[pitpatagain]

I want to emphasize that the parent comment of all this is straight up incorrect on the mechanism of action of this drug class.

"This means that before it can work the virus has already infected the cell and added its RNA to the host cells DNA permanently." is not correct, capsid inhibitors interfere before both reverse transcription and nuclear import.

Both of the drugs in Truvada, which was has had 13 years of use in the wild since approval and is very successful, are NRTIs, they work at the reverse transcription step, they are literally later in the cycle than the new drug (but before nuclear import also) and work just fine as prep.

So the whole premise for why this drug in particular shouldn't work in theory is flawed.

To your questions about how the lenacapavir trials were run and why they rule out occult infection (which is the term for what you're describing): I'd like to find more details on the study honestly. But do I think the multiple studies that convinced the FDA to give approval just completely overlook this well known concept/possibility? Not really?

[amluto]

My general level of trust in the FDA to ask the right questions is low enough that I certainly don’t believe any argument of the form “if it’s good enough for the FDA, it’s good enough for me.”

That being said, I would expect that the possibility of widespread occult infections with Truvada would be ruled out because such infections would be noticed quickly when a patient stops taking Truvada. But the newer PrEP drugs are much longer acting. Maybe the lack of occult infections with shorter acting drugs makes everyone confident that they won’t happen with longer acting drugs? Maybe the tests used are so sensitive that they would detect infections anyway? If nothing else, I would have expected the papers to have some discussion of the matter.

[pitpatagain]

> Maybe the lack of occult infections with shorter acting drugs makes everyone confident that they won’t happen with longer acting drugs?

Previous experience is definitely part of it. It's not just Truvada, this isn't the first long acting injectable prep. Cabotegravir (integrate inhibitor) was approved 4 years ago for this use and is given every two months, so there's already information from how that was studied, approved and what's happened with several years of actual use.