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Works in Progress is an online magazine devoted to new and underrated ideas about economic growth, scientific progress, and technology. Subscribe to listen to the Works in Progress podcast, plus Hard Drugs by Saloni Dattani and Jacob Trefethen.
0:00:01.200,0:00:09.040
Place yourself in the 1980s. This is
kind of hard because, as a scientist,
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you had just found out that retroviruses
could infect humans. Now you find out
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that HIV is a retrovirus. You're like,
wait, I didn't even know that RNA could
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be turned into DNA until 10 years ago. So
that's quite a tricky position to be in.
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Making effective new medicines isn't easy.
Welcome to Hard Drugs. I'm Saloni Dattani,
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a researcher on global health at Our World
in Data, and one of the founders of Works
0:00:43.920,0:00:49.600
in Progress magazine. And I'm hosting this podcast
with Jacob Trefethen, who leads science and global
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health R&D funding at Open Philanthropy, and is
one of the most fun, interesting people I know.
0:00:55.360,0:00:59.360
This show is about medical innovation:
how to speed it up, how to scale it up,
0:00:59.360,0:01:04.240
and how to make sure lifesaving tools reach the
people who need them the most. It all started with
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a conversation, a shared instinct that this was
the right time to start a podcast, to dive deep
0:01:09.440,0:01:14.960
into how to technologies for malaria, cancer,
AIDS, and other diseases, actually came to be.
0:01:14.960,0:01:22.400
Today we're going to talk about HIV. Making an HIV
vaccine has been the holy grail for many of the
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world's top scientists over the last generation.
It has proven one of the most challenging
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scientific problems too, and we don't yet have a
vaccine. But last year, one drug company announced
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they'd gone a completely different route. They
made a drug you get injected with once every
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six months, or maybe only once a year, like a
flu shot, giving you almost perfect protection
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against HIV. So how did we get here and what does
it mean for one of the world's deadliest diseases?
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I'm super excited to talk about HIV, lenacapavir
and other HIV drugs today with Jacob. Hello.
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Hey, how are you doing?
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Great. Yeah, so I'm super excited about this. I
think we have a bunch of things that we're going
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to talk about in the episode, maybe starting with
just what HIV is, how it infects people, and then
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moving on to the history of drug development
in the field, how lenacapavir was develops,
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what lenacapavir actually does, and then where we
are now, how to scale it up to people who need it.
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That sounds good to me. I feel like I first
really heard about or realised what a big
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deal lenacapavir was from a tweet from you.
So I get to be the lucky guy who gets to be
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taught some of that history of HIV and how
it all fits together from you. Hopefully I
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can chip in some of my knowledge from working
at Open Philanthropy on Global Health R&D as
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well. That's this conversation. There's a lot to
cover. I hope we cover the stuff that matters,
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and get to the finish line of what are
these magical new drugs really doing.
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There are a lot of, I think, subplots that we're
going to go through. The whole process of drug
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discovery in this field has been really amazing.
If you think about what HIV was like in the 1980s,
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where people would only have a few years of
survival after being diagnosed to now, where,
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if people take treatment early enough, they can
expect to live almost a normal life expectancy.
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I think talking about how that's happened, how
that's been made possible, is really important.
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I agree. It sounds like we're
going to have to start with:
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what the heck is HIV itself?
Should we begin there?
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HIV is a virus that causes AIDS, the
acquired immunodeficiency syndrome,
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which is associated with lots of
different infectious diseases,
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cancers, and conditions that people suffer from
if they've been infected with the virus for long
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enough. But what's interesting about HIV, to begin
with, is that it's not a typical type of virus.
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It's something called a retrovirus. "Retrovirus"
itself is a new concept to a lot of scientists,
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historically speaking. The first retrovirus that
infected humans was only discovered in 1979, which
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is just two years before the first reported cases
of HIV in the US. Before that, people had no idea-
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And that was not HIV.
That was not HIV.
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Okay. That was a different retrovirus.
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That was human T lymphotropic virus,
the first human retrovirus discovered.
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I think that itself has a really interesting
story. When I was first reading about this,
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I was really struck by the fact that there
was only this two year gap. We essentially
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figured out what [human] retroviruses were in the
first place just shortly before discovering this
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deadly new disease that was caused by one. I
think that's an important thing to think about,
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when we're thinking about what scientists
at the time would've been working on,
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and how they would've figured
out that it caused AIDS.
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What is similar about that virus
and HIV? What makes it a retrovirus?
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A retrovirus — maybe I could kind of step
back a bit and talk about how the usual
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process of DNA works, just to give you some
context. Great. Almost every cell in our body
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has DNA. DNA is the genetic code to tell us
which proteins to make, but it contains all
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of that genetic code. All of our cells don't
need to be producing all of those proteins,
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and they don't need to be producing them
all of the time. So instead of using the
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entire genetic code, we use our enzymes to
find segments of the DNA, to turn into RNA,
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which is this intermediate molecule that's
also used for various other things. And then
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we turn this RNA into protein; proteins that
are used in all kinds of processes in our body.
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This direction — from DNA to RNA to protein
— was how biologists and scientists typically
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understood cells and how biological life worked.
And that was overturned with the discovery of
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retroviruses. What happened here was that
people found out that there were certain
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viruses that could turn their RNA into DNA,
using an enzyme called reverse transcriptase.
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They're in the other direction.
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Yeah. This was a huge discovery in 1970
by Howard Temin and David Baltimore. They
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discovered this enzyme, reverse transcriptase.
They discovered that retroviruses could reverse
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transcribe RNA into DNA, and then they tried to
find other retroviruses that infected humans.
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For a long time, no one succeeded in finding
any of these viruses, until 1979. So it was
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about almost 10 years of people trying to find
real examples of these, and they couldn't.
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And is that related to HIV in 1981? We
just got lucky? Or yeah, why so close?
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So I think we did get lucky, and I think it
would've been really difficult to figure out
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that HIV was causing AIDS if not for that — or to
even know where to look. What's really interesting
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about this is, the scientist who discovered
the first retrovirus that infected humans,
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Robert Gallo, was also one of the scientists
who discovered HIV as being the cause of AIDS.
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I really like kind of reading
through reviews, or retrospectives,
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written by scientists themselves on how they
figured out something, what research they did,
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and so I was reading this retrospective that he
wrote on the discovery of retroviruses and HIV,
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and it was really interesting because
he talks about how people were really
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sceptical that there were any other
retroviruses that infected humans.
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The reason for that was: people had found
retroviruses that infected other animals,
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other primates. And in those primates, it seemed
to be pretty abundant — or ubiquitous — across
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their organs, but that wasn't the case in
humans, and it was just hard to find them.
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So they assumed that maybe there's something
that prevents us from being infected by them.
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Scientists also found that if you put the animal
retroviruses into human blood — human serum — that
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would immediately inactivate those viruses, using
our complement system, which is one component of
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our immune system. So this suggested that maybe
there's some way that we're just protected
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against them; they're not going to affect us.
I think Robert Gallo just had this idea that
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that might be wrong: maybe there are some other
types of retroviruses that we hadn't studied.
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And so he started looking at T-cell cancers.
In animals, the retroviruses that infected
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those animals would typically cause T-cell
leukemias; T-cells are a type of white
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blood cell. So he thought maybe they're also
causing leukemias in humans, and he started
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working on finding patients with T-cell leukemias.
Eventually he did actually discover a retrovirus
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in them. This retrovirus was using reverse
transcriptase to turn its RNA back into DNA.
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And the reason that this is important for HIV is
that they actually developed the tools — to test
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out whether there are retroviruses infecting a
sample — as part of that process. They started
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working on potential drugs that could be used
to target reverse transcriptase. They also just
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generally had the idea that humans can be
infected by retroviruses, and retroviruses
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infect humans in their T-cells. And as we'll
come to later on, that's very relevant in HIV.
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Okay, so just stepping back for a second.
Beforehand, scientists thought: well, maybe these
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retroviruses that we're seeing in other animals
aren't infecting humans, and the human immune
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system's basically winning against them. We've
got this under control. But then, it looked like
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they may infect some cell types and we might not
be winning fully. I mean, my question then is — it
0:11:21.280,0:11:28.640
sounds like such a good strategy for a virus. If
I'm a virus, I would love to reverse transcribe
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and integrate in your DNA. So how come if it's
possible for HIV, we don't see this in lots of
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viruses? I mean other viruses, other than HTLV,
you mention, how come there are not lots and lots?
0:11:42.720,0:11:48.800
That's a really interesting question. And
retroviruses, it turns out are really ancient.
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Parts of their genomes are integrated into
our normal DNA and they've just been passed
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down over time — so this is called endogenous
retroviruses. I don't really know much more
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than that about that topic. But on your question
on why aren't there more retroviruses infecting
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humans? I think there's potentially three or four
things going on. I am sort of wary of saying that
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something's not possible, because sometimes
people say that, even in the case of this,
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and then they figure out that it's wrong.
We just haven't found those other retroviruses.
0:12:28.800,0:12:39.120
But some of the reasons, probably: one, it's like
an error-prone process. If you're a virus — sorry,
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you're not a virus. But for a virus that's
transcribing its RNA genome into DNA,
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the reverse transcriptase enzyme is not very
precise in how it does that. It introduces
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errors into the code. That's probably a little bit
dangerous for the viruses themselves. Secondly,
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they have this RNA genome, they then transcribe
it into DNA, and then they get our cells to
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transcribe the DNA back into RNA — which
just seems a little bit inefficient. It
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would just take a longer amount of time. It
introduces errors. That's not super useful,
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maybe, but obviously in some cases, it
actually is, and it's worth that trade off.
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You mentioned T-cells — it's going after these. I
mean this is really, it's clever, but it's creepy.
0:13:37.280,0:13:44.720
So there's a reverse transcription where it's
then going to integrate into my DNA, which is
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disturbing in its own way. And then, additionally,
you're telling me it's going to do that not just
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anywhere, but in one of my immune cells — which
is what's meant to be fighting infections. It's
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going to hijack and integrate there. So
is that right? And those are the T-cells?
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That's right. So HIV infects various immune cells,
but usually a specific type of T-cell called a CD4
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T-cell. And the "CD4" just describes one receptor
on the surface of this T-cell that is very crucial
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in signalling. But also kind of defines that type
of T-cell. And these types of T-cells- I guess I
0:14:32.480,0:14:37.280
should just describe what those actually are.
We have different types of white blood cells
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in our body; T-cells are an important type. In
this case, what they do is: they help the body
0:14:44.480,0:14:52.800
recognise pathogens or things that we've seen
before, by presenting parts of that pathogen to
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our other immune cells that can last much longer
in the body and remember them if they appear
0:15:00.560,0:15:08.240
ever again. HIV is essentially infecting these
quite important white blood cells in our body.
0:15:08.240,0:15:15.280
What happens then? We've entered the cell. Why
is that a problem? How does it cause disease?
0:15:15.280,0:15:21.920
We've entered the cell. Well, there's quite a
long process. Initially, when people get infected,
0:15:21.920,0:15:28.160
they have this short term infection —
some kind of fevers, flu-like symptoms,
0:15:28.160,0:15:34.640
things like that; and the virus quickly
replicates itself, multiplies into many
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copies. Those copies then infect other T-cells.
They then go into our lymph nodes, which are
0:15:43.520,0:15:48.160
basically these little hubs of immune
activity. There's some in your neck,
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some under your arms, other parts of
your body. It infects these different
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immune related tissues and depletes them.
And that means that people become more vulnerable
0:16:01.760,0:16:10.240
to all sorts of other infections that are normally
mild to people, or just infections in general,
0:16:10.240,0:16:17.600
and some cancers. Our white blood cells are also
useful in detecting tumour cells and trying to
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eradicate them. And by depleting those important
cells, people also have a higher risk of certain
0:16:25.440,0:16:31.360
cancers. So we have this short-term infection
that immediately depletes a lot of our immune
0:16:31.360,0:16:37.200
cells. Eventually, there's this kind of slowdown
in how much it replicates, and you get to this
0:16:37.200,0:16:43.440
equilibrium — but that equilibrium is still much
worse than if someone hadn't been infected. And
0:16:43.440,0:16:52.800
over a long period of time, this reduction in
immune cells means that people are vulnerable to
0:16:52.800,0:16:59.840
various diseases. And as time goes by, they get
sicker and sicker from those other infections.
0:16:59.840,0:17:04.560
Before HIV, were there infections that were known
0:17:04.560,0:17:10.960
to cause cancers now something
that we're more familiar with,
0:17:10.960,0:17:19.600
but was that connection a surprise and made it
harder to figure out what the real cause was?
0:17:19.600,0:17:25.360
HTLV, the first retrovirus that was discovered
just two years before that was the first
0:17:25.360,0:17:30.240
pathogen that was clearly causing cancer
[in humans]. After that, there were, I mean,
0:17:30.240,0:17:35.280
there've been a bunch of other pathogens
that are now known to be cancer-causing.
0:17:37.120,0:17:44.160
One is hepatitis B, which you do a lot of research
on; HPV, human papillomavirus, that causes various
0:17:44.160,0:17:52.000
cancers including cervical cancer. There's
Helicobacter pylori: this bacterium that causes
0:17:52.000,0:17:58.560
stomach cancer. I think there's more; maybe
you remember some others. And there's HTLV.
0:17:58.560,0:18:00.080
Hepatitis C, which causes hepatitis.
0:18:00.080,0:18:02.640
Oh, hepatitis C. That's right.
0:18:02.640,0:18:06.240
Yeah. Those hepatitis viruses are sneaky.
0:18:06.800,0:18:15.760
So coming back to your question: the cancers
were the first, I think, surprising thing about
0:18:15.760,0:18:22.400
people who had AIDS. One of the types of cancers
that they became vulnerable to was called Kaposi
0:18:22.400,0:18:30.080
sarcoma, which is this tumour. What was surprising
about that was: usually doctors who saw patients
0:18:30.080,0:18:37.040
with this type of cancer would see them in
quite old- elderly patients, or people with,
0:18:37.040,0:18:41.680
I don't know, severe immune deficiencies
and things like that. And in this case,
0:18:41.680,0:18:48.400
they were seeing them in young adults, which
was really surprising. They were also quite
0:18:48.400,0:18:53.760
severe cancers: they were hard to treat with
the usual treatments that were available.
0:18:54.960,0:19:01.680
And the fact that this was growing in prevalence
was also really surprising and worrying to people.
0:19:01.680,0:19:07.360
So I think that was one of the first noticeable
kind of warning signs that there was some kind of
0:19:07.360,0:19:16.320
epidemic spreading. It was probably an epidemic
disease that was caused by some pathogen.
0:19:16.320,0:19:22.880
I think there were, maybe, a few months or a year
or so before people realised that it was probably
0:19:22.880,0:19:30.640
caused by a virus. And I think the reason for that
was that there were some cases of people being
0:19:30.640,0:19:38.640
infected through blood transfusion; so they had no
other connection to other people with the disease,
0:19:38.640,0:19:44.640
and they had no other environmental risk factors
or anything like that. But they had recently had
0:19:44.640,0:19:48.880
a transfusion, or an organ transplant, or
something like that, and then suddenly,
0:19:48.880,0:19:55.920
they got infected. And the reason that this links
to being a virus is because you can usually filter
0:19:55.920,0:20:05.600
out or purify some of the blood that you're
using, or the organs, with filters that get rid
0:20:05.600,0:20:11.760
of bacteria — which are bigger. But that doesn't
always work for viruses, which are much smaller.
0:20:11.760,0:20:15.440
So the viruses were getting through and they
were still infecting people. And the fact that
0:20:16.880,0:20:21.680
this was infecting people far away, with no
other connection, suggested that it was a virus.
0:20:21.680,0:20:25.360
I see. I mean, maybe that's a good
point to just talk a bit about
0:20:25.360,0:20:31.280
transmission. So how does the virus
transmit? I've got some ideas, but.
0:20:31.280,0:20:37.920
There are different types of modes of
transport. One is, as we just talked about,
0:20:37.920,0:20:45.200
blood transfusions and organ transplants. So if
there is contaminated blood with HIV, the risk
0:20:45.200,0:20:53.520
of an infection to someone else is quite high.
It's some- I was looking at the data from the
0:20:53.520,0:21:00.320
systematic review and they estimate that the risk
of infection is about 92% from a transfusion of
0:21:00.320,0:21:06.080
contaminated blood, which is quite high. Mother to
child transmission? For mothers who are infected
0:21:06.080,0:21:16.080
with HIV, a quarter of them would pass HIV down
to their baby, and this was before treatment
0:21:16.080,0:21:23.440
was available. Now, the chances are much lower if
people use antiviral treatments around the time of
0:21:23.440,0:21:31.840
pregnancy and childbirth; but that was obviously
very scary. And then there's sexual transmission,
0:21:31.840,0:21:38.880
which is probably the most common route that
most people have heard of for HIV. And then,
0:21:38.880,0:21:45.280
finally, injection and drug use; using
shared contaminated needles with HIV.
0:21:45.280,0:21:48.560
So before drug development, how come we
need drugs? How come the immune system
0:21:48.560,0:21:54.000
doesn't control HIV better? I mean, I have a
stereotype that it's extremely hard to control.
0:21:55.040,0:22:00.960
If infection gets established, it's
really tough for us. So why is that?
0:22:00.960,0:22:04.560
One really interesting thing that
I learned while trying to read
0:22:04.560,0:22:10.560
about this was that HIV is usually
caused by a single virus particle,
0:22:11.360,0:22:16.160
and that's one particle replicates enough
that it can cause a whole infection.
0:22:16.160,0:22:22.080
You're scaring me, Saloni. That's scary;
that's scary. So do you mean that one
0:22:22.080,0:22:28.800
particle entering my bloodstream is all
it takes, or you mean something else?
0:22:28.800,0:22:34.400
I actually mean something else. If you
look retrospectively at people who have
0:22:34.400,0:22:40.160
HIV — you take a sample of their blood and
you look at the different virus particles;
0:22:40.160,0:22:45.360
if you then trace back the
genetics of those virus particles,
0:22:45.360,0:22:53.280
you then find that they all have one common
ancestor, in around three quarters of cases.
0:22:53.280,0:22:54.240
I see. I see.
0:22:54.240,0:23:01.200
But that doesn't necessarily mean that just one
particle is enough to infect someone, because we
0:23:01.200,0:23:07.600
have enough barriers in our immune system. I mean,
if you think about a skin infection or something,
0:23:07.600,0:23:14.160
we have our skin, we have several layers of skin.
We have immune cells protecting us within our
0:23:14.160,0:23:19.760
body. There are various barriers that prevent
a bacterium or something from infecting us,
0:23:19.760,0:23:25.920
and that's the same is true with HIV. So I think
what's happening here is that: if you think about
0:23:25.920,0:23:31.040
this from the perspective of probability,
there are many barriers, but eventually one
0:23:31.040,0:23:36.560
of them might be able to cross all of those
barriers and cause an infection, and if it's
0:23:36.560,0:23:43.600
able to do that, it can replicate very quickly.
I think that gets us to why it's difficult to
0:23:43.600,0:23:51.760
control an infection. Even though we do have these
barriers, HIV is just very fast at replicating,
0:23:51.760,0:24:00.640
mutating. The reason that HIV can mutate so
quickly — it basically becomes really genetically
0:24:00.640,0:24:07.680
diverse within a person who is infected, and
that means that our immune cells might be able
0:24:07.680,0:24:15.200
to recognise some of the HIV strains that are
in our body, but it's very difficult for it
0:24:15.200,0:24:22.480
to keep up with the rapid evolution and increased
diversity. But there are several reasons for that.
0:24:22.480,0:24:30.000
One is the reverse transcriptase enzyme that we
talked about that turns RNA into DNA; that enzyme
0:24:30.000,0:24:37.280
is not very precise, and that introduces errors.
The errors allow it to potentially get beneficial
0:24:37.280,0:24:45.680
mutations sometimes, and that means that it can
genetically diverge. The other is that the HIV
0:24:45.680,0:24:54.160
particle has two copies of RNA inside it, and
those two copies can recombine with each other.
0:24:54.160,0:25:01.440
Wait, hold on, hold on, hold on. It
comes in with two of the same thing?
0:25:02.160,0:25:04.800
Two of almost the same thing. It has two,
0:25:05.360,0:25:09.760
in the same way that we have two
sets of chromosomes in our cells.
0:25:09.760,0:25:13.913
Okay, fair enough. I guess
that's true, yes. Oh, wow, okay.
0:25:13.913,0:25:15.760
It has two copies of RNA.
0:25:16.320,0:25:19.580
It's not a double-stranded RNA; they're separate.
0:25:19.580,0:25:25.840
Yeah, that's right. They're two single-stranded
RNA viruses, two single-stranded RNA particles;
0:25:25.840,0:25:32.080
and they can get reverse transcribed
separately. They can also recombine
0:25:32.080,0:25:39.360
with each other. So I was reading this review
paper about how all this worked — why there was
0:25:39.360,0:25:44.880
such rapid mutation — and they said- they were
talking about this recombination and they said,
0:25:44.880,0:25:50.040
"This can be considered a primitive form
of sexual reproduction." And I was —
0:25:50.040,0:25:55.600
No, no, no, no. This is a virus. If
there's one thing I know it's that
0:25:55.600,0:26:02.520
that is too complicated. I don't
believe this review paper. Okay.
0:26:02.520,0:26:10.880
Right, that's crazy. And there's a third thing
actually, which is that our enzymes introduce
0:26:10.880,0:26:19.520
errors and mutations into HIV. We have this
family of enzymes called the APOBEC family;
0:26:19.520,0:26:26.640
they insert mutations into HIV to try to
damage it. What they do is: they change
0:26:26.640,0:26:35.520
the G's in our bases, in our DNA, into A; and
they do that on a single-stranded DNA particle.
0:26:36.560,0:26:45.360
The HIV virus has these two single-stranded
RNA molecules: they get turned into DNA,
0:26:45.360,0:26:50.880
then our enzymes introduce errors into
it, by turning some of the G's into A's.
0:26:52.400,0:26:57.760
Just taking a step back, you're saying that
the virus itself mutates a lot? So the reverse
0:26:57.760,0:27:04.080
transcription stage introduces errors, and that,
actually, in a sense, helps the virus evade our
0:27:04.080,0:27:09.200
immune system. So it is introducing errors that
make it hard for us, and then you're saying we
0:27:09.200,0:27:14.720
also are introducing errors that make it easier
for us, or rather harder for the virus. So we are
0:27:14.720,0:27:19.040
both sort of fighting fire with fire of: I'm
going to make you different, and it's saying,
0:27:19.040,0:27:24.320
no, I'm going to make myself different. And
we're in a kind of ratchet situation there.
0:27:24.320,0:27:29.520
Yeah, it's very funny. I learned
about this first, actually,
0:27:29.520,0:27:41.280
in 2022, this process, during the Mpox epidemic.
I'd just been following the literature — what the
0:27:41.280,0:27:47.520
virologists are working out on the epidemic
and so on — and they found out at that point
0:27:47.520,0:27:54.320
that the viruses from Mpox were mutating much
faster than expected, than had been seen before.
0:27:55.680,0:28:00.960
And it turned out that the types of mutations that
they were seeing, that were happening rapidly,
0:28:00.960,0:28:09.760
were very similar to this, APOBEC- kind of
known-mutation change, and that led scientists
0:28:09.760,0:28:18.048
to think: maybe our enzymes are also working
on this Mpox virus. So learning about that —
0:28:18.048,0:28:18.076
Oh I see what you're saying.
0:28:18.076,0:28:24.800
— testing that out, helped to figure out:
we were introducing errors into the Mpox
0:28:24.800,0:28:31.920
virus very quickly, which made it mutate much
faster than usual; and that knowledge helped
0:28:31.920,0:28:38.560
to figure out better when Mpox actually
emerged, and when it started to spread.
0:28:38.560,0:28:42.960
Oh, interesting. You can somehow
work backwards from that information.
0:28:42.960,0:28:43.920
Right.
0:28:43.920,0:28:50.080
Wow. Okay. Okay. Well, that's it. I am
feeling grateful for my immune system;
0:28:50.080,0:28:55.040
has a bunch of tricks I didn't even
know about, so thank you, immune system.
0:28:55.040,0:29:01.040
I think, one more thing is, the
types of infections and cancers
0:29:01.040,0:29:07.760
that HIV makes people vulnerable to. I think,
probably, that's not very obvious to people;
0:29:07.760,0:29:11.760
maybe they've heard of a few of them.
So we talked about Kaposi sarcoma,
0:29:11.760,0:29:17.600
there are also a bunch of others. There's PCP,
which is this fungal lung infection. There's
0:29:17.600,0:29:25.200
toxoplasmosis, which is this parasitic brain
infection. There's cytomegalovirus retinitis,
0:29:25.200,0:29:32.240
that can cause blindness. There's tuberculosis
— we already know about tuberculosis, probably,
0:29:32.240,0:29:38.320
most people here know about that — that is
the leading cause of death in people with HIV
0:29:38.320,0:29:45.280
worldwide. The reason is that, because of this
immune suppression, because of the fact that
0:29:45.280,0:29:52.160
HIV is depleting our immune cells, it makes us
more vulnerable to infections like tuberculosis,
0:29:52.160,0:30:00.320
which are often easier to clear for people.
And then, some of these are also related — I think
0:30:00.320,0:30:06.800
I talked about a few that were brain infections
or that cause blindness — some of these can also
0:30:06.800,0:30:14.160
cause AIDS-related dementias, where people lose
their ability to think, and make decisions, and
0:30:14.960,0:30:21.680
generally lose their memory. And then there are
a bunch of cancers as well that HIV is associated
0:30:21.680,0:30:29.200
with. As we talked about earlier, some of our
T-cells are really important in trying to find
0:30:29.200,0:30:35.440
potentially cancerous cells and eliminating them.
If those T-cells are depleted, that makes us more
0:30:35.440,0:30:41.360
vulnerable to cancers continuing to grow. So that
includes Kaposi sarcoma, which we talked about,
0:30:41.360,0:30:50.400
and then non-Hodgkin lymphoma, and it also
increases the risk of cervical cancer.
0:30:50.400,0:30:54.080
So I think I have a rough understanding
of the virus and a rough understanding of
0:30:54.080,0:30:59.040
how it leads to AIDS, and to disease, and
opportunistic infections. Maybe quickly,
0:30:59.040,0:31:03.520
where did it come from originally?
Where did this virus start out?
0:31:03.520,0:31:11.760
So... this, I think, has had a lot of research
go into it, and the likely answer is that it
0:31:11.760,0:31:22.880
came from chimpanzees and gorillas in Central and
Western Africa. There are different types of HIV.
0:31:22.880,0:31:28.640
As we talked about, HIV mutates very quickly;
creates this huge amount of genetic diversity,
0:31:28.640,0:31:35.120
and that also means that there are multiple
different types of HIV. The one that's found
0:31:35.120,0:31:42.480
across the world is called HIV-1. There's
also an HIV-2. Both of them are from different
0:31:42.480,0:31:50.720
kinds of primates from Central and Western
Africa. And I think the current understanding
0:31:50.720,0:32:03.200
is that HIV one came from a type of chimpanzee
somewhere near the southeastern area of Cameroon.
0:32:03.760,0:32:12.080
And probably — so this is interesting: the way
that we understand this is by collecting a lot
0:32:12.080,0:32:21.200
of samples of HIV from different people, ideally
as early as possible. The earlier the cases are,
0:32:21.200,0:32:28.080
the easier it is to try to estimate where they
all came from, or when they converged back in
0:32:28.080,0:32:36.480
history. What was super interesting to me, that I
was reading about recently, was that the earliest
0:32:36.480,0:32:48.960
genome of HIV was recovered from someone who died
in 1966 in Africa. That's 15 years before the
0:32:48.960,0:32:55.680
first cases were reported. There were definitely
cases of HIV before that; probably for decades
0:32:55.680,0:33:02.240
before that. If you use this sample, but also
all of the other early samples that we have,
0:33:02.240,0:33:09.040
you can kind of trace back where they have shared
ancestry — in the same way that you might be able
0:33:09.040,0:33:16.560
to do with a family tree. If you do that with
genomics, you can try to trace back where they
0:33:16.560,0:33:25.360
have similarities, and that suggests that the
pandemic originated at the turn of 20th century.
0:33:26.320,0:33:28.720
Hundred years ago.
0:33:28.720,0:33:36.560
Yeah. Well, so we don't have — because
the earliest case we have is from 1966,
0:33:36.560,0:33:41.920
that's still not very early, and that
means that there's still some uncertainty
0:33:41.920,0:33:46.000
in when it actually originated.
There's this uncertainty between,
0:33:46.000,0:33:53.280
so somewhere between 1881 and 1918 is
probably around when it first emerged.
0:33:53.280,0:34:00.720
Okay, well, and in humans. So basically, there
was this virus that infected other primates,
0:34:00.720,0:34:06.400
chimps; maybe goes back much longer, I don't
know if that's known. And then at some point,
0:34:06.400,0:34:10.480
someone was probably hunting
a chimp and there was a blood,
0:34:11.120,0:34:20.480
the blood sort of got into their food, or was
it, you're eating uncooked chimp or? Oh God.
0:34:20.480,0:34:28.320
That's probably it. So probably through hunting
primates and consuming them from the, kind of,
0:34:28.320,0:34:36.080
butchery of that process, and being exposed to
their infected body fluids. So the virus that
0:34:36.080,0:34:43.280
infects chimpanzees and other monkeys is called
Simian Immunodeficiency Virus rather than human.
0:34:43.920,0:34:44.720
SIM [SIV], okay.
0:34:44.720,0:34:53.120
That, it seems like, has crossed over
to humans dozens of times over history.
0:34:53.120,0:34:57.520
As in, since the 1900s?
0:34:57.520,0:34:57.920
In total.
0:34:57.920,0:35:00.400
Okay. Okay. Interesting. I didn't know that.
0:35:01.040,0:35:08.080
And I think there's around four of those
"spillover events", is what they're called.
0:35:08.080,0:35:13.520
At least four of those spillover events
have led to sustained epidemics that —
0:35:13.520,0:35:13.960
Oh my gosh.
0:35:13.960,0:35:18.160
— people are still infected by today.
0:35:18.160,0:35:25.360
Wow, okay. So it's been with us for a long time,
and we haven't known the extent of it so well
0:35:25.360,0:35:32.720
as a species until the more recent epidemic
starting in the '80s. Is that a fair summary?
0:35:32.720,0:35:37.040
That is a fair summary. I think, this
really reminds me of some of the work
0:35:37.040,0:35:44.480
and writing I do about missing data.
I mean, on a lot of topics in health, but
0:35:44.480,0:35:52.160
also in other areas, we tend to have much better
data collection and understanding of epidemics,
0:35:52.160,0:36:00.800
but also other diseases, in richer countries,
because of the institutions that can collect
0:36:00.800,0:36:12.880
that data. Having the resources and the people to
collect that data is not super easy. The fact that
0:36:12.880,0:36:20.560
we know about the first cases of AIDS that had
been reported were in the US, is not because it
0:36:20.560,0:36:29.360
started in the US — it's because the US had good
detection and disease control research going on.
0:36:29.360,0:36:34.800
Oh yeah. I mean, it reminds me of the
extremely frustrating initial COVID graphs,
0:36:34.800,0:36:41.840
where reports of number of cases would actually be
number of confirmed cases — vastly different than
0:36:41.840,0:36:48.400
what you could interpolate must be happening
in reality. But, you know, whoever gets tested
0:36:48.400,0:36:55.280
ends up getting reported and whoever doesn't
doesn't. It can lead to missed inferences.
0:36:55.280,0:36:56.880
Exactly. That's right.
0:36:56.880,0:37:05.120
I feel like we should get to drugs. And as you've
described HIV so far, as a drug developer, which
0:37:05.120,0:37:12.960
I've never been yet, but moonlight as in my head,
I'm thinking: the different parts you've described
0:37:12.960,0:37:20.480
are each potential targets that I could maybe
make a chemical small molecule to interfere with,
0:37:20.480,0:37:27.040
to sort of mess up its lifecycle. I know
my immune system's not going to sort it
0:37:27.040,0:37:34.000
out all on its own. So some of those non-human
chemicals might be pretty useful too. So firstly,
0:37:34.640,0:37:38.160
is that right? And then, am I thinking about
that right? And maybe that means we're going
0:37:38.160,0:37:43.680
to have to go in a bit more detail about the
infection cycle, because the virus is going to
0:37:43.680,0:37:51.440
look different at different points and that will
maybe give us a clue about what drugs we can make.
0:37:51.440,0:37:57.680
No, exactly. I think, actually, it would
be probably easier to think about where
0:37:57.680,0:38:03.760
scientists were at the time, how much they
knew, and how they were developing drugs,
0:38:03.760,0:38:07.840
and then we can talk about the
broader life cycle of the virus.
0:38:07.840,0:38:12.880
Let's do it. Sounds good.
0:38:12.880,0:38:23.440
So place yourself in the 1980s. This is kind of
hard because, as a scientist, you had just found
0:38:23.440,0:38:32.480
out that retroviruses could infect humans. Now you
find out that HIV is a retrovirus. You're like,
0:38:32.480,0:38:40.080
wait, I didn't even know that RNA could be turned
into DNA until 10 years ago. So that's quite a
0:38:40.080,0:38:47.600
tricky position to be in. At this point, in the
early 1980s, there were no antiviral drugs for
0:38:47.600,0:38:57.760
retroviruses. Also, antivirals in total were kind
of new. I did not know this before reading about
0:38:57.760,0:39:07.160
it for this episode, but the first antiviral drug
of any kind was approved in 1963, which is, again-
0:39:07.160,0:39:10.640
1963, really? Not even flu. We
didn't have nothing. That's crazy.
0:39:10.640,0:39:16.880
No, we didn't. We had flu vaccines. We had a bunch
of vaccines before that. But the first antiviral
0:39:16.880,0:39:24.960
drug was for treating the herpes simplex virus
— infections of the eye — and that was in 1963.
0:39:24.960,0:39:25.680
Wow.
0:39:25.680,0:39:31.760
Also, if you were in the early 1980s,
you wouldn't have PCR. PCR is polymerase-
0:39:31.760,0:39:33.263
Of course. Yes, of course.
0:39:33.263,0:39:39.120
-chain reaction, which is used to multiply
samples of genetic material so you can study it
0:39:39.120,0:39:46.240
more easily. And that would've been really useful
for being able to detect the level of infection,
0:39:46.240,0:39:52.800
and the level of virus in someone. You would
be very new to knowing about retroviruses to
0:39:52.800,0:39:56.880
begin with. You wouldn't have any antivirals
for them. You wouldn't have a great idea of
0:39:56.880,0:40:03.120
how to even develop antivirals at all.
You didn't have PCR, you didn't have
0:40:03.120,0:40:09.200
multi-center trials, so you wouldn't be
able to test drugs in multiple hospitals.
0:40:09.200,0:40:09.440
Multi-center? Oh, I see. Got it. Yep, got it.
0:40:09.440,0:40:15.600
You wouldn't be able to test whether
people were resistant to the virus,
0:40:15.600,0:40:24.960
through the genetics of the virus, again, because
of the lack of PCR testing. And so there was just
0:40:24.960,0:40:32.720
this complete lack of — what are we going to do
now? We have no idea. This is super new to us.
0:40:32.720,0:40:39.760
I think a lot of people at the time might've
thought it's impossible to treat this disease.
0:40:39.760,0:40:46.320
It's so new, it's so different. How
are we gonna make any progress on it?
0:40:46.320,0:40:50.240
You don't have a proof point
you can hang your hat on.
0:40:50.240,0:40:52.000
That's right.
0:40:52.000,0:40:55.200
Very... yeah, the unknown beckons.
0:40:55.200,0:41:02.320
And so again, I was trying to find retrospective
written by someone who works in this field,
0:41:02.320,0:41:06.800
and I found one that was really
interesting by Samuel Broder.
0:41:06.800,0:41:13.760
He was one of the scientists who
developed AZT, the first HIV drug.
0:41:13.760,0:41:14.260
AZT.
0:41:15.120,0:41:21.440
His team found that it was effective against
HIV. They also developed various other drugs
0:41:21.440,0:41:29.360
against it. And he wrote this retrospective on
how they discovered the first antivirals and
0:41:29.360,0:41:34.480
how pessimistic people were at the time — that
it was possible to make any treatments against
0:41:34.480,0:41:43.760
it. So maybe a bit of background on who he was.
Samuel Broder was this cancer and immunology
0:41:43.760,0:41:51.360
researcher at the National Cancer Institute in
the US. And this itself is quite interesting.
0:41:51.360,0:41:57.200
You're thinking HIV, this is an infectious
disease. But the people who were studying it,
0:41:59.040,0:42:03.760
who made these first effective
antivirals, were cancer researchers.
0:42:03.760,0:42:10.800
So he was part of the NIH, the division that
works on cancer. And so he was employed by
0:42:10.800,0:42:17.360
the US government and had a lab in the
cancer part. And okay, got it. Keep going.
0:42:17.360,0:42:21.920
So I think the reason that he
was working on it was, as I said,
0:42:21.920,0:42:28.480
the first thing that was noticed in AIDS patients,
that was surprising to people, was Kaposi sarcoma,
0:42:28.480,0:42:35.600
this type of cancer of the skin. And so he was
trying to figure out what was going on here.
0:42:37.520,0:42:46.960
I read this book about the drug development in
HIV and AIDS called How to Survive a Plague. And
0:42:46.960,0:42:55.840
there they describe this period very humorously
to me. I mean, it's obviously not humorous,
0:42:55.840,0:43:02.960
but the way that they say it, was that he
was really excited to see this first HIV
0:43:02.960,0:43:09.920
patient come to the National Cancer Institute.
He saw it as this once-in-a-lifetime scientific
0:43:09.920,0:43:15.840
challenge that brought together two of his
interests of immunodeficiency and cancer.
0:43:15.840,0:43:22.160
And they thought, if we're able to crack
this, this is going to be really important.
0:43:22.160,0:43:32.080
So I think the first thing they noticed was
the virus was probably infecting CD4 T-cells.
0:43:32.080,0:43:38.320
The reason that they thought this was one of the
first signs that you would see in someone who was
0:43:38.320,0:43:46.720
infected was that their T-cell count would drop.
They at least had some blood testing and they had
0:43:46.720,0:43:53.280
some of the tools and technology to measure CD4
T-cells at the time. So they knew that there's
0:43:53.280,0:43:59.520
this massive drop, and they thought maybe it's
because the virus is multiplying in these cells.
0:43:59.520,0:44:02.000
Seems like a link to make.
0:44:03.280,0:44:07.840
So they thought, okay, let's — we've
hypothesised that the virus is replicating
0:44:07.840,0:44:14.960
in these cells — maybe we should test compounds
to interrupt this process, to prevent it from
0:44:14.960,0:44:22.720
replicating in these CD4 T-cells. And so he then
approached different pharmaceutical firms to try
0:44:22.720,0:44:28.720
to get funding to work on this project, and
also to potentially commercialise a drug if
0:44:28.720,0:44:37.280
they found one. I think he approached several
firms. Most of them said no, but one of them
0:44:37.280,0:44:43.989
said yes. And that company was Borroughs
Wellcome. So we probably haven't heard of-
0:44:43.989,0:44:47.760
Yes, which now has a philanthropy,
Burroughs Wellcome fund.
0:44:47.760,0:44:53.920
And this was a pharmaceutical firm that no
longer exists. It was merged into what became
0:44:53.920,0:45:00.560
GSK or GlaxoSmithKlein, and they were the
only company at this time that were willing
0:45:00.560,0:45:10.400
to consider funding or commercialising HIV
drugs. But they were very afraid that their
0:45:10.400,0:45:17.200
researchers or their scientists would
get infected with stab that people were
0:45:17.200,0:45:22.400
working with. So they refused to work with
these live virus samples, and they said-
0:45:22.400,0:45:22.960
Oh my god.
0:45:22.960,0:45:26.960
-nope, you've got to work on it yourself.
They were saying this to Samuel Broder and
0:45:26.960,0:45:33.600
his team. And so Samuel Broder's team had
to do all of the screening of these drugs,
0:45:33.600,0:45:39.280
running the trials all on their
own, despite Burroughs Wellcome
0:45:39.280,0:45:44.312
then getting the credit for it, and
then being able to commercialise it.
0:45:44.312,0:45:51.440
Oh god. Well, it reminds me of streptomycin, the
first TB drug, where there was Albert Schatz,
0:45:51.440,0:45:56.640
the PhD student, and Waxman, what was his
first name? Henry Waxman, something? Waxman-
0:45:56.640,0:45:57.760
Selman Waxman.
0:45:57.760,0:46:03.760
Selman Waxman, there we go, the professor
who then got the Nobel Prize. They didn't
0:46:03.760,0:46:06.400
share it in the end, did they? I don't
know. I'm going to forget the story.
0:46:06.400,0:46:12.000
They didn't share it. I also read the story
because I was writing about antibiotics,
0:46:12.000,0:46:15.440
and it was really interesting, because he
0:46:15.440,0:46:20.640
discovered this group of bacteria
that produced antibiotics, right?
0:46:20.640,0:46:22.080
Right, in soil? Yeah.
0:46:25.120,0:46:29.200
It's so weird to think about bacteria that are
producing antibiotics, but basically they're
0:46:29.200,0:46:36.240
producing it to compete with other bacteria.
And somehow he found that this specific type,
0:46:36.240,0:46:41.120
or this group, of bacteria were producing a lot
of antibiotics. He thought, okay, maybe there's
0:46:41.120,0:46:45.920
something there. They seem to be killing the other
bacteria around them, maybe we could use that as a
0:46:45.920,0:46:51.600
treatment for our own bacterial infections.
And he started to recruit PhD students to
0:46:51.600,0:46:56.231
work on that. One of them was Albert Schatz.
And what was really interesting about this-
0:46:56.231,0:46:58.000
This was Second World War era, right?
0:46:58.000,0:47:04.640
This was during the Second World War. Well, the
1930s, I think, and he had Albert Schatz start
0:47:04.640,0:47:11.989
to work on this project in a basement's room
that he never, I think, Waxman never visited.
0:47:11.989,0:47:16.400
He's like, try this out on
some TB, I'll be upstairs.
0:47:16.400,0:47:19.360
And so Schatz was working on this,
0:47:19.360,0:47:24.320
and then what was really strange was
that Schatz was drafted into war!
0:47:24.320,0:47:24.880
Oh, yes.
0:47:24.880,0:47:30.800
And the project, basically, was on
pause for a few months. Apparently
0:47:30.800,0:47:33.754
he then got a back injury and then was sent home.
0:47:33.754,0:47:34.880
Thank goodness!
0:47:34.880,0:47:37.920
And thank goodness, he discovered streptomycin.
0:47:37.920,0:47:38.720
Wow.
0:47:38.720,0:47:41.440
That was the first, I think, first
antibiotic compound that was found
0:47:41.440,0:47:45.920
from this type of bacteria,
which is called actinomycetes,
0:47:45.920,0:47:52.240
and that group also led to the
discovery of various other antibiotics.
0:47:52.240,0:47:59.120
Okay. Well, Albert Schatz, legend. Grad students
have been abused for decades, it turns out. And
0:47:59.840,0:48:04.880
I guess, back to HIV, which we are currently
dealing with, it sounds like a very virtuous
0:48:04.880,0:48:09.120
academic group. And I don't want to insult
Burroughs Wellcome. I'm very glad they brought
0:48:09.120,0:48:14.720
this to market. So kudos that there was at least
one company willing to stand up. So maybe I'll
0:48:14.720,0:48:20.400
reserve my vitriol in case there are other bad
forces I need to get mad at, later in the story.
0:48:20.400,0:48:25.040
Well, yeah. So this is also not quite as similar
0:48:25.040,0:48:30.480
because I think Schatz and Waxman
then got into this big fight.
0:48:31.120,0:48:36.720
Yeah, I remember this, yeah. And Waxman was
withholding royalties from Merck or yeah.
0:48:36.720,0:48:40.000
There was something like that. But in this case,
0:48:40.000,0:48:45.360
I think they seem to work together fine.
In this case, in Samuel Broder's team,
0:48:45.360,0:48:50.800
there were a few scientists who were really
involved in this. One was Hiroaki Mitsuya,
0:48:50.800,0:48:58.880
and he was doing the day-to-day research on
potential drugs that could work against HIV.
0:48:58.880,0:49:05.360
And I said, day to day, but actually they were
doing this research in the night, after the other
0:49:05.360,0:49:11.584
colleagues at the National Cancer Institute went
home, because apparently they were also afraid-
0:49:11.584,0:49:11.600
Oh my gosh. Wow.
0:49:11.600,0:49:19.520
-of potentially being contaminated or
getting infected. Also, there was another
0:49:19.520,0:49:31.280
scientist called Robert Yarchoan. So these
two scientists tested over 180- well, okay,
0:49:31.840,0:49:37.040
let's back up to what we said before. You're
in the 1980s, you have no idea how to tackle
0:49:37.040,0:49:43.280
this disease. You have various reasons to doubt
whether you can even develop a treatment at all.
0:49:43.280,0:49:47.440
And the only clue that you have at this
point, really, is that it infects CD4
0:49:47.440,0:49:55.680
T-cells. So that probably helps you to test
things in a lab. You can probably test how
0:49:55.680,0:50:01.680
these different drugs affect HIV's ability to
infect these CD4 T-cells, but you don't really
0:50:01.680,0:50:08.160
have anything else to go on. So what would
you do? And the thing that they did was,
0:50:08.160,0:50:13.360
they just tried anything. They just
tried any drug compounds that they had.
0:50:14.320,0:50:20.960
So Mitsuya tested over 180 different compounds
and they would be coded with different code names,
0:50:21.520,0:50:28.080
and you would ask people for whatever they
thought might be potentially effective.
0:50:28.960,0:50:33.920
So there's no unifying hypothesis per se, it's
more like, ask around, see what people think might
0:50:33.920,0:50:40.160
work, see what you have lying in the fridge
at the cancer institute, that kind of thing?
0:50:40.160,0:50:44.480
Well, even if you did have hypotheses,
many of them would just turn out to
0:50:44.480,0:50:47.760
not work and then you would have
to try something else. So okay,
0:50:47.760,0:50:52.720
there were a bunch of hypotheses, but there
were also just, let's just see what happens,
0:50:52.720,0:50:57.360
let's just use this trial-and-error kind
of approach and see if anything works.
0:50:58.000,0:51:03.360
Well, now I think about high-throughput
screening where you screen hundreds of thousands,
0:51:03.360,0:51:07.600
sometimes more, drug candidates
or molecules all at once. Should
0:51:07.600,0:51:13.840
I be visualising that, or that comes much
after, and we're dealing with hundreds?
0:51:13.840,0:51:20.880
Well, yeah. So I think this might've been before
high-throughput screening became much more
0:51:20.880,0:51:27.120
popular. This is probably early days where you're
doing this one at a time. You have these different
0:51:28.080,0:51:33.920
cultures of the virus in the lab and you're
just testing out random drugs, one for each
0:51:33.920,0:51:40.000
one or whatever, and maybe you have a bunch for
each one, just to see if it's really working.
0:51:40.000,0:51:47.040
And at one point they find this one little
vial, or a bottle, with something called
0:51:47.040,0:51:55.360
"compound S" — so that's the code name — and that
somehow seems to keep the infected cells alive.
0:51:55.360,0:52:05.680
So this was a real breakthrough and this compound
turned out to be AZT, or azidothymidine. What was
0:52:05.680,0:52:11.680
this compound? This was a compound that already
existed, and it was developed in the 1960s — in
0:52:11.680,0:52:20.960
1964 — by another cancer researcher called Jerome
Horwitz. And I had found- I was trying to look up,
0:52:20.960,0:52:27.440
who was the discoverer of each important antiviral
in HIV? And I found this name, and I thought,
0:52:27.440,0:52:31.360
okay, well let me try to find a retrospective
written by him and I couldn't find one.
0:52:32.240,0:52:38.480
And the reason was that, when he was working
on this in the 1960s, he was developing this
0:52:38.480,0:52:44.800
as a potential cancer drug. He had this
idea that — if you think about cancers,
0:52:44.800,0:52:50.480
the thing that people know about cancers is
they grow quickly. They have these tumours
0:52:50.480,0:52:55.360
and the tumours grow quickly, and the
way that they do that is by replicating;
0:52:55.360,0:53:04.000
they need to replicate their DNA in order to
divide. So his idea was, if you have the DNA code,
0:53:04.000,0:53:13.280
and the DNA code is duplicated by adding
these bases one at a time, by our enzymes,
0:53:13.280,0:53:21.600
into this longer DNA structure. What if, instead
of a normal base, you had a fake base that was
0:53:21.600,0:53:30.360
kind of like a normal base except it didn't allow
any more bases to join to it. And so he found-
0:53:30.360,0:53:31.120
Sounds clever.
0:53:31.120,0:53:40.720
-a compound that, it essentially was this type of
fake base — di-deoxynucleoside. And he thought,
0:53:40.720,0:53:44.720
okay, maybe this is going to stop the
cancers from growing. But it turned out,
0:53:44.720,0:53:50.800
it didn't work for cancer, and he was so
disappointed with it that he apparently
0:53:50.800,0:53:56.160
threw away his lab notes — essentially
just trashed it and forgot about it;
0:53:56.160,0:54:01.760
didn't even apply for a patent. So it was
just in the National Cancer Institute,
0:54:01.760,0:54:07.280
where he also worked, and it was just there as
one of the compounds that had been developed.
0:54:07.280,0:54:11.520
Don't throw away your lab notes. Don't
throw away your lab notes. But I'm glad
0:54:11.520,0:54:17.520
he didn't throw away the samples?
That sounds great to me. I'm happy.
0:54:19.200,0:54:25.360
We said that the AZT — this new
compound — it was able to mimic
0:54:25.360,0:54:32.640
the bases in our DNA. So why did it
work for HIV, but not for cancer?
0:54:32.640,0:54:38.880
That's something I don't know. But what it
does here is almost the same process. When
0:54:38.880,0:54:47.200
HIV's reverse transcriptase is turning the RNA
into DNA, so that it can integrate into our own
0:54:47.200,0:54:53.920
genome, it introduces this fake base,
which blocks the chain from getting longer;
0:54:53.920,0:55:00.960
it blocks the rest of the DNA from forming,
and that halts the virus's replication.
0:55:00.960,0:55:03.400
That's epic. Go AZT.
0:55:03.400,0:55:10.400
Super interesting. Yeah, it was just, I think
it's this trial-and-error approach that sometimes
0:55:10.400,0:55:16.800
works. What's really useful about things like this
is that, once you do find a compound that works,
0:55:16.800,0:55:24.480
you can then try to make modifications that
create new related drugs that you now will
0:55:24.480,0:55:29.760
hope will also work. That is possible because
if there's something about the structure that
0:55:29.760,0:55:34.480
is allowing it to have this function, then
making these different modifications could
0:55:34.480,0:55:39.520
lead to additional compounds, or maybe it could
make it more effective, or more safe in some way,
0:55:39.520,0:55:45.200
and so you could now have this wider
range of compounds that you can work with.
0:55:45.200,0:55:53.360
And my stereotype of AZT is that it was not
very safe, in the sense of, many side effects?
0:55:53.360,0:56:00.000
That's right. Yeah, I mean, I think
if you were a patient at the time,
0:56:00.000,0:56:09.520
you would still see it as much better than the
prospects of a continued progression of HIV,
0:56:09.520,0:56:19.360
but it was pretty toxic. It affected people's bone
marrows, it led to anaemia; also just made them
0:56:19.360,0:56:26.720
feel quite physically weak in some ways. But it
did clear out some of the virus from their bodies;
0:56:26.720,0:56:33.680
it restored their immune function, it cleared
infections. One interesting thing I read was
0:56:33.680,0:56:41.760
that it, surprisingly, also reversed some of
these AIDS-related dementias that I mentioned.
0:56:42.480,0:56:48.880
Because those dementias were actually caused by
infections, if you can clear some of the HIV,
0:56:48.880,0:56:55.280
which is reducing your immune function, which was
previously suppressing these infections — if you
0:56:55.280,0:57:02.080
can, kind of, revert that immune depletion,
then you can now fight off these infections
0:57:02.080,0:57:09.760
that caused brain dysfunction and so on.
This was really astonishing, I think,
0:57:09.760,0:57:15.120
according to Samuel Broder, to the doctors
who saw people who were being treated with
0:57:15.120,0:57:19.600
AZT at the time — they were genuinely
shocked that this was even possible.
0:57:19.600,0:57:26.160
And we went from not knowing if any antiviral
was going to be possible to... you're actually
0:57:26.160,0:57:35.200
seeing as a doctor people reverse even
some of the cognitive effects. What a time.
0:57:35.200,0:57:41.040
What a time, yeah. And also, the other
downside was, not just the side effects,
0:57:41.040,0:57:47.680
but this drug seemed to work for at least a few
months in people, and then they would start to get
0:57:47.680,0:57:54.720
worse again, and the reason was that HIV would
find a way to evade the action of this drug.
0:57:54.720,0:58:01.520
Because it was mutating so quickly, it was able
to find ways to either get rid of this drug, or to
0:58:01.520,0:58:09.200
develop certain changes in its proteins that would
mean that the drug was no longer able to work.
0:58:09.760,0:58:17.360
So that rapid mutation that made it so hard
for our immune system to operate against HIV,
0:58:17.360,0:58:24.160
now is making it hard for AZT
to durably operate against HIV.
0:58:24.160,0:58:27.520
But it was really important
because it was the first
0:58:27.520,0:58:32.720
drug. It was a drug against a disease
that people thought was untreatable.
0:58:32.720,0:58:33.040
Yes, totally.
0:58:33.040,0:58:39.600
And this completely shifted the perception
of the disease. Samuel Broder has this line
0:58:40.640,0:58:45.520
in his retrospective review where he says,
"The question at that point was no longer
0:58:45.520,0:58:51.680
whether HIV-1 could ever be successfully
treated, but rather how fast more therapies
0:58:51.680,0:58:58.880
could be developed." And their drug, AZT
moves from research in the lab to drug
0:58:58.880,0:59:03.920
approval within just two years, and this
is partly a result of how the trials work,
0:59:03.920,0:59:09.200
but it's also partly because of activism
around trying to make it available quickly.
0:59:09.200,0:59:12.560
I mean, it's... that's both so inspiring and
0:59:12.560,0:59:20.720
so infuriating. So when was AZT
available, did you say? In 19-?
0:59:20.720,0:59:22.720
I think 1987.
0:59:22.720,0:59:27.600
1987, okay, so from 1981 to 1987.
If the clock starts at 1981,
0:59:27.600,0:59:31.920
when HIV was discovered; if there
had been more energy earlier,
0:59:31.920,0:59:41.440
more funding, more support, if it only took
two years once you started investigating...
0:59:41.440,0:59:42.623
It is really frustrating.
0:59:42.623,0:59:44.720
Anyway, I should celebrate
it was two years, but...
0:59:44.720,0:59:51.840
It's really frustrating because, so I have
been reading this book, the audiobook version,
0:59:51.840,1:00:00.160
of How to Survive a Plague by David France, which
is this amazing, very well written book on drug
1:00:00.160,1:00:07.840
development. "How scientists and activists came
together to treat AIDS" is the tagline, I think.
1:00:08.960,1:00:20.320
It starts, I think, in 1981, and it's genuinely
so depressing to read it — obviously — for several
1:00:20.320,1:00:26.800
years. You're getting through this book, and
you're just so frustrated with how slow people
1:00:26.800,1:00:32.160
are; how unresponsive, how much they don't
treat it as an urgent problem — even when
1:00:32.160,1:00:38.800
it's clearly an epidemic disease that's growing
exponentially over time. That people are just
1:00:38.800,1:00:44.400
unwilling to consider that there are potential
treatments out there, or they're in these petty
1:00:44.400,1:00:50.080
arguments with each other about what we should be
doing. Should we be saying enough? Are we scaring
1:00:50.080,1:00:56.800
people by telling them that this is a deadly
disease? And so on. And it was just, it was really
1:00:56.800,1:01:00.400
frustrating to read. It was a very well-written
book, but it was very frustrating to read.
1:01:01.280,1:01:08.080
I remember I read "And The Band Played On"
by Randy Shilts covering some of the initial
1:01:08.080,1:01:14.080
years and had the same experience
— just a very, very tough read.
1:01:14.080,1:01:21.120
But I think one interesting thing about Samuel
Broder and the, kind of, cancer approach to
1:01:21.120,1:01:27.680
studying HIV is that, I think, — so we said
that the reason that they were studying this
1:01:27.680,1:01:32.800
was because of Kaposi's sarcoma, which was
one of the cancers that HIV made people more
1:01:32.800,1:01:38.320
vulnerable to. But I actually think that being a
cancer researcher was probably the right mindset
1:01:38.320,1:01:43.360
that you needed to have, as a scientist,
if you wanted to develop drugs against HIV.
1:01:44.560,1:01:49.920
One reason for that was, cancer research
at the time, they were, I think,
1:01:49.920,1:01:57.280
the only group in the NIH that were experienced
with drug development. But the other was just:
1:01:57.280,1:02:03.360
you're facing this horrible disease
that's very rapidly progressing,
1:02:04.000,1:02:11.200
similar to cancer. You're also in the situation
where action is much more important than inaction,
1:02:11.200,1:02:16.320
because it's just going to get worse. You're
also in the situation where you're willing to
1:02:16.320,1:02:25.600
take drugs that have toxic side effects, even if
that, because they might be able to slow down the
1:02:25.600,1:02:31.520
disease, and that's more important right now,
because the disease progression is so deadly.
1:02:32.080,1:02:39.280
But I think the next thing is, because you
would realise that what was really important
1:02:39.280,1:02:46.640
here was not just using a single drug. Just like
with cancer, just like the connection to Jerome
1:02:46.640,1:02:53.200
Horowitz, who discovered AZT, who was also a
cancer researcher, you would know that cancer
1:02:53.200,1:02:59.840
and HIV were rapidly able to evolve to mutate
and develop resistance against any drug that
1:02:59.840,1:03:07.040
you developed. So the aim would not be to develop
a single drug, but to use a combination of drugs,
1:03:07.040,1:03:13.760
and that was the goal that these researchers had
even in the 1980s, even though they developed
1:03:13.760,1:03:20.480
AZT — it did work, but people eventually
started to develop resistance against it,
1:03:20.480,1:03:24.468
but that was okay from their perspective because
they knew that this was not the end goal.
1:03:24.468,1:03:25.426
This is the beginning.
1:03:25.426,1:03:29.040
It was not to develop one
drug, we had to develop many.
1:03:29.040,1:03:33.920
We have to develop many. Not just
because they're going to get used
1:03:33.920,1:03:37.840
one by one and then become resistant, but
to use in combination from the beginning.
1:03:37.840,1:03:42.240
So they were thinking that way
from the beginning. Yeah, okay.
1:03:42.240,1:03:50.080
Yeah, I mean this was so interesting to me
just as a 'how to develop drugs', what is the
1:03:50.080,1:03:54.800
mindset that's required? What is the type of
approach you use? Of just trying everything,
1:03:54.800,1:03:59.600
essentially having different hypotheses, just
seeing what works. I thought it was really
1:03:59.600,1:04:07.200
interesting to read about. This, I think, then
spurred a lot of other pharmaceutical firms and
1:04:07.200,1:04:12.400
researchers to work in the area to develop
other types of drugs. Samuel Broder's team
1:04:12.400,1:04:20.720
then developed a bunch of other similar drugs.
We just talked about AZT, which is a type of
1:04:20.720,1:04:29.440
nucleoside reverse transcriptase inhibitor, NRTI,
and as we said, it's a drug that is this "mimic",
1:04:29.440,1:04:36.160
or this fake, version of a nucleoside
base of the DNA molecule of HIV.
1:04:36.160,1:04:41.280
Let's pause there, and let me see if I
can remember everything I just learned.
1:04:41.280,1:04:48.320
So I am putting myself in the headspace of a drug
developer who doesn't have the tools of 2025,
1:04:48.320,1:04:55.840
when we're recording today. And there's quite
a few tools I don't have. I don't have PCR.
1:04:55.840,1:05:00.320
I don't have, and don't have modern
genomics. I probably don't have high
1:05:00.320,1:05:05.920
throughput screening. I definitely don't have
knowledge of what HIV looks like, in terms of,
1:05:07.760,1:05:14.720
visually as a 3D structure — that's probably
far away. And I don't really know the whole
1:05:14.720,1:05:18.880
process of the lifecycle of the virus.
But what I do know is that, probably,
1:05:18.880,1:05:24.160
CD4 T-cells are implicated, because I'm seeing
these counts drop. I've taken blood samples,
1:05:24.160,1:05:29.760
and those counts are not looking so good for
patients. And what I do know is that, if I
1:05:29.760,1:05:34.480
rummage around, there are going to be some failed
cancer drugs somewhere that I can at least try.
1:05:34.480,1:05:40.880
And so, sure enough, and because well,
in addition, if I'm a cancer researcher,
1:05:40.880,1:05:48.080
I think about resistance and I think about
combination drugs. So what I'm going to do is,
1:05:48.080,1:05:55.520
I'm going to go around and try a bunch of stuff.
I mean, my takeaway from this is, it was just
1:05:55.520,1:06:03.760
incredibly empirical. You didn't have much in
the way of theory, beyond the CD4 implication,
1:06:04.880,1:06:12.640
link, and you would try and stuff, and a bunch of
stuff probably did not work, and then guess what?
1:06:12.640,1:06:21.200
One thing did work, and that gave everyone
some hope, and changed things going forward.
1:06:21.200,1:06:27.120
Yeah, I mean, it's so amazing to read about
drug development during that time and what
1:06:27.120,1:06:32.240
happened after that, as well. So maybe
this is the time to actually talk about
1:06:32.240,1:06:41.030
the HIV life cycle and what the other types of
drugs that have been developed are. And so...
1:06:41.030,1:06:41.040
I'm ready.
1:06:41.040,1:06:46.160
We should start with how an infection
happens, at a molecular level.
1:06:46.160,1:06:46.560
Great.
1:06:46.560,1:06:52.320
So we have the HIV virus particle.
I don't know if people have seen an
1:06:52.320,1:06:58.960
image or diagram or something of
HIV, but essentially it has this-
1:06:58.960,1:07:04.080
I'm holding up my hands for people
watching the video. Does this look right?
1:07:04.080,1:07:11.840
That looks right. So this is a spherical particle,
it has a bunch of proteins coming out of it,
1:07:11.840,1:07:22.320
and inside the spherical particle is a bunch
of stuff including a capsid. This capsid is
1:07:22.320,1:07:30.073
the core of the HIV virus. You can think of
it as looking — oh wow! Is that an actual-?
1:07:30.073,1:07:35.440
I just picked up something to mislead people.
It's a sun-bleached version of a vaccine,
1:07:35.440,1:07:39.920
but that mimics a viruses structure, so
that you can present to the immune system.
1:07:39.920,1:07:44.240
This is a COVID vaccine that the
Institute for Protein Design made.
1:07:44.240,1:07:45.840
Wait, can you hold it up to the camera?
1:07:45.840,1:07:52.720
Yeah, oh yes, I'm looking at it for myself. Anyone
watching the video here: this looks like a virus,
1:07:52.720,1:08:01.040
it is not a virus. It presents the receptor
binding domain of the spike protein of COVID,
1:08:01.040,1:08:06.480
or SARS-CoV-2, to the immune system on lots of
different places so you can get antibodies that
1:08:06.480,1:08:11.920
bind. It doesn't look that far off. I mean,
it's better than when I held my hands up, so.
1:08:11.920,1:08:13.440
It looks kind of cute, also.
1:08:13.440,1:08:15.040
It is cute. It is cute.
1:08:15.040,1:08:23.760
I had a stuffed toy version of the
coronavirus that I got from this museum,
1:08:23.760,1:08:27.600
and I thought it would be really
funny to get this as a gift,
1:08:27.600,1:08:32.160
and then to give it to someone
and say, Ha! I've given you COVID.
1:08:32.160,1:08:38.240
You know, it's crucial to get
good bits in, so I support.
1:08:38.240,1:08:48.480
So the HIV virus, you showed this spherical
particle. We have this envelope that is a sphere,
1:08:48.480,1:08:54.960
and then it has some protein sticking out of
it. Inside it, it has a capsid. The capsid sort
1:08:54.960,1:09:02.720
of looks like a thimble, or maybe more like
a bullet. This kind of interesting because
1:09:02.720,1:09:08.720
the bullet — or the capsid — contains a bunch
of the really important stuff, for the virus.
1:09:08.720,1:09:15.280
It contains the RNA molecules that's its genetic
code. It also contains a bunch of other enzymes
1:09:15.280,1:09:20.240
that it needs to do important stuff, including
reverse transcriptase, which it needs to turn its
1:09:20.240,1:09:29.440
RNA into DNA, and a bunch of other enzymes that
we'll come to. We have this HIV virus particle,
1:09:29.440,1:09:34.160
this spherical thing with the protein sticking
out of it. One of those proteins is called
1:09:34.160,1:09:44.880
GP-120. That protein — when the virus gets into
our body, it targets our white blood cells,
1:09:44.880,1:09:56.880
our T-cells primarily, and this GP-120 protein
attaches to a CD4 receptor on our T-cells.
1:09:56.880,1:09:57.440
Got it.
1:09:57.440,1:09:59.200
They get attached.
1:09:59.200,1:10:05.840
So the virus is currently outside of the
cell, and it attaches to CD4 on the outside.
1:10:05.840,1:10:10.400
Then, it starts to also attach to another protein,
1:10:11.120,1:10:23.920
CCR5 or CXCR5. There's a — initially, it starts
by infecting CCR5 T-cells. It uses these two
1:10:23.920,1:10:32.720
receptors, it binds to these two receptors,
and then it injects itself into our cells.
1:10:32.720,1:10:38.720
So it binds to two proteins on the outside of
the cell; it uses that as a way to get inside.
1:10:38.720,1:10:46.560
So it fuses with our cell membranes.
Inserts the contents of this HIV
1:10:46.560,1:10:53.200
virus into our cells. That includes the
capsid, the bullet, the bullet-like thing.
1:10:53.200,1:10:53.440
Bullet
1:10:53.440,1:10:58.800
But actually, I think a really good analogy,
maybe, is like a rocket. You know how, when a
1:10:58.800,1:11:07.680
rocket launches, most of it falls off, but there's
this core part of the rocket that continues going.
1:11:07.680,1:11:14.160
Right, and usually that's something I like
because it contains astronauts. In this case-
1:11:14.160,1:11:14.960
It's not.
1:11:14.960,1:11:22.080
I don't like it. I don't like it. So instead
of space, we're now in the cytoplasm.
1:11:22.080,1:11:28.320
That's right. So we're now in the cytoplasm
— the inside of the cell. At this point,
1:11:28.320,1:11:36.800
the capsid then makes its way to our cell's
nucleus. This was really interesting,
1:11:36.800,1:11:41.920
because we found out — so I had watched this
video to try to understand what was going on,
1:11:41.920,1:11:46.560
what was the pathway? I feel like videos
kind of help me remember things better,
1:11:46.560,1:11:53.920
and this video was from 2010, I think. Then I
started reading about this process separately,
1:11:53.920,1:11:58.160
in research papers, and they described
it differently. And it turned out that
1:11:58.160,1:12:05.760
our understanding of this life lifecycle has
actually changed in the last five years, right?
1:12:05.760,1:12:15.280
Yes. I actually talked to a friend who did her
PhD, who I think graduated in 2018, and did
1:12:15.280,1:12:24.960
her PhD on the HIV capsid. And she was saying to
me, oh, back when we were doing it back in 2018,
1:12:24.960,1:12:34.080
all those centuries ago, we actually didn't
yet know that the capsid, at least sometimes,
1:12:34.080,1:12:40.960
makes it all the way intact into the nucleus!
I was like, what? But that's so basic,
1:12:40.960,1:12:48.640
that's the whole game. It turns out no, even
now, we are getting tools that are making it
1:12:48.640,1:12:54.320
easier to actually see what the heck is going
on inside these incredibly busy cells. And yeah,
1:12:54.320,1:12:59.520
it's makes you wonder, if you do your PhD in five
years? What the heck are we going to know now?
1:12:59.520,1:13:06.000
I mean, I think one of the reasons for this is
that, it's really hard to observe an infection
1:13:06.000,1:13:12.560
happening. It's obviously very harmful and
probably very unethical to infect someone
1:13:13.120,1:13:19.840
directly with HIV, if you wanted to study what
happens in this early part. The people with HIV,
1:13:19.840,1:13:24.240
that have been part of research, have
obviously been much further along than
1:13:24.240,1:13:29.120
just being infected. So it's hard to
actually study those earliest stages,
1:13:29.120,1:13:33.680
and that's especially true because
HIV doesn't infect other animals.
1:13:33.680,1:13:40.560
The closest that we could use is SIV — simian
immunodeficiency virus — which is slightly
1:13:40.560,1:13:46.960
different. That means that there are various
things about this early stage that, I think,
1:13:46.960,1:13:54.480
weren't very clear. And I think that the change
in the last few years was better microscopy.
1:13:54.480,1:14:02.560
That is what my friend was basically
saying. She was saying, before we had
1:14:03.120,1:14:09.200
cryo-electron microscopy, we just couldn't
visualise things as well. She was using other
1:14:09.200,1:14:15.280
techniques to do her best, and now you have
this atomic resolution of these systems that
1:14:15.280,1:14:21.520
we haven't ever seen. I mean, it's beautiful. You
can actually see what's happening. We never knew.
1:14:21.520,1:14:22.320
Yeah,
1:14:22.320,1:14:28.640
It's genuinely crazy. I mean, like, I've
been reading about vaccine development;
1:14:28.640,1:14:33.840
biology over the 20th century, and what is
really surprising to me is that — we didn't have
1:14:33.840,1:14:41.680
any way to visualize viruses until the 1930s.
Before that- so we have the smallpox vaccine,
1:14:41.680,1:14:46.080
which is against a virus, but this is
before anyone knows what viruses are;
1:14:46.080,1:14:52.320
that's before germ theory was developed. We just
happened to get quite lucky with observation
1:14:52.320,1:15:00.080
and testing. But it's only in the 1930s that
we actually got this ability, this type of new
1:15:00.080,1:15:06.080
microscopy technique called "electron microscopy"
that allowed us to see things at the resolution
1:15:06.080,1:15:13.920
that would let us see viruses that are much
smaller than other bacteria, parasites and so on.
1:15:13.920,1:15:17.440
Okay, we're getting too excited, and we
need to focus on the lifecycle. I can tell,
1:15:17.440,1:15:20.000
I can tell, I can tell. Because
right now, I'm a capsid and I'm
1:15:20.000,1:15:22.720
about to enter the nucleus. I'm in the
nucleus. What's happening after that?
1:15:22.720,1:15:30.240
Okay, so let's recap. So the virus attaches
to the cell with GP120, it attaches to CD4
1:15:30.240,1:15:38.160
and CCR5. It inserts itself, fuses with our
cell membrane, inserts its content into our
1:15:38.160,1:15:44.080
cells. That includes the rocket, or the
rocket core, or the capsid, or the bullet,
1:15:44.080,1:15:53.280
whatever. That capsid makes its way to our
cell's nucleus. It then actually gets inside
1:15:53.280,1:16:02.400
the nucleus. So our nucleus has these entry
points, which are called pores, and the capsid
1:16:02.400,1:16:09.200
kind of snuggles through, kind of wiggles through
those. And this is going to be important later on,
1:16:09.200,1:16:19.040
the wiggling. So it gets into the nucleus and then
it starts reverse transcription. So at this point-
1:16:19.040,1:16:23.920
Question! Question, question. Does it do
another? So I came as a full package and
1:16:23.920,1:16:29.120
then I unfilled myself for the inner package. Do
I unfill myself again? So the capsid, kind of,
1:16:29.120,1:16:32.160
lets all the inner contents out into the nucleus?
1:16:32.160,1:16:37.520
I think so. And I am afraid of
saying anything too definitively,
1:16:37.520,1:16:42.640
because I'm thinking, what if this
knowledge changes in a few years or
1:16:42.640,1:16:47.200
something like that? But I think the
capsid also dissolves at this point.
1:16:47.200,1:16:47.840
Okay.
1:16:47.840,1:16:56.480
Within the capsid we said that there was the RNA
— the two RNA molecules — and there's the enzymes,
1:16:56.480,1:17:01.760
including reverse transcriptase.
Reverse transcriptase turns the
1:17:01.760,1:17:09.680
RNA molecule into DNA. Then, now
it has DNA, we also have DNA!
1:17:09.680,1:17:17.440
It can then insert itself into our cell's
DNA, using an enzyme called integrase,
1:17:17.440,1:17:27.600
which integrates it. Makes sense. So the virus
is now integrated itself into our cell's DNA.
1:17:27.600,1:17:36.400
Now, at some point, our cells will decide
to turn our DNA into other RNA molecules,
1:17:36.400,1:17:41.200
and to proteins, because we need parts of our
genetic code to do stuff at different times.
1:17:41.200,1:17:43.920
I don't want to brag, but
I'm doing that all the time.
1:17:43.920,1:17:47.840
We're doing it all the time. I don't
know the maths on this, but I know
1:17:47.840,1:17:55.680
there's a lot of it going on at any given time.
So it basically uses our own cells' machinery to
1:17:55.680,1:18:05.600
turn its DNA now into its RNA particles, and also
to transcribe the other proteins and enzymes that
1:18:05.600,1:18:13.440
it needs for its functions. These proteins and
enzymes and the RNA molecule somehow make their
1:18:13.440,1:18:23.360
way to the surface of our cells. They then bud
out of the cell. The cell membrane of our cell,
1:18:23.360,1:18:31.840
which previously was fused with the previous virus
particles, they bud into this new little particle,
1:18:32.400,1:18:38.960
and there's now an immature
virus, a new HIV virus particle.
1:18:38.960,1:18:45.360
But there's lots of them, because it's not just
that our body has transcribed one of these. It's
1:18:45.360,1:18:54.320
transcribing loads of these proteins and enzymes
at a time. So this one HIV that has infected our
1:18:54.320,1:19:00.960
cells and integrated into our DNA can then
multiply into many, many more that, and but out of
1:19:00.960,1:19:08.640
the cell. But at this point, it's still immature.
It's still not able to cause an infection,
1:19:08.640,1:19:17.600
because it hasn't- the proteins that we've made
for the virus are actually in this big compound,
1:19:17.600,1:19:25.920
of what is called a "polyprotein". So it's
multiple proteins that are fused together.
1:19:25.920,1:19:27.040
At this point,
1:19:27.040,1:19:33.600
So it was maybe more efficient for
the virus to do 'em all at once,
1:19:33.600,1:19:37.440
but they're now in a big string, so you
can't actually- they aren't going to
1:19:37.440,1:19:41.040
perform their function. There are many different
proteins that it wants from you. For example,
1:19:41.040,1:19:45.040
the integrase, maybe it's still
part of that? Is that right?
1:19:45.040,1:19:48.640
They're all part of- Well, no, I
think there are multiple polyproteins,
1:19:48.640,1:19:53.040
but one really big one has
reverse transcriptase, integrase,
1:19:53.040,1:19:58.800
and a bunch of other important proteins. And
they're all kind of in this huge polyprotein,
1:19:58.800,1:20:05.200
and then there's a separate enzyme
that's produced called "protease" in HIV.
1:20:05.200,1:20:09.520
That's what I would do, if I had something that-
I think I know what's going to happen. Keep going.
1:20:09.520,1:20:16.080
Okay. So this protease is what is
commonly called a "molecular scissor".
1:20:16.080,1:20:16.240
Right!
1:20:16.240,1:20:24.080
It cuts this giant polyprotein into its components
— into the individual enzymes that it then needs.
1:20:24.080,1:20:33.680
And that also creates, that also cuts off
capsid proteins, which then form a new capsid.
1:20:33.680,1:20:37.600
Oh wow. Sorry, we're inside of the
envelope, right now, of the virus?
1:20:37.600,1:20:38.708
We are now inside of the envelope.
1:20:38.708,1:20:43.680
But there's just a lot of mess in the immature
state. We don't have a capsid yet. Okay.
1:20:43.680,1:20:51.280
So we now have- the protease has cut this
giant protein, it has cut them into lots of
1:20:51.280,1:20:57.840
capsid proteins. The capsid proteins
start to assemble into a new capsid.
1:20:57.840,1:21:01.440
Which, in itself, I mean, that's so cool.
Because there are loads of different proteins,
1:21:01.440,1:21:07.760
right? That's going to be lots of different
individual units that are due to, you know,
1:21:07.760,1:21:11.200
thermodynamics, I guess, sort of
gravitating towards this configuration,
1:21:11.200,1:21:14.560
that is a bullet or that. Yeah, it's wild.
1:21:14.560,1:21:22.320
I mean, it's crazy. So this protease is what I
wanted to talk about a little more. And I think it
1:21:22.907,1:21:28.720
is probably really useful to hear about this whole
lifecycle in order to know what protease even is.
1:21:28.720,1:21:35.760
And so the HIV's protease, which is cutting
up this giant protein into its components,
1:21:35.760,1:21:43.920
that is what I think is the next big advance in
HIV drug development. There are a bunch of other
1:21:44.480,1:21:49.520
nucleoside analogues, the mimics like
AZT, that are developed around this time.
1:21:49.520,1:21:58.560
A bunch of other drugs are developed, but I
think the proteases are the next big step.
1:21:58.560,1:22:05.600
Alright. So we talked about protease, and
the reason that's important is because the
1:22:05.600,1:22:14.000
next big advance, in my view, is drugs that
targeted HIV's protease enzyme. I think I'll
1:22:14.000,1:22:19.440
talk a little bit about the first one that
was developed. This was called saquinavir,
1:22:19.440,1:22:30.160
and it was developed by scientists at Roche.
They were trying to figure out if there were any
1:22:30.160,1:22:35.440
drugs that could target this protein. So they
knew that this was probably important, because
1:22:35.440,1:22:44.800
they could see that- I think they were able to
test whether it was present in people with HIV.
1:22:44.800,1:22:52.720
And they knew that it was important in the process
of breaking down that giant protein polypeptide
1:22:52.720,1:23:01.200
into the smaller components. And so they started
to study its structure and its cutting pattern.
1:23:01.200,1:23:08.240
As we said, protease is often called a molecular
scissor. It doesn't literally look like a scissor,
1:23:08.240,1:23:18.640
I assume it just looks like a blob or something.
But when it's trying to cut down this giant
1:23:18.640,1:23:25.920
polyprotein, it slightly changes shape, I guess,
it opens up. It gets into this transition stage,
1:23:26.720,1:23:35.120
attaches to the polyprotein and then snips it into
separate proteins. And what they were trying to do
1:23:35.120,1:23:42.560
was, they were trying to find something that could
jam that transition state, so it couldn't actually
1:23:42.560,1:23:53.520
cut the protein. You have to look at what this
transition state might be, what specific part of
1:23:53.520,1:24:03.600
the protease enzyme is doing that snipping, and
then, can we fit something into this little gap?
1:24:03.600,1:24:09.760
Okay, so we've got this protease
— scissors — and we got my long
1:24:09.760,1:24:16.320
string of proteins — paper — and
we're going to jam a rock in there,
1:24:16.320,1:24:19.840
and rock beats scissors. And that's
one thing I learned many years ago.
1:24:19.840,1:24:21.040
Very good.
1:24:21.040,1:24:23.040
Thank you.
1:24:23.040,1:24:32.000
So what was interesting, I think, to them. I
think, at this point, there is PCR testing,
1:24:32.000,1:24:39.280
because this is 1986. So now, PCR is available,
but they could also try to look at where exactly
1:24:39.280,1:24:45.200
the protease was typically cutting. And
they found that if you looked at protease
1:24:46.000,1:24:53.920
in other proteins in the lab, it was
cutting at specific sequences in a protein.
1:24:53.920,1:24:59.360
A protein is made of many amino acids
joined together, and it was typically
1:24:59.360,1:25:04.880
cutting in places with a tyrosine, which is
one type of amino acid, or a phenylalanine,
1:25:04.880,1:25:11.600
which is another — and either of those followed
by a proline. So it was a sequence of either
1:25:11.600,1:25:17.520
tyrosine or phenylalanine followed by proline.
And this combination, of cutting at this point,
1:25:17.520,1:25:23.040
is something that human enzymes almost never do,
which is really useful, because it means that if
1:25:23.040,1:25:30.400
they're able to target this something that is
cutting at this point, then they're hopefully
1:25:30.400,1:25:37.600
not going to be affecting any human enzymes that
are important to us, for our other functions.
1:25:39.280,1:25:49.280
So what they then did was try to look for
other molecules that could fit into this
1:25:49.280,1:25:58.080
transition state, where the enzyme is snipping
the polyprotein. As part of designing the first
1:25:58.080,1:26:05.040
protease drug, they also had to develop tools to
test how well their drugs were working against it.
1:26:05.040,1:26:11.760
So they developed a dye reaction test, to
detect these proline-containing fragments.
1:26:13.120,1:26:19.920
They also worked on cloning and purifying the
protease enzyme, using recombinant DNA methods,
1:26:19.920,1:26:27.520
which were also fairly recent. The first
recombinant DNA that was produced was in 1972,
1:26:27.520,1:26:36.000
and the first time that was used for human enzymes
was insulin in 1978 — so this was the first time
1:26:36.000,1:26:45.200
that we could produce insulin in bacteria,
instead of extracting it from the pancreases?
1:26:45.200,1:26:46.160
Pigs, was it?
1:26:47.840,1:26:55.040
I think pigs. Previously to that, it was
dogs, and it was also cows and other mammals,
1:26:55.040,1:27:00.560
which is horrible. But there was no other
way to treat diabetes except to extract
1:27:00.560,1:27:05.520
insulin from various animals, until the
1970s. So this was a huge development
1:27:05.520,1:27:11.840
that was also very useful for testing
out potential drugs against protease.
1:27:11.840,1:27:17.520
I mean, yeah, we now take this for granted.
In any lab you're in, or most labs you're in,
1:27:17.520,1:27:23.600
you'll have some way of growing up proteins you
want to study in a biological system — probably
1:27:23.600,1:27:28.480
in a bacteria, but maybe in mammalian cells, maybe
in yeast. And that means you can study proteins
1:27:28.480,1:27:34.320
all day long. But back then, this would've
been recent. You could only do that from the
1:27:34.320,1:27:43.120
seventies as you said. So yeah, that's another
nice intersecting biotech improvement there.
1:27:43.120,1:27:49.360
It's so interesting to me, just how much
the technology kind of happens along side
1:27:49.360,1:27:55.360
and how much is dependent on other tools
being available and what new things that
1:27:55.360,1:28:01.840
allows you to, allows scientists to, do.
Okay, so back to protease inhibitors.
1:28:01.840,1:28:08.320
We're trying to test any drugs that fit
into these. The transition state — the
1:28:08.320,1:28:15.760
little wedge — where the scissors are cutting.
They tried a bunch of different drugs. One type,
1:28:15.760,1:28:25.200
called hydroxyethylamines, worked especially
well. When they found that that was working,
1:28:25.200,1:28:30.640
they started making adjustments to it, to
see if they could improve on that result.
1:28:30.640,1:28:35.360
They changed the ends of the molecules,
they tweaked the sizes of chemical rings,
1:28:35.360,1:28:42.320
they swapped side chains, and they found
that having a larger, fused ring structure
1:28:42.320,1:28:48.400
made it much easier for this compound to latch
onto the protease and block it from cutting.
1:28:48.400,1:28:55.440
I find this kind of stuff crazy, just because
the tweaking is so important. We're talking
1:28:55.440,1:29:02.480
about very small molecules, well, small
areas we're tweaking. We're talking about
1:29:02.480,1:29:07.680
not that many... atoms! We're talking about-
you add up all the atoms at the cleavage site,
1:29:07.680,1:29:14.480
I dunno, not that many. So yeah, it's
wild that chemistry gets so specific,
1:29:14.480,1:29:21.680
and that means that you can have these small
changes that have enormous changes for patients.
1:29:21.680,1:29:25.920
I mean, I think it shows how much
different fields of research come
1:29:25.920,1:29:32.320
together in developing new drugs. We have
people who work in the clinic with patients,
1:29:32.320,1:29:37.200
and they might see something that seems to be
having an effect, so they try it out. Then,
1:29:37.200,1:29:42.480
there's the people working on microscopy,
who are really important, the chemists, the
1:29:42.480,1:29:47.760
pharmacologists, who are testing out toxicity and
drug reactions and things like that. It's like,
1:29:47.760,1:29:54.080
everything comes together, and that is
really important here. And so this drug
1:29:54.080,1:30:05.360
that they then developed after these dozens of
adjustments was initially called Ro-31-8159.
1:30:05.360,1:30:09.120
Ro-31-8159. It rolls off the tongue!
1:30:09.120,1:30:16.320
That was later named saquinavir, which is the
first protease inhibitor that was approved. As
1:30:16.320,1:30:23.280
I said, this drug, because it was targeting
the enzyme, that was cutting in the specific
1:30:23.280,1:30:32.240
place that was not the case in human enzymes.
It was extremely selective to HIV protease,
1:30:32.240,1:30:39.520
and barely affected human enzymes, even at very
high concentrations. That meant that it was
1:30:39.520,1:30:45.760
much safer. But at the same time, what
I found kind of interesting was that,
1:30:45.760,1:30:54.560
this drug, if you gave it to people, most of
the drug was excreted very quickly. About 96%,
1:30:54.560,1:31:01.680
I think, was excreted in the urine. So having a
high concentration of the drug, thankfully, didn't
1:31:01.680,1:31:06.720
have these side effects, because you'd have to
compensate for the amount that just gets peed out.
1:31:08.560,1:31:17.680
I think this is also interesting because we're
at this point now — this was approved in 1995,
1:31:17.680,1:31:25.280
saquinavir. And at this point, there are, I
think, around a dozen different antiviral drugs,
1:31:25.280,1:31:30.640
which again is amazing, because
just 10 years before that,
1:31:30.640,1:31:37.760
people thought no drugs would work against
this disease, but now they have 10, or so.
1:31:37.760,1:31:39.200
Progress.
1:31:39.200,1:31:44.720
So, at this point, there are a bunch of drugs,
but none of them really work in a long lasting
1:31:44.720,1:31:50.240
way. People develop HIV, it manages to
evolve resistance against the drugs that
1:31:50.240,1:31:56.720
are being used after a few months. And this
seems like it's just another one of those,
1:31:56.720,1:32:01.440
okay, we've got a new drug, but is it really
going to make a difference in the long term?
1:32:01.440,1:32:08.960
And I think people were, in terms of people
with HIV, they were probably quite pessimistic,
1:32:08.960,1:32:16.080
in some ways. They want new drugs to be developed
for their condition, but how is this going to
1:32:16.080,1:32:23.760
make a difference after a few months? But this
is actually where things change, because now
1:32:23.760,1:32:33.680
that we have a protease inhibitor and we have
nucleoside — the fake nucleosides — like AZT,
1:32:33.680,1:32:40.000
and we have a few other drugs, we can now combine
them, and give them as combination treatment.
1:32:40.000,1:32:44.400
Ding, ding, ding, here we go.
I don't know if, literally,
1:32:44.400,1:32:50.080
the combination involved AZT or some
of the other antibodies you mentioned,
1:32:50.080,1:32:56.800
but I did notice that the protease is operating
right near the end of the viral lifecycle. AZT,
1:32:56.800,1:33:01.360
as you described, it's operating much earlier.
These are really different parts of the lifecycle,
1:33:01.360,1:33:07.280
and it's quite unlikely intuitively the virus
would, at the same time, mutate against both.
1:33:09.040,1:33:14.080
So I think this is something that the cancer
researchers, or the virologists, working on
1:33:14.080,1:33:20.000
this would now have realised: that we're now
working on different aspects of the virus's life
1:33:20.000,1:33:27.120
cycle. It's fairly unlikely that it's going to be
able to resist all of these drugs coming at it,
1:33:27.120,1:33:35.200
in different parts. And I think this is when
this combination therapy started to be used, and
1:33:35.200,1:33:44.880
it was being tested alongside these new protease
inhibitors. This new type of combination therapy
1:33:44.880,1:33:52.000
is called HAART, which stands for "highly active
antiretroviral therapy". It's a combination of,
1:33:52.000,1:33:59.920
typically, one nucleoside reverse transcriptase
inhibitor, like AZT, another drug inhibitor that
1:33:59.920,1:34:06.720
directly inhibits reverse transcriptase — so it's
not a fake base — and then, a protease inhibitor.
1:34:06.720,1:34:12.000
There were multiple protease inhibitors that
were introduced around the same time in 1995,
1:34:12.000,1:34:17.040
like a bunch of different pharmaceutical firms
essentially racing to get their to market.
1:34:17.040,1:34:25.120
This is a huge change in terms of how HIV
treatment works, how effective it is, in the US.
1:34:25.120,1:34:32.560
I'm showing this chart that I worked on earlier,
just to show what impacts it had. You can see this
1:34:32.560,1:34:42.560
massive rise in mortality rates from HIV and AIDS
from the 1980s to the 1990s; rapidly grows as an
1:34:42.560,1:34:51.600
epidemic disease growing exponentially. In 1995,
in December, highly active antiretroviral therapy,
1:34:51.600,1:34:59.520
the combination treatment, is introduced,
and it's just this huge drop in death rates.
1:35:00.480,1:35:07.280
The way that people talk about it is, as if people
are on death row and they're coming back to life
1:35:07.280,1:35:12.240
suddenly with this new combination therapy,
because it's something that the virus is very
1:35:12.240,1:35:21.440
hard- not able to evolve resistance to. I wanted
to bring this up because I was reading that book,
1:35:21.440,1:35:29.680
How to Survive a Plague by David France, and
he talks about his own- he was a reporter at
1:35:29.680,1:35:38.080
the time, and he was at one of these scientific
conferences on protease inhibitors learning about
1:35:38.080,1:35:44.400
the science, what new drugs were available.
He describes one of his experiences towards
1:35:44.400,1:35:52.400
the end of the book, and this is what he says.
He says: "One of the scientists interrupted his
1:35:52.400,1:35:59.120
presentation abruptly and he said, 'Maybe you
are not understanding what I am saying. This
1:35:59.120,1:36:04.320
is the biggest news ever in this epidemic.
This stuff is actually clearing virus out
1:36:04.320,1:36:09.040
of people's bodies. People are getting better.
We don't know for sure yet, but we think these
1:36:09.040,1:36:15.200
drugs — this whole class of drugs — might allow
people to live a normal life. This is what we've
1:36:15.200,1:36:19.840
been working for all these years. They're not
a cure. We don't know what they are, in effect,
1:36:19.840,1:36:25.600
but this is the first major piece of good news
we've had in all these years. They're calling it
1:36:25.600,1:36:31.680
the Lazarus effect. People who were in hospitals
on their last breath are getting up and going back
1:36:31.680,1:36:38.720
to work. We've never seen anything like it.'"
And that's just an incredible change, I think,
1:36:38.720,1:36:48.000
from how scary it must have been in the 1980s,
seeing some drugs really promising. But eventually
1:36:48.000,1:36:54.320
they start to fail and then you get this
combination of therapy that changes everything.
1:36:54.320,1:37:01.200
A complete change, and it breaks your heart
to think of people who didn't make it to see
1:37:01.200,1:37:11.280
that change. Oh, what a graph. Okay,
you're going to have make some nice,
1:37:11.280,1:37:16.000
less emotionally-intense
graphs for me to calm down now.
1:37:16.720,1:37:23.120
There are a bunch of other drugs that I think we
aren't going to talk about. But apart from the
1:37:23.120,1:37:29.040
protease inhibitors, the nucleoside analogues,
and other reverse transcriptase inhibitors,
1:37:29.040,1:37:34.880
there are other drugs that targets how
HIV enters the cell. I think there are
1:37:34.880,1:37:41.680
also some that targets the integrase enzyme
— that allows its DNA to integrate into our
1:37:41.680,1:37:49.200
DNA — and then there are some others as
well. But I think that kind of covers
1:37:49.200,1:37:56.480
much of the major story in the 1980s
and '90s on HIV and drug development.
1:37:56.480,1:38:04.240
Okay, so taking a step back, we know what HIV
looks like. We know roughly where it came from.
1:38:04.240,1:38:08.880
We now know a bit about the lifecycle,
and we know about combination drugs that,
1:38:08.880,1:38:16.640
together, prevent HIV from taking
over, and are less prone to resistance,
1:38:16.640,1:38:24.480
because there's many of them you're on at once.
Okay, what about, what's happening with vaccines
1:38:24.480,1:38:30.400
at this point? And are people talking about
curing HIV? I mean, these drugs control HIV.
1:38:31.040,1:38:39.200
I think this is interesting because we don't
have a vaccine for HIV yet, right? It's been
1:38:39.200,1:38:47.280
more than 40 years since the first AIDS case
was reported. We have loads of antivirals now,
1:38:47.840,1:38:53.360
working in different ways, but we don't have
any vaccines. I think this would have been
1:38:53.360,1:38:59.280
really depressing if vaccines were the only
things that were being worked on at the time.
1:38:59.280,1:39:04.880
But thankfully people were trying out random drug
combinations, and that's why I think this first
1:39:04.880,1:39:10.800
step, of getting AZT, was so important.
But my understanding is there aren't any
1:39:10.800,1:39:16.880
working vaccines that we know of yet... so
I didn't actually read anything about them.
1:39:16.880,1:39:25.520
Well, I know a little smidgen. At
Open Philanthropy where I work,
1:39:26.160,1:39:34.960
the team I work on supports a bunch of different
biomedical research, and roughly a third of what
1:39:34.960,1:39:46.320
we fund in grants is, in some way or other,
vaccinology or focused on vaccines. The area of
1:39:46.320,1:39:55.920
vaccines we've done may be the least in is HIV,
and the reason for that is that it's very hard,
1:39:55.920,1:40:03.040
and now people have more knowledge of why
it's hard. It also, happily, despite being
1:40:03.040,1:40:09.600
so underfunded at the beginning of the crisis in
the US and elsewhere, now has attracted much more
1:40:09.600,1:40:14.560
attention and funding. So there's actually been
tens of billions of dollars thrown at this problem
1:40:14.560,1:40:21.440
of 'How do you make an HIV vaccine?' The reason
it's so difficult, I think, the clues to that
1:40:21.440,1:40:33.520
are located in what you've already said about the
virus. Well, firstly, clue number one is that our
1:40:33.520,1:40:40.720
immune system doesn't control the virus naturally
very well, once an infection is established.
1:40:42.400,1:40:49.120
Most people are not able to control an infection,
once it's established, and that implies, okay,
1:40:49.120,1:40:56.160
well, what is a vaccine? A vaccine is trying
to trigger your immune system to be prepared
1:40:56.160,1:41:03.280
for future invaders. If hardly anyone has a
prepared successful immune response, what are
1:41:03.280,1:41:11.120
we even trying to mimic here? It's a tough problem
statement, whereas something like COVID, plenty of
1:41:11.120,1:41:18.000
people do manage to control and their immune
response is productive. You can pretty easily
1:41:18.000,1:41:22.400
see with COVID, especially at the beginning, well
there's one protein on the outside of this virus,
1:41:22.400,1:41:27.360
the spike protein, that if you block it with
antibodies, it is not getting into your cell.
1:41:27.360,1:41:35.120
So let's try and mimic that immune response.
And then another clue is about the rapid mutation.
1:41:35.120,1:41:43.680
So if your immune system is trying to prevent
something that keeps changing, it's going to be
1:41:43.680,1:41:50.560
harder. And sure enough, if you create a vaccine
which is less dynamic than your immune system,
1:41:50.560,1:42:02.080
and is only one thing, then you're not going to
be clearing all of these different permutations of
1:42:02.080,1:42:08.880
the virus. These days, because the understanding
of the immune system has progressed even outside
1:42:08.880,1:42:14.880
of HIV, over the last few decades, and because we
have so much better tools, people are still going
1:42:14.880,1:42:22.800
at the problem, and have sort of ingenious and
complicated ideas about how to make a HIV vaccine.
1:42:25.680,1:42:31.680
You may have heard the phrase "broadly
neutralising antibodies" — that's all the rage
1:42:31.680,1:42:41.280
for what people are using to develop vaccines,
and going after. But that's, importantly,
1:42:41.280,1:42:46.960
not what we're here to discuss today. I think you
and I really are focused on medical impact and
1:42:46.960,1:42:54.880
this podcast is too, and it's so interesting
that what we are here to discuss is a drug,
1:42:54.880,1:43:00.720
in the sense of, it's not prompting your immune
system to respond in a certain way, like a vaccine
1:43:00.720,1:43:06.560
would. It's trying to avoid getting rejected
by your immune system, and instead is trying to
1:43:06.560,1:43:12.160
just be a chemical that's hanging around, and the
chemical's doing the work, not your immune system.
1:43:12.160,1:43:19.840
I was thinking about the broadly utilising
antibodies. Just in case people are not aware,
1:43:21.680,1:43:28.960
I guess a fraction of people seem to be able
to develop an immune response to a wider range
1:43:28.960,1:43:35.040
of HIV strains after it's diverged.
So trying to find those antibodies,
1:43:35.040,1:43:42.480
that seem to be working against this broad range,
that is what people are looking for. Right? The
1:43:42.480,1:43:49.600
other thing is there are some people who are
still, we're working on combination vaccines,
1:43:49.600,1:43:58.320
I think. So vaccines that include multiple
different components of the HIV virus. And this,
1:43:58.320,1:44:04.720
I know from direct experience, because
I was once in an HIV vaccine trial.
1:44:04.720,1:44:08.560
Aha! So when was this?
1:44:08.560,1:44:11.280
This was in 2019.
1:44:11.280,1:44:11.780
2019.
1:44:12.640,1:44:16.560
You might be wondering, why am I getting
an HIV vaccine? Why am I in this trial?
1:44:16.560,1:44:23.760
It was this phase one trial. So essentially,
they're just testing the safety and some basic
1:44:24.800,1:44:30.160
reactions — immunological reactions
— you have to a potential vaccine.
1:44:30.160,1:44:37.040
And I got contacted through Imperial where I
think I was studying at the time or had been,
1:44:37.600,1:44:43.760
and I was like, I love science,
I want to be part of this trial.
1:44:43.760,1:44:46.240
We need more Saloni's in this world.
1:44:46.240,1:44:52.080
Also I was thinking, well what if this
candidate vaccine actually works? I'll
1:44:52.080,1:44:54.720
be immune to HIV. That would be so cool.
1:44:54.720,1:45:00.080
Well, oh yeah. So this was not controlled. It was
a phase one, so you were definitely getting it?
1:45:00.080,1:45:06.240
Oh, I actually don't know. I mean, I could have
been on placebo, but still you have a 50%-ish
1:45:06.240,1:45:14.320
chance, probably, get it for free getting an
HIV vaccine for free if it works. It was a
1:45:14.320,1:45:22.320
really funny experience because... if you have
met me or seen me in person, I'm quite small.
1:45:22.320,1:45:30.240
I thought that, well, I knew that this trial
had this eligibility requirement that you had
1:45:30.240,1:45:37.280
to be within normal BMI. I am essentially
on the cutoff of underweight and normal,
1:45:37.280,1:45:42.800
whenever I've checked. And that's just been true
for years. So I was really worried that I would
1:45:42.800,1:45:47.680
just fall under the threshold, and I would
not be allowed to participate in the trial.
1:45:47.680,1:45:53.600
I love that you are hustling to
get into an HIV vaccine trial.
1:45:53.600,1:45:58.400
Like, eating more food to get in. Exactly.
1:45:58.400,1:46:01.760
Bulk season is on.
1:46:02.400,1:46:08.240
Okay. So I was trying, I was really hoping
that I would get into this trial. I got to
1:46:08.240,1:46:16.160
the clinical trial site. They asked me a
few questions, they asked for my consent,
1:46:16.160,1:46:22.000
et cetera. And then, they also wanted to measure
me, to check that I met the requirements. So
1:46:22.000,1:46:29.120
they were measuring my weight and my height. They
then put that into their computer and they said,
1:46:29.120,1:46:35.680
'Oh great, you've passed this threshold', and I
saw this BMI value on their screen. I was like,
1:46:35.680,1:46:41.840
that's surprising. Great, but surprising. And
then, I looked at the values that they had
1:46:41.840,1:46:49.760
entered, and it turned out that I was shorter
than I thought I was... so my BMI was normal.
1:46:49.760,1:46:58.320
So it took medical development of HIV to
get you to understand your height. I mean,
1:46:58.320,1:47:01.600
there's a lesson here, but I'm
not quite sure what the lesson is.
1:47:01.600,1:47:05.280
Well, it's also, it's hard
to measure your own height.
1:47:05.280,1:47:06.720
Great point.
1:47:06.720,1:47:14.720
I dunno. It was both exciting because I could
now participate in this trial, but also there
1:47:14.720,1:47:22.640
was this sadness that I felt, realising that
I was even shorter than I thought I was.
1:47:22.640,1:47:27.200
Oh God. Wait, so what happened? Are you protected?
1:47:27.200,1:47:35.600
I don't know. Well, they didn't unblind me from
whether I was getting the vaccine or the placebo,
1:47:35.600,1:47:40.960
but I did go in; I think I was in for
some eight sessions. They did a bunch of,
1:47:40.960,1:47:47.840
was it blood testing? They did some
testing of uncomfortable parts of my body,
1:47:47.840,1:47:52.960
to see the effects of this vaccine.
I don't think I had any side effects,
1:47:52.960,1:47:59.920
maybe a headache at some point, but that was all.
It was pretty nice. It was a great experience.
1:47:59.920,1:48:01.280
Nice. Cool.
1:48:01.280,1:48:07.520
I mean, I would say I would recommend it, but
really you should decide that for yourself.
1:48:07.520,1:48:18.560
Sounds good. I just recently was screening to
sign up for a vaccine trial here in San Francisco,
1:48:19.120,1:48:23.760
and I did the 15 minute screen, and they
signed me up to go in person. And then,
1:48:23.760,1:48:27.920
the day I was going to go in person, I had a
meeting that clashed, and I haven't got around
1:48:27.920,1:48:35.920
to enrolling, so I'm feeling a lot of guilt. So
now I have an extra incentive though. Maybe I'll
1:48:35.920,1:48:39.600
figure out I'm taller than I think I am.
Maybe I'll figure out I'm shorter though.
1:48:42.160,1:48:48.320
Well, so the reason I brought this up was because
it was a combination vaccine, but also it was a
1:48:48.320,1:48:56.160
funny story. But the vaccine that they were trying
contained, I think, three different proteins of
1:48:56.160,1:49:05.440
the HIV. So I think it was one adenovirus that was
modified to carry an HIV coat protein. There was
1:49:05.440,1:49:13.840
another that was a vaccinia virus, which is...
is that the smallpox vaccine virus, I think?
1:49:13.840,1:49:15.760
Hmm, yeah, probably.
1:49:15.760,1:49:21.840
And then there was another, that was another
coat protein. So they had tried out, I think,
1:49:21.840,1:49:24.720
one or two of these before in trials, and then
1:49:24.720,1:49:29.200
this was putting them together
into this combination vaccine.
1:49:29.200,1:49:30.371
It's interesting-
1:49:30.371,1:49:31.520
And then I don't know How it worked out.
1:49:31.520,1:49:37.360
Yeah, it's interesting you mentioned a
coat protein. It makes me think of the
1:49:37.360,1:49:41.040
design differences you are dealing with
when you're trying to make therapeutics,
1:49:41.040,1:49:46.640
and when you're trying to make vaccines.
With vaccines, stereotypically,
1:49:46.640,1:49:52.240
especially for antibody responses, you wanna
look on what's on the outside of an invader,
1:49:52.240,1:49:57.760
what's sticking out that my antibodies can glue
to, and maybe a coat protein is a good choice
1:49:57.760,1:50:02.960
because it might be sticking out? And you know
what is not sticking out? Those strands of RNA,
1:50:02.960,1:50:08.400
that are not only inside the envelope, they're
inside a capsid; your antibody is not getting in
1:50:08.400,1:50:15.200
there. However, a small molecule drug, which is
a nice tiny little chemical, can diffuse to many
1:50:15.200,1:50:21.680
places very surreptitiously. So you really might
be able to interfere with something that the virus
1:50:21.680,1:50:29.920
has tried to protect from your immune system,
but has failed to protect from genius humans,
1:50:29.920,1:50:36.720
who are using good tools to make something that
nature actually couldn't have really got to.
1:50:36.720,1:50:40.800
No, exactly. Yeah, that's a really good point.
1:50:42.240,1:50:49.760
Shall we talk a little bit about
treatment for HIV and what that's like?
1:50:49.760,1:50:58.160
Sounds great. And maybe we should even skip
to prevention! We've talked a bit about-
1:50:58.160,1:50:59.200
Let's do that.
1:50:59.200,1:51:05.200
Let's do it, because you've given us a good
overview of how in the '90s, these new drugs
1:51:05.200,1:51:13.680
allowed patients who had HIV infections to have
much longer life expectancy, and control their
1:51:13.680,1:51:19.440
infections. There's a lot more that we could say
about the different improvements since then in
1:51:19.440,1:51:27.040
treatment. But the principle is somewhat similar,
if you want to be on these combination therapies.
1:51:27.040,1:51:39.520
So let's skip to prevention because prevention
has some overlapping path and some different path.
1:51:39.520,1:51:46.240
What were the first ways that you could try and
prevent getting HIV, if you didn't have it yet?
1:51:46.240,1:51:53.760
Well, you could change the way you were having
sex, the type of sex you were having. You could
1:51:53.760,1:52:01.440
have sex with fewer partners, and you could have
sex with condoms, which provide a barrier. The
1:52:01.440,1:52:09.520
thing that really changed preventive strategies
more recently though, was drug availability for
1:52:09.520,1:52:15.600
PrEP — pre-exposure prophylaxis. So that's
different than post-exposure prophylaxis,
1:52:15.600,1:52:22.800
which is PEP. And the pre- means you're
taking the drug before you have sex,
1:52:22.800,1:52:29.920
or before you get exposed in some other way.
That means that, if any HIV particles enter
1:52:29.920,1:52:38.880
your system, the drug is going to help block
an infection getting established. So PrEP as a
1:52:38.880,1:52:46.960
drug regimen first became available in
the US at least, in 2012. So Truvada
1:52:46.960,1:52:55.040
is a combination of two drugs, tenofovir and
emtricitabine. Do you know how to say that one?
1:52:55.040,1:52:55.600
No.
1:52:55.600,1:53:03.440
Okay. I mean, they put them
in one daily oral pill. So,
1:53:03.440,1:53:08.720
more specifically, it's actually
tenofovir disoproxil fumarate,
1:53:08.720,1:53:16.240
which I'm sure I'm also mispronouncing, or
"TDF", in combination with emtricitabine. And
1:53:17.200,1:53:27.040
those were two separate drugs that had been
approved for treatment of HIV in 2001 and 2003.
1:53:27.040,1:53:36.240
The combination of them was approved as a
treatment called Truvada in 2004. Then by 2012,
1:53:36.240,1:53:43.280
the FDA approved Truvada as the first PrEP
regimen, after a clinical trial showed that
1:53:43.280,1:53:47.674
it had high efficacy in preventing
infection. And I, yeah, go ahead.
1:53:47.674,1:53:51.840
Yeah, it's so interesting that some of the
same antivirals that are used in treatment
1:53:51.840,1:53:59.040
were also used in prevention. One thing that
made me think about was, I was reading about
1:53:59.040,1:54:06.960
was azidothymidine — AZT — the first HIV drug,
and I think there's a part of that story that
1:54:06.960,1:54:15.440
gave them a clue that antivirals could be used
as prevention as well. That was that pregnant
1:54:15.440,1:54:24.800
women who had HIV who were taking AZT, were not
passing it on to their babies at the same rate.
1:54:24.800,1:54:31.840
They started running this trial in the '90s,
and in 1994, I think, the study was published.
1:54:31.840,1:54:39.120
There was this massive drop in the rates of
transmission, from mother to child, of HIV.
1:54:39.120,1:54:45.440
And that is really interesting as well, because
even though people were developing resistance
1:54:45.440,1:54:54.240
to different HIV drugs, if they were pregnant
and taking it, the drug resistance was not as
1:54:54.240,1:54:59.360
much of a problem if they were taking it
late enough, because you only need this
1:54:59.360,1:55:04.240
particular time span for it to be effective.
It doesn't have to be effective for years.
1:55:04.960,1:55:06.400
Of course. I see.
1:55:07.280,1:55:09.600
But also I think that just gave people a hint
1:55:09.600,1:55:14.240
that this is something that
could be used in prevention.
1:55:14.800,1:55:19.760
Yeah, that's such a neat real world
proof-of-concept of what you can do
1:55:19.760,1:55:26.240
there. Truvada has been improved on since.
So maybe I'll just go through a couple of
1:55:26.240,1:55:37.200
those improvements. The fundamental idea is
similar for the main improvement drug. In 2019,
1:55:37.200,1:55:43.120
there was a new regimen called Descovy.
And you might be wondering, is this from
1:55:43.120,1:55:50.320
a competitor who's trying to outdo Truvada?
And it's from the same company, Gilead, who,
1:55:50.320,1:55:57.520
as a bit of a spoiler, developed Lenacapavir later
in life. Descovy does have a longer patent though,
1:55:57.520,1:56:04.400
so it's a better variation for men, it's
emtricitabine again, which I've probably
1:56:04.400,1:56:10.240
said three times in three different ways, and it's
tenofovir again. It's the same dose actually of
1:56:10.240,1:56:17.360
emtricitabine. I think it's 200 milligrammes. The
tenofovir is in a new form though. Instead of TDF,
1:56:17.360,1:56:27.600
it's TAF, which stands for tenofovir
alafenamide. And both TDF and TAF are
1:56:27.600,1:56:34.240
"pro drugs". For tenofovir, that means that means
your body is sort of doing some work once you
1:56:34.960,1:56:42.400
ingest them to enzymatically, convert them into
tenofovir, and then into tenofovir diphosphate,
1:56:42.400,1:56:48.320
which is the active formula drug. My
understanding of the difference is that,
1:56:48.320,1:56:56.000
for TDF, so the original one, that primarily
happens in blood plasma and for TAF-
1:56:56.000,1:56:57.600
What happens? The, the change?
1:56:57.600,1:57:05.040
The conversion... into the active drug. And for
TAF, that primarily happens in the immune cells.
1:57:05.040,1:57:08.960
You know, if you think about the difference there,
well, getting the same thing out the other end,
1:57:08.960,1:57:12.800
why do I care? Well, if you're doing it in the
blood, then your blood's circulating everywhere,
1:57:12.800,1:57:17.360
including your kidneys, and you can actually
have more unwanted effects from that,
1:57:17.360,1:57:23.520
than if you're more secluded when you're
making your active drugs. I think that's
1:57:23.520,1:57:27.120
why the safety profile of Descovy
looks a little bit better. You have,
1:57:27.120,1:57:33.520
if you're on long-term daily use of the first
one, it's got a pretty good safety profile,
1:57:33.520,1:57:43.280
but it can have negative effects on kidneys and
bones — so bone density and kidney toxicity. And
1:57:43.280,1:57:50.320
so, here's where, if anyone's on the video, I'm
going to do some show and tell. I don't know if,
1:57:50.320,1:57:55.680
are you the kind of person-? I keep all of my
empty pill bottles into the future indefinitely?
1:57:55.680,1:57:57.440
Oh, I don't do that.
1:57:58.800,1:57:59.437
I do this.
1:57:59.437,1:58:00.640
So these are empty pill bottles.
1:58:00.640,1:58:05.760
These are empty pill bottles, which hopefully
don't have private information on them. But
1:58:05.760,1:58:11.600
basically I think I do it because I have some
vision of, I'm going to do some art project about
1:58:12.320,1:58:16.000
what it's like to be a modern human in the future,
and you do that. But I think I actually stole that
1:58:16.000,1:58:19.920
from, I think I've seen an art project, which
had loads of entry pill bottles. So I actually
1:58:19.920,1:58:24.240
don't have a plan for these pill bottles.
But basically, here's what you can learn. So
1:58:25.120,1:58:31.680
take one tablet by mouth every day.
This is emtricitabine and tenofovir,
1:58:32.560,1:58:38.080
200 to 300 milligrams. Here's another
thing you can learn. So this one is this
1:58:38.080,1:58:43.520
empty pill bottle says Laurus labs on it.
And you might be thinking Laurus labs,
1:58:43.520,1:58:50.240
that doesn't sound like Gilead true. And this
other empty pill bottle says Amneal on it; doesn't
1:58:50.240,1:58:58.800
sound like Gilead either. The reason for that, is
that the Truvada patent expired in 2020. So there
1:58:58.800,1:59:08.080
are now many generic drug manufacturers who make
Truvada, which is why I am on Truvada, because
1:59:08.080,1:59:15.200
when I first asked to go on Descovy, my doctor at
the time was like — I think that patent exposed
1:59:15.200,1:59:21.600
in 2031 — was like, uh, no, no, no, we're going
to give you Truvada. And then I did the classic-
1:59:21.600,1:59:23.040
Because it's cheaper, or?
1:59:23.040,1:59:30.000
Yes, correct. So it's made by drug companies
outside of the US, usually in middle income
1:59:30.000,1:59:34.960
countries or in lower income countries, a lot
based in India, but other countries too. I
1:59:34.960,1:59:40.960
actually don't, I feel like one of these is an
American company, but I might be wrong. And by
1:59:41.680,1:59:48.000
making these generic competitors, where they only
have to prove to the FDA that it is similar enough
1:59:48.000,1:59:53.280
in terms of its pharmacodynamics and all that,
they don't have to redo all the clinical trials.
1:59:54.080,2:00:00.800
They can sell for a cheaper price than Gilead
might. I actually remember later on, the first
2:00:00.800,2:00:09.040
injectable PrEP came about, cabotegravir, and
that is made by a different company called Viiv,
2:00:09.040,2:00:19.040
V-I-I-V. That, I believe, was approved in
2021, if I'm remembering right. That is:
2:00:19.040,2:00:26.800
you only get one injection every two months.
So I had heard about it and asked a different
2:00:26.800,2:00:31.040
doctor I had at the time, could I, just
asked about it, wasn't sure if I do it,
2:00:31.040,2:00:35.760
wasn't sure if I'd stick with what I
was doing. And that was very expensive,
2:00:35.760,2:00:44.000
so that was a quick no. My insurance at that time
was not enthused about that one. If memory serves,
2:00:44.000,2:00:51.520
it was roughly $4,000 a dose, and it's every
two months, that's six doses a year. I think
2:00:51.520,2:00:58.640
it was roughly $20,000 a year. And the patient
benefits sure enough was not, I shouldn't really
2:00:58.640,2:01:02.160
have been paying that much, because the
drugs I was on were working perfectly fine.
2:01:02.160,2:01:08.320
I guess I'm interested about how
PrEP works on a day-to-day basis.
2:01:08.320,2:01:14.560
Do you take it every day? Do you only
take it sometimes? What's the pattern?
2:01:14.560,2:01:20.720
So it's the default is you take it every
day; it's a daily oral pill, and that makes
2:01:20.720,2:01:27.520
sure that there's enough of the drug in your
system that you are safe, whatever happens.
2:01:27.520,2:01:34.400
There is another regimen that men can take for
Truvada, which is often referred to as 2-1-1,
2:01:34.400,2:01:44.800
so I do. Where instead of doing it every day, you
take two doses, so two pills, the day of sexual
2:01:44.800,2:01:52.080
activity or some risk you're exposing yourself
to, one pill the next day, one pill the day after,
2:01:52.080,2:01:58.000
and then, the rest of the time, you just don't
take anything. That is easier for some people.
2:01:58.000,2:02:03.280
And that said, if I think about, if I do
an informal poll in my head right now,
2:02:03.280,2:02:07.680
with my gay friends in San Francisco, I would
say most probably do daily, just because it's
2:02:07.680,2:02:16.480
easy. Actually, recently, my doctor tried to move
me onto Descovy, which is the second one, just
2:02:16.480,2:02:22.400
because it's better for kidneys and when I was
a baby, I had some kidney issues. That I do not
2:02:22.400,2:02:29.920
believe doctors do recommend 2-1-1. And certainly
my doctor and I asked him, well, I'm doing 2 1 1,
2:02:29.920,2:02:36.080
can I do that with Descovy? And he said, "Well,
I'm not allowed to say yes to that." I said, "Oh,
2:02:36.080,2:02:40.400
what do you mean?" And he was like, "I don't
think that they've studied it with Descovy."
2:02:40.400,2:02:46.320
And I was like, "Okay, so we're sort of going to
move on from that. Are we? And you're going to
2:02:46.320,2:02:50.880
give me Descovy?" And he's like, "Yes, I'm going
to give you Descovy." So I'm in a sort of grey
2:02:50.880,2:02:55.760
area on that, and anyone listening, don't treat
me as a doctor and my recommendation on Descovy.
2:02:55.760,2:02:58.720
But so you've now moved to Descovy?
2:02:58.720,2:03:08.640
I'm in the process, which is... you know, I'm a
fairly plugged in, good health-seeking-behaviour
2:03:08.640,2:03:14.620
type person in the statistics. And I still haven't
got around to being on the best one. So I dunno,
2:03:16.240,2:03:21.520
if it's not top priority in a given month,
I might not get around to changing to the
2:03:21.520,2:03:26.000
better drug. You know, I was talking to
someone yesterday actually, because I said,
2:03:26.000,2:03:32.960
"I'm about to record this podcast, what are
you on?" And he said, "Oh, I am on the daily
2:03:32.960,2:03:38.640
pills." Most people on the daily pills probably
couldn't even tell you if they're on, they both
2:03:38.640,2:03:43.120
work really well, it doesn't matter that much.
But he said, "Oh, I was thinking of going onto
2:03:43.120,2:03:49.360
the injectable every two months. But then as I
thought about it more, I have to travel for my
2:03:49.360,2:03:55.040
job. So I was worried, well, am I definitely
going to be back in San Francisco at the time
2:03:55.040,2:04:00.640
I need to get the injection? Or is there going to
be a two week delay where I'm somewhere else? And
2:04:00.640,2:04:06.080
then actually, I'm more at risk, and actually I
think it's easier if I just do the daily pills."
2:04:06.080,2:04:13.360
And I think that actually gets to how these
drugs can be. It can be complicated how they
2:04:13.360,2:04:18.800
interact with someone's life. And it's not just
something you can read off a clinical trial, of
2:04:18.800,2:04:25.360
how useful they'll be. You have to think about —
well, how is someone who needs this drug going to
2:04:25.360,2:04:35.920
use it in their real life? And what there might be
counterintuitive kind of pros and cons of having a
2:04:35.920,2:04:42.800
big gap of two months between that sounds great
on paper, but there you go, someone didn't want
2:04:42.800,2:04:47.520
it. They wanted to just do it every day. And I
actually think about this with treatment as well.
2:04:48.960,2:04:55.600
I have a friend who started dating someone
who was HIV-positive. He was HIV-negative,
2:04:55.600,2:05:02.560
he started to date someone HIV-positive.
And now, with the great drugs that we have,
2:05:03.360,2:05:10.080
if you are positive and on treatment, you will
be undetectable, you won't transmit the virus to
2:05:10.080,2:05:18.880
partners, which is incredible. But my friend, he
knew that, sort of rationally, and he was still
2:05:18.880,2:05:25.520
anxious around sex. It was a scary topic, even
if he could sort of rationally tell himself he
2:05:25.520,2:05:30.720
shouldn't be scared, and then that can be a tough
thing for a partner to deal with. And one day,
2:05:30.720,2:05:41.360
his new boyfriend actually took his daily pills
in front of my friend as a way to basically build
2:05:41.360,2:05:47.040
trust, and that was a kind of beautiful thing
to do. I think, if I were in his position,
2:05:47.040,2:05:52.640
I probably would've been offended and annoyed,
and he was so generous. And then sure enough,
2:05:52.640,2:05:58.880
my friend did build trust and fall in love and
have, I think, they had a wonderful sex life.
2:05:58.880,2:06:01.920
But that is the kind of thing you wouldn't
think about when designing a drug. It's like,
2:06:01.920,2:06:08.080
if you are on a treatment drug that was
an injection, that was once every whatever
2:06:08.080,2:06:12.960
period. Well okay, that particular trust-building
exercise would not be available to you. So oh,
2:06:12.960,2:06:22.240
it gets so complicated. And then the people most
affected by HIV and AIDS these days — it affects
2:06:22.240,2:06:29.920
women in Africa more than it affects men now,
especially in Southern Africa. And there the
2:06:29.920,2:06:37.280
complexities are very different and I won't be
able to rightly summarise them. But for example,
2:06:37.280,2:06:43.760
if having to go to a clinic for a procedure or
injection might be different than having to go
2:06:43.760,2:06:48.480
to a pharmacy to pick up pills, which might
be different than having pills on your shelf
2:06:48.480,2:06:53.280
for many weeks, versus having to go more
regularly and all of that matters a lot.
2:06:53.280,2:06:59.360
No, that's super interesting. I think one thing
I was thinking about when you were talking about
2:06:59.360,2:07:09.760
this was, what are the different problems that
people will face apart from- So we have this
2:07:09.760,2:07:13.840
sort of struggle to, I dunno, schedule some of
these appointments, things like that. I think,
2:07:13.840,2:07:19.040
one thing on that front was, with some of
these injectables, I think there's a kind
2:07:19.040,2:07:24.320
of leeway that you have for when you get the
next dose. You don't have to get it exactly,
2:07:25.040,2:07:30.880
let's say, six months or exactly two months after,
but there is a little grace period that you can
2:07:30.880,2:07:36.880
get it in. But that's still, probably sometimes,
quite inconvenient for people if something happens
2:07:36.880,2:07:43.280
if they're in a different country or so.
But there's the issue of, I dunno, taking
2:07:43.280,2:07:50.960
a daily pill every day for many years, that might
be hard for some people in terms of remembering,
2:07:50.960,2:07:56.560
especially if it's a preventive pill. It's not
something that is necessarily super salient to
2:07:56.560,2:08:03.040
them as if it's a condition they already have. But
also, it's this access, like, what if the clinic
2:08:03.040,2:08:09.600
is closed one day? What if something happens?
What if, I don't know, someone takes your pills
2:08:09.600,2:08:16.400
or they drop out of your bag, or something like
that. How are you going to get the next dose?
2:08:16.960,2:08:21.040
You know, I can answer that for me,
and I pick 'em up once every month,
2:08:21.040,2:08:30.880
but I'm just one guy and I think we need
to get a better answer for people who are
2:08:30.880,2:08:35.680
affected in other contexts. So I think
it's time to phone a friend, Saloni.
2:08:35.680,2:08:37.920
We're going to phone a
friend. This is so exciting.
2:08:37.920,2:08:38.800
We're going to phone a friend.
2:08:38.800,2:08:40.160
Who are we phoning?
2:08:40.160,2:08:43.200
We're going to phone my friend Douglas Chukwu,
2:08:43.200,2:08:50.480
who works at Open Philanthropy with me, and
before that was a medical doctor in Nigeria,
2:08:50.480,2:08:58.240
and worked in public health on HIV treatment
and prevention. So should we dial him up?
2:08:58.880,2:09:02.320
Hello Douglas. How are you
doing? Thanks for joining.
2:09:02.320,2:09:04.640
Good, good. Great to be here.
2:09:04.640,2:09:09.280
Well, thanks for taking time out of
your day. So, we worked together,
2:09:09.840,2:09:14.400
but before we worked together at Open
Philanthropy, you were trained as a doctor
2:09:14.400,2:09:20.640
and worked on other things in public health, which
is why we wanted to bring you on today. So yeah,
2:09:20.640,2:09:23.680
what's your background and what were you
working on, before Open Philanthropy?
2:09:23.680,2:09:27.120
I trained as a medical doctor in Nigeria.
So I had a couple of years of clinical
2:09:27.120,2:09:31.120
practice working as a medical officer in a
government establishment and also a private
2:09:31.120,2:09:35.760
establishment. So had that dual experience
and then piloted to work in public health.
2:09:35.760,2:09:39.680
Interestingly, most of my public health
experience was in the field of HIV and AIDS.
2:09:39.680,2:09:46.080
Are people getting a weekly stock of treatment
of PrEP, or will it last them months or
2:09:46.080,2:09:50.800
years? Like how long does- maybe this varies
depending on the type of drug that they're using.
2:09:50.800,2:09:58.800
Yeah, so oral PrEP comes in, the commonest is
the pack of 30 tablets, and oral PrEP is to be
2:09:58.800,2:10:05.040
administered daily. So the common, it varies
from a range of one month to three months;
2:10:05.040,2:10:09.360
three months being the maximum, because for
individuals on PrEP, they need to be tested every
2:10:09.360,2:10:15.280
three months, as per the national guidelines,
so that's the touchpoint with the facility. The
2:10:15.280,2:10:19.760
treatment duration of prescription helps to
make sure that they come for their refills,
2:10:19.760,2:10:25.280
they're assessed for adherence, they're tested for
HIV and they're also monitored for side effects.
2:10:25.280,2:10:31.600
How important is public funding from
donor countries like the US and the UK,
2:10:31.600,2:10:34.320
when it comes to HIV particularly?
2:10:34.320,2:10:37.280
Absolutely important, right? I'll give an example.
There are various access- let's say for example,
2:10:37.280,2:10:41.600
there are a lot of individuals that have accessed
treatment that wouldn't have accessed treatment
2:10:41.600,2:10:46.400
if the HIV programs in countries were
entirely reliant on domestic funding.
2:10:46.400,2:10:51.520
And this varies across African countries, but in
Nigeria, for example, over 80% of the funding for
2:10:51.520,2:10:59.440
HIV programs is via external funding. And then,
there are some countries like South Africa,
2:10:59.440,2:11:04.160
where they've made some progress in terms
of domestic financing for HIV programs,
2:11:04.160,2:11:13.760
I think as high as 70%. But overwhelmingly, in
Africa, there are various country programs that
2:11:13.760,2:11:18.480
are hugely reliant on external funding
for sustaining and delivering for HIV.
2:11:18.480,2:11:25.360
We are recording this at the beginning of
April and I've still found it difficult to
2:11:25.360,2:11:35.680
get good reporting on quite what's happening with
PEPFAR, the US- the main way that the US supports
2:11:35.680,2:11:42.480
HIV programming. And the answer of, what's
happening may change in the coming months. But,
2:11:42.480,2:11:48.720
as you talk to your friends who work in
public health, what are you hearing at
2:11:48.720,2:11:59.840
the moment? What has happened at facilities or on
the ground, in reaction to the PEPFAR uncertainty?
2:12:00.560,2:12:04.880
The effects of this cut across not just the
healthcare workers. But healthcare workers,
2:12:04.880,2:12:09.840
patient communities; there's a lot of uncertainty.
There's a lot of unease and a lot of worry
2:12:09.840,2:12:16.720
about what the future holds. And a lot of these
suspensions were abrupt. So people got stop work
2:12:16.720,2:12:20.880
orders. As I mentioned, there is a community
component of healthcare service delivery.
2:12:20.880,2:12:25.040
There are community healthcare workers
that are supported by the PEPFAR funding,
2:12:25.040,2:12:30.960
and having the stop-work orders meant people
stopped getting tested in communities,
2:12:30.960,2:12:36.080
access to some medications were threatened, even
though perhaps there were some stock to sustain
2:12:36.080,2:12:41.200
initial dispensing of ARVs (antiretrovirals). But
clients were being told that if this continues,
2:12:41.200,2:12:45.840
you'd have to pay out of pocket for
your medications and that's actually
2:12:46.560,2:12:51.760
troubling for the patient community. Additionally,
I think about the broader implication of this,
2:12:51.760,2:12:58.880
which is knowing that the funding for HIV
programs is actually threatened, that also
2:12:58.880,2:13:06.160
affects manufacturers thinking about maybe wanting
to exit some markets. That kind of damages a lot
2:13:06.160,2:13:10.960
of the progress that has been made over the past
couple of years in the field of HIV and AIDS.
2:13:10.960,2:13:17.600
There are country governments rallying up to
cover some of those gaps. But those resources
2:13:17.600,2:13:25.360
pale in comparison to the amount of resources
that the US government devotes to supporting this.
2:13:25.360,2:13:34.160
As a- if someone needed treatments, I guess
in the last three months, or even now,
2:13:35.040,2:13:43.360
how would the cuts and the stop works order
affect them? What would they be experiencing?
2:13:43.360,2:13:51.200
I would say to paint the picture, imagine a status
quo where every day, community health care workers
2:13:51.200,2:13:54.720
report to the facility, gear up with their mobile
testing kits, with their ARVs [antiretrovirals],
2:13:54.720,2:14:00.000
and they go out into hard to reach areas. They
identify people who are positive for HIV, place
2:14:00.000,2:14:05.280
them on treatment. Some of these are pregnant
mother who don't have the resources to come to the
2:14:05.280,2:14:11.840
facility. So that abrupt suspension means those
individuals will not benefit from those services.
2:14:11.840,2:14:16.960
Now, beyond those who are yet to be identified,
because that's the category I just talked about,
2:14:16.960,2:14:21.840
there are people who rely on these healthcare
workers to reach them to receive their refills
2:14:21.840,2:14:27.360
for ARVs, right? So the suspension was abrupt, as
you know. So people were just told to stop work,
2:14:27.360,2:14:32.720
and their clients who likely would be expecting
their healthcare workers to deliver ARVs to them
2:14:32.720,2:14:41.840
and would have been affected by such stop work
orders, so that's pretty much it. Because there
2:14:41.840,2:14:48.000
are those who still have drugs, but there are
those who are actually suffering from these cuts.
2:14:48.000,2:14:52.880
My sort of understanding, I was
reading a few articles about this
2:14:52.880,2:14:57.280
and the impression that I had was, the
clinics might have some of the treatment,
2:14:57.280,2:15:05.120
but they're just shut and there's no one; the
staff who are paid or supported by the US are
2:15:05.120,2:15:10.560
not allowed to go in, and people can't get
treatment even if it's in the clinics there.
2:15:10.560,2:15:16.400
Absolutely, yes. And the staffing, as I
mentioned, the staffing support, it's not limited
2:15:17.760,2:15:22.480
to the community setting. Even in healthcare
facilities, there are one-stop shops that are
2:15:22.480,2:15:28.320
staffed by individuals that are supported by
the performing, as you rightly pointed out,
2:15:28.320,2:15:31.840
that stop work affected those
individuals and perhaps clients
2:15:31.840,2:15:38.640
would've presented to facilities and wouldn't
have had, maybe, individuals to attend to them.
2:15:38.640,2:15:44.960
And I think we were talking about refills and how
often people get refills, and if that's every 30
2:15:44.960,2:15:50.320
days or every three months or so, that probably
adds up to quite a lot of people who have been
2:15:50.320,2:15:56.400
directly affected by these cuts over the last,
almost, I guess, two and a half months, maybe.
2:15:56.400,2:16:00.000
Absolutely. Because people, I mean it's a
three month cycle. It can be a six month
2:16:00.000,2:16:06.800
cycle for people who are stable, but every day
marks someone's clinic appointment, right, so.
2:16:06.800,2:16:10.560
It's a scary time for a lot of people with HIV.
2:16:10.560,2:16:18.400
How excited are you for lenacapavir in the field?
I think one reason, I think, it's going to be
2:16:18.400,2:16:23.840
quite important is because of this adherence
issue that you mentioned, but also meaning
2:16:23.840,2:16:30.400
that people don't need to get refills as often,
so there's a bit more stability for someone who
2:16:30.400,2:16:38.640
has had an injectable. Is that also your view? Are
there other things that you see as part of this?
2:16:38.640,2:16:44.000
One of the challenges with oral PrEP is having to
take it every day. And with suboptimal adherence,
2:16:44.000,2:16:50.160
there's the risk of resistance developing. So
having a drug that's administered twice a year,
2:16:50.160,2:16:54.559
I mean, I won't say it's as good as a vaccine,
but there are challenges with developing the
2:16:54.560,2:17:01.360
HIV vaccine. So this is as good as we are
currently towards making sure that people
2:17:02.479,2:17:09.839
keep from getting infected with HIV. It's very
exciting in the HIV prevention landscape, having
2:17:09.840,2:17:16.000
an injectable once a year, fingers crossed, but
that would be amazing. That would be phenomenal.
2:17:16.000,2:17:18.160
We're almost there. We're almost there.
2:17:18.160,2:17:21.120
That was really helpful. Thank you so much
2:17:21.120,2:17:23.200
Thank you so much Douglas.
2:17:23.200,2:17:27.040
Thanks so much. Thanks so much. Happy to
talk about this and very excited about
2:17:27.040,2:17:31.280
the development in the HIV prevention
space. Hopefully these developments
2:17:31.280,2:17:37.104
continue and move the needle in terms of
achieving epidemic control of HIV and AIDS.
2:17:37.104,2:17:41.359
That was great. This was so cool, to phone
a friend and learn about what things are
2:17:41.359,2:17:47.040
like in treatment in Nigeria, the
future of lenacapavir. But also,
2:17:47.040,2:17:55.439
all of the funding cuts and the disruption that's
going on there right now. I think it really made
2:17:55.439,2:18:04.399
me think of how important some of these new drugs
could be in terms of changing around the epidemic
2:18:05.120,2:18:14.000
in HIV, the possibility of using long-acting
drugs, and by that we mean drugs that have an
2:18:14.000,2:18:20.720
effect for a really long period. Currently we
have cabotegravir, which is a two monthly drug.
2:18:20.720,2:18:25.920
There's also lenacapavir, which is
a six monthly drug. And potentially,
2:18:26.640,2:18:32.240
Gilead is also working on a once-yearly
drug. And if that pans out, again,
2:18:32.240,2:18:38.479
I think it would completely change our ability
to respond. Whether that is actually scaled up
2:18:38.479,2:18:46.639
is another question, and that's something
we'll talk about later on. But it's really,
2:18:46.640,2:18:52.880
I think it's a change in what's
possible in treating and preventing HIV.
2:18:52.880,2:18:59.439
Yes. And I feel like I have a lot to
digest and we have a lot still to discuss.
2:18:59.439,2:19:10.639
So lemme go away for a second and think.
Okay, Saloni, we're back. How you doing?
2:19:10.640,2:19:16.560
I'm doing great. It's been five days.
I've had a lot to think about. You look
2:19:16.560,2:19:19.600
like you're in a completely
different place from before.
2:19:19.600,2:19:27.520
That's right. New shirt, new background.
I am in New York City. I'm in the village,
2:19:27.520,2:19:34.720
the East Village — or at least I thought I was.
I arrived and was informed by someone who lives
2:19:34.720,2:19:40.640
here that I'm actually in Stuy Town, which
is not the same thing as the East Village,
2:19:40.640,2:19:47.359
but I've decided to kind of squint and it feels
about the same and I'm having a good time. It
2:19:47.359,2:19:57.839
feels, I wish I could say I was here funded by our
podcast to do some historical analysis of the AIDS
2:19:57.840,2:20:02.720
epidemic because I was in Castro before and now
I'm in the Village. And those are two important
2:20:02.720,2:20:07.439
parts to the story. However, I am actually just
here visiting a friend. Totally unrelatedly.
2:20:07.439,2:20:13.040
I really enjoyed thinking about
what Douglas told us about how
2:20:13.040,2:20:19.280
treatment works in the field in a clinic
in Nigeria. But also just thinking about
2:20:19.280,2:20:25.439
the different approaches that people
have to prevention, whether that's
2:20:25.439,2:20:34.160
with condoms or behavioural changes or
PrEP, this amazing breakthrough in 2012,
2:20:34.160,2:20:42.240
of multiple drugs in a combination that
can reduce the chances of infection. And
2:20:42.240,2:20:48.719
it's really interesting first to think about the
behavioural aspects that lead to, basically, how
2:20:48.720,2:20:54.960
do people actually take these drugs in practice
and how does that inform drug development? How
2:20:54.960,2:21:02.399
does that inform the kinds of new treatments
that we need and whether they're effective.
2:21:02.399,2:21:10.000
I think that's ultimately the key breakthrough
of this new drug that we're going to talk about,
2:21:10.000,2:21:17.600
lenacapavir, that instead of being a daily pill
that people would take as they do with PrEP,
2:21:17.600,2:21:24.479
it's this long-acting injectable. So it's an
injection that you would take. So there's,
2:21:24.479,2:21:30.559
I guess, two injections every six
months, and this massively reduces
2:21:30.560,2:21:38.640
the chances of infection. It's also been used as
a treatment for people with drug-resistant HIV,
2:21:38.640,2:21:43.120
and there could be other purposes for it as well.
So I think that's really the key breakthrough and
2:21:43.120,2:21:51.439
I think I really started to understand exactly
how that would matter for someone who has HIV,
2:21:51.439,2:21:58.559
thinking about how do they get their next supply
of the drug; how this makes a difference to them.
2:21:58.560,2:22:06.640
Yeah. It also got me thinking about the costs;
how can we get the costs low for new drugs so
2:22:06.640,2:22:13.280
that they can get used more. And that's something
that I'm interested to talk about with lenacapavir
2:22:13.280,2:22:19.359
too. But what is lenacapavir, Saloni? It's
time for you to teach me something new.
2:22:20.399,2:22:27.120
I think to teach you about what lenacapavir is,
we have to go back a little bit and talk about
2:22:27.120,2:22:35.840
the capsid. So if you remember from before, the
capsid is this thimble-like structure within the
2:22:35.840,2:22:44.399
HIV virus that contains the RNA molecule, and it
contains a bunch of other enzymes. It's the core
2:22:44.399,2:22:53.519
that stays intact when HIV enters cell, and this
capsid takes that information, and those enzymes,
2:22:53.520,2:23:03.120
into the cell's nucleus. They then allow the
RNA molecule — the genetic code of HIV — to
2:23:03.120,2:23:12.479
turn into DNA to integrate into our own cellular
DNA, and then to proliferate into many more HIV
2:23:12.479,2:23:21.040
particles. So it's this key structure that's kept
intact throughout this process. Once it gets to
2:23:21.040,2:23:29.840
the nucleus, it then starts to dissolve, letting
the RNA molecule out, letting the enzymes out to
2:23:29.840,2:23:38.399
do their jobs. And then, later on, when the new
HIV particles start to be formed, it then starts
2:23:38.399,2:23:44.639
to form; the capsid starts to form again.
This process is actually really interesting;
2:23:45.760,2:23:51.439
and quite interesting, both as a process
but also in terms of what it looks like.
2:23:51.439,2:23:51.600
Yes!
2:23:51.600,2:24:03.439
This HIV capsid is made up of, I think, more
than 1,500 or so proteins. But each of these
2:24:03.439,2:24:09.679
proteins comes in groups. So some of the
groups of this protein are in groups of six,
2:24:09.680,2:24:15.439
which are called hexamers. So hex- is
six, and some of them are in pentamers;
2:24:15.439,2:24:26.160
penta- means five, but there are 250 hexamers or
so, it kind of varies. And exactly 12 pentamers.
2:24:26.160,2:24:30.160
I'm looking at it now, and it looks
like flower petals that are falling
2:24:30.160,2:24:35.760
into place. How on earth is it so exact?
Why are there 12? Why are there 12? And
2:24:35.760,2:24:43.760
the 12 are not exactly... they're sort
of dotted around in a pretty pattern,
2:24:43.760,2:24:49.359
but not necessarily how I would've
designed it, if I were thermodynamic.
2:24:49.359,2:24:55.120
Yeah, I mean if you're listening, it's
this thimble-shaped structure. Most of
2:24:55.120,2:25:02.399
that is made of hexamers of this protein. So,
imagine some six-shaped thing, maybe like a
2:25:02.399,2:25:11.345
star-shaped cereal that I used to have called
Honey Stars. Oh yeah. And they were very tasty.
2:25:11.345,2:25:13.040
Or Shreddies, which I'll
never say a bad word against.
2:25:14.560,2:25:21.360
And then, in a few places in this capsid,
there are other structures that are only five
2:25:22.080,2:25:28.800
that only have five proteins. So they're
like five-star shapes. And these look,
2:25:28.800,2:25:37.359
I mean, where these are organised in the whole
capsid doesn't look very symmetrical to me.
2:25:37.359,2:25:37.920
No.
2:25:38.880,2:25:46.240
And it's quite strange, but what I was reading
was that: the placement or the number of these
2:25:46.240,2:25:52.960
pentamers within the whole structure changes
the whole shape of it. It's sort of like,
2:25:52.960,2:25:58.080
this structure, that's where the hexamer
are tesselating. So they're all fitting
2:25:58.080,2:26:04.000
together in this very symmetrical way
between them, but then these five-shaped
2:26:04.000,2:26:11.040
pentamers determine the curve, I think,
of the capsid. That's very interesting.
2:26:11.040,2:26:15.920
Yeah. I feel like I want... if I redo
the tiles in my bathroom or something,
2:26:15.920,2:26:21.600
I want to do this. But now that you've
told me the shape, the 3D structure,
2:26:21.600,2:26:27.359
is an important property, that wouldn't be so
good on tiles. So I'm going to have to rethink.
2:26:27.359,2:26:30.559
You would have... Maybe it would
be more like a flower vase?
2:26:30.560,2:26:34.880
Yeah. Oh, great idea actually. Yeah,
it's very floral, it's just so,
2:26:34.880,2:26:41.920
it is very beautiful. I recommend people
listening Google it. And I think recently,
2:26:41.920,2:26:45.040
it's only the last 10 years or something
where we've really known what these
2:26:45.040,2:26:48.960
different polymers look like and how they
assemble and all that. Is that right?
2:26:48.960,2:26:58.880
I think that's right. Only since the 2010s have
we had advances in microscopy that allow us to see
2:26:58.880,2:27:03.040
some of these particles, with enough
resolution to see what they actually
2:27:03.040,2:27:09.760
would look like in this coherent
structure. That is super interesting.
2:27:09.760,2:27:15.359
As I think about the drugs you've described
previously, what is interesting about this one:
2:27:15.359,2:27:19.920
if we're talking about the capsid and we're
going to try and go after the capsid with a drug,
2:27:22.000,2:27:29.040
this is a structural part of the
virus, but it's not as functional
2:27:29.040,2:27:33.680
in the direct sense. I'm not imagining
something getting integrated into my DNA,
2:27:33.680,2:27:40.880
so I'm going after the integrase; and I'm not
imagining I'm chopping up the large string of
2:27:40.880,2:27:46.640
proteins into smaller proteins, and going after
the protease. This is more like just a package,
2:27:46.640,2:27:51.680
a thimble, a bullet; that it must be
required, because why would it still
2:27:51.680,2:27:58.560
be there? But the function is not as direct.
I don't know. Does that ring through to you?
2:27:58.560,2:28:04.160
I think you're kind of right, but I think
it is important. Because to make sure all
2:28:04.160,2:28:09.040
of this stuff doesn't fall out, I guess,
in some other part of the cell. Like,
2:28:09.040,2:28:17.120
we need to carry or transport the RNA molecule
and the other enzymes to the nucleus. But it
2:28:17.120,2:28:24.960
also has these functions where, based on
the structure, based on the shape of this
2:28:24.960,2:28:32.319
capsid — that allows it to enter the nuclear
pores and the nucleus, the little holes and
2:28:32.319,2:28:39.759
this shape allows it to wiggle through. And I
think it might also be involved in stimulating
2:28:39.760,2:28:47.680
the reverse transcriptase step. So the capsid
is somehow involved in making that start,
2:28:47.680,2:28:54.080
and I think that is also quite a new discovery
that people have had within the last five years.
2:28:54.080,2:28:58.800
Got it. Anyway, keep going.
Thanks for pausing for me.
2:28:58.800,2:29:04.880
Not at all. Okay. So we've talked about what the
capsid looked like. What does lenacapavir have
2:29:04.880,2:29:13.920
to do with this? This also, it really helps to
have a visual, but I'm going to try to explain it
2:29:14.640,2:29:20.560
in words as well. So we have this structure
where, the capsid is made out of these proteins.
2:29:20.560,2:29:26.080
The proteins are sometimes in hexamers,
sometimes in pentamers; I guess if you
2:29:26.080,2:29:31.359
imagine that these hexamers or pentamers
are fitting together, they're a bit like,
2:29:31.359,2:29:39.280
putting your hands together with your knuckles.
They're kind of fitting together between your
2:29:39.280,2:29:47.359
fingers. And imagine doing that lightly;
you're not fitting them too strongly. So
2:29:47.359,2:29:53.200
there's a little bit of space and flexibility
between your two hands. But then, lenacapavir,
2:29:54.479,2:30:02.879
it wedges itself into those gaps between
both of your hands' knuckles. And that
2:30:02.880,2:30:10.080
means that it now becomes very stiff. Now
you don't have this much ability to move,
2:30:10.080,2:30:18.640
to move the structure around. This stiffness
becomes a problem in several ways during the
2:30:18.640,2:30:27.920
HIV's life cycle. I think that's quite cool just
to think about how the overall shape of this
2:30:27.920,2:30:35.520
capsid changes, based on lenacapavir fitting
into these little gaps between the proteins.
2:30:35.520,2:30:38.560
That is good. It's quite subtle as
well. 'Cause it's not, I think of a
2:30:38.560,2:30:42.319
drug coming in and trying to nuke some
structure, you know, blow it up. But
2:30:42.319,2:30:49.439
actually you're saying no, we're just going
to change properties of how squidgy it is.
2:30:49.439,2:30:55.839
No, exactly. And yeah, I mean, I think it's
fascinating. So we have all of these little
2:30:55.840,2:31:02.000
lenacapavir molecules. Lenacapavir itself
is quite a small molecule, so it fits into
2:31:02.000,2:31:08.479
these little gaps. And if we go back to this
lifecycle of where the capsid is imported,
2:31:08.479,2:31:16.080
so we have: the HIV virus has entered the cell,
has released some of its contents, which includes
2:31:16.080,2:31:23.040
the capsid. The capsid is then trying to enter the
nucleus. In order to get into the nucleus, it has
2:31:23.040,2:31:30.880
to fit through these holes, the nuclear pores.
And to do that, it binds to certain proteins on
2:31:30.880,2:31:39.200
the nuclear pore. And it turns out that those
binding spots are blocked by lenacapavir.
2:31:39.200,2:31:39.600
Okay.
2:31:39.600,2:31:46.160
So it binds in exactly the same spots where those
proteins would attach and let it squeeze through
2:31:46.160,2:31:54.479
those gaps. And the second thing is, the capsid
is now too stiff, because of lenacapavir blocking,
2:31:54.479,2:31:57.599
so it's less flexible.
Knuckles are engaged.
2:31:57.600,2:32:05.760
Exactly. Your knuckles are engaged. You can't
squeeze through the little holes of the nucleus.
2:32:05.760,2:32:11.840
So that's another important thing.
Then, the next step, and this is super
2:32:11.840,2:32:17.280
interesting, so it's not just that one step that
lenacapavir disrupts, but it's actually multiple
2:32:17.280,2:32:25.519
steps during this life cycle. Imagine that some of
the capsids have still somehow made it through to
2:32:25.520,2:32:37.520
the nucleus. Now the capsid needs to dissolve and
allow the RNA molecule out, and allow the reverse
2:32:37.520,2:32:45.439
transcriptase to turn the RNA into DNA. It needs
integrase to turn that DNA into a part of our
2:32:45.439,2:32:54.479
own cell's DNA. But now it can't break; it can't
dissolve. It can't uncoat anymore, because of this
2:32:54.479,2:33:06.639
rigidness. It's just too rigid. But also sometimes
it's so rigid that it cracks too early, and that
2:33:06.640,2:33:15.280
early cracking makes it hard for the capsid
stimulating the reverse transcriptase, to start
2:33:15.280,2:33:26.880
doing that process. So that is super interesting.
We've now blocked it from entering the nucleus. If
2:33:26.880,2:33:33.120
some gets through, it's now not able to release
its contents, or it breaks too early. And then,
2:33:33.120,2:33:41.040
there's a third part that lenacapavir disrupts
as well. So imagine that you've now, somehow,
2:33:41.920,2:33:46.800
some of the virus particles or some of the capsids
have still made it through, or maybe you're in a
2:33:46.800,2:33:54.800
different part of the HIV virus lifecycle. You're
now trying to create these new virus particles,
2:33:54.800,2:34:04.399
the descendants of the initial one. In order to
do that, we have this, the immature HIV virus, and
2:34:04.399,2:34:05.359
I remember, yeah,
2:34:05.359,2:34:11.439
This now has protease involved, right? So
we have protease cutting up these giant
2:34:11.439,2:34:19.839
polyproteins into their proper form, and
we have this new capsid trying to form,
2:34:19.840,2:34:27.920
to surround all of the RNA and the other enzymes.
But what happens with lenacapavir is that, because
2:34:27.920,2:34:41.200
it's in this too stiff kind of formation, it's
unable to form in the correct shape and it just
2:34:41.200,2:34:50.399
doesn't fully form. So there's this image here,
where you can see that the normal way that all
2:34:50.399,2:34:58.719
of these proteins in the capsid form is that- We,
okay, so we have all these hexamers and pentamers;
2:34:58.720,2:35:04.479
they create these little clusters, they
somehow self-assemble. Maybe this is just
2:35:04.479,2:35:09.520
something that we don't understand yet, but
somehow they self-assemble into a bigger.
2:35:09.520,2:35:14.160
Which blows my mind just from, if I'm
visualising the cytoplasm of a cell, I'm like,
2:35:14.160,2:35:20.240
there's so much going on there. How do these all
stay together and not get distracted? But anyway.
2:35:20.240,2:35:28.719
Exactly. So we're getting these clusters of
multiple hexamers and pentamers. That happens,
2:35:28.720,2:35:33.840
but now because of the stiffness,
the shape isn't forming correctly,
2:35:33.840,2:35:41.600
and the full shape just doesn't work anymore.
So I mean I think this whole process to me was
2:35:41.600,2:35:48.960
really interesting to learn about. I knew that
lenacapavir somehow had this amazing effect,
2:35:48.960,2:35:54.479
at very low concentrations. It somehow has
a really long effect lasting for at least
2:35:54.479,2:36:01.280
six months. But I didn't really know about the
mechanics of that works. And the other thing I
2:36:01.280,2:36:08.160
didn't realize, until reading for this episode,
was multiple steps are inhibited. So it disrupts
2:36:08.160,2:36:14.479
this process at multiple steps. I think that...
Now, I would say this doesn't mean that it's
2:36:14.479,2:36:21.679
impossible to develop resistance against it, but
it does probably explain why it's so effective,
2:36:21.680,2:36:25.200
that it's targeting these multiple
steps. It's reducing the probability
2:36:25.200,2:36:31.599
that an infection can and multiply, and
so I think that was very interesting.
2:36:31.600,2:36:34.960
Yeah, I was going to say, it sounds almost
like a combination drug itself. If you've
2:36:34.960,2:36:41.600
got three different stages it's acting at. But I
don't know if the mutations that would generate
2:36:41.600,2:36:46.479
resistance to are correlated there or not.
It makes sense to me they'd have a fail safe,
2:36:46.479,2:36:51.040
for mopping up the capsids that
try and form out the other end.
2:36:51.040,2:36:56.560
I think what I've learned is that there
is still... drug resistance can form,
2:36:56.560,2:37:03.439
but it's something that forms if someone is
on long-term treatments with lenacapavir;
2:37:03.439,2:37:07.599
it's not something that they would
have before the infection. And so,
2:37:07.600,2:37:16.080
it is still useful as a preventive, sort
of, anti-infection tool. But as a treatment,
2:37:16.080,2:37:21.200
there have been cases of people developing
resistance and that would be through exactly
2:37:21.200,2:37:25.276
how lenacapavir fits into the little
gaps between the capsid proteins.
2:37:25.276,2:37:26.000
The gaps.
2:37:27.600,2:37:29.840
If you change the shape of that, yeah.
2:37:29.840,2:37:36.000
It makes just from a selection pressure point of
view. If you've got many more viral particles,
2:37:36.000,2:37:39.359
you're infected already, then
you've got higher probability,
2:37:39.359,2:37:47.280
probably, of a mutation that's good
for HIV. Neat. I like it. How did
2:37:47.280,2:37:52.719
it come about from a- was this the
first capsid inhibitor? Lenacapavir?
2:37:52.720,2:37:57.200
This wasn't the first capsid inhibitor,
I think people had been trying to target
2:37:57.200,2:38:08.160
it for a while. And in 2010, Pfizer had
developed another molecule called PF-74,
2:38:08.160,2:38:17.519
and that seemed to bind to this little gap,
this pocket as well, and it could block and
2:38:17.520,2:38:27.280
hyper stabilize the whole capsid shape. But
it didn't work so much in the human body;
2:38:27.280,2:38:32.639
this drug, it was taken orally, and it
just didn't stick around in your body.
2:38:32.640,2:38:41.120
And so they gave up on the drug and they
started working on other drugs instead. Instead,
2:38:41.120,2:38:50.240
what happened was Gilead tried to build
on this PF-74. It seemed quite promising,
2:38:50.240,2:38:58.399
because you do have this, you have a potential
way of targeting the capsid protein. But we're
2:38:58.399,2:39:06.719
just missing out on making it more available
in the body and long lasting. And so they did
2:39:06.720,2:39:12.399
something called "parallel synthesis". They just
tried creating lots of very similar compounds
2:39:12.399,2:39:18.160
to that — using the same molecule, but then
adjusting it in lots of different ways. And
2:39:18.160,2:39:24.319
the way that happens in the lab is, you have lots
of test tubes or plate wells, where you have the
2:39:24.319,2:39:33.359
initial molecule PF-74, and then you run lots of
different reactions in those different test tubes,
2:39:33.359,2:39:39.200
under the same conditions — so you have maybe
three or four, with some reaction going on and
2:39:39.200,2:39:50.479
so on. And they did a lot of iteration based
on that and eventually resulted in lenacapavir.
2:39:50.479,2:39:56.799
Got it. Well, thank you PF-74 for trying
first. It's interesting. It sounds like
2:39:56.800,2:40:03.840
we had the idea and there was some binding
going on and it was working okay. But then,
2:40:03.840,2:40:09.120
the practicality of the human body — you've got
a lot more steps. You don't just have to bind
2:40:09.120,2:40:16.080
the part of the HIV virus, you also have to
survive the machinations of the human organs.
2:40:16.080,2:40:22.319
And this is the really interesting thing
that we'll talk about later. In terms of,
2:40:22.319,2:40:28.479
how does this actually stick around for so long
in the body? How does this have an effect for over
2:40:28.479,2:40:35.359
six months? That itself is really impressive to
me. I thought they could maybe just briefly talk
2:40:35.359,2:40:40.960
about some of the different kind of iterations
that people do and how important they are
2:40:40.960,2:40:43.120
To lenacapavir, or?
2:40:43.120,2:40:52.240
Yeah, exactly. So we have PF-74. Actually
don't you know someone who worked on this?
2:40:52.240,2:40:59.040
I do, I do. I was wondering whether to say,
but I think I may have mentioned her earlier
2:40:59.040,2:41:07.600
and she in her PhD worked on PF-74, so in an
academic setting, not at one of the companies,
2:41:07.600,2:41:11.600
but I think she knows a bunch of the
iterations that you're about to tell me,
2:41:11.600,2:41:16.319
but I don't know; I should have
asked her more questions first.
2:41:16.319,2:41:23.120
Yeah, I mean it's so fascinating to
know that there are people surrounding
2:41:23.120,2:41:28.720
us that have been responsible for these huge
breakthroughs, and they're just normal people-
2:41:28.720,2:41:29.220
I know.
2:41:30.240,2:41:31.679
Sometimes friends.
2:41:31.680,2:41:36.640
I had to tell her I was about to talk
about lenacapavir, before I realised
2:41:36.640,2:41:43.680
that she had done all the- well, so much of
the work, that led up to it. It's wild. Yeah.
2:41:43.680,2:41:50.319
I think, yeah, it's incredible. Okay, so
we have PF-74, what happens now? So we
2:41:50.319,2:41:54.880
have all of these little reaction
test tubes going on. One of them,
2:41:54.880,2:42:00.960
they introduced a hydroxyl group — that's
basically an oxygen and a hydrogen,
2:42:00.960,2:42:07.600
and then they added an indole ring — that's
a fused ring structure. So there's multiple
2:42:07.600,2:42:16.000
atoms in a ring with a nitrogen group. This
massively increased the effect of the drug,
2:42:16.000,2:42:20.960
but it didn't work in the body, because it
was broken down by enzymes in the liver.
2:42:20.960,2:42:21.460
Okay.
2:42:21.840,2:42:29.040
Okay, we've got, this one, it didn't really work
out. Then they tried another type of ring. This
2:42:29.040,2:42:37.120
is a six structured ring with one nitrogen atom
instead. This then improved how stable it was
2:42:37.120,2:42:43.840
in the body. It was not broken down very quickly
anymore, but now, the effectiveness was reduced.
2:42:44.640,2:42:49.120
I love how we're making atomic
level differences here. Anyway,
2:42:49.120,2:42:51.840
keep going. Okay, so we tried that one. No luck.
2:42:51.840,2:42:59.680
They did a bunch of other changes. There
were some seven or eight compounds they made,
2:42:59.680,2:43:05.520
before getting to this breakthrough. This actually
comes from this really interesting book that I was
2:43:05.520,2:43:14.160
reading called Drug Development Stories, and
these researchers just put together how all of
2:43:14.160,2:43:20.240
these different types of breakthrough drugs in the
last few years were developed. And so this last-
2:43:20.240,2:43:24.960
I have few books like that that I'm trying
to, I can't remember if I own that one,
2:43:24.960,2:43:28.399
but they're fun to flick through some.
I'm going to have to check my bookshelf
2:43:28.399,2:43:33.759
when I get back to San Francisco. If
not, it's going on the order list.
2:43:33.760,2:43:40.160
It's often hard to find the exact stories
about- behind how these drugs are developed,
2:43:40.160,2:43:45.439
and I assume part of that is because it might be
some kind of trade secret or something like that.
2:43:46.319,2:43:51.599
But when I do come across someone writing a
retrospective or, you know, someone giving
2:43:51.600,2:43:56.880
me the details, it's just a completely
different picture. It really helps you
2:43:56.880,2:44:02.720
understand exactly what they struggled with, how
they were thinking about the process, and so on.
2:44:02.720,2:44:04.800
So if you're listening and you're working on
2:44:04.800,2:44:09.520
drug development in some form and you're
wondering, oh, if I write up my process,
2:44:09.520,2:44:15.600
is anyone even going to read it? We're gonna
to read it. Write it up! Saloni needs it!
2:44:15.600,2:44:22.319
I need it. I love it. Okay, so now
we have this breakthrough compound,
2:44:22.319,2:44:28.080
I think, which might've been the ninth
one that they made as an adjustment.
2:44:28.080,2:44:34.720
They now replaced the amide group with an
amino indisole group. And that is a ring
2:44:35.600,2:44:44.240
with two nitrogen atoms. This improved both the
potency, how well it fit, and also reduced the
2:44:44.240,2:44:51.679
level of breakdown in the body. This felt
like, okay, we're making something that
2:44:52.640,2:44:57.359
effectively tracks both of these key things
that are important in drug development.
2:44:57.359,2:44:58.319
Got it.
2:44:58.319,2:45:04.880
Then it was just slight adjustments, slight
tweakings from there. They added another
2:45:05.600,2:45:10.479
amino group, they changed the placement of
the amino group. They introduced a sulfone
2:45:10.479,2:45:17.040
group — that's a sulphur with two oxygens,
and that was what resulted in this very
2:45:17.040,2:45:23.799
highly potent molecule that was very stable
in the body, and that became lenacapavir.
2:45:23.799,2:45:29.920
Wow! We made it. Highly potent,
highly stable. And it's funny,
2:45:29.920,2:45:35.439
I think when you say, "The body's not breaking
it down well", to me it sounds like, "Oh God,
2:45:35.439,2:45:40.160
the body's not breaking it down well?" And
in fact, we've been seeking a molecule the
2:45:40.160,2:45:45.920
body doesn't break down well, because it can
last for longer and protect you for longer.
2:45:47.120,2:45:52.800
It's different purposes, right? If you're trying
to reduce maybe the side effects of some drug,
2:45:52.800,2:45:59.760
you want it to get broken down very quickly,
just have its action; disappear. But if you're
2:45:59.760,2:46:04.640
trying to develop some drug that has a
very long lasting effect, then you want
2:46:04.640,2:46:13.600
it to stick around for a long time. So, I mean,
finding something that is both very safe, very
2:46:14.240,2:46:24.080
highly effective — potent — and also very stable
in the body that makes a great long lasting drug.
2:46:24.080,2:46:27.920
That's the trio. And we got there.
2:46:27.920,2:46:34.240
The other interesting thing I learned about
lenacapavir, and I think you might maybe come
2:46:34.240,2:46:40.719
to this later on, but it's the drug with the
most fluorine atoms in it that's approved by the
2:46:40.720,2:46:49.680
FDA in the US. So fluorines are often used to
increase the stability, I think, in the body,
2:46:49.680,2:46:57.920
and lenacapavir has 10 of these atoms in the
whole molecule. Usually, that has led to drugs
2:46:57.920,2:47:04.319
that are unsafe in some way, but in this case
it has a very high safety profile as well.
2:47:04.960,2:47:11.279
I remember seeing that, and I'm not enough of
a chemist to tell you why there aren't more,
2:47:12.880,2:47:14.640
but I do like the idea that there's fluorine
2:47:14.640,2:47:20.080
in the aqueous solution. There's
fluorine in the water, you know.
2:47:20.080,2:47:25.279
What did we- we talked to your
friend, Sanela, is that right?
2:47:25.279,2:47:25.920
Yeah.
2:47:27.040,2:47:34.319
Was there stuff that you learned from her on
lenacapavir and capsid inhibitors as well,
2:47:34.319,2:47:36.719
beyond what we've talked about?
2:47:36.720,2:47:44.000
The thing that she emphasized to me was really in
line with what you just said, about how iterative
2:47:44.000,2:47:56.240
the process was. That starting with PF-74, as a
great binder, there was a lot of tries for just...
2:47:56.240,2:48:01.359
getting the other properties that could make this
into a useful drug. So I think the thing she was
2:48:01.359,2:48:09.120
really struck by was the "PK", as drug developers
say, looking really good for lenacapavir.
2:48:09.120,2:48:10.479
What's the PK?
2:48:10.479,2:48:19.040
The pharmacokinetics, I want to say, and there's
again: this will betray that I'm not a medicinal
2:48:19.040,2:48:25.760
chemist. But pharmacokinetics and pharmacodynamics
are the two things that you'll hear people talk
2:48:25.760,2:48:32.319
about all the time, about how the body processes
drugs. But I mean also, she was really emphasising
2:48:32.319,2:48:37.920
that previous molecules' stability was an
issue. And then seeing lenacapavir being so
2:48:37.920,2:48:44.560
stable and so low toxicity. You know, you have
such a small amount and it can stick around for
2:48:44.560,2:48:52.640
six months; and it's getting to the 20th or 15th
iteration of the initial principle. Then getting
2:48:52.640,2:48:59.439
those great properties, it was wonderful
for her to see as someone in the field. And
2:48:59.439,2:49:06.000
as someone outside of the field, I didn't realise.
I'd heard of lenacapavir as this miracle drug,
2:49:06.000,2:49:11.279
and I didn't realise, of course, what came
before. There's a lot of steps to get there.
2:49:11.279,2:49:16.719
It's not that you suddenly come out swinging
and suddenly discover the exact perfect thing.
2:49:18.160,2:49:23.680
Right. I mean, the thing that I remember,
I did my undergraduate degree in biomedical
2:49:23.680,2:49:30.640
science like 10 years ago, I think? And I
remember a little bit about pharmacology
2:49:30.640,2:49:39.360
on PK as, it's more, you're measuring
both how fast is the drug broken down,
2:49:40.240,2:49:47.679
how much of the drug is broken down, how quickly,
but also how available is it? How much does it
2:49:47.680,2:49:54.800
actually get to the organs that you need it to
get to? Is it able to have its effect there?
2:49:54.800,2:50:01.600
And I think with lenacapavir, it seems to be very
effective even at small doses. So if you imagine
2:50:01.600,2:50:07.920
that over time, so you have this injection
first, of lenacapavir, and then, over time,
2:50:07.920,2:50:15.359
there's this decaying exponential curve. So it
just quickly starts to break down, and then that
2:50:15.359,2:50:25.279
break down process slows down. But even at the
very low levels, it's still very effective, and
2:50:25.279,2:50:37.200
able to block this little site within the capsid
proteins. And that is what makes it so effective.
2:50:39.439,2:50:48.559
Well, let's do a quick detour, if you'll let
me, on long-acting drugs other than lenacapavir.
2:50:48.560,2:50:58.720
Because the principle we're talking about
applies not just to this molecule. The nature
2:50:58.720,2:51:03.840
of a long-acting injectable or a long-acting
drug, well, what makes it long lasting? What
2:51:03.840,2:51:09.520
makes it long-acting? It's relative to what we're
used to; relative to immediate release drugs.
2:51:09.520,2:51:16.640
You know, if you think about the PrEP drugs that
we talked about earlier in the episode — those you
2:51:16.640,2:51:24.000
take daily, and that's because you want to have
enough of the active ingredient in circulation,
2:51:24.000,2:51:32.960
in case HIV enters your system during that period.
But pretty quickly, most drugs get metabolised and
2:51:32.960,2:51:39.920
get filtered out and leave your body in urine,
and sometimes other ways, but that's the main one.
2:51:40.800,2:51:48.319
So an issue that you mentioned is: if you have to
take a drug every day, you might forget to take
2:51:48.319,2:51:52.799
it. You might run out of the drug and not have
time to get a refill for a few days, or a week,
2:51:52.800,2:52:00.560
or I actually am behind on refills, because I'm in
New York right now. Or you might not want people
2:52:00.560,2:52:09.440
who you live with to see that you take pills
regularly, so keeping them around is not ideal.
2:52:10.240,2:52:16.719
This is important with HIV as well,
because some of the preventive drugs
2:52:16.720,2:52:21.680
might also look like treatment drugs.
I think you mentioned this earlier. And
2:52:21.680,2:52:27.840
so there's also the stigma around people
thinking that you have an HIV infection,
2:52:27.840,2:52:31.920
and then they're worried about that, even
though these drugs are very effective and
2:52:31.920,2:52:40.560
it's very unlikely to transmit, if you're using
these drugs. But I think this whole thing of:
2:52:40.560,2:52:47.920
"how do people actually take it in their daily
life?" is so relevant through drug development.
2:52:47.920,2:52:53.840
Absolutely. And the long lasting prevention
that people might be most familiar with is birth
2:52:53.840,2:53:04.720
control. Where a lot of, some similar issues are
a big part of what can drive different women to
2:53:04.720,2:53:11.200
want to make different choices with birth control.
So the pill was first approved by the FDA in 1960,
2:53:11.200,2:53:17.040
after development in the '50s, as daily oral
contraception. And then from the '60s onwards,
2:53:17.040,2:53:25.680
there was a lot of work to see if you could
make the different options for birth control
2:53:25.680,2:53:32.800
long lasting. So can you have hormones that are
inside a silicone tube of some form, that you can
2:53:32.800,2:53:40.720
control the diffusion over time, so that you don't
have to take daily pills or take a daily hormones.
2:53:41.920,2:53:48.800
And now there are multiple options for that.
So you can have hormonal IUDs that release
2:53:48.800,2:53:56.880
progestin slowly over time. You can have arm
implants. The approach there, is to take an
2:53:56.880,2:54:03.520
existing biological molecule, or synthesise
an alternate of a hormone, and then have a
2:54:03.520,2:54:08.479
different packet that controls the diffusion.
So it's a bit different than what we just talked
2:54:08.479,2:54:19.599
about with lenacapavir, where the drug itself
is so insoluble and stable and it itself sticks
2:54:19.600,2:54:24.800
around. Whereas, let's say you have a drug
that doesn't naturally stick around, well,
2:54:24.800,2:54:34.399
maybe you can design a delivery mode — a polymer,
a liposome, that you can keep it inside of, and
2:54:34.399,2:54:40.080
slowly diffuse, and you can achieve the same goal.
Maybe you could just put it in a drop of oil,
2:54:40.080,2:54:45.120
or you could suspend it in some other
way, maybe you could put it in a device.
2:54:45.920,2:54:52.240
And sure enough, for HIV one new mode of
prevention that we haven't talked much about
2:54:52.240,2:54:59.920
yet is vaginal rings — where you can have a slow
release, you can insert a vaginal ring monthly,
2:54:59.920,2:55:06.560
say, and have a slow release that a
woman, who wants to not be a risk of HIV,
2:55:06.560,2:55:13.600
has more control over if you have to get in
some circumstances, than if she had to get
2:55:14.479,2:55:19.839
pills that were more visible to people in her
household or her husband or something like that.
2:55:19.840,2:55:30.160
So there are a lot of different strategies here.
When it comes to HIV, what's interesting to me is
2:55:30.160,2:55:37.519
that there are a few long lasting drugs that are
being tested now, or are near the finish line now,
2:55:37.520,2:55:46.880
that use different approaches and yet achieve
this kind of similar goal. The three that come
2:55:46.880,2:55:53.200
to mind for me are lenacapavir, which we've been
talking about a lot, but then also cabotegravir,
2:55:53.200,2:55:59.840
which is already approved in some countries —
in the US — which is this injection every two
2:55:59.840,2:56:06.479
months. And then also islatravir, and other
follower drugs, that are being made by Merck,
2:56:06.479,2:56:12.160
that are oral drugs that you might be
able to take once a month for prevention;
2:56:12.160,2:56:15.840
or for treatment, maybe you take once a
week. There's a few different regimens
2:56:15.840,2:56:24.560
being tested. And my understanding of why
islatravir sticks around for a month is-
2:56:24.560,2:56:26.080
Which one is islatravir?
2:56:26.080,2:56:29.024
Islatravir is a drug-
2:56:29.024,2:56:29.040
Is that Merck's?
2:56:29.040,2:56:37.439
Yes. Made by Merck. You know, imagine instead of
taking daily oral PrEP, you take one pill once a
2:56:37.439,2:56:47.279
month say, and they've tested that regimen.
What happens after you ingest that pill is,
2:56:49.680,2:56:56.800
the active ingredient sticks around
intracellularly. So it's not- when you're
2:56:56.800,2:57:02.080
imagining lenacapavir, what you should imagine is:
you've got a drug substance dissolved, in a liquid
2:57:02.080,2:57:09.439
that's 40% water; you are getting injected
with that. The liquid's kind of dispersing,
2:57:09.439,2:57:14.879
and the drug is sticking around and forming
a solid on the video just pointed at my arm,
2:57:14.880,2:57:20.880
but it's not in your arm, it's your stomach
or in your butt. Then that active ingredient
2:57:20.880,2:57:28.000
is slowly dissolving, over the course of
many months. Whereas, with islatravir,
2:57:28.000,2:57:34.479
you should imagine that the active ingredient is,
in some way — and I wish I knew more about this,
2:57:34.479,2:57:40.319
I don't — is in some ways sticking around in
your cell. So that if the HIV virus is entering
2:57:40.319,2:57:46.399
your cell, it's going to do its work, which is
wonderful, but it's not some big depot or some
2:57:46.399,2:57:52.399
big lump. It's totally different and it might
stick around for different biological reasons.
2:57:52.399,2:58:00.960
That is so interesting. I had no idea I was going
to ask about this container or the package. Does
2:58:00.960,2:58:07.359
the package dissolve? Is the package, is that
actually a separate molecule, or something
2:58:07.359,2:58:12.399
like that? But you answered my question.
I guess that also varies with other drugs.
2:58:12.399,2:58:17.439
Yes, it does vary with other drugs, and
the answer will differ for other drugs,
2:58:17.439,2:58:26.240
because there are different ways to achieve the
goal. If you don't get a drug like lenacapavir
2:58:26.240,2:58:35.279
that has properties of slow degradation, then
you might want to achieve the goal via packaging
2:58:35.279,2:58:40.319
your active ingredient differently.
One thing that I think is, in a way,
2:58:40.319,2:58:48.399
fortunate about both lenacapavir and islatravir
and cabotegravir — which is also an injection
2:58:48.399,2:58:56.240
that's a suspended solid that slowly degrades —
is that you don't need a very complicated package.
2:58:56.240,2:59:05.920
Because a complicated package adds complexity,
manufacturing cost, and makes me less optimistic
2:59:05.920,2:59:13.600
that in the near-term a drug will get used in
lower resource settings. Whereas the simpler you
2:59:13.600,2:59:21.920
can make the package, the more likely you can use
a drug in many settings. In this case, it's just
2:59:21.920,2:59:29.520
the drug itself — well, simplifying a little — but
it's mostly the drug itself in a syrup solution.
2:59:29.520,2:59:34.241
And you know what? I could take a look at that. I
might be able to one day inject myself with that.
2:59:34.800,2:59:38.880
This is so interesting. I mean, the other
thing that reminded me was, I think what
2:59:38.880,2:59:45.680
I read about the fluorine atoms, is that those
help it stick around in your fat. So you have
2:59:45.680,2:59:53.120
the injection either in your abdomen or your
butt, and then I think the fluorine atoms keep
2:59:53.120,3:00:04.080
it around the fatty areas, but also they create
this little lump underneath your skin, right?
3:00:04.080,3:00:10.160
Yes. Well, I mean, absolutely.
And as I think about the lump,
3:00:10.160,3:00:13.200
I was just thinking about it spatially,
and I would love someone who's worked on
3:00:13.200,3:00:18.319
injectables and on lenacapavir to correct
me in the comments, if I'm thinking about
3:00:18.319,3:00:25.920
it spatially wrong, but. Is lenacapavir a one or
two millilitre injection? Do you happen to recall?
3:00:25.920,3:00:28.000
Yes. Yeah, it is one to two.
3:00:28.000,3:00:35.760
Okay. So my memory of how millilitres work is that
that's one cubic centimetre. Is that right? Okay,
3:00:35.760,3:00:41.359
so now I'm visualising we've got some liquid
that's one by one by one centimetre. That's quite
3:00:41.359,3:00:48.799
a lot. And you get injected somewhere, and the
liquid does disperse it. You've only got some of
3:00:48.800,3:00:54.080
it left, but a good amount of what you're getting
injected with is this high concentration drug that
3:00:54.080,3:01:01.040
becomes solid. So sure enough, you should expect
that to be a lump. You just got injected with a
3:01:01.040,3:01:05.920
decent volume of stuff and fair enough, some
of it precipitates and becomes solid. If there
3:01:05.920,3:01:10.560
wasn't a lump, I'd almost be confused. I'd be
like, where did it go? I thought it was meant
3:01:10.560,3:01:16.480
to stick around for six months, and anyway, so I
think lumps form, definitely in different people.
3:01:17.120,3:01:24.559
I think what I read was also that the first
injection typically leads to this lump forming,
3:01:24.560,3:01:32.880
but the subsequent doses don't. So that makes me
think that maybe there's some bodily reaction to
3:01:32.880,3:01:39.200
the drug substance that creates the lump, and that
the second or third time, your body gets used to
3:01:39.200,3:01:44.639
it in some way, or it just doesn't have the same
reaction. But that was also really interesting.
3:01:45.920,3:01:54.720
It reminds me a little bit about when people
had smallpox vaccines, you could see that from
3:01:55.439,3:02:05.200
the little mark on their shoulder. With this,
you have this tangible little bump in your butt
3:02:05.200,3:02:13.519
or your stomach that typically shows you
if the drug has formed this little depot.
3:02:13.520,3:02:19.520
I'm curious about these other
long-acting injectable drugs
3:02:19.520,3:02:27.279
that you've read about. So how else do they
differ from regular drugs that only last a
3:02:27.279,3:02:33.759
short amount of time? Are they more expensive?
What's their safety like? What's all of that?
3:02:33.760,3:02:39.680
Great questions. And they, again, are going to
have variable answers rather than an easy one.
3:02:40.479,3:02:47.519
It depends on what package you're including.
On the safety front, you really want to have,
3:02:47.520,3:02:52.320
if anything, higher safety standards when
you're doing something long lasting. Because
3:02:53.200,3:02:59.040
with a drug that washes out of your system
within a day, there's only so bad it can be.
3:02:59.040,3:03:03.840
But with something that sticks around for a
long time, you want to make sure it's harder
3:03:03.840,3:03:08.240
to get rid of, so you want to make sure that,
before you get injected or before you take it,
3:03:08.240,3:03:15.200
there's not going to be toxicity or longer issues.
I think that that is part of why, with lenacapavir
3:03:15.200,3:03:22.399
and with other drugs, you get an oral lead-in
for two days before you get long injections,
3:03:22.399,3:03:30.639
just to check tolerability. It's interesting
though, on efficacy as well, that you can
3:03:30.640,3:03:40.240
sometimes have the same underlying chemical,
that is trying to achieve some medical goal,
3:03:40.240,3:03:47.200
but it can be higher efficacy in a long
lasting injectable for a couple reasons.
3:03:47.200,3:03:55.840
One that we've mentioned is the real world and
having- it's much more reliable if you just have
3:03:55.840,3:04:02.479
to get one injection or swallow one pill, than if
you have to remember to do it all the time. But
3:04:02.479,3:04:08.559
another is more chemical or more to do with the
body — which is that when you take daily pills,
3:04:08.560,3:04:16.560
you get this spike in how much of the drug
you have, relatively soon after you take it,
3:04:16.560,3:04:23.520
operating in the bloodstream or elsewhere, that
then decays relatively quickly. So you're kind of
3:04:23.520,3:04:29.920
doing this: spike and drop, spike and drop, spike
and drop, for a daily drug. And that's not ideal.
3:04:30.880,3:04:37.279
Often you want to be in a therapeutic window
that is not so spiky. With these long lasting
3:04:37.279,3:04:44.880
injectables, you have a lot more control, and you
can tune that a lot more easily. You can predict,
3:04:44.880,3:04:49.680
okay, on a given day, how much am
I going to have in my bloodstream,
3:04:49.680,3:04:55.520
based on how much I was initially injected with,
and how much time it's been since then. You can
3:04:55.520,3:05:01.200
really hit that therapeutic window perfectly, so
you can end up with a chemically more effective
3:05:01.200,3:05:07.439
drug. And you know, as I said, you want
to check the safety a bit more though.
3:05:07.439,3:05:12.399
That totally makes sense. So the
therapeutic window — that's the range of,
3:05:13.439,3:05:20.240
I guess, the volume or something of that drug in
your system, and having that in the ideal range,
3:05:20.240,3:05:25.439
right? Yeah. And I guess the other
thing I was thinking about was:
3:05:25.439,3:05:30.799
maybe it's not just about the predictability,
it's also that there's less of a fluctuation.
3:05:30.800,3:05:40.399
Maybe some people react badly to these spikes,
or the lack of- if the dosage suddenly drops,
3:05:40.399,3:05:46.559
does that mean the effectiveness is now not high
enough? But if you can manage to get a stable
3:05:47.520,3:05:53.760
level of this drug for really long time,
that is probably better in some respects.
3:05:53.760,3:06:00.640
Yep, absolutely. And my mind goes to:
what other diseases for prevention or
3:06:00.640,3:06:10.960
for treatment — other than HIV — would you want
those properties most? That's beyond the bounds
3:06:10.960,3:06:17.920
of this short podcast. But the ones that I
can't wait to learn more about myself are...
3:06:17.920,3:06:25.920
So, malaria is one, where if you are
under five and live in West Africa,
3:06:25.920,3:06:31.520
if you're a kid in West Africa, you will get
preventive malaria drugs during the rainy season,
3:06:31.520,3:06:36.960
where you're most likely to get malaria;
that's about four months long. Currently,
3:06:36.960,3:06:44.080
kids will get three-days-in-a-row worth of drugs,
each month. So that's four times three. And the
3:06:44.080,3:06:51.439
drugs, they don't taste great, or kids don't
always like 'em, and don't always take them all,
3:06:51.439,3:06:56.559
all three days in a row. If you're a busy
parent and your kid is making a scene,
3:06:56.560,3:07:04.240
then you might not make sure to force all
12 of those doses. But if you could get a
3:07:04.240,3:07:13.040
long lasting injectable for a season, that could
cover that season and make sure you had the right
3:07:13.040,3:07:17.120
amount of preventive drug in your system,
if you got bit by a mosquito. My goodness,
3:07:17.120,3:07:24.240
that could be an enormous deal. I don't
think, based on my knowledge of malaria drugs,
3:07:24.240,3:07:28.080
that we're close to rolling out something like
that. But I do know that people are working on
3:07:28.080,3:07:34.479
that problem, and it's very interesting.
I think that tuberculosis is another area;
3:07:34.479,3:07:39.759
Hepatitis C is another area, rheumatic heart
disease is another area. So a few infectious
3:07:39.760,3:07:48.080
disease areas that I'm sort of — ooh, I'm getting
excited about, but don't know in super depth.
3:07:48.080,3:07:53.680
And then, beyond infectious disease too,
there's a bunch of potential applications.
3:07:54.479,3:07:59.679
I think there's a psychosis drug; there's
a schizophrenia or bipolar disorder drug,
3:07:59.680,3:08:05.200
I think, that's also long-acting. What I
was thinking about was: maybe it's useful
3:08:05.200,3:08:10.559
for things that are hard to predict when you're
going to be infected by them, so you would prefer
3:08:10.560,3:08:17.279
to take something that lasts a long time, and
so for various infectious diseases, that seems
3:08:17.279,3:08:23.120
useful. Maybe also for chronic diseases, where
you have the condition for a really long time,
3:08:23.120,3:08:29.279
therefore it's useful to have this long
acting treatment, instead of doing something
3:08:29.279,3:08:35.759
where you have to take it every day. But, I
mean, that kind of covers most diseases...
3:08:36.319,3:08:41.359
There could be lot that fit that description
and that you should also think about:
3:08:41.359,3:08:47.679
when do you want something to end? And
I think, for a lot of those diseases,
3:08:47.680,3:08:53.920
you would not want a drug necessarily that lasted
for life. If you could have one stick around-
3:08:53.920,3:08:54.640
That is very true.
3:08:55.840,3:09:01.760
For some drugs, for example, if you think, "Oh,
there's a chance I want to get pregnant in the
3:09:01.760,3:09:07.279
next few years," then you might want more control
over when the drug's out of your system, in case
3:09:07.279,3:09:13.840
that drug hasn't been tested as much in pregnancy,
or has been tested and isn't as safe in pregnancy.
3:09:15.040,3:09:22.800
There's one thing that in the literature that I've
found interesting to read is: the limitations, in
3:09:22.800,3:09:27.439
children, of long lasting drugs. I was wondering,
oh, that's such a shame because of, for example,
3:09:27.439,3:09:35.200
the malaria thing. I was just talking about why
is there a limitation? One reason is that the
3:09:35.200,3:09:43.519
dose that you get given, of different drugs, is
relative to how big you are. And the correct dose
3:09:43.520,3:09:49.760
is often bigger, the bigger you are. The trouble
is, with a child, that in six months, their size
3:09:49.760,3:09:54.479
is going to change a lot, and that means you
might want to be dealing with a different
3:09:54.479,3:09:59.759
drug dose in six months time. So there's reasons
like that, that you don't want to last forever.
3:09:59.760,3:10:08.240
That contrasts, usually, with vaccines where
you actually wouldn't mind having as long a
3:10:08.240,3:10:18.080
lasting memory response as you can. And there
are some vaccines that are known to be pretty
3:10:18.080,3:10:24.160
poor at generating long-lasting memories:
flu vaccines are sort of a famous example;
3:10:24.160,3:10:30.639
the malaria vaccines so far aren't that
durable, but are getting better. And then,
3:10:30.640,3:10:36.960
really, the best vaccine immunologists talk about
is yellow fever vaccine, where you could live for
3:10:36.960,3:10:40.399
10,000 years and you wouldn't be getting
yellow fever after you got that vaccine.
3:10:40.399,3:10:42.960
Wow, I didn't know that.
3:10:42.960,3:10:43.920
Yes. Well, that will-
3:10:43.920,3:10:46.800
I can live for 10,000 years?
3:10:46.800,3:10:49.200
That's what I've heard, but I don't know how they
3:10:49.200,3:10:53.120
extrapolated that. I think you can
live for 10,000 years, and I think-
3:10:53.120,3:10:56.960
I mean, I kind of want to
live for 10,000 years now,
3:10:56.960,3:11:01.359
just to see this vaccine
lasting that long against it.
3:11:01.359,3:11:07.040
Imagine if you got a challenge with yellow
fever at the end of 10,000 years to prove it,
3:11:07.040,3:11:12.399
and then it actually got you. Throwing
up black bile and everything else.
3:11:12.399,3:11:18.319
The other thing I was thinking about, when
you mentioned that on the size of the body,
3:11:18.319,3:11:25.840
was with lenacapavir: so, what I understood was,
okay, the fluorine atoms keep lenacapavir in
3:11:25.840,3:11:30.399
fat tissue, but again, this is a problem for
the same reason that you mentioned. If your
3:11:30.399,3:11:35.279
body size changes, that could affect
how quickly it dissolves, I think,
3:11:35.279,3:11:44.160
or how much is remaining in this little depot. So
imagine if you lost weight, for whatever reason,
3:11:44.160,3:11:49.760
you're on a diet or something, and somehow,
suddenly, this drug becomes more potent or
3:11:49.760,3:11:55.200
effective in your body. I just thought that
was a funny thing that I hadn't thought about.
3:11:55.200,3:11:59.599
No, totally. Another one is, that's
hard to predict ahead of time is,
3:11:59.600,3:12:05.840
are you going to want to go on another drug,
for another reason, that might have a negative
3:12:05.840,3:12:12.479
interaction with a long-lasting drug you're
already on? My understanding of lenacapavir is,
3:12:12.479,3:12:16.319
they haven't discovered many drug
interactions that are that concerning.
3:12:16.319,3:12:21.279
But that might apply to other long lasting
drugs, so you got to think about that.
3:12:21.279,3:12:27.120
That's a really good point. The thing
that reminds me of is grapefruit juice.
3:12:27.120,3:12:33.840
Have you read about this thing with-
so, grapefruit juice has this chemical
3:12:33.840,3:12:40.800
that interferes with your liver's metabolism
of lots of different drugs. And if you were-
3:12:40.800,3:12:43.200
I had grapefruit juice
three days ago. I'm nervous.
3:12:43.200,3:12:44.720
Oh, did you? Yeah.
3:12:44.720,3:12:45.439
Well that explains-
3:12:45.439,3:12:50.799
Well, I mean, it's not all of the drugs, but
it seems like it's quite a number of drugs
3:12:50.800,3:12:57.439
that are affected by this. And so, if you're
drinking grapefruit juice, for whatever reason,
3:12:57.439,3:13:02.080
it sometimes makes various
drugs last longer in your body,
3:13:02.080,3:13:05.680
because it interferes with their
breakdown. This is true for, I think,
3:13:05.680,3:13:15.359
some other chemicals and drinks as well, but
that's the most commonly-known in medicine.
3:13:15.359,3:13:18.719
So if you're getting towards the tail-end of
3:13:18.720,3:13:23.279
your six months of lenacapavir, just
start doing shots of grapefruit juice?
3:13:23.279,3:13:29.120
I don't know if it interferes with lenacapavir
specifically, but it seems to be a bunch of other
3:13:29.120,3:13:36.160
drugs. But I mean, it's just an interesting thing
to think about, because now you're on this- okay,
3:13:36.160,3:13:42.080
you're on this six-monthly drug. What are the
things that you now have to be thinking about,
3:13:42.080,3:13:48.880
to make sure that this drug is still working as
expected? It's great to hear that it doesn't have
3:13:49.439,3:13:52.879
many drug interactions, but I
think that's the other thing that,
3:13:53.600,3:13:56.960
if I was a drug developer,
I would be thinking about.
3:13:56.960,3:14:00.479
And I'm sure there's more still
to learn about drug interactions,
3:14:00.479,3:14:11.439
so we'll find out. The reversibility of some other
preventive tools is a key part of why people want
3:14:11.439,3:14:18.559
to use them. For IUDs, for example, you can get an
IUD removed and it will not affect your long-term
3:14:18.560,3:14:27.520
fertility. Whereas for lenacapavir, you got to
wait it out. Once it's in there, it's in there.
3:14:28.080,3:14:34.399
I would find that exciting. But yeah, you're
right. If there's something that could go wrong,
3:14:34.399,3:14:38.399
that is something that, this
is why we need these long
3:14:38.960,3:14:44.640
clinical trials to make sure that this drug
is safe, in the way that people take them,
3:14:44.640,3:14:53.342
in their daily lives. Maybe we should talk
about the clinical trials and what they should-
3:14:53.342,3:14:57.439
I would love to, yes. I was wondering
about the clinical trials. How did we
3:14:57.439,3:15:05.200
confirm that lenacapavir does actually work
in the way we hoped, and that it is safe?
3:15:06.800,3:15:10.880
Where did we go once the scientists
had done the experiments in the lab?
3:15:13.200,3:15:21.599
The period when lenacapavir was developed
was the late 2010s. They did some molecular
3:15:21.600,3:15:28.479
studies to develop lenacapavir. They then did
a phase one study — which is you're testing
3:15:28.479,3:15:35.919
the safety in a small number of participants, and
you're checking basic things about the properties,
3:15:35.920,3:15:43.600
the pharmacokinetics, how long does it stay in the
body, how effective is it in very specific ways,
3:15:43.600,3:15:49.360
in a small number of people — I
think there's usually dozens or so.
3:15:50.160,3:15:57.760
Then after that, they moved on to phase two
trials; this is a second part where it's a larger
3:15:57.760,3:16:03.120
number of people. Now, you're testing a little
more about the safety, because now you have a
3:16:03.120,3:16:09.519
wider range of people with different backgrounds;
they might be taking other drugs at the same time;
3:16:09.520,3:16:15.760
they have different behaviours and so on. So you
can find out a little bit more about the safety.
3:16:15.760,3:16:23.360
But also, now with a larger sample, you can see
how effective the drug is. They did this with
3:16:23.920,3:16:31.359
people who already had HIV and were
taking other antiretroviral drugs,
3:16:32.000,3:16:37.840
and they saw how this combination of
lenacapavir plus those other drugs worked.
3:16:37.840,3:16:47.439
Then, the breakthrough that really got me to
notice this drug was their phase three trial; and
3:16:47.439,3:17:02.639
their phase three trial was- I think it started in
2021. They had two different trials. One was with,
3:17:02.640,3:17:10.319
I think, one was with men; the other one was with
cisgender women — specifically adolescent girls
3:17:10.319,3:17:16.880
and young women. This quite important because
the transmission, and the effect of these drugs,
3:17:16.880,3:17:23.680
can vary for women who are trans because the
route of infection, their sexual activity,
3:17:24.560,3:17:30.720
how that actually works, is different.
So they're focusing specifically on cisgender
3:17:30.720,3:17:40.239
women aged between 16 and 25; girls who were not
using PrEP; they hadn't done HIV testing, or they
3:17:40.239,3:17:48.160
hadn't done it in the last three months. I think
it was several thousand- it was around 8,000 women
3:17:48.160,3:17:58.559
in this trial across Uganda and South Africa. This
is important because, if you're trying to test how
3:17:58.560,3:18:06.800
effective a drug is, you need enough, well- there
need to be enough people, at least on the placebo,
3:18:06.800,3:18:14.080
who are getting infected, so that you can see
what the difference would be with lenacapavir.
3:18:14.080,3:18:21.519
So they focused on these areas where HIV
incidence rates were relatively high,
3:18:21.520,3:18:30.000
meaning that more than three or four people per
hundred people were being infected per year. So
3:18:30.000,3:18:36.880
imagine 3% of the population of this age is
being infected with HIV per year. That's,
3:18:37.520,3:18:43.840
to me, that's really high. This is quite
common in some areas of South Africa and
3:18:43.840,3:18:52.000
Uganda. That means that it's much easier
to tell if lenacapavir has an effect.
3:18:52.000,3:19:00.560
Because you'll detect in the other arm of the
trial that there were HIV infections occurring.
3:19:00.560,3:19:05.920
Right. If you imagine, okay, if you were
doing a trial in the UK or in the US,
3:19:05.920,3:19:14.080
where people are already taking PrEP or
the rate of HIV is just so low to begin
3:19:14.800,3:19:21.279
with, then imagine no one in the
placebo group gets HIV. How are
3:19:21.279,3:19:22.145
you going to tell if lenacapavir is better
than that? There's nothing lower than zero.
3:19:22.145,3:19:28.880
You have to be able to distinguish,
because happily, its transmission is
3:19:28.880,3:19:34.800
lower than it was twenty years ago or thirty.
Yeah, it's interesting. It's a very clear case,
3:19:34.800,3:19:43.920
I guess, of trials in- well, I'm in the US, you're
in the UK, but I may benefit from this drug,
3:19:43.920,3:19:51.279
living in the US, based on trials that occurred
in other countries — because those trials were
3:19:53.359,3:20:00.559
in higher transmission settings. So you can
get a statistical answer to the question;
3:20:00.560,3:20:08.160
that would've been harder if you were just doing
the trials in the US. So that's a kind of selfish
3:20:08.160,3:20:16.479
benefit that the US, and people like me, get
from the global nature of clinical trials.
3:20:16.479,3:20:22.080
That's what I think makes it really important to-
we'll come to talk about this later on, but this
3:20:22.080,3:20:27.519
is what makes it really important to think about
how to actually get it to be accessible. How to
3:20:27.520,3:20:35.200
scale up this drug, in the future, to the people
who need it. This wasn't developed without the
3:20:35.200,3:20:41.599
help of all of these participants who agreed to be
in this trial, who are living thousands of miles
3:20:41.600,3:20:49.439
away from us, and who are responsible for this
breakthrough being tested, and the fact that we
3:20:49.439,3:20:54.399
know that it works, and so on. One of the other
things that I found quite interesting about this
3:20:54.399,3:21:01.679
trial is: how trials actually work in terms
of the healthcare and the screening involved.
3:21:02.560,3:21:10.720
So I think when people think of a trial, maybe
they don't realise that you're not just receiving
3:21:10.720,3:21:17.712
the treatment itself, but people are doing
other types of screening to monitor how you
3:21:17.712,3:21:24.960
are responding to the drug. They're also, in this
case, doing tests and screening for other types of
3:21:24.960,3:21:33.520
related diseases. What they did in this trial was:
they provided individual counselling to people;
3:21:33.520,3:21:39.439
they provided condoms, lubricants; they'd
have support for reproductive health in
3:21:39.439,3:21:44.879
general. They also provided treatments
for other sexually transmitted infections,
3:21:44.880,3:21:51.760
and they did routine tests for some common
sexually transmitted infections, like chlamydia,
3:21:51.760,3:21:59.439
gonorrhoea, and syphilis there. Which means that,
by participating in this trial, not only do you
3:21:59.439,3:22:05.200
get the potential of this drug and also the side
potential side effects, or risks, of participating
3:22:05.200,3:22:12.080
in trial — but you also get the actual
healthcare because of the clinical trial setting.
3:22:12.080,3:22:19.040
I think that's something that people might not
realise: we have this system where we have these
3:22:19.040,3:22:23.279
clinics, or these hospitals, that are running
these clinical trials; they're also providing
3:22:23.840,3:22:30.239
care to the people in the trial. When we think
about how to actually set up these clinical
3:22:30.239,3:22:37.359
trials in countries in Africa, it's not just about
doing the testing. The researchers, sometimes,
3:22:37.359,3:22:44.719
are involved in setting up new clinics, they're
involved in recruiting staff to work on all of
3:22:44.720,3:22:51.760
this testing, and stuff like that, and that has
various other benefits for the people in the area.
3:22:51.760,3:22:57.920
One thing that we've worked on at Open
Philanthropy is — an area that's not HIV
3:22:57.920,3:23:08.239
but relates — is congenital syphilis.
Syphilis is- nowhere is it incredibly
3:23:08.239,3:23:13.200
prevalent, but in some places, maybe one
to three percent of people have syphilis.
3:23:15.279,3:23:21.200
That is not something you want for yourself,
but it also is really bad if you're pregnant,
3:23:21.200,3:23:27.200
because you may have a birth complication
basically, or a miscarriage, or being born
3:23:27.200,3:23:36.880
with congenital syphilis is very dangerous.
One thing that HIV care has brought in many
3:23:36.880,3:23:45.760
countries is better antenatal screening, prenatal
screening for HIV for many women. You'll get at
3:23:45.760,3:23:50.640
least one visit with a doctor, whereas in many
areas before, if you were pregnant, you might
3:23:50.640,3:23:56.640
not have even had one visit with a doctor.
So that infrastructure set up to screen for,
3:23:56.640,3:24:04.160
or to give you a touch point and some care while
you're pregnant — mostly funded by the HIV world,
3:24:04.160,3:24:12.399
and by PEPFAR, and other donor countries —
has enabled screening for syphilis as well.
3:24:12.399,3:24:18.960
There's now a dual test where — it's a rapid test;
it costs just under a dollar — you can screen for
3:24:18.960,3:24:24.800
HIV and syphilis at the same time. And then,
if you are positive for syphilis, you can get
3:24:24.800,3:24:32.560
relatively easy treatment on penicillin. That's
such a clear example of the benefits of this
3:24:32.560,3:24:40.560
infrastructure, that were not initially planned
from when HIV donors made those investments,
3:24:40.560,3:24:47.840
but that spill over. So it makes sense to me
that, not only are there benefits from the
3:24:47.840,3:24:52.640
knowledge gained, of these lenacapavir trials,
but people in the trials got better care too,
3:24:52.640,3:24:59.120
and there's now probably better trained doctors
in the area and that kind of thing, yeah.
3:24:59.120,3:25:06.720
We have thousands of young women in this trial.
First, they were tested for whether they already
3:25:06.720,3:25:13.279
had HIV at that point. This was useful, as I'll
come back to later, this is useful to know: What
3:25:13.279,3:25:20.719
is the rate of HIV in the population? It turned
out that it was about 2.5 per hundred people per
3:25:20.720,3:25:30.399
year, which is, so 2.5% of people in this age
group are infected by HIV per year — which is,
3:25:30.399,3:25:38.559
to me, really difficult to think about. Those
women would not necessarily benefit from this
3:25:38.560,3:25:42.800
treatment; that was not the purpose of this
trial — it was to find out whether we could
3:25:42.800,3:25:50.479
prevent new infections. Those participants were
not included in the rest of the study, I think.
3:25:50.479,3:25:53.200
So, you screen at the beginning for HIV;
3:25:53.200,3:25:56.960
if you're already positive, then
this is not the trial for you.
3:25:56.960,3:26:05.840
Right. And the women who were HIV-negative were
then randomly assigned to getting either this
3:26:05.840,3:26:12.880
lenacapavir injection, or- I think this
is Descovy — it's the oral PrEP pill,
3:26:12.880,3:26:22.160
which is emtricitabine and tenofovir
alafenamide. Or the third option was F/TDF,
3:26:22.160,3:26:24.369
I think there's another name
for this, is that Truvada?
3:26:24.369,3:26:24.399
Truvada? That's Truvada, yeah.
3:26:24.399,3:26:32.799
That's Truvada; that's also an oral pill that
people take daily; that is also emtricitabine,
3:26:32.800,3:26:40.479
but this time it's tenofovir disoproxil fumarate.
And I think what they did was — because one of
3:26:40.479,3:26:47.919
them is an injection; the other two are oral
pills — they actually gave fake version of the
3:26:47.920,3:26:51.520
opposites to all the participants, so that
they don't know which one they're getting.
3:26:51.520,3:26:52.560
Oh, okay. Nice.
3:26:52.560,3:26:57.840
They're all getting an oral pill and
they're also all getting an injection.
3:26:57.840,3:27:01.520
But some of the people who are getting
the injection are getting lenacapavir,
3:27:01.520,3:27:05.840
the others are just getting a placebo — which
is just some water or something like that.
3:27:05.840,3:27:11.359
Which, you know, I'm already curious about.
Three things from what you said: number one is,
3:27:11.359,3:27:18.399
if I get the fake lenacapavir injection, does it
form a depot? And can I tell that it's actually
3:27:19.040,3:27:25.680
fake, because it doesn't form a lump? But my
other two reactions are maybe more fundamental.
3:27:25.680,3:27:30.720
So it sounds like there's no placebo here — in the
sense of, there's no one who's getting no drugs,
3:27:30.720,3:27:36.720
because that would be unethical. We already
have drugs that we know will reduce your
3:27:36.720,3:27:42.319
chance of acquiring HIV if you're on
them. So the arms that you described
3:27:42.319,3:27:48.639
are the lenacapavir arm, descovy arm,
truvada arm, and there's no zero arm.
3:27:48.640,3:27:55.600
Right, and in other clinical trials, you're
not necessarily preventing people from getting
3:27:55.600,3:27:58.800
other treatments; they could be taking
other treatments for the same disease,
3:27:58.800,3:28:04.479
at the same time. But, in this case, they
wanted to see: How effective was this as
3:28:04.479,3:28:11.919
a prevention? And to get enough statistical
power, you need everyone to be in the trial,
3:28:11.920,3:28:17.279
and you're having this situation where you
don't want any of them to be taking PrEP
3:28:17.279,3:28:25.759
that you can't analyse in a consistent way.
It's both ethical in the sense that they're
3:28:25.760,3:28:30.399
providing all of the participants with
one of the three PrEP drugs, but it also
3:28:30.399,3:28:36.239
helps because it makes these comparisons
simpler. They're not taking an additional
3:28:36.239,3:28:43.040
PrEP- some of them are not taking an additional
PrEP drug that could complicate the analysis.
3:28:43.040,3:28:47.359
Okay. Got it. Makes sense. And then my third
reaction was, it's interesting that Descovy
3:28:47.359,3:28:53.839
was in the mix because I thought that Descovy
was not approved for use in cisgender women.
3:28:53.840,3:29:02.960
Yes, you're right, it hadn't been tested before in
women. The company, Gilead had been criticised for
3:29:02.960,3:29:08.640
this, having this approved but not testing
it beforehand. So this also functioned as,
3:29:08.640,3:29:14.960
not just the trial for lenacapavir, but it also
tested how effective Truvada and Descovy are-
3:29:14.960,3:29:15.279
Great, okay.
3:29:15.279,3:29:19.040
-in the same population. So you get
to have the answer to three questions.
3:29:19.040,3:29:25.040
You have the answer to how effective
lenacapavir is, descovy, and truvada.
3:29:25.040,3:29:29.600
And then because of what you said, about the
screening on the way in, can they compare it
3:29:29.600,3:29:34.319
to what they think the background rate,
if you're on nothing, probably would be?
3:29:34.319,3:29:38.799
Yes, yes. So actually we have
four things you can find out.
3:29:38.800,3:29:43.920
Well, that one's not measured.
I guess that one's interpolated.
3:29:43.920,3:29:50.880
So you can now compare these three drugs, but you
can also compare them all to not taking any drugs.
3:29:50.880,3:29:56.800
Okay. Well, I feel- I'm on the edge
of my seat. So, what were the results?
3:29:56.800,3:30:04.160
What were the results? I'm going to show this
chart. So this chart compares the outcomes in
3:30:04.160,3:30:08.319
each of these groups. The first bar
is showing the background incidence;
3:30:08.319,3:30:14.319
these are the women who tested positive at
the start of the trial, and around 2.4% of
3:30:14.319,3:30:27.587
them got infected with HIV per year in FTAF,
which is Descovy? That had a rates of 2.02.
3:30:27.588,3:30:28.633
That's very similar to the background, right?
3:30:28.633,3:30:36.720
And in Truvada, it's around 1.69. These numbers
are the point estimates, and that's our best
3:30:36.720,3:30:44.399
guess. But there's uncertainty around just
what the number is; they all roughly fit
3:30:44.399,3:30:55.679
into the same range. So without drugs, Descovy,
and Truvada have similar rates of HIV infection.
3:30:55.680,3:31:03.200
And I think the reason for this is because it's
hard to take these on a consistent basis over
3:31:03.200,3:31:10.960
time — these are daily pills where the problem
is: one, maybe remembering to take it every day;
3:31:10.960,3:31:16.720
second, having enough supplies with you
every day; the stigma that we talked about;
3:31:16.720,3:31:21.760
maybe these issues around getting a refill
on time. So there are all of these issues
3:31:21.760,3:31:29.120
that make it difficult to take these drugs in the
long term, for women in Uganda and South Africa,
3:31:29.120,3:31:33.519
where this trial was done. What was
interesting about the study is that
3:31:33.520,3:31:40.160
they could actually measure how regularly people
were taking these drugs through blood testing.
3:31:40.160,3:31:42.479
Is that because they're taking samples? Wow.
3:31:42.479,3:31:50.160
They're taking dried blood spot samples from
people and then they're testing the level of
3:31:50.160,3:31:56.479
tenofovir in their red blood cells. So this
directly tells them what is a concentration
3:31:56.479,3:32:03.200
of this drug in this participant?
With this, you can see how, over time,
3:32:03.200,3:32:11.120
the expected- how frequently people are taking
them, that reduces over months of the study.
3:32:11.120,3:32:18.080
People, on average, are taking them quite often,
but over time that adherence gets much lower,
3:32:18.080,3:32:24.800
so they're mostly taking them two or- one or
two times per week, by the end of the trial.
3:32:26.319,3:32:35.439
And this gets back to this previous chart. So
we've seen what happens with Descovy and Truvada,
3:32:35.439,3:32:46.639
what happens with lenacapavir? Zero women
out of 2,134 get infected with HIV. That is
3:32:46.640,3:32:54.560
just an incredible result. And there is some
uncertainty around that. The efficacy — so
3:32:54.560,3:33:01.760
how much lower the rate of HIV infection
is, compared to the background rates — is
3:33:01.760,3:33:08.319
96 to a hundred percent. So it's somewhere-
it's not completely effective, necessarily,
3:33:08.319,3:33:14.541
because there isn't a large enough sample to say
that this is a hundred percent efficacy rate-
3:33:14.542,3:33:17.600
We can't rule out-
-but it is more than 96% of a reduction.
3:33:17.600,3:33:24.880
That is so incredible. So incredible.
That is so incredible. Zero cases.
3:33:24.880,3:33:32.239
Zero cases. I was reading about this, I
think, on STAT news — the health and medicine
3:33:32.239,3:33:37.679
magazine — and they mentioned how these results
were presented at this conference, and they just
3:33:37.680,3:33:44.080
got this standing ovation where people, I mean,
unsurprisingly, this is just an incredible result.
3:33:44.080,3:33:45.439
Unbelievable.
3:33:45.439,3:33:51.599
One last thing about lenacapavir,
truvada, and descovy is the side
3:33:51.600,3:33:55.680
effects. We talked about- okay,
we have this long-lasting drug,
3:33:55.680,3:34:02.640
that means there's a risk of long-lasting side
effects as well. What happened in this trial was,
3:34:02.640,3:34:07.840
they didn't find that much of a difference between
the different groups. Most of the side effects
3:34:07.840,3:34:13.279
were similarly seen in the different groups,
and those are mostly things like headaches,
3:34:13.279,3:34:20.880
fevers — but again, when we record side effects
in a trial, we can't necessarily, conclusively,
3:34:20.880,3:34:25.120
say that these are because of drugs. People
have headaches, fevers just anyway in a typical-
3:34:25.120,3:34:30.239
We don't have a clean placebo here, I guess.
I mean it's interesting that, when I think
3:34:30.239,3:34:35.679
about what friends report as side effects of
oral PrEP — because it's oral, there's often
3:34:35.680,3:34:42.399
digestive issues or stomach problems. I wonder
if they tested for that, because I would guess
3:34:42.399,3:34:47.599
intuitively that lenacapavir would've fewer of
those ones. But I dunno if they tested for that.
3:34:47.600,3:34:55.120
And you would be right! They did find lower
rates of nausea and vomiting with lenacapavir,
3:34:55.120,3:35:01.040
and I guess this is because of the difference —
where it's not an oral drug, it's an injectable,
3:35:01.040,3:35:05.279
so it's not passing through your
digestive tract and your stomach.
3:35:05.279,3:35:09.840
We don't need to do trials. You
can just quiz me on my guesses.
3:35:09.840,3:35:18.479
The other thing was the little bumps on people's
skin, the depots of lenacapavir — so that was
3:35:18.479,3:35:24.639
quite common. About 70% of the people
who got lenacapavir develop these little
3:35:24.640,3:35:34.960
bumps — nodules — under their skin, and those
typically shrunk down to normal after a while,
3:35:34.960,3:35:41.120
but also, the next doses tended to
not- you wouldn't tend to see those.
3:35:41.120,3:35:46.800
Yeah, I'd love to learn more about that. To me,
it sounds like success: I want a little nodule,
3:35:46.800,3:35:51.760
I want to know that drug is there, and, sure
enough, in six months, I want the nodule to be
3:35:51.760,3:35:58.880
gone because the drug is gone. But I guess there's
more going on in the body than I'm projecting.
3:35:58.880,3:36:06.720
I was also surprised that 30% of people who get
lenacapavir don't develop these nodules. What is
3:36:06.720,3:36:12.000
causing this difference? And I, sadly, don't know
the answer to that, but it's quite interesting.
3:36:14.479,3:36:20.399
I was about to ask about other trials,
outside of women, but is there anything else,
3:36:20.399,3:36:27.439
on this trial, that I should know first?
I think, maybe, we should talk a little bit
3:36:27.439,3:36:35.759
about why was there almost no difference between
Descovy and Truvada and the background rates,
3:36:35.760,3:36:41.279
and why is it that lenacapavir is so
effective in these trials, or like,
3:36:41.279,3:36:48.719
in the real world? I think there's- so I would
say that it's not entirely clear how effective
3:36:49.359,3:36:56.559
Descovy and Truvada are, compared to not taking
any drugs. That's just because the uncertainty on
3:36:56.560,3:37:05.279
those is fairly moderate, so there isn't a very
precise figure that we would have; it seems like
3:37:05.279,3:37:10.160
they're roughly similar, but there could still
be some meaningful reduction that these are
3:37:10.160,3:37:16.720
providing. I guess the other reason is, if people
are not taking it regularly — these oral pills
3:37:16.720,3:37:25.279
regularly — for whatever reason, in the long term,
that reduces the efficacy. So even if someone
3:37:25.279,3:37:31.120
was taking it every day, it would be a higher
level of effectiveness than in the real world,
3:37:31.120,3:37:38.000
where people are taking it less often. And I think
this is why lenacapavir is so much more effective:
3:37:38.000,3:37:45.760
it's not just that it's highly effective on its
own, but it's also really long lasting, and that
3:37:45.760,3:37:53.840
both of those contrast with Descovy and Truvada.
Yeah, I guess it's proving the hypothesis with
3:37:53.840,3:37:59.359
data; that's what we were wondering,
and we were hopeful that lenacapavir's
3:37:59.359,3:38:04.319
long-lasting properties would pay
off, and it looks like they did.
3:38:04.319,3:38:12.960
They did. And they did another trial with men and
gender-diverse people — this was in six countries:
3:38:12.960,3:38:18.640
the US, I think, some South American and
central American countries as well. Again,
3:38:18.640,3:38:22.640
the reduction you would see — with
lenacapavir, on how likely it is for
3:38:22.640,3:38:31.600
an infection — was massive. It was two people
out of thousands who contracted HIV versus,
3:38:31.600,3:38:36.000
I think, more than a dozen, or a
dozen, in the other groups. So again,
3:38:37.359,3:38:46.880
this time their estimate was that there was
82 to 99% efficacy for this drug. And again,
3:38:46.880,3:38:54.960
they saw that Descovy and Truvada had a very
little impact compared to the background rate.
3:38:54.960,3:39:00.880
It's a big win. Okay, so there were
two cases; so it wasn't zero. Two out
3:39:00.880,3:39:06.080
of a couple thousand, but the
reduction in risk is enormous.
3:39:06.080,3:39:11.200
Is huge. I would say that,
you shouldn't go away from
3:39:11.200,3:39:15.200
this thinking this completely prevents infections;
3:39:15.200,3:39:23.279
there is still a chance. But the reduction is so
large that it's a really important breakthrough.
3:39:24.160,3:39:31.920
My hope, and I hate to be hopeful, but you can get
non-linear population effects with transmission
3:39:31.920,3:39:41.120
reductions, where, if a transmission per event
drops 90% at a background rate, the background
3:39:41.120,3:39:46.559
rate might start dropping too. I mean, it depends
on interactions with treatment drugs and a lot of
3:39:46.560,3:39:52.800
other factors — but if you can imagine that,
per event, your risk is going down and then,
3:39:52.800,3:39:59.680
over time, the background rate going down,
that's actually a very large effect together.
3:40:00.560,3:40:05.520
That reminds me of this concept of the
reproductive number, that a lot of people
3:40:05.520,3:40:12.960
would've heard about during the COVID pandemic-
R nought. The R nought. So this is the number of
3:40:12.960,3:40:20.880
people, on average, that someone infects, if
they've been infected. So if I was infected,
3:40:20.880,3:40:26.640
maybe I would infect three other
people on average with the coronavirus,
3:40:26.640,3:40:32.479
in this case. The higher the number,
the harder it is to control the disease,
3:40:32.479,3:40:40.000
but also the faster it spreads in the population.
And if it gets below one — if I'm spreading it
3:40:40.000,3:40:47.760
to less than one person on average —
eventually that disease will die out.
3:40:47.760,3:40:52.160
It's a dream that we can head towards
now, maybe. Okay, that's PrEP.
3:40:52.880,3:41:00.479
Did lenacapavir get tested in trials for
treatment as well, not just prevention?
3:41:00.479,3:41:07.759
Yes! It was actually tested and approved as a
treatment drug before these preventive trials
3:41:07.760,3:41:14.800
and results. The first trial was as a treatment
for drug-resistant HIV, where they're testing
3:41:14.800,3:41:21.840
lenacapavir plus the standard regimen that
people are having, in people who have tried
3:41:21.840,3:41:30.880
many different treatments so far, and this is plan
C or D. So it was effective in those trials; it
3:41:30.880,3:41:38.720
was approved as a treatment for drug-resistant HIV
based on that. They also did a phase two trial,
3:41:38.720,3:41:46.000
where they tested it as a first line treatment —
so that means that would be: How effective is it,
3:41:46.000,3:41:50.880
as the first treatment that someone receives
if they have been diagnosed with HIV? So they
3:41:50.880,3:41:58.319
compared lenacapavir with other existing drugs.
There are a bunch of other ongoing trials,
3:41:58.319,3:42:05.519
still. So I think there are more
long-acting treatments, where they're
3:42:05.520,3:42:11.040
testing a combination of lenacapavir
and islatravir, which you mentioned.
3:42:11.040,3:42:11.680
The Merck one.
3:42:11.680,3:42:17.279
That was the Merck oral pill,
which are both long-acting, right?
3:42:17.279,3:42:18.479
Yeah.
3:42:18.479,3:42:22.799
And then, there were a bunch of other
types of treatments: so they're doing
3:42:23.840,3:42:30.880
testing in children and adolescents;
they're also testing whether it can
3:42:30.880,3:42:39.040
be used in people who have been receiving other
types of antiretroviral drugs, but they still
3:42:39.040,3:42:46.720
have some HIV that's suppressed in their body.
As we talked about, hours ago, one of the things
3:42:46.720,3:42:55.760
that you see with HIV is that these drugs can
block the multiplication of HIV in your body. But
3:42:55.760,3:43:02.960
there are also particles that would stay in some
parts of your body, hidden in silence, and these
3:43:02.960,3:43:10.720
reservoirs of HIV are difficult to get rid of.
So is it possible to use lenacapavir to disrupt
3:43:10.720,3:43:16.080
these reservoirs? That is one of the questions
that they're looking at in this other trial.
3:43:16.080,3:43:21.040
And then there are a bunch of others, so they
think there's another one with lenacapavir plus
3:43:21.040,3:43:27.920
cabotegravir in people who have taken lots
of other treatments. And these trials are
3:43:27.920,3:43:32.880
being conducted, essentially, almost like,
all over the world — it's North America,
3:43:32.880,3:43:41.680
Europe, and Southern Africa; many different
countries. It's basically quite a big process:
3:43:41.680,3:43:47.439
to do this lab testing, to develop these
drugs, to then test them in some places,
3:43:47.439,3:43:53.519
in certain countries like the US or like Southern
Africa, and then to scale it up, to these massive
3:43:53.520,3:44:03.600
trials — is quite interesting, but also, to me,
quite impressive how fast this has happened. That
3:44:03.600,3:44:14.080
drug was only developed in 2018 and it's been —
well, okay, it has been seven years since then.
3:44:14.080,3:44:20.160
I'm used to seeing timelines that are so long,
and this was approved for the first time in 2022,
3:44:20.160,3:44:27.279
I think, as a treatment for drug-resistant HIV,
which is only four years in trials. I think that,
3:44:27.279,3:44:35.439
I mean, on a personal level, I think that could
still be sped up, but that is an impressive speed.
3:44:35.439,3:44:43.359
Yeah, it's a four year starting clock to finish
line, not so bad. But we're not at the finish line
3:44:43.359,3:44:51.759
yet. The finish line is, is this really going to
impact people's lives who are at risk of HIV? So
3:44:51.760,3:45:00.560
just summing up what we just covered: we have
now looked at long-lasting drugs as a concept,
3:45:00.560,3:45:09.439
and other HIV long-lasting drugs, and long-lasting
drugs in other areas that we're excited about,
3:45:09.439,3:45:14.399
but are still in development.
And then, you just outlined with lenacapavir,
3:45:14.399,3:45:23.359
what was the clinical story to get here and who
can benefit from lenacapavir? And it sounds like,
3:45:23.359,3:45:30.239
the people who've called this a miracle drug, to
me, are basically right. In the clinical trial for
3:45:30.239,3:45:38.800
cisgender women, there were zero HIV infections
among the 2,000 women who got this injection, and
3:45:38.800,3:45:46.880
there were tens of infections in the other arms,
for women on other forms of PrEP; so this is a
3:45:46.880,3:45:54.479
totally different situation. And for men who have
sex with men, and other trans people who are in
3:45:54.479,3:46:02.319
the other trial, the other phase three — there was
also a massive drop of, say, 80, 90 more percent
3:46:02.319,3:46:11.040
in transmission. So, how do we get this drug
to people, Saloni? That's what I want to know.
3:46:11.040,3:46:18.880
Maybe, also, just to think back to the whole
timeline of drug development in this field. In
3:46:18.880,3:46:24.640
the 1980s, in the early 1980s, when the first
case was reported — no drugs; people thought
3:46:24.640,3:46:31.199
this was an untreatable disease, or they wanted
to treat it, but they had no idea how. In 1987,
3:46:31.199,3:46:39.519
the first HIV drug, azidothymidine. '95, the first
protease inhibitor, and the start of combination
3:46:39.520,3:46:46.640
therapy that completely changed the survival
for people with HIV. In 2012, is that right?
3:46:46.640,3:46:54.640
We have PrEP — truvada — introduced, and then, in
2022, we have lenacapavir, as this drug-resistant
3:46:54.640,3:47:03.760
treatment. Then, now, we have lenacapavir as
a preventive drug, that is so long-lasting,
3:47:03.760,3:47:10.080
and both a breakthrough in terms of the
effectiveness, in terms of how you take it,
3:47:10.080,3:47:15.600
how long it lasts in the body, but also,
because it was a completely new type of
3:47:15.600,3:47:25.279
treatment. It works- it inhibits the capsid of the
HIV virus; it's not just tweaking existing drugs,
3:47:25.279,3:47:30.239
it's this whole new type of treatment
that now opens up the field of research
3:47:30.239,3:47:39.199
to developing more capsid drugs, I think, as
well as more long-lasting drugs in the body.
3:47:39.199,3:47:42.160
All of that building on each other to get us to
3:47:42.160,3:47:46.880
this moment. The decades of
science. I feel so grateful.
3:47:46.880,3:47:55.359
Decades of science. Let's talk about where we are
now, in terms of, how are we going to scale this?
3:47:55.359,3:48:01.905
I mean, not us, specifically, but how are people
going to scale up this drug? — you and me, back
3:48:01.905,3:48:07.040
of the van — getting them to everyone who- Like,
just driving this van around in small villages.
3:48:07.040,3:48:10.720
I'm ready. Road trip?
3:48:10.720,3:48:20.560
So how is this going to be rolled out to
people who need it, across the world? I think,
3:48:20.560,3:48:26.239
the most important continent here is Africa,
and Southern Africa. Maybe we should talk a
3:48:26.239,3:48:33.120
little bit about: What has the situation
been like until now? How does that process
3:48:33.120,3:48:39.279
work? How are people getting treatments
across Africa, and how has that happened?
3:48:39.279,3:48:40.479
I love it.
3:48:40.479,3:48:48.719
Let's talk about HIV treatment and prevention
around the world, how that's worked so far.
3:48:48.720,3:48:56.720
Where we are now, where we could go from
here. I didn't know, until a few years ago,
3:48:56.720,3:49:06.960
how big the HIV treatment and prevention programs
were worldwide. The biggest progra is PEPFAR, the
3:49:06.960,3:49:14.960
President's Emergency Plan for AIDS Relief, which
was launched in 2003 by the Bush administration.
3:49:14.960,3:49:21.439
That was, at that point, the largest ever
US global health initiative for a single
3:49:21.439,3:49:31.599
disease. It was 15 billion, as a commitment
over five years, to fight HIV and AIDS in
3:49:31.600,3:49:38.319
affected countries — mostly in Southern Africa,
but also other countries. I remember reading
3:49:38.319,3:49:45.840
about how this was formed, how the whole program
came together, and it was super interesting and
3:49:45.840,3:49:52.960
inspiring — this idea that you could actually
set up this huge program to treat millions of
3:49:52.960,3:50:02.800
people in the poorest parts of the world against
this really deadly, scary disease. At that point,
3:50:02.800,3:50:08.720
there were effective combination drugs available,
to people in the US and other richer countries,
3:50:08.720,3:50:15.040
but people in Africa were not, you
know, they weren't able to access them,
3:50:16.560,3:50:22.960
which is quite scary. You have such a hugely
unequal outcomes just based on where you live,
3:50:22.960,3:50:29.520
but also there is this drug that feels just
out of reach that wasn't getting to people.
3:50:29.520,3:50:38.800
And what I read was that Bush wanted to do
something big on HIV and AIDS and he asked
3:50:38.800,3:50:47.680
several people working with him on health in
the US including Anthony Fauci and Dr. Mark
3:50:47.680,3:50:56.880
Dybul to figure out what was possible, and they
looked at what was already being done in Africa.
3:50:57.840,3:51:02.720
Was there anyone who was receiving treatment
at this time? How were they getting it? And
3:51:02.720,3:51:09.120
the main source that they found at the time was
TASO, The AIDS Support Organisation and Doctors
3:51:09.120,3:51:16.640
Without Borders or Medicins Sans Frontieres —
and they had been providing treatments to people,
3:51:18.479,3:51:24.479
I think it was in one- two countries, South
Africa and Malawi. They were providing these
3:51:24.479,3:51:34.080
generic versions of antiretrovirals to them, on a
voluntary basis. But what really stuck in my mind
3:51:34.080,3:51:39.439
was, when I was reading this interview of Mark
Dybul — one of the people who worked on setting
3:51:39.439,3:51:46.160
up this program and planning it out — was that
he mentioned that, at that point, TASO, the AIDS
3:51:46.160,3:51:52.639
support organisation, were actually transporting
this in little, I think, fridges on their bags-
3:51:52.640,3:51:53.140
Wow.
3:51:54.239,3:51:59.920
-that they were carrying around on
motorbikes around to remote villages,
3:51:59.920,3:52:07.760
to get these drugs to people who needed them.
That was very inspiring. But the success of
3:52:07.760,3:52:14.239
Doctors Without Borders, in small scale-
in providing treatment at a small scale,
3:52:14.239,3:52:19.279
showed that this was possible. Could it be scaled-
3:52:19.279,3:52:20.800
It's a proof of concept?
3:52:20.800,3:52:26.000
It's a proof of concept. So now what's needed is
to set up these supply chains to do this at a much
3:52:26.000,3:52:34.239
bigger scale — to set up the drug development and
manufacturing; set up the networks of clinics,
3:52:34.239,3:52:40.000
and the people who would be providing
treatment to people in remote villages,
3:52:40.000,3:52:49.520
and so on. So Mark Dybul and Anthony Fauci put
together these plans of: how much this would cost,
3:52:49.520,3:52:58.160
what it would look like to operate this, how it
might look like at scale. The other reason this
3:52:58.160,3:53:04.479
is really interesting is because, at the time,
people didn't think it was possible to do this.
3:53:04.479,3:53:11.279
They thought this was just some pipe dream.
Several reasons: one is this is a really poor
3:53:11.279,3:53:18.000
region. Trying to set up something like this
at scale requires a lot of work; you have to
3:53:18.000,3:53:24.960
work with community leaders, you need to hire
people, train people to provide this treatment.
3:53:24.960,3:53:31.279
I think there was also this perception,
that some people had, was that poor people
3:53:31.279,3:53:39.519
in Africa couldn't take daily pills; they
couldn't follow these regimens. And I mean,
3:53:40.080,3:53:45.600
the fact that this program is so effective
has, I think, has shown that that's not the
3:53:45.600,3:53:52.800
case. But it's also this idea that, just because
something is difficult to take regularly doesn't
3:53:52.800,3:53:58.560
necessarily mean that we should stop there, and
accept that as status quo. You could eventually
3:53:58.560,3:54:04.560
develop long-lasting drugs, you could find some
way to make it easier for people to access these
3:54:04.560,3:54:11.360
treatments on a regular basis. And I think that
kind of attitude shift is really important here.
3:54:14.560,3:54:18.720
You can do big things and sometimes they
work, and at the turn of the century,
3:54:18.720,3:54:27.279
I feel like there was more optimism around big
global health improvements and projects. And at
3:54:27.279,3:54:33.519
the same time as PEPFAR was getting started, or a
similar time, the Global Fund was getting started,
3:54:33.520,3:54:40.800
which was not just a US program, but
was a multilateral program that involved
3:54:40.800,3:54:47.279
many different donor countries. So higher income
countries contributing into a pooled fund,
3:54:47.279,3:54:52.639
which would focus on HIV/AIDS, and
malaria, and tuberculosis. Three
3:54:52.640,3:54:58.319
of the biggest infectious disease killers
around the world, at the time and still now.
3:54:58.319,3:55:06.960
And since then, we have as a species, as a global
society, made a huge amount of progress on all
3:55:06.960,3:55:16.479
three of those diseases. We should probably show a
graph of HIV/AIDS incidence, but also AIDS deaths,
3:55:16.479,3:55:23.199
because the curve really bent down with these
commitments from the Global Fund and from PEPFAR.
3:55:23.199,3:55:29.760
It was a problem that seemed to be spiralling
out of control, and then lots of energy, focus,
3:55:29.760,3:55:36.319
attention, resources were put into it, on
really scaling up proofs-of-concepts, and
3:55:36.319,3:55:42.319
really committing to it. Lo and behold, there were
results. And that's inspiring to look back on,
3:55:42.319,3:55:47.359
and I wonder what it would've been like to be in
the room when people thought it was impossible,
3:55:47.359,3:55:52.880
and you really thought, like Mark Dybul
and others, but we gotta go for it.
3:55:52.880,3:56:02.720
It's also incredible to think about, from the
perspective of people in Africa, how common HIV
3:56:02.720,3:56:09.920
was, at the time, is probably not obvious to
some of us. But, in the year 2000, there were
3:56:09.920,3:56:20.479
several countries in Southern Africa where, some
twenty, 15 to 30% of the adult population had HIV.
3:56:20.479,3:56:29.599
That is scary to think about, for such a deadly
disease: how it affects the people themselves,
3:56:29.600,3:56:38.960
their families, the society as a whole. This was
really effective and successful, both at changing
3:56:38.960,3:56:48.319
what life was like for people with HIV, but just
also the culture around it, and it's continued
3:56:48.319,3:56:55.840
since 2003, so it's just an incredible program.
It's one of the biggest global health programs.
3:56:55.840,3:57:03.840
But at the same time, it costs a very small
fraction of our incomes here, or in the US,
3:57:03.840,3:57:11.439
to contribute to PEPFAR or the Global Fund, and it
makes a massive impact on people around the world.
3:57:11.439,3:57:17.839
Well, it reminds me of the graph that
you showed earlier in this episode,
3:57:17.840,3:57:23.040
when combination treatment first came out
in the nineties, and you saw this totally
3:57:23.040,3:57:34.399
discontinuous drop in mortality rates. This was
scaling that drop up to people who did not have
3:57:34.399,3:57:41.120
access to the drugs, until there was a global
commitment behind them. That means that there
3:57:41.120,3:57:47.920
are many people — not just millions, but tens
of millions of people — who are alive right now,
3:57:47.920,3:57:55.840
who are on drugs that control their infection,
who would not have been alive. And it's so heady,
3:57:55.840,3:58:04.319
it's impossible to, at least for me, to
get my head around that, but friends, so
3:58:04.319,3:58:13.199
many families. So it's mind blowing to think how
different the world would be for so many people.
3:58:13.199,3:58:22.479
The scale of this is also incredible to me. The
estimates are that there've been 25 million people
3:58:24.479,3:58:31.599
whose early deaths were prevented because of
PEPFAR as a program. 25 million is such a,
3:58:32.560,3:58:37.920
in terms of the number of lives saved, it's
just so huge to think about, it's like London's
3:58:37.920,3:58:47.920
population is what, 11, 12 million? That's two,
more than two of the entire... Wow. It's just,
3:58:47.920,3:58:56.160
imagine that not existing; all those people
not being alive. It's just a huge impact.
3:58:56.160,3:58:58.479
20 San Franciscos.
3:58:58.479,3:59:01.519
20 San Franciscos.
3:59:01.520,3:59:07.439
So what's happening now, then? It's
all good news, by the sounds of things.
3:59:07.439,3:59:15.439
It's not good news, sadly. It's April when
we're recording this and there's- in the
3:59:15.439,3:59:21.839
last few months, the picture around PEPFAR
and various other global health programs has
3:59:21.840,3:59:30.720
completely changed. At the end of January,
there was a foreign aid spending freeze. So,
3:59:30.720,3:59:37.199
all funding to various global health,
humanitarian programs was frozen. Also,
3:59:37.199,3:59:47.120
staff who were working at the US aid agency,
USAID, — some thousands of them were laid off.
3:59:47.120,3:59:52.880
The remaining ones were asked not to talk to
the public, but also, they weren't able to keep
3:59:52.880,3:59:58.960
in contact with the programs in the field;
they were just banned from communicating.
3:59:59.920,4:00:06.160
There was also this — because of all the layoffs —
that also meant running the programs on the field
4:00:06.160,4:00:15.680
was difficult, for people who were working
overseas. This freeze was meant to be — this
4:00:15.680,4:00:23.439
is the stated intention — which is that it was
for a three-month-long review of these programs,
4:00:23.439,4:00:30.319
of all foreign aid programs, to see if they
aligned with the Trump administration's interests,
4:00:30.319,4:00:36.719
such as national security and things like that.
But a lot of them were, I mean, this just froze
4:00:36.720,4:00:43.279
all of them at once, rather than doing a review at
the same time while they were ongoing. But also,
4:00:43.279,4:00:50.080
even after this freeze was ended, which
was after- I think it was 39 or so,
4:00:50.080,4:01:01.279
35 business days, instead of three months, and
some 80 to 90% of programs were just cancelled.
4:01:01.279,4:01:08.399
Because programs refers to specific recipients
of funds, I think for specific purposes, that
4:01:08.399,4:01:18.319
doesn't mean that that PEPFAR was cut by 90% or
so. For HIV and AIDS, I think it was around 23%,
4:01:18.319,4:01:24.239
if you roughly estimate based on the amount of
funding those specific council programs received,
4:01:24.239,4:01:33.199
that were cut. And that seems like maybe
just a fraction of this worst-case scenario,
4:01:34.000,4:01:39.359
of the whole thing being paused, but I think
because so many thousands of staff were laid
4:01:39.359,4:01:44.960
off — and because of this uncertainty
and this freeze — that actually had,
4:01:44.960,4:01:51.520
from what I can understand, quite a large impact.
One reason for that is: clinics, or programs,
4:01:51.520,4:01:56.960
receiving the funding, some of them weren't
able to survive more than a few months without
4:01:56.960,4:02:01.680
continued funding. Some of the funding was
for stuff that they had already completed,
4:02:01.680,4:02:07.279
and they were just waiting to receive the payment
for it, and that was cancelled as well. Some of
4:02:07.279,4:02:13.920
them were for continued work, and this was
cancelled. If clinics are not able to survive
4:02:13.920,4:02:18.960
for more than a few weeks, or a few months,
without this funding that they're expecting, they
4:02:18.960,4:02:28.880
might just shut down. So in the field, what people
might have seen would be a physical clinic that's
4:02:28.880,4:02:34.160
there — sometimes the treatment is actually inside
the clinic — but they can't access it, because the
4:02:34.160,4:02:42.239
clinic is shut down, and/or the staff is just not
around. There aren't people working the clinics.
4:02:42.239,4:02:50.399
And thirdly, trying to get new supplies to these
clinics was also disrupted, so they weren't able
4:02:50.399,4:02:56.559
to restock on a lot of the treatments.
At the point where we are now, I think
4:02:56.560,4:03:03.920
there's been a lot of disruption, but there's
a rough plan to merge all of these foreign aid
4:03:03.920,4:03:10.560
programs under USAID into the State Department
of the US. I think this is still a little bit
4:03:10.560,4:03:16.560
up in the air, in terms of how that will
actually work, how will it affect PEPFAR?
4:03:16.560,4:03:24.239
One thing I'm slightly worried about is
what will they actually cut? What aligns
4:03:24.239,4:03:29.199
with the Trump administration's interests,
and what doesn't? And I think you can get
4:03:29.199,4:03:37.120
a little bit of a clue from how they responded
when this funding aid freeze began in January.
4:03:37.120,4:03:42.319
They initially said that there were certain
parts of the program that would continue,
4:03:42.880,4:03:48.960
such as treatments for pregnant women. But
from what I understand, that actually didn't
4:03:48.960,4:03:55.120
happen in practice, because of all of these
layoffs, and the funding cuts, and so on.
4:03:55.120,4:04:02.880
But what I'm worried about is, what about
prevention as a whole? We think about the critical
4:04:02.880,4:04:10.640
part of PEPFAR as being preventing mother-to-child
transmission, but it's also the broader thing of:
4:04:10.640,4:04:17.600
how do we reduce the spread of HIV? How do we
treat everyone who has HIV? This began as such
4:04:17.600,4:04:29.920
an ambitious and effective program that managed
to treat some 20.5 million people last year,
4:04:29.920,4:04:37.359
and now that's massively been frozen and we
don't know how much of it's going to remain.
4:04:37.359,4:04:45.839
It's so frustrating. It's so frustrating
to see such a good use of money that,
4:04:45.840,4:04:52.160
in the grand scheme of things, is not that much
money from the US government's perspective.
4:04:52.160,4:04:55.840
I mean, it's frustrating in the short term. I'm
more nervous about treatment than prevention;
4:04:55.840,4:05:04.160
of what you're describing of clinics being closed.
If you have HIV, you need to be on daily drugs,
4:05:04.160,4:05:12.559
and if you run out and can't get a refill, oh God,
it must just be so scary. It must be so scary. And
4:05:12.560,4:05:19.840
then I totally agree. We're at this present, we
at this wonderful moment of prevention and driving
4:05:19.840,4:05:26.640
down transmission is just becoming more and more
possible with lenacapavir and with other drugs.
4:05:27.760,4:05:34.640
It's... I find it really heartbreaking because,
until this point, until this year, I was so
4:05:34.640,4:05:41.520
excited about how would lenacapavir or other
long-acting treatments change the picture? Like,
4:05:41.520,4:05:46.880
would we be able to effectively eliminate
the transmission of HIV, in some of these
4:05:46.880,4:05:52.080
countries? And I think that's possible, and I
think that's a little bit ambitious, just like
4:05:52.080,4:05:58.000
PEPFAR is. I think it's possible. But instead
of going ahead, and kind of going big on this,
4:05:58.000,4:06:04.560
trying to really cut it down, and actually, then,
not needing such a large program because you've
4:06:04.560,4:06:10.880
managed to reduce the number of people who
are affected by this. Instead of doing that,
4:06:10.880,4:06:18.800
were on this road of a lot of uncertainty and
disruption, and that it's come so suddenly that
4:06:18.800,4:06:26.479
people couldn't plan for it. They didn't expect
that their treatment would suddenly disappear. I
4:06:26.479,4:06:33.839
think what the figures were showing, that I was
reading, was- the program, PEPFAR is so big,
4:06:33.840,4:06:42.000
there's 20 and a half million people receiving
treatment from PEPFAR per year. On a daily level,
4:06:42.000,4:06:50.800
that's 200,000 people who are getting their
refills; 200,000 people who are realising
4:06:50.800,4:06:58.080
the clinics are shut, and they don't know
how they're going to get their next supply.
4:06:58.080,4:07:05.519
Well, and that's 200,000 cases of higher
risk of mutated viruses as well, presumably.
4:07:05.520,4:07:13.920
There's a risk of the resurgence of HIV, if
people stop taking treatment for, I think,
4:07:13.920,4:07:20.319
it's a few months or so, and that has some
quite nasty side effects in the initial period;
4:07:20.319,4:07:28.799
and then there's also of the complications that
people would have with HIV as a disease itself.
4:07:28.800,4:07:33.600
Okay, so to summarise: the launch of
PEPFAR, the launch of the Global Fund
4:07:33.600,4:07:40.399
were a particularly ambitious moment, and
there were people around who thought maybe
4:07:40.399,4:07:43.679
they would not achieve their aims,
because it never been done before.
4:07:43.680,4:07:49.359
And lo and behold, they achieved great
things for tens of millions of people.
4:07:49.359,4:07:51.759
For over two decades.
4:07:51.760,4:07:59.439
Over two decades. And now we're not only,
we've been talking, in this episode,
4:07:59.439,4:08:04.479
about great technical achievement. That could be a
launch of a new ambitious program and really drive
4:08:04.479,4:08:10.959
down transmission, but really, we're at a state
where, not only are the ambition levels lower,
4:08:10.960,4:08:20.560
but the basics are not, as we record,
being provided for everyone who needs them.
4:08:20.560,4:08:25.920
Right. It brings me to this point that I
often think about. So when I write this
4:08:25.920,4:08:33.120
Substack newsletter on medical innovation, and
what is the use of new treatments if there's
4:08:33.120,4:08:41.840
no one to distribute them, or if there's no one
that can access them. This is the whole point of
4:08:41.840,4:08:48.560
medical- or, these breakthroughs don't matter, if
they're not getting to the people who need them.
4:08:48.560,4:08:54.479
Okay, so do we have any hope for the Global
Fund? So listeners who are in the US, think about
4:08:54.479,4:09:02.719
PEPFAR. Listeners in other countries, think about
your own health systems and think about the Global
4:09:02.720,4:09:08.640
Fund, which, I assume, is up for replenishment
pretty soon, and is doing a lot of this work too.
4:09:08.640,4:09:15.439
Replenishment is when they get funding
replenished from various countries.
4:09:15.439,4:09:16.000
Yes, exactly.
4:09:16.000,4:09:19.600
And those are decided by
their foreign aid budgets.
4:09:19.600,4:09:30.160
Correct. So foreign aid in many higher-income
and middle-income countries will contribute
4:09:30.160,4:09:37.359
some amount of tax revenues, or of government
revenues, to foreign aid to other countries.
4:09:37.359,4:09:46.239
A good slice of that is global health; and HIV
treatment and prevention is a reasonable portion
4:09:46.239,4:09:56.559
of that global health contribution, often via the
Global Fund. And the UK is not in a particularly
4:09:56.560,4:10:03.600
ambitious moment either. At the time of recording,
we are a month in, or possibly two months now,
4:10:03.600,4:10:13.040
into an announcement under the Labour government
that, instead of returning to 0.7% of GNI,
4:10:13.040,4:10:20.800
basically GDP, being contributed to foreign aid —
as was the case under the last Labour government
4:10:20.800,4:10:24.560
and the beginning of the last Conservative
government — we are going to drop down
4:10:24.560,4:10:32.800
to 0.3. So under COVID, we dropped from 0.7 to
0.5 in what was termed a temporary measure for
4:10:32.800,4:10:42.714
COVID. And now instead of returning to 0.7, we're
dropping down to 0.3 and we're going through-
4:10:42.714,4:10:43.760
0.3%, wow.
4:10:43.760,4:10:44.319
Yes.
4:10:44.319,4:10:50.399
So small. I mean, to me it seems so small
as well, because I have read about some of
4:10:50.399,4:10:55.120
these other programs that our foreign aid has
funded, and some of them are really impactful.
4:10:55.840,4:11:02.160
It's stuff like — oh my gosh — it's vaccination
of millions of children against these deadly
4:11:02.160,4:11:10.239
diseases that don't really affect us very much
in wealthier countries. It's stuff like trachoma,
4:11:10.239,4:11:16.559
which is this bacterial eye infection. The US
and the UK, and some other philanthropic donors,
4:11:16.560,4:11:23.439
came together to fund this really ambitious
program to supply antibiotic treatments,
4:11:23.439,4:11:28.879
better sanitation measures, and so on, to
hundreds of millions of people across Africa,
4:11:28.880,4:11:34.319
and they've massively reduced this... really
painful bacterial eye infection that can lead
4:11:34.319,4:11:41.679
to blindness in children. These are some huge
successes that many people don't even know about.
4:11:41.680,4:11:47.600
Tuberculosis — way down from 20 years ago.
Malaria, recently stalling, but has been
4:11:47.600,4:11:56.479
driven down a lot since 2000; mostly affects
children. Progress is possible. Okay, well,
4:11:56.479,4:12:04.080
now that we've depressed ourselves sufficiently,
there's both the financing that is not looking
4:12:04.080,4:12:10.800
so hot right now. The ambition not looking so
hot right now. Another thing that you can do,
4:12:10.800,4:12:19.199
to try and get more people access to treatment
and prevention, is to drive the cost down of
4:12:19.199,4:12:26.960
the actual drugs themselves. And maybe it's time
we talk about that with respect to lenacapavir.
4:12:26.960,4:12:32.319
What do we know about the
cost of lenacapavir right now?
4:12:32.319,4:12:39.199
Well, there's the cost of production and then
there's the price that the company selling the
4:12:39.199,4:12:49.679
drug charges. The price that Gilead is charging,
in the US, is $42,250 — is the last number I saw.
4:12:49.680,4:12:50.800
Per person?
4:12:50.800,4:12:57.199
Per person, per year. So that covers all
the injections for the first year. That
4:12:57.199,4:13:05.359
is about double what cabotegravir — the
Viiv injectable — is priced at in the US.
4:13:05.359,4:13:12.399
I was priced out of Cabotegravir; I assume I will
be priced out of lenacapavir in the short term.
4:13:12.399,4:13:18.879
Why do they charge that much money? Well, a lot
of the development that we talked about earlier
4:13:18.880,4:13:26.239
in the episode is done as a pure expense. So
all of the scientists who are working at Gilead,
4:13:26.239,4:13:31.199
trying to iterate on the drugs to make them
better, the funding for all the, or at least
4:13:31.199,4:13:36.080
most of the, clinical trials we discussed —
that's all done as an expense. So they want to
4:13:36.080,4:13:42.319
charge more out the other end, to some patients,
so that they can recoup some of that money. And
4:13:42.319,4:13:48.000
if they make any profit, hopefully some of it
will get reinvested in more drug development,
4:13:48.000,4:13:53.520
not just distributed to shareholders.
That, of course, raises questions:
4:13:53.520,4:13:58.640
well, do you think that someone in
Botswana is going to pay $42,000?
4:13:59.600,4:14:05.920
My guess is no, and I'm not going to pay $42,000,
so I'm with them. The price versus cost is very
4:14:05.920,4:14:11.680
different for patented medicines, often.
There are estimates for how much it will
4:14:11.680,4:14:19.520
cost to produce a generic version of lenacapavir
that are under a hundred dollars; I've seen as
4:14:19.520,4:14:24.479
low as $40. I haven't looked into the
drivers of those estimates, or how much
4:14:24.479,4:14:30.959
Gilead has really revealed about the production
methods in public — which would give you better
4:14:30.960,4:14:38.239
methods of coming up with estimates there.
The good news, though, is that Gilead has
4:14:38.239,4:14:48.319
already signed agreements with six generic
suppliers of lenacapavir for 120 countries;
4:14:48.319,4:14:54.080
so, plenty of low-income and middle-income
countries in that mix. And you may recall there
4:14:54.080,4:14:59.680
are about 200 countries in the world, so there's a
lot that are not covered there, but for those 120
4:14:59.680,4:15:08.640
countries, these suppliers will be able to provide
versions of lenacapavir that have been shown to
4:15:08.640,4:15:17.199
be therapeutically-equivalent to the initial
drug that Gilead used, in the clinical trials.
4:15:17.199,4:15:26.319
Though these new production runs will be made
by different companies, that have been given the
4:15:26.319,4:15:36.080
rights and taught a bit by Gilead how to do it.
Those generic companies will be manufacturing,
4:15:36.080,4:15:42.559
hopefully, eventually, enough supply for
use in those 120 countries. What Gilead,
4:15:42.560,4:15:49.760
in their press release in October, has
committed to is that they plan to provide
4:15:49.760,4:15:57.040
Gilead-supplied product at no profit to Gilead,
until generic manufacturers are able to fully
4:15:57.040,4:16:05.279
support demand in high-incidence, resource-limited
countries. So that's a great start, to be honest.
4:16:05.279,4:16:15.920
The questions that leaves me are, well, how
quickly- what is the supply? How quickly could
4:16:15.920,4:16:21.199
demand be met? And, are we sure that they're going
to ramp up quickly enough? I mean, number one. But
4:16:21.199,4:16:27.840
then, secondly, what about the other 80 countries?
So there are plenty of countries in South America,
4:16:27.840,4:16:35.760
for example, that are not in the 120 covered by
this generic agreement, and that have relatively
4:16:35.760,4:16:44.880
have medium HIV incidence — where a lot of people
could be protected by this drug that now exists.
4:16:44.880,4:16:49.920
Some of them were part of the clinical
trials for lenacapavir as well,
4:16:50.479,4:16:57.519
which is quite depressing. But, I think, what
I've read is that they plan to provide it
4:16:58.399,4:17:05.120
to people in the trial. I'm not sure that
that extends to the whole country. I mean,
4:17:05.120,4:17:09.840
could someone just make this drug themselves?
Or, I mean, not like an individual.
4:17:15.840,4:17:21.120
There's something beyond that, which are:
global intellectual property, and patents,
4:17:21.120,4:17:25.680
and enforcing those; then, there may
also be some technical barriers. So
4:17:25.680,4:17:30.560
I'll talk about the patents and then the
technical barriers. On the patents front,
4:17:30.560,4:17:38.960
there's a long history — with HIV specifically —
of the tension of global pharmaceutical companies,
4:17:38.960,4:17:46.640
who want to enforce patents and high prices, and
patients and activists and advocates, who want
4:17:46.640,4:17:54.319
medicines to be available for more people sooner.
And there's two broad solutions to this problem.
4:17:54.319,4:18:01.120
One is, what I just described, with Gilead,
which is voluntary licensing, where Gilead
4:18:02.319,4:18:08.000
arranges with other generic companies: 'Okay,
you can do this and we will not sue you for
4:18:08.000,4:18:13.760
selling these drugs in these 120 countries. But
if you sell them elsewhere, maybe we will sue
4:18:13.760,4:18:20.159
you.' That's voluntary [licensing].
Then there's compulsory licensing,
4:18:20.159,4:18:29.199
where a country may determine that they have a
public health crisis, to the extent that they
4:18:29.199,4:18:35.519
are not going to- the normal patent rules are out
the window. So this almost happened with HIV in
4:18:35.520,4:18:41.359
South Africa in the late '90s, early 2000s,
and more recently, I believe, in Colombia,
4:18:41.359,4:18:48.319
where the government's like, 'Make drugs, that's
okay, so long as people get the drugs.' I think
4:18:48.319,4:18:55.599
that is appropriate in some medical emergencies.
It was a big topic of dispute and debate in COVID
4:18:55.600,4:19:00.560
as well, where I think the debate actually
goes a bit of a different direction — probably
4:19:00.560,4:19:08.319
not worth getting into now, but vaccine
manufacturing is quite different to generic
4:19:08.319,4:19:14.799
small molecule manufacturing. Small molecules are,
in general, pretty commoditized: there are many,
4:19:14.800,4:19:19.600
many companies who can make them in
many, many countries. And vaccines,
4:19:19.600,4:19:25.600
the product is the process to some degree —
how you actually manufacture a given vaccine,
4:19:25.600,4:19:30.560
in a particular bioreactor, with particular cells,
with particular growth medium, you got to kind
4:19:30.560,4:19:35.120
of get taught by the original manufacturer.
It's harder to just scale up, and it's harder
4:19:35.120,4:19:41.760
to even infringe on a patent, if you wanted to.
That brings me to the technical blockades here,
4:19:41.760,4:19:49.199
where, for a traditional generic drug, a small
molecule, there are not many technical blockades;
4:19:49.199,4:19:55.199
you can just- even if a company has not revealed
all the secrets of how they made something,
4:19:55.199,4:20:00.960
they have to file with a regulator, and give some
information — some of which is then made public,
4:20:00.960,4:20:08.479
once a drug approval is given. They have to list
certain information on a label for patients,
4:20:08.479,4:20:12.799
of what the heck is in this drug.
And also, if you're a competitor,
4:20:12.800,4:20:18.399
you can simply buy their drug once it's on the
market, and analyse what's in it. So you have
4:20:18.399,4:20:27.439
a lot of tools where you can basically enter as a
competitor, from a technical point of view. Then,
4:20:27.439,4:20:36.479
the difficulty with some long-acting drugs
is that they are more complicated to copy. If
4:20:36.479,4:20:44.799
you were dealing with a long-acting drug that
had a liposome, or had a particular polymer-
4:20:44.800,4:20:46.159
What's a liposome?
4:20:46.159,4:20:50.159
You know, I don't want to answer that
question because I'll get it wrong.
4:20:50.159,4:20:51.760
It's a fatty blob, right?
4:20:51.760,4:20:52.800
Say it again?
4:20:52.800,4:20:55.323
It's a fatty blob.
4:20:55.323,4:20:55.359
Exactly, thank you!
"Lipo" means fat.
4:20:55.359,4:20:59.199
It's a fatty blob, I think it's probably
a bilayer. I think, basically imagine a
4:20:59.199,4:21:04.239
fatty blob that encapsulates the thing you
care about, but there are different fatty
4:21:04.239,4:21:08.800
blobs you might want to make, and there are
companies trying to improve their fatty blobs,
4:21:08.800,4:21:13.840
and it's harder to copy the fatty blobs that are
right at the frontier of fatty blob technology
4:21:13.840,4:21:18.720
than it is to copy the small molecule.
Now, the good news about lenacapavir,
4:21:18.720,4:21:24.159
and the good news about cabotegravir, and the good
news about islatravir — three of the long-lasting
4:21:24.159,4:21:30.239
drugs we've talked about for HIV — is that they
don't seem to be right at the hardest end. We
4:21:30.239,4:21:36.080
don't have a liposome, for example, involved.
We do, potentially, have some things that make
4:21:36.080,4:21:43.840
it a little harder than usual and — I'm a little
bit beyond my knowledge about how it applies to
4:21:43.840,4:21:51.199
lenacapavir, and I would love to see how it goes —
but, for example, I think you need a nano miller,
4:21:51.199,4:21:58.000
where you grind up your drugs! This is true for
Cabotegravir and, I think, probably not true for
4:21:58.000,4:22:04.640
lenacapavir. You grind up your drug crystal, so
they're tiny, tiny, tiny, tiny, so that when you
4:22:04.640,4:22:10.880
disperse them in a liquid, and then when you
inject that liquid with the solids, you've got
4:22:10.880,4:22:20.319
solids that are high-surface-area-to-volume-ratio.
So the question that comes to mind for me is:
4:22:20.319,4:22:26.799
Which generic companies own a nano miller, for
example, and does that machine cost $8 million,
4:22:26.800,4:22:32.319
you know, how much? Those questions start rearing
their head, and the next set of questions for me
4:22:32.319,4:22:41.359
is... there's a tried-and-true regulatory pathway
at the FDA and other regulators, for generic
4:22:41.359,4:22:48.719
equivalents to small molecules: you have to prove
only that they are equivalent in certain respects;
4:22:48.720,4:22:56.720
you do not have to redo everything else.
Are we sure that those tests are going to
4:22:56.720,4:23:03.279
be good enough, for long-acting injectables, or
for long-acting drugs in general? Or is there
4:23:03.279,4:23:08.880
some other reason why, towards the tail end
of many months, there may be more deviation
4:23:08.880,4:23:13.520
than you got from just testing the batch
chemically, and well- should we actually,
4:23:13.520,4:23:17.600
therefore, rerun a big clinical trial?
And that would be cost-prohibitive;
4:23:17.600,4:23:22.319
then you really would not see much generic entry.
I don't think that that's the way lenacapavir
4:23:22.319,4:23:29.759
will go. It certainly would get my hair up
if people started worrying about it though.
4:23:29.760,4:23:36.159
I mean, I guess this also makes me think about
Gilead producing it, probably, with multiple
4:23:36.159,4:23:42.720
manufacturing plants or so, and they would have to
do this internal testing, presumably. Hopefully,
4:23:42.720,4:23:46.720
there's a way to do that in the same way — or
they're producing it in a very similar way,
4:23:46.720,4:23:52.239
that they would be able to know early on, is this
the equivalent; are these molecules equivalent
4:23:52.239,4:24:00.479
across these different sites? The other question
that I had was, I had heard of this thing called
4:24:00.479,4:24:05.839
the Medicines Patent Pool? Is that something-
have we already covered that, or what is that?
4:24:05.840,4:24:12.319
Well, conceptually, a little bit, but actually
no. They are kind of an intermediary. They're
4:24:12.319,4:24:19.920
a UN-backed non-profit that tries to help match
up originator companies — that are filing patents
4:24:19.920,4:24:24.399
on new medicines, taking those medicines
through clinical trials, marketing them
4:24:24.399,4:24:33.279
in some countries — trying to match them up with
generic companies, who might want to market the
4:24:33.279,4:24:40.559
drug in countries the originator company doesn't
focus on as much, or doesn't care about as much,
4:24:40.560,4:24:47.920
in terms of making a profit, for example.
Often, there's a match to be made there,
4:24:47.920,4:24:51.600
that both companies are very happy with.
You know, especially if you're a smaller
4:24:51.600,4:24:58.239
originator company, who doesn't have any
experience selling into Bangladesh, then
4:24:58.239,4:25:03.920
you might very well want your drug to be used by
people in Bangladesh who want your drug... but you
4:25:03.920,4:25:09.359
just don't have the resources to get up to speed
with the drug regulator in Bangladesh. You're
4:25:09.359,4:25:16.000
going to be on the hook if anyone sues you for
side effects in Bangladesh; it's a big proposal.
4:25:16.000,4:25:21.760
But the Medicine Patents Pool, MPP, will sit in
the middle and say, 'Look, we have relationships
4:25:21.760,4:25:27.760
with many generic manufacturers, many of whom
have lots of experience in Bangladesh. If you just
4:25:28.479,4:25:33.359
sign on the dotted line here and say, you're not,
basically, you're not going to sue them if they
4:25:33.359,4:25:40.719
sell in Bangladesh, then you can both be happy
and patients get to benefit.' And they've had some
4:25:40.720,4:25:48.399
successes, in particular with HIV over the years.
I think they were set up in 2010 so, for the more
4:25:48.399,4:25:55.439
recent round of voluntary licensing. But they
worked on Cabotegravir, the initial long-lasting
4:25:55.439,4:26:02.719
injectable drug, and sort of sat between
Viiv, the originator company, and, I believe,
4:26:02.720,4:26:08.960
three generic companies there, to help transition
that- help get that out into more countries.
4:26:08.960,4:26:15.120
I didn't know much of that at all. That's
really cool. I'm kind of thinking about,
4:26:15.120,4:26:20.800
okay, we heard a little bit about how PEPFAR
was formed and that was set up, and yeah,
4:26:20.800,4:26:27.040
I'd very curious about that. The other thing
I was thinking was, okay, given that we have
4:26:27.040,4:26:34.560
all of this — we have the Medicines Patent Pool,
we have these licenses with generic manufacturers.
4:26:34.560,4:26:41.680
Also, Gilead, I think, they've said that
they have the capacity to manufacture upto
4:26:41.680,4:26:49.199
10 million doses this year. I initially thought
that was a big number, but if you think about it,
4:26:49.199,4:26:55.920
it's two doses per six months, so divide
by four. Divide 10 million by four. That's
4:26:55.920,4:27:04.640
roughly 2.5 million people who would get this.
And it's both a treatment for drug-resistant HIV,
4:27:04.640,4:27:11.920
and it's going to be used for prevention,
so that's actually a small fraction. So
4:27:11.920,4:27:17.279
hopefully the generic manufacturers
help to scale that up to some degree.
4:27:17.279,4:27:22.559
But aside from that, okay, if PEPFAR has
this uncertain future right now, I think
4:27:22.560,4:27:29.920
we do know that the Global Fund is going to try
and roll it out, but trying to scale that up is,
4:27:29.920,4:27:36.319
I think, maybe the next big thing to try to
focus on — if people are listening and have
4:27:36.319,4:27:42.159
some way to convince their government that
this is a really important thing to work on.
4:27:42.159,4:27:48.159
I think the Global Fund seems like it's going to
be doing lots of the work, in terms of funding
4:27:48.159,4:27:55.760
these programs to roll it out and administering
it worldwide. But I'm curious if there are
4:27:55.760,4:28:01.760
other things that come to mind, in terms of how
you're thinking about the potential future here.
4:28:01.760,4:28:09.199
Those are the main ones to me. I think the time is
now and the opportunity is here, and if you really
4:28:09.199,4:28:20.239
just take a step back, a whole 'nother level —
what is happening in many countries most affected
4:28:20.239,4:28:33.359
by HIV? Well, a happy piece of news is that-
I am cautious saying this in April 2025, where
4:28:33.359,4:28:38.239
trade relations are also a little bit up in the
air, but the happy news from the last few decades
4:28:38.239,4:28:47.760
is that most lower- and middle-income countries
have been growing economically, and that was not
4:28:47.760,4:28:57.279
true in the 1960s, for example. We, in fact, in
most countries, have been seeing income growth for
4:28:57.279,4:29:04.559
people, and seeing the tax base of those countries
also grow — meaning those countries can do more
4:29:04.560,4:29:15.279
public health interventions, too. And you know,
that is really the future that will make a lot of
4:29:15.279,4:29:21.920
people with HIV have more sustainable healthcare-
is that if you are in Nigeria, you should not have
4:29:21.920,4:29:27.920
to rely on the whims of the American public,
and in the future you hopefully will not.
4:29:27.920,4:29:34.319
But that, unfortunately, is decades away. The
tax base of many countries is not high enough
4:29:34.319,4:29:42.399
to provide lenacapavir to people who need it, and
people are not individually rich enough to pay for
4:29:42.399,4:29:51.759
lenacapavir, if they need it. So now is a moment
for people, especially voters, in richer countries
4:29:51.760,4:30:01.199
to kind of do our part. It's not a permanent
humanitarian effort, I think it's a decadal- the
4:30:01.199,4:30:07.840
next few decades really matter. And we have these
amazing new technologies that actually enable a
4:30:07.840,4:30:15.680
dent to be made. That would be where I would leave
the topic of scale up is... now's the moment,
4:30:15.680,4:30:23.920
and I hope, I hope, that when you and I are 30
years older, this kind of topic doesn't exist
4:30:23.920,4:30:34.479
in the same way, because we don't have to think
about external sources of financing quite as much.
4:30:34.479,4:30:40.159
No, I really hope so as well. I mean, I
think, right now, where we are, this still
4:30:40.159,4:30:46.080
seems quite out of reach for a lot of people in
the most-affected countries, in Southern Africa.
4:30:46.080,4:30:54.479
I think I was reading... the average spending
on healthcare some $80 per person per year in
4:30:54.479,4:31:02.399
Southern Africa, whereas it's, what is it, like 80
times that or something in the US? And meanwhile,
4:31:02.399,4:31:08.960
I mean, that's not just for lenacapavir, which
would be some $40 or so at a generic price,
4:31:08.960,4:31:16.000
it's also all the other treatments,
preventions, testing, and so on. Right now,
4:31:16.000,4:31:25.199
it still feels quite out of reach, and I'm just-
The Global Fund is going to be really important;
4:31:25.199,4:31:34.880
trying to keep PEPFAR running; but also trying
to build up more capacity within these countries
4:31:34.880,4:31:43.680
to protect the people who are affected by HIV
right now. That seems like a difficult problem.
4:31:43.680,4:31:50.319
It sounds like there's some uncertainty in the
next decade then. So are there other tools that
4:31:50.319,4:31:58.080
are maybe not scientific, but more economic or
financial, that we can apply to be more ambitious?
4:31:58.080,4:32:06.239
I think there are a few. I mean, it's not
just lenacapavir. I think this is one really
4:32:06.239,4:32:11.279
important area that we want to scale up,
but there are also these other potential
4:32:11.279,4:32:17.439
future drugs like islatravir, any other
potential long-acting drugs that might work.
4:32:17.439,4:32:25.679
How do people get the funding model so that
we're not having to be in the situation where
4:32:25.680,4:32:33.760
a pharmaceutical company is trying to recoup their
costs at a very high price in richer countries,
4:32:33.760,4:32:42.080
and then hopefully, voluntarily, agreeing to these
agreements, which may or may not be scaled up. One
4:32:42.080,4:32:50.319
idea that comes to mind for me is this idea of
an Advance Market Commitments, or an AMC. And
4:32:50.319,4:32:59.040
I love the idea of AMCs. I've written about them
a bunch, read a lot of stuff about them. I think,
4:32:59.040,4:33:07.199
the way to think about this is to contrast it with
the regular approach to funding drugs or vaccines.
4:33:07.199,4:33:13.599
So we usually have this situation where a
pharmaceutical company, or philanthropic funder,
4:33:13.600,4:33:20.160
or some government is trying to decide upfront
which bets might work out — which companies
4:33:20.160,4:33:27.359
or which researchers might develop an effective
drug — and they're funding those groups directly,
4:33:27.359,4:33:32.480
and then some of them will work out, some of them
won't. In drug development, the success rate is
4:33:32.480,4:33:38.480
very low, and that means most of these bets
are going to fail. There's going to be a lot of
4:33:38.480,4:33:47.759
wasted money on the funder's side. And secondly,
there's this huge expense covered by individual
4:33:47.760,4:33:51.920
pharmaceutical companies, in developing
the drug, that they now want to recoup,
4:33:51.920,4:33:59.039
so they charge these very high prices. It takes
a while, usually, for a drug to go off-patent,
4:33:59.039,4:34:08.959
or for them to agree to these generic-licensing
approaches, and that is a lot of time wasted;
4:34:08.959,4:34:13.520
it's a lot of people who are not getting
the drugs or the vaccines that they need.
4:34:14.080,4:34:19.039
Is there another way to do it? And
I think AMCs are one answer to that.
4:34:20.240,4:34:29.119
An AMC is kind of an inversion of this —
where, instead of funding the groups directly,
4:34:29.119,4:34:36.160
you're funding the potential successful products
at the end. So, you're setting up this pool of
4:34:36.160,4:34:43.680
funding — which might be some billions of dollars
or so — if a company or a research group can
4:34:43.680,4:34:53.199
develop a drug or vaccine that meets certain
standards. The amount that's given to these
4:34:53.199,4:35:00.719
companies, or manufacturers, depends on how much
they're manufacturing. It's usually on a per-dose
4:35:00.719,4:35:07.439
basis — essentially, how many doses have you
administered? You get more funding based on that.
4:35:07.439,4:35:13.919
I think this is a really cool idea
for two reasons. One is, as a funder,
4:35:13.920,4:35:20.959
you don't have to know who is going to succeed.
You have this pool of funding if something
4:35:20.959,4:35:27.439
succeeds. If nothing succeeds, you don't pay that
money. So you are saving on that. And secondly,
4:35:28.240,4:35:34.719
you're also rewarding companies that scale up
the drug faster and get it out to people who
4:35:34.719,4:35:42.080
need it. At the same time, you're only doing
this for the successful drug. So you're giving
4:35:42.080,4:35:51.199
this stable potential future market to companies;
they're going to have this commitment in advance,
4:35:51.199,4:35:55.439
often years in advance, of what the
price is going to be, and they can plan
4:35:55.439,4:36:00.878
much more effectively based on that.
This has been tried for pneumococcal
4:36:00.879,4:36:06.799
vaccines in the past. I think this was in the late
2000s, there was this advance market commitment
4:36:06.799,4:36:14.080
set up to try to speed up the production of
pneumococcal vaccines. Pneumococcal disease
4:36:14.080,4:36:21.840
is a respiratory lung infection that affects
people worldwide, and we already had effective
4:36:21.840,4:36:27.520
vaccines for it in richer countries, but in
Africa, there were different strains of the
4:36:27.520,4:36:36.000
bacteria that weren't targeted for the vaccines.
So this AMC was set up, knowing that it was
4:36:36.000,4:36:43.199
possible to develop a vaccine for these
other strains. There was this pool of 1.5
4:36:43.199,4:36:49.920
billion dollars that was there for companies to
receive, depending on how much they produced,
4:36:49.920,4:36:57.600
if they managed to get a vaccine through clinical
trials to show safety and efficacy. And it was
4:36:57.600,4:37:02.000
very successful — so the scale-up of this
pneumococcal vaccine in African countries was
4:37:02.000,4:37:09.840
very fast. I think three or four companies managed
to produce effective vaccines including the Serum
4:37:09.840,4:37:15.680
institute and I think Pfizer was another one of
them. It just shows this model, of how this can
4:37:15.680,4:37:22.000
work, and you don't even to have it for- you don't
even need to believe that it's possible to develop
4:37:22.000,4:37:28.400
a drug or vaccine for it, because if it doesn't
work out, you don't have to pay that funding out.
4:37:28.400,4:37:35.039
The people who do have to pay are, like,
the pharmaceutical company themselves in the
4:37:35.039,4:37:40.799
early stages — they will still have to make the
decision on whether this is a good bet for them.
4:37:40.799,4:37:47.600
Yeah, I think in that case, in the pneumococcal
case, the Pfizer vaccine did — people reviewing
4:37:47.600,4:37:54.879
what effect did this really have — they think that
did get rolled out quicker, maybe scale up years
4:37:54.879,4:37:59.439
quicker than it would've otherwise. I think
the Serum one ended up coming through later,
4:37:59.439,4:38:05.919
and maybe being less affected. But the scale
up is so important for actually getting drugs
4:38:05.920,4:38:11.199
to people who need them, not just inventing
cool stuff. And when I think of applying this
4:38:11.199,4:38:20.560
across to lenacapavir, I think to this great
piece that Kamal Nahas wrote in Asimov Press
4:38:20.561,4:38:27.279
about lenacapavir, and where he touched a bit
on the voluntary agreements in 120 countries,
4:38:27.279,4:38:35.840
and what's happening outside of those countries.
Maybe this is the shape of problem that,
4:38:35.840,4:38:44.000
for those 80 countries, where there's not in
each country, enough demand, or there's too
4:38:44.000,4:38:53.520
much uncertainty around demand, for a company —
Gilead or generic company — to enter that market,
4:38:53.520,4:38:59.920
and try and start selling to the public
healthcare systems. If there were an AMC
4:38:59.920,4:39:08.959
that aggregated across those countries, and made
the demand clearer, and had a price that was fair,
4:39:08.959,4:39:15.199
but also enough that money could be made to
make it sustainable for the companies entering,
4:39:16.080,4:39:19.439
maybe that's a place for an AMC, I don't know.
What do you think of that?
4:39:19.439,4:39:25.199
That's a great example of where it can be used.
I actually also think it could be used in scaling
4:39:25.199,4:39:31.359
up a drug even once it's been approved, because
this second part of what an AMC is used for, in
4:39:31.359,4:39:40.400
the scale up — having the amounts that companies
receive be based on the amount they manufacture
4:39:40.400,4:39:47.279
means that you're incentivizing this large-scale
manufacturing, and actually administering it to
4:39:47.279,4:39:56.000
people. That is something that could still be
used even now. But one of the other applications
4:39:56.000,4:40:05.039
is as a way to pull funding towards some drug or
vaccine or some product that hasn't yet been made,
4:40:05.039,4:40:10.959
so that would be another option. Can we
develop a drug that's better than lenacapavir,
4:40:10.959,4:40:19.680
or easier to take, or so on, and fund it with this
new model. And I think this reminds me as well,
4:40:19.680,4:40:26.160
I don't know if we mentioned it earlier, but as
far as I know, Gilead is also trying to produce
4:40:26.160,4:40:33.279
improvements on lenacapavir that would be taken
once per year instead of once per six months.
4:40:33.279,4:40:35.039
Imagine that, wow.
4:40:35.039,4:40:42.879
That would be very cool. I was wondering
about why they were doing this. I mean,
4:40:42.879,4:40:50.080
if you were self-interested profit-making company,
why not just stick with this already-amazing drug?
4:40:50.080,4:40:56.879
And it occurred to me, when you were talking
about Merck's drug islatravir — that's this
4:40:56.879,4:41:02.639
oral pill that's once-per-month. If someone could
choose between an oral pill once per month and
4:41:02.639,4:41:10.561
an injected drug once per six months, they might
choose the pill. Not only the person themselves,
4:41:10.561,4:41:16.400
but the clinics might find it easier to distribute
the drugs. It's just, you don't need a healthcare
4:41:16.400,4:41:22.798
worker, or a nurse, or someone to inject the
drug if it's a pill. And that made me wonder,
4:41:22.799,4:41:26.959
maybe that was the incentive. That
was the reason that they decided:
4:41:26.959,4:41:32.080
'Let's go even further, to make this
thing that's even harder for Merck's
4:41:32.080,4:41:36.320
drug to beat.' I don't know if that's
the case, but that's what I would guess.
4:41:36.320,4:41:41.920
And it just goes to show how much progress
we've made with HIV. Because when you were
4:41:41.920,4:41:47.600
describing the first drugs around, they were
not so good and there were no competitors,
4:41:47.600,4:41:54.639
and now we have great options for
patients, and great options for people who
4:41:54.639,4:42:03.119
don't even have HIV yet who want to reduce
their risk. So I'm glad to be alive today.
4:42:03.119,4:42:12.240
It's so much- I mean, the whole timeline is just
incredible to think about. We talked about how,
4:42:12.240,4:42:20.160
in the early 1980s, how pessimistic or
how scary it would've been to have HIV,
4:42:20.160,4:42:25.786
not have any treatments, have this-
thought-of-as-this untreatable disease,
4:42:25.786,4:42:33.119
as just this behavioural problem; there's nothing
that someone can really do medically to treat it.
4:42:34.879,4:42:41.279
Contrast that with where we are now. I think,
personally, that process, that timeline could
4:42:41.279,4:42:49.039
have been sped up. Just reading about some of
the details of early research in the 1980s,
4:42:49.039,4:42:54.240
but also, knowing about how long it takes to
run a clinical trial, how long it takes to set
4:42:54.240,4:43:01.279
up the trial sites, or train the nurses and the
healthcare workers, or to share this information
4:43:01.279,4:43:09.279
between different research groups and so on. But
at the same time, it is just an incredible story.
4:43:09.279,4:43:18.959
Now is probably the time to step back on this
story that we have told and conclude. I am sure
4:43:18.959,4:43:27.199
we missed out many subplots that are also ripe for
discussion. But among what we have discussed, I'm
4:43:27.199,4:43:34.400
interested to hear: What were your main takeaways
from this story over the last fifty years?
4:43:34.400,4:43:41.839
My takeaway... I mean, I had so many takeaways.
One of them was just how many different ways
4:43:41.840,4:43:47.119
you can approach medical innovation. Like,
what are the different things that you could
4:43:47.119,4:43:52.080
think are important here? I mean, partly
it's 'Let's make a really effective drug',
4:43:52.080,4:43:59.279
but it's also 'How do we make a drug that's easier
for people to take on a regular basis?' It's,
4:43:59.279,4:44:05.679
maybe, refining drugs that already exist — trying
to improve on them, in terms of their safety,
4:44:05.680,4:44:12.480
efficacy, or again, how people take them.
The other was the different types of
4:44:12.480,4:44:19.759
drug development. So we talked about this
trial-and-error process with the first drug
4:44:19.760,4:44:28.400
azidothymidine, where they just looked at some 180
compounds: tried each of them in the lab, saw what
4:44:28.400,4:44:37.039
worked in cells in the lab, and then scaled up
based on that. The other is, this is an example of
4:44:37.039,4:44:44.879
screening existing compounds, or just compounds
in nature, that helps repurpose this previous
4:44:44.879,4:44:52.959
cancer therapeutic that didn't work, for HIV.
Then we had some examples where this understanding
4:44:52.959,4:44:59.039
of the specifics of HIV, or how the enzymes
work, what they look like, what will fit
4:44:59.039,4:45:08.719
into these little gaps between them — that was
another option for developing a new drug. But,
4:45:08.719,4:45:14.080
at the same time, there was so much iteration
and adjustment — that was tinkering — that was
4:45:14.080,4:45:21.039
important there. The move from this drug that was
potentially promising, to one that actually met
4:45:21.039,4:45:27.680
several criteria that you would have, with the
efficacy, the safety, how long lasting it was.
4:45:27.680,4:45:35.119
And then I guess, there are these other-
improving on the drugs that already exist,
4:45:35.119,4:45:43.680
that is not just trying to use existing
information. If there has been, already,
4:45:43.680,4:45:50.320
a protease inhibitor invented, can you now develop
a new one based on that knowledge? Can you develop
4:45:50.320,4:45:59.039
a different type of nucleoside inhibitor, like
AZT? Will people develop more capsid inhibitors,
4:45:59.039,4:46:05.039
based on the knowledge that they have from this? I
mean, all of this, I think, is super interesting.
4:46:05.039,4:46:14.959
I totally agree on how much the tinkering and
iteration stands out, as important. Basically,
4:46:14.959,4:46:19.680
at every level, there's.. so much of
that's happening at the screening stage,
4:46:19.680,4:46:26.719
so much of that is happening, as you just said,
at designing a capsid inhibitor that makes sense
4:46:26.719,4:46:32.879
for patients in a particular context.
Another thing that stood out to me is
4:46:32.879,4:46:42.480
how hard science is to predict — in the sense
of, thank goodness people in the last forty,
4:46:42.480,4:46:50.638
fifty years, scientists did not only work
on vaccines. We don't have an HIV vaccine,
4:46:50.639,4:46:56.639
and we do have a HIV preventive
drug that you can get injected with,
4:46:56.639,4:47:02.320
and kind of feels like a vaccine. I'm
so grateful that people were exploring
4:47:02.320,4:47:09.759
different parts of the technology tree there.
We don't have a cure either. We don't have
4:47:09.760,4:47:15.199
a cure for HIV and we don't have a vaccine,
but guess what? We have game-changing tools,
4:47:15.199,4:47:22.560
and that came from a part of exploration you
may not have been able to predict back in 1981.
4:47:22.561,4:47:30.799
Also, the fact that the treatments could be used
as a prevention as preventive drugs was probably
4:47:30.799,4:47:37.199
not that obvious to scientists at the time.
That itself was quite unpredictable, I think.
4:47:37.199,4:47:38.400
Absolutely.
4:47:38.400,4:47:43.839
The other thing that reminded me of
was just how many different aspects,
4:47:43.840,4:47:49.359
or how many different types of science-
or what is involved in developing a drug,
4:47:49.359,4:47:58.240
is not just one person tinkering with it in the
lab. It's this whole network of clinical trials
4:47:58.240,4:48:05.840
that are running; there's the basic research,
there's stuff like developing microscopes
4:48:05.840,4:48:10.719
with a high-enough resolution that you can
really see what is happening inside the cell,
4:48:10.719,4:48:17.840
what this virus looks like, what the proteins look
like. There's the DNA sequencing technologies,
4:48:17.840,4:48:25.359
there's the protein development. Like, all
of this stuff comes together to develop these
4:48:25.359,4:48:30.320
drugs. And then there's the medicinal chemistry,
and the pharmacology — which I think, probably,
4:48:30.320,4:48:37.439
I had kind of underrated before as just, okay,
this seems like this last-minute thing; after
4:48:37.439,4:48:42.878
you've developed a drug, you now want to make
sure that it's safe and effective. I previously
4:48:42.879,4:48:49.600
had this assumption that that was what medicinal
chemistry was about, and now I'm thinking this
4:48:50.480,4:48:57.519
can make a huge difference on whether a drug is
useful or effective at all in the real world.
4:48:57.520,4:49:03.039
Even right at the discovery stage of lenacapavir.
So important, how stable it is and how it doesn't
4:49:03.039,4:49:09.600
break down very quickly. I totally agree with
what you just said about interlocking parts of
4:49:09.600,4:49:20.240
the medical innovation system. It's amazing that
we just about had recombinant DNA at the time when
4:49:20.240,4:49:28.879
HIV started becoming a crisis. So we could use
recombinant DNA in the lab as a research tool
4:49:28.879,4:49:33.600
and that we did not have all of those other things
we just mentioned. We didn't have PCR, we didn't
4:49:33.600,4:49:35.039
have electron microscopes- well, I dunno about
that- we didn't have cryo-electron microscopes,
4:49:35.039,4:49:41.920
certainly. We, only in the last few years, have
learned the capsid, which we are now inhibiting
4:49:41.920,4:49:48.639
with lenacapavir, in fact stays intact into the
nucleus. There's so much more that we're still
4:49:48.639,4:49:55.520
going to learn over the next coming years that
might open up new frontiers. And that's true not
4:49:55.520,4:50:02.240
just for HIV, I bet you that things that HIV
researchers have learned will be useful for
4:50:02.240,4:50:09.519
hepatitis B, for other cancers, for this, that,
and the other. And the final interlocking surprise
4:50:09.520,4:50:19.199
of science that I learned from you many hours
ago was that it was only two years before 1981
4:50:19.199,4:50:26.240
that the first human retrovirus was discovered.
Thank goodness for that. And it makes you wonder
4:50:26.240,4:50:33.359
what we don't yet understand, that will make
solving and curing diseases in the future easier.
4:50:33.359,4:50:41.279
Yes! And, and, above all of that, the other
interesting thing for me was learning about
4:50:41.279,4:50:47.119
how drug pricing works or how these patents
work. How does manufacturing actually work
4:50:47.119,4:50:55.119
at large scale? What do the funding models- what
they have to do with whether drugs are developed,
4:50:55.119,4:51:03.599
how fast they're rolled out, who's ready to
pay for certain drugs? And it's every aspect
4:51:03.600,4:51:09.920
of this whole process: not just the lab, not
just the clinical trials, but the funders,
4:51:09.920,4:51:15.760
the people who decide, who show support
for foreign aid spending, for example.
4:51:15.760,4:51:22.799
Everything comes together when we're talking
about any disease, but particularly for HIV, it's
4:51:22.799,4:51:30.561
so salient because of these huge programs that
have transformed the lives of millions of people.
4:51:30.561,4:51:36.320
And going into the future. There's no point for
all of this wonderful science unless we remain
4:51:36.320,4:51:43.439
ambitious. And unless we make sure that people who
need these drugs can access them. It's possible,
4:51:43.439,4:51:55.839
we've done it before and into the future
we go, with uncertainty and with resolve.
4:51:55.840,4:52:01.039
This episode was only possible from a lot of
work done by a lot of people publishing in the
4:52:01.039,4:52:05.600
open — whose papers we read and whose reviews
we read. I won't thank them all here, but we'll
4:52:05.600,4:52:10.400
leave, in the show notes, some of the research
that we base this episode on. I, in particular,
4:52:10.400,4:52:17.359
would like to thank Anne de Bruyn Kops, who wrote
a great review of long-lasting injectables for
4:52:17.359,4:52:23.279
many different diseases for Open Philanthropy,
that I learned a lot from. I want to thank Sanela
4:52:23.279,4:52:31.679
Rankovic, who was the HIV researcher who knows
all about PF-74. And then, of course, I'm sure
4:52:31.680,4:52:38.160
we both want to thank Douglas Chukwu, who joined
us for our first ever phone-a-friend section.
4:52:38.959,4:52:45.359
Yes. And the team at our Works in
Progress, Aria Babu, who helped
4:52:45.359,4:52:50.480
us really, actually, get this
podcast to run Adrian Bradley,
4:52:50.480,4:52:57.279
who's here with us now producing and keeping
us on track with this episode. Then, the team
4:52:57.279,4:53:04.080
at Works in Progress and Open Philanthropy,
who were sponsoring this podcast. And then,
4:53:04.080,4:53:10.320
I would say, also, all of the scientists who
were involved in developing all of these drugs,
4:53:10.320,4:53:14.799
all the people who were participating in all
the clinical trials, all the healthcare workers
4:53:14.799,4:53:22.320
who worked in them, everyone involved in this
massive program, PEPFAR, everything. It's just-
4:53:23.279,4:53:24.080
It's so cool.
4:53:24.080,4:53:25.600
It's very inspiring.
4:53:25.600,4:53:30.400
And with that, I will ask you as
listeners, if you enjoyed this episode,
4:53:30.400,4:53:36.240
feel free to subscribe. We will be talking
about other Hard Drugs in the future,
4:53:36.240,4:53:39.920
and check out the show notes
for more details on this one.
4:53:39.920,4:53:43.359
Bye. Bye.