Thread by @anupampom

A thread on Remdesivir and its role post SOLIDARITY trial.

There have been 4 trials of Remdesivir so far.(Two predominantly in US/Two outside)
First was Wuhan trial(published Mid April) which was cut short due to lack of cases ,which showed no mortality benefit with Remdesivir and a trend towards faster recovery.
thelancet.com/journals/lance…

In the US trial (NIH-ACTT1)(published Mid May) of patients admitted with Severe COVID ..(poor oxygen level+pneumonia) Remdesivir did cut short Time to Recovery by 4 days .
nejm.org/doi/full/10.10…

There was also a trend of mortality benefit in less severe cases(on low flow oxygen) ,but no benefit in Patients on Ventilator/ECMO

Above trial established Remdesivir as Standard of Care in Severe COVID cases along with Steroids which were proven to be of benefit in Patients in Hospitalised severe COVID pneumonia patients in RECOVERY trial (needing oxygen and Ventilator)

In August, a third trial came out where Remdesivir was used in moderate COVID patients (pneumonia,but no oxygen requirement) and had modest benefits. It led to its use being expanded to Moderate cases as well by FDA.
jamanetwork.com/journals/jama/…

A question remained at this stage..Would Remedesivir be still as Effective if used with Steroids ,as US trials(ACTT-1 and SIMPLE) didn't use Steroids

Now Finally SOLIDARITY TRIAL (by WHO arrived, 50% of Patients were given Steroids) which showed none of the benefits (discharge time, time to initiate Ventilator,mortality) shown by Remdesivir in US trials.

However even in this trial there is a signal of small benefit in low Risk cases (low oxygen flow) while RDV is of no use ICU onwards.(so it isn't incompatible with US trial). Figure from a meta-analysis from SOLIDARITY paper

Some Comments on SOLIDARITY trial-
A. It is possible that Steroid used here and in China Remdesivir trial in 50% of cases masked effect of Remdesivir . And Remedesivir is of no benefit if it is used with steroids.

B.SOLIDARITY trial is Larger but of slightly inferior quality than US trial (too many centres,open label).But Importantly shows no benefit in mortality which is a hard end point even in open label trials ,showing Remedesivir too expensive for its price n less value for money

SOLIDARITY trial Can't reliably measure time to discharge as many patients might stay in Hospital for 10 days of Remedesivir course. (It happened in US trials using Remedesivir for 10 days as well). So It is possible faster recovery might have been missed

So where do we go from here-
1. Aura of Remdesivir is greatly reduced. Should definitely not be used in Sicker Patients (ICU,High Flow Oxygen stage). And definitely not worth its price .

2. Remedesivir Still has role in low Risk/Viremia stage (pneumonia ,but low/no oxygen) requirement where you will be hesitant to use steroid early (think Patients having cancer,HIV, serious co-infection, RECOVERY trial shows harm with steroids at this stage)

Search for cheaper better Antivirals would/should continue as we are seeing a lot of Long COVID Symptoms(chronic fatigue/breathlessness) in Patients who have spontaneous Recovered only with mild Infections as well.

A better Antiviral will make you non-infectious faster-> stop transmission to your family, stop rogression to Hypoxia stage and long COVID Symptoms even if you recover.

So far in small trials Favipiravir (most promising of currently available lot in India) has cut short duration of Fever,led to pneumonia resolution but hasn't led to significant decrease in Patients progressing to ICU/hypoxia.

So we need large trial,newer more potent agents (Monoclonal Antibody, Antivirals - Molnupiravir,earlier/nebulised Interferon) as this Critical phase of Viremia is still open to intervention and world would never have enough plasma/monoclonal Antibody to address this phase.