A 57-year-old obese Australian incompletely vaccinated woman with diabetes, hypertension and atrial fibrillation tests positive for COVID-19 after experiencing symptoms for 2 days. According to the Pharmaceutical Benefits Scheme (PBS) criteria, despite her risk factors for severe disease, she is not eligible to receive a subsidised oral antiviral treatment that could keep her out of hospital.
The patient is ineligible under the PBS criteria, not because her risk factors are not significant, but because she is under 65 years of age, the lower limit set by the Pharmaceutical Benefits Advisory Committee (PBAC). If she were in the UK or the US, she would be immediately eligible once her diagnosis was confirmed by PCR test.
Two oral antivirals are now available in Australia on the PBS for the treatment of mild COVID-19.
Paxlovid (Pfizer) – a combination of nirmatrelvir and ritonavir – has been on the PBS since 1 May 2022 as an Authority Required prescription. It must be started within 5 days of the patient developing COVID-19 symptoms and involves taking two tablets (one for each drug) twice a day for 5 days. Paxlovid has already been in use in hospitals, with more than 40 000 prescriptions dispensed as of early April 2022.
Lagevrio (Merck, Sharp and Dohme) – molnupiravir – has been on the PBS since 1 March 2022 and is also an Authority Required prescription. It must be started within 5 days of the patient developing COVID-19 symptoms. More than 12 000 prescriptions have been dispensed since it became available on the PBS.
Both drugs have the same PBS eligibility criteria, that is, according to the federal Department of Health guidelines:
- people 65 years or older with two additional high risk factors for developing severe disease;
- people 75 years or older with one additional high risk factor for developing severe disease;
- moderately to severely immunocompromised people irrespective of vaccination status; and
- Aboriginal and Torres Strait Islander people aged 50 years or older with two additional high risk factors for developing severe disease.
Patients judged low risk aren’t given the antivirals because both drugs have potential side effects. Paxlovid, in particular, can cause diarrhoea in 3% of people, and dysgeusia – where all food tastes sour, sweet, bitter, or metallic – in 6%.
Professor Mark Morgan, Professor of General Practice at Bond University, and co-Chair of the Primary and Chronic Care Panel at the National COVID-19 Clinical Evidence Taskforce (the Taskforce), told InSight+ that the PBS criteria were to ensure that the treatments were offered to the people “where there’s going to be the most value, and so you don’t go the wrong side of the benefit versus harm equation”.
“If you have very low risk of ending up with serious COVID, or ending up with being in hospital with COVID, then putting up with any of the side effects or harms [from the antivirals] is just not worth it,” he told the ABC.
But, he told InSight+, more nuance was needed.
“It does seem to me there’s an overemphasis on prevention of overuse, at the cost of clinical decision making,” he said. “We can’t have a system where the computer says no, and that’s it.”
Professor Morgan said the Taskforce recommendations were based strictly on the evidence available.
“There’s the evidence base, and then there’s an expert opinion component to the Taskforce’s work,” he said.
“Then the PBAC has to find a simple implementable way of describing that, that is easy enough to be used in general practice and by other people who are prescribing.”
While the PBS criteria were important to ensure treatments were getting to those patients who needed them most, Professor Morgan said he would like to see more flexibility.
“Allow for some clinical judgment and expertise to apply around the gray areas and around people who are at risk but don’t fall nicely within the PBS criteria,” he said.
The cost of being ineligible
GPs are being discouraged from prescribing Paxlovid and Lagevrio privately – that is, outside the bounds of the PBS criteria – because of concerns about supply, and because without PBS subsidisation patients are up for an outlay of $1000 per 5-day treatment course.
Speaking in a webinar hosted by the Department of Health on 2 May 2022, Professor Michael Kidd AM, the Deputy Chief Medical Officer, said:
“We’re discouraging private prescriptions because we don’t have an unlimited supply of either Paxlovid or Lagevrio. It’s currently been manufactured for delivery all around the world, so it does need to be prioritised for those people who are most at risk of becoming severely unwell if infected with COVID-19.”
A spokesperson for the Department of Health told InSight+ there was no issue with supply.
“More than 700 000 treatment courses of the oral antivirals have been supplied to Australia to date. They are available through the normal PBS supply chain supporting the delivery of PBS medicines through approved pharmacies,” the spokesperson said.
How the PBS criteria were informed
The PBS criteria were informed by the Taskforce recommendations for the use of oral antivirals “as one of a range of considerations”, said the Department of Health spokesperson, but they differ slightly. For both drugs the Taskforce says:
“Evidence demonstrates a reduction in hospitalisation when used in individuals with one or more of the following risk factors for disease progression:
- age ≥ 60 years;
- diabetes (requiring medication);
- body mass index ≥ 25 kg/m2;
- cardiovascular disease;
- chronic lung disease.”
For molnupiravir, the consensus recommendation is: “In addition to at-risk unvaccinated adults, also consider using molnupiravir within 5 days of symptom onset in adults with COVID-19 who do not require oxygen and:
- are immunocompromised regardless of vaccination status; or
- who are not up-to-date with vaccination and who are at high risk of severe disease on the basis of age and multiple risk factors;
“AND where other treatments (such as sotrovimab or nirmatrelvir plus ritonavir) are not suitable or available.”
For Paxlovid, the consensus recommendation is: “In addition to at-risk unvaccinated adults, also consider using nirmatrelvir plus ritonavir (Paxlovid) within 5 days of symptom onset in adults with COVID-19 who do not require oxygen and:
- are immunocompromised regardless of vaccination status; or
- who are not up-to-date with vaccination and who are at high risk of severe disease on the basis of age and multiple risk factors.”
The evidence for molnupiravar consists of one trial, published in the New England Journal of Medicine, in which unvaccinated adults were treated with 800 mg of molnupiravir twice daily for 5 days.
The Taskforce described the evidence as “limited, effect sizes are small and there are limited safety data”.
“Until further evidence is available, use of molnupiravir should only be considered where other treatments (such as sotrovimab or nirmatrelvir plus ritonavir) are not suitable or available.”
The evidence for Paxlovid is one trial that compared nirmatrelvir plus ritonavir with placebo in 2246 unvaccinated adults with PCR-confirmed COVID-19 and mild illness.
“Available research does not currently provide enough evidence to determine the benefits of nirmatrelvir plus ritonavir in specific subgroups of patients,” the Taskforce wrote. “There is no evidence evaluating the effectiveness of nirmatrelvir plus ritonavir in individuals who are up-to-date with vaccination or partially vaccinated.”
Lack of awareness
One major barrier to oral antivirals reaching the people who need them most, was a lack of awareness by the public of availability of treatments, say the experts.
“The main issue is that a patient needs to take the first tablet within 5 days of first experiencing symptoms,” said Adjunct Professor Karen Price, President of the Royal Australasian College of GPs.
“Within that time they need to get tested, notify or have their GP be notified of their positive status, be determined as eligible for the medicines, and then get their script filled at a pharmacy.
“This is why it’s important that there’s more public awareness of the medicines and who is eligible so that people know that if they test positive, they should contact their GP as soon as possible.
“GPs need to be included in a patient’s care when they test positive for COVID-19, and notified early, particularly for patients at-risk of more severe symptoms. Early notification is critical to ensure patients receive the care they need, including access to antivirals.
“It’s also important that GPs proactively let their eligible patients know to contact them, should they test positive within the specified time frame.
“So, for example, when a GP sees such a patient for routine care, it’s an opportunity to have a conversation about accessing antivirals, the urgency to get tested, and to notify your GP of a positive result,” Dr Price said.
Are patients who need antivirals missing out on treatment because of the PBS criteria?
“Possibly,” said Professor Morgan. “But the bigger factor is lack of awareness of eligibility and delays leading to more than 5 days since the start of symptoms.
“I would very much like GPs to have that discussion when patients come in for routine health checks, monitoring their long-term medical conditions, or when they come in for their influenza vaccination, to be using that opportunity to highlight if you ever get COVID, contact us straight away, because we have a treatment that might help — but only if we catch it at the beginning,” he told the ABC.
Where does that leave our 57-year-old patient and her GP?
“GPs are not given the support they need, or the patients are not given the rebates they need for long enough consults to do many of these tasks to the thoroughness that we would like,” said Professor Morgan.
“GPs are being bombarded with a lot of information from a lot of different sources at the moment. There’s a constant stream from the [Primary Health Networks], who quite rightly feel that they have a role in supporting general practice by informing them.
“But they’re getting fed by both federal sources and state-based sources. And the two things aren’t always agreeing with each other.”
One alternative is access via the National Medicines Stockpile (NMS). Indeed supplies of oral antivirals have been provided to state and territory governments from the NMS for use in rural and remote areas, “particularly in locations with high Aboriginal and Torres Strait Islander populations, and people with disability, especially in supported living settings”.
Lagevrio has also been distributed to residential aged care facilities.
“The stockpile medications are the mechanism for [those patients] outside of and beyond the PBS criteria,” Professor Morgan said.
“Unless you’re prepared to prescribe privately, they are the only mechanism to obtain the treatment for somebody that’s high risk, but outside the PBS criteria.”
There is some good news for those not currently eligible under the PBS criteria.
“The Taskforce continue to review any randomised controlled trial data and evidence to consider if the population recommended for treatment should be expanded,” said the Department of Health spokesperson.
“As more data becomes available, the Taskforce will review and incorporate new findings into the evidence profile and then update the recommendations accordingly.
“The PBAC will continue monitoring the eligibility criteria for PBS access to Lagevrio and Paxlovid. The PBAC may recommend changes to the eligibility criteria as needed, considering new evidence for the effectiveness and safety of these antivirals in other patient groups as well as the evolving epidemiology of COVID-19.”
In the meantime, GPs are left to assess each patient on a case-by-case basis, with the PBS criteria, Taskforce recommendations and state-by-state variations as guidance.
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