COVID treatments – where are we?

There appears to be a myriad of potential treatments for our current health threat – COVID19. But just how real are these options? And which if any of these are likely to make it into our treatment regimens? A review just published online in JAMA gives us a neat summary of where we are up to in terms of treatment.

Firstly, it needs to be understood that ‘no proven effective therapies currently exist’, the review authors state. But despite this depressing reality, the upside is we already know a significant amount of detail about this novel coronavirus and its lifecycle in host cells, which provides scientists many potential targets for treatments. We also have the opportunity to review agents used in the past to treat SARS and MERS, which are similar viruses to COVID-19.

Courtesy of this past experience, chloroquine and hydroxychloroquine were very early front-runners in the potential treatment stakes. Their mechanism of action is to hinder the entry of the virus into the cells, with invitro studies suggesting hydroxychloroquine is more effective at this than chloroquine.

The Chinese announced they had shown, in a trial of 100 patients, that chloroquine was an effective treatment for COVID-19 – reducing disease progression and enhancing viral clearance. Unfortunately this trial has yet to be published anywhere. A much smaller, but published, non-randomised French study showed a similar benefit with hydroxychloroquine (given 200mg tds), and the few that didn’t respond to hydroxychloroquine recovered with the addition of azithromycin.

But while that all sounds promising, another small but randomised study, again using hydroxychloroquine, showed no difference in virological outcomes. Nonetheless, these drugs are very available and they have a pretty good safety profile – even with the very rare side effects of QT prolongation, hypoglycaemia, neuropsychiatric effects and retinopathy. This might be more of an issue with hydroxychloroquine, as the dose required to treat COVID-19 is higher than that used to treat SLE.

Currently there are RCTs underway looking at these agents both as treatments and as prophylaxis.

The antiretrovirals are another group of drugs being looked at as COVID-19 treatments. In particular scientists are interested in the lopinavir/ritonavir combination which has been shown to have invitro activity against other coronaviruses, mainly SARS, and it can reduce mortality. The evidence supporting this treatment so far has been pretty weak, but researchers think that this may be, in part, because the combination has to be given early in the disease and in most retrospective studies, there is delayed initiation of treatment. While research is ongoing, the significant risk of drug-drug interactions and the high risk of side effects makes this treatment option less appealing.

Another touted potential remedy for COVID-19 is the hepatitis C treatment, ribavirin. It looked promising because it had been shown to have activity against other novel coronaviruses. But the review authors said that of 30 studies that examined the use of ribavirin against SARS, 26 were inconclusive and four showed the drug was associated with harm. The high doses required to treat SARS saw 60% of patients develop haemolytic anaemia.

And what about our well-known flu drug oseltamivir. Unfortunately it’s a dud against COVID-19. Courtesy of the fact that it was flu season when the new coronavirus struck China, many people with COVID-19 were originally treated with oseltamivir. It made no difference and the review authors say definitively that it has no role in the management of COVID-19.

However, another flu drug is showing much more promise. Umefenovir, used in Russia and China for both prophylaxis and treatment of flu, was shown in a non-randomised study among COVID-19 patients in China to lower mortality rates and increase hospital discharge rates. This was an observational study so it can’t be used as practice-changing evidence, but umefenovir is currently the subject of a number of RCTs using the same dose as is used to treat flu – namely 200mg every eight hours.

Similarly, a traditional anti-helminthic agent is being investigated as a possible treatment for this novel coronavirus. Nitazoxanide has been shown to have broad antiviral properties, with evidence of invitro activity against both MERS and SARS-COV-2. Given its high safety profile, this agent has been touted as one that warrants further study. There is also a drug used in Japan to treat pancreatitis that researchers suggest is worthy of further investigation, mainly because it has quite a unique mechanism of action. Camostat mesylate prevents the novel coronavirus from entering the cell by means of inhibiting a certain protease, which the authors suggest opens up a whole new target for investigation and targeting.

In speaking of areas to target, it is true that this novel coronavirus utilises the ACE receptor to access the host cells. This has caused a good deal of controversy about whether or not people taking ACE inhibitors for hypertension should continue taking them.

“These drugs upregulate ACE2 receptors, which could theoretically lead to worse outcomes if viral entry is enhanced. In contrast, angiotensin receptor blockers could theoretically provide clinical benefit via blockade of ACE2 receptors”, the review states. Until more evidence comes to light on whether these drugs have a protective or detrimental effect on patients exposed to COVID-19, health exports are suggesting people stay on their medication.

Finally, the review discussed two promising ‘investigational’ drugs which are both given by infusion and both aimed at treating more severe COVID-19 patients than would be seen in general practice.

The first is remdesivir which was one of the antimicrobials with activity against RNA viruses that showed promise against Ebola. The other is favipiravir which is currently available in Japan for treatment of severe flu and works by inhibiting viral replication. While both these drugs show considerable promise, their limited availability make their widespread use for clinical investigation and use difficult at present.

The review authors concede this analysis of the current state of play of treatments for COVID-19 is very selective. There are literally hundreds of patents currently in place for various molecules and formulations that will hopefully prove effective against this highly infectious virus.

“This large amount of potential agents will hopefully yield more candidate therapeutics in the race to find effective treatments or preventive strategies against COVID-19”, they conclude.

JAMA published online April 13,2020. Doi 10:1001/jama2020.6019

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