**2.6 Remdesivir**

Remdesivir is a 1′-cyano-substituted adenosine nucleotide analog prodrug, which was found to be effective against several RNA viruses. It was initially developed in 2017 by Gilead science for the treatment of the Ebola virus [38]. It has demonstrated extensive antiviral activity & effective treatment of lethal Ebola and Nipah virus infections in nonhuman primates [39]. Subsequently, it was investigated for SARS-CoV and MERS-CoV. Studies have shown that Remdesivir inhibits viral replication in human airway epithelial cell culture by affecting the early stages of viral replication through viral RNA synthesis inhibition, as an RNA-dependent RNA polymerase (RdRp) inhibitor [39]. This may be due to the absence of Exonmediated proofreading in viruses sensitive to Remdesivir [40]. One of the first trials of Remdesivir was performed by the Gilead sciences center in hospitalized patients with confirmed SARS-CoV-2 having oxygen saturation < 94% or a need for oxygen support. Till 28 days of follow-up, the cumulative incidence of clinical improvement was 84% (95% CI 70–99) by Kaplan–Meier analysis and it was less among patients receiving invasive ventilation compared to non-invasive ventilation [41]. In another randomized, double-blind, placebo-controlled, multicentre trial at 10 hospitals in Hubei, China, Remdesivir use was not associated with any difference in time to clinical improvement [42]. In February 2020, WHO cast a vote of confidence for remdesivir, indicating that it has great potential. In April 2020, the US National Institute of Allergy and Infectious Diseases (NIAID), announced that a clinical trial in >1,000 people showed that those taking remdesivir recovered in 11 days on average, compared with 15 days for those on a placebo, even adding that remdesivir may become a standard for COVID treatment [43]. US FDA had issued a EUA for remdesivir for severe COVID-19 disease. On 22nd October 2020, the FDA approved remdesivir for use in adult and pediatric patients (≥12 years, ≥40 kg) requiring hospitalization [44]. In October 2020 itself, an interim analysis of the WHO-led, open-label, randomized SOLIDARITY trial demonstrated that 301 (11·0%) of 2743 patients who received remdesivir and 303 (11·2%) of 2708 patients who received standard care died by day 28 (Kaplan–Meier rate ratio 0·95, 95% CI 0·81–1·11; p = 0·50) [45]. The ACTT-1 study had also reported a 29-day mortality of 11·4% in patients receiving remdesivir as compared to 15·2% in placebo (hazard ratio 0·73, 95% CI 0·52–1·03) [43]. Hence in November 2020, WHO issued a conditional recommendation against remdesivir utilization in hospitalized patients, regardless

of their disease severity. This was because they could not find evidence of remdesivir improving survival and other outcomes in the patients [46]. Infectious Disease Society of America (IDSA) still suggests the use of remdesivir in severe and critical patients, as does NIH [47, 48].
