Doubts over impact of key antiviral treatment

The efficacy of Australia’s most widely prescribed COVID-19 oral antiviral treatment has been called into question following the early results of a significant trial in England.
 
The research, the largest randomised real-world study to date, was conducted by the University of Oxford to track the safety, efficacy and cost-effectiveness of COVID-19 oral antivirals. Its preliminary data analysis on the use of molnupiravir suggests the treatment has no overall impact on hospitalisations and deaths – but could help people to recover more swiftly.
 
The drug is by far the most prescribed COVID-19 oral antiviral in Australia, with around 237,440 prescriptions reported in the latest Primary Care COVID-19 update published last Thursday.
 
Sold as Lagevrio, it became available on the PBS in March this year. A second oral antiviral, nirmatrelvir with ritanovir – sold as Paxlovid – was released onto the PBS in May. By way of comparison, the latter treatment, which has many more drug interactions, had been prescribed 60,350 times as of last Friday.
 
The findings, which are likely to have implications for GPs prescribing oral antiviral treatments, emerged from the UK’s ‘PANORAMIC’ trial, which ran from 8 December 2021 to 27 April 2022.
 
The analysis included data from 25,000 participants comprising people aged over 50, as well as patients aged over 18 with co-morbidities that increased their risk of severe illness.
 
Of those who took part, 12,516 were randomised to molnupiravir and usual care, while 12,484 had usual care alone. The report records 103 hospitalisations or deaths among the molnupiravir group, compared to 96 among the usual care cohort – the equivalent of 0.8% for both groups.
 
‘In this preliminary analysis, we found that molnupiravir did not reduce already low hospitalisations/deaths among higher risk, vaccinated adults with COVID-19 in the community, but resulted in faster time to recovery, and reduced viral detection and load,’ the authors wrote.
 
For Professor Robert Booy, an infectious diseases and vaccine expert at the University of Sydney, the sample size is significant.
 
‘Once you’ve got a very large study, you have to pay attention,’ he told newsGP.
 
He describes the analysis as ‘disconcerting’ and says it may increase the focus on other treatments such as Evusheld and sotrovimab, as well as nirmatrelvir with ritanovir.
 
‘It’s easy for GPs to prescribe molnupiravir because they don’t have to spend 10 minutes going through all the possible drug interactions,’ he said. ‘It’s potentially been oversubscribed.
 
‘And Paxlovid may have [been] under-subscribed because people need 10–15 minutes to check whether drugs they’re already on can be ceased for 5–10 days.’
 
Dr Anthony Marinucci, the incoming Chair of RACGP Specific Interests Aged Care, said he has been ‘reliant’ on molnupiravir and estimates having prescribed it more than 100 times, which he puts down to two main reasons.
 
‘It’s been given as emergency stock for aged care facilities by the Federal Government, so they normally have it in stock and ready to go,’ he told newsGP.
 
‘And secondly, the other antivirals have a lot of drug–drug interactions. It’s probably the safest in the sense of adverse reactions or interactions with other meds.
 
‘Most of my patients are on a significant amount of other medications. I’m heavily dependent [on prescribing molnupiravir], I use it all the time.’
 
The manufacturer of molnupiravir, Merck, acknowledged that the PANORAMIC results show no evidence of the drug making a difference to hospitalisations or deaths among highly-vaccinated adults, noting that most in the study were younger than 65.
 
It also highlights that for the time to self-reported recovery, a secondary endpoint of the study, the molnupiravir group was six days faster when compared to the usual care group.
 
‘In addition, the use of [molnupiravir] also was associated with earlier recovery across a wide range of other symptom measures, as compared to the usual care group,’ the company stated.
 
This tallies with the experience of Dr Marinucci.
 
‘Anecdotally, a generally stable, otherwise well, fully vaccinated 80-year-old person who gets coronavirus, and who also has a course of Lagevrio, tends to recover quickly,’ he said. ‘Although it is very possible these same patients may have done equally as well without Lagevrio.’

Dr Marinucci also points to details in the appendix of the PANORAMIC analysis, which showed more positive results in preventing hospitalisations and deaths among older age groups – but with wide confidence intervals.
 
He believes more evidence is still required for the impact on vulnerable, older subgroups.
 
‘I don’t think anyone could really give you a 100% answer at the moment because we’re too early on,’ he said.
 
The main ‘MOVe-OUT’ clinical trial used as evidence for molnupiravir’s provisional approval in Australia took place among unvaccinated people. Researchers concluded that early treatment with the drug reduced the risk of hospitalisation or death.
 
Professor Booy said COVID variants that evolved after that research could have had an impact on the efficacy of the treatment – and noted the difference in vaccination status between the population in the early trial and those in later, real-world studies.
 
‘Going back to the original trial, the product seemed more effective in the first half of the trial than the second half,’ he said.
 
‘Whether the virus mutated and evolved so that the drug was less effective by the end of the trial has to be asked.’
 
The UK was the first country to approve molnupiravir, and it is also being used in the United States. However, it has not been approved for use in the European Union.
 
The National COVID-19 Evidence Taskforce said it is aware of the data from the PANORAMIC trial.
 
‘The results are currently under review by the Taskforce Evidence Team and the Disease-Modifying Treatment and Chemoprophylaxis Panel [DMTC] Panel,’ a statement on its website reads.
 
‘An update to existing recommendations will be published in the next version of the guideline.’
 
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