Remdesivir, one of the first drugs to be approved by the FDA for treating the SARS-CoV-2 virus has recently been in the news, highlighting how its scarcity is affecting patients. Hence, prescribing the injection considering patients' medical history and severity of their present health condition is key. This article provides information on how to use remdesivir optimally.

For our comprehensive coverage and latest updates on COVID-19 click here.

Repurposed drugs are an urgent solution to an emergency that has outgrown the COVID19 pandemic's prevention techniques. They are time savers due to the fact that these medications have been shown to be effective in preclinical and early clinical trials. They can be advanced directly to the final stage of drug development, phase III, and their safety and effectiveness as COVID19 therapy can be quickly tested. The same has been done for medications such as Remdesivir, which is used to treat patients with moderate or moderate escalating to severe' COVID19 infection.

Remdesivir – Mode of action

When a virus infects a human cell, it releases genetic material, which is then copied by the body's natural mechanisms. At each point of the infection, a variety of human and viral proteins, as well as their associations, are involved. During the replication point, the critical viral protein RdRp serves as the virus' driver. Remdesivir exerts its effect by specifically targeting RdRp. Remdesivir acts as a 'feeding' material for the virus, preventing it from replicating further.

Remdesivir - A timeline

1. The FDA approved remdesivir as the first drug to control the SARS-CoV-2 virus. It is used to combat COVID-19 infection in hospitalised adults, and children aged 12 who weigh at least 40 kg. A nucleotide analogue prodrug is used as a broad-spectrum antiviral.
2. On May 1st, 2020 the US FDA issued an EUA (emergency use authorisation), which was followed by full approval. The EUA was revised following the approval of remdesivir in adults and teenagers to enable prescribers to handle paediatric patients weighing 3.5 kg to less than 40 kg or children younger than 12 years who weigh at least 3.5 kg.
3. On August 28, 2020, the remdesivir EUA was extended to include mild illness. The previous authorisation to treat all hospitalised patients with COVID-19, regardless of oxygen level, has been expanded.
4. In August 2020, the FDA received a new drug application (NDA) for remdesivir.
5. In late June 2020, a phase 1b trial of an inhaled nebulised variant of remdesivir was launched to see how it could be used as an outpatient treatment and at earlier stages of the disease.
6. Remdesivir has been studied in some phase 3 clinical trials for the treatment of COVID-19. The use of remdesivir by the University of Washington in the first case of COVID-19 was reported on US soil in January 2020, which yielded positive results.
7. The National Institute of Health (NIH) began an adaptive randomised trial of remdesivir (NCT04280705) versus placebo, but when more data and therapeutic options were available, more treatments were introduced to the regimen. The first time this research was used, passengers on the Diamond Princess cruise ship were quarantined at the University of Nebraska Medical Center after returning to the United States from Japan following a COVID-19 outbreak on board.
8. Remdesivir is currently being tested in comparison to the quality of care for mild and serious COVID-19 with different treatment durations.
9. Remdesivir's initial EUA was announced on April 29, 2020, based on a preliminary data review from the Adaptive COVID-19 Treatment Trial (ACTT). The final study involved 1,062 hospitalised patients with advanced COVID-19 and lung involvement and revealed that patients treated with Remdesivir for 10 days recovered 31% better than those related with placebo (15 days vs. 10 days; P 0.001). The median time to remission for patients with serious disease (n = 957) was 11 days, compared to 18 days for placebo. By day 15 (remdesivir 6.7 per cent vs placebo 11.9 per cent), nor by day 29 was a statistically meaningful discrepancy in mortality observed (remdesivir 6.7 per cent vs placebo 11.9 per cent). (remdesivir 11.4 percent vs placebo 15.2 percent ).
10. The final ACTT-1 data at the time of recovery was inconsistent with interim findings from the WHO Solidarity trial for remdesivir. These contradictory findings are complex and perplexing, as the Solidarity study enrolled patients with ACTT-1. The SIMPLE trial (n = 397) found that the 5-day remdesivir regimen improved clinical status, similar to the 10-day regimen on day 14 in hospitalised patients with serious COVID-19 disease who did not need mechanical ventilation (odds ratio, 0.75). Since adjusting for baseline clinical condition imbalances, patients taking a 10-day course of remdesivir had a clinical status distribution close to that of patients receiving a 5-day course at day 14 (P = 0.14). The results have the potential to greatly increase the number of patients treating with the existing availability of remdesivir. The research is now recruiting patients and has a target enrollment of 6,000 patients.
11. Likewise, the SIMPLE II phase 3 trial in patients with moderate COVID-19 disease (n = 596) found that 5 days of remdesivir therapy resulted in a statistically important higher likelihood of an improved health condition distribution on day 11 than normal care (odds ratio, 1.65; P = 0.02). On day 11, there was no difference in improvement between the 10-day remdesivir group and the quality of the treatment group (P = 0.18). The data keeps coming in. In pregnant women with COVID-19, a case series of five patients reports good care, and surveillance during treatment with remdesivir.

NIH recommendations

When is the best time to use remdesivir?

Remdesivir was the first medication approved by the US Food and Drug Administration in the first phase of 1-7 days complications in serious and extreme COVID-19 patients, and complications after 7-8 days caused by an inflammatory reaction (SIRS). To reduce the viral load in the body, this drug can be used in the initial phases, between the 2nd and 10th day, when viral replication is occurring.

Using remdesivir with caution

1. There is no information available regarding maternity or breastfeeding safety.
2. It has been advised to avoid it in patients who have hepatic cirrhosis, or if the alanine aminotransferase or aspartate aminotransferase levels are higher than five times the upper limit of average- established serious renal dysfunction (glomerular filtration rate <30 mL/min per 1•73 m²) or on continuous renal replacement therapy, haemodialysis, or peritoneal dialysis).
3. Many centres, however, are using remdesivir in compensated cirrhosis patients, renally affected patients, and haemodialysis patients with close supervision and no significant problems.
4. Remdesivir is not recommended for patients with an eGFR <30 mL/min due to a lack of data. Renal function should be monitored before and during remdesivir treatment as clinically indicated.
5. Use it early as the saturation starts to decline. Earlier than the oxygen requiring stage, (especially if the 6 minute walk test is positive), with steroids and heparin along with it as per decision individualised to your patient. Wait for 3-4 days for the clinical improvement.
6. It may not help if used after the patient desaturates with higher oxygen requirement.

Conclusion

Remdesivir should not be given to patients who are asymptomatic, mildly symptomatic, or who have serious infections with multi-organ dysfunction, and the patient should be carefully tested before being given the medication. Remdesivir plays an important role in the first ten days, in appropriate patients. 

Finally, we must acknowledge that many patients who are in need of this medication are not accessing it on time. As a society, we must behave responsibly to ensure that it is used and supplied appropriately. Let's change the course and make sure that more people survive and that this war is won successfully.

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.