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One other very cool thing here is that this new treatment represents a whole new family of drugs (very sophisticated at that, per Derek Lowe's assessment). I thought back in the late 2010s with integrase inhibitors (e.g. dolutegravir), there was a real chance they could achieve the 90-95% reduction targets in new cases, and hopefully this new drug makes that even more feasible.

There's always the risk of losing previously effective drugs due to resistance, so the value of redundancy cannot be overstated

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Here's a summary including the mechanism of action from a UW professor in 2022:

https://www.youtube.com/watch?v=9IbzMbfEMIY

Not my field so please bear with me. Before watching the video the notion of interfering with the capsid as a mechanism for stopping the virus made sense.

However, what I still don't have a handle on is how does lenacapavir act so long that it only needs to be administered every six months?

From the explanation lenacapavir works on the capsid directly, it's not acting on the immune system by training the body's defences as with a traditional vaccine. Surely this molecule can't just hang around for six months without being gobbled up by the liver or such.

What am I missing here?

It's got so many fluorines running around that intuitively as an amateur chemist I would expect it to have an extraordinarily long half life in the human body, especially so if it's administered as a depot injection in something with a large molecular weight. It takes your body a long time to chew through the inactive components in a depot injection.

Yeah, I also noted the fluorines (and Lowe's comment), and I know they're used to prolong action such as with, say, fluoxetine with its three fluorines but six months seems extremely long. I'd have thought it'd have been flushed out long before that. Presumably, it must bind to lipids, fats etc.

Anyway, whatever, it's clearly a brilliant bit of chem eng.

The drug is a PFAS (as nearly half of new drugs are), so it can act that way in the body.

I thought PFAS are toxic?

It's somewhat unclear, but given that they've been found in every piece of human tissue tested for it, I'd say at the very least it kills slower than HIV. Of course there are many different kinds of PFAS, some might be worse than others.

Most vaccines have had some toxic component in them particularly historicaly. If you look up different vaccine types over the past 50 years you'll see often ingredients are removed or replaced because of it. The general wisdom is that it's either small enough quantities that you'd have less negatives from the toxicity than you have from being able to prevent the disease at a population level.

PFAS only describe one part of the overall molecule. It doesn't necessarily tells if the rest of the structure is toxic or not. It's like saying "I though canine were dangerous?" (yes for big cats, no so much for your average French bulldog).

Also, the dose makes the poison, etc.

> It's like saying "I though canine were dangerous?" (yes for big cats, no so much for your average French bulldog).

Big cats are not canines :(

Cats, big as well as small, are feline :)

Ah sorry, my French bias is shining through. I meant "canine tooth" (also known as a fang), not the Canis genus.

Ah, that totally makes sense! No worries :)

‘PFAS toxic’ is about as sophisticated as saying ‘Nuclear bad’.

Western society isn’t scientifically literate enough to develop these things at the moment, so they will happen in APEC for now.

No. The drug is not a PFAS.

PFAS stands for a very specific thing: perfluorinated alkenes. The drugs in question are not alkenes.

Damn it, autocomplete. Alk_a_nes, not alkenes.

> Surely this molecule can't just hang around for six months without being gobbled up by the liver or such.

It can! The fluorines likely protect the metabolic target. At that point you're relying on excretion of unchanged drug through the kidneys or liver (which excrete into bile, and then eliminated in feces).

Google tells me the half-life of the subcutaneous administration is 2 to 3 months, so twice yearly injections makes sense.

I would have thought that too but at one point I had clients taking a bone loss drug called Alendronate. Looking up the drug I was shocked to see that it has a 10 year half life in bone tissue. So yes some drugs once taken will stay in certain tissues for a very long time.

For someone with bone loss, isn't the long half life a good thing?

It is. It's also very impressive for a medicine to exhibit such a long half life.

"I was shocked to see that it has a 10 year half life in bone tissue."

Well so am I. One of the great things about HN is the sheer amount of stuff I learn from others who post here. Alendronate is yet another instance. :-)

As Alendronate, Alendronic acid, is not a drug I'm familiar with I've just looked it and its structure up on Wiki to get a rough idea what it's about.

I'm not doubting Alendronic acid's 10 year half life in bone tissue but I'm now curious how that comes about. It has five hydroxy groups which I'd have thought would have made it highly soluble in water. And —OH groups tend to be reactive.

As I said, biochemistry isn't my field but I'm now intrigued about how it actually works. No doubt the phosphorus bonds to or goes into strengthening bones but why that doesn't happen immediately has me stumped. So experts I need your help.

Clearly, many chemicals can and do survive in tissue for years, PFAS being an example but we don't think of them being highly reactive either. Obvious examples of chemicals that aren't eliminated by the body that everyone is familiar with are tattoo dyes. No doubt a bad example as they don't seem to be biologically active and remain more by mechanical adhesion than by any other means.

The issue I don't have a good handle on is how biologically active drugs can remain unchanged for so long before being taken up and used by the body. Perhaps they're stored as intermediate metabolites or similar.

This is a paper describing the pharmacokinetics (the rates of various phases of entering the blood and clearing out of the body) for various formulations of the drug, and their hypotheses for why this might be the case:

https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.3c00626

tl;dr: the molecule is poorly soluble in water, so by suspending a bunch of microparticles and injecting them subcutaneously, the drug very slowly dissolves over time, and it’s very potent, so only a little bit is necessary to do its job.

No problem with this is it it does not interfere with infection. Only with replication. So it will not stop people from becoming infected.

It does in fact prevent infection you have misunderstood.

It very clearly prevents infection incredibly well, proof of that in the real world is exactly why there is excitement over this drug.

It also sounds as though you misunderstood the mechanism, it interferes in both an early and a late step in the viral process, there no theoretical reason to describe it as "not interfering with infection".

From what I read, it interferes with capsid formation. Since HIV is a retrovirus, by the time capsid formation is happening it has already integrated itself with the host cell’s DNA.

That implies that as long as the drug is present, the virus won’t be able to replicate, however as soon as the drug is no longer present the virus will start replicating. Because the cell has been infected.

There's no infection without replication.

Of course, the illness cannot get worse without the virus first infecting a cell, and then replicating in that cell to infect other cells in the body, and then potentially infecting other hosts; that is how a virus works, right?

Now, if replication is stopped, AND the body is able to destroy the first infected cell, then the patient is cured, but otherwise?

I guess that even if the body's immune system cannot get rid of that "patient cell zero", it is quite possible that a 6 month period is enough for the cell to die from the virus.

I do not have any medical training though, so please correct me if I am wrong.

Epithelial skin / mucosa cells are the most likely "patient zero" cells, and those are shed regularly.

Infection is when the virus replicates faster than the body can eliminate it.

>There's always the risk of losing previously effective drugs due to resistance, so the value of redundancy cannot be overstated

Redundancy in HIV drugs is extremely important and significantly more resources should be applied to such drugs, as well as to treatment regimens and vaccines that can significantly reduce HIV infection and the horrible effects of AIDS.

In fact, we've made enormous advances over the past 35+ years. My (late) sister's (late) husband was a hemophiliac and, like most American hemophiliacs[0], was infected with HIV because big pharma refused to test the blood products[1] they were selling to hemophiliacs, even though they knew there was a significant risk in doing so.

In any case, my sister took care of her husband for nearly 15 years, until he finally died a slow, painful death in 1996. My sister was also HIV+ and didn't wish to suffer the way her husband had, especially since there was no one to care for her the way she cared for him. And so, over Memorial Day weekend, 1996, my sister took her own life rather than die a slow, painful death.

The irony, of course, was that the first protease inhibitors were approved by the FDA five or six months later. Had she waited, she might well be alive today. And more's the pity.

As such, I strongly believe in research to prevent, treat and cure HIV/AIDS, and heartily agree that we need more good drugs and treatments.

However, the value of anything can be overstated, including redundancy in HIV drugs.

"Without significant redundancy in HIV drugs, all life in the universe will be extinguished."

"Without significant redundancy in HIV drugs, our sun will explode in 2043."

"Without significant redundancy in HIV drugs, the oceans will boil, then evaporate in the next six weeks."

I could go on, but I presume you get the idea.

Hyperbole can be a short-term motivator, but we need to continue over the long term to stop HIV/AIDS. So, please do advocate for more research/drugs/treatments, but please don't use such language in doing so -- it cheapens the argument and potentially reduces the resources available for the efforts you clearly want.

Feel free to disagree, but doing so will give you terminal cancer.[2]

[0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917149/

[1] https://www.cbsnews.com/news/bayer-says-it-settled-decades-o...

[2] See what I did there?

I’m sorry your family was put through so much termoil.

> Redundancy in HIV drugs is extremely important and significantly more resources should be applied to such drugs

Does HIV prevention research get more resources than curing cancer? I'm looking through the NIH website and asking Claude and so far the evidence I've seen is leading me to believe that's true, but I could be mistaken.

Maybe? But Cancer isn't a single disease, it's a class of diseases, it has a lot more causes and symptoms and treatments than HIV.

Which is why it would be so shocking if HIV received more research funding than all of them put together.

>Does HIV prevention research get more resources than curing cancer? I'm looking through the NIH website and asking Claude and so far the evidence I've seen is leading me to believe that's true, but I could be mistaken.

I don't know. Does it matter? If you think it does, why?

Note that I wasn't advocating for resources to be taken away from research on treatment/cures for other diseases.

That said, more resources should be applied to curing cancers and other deadly diseases as well.

> Hyperbole can be a short-term motivator, but we need to continue over the long term to stop HIV/AIDS.

I am expecting the findings of this trial to be regurgitated by the general population who refer to the science community. “THEY cured AIDS” will be declared without the nuance of “well, new infections are prevented with a biannual depot injection …”

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