Highlights:
- Nirmatrelvir-ritonavir, or Paxlovid, is an effective antiviral for COVID-19, but some patients experience a rebound infection after treatment.
- Using a mathematical model, researchers unearthed a plausible explanation: the treatment can leave behind vulnerable cells that may become infected by lingering infectious viral particles.
- The findings suggest a 10-day antiviral course as opposed to the standard 5 days may be more beneficial for people at high risk of serious infection
Washington, D.C.-The antiviral combination of nirmatrelvir and ritonavir (brand name Paxlovid) is an effective treatment for people with COVID-19 who have mild symptoms and face a high risk of hospitalization. For some of those people, however, the virus returns, and those patients may experience more symptoms and spread the virus to others.
This week in Journal of Virology, researchers report on the likely reason behind the rebound. They found that the antiviral treatment, especially when given early in the course of the infection, can leave behind target cells that can still be infected with the virus. In addition, the treatment may not completely clear the virus, leaving behind infectious particles that invade the target cells.
"If at the end of 5 days of treatment, there's still virus and target cells around, then the infection can basically restart," said Alan Perelson, Ph.D, a theoretical immunologist and mathematical modeler at Los Alamos National Laboratory who led the study. Though the antiviral stops existing viruses from replicating, it doesn't remove the viral particles or the infected cells.
The antiviral drug Paxlovid was approved by the U.S. Food and Drug Administration for emergency use in December 2021. In 2022, Perelson, who has been studying the progression of viral infections for about 40 years, began hearing reports of people who first responded to the treatment and then experienced a rebound.
To better understand the underlying mechanism, he and his colleagues used a mathematical model to analyze changes in the viral load of 51 patients, all treated with nirmatrelvir-ritonavir and 20 of whom experienced a rebound case. The clinical data came from Perelson's collaborators at Massachusetts General Hospital.
The model incorporated what researchers knew about how the viral load changed over the course of an infection. The amount of virus grows rapidly at first and peaks after 3 or 4 days, which is when symptoms become apparent. Cells in the body respond by secreting a protein called interferon that interferes with the infection. Over the first week or so, the adaptive immune system responds by producing antibodies that coat the virus and prevent spreading and infection.
"The real cleaning up of [the virus] is done by the adaptive immune response," Perelson said.
When the researchers added patient data about the antiviral treatment to the model, they observed that the dynamics changed. While the remaining virus could no longer replicate, it could still infect cells that hadn't been killed by the virus or were not protected by interferon. Notably, starting antiviral treatment earlier preserved more target cells, which increased the likelihood of a rebound after treatment was stopped.
"The way we're describing what goes on in these individuals, mathematically, was accurate both for the individuals who experienced rebound and those that didn't," Perelson said.
Patients take antiviral treatment for 5 days as the standard of care. The new study suggests that a 10-day course may more effectively reduce a person's risk of a rebound. That duration may give the body enough time to develop a robust immune response.
