Rational Defensive Medicine: Putting an End to the Nationwide Favipiravir Debate.

To the Editor,

I have read the scientific letter by Karabayır et al[1] concerning favipiravir use in a lactating mother with great interest. It has reminded me of the favipiravir debate, which is going on nationwide nowadays.

Favipiravir, a medicine once used to be given to almost every severe acute respiratory syndrome coronavirus-2 polymerase chain reaction-positive individual in Turkey, regardless of the individual’s symptomatology, has recently fallen from grace. As a result of accumulating scientific evidence with randomized clinical trials, especially the announcement of the results of the long-awaited PRESECO (PREventing SEvere COVID-19) study, many experts, particularly those who are active in social media, raised their voices in favor of favipiravir’s removal from national coronavirus disease 2019 (COVID-19) guidelines.[2,3] Some even went so far as to suggest that favipiravir should have never been mentioned in these guidelines. This understandable and, to a certain extent, reasonable pressure from national infectious diseases circles eventually took its effect in the decisions of the Scientific Committee for COVID-19 and subsequently paved the way to related changes in national guidelines. The use of favipiravir is left to the physician’s discretion in the latest edition of the Ministry of Health guideline on adult patients’ management for COVID-19.[4] In the pediatric counterpart of the guideline, a more straightforward approach has been adopted such that its use is no longer recommended.[5] Turkish Clinical Microbiology and Infectious Diseases Society (KLIMIK) does not recommend favipiravir even in critical/intensive care patients.[6]

Looking at the heap of publications heralding the effectiveness of favipiravir in COVID-19, they are hard to rely on, because they are problematic in one or several ways including inadequate number of patients, a lack of placebo control, heterogeneity in study arms, primary endpoints not having been identified as to prove the definitive benefit of the drug, and last but not least, they have conflicting results.[7] What is more, two meta-analyses, both published in May 2021 have conflicting conclusions: one in favor of, the other disfavoring the use of favipiravir in COVID-19.[8,9]

One way or another, they are here glittering in the public eye with their results favoring the use of favipiravir. Therefore, there may be times that it would be hard to explain to ourselves and to the court, as well, why we have not given favipiravir to our little deceased patient. Remember, most of the time, physicians are charged with what they have not done or given, not with what they have done or given. Here, we are talking about the last resort, the presence of the slightest chance that favipiravir would work, a beneficial effect, which is tiny, but big enough to save the child.

My humble interim recommendation, until the ineffectiveness of favipiravir has been more firmly established by studies like PRINCIPLE (Platform Randomised trial of INterventions against COVID-19 In older peoPLE) and the disappearance of the drug from pharmacies, would be to inform the patient or the caregivers, of the presence of an antiviral drug whose expected efficiency would be very low and to take a written informed consent, for or against the use of favipiravir, regardless of the patient’s age.[10] This is exactly the same approach we have used so far for every severe or critically ill child with COVID-19.

The presence of favipiravir in hospital pharmacy takes the freedom of the physician from not using it. If favipiravir is not recommended in the guidelines because the chances that it may be useful are so low and pediatricians are expected to abide by the guidelines, favipiravir should not be made available in hospital pharmacy, coherent with the guidelines.

Until then, I propose that favipiravir should continue to be offered to critically ill children with COVID-19 as a last resort, just in case. That is what I call “rational defensive medicine.”