Remdesivir: Expensive But Not Very Effective Against Covid-19

Shin

As more clinical data are out, scientists are doubting the efficacy of this costly drug.

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Remdesivir is an antiviral agent that is said to work against Covid-19. Gilead Sciences developed it in 2017 to treat Ebola. Although the drug did not work well against Ebola, it showed promising results against coronaviruses in cell culture and animal studies. Remdesivir interrupts the enzyme the coronavirus needs to make its genes and, thus, decreases viral replication.

Remdesivir is now widely used to treat Covid-19 patients since 2020. Remdesivir costs about 2–3k USD for a five-day course, although it can be cheaper in developing countries. But the scientific community has raised skepticism in the efficacy of this costly drug against Covid-19. Why?

Dubious results from RCTs

A randomized placebo-controlled trial (RCT) published in May 2020 in The New England Journal of Medicine (NEJM) recruited 1063 Covid-19 patients, of which 88.7% had severe Covid-19 at enrollment, across ten countries. Investigators found that a 10-day remdesivir course enhanced recovery rate from 15 to 11 days compared to standard care (placebo). But no significant differences in death rate were observed.

Another RCT in China published in May 2020 in The Lancet with 237 patients with severe Covid-19 found that a 10-day remdesivir course improved neither disease duration nor death rate compared to placebo. And serious side effects were observed that the trial was terminated early. No wonder China does not use remdesivir for Covid-19.

A third RCT published in August 2020 in the Journal of American Medical Association (JAMA) enrolled 584 patients with moderate Covid-19 from hospitals in the US, Europe, and Asia. Results showed 70% of patients treated with a 5-day remdesivir course had clinical improvement compared to 61% of patients receiving standard care, “but the difference was of uncertain clinical importance.” This means that while results reached statistical significance, the effect size is small. Oddly, the 10-day remdesivir course did not provide any more clinical benefits than standard care.

Notably, a non-RCT study showed that a 5-day and 10-day remdesivir courses both provided the same but slight improvement in clinical outcomes in a sample of 397 patients with severe Covid-19. But this study has no control group to which the results can be compared. Nonetheless, this study’s results contradict the third clinical trial (mentioned above) where a 5-day remdesivir course, not the 10-day one, provided some clinical benefits.

A more recent Solidarity phase III/IV clinical trial organized by the WHO does not support remdesivir use for Covid-19 mortality, need for ventilation, or hospitalization duration. Results found that “no study drug [including remdesivir] definitely reduced mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation, or hospitalization duration," the authors wrote.

Taking a step further, the Solidarity study authors did a meta-analysis of their own data plus three existing RCTs on remdesivir. The pooled results found that remdesivir does not lower Covid-19 mortality. “Combining data appropriately from all 4 trials, the remdesivir vs. control death rate ratio (RR) is 0.91 (95% CI 0.79–1.05),” the study stated. “This absolutely excludes the suggestion that remdesivir can prevent a substantial fraction of all deaths.”

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What academics think

“Thus, there are now 3 RCTs of remdesivir in hospitalized patients with differing results, raising the question of whether the discrepancies are artifacts of study design choices, including patient populations, or whether the drug is less efficacious than hoped,” said an editorial of the JAMA upon reviewing the three RCTs above. “As today no study convincingly supports the use of remdesivir in severe patients,” agreed a mini-research review in the journal New Microbes and New Infections.

There is also no convincing evidence that giving remdesivir to mild cases of Covid-19 would prevent disease progression. “It is not yet clear whether early administration of remdesivir in mild/moderate disease may prevent hospital admission, clinical deterioration, or impact on transmission,” a research review published in Clinical Medicine stated.

“Is the remdesivir a definitive treatment regimen for Covid-19? Regrettably, the current assessment of remdesivir does not seem to be entirely positive,” said a research review of Jin-Hong Yoo, a professor of infectious diseases and internal medicine at the Catholic University of Korea. “In a word, at least now remdesivir is not a magic panacea.”

Remdesivir alone may not be enough

One drawback of remdesivir is it does not block the body’s overzealous immune responses that cause additional damage to organs. Further, remdesivir is administered over five to ten days through an intravenous (IV) route. It requires healthcare supervision and not as simple as swallowing a pill.

Research has now focused on combinational therapy against Covid-19 — to attack the disease in many different, synergistic ways. It makes sense for a complicated illness to be treated in complicated ways, after all.

However, drug combinations do not always work wonders. Hydroxychloroquine (antimalarial) plus azithromycin (antibiotic) and lopinavir plus ritonavir (both antivirals) have been used for Covid-19, but both combinations failed to show encouraging clinical results.

That said, a drug duo that is said to be useful is remdesivir plus dexamethasone. Dexamethasone is a cheap and widely available immunosuppressive and anti-inflammatory steroid known as the first lifesaving drug for severe Covid-19. However, there is no clinical trial comparing dexamethasone plus remdesivir to dexamethasone alone. So, the contribution of remdesivir, in this case, is ambiguous. But it should work in theory, remdesivir would slow the virus replication while dexamethasone controls the immune system.

Another promising drug combination is remdesivir plus interferon-beta (IFN-ß; an anti-inflammatory drug used to treat multiple sclerosis) that is entering phase III clinical trial in August. Specifically, the trial will compare remdesivir plus IFN-ß with remdesivir alone.

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To conclude

Current evidence shows that remdesivir provides modest clinical benefits for moderate-to-severe Covid-19, particularly in shortening symptom duration. But the important issue is how substantial (i.e., effect size) is the clinical improvement? Concerningly, all RCTs on remdesivir to date can’t seem to agree on this question. And experts have raised concerns if remdesivir is really useful for Covid-19, especially when the drug is so expensive, which may exacerbate existing health inequities.

This article was previously published in Microbial Instincts with some modifications.

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