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Where are all the drugs to treat Covid-19? As vaccines against the virus make such a welcome impact in preventing the disease, the cupboard of antivirals that could be used to treat the illness is notably bare.
The World Health Organisation (WHO) launched the Solidarity clinical trial, focused on antiviral drugs, in March 2020. By October, the trial had enrolled more than 11,000 participants hospitalised with Covid-19 in 30 countries. But it found that none of the four drugs that it tested – remdesivir, interferon, the malaria drug hydroxychloroquine and the HIV drugs lopinavir and ritonavir – saved lives or shortened hospital stays. It seems that giving the drugs after hospitalisation is too late to have a useful effect.
The narrow activity of existing antivirals reflects the nature of viruses themselves. Other microbes – bacteria, fungi, parasites – have cellular characteristics that offer a range of targets for drug activity. Penicillin, for example, blocks cell-wall synthesis in bacteria. Some antifungal agents attack the cell membrane. However, viruses, with their lack of cellular anatomy, offer fewer targets for drugs to penetrate and work on. When you add in a high rate of replication – a typical SARS-CoV-2 infection is estimated to produce more than one million virus particles per person per day – the challenges facing existing antivirals become all too clear.
Immune response
So, as the WHO launches the second phase of the Solidarity clinical trial, it comes as no surprise to learn that this time it is focusing on treatments aimed at controlling the rampant immune response associated with Covid-19. According to a report in Nature, the clinical trial will test three drugs that dampen inflammation. All three drugs were carefully chosen on the basis of the promise they showed in smaller clinical trials and widespread availability, says John-Arne Røttingen, scientific director of the Norwegian Institute of Public Health and chair of the Solidarity trial's international steering committee.
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“You need at least promising signals that some of them will work,” he says. “And we need to study drugs that we can deliver in a broad group of countries.”
Researchers have to be careful that they don't suppress immune responses so much that people become vulnerable to other infections
One of the lessons from Covid-19 is how, in some people, the body’s own immune responses can cause harm, damaging healthy tissue as well as killing infected cells. In one of the first breakthroughs in treating the novel coronavirus last June, a UK-based study called Recovery found that the immune system suppressant steroid dexamethasone reduced deaths among patients on ventilators or those who needed supplemental oxygen. And an international trial called Remap-Cap found that drugs that block an immune protein – the interleukin-6 (IL-6) receptor – can reduce deaths among those critically ill with Covid-19.
Other mechanisms
But there is a need to find other mechanisms to shut down certain immune responses in the Solidarity trial. One of the three drugs to be tested is infliximab, used to treat autoimmune conditions such as Crohn’s disease and rheumatoid arthritis. It blocks a protein called tumour necrosis factor alpha (TNF-a), which is released by cells in the immune system that promote inflammation. The second treatment to be used in the trial is a cancer drug called imatinib, in the hope that it will target both the coronavirus and inflammation by blocking viral infiltration of human cells and by reducing the activity of inflammatory proteins called cytokines. Finally, Solidarity is testing artesunate, an anti-malaria drug with potential anti-inflammatory effects.
With all of these ways to cool down the immune system, researchers have to be careful that they don't suppress immune responses so much that people become vulnerable to other infections, Djillali Annane, an intensive care physician at the University of Versailles in Saint-Quentin-en-Yvelines, France, told Nature. So trials will focus on patients who haven't responded to steroids or IL-6 receptor blockers.
Meanwhile, other scientists will concentrate on the difficult task of developing broad-spectrum antiviral drugs for the next pandemic.