Science Talk: Hope and concern for two novel Covid-19 antivirals

Public health measures, vaccines and antimicrobials – which kill micro-organisms or stop their growth – are the hallmarks to keeping plague-causing microbes at bay and, in exceedingly rare instances, even to eradicating them.

Nearly two years into the pandemic, we now have all three at hand for Covid-19, with the most recent development being announcements by pharmaceutical giants Merck and Pfizer on the effectiveness of their antiviral pills.

Oral antiviral drugs could be one of the most powerful tools at our disposal to control the scope of the pandemic.

They could be used as a treatment for those infected, to reduce the risk of hospitalisation or death.

In an ideal world, they could also be used prophylactically to prevent those who may be exposed to the disease from ever becoming ill, just like we do with other diseases like the flu and HIV.

No other proven treatments for Covid-19 can be used to this effect.

The monoclonal antibodies and convalescent plasma therapies that are known to treat the disease are expensive and must currently be administered intravenously (in the vein) or subcutaneously (under the skin) usually in a clinical setting.

That makes the treatments near out of reach for the vast majority of those infected, and largely unrealistic as a method of prevention.

Merck and Pfizer’s oral antivirals have shown potential as a treatment, but there are still some important questions that need to be answered before either could be considered ready for use on a mass scale, especially for use prophylactically.

Let’s take a look first at the drug shown to be most effective in clinical trials, Pfizer’s protease inhibitor, paxlovid (PF-07321332), which prevents the virus from replicating by binding to parts of it.

Paxlovid, a new molecule developed specifically to disable Sars-CoV-2, which causes Covid-19, is used in combination with another drug, ritonavir, that has been used for decades in the treatment of HIV.

In the clinical trial, among participants who received treatment within three days of the start of symptoms, the risk of hospital admission or death was 89 per cent lower in the paxlovid group than the placebo group.

Pfizer shows the making of its experimental Covid-19 antiviral pills inside a laboratory in Freiburg, Germany. PHOTO: AFP/PFIZER

Among those who received treatment five days out from symptoms starting, the reduction was 85 per cent, still a very strong showing.

The Merck drug saw a more modest 50 per cent reduction in hospitalisation or death.

Merck’s drug, molnupiravir (MK-4822), is a nucleoside analogue – part of an important class of antiviral agents used to treat HIV infection and hepatitis, among others. These work by blocking cellular division or viral replication by impairing DNA/RNA synthesis.

Molnupiravir carries with it two substantial concerns.

The first is whether the drug, meant to attack viral RNA, could also damage healthy DNA.

A study published earlier this year shows that the active compound in the drug can indeed be incorporated into and mutate host DNA – which in this case would be the Covid-19 patient.

The result of this mutagenesis is not fully clear, but the possibilities could include birth defects or cancers.

Certainly, there is enough of a risk with the Merck drug that it should never be used widely and certainly not among pregnant women or for any man or woman actively trying to conceive.

Beyond damage to the patients themselves, the Merck drug also carries with it the possibility of introducing mutations to the virus itself which may create Sars-CoV-2 variants that are more transmissible and more deadly than others we’ve seen.

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This concern is not entirely theoretical.

A study published prior to the pandemic tested molnupiravir against two other highly pathogenic coronaviruses: Mers-CoV – the virulent coronavirus which was first reported in Saudi Arabia in 2012, and the mouse hepatitis virus.

The researchers found that the drug could introduce hundreds of mutations in the populations of cells infected with the viruses.

While most of the mutations harmed the virus, the possibility that the drug may introduce mutations that help the virus does indeed exist, and may be made more likely in real world use, when people forget or choose not to take the full course of treatment.

Molnupiravir is meant to be taken as four large pills every 12 hours for five days. If pills are forgotten and suboptimal doses are delivered, it is difficult to say what may arise.

One thing we do know is that both antiviral pills may eventually fail over time if administered on their own.

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HIV taught us that antiviral monotherapies – used on their own – are bound to eventually fail as antiviral resistance develops.

Clinical trials should, therefore, begin on the use of combination therapies, for instance, molnupiravir alongside paxlovid, to mitigate this risk.

And efforts should be made to answer the main questions around the Merck drug in particular before further regulatory approvals are granted.

In the meantime, we must continue to rely on public health measures and top of the line vaccines to hold off the full force of the pandemic long enough to allow affordable and easy to administer treatments to fully develop.

We could be on the cusp of total control of Covid-19, but only if all countries are willing to apply the full force of our knowledge and tools – vaccines, antimicrobials and public health measures – against the vaccine.

  • Dr William A. Haseltine is the chair of Access Health International, a non-profit think-tank and advisory group which aims to improve access to high quality and affordable healthcare for all. Known for his groundbreaking work on HIV/Aids and the human genome, he is a former Harvard Medical School professor and founder of the university’s cancer and HIV/Aids research departments.
  • Dr Roberto Patarca is chief medical officer of Access Health International and has been an executive, clinical trialist and basic science researcher in academia and industry.

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