An increasing number of anti-COVID-19 therapies raises hopes that they will enable us to return to the pre-pandemic normal. Although new therapeutics will play a part in the fight against COVID-19, such far-reaching hopes are unrealistic due the nature of the disease. Drugs will not be our free ticket out of the pandemic. By Martin Michaelis and Mark Wass.
Currently, we are frequently told in the UK and in other countries, which can afford effective vaccination programmes, that we are in a much better place regarding COVID-19 than we used to be thanks to increased immunity levels due to vaccinations and previous infections.
This is true, as we can see in the ongoing Omicron wave that has caused less damage than previous waves despite fewer restrictions. However, it is not clear the extent to which this will apply to future COVID-19 waves, some of which are likely to be more severe.
Moreover, there is a considerable proportion of people who cannot effectively protect themselves with vaccines due to various immune conditions. In this context, the availability of antiviral drugs for the treatment of people infected with SARS-CoV-2, the coronavirus that causes COVID-19, is often referred to as another game changer.
At a closer look, however, the use of drugs for the treatment of COVID-19 is much more complicated than it may initially seem. Two kinds of drugs are used for COVID-19 treatment, immunosuppressants and antivirals.
The use of immunosuppressants may appear counterintuitive, given that our immune systems are meant to fight SARS-CoV-2 and protect us from severe disease. However, most COVID-19 victims are not directly killed by the virus. Rather, the virus induces an excessive immune response resulting in generalised inflammation (also called ‘cytokine storm’) that is eventually the cause of death at a time when there is no or very little virus left in the body.
In agreement, the first drug that was found to reduce COVD-19 deaths was dexamethasone, a corticosteroid that reduces the excessive immune response. Dexamethasone reduced the number of deaths of COVID-19 patients on ventilators by about a third and also had a small beneficial effect on patients on oxygen support, who did not require a ventilator. In contrast, hospitalised patients, who did not need oxygen support, had a higher chance of dying with dexamethasone than without. This illustrates that the use of immunosuppressants like dexamethasone for COVID-19 is always a ride on a knife’s edge and that you only try this in the most desperate situation for the sickest patients. In all other patients, you will suppress the protective immune response and do more harm than good.
This example also illustrates the limitations of antiviral drugs, which directly inhibit virus replication, for the treatment of a disease like COVID-19. Antivirals can only have a significant effect when they are given early during the disease course, before the disease is driven by the excessive immune reaction.
This means that the time window for intervention is very short and that the decision to treat patients needs to be taken before we know, whether a patient will actually become severely ill. Once we know for sure that a patient’s life is at threat, it is already too late for antivirals.
Consequently, many patients will have to be treated with antiviral drugs as soon as possible after they have been infected in order to save lives. However, there are inevitable delays. The virus load typically peaks within 24 to 72 hours after the onset of symptoms. Hence, there is not much time to start antiviral treatment. Patients must realise that they are having symptoms, get a test, receive the test results, and obtain the drugs ideally within hours but at least within a few days. This is complicated at the best of times and even more difficult when testing capacities are scaled back as currently planned. Since the time limits are determined by the virus biology, they apply to all antiviral drugs.
Moreover, antiviral drugs will have to be incredibly safe, because they will have to be taken by many people, who do not need them, as we cannot reliably identify those who do. On top of this, large amounts of drugs will be required that will also come at a considerable cost. This is not a cheap solution.
Taken together, it seems inconceivable that antiviral drugs could be delivered at scale to a large number of infected individuals, which will be necessary to make a significant difference during a larger wave. Antiviral drugs are an additional tool in our arsenal for tackling COVID-19 and will help many individuals, but they are just one measure of limited impact among many. They are not a free ticket out of the pandemic. Just a little piece in the puzzle, no game changer on their own…