Paxlovid Becoming Less Effective as COVID-19 Develops Resistance

Drug-resistant variants of COVID-19 have appeared around the world, leading to concerns that Paxlovid will become increasingly less effective against SARS-CoV-2 infection. Find out why the authors suggest treatment with multiple agents would be better and how future protease inhibitors might become more effective against newer COVID-19 strains.

MINNEAPOLIS, MN – A new study warns that the protease inhibitor Paxlovid is increasingly less effective against COVID-19 infections.

A report in Science Advances points out that resistance to Paxlovid is already evident among viral SARS-CoV-2 variants currently circulating globally.

Researchers from the Midwest Antiviral Drug Discovery (AViDD) Center at the University of Minnesota point out that drug-resistant variants have appeared multiple times independently in different parts of the world, adding that regional clusters have provided evidence for person-to-person transmission.

Not only do the mutations show resistance to the protease inhibitor nirmatrelvir, the active component of Paxlovid, but the study also reports that a different set of mutations currently in circulation can transfer resistance to ensitrelvir (Xocova), a protease inhibitor now approved in Japan.

The authors warn that simple single amino acid changes in SARS-CoV-2 main protease could undermine the efficacy of these antiviral drugs. 

Reuben Harris, PhD, co-director of the Midwest AViDD Center, explained that “although our study demonstrates the existence of natural circulating SARS-CoV-2 variants with resistance to two different drugs, the good news is that their resistance profiles are distinct. This means that if one of these drugs fails due to the emergence of resistance in viral variants, the other drug may still work.”

“Vaccines and drugs have helped reduce disease severity and blunt the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),’ the study authors write. “However, ongoing virus transmission, continuous evolution, and increasing selective pressures have the potential to yield viral variants capable of resisting these interventions.”

The study team says the results “encourage the monitoring of resistance variants and the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles for combinatorial therapy.

The good news, according to the study, is that additional next-generation protease inhibitors with different resistance profiles, as well as drugs that target different viral processes such as replication or cell entry, will be developed. The authors advise that the use of a multi-drug approach—like existing therapies for HIV and Hepatitis C virus — could help protect against resistance and cure SARS-CoV-2-infected patiens. 

“Despite Paxlovid’s proven success in blunting COVID-19 symptoms, the long-term consequences of its widespread use in speeding up resistance are unknown,” said S. Arad Moghadasi, co-author of the study and a University of Minnesota Medical School graduate student. “Drugs with the highest barriers to resistance are likely to prove more effective and have longer-term durability.”

“We are optimistic that ongoing studies will develop additional compounds to avoid cross-resistance and help combat the current COVID-19 pandemic and future coronavirus outbreaks,” Harris added.

This research was supported by the National Institute of Allergy and Infectious Diseases.