Thread by @StevePhillipsMD

I think the authors put forth a good effort, but there are significant issues with this study, which was intended to evaluate #COVIDー19 post-exposure prophylaxis with #HCQ. My two cents:👇nejm.org/doi/full/10.10…

Planned enrollment threshold was within 3 days of exposure due to the average incubation period of 5.5 days. But then the threshold was changed to 4 days. Cutting it close. One can argue that the study nearly misses its basic premise of being a PEP trial. And then this: 👇

Authors wrote that the "vast majority of the participants" couldn't get diagnostic testing for #Covid. Instead, they looked at symptoms and labeled some cases as "probable," about which they admit, "predictive power of this case definition is unknown." Is this OK?👇

No, it's not. For a study of an infection for which direct detection testing is available, we need firm data for who has, and who doesn't have, the infection being studied. Public health policy decisions depend on the data being definitive. Here are other methodology concerns:👇

Authors referenced the Korean post-exposure trial which found 100% prophylaxis among 211 people in a hospital exposure setting, but they failed to duplicate a key metric of that study. Does this help explain the discrepancy between these two studies?👇sciencedirect.com/science/articl…

In the Korean study, 14 days #HCQ with compliance 97%. In the @NEJM article, only 5 days & compliance 75% . Treatment duration was already so short & made shorter by high non-compliance rate. So is short term HCQ a viable treatment for #COVID? I don't think so & here's why:👇

A cell culture study of SARS, cousin to #C19, had findings described by its authors as "striking" when applying short term NH4Cl to infected cells. NH4Cl has the same action on endolysosomes as #HCQ, ie making them less acidic & inhibiting their maturation. Unexpected findings:👇

Infection increased by 2-4 times.

"The inhibition of endosomal acidification prevents their degradation [virus] and grants them opportunity to accumulate and more efficiently infect cells upon removal of the drug..."

Too short treatment--not good.
ncbi.nlm.nih.gov/pmc/articles/P…

What's the minimum #HCQ treatment duration for good effects while preventing possible bad effects from too short treatment? I think more than 5 days complicated by a 75% compliance rate. Can't calculate true duration of treatment for this study, wording was too vague.👇

Tips for an improved PEP study design:
1. HCQ 14-day arm at normal doses. High doses have side effects. Regular doses can increase compliance.
2. Actual early treatment--first 2 days of exposure.
3. Diagnostic testing of all participants.