The emergence of novel variants have brought forward the concept of “Hit early, Hit hard” to prevent the progression of mild/moderate illness by accelerating viral clearance. 

A letter addresses the rationale, unmet need, scientific evidence and the associated controversies with the novel oral antiviral therapies in COVID-19 treatment.

Molnupiravir substitutes cytidine and uridine triphosphates with either Adenine or Guanine forms, leading to lethal mutagenesis and inhibition of viral propagation.

 This drug has received FDA emergency use authorization (EUA) for use in mild to moderate COVID-19 cases with risk factors for progression to severe illness. Subsequent approval by the Drug Controller of India (CDSCO) coupled with ​​Mercks decision of global access to Molnupiravir through generics manufacturers has made it available widely in Indian markets during the recent surge of Omicron. 

Along with this, FDA has issued a warning against its use in pregnancy due to potential embryo-foetal toxicity, and in children due to potential cartilage and bone toxicity demonstrated in host animal cell culture assay. As Molnupiravir induces errors in the viral RNA, concern remains regarding the emergence of newer variants, especially in underdosing or premature termination of therapy. Furthermore, a theoretical risk of mutagenesis was shown in Chinese hamster ovary cells. However, extensive studies in-vivo whole animal mutagenicity assays (Pig-a mutagenicity assay and Big Blue [cII locus] transgenic rodent assay) do not indicate any distinct mutagenicity. Thus Molnupiravir should be used rationally, only on the advice of a registered medical practitioner (symptomatic patients with risk for progression to severe illness).

Paxlovid is an oral antiviral drug, which is a combination of protease inhibitors Nirmatrelvir and Ritonavir. Nirmatrelvir, an orally active main protease (Mpro) inhibitor, limits the activity of viral proteases thus preventing viral replication. It is co-administered with Ritonavir which has inhibitory effects on cytochrome P450 and slows down the metabolism of Nirmatrelvir accordingly increasing its bioavailability. FDA has given a EUA for use in non-hospitalised adults with mild to moderate COVID-19 infection and with pre-specified risk factors for disease progression. Paxlovid has shown a ten-fold reduction in viral load, with effectiveness even against Delta and Omicron variants and effective in mild to moderate COVID-19 patients at low risk of hospitalization/death. Paxlovid use is limiting pertaining to its cost, multiple drug interactions with CYP3A enzyme inducers/inhibitors, causing HIV drug resistance in individuals with uncontrolled/undiagnosed HIV-1 infection and dose modification requirement in moderate renal dysfunction.

Favipiravir is an inhibitor of the viral RNA-dependent RNA polymerase, which shows fast viral clearance and a greater clinical recovery rate. Further, its availability as an oral drug and a proven safety profile makes it a fortunate therapy for COVID-19. The Drug Controller of India (CDSCO) has given a EUA for favipiravir and multiple state governments have considered it for treatment cocktail, however proof for objective benefit is still lacking. Open-label studies have reported initial promising results; however, the cost of therapy and pill burden remains major limitations.

Source- Heart and Lung, 2022:1-4. DOI:https://doi.org/10.1016/j.hrtlng.2022.01.011