Experts on Twitter have discussed how the results of these two trials can be reconciled (acknowledging that results for Solidarity are, as yet, only available in preprint form). The main questions seem to be:
- IF remdesivir helps, HOW does it help?
Some have speculated that remdesivir might only offer benefit if given early in the disease course, during a time of rapid viral replication. Many antivirals we give for other illnesses are considered only to offer benefit (i.e., shorter disease course, milder symptoms) if given in the first few days of symptoms (e.g, antivirals for HSV and HZV, oseltamivir for influenza). If this is also the mechanism of benefit for remdesivir, then ACTT-1 findings would suggest that there is still a sufficiently high level of viral replication ongoing many days after COVID symptom onset that remdesivir can offer benefit even if given relatively late in the disease course. Median time to start of treatment with remdesivir in ACTT-1 was many days after symptom onset. To this end, has anyone shown (quantitatively rather than clinically) more rapid viral clearance among patients treated with remdesivir vs comparator, even with a treatment start many days after symptom onset?
- If the results of both trials are accepted at face value, can we reconcile the ACTT-1 finding that remdesivir improves time to recovery with Solidarity’s failure to identify a mortality benefit?
Plausibly, these findings could be reconciled if there were some type of physiologic “tripwire” for certain patients with COVID, after which they are more likely than other patients to fare worse, regardless of treatments they might receive. I’m not an expert in ID, but I think this is the idea underlying the discussions of “cytokine storm.” Since remdesivir was generally given many days after symptom onset for patients in ACTT-1 (and although we don’t know for sure, it’s reasonable to assume a similar lag for patients in Solidarity since it generally takes several days for patients to present to hospital after illness onset), might patients’ likelihood of responding to remdesivir have been “predestined” by the time they presented to hospital? If this were the case, then the next logical question to ask would be whether, if administered very early in the disease course, remdesivir might be able to prevent triggering of the tripwire and thereby demonstrate a mortality benefit.
Unfortunately, trying to corroborate this theory would prove difficult for several reasons:
- Remdesivir has already been approved in at least some countries, so the sponsor’s incentive to fund additional trials might be lower;
- Remdesivir is administered intravenously and is very expensive. We can’t afford to hospitalize huge numbers of people early in their disease course for the sole purpose of administering intravenous remdesivir. In the context of a clinical trial assessing the efficacy of early remdesivir administration, it might be feasible to arrange daily IV dosing through outpatient clinics. But positive results from such a trial could create a logistical nightmare. Daily outpatient IV administration isn’t likely scalable to huge numbers of people for many reasons. If we could reliably predict which patients were destined for a more fulminant disease course, then perhaps we could direct a limited drug supply toward this group - but this seems like a predictive modelling minefield (?). In an ideal world, cheap and effective oral versions of remdesivir would become available if early administration could be shown to reduce mortality.
So at the end of the day, unless someone invests in additional studies of remdesivir administration at the earliest stage of coronavirus infections AND unless it’s feasible to develop both cheap and effective oral versions of remdesivir, the drug seems destined to be used exclusively in patients sick enough to require hospitalization. And by the time most patients are sick enough to be hospitalized, it seems plausible that an unfortunate subset might already be on an inevitable trajectory toward a poor outcome, regardless of whether remdesivir is administered or not. For the larger number of hospitalized patients who have not passed some undefined “point of no return” (?maybe identified by the need for mechanical ventilation), ACTT-1 seems to suggest that remdesivir might help them to get better a bit faster (perhaps freeing up desperately-needed hospital beds).