COVID: remdesivir may help; asymptomatic homeless shelter paper

A recent drug-company sponsored article just reviewed the data on compassionate use of remdesivir for COVID-19 infection, finding significant benefit (see covid remdesivir compassionate use NEJM2020 in dropbox, or DOI: 10.1056/NEJMoa2007016 )

Details:

--61 patients received at least one dose of remdesivir, though 8 (of the 61 patients) did not have either post-treatment data or had a dosing error, so were not included. From 1/25/20 to 3/7/20

--median age 64, 75% men, 26% <50yo/40% 50-70/34% >70yo,

--inclusion criteria included eGFR >30 and ALT and AST <5x upper limit of normal

--median duration of symptoms prior to  remdesivir: 12 days

--coexisting conditions: hypertension 25%, diabetes 17%, hyperlipidemia 11%, asthma 11%

--30 patients (57%) were on mechanical ventilation; 4 (8%) ECMO

--22 patients were from the US, 22 from Canada or Europe, 9 from Japan.

--all patients had confirmed Covid-19 infections, oxygen saturation <95% on room air or on oxygen support

--patients received remdesivir 200mg IV on day 1, followed by 100mg for days 2-10

    --40 (75%) of patients received the full 10-day course, 10 (19%) 5-9 days, and 3 (6%) <5 days

--followup 28 days

Results:

--improvement in oxygen-support class (not specifically defined): 36 patients (68%) [note: these percentages were not from the total group of 61, only the 53 who had data, as above]

     --if on mechanical ventilation, 17 of 30 (57%) were extubated

     --improvement on 12 of 12 patients who were on room air or low-flow oxygen, and in 5 of 7 on noninvasive oxygen support

--discharged from hospital: 25 patients (47%)

--8 of 53 patient (15%) worsened on remdesivir

--deaths: 7 patients (13%), a median of 15 days after starting remdiesivir

    --of those on vents, 6 of 34 died (18%) vs 1 of 19 not on vents (5%)

--overall clinicial improvement was less frequent in those on invasive ventilation vs noninvasive, with HR 0.33 (0.16-0.68), and those >70yo vs <50yo, HR 0.29 (0.11-0.74)

--risk of death was much higher in those >70yo vs <70yo, with HR 11.34 (1.36-94.17)

--adverse events: 32 patients (60%), mostly increased hepatic enzymes in 23%, diarrhea (9%), rash (8%), renal impairment (8%), and hypotension (8%). 12 patients (23%) had serious adverse events (esp multiple-organ-dysfunction syndrome, septic shock, acute kidney injury and hypotension)

Commentary:

--remdesivir is a pro-drug metabolized to an analogue of ATP that inhibits viral RNA polymerases, with broad anti-viral activity: filoviruses (eg Ebola) and coronaviruses (SARS-CoV and MERS-CoV), with in vitro testing finding both prophylactic and therapeutic efficacy (in nonclinical models). And in vitro efficacy has been shown against SARS-CoV-2.

--good safety profile in 500 people in the past (including healthy volunteers and people treated for acute Ebola infection). though numbers of adverse effects noted above do seem to belie that...

--as a perspective: the overall mortality rate in this study of 13% is significantly lower than in most other reports (eg, the lopinavir/ritonavir study had 19%: see http://gmodestmedblogs.blogspot.com/2020/03/covid-19-lopinavir-does-not-work-but-is.html ; though of note, the remdisivir study states it was 22% mortality  with lopinavir, a bit of an overstatement.....  one does need to check the references, unfortunately. and this is hardly the first time i've seen errors, some far worse). in China mortality varied by study, as low as 17% and as high as almost 80%. in italy, those in ICU had a mortality overall 26%, but increased with age, maxing out at 40% in those 71-80yo but only 15% in those <63yo: see http://gmodestmedblogs.blogspot.com/2020/04/covid-italys-icu-outcomes-end-of-life.html 

--limitations:

    --this was NOT an RCT: was it remdesivir that helped? was it that those on remdesivir were treated differently/better than those not on compassionate use of the drug? were they monitored more? was it happenstance (there are many cases of people getting better on their own, independent of an intervention)?  the non-RCT trials on hydroxychlorquine also have had pretty dramatic improvements soon after starting the med. and the lopinivir/ritonavir study found pretty impressive results, though not quite reaching statistical significance. is remdesivir any different?

    --small numbers of people involved: conclusions are less reliable with small numbers of patients; and why did 10+% of the patients not have post-treatment data and were excluded from these statistics? did they do terribly right away and were not reported?? (which, of course, would make their numbers look worse...). is this another case of drug companies massaging their results to make their drug look better?

    --was there a selection bias in who got compassionate use of remdesivir?? these were patients where clinicians appealed for compassionate care. likely inherent biases in who had these appeals filed for them. wealthier people? more public figures? fewer minorities? fewer in hospitals serving those of lower socioeconomic status? fewer homeless? and, why were men so over-represented in this study (though men do seem to have worse outcomes, but 75% men??)

    --no data provided on outcomes in the few patients on less than full-course therapy vs full-course

    --and, there were lots of adverse reactions to the drug, with 1 in 4 having a serious one

so, pretty impressive results in their study, though we really do need the results from a large RCT (trials ongoing) to be certain of benefit, how much benefit, and does this benefit (if found) exceed the rather large number of serious adverse events. their conclusions, as with other med reports, do suggest that earlier treatment (perhaps prophylaxis) leads to better results (and maybe fewer serious adverse events). this all needs to be evaluated. my guess is that the leading contenders for benefit now include remdesivir, hydroxychloroquine (despite the recent "negative" study: http://gmodestmedblogs.blogspot.com/2020/04/covid-hydroxychloroquine-trial-in.html ), convalescent plasma (see http://gmodestmedblogs.blogspot.com/2020/04/covid-convalescent-plasma-seems-to-help.html), some new studies of meds that might counteract the cytokine storm, and (most likely truly beneficial on a large scale) an effective vaccine

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here is the PDF of the pre-print  Boston study on asymptomatic SARS-CoV-2 in the homeless shelter: https://www.medrxiv.org/content/10.1101/2020.04.12.20059618v1.full.pdf

 

geoff

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