Favipiravir in COVID-19- is it worth the hype?
The authors on their opinion article “The many Questions about Favipiravir”, Page 7, June 25, 2020 have rightly raised concerns about the approval process undertaken by DCGI for Favipiravir in COVID-19 treatment.
Glenmark, the company launching the drug for the first time in India claims that the approval was given for Favipiravir after the positive results of a randomized study in India with 150 patients randomized to Favipiravir with standard of care (SOC) versus patients who had only SOC. The results have not been published in any peer reviewed journal yet nor available in public domain. However, Glenmark quote the results from 4 other studies which were conducted outside India (2 from China, one from Russia and Japan each) showing benefit with the use of Favipiravir. Out of these, only the Japanese registry study included large patient population of around 2000 patients (20 and 236 patients in Chinese studies and 330 patients in the Russian study). This Japanese study is not yet published in medical journal, but available online for access- https://www.news-medical.net/news/20200602/Preliminary-report-of-Favipiravir-Observational-Study-in-Japan-released.aspx
The main information given by Glenmark quoting 88% improvement in mild COVID-19 patients were derived from this large Japanese observational registry of 2158 patients. This is an one arm study with no comparative subjects. Favipravir was administered to all 2158 patients with mild (45%), moderate (44%) and severe (11%) COVID-19 disease. The classification of mild, moderate and severe COVID-19 was based on oxygen and ventilator need as in most other COVID-19 studies- mild means no oxygen needed, moderate means patients needing supplemental oxygen and severe means those who needs ventilator support. The Japanese study reports 88% improvement in clinical symptoms in mild group, 85% improvement in moderate group and 60% improvement in severe group at 14 days (but the 14-day data is available only for 1282 patients leaving behind nearly 800 patients who had Favipiravir (40% drop out of data). This itself suggest the quality of the study and would not be published in quality peer review medical journals.
We already have large randomized data results from RECOVERY trial, showing dexamethasone improved survival in moderate (20%) and severe (35%) COVID-19 patients compared to patients who had SOC alone. Considering this data as well as the cost benefit, dexamethasone should be the first choice for patients who have moderate and severe COVID-19 disease, (as anyone would agree mortality benefit is more important than clinical improvement). So, if we analyse the mild symptom patients alone, the big question is how many mild symptom patients progress to moderate or severe if not on Favipiravir. The Japanese study did not address this as there was no comparative group. The authors of the study themselves have acknowledged this in their paper, at the last but one paragraph and suggested that the previous data from china have shown that nearly 80% patients with mild symptom improves with supportive therapy alone. Therefore, there seems to be not a major benefit of giving Favipiravir in mild COVID-19 cases for clinical improvement.
So, the question is where will this drug fits into? The small Chinese study (80 patients) have shown that there was significant reduction in viral load at a median of 4 days compared to Lopinavir+Ritonavir combination. If this small study is taken into account, there may be a role of this drug to reduce the duration of quarantine (from 14 days to 7 days) for patients with mild symptoms. But this should only be from a recommendation from ICMR, after confirming the finding in a larger study.
So, what about moderate disease patients- as we discussed earlier, since Dexamethasone has already shown mortality benefit, the only way Favipiravir can fit into is as an additional medication with dexamethasone to see if this combination will improve outcomes further than dexamethasone alone. Again, this is only hypothesis generating, until proven with randomised studies, as the combination should not cause more harm to patients.
Therefore, clinicians really need to think before prescribing Favipiravir, as the drug comes with a huge price tag, costing nearly Rs 14,000 for a treatment course.
And last but not the least, the 30-day mortality rates in the Japanese Favipiravir study was 5.1%, 12.7% and 31.7% for mild, moderate and severe disease, respectively which is much higher than what we see in India now. And I do not think the results of the randomised study of 150 patients (which is ongoing in India) will add more information, considering the small sample size for a pandemic of this enormity.