Source: The Conversation (Au and NZ)
If you’re aged over 70, or over 50 with underlying health conditions, and have tested positive for COVID, you might have been offered free or subsidised antivirals.
Earlier in the pandemic, these medicines were an important way to reduce the chance of people becoming severely ill with COVID, needing to be hospitalised, or dying.
But our new research suggests that with high levels of vaccination and immunity from previous infections, COVID antivirals are no longer working as well.
From no treatment to an effective one
When SARS-CoV-2, the virus that causes COVID, first emerged in late 2019, no treatment was available. Existing influenza antivirals, which had been stockpiled by governments, were ineffective and couldn’t be used.
Scientists rapidly tried to figure out which existing or new drugs could be used. In 2021, two industry-sponsored clinical trials reported promising results.
One was for nirmatrelvir-ritonavir (Paxlovid), which reported an 89% reduction in severe illness. The other was a trial of molnupiravir (Lagevrio), which reported a 30% reduction.
Paxlovid and Lagevrio work by stopping SARS-CoV-2 from replicating. So they need to be taken early in the course of illness – within five days – to be effective.
Both drugs became available in Australia and were listed on the Pharmaceutical Benefits Scheme (PBS) in early and mid-2022. This ensured people most at risk of severe illness had access to drugs at low or no cost.
Paxlovid and Lagevrio are expensive. A course of treatment cost the government around A$1,100 from 2022 to 2025, much more than the treatment for influenza, oseltamivir (Tamiflu), which is only around $40.
Between mid-2022 and mid-2025 the Australian government spent more than $2 billion on Paxlovid and Lagevrio.
What’s different now?
Most Australians have now been vaccinated against COVID and infected with SARS-CoV-2 more than once. This results in hybrid immunity and reduces the likelihood and severity of future infections.
The virus itself has also changed, with the original variants replaced by new ones that appear to be less severe than early in the pandemic.
These changes prompted us to evaluate the more recent evidence.
What did we study and find?
First, we examined randomised controlled trials – the gold standard of evidence. We found eight trials of Paxlovid and Lagevrio, but most were done before people were vaccinated.
When we looked at the two randomised control trials in vaccinated people, neither reported a reduction in severe outcomes after taking either Paxlovid or Lagevrio.
The Lagevrio trial reported no statistical difference in hospitalisation or death in people who did and didn’t receive treatment.
The other was a trial of people in hospital who were treated with Paxlovid. It found no difference in the people treated and not treated.
There were some nuances to these findings. Randomised controlled trials are expensive and resource-intensive. As COVID went from being the leading cause of death worldwide in 2021 to the 20th in 2023, it became more difficult to justify the costs and recruit enough participants, so some trials were stopped early.
However, two randomised controlled trials of Paxlovid have been published since our work, and neither reported a reduction in hospitalisation or death.
In phase two of our research, we looked at the 35 observational studies, where researchers can include many more people but can’t control who gets the treatment. We pooled the results from the studies to estimate the effectiveness for each drug against hospitalisation and death.
This meta-analysis found Paxlovid, but not Lagevrio, reduced hospitalisation and death.
Paxlovid was associated with a 40% reduction in hospitalisation and a 67% reduction in death.
Lagevrio wasn’t associated with a significant reduction in hospitalisation and the results were mixed against death.
Because the treatment wasn’t randomised, there may be differences between people who received treatment and those who didn’t. People accessing treatment, for example, may have greater health literacy or access to other health services.
While some studies use methods to adjust for differences in people who do and don’t receive treatment, it’s usually not possible to adjust for every difference.
COVID is still a concern for at-risk groups
SARS-CoV-2, like influenza and respiratory syncytial virus (RSV), remains a common cause of acute respiratory illness in Australia. In 2025, there were:
- 186,000 cases of COVID reported
- 178,000 cases of RSV
- 503,000 cases of influenza.
But the number of COVID, RSV and influenza cases reported is well below the true number, as most people don’t get tested.
COVID is still claiming lives. There were 2,227 deaths involving COVID in 2025. This is more than the 1,784 deaths involving influenza. Three quarters of deaths were among people aged 80 and over.
The rates of COVID-related hospitalisations so far this year have been lower than last year, with 839 admissions at “sentinel hospitals” (those chosen to monitor disease trends) in the first half of this year. This compares to 1,740 in the same period last year.
What does this mean?
COVID can still cause severe illness, hospitalisation and death, particularly in older people.
If you test positive for COVID, talk to your GP about whether antivirals may be appropriate for you.
Our work shows there may be some benefit from Paxlovid. But as the number of cases and the risk of severe illness continues to fall, this benefit is becoming very small.
Given how little evidence there is for Lagevrio, its role in treating COVID should be carefully considered.
Harms of antivirals can include side effects – such as taste changes, nausea and vomiting – and allergic reactions.
Paxlovid can also interact with other drugs, causing serious reactions. It should be avoided, or the dose adjusted, in people with severe liver or kidney disease because it can make these conditions worse.
Australia’s independent Pharmaceutical Benefits Advisory Committee (PBAC) is set to review COVID antivirals later in 2026. It will assess the costs and benefits of Paxlovid and Lagevrio and it may change its recommendations about who can access the drugs on the PBS.
Our findings support this reassessment.
Laura Edwards receives funding from the National Health and Medical Research Council.
Allen Cheng receives funding from the Australian Centre for Disease Control for respiratory virus infection surveillance. He was previously a member of the National COVID-19 Evidence Task Force, which developed guidelines for the use of antivirals for COVID. He was also previously a member of the Scientific and Industry Technical Advisory Group which advised the Australian government of COVID-19 vaccines and treatments. He is a director of Therapeutic Guidelines Ltd, which publishes clinical treatment guidelines.
Bette Liu has received funding from the National Health and Medical Research Council, the Medical Research Future Fund and the Australian government Department of Health for work related to COVID. She sits on the Therapeutic Goods Administration’s vaccines advisory committee.
James Wood receives funding from the National Health and Medical Research Council for research on respiratory viruses including SARS-CoV-2. He is also a voting member of the Australian Technical Advisory Group on Immunisation.
Original source: https://analysis1.mil-osi.com/2026/08/23/how-well-do-covid-antivirals-actually-work-not-as-well-as-we-thought/