Should Doctors Continue to Use Remdesivir for COVID-19 Treatment?

“Remdesivir is a drug in search of a disease. It failed in Ebola, it failed in SARS and MERS. So we are skeptical.”

The latest findings from the World Health Organisation’s (WHO) Solidarity Trials may complicate India’s COVID-19 treatment plan.

On 15 October, the WHO released the results from their Solidarity Therapeutics Trial and found that Gilead Sciences Inc’s Remdesivir had either no or very little effect on a COVID-19 patient’s chances of survival or length of hospital stay.

Dr SP Kalantri, Medical Superintendent of Kasturba Hospital and MGIMS, Wardha, Maharashtra, tweeted about the same,

What does this mean for India, where Remdesivir is part of the Health Ministry’s protocol for COVID-19 treatment?

FIT speaks to intensivist Dr Sumit Ray, a senior consultant of Critical Care Medicine at the Holy Family Hospital in Delhi, who runs a COVID ward, to find out more.

“There was an article that said Remdesivir is a drug in search of a disease. It failed in Ebola, it failed in SARS and MERS. So, we were skeptical.”

Dr Sumit Ray

But first, let’s get back to the basics. What is Remdesivir and how was it supposed to help?

Remdesivir: What is It?

Remdesivir is an antiviral drug developed by American pharmaceutical giant Gilead Sciences. It was made to treat hepatitis C and respiratory syncytial viruses over a decade ago, but it never got marketing approval.

Antivirals are drugs used for treating viral infections.

COVID-19 brought the drug back into the picture, and US President Trump offered Remdesivir to UK Prime Minister Boris Johnson, despite no clinical evidence that it worked for COVID-19.

Gilead too did not claim it worked, but it became thrust into the limelight as a potentially promising drug. Soon in April, the New England Journal of Medicine published a study where out of 61 patients who were hospitalised with COVID-19, 53 were given the drug and 68 percent improved while 13 percent died.

However, they were not able to say this was due to the drug as there was no control group. It is important to note that Gilead employees co-authored the paper. “This presents a huge conflict of interest,” says Dr Ray.

Remdesivir and COVID-19: When Should It Be Given?

“COVID-19 is a fast replicating, respiratory virus – unlike HIV, Hepatitis B or C which are much slower viruses. Antivirals work in slower replicating viruses because the build-up takes time, so you can block that by antivirals. But in faster replicating viruses, the ideal time to give the antiviral is before the symptoms even start and before the virus starts rapidly replicating – if you can tell the patient has the infection by then.”

Dr Sumit Ray

He adds that you will not need this for “90 percent of patients.” Hypothetically, if you could detect that someone has the viral infection without symptoms, that is the best time for the antiviral to be given for it to work. “Once the virus starts replicating there is not much the antiviral can do,” adds Dr Ray.

This is no mean feat – how can we determine who has the virus before symptoms persist? “This has always been the chicken and egg question with antivirals for respiratory illnesses.”

This happens in general with all antivirals, but focusing on Remdesivir and COVID-19, Dr Ray says that we need to examine the results from Solidarity Trial and the Adaptive COVID-19 Treatment Trial (ACCT1), which was a large trial in the UK and Europe. Now, the ACCT1 trial showed a reduction in the length of hospital stay but it is important to analyse the sub-groups of patients from the large trial.

“The positive result that came in the ACCT1 trial was predominately because it seems to have worked in patients who got Remdesivir early and needed low oxygen requirement. So those who did not get oxygen also did not benefit, those who got very high oxygen (ie, they needed more oxygen support) or ventilators, which means they had a severe disease, also did not benefit [sic].”

Dr Sumit Ray

So, the timing of administering the drug and the severity of the infection are crucial determinants.

“On the other hand, if the patient had a mild disease that did not require oxygen, they were not benefited, because anyway the person would improve on their own, and therefore, Remdesivir would not show any difference in the outcomes.”

Dr Sumit Ray

Therefore, from the sub-group analysis from the ACCT1 trial, it’s clear that if at all anyone benefited, it was those patients on low oxygen. Dr Ray added that among the sub-group, racially and geographically, it was only beneficial to white people from North America – not in Europeans, Asians or Black people. “So its role is questionable,” adds Dr Ray.

However, in the Solidarity Trial, no one benefited from any sub-group.

“Like in most respiratory diseases, most antivirals do not seem to have any benefit. Usually, the focus on those patients who have a severe disease is ICU care, oxygen etc,” says Dr Ray.

What Will Happen to Remdesivir Post These Results?

So COVID-19 has 2 phases:

1. Viremia phase: where the virus is in the body
2. Acute phase where the immune response creates an issue

“The role of steroids is usually when our immune response is causing a problem, and here those on oxygen and ventilators benefit the most,” says Dr Ray. “Because steroids are so successful, everyone is prescribing steroids the day COVID-19 is detected and that is actually causing a big problem. It is prolonging the viremia and suppressing the immune response when at that phase, it is necessary. The immune response is a necessary evil, and we need a balanced one for COVID-19 – one that attacks the virus well but not our body. ”

Now, if steroids are needed, doctors were administering Remdesivir. “But with this trial, the role of Remdesivir becomes questionable.”

“See, we stopped hydroxychloroquine (HCQ) early on, despite the government recommending it because the recovery trials started showing that outcomes were poor – though it continued to be recommended. For Remdesivir, we have not stopped it, but we are using it judiciously and keeping in mind the timeline of the disease.”

Dr Sumit Ray

So doctors are using it in the early subset of patients with low oxygen requirements. “We are using it much more aggressively early in the phase, and once the patient is on the ventilator or more serious, then the possibility of using Remdesivir is more questionable. Though we did use it, as it was recommended and we thought there was space for it.”

“We are now questioning its use. This doesn’t mean we have completely stopped using Remdesivir, because these are difficult questions in the clinical practice regarding COVID patients.”

Dr Sumit Ray

Dr Ray adds that they faced similar issues with convalescent plasma. Finally, the ICMR study found it to be ineffective.

While doctors are the ultimate decision-makers in treating COVID, the patient also does have a say.

What happens when a drug like Remdesivir (or convalescent plasma) is highly publicised despite ineffective clinical results? Especially given the fact that COVID-19 is a virus that has taken over the world and patients are doubly worried. “So imagine if a patient is sick, and we don’t give them Remdesivir despite it being part of the government guidelines, and the patient dies. Then the family will blame us for not giving the drug,” ponders Dr Ray.

For plasma, there was not enough evidence, so it was still easier to convince patients to wait for more information. “We fought hard against it, we gave it only to four out of 300 patients, and only because they really demanded it and we were under pressure.”

“There are a lot of medications that become publicised or recommended without proof.”

Dr Sumit Ray

The guideline needs to be worded very precisely, says Dr Ray, where there is freedom given to doctors in critical care to give the drug to specific patients who are in specific sub-sets.

So, for now, the ministry has said they are examining the data from the Solidarity Trials and taking another look at the current guidelines.

(The article was first published in FIT and has been republished with permission.)