesivir – In patients: Updated Recommendation

A conditional recommendation is one for which the panel is less confident about the balance between desirable and undesirable effects of the intervention, or other aspects, such as cost and feasibility.

Definition of moderate illness:

• Pneumonia (clinical or radiological) OR hypoxia (SpO2 <94% in adults with no underlying lung disease)
• AND respiratory rate ≤30/min
• AND SpO2 ≥90% on room air

Definition of severe:

Pneumonia with ANY ONE of the following:

• Respiratory rate >30/min
• Severe respiratory distress
• SpO2 <90% on room air
• NO invasive or non-invasive respiratory support needed

Definition of critical:

• Requirement for high-level respiratory support: non-invasive ventilation, high-flow oxygen (≥20 litres per minute) or invasive mechanical ventilation
• OR acute respiratory distress syndrome (PaO2/FiO2 ratio of <300)
• OR sepsis
• OR shock

It has long been suggested that Remdesivir an antiviral is likely to be most beneficial in the early stages of the disease before the hyperinflammatory phase has set in, and hence should preferably be given early in the course of the disease with symptom onset less than 5 days. However, till recently this effect was not demonstrable.

Updation of recommendations with the findings from few new trials and final results of the Solidarity trial revealed that Remdesivir probably reduces all-cause mortality, time to clinical improvement, progression to NIV/HFNO, secondary infections and any adverse events. Remdesivir may reduce thrombotic complications, time to clinical recovery, progression to oxygen therapy, non-invasive, invasive and ECMO in hospitalized COVID-19 patients. The evidence was very uncertain for progression to invasive mechanical ventilation (IMV), serious adverse events and adverse event leading to drug interruption.

The earlier trials were conducted when steroids were not the standard of care, and other respiratory treatment protocols were unclear, which may have impacted the benefit of Remdesivir. However, with steroids becoming the standard of care and improved respiratory therapy protocols with regard to non invasive ventilation and invasive mechanical ventilation in hypoxic hospitalized patients, the overall data now indicates that Remdesivir provides a benefit over and above that demonstrated by steroids in those who have moderate to critical COVID-19. Though the mortality benefit of 10% is not dramatic, the benefit of 28% in prevention of progression to high flow nasal oxygen or NIV is indeed remarkable and will likely help with de congestion of hospitals and more beds and treatment modalities being available to deserving patients.

Date of latest search: 04th May 2022

Date of completion & presentation to Anti-Viral Expert Working Group: 07th June 2022

Date of planned review: January 2023

Evidence synthesis team: Naveena G Princy ,Hanna Alexander, Anupa Thampy, Richard Kirubakaran, Bhagteshwar Singh and Priscilla Rupali.

The Antiviral Expert Working Group met on 07^th June 2022  to consider Remdesivir as a treatment for COVID-19. Conflict of interest declarations were reviewed by the Steering Committee; none were found to be relevant to remdesivir.

A summary and then more detailed explanations of the Expert Working Group's judgements follow.

Problem

The COVID-19 pandemic in India with more than 43 million cases and over 0.52 million deaths has significantly impacted and stressed the health structure of the country. With a shortage of intensive care unit beds, oxygen and trained personnel the country is facing a major health crisis. This has prompted many irrational treatment interventions which are neither beneficial nor cost effective. Remdesivir, similar to other antivirals was believed to have a possible benefit in the early viral replication phase of the disease, and data now shows that there is a mortality reduction in mild to moderate COVID-19 disease in the out-patients. Most recently SOLIDARITY trial data has become available which provided useful information regarding its use in hospitalized patients with COVID-19 infection. However, it continues to be prescribed widely and the group judged the problem to be of the utmost priority.

Desirable effects

The group agreed that Remdesivir may have a beneficial effect on mortality and progression to oxygen therapy or non-invasive mechanical ventilation and they have noticed this personally even when treating patients. The group agreed there was a benefit in time to clinical improvement (2 point reduction in WHO ordinal scale) and clinical recovery (not requiring hospitalization for oxygen or medical care) when Remdesivir was compared with placebo/SOC, however the magnitude of this reduction in days was unclear.

The group also noted that the early trials did not use steroids as much as they are used now and the benefit of Remdesivir when steroids was on board was unclear in the past. In addition, the median duration of oxygen requirement was around 3 weeks in the ACTT-1 trial (8), which is quite prolonged compared to what we have seen more recently suggesting that treatment protocols have since evolved and we have data which now clearly suggests that there is a clearcut benefit across all clinical outcomes. This does have implications for a health system which is overwhelmed with a shortage of supplies and hospital beds. Taking these factors into consideration, overall the group members suggested a small to moderate benefit for Remdesivir.

Undesirable effects

Adverse events were not different between groups, nor were there adverse events leading to discontinuation and serious adverse events, suggesting this drug may be safe. The group noted evidence was lacking in pregnancy, renal and liver disease and overall judged the undesirable effects as trivial.

Certainty of evidence

The group felt that there was moderate  to low certainty evidence for all outcomes, including those judged as critical.

Values

The group felt that there is possibly no important uncertainty or variability regarding values. In the initial stages, with the available data this result was unclear; however though the certainty of evidence was moderate regarding the effect estimate, the group agreed that stakeholders (for e.g., individual patient, health care providers, public or private health systems etc.) may value the beneficial effect of Remdesivir on these outcomes differently.

Balance of effects

The group discussed at length on many an occasion regarding the beneficial effects of Remdesivir. Data has evolved since the initial stages of the pandemic and now there is data to suggest that Remdesivir reduces mortality, time to clinical improvement/clinical recovery, progression to oxygen, non invasive or invasive mechanical ventilation. The group judged that at present with the evidence available the balance of effects seemed to favour the intervention, though the magnitude of benefit was moderate to low certainty of evidence. The group was clear they were not worried about adverse events. It is quite safe and has been extensively used in the country with no signal of harm. It could contribute to indirect benefits as it could free up the resources like hospital beds, oxygen supplies and impact patients' risk of nosocomial infections and other complications.

Resources required

The group felt that the costs were moderate. The group includes clinicians in different types of Indian hospitals who have a good idea of drug and hospitalization costs.

Certainty of evidence of required resources

No studies reporting this were reviewed by the group.

Cost effectiveness

The group noted the lack of data from available cost effectiveness studies relevant to the Indian context. There are only benefits in time to clinical improvement and progression to NIV/high flow oxygen which may result in early discharge and save hospital beds, supplies and costs; however this was low certainty evidence. This highlights the uncertainty regarding cost effectiveness that requires evidence from new clinical studies specific to the Indian context.

Equity

At this point in time this intervention would ‘reduce equity’ if found efficacious in Indian settings.

Acceptability

The group felt that this intervention is likely to have wide acceptance by all the relevant stakeholders (policy-makers, patients and clinicians), if further research proves its efficacy in the absence of increased adverse events.

Feasibility

This is a feasible intervention in the moderate to severe groups requiring oxygen as they are likely to need hospitalization by virtue of oxygen support.

Remdesivir should be considered in all hospitalized patients if cost and availability is not an issue. It should be given especially if in the early stages of the disease in all hospitalized patients. There is reduction in mortality, progression to oxygen therapy, non invasive and invasive ventilation as well as time to clinical improvement and recovery. Though this reduction in time to clinical improvement and recovery was seen, it was not quantifiable in number of days. However this does signal saving hospital resources for sicker patients. This effect seems to be over and above that seen with steroids.

Clinicians are familiar with this drug and wide use has revealed very low incidence of adverse effects. However, patients need to be given this drug by trained health care personnel either at a clinic or hospital or if at home by a skilled health care worker.

The group considered a potential subgroup effect across patients with early administration of Remdesivir.

(a) Oxygen requirement:  For this analysis, the participants were stratified as: no supplemental oxygen requirement, low flow oxygen, high flow oxygen and non-invasive ventilation and invasive mechanical ventilation. In three RCTs (3, 8, 12) with 1332 participants, in the subgroup with low flow oxygen   it did show a mortality benefit (RR 0.57; 95% CI 0.34 to 0.95).

(b)Early administration: Subgroup analysis to determine if Remdesivir benefits those patients who present early (<10 days) was considered, however only one study (9) addressed this and no mortality benefit was reported.

The committee had requested analyses of other important subgroups of patients including children, age > 50 years and those with co-morbidities, but unfortunately there was no data to address outcomes in these subgroups specifically.

New evidence suggests that Remdesivir is beneficial even in hospitalized patients with COVID-19 infection. Pharmacovigilance data over 2 years has suggested that this a safe drug with few adverse effects which should be easy to monitor even in an out-patient setting like bradycardia, hypotension and liver dysfunction. The certainty of evidence for any adverse events was low and for adverse events leading to drug discontinuation was very low, thus potential drug-related harm has still not been ruled out.

There is considerable uncertainty surrounding the benefits or harms of using Remdesivir in pre-specified subgroups such as immunocompromised, renal failure patients on dialysis, pregnant women and children. Hence there is a felt need to evaluate the efficacy of Remdesivir in the above sub groups.

1. Eastman RT, Roth JS, Brimacombe KR, Simeonov A, Shen M, Patnaik S, et al. Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Cent Sci. 2020 May 27;6(5):672–83.
2. Frediansyah A, Nainu F, Dhama K, Mudatsir M, Harapan H. Remdesivir and its antiviral activity against COVID-19: A systematic review. Clin Epidemiol Glob Health. 2021;9:123–7.
3. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269–71.
4. Rochwerg B, Agarwal A, Zeng L, Leo YS, Appiah JA, Agoritsas T, et al. Remdesivir for severe covid-19: a clinical practice guideline. BMJ. 2020 Jul 30;m2924.
5. Therapeutics and COVID-19: living guideline [Internet]. [cited 2022 May 11]. Available from: https://www.who.int/publications-detail-redirect/WHO-2019-nCoV-therapeutics-2022.3
6. Remdesivir [Internet]. COVID-19 Treatment Guidelines. [cited 2022 May 11]. Available from: https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/remdesivir/
7. Sharma DL. Clinical Guidance for Management of Adult COVID-19 Patients (Revised: 14/01/2022). :1.
8. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med. 2020 Oct 8;NEJMoa2007764.
9. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet Lond Engl. 2020;395(10236):1569–78.
10. Spinner CD, Gottlieb RL, Criner GJ, Arribas López JR, Cattelan AM, Soriano Viladomiu A, et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19. JAMA. 2020 Sep 15;324(11):1–10.
11. Mahajan L, Singh AP, Gifty. Clinical outcomes of using remdesivir in patients with moderate to severe COVID-19: A prospective randomised study. Indian J Anaesth. 2021 Mar;65(Suppl 1):S41–6.
12. Ali K, Azher T, Baqi M, Binnie A, Borgia S, Carrier FM, et al. Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial. CMAJ. 2022 Feb 22;194(7):E242–51.
13. Abd-Elsalam S, Salama M, Soliman S, Naguib AM, Ibrahim IS, Torky M, et al. Remdesivir Efficacy in COVID-19 Treatment: A Randomized Controlled Trial. Am J Trop Med Hyg. 2022 Mar 9;106(3):886–90.
14. Ader F, Bouscambert-Duchamp M, Hites M, Peiffer-Smadja N, Poissy J, Belhadi D, et al. Remdesivir for the treatment of hospitalised patients with COVID-19: final results from the DisCoVeRy randomised, controlled, open-label trial [Internet]. medRxiv; 2022 [cited 2022 May 2]. p. 2022.03.30.22273206. Available from: https://www.medrxiv.org/content/10.1101/2022.03.30.22273206v2
15. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. The Lancet. 2022 May;S0140673622005190.
16. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results | NEJM [Internet].

Covid management Guidelines India Group- Anti-viral Working Group.  Updated Remdesivir. Covid Guidelines India: Published online on June 16, 2022; URL: https://indiacovidguidelines.org/remdesivir-inpatient/