How well do COVID antivirals actually work? Not as well as we thought

A Shift in Antiviral Effectiveness

When COVID-19 emerged in late 2019, no treatment was available. Existing influenza antivirals, stockpiled by governments, proved ineffective. Scientists quickly sought existing or new drugs, and by 2021, two industry-sponsored clinical trials reported promising results: nirmatrelvir-ritonavir (Paxlovid) showed an 89% reduction in severe illness, while molnupiravir (Lagevrio) showed a 30% reduction. Both drugs work by stopping SARS-CoV-2 from replicating and must be taken within five days of illness onset.

However, new research suggests that with high levels of vaccination and immunity from previous infections, these antivirals are no longer working as well. The research, reported by Hindustan Times and The Hindu Business Line, indicates that the benefits of these drugs have diminished significantly.

The Australian Context

Both drugs were listed on Australia's Pharmaceutical Benefits Scheme (PBS) in early and mid-2022, ensuring access at low or no cost for those most at risk. A course of treatment cost the government around A$1,100, considerably more than influenza treatment oseltamivir (Tamiflu), which costs about $40. Between mid-2022 and mid-2025, the Australian government spent over $2 billion on Paxlovid and Lagevrio.

Most Australians have now been vaccinated against COVID and infected with SARS-CoV-2 more than once, resulting in hybrid immunity that reduces the likelihood and severity of future infections. The virus itself has also changed, with newer variants appearing less severe than those early in the pandemic.

Examining the Latest Evidence

In the two randomised controlled trials conducted in vaccinated people, neither reported a reduction in severe outcomes after taking either Paxlovid or Lagevrio. One trial, involving hospitalised patients treated with Paxlovid, found no difference between treated and untreated groups. The Lagevrio trial in vaccinated people reported no statistical difference in hospitalisation or death between those who did and did not receive treatment.

A meta-analysis of 35 observational studies found that Paxlovid was associated with a 40% reduction in hospitalisation and a 67% reduction in death, while Lagevrio was not associated with a significant reduction in hospitalisation and had mixed results against death. Researchers noted that there were eight randomised controlled trials of Paxlovid and Lagevrio identified, but most were conducted before people were vaccinated. Two further randomised controlled trials of Paxlovid published since the research also reported no reduction in hospitalisation or death.

"Our work shows there may be some benefit from Paxlovid," the researchers said. "But as the number of cases and the risk of severe illness continues to fall, this benefit is becoming very small."

Public Health Impact

In 2025, Australia reported 186,000 COVID cases, 178,000 RSV cases, and 503,000 influenza cases. COVID was involved in 2,227 deaths, with three quarters of those among people aged 80 and over, while influenza was involved in 1,784 deaths. COVID-related hospitalisations at sentinel hospitals in the first half of the year were 839, compared to 1,740 in the same period last year. The reported numbers are well below the true figures because most people do not get tested.

COVID went from being the leading cause of death worldwide in 2021 to the 20th in 2023, reflecting the reduced severity of the disease.

Antiviral Harms and Eligibility

Antivirals can cause side effects such as taste changes, nausea, vomiting, and allergic reactions. Paxlovid can interact with other drugs, causing serious reactions. It should be avoided or the dose adjusted in people with severe liver or kidney disease, as it can worsen these conditions.

Eligibility for free or subsidised antivirals may include being aged over 70, or over 50 with underlying health conditions, and having tested positive for COVID. As reported by The Hindu Business Line, if you test positive for COVID, it is advisable to talk to your GP about whether antivirals may be appropriate for you.

Looking Ahead

The Pharmaceutical Benefits Advisory Committee is set to review COVID antivirals later in 2026, a move that will likely consider the evolving evidence on their effectiveness.