This is how the most promising antivirals work against COVID-19

By Vicente Soriano, UNIR – International University of La Rioja

The instructions that doctors have these days are clear: if a patient consults them for respiratory symptoms, it must be presumed that they have COVID-19. A chest x-ray and oximetry can help diagnose who is at risk for complications – mainly pneumonia – and requires hospitalization. For the rest, with a milder clinic, home control by phone is sufficient.

COVID-19 is an acute self-limiting disease, so what is expected when taking antivirals is to shorten the duration of symptoms and reduce their severity. As with the flu, in these cases it is essential that the treatment be done early. That is, that antiviral medication is administered during the first two days with cough and fever.

Three hopeful options

Although there are currently no approved antivirals against the new coronavirus, some drugs are quite promising. Given the difficulty in identifying and developing molecules from scratch that specifically inhibit replication of the new coronavirus, antivirals already approved for other infections are being examined. This modality of clinical drug development is known as drug repurposing and its objective is to shorten the approval time of medications for another indication.

The jewel in the crown at the moment is the remdesivir, a broad-spectrum antiviral against RNA virus, which is in a clinical trial phase against Ebola. It is an analogue of a nucleotide (adenine) that joins the viral RNA chain and interrupts its synthesis. The only downside is that coronaviruses like SARS-CoV-2 have an enzyme called exonuclease that corrects copy errors in nucleic acid replication and thus limits the inhibitory effect of remdesivir.

Gilead, the pharmaceutical company that has discovered remdesivir, has forgone the benefits of its marketing compared to COVID-19. This American company has been (and is) a world leader in the commercialization of other antivirals against HIV-AIDS, hepatitis B and hepatitis C.

It also doesn't look bad favipiravir, a guanine analog that inhibits the polymerase of various RNA viruses. It was developed in Japan and is approved to treat the flu. In the laboratory, it has antiviral activity against SARS-CoV-2. In two studies conducted in China that have included a total of 340 patients with COVID-19, favipiravir has accelerated healing, with virological remission and faster radiological improvement.

Then we have the chloroquine, a drug used against malaria and some autoimmune diseases, such as lupus or rheumatoid arthritis. Chloroquine has been observed to have an antiviral effect against the coronavirus, modifying the pH of lysosomes – the organelles of the cell – where it takes refuge and multiplies. In addition, it exerts an anti-inflammatory action that reduces cytokine storm that can cause respiratory problems in COVID-19. It is generally well tolerated and has few side effects. However, it has been found that in high doses it can cause heart problems.

Expectations to treat COVID-19 with another family of drugs called HIV protease inhibitors, such as lopinavir or darunavir, have waned, following the publication of a prospective clinical trial in China with lopinavir.

Genetic mutations and future

Most RNA viruses have great genetic variability. However, it is less than expected in coronaviruses. Its higher copy fidelity with respect to other RNA viruses, such as HIV or the hepatitis C virus, is due to the fact that coronaviruses have an enzyme called exonuclease, which corrects errors made during viral replication. A kind of viral "typex".

It has been said that the mutations generated during the replication of SARS-CoV-2 and that have allowed its transmission between humans should, over time, mitigate its virulence as they adapt better to the new host. Hopefully it's true!

In any case, the figures for new cases and deaths from COVID-19 in Spain are expected to reach their maximum in 2-4 weeks. By then, the proportion of people susceptible to contagion will have decreased, since the cured and immunized cases will represent a high proportion.

Furthermore, during the summer, it is to be hoped that the new infections are only sporadic. Furthermore, mortality will drop dramatically from the time that healthcare can be adequate again and is not oversaturated as it is now. All these predictions are in accordance with models and projections that use mathematical simulations, with data from China and Italy.

Projection of cases in Spain. Author provided

The current scenario for the COVID-19 pandemic is dramatic and unprecedented. The impact will go far beyond the realm of health and will transform our societies. COVID-19 is going to be a before and after. On a personal level, it would be desirable for this tremendous shock to bring out the best in everyone. Hopefully it will serve to rediscover the infinite value of human life and start again with other priorities in our actions.

The genetic factors that modulate the susceptibility and severity of COVID-19 are the reason for a special session entitled “Clinical genetics in the COVID-19 era” broadcast online on April 1 at 5:00 pm (GMT + 2) for free , with the participation of speakers from the University of Cambridge and UNIR.

Vicente Soriano, Faculty of Health Sciences & Medical Center, UNIR – International University of La Rioja

This article was originally published in The Conversation. Read the original.