23 Oct Episode 77 a state of treatment general

Dear colleagues,

My focus for today is on treatment.  All papers can be found at:

1. Controversy over Remdesivir: As you know, Remdesivir is a polymerase inhibitor, shown to be active against SARS-CoV and MERS in a primate model, when administred early.  

• De results of the Solidarity trial, published on 15 Oct in medRxiv are sobering: No study drug (Remdesivir, Hydrocholoroquine, Lopinavir or Interferon) definitely reduced mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalisation duration.

• However, the completed trial of NIAID on Remdesivir, published in NEJM on Oct 21, however, confirms the interim analysis in that the drug could significantly (P<0.001,)shorten the recovery time from a median of 15 days in the placebo to 10 days in the Remdesivir group.  There was also a reduction in mortality with hazard ratio 0.73, but this was just not significant (CI 0.52 -1.03). Reassuring was also that there was no increase in side effects with Remdesivir.

• How comes? 
  • The dosage of Remdesivir was identical (200 mg loading and then 100 mg daily for 9 days) . 
  • The inclusion criteria seem broader in Solidarity and maybe more mild patients were included?:

Solidarity: Eligible patients were age ≥18 years, hospitalized with a diagnosis of COVID-19, not known to have received any study drug, without anticipated transfer elsewhere within 72 hours, and, in the physician’s view, with no contra-indication to any study drug. 

→ In Fig 3, it seems that at least 2/3 were “not ventilated”.

NIAID: Patients were considered to have severe disease if they required mechanical ventilation, if they required supplemental oxygen Patients were considered to have severe disease if they required mechanical ventilation, if they required supplemental oxygen, if the oxygen saturation as measured by

pulse oximetry (Spo2) was 94% or lower while they were breathing ambient air, or if they had tachypnea (respiratory rate ≥24 breaths per minute).

→ in the first line of “Result” it seems that the majority (85%) are severe cases.

2. Hope on Favipiravir?: Favipiravir is a broad spectrum polymerase inhibitor for RNA viruses (both + and -). It has been shown to be active in vitro against SARS-CoV-2, but requires high doses. 

• The first comment by Coomes in JAC reminds us that it was shown to be effective against EBOLA in retrospective studies and has been approved for treatment of influenza in Japan (if unresponsive to other antivirals).  Also the results of an open label study in Chinese COVID patients were promising.
•  
• The PNAS paper from Johan Neyts group elegantly shows in a hamster model that, in contrast to chloroquine (+Azitromycin ) or low-medium doses of favipriravir,  high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact,

• The minireview by Du and Chen gives a nice overview of ongoing clinical trials (Table 1) and pharmacokinetics of Favipiravir.  It is suggested to use a similar dose as for Influenza but for a longer time: loading with 3200 mg on day 1 followed by 1200 mg from day 2 to day 14 (instead of only till day 5 for Flu). The side  effect in Influenza were acceptable (but it remains to b e seen if the treatment is prolonged).  The caveat of these  authors is that a number of drug-drug interactions (Table 2) are to be expected, in view of the common use of aldehyde oxidase as the main metabolizing route.     

3. Hope on monoclonal antibodies and nanobodies against Spike?:

• Several single and combinations of human monoclonal antibodies have been described (see two added papers)  and some are being developed by at least two companies (Regeneron and Eli Lilly).  Although, one would think few side effects are to be expected, it has been announced recently that the Eli Lilly trial is on hold for severe patients, while still continuing for mild cases and as a prophylactic.     Is it because antibodies in late stage could have “enhancing effect” in some patients or because of issues in quality control?  See https://www.nytimes.com/2020/10/13/health/eli-lilly-antibody.html   and

https://nypost.com/2020/10/14/fda-found-lapses-at-eli-lilly-plant-making-covid-19-drug-report/

• A very interesting evolution is the report by Xavierc Saelens group on a camelid “single chain VHH” (nanobody), elicited by SARS-CoV-1 that cross-neutralizes SATS-CoV-2, because it binds to a very conserved part of Spike adjacent to the receptor-binding domain.  

4. Controversy over Ivermectin: Despite the fact that the regular dose of Ivermectin (given as a single dose of 0.2 mg/kg) is orders of magnitude too low to have any antiviral effect (as shown again by Pena-Silva in BJCP), this drug is being used in various LMIC of Asia and Latin America to hospitalized COVID patients. I made a special folder under Episode 77b with papers in local journals and press releases, kindly provided by a colleague).  As you can see, the results seem impressive, but none of these studies is really prospective and double blind.   

Clinicians of these countries are very convinced, but, clearly, as with chloroquine, we need double bind prospective studies first.  A possible explanation for an unexpected positive effect is offered in editorial of “OpenHeart”: the suggestion is that Ivermectin mlay have an anti-inflammatory effect and would mitigate the “cytokine storm”.  However, this hypothesis is only based on mice experiments with LPS and allergic inflammation in mice models and at 10 X the regular dose….

5. Blocking IL-6 to stop the cytokine storm?  

• A single center open study with the anti-IL6 receptor mAb Tocilizumab (TCZ) in Brescia showed “encouraging results”
• Clinical improvement in more than three quarters of patients
• Response to TCZ was rapid, within 12 to 72 h, and sustained, as all patients with initial response continued to improve over the next ten days

A very sobering remark: “It is worth emphasizing that, at the time of TCZ administration, ICU beds and ventilators were not available for many of these patients, leaving little time to save their lives”  How many days are we away from this situation in Belgium today?

• A single center retrospective study with a double-sized matched control group in J Infect with a majority (70%) of critical COVID-19 disease was less enthusiastic . TCZ use was associated with a better overall survival (HR 0.499 [95% CI 0.262–0.952], p = 0.035) compared to controls but with a longer hospital stay (HR 1.658 [95% CI 1.088–2.524], p = 0.019) mainly due to biochemical, respiratory and infectious adverse events.

• A small observational study from Nijmegen in JAMA puts the elevation of  IL-6  (TNF and IL-8) in COVID ARDS into perspective. The figure is clear as is the conclusion:

In this study, critically ill patients with COVID-19 with ARDS had circulating cytokine levels that were lower compared with patients with bacterial sepsis and similar to other critically ill patients.

The findings of this preliminary analysis suggest COVID-19 may not be characterized by cytokine storm. Whether anticytokine therapies will benefit patients with COVID-19 remains to be determined.   

Nevertheless, there is an hyper-inflammatory condition in the second stage of the disease, but it might not be so easy to find the “primum movens”, the cytokine or other factor that is the culprit, the “match that lights the fire”.   

6. Leaving us with Dexamethasone:

• RECOVERY showing a clear benefit in survival in the patient group, who required mechanical ventilation 29 % died in the DEXA group versus 41 % on control), but not really in less severe patients.
• CODEX showed that dexamethasone in moderate to severe COVID resulted in a significant increase of “ventilator-free days” (from 4 to 6.6)  and a reduction in “sequential organ failure” (7.5 to 6.1), without increase in secondary infections, but no clear effect on all-cause-mortality.   

Clearly, DEX is beneficial and should be used, when indicated, but it is no miracle drug

Best wishes,

Guido