Crowds of people outside pharmacies hoping to buy doses of the antiviral drug remdesivir have been among the defining images of the second wave of Covid-19 infections in India. The drug was earlier manufactured to treat Ebola and then repurposed to treat Covid-19. Concerns remain that remdesivir, which has been shown to be ineffective in large randomised controlled trials, is being overprescribed.

Also in great demand is plasma therapy, using plasma from patients who have recovered from the disease, despite the fact that this was shown to be ineffective in reducing mortality in a trial conducted by the Indian Council for Medical Research.

On Friday, in response to a statement of the Gujarat Advocate General about the “myths of efficacy of remdesivir” and that the drug was being overprescribed, the Gujarat High Court observed that “ ...the public doesn’t know… public thinks remdesivir will save them from Covid-19… unnecessarily hype has been created… the state should have seen to it that remdesivir was not given that much of importance if it was not all that relevant.”

How have physicians dealt with the challenge of limited treatment options? How has the treatment protocol in India evolved? spoke to Dr Lancelot Pinto, consultant pulmonologist at Mumbai’s PD Hinduja Hospital.

Social media platforms are replete with appeals for help in securing remdesivir for loved ones undergoing treatment in hospital, quite like the appeals we saw for plasma donors. The majority of these appeals are from families of patients admitted to hospitals.

Does the treating physician/hospital inform the patient’s family that they are recommending the drug for treatment but because the facility does not have access to the drug/has run out, the patient’s family should arrange for it themselves?

From the first-hand accounts that I have heard from relatives of patients across the city, and from frantic messages from friends and family who have loved ones admitted at hospitals, this does seem to be the case with multiple therapies such as remdesivir, tocilizumab and plasma. The patient is often critically ill, the families desperate for something to be done, and they are often advised by multiple sources to try one of these therapies. Doctors themselves often suggest these therapies, and if the said therapy isn’t accessible to the treating physician, the family is given a prescription and asked to procure the drug (or donated plasma).

Based on the World Health Organisation solidarity trial results and three other Randomised Control Trials, the WHO issued a conditional recommendation against the use of remdesivir late last year. As recently as last week, WHO chief scientist, Dr Soumya Swaminathan, reiterated that position.

Smaller studies, like this study published in NEJM concluded that their data shows that remdesivir was superior to placebos in shortening the time to recovery in adults who were hospitalised with Covid-19 and had evidence of lower respiratory tract infection.

Dr Lancelot Pinto.

What is your own clinical experience assessment of the benefits, if any, of the use of remdesivir. And how do treating physicians take a call.

Do you rely solely on what large-scale Randomised Control Trials have shown as being the benefits or lack of it of a drug? Can the clinical experience of treating patients with the drug be markedly different from what the RCT shows? Is evidence based medicine a mix of the two approaches?

The message from multiple studies (and a systematic review which included over 7,000 patients conducted as a collaborative effort commissioned by the WHO) is clear and consistent about remdesivir: neither does it reduce mortality (i.e. it is not “life-saving”), nor does it prevent the clinical worsening of a patient to the point of being on a ventilator (i.e. it does not prevent mild/moderate disease from becoming severe).

The only possible role it may have is in reducing the length of stay in a hospital, and this has been touted as a strong reason to use it, especially when hospital beds are in shortage, and discharging a patient as soon as possible is of paramount importance. But this is a very nuanced argument, and is applicable to countries/settings in which admission criteria are very stringent.

If, for example, a person does not need to be hospitalised, or is being hospitalised only to receive remdesivir, not only is the drug unlikely to have an effect, the decision to administer remdesivir could potentially make a bed unavailable for five days [the length of a course of remdesivir].

Same argument holds true for a patient who is fit to be discharged from the hospital in two or three days but is now committed to being in the hospital for five days because of being prescribed remdesivir. What also seems to be the consensus is that if the drug does have an effect, it is more likely to do so in the early, viremic phase of the disease than the later phases.

The only situation in which I would use the drug is when a high-risk individual with early viremic symptoms is admitted in view of the high-risk. Once a patient’s oxygen levels have fallen (usually in the second week of the disease), the drug is unlikely to be of any use. Unfortunately, most of the cries for help are for patients in this stage of the disease. The desperation is understandable, but the need to “do something” does not warrant using drugs that have been clearly proven to be ineffective.

As a treating physician, it would be fallacious for me to believe that my personal clinical experience could be beyond the realm of chance; this is why science believes in the law of large numbers and not anecdotal evidence. If a physician believes strongly in an anecdotal experience, she/he should report it as a case or an experience, and such cases are often the seeds for future clinical trials. A pandemic is no excuse to trial therapies without evidence [outside the setting of a clinical trial which a patient consents to being a part of].

In a pandemic such as this one, how big a role do government-issued treatment protocol/guidelines play, particularly in regulating the unnecessary over prescription of drugs? The last time the health ministry published a clinical management protocol for Covid, was on July 3. There is of course the national task force and various states have constituted their own state task forces. Shouldn’t these panels be de-emphasising the publicity given to treatments that have now been found to be ineffective?

I couldn’t agree more. The first step, of course, is having a living guideline that constantly adapts to the available evidence. Drugs such as favipiravir, HCQ, itolizumab, and a whole gamut of vitamins and antibiotics are present in the Maharashtra task force recommendations, which were updated as recently as March 23. These drugs, to the best of my knowledge, are included in the guidelines of no other country in the world.

I have a collection of prescriptions from patients who have taken a second opinion from me, which have close to a dozen drugs for mild and asymptomatic Covid-19 being managed at home. It becomes a daily struggle for physicians who practice sound evidence-based medicine to counter the demands of patients when task forces recommend the contrary.

I think we need to start getting the message out that drugs are prescribed based on benefit-risk ratios, and when the benefit is clearly unproven, prescribing a drug equates to doing harm, violating the first principle of sound medicine. This harm has the potential to multiply several fold when polypharmacy leads to drugs interactions that can be potentially lethal. “Don’t just do something, stand there” is often what a clinical situation demands; the guidelines need to encourage us to do this rather than solve every medical concern with an added drug.

As a doctor do you come under pressure from families of patients to undertake a certain course of treatment because of the wide publicity given to certain drugs, treatments?

All the time. When patients take multiple opinions, they often choose the doctor who offers them the most number of pills. Ironically, the perception of risk plays an important role in such decisions, and doctors who prescribe less are often favoured for chronic diseases (which often may need regular and multiple drugs to prevent long-term consequences). So, the patient with chronic asthma often chooses the doctor who tells her/him that a long-term inhaler isn’t warranted (which is more often than not bad advice), while a patient full of fear and dread after being infected with Covid-19 finds it extremely unnerving to be treated by a doctor who prescribes vigilant inactivity and symptomatic treatment at home for a disease that has no drug proven to affect course in the initial stages.

It takes a lot of trust for a patient to take that leap of faith, even though it is what all physicians should be practicing. The pressure to prescribe therapies such as remdesivir, tocilizumab, and plasma is immense when patients are in severe stages of the disease, at the time when these modalities are least likely to have a meaningful effect.

You are also trained in epidemiology. Can you tell us if there is any change in age-specific incidence rates and/or deaths for Covid. Is there a case for opening up vaccination for all age groups?

The median age of the Indian population is 27 years, i.e. half of India’s population is under 27 years of age. When we have a surge in Covid-19 cases of the magnitude that we are presently experiencing, it should come as no surprise that a significant proportion of those infected are young. Indians tend to have cardiovascular risk factors (which are key predictors of the severity of Covid-19 disease) present a decade earlier than the ages at which these are incident in developed nations.

As the numbers of those infected increase to significant magnitudes in younger individuals, rare events will begin to manifest, and we have been witnessing and hearing about deaths and severe disease in younger individuals. There is a strong case for opening up vaccination not only to prevent these unfortunate deaths, but also because herd immunity is an unattainable dream if you exclude over half the country’s population from a vaccination programme.