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Comment by raylad | Hacker News Reader

The problem with this drug is that it inhibits one of the final stages in viral replication. This means that before it can work the virus has already infected the cell and added its RNA to the host cells DNA permanently.

So if a patient is exposed to HIV while on the drug, this will not prevent their cells from being infected with the virus. The infected cells will not subsequently create any virus, and therefore additional cells will not be infected, however nothing prevents actual exogenous HIV from infecting cells while on this drug.

That means that if someone discontinues the drug, cells that have been infected with HIV during the time they were on the drug can start producing it causing AIDS.

It’s great that there’s a drug that works as well as this for chronic use, but nobody should think that it’s actually preventing infection. It’s allowing infection but inhibiting viral replication post infection.

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This seems incorrect. From https://medicine.yale.edu/news-article/lenacapavir-drug-offe... :

> The medication works in two ways: First, it interrupts viral replication by preventing HIV from reaching the nucleus of an infected cell, which then blocks reproduction.

> The second mechanism is for cases in which integration of the HIV genome has already occurred. In this instance, lenacapavir interferes with production of viral progeny

In other words, it has multiple mechanisms of action and you are only discussing one of them.

Another source is https://pmc.ncbi.nlm.nih.gov/articles/PMC10705863/ (my emphasis):

> Its multistage inhibition entails the process of selective binding to the interface between capsid subunits and such interaction determines the inhibition of capsid-mediated nuclear uptake of HIV-1 proviral DNA (by blocking nuclear import proteins binding to capsid), virus assembly and release (by interfering with Gag/Gag-Pol functioning, reducing production of CA subunits), and capsid core formation (by disrupting the rate of capsid subunit association, leading to irregularly formed capsids)

This sounds like a sort of plausible mechanism, but do you have any actual evidence that this occurs in real life? I admit that I’ve wondered whether the PrEP studies with lenacapavir actually measure what they thing they measure given that the same lenacapavir may prevent HIV from replicating enough to be detectable.

That being said, Wikipedia doesn’t really agree with your mechanism. See:

https://en.m.wikipedia.org/wiki/HIV_capsid_inhibition

It seems that the drug may inhibit disassembly of the capsid.

Agree that it sounds 'close to correct.'

I think, though, that the underlying assumption is that the old virus hangs out, forever waiting for the moment to strike.

Cells senesce and die and get replaced, and the immune system is always active in the background. If the virus particles are released, the immune system is going after it and cleaning up. As essentially no new virus is being created, this is the body's opportunity to clear the virus at a slower, manageable pace where it doesn't have to contend with a rapid, expanding infection.

It feels like one of those ideas that's technically true in all the right ways, but misses one crucial piece that would make the whole thing accurate.

> Cells senesce and die and get replaced, and the immune system is always active in the background. If the virus particles are released, the immune system is going after it and cleaning up. As essentially no new virus is being created, this is the body's opportunity to clear the virus at a slower, manageable pace where it doesn't have to contend with a rapid, expanding infection.

If this really applied to HIV, then people with HIV who take effective antivirals for long enough would be cured. But they generally aren't.

This is great information and obviously new to me. I had thought it only interfered with cap formation but it appears to also interfere with capsid penetration of the nucleus and therefore integration of the virus with the host cell genome.

So obviously I retract everything I said above .

This is incredibly misinformed, the drug has been specifically studied as prep, and this is in fact not at all what happens, despite your theories about the drug's mechanism of action. It does prevent infection.

How, exactly, does the “specifically studied as prep” process determine whether a person *who is taking a very long-active antiviral medication” acquired HIV?

Here’s one of the papers:

https://en.iacld.com/UpFiles/Documents/1e4ad0d2-4a73-4365-9b...

It gives no details whatsoever about how testing was performed except to mention that both rapid and central laboratory tests were used. It does not discuss whether the study medication could interfere with testing. It does not even say whether the tests looked for antibodies, RNA or something else. The actual study protocol is in the paywalled supplement information.

I’m not saying the studies are wrong. But I would be a lot more impressed if the studies actually discussed the issue.

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?

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.

> 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.

If the virus doesn't replicate, does that also means it doesn't transfer from an infected person to their partners? If so, that would also fall under "provides protection against HIV infection" for me.

It’s an insightful and society-forward observation, but I do think a person taking the drug who found they were infected but not contagious might take issue with the “prevents infection” framing.

Assuming GP is correct, from other comments it sounds like that’s in question.

Initial infection and persistence are different things, and the reservoir for HIV builds up early on, but not immediately. There is definitely at least one reproductive cycle in between the first infected cells and the creation of a reservoir.

https://pmc.ncbi.nlm.nih.gov/articles/PMC4593515/

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