@monarchdiaries I am increasingly wondering whether the Chinese HCQ trials can be trusted.
It is possible that the government needed to quickly propose some kind of near-term solution, and may have somehow inflated efficacy estimates.
The nebulized interferon results replicate well, at least.
It is possible that the government needed to quickly propose some kind of near-term solution, and may have somehow inflated efficacy estimates.
The nebulized interferon results replicate well, at least.
@monarchdiaries It is reasonable to think an entry inhibitor might work better in the presence of an interferon inducer (or interferon), which I thought might explain the discrepancy in later results reported for HCQ alone (often RCTs) versus HCQ+AZM/IFN/etc. (often merely observational).
@monarchdiaries Some RCTs were also poorly designed in other respects, e.g. RECOVERY massively overdosing everyone and trying to treat severe cases with it.
I spent considerable time excoriating Horby over that. It is genuinely scandalous, regardless of whether HCQ helps milder cases or not.
I spent considerable time excoriating Horby over that. It is genuinely scandalous, regardless of whether HCQ helps milder cases or not.
@monarchdiaries One could also argue that mail-order post-exposure prophylaxis trials were ill-designed, and either way it does seem to provide some mild pre-exposure prophylactic benefits based on work conducted elsewhere.
@monarchdiaries But at this point, I see an ominous tendency for HCQ to look best in the lowest-quality trials and in observational studies, and much less promising in even fairly well-designed RCTs.
This one pairs it with an interferon inducer, uses appropriate patient selection, has N=667.
This one pairs it with an interferon inducer, uses appropriate patient selection, has N=667.
@monarchdiaries Beyond that, look at the results we are seeing in moderate/severe cases for common, safe, well-tolerated interventions:
- bromhexine
- dipyridamole
- famotidine
- colchicine (careful)
- *ivermectin* (anti-inflammatory effects are real and replicate)
The effect sizes are huge.
- bromhexine
- dipyridamole
- famotidine
- colchicine (careful)
- *ivermectin* (anti-inflammatory effects are real and replicate)
The effect sizes are huge.
@monarchdiaries The antiviral and combined antiviral/anti-inflammatory side is still being sorted out.
I see varying indications of potential superiority vs. HCQ from e.g. nebulized interferon, nafamostat, nitazoxanide, nelfinavir, dipyridamole (also antiviral), ciclesonide, favipiravir, etc.
I see varying indications of potential superiority vs. HCQ from e.g. nebulized interferon, nafamostat, nitazoxanide, nelfinavir, dipyridamole (also antiviral), ciclesonide, favipiravir, etc.
@monarchdiaries I think it is worth re-thinking whether endosomal entry inhibitors are useful once the virus is in the lungs.
SARS-CoV-2 begins by infecting ACE2+ ciliated and secretory cells from a distance, but can spread to adjacent endothelial cells via TMPRSS2 surface entry and filopodia.
SARS-CoV-2 begins by infecting ACE2+ ciliated and secretory cells from a distance, but can spread to adjacent endothelial cells via TMPRSS2 surface entry and filopodia.
@monarchdiaries If anything, it may even be easier to infect adjacent cells by non-endosomal routes, given the entire surface of an infected cell expresses Spike and can fuse to adjacent cells once cleaved by suitable membrane-associated proteases.
@monarchdiaries That might in part explain why potent TMPRSS2 inhibitors (nafamostat, bromhexine) still seem to help even late in the disease course. This is confounded somewhat by the fact that nafamostat is also an anticoagulant, and bromhexine helps prevent hyaline membrane formation.
@monarchdiaries But much of this is still somewhat speculative.
@monarchdiaries Either way, this has caused my view on simple entry inhibitors to update further in the direction of only being potentially useful in preventing initial or early spread into/within the lungs, and not likely useful once the virus has already become well-established in the lungs.
