Though the advent of vaccines has certainly helped mitigate the effect of the pandemic, COVID will continue to exist, which makes it crucial to develop or repurpose drugs to continue to fight symptoms. Over the last 2 years, several drugs have been studied and tried, remdesivir being one of the more popular ones. The drug has seen several ups and downs- WHO dropped it from its recommendations, labelling it as unaffecting, but the demand still soared during India's second COVID wave. Now, a large Lancet study presents some conclusive findings of its efficacy.

Images of people waiting in lengthy lines outside chemist stores/pharmacies throughout India were all over the media soon after the second wave of the COVID-19 pandemic began in India. These lines were formed to buy Remdesivir, a prescription-only medication recommended for COVID-19 sufferers.

The antiviral medication was first created in 2014 to treat Ebola virus illness and was then investigated as a therapy for hepatitis C and Middle East Respiratory Syndrome (MERS). The medication works by stopping the virus from replicating in human cells. In October 2020, the situation changed significantly with the publication of the results of the WHO-led multi-country Solidarity study, which found no impact of the drug on progression to ventilation or death in COVID-19 patients. Since then, the WHO has discontinued its recommendation for the use of remdesivir in the treatment of COVID-19.

Nonetheless, during the second wave in India, as cases rose, demand for remdesivir soared. Though Indian manufacturers were capable of producing remdesivir, the manufacturing and distribution cycle would take 20–25 days. This supply-demand imbalance resulted in lengthy lines of worried relatives of patients trying to purchase the medication. Prior to the scarcity of medical oxygen in India gaining headlines, the lineups for remdesivir injections at pharmacy shops were the focus of attention.

Remdesivir efficacy ultimately proved – Lancet

Though there is the availability of effective SARS-CoV-2 vaccinations, enhancing treatment for individuals with symptoms remains a priority. To mitigate the hyperinflammatory state associated with severe COVID-19, therapy options include broad-spectrum immunosuppressive agents such as corticosteroids, specific immunomodulatory agents such as tocilizumab or baricitinib, and direct-acting antivirals to decrease viral load.

Florence Ader and colleagues present the findings of the DisCoVeRy study, the sixth major, randomised, controlled trial using the broad-spectrum antiviral remdesivir, in The Lancet Infectious Diseases.

857 patients admitted to the hospital with severe COVID-19 (oxygen saturation SpO2 94 percent or requiring supplementary oxygen or respiratory assistance) were randomly allocated to receive remdesivir plus standard of treatment or standard of care alone.

1. At day 15, there was no significant change in the main outcome, the chances of achieving a better clinical state as determined by the WHO ordinal scale (odds ratio 0•98 [95 percent confidence interval [CI] 0•77–1•25]; p=0•85). This result held true across all prespecified subgroup analyses, regardless of the length of symptoms before to hospitalisation or the severity of illness at random assignment.
2. Additionally, there was no significant difference in 28-day mortality (0•93 [0•57–1•52]; p=0•77), and none of the time-to-improvement analyses revealed a benefit for remdesivir.
3. However, in an exploratory subgroup analysis of patients who were not receiving mechanical ventilation or extracorporeal membrane oxygenation (ECMO) at randomisation, the hazard of new mechanical ventilation, ECMO, or death was lower in the remdesivir group than in the standard-of-care group (hazard ratio [HR] 0•66 [95 percent confidence interval [CI] 0•47–0•91]; p=0•010).

How do these results stack up against those prior reports?

Remdesivir showed modest improvement in specified clinical outcomes in Spinner and colleagues' research and in the ACTT-1 cohort of patients who presented with mild COVID-19 upon admission as compared to standard of care, especially when therapy was started early after symptom onset. The ACTT-1 study demonstrated a shorter time to improvement with remdesivir in individuals with severe COVID-19, particularly when therapy started early after symptom onset.

However, excitement was quickly bashed by the findings of the WHO Solidarity study, which revealed that remdesivir had no impact on in-hospital mortality or length of stay.

Notably, systemic steroids were administered at a higher rate in the Solidarity (476%) and DisCoVeRy (40%) studies than in the ACTT-1 study (23%), which may account for some of the observed discrepancies.

While the lack of a mortality benefit seems unassailable in Solidarity, death is not the only important result. Thus, the findings of DisCoVeRy are a crucial complement to the data supporting remdesivir's impact on other clinically significant outcomes. However, would the DisCoVeRy trial's poor results ultimately end the argument for remdesivir, or do some of the study's shortcomings allow for cautious optimism?

Potential fallacies

1. To begin, the DisCoVeRy study ran the risk of missing the optimum period to evaluate clinical benefit by comparing clinical state at a set time point. Fifteen days may be too late to detect differences in patients who do not proceed to mechanical breathing and maybe too early to detect differences in those who do.
2. Second, an open-label design introduces inherent prejudice. Finally, in the DisCoVeRy study, the median duration from symptom onset and therapy start was 9 days (IQR 5–10). This is comparable to previous studies including hospitalised patients and occurs long after the peak in viral load has passed in the majority of patients. This may explain why none of these investigations saw an impact of remdesivir on virus clearance.

As thus, the DisCoVeRy findings cannot rule out or confirm a potential benefit in patients with fast-progressing illness who present early or are immunocompromised, the most probable clinical situation in which remdesivir is currently evaluated.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a practising super specialist from New Delhi.