What's the Deal with Remdesivir?
By Arunima Rajan
WHO has removed Remdesivir from its list of COVID-19 medicines. Yet, the demand for the drug doesn't seem to end anytime soon in the country. A HE report.
For *Gopi, the biggest crisis of 2021 was something unforeseen and had to do with the surge in COVID-19 cases in rural Tamil Nadu. An astronomical healthcare cost burden fell on his savings when his wife and himself tested positive for COVID. "There is considerable demand for drugs like Remdesivir. It would have been easier if I were in a metro, but sourcing a drug is a nightmare in smaller towns of Tamil Nadu," he explains.
Ever since the number of coronavirus disease cases spiked, there has been an enormous demand for Remdesivir in India. Many patients like Gopi think that it's a wonder drug.
India's Gorwing COVID-19 Black Market
Vivekanand Jha, Executive Director, The George Institute for Global Health, says that the drug has generated false hopes in people's minds because there are not too many effective therapies for COVID-19. "The data about Remdesivir is inconclusive. It doesn't reduce mortality but cuts down a patients number of days of stay at a hospital, and that only for people with moderate to severe disease. But that nuance is lost in the minds of many doctors and patients. Everybody thinks it's some magic bullet that will reduce the chance of any adverse outcome. It has become a vicious cycle. The shortage is a combination of false hope, lack of complete knowledge, market shortage and some degree of misinformation being spread through social media," he explains.
India's Remdesivir Procurement
The Department of Revenue on April 20 removed the customs duty on Remdesivir till October 31. Further, the National Pharmaceutical Pricing Authority had reduced its price to Rs 3,500.
As per an affidavit filed by the government in the Supreme Court on April 21, the current manufacturing rate of Remdesivir is about 74 lakh vials per month. The manufacturing rate will increase to over 90 lakh vials per month in May.
COVID Experiment?
Dr JA Jayalal, the national President of IMA, points out that today an artificial crisis of Remdesivir is created not because of lack of drug but due to inequitable distribution, unwarranted demand on the belief it is a wonder drug, and irrational prescription for non indicated patients.
"The Government should create a dynamic inventory, tracing mechanism from the factory to hospital door just like we trace speed post and other courier services. Black marketing should be dealt with stringent measures. The needy should be able to get the drug at the initial period of the infection. Remdesivir is a real good drug when used judiciously at the right time. The government and medical fraternity's responsibility is to make it available to all needy patients at minimal waiting time with capped pricing. Imports of drugs should be expedited, and authorities must curtail hoarding," he explains.
What is Remdesivir?
"Remdesivir is an "antiviral" drug originally intended to treat Ebola Virus (2014), but was revisited for treatment of COVID-19 as it had a broad antiviral activity demonstrated against many viruses", explains Dr Anup R Warrier, Senior Consultant, Infection Control, Aster Hospitals, India.
Most of the global guidelines recommend initiating Remdesivir in hospitalized patients with "moderate" disease - mainly at the time of requiring supplemental oxygen.
Warrier points that the course of an infection is determined by both the virus characteristics (like variants/mutations) and the host response (the way our immune system responds to the infection). "Like for all infections - including common urinary tract infection - once the immune dysregulation sets in, the role of antimicrobials diminish to a great extent and the outcomes are mostly determined by the "severity" of the organ failures. Similarly, the role of an antiviral may be present only in the early phase of the COVID infection. However, unlike a bacterial infection like a urinary tract infection, in the case of COVID, we know that more than 80% of patients improve on their own (without any medicines) - just like most of the acute viral infections (e.g. flu and dengue). Thus, taking Remdesivir too early in this 80% will not have any benefits.
Hence, it is a balance of finding which group of patients will need this drug to prevent worsening of the disease," he explains.
But What is the crux of the Remdesivir controversy?
Reshma Golamari MD, Assistant Professor of Medicine,Department of Internal Medicine at Penn State Health Milton S. Hershey Medical Center wants to clear a lot of controversies about the medication-Remdesivir. "The best study done for this medication was published in 2020," she adds.
"It revealed that Remdesivir only helps with time to recovery, i.e., patients who take this medication feel better quickly than patients who do not. It helps reduce oxygen requirement and prevents worsening disease in addition. When studied for preventing death in totality, it did not prevent death compared to patients who do not receive it. This implies that when a COVID-19 patient receives Remdesivir, it will help with symptoms and oxygen requirement, but they have an equal chance of dying from COVID-19 than a person with COVID who has not received it. The fact that Remdesivir did not prevent death was re-producible in another significant study which prompted the WHO guidelines to not recommend using it. Hence the discrepancies and why it became controversial. It was FDA approved in the United States based on symptom control. I have seen patients feel better and get discharged from the hospital, as well as patients who die while being on it. Hence, we need to pay close attention to what these studies mean and how they can be interpreted," she explains.
What are the lessons from Remdesivir usage for COVID in her organization?
"I have been working with COVID-19 patients here in the US since March 2020, and our site was one of the sites that studied Remdesivir as a part of the ACTT-1 clinical trial. We have used Remdesivir under compassionate use before the FDA approval and have been using it after approval; in my personal experience, patients feel better and have decreased oxygen requirements. At the same time, I have seen people die after receiving Remdesivir. When compared to the March-April surge in the US, we were able to discharge many more patients home during the December-January surge. I believe this was made possible by Remdesivir and steroids in patients that required oxygen. At the same time, it is highly crucial to use medications for the right reasons. For example, using steroids in patients of COVID-19 that did not require oxygen was studied to be more harmful," she explains.
Role of Media
Reshma Golamari points out that doctors use medications and treatment based on clinical trials studied from data obtained from the laboratory in medicine. "Not all drugs are used to prevent death and prolong survival, and some are used for symptom control and prevent worsening. Remdesivir was studied with the intention of improving survival, but it did not show a benefit in the overall survival, unfortunately. However, it helps with symptoms which is also a win in my own opinion. Also, sometimes studies do not have enough patients to show a significant difference between the two groups (treatment vs the non-treatment group), necessitating larger-scale studies. So no, I do not think it was premature for the media to report the positive effects of Remdesivir, but the reason why we use Remdesivir was misinterpreted. The same goes with steroids which are being misused, leading to unwarranted side effects such as black fungus," she explains.
What does published data about Remdesivir show?
Golamari notes that there are two major randomized studies done in this area. "The first one was published in November 2020, which has shown that patients receiving Remdesivir will recover by day ten compared to those not receiving it who recovered by day 15. However, the study did not show any differences in death in both groups by day 29, implying that even if you've received Remdesivir, you have a good chance of death by day 29. Another significant study named the Solidarity trial showed that a similar number of patients died whether they received Remdesivir, Hydroxychloroquine or two other less studied medications- Lopinavir or Interferon comparison not receiving any medications at all. There was an equal chance of being on a ventilator or spending the same time in the hospital. I wanted to stress the point that the purpose of using Remdesivir is for symptoms, including oxygen requirement, and it has not shown to prevent death."
Did early studies produce opposing evidence on the effectiveness of the drug?
Golamari adds that medicine is complex, especially in the ever-changing world. "Some studies provide the best possible evidence compared to others, and these studies are termed- randomized controlled trials. In these studies, patients are directly compared by receiving vs not receiving a drug. This is the best quality evidence we have to use vs not use treatments. I distinctly do not remember other types of studies on Remdesivir, but the results of the first randomized study from November were grossly misinterpreted. To summarize, Remdesivir helps symptoms and oxygen improvement, but patients that received these medications have an equal chance of dying," she says.
But has the drug undergone stringent regulatory tests?
Golamari points out that the randomized control trials published in reputed journals like the New England Journal of Medicine (NEJM) are thoroughly vetted and analyzed for any extraneous factors that affect the results. So they can be trusted, as compared to studies that come out of other not-so-well-known journals since they may not be thoroughly investigated.
How does a drug get approval from USFDA?
The FDA in the United States looks at the best quality research evidence available to authorize a medication for approval. Before any drug becomes available for use by the general public, it is studied in various phases like phase II & III. If these show a positive effect, be it for symptom control, survival, reduction of hospitalization and studied under the best possible circumstances, the FDA approves a medication. We have seen controversies in treatment for COVID-19 since numerous research studies were done and had conflicting outcomes like the utility of convalescent plasma. However, the FDA examines each piece of evidence and comes to a conclusion.
How to address the issue differently?
What is the best solution for the pandemic, vaccination or an effective antiviral drug?
Dr Anup R Warrier points out that a pandemic can be managed only by developing herd immunity, for which the safest and most proven way is by vaccination. "However, based on the transmission rates of the virus, the proportion of the population that needs to be vaccinated may vary. With the current pace of COVID vaccination, we will not achieve this soon. As we go along, high transmission rates and increasing infections will result in new variants that may render current vaccines not so effective. Hence, until our country population has been vaccinated to the extent of adequate herd immunity, the COVID appropriate behaviour must be implemented without any relaxations. This may mean another 2 -5 years of COVID protocols. We have enough experience with mass vaccination programmes in India, and in the absence of supply challenges, we should be able to do this," he concludes.