Covid antiviral found to be “less effective” than placebo
<p dir="ltr">Australia’s most widely-prescribed antiviral treatment for COVID-19 has been called into question seven months after it became available, after the results of a study into antiviral treatments found it was less effective than we initially thought.</p>
<p dir="ltr">Molnupiravir, sold as Lageviro in Australia, has been prescribed to Aussies at a higher risk of severe illness from COVID-19 around 237,440 times since it was included in the Pharmaceutical Benefits Scheme (PBS) in March, according to the <a href="https://www1.racgp.org.au/newsgp/clinical/doubts-over-impact-of-key-antiviral-treatment" target="_blank" rel="noopener">RACGP</a>.</p>
<p dir="ltr">But, preliminary data from <a href="https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4237902" target="_blank" rel="noopener">a study called PANORAMIC</a>, conducted by the University of Oxford, suggests that molnupiravir is not much better at reducing hospitalisation or deaths than those receiving standard care.</p>
<p dir="ltr">Out of 25,000 adults included in the PANORAMIC trial, 103 of the 12,516 people taking molnupiravir were hospitalised or died in comparison to 96 of the 12,484 people not taking the drug.</p>
<p dir="ltr">However, the study did find that those taking molnupiravir recovered more quickly.</p>
<p dir="ltr">While the people participating in this trial were mostly vaccinated and healthy, <a href="https://www.researchsquare.com/article/rs-2115769/v1" target="_blank" rel="noopener">another study</a> involving nearly 20,000 adults over 40 - including 1000 being treated with molnupiravir and most having immunity from vaccinations of prior Covid infections - found that the rate of hospitalisation dropped by nearly half and deaths were reduced by nearly 75 percent among those aged over 65.</p>
<p dir="ltr"><strong>The trial has confirmed long-held suspicions</strong></p>
<p dir="ltr">While the results of the PANORAMIC trial have caused a stir, with Australia’s National COVID-19 Clinical Evidence Taskforce saying it would review the study and probably update its recommendations, scientists have been sceptical of the effectiveness of molnupiravir for a while.</p>
<p dir="ltr">Professor Peter White, who researches viruses, including their evolution and treatment with antivirals at the UNSW, Sydney, is one such sceptic. </p>
<p dir="ltr">He tells <em>OverSixty</em> that we can expect to see similar results until a fundamental change is made to how we produce COVID-19 treatments.</p>
<p dir="ltr">“The drugs that we’re using on coronavirus, like molnupiravir and paxlovid, both of those are actually designed for influenza, not for coronavirus. They were repurposed,” he explains.</p>
<p dir="ltr">“And to me, that has never really worked well, like the drugs for HIV and HCV.”</p>
<p dir="ltr">Professor White says this is because molnupiravir belongs to a particular class of drug called nucleotide analogues, which he says are the most common type of antiviral we use.</p>
<p dir="ltr">“It’s a mimic of a natural RNA, what we call a nucleotide analogue, or a mimic of one of the four building blocks of life. In this case it’s an RNA molecule rather than DNA,” he explains.</p>
<p dir="ltr">These drugs, which are used to treat hepatitis B and C, HIV, and herpes viruses among others, work by mimicking RNA and DNA molecules viruses use to replicate.</p>
<p dir="ltr">“They tend to work by chain termination. The polymerase isn’t sophisticated enough to see that it’s not a true building block so they get incorporated into the new viral genomes,” Professor White explains.</p>
<p dir="ltr">“So it incorporates into the growing RNA strand, but then nothing else can get incorporated and replication of the virus is stopped and you won’t get any replication from that strand.”</p>
<p dir="ltr">But, a small percentage of nucleoside analogues don’t work like this, and molnupiravir is one of them.</p>
<p dir="ltr">Instead, they introduce more mutations to the RNA than normal, which drives the virus into ‘error catastrophe’, otherwise known as lethal mutagenesis.</p>
<p dir="ltr">“The virus ends up over-mutating and killing itself,” Professor White says.</p>
<p dir="ltr"><strong>A comedy of errors isn’t that effective for viruses</strong></p>
<p dir="ltr">Antivirals that introduce mutations, such as molnupiravir, aren’t as effective as the chain terminating antivirals, according to Professor White, </p>
<p dir="ltr">The only effective example, a drug developed to treat hepatitis C called ribavirin, came with severe side effects, including flu-like symptoms.</p>
<p dir="ltr">But, it turns out that nucleoside analogues are quite specific too, primarily working on the virus they were designed for.</p>
<p dir="ltr">“The antivirals that work really well have been designed against the virus that they were aimed to target,” Professor White explains.</p>
<p dir="ltr">“And we haven’t had enough time to design really good coronavirus-specific antivirals. We’ve had enough time to repurpose Ebola and influenza drugs for coronaviruses, but most of the time it doesn’t work well.</p>
<p dir="ltr">“And [molnupiravir] is another example of it not working.”</p>
<p dir="ltr"><strong>History repeats itself</strong></p>
<p dir="ltr">Australia was one of the more aggressive purchasers of molnupiravir, with the <em><a href="https://www.smh.com.au/national/not-having-a-big-impact-covid-drug-fails-to-beat-placebo-in-major-trial-20221010-p5bohc.html" target="_blank" rel="noopener">Sydney Morning Herald</a></em> reporting that 301,000 courses of the antiviral were purchased in late 2021, before it was approved by the Therapeutic Goods Administration (TGA).</p>
<p dir="ltr">But, this isn’t the first time we’ve secured large amounts of a drug that later proved less effective than we expected.</p>
<p dir="ltr">“This is exactly what happened with Tamiflu (the antiviral used to treat influenza),” Professor White says.</p>
<p dir="ltr">“Australia and many other countries bought millions of dollars worth of Tamiflu, which never got used. And then five years later, some clinical trials that weren’t published got released … and it was shown that they released the good (results) in the earlier trials and this drug isn’t as effective as we first thought.”</p>
<p dir="ltr">While we might be scrambling to find the next best treatment as soon as we can, Professor White says that developing effective drugs takes time - and that drugs specifically targeting Covid’s polymerase and protease enzymes will be the most effective.</p>
<p dir="ltr">“That’s the problem we’ve got at the moment. We’ve got repurposed drugs for other viruses, and maybe they work a little bit and they’ve been approved because we’ve got nothing else as yet,” he says.</p>
<p dir="ltr">“But this is not the end of the story. This is not the true, good drug that we could actually find. </p>
<p dir="ltr">“We could do a lot better, but we’re going to have to wait a couple of years.”</p>
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<p dir="ltr"><em>Image: Getty Images</em></p>
