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Can the long-term consequences of COVID 19 be reduced through the use of novel antiviral medicines? New research from the PANORAMIC trial, run in NDPCHS Clinical Trial Unit and funded and delivered by the NIHR, has found that treating vaccinated, higher-risk adults with COVID-19 with the antiviral drug molnupiravir offers only modest benefits when it comes to reducing long term effects of the acute illness.

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Published in The Lancet Infectious Diseases, the new study builds on the earlier findings from the PANORAMIC trial, which showed that while molnupiravir shortened the acute illness episode by around four days, the drug  did not significantly reduce hospitalisations or deaths in the group studied - aged 50 or older, or over 18 with underlying health conditions, and mostly having received at least one dose of a COVID-19 vaccine. 

The new findings show that patients treated with the five-day course of molnupiravir experienced continued but modest benefits in reducing the severity and persistence of certain COVID-19 symptoms at three and six months from infection. However, the benefits were modest for most outcomes and there remained no significant difference in COVID-19 hospitalisations over the longer term.  

Molnupiravir treatment outcomes after six months 

In the new paper, the researchers followed up with more than 23,000 participants from the original PANORMAIC study at three and six months after treatment for their acute illness, to assess the long-term impact of molnupiravir on COVID-19 illness. They compared the use of molnupiravir combined with usual care against usual care alone. Usual care varied according to patient needs but did not include molnupiravir. 

After both three and six months, molnupiravir recipients reported slightly higher wellness scores, fewer severe symptoms such as fatigue and shortness of breath, less use of medications to treat their symptoms, and better health-related quality of life compared to the group who only received usual care. Additionally, fewer participants in the molnupiravir group missed work or study at both follow-up points. The researchers also noted that there remained no significant difference in COVID-19 hospitalisations over the longer term.  

The researchers explain that while the differences between the groups’ experiences were statistically significant, the absolute differences were small for most outcomes. The likelihood of reporting any persistent symptoms at 6 months was reduced from 11% with usual care to 8.5% with molnupiravir, an absolute risk reduction of 2.5%. This highlights an important distinction between statistical significance and clinical significance - while the results are unlikely to be due to chance, the small absolute differences may not translate to meaningful clinical benefits for many patients.  

Assessing the impact on patient care 

To assess the clinical impact of using molnupiravir to treat COVID-19, the researchers used a common measure called ‘number needed to treat’. This measure calculates the average number of patients who need to receive a treatment to prevent one additional negative outcome compared to usual care. It can help decision-making organisations see if a new treatment makes a significant difference to the overall health of the population when balanced with the cost of the treatment.  

In this study we found that the numbers needed to treat were high, meaning a large number of patients would need to be treated with molnupiravir to see one additional beneficial outcome compared to usual care,’ explains Victoria Harris, Senior Medical Statistician at the Nuffield Department of Primary Care Health Sciences and lead author of the study. For instance, only one person would have less severe symptoms from a total of 53 people who took molnupiravir, and only one person would have used fewer NHS services from a total of 71 people who took molnupiravir. Given the small additional number of participants benefited from taking molnupiravir, compared to those who did not take the drug, long-term health benefits will need to be weighed up against costs and any unwanted effects.  

Molnupiravir is a relatively expensive drug – about £500 per course – so giving it to everyone who gets COVID-19 would be a significant financial undertaking for the NHS. The researchers explain that their findings could help policy makers and commissioners of care make decisions about the long-term treatment of COVID-19. 

Prof Phil Evans, Deputy Health and Care Director, Research Delivery Network Coordinating Centre said:  

'The award-winning PANORAMIC study continues to produce important results that will inform the treatment of COVID-19 in many countries across the world. We are enormously grateful to the many thousands of patients who volunteered to take part in this landmark study -   and to those GP practices right across the country that helped to deliver it.'

Chris Butler, Professor of Primary Care in the Nuffield Department of Primary Care Health Sciences and co-Chief Investigator of PANORAMIC, summarised the new study, saying:

‘Many people (and the healthcare professionals responsible for their treatment) wonder whether treating acute COVID-19 with a specific novel antiviral drug will reduce their chances of suffering the long-term effects of COVID-19. For the first time, we have evidence from a well-conducted large scale randomised controlled trial that answers this question. 

The absolute differences at three and six months between participants receiving molnupiravir and those receiving usual care were small which means that large numbers of patients would need to be treated with these expensive drugs to achieve relatively small benefits. These findings will be critically important to commissioners of care to inform care guidelines and decision making about the use of these novel agents. 

 

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