Pre-print studies are beginning to further develop the understanding of its efficacy, suggesting that Paxlovid may have a greater impact, especially on the elderly at risk.
The drugs work – for some people at least.
That’s the cautiously reassuring suggestion of two recent pre-print studies tracking the results of COVID-19 patients who have received two of the most widespread oral antiviral drug treatments.
They include the two oral antiviral treatments available in Australia, molnupiravir (sold as Lagevrio) and nirmatrelvir plus ritonavir (sold as Paxlovid), which are approved for use. about the Pharmaceutical Allowances (PBS) and can be prescribed by general practitioners.
But while clinical trials have led to the preliminary approval of both treatments by the Therapeutic Goods Administration (TGA), there is still a lack of understanding of their impact in the real world, especially since the rise of Omicron.
Both new studies aimed to address that knowledge gap.
A piece of research from Hong-Kong suggests that both have a positive impact on reducing serious diseases, with nirmatrelvir/ritonavir appearing to offer the better protection of the two.
Another new study from Israel focuses only on the outcomes for those treated with niramatrelvir/ritonavir. That study concludes that the oral antiviral drug is most effective in vulnerable people aged 65 and older, with “no significant impact” on a younger cohort aged 40-64.
The research in Hong Kong
The authors of a study from the University of Hong Kong claim that their research is the first real study looking at the clinical use of oral antivirals, while Omicron was the dominant strain.
The observational, retrospective cohort study took place among 40,776 hospitalized patients in Hong Kong from February 26 to April 26 this year.
Of those patients, 2359 received molnupiravir while 1000 received nirmatrelvir/ritonavir.
None of those patients required oxygen therapy when their treatment began. The results of the study were measured by disease progression, mortality, whether patients required ventilation and how quickly the viral load faded.
The outcomes for oral antiviral users were compared to controls using propensity score matching.
The use of oral antivirals was associated with a significantly lower risk of disease progression, with the study reporting a hazard ratio of 0.53 and 0.33 for molnupiravir and nirmatrelvir/ritonavir, respectively.
Similar results were also seen for all-cause mortality, with a hazard ratio of 0.55 for molnupiravir and 0.32 for nirmatrelvir/ritonavir.
The study also looked at a comparison of the two treatments, reporting a higher relative risk of death in the molnupiravir group compared to nirmatrelvir/ritonavir.
Molnupiravir was also associated with a higher risk of longer hospital stays in surviving patients.
“Early initiation of oral antivirals within two days of admission was associated with significantly lower risks of disease progression and all-cause mortality, in addition to achieving a low viral load more quickly than their respective matched controls,” the study states.
‘The use of molnupiravir was also associated with a significantly lower risk of invasive mechanical ventilation than non-use’.
Despite both treatments having an impact in limiting severe outcomes, the authors indicated a clear preference.
“Our findings also support the prioritization of nirmatrelvir/ritonavir over the use of molnupiravir in COVID-19 patients when accessible and clinically appropriate, given the significant mortality benefit of the former,” they wrote.
Researchers from Israel’s Clalit Health Services (CHS) and Ben-Gurion University of the Negev subsequently released a separate pre-print study this week, focusing only on nirmatrelvir/ritonavir.
Like the Hong Kong study, it was also an observational, retrospective cohort study, this time based on medical data from CHS, which authors describe as “a large healthcare organization covering approximately 52% of the entire Israeli population and nearly two-thirds of the elderly.” .
The study, which included all CHS members with confirmed COVID-19 considered to be at high risk for serious illness, also lasted two months from January 9 this year to March 10. Omicron was again the dominant species in the country at the time.
The study included all CHS members 40 years of age and older with confirmed SARS-CoV-2 infection.
Of the 42,819 eligible patients over 65 years of age, 2504 received nirmatrelvir plus ritonavir, while there were 66,394 eligible patients aged 40-64 years, of whom 1,435 received treatment.
The study found that hospitalizations and deaths were significantly reduced among treated patients aged 65 and older.
“Nirmatrelvir therapy was associated with a 67% reduction in COVID-19 hospitalizations and an 81% reduction in COVID-19 mortality in patients 65 years of age and older,” the authors wrote.
“However, no significant benefit was shown in avoiding severe COVID-19 outcomes in younger adults.”
The researchers found a lack of previous immunity to COVID-19 and previous hospitalizations were the factors most closely linked to the high rate of hospitalizations, with immunosuppression being “significantly associated” with hospitalizations in the 40-64 age group.
“While this study is an observation, we believe that the findings and the perceived potential for avoidance of severe COVID-19 may help decision-makers prioritize currently limited supplies to those in whom nirmatrelvir has been shown to be substantially effective,” they concluded.
While also underscoring the strength of the data used, the researchers cautioned that their study is prone to “confusing clinical and sociodemographic features” that may have biased observations.
Evidence still emerges
Clinical trials for both treatments used in Australia took place in very different conditions from the current situation.
Trials for both drugs took place during the Delta wave, before the Omicron variant of concern was identified — and were conducted on unvaccinated patients.
In the real world, the oral antiviral treatments are largely administered in a highly vaccinated population, with Omicron being the dominant strain.
Senior pharmacists and clinicians stressed in March an urgent need for greater understanding of how the new oral antivirals work†
The head of the TGA, Professor John Skerritt, has also previously referred to a lack of evidence for the actual efficacy of the oral antiviral drugs, but stated that he believes more accurate studies will appear this year.
The oral antivirals are currently aimed at patients at risk with mild to moderate symptoms, with the aim of unburdening hospitals.
Prescribers are advised to start treatments within five days of the onset of symptoms to have the most effect.
While these early studies suggest that nirmatrelvir plus ritonavir is more effective, it has many more contraindications than molnupiravir.
Who is eligible in Australia?
According to PBS Criteriathe drugs can be prescribed to people with mild to moderate COVID-19 confirmed by a PCR or rapid antigen test within five days of the onset of symptoms, in the following patient groups:
- Those 65 years of age or older, with two other risk factors for serious disease
- Those 75 years or older with one other risk factor
- Those 50 and older who are Aboriginal or Torres Strait Islander with two other risk factors for serious illness
- Those with moderate to severe immune compromise
The RACGPs COVID-19 sources contains information relevant to each state and territory.
A guide to details relevant to general practice about COVID-19 oral antivirals is also published by newsGP†
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