- As scientists try to find effective Covid-19 treatments, they are slowly discovering what works.
- Hydroxychloroquine and lopinavir-ritonavir showed some potential early in the Covid-19 outbreak.
- Now, new research from Basel shows why these two drugs shouldn't be used to treat Covid-19.
Early in the Covid-19 outbreak, researchers turned their attention to existing medicines to try and save people from deadly Covid-19 symptoms.
Lopinavir, an antiviral used for HIV, and hydroxychloroquine, a drug used to treat malaria, lupus and rheumatism, were both in the run as potential treatments, as there was evidence that they could work against Covid-19.
A research group from the University of Basel has now established why these drugs will not work. The concentration of these two drugs in the lungs of Covid-19 patients ends up not being high enough to fight the virus.
Their research was published online in the journal Antimicrobial Agents and Chemotherapy
Plasma levels investigated
In February 2020, the research group established a Covid-19 patient cohort at the University Hospital in Basel with the aim of monitoring diagnostic means and the potential use of off-label drugs to help treat the disease, including lopinavir and hydroxychloroquine.
As they monitored the use of these drugs in 92 Covid-19 patients, they observed the following:
- Lopinavir plasma levels were more than two-to-hreefold higher than typically observed in HIV patients;
- Hydroxychloroquine levels were with normal range;
- There was a significant correlation between the inflammation marker levels in the blood and lopinavir plasma levels;
- When the inflammation was blocked with the Interleukin-6 inhibitor Tocilizumab, lopinavir plasma levels were significantly lower than the ones in patients without Tozulizumab treatment.
This means that the drug metabolism enzymes were significantly affected by systemic inflammation in those Covid-19 patients, and that it’s unlikely that the drugs could reach the concentrations required to fight virus replication in the lungs.
Why are some other drugs more effective?
While lopinavir and hydroxychloroquine were found to be ineffective as a treatment for Covid-19, other clinical trials established that the corticosteroid dexamethasone and the drug previously developed against the Ebola virus, remdesivir, could help prevent Covid-19-related deaths.
In a trial, the steroid dexamethasone was found to have saved the lives of a third of the most serious Covid-19 cases. These results were hailed as a "major breakthrough" in the fight against the disease, as reported by News24 on 16 June 2020.
This steroid drug suppresses the immune system, which can help those Covid-19 patients whose lungs are severely affected by an overreactive immune response. The WHO was sceptical, as patients need a functional immune system to fight SARS-CoV-2 and the Covid-19 infection.
Also, the antiviral remdesivir was recently approved as the first Covid-19 treatment in Europe.
The drug is designed to stop some viruses from replicating inside the body, taking over the immune system and leading to severe illness. Unfortunately, it didn’t have the desired effect on the Ebola virus, the original virus it was designed to target.
Remdesivir was then provided by Gilead in 2016 as a study drug to see how it would react to SARS and MERS, two previous diseases caused by coronaviruses. Even though there was enough positive pre-clinical data, Gilead could not advance remdesivir to a clinical development for SARS and MERS because of a lack of study participants. SARS and MERS infections also started to wane and drug developments seemed irrelevant.
In January, with the emergence of Covid-19, Gilead’s team of virologists identified the need for a Covid-19 treatment and quickly generated pre-clinical data to establish remdesivir’s effect on Covid-19. More clinical trials were subsequently undertaken.
Larger, randomised trials are usually more successful
There are several factors that determine whether the results of a clinical trial will be desirable or not. Large, randomised trials are usually the gold standard for testing a drug’s efficacy, according to Science Mag.
Many experts embarked on smaller trials in a bid to lend their efforts in the fight against Covid-19. Unfortunately, the success is in the numbers, according to Ana Maria Henao Restrepo, a World Health Organization medical officer.
“Every clinician, every researcher wants to help, and then they end up having a trial with 300 or 400 patients that cannot come up with conclusive evidence.”
Among these smaller studies, the RECOVERY trial that was launched in March 2020 to test the efficacy of dexamethasone with 12 000 patients and hundreds of participating hospitals, stands out among these. According to Restrepo, this has been the most successfully conducted trial so far.
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