Hard Drugs

Saloni Dattani:
Making effective new medicines isn't easy. Welcome to Hard Drugs. I'm Saloni Dattani, a researcher on global health at Our World in Data, and one of the founders of Works in Progress magazine. And I'm hosting this podcast with Jacob Trefethen, who leads science and global health R&D funding at Open Philanthropy, and is one of the most fun, interesting people I know. This show is about medical innovation: how to speed it up, how to scale it up, and how to make sure lifesaving tools reach the people who need them the most. It all started with a conversation, a shared instinct that this was the right time to start a podcast, to dive deep into how to technologies for malaria, cancer, AIDS, and other diseases, actually came to be.

Jacob Trefethen:
Today we're going to talk about HIV. Making an HIV vaccine has been the holy grail for many of the world's top scientists over the last generation. It has proven one of the most challenging scientific problems too, and we don't yet have a vaccine. But last year, one drug company announced they'd gone a completely different route. They made a drug you get injected with once every six months, or maybe only once a year, like a flu shot, giving you almost perfect protection against HIV. So how did we get here and what does it mean for one of the world's deadliest diseases?

Saloni Dattani:
I'm super excited to talk about HIV, lenacapavir and other HIV drugs today with Jacob. Hello.

Jacob Trefethen:
Hey, how are you doing?

Saloni Dattani:
Great. Yeah, so I'm super excited about this. I think we have a bunch of things that we're going to talk about in the episode, maybe starting with just what HIV is, how it infects people, and then moving on to the history of drug development in the field, how lenacapavir was develops, what lenacapavir actually does, and then where we are now, how to scale it up to people who need it.

Jacob Trefethen:
That sounds good to me. I feel like I first really heard about or realised what a big deal lenacapavir was from a tweet from you. So I get to be the lucky guy who gets to be taught some of that history of HIV and how it all fits together from you. Hopefully I can chip in some of my knowledge from working at Open Philanthropy on Global Health R&D as well. That's this conversation. There's a lot to cover. I hope we cover the stuff that matters, and get to the finish line of what are these magical new drugs really doing.

Saloni Dattani:
There are a lot of, I think, subplots that we're going to go through. The whole process of drug discovery in this field has been really amazing. If you think about what HIV was like in the 1980s, where people would only have a few years of survival after being diagnosed to now, where, if people take treatment early enough, they can expect to live almost a normal life expectancy. I think talking about how that's happened, how that's been made possible, is really important.

Jacob Trefethen:
I agree. It sounds like we're going to have to start with: what the heck is HIV itself? Should we begin there?

Saloni Dattani:
HIV is a virus that causes AIDS, the acquired immunodeficiency syndrome, which is associated with lots of different infectious diseases, cancers, and conditions that people suffer from if they've been infected with the virus for long enough. But what's interesting about HIV, to begin with, is that it's not a typical type of virus. It's something called a retrovirus. "Retrovirus" itself is a new concept to a lot of scientists, historically speaking. The first retrovirus that infected humans was only discovered in 1979, which is just two years before the first reported cases of HIV in the US. Before that, people had no idea-

Jacob Trefethen:
And that was not HIV.

Saloni Dattani:
That was not HIV.

Jacob Trefethen:
Okay. That was a different retrovirus.

Saloni Dattani:
That was human T lymphotropic virus, the first human retrovirus discovered. I think that itself has a really interesting story. When I was first reading about this, I was really struck by the fact that there was only this two year gap. We essentially figured out what [human] retroviruses were in the first place just shortly before discovering this deadly new disease that was caused by one. I think that's an important thing to think about, when we're thinking about what scientists at the time would've been working on, and how they would've figured out that it caused AIDS.

Jacob Trefethen:
What is similar about that virus and HIV? What makes it a retrovirus?

Saloni Dattani:
A retrovirus — maybe I could kind of step back a bit and talk about how the usual process of DNA works, just to give you some context. Great. Almost every cell in our body has DNA. DNA is the genetic code to tell us which proteins to make, but it contains all of that genetic code. All of our cells don't need to be producing all of those proteins, and they don't need to be producing them all of the time. So instead of using the entire genetic code, we use our enzymes to find segments of the DNA, to turn into RNA, which is this intermediate molecule that's also used for various other things. And then we turn this RNA into protein; proteins that are used in all kinds of processes in our body.
This direction — from DNA to RNA to protein — was how biologists and scientists typically understood cells and how biological life worked. And that was overturned with the discovery of retroviruses. What happened here was that people found out that there were certain viruses that could turn their RNA into DNA, using an enzyme called reverse transcriptase.

Jacob Trefethen:
They're in the other direction.

Saloni Dattani:
Yeah. This was a huge discovery in 1970 by Howard Temin and David Baltimore. They discovered this enzyme, reverse transcriptase. They discovered that retroviruses could reverse transcribe RNA into DNA, and then they tried to find other retroviruses that infected humans. For a long time, no one succeeded in finding any of these viruses, until 1979. So it was about almost 10 years of people trying to find real examples of these, and they couldn't.

Jacob Trefethen:
And is that related to HIV in 1981? We just got lucky? Or yeah, why so close?

Saloni Dattani:
So I think we did get lucky, and I think it would've been really difficult to figure out that HIV was causing AIDS if not for that — or to even know where to look. What's really interesting about this is, the scientist who discovered the first retrovirus that infected humans, Robert Gallo, was also one of the scientists who discovered HIV as being the cause of AIDS.
I really like kind of reading through reviews, or retrospectives, written by scientists themselves on how they figured out something, what research they did, and so I was reading this retrospective that he wrote on the discovery of retroviruses and HIV, and it was really interesting because he talks about how people were really sceptical that there were any other retroviruses that infected humans.
The reason for that was: people had found retroviruses that infected other animals, other primates. And in those primates, it seemed to be pretty abundant — or ubiquitous — across their organs, but that wasn't the case in humans, and it was just hard to find them. So they assumed that maybe there's something that prevents us from being infected by them. Scientists also found that if you put the animal retroviruses into human blood — human serum — that would immediately inactivate those viruses, using our complement system, which is one component of our immune system. So this suggested that maybe there's some way that we're just protected against them; they're not going to affect us. I think Robert Gallo just had this idea that that might be wrong: maybe there are some other types of retroviruses that we hadn't studied. And so he started looking at T-cell cancers.
In animals, the retroviruses that infected those animals would typically cause T-cell leukemias; T-cells are a type of white blood cell. So he thought maybe they're also causing leukemias in humans, and he started working on finding patients with T-cell leukemias. Eventually he did actually discover a retrovirus in them. This retrovirus was using reverse transcriptase to turn its RNA back into DNA.
And the reason that this is important for HIV is that they actually developed the tools — to test out whether there are retroviruses infecting a sample — as part of that process. They started working on potential drugs that could be used to target reverse transcriptase. They also just generally had the idea that humans can be infected by retroviruses, and retroviruses infect humans in their T-cells. And as we'll come to later on, that's very relevant in HIV.

Jacob Trefethen:
Okay, so just stepping back for a second. Beforehand, scientists thought: well, maybe these retroviruses that we're seeing in other animals aren't infecting humans, and the human immune system's basically winning against them. We've got this under control. But then, it looked like they may infect some cell types and we might not be winning fully. I mean, my question then is — it sounds like such a good strategy for a virus. If I'm a virus, I would love to reverse transcribe and integrate in your DNA. So how come if it's possible for HIV, we don't see this in lots of viruses? I mean other viruses, other than HTLV, you mention, how come there are not lots and lots?

Saloni Dattani:
That's a really interesting question. And retroviruses, it turns out are really ancient. Parts of their genomes are integrated into our normal DNA and they've just been passed down over time — so this is called endogenous retroviruses. I don't really know much more than that about that topic. But on your question on why aren't there more retroviruses infecting humans? I think there's potentially three or four things going on. I am sort of wary of saying that something's not possible, because sometimes people say that, even in the case of this, and then they figure out that it's wrong.
We just haven't found those other retroviruses. But some of the reasons, probably: one, it's like an error-prone process. If you're a virus — sorry, you're not a virus. But for a virus that's transcribing its RNA genome into DNA, the reverse transcriptase enzyme is not very precise in how it does that. It introduces errors into the code. That's probably a little bit dangerous for the viruses themselves. Secondly, they have this RNA genome, they then transcribe it into DNA, and then they get our cells to transcribe the DNA back into RNA — which just seems a little bit inefficient. It would just take a longer amount of time. It introduces errors. That's not super useful, maybe, but obviously in some cases, it actually is, and it's worth that trade off.

Jacob Trefethen:
You mentioned T-cells — it's going after these. I mean this is really, it's clever, but it's creepy. So there's a reverse transcription where it's then going to integrate into my DNA, which is disturbing in its own way. And then, additionally, you're telling me it's going to do that not just anywhere, but in one of my immune cells — which is what's meant to be fighting infections. It's going to hijack and integrate there. So is that right? And those are the T-cells?

Saloni Dattani:
That's right. So HIV infects various immune cells, but usually a specific type of T-cell called a CD4 T-cell. And the "CD4" just describes one receptor on the surface of this T-cell that is very crucial in signalling. But also kind of defines that type of T-cell. And these types of T-cells- I guess I should just describe what those actually are.
We have different types of white blood cells in our body; T-cells are an important type. In this case, what they do is: they help the body recognise pathogens or things that we've seen before, by presenting parts of that pathogen to our other immune cells that can last much longer in the body and remember them if they appear ever again. HIV is essentially infecting these quite important white blood cells in our body.

Jacob Trefethen:
What happens then? We've entered the cell. Why is that a problem? How does it cause disease?

Saloni Dattani:
We've entered the cell. Well, there's quite a long process. Initially, when people get infected, they have this short term infection — some kind of fevers, flu-like symptoms, things like that; and the virus quickly replicates itself, multiplies into many copies. Those copies then infect other T-cells. They then go into our lymph nodes, which are basically these little hubs of immune activity. There's some in your neck, some under your arms, other parts of your body. It infects these different immune related tissues and depletes them.
And that means that people become more vulnerable to all sorts of other infections that are normally mild to people, or just infections in general, and some cancers. Our white blood cells are also useful in detecting tumour cells and trying to eradicate them. And by depleting those important cells, people also have a higher risk of certain cancers. So we have this short-term infection that immediately depletes a lot of our immune cells. Eventually, there's this kind of slowdown in how much it replicates, and you get to this equilibrium — but that equilibrium is still much worse than if someone hadn't been infected. And over a long period of time, this reduction in immune cells means that people are vulnerable to various diseases. And as time goes by, they get sicker and sicker from those other infections.

Jacob Trefethen:
Before HIV, were there infections that were known to cause cancers now something that we're more familiar with, but was that connection a surprise and made it harder to figure out what the real cause was?

Saloni Dattani:
HTLV, the first retrovirus that was discovered just two years before that was the first pathogen that was clearly causing cancer [in humans]. After that, there were, I mean, there've been a bunch of other pathogens that are now known to be cancer-causing. One is hepatitis B, which you do a lot of research on; HPV, human papillomavirus, that causes various cancers including cervical cancer. There's Helicobacter pylori: this bacterium that causes stomach cancer. I think there's more; maybe you remember some others. And there's HTLV.

Jacob Trefethen:
Hepatitis C, which causes hepatitis.

Saloni Dattani:
Oh, hepatitis C. That's right.

Jacob Trefethen:
Yeah. Those hepatitis viruses are sneaky.

Saloni Dattani:
So coming back to your question: the cancers were the first, I think, surprising thing about people who had AIDS. One of the types of cancers that they became vulnerable to was called Kaposi sarcoma, which is this tumour. What was surprising about that was: usually doctors who saw patients with this type of cancer would see them in quite old- elderly patients, or people with, I don't know, severe immune deficiencies and things like that. And in this case, they were seeing them in young adults, which was really surprising. They were also quite severe cancers: they were hard to treat with the usual treatments that were available. And the fact that this was growing in prevalence was also really surprising and worrying to people. So I think that was one of the first noticeable kind of warning signs that there was some kind of epidemic spreading. It was probably an epidemic disease that was caused by some pathogen.
I think there were, maybe, a few months or a year or so before people realised that it was probably caused by a virus. And I think the reason for that was that there were some cases of people being infected through blood transfusion; so they had no other connection to other people with the disease, and they had no other environmental risk factors or anything like that. But they had recently had a transfusion, or an organ transplant, or something like that, and then suddenly, they got infected. And the reason that this links to being a virus is because you can usually filter out or purify some of the blood that you're using, or the organs, with filters that get rid of bacteria — which are bigger. But that doesn't always work for viruses, which are much smaller. So the viruses were getting through and they were still infecting people. And the fact that this was infecting people far away, with no other connection, suggested that it was a virus.

Jacob Trefethen:
I see. I mean, maybe that's a good point to just talk a bit about transmission. So how does the virus transmit? I've got some ideas, but.

Saloni Dattani:
There are different types of modes of transport. One is, as we just talked about, blood transfusions and organ transplants. So if there is contaminated blood with HIV, the risk of an infection to someone else is quite high. It's some- I was looking at the data from the systematic review and they estimate that the risk of infection is about 92% from a transfusion of contaminated blood, which is quite high. Mother to child transmission? For mothers who are infected with HIV, a quarter of them would pass HIV down to their baby, and this was before treatment was available. Now, the chances are much lower if people use antiviral treatments around the time of pregnancy and childbirth; but that was obviously very scary. And then there's sexual transmission, which is probably the most common route that most people have heard of for HIV. And then, finally, injection and drug use; using shared contaminated needles with HIV.

Jacob Trefethen:
So before drug development, how come we need drugs? How come the immune system doesn't control HIV better? I mean, I have a stereotype that it's extremely hard to control. If infection gets established, it's really tough for us. So why is that?

Saloni Dattani:
One really interesting thing that I learned while trying to read about this was that HIV is usually caused by a single virus particle, and that's one particle replicates enough that it can cause a whole infection.

Jacob Trefethen:
You're scaring me, Saloni. That's scary; that's scary. So do you mean that one particle entering my bloodstream is all it takes, or you mean something else?

Saloni Dattani:
I actually mean something else. If you look retrospectively at people who have HIV — you take a sample of their blood and you look at the different virus particles; if you then trace back the genetics of those virus particles, you then find that they all have one common ancestor, in around three quarters of cases.

Jacob Trefethen:
I see. I see.

Saloni Dattani:
But that doesn't necessarily mean that just one particle is enough to infect someone, because we have enough barriers in our immune system. I mean, if you think about a skin infection or something, we have our skin, we have several layers of skin. We have immune cells protecting us within our body. There are various barriers that prevent a bacterium or something from infecting us, and that's the same is true with HIV. So I think what's happening here is that: if you think about this from the perspective of probability, there are many barriers, but eventually one of them might be able to cross all of those barriers and cause an infection, and if it's able to do that, it can replicate very quickly.
I think that gets us to why it's difficult to control an infection. Even though we do have these barriers, HIV is just very fast at replicating, mutating. The reason that HIV can mutate so quickly — it basically becomes really genetically diverse within a person who is infected, and that means that our immune cells might be able to recognise some of the HIV strains that are in our body, but it's very difficult for it to keep up with the rapid evolution and increased diversity. But there are several reasons for that.
One is the reverse transcriptase enzyme that we talked about that turns RNA into DNA; that enzyme is not very precise, and that introduces errors. The errors allow it to potentially get beneficial mutations sometimes, and that means that it can genetically diverge. The other is that the HIV particle has two copies of RNA inside it, and those two copies can recombine with each other.

Jacob Trefethen:
Wait, hold on, hold on, hold on. It comes in with two of the same thing?

Saloni Dattani:
Two of almost the same thing. It has two, in the same way that we have two sets of chromosomes in our cells.

Jacob Trefethen:
Okay, fair enough. I guess that's true, yes. Oh, wow, okay.

Saloni Dattani:
It has two copies of RNA.

Jacob Trefethen:
It's not a double-stranded RNA; they're separate.

Saloni Dattani:
Yeah, that's right. They're two single-stranded RNA viruses, two single-stranded RNA particles; and they can get reverse transcribed separately. They can also recombine with each other. So I was reading this review paper about how all this worked — why there was such rapid mutation — and they said- they were talking about this recombination and they said, "This can be considered a primitive form of sexual reproduction." And I was —

Jacob Trefethen:
No, no, no, no. This is a virus. If there's one thing I know it's that that is too complicated. I don't believe this review paper. Okay.

Saloni Dattani:
Right, that's crazy. And there's a third thing actually, which is that our enzymes introduce errors and mutations into HIV. We have this family of enzymes called the APOBEC family; they insert mutations into HIV to try to damage it. What they do is: they change the G's in our bases, in our DNA, into A; and they do that on a single-stranded DNA particle. The HIV virus has these two single-stranded RNA molecules: they get turned into DNA, then our enzymes introduce errors into it, by turning some of the G's into A's.

Jacob Trefethen:
Just taking a step back, you're saying that the virus itself mutates a lot? So the reverse transcription stage introduces errors, and that, actually, in a sense, helps the virus evade our immune system. So it is introducing errors that make it hard for us, and then you're saying we also are introducing errors that make it easier for us, or rather harder for the virus. So we are both sort of fighting fire with fire of: I'm going to make you different, and it's saying, no, I'm going to make myself different. And we're in a kind of ratchet situation there.

Saloni Dattani:
Yeah, it's very funny. I learned about this first, actually, in 2022, this process, during the Mpox epidemic. I'd just been following the literature — what the virologists are working out on the epidemic and so on — and they found out at that point that the viruses from Mpox were mutating much faster than expected, than had been seen before. And it turned out that the types of mutations that they were seeing, that were happening rapidly, were very similar to this, APOBEC- kind of known-mutation change, and that led scientists to think: maybe our enzymes are also working on this Mpox virus. So learning about that —

Jacob Trefethen:
Oh I see what you're saying.

Saloni Dattani:
— testing that out, helped to figure out: we were introducing errors into the Mpox virus very quickly, which made it mutate much faster than usual; and that knowledge helped to figure out better when Mpox actually emerged, and when it started to spread.

Jacob Trefethen:
Oh, interesting. You can somehow work backwards from that information.

Saloni Dattani:
Right.

Jacob Trefethen:
Wow. Okay. Okay. Well, that's it. I am feeling grateful for my immune system; has a bunch of tricks I didn't even know about, so thank you, immune system.

Saloni Dattani:
I think, one more thing is, the types of infections and cancers that HIV makes people vulnerable to. I think, probably, that's not very obvious to people; maybe they've heard of a few of them. So we talked about Kaposi sarcoma, there are also a bunch of others. There's PCP, which is this fungal lung infection. There's toxoplasmosis, which is this parasitic brain infection. There's cytomegalovirus retinitis, that can cause blindness. There's tuberculosis — we already know about tuberculosis, probably, most people here know about that — that is the leading cause of death in people with HIV worldwide. The reason is that, because of this immune suppression, because of the fact that HIV is depleting our immune cells, it makes us more vulnerable to infections like tuberculosis, which are often easier to clear for people.
And then, some of these are also related — I think I talked about a few that were brain infections or that cause blindness — some of these can also cause AIDS-related dementias, where people lose their ability to think, and make decisions, and generally lose their memory. And then there are a bunch of cancers as well that HIV is associated with. As we talked about earlier, some of our T-cells are really important in trying to find potentially cancerous cells and eliminating them. If those T-cells are depleted, that makes us more vulnerable to cancers continuing to grow. So that includes Kaposi sarcoma, which we talked about, and then non-Hodgkin lymphoma, and it also increases the risk of cervical cancer.

Jacob Trefethen:
So I think I have a rough understanding of the virus and a rough understanding of how it leads to AIDS, and to disease, and opportunistic infections. Maybe quickly, where did it come from originally? Where did this virus start out?

Saloni Dattani:
So... this, I think, has had a lot of research go into it, and the likely answer is that it came from chimpanzees and gorillas in Central and Western Africa. There are different types of HIV. As we talked about, HIV mutates very quickly; creates this huge amount of genetic diversity, and that also means that there are multiple different types of HIV. The one that's found across the world is called HIV-1. There's also an HIV-2. Both of them are from different kinds of primates from Central and Western Africa. And I think the current understanding is that HIV one came from a type of chimpanzee somewhere near the southeastern area of Cameroon.
And probably — so this is interesting: the way that we understand this is by collecting a lot of samples of HIV from different people, ideally as early as possible. The earlier the cases are, the easier it is to try to estimate where they all came from, or when they converged back in history. What was super interesting to me, that I was reading about recently, was that the earliest genome of HIV was recovered from someone who died in 1966 in Africa. That's 15 years before the first cases were reported. There were definitely cases of HIV before that; probably for decades before that. If you use this sample, but also all of the other early samples that we have, you can kind of trace back where they have shared ancestry — in the same way that you might be able to do with a family tree. If you do that with genomics, you can try to trace back where they have similarities, and that suggests that the pandemic originated at the turn of 20th century.

Jacob Trefethen:
Hundred years ago.

Saloni Dattani:
Yeah. Well, so we don't have — because the earliest case we have is from 1966, that's still not very early, and that means that there's still some uncertainty in when it actually originated. There's this uncertainty between, so somewhere between 1881 and 1918 is probably around when it first emerged.

Jacob Trefethen:
Okay, well, and in humans. So basically, there was this virus that infected other primates, chimps; maybe goes back much longer, I don't know if that's known. And then at some point, someone was probably hunting a chimp and there was a blood, the blood sort of got into their food, or was it, you're eating uncooked chimp or? Oh God.

Saloni Dattani:
That's probably it. So probably through hunting primates and consuming them from the, kind of, butchery of that process, and being exposed to their infected body fluids. So the virus that infects chimpanzees and other monkeys is called Simian Immunodeficiency Virus rather than human.

Jacob Trefethen:
SIM [SIV], okay.

Saloni Dattani:
That, it seems like, has crossed over to humans dozens of times over history.

Jacob Trefethen:
As in, since the 1900s?

Saloni Dattani:
In total.

Jacob Trefethen:
Okay. Okay. Interesting. I didn't know that.

Saloni Dattani:
And I think there's around four of those "spillover events", is what they're called. At least four of those spillover events have led to sustained epidemics that —

Jacob Trefethen:
Oh my gosh.

Saloni Dattani:
— people are still infected by today.

Jacob Trefethen:
Wow, okay. So it's been with us for a long time, and we haven't known the extent of it so well as a species until the more recent epidemic starting in the '80s. Is that a fair summary?

Saloni Dattani:
That is a fair summary. I think, this really reminds me of some of the work and writing I do about missing data.
I mean, on a lot of topics in health, but also in other areas, we tend to have much better data collection and understanding of epidemics, but also other diseases, in richer countries, because of the institutions that can collect that data. Having the resources and the people to collect that data is not super easy. The fact that we know about the first cases of AIDS that had been reported were in the US, is not because it started in the US — it's because the US had good detection and disease control research going on.

Jacob Trefethen:
Oh yeah. I mean, it reminds me of the extremely frustrating initial COVID graphs, where reports of number of cases would actually be number of confirmed cases — vastly different than what you could interpolate must be happening in reality. But, you know, whoever gets tested ends up getting reported and whoever doesn't doesn't. It can lead to missed inferences.

Saloni Dattani:
Exactly. That's right.

Jacob Trefethen:
I feel like we should get to drugs. And as you've described HIV so far, as a drug developer, which I've never been yet, but moonlight as in my head, I'm thinking: the different parts you've described are each potential targets that I could maybe make a chemical small molecule to interfere with, to sort of mess up its lifecycle. I know my immune system's not going to sort it out all on its own. So some of those non-human chemicals might be pretty useful too. So firstly, is that right? And then, am I thinking about that right? And maybe that means we're going to have to go in a bit more detail about the infection cycle, because the virus is going to look different at different points and that will maybe give us a clue about what drugs we can make.

Saloni Dattani:
No, exactly. I think, actually, it would be probably easier to think about where scientists were at the time, how much they knew, and how they were developing drugs, and then we can talk about the broader life cycle of the virus.

Jacob Trefethen:
Let's do it. Sounds good.

Saloni Dattani:
So place yourself in the 1980s. This is kind of hard because, as a scientist, you had just found out that retroviruses could infect humans. Now you find out that HIV is a retrovirus. You're like, wait, I didn't even know that RNA could be turned into DNA until 10 years ago. So that's quite a tricky position to be in. At this point, in the early 1980s, there were no antiviral drugs for retroviruses. Also, antivirals in total were kind of new. I did not know this before reading about it for this episode, but the first antiviral drug of any kind was approved in 1963, which is, again-

Jacob Trefethen:
1963, really? Not even flu. We didn't have nothing. That's crazy.

Saloni Dattani:
No, we didn't. We had flu vaccines. We had a bunch of vaccines before that. But the first antiviral drug was for treating the herpes simplex virus — infections of the eye — and that was in 1963.

Jacob Trefethen:
Wow.

Saloni Dattani:
Also, if you were in the early 1980s, you wouldn't have PCR. PCR is polymerase-

Jacob Trefethen:
Of course. Yes, of course.

Saloni Dattani:
-chain reaction, which is used to multiply samples of genetic material so you can study it more easily. And that would've been really useful for being able to detect the level of infection, and the level of virus in someone. You would be very new to knowing about retroviruses to begin with. You wouldn't have any antivirals for them. You wouldn't have a great idea of how to even develop antivirals at all. You didn't have PCR, you didn't have multi-center trials, so you wouldn't be able to test drugs in multiple hospitals.

Jacob Trefethen:
Multi-center? Oh, I see. Got it. Yep, got it.

Saloni Dattani:
You wouldn't be able to test whether people were resistant to the virus, through the genetics of the virus, again, because of the lack of PCR testing. And so there was just this complete lack of — what are we going to do now? We have no idea. This is super new to us. I think a lot of people at the time might've thought it's impossible to treat this disease. It's so new, it's so different. How are we gonna make any progress on it?

Jacob Trefethen:
You don't have a proof point you can hang your hat on.

Saloni Dattani:
That's right.

Jacob Trefethen:
Very... yeah, the unknown beckons.

Saloni Dattani:
And so again, I was trying to find retrospective written by someone who works in this field, and I found one that was really interesting by Samuel Broder. He was one of the scientists who developed AZT, the first HIV drug.

Jacob Trefethen:
AZT.

Saloni Dattani:
His team found that it was effective against HIV. They also developed various other drugs against it. And he wrote this retrospective on how they discovered the first antivirals and how pessimistic people were at the time — that it was possible to make any treatments against it. So maybe a bit of background on who he was. Samuel Broder was this cancer and immunology researcher at the National Cancer Institute in the US. And this itself is quite interesting. You're thinking HIV, this is an infectious disease. But the people who were studying it, who made these first effective antivirals, were cancer researchers.

Jacob Trefethen:
So he was part of the NIH, the division that works on cancer. And so he was employed by the US government and had a lab in the cancer part. And okay, got it. Keep going.

Saloni Dattani:
So I think the reason that he was working on it was, as I said, the first thing that was noticed in AIDS patients, that was surprising to people, was Kaposi sarcoma, this type of cancer of the skin. And so he was trying to figure out what was going on here.
I read this book about the drug development in HIV and AIDS called How to Survive a Plague. And there they describe this period very humorously to me. I mean, it's obviously not humorous, but the way that they say it, was that he was really excited to see this first HIV patient come to the National Cancer Institute. He saw it as this once-in-a-lifetime scientific challenge that brought together two of his interests of immunodeficiency and cancer. And they thought, if we're able to crack this, this is going to be really important.
So I think the first thing they noticed was the virus was probably infecting CD4 T-cells. The reason that they thought this was one of the first signs that you would see in someone who was infected was that their T-cell count would drop. They at least had some blood testing and they had some of the tools and technology to measure CD4 T-cells at the time. So they knew that there's this massive drop, and they thought maybe it's because the virus is multiplying in these cells.

Jacob Trefethen:
Seems like a link to make.

Saloni Dattani:
So they thought, okay, let's — we've hypothesised that the virus is replicating in these cells — maybe we should test compounds to interrupt this process, to prevent it from replicating in these CD4 T-cells. And so he then approached different pharmaceutical firms to try to get funding to work on this project, and also to potentially commercialise a drug if they found one. I think he approached several firms. Most of them said no, but one of them said yes. And that company was Borroughs Wellcome. So we probably haven't heard of-

Jacob Trefethen:
Yes, which now has a philanthropy, Burroughs Wellcome fund.

Saloni Dattani:
And this was a pharmaceutical firm that no longer exists. It was merged into what became GSK or GlaxoSmithKlein, and they were the only company at this time that were willing to consider funding or commercialising HIV drugs. But they were very afraid that their researchers or their scientists would get infected with stab that people were working with. So they refused to work with these live virus samples, and they said-

Speaker 3:
Oh my god.

Saloni Dattani:
-nope, you've got to work on it yourself. They were saying this to Samuel Broder and his team. And so Samuel Broder's team had to do all of the screening of these drugs, running the trials all on their own, despite Burroughs Wellcome then getting the credit for it, and then being able to commercialise it.

Jacob Trefethen:
Oh god. Well, it reminds me of streptomycin, the first TB drug, where there was Albert Schatz, the PhD student, and Waxman, what was his first name? Henry Waxman, something? Waxman-

Saloni Dattani:
Selman Waxman.

Jacob Trefethen:
Selman Waxman, there we go, the professor who then got the Nobel Prize. They didn't share it in the end, did they? I don't know. I'm going to forget the story.

Saloni Dattani:
They didn't share it. I also read the story because I was writing about antibiotics, and it was really interesting, because he discovered this group of bacteria that produced antibiotics, right?

Jacob Trefethen:
Right, in soil? Yeah.

Saloni Dattani:
It's so weird to think about bacteria that are producing antibiotics, but basically they're producing it to compete with other bacteria. And somehow he found that this specific type, or this group, of bacteria were producing a lot of antibiotics. He thought, okay, maybe there's something there. They seem to be killing the other bacteria around them, maybe we could use that as a treatment for our own bacterial infections. And he started to recruit PhD students to work on that. One of them was Albert Schatz. And what was really interesting about this-

Jacob Trefethen:
This was Second World War era, right?

Saloni Dattani:
This was during the Second World War. Well, the 1930s, I think, and he had Albert Schatz start to work on this project in a basement's room that he never, I think, Waxman never visited.

Jacob Trefethen:
He's like, try this out on some TB, I'll be upstairs.

Saloni Dattani:
And so Schatz was working on this, and then what was really strange was that Schatz was drafted into war!

Jacob Trefethen:
Oh, yes.

Saloni Dattani:
And the project, basically, was on pause for a few months. Apparently he then got a back injury and then was sent home.

Jacob Trefethen:
Thank goodness!

Saloni Dattani:
And thank goodness, he discovered streptomycin.

Jacob Trefethen:
Wow.

Saloni Dattani:
That was the first, I think, first antibiotic compound that was found from this type of bacteria, which is called actinomycetes, and that group also led to the discovery of various other antibiotics.

Jacob Trefethen:
Okay. Well, Albert Schatz, legend. Grad students have been abused for decades, it turns out. And I guess, back to HIV, which we are currently dealing with, it sounds like a very virtuous academic group. And I don't want to insult Burroughs Wellcome. I'm very glad they brought this to market. So kudos that there was at least one company willing to stand up. So maybe I'll reserve my vitriol in case there are other bad forces I need to get mad at, later in the story.

Saloni Dattani:
Well, yeah. So this is also not quite as similar because I think Schatz and Waxman then got into this big fight.

Jacob Trefethen:
Yeah, I remember this, yeah. And Waxman was withholding royalties from Merck or yeah.

Saloni Dattani:
There was something like that. But in this case, I think they seem to work together fine. In this case, in Samuel Broder's team, there were a few scientists who were really involved in this. One was Hiroaki Mitsuya, and he was doing the day-to-day research on potential drugs that could work against HIV. And I said, day to day, but actually they were doing this research in the night, after the other colleagues at the National Cancer Institute went home, because apparently they were also afraid-

Jacob Trefethen:
Oh my gosh. Wow.

Saloni Dattani:
-of potentially being contaminated or getting infected. Also, there was another scientist called Robert Yarchoan. So these two scientists tested over 180- well, okay, let's back up to what we said before. You're in the 1980s, you have no idea how to tackle this disease. You have various reasons to doubt whether you can even develop a treatment at all.
And the only clue that you have at this point, really, is that it infects CD4 T-cells. So that probably helps you to test things in a lab. You can probably test how these different drugs affect HIV's ability to infect these CD4 T-cells, but you don't really have anything else to go on. So what would you do? And the thing that they did was, they just tried anything. They just tried any drug compounds that they had. So Mitsuya tested over 180 different compounds and they would be coded with different code names, and you would ask people for whatever they thought might be potentially effective.

Jacob Trefethen:
So there's no unifying hypothesis per se, it's more like, ask around, see what people think might work, see what you have lying in the fridge at the cancer institute, that kind of thing?

Saloni Dattani:
Well, even if you did have hypotheses, many of them would just turn out to not work and then you would have to try something else. So okay, there were a bunch of hypotheses, but there were also just, let's just see what happens, let's just use this trial-and-error kind of approach and see if anything works.

Jacob Trefethen:
Well, now I think about high-throughput screening where you screen hundreds of thousands, sometimes more, drug candidates or molecules all at once. Should I be visualising that, or that comes much after, and we're dealing with hundreds?

Saloni Dattani:
Well, yeah. So I think this might've been before high-throughput screening became much more popular. This is probably early days where you're doing this one at a time. You have these different cultures of the virus in the lab and you're just testing out random drugs, one for each one or whatever, and maybe you have a bunch for each one, just to see if it's really working.
And at one point they find this one little vial, or a bottle, with something called "compound S" — so that's the code name — and that somehow seems to keep the infected cells alive. So this was a real breakthrough and this compound turned out to be AZT, or azidothymidine. What was this compound? This was a compound that already existed, and it was developed in the 1960s — in 1964 — by another cancer researcher called Jerome Horwitz. And I had found- I was trying to look up, who was the discoverer of each important antiviral in HIV? And I found this name, and I thought, okay, well let me try to find a retrospective written by him and I couldn't find one.
And the reason was that, when he was working on this in the 1960s, he was developing this as a potential cancer drug. He had this idea that — if you think about cancers, the thing that people know about cancers is they grow quickly. They have these tumours and the tumours grow quickly, and the way that they do that is by replicating; they need to replicate their DNA in order to divide. So his idea was, if you have the DNA code, and the DNA code is duplicated by adding these bases one at a time, by our enzymes, into this longer DNA structure. What if, instead of a normal base, you had a fake base that was kind of like a normal base except it didn't allow any more bases to join to it. And so he found-

Jacob Trefethen:
Sounds clever.

Saloni Dattani:
-a compound that, it essentially was this type of fake base — di-deoxynucleoside. And he thought, okay, maybe this is going to stop the cancers from growing. But it turned out, it didn't work for cancer, and he was so disappointed with it that he apparently threw away his lab notes — essentially just trashed it and forgot about it; didn't even apply for a patent. So it was just in the National Cancer Institute, where he also worked, and it was just there as one of the compounds that had been developed.

Jacob Trefethen:
Don't throw away your lab notes. Don't throw away your lab notes. But I'm glad he didn't throw away the samples? That sounds great to me. I'm happy.

Saloni Dattani:
We said that the AZT — this new compound — it was able to mimic the bases in our DNA. So why did it work for HIV, but not for cancer?
That's something I don't know. But what it does here is almost the same process. When HIV's reverse transcriptase is turning the RNA into DNA, so that it can integrate into our own genome, it introduces this fake base, which blocks the chain from getting longer; it blocks the rest of the DNA from forming, and that halts the virus's replication.

Jacob Trefethen:
That's epic. Go AZT.

Saloni Dattani:
Super interesting. Yeah, it was just, I think it's this trial-and-error approach that sometimes works. What's really useful about things like this is that, once you do find a compound that works, you can then try to make modifications that create new related drugs that you now will hope will also work. That is possible because if there's something about the structure that is allowing it to have this function, then making these different modifications could lead to additional compounds, or maybe it could make it more effective, or more safe in some way, and so you could now have this wider range of compounds that you can work with.

Jacob Trefethen:
And my stereotype of AZT is that it was not very safe, in the sense of, many side effects?

Saloni Dattani:
That's right. Yeah, I mean, I think if you were a patient at the time, you would still see it as much better than the prospects of a continued progression of HIV, but it was pretty toxic. It affected people's bone marrows, it led to anaemia; also just made them feel quite physically weak in some ways. But it did clear out some of the virus from their bodies; it restored their immune function, it cleared infections. One interesting thing I read was that it, surprisingly, also reversed some of these AIDS-related dementias that I mentioned. Because those dementias were actually caused by infections, if you can clear some of the HIV, which is reducing your immune function, which was previously suppressing these infections — if you can, kind of, revert that immune depletion, then you can now fight off these infections that caused brain dysfunction and so on.
This was really astonishing, I think, according to Samuel Broder, to the doctors who saw people who were being treated with AZT at the time — they were genuinely shocked that this was even possible.

Jacob Trefethen:
And we went from not knowing if any antiviral was going to be possible to... you're actually seeing as a doctor people reverse even some of the cognitive effects. What a time.

Saloni Dattani:
What a time, yeah. And also, the other downside was, not just the side effects, but this drug seemed to work for at least a few months in people, and then they would start to get worse again, and the reason was that HIV would find a way to evade the action of this drug. Because it was mutating so quickly, it was able to find ways to either get rid of this drug, or to develop certain changes in its proteins that would mean that the drug was no longer able to work.

Jacob Trefethen:
So that rapid mutation that made it so hard for our immune system to operate against HIV, now is making it hard for AZT to durably operate against HIV.

Saloni Dattani:
But it was really important because it was the first drug. It was a drug against a disease that people thought was untreatable.

Speaker 3:
Yes, totally.

Saloni Dattani:
And this completely shifted the perception of the disease. Samuel Broder has this line in his retrospective review where he says, "The question at that point was no longer whether HIV-1 could ever be successfully treated, but rather how fast more therapies could be developed." And their drug, AZT moves from research in the lab to drug approval within just two years, and this is partly a result of how the trials work, but it's also partly because of activism around trying to make it available quickly.

Jacob Trefethen:
I mean, it's... that's both so inspiring and so infuriating. So when was AZT available, did you say? In 19-?

Saloni Dattani:
I think 1987.

Jacob Trefethen:
1987, okay, so from 1981 to 1987. If the clock starts at 1981, when HIV was discovered; if there had been more energy earlier, more funding, more support, if it only took two years once you started investigating...

Saloni Dattani:
It is really frustrating.

Jacob Trefethen:
Anyway, I should celebrate it was two years, but...

Saloni Dattani:
It's really frustrating because, so I have been reading this book, the audiobook version, of How to Survive a Plague by David France, which is this amazing, very well written book on drug development. "How scientists and activists came together to treat AIDS" is the tagline, I think. It starts, I think, in 1981, and it's genuinely so depressing to read it — obviously — for several years. You're getting through this book, and you're just so frustrated with how slow people are; how unresponsive, how much they don't treat it as an urgent problem — even when it's clearly an epidemic disease that's growing exponentially over time. That people are just unwilling to consider that there are potential treatments out there, or they're in these petty arguments with each other about what we should be doing. Should we be saying enough? Are we scaring people by telling them that this is a deadly disease? And so on. And it was just, it was really frustrating to read. It was a very well-written book, but it was very frustrating to read.

Jacob Trefethen:
I remember I read "And The Band Played On" by Randy Shilts covering some of the initial years and had the same experience — just a very, very tough read.

Saloni Dattani:
But I think one interesting thing about Samuel Broder and the, kind of, cancer approach to studying HIV is that, I think, — so we said that the reason that they were studying this was because of Kaposi's sarcoma, which was one of the cancers that HIV made people more vulnerable to. But I actually think that being a cancer researcher was probably the right mindset that you needed to have, as a scientist, if you wanted to develop drugs against HIV.
One reason for that was, cancer research at the time, they were, I think, the only group in the NIH that were experienced with drug development. But the other was just: you're facing this horrible disease that's very rapidly progressing, similar to cancer. You're also in the situation where action is much more important than inaction, because it's just going to get worse. You're also in the situation where you're willing to take drugs that have toxic side effects, even if that, because they might be able to slow down the disease, and that's more important right now, because the disease progression is so deadly.
But I think the next thing is, because you would realise that what was really important here was not just using a single drug. Just like with cancer, just like the connection to Jerome Horowitz, who discovered AZT, who was also a cancer researcher, you would know that cancer and HIV were rapidly able to evolve to mutate and develop resistance against any drug that you developed. So the aim would not be to develop a single drug, but to use a combination of drugs, and that was the goal that these researchers had even in the 1980s, even though they developed AZT — it did work, but people eventually started to develop resistance against it, but that was okay from their perspective because they knew that this was not the end goal.

Jacob Trefethen:
This is the beginning.

Saloni Dattani:
It was not to develop one drug, we had to develop many.

Jacob Trefethen:
We have to develop many. Not just because they're going to get used one by one and then become resistant, but to use in combination from the beginning. So they were thinking that way from the beginning. Yeah, okay.

Saloni Dattani:
Yeah, I mean this was so interesting to me just as a 'how to develop drugs', what is the mindset that's required? What is the type of approach you use? Of just trying everything, essentially having different hypotheses, just seeing what works. I thought it was really interesting to read about. This, I think, then spurred a lot of other pharmaceutical firms and researchers to work in the area to develop other types of drugs. Samuel Broder's team then developed a bunch of other similar drugs. We just talked about AZT, which is a type of nucleoside reverse transcriptase inhibitor, NRTI, and as we said, it's a drug that is this "mimic", or this fake, version of a nucleoside base of the DNA molecule of HIV.

Jacob Trefethen:
Let's pause there, and let me see if I can remember everything I just learned. So I am putting myself in the headspace of a drug developer who doesn't have the tools of 2025, when we're recording today. And there's quite a few tools I don't have. I don't have PCR. I don't have, and don't have modern genomics. I probably don't have high throughput screening. I definitely don't have knowledge of what HIV looks like, in terms of, visually as a 3D structure — that's probably far away. And I don't really know the whole process of the lifecycle of the virus. But what I do know is that, probably, CD4 T-cells are implicated, because I'm seeing these counts drop. I've taken blood samples, and those counts are not looking so good for patients. And what I do know is that, if I rummage around, there are going to be some failed cancer drugs somewhere that I can at least try.
And so, sure enough, and because well, in addition, if I'm a cancer researcher, I think about resistance and I think about combination drugs. So what I'm going to do is, I'm going to go around and try a bunch of stuff. I mean, my takeaway from this is, it was just incredibly empirical. You didn't have much in the way of theory, beyond the CD4 implication, link, and you would try and stuff, and a bunch of stuff probably did not work, and then guess what? One thing did work, and that gave everyone some hope, and changed things going forward.

Saloni Dattani:
Yeah, I mean, it's so amazing to read about drug development during that time and what happened after that, as well. So maybe this is the time to actually talk about the HIV life cycle and what the other types of drugs that have been developed are. And so...

Jacob Trefethen:
I'm ready.

Saloni Dattani:
We should start with how an infection happens, at a molecular level.

Jacob Trefethen:
Great.

Saloni Dattani:
So we have the HIV virus particle. I don't know if people have seen an image or diagram or something of HIV, but essentially it has this-

Jacob Trefethen:
I'm holding up my hands for people watching the video. Does this look right?

Saloni Dattani:
That looks right. So this is a spherical particle, it has a bunch of proteins coming out of it, and inside the spherical particle is a bunch of stuff including a capsid. This capsid is the core of the HIV virus. You can think of it as looking — oh wow! Is that an actual-?

Jacob Trefethen:
I just picked up something to mislead people. It's a sun-bleached version of a vaccine, but that mimics a viruses structure, so that you can present to the immune system. This is a COVID vaccine that the Institute for Protein Design made.

Saloni Dattani:
Wait, can you hold it up to the camera?

Jacob Trefethen:
Yeah, oh yes, I'm looking at it for myself. Anyone watching the video here: this looks like a virus, it is not a virus. It presents the receptor binding domain of the spike protein of COVID, or SARS-CoV-2, to the immune system on lots of different places so you can get antibodies that bind. It doesn't look that far off. I mean, it's better than when I held my hands up, so.

Saloni Dattani:
It looks kind of cute, also.

Jacob Trefethen:
It is cute. It is cute.

Saloni Dattani:
I had a stuffed toy version of the coronavirus that I got from this museum, and I thought it would be really funny to get this as a gift, and then to give it to someone and say, Ha! I've given you COVID.

Jacob Trefethen:
You know, it's crucial to get good bits in, so I support.

Saloni Dattani:
So the HIV virus, you showed this spherical particle. We have this envelope that is a sphere, and then it has some protein sticking out of it. Inside it, it has a capsid. The capsid sort of looks like a thimble, or maybe more like a bullet. This kind of interesting because the bullet — or the capsid — contains a bunch of the really important stuff, for the virus. It contains the RNA molecules that's its genetic code. It also contains a bunch of other enzymes that it needs to do important stuff, including reverse transcriptase, which it needs to turn its RNA into DNA, and a bunch of other enzymes that we'll come to. We have this HIV virus particle, this spherical thing with the protein sticking out of it. One of those proteins is called GP-120. That protein — when the virus gets into our body, it targets our white blood cells, our T-cells primarily, and this GP-120 protein attaches to a CD4 receptor on our T-cells.

Jacob Trefethen:
Got it.

Saloni Dattani:
They get attached.

Jacob Trefethen:
So the virus is currently outside of the cell, and it attaches to CD4 on the outside.

Saloni Dattani:
Then, it starts to also attach to another protein, CCR5 or CXCR5. There's a — initially, it starts by infecting CCR5 T-cells. It uses these two receptors, it binds to these two receptors, and then it injects itself into our cells.

Jacob Trefethen:
So it binds to two proteins on the outside of the cell; it uses that as a way to get inside.

Saloni Dattani:
So it fuses with our cell membranes. Inserts the contents of this HIV virus into our cells. That includes the capsid, the bullet, the bullet-like thing.

Jacob Trefethen:
Bullet

Saloni Dattani:
But actually, I think a really good analogy, maybe, is like a rocket. You know how, when a rocket launches, most of it falls off, but there's this core part of the rocket that continues going.

Jacob Trefethen:
Right, and usually that's something I like because it contains astronauts. In this case-

Saloni Dattani:
It's not.

Jacob Trefethen:
I don't like it. I don't like it. So instead of space, we're now in the cytoplasm.

Saloni Dattani:
That's right. So we're now in the cytoplasm — the inside of the cell. At this point, the capsid then makes its way to our cell's nucleus. This was really interesting, because we found out — so I had watched this video to try to understand what was going on, what was the pathway? I feel like videos kind of help me remember things better, and this video was from 2010, I think. Then I started reading about this process separately, in research papers, and they described it differently. And it turned out that our understanding of this life lifecycle has actually changed in the last five years, right?

Jacob Trefethen:
Yes. I actually talked to a friend who did her PhD, who I think graduated in 2018, and did her PhD on the HIV capsid. And she was saying to me, oh, back when we were doing it back in 2018, all those centuries ago, we actually didn't yet know that the capsid, at least sometimes, makes it all the way intact into the nucleus! I was like, what? But that's so basic, that's the whole game. It turns out no, even now, we are getting tools that are making it easier to actually see what the heck is going on inside these incredibly busy cells. And yeah, it's makes you wonder, if you do your PhD in five years? What the heck are we going to know now?

Saloni Dattani:
I mean, I think one of the reasons for this is that, it's really hard to observe an infection happening. It's obviously very harmful and probably very unethical to infect someone directly with HIV, if you wanted to study what happens in this early part. The people with HIV, that have been part of research, have obviously been much further along than just being infected. So it's hard to actually study those earliest stages, and that's especially true because HIV doesn't infect other animals. The closest that we could use is SIV — simian immunodeficiency virus — which is slightly different. That means that there are various things about this early stage that, I think, weren't very clear. And I think that the change in the last few years was better microscopy.

Jacob Trefethen:
That is what my friend was basically saying. She was saying, before we had cryo-electron microscopy, we just couldn't visualise things as well. She was using other techniques to do her best, and now you have this atomic resolution of these systems that we haven't ever seen. I mean, it's beautiful. You can actually see what's happening. We never knew.
Yeah,

Saloni Dattani:
It's genuinely crazy. I mean, like, I've been reading about vaccine development; biology over the 20th century, and what is really surprising to me is that — we didn't have any way to visualize viruses until the 1930s.
Before that- so we have the smallpox vaccine, which is against a virus, but this is before anyone knows what viruses are; that's before germ theory was developed. We just happened to get quite lucky with observation and testing. But it's only in the 1930s that we actually got this ability, this type of new microscopy technique called "electron microscopy" that allowed us to see things at the resolution that would let us see viruses that are much smaller than other bacteria, parasites and so on.

Jacob Trefethen:
Okay, we're getting too excited, and we need to focus on the lifecycle. I can tell, I can tell, I can tell. Because right now, I'm a capsid and I'm about to enter the nucleus. I'm in the nucleus. What's happening after that?

Saloni Dattani:
Okay, so let's recap. So the virus attaches to the cell with GP120, it attaches to CD4 and CCR5. It inserts itself, fuses with our cell membrane, inserts its content into our cells. That includes the rocket, or the rocket core, or the capsid, or the bullet, whatever. That capsid makes its way to our cell's nucleus. It then actually gets inside the nucleus. So our nucleus has these entry points, which are called pores, and the capsid kind of snuggles through, kind of wiggles through those. And this is going to be important later on, the wiggling. So it gets into the nucleus and then it starts reverse transcription. So at this point-

Jacob Trefethen:
Question! Question, question. Does it do another? So I came as a full package and then I unfilled myself for the inner package. Do I unfill myself again? So the capsid, kind of, lets all the inner contents out into the nucleus?

Saloni Dattani:
I think so. And I am afraid of saying anything too definitively, because I'm thinking, what if this knowledge changes in a few years or something like that? But I think the capsid also dissolves at this point.

Jacob Trefethen:
Okay.

Saloni Dattani:
Within the capsid we said that there was the RNA — the two RNA molecules — and there's the enzymes, including reverse transcriptase. Reverse transcriptase turns the RNA molecule into DNA. Then, now it has DNA, we also have DNA! It can then insert itself into our cell's DNA, using an enzyme called integrase, which integrates it. Makes sense. So the virus is now integrated itself into our cell's DNA. Now, at some point, our cells will decide to turn our DNA into other RNA molecules, and to proteins, because we need parts of our genetic code to do stuff at different times.

Jacob Trefethen:
I don't want to brag, but I'm doing that all the time.

Saloni Dattani:
We're doing it all the time. I don't know the maths on this, but I know there's a lot of it going on at any given time.
So it basically uses our own cells' machinery to turn its DNA now into its RNA particles, and also to transcribe the other proteins and enzymes that it needs for its functions. These proteins and enzymes and the RNA molecule somehow make their way to the surface of our cells. They then bud out of the cell. The cell membrane of our cell, which previously was fused with the previous virus particles, they bud into this new little particle, and there's now an immature virus, a new HIV virus particle.
But there's lots of them, because it's not just that our body has transcribed one of these. It's transcribing loads of these proteins and enzymes at a time. So this one HIV that has infected our cells and integrated into our DNA can then multiply into many, many more that, and but out of the cell. But at this point, it's still immature. It's still not able to cause an infection, because it hasn't- the proteins that we've made for the virus are actually in this big compound, of what is called a "polyprotein". So it's multiple proteins that are fused together.
At this point,

Jacob Trefethen:
So it was maybe more efficient for the virus to do 'em all at once, but they're now in a big string, so you can't actually- they aren't going to perform their function. There are many different proteins that it wants from you. For example, the integrase, maybe it's still part of that? Is that right?

Saloni Dattani:
They're all part of- Well, no, I think there are multiple polyproteins, but one really big one has reverse transcriptase, integrase, and a bunch of other important proteins. And they're all kind of in this huge polyprotein, and then there's a separate enzyme that's produced called "protease" in HIV.

Jacob Trefethen:
That's what I would do, if I had something that- I think I know what's going to happen. Keep going.

Saloni Dattani:
Okay. So this protease is what is commonly called a "molecular scissor".

Jacob Trefethen:
Right!

Saloni Dattani:
It cuts this giant polyprotein into its components — into the individual enzymes that it then needs. And that also creates, that also cuts off capsid proteins, which then form a new capsid.

Jacob Trefethen:
Oh wow. Sorry, we're inside of the envelope, right now, of the virus?

Saloni Dattani:
We are now inside of the envelope.

Jacob Trefethen:
But there's just a lot of mess in the immature state. We don't have a capsid yet. Okay.

Saloni Dattani:
So we now have- the protease has cut this giant protein, it has cut them into lots of capsid proteins. The capsid proteins start to assemble into a new capsid.

Jacob Trefethen:
Which, in itself, I mean, that's so cool. Because there are loads of different proteins, right? That's going to be lots of different individual units that are due to, you know, thermodynamics, I guess, sort of gravitating towards this configuration, that is a bullet or that. Yeah, it's wild.

Saloni Dattani:
I mean, it's crazy. So this protease is what I wanted to talk about a little more. And I think it is probably really useful to hear about this whole lifecycle in order to know what protease even is. And so the HIV's protease, which is cutting up this giant protein into its components, that is what I think is the next big advance in HIV drug development. There are a bunch of other nucleoside analogues, the mimics like AZT, that are developed around this time. A bunch of other drugs are developed, but I think the proteases are the next big step.
Alright. So we talked about protease, and the reason that's important is because the next big advance, in my view, is drugs that targeted HIV's protease enzyme. I think I'll talk a little bit about the first one that was developed. This was called saquinavir, and it was developed by scientists at Roche. They were trying to figure out if there were any drugs that could target this protein. So they knew that this was probably important, because they could see that- I think they were able to test whether it was present in people with HIV. And they knew that it was important in the process of breaking down that giant protein polypeptide into the smaller components. And so they started to study its structure and its cutting pattern.
As we said, protease is often called a molecular scissor. It doesn't literally look like a scissor, I assume it just looks like a blob or something. But when it's trying to cut down this giant polyprotein, it slightly changes shape, I guess, it opens up. It gets into this transition stage, attaches to the polyprotein and then snips it into separate proteins. And what they were trying to do was, they were trying to find something that could jam that transition state, so it couldn't actually cut the protein. You have to look at what this transition state might be, what specific part of the protease enzyme is doing that snipping, and then, can we fit something into this little gap?

Jacob Trefethen:
Okay, so we've got this protease — scissors — and we got my long string of proteins — paper — and we're going to jam a rock in there, and rock beats scissors. And that's one thing I learned many years ago.

Saloni Dattani:
Very good.

Jacob Trefethen:
Thank you.

Saloni Dattani:
So what was interesting, I think, to them. I think, at this point, there is PCR testing, because this is 1986. So now, PCR is available, but they could also try to look at where exactly the protease was typically cutting. And they found that if you looked at protease in other proteins in the lab, it was cutting at specific sequences in a protein.
A protein is made of many amino acids joined together, and it was typically cutting in places with a tyrosine, which is one type of amino acid, or a phenylalanine, which is another — and either of those followed by a proline. So it was a sequence of either tyrosine or phenylalanine followed by proline. And this combination, of cutting at this point, is something that human enzymes almost never do, which is really useful, because it means that if they're able to target this something that is cutting at this point, then they're hopefully not going to be affecting any human enzymes that are important to us, for our other functions.
So what they then did was try to look for other molecules that could fit into this transition state, where the enzyme is snipping the polyprotein. As part of designing the first protease drug, they also had to develop tools to test how well their drugs were working against it. So they developed a dye reaction test, to detect these proline-containing fragments. They also worked on cloning and purifying the protease enzyme, using recombinant DNA methods, which were also fairly recent. The first recombinant DNA that was produced was in 1972, and the first time that was used for human enzymes was insulin in 1978 — so this was the first time that we could produce insulin in bacteria, instead of extracting it from the pancreases?

Jacob Trefethen:
Pigs, was it?

Saloni Dattani:
I think pigs. Previously to that, it was dogs, and it was also cows and other mammals, which is horrible. But there was no other way to treat diabetes except to extract insulin from various animals, until the 1970s. So this was a huge development that was also very useful for testing out potential drugs against protease.

Jacob Trefethen:
I mean, yeah, we now take this for granted. In any lab you're in, or most labs you're in, you'll have some way of growing up proteins you want to study in a biological system — probably in a bacteria, but maybe in mammalian cells, maybe in yeast. And that means you can study proteins all day long. But back then, this would've been recent. You could only do that from the seventies as you said. So yeah, that's another nice intersecting biotech improvement there.

Saloni Dattani:
It's so interesting to me, just how much the technology kind of happens along side and how much is dependent on other tools being available and what new things that allows you to, allows scientists to, do.
Okay, so back to protease inhibitors. We're trying to test any drugs that fit into these. The transition state — the little wedge — where the scissors are cutting. They tried a bunch of different drugs. One type, called hydroxyethylamines, worked especially well. When they found that that was working, they started making adjustments to it, to see if they could improve on that result. They changed the ends of the molecules, they tweaked the sizes of chemical rings, they swapped side chains, and they found that having a larger, fused ring structure made it much easier for this compound to latch onto the protease and block it from cutting.

Jacob Trefethen:
I find this kind of stuff crazy, just because the tweaking is so important. We're talking about very small molecules, well, small areas we're tweaking. We're talking about not that many... atoms! We're talking about- you add up all the atoms at the cleavage site, I dunno, not that many. So yeah, it's wild that chemistry gets so specific, and that means that you can have these small changes that have enormous changes for patients.

Saloni Dattani:
I mean, I think it shows how much different fields of research come together in developing new drugs. We have people who work in the clinic with patients, and they might see something that seems to be having an effect, so they try it out. Then, there's the people working on microscopy, who are really important, the chemists, the pharmacologists, who are testing out toxicity and drug reactions and things like that. It's like, everything comes together, and that is really important here. And so this drug that they then developed after these dozens of adjustments was initially called Ro-31-8159.

Jacob Trefethen:
Ro-31-8159. It rolls off the tongue!

Saloni Dattani:
That was later named saquinavir, which is the first protease inhibitor that was approved. As I said, this drug, because it was targeting the enzyme, that was cutting in the specific place that was not the case in human enzymes. It was extremely selective to HIV protease, and barely affected human enzymes, even at very high concentrations. That meant that it was much safer. But at the same time, what I found kind of interesting was that, this drug, if you gave it to people, most of the drug was excreted very quickly. About 96%, I think, was excreted in the urine. So having a high concentration of the drug, thankfully, didn't have these side effects, because you'd have to compensate for the amount that just gets peed out.
I think this is also interesting because we're at this point now — this was approved in 1995, saquinavir. And at this point, there are, I think, around a dozen different antiviral drugs, which again is amazing, because just 10 years before that, people thought no drugs would work against this disease, but now they have 10, or so.

Jacob Trefethen:
Progress.

Saloni Dattani:
So, at this point, there are a bunch of drugs, but none of them really work in a long lasting way. People develop HIV, it manages to evolve resistance against the drugs that are being used after a few months. And this seems like it's just another one of those, okay, we've got a new drug, but is it really going to make a difference in the long term?
And I think people were, in terms of people with HIV, they were probably quite pessimistic, in some ways. They want new drugs to be developed for their condition, but how is this going to make a difference after a few months? But this is actually where things change, because now that we have a protease inhibitor and we have nucleoside — the fake nucleosides — like AZT, and we have a few other drugs, we can now combine them, and give them as combination treatment.

Jacob Trefethen:
Ding, ding, ding, here we go. I don't know if, literally, the combination involved AZT or some of the other antibodies you mentioned, but I did notice that the protease is operating right near the end of the viral lifecycle. AZT, as you described, it's operating much earlier. These are really different parts of the lifecycle, and it's quite unlikely intuitively the virus would, at the same time, mutate against both.

Saloni Dattani:
So I think this is something that the cancer researchers, or the virologists, working on this would now have realised: that we're now working on different aspects of the virus's life cycle. It's fairly unlikely that it's going to be able to resist all of these drugs coming at it, in different parts. And I think this is when this combination therapy started to be used, and it was being tested alongside these new protease inhibitors. This new type of combination therapy is called HAART, which stands for "highly active antiretroviral therapy". It's a combination of, typically, one nucleoside reverse transcriptase inhibitor, like AZT, another drug inhibitor that directly inhibits reverse transcriptase — so it's not a fake base — and then, a protease inhibitor. There were multiple protease inhibitors that were introduced around the same time in 1995, like a bunch of different pharmaceutical firms essentially racing to get their to market.
This is a huge change in terms of how HIV treatment works, how effective it is, in the US. I'm showing this chart that I worked on earlier, just to show what impacts it had. You can see this massive rise in mortality rates from HIV and AIDS from the 1980s to the 1990s; rapidly grows as an epidemic disease growing exponentially. In 1995, in December, highly active antiretroviral therapy, the combination treatment, is introduced, and it's just this huge drop in death rates.
The way that people talk about it is, as if people are on death row and they're coming back to life suddenly with this new combination therapy, because it's something that the virus is very hard- not able to evolve resistance to. I wanted to bring this up because I was reading that book, How to Survive a Plague by David France, and he talks about his own- he was a reporter at the time, and he was at one of these scientific conferences on protease inhibitors learning about the science, what new drugs were available.
He describes one of his experiences towards the end of the book, and this is what he says. He says: "One of the scientists interrupted his presentation abruptly and he said, 'Maybe you are not understanding what I am saying. This is the biggest news ever in this epidemic. This stuff is actually clearing virus out of people's bodies. People are getting better. We don't know for sure yet, but we think these drugs — this whole class of drugs — might allow people to live a normal life. This is what we've been working for all these years. They're not a cure. We don't know what they are, in effect, but this is the first major piece of good news we've had in all these years. They're calling it the Lazarus effect. People who were in hospitals on their last breath are getting up and going back to work. We've never seen anything like it.'"
And that's just an incredible change, I think, from how scary it must have been in the 1980s, seeing some drugs really promising. But eventually they start to fail and then you get this combination of therapy that changes everything.

Jacob Trefethen:
A complete change, and it breaks your heart to think of people who didn't make it to see that change. Oh, what a graph. Okay, you're going to have make some nice, less emotionally-intense graphs for me to calm down now.

Saloni Dattani:
There are a bunch of other drugs that I think we aren't going to talk about. But apart from the protease inhibitors, the nucleoside analogues, and other reverse transcriptase inhibitors, there are other drugs that targets how HIV enters the cell. I think there are also some that targets the integrase enzyme — that allows its DNA to integrate into our DNA — and then there are some others as well. But I think that kind of covers much of the major story in the 1980s and '90s on HIV and drug development.

Jacob Trefethen:
Okay, so taking a step back, we know what HIV looks like. We know roughly where it came from. We now know a bit about the lifecycle, and we know about combination drugs that, together, prevent HIV from taking over, and are less prone to resistance, because there's many of them you're on at once. Okay, what about, what's happening with vaccines at this point? And are people talking about curing HIV? I mean, these drugs control HIV.

Saloni Dattani:
I think this is interesting because we don't have a vaccine for HIV yet, right? It's been more than 40 years since the first AIDS case was reported. We have loads of antivirals now, working in different ways, but we don't have any vaccines. I think this would have been really depressing if vaccines were the only things that were being worked on at the time. But thankfully people were trying out random drug combinations, and that's why I think this first step, of getting AZT, was so important. But my understanding is there aren't any working vaccines that we know of yet... so I didn't actually read anything about them.

Jacob Trefethen:
Well, I know a little smidgen. At Open Philanthropy where I work, the team I work on supports a bunch of different biomedical research, and roughly a third of what we fund in grants is, in some way or other, vaccinology or focused on vaccines. The area of vaccines we've done may be the least in is HIV, and the reason for that is that it's very hard, and now people have more knowledge of why it's hard. It also, happily, despite being so underfunded at the beginning of the crisis in the US and elsewhere, now has attracted much more attention and funding. So there's actually been tens of billions of dollars thrown at this problem of 'How do you make an HIV vaccine?' The reason it's so difficult, I think, the clues to that are located in what you've already said about the virus. Well, firstly, clue number one is that our immune system doesn't control the virus naturally very well, once an infection is established.
Most people are not able to control an infection, once it's established, and that implies, okay, well, what is a vaccine? A vaccine is trying to trigger your immune system to be prepared for future invaders. If hardly anyone has a prepared successful immune response, what are we even trying to mimic here? It's a tough problem statement, whereas something like COVID, plenty of people do manage to control and their immune response is productive. You can pretty easily see with COVID, especially at the beginning, well there's one protein on the outside of this virus, the spike protein, that if you block it with antibodies, it is not getting into your cell. So let's try and mimic that immune response.
And then another clue is about the rapid mutation. So if your immune system is trying to prevent something that keeps changing, it's going to be harder. And sure enough, if you create a vaccine which is less dynamic than your immune system, and is only one thing, then you're not going to be clearing all of these different permutations of the virus. These days, because the understanding of the immune system has progressed even outside of HIV, over the last few decades, and because we have so much better tools, people are still going at the problem, and have sort of ingenious and complicated ideas about how to make a HIV vaccine.
You may have heard the phrase "broadly neutralising antibodies" — that's all the rage for what people are using to develop vaccines, and going after. But that's, importantly, not what we're here to discuss today. I think you and I really are focused on medical impact and this podcast is too, and it's so interesting that what we are here to discuss is a drug, in the sense of, it's not prompting your immune system to respond in a certain way, like a vaccine would. It's trying to avoid getting rejected by your immune system, and instead is trying to just be a chemical that's hanging around, and the chemical's doing the work, not your immune system.

Saloni Dattani:
I was thinking about the broadly utilising antibodies. Just in case people are not aware, I guess a fraction of people seem to be able to develop an immune response to a wider range of HIV strains after it's diverged. So trying to find those antibodies, that seem to be working against this broad range, that is what people are looking for. Right? The other thing is there are some people who are still, we're working on combination vaccines, I think. So vaccines that include multiple different components of the HIV virus. And this, I know from direct experience, because I was once in an HIV vaccine trial.

Jacob Trefethen:
Aha! So when was this?

Saloni Dattani:
This was in 2019.

Jacob Trefethen:
2019.

Saloni Dattani:
You might be wondering, why am I getting an HIV vaccine? Why am I in this trial? It was this phase one trial. So essentially, they're just testing the safety and some basic reactions — immunological reactions — you have to a potential vaccine. And I got contacted through Imperial where I think I was studying at the time or had been, and I was like, I love science, I want to be part of this trial.

Jacob Trefethen:
We need more Saloni's in this world.

Saloni Dattani:
Also I was thinking, well what if this candidate vaccine actually works? I'll be immune to HIV. That would be so cool.

Jacob Trefethen:
Well, oh yeah. So this was not controlled. It was a phase one, so you were definitely getting it?

Saloni Dattani:
Oh, I actually don't know. I mean, I could have been on placebo, but still you have a 50%-ish chance, probably, get it for free getting an HIV vaccine for free if it works. It was a really funny experience because... if you have met me or seen me in person, I'm quite small. I thought that, well, I knew that this trial had this eligibility requirement that you had to be within normal BMI. I am essentially on the cutoff of underweight and normal, whenever I've checked. And that's just been true for years. So I was really worried that I would just fall under the threshold, and I would not be allowed to participate in the trial.

Jacob Trefethen:
I love that you are hustling to get into an HIV vaccine trial.

Saloni Dattani:
Like, eating more food to get in. Exactly.

Jacob Trefethen:
Bulk season is on.

Saloni Dattani:
Okay. So I was trying, I was really hoping that I would get into this trial. I got to the clinical trial site. They asked me a few questions, they asked for my consent, et cetera. And then, they also wanted to measure me, to check that I met the requirements. So they were measuring my weight and my height. They then put that into their computer and they said, 'Oh great, you've passed this threshold', and I saw this BMI value on their screen. I was like, that's surprising. Great, but surprising. And then, I looked at the values that they had entered, and it turned out that I was shorter than I thought I was... so my BMI was normal.

Jacob Trefethen:
So it took medical development of HIV to get you to understand your height. I mean, there's a lesson here, but I'm not quite sure what the lesson is.

Saloni Dattani:
Well, it's also, it's hard to measure your own height.

Jacob Trefethen:
Great point.

Saloni Dattani:
I dunno. It was both exciting because I could now participate in this trial, but also there was this sadness that I felt, realising that I was even shorter than I thought I was.

Jacob Trefethen:
Oh God. Wait, so what happened? Are you protected?

Saloni Dattani:
I don't know. Well, they didn't unblind me from whether I was getting the vaccine or the placebo, but I did go in; I think I was in for some eight sessions. They did a bunch of, was it blood testing? They did some testing of uncomfortable parts of my body, to see the effects of this vaccine. I don't think I had any side effects, maybe a headache at some point, but that was all. It was pretty nice. It was a great experience.

Jacob Trefethen:
Nice. Cool.

Saloni Dattani:
I mean, I would say I would recommend it, but really you should decide that for yourself.

Jacob Trefethen:
Sounds good. I just recently was screening to sign up for a vaccine trial here in San Francisco, and I did the 15 minute screen, and they signed me up to go in person. And then, the day I was going to go in person, I had a meeting that clashed, and I haven't got around to enrolling, so I'm feeling a lot of guilt. So now I have an extra incentive though. Maybe I'll figure out I'm taller than I think I am. Maybe I'll figure out I'm shorter though.

Saloni Dattani:
Well, so the reason I brought this up was because it was a combination vaccine, but also it was a funny story. But the vaccine that they were trying contained, I think, three different proteins of the HIV. So I think it was one adenovirus that was modified to carry an HIV coat protein. There was another that was a vaccinia virus, which is... is that the smallpox vaccine virus, I think?

Jacob Trefethen:
Hmm, yeah, probably.

Saloni Dattani:
And then there was another, that was another coat protein. So they had tried out, I think, one or two of these before in trials, and then this was putting them together into this combination vaccine.

Jacob Trefethen:
It's interesting-

Saloni Dattani:
And then I don't know How it worked out.

Jacob Trefethen:
Yeah, it's interesting you mentioned a coat protein. It makes me think of the design differences you are dealing with when you're trying to make therapeutics, and when you're trying to make vaccines. With vaccines, stereotypically, especially for antibody responses, you wanna look on what's on the outside of an invader, what's sticking out that my antibodies can glue to, and maybe a coat protein is a good choice because it might be sticking out? And you know what is not sticking out? Those strands of RNA, that are not only inside the envelope, they're inside a capsid; your antibody is not getting in there. However, a small molecule drug, which is a nice tiny little chemical, can diffuse to many places very surreptitiously. So you really might be able to interfere with something that the virus has tried to protect from your immune system, but has failed to protect from genius humans, who are using good tools to make something that nature actually couldn't have really got to.

Saloni Dattani:
No, exactly. Yeah, that's a really good point. Shall we talk a little bit about treatment for HIV and what that's like?

Jacob Trefethen:
Sounds great. And maybe we should even skip to prevention! We've talked a bit about-

Saloni Dattani:
Let's do that.

Jacob Trefethen:
Let's do it, because you've given us a good overview of how in the '90s, these new drugs allowed patients who had HIV infections to have much longer life expectancy, and control their infections. There's a lot more that we could say about the different improvements since then in treatment. But the principle is somewhat similar, if you want to be on these combination therapies. So let's skip to prevention because prevention has some overlapping path and some different path.
What were the first ways that you could try and prevent getting HIV, if you didn't have it yet? Well, you could change the way you were having sex, the type of sex you were having. You could have sex with fewer partners, and you could have sex with condoms, which provide a barrier. The thing that really changed preventive strategies more recently though, was drug availability for PrEP — pre-exposure prophylaxis. So that's different than post-exposure prophylaxis, which is PEP. And the pre- means you're taking the drug before you have sex, or before you get exposed in some other way. That means that, if any HIV particles enter your system, the drug is going to help block an infection getting established. So PrEP as a drug regimen first became available in the US at least, in 2012. So Truvada is a combination of two drugs, tenofovir and emtricitabine. Do you know how to say that one?

Saloni Dattani:
No.

Jacob Trefethen:
Okay. I mean, they put them in one daily oral pill. So, more specifically, it's actually tenofovir disoproxil fumarate, which I'm sure I'm also mispronouncing, or "TDF", in combination with emtricitabine. And those were two separate drugs that had been approved for treatment of HIV in 2001 and 2003.
The combination of them was approved as a treatment called Truvada in 2004. Then by 2012, the FDA approved Truvada as the first PrEP regimen, after a clinical trial showed that it had high efficacy in preventing infection. And I, yeah, go ahead.

Saloni Dattani:
Yeah, it's so interesting that some of the same antivirals that are used in treatment were also used in prevention. One thing that made me think about was, I was reading about was azidothymidine — AZT — the first HIV drug, and I think there's a part of that story that gave them a clue that antivirals could be used as prevention as well. That was that pregnant women who had HIV who were taking AZT, were not passing it on to their babies at the same rate. They started running this trial in the '90s, and in 1994, I think, the study was published. There was this massive drop in the rates of transmission, from mother to child, of HIV. And that is really interesting as well, because even though people were developing resistance to different HIV drugs, if they were pregnant and taking it, the drug resistance was not as much of a problem if they were taking it late enough, because you only need this particular time span for it to be effective. It doesn't have to be effective for years.

Jacob Trefethen:
Of course. I see.

Saloni Dattani:
But also I think that just gave people a hint that this is something that could be used in prevention.

Jacob Trefethen:
Yeah, that's such a neat real world proof-of-concept of what you can do there. Truvada has been improved on since. So maybe I'll just go through a couple of those improvements. The fundamental idea is similar for the main improvement drug. In 2019, there was a new regimen called Descovy. And you might be wondering, is this from a competitor who's trying to outdo Truvada? And it's from the same company, Gilead, who, as a bit of a spoiler, developed Lenacapavir later in life. Descovy does have a longer patent though, so it's a better variation for men, it's emtricitabine again, which I've probably said three times in three different ways, and it's tenofovir again. It's the same dose actually of emtricitabine. I think it's 200 milligrammes. The tenofovir is in a new form though. Instead of TDF, it's TAF, which stands for tenofovir alafenamide. And both TDF and TAF are "pro drugs". For tenofovir, that means that means your body is sort of doing some work once you ingest them to enzymatically, convert them into tenofovir, and then into tenofovir diphosphate, which is the active formula drug. My understanding of the difference is that, for TDF, so the original one, that primarily happens in blood plasma and for TAF-

Saloni Dattani:
What happens? The, the change?

Jacob Trefethen:
The conversion... into the active drug. And for TAF, that primarily happens in the immune cells. You know, if you think about the difference there, well, getting the same thing out the other end, why do I care? Well, if you're doing it in the blood, then your blood's circulating everywhere, including your kidneys, and you can actually have more unwanted effects from that, than if you're more secluded when you're making your active drugs. I think that's why the safety profile of Descovy looks a little bit better. You have, if you're on long-term daily use of the first one, it's got a pretty good safety profile, but it can have negative effects on kidneys and bones — so bone density and kidney toxicity. And so, here's where, if anyone's on the video, I'm going to do some show and tell. I don't know if, are you the kind of person-? I keep all of my empty pill bottles into the future indefinitely?

Saloni Dattani:
Oh, I don't do that.

Jacob Trefethen:
I do this.

Saloni Dattani:
So these are empty pill bottles.

Jacob Trefethen:
These are empty pill bottles, which hopefully don't have private information on them. But basically I think I do it because I have some vision of, I'm going to do some art project about what it's like to be a modern human in the future, and you do that. But I think I actually stole that from, I think I've seen an art project, which had loads of entry pill bottles. So I actually don't have a plan for these pill bottles.
But basically, here's what you can learn. So take one tablet by mouth every day. This is emtricitabine and tenofovir, 200 to 300 milligrams. Here's another thing you can learn. So this one is this empty pill bottle says Laurus labs on it.
And you might be thinking Laurus labs, that doesn't sound like Gilead true. And this other empty pill bottle says Amneal on it; doesn't sound like Gilead either. The reason for that, is that the Truvada patent expired in 2020. So there are now many generic drug manufacturers who make Truvada, which is why I am on Truvada, because when I first asked to go on Descovy, my doctor at the time was like — I think that patent exposed in 2031 — was like, uh, no, no, no, we're going to give you Truvada. And then I did the classic-

Saloni Dattani:
Because it's cheaper, or?

Jacob Trefethen:
Yes, correct. So it's made by drug companies outside of the US, usually in middle income countries or in lower income countries, a lot based in India, but other countries too. I actually don't, I feel like one of these is an American company, but I might be wrong. And by making these generic competitors, where they only have to prove to the FDA that it is similar enough in terms of its pharmacodynamics and all that, they don't have to redo all the clinical trials. They can sell for a cheaper price than Gilead might. I actually remember later on, the first injectable PrEP came about, cabotegravir, and that is made by a different company called Viiv, V-I-I-V. That, I believe, was approved in 2021, if I'm remembering right. That is: you only get one injection every two months.
So I had heard about it and asked a different doctor I had at the time, could I, just asked about it, wasn't sure if I do it, wasn't sure if I'd stick with what I was doing. And that was very expensive, so that was a quick no. My insurance at that time was not enthused about that one. If memory serves, it was roughly $4,000 a dose, and it's every two months, that's six doses a year. I think it was roughly $20,000 a year. And the patient benefits sure enough was not, I shouldn't really have been paying that much, because the drugs I was on were working perfectly fine.

Saloni Dattani:
I guess I'm interested about how PrEP works on a day-to-day basis. Do you take it every day? Do you only take it sometimes? What's the pattern?

Jacob Trefethen:
So it's the default is you take it every day; it's a daily oral pill, and that makes sure that there's enough of the drug in your system that you are safe, whatever happens. There is another regimen that men can take for Truvada, which is often referred to as 2-1-1, so I do. Where instead of doing it every day, you take two doses, so two pills, the day of sexual activity or some risk you're exposing yourself to, one pill the next day, one pill the day after, and then, the rest of the time, you just don't take anything. That is easier for some people.
And that said, if I think about, if I do an informal poll in my head right now, with my gay friends in San Francisco, I would say most probably do daily, just because it's easy. Actually, recently, my doctor tried to move me onto Descovy, which is the second one, just because it's better for kidneys and when I was a baby, I had some kidney issues. That I do not believe doctors do recommend 2-1-1. And certainly my doctor and I asked him, well, I'm doing 2 1 1, can I do that with Descovy? And he said, "Well, I'm not allowed to say yes to that." I said, "Oh, what do you mean?" And he was like, "I don't think that they've studied it with Descovy." And I was like, "Okay, so we're sort of going to move on from that. Are we? And you're going to give me Descovy?" And he's like, "Yes, I'm going to give you Descovy." So I'm in a sort of grey area on that, and anyone listening, don't treat me as a doctor and my recommendation on Descovy.

Saloni Dattani:
But so you've now moved to Descovy?

Jacob Trefethen:
I'm in the process, which is... you know, I'm a fairly plugged in, good health-seeking-behaviour type person in the statistics. And I still haven't got around to being on the best one. So I dunno, if it's not top priority in a given month, I might not get around to changing to the better drug. You know, I was talking to someone yesterday actually, because I said, "I'm about to record this podcast, what are you on?" And he said, "Oh, I am on the daily pills." Most people on the daily pills probably couldn't even tell you if they're on, they both work really well, it doesn't matter that much.
But he said, "Oh, I was thinking of going onto the injectable every two months. But then as I thought about it more, I have to travel for my job. So I was worried, well, am I definitely going to be back in San Francisco at the time I need to get the injection? Or is there going to be a two week delay where I'm somewhere else? And then actually, I'm more at risk, and actually I think it's easier if I just do the daily pills."
And I think that actually gets to how these drugs can be. It can be complicated how they interact with someone's life. And it's not just something you can read off a clinical trial, of how useful they'll be. You have to think about — well, how is someone who needs this drug going to use it in their real life? And what there might be counterintuitive kind of pros and cons of having a big gap of two months between that sounds great on paper, but there you go, someone didn't want it. They wanted to just do it every day. And I actually think about this with treatment as well.
I have a friend who started dating someone who was HIV-positive. He was HIV-negative, he started to date someone HIV-positive. And now, with the great drugs that we have, if you are positive and on treatment, you will be undetectable, you won't transmit the virus to partners, which is incredible. But my friend, he knew that, sort of rationally, and he was still anxious around sex. It was a scary topic, even if he could sort of rationally tell himself he shouldn't be scared, and then that can be a tough thing for a partner to deal with. And one day, his new boyfriend actually took his daily pills in front of my friend as a way to basically build trust, and that was a kind of beautiful thing to do. I think, if I were in his position, I probably would've been offended and annoyed, and he was so generous. And then sure enough, my friend did build trust and fall in love and have, I think, they had a wonderful sex life.
But that is the kind of thing you wouldn't think about when designing a drug. It's like, if you are on a treatment drug that was an injection, that was once every whatever period. Well okay, that particular trust-building exercise would not be available to you. So oh, it gets so complicated. And then the people most affected by HIV and AIDS these days — it affects women in Africa more than it affects men now, especially in Southern Africa. And there the complexities are very different and I won't be able to rightly summarise them. But for example, if having to go to a clinic for a procedure or injection might be different than having to go to a pharmacy to pick up pills, which might be different than having pills on your shelf for many weeks, versus having to go more regularly and all of that matters a lot.

Saloni Dattani:
No, that's super interesting. I think one thing I was thinking about when you were talking about this was, what are the different problems that people will face apart from- So we have this sort of struggle to, I dunno, schedule some of these appointments, things like that. I think, one thing on that front was, with some of these injectables, I think there's a kind of leeway that you have for when you get the next dose. You don't have to get it exactly, let's say, six months or exactly two months after, but there is a little grace period that you can get it in. But that's still, probably sometimes, quite inconvenient for people if something happens if they're in a different country or so.
But there's the issue of, I dunno, taking a daily pill every day for many years, that might be hard for some people in terms of remembering, especially if it's a preventive pill. It's not something that is necessarily super salient to them as if it's a condition they already have. But also, it's this access, like, what if the clinic is closed one day? What if something happens? What if, I don't know, someone takes your pills or they drop out of your bag, or something like that. How are you going to get the next dose?

Jacob Trefethen:
You know, I can answer that for me, and I pick 'em up once every month, but I'm just one guy and I think we need to get a better answer for people who are affected in other contexts. So I think it's time to phone a friend, Saloni.

Saloni Dattani:
We're going to phone a friend. This is so exciting.

Jacob Trefethen:
We're going to phone a friend.

Saloni Dattani:
Who are we phoning?

Jacob Trefethen:
We're going to phone my friend Douglas Chukwu, who works at Open Philanthropy with me, and before that was a medical doctor in Nigeria, and worked in public health on HIV treatment and prevention. So should we dial him up?
Hello Douglas. How are you doing? Thanks for joining.

Douglas Chukwu:
Good, good. Great to be here.

Jacob Trefethen:
Well, thanks for taking time out of your day. So, we worked together, but before we worked together at Open Philanthropy, you were trained as a doctor and worked on other things in public health, which is why we wanted to bring you on today. So yeah, what's your background and what were you working on, before Open Philanthropy?

Douglas Chukwu:
I trained as a medical doctor in Nigeria. So I had a couple of years of clinical practice working as a medical officer in a government establishment and also a private establishment. So had that dual experience and then piloted to work in public health. Interestingly, most of my public health experience was in the field of HIV and AIDS.

Saloni Dattani:
Are people getting a weekly stock of treatment of PrEP, or will it last them months or years? Like how long does- maybe this varies depending on the type of drug that they're using.

Douglas Chukwu:
Yeah, so oral PrEP comes in, the commonest is the pack of 30 tablets, and oral PrEP is to be administered daily. So the common, it varies from a range of one month to three months; three months being the maximum, because for individuals on PrEP, they need to be tested every three months, as per the national guidelines, so that's the touchpoint with the facility. The treatment duration of prescription helps to make sure that they come for their refills, they're assessed for adherence, they're tested for HIV and they're also monitored for side effects.

Jacob Trefethen:
How important is public funding from donor countries like the US and the UK, when it comes to HIV particularly?

Douglas Chukwu:
Absolutely important, right? I'll give an example. There are various access- let's say for example, there are a lot of individuals that have accessed treatment that wouldn't have accessed treatment if the HIV programs in countries were entirely reliant on domestic funding. And this varies across African countries, but in Nigeria, for example, over 80% of the funding for HIV programs is via external funding. And then, there are some countries like South Africa, where they've made some progress in terms of domestic financing for HIV programs, I think as high as 70%. But overwhelmingly, in Africa, there are various country programs that are hugely reliant on external funding for sustaining and delivering for HIV.

Jacob Trefethen:
We are recording this at the beginning of April and I've still found it difficult to get good reporting on quite what's happening with PEPFAR, the US- the main way that the US supports HIV programming. And the answer of, what's happening may change in the coming months. But, as you talk to your friends who work in public health, what are you hearing at the moment? What has happened at facilities or on the ground, in reaction to the PEPFAR uncertainty?

Douglas Chukwu:
The effects of this cut across not just the healthcare workers. But healthcare workers, patient communities; there's a lot of uncertainty. There's a lot of unease and a lot of worry about what the future holds. And a lot of these suspensions were abrupt. So people got stop work orders. As I mentioned, there is a community component of healthcare service delivery. There are community healthcare workers that are supported by the PEPFAR funding, and having the stop-work orders meant people stopped getting tested in communities, access to some medications were threatened, even though perhaps there were some stock to sustain initial dispensing of ARVs (antiretrovirals). But clients were being told that if this continues, you'd have to pay out of pocket for your medications and that's actually troubling for the patient community. Additionally, I think about the broader implication of this, which is knowing that the funding for HIV programs is actually threatened, that also affects manufacturers thinking about maybe wanting to exit some markets. That kind of damages a lot of the progress that has been made over the past couple of years in the field of HIV and AIDS. There are country governments rallying up to cover some of those gaps. But those resources pale in comparison to the amount of resources that the US government devotes to supporting this.

Saloni Dattani:
As a- if someone needed treatments, I guess in the last three months, or even now, how would the cuts and the stop works order affect them? What would they be experiencing?

Douglas Chukwu:
I would say to paint the picture, imagine a status quo where every day, community health care workers report to the facility, gear up with their mobile testing kits, with their ARVs [antiretrovirals], and they go out into hard to reach areas. They identify people who are positive for HIV, place them on treatment. Some of these are pregnant mother who don't have the resources to come to the facility. So that abrupt suspension means those individuals will not benefit from those services.
Now, beyond those who are yet to be identified, because that's the category I just talked about, there are people who rely on these healthcare workers to reach them to receive their refills for ARVs, right? So the suspension was abrupt, as you know. So people were just told to stop work, and their clients who likely would be expecting their healthcare workers to deliver ARVs to them and would have been affected by such stop work orders, so that's pretty much it. Because there are those who still have drugs, but there are those who are actually suffering from these cuts.

Saloni Dattani:
My sort of understanding, I was reading a few articles about this and the impression that I had was, the clinics might have some of the treatment, but they're just shut and there's no one; the staff who are paid or supported by the US are not allowed to go in, and people can't get treatment even if it's in the clinics there.

Douglas Chukwu:
Absolutely, yes. And the staffing, as I mentioned, the staffing support, it's not limited to the community setting. Even in healthcare facilities, there are one-stop shops that are staffed by individuals that are supported by the performing, as you rightly pointed out, that stop work affected those individuals and perhaps clients would've presented to facilities and wouldn't have had, maybe, individuals to attend to them.

Saloni Dattani:
And I think we were talking about refills and how often people get refills, and if that's every 30 days or every three months or so, that probably adds up to quite a lot of people who have been directly affected by these cuts over the last, almost, I guess, two and a half months, maybe.

Douglas Chukwu:
Absolutely. Because people, I mean it's a three month cycle. It can be a six month cycle for people who are stable, but every day marks someone's clinic appointment, right, so.

Jacob Trefethen:
It's a scary time for a lot of people with HIV.

Saloni Dattani:
How excited are you for lenacapavir in the field? I think one reason, I think, it's going to be quite important is because of this adherence issue that you mentioned, but also meaning that people don't need to get refills as often, so there's a bit more stability for someone who has had an injectable. Is that also your view? Are there other things that you see as part of this?

Douglas Chukwu:
One of the challenges with oral PrEP is having to take it every day. And with suboptimal adherence, there's the risk of resistance developing. So having a drug that's administered twice a year, I mean, I won't say it's as good as a vaccine, but there are challenges with developing the HIV vaccine. So this is as good as we are currently towards making sure that people keep from getting infected with HIV. It's very exciting in the HIV prevention landscape, having an injectable once a year, fingers crossed, but that would be amazing. That would be phenomenal.

Jacob Trefethen:
We're almost there. We're almost there.

Saloni Dattani:
That was really helpful. Thank you so much

Jacob Trefethen:
Thank you so much Douglas.

Douglas Chukwu:
Thanks so much. Thanks so much. Happy to talk about this and very excited about the development in the HIV prevention space. Hopefully these developments continue and move the needle in terms of achieving epidemic control of HIV and AIDS.

Saloni Dattani:
That was great. This was so cool, to phone a friend and learn about what things are like in treatment in Nigeria, the future of lenacapavir. But also, all of the funding cuts and the disruption that's going on there right now. I think it really made me think of how important some of these new drugs could be in terms of changing around the epidemic in HIV, the possibility of using long-acting drugs, and by that we mean drugs that have an effect for a really long period. Currently we have cabotegravir, which is a two monthly drug. There's also lenacapavir, which is a six monthly drug. And potentially, Gilead is also working on a once-yearly drug. And if that pans out, again, I think it would completely change our ability to respond. Whether that is actually scaled up is another question, and that's something we'll talk about later on. But it's really, I think it's a change in what's possible in treating and preventing HIV.

Jacob Trefethen:
Yes. And I feel like I have a lot to digest and we have a lot still to discuss. So lemme go away for a second and think.
Okay, Saloni, we're back. How you doing?

Saloni Dattani:
I'm doing great. It's been five days. I've had a lot to think about. You look like you're in a completely different place from before.

Jacob Trefethen:
That's right. New shirt, new background. I am in New York City. I'm in the village, the East Village — or at least I thought I was. I arrived and was informed by someone who lives here that I'm actually in Stuy Town, which is not the same thing as the East Village, but I've decided to kind of squint and it feels about the same and I'm having a good time. It feels, I wish I could say I was here funded by our podcast to do some historical analysis of the AIDS epidemic because I was in Castro before and now I'm in the Village. And those are two important parts to the story. However, I am actually just here visiting a friend. Totally unrelatedly.

Saloni Dattani:
I really enjoyed thinking about what Douglas told us about how treatment works in the field in a clinic in Nigeria. But also just thinking about the different approaches that people have to prevention, whether that's with condoms or behavioural changes or PrEP, this amazing breakthrough in 2012, of multiple drugs in a combination that can reduce the chances of infection. And it's really interesting first to think about the behavioural aspects that lead to, basically, how do people actually take these drugs in practice and how does that inform drug development? How does that inform the kinds of new treatments that we need and whether they're effective.
I think that's ultimately the key breakthrough of this new drug that we're going to talk about, lenacapavir, that instead of being a daily pill that people would take as they do with PrEP, it's this long-acting injectable. So it's an injection that you would take. So there's, I guess, two injections every six months, and this massively reduces the chances of infection. It's also been used as a treatment for people with drug-resistant HIV, and there could be other purposes for it as well. So I think that's really the key breakthrough and I think I really started to understand exactly how that would matter for someone who has HIV, thinking about how do they get their next supply of the drug; how this makes a difference to them.

Jacob Trefethen:
Yeah. It also got me thinking about the costs; how can we get the costs low for new drugs so that they can get used more. And that's something that I'm interested to talk about with lenacapavir too. But what is lenacapavir, Saloni? It's time for you to teach me something new.

Saloni Dattani:
I think to teach you about what lenacapavir is, we have to go back a little bit and talk about the capsid. So if you remember from before, the capsid is this thimble-like structure within the HIV virus that contains the RNA molecule, and it contains a bunch of other enzymes. It's the core that stays intact when HIV enters cell, and this capsid takes that information, and those enzymes, into the cell's nucleus. They then allow the RNA molecule — the genetic code of HIV — to turn into DNA to integrate into our own cellular DNA, and then to proliferate into many more HIV particles. So it's this key structure that's kept intact throughout this process. Once it gets to the nucleus, it then starts to dissolve, letting the RNA molecule out, letting the enzymes out to do their jobs. And then, later on, when the new HIV particles start to be formed, it then starts to form; the capsid starts to form again. This process is actually really interesting; and quite interesting, both as a process but also in terms of what it looks like.

Jacob Trefethen:
Yes!

Saloni Dattani:
This HIV capsid is made up of, I think, more than 1,500 or so proteins. But each of these proteins comes in groups. So some of the groups of this protein are in groups of six, which are called hexamers. So hex- is six, and some of them are in pentamers; penta- means five, but there are 250 hexamers or so, it kind of varies. And exactly 12 pentamers.

Jacob Trefethen:
I'm looking at it now, and it looks like flower petals that are falling into place. How on earth is it so exact? Why are there 12? Why are there 12? And the 12 are not exactly... they're sort of dotted around in a pretty pattern, but not necessarily how I would've designed it, if I were thermodynamic.

Saloni Dattani:
Yeah, I mean if you're listening, it's this thimble-shaped structure. Most of that is made of hexamers of this protein. So, imagine some six-shaped thing, maybe like a star-shaped cereal that I used to have called Honey Stars. Oh yeah. And they were very tasty.

Jacob Trefethen:
Or Shreddies, which I'll never say a bad word against.

Saloni Dattani:
And then, in a few places in this capsid, there are other structures that are only five that only have five proteins. So they're like five-star shapes. And these look, I mean, where these are organised in the whole capsid doesn't look very symmetrical to me.

Jacob Trefethen:
No.

Saloni Dattani:
And it's quite strange, but what I was reading was that: the placement or the number of these pentamers within the whole structure changes the whole shape of it. It's sort of like, this structure, that's where the hexamer are tesselating. So they're all fitting together in this very symmetrical way between them, but then these five-shaped pentamers determine the curve, I think, of the capsid. That's very interesting.

Jacob Trefethen:
Yeah. I feel like I want... if I redo the tiles in my bathroom or something, I want to do this. But now that you've told me the shape, the 3D structure, is an important property, that wouldn't be so good on tiles. So I'm going to have to rethink.

Saloni Dattani:
You would have... Maybe it would be more like a flower vase?

Jacob Trefethen:
Yeah. Oh, great idea actually. Yeah, it's very floral, it's just so, it is very beautiful. I recommend people listening Google it. And I think recently, it's only the last 10 years or something where we've really known what these different polymers look like and how they assemble and all that. Is that right?

Saloni Dattani:
I think that's right. Only since the 2010s have we had advances in microscopy that allow us to see some of these particles, with enough resolution to see what they actually would look like in this coherent structure. That is super interesting.

Jacob Trefethen:
As I think about the drugs you've described previously, what is interesting about this one: if we're talking about the capsid and we're going to try and go after the capsid with a drug, this is a structural part of the virus, but it's not as functional in the direct sense. I'm not imagining something getting integrated into my DNA, so I'm going after the integrase; and I'm not imagining I'm chopping up the large string of proteins into smaller proteins, and going after the protease. This is more like just a package, a thimble, a bullet; that it must be required, because why would it still be there? But the function is not as direct. I don't know. Does that ring through to you?

Saloni Dattani:
I think you're kind of right, but I think it is important. Because to make sure all of this stuff doesn't fall out, I guess, in some other part of the cell. Like, we need to carry or transport the RNA molecule and the other enzymes to the nucleus. But it also has these functions where, based on the structure, based on the shape of this capsid — that allows it to enter the nuclear pores and the nucleus, the little holes and this shape allows it to wiggle through. And I think it might also be involved in stimulating the reverse transcriptase step. So the capsid is somehow involved in making that start, and I think that is also quite a new discovery that people have had within the last five years.

Jacob Trefethen:
Got it. Anyway, keep going. Thanks for pausing for me.

Saloni Dattani:
Not at all. Okay. So we've talked about what the capsid looked like. What does lenacapavir have to do with this? This also, it really helps to have a visual, but I'm going to try to explain it in words as well. So we have this structure where, the capsid is made out of these proteins. The proteins are sometimes in hexamers, sometimes in pentamers; I guess if you imagine that these hexamers or pentamers are fitting together, they're a bit like, putting your hands together with your knuckles. They're kind of fitting together between your fingers. And imagine doing that lightly; you're not fitting them too strongly. So there's a little bit of space and flexibility between your two hands. But then, lenacapavir, it wedges itself into those gaps between both of your hands' knuckles. And that means that it now becomes very stiff. Now you don't have this much ability to move, to move the structure around. This stiffness becomes a problem in several ways during the HIV's life cycle. I think that's quite cool just to think about how the overall shape of this capsid changes, based on lenacapavir fitting into these little gaps between the proteins.

Jacob Trefethen:
That is good. It's quite subtle as well. 'Cause it's not, I think of a drug coming in and trying to nuke some structure, you know, blow it up. But actually you're saying no, we're just going to change properties of how squidgy it is.

Saloni Dattani:
No, exactly. And yeah, I mean, I think it's fascinating. So we have all of these little lenacapavir molecules. Lenacapavir itself is quite a small molecule, so it fits into these little gaps. And if we go back to this lifecycle of where the capsid is imported, so we have: the HIV virus has entered the cell, has released some of its contents, which includes the capsid. The capsid is then trying to enter the nucleus. In order to get into the nucleus, it has to fit through these holes, the nuclear pores. And to do that, it binds to certain proteins on the nuclear pore. And it turns out that those binding spots are blocked by lenacapavir.

Jacob Trefethen:
Okay.

Saloni Dattani:
So it binds in exactly the same spots where those proteins would attach and let it squeeze through those gaps. And the second thing is, the capsid is now too stiff, because of lenacapavir blocking, so it's less flexible.
Knuckles are engaged.
Exactly. Your knuckles are engaged. You can't squeeze through the little holes of the nucleus. So that's another important thing.
Then, the next step, and this is super interesting, so it's not just that one step that lenacapavir disrupts, but it's actually multiple steps during this life cycle. Imagine that some of the capsids have still somehow made it through to the nucleus. Now the capsid needs to dissolve and allow the RNA molecule out, and allow the reverse transcriptase to turn the RNA into DNA. It needs integrase to turn that DNA into a part of our own cell's DNA. But now it can't break; it can't dissolve. It can't uncoat anymore, because of this rigidness. It's just too rigid. But also sometimes it's so rigid that it cracks too early, and that early cracking makes it hard for the capsid stimulating the reverse transcriptase, to start doing that process. So that is super interesting. We've now blocked it from entering the nucleus. If some gets through, it's now not able to release its contents, or it breaks too early. And then, there's a third part that lenacapavir disrupts as well. So imagine that you've now, somehow, some of the virus particles or some of the capsids have still made it through, or maybe you're in a different part of the HIV virus lifecycle. You're now trying to create these new virus particles, the descendants of the initial one. In order to do that, we have this, the immature HIV virus, and

Jacob Trefethen:
I remember, yeah,

Saloni Dattani:
This now has protease involved, right? So we have protease cutting up these giant polyproteins into their proper form, and we have this new capsid trying to form, to surround all of the RNA and the other enzymes. But what happens with lenacapavir is that, because it's in this too stiff kind of formation, it's unable to form in the correct shape and it just doesn't fully form. So there's this image here, where you can see that the normal way that all of these proteins in the capsid form is that- We, okay, so we have all these hexamers and pentamers; they create these little clusters, they somehow self-assemble. Maybe this is just something that we don't understand yet, but somehow they self-assemble into a bigger.

Jacob Trefethen:
Which blows my mind just from, if I'm visualising the cytoplasm of a cell, I'm like, there's so much going on there. How do these all stay together and not get distracted? But anyway.

Saloni Dattani:
Exactly. So we're getting these clusters of multiple hexamers and pentamers. That happens, but now because of the stiffness, the shape isn't forming correctly, and the full shape just doesn't work anymore. So I mean I think this whole process to me was really interesting to learn about. I knew that lenacapavir somehow had this amazing effect, at very low concentrations. It somehow has a really long effect lasting for at least six months. But I didn't really know about the mechanics of that works. And the other thing I didn't realize, until reading for this episode, was multiple steps are inhibited. So it disrupts this process at multiple steps. I think that... Now, I would say this doesn't mean that it's impossible to develop resistance against it, but it does probably explain why it's so effective, that it's targeting these multiple steps. It's reducing the probability that an infection can and multiply, and so I think that was very interesting.

Jacob Trefethen:
Yeah, I was going to say, it sounds almost like a combination drug itself. If you've got three different stages it's acting at. But I don't know if the mutations that would generate resistance to are correlated there or not. It makes sense to me they'd have a fail safe, for mopping up the capsids that try and form out the other end.

Saloni Dattani:
I think what I've learned is that there is still... drug resistance can form, but it's something that forms if someone is on long-term treatments with lenacapavir; it's not something that they would have before the infection. And so, it is still useful as a preventive, sort of, anti-infection tool. But as a treatment, there have been cases of people developing resistance and that would be through exactly how lenacapavir fits into the little gaps between the capsid proteins.

Jacob Trefethen:
The gaps.

Saloni Dattani:
If you change the shape of that, yeah.

Jacob Trefethen:
It makes just from a selection pressure point of view. If you've got many more viral particles, you're infected already, then you've got higher probability, probably, of a mutation that's good for HIV. Neat. I like it. How did it come about from a- was this the first capsid inhibitor? Lenacapavir?

Saloni Dattani:
This wasn't the first capsid inhibitor, I think people had been trying to target it for a while. And in 2010, Pfizer had developed another molecule called PF-74, and that seemed to bind to this little gap, this pocket as well, and it could block and hyper stabilize the whole capsid shape. But it didn't work so much in the human body; this drug, it was taken orally, and it just didn't stick around in your body.
And so they gave up on the drug and they started working on other drugs instead. Instead, what happened was Gilead tried to build on this PF-74. It seemed quite promising, because you do have this, you have a potential way of targeting the capsid protein. But we're just missing out on making it more available in the body and long lasting. And so they did something called "parallel synthesis". They just tried creating lots of very similar compounds to that — using the same molecule, but then adjusting it in lots of different ways. And the way that happens in the lab is, you have lots of test tubes or plate wells, where you have the initial molecule PF-74, and then you run lots of different reactions in those different test tubes, under the same conditions — so you have maybe three or four, with some reaction going on and so on. And they did a lot of iteration based on that and eventually resulted in lenacapavir.

Jacob Trefethen:
Got it. Well, thank you PF-74 for trying first. It's interesting. It sounds like we had the idea and there was some binding going on and it was working okay. But then, the practicality of the human body — you've got a lot more steps. You don't just have to bind the part of the HIV virus, you also have to survive the machinations of the human organs.

Saloni Dattani:
And this is the really interesting thing that we'll talk about later. In terms of, how does this actually stick around for so long in the body? How does this have an effect for over six months? That itself is really impressive to me. I thought they could maybe just briefly talk about some of the different kind of iterations that people do and how important they are

Jacob Trefethen:
To lenacapavir, or?

Saloni Dattani:
Yeah, exactly. So we have PF-74. Actually don't you know someone who worked on this?

Jacob Trefethen:
I do, I do. I was wondering whether to say, but I think I may have mentioned her earlier and she in her PhD worked on PF-74, so in an academic setting, not at one of the companies, but I think she knows a bunch of the iterations that you're about to tell me, but I don't know; I should have asked her more questions first.

Saloni Dattani:
Yeah, I mean it's so fascinating to know that there are people surrounding us that have been responsible for these huge breakthroughs, and they're just normal people-

Jacob Trefethen:
I know.

Saloni Dattani:
Sometimes friends.

Jacob Trefethen:
I had to tell her I was about to talk about lenacapavir, before I realised that she had done all the- well, so much of the work, that led up to it. It's wild. Yeah.

Saloni Dattani:
I think, yeah, it's incredible. Okay, so we have PF-74, what happens now? So we have all of these little reaction test tubes going on. One of them, they introduced a hydroxyl group — that's basically an oxygen and a hydrogen, and then they added an indole ring — that's a fused ring structure. So there's multiple atoms in a ring with a nitrogen group. This massively increased the effect of the drug, but it didn't work in the body, because it was broken down by enzymes in the liver.

Jacob Trefethen:
Okay.

Saloni Dattani:
Okay, we've got, this one, it didn't really work out. Then they tried another type of ring. This is a six structured ring with one nitrogen atom instead. This then improved how stable it was in the body. It was not broken down very quickly anymore, but now, the effectiveness was reduced.

Jacob Trefethen:
I love how we're making atomic level differences here. Anyway, keep going. Okay, so we tried that one. No luck.

Saloni Dattani:
They did a bunch of other changes. There were some seven or eight compounds they made, before getting to this breakthrough. This actually comes from this really interesting book that I was reading called Drug Development Stories, and these researchers just put together how all of these different types of breakthrough drugs in the last few years were developed. And so this last-

Jacob Trefethen:
I have few books like that that I'm trying to, I can't remember if I own that one, but they're fun to flick through some. I'm going to have to check my bookshelf when I get back to San Francisco. If not, it's going on the order list.

Saloni Dattani:
It's often hard to find the exact stories about- behind how these drugs are developed, and I assume part of that is because it might be some kind of trade secret or something like that. But when I do come across someone writing a retrospective or, you know, someone giving me the details, it's just a completely different picture. It really helps you understand exactly what they struggled with, how they were thinking about the process, and so on.

Jacob Trefethen:
So if you're listening and you're working on drug development in some form and you're wondering, oh, if I write up my process, is anyone even going to read it? We're gonna to read it. Write it up! Saloni needs it!

Saloni Dattani:
I need it. I love it. Okay, so now we have this breakthrough compound, I think, which might've been the ninth one that they made as an adjustment. They now replaced the amide group with an amino indisole group. And that is a ring with two nitrogen atoms. This improved both the potency, how well it fit, and also reduced the level of breakdown in the body. This felt like, okay, we're making something that effectively tracks both of these key things that are important in drug development.

Jacob Trefethen:
Got it.

Saloni Dattani:
Then it was just slight adjustments, slight tweakings from there. They added another amino group, they changed the placement of the amino group. They introduced a sulfone group — that's a sulphur with two oxygens, and that was what resulted in this very highly potent molecule that was very stable in the body, and that became lenacapavir.

Jacob Trefethen:
Wow! We made it. Highly potent, highly stable. And it's funny, I think when you say, "The body's not breaking it down well", to me it sounds like, "Oh God, the body's not breaking it down well?" And in fact, we've been seeking a molecule the body doesn't break down well, because it can last for longer and protect you for longer.

Saloni Dattani:
It's different purposes, right? If you're trying to reduce maybe the side effects of some drug, you want it to get broken down very quickly, just have its action; disappear. But if you're trying to develop some drug that has a very long lasting effect, then you want it to stick around for a long time. So, I mean, finding something that is both very safe, very highly effective — potent — and also very stable in the body that makes a great long lasting drug.

Jacob Trefethen:
That's the trio. And we got there.

Saloni Dattani:
The other interesting thing I learned about lenacapavir, and I think you might maybe come to this later on, but it's the drug with the most fluorine atoms in it that's approved by the FDA in the US. So fluorines are often used to increase the stability, I think, in the body, and lenacapavir has 10 of these atoms in the whole molecule. Usually, that has led to drugs that are unsafe in some way, but in this case it has a very high safety profile as well.

Jacob Trefethen:
I remember seeing that, and I'm not enough of a chemist to tell you why there aren't more, but I do like the idea that there's fluorine in the aqueous solution. There's fluorine in the water, you know.

Saloni Dattani:
What did we- we talked to your friend, Sanela, is that right?

Jacob Trefethen:
Yeah.

Saloni Dattani:
Was there stuff that you learned from her on lenacapavir and capsid inhibitors as well, beyond what we've talked about?

Jacob Trefethen:
The thing that she emphasized to me was really in line with what you just said, about how iterative the process was. That starting with PF-74, as a great binder, there was a lot of tries for just... getting the other properties that could make this into a useful drug. So I think the thing she was really struck by was the "PK", as drug developers say, looking really good for lenacapavir.

Saloni Dattani:
What's the PK?

Jacob Trefethen:
The pharmacokinetics, I want to say, and there's again: this will betray that I'm not a medicinal chemist. But pharmacokinetics and pharmacodynamics are the two things that you'll hear people talk about all the time, about how the body processes drugs. But I mean also, she was really emphasising that previous molecules' stability was an issue. And then seeing lenacapavir being so stable and so low toxicity. You know, you have such a small amount and it can stick around for six months; and it's getting to the 20th or 15th iteration of the initial principle. Then getting those great properties, it was wonderful for her to see as someone in the field. And as someone outside of the field, I didn't realise. I'd heard of lenacapavir as this miracle drug, and I didn't realise, of course, what came before. There's a lot of steps to get there. It's not that you suddenly come out swinging and suddenly discover the exact perfect thing.

Saloni Dattani:
Right. I mean, the thing that I remember, I did my undergraduate degree in biomedical science like 10 years ago, I think? And I remember a little bit about pharmacology on PK as, it's more, you're measuring both how fast is the drug broken down, how much of the drug is broken down, how quickly, but also how available is it? How much does it actually get to the organs that you need it to get to? Is it able to have its effect there?
And I think with lenacapavir, it seems to be very effective even at small doses. So if you imagine that over time, so you have this injection first, of lenacapavir, and then, over time, there's this decaying exponential curve. So it just quickly starts to break down, and then that break down process slows down. But even at the very low levels, it's still very effective, and able to block this little site within the capsid proteins. And that is what makes it so effective.

Jacob Trefethen:
Well, let's do a quick detour, if you'll let me, on long-acting drugs other than lenacapavir. Because the principle we're talking about applies not just to this molecule. The nature of a long-acting injectable or a long-acting drug, well, what makes it long lasting? What makes it long-acting? It's relative to what we're used to; relative to immediate release drugs.
You know, if you think about the PrEP drugs that we talked about earlier in the episode — those you take daily, and that's because you want to have enough of the active ingredient in circulation, in case HIV enters your system during that period. But pretty quickly, most drugs get metabolised and get filtered out and leave your body in urine, and sometimes other ways, but that's the main one. So an issue that you mentioned is: if you have to take a drug every day, you might forget to take it. You might run out of the drug and not have time to get a refill for a few days, or a week, or I actually am behind on refills, because I'm in New York right now. Or you might not want people who you live with to see that you take pills regularly, so keeping them around is not ideal.

Saloni Dattani:
This is important with HIV as well, because some of the preventive drugs might also look like treatment drugs. I think you mentioned this earlier. And so there's also the stigma around people thinking that you have an HIV infection, and then they're worried about that, even though these drugs are very effective and it's very unlikely to transmit, if you're using these drugs. But I think this whole thing of: "how do people actually take it in their daily life?" is so relevant through drug development.

Jacob Trefethen:
Absolutely. And the long lasting prevention that people might be most familiar with is birth control. Where a lot of, some similar issues are a big part of what can drive different women to want to make different choices with birth control. So the pill was first approved by the FDA in 1960, after development in the '50s, as daily oral contraception. And then from the '60s onwards, there was a lot of work to see if you could make the different options for birth control long lasting. So can you have hormones that are inside a silicone tube of some form, that you can control the diffusion over time, so that you don't have to take daily pills or take a daily hormones.
And now there are multiple options for that. So you can have hormonal IUDs that release progestin slowly over time. You can have arm implants. The approach there, is to take an existing biological molecule, or synthesise an alternate of a hormone, and then have a different packet that controls the diffusion.
So it's a bit different than what we just talked about with lenacapavir, where the drug itself is so insoluble and stable and it itself sticks around. Whereas, let's say you have a drug that doesn't naturally stick around, well, maybe you can design a delivery mode — a polymer, a liposome, that you can keep it inside of, and slowly diffuse, and you can achieve the same goal. Maybe you could just put it in a drop of oil, or you could suspend it in some other way, maybe you could put it in a device.
And sure enough, for HIV one new mode of prevention that we haven't talked much about yet is vaginal rings — where you can have a slow release, you can insert a vaginal ring monthly, say, and have a slow release that a woman, who wants to not be a risk of HIV, has more control over if you have to get in some circumstances, than if she had to get pills that were more visible to people in her household or her husband or something like that. So there are a lot of different strategies here.
When it comes to HIV, what's interesting to me is that there are a few long lasting drugs that are being tested now, or are near the finish line now, that use different approaches and yet achieve this kind of similar goal. The three that come to mind for me are lenacapavir, which we've been talking about a lot, but then also cabotegravir, which is already approved in some countries — in the US — which is this injection every two months. And then also islatravir, and other follower drugs, that are being made by Merck, that are oral drugs that you might be able to take once a month for prevention; or for treatment, maybe you take once a week. There's a few different regimens being tested. And my understanding of why islatravir sticks around for a month is-

Saloni Dattani:
Which one is islatravir?

Jacob Trefethen:
Islatravir is a drug-

Saloni Dattani:
Is that Merck's?

Jacob Trefethen:
Yes. Made by Merck. You know, imagine instead of taking daily oral PrEP, you take one pill once a month say, and they've tested that regimen. What happens after you ingest that pill is, the active ingredient sticks around intracellularly. So it's not- when you're imagining lenacapavir, what you should imagine is: you've got a drug substance dissolved, in a liquid that's 40% water; you are getting injected with that. The liquid's kind of dispersing, and the drug is sticking around and forming a solid on the video just pointed at my arm, but it's not in your arm, it's your stomach or in your butt. Then that active ingredient is slowly dissolving, over the course of many months. Whereas, with islatravir, you should imagine that the active ingredient is, in some way — and I wish I knew more about this, I don't — is in some ways sticking around in your cell. So that if the HIV virus is entering your cell, it's going to do its work, which is wonderful, but it's not some big depot or some big lump. It's totally different and it might stick around for different biological reasons.

Saloni Dattani:
That is so interesting. I had no idea I was going to ask about this container or the package. Does the package dissolve? Is the package, is that actually a separate molecule, or something like that? But you answered my question. I guess that also varies with other drugs.

Jacob Trefethen:
Yes, it does vary with other drugs, and the answer will differ for other drugs, because there are different ways to achieve the goal. If you don't get a drug like lenacapavir that has properties of slow degradation, then you might want to achieve the goal via packaging your active ingredient differently.
One thing that I think is, in a way, fortunate about both lenacapavir and islatravir and cabotegravir — which is also an injection that's a suspended solid that slowly degrades — is that you don't need a very complicated package. Because a complicated package adds complexity, manufacturing cost, and makes me less optimistic that in the near-term a drug will get used in lower resource settings. Whereas the simpler you can make the package, the more likely you can use a drug in many settings. In this case, it's just the drug itself — well, simplifying a little — but it's mostly the drug itself in a syrup solution. And you know what? I could take a look at that. I might be able to one day inject myself with that.

Saloni Dattani:
This is so interesting. I mean, the other thing that reminded me was, I think what I read about the fluorine atoms, is that those help it stick around in your fat. So you have the injection either in your abdomen or your butt, and then I think the fluorine atoms keep it around the fatty areas, but also they create this little lump underneath your skin, right?

Jacob Trefethen:
Yes. Well, I mean, absolutely. And as I think about the lump, I was just thinking about it spatially, and I would love someone who's worked on injectables and on lenacapavir to correct me in the comments, if I'm thinking about it spatially wrong, but. Is lenacapavir a one or two millilitre injection? Do you happen to recall?

Saloni Dattani:
Yes. Yeah, it is one to two.

Jacob Trefethen:
Okay. So my memory of how millilitres work is that that's one cubic centimetre. Is that right? Okay, so now I'm visualising we've got some liquid that's one by one by one centimetre. That's quite a lot. And you get injected somewhere, and the liquid does disperse it. You've only got some of it left, but a good amount of what you're getting injected with is this high concentration drug that becomes solid. So sure enough, you should expect that to be a lump. You just got injected with a decent volume of stuff and fair enough, some of it precipitates and becomes solid. If there wasn't a lump, I'd almost be confused. I'd be like, where did it go? I thought it was meant to stick around for six months, and anyway, so I think lumps form, definitely in different people.

Saloni Dattani:
I think what I read was also that the first injection typically leads to this lump forming, but the subsequent doses don't. So that makes me think that maybe there's some bodily reaction to the drug substance that creates the lump, and that the second or third time, your body gets used to it in some way, or it just doesn't have the same reaction. But that was also really interesting. It reminds me a little bit about when people had smallpox vaccines, you could see that from the little mark on their shoulder. With this, you have this tangible little bump in your butt or your stomach that typically shows you if the drug has formed this little depot.
I'm curious about these other long-acting injectable drugs that you've read about. So how else do they differ from regular drugs that only last a short amount of time? Are they more expensive? What's their safety like? What's all of that?

Jacob Trefethen:
Great questions. And they, again, are going to have variable answers rather than an easy one. It depends on what package you're including. On the safety front, you really want to have, if anything, higher safety standards when you're doing something long lasting. Because with a drug that washes out of your system within a day, there's only so bad it can be.
But with something that sticks around for a long time, you want to make sure it's harder to get rid of, so you want to make sure that, before you get injected or before you take it, there's not going to be toxicity or longer issues.
I think that that is part of why, with lenacapavir and with other drugs, you get an oral lead-in for two days before you get long injections, just to check tolerability. It's interesting though, on efficacy as well, that you can sometimes have the same underlying chemical, that is trying to achieve some medical goal, but it can be higher efficacy in a long lasting injectable for a couple reasons.
One that we've mentioned is the real world and having- it's much more reliable if you just have to get one injection or swallow one pill, than if you have to remember to do it all the time. But another is more chemical or more to do with the body — which is that when you take daily pills, you get this spike in how much of the drug you have, relatively soon after you take it, operating in the bloodstream or elsewhere, that then decays relatively quickly. So you're kind of doing this: spike and drop, spike and drop, spike and drop, for a daily drug. And that's not ideal.
Often you want to be in a therapeutic window that is not so spiky. With these long lasting injectables, you have a lot more control, and you can tune that a lot more easily. You can predict, okay, on a given day, how much am I going to have in my bloodstream, based on how much I was initially injected with, and how much time it's been since then. You can really hit that therapeutic window perfectly, so you can end up with a chemically more effective drug. And you know, as I said, you want to check the safety a bit more though.

Saloni Dattani:
That totally makes sense. So the therapeutic window — that's the range of, I guess, the volume or something of that drug in your system, and having that in the ideal range, right? Yeah. And I guess the other thing I was thinking about was: maybe it's not just about the predictability, it's also that there's less of a fluctuation. Maybe some people react badly to these spikes, or the lack of- if the dosage suddenly drops, does that mean the effectiveness is now not high enough? But if you can manage to get a stable level of this drug for really long time, that is probably better in some respects.

Jacob Trefethen:
Yep, absolutely. And my mind goes to: what other diseases for prevention or for treatment — other than HIV — would you want those properties most? That's beyond the bounds of this short podcast. But the ones that I can't wait to learn more about myself are...
So, malaria is one, where if you are under five and live in West Africa, if you're a kid in West Africa, you will get preventive malaria drugs during the rainy season, where you're most likely to get malaria; that's about four months long. Currently, kids will get three-days-in-a-row worth of drugs, each month. So that's four times three. And the drugs, they don't taste great, or kids don't always like 'em, and don't always take them all, all three days in a row. If you're a busy parent and your kid is making a scene, then you might not make sure to force all 12 of those doses. But if you could get a long lasting injectable for a season, that could cover that season and make sure you had the right amount of preventive drug in your system, if you got bit by a mosquito. My goodness, that could be an enormous deal. I don't think, based on my knowledge of malaria drugs, that we're close to rolling out something like that. But I do know that people are working on that problem, and it's very interesting.
I think that tuberculosis is another area; Hepatitis C is another area, rheumatic heart disease is another area. So a few infectious disease areas that I'm sort of — ooh, I'm getting excited about, but don't know in super depth. And then, beyond infectious disease too, there's a bunch of potential applications.

Saloni Dattani:
I think there's a psychosis drug; there's a schizophrenia or bipolar disorder drug, I think, that's also long-acting. What I was thinking about was: maybe it's useful for things that are hard to predict when you're going to be infected by them, so you would prefer to take something that lasts a long time, and so for various infectious diseases, that seems useful. Maybe also for chronic diseases, where you have the condition for a really long time, therefore it's useful to have this long acting treatment, instead of doing something where you have to take it every day. But, I mean, that kind of covers most diseases...

Jacob Trefethen:
There could be lot that fit that description and that you should also think about: when do you want something to end? And I think, for a lot of those diseases, you would not want a drug necessarily that lasted for life. If you could have one stick around-

Saloni Dattani:
That is very true.

Jacob Trefethen:
For some drugs, for example, if you think, "Oh, there's a chance I want to get pregnant in the next few years," then you might want more control over when the drug's out of your system, in case that drug hasn't been tested as much in pregnancy, or has been tested and isn't as safe in pregnancy.
There's one thing that in the literature that I've found interesting to read is: the limitations, in children, of long lasting drugs. I was wondering, oh, that's such a shame because of, for example, the malaria thing. I was just talking about why is there a limitation? One reason is that the dose that you get given, of different drugs, is relative to how big you are. And the correct dose is often bigger, the bigger you are. The trouble is, with a child, that in six months, their size is going to change a lot, and that means you might want to be dealing with a different drug dose in six months time. So there's reasons like that, that you don't want to last forever.
That contrasts, usually, with vaccines where you actually wouldn't mind having as long a lasting memory response as you can. And there are some vaccines that are known to be pretty poor at generating long-lasting memories: flu vaccines are sort of a famous example; the malaria vaccines so far aren't that durable, but are getting better. And then, really, the best vaccine immunologists talk about is yellow fever vaccine, where you could live for 10,000 years and you wouldn't be getting yellow fever after you got that vaccine.

Saloni Dattani:
Wow, I didn't know that.

Jacob Trefethen:
Yes. Well, that will-

Saloni Dattani:
I can live for 10,000 years?

Jacob Trefethen:
That's what I've heard, but I don't know how they extrapolated that. I think you can live for 10,000 years, and I think-

Saloni Dattani:
I mean, I kind of want to live for 10,000 years now, just to see this vaccine lasting that long against it.

Jacob Trefethen:
Imagine if you got a challenge with yellow fever at the end of 10,000 years to prove it, and then it actually got you. Throwing up black bile and everything else.

Saloni Dattani:
The other thing I was thinking about, when you mentioned that on the size of the body, was with lenacapavir: so, what I understood was, okay, the fluorine atoms keep lenacapavir in fat tissue, but again, this is a problem for the same reason that you mentioned. If your body size changes, that could affect how quickly it dissolves, I think, or how much is remaining in this little depot. So imagine if you lost weight, for whatever reason, you're on a diet or something, and somehow, suddenly, this drug becomes more potent or effective in your body. I just thought that was a funny thing that I hadn't thought about.

Jacob Trefethen:
No, totally. Another one is, that's hard to predict ahead of time is, are you going to want to go on another drug, for another reason, that might have a negative interaction with a long-lasting drug you're already on? My understanding of lenacapavir is, they haven't discovered many drug interactions that are that concerning. But that might apply to other long lasting drugs, so you got to think about that.

Saloni Dattani:
That's a really good point. The thing that reminds me of is grapefruit juice. Have you read about this thing with- so, grapefruit juice has this chemical that interferes with your liver's metabolism of lots of different drugs. And if you were-

Jacob Trefethen:
I had grapefruit juice three days ago. I'm nervous.

Saloni Dattani:
Oh, did you? Yeah.

Jacob Trefethen:
Well that explains-

Saloni Dattani:
Well, I mean, it's not all of the drugs, but it seems like it's quite a number of drugs that are affected by this. And so, if you're drinking grapefruit juice, for whatever reason, it sometimes makes various drugs last longer in your body, because it interferes with their breakdown. This is true for, I think, some other chemicals and drinks as well, but that's the most commonly-known in medicine.

Jacob Trefethen:
So if you're getting towards the tail-end of your six months of lenacapavir, just start doing shots of grapefruit juice?

Saloni Dattani:
I don't know if it interferes with lenacapavir specifically, but it seems to be a bunch of other drugs. But I mean, it's just an interesting thing to think about, because now you're on this- okay, you're on this six-monthly drug. What are the things that you now have to be thinking about, to make sure that this drug is still working as expected? It's great to hear that it doesn't have many drug interactions, but I think that's the other thing that, if I was a drug developer, I would be thinking about.

Jacob Trefethen:
And I'm sure there's more still to learn about drug interactions, so we'll find out. The reversibility of some other preventive tools is a key part of why people want to use them. For IUDs, for example, you can get an IUD removed and it will not affect your long-term fertility. Whereas for lenacapavir, you got to wait it out. Once it's in there, it's in there.

Saloni Dattani:
I would find that exciting. But yeah, you're right. If there's something that could go wrong, that is something that, this is why we need these long clinical trials to make sure that this drug is safe, in the way that people take them, in their daily lives. Maybe we should talk about the clinical trials and what they should-

Jacob Trefethen:
I would love to, yes. I was wondering about the clinical trials. How did we confirm that lenacapavir does actually work in the way we hoped, and that it is safe? Where did we go once the scientists had done the experiments in the lab?

Saloni Dattani:
The period when lenacapavir was developed was the late 2010s. They did some molecular studies to develop lenacapavir. They then did a phase one study — which is you're testing the safety in a small number of participants, and you're checking basic things about the properties, the pharmacokinetics, how long does it stay in the body, how effective is it in very specific ways, in a small number of people — I think there's usually dozens or so.
Then after that, they moved on to phase two trials; this is a second part where it's a larger number of people. Now, you're testing a little more about the safety, because now you have a wider range of people with different backgrounds; they might be taking other drugs at the same time; they have different behaviours and so on. So you can find out a little bit more about the safety. But also, now with a larger sample, you can see how effective the drug is. They did this with people who already had HIV and were taking other antiretroviral drugs, and they saw how this combination of lenacapavir plus those other drugs worked.
Then, the breakthrough that really got me to notice this drug was their phase three trial; and their phase three trial was- I think it started in 2021. They had two different trials. One was with, I think, one was with men; the other one was with cisgender women — specifically adolescent girls and young women. This quite important because the transmission, and the effect of these drugs, can vary for women who are trans because the route of infection, their sexual activity, how that actually works, is different.
So they're focusing specifically on cisgender women aged between 16 and 25; girls who were not using PrEP; they hadn't done HIV testing, or they hadn't done it in the last three months. I think it was several thousand- it was around 8,000 women in this trial across Uganda and South Africa. This is important because, if you're trying to test how effective a drug is, you need enough, well- there need to be enough people, at least on the placebo, who are getting infected, so that you can see what the difference would be with lenacapavir.
So they focused on these areas where HIV incidence rates were relatively high, meaning that more than three or four people per hundred people were being infected per year. So imagine 3% of the population of this age is being infected with HIV per year. That's, to me, that's really high. This is quite common in some areas of South Africa and Uganda. That means that it's much easier to tell if lenacapavir has an effect.

Jacob Trefethen:
Because you'll detect in the other arm of the trial that there were HIV infections occurring.

Saloni Dattani:
Right. If you imagine, okay, if you were doing a trial in the UK or in the US, where people are already taking PrEP or the rate of HIV is just so low to begin with, then imagine no one in the placebo group gets HIV. How are you going to tell if lenacapavir is better than that? There's nothing lower than zero.

Jacob Trefethen:
You have to be able to distinguish, because happily, its transmission is lower than it was twenty years ago or thirty.
Yeah, it's interesting. It's a very clear case, I guess, of trials in- well, I'm in the US, you're in the UK, but I may benefit from this drug, living in the US, based on trials that occurred in other countries — because those trials were in higher transmission settings. So you can get a statistical answer to the question; that would've been harder if you were just doing the trials in the US. So that's a kind of selfish benefit that the US, and people like me, get from the global nature of clinical trials.

Saloni Dattani:
That's what I think makes it really important to- we'll come to talk about this later on, but this is what makes it really important to think about how to actually get it to be accessible. How to scale up this drug, in the future, to the people who need it. This wasn't developed without the help of all of these participants who agreed to be in this trial, who are living thousands of miles away from us, and who are responsible for this breakthrough being tested, and the fact that we know that it works, and so on. One of the other things that I found quite interesting about this trial is: how trials actually work in terms of the healthcare and the screening involved.
So I think when people think of a trial, maybe they don't realise that you're not just receiving the treatment itself, but people are doing other types of screening to monitor how you are responding to the drug. They're also, in this case, doing tests and screening for other types of related diseases. What they did in this trial was: they provided individual counselling to people; they provided condoms, lubricants; they'd have support for reproductive health in general. They also provided treatments for other sexually transmitted infections, and they did routine tests for some common sexually transmitted infections, like chlamydia, gonorrhoea, and syphilis there. Which means that, by participating in this trial, not only do you get the potential of this drug and also the side potential side effects, or risks, of participating in trial — but you also get the actual healthcare because of the clinical trial setting.
I think that's something that people might not realise: we have this system where we have these clinics, or these hospitals, that are running these clinical trials; they're also providing care to the people in the trial. When we think about how to actually set up these clinical trials in countries in Africa, it's not just about doing the testing. The researchers, sometimes, are involved in setting up new clinics, they're involved in recruiting staff to work on all of this testing, and stuff like that, and that has various other benefits for the people in the area.

Jacob Trefethen:
One thing that we've worked on at Open Philanthropy is — an area that's not HIV but relates — is congenital syphilis. Syphilis is- nowhere is it incredibly prevalent, but in some places, maybe one to three percent of people have syphilis. That is not something you want for yourself, but it also is really bad if you're pregnant, because you may have a birth complication basically, or a miscarriage, or being born with congenital syphilis is very dangerous. One thing that HIV care has brought in many countries is better antenatal screening, prenatal screening for HIV for many women. You'll get at least one visit with a doctor, whereas in many areas before, if you were pregnant, you might not have even had one visit with a doctor. So that infrastructure set up to screen for, or to give you a touch point and some care while you're pregnant — mostly funded by the HIV world, and by PEPFAR, and other donor countries — has enabled screening for syphilis as well.
There's now a dual test where — it's a rapid test; it costs just under a dollar — you can screen for HIV and syphilis at the same time. And then, if you are positive for syphilis, you can get relatively easy treatment on penicillin. That's such a clear example of the benefits of this infrastructure, that were not initially planned from when HIV donors made those investments, but that spill over. So it makes sense to me that, not only are there benefits from the knowledge gained, of these lenacapavir trials, but people in the trials got better care too, and there's now probably better trained doctors in the area and that kind of thing, yeah.

Saloni Dattani:
We have thousands of young women in this trial. First, they were tested for whether they already had HIV at that point. This was useful, as I'll come back to later, this is useful to know: What is the rate of HIV in the population? It turned out that it was about 2.5 per hundred people per year, which is, so 2.5% of people in this age group are infected by HIV per year — which is, to me, really difficult to think about. Those women would not necessarily benefit from this treatment; that was not the purpose of this trial — it was to find out whether we could prevent new infections. Those participants were not included in the rest of the study, I think.

Jacob Trefethen:
So, you screen at the beginning for HIV; if you're already positive, then this is not the trial for you.

Saloni Dattani:
Right. And the women who were HIV-negative were then randomly assigned to getting either this lenacapavir injection, or- I think this is Descovy — it's the oral PrEP pill, which is emtricitabine and tenofovir alafenamide. Or the third option was F/TDF, I think there's another name for this, is that Truvada?

Jacob Trefethen:
Truvada? That's Truvada, yeah.

Saloni Dattani:
That's Truvada; that's also an oral pill that people take daily; that is also emtricitabine, but this time it's tenofovir disoproxil fumarate. And I think what they did was — because one of them is an injection; the other two are oral pills — they actually gave fake version of the opposites to all the participants, so that they don't know which one they're getting.

Jacob Trefethen:
Oh, okay. Nice.

Saloni Dattani:
They're all getting an oral pill and they're also all getting an injection. But some of the people who are getting the injection are getting lenacapavir, the others are just getting a placebo — which is just some water or something like that.

Jacob Trefethen:
Which, you know, I'm already curious about. Three things from what you said: number one is, if I get the fake lenacapavir injection, does it form a depot? And can I tell that it's actually fake, because it doesn't form a lump? But my other two reactions are maybe more fundamental. So it sounds like there's no placebo here — in the sense of, there's no one who's getting no drugs, because that would be unethical. We already have drugs that we know will reduce your chance of acquiring HIV if you're on them. So the arms that you described are the lenacapavir arm, descovy arm, truvada arm, and there's no zero arm.

Saloni Dattani:
Right, and in other clinical trials, you're not necessarily preventing people from getting other treatments; they could be taking other treatments for the same disease, at the same time. But, in this case, they wanted to see: How effective was this as a prevention? And to get enough statistical power, you need everyone to be in the trial, and you're having this situation where you don't want any of them to be taking PrEP that you can't analyse in a consistent way. It's both ethical in the sense that they're providing all of the participants with one of the three PrEP drugs, but it also helps because it makes these comparisons simpler. They're not taking an additional PrEP- some of them are not taking an additional PrEP drug that could complicate the analysis.

Jacob Trefethen:
Okay. Got it. Makes sense. And then my third reaction was, it's interesting that Descovy was in the mix because I thought that Descovy was not approved for use in cisgender women.

Saloni Dattani:
Yes, you're right, it hadn't been tested before in women. The company, Gilead had been criticised for this, having this approved but not testing it beforehand. So this also functioned as, not just the trial for lenacapavir, but it also tested how effective Truvada and Descovy are-

Jacob Trefethen:
Great, okay.

Saloni Dattani:
-in the same population. So you get to have the answer to three questions. You have the answer to how effective lenacapavir is, descovy, and truvada.

Jacob Trefethen:
And then because of what you said, about the screening on the way in, can they compare it to what they think the background rate, if you're on nothing, probably would be?

Saloni Dattani:
Yes, yes. So actually we have four things you can find out.

Jacob Trefethen:
Well, that one's not measured. I guess that one's interpolated.

Saloni Dattani:
So you can now compare these three drugs, but you can also compare them all to not taking any drugs.

Jacob Trefethen:
Okay. Well, I feel- I'm on the edge of my seat. So, what were the results?

Saloni Dattani:
What were the results? I'm going to show this chart. So this chart compares the outcomes in each of these groups. The first bar is showing the background incidence; these are the women who tested positive at the start of the trial, and around 2.4% of them got infected with HIV per year in FTAF, which is Descovy? That had a rates of 2.02.

Jacob Trefethen:
That's very similar to the background, right?

Saloni Dattani:
And in Truvada, it's around 1.69. These numbers are the point estimates, and that's our best guess. But there's uncertainty around just what the number is; they all roughly fit into the same range. So without drugs, Descovy, and Truvada have similar rates of HIV infection.
And I think the reason for this is because it's hard to take these on a consistent basis over time — these are daily pills where the problem is: one, maybe remembering to take it every day; second, having enough supplies with you every day; the stigma that we talked about; maybe these issues around getting a refill on time. So there are all of these issues that make it difficult to take these drugs in the long term, for women in Uganda and South Africa, where this trial was done. What was interesting about the study is that they could actually measure how regularly people were taking these drugs through blood testing.

Jacob Trefethen:
Is that because they're taking samples? Wow.

Saloni Dattani:
They're taking dried blood spot samples from people and then they're testing the level of tenofovir in their red blood cells. So this directly tells them what is a concentration of this drug in this participant? With this, you can see how, over time, the expected- how frequently people are taking them, that reduces over months of the study. People, on average, are taking them quite often, but over time that adherence gets much lower, so they're mostly taking them two or- one or two times per week, by the end of the trial.
And this gets back to this previous chart. So we've seen what happens with Descovy and Truvada, what happens with lenacapavir? Zero women out of 2,134 get infected with HIV. That is just an incredible result. And there is some uncertainty around that. The efficacy — so how much lower the rate of HIV infection is, compared to the background rates — is 96 to a hundred percent. So it's somewhere- it's not completely effective, necessarily, because there isn't a large enough sample to say that this is a hundred percent efficacy rate-

Jacob Trefethen:
We can't rule out-

Saloni Dattani:
-but it is more than 96% of a reduction.

Jacob Trefethen:
That is so incredible. So incredible. That is so incredible. Zero cases.

Saloni Dattani:
Zero cases. I was reading about this, I think, on STAT news — the health and medicine magazine — and they mentioned how these results were presented at this conference, and they just got this standing ovation where people, I mean, unsurprisingly, this is just an incredible result.

Jacob Trefethen:
Unbelievable.

Saloni Dattani:
One last thing about lenacapavir, truvada, and descovy is the side effects. We talked about- okay, we have this long-lasting drug, that means there's a risk of long-lasting side effects as well. What happened in this trial was, they didn't find that much of a difference between the different groups. Most of the side effects were similarly seen in the different groups, and those are mostly things like headaches, fevers — but again, when we record side effects in a trial, we can't necessarily, conclusively, say that these are because of drugs. People have headaches, fevers just anyway in a typical-

Jacob Trefethen:
We don't have a clean placebo here, I guess. I mean it's interesting that, when I think about what friends report as side effects of oral PrEP — because it's oral, there's often digestive issues or stomach problems. I wonder if they tested for that, because I would guess intuitively that lenacapavir would've fewer of those ones. But I dunno if they tested for that.

Saloni Dattani:
And you would be right! They did find lower rates of nausea and vomiting with lenacapavir, and I guess this is because of the difference — where it's not an oral drug, it's an injectable, so it's not passing through your digestive tract and your stomach.

Jacob Trefethen:
We don't need to do trials. You can just quiz me on my guesses.

Saloni Dattani:
The other thing was the little bumps on people's skin, the depots of lenacapavir — so that was quite common. About 70% of the people who got lenacapavir develop these little bumps — nodules — under their skin, and those typically shrunk down to normal after a while, but also, the next doses tended to not- you wouldn't tend to see those.

Jacob Trefethen:
Yeah, I'd love to learn more about that. To me, it sounds like success: I want a little nodule, I want to know that drug is there, and, sure enough, in six months, I want the nodule to be gone because the drug is gone. But I guess there's more going on in the body than I'm projecting.

Saloni Dattani:
I was also surprised that 30% of people who get lenacapavir don't develop these nodules. What is causing this difference? And I, sadly, don't know the answer to that, but it's quite interesting.

Jacob Trefethen:
I was about to ask about other trials, outside of women, but is there anything else, on this trial, that I should know first?
I think, maybe, we should talk a little bit about why was there almost no difference between Descovy and Truvada and the background rates, and why is it that lenacapavir is so effective in these trials, or like, in the real world? I think there's- so I would say that it's not entirely clear how effective Descovy and Truvada are, compared to not taking any drugs. That's just because the uncertainty on those is fairly moderate, so there isn't a very precise figure that we would have; it seems like they're roughly similar, but there could still be some meaningful reduction that these are providing. I guess the other reason is, if people are not taking it regularly — these oral pills regularly — for whatever reason, in the long term, that reduces the efficacy. So even if someone was taking it every day, it would be a higher level of effectiveness than in the real world, where people are taking it less often. And I think this is why lenacapavir is so much more effective: it's not just that it's highly effective on its own, but it's also really long lasting, and that both of those contrast with Descovy and Truvada.
Yeah, I guess it's proving the hypothesis with data; that's what we were wondering, and we were hopeful that lenacapavir's long-lasting properties would pay off, and it looks like they did.

Saloni Dattani:
They did. And they did another trial with men and gender-diverse people — this was in six countries: the US, I think, some South American and central American countries as well. Again, the reduction you would see — with lenacapavir, on how likely it is for an infection — was massive. It was two people out of thousands who contracted HIV versus, I think, more than a dozen, or a dozen, in the other groups. So again, this time their estimate was that there was 82 to 99% efficacy for this drug. And again, they saw that Descovy and Truvada had a very little impact compared to the background rate.

Jacob Trefethen:
It's a big win. Okay, so there were two cases; so it wasn't zero. Two out of a couple thousand, but the reduction in risk is enormous.

Saloni Dattani:
Is huge. I would say that, you shouldn't go away from this thinking this completely prevents infections; there is still a chance. But the reduction is so large that it's a really important breakthrough.

Jacob Trefethen:
My hope, and I hate to be hopeful, but you can get non-linear population effects with transmission reductions, where, if a transmission per event drops 90% at a background rate, the background rate might start dropping too. I mean, it depends on interactions with treatment drugs and a lot of other factors — but if you can imagine that, per event, your risk is going down and then, over time, the background rate going down, that's actually a very large effect together.

Saloni Dattani:
That reminds me of this concept of the reproductive number, that a lot of people would've heard about during the COVID pandemic- R nought. The R nought. So this is the number of people, on average, that someone infects, if they've been infected. So if I was infected, maybe I would infect three other people on average with the coronavirus, in this case. The higher the number, the harder it is to control the disease, but also the faster it spreads in the population. And if it gets below one — if I'm spreading it to less than one person on average — eventually that disease will die out.

Jacob Trefethen:
It's a dream that we can head towards now, maybe. Okay, that's PrEP. Did lenacapavir get tested in trials for treatment as well, not just prevention?

Saloni Dattani:
Yes! It was actually tested and approved as a treatment drug before these preventive trials and results. The first trial was as a treatment for drug-resistant HIV, where they're testing lenacapavir plus the standard regimen that people are having, in people who have tried many different treatments so far, and this is plan C or D. So it was effective in those trials; it was approved as a treatment for drug-resistant HIV based on that. They also did a phase two trial, where they tested it as a first line treatment — so that means that would be: How effective is it, as the first treatment that someone receives if they have been diagnosed with HIV? So they compared lenacapavir with other existing drugs. There are a bunch of other ongoing trials, still. So I think there are more long-acting treatments, where they're testing a combination of lenacapavir and islatravir, which you mentioned.

Jacob Trefethen:
The Merck one.

Saloni Dattani:
That was the Merck oral pill, which are both long-acting, right?

Jacob Trefethen:
Yeah.

Saloni Dattani:
And then, there were a bunch of other types of treatments: so they're doing testing in children and adolescents; they're also testing whether it can be used in people who have been receiving other types of antiretroviral drugs, but they still have some HIV that's suppressed in their body. As we talked about, hours ago, one of the things that you see with HIV is that these drugs can block the multiplication of HIV in your body. But there are also particles that would stay in some parts of your body, hidden in silence, and these reservoirs of HIV are difficult to get rid of. So is it possible to use lenacapavir to disrupt these reservoirs? That is one of the questions that they're looking at in this other trial.
And then there are a bunch of others, so they think there's another one with lenacapavir plus cabotegravir in people who have taken lots of other treatments. And these trials are being conducted, essentially, almost like, all over the world — it's North America, Europe, and Southern Africa; many different countries. It's basically quite a big process: to do this lab testing, to develop these drugs, to then test them in some places, in certain countries like the US or like Southern Africa, and then to scale it up, to these massive trials — is quite interesting, but also, to me, quite impressive how fast this has happened. That drug was only developed in 2018 and it's been — well, okay, it has been seven years since then. I'm used to seeing timelines that are so long, and this was approved for the first time in 2022, I think, as a treatment for drug-resistant HIV, which is only four years in trials. I think that, I mean, on a personal level, I think that could still be sped up, but that is an impressive speed.

Jacob Trefethen:
Yeah, it's a four year starting clock to finish line, not so bad. But we're not at the finish line yet. The finish line is, is this really going to impact people's lives who are at risk of HIV? So just summing up what we just covered: we have now looked at long-lasting drugs as a concept, and other HIV long-lasting drugs, and long-lasting drugs in other areas that we're excited about, but are still in development.
And then, you just outlined with lenacapavir, what was the clinical story to get here and who can benefit from lenacapavir? And it sounds like, the people who've called this a miracle drug, to me, are basically right. In the clinical trial for cisgender women, there were zero HIV infections among the 2,000 women who got this injection, and there were tens of infections in the other arms, for women on other forms of PrEP; so this is a totally different situation. And for men who have sex with men, and other trans people who are in the other trial, the other phase three — there was also a massive drop of, say, 80, 90 more percent in transmission. So, how do we get this drug to people, Saloni? That's what I want to know.

Saloni Dattani:
Maybe, also, just to think back to the whole timeline of drug development in this field. In the 1980s, in the early 1980s, when the first case was reported — no drugs; people thought this was an untreatable disease, or they wanted to treat it, but they had no idea how. In 1987, the first HIV drug, azidothymidine. '95, the first protease inhibitor, and the start of combination therapy that completely changed the survival for people with HIV. In 2012, is that right? We have PrEP — truvada — introduced, and then, in 2022, we have lenacapavir, as this drug-resistant treatment. Then, now, we have lenacapavir as a preventive drug, that is so long-lasting, and both a breakthrough in terms of the effectiveness, in terms of how you take it, how long it lasts in the body, but also, because it was a completely new type of treatment. It works- it inhibits the capsid of the HIV virus; it's not just tweaking existing drugs, it's this whole new type of treatment that now opens up the field of research to developing more capsid drugs, I think, as well as more long-lasting drugs in the body.

Jacob Trefethen:
All of that building on each other to get us to this moment. The decades of science. I feel so grateful.

Saloni Dattani:
Decades of science. Let's talk about where we are now, in terms of, how are we going to scale this? I mean, not us, specifically, but how are people going to scale up this drug? — you and me, back of the van — getting them to everyone who- Like, just driving this van around in small villages.

Jacob Trefethen:
I'm ready. Road trip?

Saloni Dattani:
So how is this going to be rolled out to people who need it, across the world? I think, the most important continent here is Africa, and Southern Africa. Maybe we should talk a little bit about: What has the situation been like until now? How does that process work? How are people getting treatments across Africa, and how has that happened?

Jacob Trefethen:
I love it.

Saloni Dattani:
Let's talk about HIV treatment and prevention around the world, how that's worked so far. Where we are now, where we could go from here. I didn't know, until a few years ago, how big the HIV treatment and prevention programs were worldwide. The biggest progra is PEPFAR, the President's Emergency Plan for AIDS Relief, which was launched in 2003 by the Bush administration. That was, at that point, the largest ever US global health initiative for a single disease. It was 15 billion, as a commitment over five years, to fight HIV and AIDS in affected countries — mostly in Southern Africa, but also other countries. I remember reading about how this was formed, how the whole program came together, and it was super interesting and inspiring — this idea that you could actually set up this huge program to treat millions of people in the poorest parts of the world against this really deadly, scary disease. At that point, there were effective combination drugs available, to people in the US and other richer countries, but people in Africa were not, you know, they weren't able to access them, which is quite scary. You have such a hugely unequal outcomes just based on where you live, but also there is this drug that feels just out of reach that wasn't getting to people.
And what I read was that Bush wanted to do something big on HIV and AIDS and he asked several people working with him on health in the US including Anthony Fauci and Dr. Mark Dybul to figure out what was possible, and they looked at what was already being done in Africa. Was there anyone who was receiving treatment at this time? How were they getting it? And the main source that they found at the time was TASO, The AIDS Support Organisation and Doctors Without Borders or Medicins Sans Frontieres — and they had been providing treatments to people, I think it was in one- two countries, South Africa and Malawi. They were providing these generic versions of antiretrovirals to them, on a voluntary basis. But what really stuck in my mind was, when I was reading this interview of Mark Dybul — one of the people who worked on setting up this program and planning it out — was that he mentioned that, at that point, TASO, the AIDS support organisation, were actually transporting this in little, I think, fridges on their bags-

Jacob Trefethen:
Wow.

Saloni Dattani:
-that they were carrying around on motorbikes around to remote villages, to get these drugs to people who needed them. That was very inspiring. But the success of Doctors Without Borders, in small scale- in providing treatment at a small scale, showed that this was possible. Could it be scaled-

Jacob Trefethen:
It's a proof of concept?

Saloni Dattani:
It's a proof of concept. So now what's needed is to set up these supply chains to do this at a much bigger scale — to set up the drug development and manufacturing; set up the networks of clinics, and the people who would be providing treatment to people in remote villages, and so on. So Mark Dybul and Anthony Fauci put together these plans of: how much this would cost, what it would look like to operate this, how it might look like at scale. The other reason this is really interesting is because, at the time, people didn't think it was possible to do this. They thought this was just some pipe dream. Several reasons: one is this is a really poor region. Trying to set up something like this at scale requires a lot of work; you have to work with community leaders, you need to hire people, train people to provide this treatment.
I think there was also this perception, that some people had, was that poor people in Africa couldn't take daily pills; they couldn't follow these regimens. And I mean, the fact that this program is so effective has, I think, has shown that that's not the case. But it's also this idea that, just because something is difficult to take regularly doesn't necessarily mean that we should stop there, and accept that as status quo. You could eventually develop long-lasting drugs, you could find some way to make it easier for people to access these treatments on a regular basis. And I think that kind of attitude shift is really important here.

Jacob Trefethen:
You can do big things and sometimes they work, and at the turn of the century, I feel like there was more optimism around big global health improvements and projects. And at the same time as PEPFAR was getting started, or a similar time, the Global Fund was getting started, which was not just a US program, but was a multilateral program that involved many different donor countries. So higher income countries contributing into a pooled fund, which would focus on HIV/AIDS, and malaria, and tuberculosis. Three of the biggest infectious disease killers around the world, at the time and still now.
And since then, we have as a species, as a global society, made a huge amount of progress on all three of those diseases. We should probably show a graph of HIV/AIDS incidence, but also AIDS deaths, because the curve really bent down with these commitments from the Global Fund and from PEPFAR. It was a problem that seemed to be spiralling out of control, and then lots of energy, focus, attention, resources were put into it, on really scaling up proofs-of-concepts, and really committing to it. Lo and behold, there were results. And that's inspiring to look back on, and I wonder what it would've been like to be in the room when people thought it was impossible, and you really thought, like Mark Dybul and others, but we gotta go for it.

Saloni Dattani:
It's also incredible to think about, from the perspective of people in Africa, how common HIV was, at the time, is probably not obvious to some of us. But, in the year 2000, there were several countries in Southern Africa where, some twenty, 15 to 30% of the adult population had HIV. That is scary to think about, for such a deadly disease: how it affects the people themselves, their families, the society as a whole. This was really effective and successful, both at changing what life was like for people with HIV, but just also the culture around it, and it's continued since 2003, so it's just an incredible program. It's one of the biggest global health programs. But at the same time, it costs a very small fraction of our incomes here, or in the US, to contribute to PEPFAR or the Global Fund, and it makes a massive impact on people around the world.

Jacob Trefethen:
Well, it reminds me of the graph that you showed earlier in this episode, when combination treatment first came out in the nineties, and you saw this totally discontinuous drop in mortality rates. This was scaling that drop up to people who did not have access to the drugs, until there was a global commitment behind them. That means that there are many people — not just millions, but tens of millions of people — who are alive right now, who are on drugs that control their infection, who would not have been alive. And it's so heady, it's impossible to, at least for me, to get my head around that, but friends, so many families. So it's mind blowing to think how different the world would be for so many people.

Saloni Dattani:
The scale of this is also incredible to me. The estimates are that there've been 25 million people whose early deaths were prevented because of PEPFAR as a program. 25 million is such a, in terms of the number of lives saved, it's just so huge to think about, it's like London's population is what, 11, 12 million? That's two, more than two of the entire... Wow. It's just, imagine that not existing; all those people not being alive. It's just a huge impact.

Jacob Trefethen:
20 San Franciscos.

Saloni Dattani:
20 San Franciscos.

Jacob Trefethen:
So what's happening now, then? It's all good news, by the sounds of things.

Saloni Dattani:
It's not good news, sadly. It's April when we're recording this and there's- in the last few months, the picture around PEPFAR and various other global health programs has completely changed. At the end of January, there was a foreign aid spending freeze. So, all funding to various global health, humanitarian programs was frozen. Also, staff who were working at the US aid agency, USAID, — some thousands of them were laid off. The remaining ones were asked not to talk to the public, but also, they weren't able to keep in contact with the programs in the field; they were just banned from communicating. There was also this — because of all the layoffs — that also meant running the programs on the field was difficult, for people who were working overseas. This freeze was meant to be — this is the stated intention — which is that it was for a three-month-long review of these programs, of all foreign aid programs, to see if they aligned with the Trump administration's interests, such as national security and things like that.
But a lot of them were, I mean, this just froze all of them at once, rather than doing a review at the same time while they were ongoing. But also, even after this freeze was ended, which was after- I think it was 39 or so, 35 business days, instead of three months, and some 80 to 90% of programs were just cancelled.
Because programs refers to specific recipients of funds, I think for specific purposes, that doesn't mean that that PEPFAR was cut by 90% or so. For HIV and AIDS, I think it was around 23%, if you roughly estimate based on the amount of funding those specific council programs received, that were cut. And that seems like maybe just a fraction of this worst-case scenario, of the whole thing being paused, but I think because so many thousands of staff were laid off — and because of this uncertainty and this freeze — that actually had, from what I can understand, quite a large impact.
One reason for that is: clinics, or programs, receiving the funding, some of them weren't able to survive more than a few months without continued funding. Some of the funding was for stuff that they had already completed, and they were just waiting to receive the payment for it, and that was cancelled as well. Some of them were for continued work, and this was cancelled. If clinics are not able to survive for more than a few weeks, or a few months, without this funding that they're expecting, they might just shut down. So in the field, what people might have seen would be a physical clinic that's there — sometimes the treatment is actually inside the clinic — but they can't access it, because the clinic is shut down, and/or the staff is just not around. There aren't people working the clinics. And thirdly, trying to get new supplies to these clinics was also disrupted, so they weren't able to restock on a lot of the treatments.
At the point where we are now, I think there's been a lot of disruption, but there's a rough plan to merge all of these foreign aid programs under USAID into the State Department of the US. I think this is still a little bit up in the air, in terms of how that will actually work, how will it affect PEPFAR?
One thing I'm slightly worried about is what will they actually cut? What aligns with the Trump administration's interests, and what doesn't? And I think you can get a little bit of a clue from how they responded when this funding aid freeze began in January. They initially said that there were certain parts of the program that would continue, such as treatments for pregnant women. But from what I understand, that actually didn't happen in practice, because of all of these layoffs, and the funding cuts, and so on.
But what I'm worried about is, what about prevention as a whole? We think about the critical part of PEPFAR as being preventing mother-to-child transmission, but it's also the broader thing of: how do we reduce the spread of HIV? How do we treat everyone who has HIV? This began as such an ambitious and effective program that managed to treat some 20.5 million people last year, and now that's massively been frozen and we don't know how much of it's going to remain.

Jacob Trefethen:
It's so frustrating. It's so frustrating to see such a good use of money that, in the grand scheme of things, is not that much money from the US government's perspective. I mean, it's frustrating in the short term. I'm more nervous about treatment than prevention; of what you're describing of clinics being closed. If you have HIV, you need to be on daily drugs, 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 then I totally agree. We're at this present, we at this wonderful moment of prevention and driving down transmission is just becoming more and more possible with lenacapavir and with other drugs.

Saloni Dattani:
It's... I find it really heartbreaking because, until this point, until this year, I was so excited about how would lenacapavir or other long-acting treatments change the picture? Like, would we be able to effectively eliminate the transmission of HIV, in some of these countries? And I think that's possible, and I think that's a little bit ambitious, just like PEPFAR is. I think it's possible. But instead of going ahead, and kind of going big on this, trying to really cut it down, and actually, then, not needing such a large program because you've managed to reduce the number of people who are affected by this. Instead of doing that, were on this road of a lot of uncertainty and disruption, and that it's come so suddenly that people couldn't plan for it. They didn't expect that their treatment would suddenly disappear. I think what the figures were showing, that I was reading, was- the program, PEPFAR is so big, there's 20 and a half million people receiving treatment from PEPFAR per year. On a daily level, that's 200,000 people who are getting their refills; 200,000 people who are realising the clinics are shut, and they don't know how they're going to get their next supply.

Jacob Trefethen:
Well, and that's 200,000 cases of higher risk of mutated viruses as well, presumably.

Saloni Dattani:
There's a risk of the resurgence of HIV, if people stop taking treatment for, I think, it's a few months or so, and that has some quite nasty side effects in the initial period; and then there's also of the complications that people would have with HIV as a disease itself.

Jacob Trefethen:
Okay, so to summarise: the launch of PEPFAR, the launch of the Global Fund were a particularly ambitious moment, and there were people around who thought maybe they would not achieve their aims, because it never been done before. And lo and behold, they achieved great things for tens of millions of people.

Saloni Dattani:
For over two decades.

Jacob Trefethen:
Over two decades. And now we're not only, we've been talking, in this episode, about great technical achievement. That could be a launch of a new ambitious program and really drive down transmission, but really, we're at a state where, not only are the ambition levels lower, but the basics are not, as we record, being provided for everyone who needs them.

Saloni Dattani:
Right. It brings me to this point that I often think about. So when I write this Substack newsletter on medical innovation, and what is the use of new treatments if there's no one to distribute them, or if there's no one that can access them. This is the whole point of medical- or, these breakthroughs don't matter, if they're not getting to the people who need them.

Jacob Trefethen:
Okay, so do we have any hope for the Global Fund? So listeners who are in the US, think about PEPFAR. Listeners in other countries, think about your own health systems and think about the Global Fund, which, I assume, is up for replenishment pretty soon, and is doing a lot of this work too.

Saloni Dattani:
Replenishment is when they get funding replenished from various countries.

Jacob Trefethen:
Yes, exactly.

Saloni Dattani:
And those are decided by their foreign aid budgets.

Jacob Trefethen:
Correct. So foreign aid in many higher-income and middle-income countries will contribute some amount of tax revenues, or of government revenues, to foreign aid to other countries. A good slice of that is global health; and HIV treatment and prevention is a reasonable portion of that global health contribution, often via the Global Fund. And the UK is not in a particularly ambitious moment either. At the time of recording, we are a month in, or possibly two months now, into an announcement under the Labour government that, instead of returning to 0.7% of GNI, basically GDP, being contributed to foreign aid — as was the case under the last Labour government and the beginning of the last Conservative government — we are going to drop down to 0.3. So under COVID, we dropped from 0.7 to 0.5 in what was termed a temporary measure for COVID. And now instead of returning to 0.7, we're dropping down to 0.3 and we're going through-

Saloni Dattani:
0.3%, wow.

Jacob Trefethen:
Yes.

Saloni Dattani:
So small. I mean, to me it seems so small as well, because I have read about some of these other programs that our foreign aid has funded, and some of them are really impactful. It's stuff like — oh my gosh — it's vaccination of millions of children against these deadly diseases that don't really affect us very much in wealthier countries. It's stuff like trachoma, which is this bacterial eye infection. The US and the UK, and some other philanthropic donors, came together to fund this really ambitious program to supply antibiotic treatments, better sanitation measures, and so on, to hundreds of millions of people across Africa, and they've massively reduced this... really painful bacterial eye infection that can lead to blindness in children. These are some huge successes that many people don't even know about.

Jacob Trefethen:
Tuberculosis — way down from 20 years ago. Malaria, recently stalling, but has been driven down a lot since 2000; mostly affects children. Progress is possible. Okay, well, now that we've depressed ourselves sufficiently, there's both the financing that is not looking so hot right now. The ambition not looking so hot right now. Another thing that you can do, to try and get more people access to treatment and prevention, is to drive the cost down of the actual drugs themselves. And maybe it's time we talk about that with respect to lenacapavir.

Saloni Dattani:
What do we know about the cost of lenacapavir right now?

Jacob Trefethen:
Well, there's the cost of production and then there's the price that the company selling the drug charges. The price that Gilead is charging, in the US, is $42,250 — is the last number I saw.

Saloni Dattani:
Per person?

Jacob Trefethen:
Per person, per year. So that covers all the injections for the first year. That is about double what cabotegravir — the Viiv injectable — is priced at in the US. I was priced out of Cabotegravir; I assume I will be priced out of lenacapavir in the short term.
Why do they charge that much money? Well, a lot of the development that we talked about earlier in the episode is done as a pure expense. So all of the scientists who are working at Gilead, trying to iterate on the drugs to make them better, the funding for all the, or at least most of the, clinical trials we discussed — that's all done as an expense. So they want to charge more out the other end, to some patients, so that they can recoup some of that money. And if they make any profit, hopefully some of it will get reinvested in more drug development, not just distributed to shareholders.
That, of course, raises questions: well, do you think that someone in Botswana is going to pay $42,000? My guess is no, and I'm not going to pay $42,000, so I'm with them. The price versus cost is very different for patented medicines, often. There are estimates for how much it will cost to produce a generic version of lenacapavir that are under a hundred dollars; I've seen as low as $40. I haven't looked into the drivers of those estimates, or how much Gilead has really revealed about the production methods in public — which would give you better methods of coming up with estimates there.
The good news, though, is that Gilead has already signed agreements with six generic suppliers of lenacapavir for 120 countries; so, plenty of low-income and middle-income countries in that mix. And you may recall there are about 200 countries in the world, so there's a lot that are not covered there, but for those 120 countries, these suppliers will be able to provide versions of lenacapavir that have been shown to be therapeutically-equivalent to the initial drug that Gilead used, in the clinical trials.
Though these new production runs will be made by different companies, that have been given the rights and taught a bit by Gilead how to do it. Those generic companies will be manufacturing, hopefully, eventually, enough supply for use in those 120 countries. What Gilead, in their press release in October, has committed to is that they plan to provide Gilead-supplied product at no profit to Gilead, until generic manufacturers are able to fully support demand in high-incidence, resource-limited countries. So that's a great start, to be honest.
The questions that leaves me are, well, how quickly- what is the supply? How quickly could demand be met? And, are we sure that they're going to ramp up quickly enough? I mean, number one. But then, secondly, what about the other 80 countries? So there are plenty of countries in South America, for example, that are not in the 120 covered by this generic agreement, and that have relatively have medium HIV incidence — where a lot of people could be protected by this drug that now exists.

Saloni Dattani:
Some of them were part of the clinical trials for lenacapavir as well, which is quite depressing. But, I think, what I've read is that they plan to provide it to people in the trial. I'm not sure that that extends to the whole country. I mean, could someone just make this drug themselves? Or, I mean, not like an individual.

Jacob Trefethen:
There's something beyond that, which are: global intellectual property, and patents, and enforcing those; then, there may also be some technical barriers. So I'll talk about the patents and then the technical barriers. On the patents front, there's a long history — with HIV specifically — of the tension of global pharmaceutical companies, who want to enforce patents and high prices, and patients and activists and advocates, who want medicines to be available for more people sooner.
And there's two broad solutions to this problem. One is, what I just described, with Gilead, which is voluntary licensing, where Gilead arranges with other generic companies: 'Okay, you can do this and we will not sue you for selling these drugs in these 120 countries. But if you sell them elsewhere, maybe we will sue you.' That's voluntary [licensing].
Then there's compulsory licensing, where a country may determine that they have a public health crisis, to the extent that they are not going to- the normal patent rules are out the window. So this almost happened with HIV in South Africa in the late '90s, early 2000s, and more recently, I believe, in Colombia, where the government's like, 'Make drugs, that's okay, so long as people get the drugs.' I think that is appropriate in some medical emergencies.
It was a big topic of dispute and debate in COVID as well, where I think the debate actually goes a bit of a different direction — probably not worth getting into now, but vaccine manufacturing is quite different to generic small molecule manufacturing. Small molecules are, in general, pretty commoditized: there are many, many companies who can make them in many, many countries. And vaccines, the product is the process to some degree — how you actually manufacture a given vaccine, in a particular bioreactor, with particular cells, with particular growth medium, you got to kind of get taught by the original manufacturer. It's harder to just scale up, and it's harder to even infringe on a patent, if you wanted to.
That brings me to the technical blockades here, where, for a traditional generic drug, a small molecule, there are not many technical blockades; you can just- even if a company has not revealed all the secrets of how they made something, they have to file with a regulator, and give some information — some of which is then made public, once a drug approval is given. They have to list certain information on a label for patients, of what the heck is in this drug. And also, if you're a competitor, you can simply buy their drug once it's on the market, and analyse what's in it. So you have a lot of tools where you can basically enter as a competitor, from a technical point of view. Then, the difficulty with some long-acting drugs is that they are more complicated to copy. If you were dealing with a long-acting drug that had a liposome, or had a particular polymer-

Saloni Dattani:
What's a liposome?

Jacob Trefethen:
You know, I don't want to answer that question because I'll get it wrong.

Saloni Dattani:
It's a fatty blob, right?

Jacob Trefethen:
Say it again?

Saloni Dattani:
It's a fatty blob.

Jacob Trefethen:
Exactly, thank you!

Saloni Dattani:
"Lipo" means fat.

Jacob Trefethen:
It's a fatty blob, I think it's probably a bilayer. I think, basically imagine a fatty blob that encapsulates the thing you care about, but there are different fatty blobs you might want to make, and there are companies trying to improve their fatty blobs, and it's harder to copy the fatty blobs that are right at the frontier of fatty blob technology than it is to copy the small molecule.
Now, the good news about lenacapavir, and the good news about cabotegravir, and the good news about islatravir — three of the long-lasting drugs we've talked about for HIV — is that they don't seem to be right at the hardest end. We don't have a liposome, for example, involved. We do, potentially, have some things that make it a little harder than usual and — I'm a little bit beyond my knowledge about how it applies to lenacapavir, and I would love to see how it goes — but, for example, I think you need a nano miller, where you grind up your drugs! This is true for Cabotegravir and, I think, probably not true for lenacapavir. You grind up your drug crystal, so they're tiny, tiny, tiny, tiny, so that when you disperse them in a liquid, and then when you inject that liquid with the solids, you've got solids that are high-surface-area-to-volume-ratio. So the question that comes to mind for me is: Which generic companies own a nano miller, for example, and does that machine cost $8 million, you know, how much? Those questions start rearing their head, and the next set of questions for me is... there's a tried-and-true regulatory pathway at the FDA and other regulators, for generic equivalents to small molecules: you have to prove only that they are equivalent in certain respects; you do not have to redo everything else.
Are we sure that those tests are going to be good enough, for long-acting injectables, or for long-acting drugs in general? Or is there some other reason why, towards the tail end of many months, there may be more deviation than you got from just testing the batch chemically, and well- should we actually, therefore, rerun a big clinical trial? And that would be cost-prohibitive; then you really would not see much generic entry. I don't think that that's the way lenacapavir will go. It certainly would get my hair up if people started worrying about it though.

Saloni Dattani:
I mean, I guess this also makes me think about Gilead producing it, probably, with multiple manufacturing plants or so, and they would have to do this internal testing, presumably. Hopefully, there's a way to do that in the same way — or they're producing it in a very similar way, that they would be able to know early on, is this the equivalent; are these molecules equivalent across these different sites? The other question that I had was, I had heard of this thing called the Medicines Patent Pool? Is that something- have we already covered that, or what is that?

Jacob Trefethen:
Well, conceptually, a little bit, but actually no. They are kind of an intermediary. They're a UN-backed non-profit that tries to help match up originator companies — that are filing patents on new medicines, taking those medicines through clinical trials, marketing them in some countries — trying to match them up with generic companies, who might want to market the drug in countries the originator company doesn't focus on as much, or doesn't care about as much, in terms of making a profit, for example. Often, there's a match to be made there, that both companies are very happy with.
You know, especially if you're a smaller originator company, who doesn't have any experience selling into Bangladesh, then you might very well want your drug to be used by people in Bangladesh who want your drug... but you just don't have the resources to get up to speed with the drug regulator in Bangladesh. You're going to be on the hook if anyone sues you for side effects in Bangladesh; it's a big proposal. But the Medicine Patents Pool, MPP, will sit in the middle and say, 'Look, we have relationships with many generic manufacturers, many of whom have lots of experience in Bangladesh. If you just sign on the dotted line here and say, you're not, basically, you're not going to sue them if they sell in Bangladesh, then you can both be happy and patients get to benefit.' And they've had some successes, in particular with HIV over the years. I think they were set up in 2010 so, for the more recent round of voluntary licensing. But they worked on Cabotegravir, the initial long-lasting injectable drug, and sort of sat between Viiv, the originator company, and, I believe, three generic companies there, to help transition that- help get that out into more countries.

Saloni Dattani:
I didn't know much of that at all. That's really cool. I'm kind of thinking about, okay, we heard a little bit about how PEPFAR was formed and that was set up, and yeah, I'd very curious about that. The other thing I was thinking was, okay, given that we have all of this — we have the Medicines Patent Pool, we have these licenses with generic manufacturers.
Also, Gilead, I think, they've said that they have the capacity to manufacture upto 10 million doses this year. I initially thought that was a big number, but if you think about it, it's two doses per six months, so divide by four. Divide 10 million by four. That's roughly 2.5 million people who would get this. And it's both a treatment for drug-resistant HIV, and it's going to be used for prevention, so that's actually a small fraction. So hopefully the generic manufacturers help to scale that up to some degree.
But aside from that, okay, if PEPFAR has this uncertain future right now, I think we do know that the Global Fund is going to try and roll it out, but trying to scale that up is, I think, maybe the next big thing to try to focus on — if people are listening and have some way to convince their government that this is a really important thing to work on.
I think the Global Fund seems like it's going to be doing lots of the work, in terms of funding these programs to roll it out and administering it worldwide. But I'm curious if there are other things that come to mind, in terms of how you're thinking about the potential future here.

Jacob Trefethen:
Those are the main ones to me. I think the time is now and the opportunity is here, and if you really just take a step back, a whole 'nother level — what is happening in many countries most affected by HIV? Well, a happy piece of news is that- I am cautious saying this in April 2025, where trade relations are also a little bit up in the air, but the happy news from the last few decades is that most lower- and middle-income countries have been growing economically, and that was not true in the 1960s, for example. We, in fact, in most countries, have been seeing income growth for people, and seeing the tax base of those countries also grow — meaning those countries can do more public health interventions, too. And you know, that is really the future that will make a lot of people with HIV have more sustainable healthcare- is that if you are in Nigeria, you should not have to rely on the whims of the American public, and in the future you hopefully will not.
But that, unfortunately, is decades away. The tax base of many countries is not high enough to provide lenacapavir to people who need it, and people are not individually rich enough to pay for lenacapavir, if they need it. So now is a moment for people, especially voters, in richer countries to kind of do our part. It's not a permanent humanitarian effort, I think it's a decadal- the next few decades really matter. And we have these amazing new technologies that actually enable a dent to be made. That would be where I would leave the topic of scale up is... now's the moment, and I hope, I hope, that when you and I are 30 years older, this kind of topic doesn't exist in the same way, because we don't have to think about external sources of financing quite as much.

Saloni Dattani:
No, I really hope so as well. I mean, I think, right now, where we are, this still seems quite out of reach for a lot of people in the most-affected countries, in Southern Africa. I think I was reading... the average spending on healthcare some $80 per person per year in Southern Africa, whereas it's, what is it, like 80 times that or something in the US? And meanwhile, I mean, that's not just for lenacapavir, which would be some $40 or so at a generic price, it's also all the other treatments, preventions, testing, and so on. Right now, it still feels quite out of reach, and I'm just- The Global Fund is going to be really important; trying to keep PEPFAR running; but also trying to build up more capacity within these countries to protect the people who are affected by HIV right now. That seems like a difficult problem.

Jacob Trefethen:
It sounds like there's some uncertainty in the next decade then. So are there other tools that are maybe not scientific, but more economic or financial, that we can apply to be more ambitious?

Saloni Dattani:
I think there are a few. I mean, it's not just lenacapavir. I think this is one really important area that we want to scale up, but there are also these other potential future drugs like islatravir, any other potential long-acting drugs that might work.
How do people get the funding model so that we're not having to be in the situation where a pharmaceutical company is trying to recoup their costs at a very high price in richer countries, and then hopefully, voluntarily, agreeing to these agreements, which may or may not be scaled up. One idea that comes to mind for me is this idea of an Advance Market Commitments, or an AMC. And I love the idea of AMCs. I've written about them a bunch, read a lot of stuff about them. I think, the way to think about this is to contrast it with the regular approach to funding drugs or vaccines.
So we usually have this situation where a pharmaceutical company, or philanthropic funder, or some government is trying to decide upfront which bets might work out — which companies or which researchers might develop an effective drug — and they're funding those groups directly, and then some of them will work out, some of them won't. In drug development, the success rate is very low, and that means most of these bets are going to fail. There's going to be a lot of wasted money on the funder's side. And secondly, there's this huge expense covered by individual pharmaceutical companies, in developing the drug, that they now want to recoup, so they charge these very high prices. It takes a while, usually, for a drug to go off-patent, or for them to agree to these generic-licensing approaches, and that is a lot of time wasted; it's a lot of people who are not getting the drugs or the vaccines that they need.
Is there another way to do it? And I think AMCs are one answer to that. An AMC is kind of an inversion of this — where, instead of funding the groups directly, you're funding the potential successful products at the end. So, you're setting up this pool of funding — which might be some billions of dollars or so — if a company or a research group can develop a drug or vaccine that meets certain standards. The amount that's given to these companies, or manufacturers, depends on how much they're manufacturing. It's usually on a per-dose basis — essentially, how many doses have you administered? You get more funding based on that.
I think this is a really cool idea for two reasons. One is, as a funder, you don't have to know who is going to succeed. You have this pool of funding if something succeeds. If nothing succeeds, you don't pay that money. So you are saving on that. And secondly, you're also rewarding companies that scale up the drug faster and get it out to people who need it. At the same time, you're only doing this for the successful drug. So you're giving this stable potential future market to companies; they're going to have this commitment in advance, often years in advance, of what the price is going to be, and they can plan much more effectively based on that.
This has been tried for pneumococcal vaccines in the past. I think this was in the late 2000s, there was this advance market commitment set up to try to speed up the production of pneumococcal vaccines. Pneumococcal disease is a respiratory lung infection that affects people worldwide, and we already had effective vaccines for it in richer countries, but in Africa, there were different strains of the bacteria that weren't targeted for the vaccines.
So this AMC was set up, knowing that it was possible to develop a vaccine for these other strains. There was this pool of 1.5 billion dollars that was there for companies to receive, depending on how much they produced, if they managed to get a vaccine through clinical trials to show safety and efficacy. And it was very successful — so the scale-up of this pneumococcal vaccine in African countries was very fast. I think three or four companies managed to produce effective vaccines including the Serum institute and I think Pfizer was another one of them. It just shows this model, of how this can work, and you don't even to have it for- you don't even need to believe that it's possible to develop a drug or vaccine for it, because if it doesn't work out, you don't have to pay that funding out. The people who do have to pay are, like, the pharmaceutical company themselves in the early stages — they will still have to make the decision on whether this is a good bet for them.

Jacob Trefethen:
Yeah, I think in that case, in the pneumococcal case, the Pfizer vaccine did — people reviewing what effect did this really have — they think that did get rolled out quicker, maybe scale up years quicker than it would've otherwise. I think the Serum one ended up coming through later, and maybe being less affected. But the scale up is so important for actually getting drugs to people who need them, not just inventing cool stuff. And when I think of applying this across to lenacapavir, I think to this great piece that Kamal Nahas wrote in Asimov Press about lenacapavir, and where he touched a bit on the voluntary agreements in 120 countries, and what's happening outside of those countries.
Maybe this is the shape of problem that, for those 80 countries, where there's not in each country, enough demand, or there's too much uncertainty around demand, for a company — Gilead or generic company — to enter that market, and try and start selling to the public healthcare systems. If there were an AMC that aggregated across those countries, and made the demand clearer, and had a price that was fair, but also enough that money could be made to make it sustainable for the companies entering, maybe that's a place for an AMC, I don't know.
What do you think of that?

Saloni Dattani:
That's a great example of where it can be used. I actually also think it could be used in scaling up a drug even once it's been approved, because this second part of what an AMC is used for, in the scale up — having the amounts that companies receive be based on the amount they manufacture means that you're incentivizing this large-scale manufacturing, and actually administering it to people. That is something that could still be used even now. But one of the other applications is as a way to pull funding towards some drug or vaccine or some product that hasn't yet been made, so that would be another option. Can we develop a drug that's better than lenacapavir, or easier to take, or so on, and fund it with this new model. And I think this reminds me as well, I don't know if we mentioned it earlier, but as far as I know, Gilead is also trying to produce improvements on lenacapavir that would be taken once per year instead of once per six months.

Jacob Trefethen:
Imagine that, wow.

Saloni Dattani:
That would be very cool. I was wondering about why they were doing this. I mean, if you were self-interested profit-making company, why not just stick with this already-amazing drug? And it occurred to me, when you were talking about Merck's drug islatravir — that's this oral pill that's once-per-month. If someone could choose between an oral pill once per month and an injected drug once per six months, they might choose the pill. Not only the person themselves, but the clinics might find it easier to distribute the drugs. It's just, you don't need a healthcare worker, or a nurse, or someone to inject the drug if it's a pill. And that made me wonder, maybe that was the incentive. That was the reason that they decided: 'Let's go even further, to make this thing that's even harder for Merck's drug to beat.' I don't know if that's the case, but that's what I would guess.

Jacob Trefethen:
And it just goes to show how much progress we've made with HIV. Because when you were describing the first drugs around, they were not so good and there were no competitors, and now we have great options for patients, and great options for people who don't even have HIV yet who want to reduce their risk. So I'm glad to be alive today.

Saloni Dattani:
It's so much- I mean, the whole timeline is just incredible to think about. We talked about how, in the early 1980s, how pessimistic or how scary it would've been to have HIV, not have any treatments, have this- thought-of-as-this untreatable disease, as just this behavioural problem; there's nothing that someone can really do medically to treat it. Contrast that with where we are now. I think, personally, that process, that timeline could have been sped up. Just reading about some of the details of early research in the 1980s, but also, knowing about how long it takes to run a clinical trial, how long it takes to set up the trial sites, or train the nurses and the healthcare workers, or to share this information between different research groups and so on. But at the same time, it is just an incredible story.

Jacob Trefethen:
Now is probably the time to step back on this story that we have told and conclude. I am sure we missed out many subplots that are also ripe for discussion. But among what we have discussed, I'm interested to hear: What were your main takeaways from this story over the last fifty years?

Saloni Dattani:
My takeaway... I mean, I had so many takeaways. One of them was just how many different ways you can approach medical innovation. Like, what are the different things that you could think are important here? I mean, partly it's 'Let's make a really effective drug', but it's also 'How do we make a drug that's easier for people to take on a regular basis?' It's, maybe, refining drugs that already exist — trying to improve on them, in terms of their safety, efficacy, or again, how people take them.
The other was the different types of drug development. So we talked about this trial-and-error process with the first drug azidothymidine, where they just looked at some 180 compounds: tried each of them in the lab, saw what worked in cells in the lab, and then scaled up based on that. The other is, this is an example of screening existing compounds, or just compounds in nature, that helps repurpose this previous cancer therapeutic that didn't work, for HIV.
Then we had some examples where this understanding of the specifics of HIV, or how the enzymes work, what they look like, what will fit into these little gaps between them — that was another option for developing a new drug. But, at the same time, there was so much iteration and adjustment — that was tinkering — that was important there. The move from this drug that was potentially promising, to one that actually met several criteria that you would have, with the efficacy, the safety, how long lasting it was.
And then I guess, there are these other- improving on the drugs that already exist, that is not just trying to use existing information. If there has been, already, a protease inhibitor invented, can you now develop a new one based on that knowledge? Can you develop a different type of nucleoside inhibitor, like AZT? Will people develop more capsid inhibitors, based on the knowledge that they have from this? I mean, all of this, I think, is super interesting.

Jacob Trefethen:
I totally agree on how much the tinkering and iteration stands out, as important. Basically, at every level, there's.. so much of that's happening at the screening stage, so much of that is happening, as you just said, at designing a capsid inhibitor that makes sense for patients in a particular context.
Another thing that stood out to me is how hard science is to predict — in the sense of, thank goodness people in the last forty, fifty years, scientists did not only work on vaccines. We don't have an HIV vaccine, and we do have a HIV preventive drug that you can get injected with, and kind of feels like a vaccine. I'm so grateful that people were exploring different parts of the technology tree there. We don't have a cure either. We don't have a cure for HIV and we don't have a vaccine, but guess what? We have game-changing tools, and that came from a part of exploration you may not have been able to predict back in 1981.

Saloni Dattani:
Also, the fact that the treatments could be used as a prevention as preventive drugs was probably not that obvious to scientists at the time. That itself was quite unpredictable, I think.

Jacob Trefethen:
Absolutely.

Saloni Dattani:
The other thing that reminded me of was just how many different aspects, or how many different types of science- or what is involved in developing a drug, is not just one person tinkering with it in the lab. It's this whole network of clinical trials that are running; there's the basic research, there's stuff like developing microscopes with a high-enough resolution that you can really see what is happening inside the cell, what this virus looks like, what the proteins look like. There's the DNA sequencing technologies, there's the protein development. Like, all of this stuff comes together to develop these drugs. And then there's the medicinal chemistry, and the pharmacology — which I think, probably, I had kind of underrated before as just, okay, this seems like this last-minute thing; after you've developed a drug, you now want to make sure that it's safe and effective. I previously had this assumption that that was what medicinal chemistry was about, and now I'm thinking this can make a huge difference on whether a drug is useful or effective at all in the real world.

Jacob Trefethen:
Even right at the discovery stage of lenacapavir. So important, how stable it is and how it doesn't break down very quickly. I totally agree with what you just said about interlocking parts of the medical innovation system. It's amazing that we just about had recombinant DNA at the time when HIV started becoming a crisis. So we could use recombinant DNA in the lab as a research tool and that we did not have all of those other things we just mentioned. We didn't have PCR, we didn't have electron microscopes- well, I dunno about that- we didn't have cryo-electron microscopes, certainly. We, only in the last few years, have learned the capsid, which we are now inhibiting with lenacapavir, in fact stays intact into the nucleus. There's so much more that we're still going to learn over the next coming years that might open up new frontiers. And that's true not just for HIV, I bet you that things that HIV researchers have learned will be useful for hepatitis B, for other cancers, for this, that, and the other. And the final interlocking surprise of science that I learned from you many hours ago was that it was only two years before 1981 that the first human retrovirus was discovered. Thank goodness for that. And it makes you wonder what we don't yet understand, that will make solving and curing diseases in the future easier.

Saloni Dattani:
Yes! And, and, above all of that, the other interesting thing for me was learning about how drug pricing works or how these patents work. How does manufacturing actually work at large scale? What do the funding models- what they have to do with whether drugs are developed, how fast they're rolled out, who's ready to pay for certain drugs? And it's every aspect of this whole process: not just the lab, not just the clinical trials, but the funders, the people who decide, who show support for foreign aid spending, for example. Everything comes together when we're talking about any disease, but particularly for HIV, it's so salient because of these huge programs that have transformed the lives of millions of people.

Jacob Trefethen:
And going into the future. There's no point for all of this wonderful science unless we remain ambitious. And unless we make sure that people who need these drugs can access them. It's possible, we've done it before and into the future we go, with uncertainty and with resolve.
This episode was only possible from a lot of work done by a lot of people publishing in the open — whose papers we read and whose reviews we read. I won't thank them all here, but we'll leave, in the show notes, some of the research that we base this episode on. I, in particular, would like to thank Anne de Bruyn Kops, who wrote a great review of long-lasting injectables for many different diseases for Open Philanthropy, that I learned a lot from. I want to thank Sanela Rankovic, who was the HIV researcher who knows all about PF-74. And then, of course, I'm sure we both want to thank Douglas Chukwu, who joined us for our first ever phone-a-friend section.

Saloni Dattani:
Yes. And the team at our Works in Progress, Aria Babu, who helped us really, actually, get this podcast to run Adrian Bradley, who's here with us now producing and keeping us on track with this episode. Then, the team at Works in Progress and Open Philanthropy, who were sponsoring this podcast. And then, I would say, also, all of the scientists who were involved in developing all of these drugs, all the people who were participating in all the clinical trials, all the healthcare workers who worked in them, everyone involved in this massive program, PEPFAR, everything. It's just-

Jacob Trefethen:
It's so cool.

Saloni Dattani:
It's very inspiring.

Jacob Trefethen:
And with that, I will ask you as listeners, if you enjoyed this episode, feel free to subscribe. We will be talking about other Hard Drugs in the future, and check out the show notes for more details on this one.

Saloni Dattani:
Bye. Bye.