Updated: Study identifies Covid-19 patients with mutations indicating remdesivir resistance
As the bivalent booster season kicks off in earnest, a new study published yesterday from NYU researchers identifies two cases of mutated coronavirus resistant to Gilead’s remdesivir in immunocompromised individuals.
The two patients in their 50s and 60s had both undergone kidney transplants (and were both vaccinated prior to those transplants), with one experiencing Covid for several months while receiving rituximab and bendamustine for lymphoma.
“The combined effect of these mutations may limit the clinical efficacy of remdesivir,” the researchers wrote, adding:
remdesivir use has become widespread, and we show that mutations associated with remdesivir resistance arise in vivo, our work emphasizes surveillance efforts to detect mutations in immunocompromised patients. Potentially foreshadowing an “end-game” scenario for the COVID-19 pandemic, complex cases like the ones we describe highlight the need for more advanced molecular diagnostics at the onset of illness to guide therapeutic decisions. Additionally, our work emphasizes the risk of immune escape in immunocompromised hosts, with novel mutations contributing to recrudescence of infection. Equally concerning are recent reports in immunocompromised hosts highlighting the development of SARS-CoV-2 spike mutations conferring resistance to immunotherapeutics after treatment with monoclonal antibodies.
First fully approved by FDA in October 2020, remdesivir has proven to be a blockbuster, pulling in more than $5.5 billion last year, but unlike other Covid blockbuster therapeutics (e.g. Regeneron’s mAb and Lilly’s mAb combo treatment) remdesivir has managed to stay effective with each new variant so far.
Gilead said in an emailed statement that it
has reviewed a report of a resistance mutation (V792I) in the viral RNA polymerase, the target of remdesivir, which occurred in two hospitalized renal transplant recipients with severely compromised immune function and chronic SARS-CoV-2 infection, after repeated remdesivir exposure. One patient had high viremia (presence of a virus in the blood) and was treated with a 5-day course of remdesivir 6 months after transplant and another 5-day course upon readmission 24 days after initial COVID-19 diagnosis. The second patient had high viremia and was treated with a 3-day course of remdesivir fourteen months after transplant and another 5-day course upon readmission 18 days after initial COVID-19 diagnosis. It is known that unchecked, prolonged viral replication in patients with immunocompromised status can result in viral genetic diversity within such individuals and proactive therapy is warranted in patients requiring hospitalization. It is in the best interest of patients to treat SARS-CoV-2 infection as soon as possible and, as the article suggests, further efforts are needed to identify concerning mutations conferring resistance to SARS-CoV-2 therapeutics and address their clinical implications. The V792I mutation has been previously identified in an in vitro selection study, which showed that this mutation alone reduces the antiviral activity of remdesivir by 2.6-fold, indicating that other mutations might be required to further reduce the sensitivity of virus to the drug.
But in vitro studies indicate that Veklury (remdesivir) continues to be active against Omicron variants including the current BA.4 and BA.5, Gilead said, adding that at this time, more than half of patients hospitalized with Covid in the US are treated with Veklury and it is approved or authorized for temporary use in approximately 50 countries worldwide.