Lenacapavir: The miracle drug that could end AIDS

Works in Progress Podcast

Jun 11, 2025•4 hr 54 min•Ep. 1

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Episode description

Lenacapavir is a new HIV drug that blocks infections with an efficacy rate of nearly 100%, and it could completely change the fight against HIV worldwide. Saloni and Jacob talk about the development and prospects for this new drug, as well as the history of HIV, the initial discovery of retroviruses, and how HIV was transformed from a death sentence to a manageable condition.

Hard Drugs is a new podcast from Works in Progress and Open Philanthropy about medical innovation presented by Saloni Dattani and Jacob Trefethen.

00:00 Intro
03:52 How was HIV discovered? Where did it come from, and how does it attack the body and cause AIDS?
38:10 Antiretrovirals: How did scientists develop breakthrough HIV drugs — from azidothymidine to protease inhibitors to PrEP?
1:51:35 How does prevention and treatment work today?
2:19:03 HIV’s capsid and the breakthrough of lenacapavir, the first-approved HIV capsid inhibitor
2:50:36 How to develop long-lasting treatments
3:14:45 Lenacapavir’s near 100% efficacy in clinical trials
3:48:40 The impact of global programs against HIV, and can we now end HIV?

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Books:

How to Survive a Plague — by David France (2016). [Mentioned as a history of the science and activism against the AIDS epidemic, and the protease-inhibitor breakthrough.] https://surviveaplague.com/
And the Band Played On — Randy Shilts (1987). [Mentioned as an account of the early years of AIDS.] https://us.macmillan.com/books/9780312374631/andthebandplayedon/
Drug development stories: From bench to bedside — Elsevier (2024). [Mentioned as containing a history of the development of lenacapavir] https://shop.elsevier.com/books/drug-discovery-stories/yu/978-0-443-23932-8

Retrospectives:

The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic — Samuel Broder (2015). https://doi.org/10.1016/j.antiviral.2009.10.002
History of the discoveries of the first human retroviruses: HTLV-1 and HTLV-2 — Robert Gallo (2005). https://doi.org/10.1038/sj.onc.1208980
A Look at Long Acting Drugs — Anne de Bruyn Kops for Open Philanthropy (2025). https://bit.ly/long-acting-drugs-op
How To Save Twenty Million Lives, with Dr Mark Dybul — Statecraft (2023) https://www.statecraft.pub/p/saving-twenty-million-lives
The Road to Fortovase. A History of Saquinavir, the First Human Immunodeficiency Virus Protease Inhibitor — Redshaw et al. (2000) https://link.springer.com/chapter/10.1007/978-3-642-57092-6_1

Articles:

The origin of genetic diversity in HIV-1 — Smyth et al. (2012). [Mentioned as a review about HIV’s recombination, which described it as “a primitive form of sexual reproduction”] https://www.sciencedirect.com/science/article/pii/S0168170212002122
PF74 Reinforces the HIV-1 Capsid To Impair Reverse Transcription-Induced Uncoating — Rankovic et al. (2018) https://doi.org/10.1128/JVI.00845-18
Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons — Kelley et al. (2024) https://www.nejm.org/doi/full/10.1056/NEJMoa2411858
Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women — Bekker et al. (2024) https://www.nejm.org/doi/10.1056/NEJMoa2407001
The evolution of HIV-1 and the origin of AIDS — Sharp and Hahn (2010) https://doi.org/10.1098/rstb.2010.0031
Pathogenic mechanisms of HIV disease — Moir et al. (2011) https://doi.org/10.1146/annurev-pathol-011110-130254
Estimating per-act HIV transmission risk: a systematic review — Patel et al. (2012) https://journals.lww.com/aidsonline/fulltext/2014/06190/Estimating_per_act_HIV_transmission_risk__a.14.aspx
The structural biology of HIV-1: mechanistic and therapeutic insights — Engelman and Cherepanov (2012) https://doi.org/10.1038/nrmicro2747
Challenges and opportunities in the development of complex generic long-acting injectable drug products — O’Brien et al. (2021) https://doi.org/10.1016/j.jconrel.2021.06.017
Making a “Miracle” HIV Medicine — Nahas (2025) https://press.asimov.com/articles/hiv-medicine
Highly active antiretroviral therapy transformed the lives of people with HIV — Dattani (2024) https://ourworldindata.org/data-insights/highly-active-antiretroviral-therapy-transformed-the-lives-of-people-with-hiv

Videos:

Mini-Lecture Series: HIV Capsid Inhibitors: Mechanism of Action — David Spach, National HIV Curriculum (2024) https://www.youtube.com/watch?v=iZ9KDxV5Zbs&ab_channel=NationalHIVCurriculum

Image credits:

Mini-Lecture Series: HIV Capsid Inhibitors: Mechanism of Action — David Spach, National HIV Curriculum (2024) [Multiple diagrams of HIV capsid and lenacapavir’s effect.]
Saloni Dattani; Our World in Data (2024) Highly active antiretroviral therapy transformed the lives of people with HIV. [Graph of decline in HIV/AIDS mortality after HAART was introduced.]
Engelman and Cherepanov (2012). The structural biology of HIV-1: mechanistic and therapeutic insights. [Diagram of HIV’s entry into the cell.]
Susan Moir, Tae-Wook Chun, Anthony S Fauci (2011). Pathogenic mechanisms of HIV disease. [Diagram of HIV replication rates over time, contrasting acute and chronic infection.]
Saloni Dattani, adapted from Patel et al. (2014). Estimating per-act HIV transmission risk: a systematic review. [Bar chart of risks of contracting HIV from different sources when unprotected.]
Thomas Splettstoesser under CC-BY. [Diagram of HIV’s internal structure.]
Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women — Bekker et al. (2024) [Chart of lenacapavir’s efficacy.]
Our World in Data based on Joint United Nations Programme on HIV/AIDS (2024). [Chart of global HIV deaths over time.]

Acknowledgements:

Douglas Chukwu, researcher at Open Philanthropy
Sanela Rankovic, Acting Instructor at the In...

Transcript

0:00:01.200,0:00:09.040 Place yourself in the 1980s. This is kind of hard because, as a scientist, 0:00:09.040,0:00:16.480 you had just found out that retroviruses could infect humans. Now you find out 0:00:16.480,0:00:22.960 that HIV is a retrovirus. You're like, wait, I didn't even know that RNA could 0:00:22.960,0:00:29.280 be turned into DNA until 10 years ago. So that's quite a tricky position to be in. 0:00:33.920,0:00:39.760 Making effective new medicines isn't easy. Welcome to Hard Drugs. I'm Saloni Dattani, 0:00:39.760,0:00:43.920 a researcher on global health at Our World in Data, and one of the founders of Works 0:00:43.920,0:00:49.600 in Progress magazine. And I'm hosting this podcast with Jacob Trefethen, who leads science and global 0:00:49.600,0:00:55.360 health R&D funding at Open Philanthropy, and is one of the most fun, interesting people I know. 0:00:55.360,0:00:59.360 This show is about medical innovation: how to speed it up, how to scale it up, 0:00:59.360,0:01:04.240 and how to make sure lifesaving tools reach the people who need them the most. It all started with 0:01:04.240,0:01:09.440 a conversation, a shared instinct that this was the right time to start a podcast, to dive deep 0:01:09.440,0:01:14.960 into how to technologies for malaria, cancer, AIDS, and other diseases, actually came to be. 0:01:14.960,0:01:22.400 Today we're going to talk about HIV. Making an HIV vaccine has been the holy grail for many of the 0:01:22.400,0:01:27.360 world's top scientists over the last generation. It has proven one of the most challenging 0:01:27.360,0:01:33.200 scientific problems too, and we don't yet have a vaccine. But last year, one drug company announced 0:01:33.200,0:01:39.200 they'd gone a completely different route. They made a drug you get injected with once every 0:01:39.200,0:01:45.200 six months, or maybe only once a year, like a flu shot, giving you almost perfect protection 0:01:45.200,0:01:57.840 against HIV. So how did we get here and what does it mean for one of the world's deadliest diseases? 0:01:57.840,0:02:07.040 I'm super excited to talk about HIV, lenacapavir and other HIV drugs today with Jacob. Hello. 0:02:07.040,0:02:09.200 Hey, how are you doing? 0:02:09.200,0:02:15.680 Great. Yeah, so I'm super excited about this. I think we have a bunch of things that we're going 0:02:15.680,0:02:22.080 to talk about in the episode, maybe starting with just what HIV is, how it infects people, and then 0:02:22.080,0:02:28.800 moving on to the history of drug development in the field, how lenacapavir was develops, 0:02:28.800,0:02:36.240 what lenacapavir actually does, and then where we are now, how to scale it up to people who need it. 0:02:36.240,0:02:41.600 That sounds good to me. I feel like I first really heard about or realised what a big 0:02:41.600,0:02:47.680 deal lenacapavir was from a tweet from you. So I get to be the lucky guy who gets to be 0:02:47.680,0:02:51.280 taught some of that history of HIV and how it all fits together from you. Hopefully I 0:02:51.280,0:02:58.400 can chip in some of my knowledge from working at Open Philanthropy on Global Health R&D as 0:02:58.400,0:03:05.280 well. That's this conversation. There's a lot to cover. I hope we cover the stuff that matters, 0:03:05.280,0:03:09.360 and get to the finish line of what are these magical new drugs really doing. 0:03:09.360,0:03:13.920 There are a lot of, I think, subplots that we're going to go through. The whole process of drug 0:03:13.920,0:03:23.200 discovery in this field has been really amazing. If you think about what HIV was like in the 1980s, 0:03:23.200,0:03:28.960 where people would only have a few years of survival after being diagnosed to now, where, 0:03:28.960,0:03:35.200 if people take treatment early enough, they can expect to live almost a normal life expectancy. 0:03:36.080,0:03:41.840 I think talking about how that's happened, how that's been made possible, is really important. 0:03:41.840,0:03:44.800 I agree. It sounds like we're going to have to start with: 0:03:44.800,0:03:47.440 what the heck is HIV itself? Should we begin there? 0:03:51.440,0:03:59.280 HIV is a virus that causes AIDS, the acquired immunodeficiency syndrome, 0:03:59.280,0:04:02.640 which is associated with lots of different infectious diseases, 0:04:02.640,0:04:09.360 cancers, and conditions that people suffer from if they've been infected with the virus for long 0:04:09.360,0:04:17.200 enough. But what's interesting about HIV, to begin with, is that it's not a typical type of virus. 0:04:17.200,0:04:26.400 It's something called a retrovirus. "Retrovirus" itself is a new concept to a lot of scientists, 0:04:26.400,0:04:34.880 historically speaking. The first retrovirus that infected humans was only discovered in 1979, which 0:04:34.880,0:04:41.920 is just two years before the first reported cases of HIV in the US. Before that, people had no idea- 0:04:41.920,0:04:43.440 And that was not HIV. That was not HIV. 0:04:43.440,0:04:44.960 Okay. That was a different retrovirus. 0:04:46.400,0:04:52.080 That was human T lymphotropic virus, the first human retrovirus discovered. 0:04:52.080,0:04:57.600 I think that itself has a really interesting story. When I was first reading about this, 0:04:57.600,0:05:01.360 I was really struck by the fact that there was only this two year gap. We essentially 0:05:01.360,0:05:08.160 figured out what [human] retroviruses were in the first place just shortly before discovering this 0:05:08.160,0:05:14.560 deadly new disease that was caused by one. I think that's an important thing to think about, 0:05:14.560,0:05:19.280 when we're thinking about what scientists at the time would've been working on, 0:05:19.280,0:05:22.400 and how they would've figured out that it caused AIDS. 0:05:22.400,0:05:28.560 What is similar about that virus and HIV? What makes it a retrovirus? 0:05:28.560,0:05:35.520 A retrovirus — maybe I could kind of step back a bit and talk about how the usual 0:05:35.520,0:05:43.280 process of DNA works, just to give you some context. Great. Almost every cell in our body 0:05:43.280,0:05:51.760 has DNA. DNA is the genetic code to tell us which proteins to make, but it contains all 0:05:51.760,0:05:57.680 of that genetic code. All of our cells don't need to be producing all of those proteins, 0:05:57.680,0:06:02.160 and they don't need to be producing them all of the time. So instead of using the 0:06:02.160,0:06:09.760 entire genetic code, we use our enzymes to find segments of the DNA, to turn into RNA, 0:06:09.760,0:06:14.880 which is this intermediate molecule that's also used for various other things. And then 0:06:14.880,0:06:22.080 we turn this RNA into protein; proteins that are used in all kinds of processes in our body. 0:06:23.040,0:06:31.600 This direction — from DNA to RNA to protein — was how biologists and scientists typically 0:06:31.600,0:06:40.560 understood cells and how biological life worked. And that was overturned with the discovery of 0:06:40.560,0:06:46.720 retroviruses. What happened here was that people found out that there were certain 0:06:46.720,0:06:56.000 viruses that could turn their RNA into DNA, using an enzyme called reverse transcriptase. 0:06:57.040,0:06:59.360 They're in the other direction. 0:06:59.360,0:07:06.080 Yeah. This was a huge discovery in 1970 by Howard Temin and David Baltimore. They 0:07:07.040,0:07:12.880 discovered this enzyme, reverse transcriptase. They discovered that retroviruses could reverse 0:07:12.880,0:07:21.040 transcribe RNA into DNA, and then they tried to find other retroviruses that infected humans. 0:07:21.040,0:07:28.480 For a long time, no one succeeded in finding any of these viruses, until 1979. So it was 0:07:28.480,0:07:37.520 about almost 10 years of people trying to find real examples of these, and they couldn't. 0:07:37.520,0:07:49.840 And is that related to HIV in 1981? We just got lucky? Or yeah, why so close? 0:07:49.840,0:07:55.200 So I think we did get lucky, and I think it would've been really difficult to figure out 0:07:55.200,0:08:04.400 that HIV was causing AIDS if not for that — or to even know where to look. What's really interesting 0:08:04.400,0:08:10.880 about this is, the scientist who discovered the first retrovirus that infected humans, 0:08:10.880,0:08:18.560 Robert Gallo, was also one of the scientists who discovered HIV as being the cause of AIDS. 0:08:20.720,0:08:24.880 I really like kind of reading through reviews, or retrospectives, 0:08:24.880,0:08:30.240 written by scientists themselves on how they figured out something, what research they did, 0:08:30.240,0:08:37.200 and so I was reading this retrospective that he wrote on the discovery of retroviruses and HIV, 0:08:37.200,0:08:40.880 and it was really interesting because he talks about how people were really 0:08:40.880,0:08:44.320 sceptical that there were any other retroviruses that infected humans. 0:08:44.880,0:08:51.200 The reason for that was: people had found retroviruses that infected other animals, 0:08:51.200,0:08:57.520 other primates. And in those primates, it seemed to be pretty abundant — or ubiquitous — across 0:08:57.520,0:09:02.960 their organs, but that wasn't the case in humans, and it was just hard to find them. 0:09:02.960,0:09:08.240 So they assumed that maybe there's something that prevents us from being infected by them. 0:09:09.520,0:09:19.760 Scientists also found that if you put the animal retroviruses into human blood — human serum — that 0:09:19.760,0:09:27.760 would immediately inactivate those viruses, using our complement system, which is one component of 0:09:27.760,0:09:32.720 our immune system. So this suggested that maybe there's some way that we're just protected 0:09:32.720,0:09:38.400 against them; they're not going to affect us. I think Robert Gallo just had this idea that 0:09:38.400,0:09:44.320 that might be wrong: maybe there are some other types of retroviruses that we hadn't studied. 0:09:44.320,0:09:52.160 And so he started looking at T-cell cancers. In animals, the retroviruses that infected 0:09:52.160,0:09:58.000 those animals would typically cause T-cell leukemias; T-cells are a type of white 0:09:58.000,0:10:05.200 blood cell. So he thought maybe they're also causing leukemias in humans, and he started 0:10:05.200,0:10:13.920 working on finding patients with T-cell leukemias. Eventually he did actually discover a retrovirus 0:10:13.920,0:10:20.880 in them. This retrovirus was using reverse transcriptase to turn its RNA back into DNA. 0:10:20.880,0:10:30.960 And the reason that this is important for HIV is that they actually developed the tools — to test 0:10:30.960,0:10:38.240 out whether there are retroviruses infecting a sample — as part of that process. They started 0:10:38.240,0:10:45.520 working on potential drugs that could be used to target reverse transcriptase. They also just 0:10:45.520,0:10:51.200 generally had the idea that humans can be infected by retroviruses, and retroviruses 0:10:51.200,0:10:58.560 infect humans in their T-cells. And as we'll come to later on, that's very relevant in HIV. 0:10:58.560,0:11:04.640 Okay, so just stepping back for a second. Beforehand, scientists thought: well, maybe these 0:11:04.640,0:11:09.840 retroviruses that we're seeing in other animals aren't infecting humans, and the human immune 0:11:09.840,0:11:15.120 system's basically winning against them. We've got this under control. But then, it looked like 0:11:15.120,0:11:21.280 they may infect some cell types and we might not be winning fully. I mean, my question then is — it 0:11:21.280,0:11:28.640 sounds like such a good strategy for a virus. If I'm a virus, I would love to reverse transcribe 0:11:28.640,0:11:35.920 and integrate in your DNA. So how come if it's possible for HIV, we don't see this in lots of 0:11:35.920,0:11:42.720 viruses? I mean other viruses, other than HTLV, you mention, how come there are not lots and lots? 0:11:42.720,0:11:48.800 That's a really interesting question. And retroviruses, it turns out are really ancient. 0:11:49.520,0:11:57.520 Parts of their genomes are integrated into our normal DNA and they've just been passed 0:11:57.520,0:12:03.760 down over time — so this is called endogenous retroviruses. I don't really know much more 0:12:03.760,0:12:10.400 than that about that topic. But on your question on why aren't there more retroviruses infecting 0:12:10.400,0:12:18.880 humans? I think there's potentially three or four things going on. I am sort of wary of saying that 0:12:18.880,0:12:23.200 something's not possible, because sometimes people say that, even in the case of this, 0:12:23.200,0:12:28.800 and then they figure out that it's wrong. We just haven't found those other retroviruses. 0:12:28.800,0:12:39.120 But some of the reasons, probably: one, it's like an error-prone process. If you're a virus — sorry, 0:12:39.120,0:12:49.440 you're not a virus. But for a virus that's transcribing its RNA genome into DNA, 0:12:49.440,0:12:56.320 the reverse transcriptase enzyme is not very precise in how it does that. It introduces 0:12:56.320,0:13:04.160 errors into the code. That's probably a little bit dangerous for the viruses themselves. Secondly, 0:13:04.160,0:13:11.840 they have this RNA genome, they then transcribe it into DNA, and then they get our cells to 0:13:11.840,0:13:18.480 transcribe the DNA back into RNA — which just seems a little bit inefficient. It 0:13:18.480,0:13:25.280 would just take a longer amount of time. It introduces errors. That's not super useful, 0:13:25.280,0:13:30.400 maybe, but obviously in some cases, it actually is, and it's worth that trade off. 0:13:30.400,0:13:37.280 You mentioned T-cells — it's going after these. I mean this is really, it's clever, but it's creepy. 0:13:37.280,0:13:44.720 So there's a reverse transcription where it's then going to integrate into my DNA, which is 0:13:44.720,0:13:50.720 disturbing in its own way. And then, additionally, you're telling me it's going to do that not just 0:13:50.720,0:13:56.080 anywhere, but in one of my immune cells — which is what's meant to be fighting infections. It's 0:13:56.080,0:14:02.240 going to hijack and integrate there. So is that right? And those are the T-cells? 0:14:02.240,0:14:13.120 That's right. So HIV infects various immune cells, but usually a specific type of T-cell called a CD4 0:14:13.120,0:14:25.760 T-cell. And the "CD4" just describes one receptor on the surface of this T-cell that is very crucial 0:14:25.760,0:14:32.480 in signalling. But also kind of defines that type of T-cell. And these types of T-cells- I guess I 0:14:32.480,0:14:37.280 should just describe what those actually are. We have different types of white blood cells 0:14:37.280,0:14:44.480 in our body; T-cells are an important type. In this case, what they do is: they help the body 0:14:44.480,0:14:52.800 recognise pathogens or things that we've seen before, by presenting parts of that pathogen to 0:14:52.800,0:15:00.560 our other immune cells that can last much longer in the body and remember them if they appear 0:15:00.560,0:15:08.240 ever again. HIV is essentially infecting these quite important white blood cells in our body. 0:15:08.240,0:15:15.280 What happens then? We've entered the cell. Why is that a problem? How does it cause disease? 0:15:15.280,0:15:21.920 We've entered the cell. Well, there's quite a long process. Initially, when people get infected, 0:15:21.920,0:15:28.160 they have this short term infection — some kind of fevers, flu-like symptoms, 0:15:28.160,0:15:34.640 things like that; and the virus quickly replicates itself, multiplies into many 0:15:34.640,0:15:42.720 copies. Those copies then infect other T-cells. They then go into our lymph nodes, which are 0:15:43.520,0:15:48.160 basically these little hubs of immune activity. There's some in your neck, 0:15:48.160,0:15:52.720 some under your arms, other parts of your body. It infects these different 0:15:52.720,0:16:01.760 immune related tissues and depletes them. And that means that people become more vulnerable 0:16:01.760,0:16:10.240 to all sorts of other infections that are normally mild to people, or just infections in general, 0:16:10.240,0:16:17.600 and some cancers. Our white blood cells are also useful in detecting tumour cells and trying to 0:16:17.600,0:16:25.440 eradicate them. And by depleting those important cells, people also have a higher risk of certain 0:16:25.440,0:16:31.360 cancers. So we have this short-term infection that immediately depletes a lot of our immune 0:16:31.360,0:16:37.200 cells. Eventually, there's this kind of slowdown in how much it replicates, and you get to this 0:16:37.200,0:16:43.440 equilibrium — but that equilibrium is still much worse than if someone hadn't been infected. And 0:16:43.440,0:16:52.800 over a long period of time, this reduction in immune cells means that people are vulnerable to 0:16:52.800,0:16:59.840 various diseases. And as time goes by, they get sicker and sicker from those other infections. 0:16:59.840,0:17:04.560 Before HIV, were there infections that were known 0:17:04.560,0:17:10.960 to cause cancers now something that we're more familiar with, 0:17:10.960,0:17:19.600 but was that connection a surprise and made it harder to figure out what the real cause was? 0:17:19.600,0:17:25.360 HTLV, the first retrovirus that was discovered just two years before that was the first 0:17:25.360,0:17:30.240 pathogen that was clearly causing cancer [in humans]. After that, there were, I mean, 0:17:30.240,0:17:35.280 there've been a bunch of other pathogens that are now known to be cancer-causing. 0:17:37.120,0:17:44.160 One is hepatitis B, which you do a lot of research on; HPV, human papillomavirus, that causes various 0:17:44.160,0:17:52.000 cancers including cervical cancer. There's Helicobacter pylori: this bacterium that causes 0:17:52.000,0:17:58.560 stomach cancer. I think there's more; maybe you remember some others. And there's HTLV. 0:17:58.560,0:18:00.080 Hepatitis C, which causes hepatitis. 0:18:00.080,0:18:02.640 Oh, hepatitis C. That's right. 0:18:02.640,0:18:06.240 Yeah. Those hepatitis viruses are sneaky. 0:18:06.800,0:18:15.760 So coming back to your question: the cancers were the first, I think, surprising thing about 0:18:15.760,0:18:22.400 people who had AIDS. One of the types of cancers that they became vulnerable to was called Kaposi 0:18:22.400,0:18:30.080 sarcoma, which is this tumour. What was surprising about that was: usually doctors who saw patients 0:18:30.080,0:18:37.040 with this type of cancer would see them in quite old- elderly patients, or people with, 0:18:37.040,0:18:41.680 I don't know, severe immune deficiencies and things like that. And in this case, 0:18:41.680,0:18:48.400 they were seeing them in young adults, which was really surprising. They were also quite 0:18:48.400,0:18:53.760 severe cancers: they were hard to treat with the usual treatments that were available. 0:18:54.960,0:19:01.680 And the fact that this was growing in prevalence was also really surprising and worrying to people. 0:19:01.680,0:19:07.360 So I think that was one of the first noticeable kind of warning signs that there was some kind of 0:19:07.360,0:19:16.320 epidemic spreading. It was probably an epidemic disease that was caused by some pathogen. 0:19:16.320,0:19:22.880 I think there were, maybe, a few months or a year or so before people realised that it was probably 0:19:22.880,0:19:30.640 caused by a virus. And I think the reason for that was that there were some cases of people being 0:19:30.640,0:19:38.640 infected through blood transfusion; so they had no other connection to other people with the disease, 0:19:38.640,0:19:44.640 and they had no other environmental risk factors or anything like that. But they had recently had 0:19:44.640,0:19:48.880 a transfusion, or an organ transplant, or something like that, and then suddenly, 0:19:48.880,0:19:55.920 they got infected. And the reason that this links to being a virus is because you can usually filter 0:19:55.920,0:20:05.600 out or purify some of the blood that you're using, or the organs, with filters that get rid 0:20:05.600,0:20:11.760 of bacteria — which are bigger. But that doesn't always work for viruses, which are much smaller. 0:20:11.760,0:20:15.440 So the viruses were getting through and they were still infecting people. And the fact that 0:20:16.880,0:20:21.680 this was infecting people far away, with no other connection, suggested that it was a virus. 0:20:21.680,0:20:25.360 I see. I mean, maybe that's a good point to just talk a bit about 0:20:25.360,0:20:31.280 transmission. So how does the virus transmit? I've got some ideas, but. 0:20:31.280,0:20:37.920 There are different types of modes of transport. One is, as we just talked about, 0:20:37.920,0:20:45.200 blood transfusions and organ transplants. So if there is contaminated blood with HIV, the risk 0:20:45.200,0:20:53.520 of an infection to someone else is quite high. It's some- I was looking at the data from the 0:20:53.520,0:21:00.320 systematic review and they estimate that the risk of infection is about 92% from a transfusion of 0:21:00.320,0:21:06.080 contaminated blood, which is quite high. Mother to child transmission? For mothers who are infected 0:21:06.080,0:21:16.080 with HIV, a quarter of them would pass HIV down to their baby, and this was before treatment 0:21:16.080,0:21:23.440 was available. Now, the chances are much lower if people use antiviral treatments around the time of 0:21:23.440,0:21:31.840 pregnancy and childbirth; but that was obviously very scary. And then there's sexual transmission, 0:21:31.840,0:21:38.880 which is probably the most common route that most people have heard of for HIV. And then, 0:21:38.880,0:21:45.280 finally, injection and drug use; using shared contaminated needles with HIV. 0:21:45.280,0:21:48.560 So before drug development, how come we need drugs? How come the immune system 0:21:48.560,0:21:54.000 doesn't control HIV better? I mean, I have a stereotype that it's extremely hard to control. 0:21:55.040,0:22:00.960 If infection gets established, it's really tough for us. So why is that? 0:22:00.960,0:22:04.560 One really interesting thing that I learned while trying to read 0:22:04.560,0:22:10.560 about this was that HIV is usually caused by a single virus particle, 0:22:11.360,0:22:16.160 and that's one particle replicates enough that it can cause a whole infection. 0:22:16.160,0:22:22.080 You're scaring me, Saloni. That's scary; that's scary. So do you mean that one 0:22:22.080,0:22:28.800 particle entering my bloodstream is all it takes, or you mean something else? 0:22:28.800,0:22:34.400 I actually mean something else. If you look retrospectively at people who have 0:22:34.400,0:22:40.160 HIV — you take a sample of their blood and you look at the different virus particles; 0:22:40.160,0:22:45.360 if you then trace back the genetics of those virus particles, 0:22:45.360,0:22:53.280 you then find that they all have one common ancestor, in around three quarters of cases. 0:22:53.280,0:22:54.240 I see. I see. 0:22:54.240,0:23:01.200 But that doesn't necessarily mean that just one particle is enough to infect someone, because we 0:23:01.200,0:23:07.600 have enough barriers in our immune system. I mean, if you think about a skin infection or something, 0:23:07.600,0:23:14.160 we have our skin, we have several layers of skin. We have immune cells protecting us within our 0:23:14.160,0:23:19.760 body. There are various barriers that prevent a bacterium or something from infecting us, 0:23:19.760,0:23:25.920 and that's the same is true with HIV. So I think what's happening here is that: if you think about 0:23:25.920,0:23:31.040 this from the perspective of probability, there are many barriers, but eventually one 0:23:31.040,0:23:36.560 of them might be able to cross all of those barriers and cause an infection, and if it's 0:23:36.560,0:23:43.600 able to do that, it can replicate very quickly. I think that gets us to why it's difficult to 0:23:43.600,0:23:51.760 control an infection. Even though we do have these barriers, HIV is just very fast at replicating, 0:23:51.760,0:24:00.640 mutating. The reason that HIV can mutate so quickly — it basically becomes really genetically 0:24:00.640,0:24:07.680 diverse within a person who is infected, and that means that our immune cells might be able 0:24:07.680,0:24:15.200 to recognise some of the HIV strains that are in our body, but it's very difficult for it 0:24:15.200,0:24:22.480 to keep up with the rapid evolution and increased diversity. But there are several reasons for that. 0:24:22.480,0:24:30.000 One is the reverse transcriptase enzyme that we talked about that turns RNA into DNA; that enzyme 0:24:30.000,0:24:37.280 is not very precise, and that introduces errors. The errors allow it to potentially get beneficial 0:24:37.280,0:24:45.680 mutations sometimes, and that means that it can genetically diverge. The other is that the HIV 0:24:45.680,0:24:54.160 particle has two copies of RNA inside it, and those two copies can recombine with each other. 0:24:54.160,0:25:01.440 Wait, hold on, hold on, hold on. It comes in with two of the same thing? 0:25:02.160,0:25:04.800 Two of almost the same thing. It has two, 0:25:05.360,0:25:09.760 in the same way that we have two sets of chromosomes in our cells. 0:25:09.760,0:25:13.913 Okay, fair enough. I guess that's true, yes. Oh, wow, okay. 0:25:13.913,0:25:15.760 It has two copies of RNA. 0:25:16.320,0:25:19.580 It's not a double-stranded RNA; they're separate. 0:25:19.580,0:25:25.840 Yeah, that's right. They're two single-stranded RNA viruses, two single-stranded RNA particles; 0:25:25.840,0:25:32.080 and they can get reverse transcribed separately. They can also recombine 0:25:32.080,0:25:39.360 with each other. So I was reading this review paper about how all this worked — why there was 0:25:39.360,0:25:44.880 such rapid mutation — and they said- they were talking about this recombination and they said, 0:25:44.880,0:25:50.040 "This can be considered a primitive form of sexual reproduction." And I was — 0:25:50.040,0:25:55.600 No, no, no, no. This is a virus. If there's one thing I know it's that 0:25:55.600,0:26:02.520 that is too complicated. I don't believe this review paper. Okay. 0:26:02.520,0:26:10.880 Right, that's crazy. And there's a third thing actually, which is that our enzymes introduce 0:26:10.880,0:26:19.520 errors and mutations into HIV. We have this family of enzymes called the APOBEC family; 0:26:19.520,0:26:26.640 they insert mutations into HIV to try to damage it. What they do is: they change 0:26:26.640,0:26:35.520 the G's in our bases, in our DNA, into A; and they do that on a single-stranded DNA particle. 0:26:36.560,0:26:45.360 The HIV virus has these two single-stranded RNA molecules: they get turned into DNA, 0:26:45.360,0:26:50.880 then our enzymes introduce errors into it, by turning some of the G's into A's. 0:26:52.400,0:26:57.760 Just taking a step back, you're saying that the virus itself mutates a lot? So the reverse 0:26:57.760,0:27:04.080 transcription stage introduces errors, and that, actually, in a sense, helps the virus evade our 0:27:04.080,0:27:09.200 immune system. So it is introducing errors that make it hard for us, and then you're saying we 0:27:09.200,0:27:14.720 also are introducing errors that make it easier for us, or rather harder for the virus. So we are 0:27:14.720,0:27:19.040 both sort of fighting fire with fire of: I'm going to make you different, and it's saying, 0:27:19.040,0:27:24.320 no, I'm going to make myself different. And we're in a kind of ratchet situation there. 0:27:24.320,0:27:29.520 Yeah, it's very funny. I learned about this first, actually, 0:27:29.520,0:27:41.280 in 2022, this process, during the Mpox epidemic. I'd just been following the literature — what the 0:27:41.280,0:27:47.520 virologists are working out on the epidemic and so on — and they found out at that point 0:27:47.520,0:27:54.320 that the viruses from Mpox were mutating much faster than expected, than had been seen before. 0:27:55.680,0:28:00.960 And it turned out that the types of mutations that they were seeing, that were happening rapidly, 0:28:00.960,0:28:09.760 were very similar to this, APOBEC- kind of known-mutation change, and that led scientists 0:28:09.760,0:28:18.048 to think: maybe our enzymes are also working on this Mpox virus. So learning about that — 0:28:18.048,0:28:18.076 Oh I see what you're saying. 0:28:18.076,0:28:24.800 — testing that out, helped to figure out: we were introducing errors into the Mpox 0:28:24.800,0:28:31.920 virus very quickly, which made it mutate much faster than usual; and that knowledge helped 0:28:31.920,0:28:38.560 to figure out better when Mpox actually emerged, and when it started to spread. 0:28:38.560,0:28:42.960 Oh, interesting. You can somehow work backwards from that information. 0:28:42.960,0:28:43.920 Right. 0:28:43.920,0:28:50.080 Wow. Okay. Okay. Well, that's it. I am feeling grateful for my immune system; 0:28:50.080,0:28:55.040 has a bunch of tricks I didn't even know about, so thank you, immune system. 0:28:55.040,0:29:01.040 I think, one more thing is, the types of infections and cancers 0:29:01.040,0:29:07.760 that HIV makes people vulnerable to. I think, probably, that's not very obvious to people; 0:29:07.760,0:29:11.760 maybe they've heard of a few of them. So we talked about Kaposi sarcoma, 0:29:11.760,0:29:17.600 there are also a bunch of others. There's PCP, which is this fungal lung infection. There's 0:29:17.600,0:29:25.200 toxoplasmosis, which is this parasitic brain infection. There's cytomegalovirus retinitis, 0:29:25.200,0:29:32.240 that can cause blindness. There's tuberculosis — we already know about tuberculosis, probably, 0:29:32.240,0:29:38.320 most people here know about that — that is the leading cause of death in people with HIV 0:29:38.320,0:29:45.280 worldwide. The reason is that, because of this immune suppression, because of the fact that 0:29:45.280,0:29:52.160 HIV is depleting our immune cells, it makes us more vulnerable to infections like tuberculosis, 0:29:52.160,0:30:00.320 which are often easier to clear for people. And then, some of these are also related — I think 0:30:00.320,0:30:06.800 I talked about a few that were brain infections or that cause blindness — some of these can also 0:30:06.800,0:30:14.160 cause AIDS-related dementias, where people lose their ability to think, and make decisions, and 0:30:14.960,0:30:21.680 generally lose their memory. And then there are a bunch of cancers as well that HIV is associated 0:30:21.680,0:30:29.200 with. As we talked about earlier, some of our T-cells are really important in trying to find 0:30:29.200,0:30:35.440 potentially cancerous cells and eliminating them. If those T-cells are depleted, that makes us more 0:30:35.440,0:30:41.360 vulnerable to cancers continuing to grow. So that includes Kaposi sarcoma, which we talked about, 0:30:41.360,0:30:50.400 and then non-Hodgkin lymphoma, and it also increases the risk of cervical cancer. 0:30:50.400,0:30:54.080 So I think I have a rough understanding of the virus and a rough understanding of 0:30:54.080,0:30:59.040 how it leads to AIDS, and to disease, and opportunistic infections. Maybe quickly, 0:30:59.040,0:31:03.520 where did it come from originally? Where did this virus start out? 0:31:03.520,0:31:11.760 So... this, I think, has had a lot of research go into it, and the likely answer is that it 0:31:11.760,0:31:22.880 came from chimpanzees and gorillas in Central and Western Africa. There are different types of HIV. 0:31:22.880,0:31:28.640 As we talked about, HIV mutates very quickly; creates this huge amount of genetic diversity, 0:31:28.640,0:31:35.120 and that also means that there are multiple different types of HIV. The one that's found 0:31:35.120,0:31:42.480 across the world is called HIV-1. There's also an HIV-2. Both of them are from different 0:31:42.480,0:31:50.720 kinds of primates from Central and Western Africa. And I think the current understanding 0:31:50.720,0:32:03.200 is that HIV one came from a type of chimpanzee somewhere near the southeastern area of Cameroon. 0:32:03.760,0:32:12.080 And probably — so this is interesting: the way that we understand this is by collecting a lot 0:32:12.080,0:32:21.200 of samples of HIV from different people, ideally as early as possible. The earlier the cases are, 0:32:21.200,0:32:28.080 the easier it is to try to estimate where they all came from, or when they converged back in 0:32:28.080,0:32:36.480 history. What was super interesting to me, that I was reading about recently, was that the earliest 0:32:36.480,0:32:48.960 genome of HIV was recovered from someone who died in 1966 in Africa. That's 15 years before the 0:32:48.960,0:32:55.680 first cases were reported. There were definitely cases of HIV before that; probably for decades 0:32:55.680,0:33:02.240 before that. If you use this sample, but also all of the other early samples that we have, 0:33:02.240,0:33:09.040 you can kind of trace back where they have shared ancestry — in the same way that you might be able 0:33:09.040,0:33:16.560 to do with a family tree. If you do that with genomics, you can try to trace back where they 0:33:16.560,0:33:25.360 have similarities, and that suggests that the pandemic originated at the turn of 20th century. 0:33:26.320,0:33:28.720 Hundred years ago. 0:33:28.720,0:33:36.560 Yeah. Well, so we don't have — because the earliest case we have is from 1966, 0:33:36.560,0:33:41.920 that's still not very early, and that means that there's still some uncertainty 0:33:41.920,0:33:46.000 in when it actually originated. There's this uncertainty between, 0:33:46.000,0:33:53.280 so somewhere between 1881 and 1918 is probably around when it first emerged. 0:33:53.280,0:34:00.720 Okay, well, and in humans. So basically, there was this virus that infected other primates, 0:34:00.720,0:34:06.400 chimps; maybe goes back much longer, I don't know if that's known. And then at some point, 0:34:06.400,0:34:10.480 someone was probably hunting a chimp and there was a blood, 0:34:11.120,0:34:20.480 the blood sort of got into their food, or was it, you're eating uncooked chimp or? Oh God. 0:34:20.480,0:34:28.320 That's probably it. So probably through hunting primates and consuming them from the, kind of, 0:34:28.320,0:34:36.080 butchery of that process, and being exposed to their infected body fluids. So the virus that 0:34:36.080,0:34:43.280 infects chimpanzees and other monkeys is called Simian Immunodeficiency Virus rather than human. 0:34:43.920,0:34:44.720 SIM [SIV], okay. 0:34:44.720,0:34:53.120 That, it seems like, has crossed over to humans dozens of times over history. 0:34:53.120,0:34:57.520 As in, since the 1900s? 0:34:57.520,0:34:57.920 In total. 0:34:57.920,0:35:00.400 Okay. Okay. Interesting. I didn't know that. 0:35:01.040,0:35:08.080 And I think there's around four of those "spillover events", is what they're called. 0:35:08.080,0:35:13.520 At least four of those spillover events have led to sustained epidemics that — 0:35:13.520,0:35:13.960 Oh my gosh. 0:35:13.960,0:35:18.160 — people are still infected by today. 0:35:18.160,0:35:25.360 Wow, okay. So it's been with us for a long time, and we haven't known the extent of it so well 0:35:25.360,0:35:32.720 as a species until the more recent epidemic starting in the '80s. Is that a fair summary? 0:35:32.720,0:35:37.040 That is a fair summary. I think, this really reminds me of some of the work 0:35:37.040,0:35:44.480 and writing I do about missing data. I mean, on a lot of topics in health, but 0:35:44.480,0:35:52.160 also in other areas, we tend to have much better data collection and understanding of epidemics, 0:35:52.160,0:36:00.800 but also other diseases, in richer countries, because of the institutions that can collect 0:36:00.800,0:36:12.880 that data. Having the resources and the people to collect that data is not super easy. The fact that 0:36:12.880,0:36:20.560 we know about the first cases of AIDS that had been reported were in the US, is not because it 0:36:20.560,0:36:29.360 started in the US — it's because the US had good detection and disease control research going on. 0:36:29.360,0:36:34.800 Oh yeah. I mean, it reminds me of the extremely frustrating initial COVID graphs, 0:36:34.800,0:36:41.840 where reports of number of cases would actually be number of confirmed cases — vastly different than 0:36:41.840,0:36:48.400 what you could interpolate must be happening in reality. But, you know, whoever gets tested 0:36:48.400,0:36:55.280 ends up getting reported and whoever doesn't doesn't. It can lead to missed inferences. 0:36:55.280,0:36:56.880 Exactly. That's right. 0:36:56.880,0:37:05.120 I feel like we should get to drugs. And as you've described HIV so far, as a drug developer, which 0:37:05.120,0:37:12.960 I've never been yet, but moonlight as in my head, I'm thinking: the different parts you've described 0:37:12.960,0:37:20.480 are each potential targets that I could maybe make a chemical small molecule to interfere with, 0:37:20.480,0:37:27.040 to sort of mess up its lifecycle. I know my immune system's not going to sort it 0:37:27.040,0:37:34.000 out all on its own. So some of those non-human chemicals might be pretty useful too. So firstly, 0:37:34.640,0:37:38.160 is that right? And then, am I thinking about that right? And maybe that means we're going 0:37:38.160,0:37:43.680 to have to go in a bit more detail about the infection cycle, because the virus is going to 0:37:43.680,0:37:51.440 look different at different points and that will maybe give us a clue about what drugs we can make. 0:37:51.440,0:37:57.680 No, exactly. I think, actually, it would be probably easier to think about where 0:37:57.680,0:38:03.760 scientists were at the time, how much they knew, and how they were developing drugs, 0:38:03.760,0:38:07.840 and then we can talk about the broader life cycle of the virus. 0:38:07.840,0:38:12.880 Let's do it. Sounds good. 0:38:12.880,0:38:23.440 So place yourself in the 1980s. This is kind of hard because, as a scientist, you had just found 0:38:23.440,0:38:32.480 out that retroviruses could infect humans. Now you find out that HIV is a retrovirus. You're like, 0:38:32.480,0:38:40.080 wait, I didn't even know that RNA could be turned into DNA until 10 years ago. So that's quite a 0:38:40.080,0:38:47.600 tricky position to be in. At this point, in the early 1980s, there were no antiviral drugs for 0:38:47.600,0:38:57.760 retroviruses. Also, antivirals in total were kind of new. I did not know this before reading about 0:38:57.760,0:39:07.160 it for this episode, but the first antiviral drug of any kind was approved in 1963, which is, again- 0:39:07.160,0:39:10.640 1963, really? Not even flu. We didn't have nothing. That's crazy. 0:39:10.640,0:39:16.880 No, we didn't. We had flu vaccines. We had a bunch of vaccines before that. But the first antiviral 0:39:16.880,0:39:24.960 drug was for treating the herpes simplex virus — infections of the eye — and that was in 1963. 0:39:24.960,0:39:25.680 Wow. 0:39:25.680,0:39:31.760 Also, if you were in the early 1980s, you wouldn't have PCR. PCR is polymerase- 0:39:31.760,0:39:33.263 Of course. Yes, of course. 0:39:33.263,0:39:39.120 -chain reaction, which is used to multiply samples of genetic material so you can study it 0:39:39.120,0:39:46.240 more easily. And that would've been really useful for being able to detect the level of infection, 0:39:46.240,0:39:52.800 and the level of virus in someone. You would be very new to knowing about retroviruses to 0:39:52.800,0:39:56.880 begin with. You wouldn't have any antivirals for them. You wouldn't have a great idea of 0:39:56.880,0:40:03.120 how to even develop antivirals at all. You didn't have PCR, you didn't have 0:40:03.120,0:40:09.200 multi-center trials, so you wouldn't be able to test drugs in multiple hospitals. 0:40:09.200,0:40:09.440 Multi-center? Oh, I see. Got it. Yep, got it. 0:40:09.440,0:40:15.600 You wouldn't be able to test whether people were resistant to the virus, 0:40:15.600,0:40:24.960 through the genetics of the virus, again, because of the lack of PCR testing. And so there was just 0:40:24.960,0:40:32.720 this complete lack of — what are we going to do now? We have no idea. This is super new to us. 0:40:32.720,0:40:39.760 I think a lot of people at the time might've thought it's impossible to treat this disease. 0:40:39.760,0:40:46.320 It's so new, it's so different. How are we gonna make any progress on it? 0:40:46.320,0:40:50.240 You don't have a proof point you can hang your hat on. 0:40:50.240,0:40:52.000 That's right. 0:40:52.000,0:40:55.200 Very... yeah, the unknown beckons. 0:40:55.200,0:41:02.320 And so again, I was trying to find retrospective written by someone who works in this field, 0:41:02.320,0:41:06.800 and I found one that was really interesting by Samuel Broder. 0:41:06.800,0:41:13.760 He was one of the scientists who developed AZT, the first HIV drug. 0:41:13.760,0:41:14.260 AZT. 0:41:15.120,0:41:21.440 His team found that it was effective against HIV. They also developed various other drugs 0:41:21.440,0:41:29.360 against it. And he wrote this retrospective on how they discovered the first antivirals and 0:41:29.360,0:41:34.480 how pessimistic people were at the time — that it was possible to make any treatments against 0:41:34.480,0:41:43.760 it. So maybe a bit of background on who he was. Samuel Broder was this cancer and immunology 0:41:43.760,0:41:51.360 researcher at the National Cancer Institute in the US. And this itself is quite interesting. 0:41:51.360,0:41:57.200 You're thinking HIV, this is an infectious disease. But the people who were studying it, 0:41:59.040,0:42:03.760 who made these first effective antivirals, were cancer researchers. 0:42:03.760,0:42:10.800 So he was part of the NIH, the division that works on cancer. And so he was employed by 0:42:10.800,0:42:17.360 the US government and had a lab in the cancer part. And okay, got it. Keep going. 0:42:17.360,0:42:21.920 So I think the reason that he was working on it was, as I said, 0:42:21.920,0:42:28.480 the first thing that was noticed in AIDS patients, that was surprising to people, was Kaposi sarcoma, 0:42:28.480,0:42:35.600 this type of cancer of the skin. And so he was trying to figure out what was going on here. 0:42:37.520,0:42:46.960 I read this book about the drug development in HIV and AIDS called How to Survive a Plague. And 0:42:46.960,0:42:55.840 there they describe this period very humorously to me. I mean, it's obviously not humorous, 0:42:55.840,0:43:02.960 but the way that they say it, was that he was really excited to see this first HIV 0:43:02.960,0:43:09.920 patient come to the National Cancer Institute. He saw it as this once-in-a-lifetime scientific 0:43:09.920,0:43:15.840 challenge that brought together two of his interests of immunodeficiency and cancer. 0:43:15.840,0:43:22.160 And they thought, if we're able to crack this, this is going to be really important. 0:43:22.160,0:43:32.080 So I think the first thing they noticed was the virus was probably infecting CD4 T-cells. 0:43:32.080,0:43:38.320 The reason that they thought this was one of the first signs that you would see in someone who was 0:43:38.320,0:43:46.720 infected was that their T-cell count would drop. They at least had some blood testing and they had 0:43:46.720,0:43:53.280 some of the tools and technology to measure CD4 T-cells at the time. So they knew that there's 0:43:53.280,0:43:59.520 this massive drop, and they thought maybe it's because the virus is multiplying in these cells. 0:43:59.520,0:44:02.000 Seems like a link to make. 0:44:03.280,0:44:07.840 So they thought, okay, let's — we've hypothesised that the virus is replicating 0:44:07.840,0:44:14.960 in these cells — maybe we should test compounds to interrupt this process, to prevent it from 0:44:14.960,0:44:22.720 replicating in these CD4 T-cells. And so he then approached different pharmaceutical firms to try 0:44:22.720,0:44:28.720 to get funding to work on this project, and also to potentially commercialise a drug if 0:44:28.720,0:44:37.280 they found one. I think he approached several firms. Most of them said no, but one of them 0:44:37.280,0:44:43.989 said yes. And that company was Borroughs Wellcome. So we probably haven't heard of- 0:44:43.989,0:44:47.760 Yes, which now has a philanthropy, Burroughs Wellcome fund. 0:44:47.760,0:44:53.920 And this was a pharmaceutical firm that no longer exists. It was merged into what became 0:44:53.920,0:45:00.560 GSK or GlaxoSmithKlein, and they were the only company at this time that were willing 0:45:00.560,0:45:10.400 to consider funding or commercialising HIV drugs. But they were very afraid that their 0:45:10.400,0:45:17.200 researchers or their scientists would get infected with stab that people were 0:45:17.200,0:45:22.400 working with. So they refused to work with these live virus samples, and they said- 0:45:22.400,0:45:22.960 Oh my god. 0:45:22.960,0:45:26.960 -nope, you've got to work on it yourself. They were saying this to Samuel Broder and 0:45:26.960,0:45:33.600 his team. And so Samuel Broder's team had to do all of the screening of these drugs, 0:45:33.600,0:45:39.280 running the trials all on their own, despite Burroughs Wellcome 0:45:39.280,0:45:44.312 then getting the credit for it, and then being able to commercialise it. 0:45:44.312,0:45:51.440 Oh god. Well, it reminds me of streptomycin, the first TB drug, where there was Albert Schatz, 0:45:51.440,0:45:56.640 the PhD student, and Waxman, what was his first name? Henry Waxman, something? Waxman- 0:45:56.640,0:45:57.760 Selman Waxman. 0:45:57.760,0:46:03.760 Selman Waxman, there we go, the professor who then got the Nobel Prize. They didn't 0:46:03.760,0:46:06.400 share it in the end, did they? I don't know. I'm going to forget the story. 0:46:06.400,0:46:12.000 They didn't share it. I also read the story because I was writing about antibiotics, 0:46:12.000,0:46:15.440 and it was really interesting, because he 0:46:15.440,0:46:20.640 discovered this group of bacteria that produced antibiotics, right? 0:46:20.640,0:46:22.080 Right, in soil? Yeah. 0:46:25.120,0:46:29.200 It's so weird to think about bacteria that are producing antibiotics, but basically they're 0:46:29.200,0:46:36.240 producing it to compete with other bacteria. And somehow he found that this specific type, 0:46:36.240,0:46:41.120 or this group, of bacteria were producing a lot of antibiotics. He thought, okay, maybe there's 0:46:41.120,0:46:45.920 something there. They seem to be killing the other bacteria around them, maybe we could use that as a 0:46:45.920,0:46:51.600 treatment for our own bacterial infections. And he started to recruit PhD students to 0:46:51.600,0:46:56.231 work on that. One of them was Albert Schatz. And what was really interesting about this- 0:46:56.231,0:46:58.000 This was Second World War era, right? 0:46:58.000,0:47:04.640 This was during the Second World War. Well, the 1930s, I think, and he had Albert Schatz start 0:47:04.640,0:47:11.989 to work on this project in a basement's room that he never, I think, Waxman never visited. 0:47:11.989,0:47:16.400 He's like, try this out on some TB, I'll be upstairs. 0:47:16.400,0:47:19.360 And so Schatz was working on this, 0:47:19.360,0:47:24.320 and then what was really strange was that Schatz was drafted into war! 0:47:24.320,0:47:24.880 Oh, yes. 0:47:24.880,0:47:30.800 And the project, basically, was on pause for a few months. Apparently 0:47:30.800,0:47:33.754 he then got a back injury and then was sent home. 0:47:33.754,0:47:34.880 Thank goodness! 0:47:34.880,0:47:37.920 And thank goodness, he discovered streptomycin. 0:47:37.920,0:47:38.720 Wow. 0:47:38.720,0:47:41.440 That was the first, I think, first antibiotic compound that was found 0:47:41.440,0:47:45.920 from this type of bacteria, which is called actinomycetes, 0:47:45.920,0:47:52.240 and that group also led to the discovery of various other antibiotics. 0:47:52.240,0:47:59.120 Okay. Well, Albert Schatz, legend. Grad students have been abused for decades, it turns out. And 0:47:59.840,0:48:04.880 I guess, back to HIV, which we are currently dealing with, it sounds like a very virtuous 0:48:04.880,0:48:09.120 academic group. And I don't want to insult Burroughs Wellcome. I'm very glad they brought 0:48:09.120,0:48:14.720 this to market. So kudos that there was at least one company willing to stand up. So maybe I'll 0:48:14.720,0:48:20.400 reserve my vitriol in case there are other bad forces I need to get mad at, later in the story. 0:48:20.400,0:48:25.040 Well, yeah. So this is also not quite as similar 0:48:25.040,0:48:30.480 because I think Schatz and Waxman then got into this big fight. 0:48:31.120,0:48:36.720 Yeah, I remember this, yeah. And Waxman was withholding royalties from Merck or yeah. 0:48:36.720,0:48:40.000 There was something like that. But in this case, 0:48:40.000,0:48:45.360 I think they seem to work together fine. In this case, in Samuel Broder's team, 0:48:45.360,0:48:50.800 there were a few scientists who were really involved in this. One was Hiroaki Mitsuya, 0:48:50.800,0:48:58.880 and he was doing the day-to-day research on potential drugs that could work against HIV. 0:48:58.880,0:49:05.360 And I said, day to day, but actually they were doing this research in the night, after the other 0:49:05.360,0:49:11.584 colleagues at the National Cancer Institute went home, because apparently they were also afraid- 0:49:11.584,0:49:11.600 Oh my gosh. Wow. 0:49:11.600,0:49:19.520 -of potentially being contaminated or getting infected. Also, there was another 0:49:19.520,0:49:31.280 scientist called Robert Yarchoan. So these two scientists tested over 180- well, okay, 0:49:31.840,0:49:37.040 let's back up to what we said before. You're in the 1980s, you have no idea how to tackle 0:49:37.040,0:49:43.280 this disease. You have various reasons to doubt whether you can even develop a treatment at all. 0:49:43.280,0:49:47.440 And the only clue that you have at this point, really, is that it infects CD4 0:49:47.440,0:49:55.680 T-cells. So that probably helps you to test things in a lab. You can probably test how 0:49:55.680,0:50:01.680 these different drugs affect HIV's ability to infect these CD4 T-cells, but you don't really 0:50:01.680,0:50:08.160 have anything else to go on. So what would you do? And the thing that they did was, 0:50:08.160,0:50:13.360 they just tried anything. They just tried any drug compounds that they had. 0:50:14.320,0:50:20.960 So Mitsuya tested over 180 different compounds and they would be coded with different code names, 0:50:21.520,0:50:28.080 and you would ask people for whatever they thought might be potentially effective. 0:50:28.960,0:50:33.920 So there's no unifying hypothesis per se, it's more like, ask around, see what people think might 0:50:33.920,0:50:40.160 work, see what you have lying in the fridge at the cancer institute, that kind of thing? 0:50:40.160,0:50:44.480 Well, even if you did have hypotheses, many of them would just turn out to 0:50:44.480,0:50:47.760 not work and then you would have to try something else. So okay, 0:50:47.760,0:50:52.720 there were a bunch of hypotheses, but there were also just, let's just see what happens, 0:50:52.720,0:50:57.360 let's just use this trial-and-error kind of approach and see if anything works. 0:50:58.000,0:51:03.360 Well, now I think about high-throughput screening where you screen hundreds of thousands, 0:51:03.360,0:51:07.600 sometimes more, drug candidates or molecules all at once. Should 0:51:07.600,0:51:13.840 I be visualising that, or that comes much after, and we're dealing with hundreds? 0:51:13.840,0:51:20.880 Well, yeah. So I think this might've been before high-throughput screening became much more 0:51:20.880,0:51:27.120 popular. This is probably early days where you're doing this one at a time. You have these different 0:51:28.080,0:51:33.920 cultures of the virus in the lab and you're just testing out random drugs, one for each 0:51:33.920,0:51:40.000 one or whatever, and maybe you have a bunch for each one, just to see if it's really working. 0:51:40.000,0:51:47.040 And at one point they find this one little vial, or a bottle, with something called 0:51:47.040,0:51:55.360 "compound S" — so that's the code name — and that somehow seems to keep the infected cells alive. 0:51:55.360,0:52:05.680 So this was a real breakthrough and this compound turned out to be AZT, or azidothymidine. What was 0:52:05.680,0:52:11.680 this compound? This was a compound that already existed, and it was developed in the 1960s — in 0:52:11.680,0:52:20.960 1964 — by another cancer researcher called Jerome Horwitz. And I had found- I was trying to look up, 0:52:20.960,0:52:27.440 who was the discoverer of each important antiviral in HIV? And I found this name, and I thought, 0:52:27.440,0:52:31.360 okay, well let me try to find a retrospective written by him and I couldn't find one. 0:52:32.240,0:52:38.480 And the reason was that, when he was working on this in the 1960s, he was developing this 0:52:38.480,0:52:44.800 as a potential cancer drug. He had this idea that — if you think about cancers, 0:52:44.800,0:52:50.480 the thing that people know about cancers is they grow quickly. They have these tumours 0:52:50.480,0:52:55.360 and the tumours grow quickly, and the way that they do that is by replicating; 0:52:55.360,0:53:04.000 they need to replicate their DNA in order to divide. So his idea was, if you have the DNA code, 0:53:04.000,0:53:13.280 and the DNA code is duplicated by adding these bases one at a time, by our enzymes, 0:53:13.280,0:53:21.600 into this longer DNA structure. What if, instead of a normal base, you had a fake base that was 0:53:21.600,0:53:30.360 kind of like a normal base except it didn't allow any more bases to join to it. And so he found- 0:53:30.360,0:53:31.120 Sounds clever. 0:53:31.120,0:53:40.720 -a compound that, it essentially was this type of fake base — di-deoxynucleoside. And he thought, 0:53:40.720,0:53:44.720 okay, maybe this is going to stop the cancers from growing. But it turned out, 0:53:44.720,0:53:50.800 it didn't work for cancer, and he was so disappointed with it that he apparently 0:53:50.800,0:53:56.160 threw away his lab notes — essentially just trashed it and forgot about it; 0:53:56.160,0:54:01.760 didn't even apply for a patent. So it was just in the National Cancer Institute, 0:54:01.760,0:54:07.280 where he also worked, and it was just there as one of the compounds that had been developed. 0:54:07.280,0:54:11.520 Don't throw away your lab notes. Don't throw away your lab notes. But I'm glad 0:54:11.520,0:54:17.520 he didn't throw away the samples? That sounds great to me. I'm happy. 0:54:19.200,0:54:25.360 We said that the AZT — this new compound — it was able to mimic 0:54:25.360,0:54:32.640 the bases in our DNA. So why did it work for HIV, but not for cancer? 0:54:32.640,0:54:38.880 That's something I don't know. But what it does here is almost the same process. When 0:54:38.880,0:54:47.200 HIV's reverse transcriptase is turning the RNA into DNA, so that it can integrate into our own 0:54:47.200,0:54:53.920 genome, it introduces this fake base, which blocks the chain from getting longer; 0:54:53.920,0:55:00.960 it blocks the rest of the DNA from forming, and that halts the virus's replication. 0:55:00.960,0:55:03.400 That's epic. Go AZT. 0:55:03.400,0:55:10.400 Super interesting. Yeah, it was just, I think it's this trial-and-error approach that sometimes 0:55:10.400,0:55:16.800 works. What's really useful about things like this is that, once you do find a compound that works, 0:55:16.800,0:55:24.480 you can then try to make modifications that create new related drugs that you now will 0:55:24.480,0:55:29.760 hope will also work. That is possible because if there's something about the structure that 0:55:29.760,0:55:34.480 is allowing it to have this function, then making these different modifications could 0:55:34.480,0:55:39.520 lead to additional compounds, or maybe it could make it more effective, or more safe in some way, 0:55:39.520,0:55:45.200 and so you could now have this wider range of compounds that you can work with. 0:55:45.200,0:55:53.360 And my stereotype of AZT is that it was not very safe, in the sense of, many side effects? 0:55:53.360,0:56:00.000 That's right. Yeah, I mean, I think if you were a patient at the time, 0:56:00.000,0:56:09.520 you would still see it as much better than the prospects of a continued progression of HIV, 0:56:09.520,0:56:19.360 but it was pretty toxic. It affected people's bone marrows, it led to anaemia; also just made them 0:56:19.360,0:56:26.720 feel quite physically weak in some ways. But it did clear out some of the virus from their bodies; 0:56:26.720,0:56:33.680 it restored their immune function, it cleared infections. One interesting thing I read was 0:56:33.680,0:56:41.760 that it, surprisingly, also reversed some of these AIDS-related dementias that I mentioned. 0:56:42.480,0:56:48.880 Because those dementias were actually caused by infections, if you can clear some of the HIV, 0:56:48.880,0:56:55.280 which is reducing your immune function, which was previously suppressing these infections — if you 0:56:55.280,0:57:02.080 can, kind of, revert that immune depletion, then you can now fight off these infections 0:57:02.080,0:57:09.760 that caused brain dysfunction and so on. This was really astonishing, I think, 0:57:09.760,0:57:15.120 according to Samuel Broder, to the doctors who saw people who were being treated with 0:57:15.120,0:57:19.600 AZT at the time — they were genuinely shocked that this was even possible. 0:57:19.600,0:57:26.160 And we went from not knowing if any antiviral was going to be possible to... you're actually 0:57:26.160,0:57:35.200 seeing as a doctor people reverse even some of the cognitive effects. What a time. 0:57:35.200,0:57:41.040 What a time, yeah. And also, the other downside was, not just the side effects, 0:57:41.040,0:57:47.680 but this drug seemed to work for at least a few months in people, and then they would start to get 0:57:47.680,0:57:54.720 worse again, and the reason was that HIV would find a way to evade the action of this drug. 0:57:54.720,0:58:01.520 Because it was mutating so quickly, it was able to find ways to either get rid of this drug, or to 0:58:01.520,0:58:09.200 develop certain changes in its proteins that would mean that the drug was no longer able to work. 0:58:09.760,0:58:17.360 So that rapid mutation that made it so hard for our immune system to operate against HIV, 0:58:17.360,0:58:24.160 now is making it hard for AZT to durably operate against HIV. 0:58:24.160,0:58:27.520 But it was really important because it was the first 0:58:27.520,0:58:32.720 drug. It was a drug against a disease that people thought was untreatable. 0:58:32.720,0:58:33.040 Yes, totally. 0:58:33.040,0:58:39.600 And this completely shifted the perception of the disease. Samuel Broder has this line 0:58:40.640,0:58:45.520 in his retrospective review where he says, "The question at that point was no longer 0:58:45.520,0:58:51.680 whether HIV-1 could ever be successfully treated, but rather how fast more therapies 0:58:51.680,0:58:58.880 could be developed." And their drug, AZT moves from research in the lab to drug 0:58:58.880,0:59:03.920 approval within just two years, and this is partly a result of how the trials work, 0:59:03.920,0:59:09.200 but it's also partly because of activism around trying to make it available quickly. 0:59:09.200,0:59:12.560 I mean, it's... that's both so inspiring and 0:59:12.560,0:59:20.720 so infuriating. So when was AZT available, did you say? In 19-? 0:59:20.720,0:59:22.720 I think 1987. 0:59:22.720,0:59:27.600 1987, okay, so from 1981 to 1987. If the clock starts at 1981, 0:59:27.600,0:59:31.920 when HIV was discovered; if there had been more energy earlier, 0:59:31.920,0:59:41.440 more funding, more support, if it only took two years once you started investigating... 0:59:41.440,0:59:42.623 It is really frustrating. 0:59:42.623,0:59:44.720 Anyway, I should celebrate it was two years, but... 0:59:44.720,0:59:51.840 It's really frustrating because, so I have been reading this book, the audiobook version, 0:59:51.840,1:00:00.160 of How to Survive a Plague by David France, which is this amazing, very well written book on drug 1:00:00.160,1:00:07.840 development. "How scientists and activists came together to treat AIDS" is the tagline, I think. 1:00:08.960,1:00:20.320 It starts, I think, in 1981, and it's genuinely so depressing to read it — obviously — for several 1:00:20.320,1:00:26.800 years. You're getting through this book, and you're just so frustrated with how slow people 1:00:26.800,1:00:32.160 are; how unresponsive, how much they don't treat it as an urgent problem — even when 1:00:32.160,1:00:38.800 it's clearly an epidemic disease that's growing exponentially over time. That people are just 1:00:38.800,1:00:44.400 unwilling to consider that there are potential treatments out there, or they're in these petty 1:00:44.400,1:00:50.080 arguments with each other about what we should be doing. Should we be saying enough? Are we scaring 1:00:50.080,1:00:56.800 people by telling them that this is a deadly disease? And so on. And it was just, it was really 1:00:56.800,1:01:00.400 frustrating to read. It was a very well-written book, but it was very frustrating to read. 1:01:01.280,1:01:08.080 I remember I read "And The Band Played On" by Randy Shilts covering some of the initial 1:01:08.080,1:01:14.080 years and had the same experience — just a very, very tough read. 1:01:14.080,1:01:21.120 But I think one interesting thing about Samuel Broder and the, kind of, cancer approach to 1:01:21.120,1:01:27.680 studying HIV is that, I think, — so we said that the reason that they were studying this 1:01:27.680,1:01:32.800 was because of Kaposi's sarcoma, which was one of the cancers that HIV made people more 1:01:32.800,1:01:38.320 vulnerable to. But I actually think that being a cancer researcher was probably the right mindset 1:01:38.320,1:01:43.360 that you needed to have, as a scientist, if you wanted to develop drugs against HIV. 1:01:44.560,1:01:49.920 One reason for that was, cancer research at the time, they were, I think, 1:01:49.920,1:01:57.280 the only group in the NIH that were experienced with drug development. But the other was just: 1:01:57.280,1:02:03.360 you're facing this horrible disease that's very rapidly progressing, 1:02:04.000,1:02:11.200 similar to cancer. You're also in the situation where action is much more important than inaction, 1:02:11.200,1:02:16.320 because it's just going to get worse. You're also in the situation where you're willing to 1:02:16.320,1:02:25.600 take drugs that have toxic side effects, even if that, because they might be able to slow down the 1:02:25.600,1:02:31.520 disease, and that's more important right now, because the disease progression is so deadly. 1:02:32.080,1:02:39.280 But I think the next thing is, because you would realise that what was really important 1:02:39.280,1:02:46.640 here was not just using a single drug. Just like with cancer, just like the connection to Jerome 1:02:46.640,1:02:53.200 Horowitz, who discovered AZT, who was also a cancer researcher, you would know that cancer 1:02:53.200,1:02:59.840 and HIV were rapidly able to evolve to mutate and develop resistance against any drug that 1:02:59.840,1:03:07.040 you developed. So the aim would not be to develop a single drug, but to use a combination of drugs, 1:03:07.040,1:03:13.760 and that was the goal that these researchers had even in the 1980s, even though they developed 1:03:13.760,1:03:20.480 AZT — it did work, but people eventually started to develop resistance against it, 1:03:20.480,1:03:24.468 but that was okay from their perspective because they knew that this was not the end goal. 1:03:24.468,1:03:25.426 This is the beginning. 1:03:25.426,1:03:29.040 It was not to develop one drug, we had to develop many. 1:03:29.040,1:03:33.920 We have to develop many. Not just because they're going to get used 1:03:33.920,1:03:37.840 one by one and then become resistant, but to use in combination from the beginning. 1:03:37.840,1:03:42.240 So they were thinking that way from the beginning. Yeah, okay. 1:03:42.240,1:03:50.080 Yeah, I mean this was so interesting to me just as a 'how to develop drugs', what is the 1:03:50.080,1:03:54.800 mindset that's required? What is the type of approach you use? Of just trying everything, 1:03:54.800,1:03:59.600 essentially having different hypotheses, just seeing what works. I thought it was really 1:03:59.600,1:04:07.200 interesting to read about. This, I think, then spurred a lot of other pharmaceutical firms and 1:04:07.200,1:04:12.400 researchers to work in the area to develop other types of drugs. Samuel Broder's team 1:04:12.400,1:04:20.720 then developed a bunch of other similar drugs. We just talked about AZT, which is a type of 1:04:20.720,1:04:29.440 nucleoside reverse transcriptase inhibitor, NRTI, and as we said, it's a drug that is this "mimic", 1:04:29.440,1:04:36.160 or this fake, version of a nucleoside base of the DNA molecule of HIV. 1:04:36.160,1:04:41.280 Let's pause there, and let me see if I can remember everything I just learned. 1:04:41.280,1:04:48.320 So I am putting myself in the headspace of a drug developer who doesn't have the tools of 2025, 1:04:48.320,1:04:55.840 when we're recording today. And there's quite a few tools I don't have. I don't have PCR. 1:04:55.840,1:05:00.320 I don't have, and don't have modern genomics. I probably don't have high 1:05:00.320,1:05:05.920 throughput screening. I definitely don't have knowledge of what HIV looks like, in terms of, 1:05:07.760,1:05:14.720 visually as a 3D structure — that's probably far away. And I don't really know the whole 1:05:14.720,1:05:18.880 process of the lifecycle of the virus. But what I do know is that, probably, 1:05:18.880,1:05:24.160 CD4 T-cells are implicated, because I'm seeing these counts drop. I've taken blood samples, 1:05:24.160,1:05:29.760 and those counts are not looking so good for patients. And what I do know is that, if I 1:05:29.760,1:05:34.480 rummage around, there are going to be some failed cancer drugs somewhere that I can at least try. 1:05:34.480,1:05:40.880 And so, sure enough, and because well, in addition, if I'm a cancer researcher, 1:05:40.880,1:05:48.080 I think about resistance and I think about combination drugs. So what I'm going to do is, 1:05:48.080,1:05:55.520 I'm going to go around and try a bunch of stuff. I mean, my takeaway from this is, it was just 1:05:55.520,1:06:03.760 incredibly empirical. You didn't have much in the way of theory, beyond the CD4 implication, 1:06:04.880,1:06:12.640 link, and you would try and stuff, and a bunch of stuff probably did not work, and then guess what? 1:06:12.640,1:06:21.200 One thing did work, and that gave everyone some hope, and changed things going forward. 1:06:21.200,1:06:27.120 Yeah, I mean, it's so amazing to read about drug development during that time and what 1:06:27.120,1:06:32.240 happened after that, as well. So maybe this is the time to actually talk about 1:06:32.240,1:06:41.030 the HIV life cycle and what the other types of drugs that have been developed are. And so... 1:06:41.030,1:06:41.040 I'm ready. 1:06:41.040,1:06:46.160 We should start with how an infection happens, at a molecular level. 1:06:46.160,1:06:46.560 Great. 1:06:46.560,1:06:52.320 So we have the HIV virus particle. I don't know if people have seen an 1:06:52.320,1:06:58.960 image or diagram or something of HIV, but essentially it has this- 1:06:58.960,1:07:04.080 I'm holding up my hands for people watching the video. Does this look right? 1:07:04.080,1:07:11.840 That looks right. So this is a spherical particle, it has a bunch of proteins coming out of it, 1:07:11.840,1:07:22.320 and inside the spherical particle is a bunch of stuff including a capsid. This capsid is 1:07:22.320,1:07:30.073 the core of the HIV virus. You can think of it as looking — oh wow! Is that an actual-? 1:07:30.073,1:07:35.440 I just picked up something to mislead people. It's a sun-bleached version of a vaccine, 1:07:35.440,1:07:39.920 but that mimics a viruses structure, so that you can present to the immune system. 1:07:39.920,1:07:44.240 This is a COVID vaccine that the Institute for Protein Design made. 1:07:44.240,1:07:45.840 Wait, can you hold it up to the camera? 1:07:45.840,1:07:52.720 Yeah, oh yes, I'm looking at it for myself. Anyone watching the video here: this looks like a virus, 1:07:52.720,1:08:01.040 it is not a virus. It presents the receptor binding domain of the spike protein of COVID, 1:08:01.040,1:08:06.480 or SARS-CoV-2, to the immune system on lots of different places so you can get antibodies that 1:08:06.480,1:08:11.920 bind. It doesn't look that far off. I mean, it's better than when I held my hands up, so. 1:08:11.920,1:08:13.440 It looks kind of cute, also. 1:08:13.440,1:08:15.040 It is cute. It is cute. 1:08:15.040,1:08:23.760 I had a stuffed toy version of the coronavirus that I got from this museum, 1:08:23.760,1:08:27.600 and I thought it would be really funny to get this as a gift, 1:08:27.600,1:08:32.160 and then to give it to someone and say, Ha! I've given you COVID. 1:08:32.160,1:08:38.240 You know, it's crucial to get good bits in, so I support. 1:08:38.240,1:08:48.480 So the HIV virus, you showed this spherical particle. We have this envelope that is a sphere, 1:08:48.480,1:08:54.960 and then it has some protein sticking out of it. Inside it, it has a capsid. The capsid sort 1:08:54.960,1:09:02.720 of looks like a thimble, or maybe more like a bullet. This kind of interesting because 1:09:02.720,1:09:08.720 the bullet — or the capsid — contains a bunch of the really important stuff, for the virus. 1:09:08.720,1:09:15.280 It contains the RNA molecules that's its genetic code. It also contains a bunch of other enzymes 1:09:15.280,1:09:20.240 that it needs to do important stuff, including reverse transcriptase, which it needs to turn its 1:09:20.240,1:09:29.440 RNA into DNA, and a bunch of other enzymes that we'll come to. We have this HIV virus particle, 1:09:29.440,1:09:34.160 this spherical thing with the protein sticking out of it. One of those proteins is called 1:09:34.160,1:09:44.880 GP-120. That protein — when the virus gets into our body, it targets our white blood cells, 1:09:44.880,1:09:56.880 our T-cells primarily, and this GP-120 protein attaches to a CD4 receptor on our T-cells. 1:09:56.880,1:09:57.440 Got it. 1:09:57.440,1:09:59.200 They get attached. 1:09:59.200,1:10:05.840 So the virus is currently outside of the cell, and it attaches to CD4 on the outside. 1:10:05.840,1:10:10.400 Then, it starts to also attach to another protein, 1:10:11.120,1:10:23.920 CCR5 or CXCR5. There's a — initially, it starts by infecting CCR5 T-cells. It uses these two 1:10:23.920,1:10:32.720 receptors, it binds to these two receptors, and then it injects itself into our cells. 1:10:32.720,1:10:38.720 So it binds to two proteins on the outside of the cell; it uses that as a way to get inside. 1:10:38.720,1:10:46.560 So it fuses with our cell membranes. Inserts the contents of this HIV 1:10:46.560,1:10:53.200 virus into our cells. That includes the capsid, the bullet, the bullet-like thing. 1:10:53.200,1:10:53.440 Bullet 1:10:53.440,1:10:58.800 But actually, I think a really good analogy, maybe, is like a rocket. You know how, when a 1:10:58.800,1:11:07.680 rocket launches, most of it falls off, but there's this core part of the rocket that continues going. 1:11:07.680,1:11:14.160 Right, and usually that's something I like because it contains astronauts. In this case- 1:11:14.160,1:11:14.960 It's not. 1:11:14.960,1:11:22.080 I don't like it. I don't like it. So instead of space, we're now in the cytoplasm. 1:11:22.080,1:11:28.320 That's right. So we're now in the cytoplasm — the inside of the cell. At this point, 1:11:28.320,1:11:36.800 the capsid then makes its way to our cell's nucleus. This was really interesting, 1:11:36.800,1:11:41.920 because we found out — so I had watched this video to try to understand what was going on, 1:11:41.920,1:11:46.560 what was the pathway? I feel like videos kind of help me remember things better, 1:11:46.560,1:11:53.920 and this video was from 2010, I think. Then I started reading about this process separately, 1:11:53.920,1:11:58.160 in research papers, and they described it differently. And it turned out that 1:11:58.160,1:12:05.760 our understanding of this life lifecycle has actually changed in the last five years, right? 1:12:05.760,1:12:15.280 Yes. I actually talked to a friend who did her PhD, who I think graduated in 2018, and did 1:12:15.280,1:12:24.960 her PhD on the HIV capsid. And she was saying to me, oh, back when we were doing it back in 2018, 1:12:24.960,1:12:34.080 all those centuries ago, we actually didn't yet know that the capsid, at least sometimes, 1:12:34.080,1:12:40.960 makes it all the way intact into the nucleus! I was like, what? But that's so basic, 1:12:40.960,1:12:48.640 that's the whole game. It turns out no, even now, we are getting tools that are making it 1:12:48.640,1:12:54.320 easier to actually see what the heck is going on inside these incredibly busy cells. And yeah, 1:12:54.320,1:12:59.520 it's makes you wonder, if you do your PhD in five years? What the heck are we going to know now? 1:12:59.520,1:13:06.000 I mean, I think one of the reasons for this is that, it's really hard to observe an infection 1:13:06.000,1:13:12.560 happening. It's obviously very harmful and probably very unethical to infect someone 1:13:13.120,1:13:19.840 directly with HIV, if you wanted to study what happens in this early part. The people with HIV, 1:13:19.840,1:13:24.240 that have been part of research, have obviously been much further along than 1:13:24.240,1:13:29.120 just being infected. So it's hard to actually study those earliest stages, 1:13:29.120,1:13:33.680 and that's especially true because HIV doesn't infect other animals. 1:13:33.680,1:13:40.560 The closest that we could use is SIV — simian immunodeficiency virus — which is slightly 1:13:40.560,1:13:46.960 different. That means that there are various things about this early stage that, I think, 1:13:46.960,1:13:54.480 weren't very clear. And I think that the change in the last few years was better microscopy. 1:13:54.480,1:14:02.560 That is what my friend was basically saying. She was saying, before we had 1:14:03.120,1:14:09.200 cryo-electron microscopy, we just couldn't visualise things as well. She was using other 1:14:09.200,1:14:15.280 techniques to do her best, and now you have this atomic resolution of these systems that 1:14:15.280,1:14:21.520 we haven't ever seen. I mean, it's beautiful. You can actually see what's happening. We never knew. 1:14:21.520,1:14:22.320 Yeah, 1:14:22.320,1:14:28.640 It's genuinely crazy. I mean, like, I've been reading about vaccine development; 1:14:28.640,1:14:33.840 biology over the 20th century, and what is really surprising to me is that — we didn't have 1:14:33.840,1:14:41.680 any way to visualize viruses until the 1930s. Before that- so we have the smallpox vaccine, 1:14:41.680,1:14:46.080 which is against a virus, but this is before anyone knows what viruses are; 1:14:46.080,1:14:52.320 that's before germ theory was developed. We just happened to get quite lucky with observation 1:14:52.320,1:15:00.080 and testing. But it's only in the 1930s that we actually got this ability, this type of new 1:15:00.080,1:15:06.080 microscopy technique called "electron microscopy" that allowed us to see things at the resolution 1:15:06.080,1:15:13.920 that would let us see viruses that are much smaller than other bacteria, parasites and so on. 1:15:13.920,1:15:17.440 Okay, we're getting too excited, and we need to focus on the lifecycle. I can tell, 1:15:17.440,1:15:20.000 I can tell, I can tell. Because right now, I'm a capsid and I'm 1:15:20.000,1:15:22.720 about to enter the nucleus. I'm in the nucleus. What's happening after that? 1:15:22.720,1:15:30.240 Okay, so let's recap. So the virus attaches to the cell with GP120, it attaches to CD4 1:15:30.240,1:15:38.160 and CCR5. It inserts itself, fuses with our cell membrane, inserts its content into our 1:15:38.160,1:15:44.080 cells. That includes the rocket, or the rocket core, or the capsid, or the bullet, 1:15:44.080,1:15:53.280 whatever. That capsid makes its way to our cell's nucleus. It then actually gets inside 1:15:53.280,1:16:02.400 the nucleus. So our nucleus has these entry points, which are called pores, and the capsid 1:16:02.400,1:16:09.200 kind of snuggles through, kind of wiggles through those. And this is going to be important later on, 1:16:09.200,1:16:19.040 the wiggling. So it gets into the nucleus and then it starts reverse transcription. So at this point- 1:16:19.040,1:16:23.920 Question! Question, question. Does it do another? So I came as a full package and 1:16:23.920,1:16:29.120 then I unfilled myself for the inner package. Do I unfill myself again? So the capsid, kind of, 1:16:29.120,1:16:32.160 lets all the inner contents out into the nucleus? 1:16:32.160,1:16:37.520 I think so. And I am afraid of saying anything too definitively, 1:16:37.520,1:16:42.640 because I'm thinking, what if this knowledge changes in a few years or 1:16:42.640,1:16:47.200 something like that? But I think the capsid also dissolves at this point. 1:16:47.200,1:16:47.840 Okay. 1:16:47.840,1:16:56.480 Within the capsid we said that there was the RNA — the two RNA molecules — and there's the enzymes, 1:16:56.480,1:17:01.760 including reverse transcriptase. Reverse transcriptase turns the 1:17:01.760,1:17:09.680 RNA molecule into DNA. Then, now it has DNA, we also have DNA! 1:17:09.680,1:17:17.440 It can then insert itself into our cell's DNA, using an enzyme called integrase, 1:17:17.440,1:17:27.600 which integrates it. Makes sense. So the virus is now integrated itself into our cell's DNA. 1:17:27.600,1:17:36.400 Now, at some point, our cells will decide to turn our DNA into other RNA molecules, 1:17:36.400,1:17:41.200 and to proteins, because we need parts of our genetic code to do stuff at different times. 1:17:41.200,1:17:43.920 I don't want to brag, but I'm doing that all the time. 1:17:43.920,1:17:47.840 We're doing it all the time. I don't know the maths on this, but I know 1:17:47.840,1:17:55.680 there's a lot of it going on at any given time. So it basically uses our own cells' machinery to 1:17:55.680,1:18:05.600 turn its DNA now into its RNA particles, and also to transcribe the other proteins and enzymes that 1:18:05.600,1:18:13.440 it needs for its functions. These proteins and enzymes and the RNA molecule somehow make their 1:18:13.440,1:18:23.360 way to the surface of our cells. They then bud out of the cell. The cell membrane of our cell, 1:18:23.360,1:18:31.840 which previously was fused with the previous virus particles, they bud into this new little particle, 1:18:32.400,1:18:38.960 and there's now an immature virus, a new HIV virus particle. 1:18:38.960,1:18:45.360 But there's lots of them, because it's not just that our body has transcribed one of these. It's 1:18:45.360,1:18:54.320 transcribing loads of these proteins and enzymes at a time. So this one HIV that has infected our 1:18:54.320,1:19:00.960 cells and integrated into our DNA can then multiply into many, many more that, and but out of 1:19:00.960,1:19:08.640 the cell. But at this point, it's still immature. It's still not able to cause an infection, 1:19:08.640,1:19:17.600 because it hasn't- the proteins that we've made for the virus are actually in this big compound, 1:19:17.600,1:19:25.920 of what is called a "polyprotein". So it's multiple proteins that are fused together. 1:19:25.920,1:19:27.040 At this point, 1:19:27.040,1:19:33.600 So it was maybe more efficient for the virus to do 'em all at once, 1:19:33.600,1:19:37.440 but they're now in a big string, so you can't actually- they aren't going to 1:19:37.440,1:19:41.040 perform their function. There are many different proteins that it wants from you. For example, 1:19:41.040,1:19:45.040 the integrase, maybe it's still part of that? Is that right? 1:19:45.040,1:19:48.640 They're all part of- Well, no, I think there are multiple polyproteins, 1:19:48.640,1:19:53.040 but one really big one has reverse transcriptase, integrase, 1:19:53.040,1:19:58.800 and a bunch of other important proteins. And they're all kind of in this huge polyprotein, 1:19:58.800,1:20:05.200 and then there's a separate enzyme that's produced called "protease" in HIV. 1:20:05.200,1:20:09.520 That's what I would do, if I had something that- I think I know what's going to happen. Keep going. 1:20:09.520,1:20:16.080 Okay. So this protease is what is commonly called a "molecular scissor". 1:20:16.080,1:20:16.240 Right! 1:20:16.240,1:20:24.080 It cuts this giant polyprotein into its components — into the individual enzymes that it then needs. 1:20:24.080,1:20:33.680 And that also creates, that also cuts off capsid proteins, which then form a new capsid. 1:20:33.680,1:20:37.600 Oh wow. Sorry, we're inside of the envelope, right now, of the virus? 1:20:37.600,1:20:38.708 We are now inside of the envelope. 1:20:38.708,1:20:43.680 But there's just a lot of mess in the immature state. We don't have a capsid yet. Okay. 1:20:43.680,1:20:51.280 So we now have- the protease has cut this giant protein, it has cut them into lots of 1:20:51.280,1:20:57.840 capsid proteins. The capsid proteins start to assemble into a new capsid. 1:20:57.840,1:21:01.440 Which, in itself, I mean, that's so cool. Because there are loads of different proteins, 1:21:01.440,1:21:07.760 right? That's going to be lots of different individual units that are due to, you know, 1:21:07.760,1:21:11.200 thermodynamics, I guess, sort of gravitating towards this configuration, 1:21:11.200,1:21:14.560 that is a bullet or that. Yeah, it's wild. 1:21:14.560,1:21:22.320 I mean, it's crazy. So this protease is what I wanted to talk about a little more. And I think it 1:21:22.907,1:21:28.720 is probably really useful to hear about this whole lifecycle in order to know what protease even is. 1:21:28.720,1:21:35.760 And so the HIV's protease, which is cutting up this giant protein into its components, 1:21:35.760,1:21:43.920 that is what I think is the next big advance in HIV drug development. There are a bunch of other 1:21:44.480,1:21:49.520 nucleoside analogues, the mimics like AZT, that are developed around this time. 1:21:49.520,1:21:58.560 A bunch of other drugs are developed, but I think the proteases are the next big step. 1:21:58.560,1:22:05.600 Alright. So we talked about protease, and the reason that's important is because the 1:22:05.600,1:22:14.000 next big advance, in my view, is drugs that targeted HIV's protease enzyme. I think I'll 1:22:14.000,1:22:19.440 talk a little bit about the first one that was developed. This was called saquinavir, 1:22:19.440,1:22:30.160 and it was developed by scientists at Roche. They were trying to figure out if there were any 1:22:30.160,1:22:35.440 drugs that could target this protein. So they knew that this was probably important, because 1:22:35.440,1:22:44.800 they could see that- I think they were able to test whether it was present in people with HIV. 1:22:44.800,1:22:52.720 And they knew that it was important in the process of breaking down that giant protein polypeptide 1:22:52.720,1:23:01.200 into the smaller components. And so they started to study its structure and its cutting pattern. 1:23:01.200,1:23:08.240 As we said, protease is often called a molecular scissor. It doesn't literally look like a scissor, 1:23:08.240,1:23:18.640 I assume it just looks like a blob or something. But when it's trying to cut down this giant 1:23:18.640,1:23:25.920 polyprotein, it slightly changes shape, I guess, it opens up. It gets into this transition stage, 1:23:26.720,1:23:35.120 attaches to the polyprotein and then snips it into separate proteins. And what they were trying to do 1:23:35.120,1:23:42.560 was, they were trying to find something that could jam that transition state, so it couldn't actually 1:23:42.560,1:23:53.520 cut the protein. You have to look at what this transition state might be, what specific part of 1:23:53.520,1:24:03.600 the protease enzyme is doing that snipping, and then, can we fit something into this little gap? 1:24:03.600,1:24:09.760 Okay, so we've got this protease — scissors — and we got my long 1:24:09.760,1:24:16.320 string of proteins — paper — and we're going to jam a rock in there, 1:24:16.320,1:24:19.840 and rock beats scissors. And that's one thing I learned many years ago. 1:24:19.840,1:24:21.040 Very good. 1:24:21.040,1:24:23.040 Thank you. 1:24:23.040,1:24:32.000 So what was interesting, I think, to them. I think, at this point, there is PCR testing, 1:24:32.000,1:24:39.280 because this is 1986. So now, PCR is available, but they could also try to look at where exactly 1:24:39.280,1:24:45.200 the protease was typically cutting. And they found that if you looked at protease 1:24:46.000,1:24:53.920 in other proteins in the lab, it was cutting at specific sequences in a protein. 1:24:53.920,1:24:59.360 A protein is made of many amino acids joined together, and it was typically 1:24:59.360,1:25:04.880 cutting in places with a tyrosine, which is one type of amino acid, or a phenylalanine, 1:25:04.880,1:25:11.600 which is another — and either of those followed by a proline. So it was a sequence of either 1:25:11.600,1:25:17.520 tyrosine or phenylalanine followed by proline. And this combination, of cutting at this point, 1:25:17.520,1:25:23.040 is something that human enzymes almost never do, which is really useful, because it means that if 1:25:23.040,1:25:30.400 they're able to target this something that is cutting at this point, then they're hopefully 1:25:30.400,1:25:37.600 not going to be affecting any human enzymes that are important to us, for our other functions. 1:25:39.280,1:25:49.280 So what they then did was try to look for other molecules that could fit into this 1:25:49.280,1:25:58.080 transition state, where the enzyme is snipping the polyprotein. As part of designing the first 1:25:58.080,1:26:05.040 protease drug, they also had to develop tools to test how well their drugs were working against it. 1:26:05.040,1:26:11.760 So they developed a dye reaction test, to detect these proline-containing fragments. 1:26:13.120,1:26:19.920 They also worked on cloning and purifying the protease enzyme, using recombinant DNA methods, 1:26:19.920,1:26:27.520 which were also fairly recent. The first recombinant DNA that was produced was in 1972, 1:26:27.520,1:26:36.000 and the first time that was used for human enzymes was insulin in 1978 — so this was the first time 1:26:36.000,1:26:45.200 that we could produce insulin in bacteria, instead of extracting it from the pancreases? 1:26:45.200,1:26:46.160 Pigs, was it? 1:26:47.840,1:26:55.040 I think pigs. Previously to that, it was dogs, and it was also cows and other mammals, 1:26:55.040,1:27:00.560 which is horrible. But there was no other way to treat diabetes except to extract 1:27:00.560,1:27:05.520 insulin from various animals, until the 1970s. So this was a huge development 1:27:05.520,1:27:11.840 that was also very useful for testing out potential drugs against protease. 1:27:11.840,1:27:17.520 I mean, yeah, we now take this for granted. In any lab you're in, or most labs you're in, 1:27:17.520,1:27:23.600 you'll have some way of growing up proteins you want to study in a biological system — probably 1:27:23.600,1:27:28.480 in a bacteria, but maybe in mammalian cells, maybe in yeast. And that means you can study proteins 1:27:28.480,1:27:34.320 all day long. But back then, this would've been recent. You could only do that from the 1:27:34.320,1:27:43.120 seventies as you said. So yeah, that's another nice intersecting biotech improvement there. 1:27:43.120,1:27:49.360 It's so interesting to me, just how much the technology kind of happens along side 1:27:49.360,1:27:55.360 and how much is dependent on other tools being available and what new things that 1:27:55.360,1:28:01.840 allows you to, allows scientists to, do. Okay, so back to protease inhibitors. 1:28:01.840,1:28:08.320 We're trying to test any drugs that fit into these. The transition state — the 1:28:08.320,1:28:15.760 little wedge — where the scissors are cutting. They tried a bunch of different drugs. One type, 1:28:15.760,1:28:25.200 called hydroxyethylamines, worked especially well. When they found that that was working, 1:28:25.200,1:28:30.640 they started making adjustments to it, to see if they could improve on that result. 1:28:30.640,1:28:35.360 They changed the ends of the molecules, they tweaked the sizes of chemical rings, 1:28:35.360,1:28:42.320 they swapped side chains, and they found that having a larger, fused ring structure 1:28:42.320,1:28:48.400 made it much easier for this compound to latch onto the protease and block it from cutting. 1:28:48.400,1:28:55.440 I find this kind of stuff crazy, just because the tweaking is so important. We're talking 1:28:55.440,1:29:02.480 about very small molecules, well, small areas we're tweaking. We're talking about 1:29:02.480,1:29:07.680 not that many... atoms! We're talking about- you add up all the atoms at the cleavage site, 1:29:07.680,1:29:14.480 I dunno, not that many. So yeah, it's wild that chemistry gets so specific, 1:29:14.480,1:29:21.680 and that means that you can have these small changes that have enormous changes for patients. 1:29:21.680,1:29:25.920 I mean, I think it shows how much different fields of research come 1:29:25.920,1:29:32.320 together in developing new drugs. We have people who work in the clinic with patients, 1:29:32.320,1:29:37.200 and they might see something that seems to be having an effect, so they try it out. Then, 1:29:37.200,1:29:42.480 there's the people working on microscopy, who are really important, the chemists, the 1:29:42.480,1:29:47.760 pharmacologists, who are testing out toxicity and drug reactions and things like that. It's like, 1:29:47.760,1:29:54.080 everything comes together, and that is really important here. And so this drug 1:29:54.080,1:30:05.360 that they then developed after these dozens of adjustments was initially called Ro-31-8159. 1:30:05.360,1:30:09.120 Ro-31-8159. It rolls off the tongue! 1:30:09.120,1:30:16.320 That was later named saquinavir, which is the first protease inhibitor that was approved. As 1:30:16.320,1:30:23.280 I said, this drug, because it was targeting the enzyme, that was cutting in the specific 1:30:23.280,1:30:32.240 place that was not the case in human enzymes. It was extremely selective to HIV protease, 1:30:32.240,1:30:39.520 and barely affected human enzymes, even at very high concentrations. That meant that it was 1:30:39.520,1:30:45.760 much safer. But at the same time, what I found kind of interesting was that, 1:30:45.760,1:30:54.560 this drug, if you gave it to people, most of the drug was excreted very quickly. About 96%, 1:30:54.560,1:31:01.680 I think, was excreted in the urine. So having a high concentration of the drug, thankfully, didn't 1:31:01.680,1:31:06.720 have these side effects, because you'd have to compensate for the amount that just gets peed out. 1:31:08.560,1:31:17.680 I think this is also interesting because we're at this point now — this was approved in 1995, 1:31:17.680,1:31:25.280 saquinavir. And at this point, there are, I think, around a dozen different antiviral drugs, 1:31:25.280,1:31:30.640 which again is amazing, because just 10 years before that, 1:31:30.640,1:31:37.760 people thought no drugs would work against this disease, but now they have 10, or so. 1:31:37.760,1:31:39.200 Progress. 1:31:39.200,1:31:44.720 So, at this point, there are a bunch of drugs, but none of them really work in a long lasting 1:31:44.720,1:31:50.240 way. People develop HIV, it manages to evolve resistance against the drugs that 1:31:50.240,1:31:56.720 are being used after a few months. And this seems like it's just another one of those, 1:31:56.720,1:32:01.440 okay, we've got a new drug, but is it really going to make a difference in the long term? 1:32:01.440,1:32:08.960 And I think people were, in terms of people with HIV, they were probably quite pessimistic, 1:32:08.960,1:32:16.080 in some ways. They want new drugs to be developed for their condition, but how is this going to 1:32:16.080,1:32:23.760 make a difference after a few months? But this is actually where things change, because now 1:32:23.760,1:32:33.680 that we have a protease inhibitor and we have nucleoside — the fake nucleosides — like AZT, 1:32:33.680,1:32:40.000 and we have a few other drugs, we can now combine them, and give them as combination treatment. 1:32:40.000,1:32:44.400 Ding, ding, ding, here we go. I don't know if, literally, 1:32:44.400,1:32:50.080 the combination involved AZT or some of the other antibodies you mentioned, 1:32:50.080,1:32:56.800 but I did notice that the protease is operating right near the end of the viral lifecycle. AZT, 1:32:56.800,1:33:01.360 as you described, it's operating much earlier. These are really different parts of the lifecycle, 1:33:01.360,1:33:07.280 and it's quite unlikely intuitively the virus would, at the same time, mutate against both. 1:33:09.040,1:33:14.080 So I think this is something that the cancer researchers, or the virologists, working on 1:33:14.080,1:33:20.000 this would now have realised: that we're now working on different aspects of the virus's life 1:33:20.000,1:33:27.120 cycle. It's fairly unlikely that it's going to be able to resist all of these drugs coming at it, 1:33:27.120,1:33:35.200 in different parts. And I think this is when this combination therapy started to be used, and 1:33:35.200,1:33:44.880 it was being tested alongside these new protease inhibitors. This new type of combination therapy 1:33:44.880,1:33:52.000 is called HAART, which stands for "highly active antiretroviral therapy". It's a combination of, 1:33:52.000,1:33:59.920 typically, one nucleoside reverse transcriptase inhibitor, like AZT, another drug inhibitor that 1:33:59.920,1:34:06.720 directly inhibits reverse transcriptase — so it's not a fake base — and then, a protease inhibitor. 1:34:06.720,1:34:12.000 There were multiple protease inhibitors that were introduced around the same time in 1995, 1:34:12.000,1:34:17.040 like a bunch of different pharmaceutical firms essentially racing to get their to market. 1:34:17.040,1:34:25.120 This is a huge change in terms of how HIV treatment works, how effective it is, in the US. 1:34:25.120,1:34:32.560 I'm showing this chart that I worked on earlier, just to show what impacts it had. You can see this 1:34:32.560,1:34:42.560 massive rise in mortality rates from HIV and AIDS from the 1980s to the 1990s; rapidly grows as an 1:34:42.560,1:34:51.600 epidemic disease growing exponentially. In 1995, in December, highly active antiretroviral therapy, 1:34:51.600,1:34:59.520 the combination treatment, is introduced, and it's just this huge drop in death rates. 1:35:00.480,1:35:07.280 The way that people talk about it is, as if people are on death row and they're coming back to life 1:35:07.280,1:35:12.240 suddenly with this new combination therapy, because it's something that the virus is very 1:35:12.240,1:35:21.440 hard- not able to evolve resistance to. I wanted to bring this up because I was reading that book, 1:35:21.440,1:35:29.680 How to Survive a Plague by David France, and he talks about his own- he was a reporter at 1:35:29.680,1:35:38.080 the time, and he was at one of these scientific conferences on protease inhibitors learning about 1:35:38.080,1:35:44.400 the science, what new drugs were available. He describes one of his experiences towards 1:35:44.400,1:35:52.400 the end of the book, and this is what he says. He says: "One of the scientists interrupted his 1:35:52.400,1:35:59.120 presentation abruptly and he said, 'Maybe you are not understanding what I am saying. This 1:35:59.120,1:36:04.320 is the biggest news ever in this epidemic. This stuff is actually clearing virus out 1:36:04.320,1:36:09.040 of people's bodies. People are getting better. We don't know for sure yet, but we think these 1:36:09.040,1:36:15.200 drugs — this whole class of drugs — might allow people to live a normal life. This is what we've 1:36:15.200,1:36:19.840 been working for all these years. They're not a cure. We don't know what they are, in effect, 1:36:19.840,1:36:25.600 but this is the first major piece of good news we've had in all these years. They're calling it 1:36:25.600,1:36:31.680 the Lazarus effect. People who were in hospitals on their last breath are getting up and going back 1:36:31.680,1:36:38.720 to work. We've never seen anything like it.'" And that's just an incredible change, I think, 1:36:38.720,1:36:48.000 from how scary it must have been in the 1980s, seeing some drugs really promising. But eventually 1:36:48.000,1:36:54.320 they start to fail and then you get this combination of therapy that changes everything. 1:36:54.320,1:37:01.200 A complete change, and it breaks your heart to think of people who didn't make it to see 1:37:01.200,1:37:11.280 that change. Oh, what a graph. Okay, you're going to have make some nice, 1:37:11.280,1:37:16.000 less emotionally-intense graphs for me to calm down now. 1:37:16.720,1:37:23.120 There are a bunch of other drugs that I think we aren't going to talk about. But apart from the 1:37:23.120,1:37:29.040 protease inhibitors, the nucleoside analogues, and other reverse transcriptase inhibitors, 1:37:29.040,1:37:34.880 there are other drugs that targets how HIV enters the cell. I think there are 1:37:34.880,1:37:41.680 also some that targets the integrase enzyme — that allows its DNA to integrate into our 1:37:41.680,1:37:49.200 DNA — and then there are some others as well. But I think that kind of covers 1:37:49.200,1:37:56.480 much of the major story in the 1980s and '90s on HIV and drug development. 1:37:56.480,1:38:04.240 Okay, so taking a step back, we know what HIV looks like. We know roughly where it came from. 1:38:04.240,1:38:08.880 We now know a bit about the lifecycle, and we know about combination drugs that, 1:38:08.880,1:38:16.640 together, prevent HIV from taking over, and are less prone to resistance, 1:38:16.640,1:38:24.480 because there's many of them you're on at once. Okay, what about, what's happening with vaccines 1:38:24.480,1:38:30.400 at this point? And are people talking about curing HIV? I mean, these drugs control HIV. 1:38:31.040,1:38:39.200 I think this is interesting because we don't have a vaccine for HIV yet, right? It's been 1:38:39.200,1:38:47.280 more than 40 years since the first AIDS case was reported. We have loads of antivirals now, 1:38:47.840,1:38:53.360 working in different ways, but we don't have any vaccines. I think this would have been 1:38:53.360,1:38:59.280 really depressing if vaccines were the only things that were being worked on at the time. 1:38:59.280,1:39:04.880 But thankfully people were trying out random drug combinations, and that's why I think this first 1:39:04.880,1:39:10.800 step, of getting AZT, was so important. But my understanding is there aren't any 1:39:10.800,1:39:16.880 working vaccines that we know of yet... so I didn't actually read anything about them. 1:39:16.880,1:39:25.520 Well, I know a little smidgen. At Open Philanthropy where I work, 1:39:26.160,1:39:34.960 the team I work on supports a bunch of different biomedical research, and roughly a third of what 1:39:34.960,1:39:46.320 we fund in grants is, in some way or other, vaccinology or focused on vaccines. The area of 1:39:46.320,1:39:55.920 vaccines we've done may be the least in is HIV, and the reason for that is that it's very hard, 1:39:55.920,1:40:03.040 and now people have more knowledge of why it's hard. It also, happily, despite being 1:40:03.040,1:40:09.600 so underfunded at the beginning of the crisis in the US and elsewhere, now has attracted much more 1:40:09.600,1:40:14.560 attention and funding. So there's actually been tens of billions of dollars thrown at this problem 1:40:14.560,1:40:21.440 of 'How do you make an HIV vaccine?' The reason it's so difficult, I think, the clues to that 1:40:21.440,1:40:33.520 are located in what you've already said about the virus. Well, firstly, clue number one is that our 1:40:33.520,1:40:40.720 immune system doesn't control the virus naturally very well, once an infection is established. 1:40:42.400,1:40:49.120 Most people are not able to control an infection, once it's established, and that implies, okay, 1:40:49.120,1:40:56.160 well, what is a vaccine? A vaccine is trying to trigger your immune system to be prepared 1:40:56.160,1:41:03.280 for future invaders. If hardly anyone has a prepared successful immune response, what are 1:41:03.280,1:41:11.120 we even trying to mimic here? It's a tough problem statement, whereas something like COVID, plenty of 1:41:11.120,1:41:18.000 people do manage to control and their immune response is productive. You can pretty easily 1:41:18.000,1:41:22.400 see with COVID, especially at the beginning, well there's one protein on the outside of this virus, 1:41:22.400,1:41:27.360 the spike protein, that if you block it with antibodies, it is not getting into your cell. 1:41:27.360,1:41:35.120 So let's try and mimic that immune response. And then another clue is about the rapid mutation. 1:41:35.120,1:41:43.680 So if your immune system is trying to prevent something that keeps changing, it's going to be 1:41:43.680,1:41:50.560 harder. And sure enough, if you create a vaccine which is less dynamic than your immune system, 1:41:50.560,1:42:02.080 and is only one thing, then you're not going to be clearing all of these different permutations of 1:42:02.080,1:42:08.880 the virus. These days, because the understanding of the immune system has progressed even outside 1:42:08.880,1:42:14.880 of HIV, over the last few decades, and because we have so much better tools, people are still going 1:42:14.880,1:42:22.800 at the problem, and have sort of ingenious and complicated ideas about how to make a HIV vaccine. 1:42:25.680,1:42:31.680 You may have heard the phrase "broadly neutralising antibodies" — that's all the rage 1:42:31.680,1:42:41.280 for what people are using to develop vaccines, and going after. But that's, importantly, 1:42:41.280,1:42:46.960 not what we're here to discuss today. I think you and I really are focused on medical impact and 1:42:46.960,1:42:54.880 this podcast is too, and it's so interesting that what we are here to discuss is a drug, 1:42:54.880,1:43:00.720 in the sense of, it's not prompting your immune system to respond in a certain way, like a vaccine 1:43:00.720,1:43:06.560 would. It's trying to avoid getting rejected by your immune system, and instead is trying to 1:43:06.560,1:43:12.160 just be a chemical that's hanging around, and the chemical's doing the work, not your immune system. 1:43:12.160,1:43:19.840 I was thinking about the broadly utilising antibodies. Just in case people are not aware, 1:43:21.680,1:43:28.960 I guess a fraction of people seem to be able to develop an immune response to a wider range 1:43:28.960,1:43:35.040 of HIV strains after it's diverged. So trying to find those antibodies, 1:43:35.040,1:43:42.480 that seem to be working against this broad range, that is what people are looking for. Right? The 1:43:42.480,1:43:49.600 other thing is there are some people who are still, we're working on combination vaccines, 1:43:49.600,1:43:58.320 I think. So vaccines that include multiple different components of the HIV virus. And this, 1:43:58.320,1:44:04.720 I know from direct experience, because I was once in an HIV vaccine trial. 1:44:04.720,1:44:08.560 Aha! So when was this? 1:44:08.560,1:44:11.280 This was in 2019. 1:44:11.280,1:44:11.780 2019. 1:44:12.640,1:44:16.560 You might be wondering, why am I getting an HIV vaccine? Why am I in this trial? 1:44:16.560,1:44:23.760 It was this phase one trial. So essentially, they're just testing the safety and some basic 1:44:24.800,1:44:30.160 reactions — immunological reactions — you have to a potential vaccine. 1:44:30.160,1:44:37.040 And I got contacted through Imperial where I think I was studying at the time or had been, 1:44:37.600,1:44:43.760 and I was like, I love science, I want to be part of this trial. 1:44:43.760,1:44:46.240 We need more Saloni's in this world. 1:44:46.240,1:44:52.080 Also I was thinking, well what if this candidate vaccine actually works? I'll 1:44:52.080,1:44:54.720 be immune to HIV. That would be so cool. 1:44:54.720,1:45:00.080 Well, oh yeah. So this was not controlled. It was a phase one, so you were definitely getting it? 1:45:00.080,1:45:06.240 Oh, I actually don't know. I mean, I could have been on placebo, but still you have a 50%-ish 1:45:06.240,1:45:14.320 chance, probably, get it for free getting an HIV vaccine for free if it works. It was a 1:45:14.320,1:45:22.320 really funny experience because... if you have met me or seen me in person, I'm quite small. 1:45:22.320,1:45:30.240 I thought that, well, I knew that this trial had this eligibility requirement that you had 1:45:30.240,1:45:37.280 to be within normal BMI. I am essentially on the cutoff of underweight and normal, 1:45:37.280,1:45:42.800 whenever I've checked. And that's just been true for years. So I was really worried that I would 1:45:42.800,1:45:47.680 just fall under the threshold, and I would not be allowed to participate in the trial. 1:45:47.680,1:45:53.600 I love that you are hustling to get into an HIV vaccine trial. 1:45:53.600,1:45:58.400 Like, eating more food to get in. Exactly. 1:45:58.400,1:46:01.760 Bulk season is on. 1:46:02.400,1:46:08.240 Okay. So I was trying, I was really hoping that I would get into this trial. I got to 1:46:08.240,1:46:16.160 the clinical trial site. They asked me a few questions, they asked for my consent, 1:46:16.160,1:46:22.000 et cetera. And then, they also wanted to measure me, to check that I met the requirements. So 1:46:22.000,1:46:29.120 they were measuring my weight and my height. They then put that into their computer and they said, 1:46:29.120,1:46:35.680 'Oh great, you've passed this threshold', and I saw this BMI value on their screen. I was like, 1:46:35.680,1:46:41.840 that's surprising. Great, but surprising. And then, I looked at the values that they had 1:46:41.840,1:46:49.760 entered, and it turned out that I was shorter than I thought I was... so my BMI was normal. 1:46:49.760,1:46:58.320 So it took medical development of HIV to get you to understand your height. I mean, 1:46:58.320,1:47:01.600 there's a lesson here, but I'm not quite sure what the lesson is. 1:47:01.600,1:47:05.280 Well, it's also, it's hard to measure your own height. 1:47:05.280,1:47:06.720 Great point. 1:47:06.720,1:47:14.720 I dunno. It was both exciting because I could now participate in this trial, but also there 1:47:14.720,1:47:22.640 was this sadness that I felt, realising that I was even shorter than I thought I was. 1:47:22.640,1:47:27.200 Oh God. Wait, so what happened? Are you protected? 1:47:27.200,1:47:35.600 I don't know. Well, they didn't unblind me from whether I was getting the vaccine or the placebo, 1:47:35.600,1:47:40.960 but I did go in; I think I was in for some eight sessions. They did a bunch of, 1:47:40.960,1:47:47.840 was it blood testing? They did some testing of uncomfortable parts of my body, 1:47:47.840,1:47:52.960 to see the effects of this vaccine. I don't think I had any side effects, 1:47:52.960,1:47:59.920 maybe a headache at some point, but that was all. It was pretty nice. It was a great experience. 1:47:59.920,1:48:01.280 Nice. Cool. 1:48:01.280,1:48:07.520 I mean, I would say I would recommend it, but really you should decide that for yourself. 1:48:07.520,1:48:18.560 Sounds good. I just recently was screening to sign up for a vaccine trial here in San Francisco, 1:48:19.120,1:48:23.760 and I did the 15 minute screen, and they signed me up to go in person. And then, 1:48:23.760,1:48:27.920 the day I was going to go in person, I had a meeting that clashed, and I haven't got around 1:48:27.920,1:48:35.920 to enrolling, so I'm feeling a lot of guilt. So now I have an extra incentive though. Maybe I'll 1:48:35.920,1:48:39.600 figure out I'm taller than I think I am. Maybe I'll figure out I'm shorter though. 1:48:42.160,1:48:48.320 Well, so the reason I brought this up was because it was a combination vaccine, but also it was a 1:48:48.320,1:48:56.160 funny story. But the vaccine that they were trying contained, I think, three different proteins of 1:48:56.160,1:49:05.440 the HIV. So I think it was one adenovirus that was modified to carry an HIV coat protein. There was 1:49:05.440,1:49:13.840 another that was a vaccinia virus, which is... is that the smallpox vaccine virus, I think? 1:49:13.840,1:49:15.760 Hmm, yeah, probably. 1:49:15.760,1:49:21.840 And then there was another, that was another coat protein. So they had tried out, I think, 1:49:21.840,1:49:24.720 one or two of these before in trials, and then 1:49:24.720,1:49:29.200 this was putting them together into this combination vaccine. 1:49:29.200,1:49:30.371 It's interesting- 1:49:30.371,1:49:31.520 And then I don't know How it worked out. 1:49:31.520,1:49:37.360 Yeah, it's interesting you mentioned a coat protein. It makes me think of the 1:49:37.360,1:49:41.040 design differences you are dealing with when you're trying to make therapeutics, 1:49:41.040,1:49:46.640 and when you're trying to make vaccines. With vaccines, stereotypically, 1:49:46.640,1:49:52.240 especially for antibody responses, you wanna look on what's on the outside of an invader, 1:49:52.240,1:49:57.760 what's sticking out that my antibodies can glue to, and maybe a coat protein is a good choice 1:49:57.760,1:50:02.960 because it might be sticking out? And you know what is not sticking out? Those strands of RNA, 1:50:02.960,1:50:08.400 that are not only inside the envelope, they're inside a capsid; your antibody is not getting in 1:50:08.400,1:50:15.200 there. However, a small molecule drug, which is a nice tiny little chemical, can diffuse to many 1:50:15.200,1:50:21.680 places very surreptitiously. So you really might be able to interfere with something that the virus 1:50:21.680,1:50:29.920 has tried to protect from your immune system, but has failed to protect from genius humans, 1:50:29.920,1:50:36.720 who are using good tools to make something that nature actually couldn't have really got to. 1:50:36.720,1:50:40.800 No, exactly. Yeah, that's a really good point. 1:50:42.240,1:50:49.760 Shall we talk a little bit about treatment for HIV and what that's like? 1:50:49.760,1:50:58.160 Sounds great. And maybe we should even skip to prevention! We've talked a bit about- 1:50:58.160,1:50:59.200 Let's do that. 1:50:59.200,1:51:05.200 Let's do it, because you've given us a good overview of how in the '90s, these new drugs 1:51:05.200,1:51:13.680 allowed patients who had HIV infections to have much longer life expectancy, and control their 1:51:13.680,1:51:19.440 infections. There's a lot more that we could say about the different improvements since then in 1:51:19.440,1:51:27.040 treatment. But the principle is somewhat similar, if you want to be on these combination therapies. 1:51:27.040,1:51:39.520 So let's skip to prevention because prevention has some overlapping path and some different path. 1:51:39.520,1:51:46.240 What were the first ways that you could try and prevent getting HIV, if you didn't have it yet? 1:51:46.240,1:51:53.760 Well, you could change the way you were having sex, the type of sex you were having. You could 1:51:53.760,1:52:01.440 have sex with fewer partners, and you could have sex with condoms, which provide a barrier. The 1:52:01.440,1:52:09.520 thing that really changed preventive strategies more recently though, was drug availability for 1:52:09.520,1:52:15.600 PrEP — pre-exposure prophylaxis. So that's different than post-exposure prophylaxis, 1:52:15.600,1:52:22.800 which is PEP. And the pre- means you're taking the drug before you have sex, 1:52:22.800,1:52:29.920 or before you get exposed in some other way. That means that, if any HIV particles enter 1:52:29.920,1:52:38.880 your system, the drug is going to help block an infection getting established. So PrEP as a 1:52:38.880,1:52:46.960 drug regimen first became available in the US at least, in 2012. So Truvada 1:52:46.960,1:52:55.040 is a combination of two drugs, tenofovir and emtricitabine. Do you know how to say that one? 1:52:55.040,1:52:55.600 No. 1:52:55.600,1:53:03.440 Okay. I mean, they put them in one daily oral pill. So, 1:53:03.440,1:53:08.720 more specifically, it's actually tenofovir disoproxil fumarate, 1:53:08.720,1:53:16.240 which I'm sure I'm also mispronouncing, or "TDF", in combination with emtricitabine. And 1:53:17.200,1:53:27.040 those were two separate drugs that had been approved for treatment of HIV in 2001 and 2003. 1:53:27.040,1:53:36.240 The combination of them was approved as a treatment called Truvada in 2004. Then by 2012, 1:53:36.240,1:53:43.280 the FDA approved Truvada as the first PrEP regimen, after a clinical trial showed that 1:53:43.280,1:53:47.674 it had high efficacy in preventing infection. And I, yeah, go ahead. 1:53:47.674,1:53:51.840 Yeah, it's so interesting that some of the same antivirals that are used in treatment 1:53:51.840,1:53:59.040 were also used in prevention. One thing that made me think about was, I was reading about 1:53:59.040,1:54:06.960 was azidothymidine — AZT — the first HIV drug, and I think there's a part of that story that 1:54:06.960,1:54:15.440 gave them a clue that antivirals could be used as prevention as well. That was that pregnant 1:54:15.440,1:54:24.800 women who had HIV who were taking AZT, were not passing it on to their babies at the same rate. 1:54:24.800,1:54:31.840 They started running this trial in the '90s, and in 1994, I think, the study was published. 1:54:31.840,1:54:39.120 There was this massive drop in the rates of transmission, from mother to child, of HIV. 1:54:39.120,1:54:45.440 And that is really interesting as well, because even though people were developing resistance 1:54:45.440,1:54:54.240 to different HIV drugs, if they were pregnant and taking it, the drug resistance was not as 1:54:54.240,1:54:59.360 much of a problem if they were taking it late enough, because you only need this 1:54:59.360,1:55:04.240 particular time span for it to be effective. It doesn't have to be effective for years. 1:55:04.960,1:55:06.400 Of course. I see. 1:55:07.280,1:55:09.600 But also I think that just gave people a hint 1:55:09.600,1:55:14.240 that this is something that could be used in prevention. 1:55:14.800,1:55:19.760 Yeah, that's such a neat real world proof-of-concept of what you can do 1:55:19.760,1:55:26.240 there. Truvada has been improved on since. So maybe I'll just go through a couple of 1:55:26.240,1:55:37.200 those improvements. The fundamental idea is similar for the main improvement drug. In 2019, 1:55:37.200,1:55:43.120 there was a new regimen called Descovy. And you might be wondering, is this from 1:55:43.120,1:55:50.320 a competitor who's trying to outdo Truvada? And it's from the same company, Gilead, who, 1:55:50.320,1:55:57.520 as a bit of a spoiler, developed Lenacapavir later in life. Descovy does have a longer patent though, 1:55:57.520,1:56:04.400 so it's a better variation for men, it's emtricitabine again, which I've probably 1:56:04.400,1:56:10.240 said three times in three different ways, and it's tenofovir again. It's the same dose actually of 1:56:10.240,1:56:17.360 emtricitabine. I think it's 200 milligrammes. The tenofovir is in a new form though. Instead of TDF, 1:56:17.360,1:56:27.600 it's TAF, which stands for tenofovir alafenamide. And both TDF and TAF are 1:56:27.600,1:56:34.240 "pro drugs". For tenofovir, that means that means your body is sort of doing some work once you 1:56:34.960,1:56:42.400 ingest them to enzymatically, convert them into tenofovir, and then into tenofovir diphosphate, 1:56:42.400,1:56:48.320 which is the active formula drug. My understanding of the difference is that, 1:56:48.320,1:56:56.000 for TDF, so the original one, that primarily happens in blood plasma and for TAF- 1:56:56.000,1:56:57.600 What happens? The, the change? 1:56:57.600,1:57:05.040 The conversion... into the active drug. And for TAF, that primarily happens in the immune cells. 1:57:05.040,1:57:08.960 You know, if you think about the difference there, well, getting the same thing out the other end, 1:57:08.960,1:57:12.800 why do I care? Well, if you're doing it in the blood, then your blood's circulating everywhere, 1:57:12.800,1:57:17.360 including your kidneys, and you can actually have more unwanted effects from that, 1:57:17.360,1:57:23.520 than if you're more secluded when you're making your active drugs. I think that's 1:57:23.520,1:57:27.120 why the safety profile of Descovy looks a little bit better. You have, 1:57:27.120,1:57:33.520 if you're on long-term daily use of the first one, it's got a pretty good safety profile, 1:57:33.520,1:57:43.280 but it can have negative effects on kidneys and bones — so bone density and kidney toxicity. And 1:57:43.280,1:57:50.320 so, here's where, if anyone's on the video, I'm going to do some show and tell. I don't know if, 1:57:50.320,1:57:55.680 are you the kind of person-? I keep all of my empty pill bottles into the future indefinitely? 1:57:55.680,1:57:57.440 Oh, I don't do that. 1:57:58.800,1:57:59.437 I do this. 1:57:59.437,1:58:00.640 So these are empty pill bottles. 1:58:00.640,1:58:05.760 These are empty pill bottles, which hopefully don't have private information on them. But 1:58:05.760,1:58:11.600 basically I think I do it because I have some vision of, I'm going to do some art project about 1:58:12.320,1:58:16.000 what it's like to be a modern human in the future, and you do that. But I think I actually stole that 1:58:16.000,1:58:19.920 from, I think I've seen an art project, which had loads of entry pill bottles. So I actually 1:58:19.920,1:58:24.240 don't have a plan for these pill bottles. But basically, here's what you can learn. So 1:58:25.120,1:58:31.680 take one tablet by mouth every day. This is emtricitabine and tenofovir, 1:58:32.560,1:58:38.080 200 to 300 milligrams. Here's another thing you can learn. So this one is this 1:58:38.080,1:58:43.520 empty pill bottle says Laurus labs on it. And you might be thinking Laurus labs, 1:58:43.520,1:58:50.240 that doesn't sound like Gilead true. And this other empty pill bottle says Amneal on it; doesn't 1:58:50.240,1:58:58.800 sound like Gilead either. The reason for that, is that the Truvada patent expired in 2020. So there 1:58:58.800,1:59:08.080 are now many generic drug manufacturers who make Truvada, which is why I am on Truvada, because 1:59:08.080,1:59:15.200 when I first asked to go on Descovy, my doctor at the time was like — I think that patent exposed 1:59:15.200,1:59:21.600 in 2031 — was like, uh, no, no, no, we're going to give you Truvada. And then I did the classic- 1:59:21.600,1:59:23.040 Because it's cheaper, or? 1:59:23.040,1:59:30.000 Yes, correct. So it's made by drug companies outside of the US, usually in middle income 1:59:30.000,1:59:34.960 countries or in lower income countries, a lot based in India, but other countries too. I 1:59:34.960,1:59:40.960 actually don't, I feel like one of these is an American company, but I might be wrong. And by 1:59:41.680,1:59:48.000 making these generic competitors, where they only have to prove to the FDA that it is similar enough 1:59:48.000,1:59:53.280 in terms of its pharmacodynamics and all that, they don't have to redo all the clinical trials. 1:59:54.080,2:00:00.800 They can sell for a cheaper price than Gilead might. I actually remember later on, the first 2:00:00.800,2:00:09.040 injectable PrEP came about, cabotegravir, and that is made by a different company called Viiv, 2:00:09.040,2:00:19.040 V-I-I-V. That, I believe, was approved in 2021, if I'm remembering right. That is: 2:00:19.040,2:00:26.800 you only get one injection every two months. So I had heard about it and asked a different 2:00:26.800,2:00:31.040 doctor I had at the time, could I, just asked about it, wasn't sure if I do it, 2:00:31.040,2:00:35.760 wasn't sure if I'd stick with what I was doing. And that was very expensive, 2:00:35.760,2:00:44.000 so that was a quick no. My insurance at that time was not enthused about that one. If memory serves, 2:00:44.000,2:00:51.520 it was roughly $4,000 a dose, and it's every two months, that's six doses a year. I think 2:00:51.520,2:00:58.640 it was roughly $20,000 a year. And the patient benefits sure enough was not, I shouldn't really 2:00:58.640,2:01:02.160 have been paying that much, because the drugs I was on were working perfectly fine. 2:01:02.160,2:01:08.320 I guess I'm interested about how PrEP works on a day-to-day basis. 2:01:08.320,2:01:14.560 Do you take it every day? Do you only take it sometimes? What's the pattern? 2:01:14.560,2:01:20.720 So it's the default is you take it every day; it's a daily oral pill, and that makes 2:01:20.720,2:01:27.520 sure that there's enough of the drug in your system that you are safe, whatever happens. 2:01:27.520,2:01:34.400 There is another regimen that men can take for Truvada, which is often referred to as 2-1-1, 2:01:34.400,2:01:44.800 so I do. Where instead of doing it every day, you take two doses, so two pills, the day of sexual 2:01:44.800,2:01:52.080 activity or some risk you're exposing yourself to, one pill the next day, one pill the day after, 2:01:52.080,2:01:58.000 and then, the rest of the time, you just don't take anything. That is easier for some people. 2:01:58.000,2:02:03.280 And that said, if I think about, if I do an informal poll in my head right now, 2:02:03.280,2:02:07.680 with my gay friends in San Francisco, I would say most probably do daily, just because it's 2:02:07.680,2:02:16.480 easy. Actually, recently, my doctor tried to move me onto Descovy, which is the second one, just 2:02:16.480,2:02:22.400 because it's better for kidneys and when I was a baby, I had some kidney issues. That I do not 2:02:22.400,2:02:29.920 believe doctors do recommend 2-1-1. And certainly my doctor and I asked him, well, I'm doing 2 1 1, 2:02:29.920,2:02:36.080 can I do that with Descovy? And he said, "Well, I'm not allowed to say yes to that." I said, "Oh, 2:02:36.080,2:02:40.400 what do you mean?" And he was like, "I don't think that they've studied it with Descovy." 2:02:40.400,2:02:46.320 And I was like, "Okay, so we're sort of going to move on from that. Are we? And you're going to 2:02:46.320,2:02:50.880 give me Descovy?" And he's like, "Yes, I'm going to give you Descovy." So I'm in a sort of grey 2:02:50.880,2:02:55.760 area on that, and anyone listening, don't treat me as a doctor and my recommendation on Descovy. 2:02:55.760,2:02:58.720 But so you've now moved to Descovy? 2:02:58.720,2:03:08.640 I'm in the process, which is... you know, I'm a fairly plugged in, good health-seeking-behaviour 2:03:08.640,2:03:14.620 type person in the statistics. And I still haven't got around to being on the best one. So I dunno, 2:03:16.240,2:03:21.520 if it's not top priority in a given month, I might not get around to changing to the 2:03:21.520,2:03:26.000 better drug. You know, I was talking to someone yesterday actually, because I said, 2:03:26.000,2:03:32.960 "I'm about to record this podcast, what are you on?" And he said, "Oh, I am on the daily 2:03:32.960,2:03:38.640 pills." Most people on the daily pills probably couldn't even tell you if they're on, they both 2:03:38.640,2:03:43.120 work really well, it doesn't matter that much. But he said, "Oh, I was thinking of going onto 2:03:43.120,2:03:49.360 the injectable every two months. But then as I thought about it more, I have to travel for my 2:03:49.360,2:03:55.040 job. So I was worried, well, am I definitely going to be back in San Francisco at the time 2:03:55.040,2:04:00.640 I need to get the injection? Or is there going to be a two week delay where I'm somewhere else? And 2:04:00.640,2:04:06.080 then actually, I'm more at risk, and actually I think it's easier if I just do the daily pills." 2:04:06.080,2:04:13.360 And I think that actually gets to how these drugs can be. It can be complicated how they 2:04:13.360,2:04:18.800 interact with someone's life. And it's not just something you can read off a clinical trial, of 2:04:18.800,2:04:25.360 how useful they'll be. You have to think about — well, how is someone who needs this drug going to 2:04:25.360,2:04:35.920 use it in their real life? And what there might be counterintuitive kind of pros and cons of having a 2:04:35.920,2:04:42.800 big gap of two months between that sounds great on paper, but there you go, someone didn't want 2:04:42.800,2:04:47.520 it. They wanted to just do it every day. And I actually think about this with treatment as well. 2:04:48.960,2:04:55.600 I have a friend who started dating someone who was HIV-positive. He was HIV-negative, 2:04:55.600,2:05:02.560 he started to date someone HIV-positive. And now, with the great drugs that we have, 2:05:03.360,2:05:10.080 if you are positive and on treatment, you will be undetectable, you won't transmit the virus to 2:05:10.080,2:05:18.880 partners, which is incredible. But my friend, he knew that, sort of rationally, and he was still 2:05:18.880,2:05:25.520 anxious around sex. It was a scary topic, even if he could sort of rationally tell himself he 2:05:25.520,2:05:30.720 shouldn't be scared, and then that can be a tough thing for a partner to deal with. And one day, 2:05:30.720,2:05:41.360 his new boyfriend actually took his daily pills in front of my friend as a way to basically build 2:05:41.360,2:05:47.040 trust, and that was a kind of beautiful thing to do. I think, if I were in his position, 2:05:47.040,2:05:52.640 I probably would've been offended and annoyed, and he was so generous. And then sure enough, 2:05:52.640,2:05:58.880 my friend did build trust and fall in love and have, I think, they had a wonderful sex life. 2:05:58.880,2:06:01.920 But that is the kind of thing you wouldn't think about when designing a drug. It's like, 2:06:01.920,2:06:08.080 if you are on a treatment drug that was an injection, that was once every whatever 2:06:08.080,2:06:12.960 period. Well okay, that particular trust-building exercise would not be available to you. So oh, 2:06:12.960,2:06:22.240 it gets so complicated. And then the people most affected by HIV and AIDS these days — it affects 2:06:22.240,2:06:29.920 women in Africa more than it affects men now, especially in Southern Africa. And there the 2:06:29.920,2:06:37.280 complexities are very different and I won't be able to rightly summarise them. But for example, 2:06:37.280,2:06:43.760 if having to go to a clinic for a procedure or injection might be different than having to go 2:06:43.760,2:06:48.480 to a pharmacy to pick up pills, which might be different than having pills on your shelf 2:06:48.480,2:06:53.280 for many weeks, versus having to go more regularly and all of that matters a lot. 2:06:53.280,2:06:59.360 No, that's super interesting. I think one thing I was thinking about when you were talking about 2:06:59.360,2:07:09.760 this was, what are the different problems that people will face apart from- So we have this 2:07:09.760,2:07:13.840 sort of struggle to, I dunno, schedule some of these appointments, things like that. I think, 2:07:13.840,2:07:19.040 one thing on that front was, with some of these injectables, I think there's a kind 2:07:19.040,2:07:24.320 of leeway that you have for when you get the next dose. You don't have to get it exactly, 2:07:25.040,2:07:30.880 let's say, six months or exactly two months after, but there is a little grace period that you can 2:07:30.880,2:07:36.880 get it in. But that's still, probably sometimes, quite inconvenient for people if something happens 2:07:36.880,2:07:43.280 if they're in a different country or so. But there's the issue of, I dunno, taking 2:07:43.280,2:07:50.960 a daily pill every day for many years, that might be hard for some people in terms of remembering, 2:07:50.960,2:07:56.560 especially if it's a preventive pill. It's not something that is necessarily super salient to 2:07:56.560,2:08:03.040 them as if it's a condition they already have. But also, it's this access, like, what if the clinic 2:08:03.040,2:08:09.600 is closed one day? What if something happens? What if, I don't know, someone takes your pills 2:08:09.600,2:08:16.400 or they drop out of your bag, or something like that. How are you going to get the next dose? 2:08:16.960,2:08:21.040 You know, I can answer that for me, and I pick 'em up once every month, 2:08:21.040,2:08:30.880 but I'm just one guy and I think we need to get a better answer for people who are 2:08:30.880,2:08:35.680 affected in other contexts. So I think it's time to phone a friend, Saloni. 2:08:35.680,2:08:37.920 We're going to phone a friend. This is so exciting. 2:08:37.920,2:08:38.800 We're going to phone a friend. 2:08:38.800,2:08:40.160 Who are we phoning? 2:08:40.160,2:08:43.200 We're going to phone my friend Douglas Chukwu, 2:08:43.200,2:08:50.480 who works at Open Philanthropy with me, and before that was a medical doctor in Nigeria, 2:08:50.480,2:08:58.240 and worked in public health on HIV treatment and prevention. So should we dial him up? 2:08:58.880,2:09:02.320 Hello Douglas. How are you doing? Thanks for joining. 2:09:02.320,2:09:04.640 Good, good. Great to be here. 2:09:04.640,2:09:09.280 Well, thanks for taking time out of your day. So, we worked together, 2:09:09.840,2:09:14.400 but before we worked together at Open Philanthropy, you were trained as a doctor 2:09:14.400,2:09:20.640 and worked on other things in public health, which is why we wanted to bring you on today. So yeah, 2:09:20.640,2:09:23.680 what's your background and what were you working on, before Open Philanthropy? 2:09:23.680,2:09:27.120 I trained as a medical doctor in Nigeria. So I had a couple of years of clinical 2:09:27.120,2:09:31.120 practice working as a medical officer in a government establishment and also a private 2:09:31.120,2:09:35.760 establishment. So had that dual experience and then piloted to work in public health. 2:09:35.760,2:09:39.680 Interestingly, most of my public health experience was in the field of HIV and AIDS. 2:09:39.680,2:09:46.080 Are people getting a weekly stock of treatment of PrEP, or will it last them months or 2:09:46.080,2:09:50.800 years? Like how long does- maybe this varies depending on the type of drug that they're using. 2:09:50.800,2:09:58.800 Yeah, so oral PrEP comes in, the commonest is the pack of 30 tablets, and oral PrEP is to be 2:09:58.800,2:10:05.040 administered daily. So the common, it varies from a range of one month to three months; 2:10:05.040,2:10:09.360 three months being the maximum, because for individuals on PrEP, they need to be tested every 2:10:09.360,2:10:15.280 three months, as per the national guidelines, so that's the touchpoint with the facility. The 2:10:15.280,2:10:19.760 treatment duration of prescription helps to make sure that they come for their refills, 2:10:19.760,2:10:25.280 they're assessed for adherence, they're tested for HIV and they're also monitored for side effects. 2:10:25.280,2:10:31.600 How important is public funding from donor countries like the US and the UK, 2:10:31.600,2:10:34.320 when it comes to HIV particularly? 2:10:34.320,2:10:37.280 Absolutely important, right? I'll give an example. There are various access- let's say for example, 2:10:37.280,2:10:41.600 there are a lot of individuals that have accessed treatment that wouldn't have accessed treatment 2:10:41.600,2:10:46.400 if the HIV programs in countries were entirely reliant on domestic funding. 2:10:46.400,2:10:51.520 And this varies across African countries, but in Nigeria, for example, over 80% of the funding for 2:10:51.520,2:10:59.440 HIV programs is via external funding. And then, there are some countries like South Africa, 2:10:59.440,2:11:04.160 where they've made some progress in terms of domestic financing for HIV programs, 2:11:04.160,2:11:13.760 I think as high as 70%. But overwhelmingly, in Africa, there are various country programs that 2:11:13.760,2:11:18.480 are hugely reliant on external funding for sustaining and delivering for HIV. 2:11:18.480,2:11:25.360 We are recording this at the beginning of April and I've still found it difficult to 2:11:25.360,2:11:35.680 get good reporting on quite what's happening with PEPFAR, the US- the main way that the US supports 2:11:35.680,2:11:42.480 HIV programming. And the answer of, what's happening may change in the coming months. But, 2:11:42.480,2:11:48.720 as you talk to your friends who work in public health, what are you hearing at 2:11:48.720,2:11:59.840 the moment? What has happened at facilities or on the ground, in reaction to the PEPFAR uncertainty? 2:12:00.560,2:12:04.880 The effects of this cut across not just the healthcare workers. But healthcare workers, 2:12:04.880,2:12:09.840 patient communities; there's a lot of uncertainty. There's a lot of unease and a lot of worry 2:12:09.840,2:12:16.720 about what the future holds. And a lot of these suspensions were abrupt. So people got stop work 2:12:16.720,2:12:20.880 orders. As I mentioned, there is a community component of healthcare service delivery. 2:12:20.880,2:12:25.040 There are community healthcare workers that are supported by the PEPFAR funding, 2:12:25.040,2:12:30.960 and having the stop-work orders meant people stopped getting tested in communities, 2:12:30.960,2:12:36.080 access to some medications were threatened, even though perhaps there were some stock to sustain 2:12:36.080,2:12:41.200 initial dispensing of ARVs (antiretrovirals). But clients were being told that if this continues, 2:12:41.200,2:12:45.840 you'd have to pay out of pocket for your medications and that's actually 2:12:46.560,2:12:51.760 troubling for the patient community. Additionally, I think about the broader implication of this, 2:12:51.760,2:12:58.880 which is knowing that the funding for HIV programs is actually threatened, that also 2:12:58.880,2:13:06.160 affects manufacturers thinking about maybe wanting to exit some markets. That kind of damages a lot 2:13:06.160,2:13:10.960 of the progress that has been made over the past couple of years in the field of HIV and AIDS. 2:13:10.960,2:13:17.600 There are country governments rallying up to cover some of those gaps. But those resources 2:13:17.600,2:13:25.360 pale in comparison to the amount of resources that the US government devotes to supporting this. 2:13:25.360,2:13:34.160 As a- if someone needed treatments, I guess in the last three months, or even now, 2:13:35.040,2:13:43.360 how would the cuts and the stop works order affect them? What would they be experiencing? 2:13:43.360,2:13:51.200 I would say to paint the picture, imagine a status quo where every day, community health care workers 2:13:51.200,2:13:54.720 report to the facility, gear up with their mobile testing kits, with their ARVs [antiretrovirals], 2:13:54.720,2:14:00.000 and they go out into hard to reach areas. They identify people who are positive for HIV, place 2:14:00.000,2:14:05.280 them on treatment. Some of these are pregnant mother who don't have the resources to come to the 2:14:05.280,2:14:11.840 facility. So that abrupt suspension means those individuals will not benefit from those services. 2:14:11.840,2:14:16.960 Now, beyond those who are yet to be identified, because that's the category I just talked about, 2:14:16.960,2:14:21.840 there are people who rely on these healthcare workers to reach them to receive their refills 2:14:21.840,2:14:27.360 for ARVs, right? So the suspension was abrupt, as you know. So people were just told to stop work, 2:14:27.360,2:14:32.720 and their clients who likely would be expecting their healthcare workers to deliver ARVs to them 2:14:32.720,2:14:41.840 and would have been affected by such stop work orders, so that's pretty much it. Because there 2:14:41.840,2:14:48.000 are those who still have drugs, but there are those who are actually suffering from these cuts. 2:14:48.000,2:14:52.880 My sort of understanding, I was reading a few articles about this 2:14:52.880,2:14:57.280 and the impression that I had was, the clinics might have some of the treatment, 2:14:57.280,2:15:05.120 but they're just shut and there's no one; the staff who are paid or supported by the US are 2:15:05.120,2:15:10.560 not allowed to go in, and people can't get treatment even if it's in the clinics there. 2:15:10.560,2:15:16.400 Absolutely, yes. And the staffing, as I mentioned, the staffing support, it's not limited 2:15:17.760,2:15:22.480 to the community setting. Even in healthcare facilities, there are one-stop shops that are 2:15:22.480,2:15:28.320 staffed by individuals that are supported by the performing, as you rightly pointed out, 2:15:28.320,2:15:31.840 that stop work affected those individuals and perhaps clients 2:15:31.840,2:15:38.640 would've presented to facilities and wouldn't have had, maybe, individuals to attend to them. 2:15:38.640,2:15:44.960 And I think we were talking about refills and how often people get refills, and if that's every 30 2:15:44.960,2:15:50.320 days or every three months or so, that probably adds up to quite a lot of people who have been 2:15:50.320,2:15:56.400 directly affected by these cuts over the last, almost, I guess, two and a half months, maybe. 2:15:56.400,2:16:00.000 Absolutely. Because people, I mean it's a three month cycle. It can be a six month 2:16:00.000,2:16:06.800 cycle for people who are stable, but every day marks someone's clinic appointment, right, so. 2:16:06.800,2:16:10.560 It's a scary time for a lot of people with HIV. 2:16:10.560,2:16:18.400 How excited are you for lenacapavir in the field? I think one reason, I think, it's going to be 2:16:18.400,2:16:23.840 quite important is because of this adherence issue that you mentioned, but also meaning 2:16:23.840,2:16:30.400 that people don't need to get refills as often, so there's a bit more stability for someone who 2:16:30.400,2:16:38.640 has had an injectable. Is that also your view? Are there other things that you see as part of this? 2:16:38.640,2:16:44.000 One of the challenges with oral PrEP is having to take it every day. And with suboptimal adherence, 2:16:44.000,2:16:50.160 there's the risk of resistance developing. So having a drug that's administered twice a year, 2:16:50.160,2:16:54.559 I mean, I won't say it's as good as a vaccine, but there are challenges with developing the 2:16:54.560,2:17:01.360 HIV vaccine. So this is as good as we are currently towards making sure that people 2:17:02.479,2:17:09.839 keep from getting infected with HIV. It's very exciting in the HIV prevention landscape, having 2:17:09.840,2:17:16.000 an injectable once a year, fingers crossed, but that would be amazing. That would be phenomenal. 2:17:16.000,2:17:18.160 We're almost there. We're almost there. 2:17:18.160,2:17:21.120 That was really helpful. Thank you so much 2:17:21.120,2:17:23.200 Thank you so much Douglas. 2:17:23.200,2:17:27.040 Thanks so much. Thanks so much. Happy to talk about this and very excited about 2:17:27.040,2:17:31.280 the development in the HIV prevention space. Hopefully these developments 2:17:31.280,2:17:37.104 continue and move the needle in terms of achieving epidemic control of HIV and AIDS. 2:17:37.104,2:17:41.359 That was great. This was so cool, to phone a friend and learn about what things are 2:17:41.359,2:17:47.040 like in treatment in Nigeria, the future of lenacapavir. But also, 2:17:47.040,2:17:55.439 all of the funding cuts and the disruption that's going on there right now. I think it really made 2:17:55.439,2:18:04.399 me think of how important some of these new drugs could be in terms of changing around the epidemic 2:18:05.120,2:18:14.000 in HIV, the possibility of using long-acting drugs, and by that we mean drugs that have an 2:18:14.000,2:18:20.720 effect for a really long period. Currently we have cabotegravir, which is a two monthly drug. 2:18:20.720,2:18:25.920 There's also lenacapavir, which is a six monthly drug. And potentially, 2:18:26.640,2:18:32.240 Gilead is also working on a once-yearly drug. And if that pans out, again, 2:18:32.240,2:18:38.479 I think it would completely change our ability to respond. Whether that is actually scaled up 2:18:38.479,2:18:46.639 is another question, and that's something we'll talk about later on. But it's really, 2:18:46.640,2:18:52.880 I think it's a change in what's possible in treating and preventing HIV. 2:18:52.880,2:18:59.439 Yes. And I feel like I have a lot to digest and we have a lot still to discuss. 2:18:59.439,2:19:10.639 So lemme go away for a second and think. Okay, Saloni, we're back. How you doing? 2:19:10.640,2:19:16.560 I'm doing great. It's been five days. I've had a lot to think about. You look 2:19:16.560,2:19:19.600 like you're in a completely different place from before. 2:19:19.600,2:19:27.520 That's right. New shirt, new background. I am in New York City. I'm in the village, 2:19:27.520,2:19:34.720 the East Village — or at least I thought I was. I arrived and was informed by someone who lives 2:19:34.720,2:19:40.640 here that I'm actually in Stuy Town, which is not the same thing as the East Village, 2:19:40.640,2:19:47.359 but I've decided to kind of squint and it feels about the same and I'm having a good time. It 2:19:47.359,2:19:57.839 feels, I wish I could say I was here funded by our podcast to do some historical analysis of the AIDS 2:19:57.840,2:20:02.720 epidemic because I was in Castro before and now I'm in the Village. And those are two important 2:20:02.720,2:20:07.439 parts to the story. However, I am actually just here visiting a friend. Totally unrelatedly. 2:20:07.439,2:20:13.040 I really enjoyed thinking about what Douglas told us about how 2:20:13.040,2:20:19.280 treatment works in the field in a clinic in Nigeria. But also just thinking about 2:20:19.280,2:20:25.439 the different approaches that people have to prevention, whether that's 2:20:25.439,2:20:34.160 with condoms or behavioural changes or PrEP, this amazing breakthrough in 2012, 2:20:34.160,2:20:42.240 of multiple drugs in a combination that can reduce the chances of infection. And 2:20:42.240,2:20:48.719 it's really interesting first to think about the behavioural aspects that lead to, basically, how 2:20:48.720,2:20:54.960 do people actually take these drugs in practice and how does that inform drug development? How 2:20:54.960,2:21:02.399 does that inform the kinds of new treatments that we need and whether they're effective. 2:21:02.399,2:21:10.000 I think that's ultimately the key breakthrough of this new drug that we're going to talk about, 2:21:10.000,2:21:17.600 lenacapavir, that instead of being a daily pill that people would take as they do with PrEP, 2:21:17.600,2:21:24.479 it's this long-acting injectable. So it's an injection that you would take. So there's, 2:21:24.479,2:21:30.559 I guess, two injections every six months, and this massively reduces 2:21:30.560,2:21:38.640 the chances of infection. It's also been used as a treatment for people with drug-resistant HIV, 2:21:38.640,2:21:43.120 and there could be other purposes for it as well. So I think that's really the key breakthrough and 2:21:43.120,2:21:51.439 I think I really started to understand exactly how that would matter for someone who has HIV, 2:21:51.439,2:21:58.559 thinking about how do they get their next supply of the drug; how this makes a difference to them. 2:21:58.560,2:22:06.640 Yeah. It also got me thinking about the costs; how can we get the costs low for new drugs so 2:22:06.640,2:22:13.280 that they can get used more. And that's something that I'm interested to talk about with lenacapavir 2:22:13.280,2:22:19.359 too. But what is lenacapavir, Saloni? It's time for you to teach me something new. 2:22:20.399,2:22:27.120 I think to teach you about what lenacapavir is, we have to go back a little bit and talk about 2:22:27.120,2:22:35.840 the capsid. So if you remember from before, the capsid is this thimble-like structure within the 2:22:35.840,2:22:44.399 HIV virus that contains the RNA molecule, and it contains a bunch of other enzymes. It's the core 2:22:44.399,2:22:53.519 that stays intact when HIV enters cell, and this capsid takes that information, and those enzymes, 2:22:53.520,2:23:03.120 into the cell's nucleus. They then allow the RNA molecule — the genetic code of HIV — to 2:23:03.120,2:23:12.479 turn into DNA to integrate into our own cellular DNA, and then to proliferate into many more HIV 2:23:12.479,2:23:21.040 particles. So it's this key structure that's kept intact throughout this process. Once it gets to 2:23:21.040,2:23:29.840 the nucleus, it then starts to dissolve, letting the RNA molecule out, letting the enzymes out to 2:23:29.840,2:23:38.399 do their jobs. And then, later on, when the new HIV particles start to be formed, it then starts 2:23:38.399,2:23:44.639 to form; the capsid starts to form again. This process is actually really interesting; 2:23:45.760,2:23:51.439 and quite interesting, both as a process but also in terms of what it looks like. 2:23:51.439,2:23:51.600 Yes! 2:23:51.600,2:24:03.439 This HIV capsid is made up of, I think, more than 1,500 or so proteins. But each of these 2:24:03.439,2:24:09.679 proteins comes in groups. So some of the groups of this protein are in groups of six, 2:24:09.680,2:24:15.439 which are called hexamers. So hex- is six, and some of them are in pentamers; 2:24:15.439,2:24:26.160 penta- means five, but there are 250 hexamers or so, it kind of varies. And exactly 12 pentamers. 2:24:26.160,2:24:30.160 I'm looking at it now, and it looks like flower petals that are falling 2:24:30.160,2:24:35.760 into place. How on earth is it so exact? Why are there 12? Why are there 12? And 2:24:35.760,2:24:43.760 the 12 are not exactly... they're sort of dotted around in a pretty pattern, 2:24:43.760,2:24:49.359 but not necessarily how I would've designed it, if I were thermodynamic. 2:24:49.359,2:24:55.120 Yeah, I mean if you're listening, it's this thimble-shaped structure. Most of 2:24:55.120,2:25:02.399 that is made of hexamers of this protein. So, imagine some six-shaped thing, maybe like a 2:25:02.399,2:25:11.345 star-shaped cereal that I used to have called Honey Stars. Oh yeah. And they were very tasty. 2:25:11.345,2:25:13.040 Or Shreddies, which I'll never say a bad word against. 2:25:14.560,2:25:21.360 And then, in a few places in this capsid, there are other structures that are only five 2:25:22.080,2:25:28.800 that only have five proteins. So they're like five-star shapes. And these look, 2:25:28.800,2:25:37.359 I mean, where these are organised in the whole capsid doesn't look very symmetrical to me. 2:25:37.359,2:25:37.920 No. 2:25:38.880,2:25:46.240 And it's quite strange, but what I was reading was that: the placement or the number of these 2:25:46.240,2:25:52.960 pentamers within the whole structure changes the whole shape of it. It's sort of like, 2:25:52.960,2:25:58.080 this structure, that's where the hexamer are tesselating. So they're all fitting 2:25:58.080,2:26:04.000 together in this very symmetrical way between them, but then these five-shaped 2:26:04.000,2:26:11.040 pentamers determine the curve, I think, of the capsid. That's very interesting. 2:26:11.040,2:26:15.920 Yeah. I feel like I want... if I redo the tiles in my bathroom or something, 2:26:15.920,2:26:21.600 I want to do this. But now that you've told me the shape, the 3D structure, 2:26:21.600,2:26:27.359 is an important property, that wouldn't be so good on tiles. So I'm going to have to rethink. 2:26:27.359,2:26:30.559 You would have... Maybe it would be more like a flower vase? 2:26:30.560,2:26:34.880 Yeah. Oh, great idea actually. Yeah, it's very floral, it's just so, 2:26:34.880,2:26:41.920 it is very beautiful. I recommend people listening Google it. And I think recently, 2:26:41.920,2:26:45.040 it's only the last 10 years or something where we've really known what these 2:26:45.040,2:26:48.960 different polymers look like and how they assemble and all that. Is that right? 2:26:48.960,2:26:58.880 I think that's right. Only since the 2010s have we had advances in microscopy that allow us to see 2:26:58.880,2:27:03.040 some of these particles, with enough resolution to see what they actually 2:27:03.040,2:27:09.760 would look like in this coherent structure. That is super interesting. 2:27:09.760,2:27:15.359 As I think about the drugs you've described previously, what is interesting about this one: 2:27:15.359,2:27:19.920 if we're talking about the capsid and we're going to try and go after the capsid with a drug, 2:27:22.000,2:27:29.040 this is a structural part of the virus, but it's not as functional 2:27:29.040,2:27:33.680 in the direct sense. I'm not imagining something getting integrated into my DNA, 2:27:33.680,2:27:40.880 so I'm going after the integrase; and I'm not imagining I'm chopping up the large string of 2:27:40.880,2:27:46.640 proteins into smaller proteins, and going after the protease. This is more like just a package, 2:27:46.640,2:27:51.680 a thimble, a bullet; that it must be required, because why would it still 2:27:51.680,2:27:58.560 be there? But the function is not as direct. I don't know. Does that ring through to you? 2:27:58.560,2:28:04.160 I think you're kind of right, but I think it is important. Because to make sure all 2:28:04.160,2:28:09.040 of this stuff doesn't fall out, I guess, in some other part of the cell. Like, 2:28:09.040,2:28:17.120 we need to carry or transport the RNA molecule and the other enzymes to the nucleus. But it 2:28:17.120,2:28:24.960 also has these functions where, based on the structure, based on the shape of this 2:28:24.960,2:28:32.319 capsid — that allows it to enter the nuclear pores and the nucleus, the little holes and 2:28:32.319,2:28:39.759 this shape allows it to wiggle through. And I think it might also be involved in stimulating 2:28:39.760,2:28:47.680 the reverse transcriptase step. So the capsid is somehow involved in making that start, 2:28:47.680,2:28:54.080 and I think that is also quite a new discovery that people have had within the last five years. 2:28:54.080,2:28:58.800 Got it. Anyway, keep going. Thanks for pausing for me. 2:28:58.800,2:29:04.880 Not at all. Okay. So we've talked about what the capsid looked like. What does lenacapavir have 2:29:04.880,2:29:13.920 to do with this? This also, it really helps to have a visual, but I'm going to try to explain it 2:29:14.640,2:29:20.560 in words as well. So we have this structure where, the capsid is made out of these proteins. 2:29:20.560,2:29:26.080 The proteins are sometimes in hexamers, sometimes in pentamers; I guess if you 2:29:26.080,2:29:31.359 imagine that these hexamers or pentamers are fitting together, they're a bit like, 2:29:31.359,2:29:39.280 putting your hands together with your knuckles. They're kind of fitting together between your 2:29:39.280,2:29:47.359 fingers. And imagine doing that lightly; you're not fitting them too strongly. So 2:29:47.359,2:29:53.200 there's a little bit of space and flexibility between your two hands. But then, lenacapavir, 2:29:54.479,2:30:02.879 it wedges itself into those gaps between both of your hands' knuckles. And that 2:30:02.880,2:30:10.080 means that it now becomes very stiff. Now you don't have this much ability to move, 2:30:10.080,2:30:18.640 to move the structure around. This stiffness becomes a problem in several ways during the 2:30:18.640,2:30:27.920 HIV's life cycle. I think that's quite cool just to think about how the overall shape of this 2:30:27.920,2:30:35.520 capsid changes, based on lenacapavir fitting into these little gaps between the proteins. 2:30:35.520,2:30:38.560 That is good. It's quite subtle as well. 'Cause it's not, I think of a 2:30:38.560,2:30:42.319 drug coming in and trying to nuke some structure, you know, blow it up. But 2:30:42.319,2:30:49.439 actually you're saying no, we're just going to change properties of how squidgy it is. 2:30:49.439,2:30:55.839 No, exactly. And yeah, I mean, I think it's fascinating. So we have all of these little 2:30:55.840,2:31:02.000 lenacapavir molecules. Lenacapavir itself is quite a small molecule, so it fits into 2:31:02.000,2:31:08.479 these little gaps. And if we go back to this lifecycle of where the capsid is imported, 2:31:08.479,2:31:16.080 so we have: the HIV virus has entered the cell, has released some of its contents, which includes 2:31:16.080,2:31:23.040 the capsid. The capsid is then trying to enter the nucleus. In order to get into the nucleus, it has 2:31:23.040,2:31:30.880 to fit through these holes, the nuclear pores. And to do that, it binds to certain proteins on 2:31:30.880,2:31:39.200 the nuclear pore. And it turns out that those binding spots are blocked by lenacapavir. 2:31:39.200,2:31:39.600 Okay. 2:31:39.600,2:31:46.160 So it binds in exactly the same spots where those proteins would attach and let it squeeze through 2:31:46.160,2:31:54.479 those gaps. And the second thing is, the capsid is now too stiff, because of lenacapavir blocking, 2:31:54.479,2:31:57.599 so it's less flexible. Knuckles are engaged. 2:31:57.600,2:32:05.760 Exactly. Your knuckles are engaged. You can't squeeze through the little holes of the nucleus. 2:32:05.760,2:32:11.840 So that's another important thing. Then, the next step, and this is super 2:32:11.840,2:32:17.280 interesting, so it's not just that one step that lenacapavir disrupts, but it's actually multiple 2:32:17.280,2:32:25.519 steps during this life cycle. Imagine that some of the capsids have still somehow made it through to 2:32:25.520,2:32:37.520 the nucleus. Now the capsid needs to dissolve and allow the RNA molecule out, and allow the reverse 2:32:37.520,2:32:45.439 transcriptase to turn the RNA into DNA. It needs integrase to turn that DNA into a part of our 2:32:45.439,2:32:54.479 own cell's DNA. But now it can't break; it can't dissolve. It can't uncoat anymore, because of this 2:32:54.479,2:33:06.639 rigidness. It's just too rigid. But also sometimes it's so rigid that it cracks too early, and that 2:33:06.640,2:33:15.280 early cracking makes it hard for the capsid stimulating the reverse transcriptase, to start 2:33:15.280,2:33:26.880 doing that process. So that is super interesting. We've now blocked it from entering the nucleus. If 2:33:26.880,2:33:33.120 some gets through, it's now not able to release its contents, or it breaks too early. And then, 2:33:33.120,2:33:41.040 there's a third part that lenacapavir disrupts as well. So imagine that you've now, somehow, 2:33:41.920,2:33:46.800 some of the virus particles or some of the capsids have still made it through, or maybe you're in a 2:33:46.800,2:33:54.800 different part of the HIV virus lifecycle. You're now trying to create these new virus particles, 2:33:54.800,2:34:04.399 the descendants of the initial one. In order to do that, we have this, the immature HIV virus, and 2:34:04.399,2:34:05.359 I remember, yeah, 2:34:05.359,2:34:11.439 This now has protease involved, right? So we have protease cutting up these giant 2:34:11.439,2:34:19.839 polyproteins into their proper form, and we have this new capsid trying to form, 2:34:19.840,2:34:27.920 to surround all of the RNA and the other enzymes. But what happens with lenacapavir is that, because 2:34:27.920,2:34:41.200 it's in this too stiff kind of formation, it's unable to form in the correct shape and it just 2:34:41.200,2:34:50.399 doesn't fully form. So there's this image here, where you can see that the normal way that all 2:34:50.399,2:34:58.719 of these proteins in the capsid form is that- We, okay, so we have all these hexamers and pentamers; 2:34:58.720,2:35:04.479 they create these little clusters, they somehow self-assemble. Maybe this is just 2:35:04.479,2:35:09.520 something that we don't understand yet, but somehow they self-assemble into a bigger. 2:35:09.520,2:35:14.160 Which blows my mind just from, if I'm visualising the cytoplasm of a cell, I'm like, 2:35:14.160,2:35:20.240 there's so much going on there. How do these all stay together and not get distracted? But anyway. 2:35:20.240,2:35:28.719 Exactly. So we're getting these clusters of multiple hexamers and pentamers. That happens, 2:35:28.720,2:35:33.840 but now because of the stiffness, the shape isn't forming correctly, 2:35:33.840,2:35:41.600 and the full shape just doesn't work anymore. So I mean I think this whole process to me was 2:35:41.600,2:35:48.960 really interesting to learn about. I knew that lenacapavir somehow had this amazing effect, 2:35:48.960,2:35:54.479 at very low concentrations. It somehow has a really long effect lasting for at least 2:35:54.479,2:36:01.280 six months. But I didn't really know about the mechanics of that works. And the other thing I 2:36:01.280,2:36:08.160 didn't realize, until reading for this episode, was multiple steps are inhibited. So it disrupts 2:36:08.160,2:36:14.479 this process at multiple steps. I think that... Now, I would say this doesn't mean that it's 2:36:14.479,2:36:21.679 impossible to develop resistance against it, but it does probably explain why it's so effective, 2:36:21.680,2:36:25.200 that it's targeting these multiple steps. It's reducing the probability 2:36:25.200,2:36:31.599 that an infection can and multiply, and so I think that was very interesting. 2:36:31.600,2:36:34.960 Yeah, I was going to say, it sounds almost like a combination drug itself. If you've 2:36:34.960,2:36:41.600 got three different stages it's acting at. But I don't know if the mutations that would generate 2:36:41.600,2:36:46.479 resistance to are correlated there or not. It makes sense to me they'd have a fail safe, 2:36:46.479,2:36:51.040 for mopping up the capsids that try and form out the other end. 2:36:51.040,2:36:56.560 I think what I've learned is that there is still... drug resistance can form, 2:36:56.560,2:37:03.439 but it's something that forms if someone is on long-term treatments with lenacapavir; 2:37:03.439,2:37:07.599 it's not something that they would have before the infection. And so, 2:37:07.600,2:37:16.080 it is still useful as a preventive, sort of, anti-infection tool. But as a treatment, 2:37:16.080,2:37:21.200 there have been cases of people developing resistance and that would be through exactly 2:37:21.200,2:37:25.276 how lenacapavir fits into the little gaps between the capsid proteins. 2:37:25.276,2:37:26.000 The gaps. 2:37:27.600,2:37:29.840 If you change the shape of that, yeah. 2:37:29.840,2:37:36.000 It makes just from a selection pressure point of view. If you've got many more viral particles, 2:37:36.000,2:37:39.359 you're infected already, then you've got higher probability, 2:37:39.359,2:37:47.280 probably, of a mutation that's good for HIV. Neat. I like it. How did 2:37:47.280,2:37:52.719 it come about from a- was this the first capsid inhibitor? Lenacapavir? 2:37:52.720,2:37:57.200 This wasn't the first capsid inhibitor, I think people had been trying to target 2:37:57.200,2:38:08.160 it for a while. And in 2010, Pfizer had developed another molecule called PF-74, 2:38:08.160,2:38:17.519 and that seemed to bind to this little gap, this pocket as well, and it could block and 2:38:17.520,2:38:27.280 hyper stabilize the whole capsid shape. But it didn't work so much in the human body; 2:38:27.280,2:38:32.639 this drug, it was taken orally, and it just didn't stick around in your body. 2:38:32.640,2:38:41.120 And so they gave up on the drug and they started working on other drugs instead. Instead, 2:38:41.120,2:38:50.240 what happened was Gilead tried to build on this PF-74. It seemed quite promising, 2:38:50.240,2:38:58.399 because you do have this, you have a potential way of targeting the capsid protein. But we're 2:38:58.399,2:39:06.719 just missing out on making it more available in the body and long lasting. And so they did 2:39:06.720,2:39:12.399 something called "parallel synthesis". They just tried creating lots of very similar compounds 2:39:12.399,2:39:18.160 to that — using the same molecule, but then adjusting it in lots of different ways. And 2:39:18.160,2:39:24.319 the way that happens in the lab is, you have lots of test tubes or plate wells, where you have the 2:39:24.319,2:39:33.359 initial molecule PF-74, and then you run lots of different reactions in those different test tubes, 2:39:33.359,2:39:39.200 under the same conditions — so you have maybe three or four, with some reaction going on and 2:39:39.200,2:39:50.479 so on. And they did a lot of iteration based on that and eventually resulted in lenacapavir. 2:39:50.479,2:39:56.799 Got it. Well, thank you PF-74 for trying first. It's interesting. It sounds like 2:39:56.800,2:40:03.840 we had the idea and there was some binding going on and it was working okay. But then, 2:40:03.840,2:40:09.120 the practicality of the human body — you've got a lot more steps. You don't just have to bind 2:40:09.120,2:40:16.080 the part of the HIV virus, you also have to survive the machinations of the human organs. 2:40:16.080,2:40:22.319 And this is the really interesting thing that we'll talk about later. In terms of, 2:40:22.319,2:40:28.479 how does this actually stick around for so long in the body? How does this have an effect for over 2:40:28.479,2:40:35.359 six months? That itself is really impressive to me. I thought they could maybe just briefly talk 2:40:35.359,2:40:40.960 about some of the different kind of iterations that people do and how important they are 2:40:40.960,2:40:43.120 To lenacapavir, or? 2:40:43.120,2:40:52.240 Yeah, exactly. So we have PF-74. Actually don't you know someone who worked on this? 2:40:52.240,2:40:59.040 I do, I do. I was wondering whether to say, but I think I may have mentioned her earlier 2:40:59.040,2:41:07.600 and she in her PhD worked on PF-74, so in an academic setting, not at one of the companies, 2:41:07.600,2:41:11.600 but I think she knows a bunch of the iterations that you're about to tell me, 2:41:11.600,2:41:16.319 but I don't know; I should have asked her more questions first. 2:41:16.319,2:41:23.120 Yeah, I mean it's so fascinating to know that there are people surrounding 2:41:23.120,2:41:28.720 us that have been responsible for these huge breakthroughs, and they're just normal people- 2:41:28.720,2:41:29.220 I know. 2:41:30.240,2:41:31.679 Sometimes friends. 2:41:31.680,2:41:36.640 I had to tell her I was about to talk about lenacapavir, before I realised 2:41:36.640,2:41:43.680 that she had done all the- well, so much of the work, that led up to it. It's wild. Yeah. 2:41:43.680,2:41:50.319 I think, yeah, it's incredible. Okay, so we have PF-74, what happens now? So we 2:41:50.319,2:41:54.880 have all of these little reaction test tubes going on. One of them, 2:41:54.880,2:42:00.960 they introduced a hydroxyl group — that's basically an oxygen and a hydrogen, 2:42:00.960,2:42:07.600 and then they added an indole ring — that's a fused ring structure. So there's multiple 2:42:07.600,2:42:16.000 atoms in a ring with a nitrogen group. This massively increased the effect of the drug, 2:42:16.000,2:42:20.960 but it didn't work in the body, because it was broken down by enzymes in the liver. 2:42:20.960,2:42:21.460 Okay. 2:42:21.840,2:42:29.040 Okay, we've got, this one, it didn't really work out. Then they tried another type of ring. This 2:42:29.040,2:42:37.120 is a six structured ring with one nitrogen atom instead. This then improved how stable it was 2:42:37.120,2:42:43.840 in the body. It was not broken down very quickly anymore, but now, the effectiveness was reduced. 2:42:44.640,2:42:49.120 I love how we're making atomic level differences here. Anyway, 2:42:49.120,2:42:51.840 keep going. Okay, so we tried that one. No luck. 2:42:51.840,2:42:59.680 They did a bunch of other changes. There were some seven or eight compounds they made, 2:42:59.680,2:43:05.520 before getting to this breakthrough. This actually comes from this really interesting book that I was 2:43:05.520,2:43:14.160 reading called Drug Development Stories, and these researchers just put together how all of 2:43:14.160,2:43:20.240 these different types of breakthrough drugs in the last few years were developed. And so this last- 2:43:20.240,2:43:24.960 I have few books like that that I'm trying to, I can't remember if I own that one, 2:43:24.960,2:43:28.399 but they're fun to flick through some. I'm going to have to check my bookshelf 2:43:28.399,2:43:33.759 when I get back to San Francisco. If not, it's going on the order list. 2:43:33.760,2:43:40.160 It's often hard to find the exact stories about- behind how these drugs are developed, 2:43:40.160,2:43:45.439 and I assume part of that is because it might be some kind of trade secret or something like that. 2:43:46.319,2:43:51.599 But when I do come across someone writing a retrospective or, you know, someone giving 2:43:51.600,2:43:56.880 me the details, it's just a completely different picture. It really helps you 2:43:56.880,2:44:02.720 understand exactly what they struggled with, how they were thinking about the process, and so on. 2:44:02.720,2:44:04.800 So if you're listening and you're working on 2:44:04.800,2:44:09.520 drug development in some form and you're wondering, oh, if I write up my process, 2:44:09.520,2:44:15.600 is anyone even going to read it? We're gonna to read it. Write it up! Saloni needs it! 2:44:15.600,2:44:22.319 I need it. I love it. Okay, so now we have this breakthrough compound, 2:44:22.319,2:44:28.080 I think, which might've been the ninth one that they made as an adjustment. 2:44:28.080,2:44:34.720 They now replaced the amide group with an amino indisole group. And that is a ring 2:44:35.600,2:44:44.240 with two nitrogen atoms. This improved both the potency, how well it fit, and also reduced the 2:44:44.240,2:44:51.679 level of breakdown in the body. This felt like, okay, we're making something that 2:44:52.640,2:44:57.359 effectively tracks both of these key things that are important in drug development. 2:44:57.359,2:44:58.319 Got it. 2:44:58.319,2:45:04.880 Then it was just slight adjustments, slight tweakings from there. They added another 2:45:05.600,2:45:10.479 amino group, they changed the placement of the amino group. They introduced a sulfone 2:45:10.479,2:45:17.040 group — that's a sulphur with two oxygens, and that was what resulted in this very 2:45:17.040,2:45:23.799 highly potent molecule that was very stable in the body, and that became lenacapavir. 2:45:23.799,2:45:29.920 Wow! We made it. Highly potent, highly stable. And it's funny, 2:45:29.920,2:45:35.439 I think when you say, "The body's not breaking it down well", to me it sounds like, "Oh God, 2:45:35.439,2:45:40.160 the body's not breaking it down well?" And in fact, we've been seeking a molecule the 2:45:40.160,2:45:45.920 body doesn't break down well, because it can last for longer and protect you for longer. 2:45:47.120,2:45:52.800 It's different purposes, right? If you're trying to reduce maybe the side effects of some drug, 2:45:52.800,2:45:59.760 you want it to get broken down very quickly, just have its action; disappear. But if you're 2:45:59.760,2:46:04.640 trying to develop some drug that has a very long lasting effect, then you want 2:46:04.640,2:46:13.600 it to stick around for a long time. So, I mean, finding something that is both very safe, very 2:46:14.240,2:46:24.080 highly effective — potent — and also very stable in the body that makes a great long lasting drug. 2:46:24.080,2:46:27.920 That's the trio. And we got there. 2:46:27.920,2:46:34.240 The other interesting thing I learned about lenacapavir, and I think you might maybe come 2:46:34.240,2:46:40.719 to this later on, but it's the drug with the most fluorine atoms in it that's approved by the 2:46:40.720,2:46:49.680 FDA in the US. So fluorines are often used to increase the stability, I think, in the body, 2:46:49.680,2:46:57.920 and lenacapavir has 10 of these atoms in the whole molecule. Usually, that has led to drugs 2:46:57.920,2:47:04.319 that are unsafe in some way, but in this case it has a very high safety profile as well. 2:47:04.960,2:47:11.279 I remember seeing that, and I'm not enough of a chemist to tell you why there aren't more, 2:47:12.880,2:47:14.640 but I do like the idea that there's fluorine 2:47:14.640,2:47:20.080 in the aqueous solution. There's fluorine in the water, you know. 2:47:20.080,2:47:25.279 What did we- we talked to your friend, Sanela, is that right? 2:47:25.279,2:47:25.920 Yeah. 2:47:27.040,2:47:34.319 Was there stuff that you learned from her on lenacapavir and capsid inhibitors as well, 2:47:34.319,2:47:36.719 beyond what we've talked about? 2:47:36.720,2:47:44.000 The thing that she emphasized to me was really in line with what you just said, about how iterative 2:47:44.000,2:47:56.240 the process was. That starting with PF-74, as a great binder, there was a lot of tries for just... 2:47:56.240,2:48:01.359 getting the other properties that could make this into a useful drug. So I think the thing she was 2:48:01.359,2:48:09.120 really struck by was the "PK", as drug developers say, looking really good for lenacapavir. 2:48:09.120,2:48:10.479 What's the PK? 2:48:10.479,2:48:19.040 The pharmacokinetics, I want to say, and there's again: this will betray that I'm not a medicinal 2:48:19.040,2:48:25.760 chemist. But pharmacokinetics and pharmacodynamics are the two things that you'll hear people talk 2:48:25.760,2:48:32.319 about all the time, about how the body processes drugs. But I mean also, she was really emphasising 2:48:32.319,2:48:37.920 that previous molecules' stability was an issue. And then seeing lenacapavir being so 2:48:37.920,2:48:44.560 stable and so low toxicity. You know, you have such a small amount and it can stick around for 2:48:44.560,2:48:52.640 six months; and it's getting to the 20th or 15th iteration of the initial principle. Then getting 2:48:52.640,2:48:59.439 those great properties, it was wonderful for her to see as someone in the field. And 2:48:59.439,2:49:06.000 as someone outside of the field, I didn't realise. I'd heard of lenacapavir as this miracle drug, 2:49:06.000,2:49:11.279 and I didn't realise, of course, what came before. There's a lot of steps to get there. 2:49:11.279,2:49:16.719 It's not that you suddenly come out swinging and suddenly discover the exact perfect thing. 2:49:18.160,2:49:23.680 Right. I mean, the thing that I remember, I did my undergraduate degree in biomedical 2:49:23.680,2:49:30.640 science like 10 years ago, I think? And I remember a little bit about pharmacology 2:49:30.640,2:49:39.360 on PK as, it's more, you're measuring both how fast is the drug broken down, 2:49:40.240,2:49:47.679 how much of the drug is broken down, how quickly, but also how available is it? How much does it 2:49:47.680,2:49:54.800 actually get to the organs that you need it to get to? Is it able to have its effect there? 2:49:54.800,2:50:01.600 And I think with lenacapavir, it seems to be very effective even at small doses. So if you imagine 2:50:01.600,2:50:07.920 that over time, so you have this injection first, of lenacapavir, and then, over time, 2:50:07.920,2:50:15.359 there's this decaying exponential curve. So it just quickly starts to break down, and then that 2:50:15.359,2:50:25.279 break down process slows down. But even at the very low levels, it's still very effective, and 2:50:25.279,2:50:37.200 able to block this little site within the capsid proteins. And that is what makes it so effective. 2:50:39.439,2:50:48.559 Well, let's do a quick detour, if you'll let me, on long-acting drugs other than lenacapavir. 2:50:48.560,2:50:58.720 Because the principle we're talking about applies not just to this molecule. The nature 2:50:58.720,2:51:03.840 of a long-acting injectable or a long-acting drug, well, what makes it long lasting? What 2:51:03.840,2:51:09.520 makes it long-acting? It's relative to what we're used to; relative to immediate release drugs. 2:51:09.520,2:51:16.640 You know, if you think about the PrEP drugs that we talked about earlier in the episode — those you 2:51:16.640,2:51:24.000 take daily, and that's because you want to have enough of the active ingredient in circulation, 2:51:24.000,2:51:32.960 in case HIV enters your system during that period. But pretty quickly, most drugs get metabolised and 2:51:32.960,2:51:39.920 get filtered out and leave your body in urine, and sometimes other ways, but that's the main one. 2:51:40.800,2:51:48.319 So an issue that you mentioned is: if you have to take a drug every day, you might forget to take 2:51:48.319,2:51:52.799 it. You might run out of the drug and not have time to get a refill for a few days, or a week, 2:51:52.800,2:52:00.560 or I actually am behind on refills, because I'm in New York right now. Or you might not want people 2:52:00.560,2:52:09.440 who you live with to see that you take pills regularly, so keeping them around is not ideal. 2:52:10.240,2:52:16.719 This is important with HIV as well, because some of the preventive drugs 2:52:16.720,2:52:21.680 might also look like treatment drugs. I think you mentioned this earlier. And 2:52:21.680,2:52:27.840 so there's also the stigma around people thinking that you have an HIV infection, 2:52:27.840,2:52:31.920 and then they're worried about that, even though these drugs are very effective and 2:52:31.920,2:52:40.560 it's very unlikely to transmit, if you're using these drugs. But I think this whole thing of: 2:52:40.560,2:52:47.920 "how do people actually take it in their daily life?" is so relevant through drug development. 2:52:47.920,2:52:53.840 Absolutely. And the long lasting prevention that people might be most familiar with is birth 2:52:53.840,2:53:04.720 control. Where a lot of, some similar issues are a big part of what can drive different women to 2:53:04.720,2:53:11.200 want to make different choices with birth control. So the pill was first approved by the FDA in 1960, 2:53:11.200,2:53:17.040 after development in the '50s, as daily oral contraception. And then from the '60s onwards, 2:53:17.040,2:53:25.680 there was a lot of work to see if you could make the different options for birth control 2:53:25.680,2:53:32.800 long lasting. So can you have hormones that are inside a silicone tube of some form, that you can 2:53:32.800,2:53:40.720 control the diffusion over time, so that you don't have to take daily pills or take a daily hormones. 2:53:41.920,2:53:48.800 And now there are multiple options for that. So you can have hormonal IUDs that release 2:53:48.800,2:53:56.880 progestin slowly over time. You can have arm implants. The approach there, is to take an 2:53:56.880,2:54:03.520 existing biological molecule, or synthesise an alternate of a hormone, and then have a 2:54:03.520,2:54:08.479 different packet that controls the diffusion. So it's a bit different than what we just talked 2:54:08.479,2:54:19.599 about with lenacapavir, where the drug itself is so insoluble and stable and it itself sticks 2:54:19.600,2:54:24.800 around. Whereas, let's say you have a drug that doesn't naturally stick around, well, 2:54:24.800,2:54:34.399 maybe you can design a delivery mode — a polymer, a liposome, that you can keep it inside of, and 2:54:34.399,2:54:40.080 slowly diffuse, and you can achieve the same goal. Maybe you could just put it in a drop of oil, 2:54:40.080,2:54:45.120 or you could suspend it in some other way, maybe you could put it in a device. 2:54:45.920,2:54:52.240 And sure enough, for HIV one new mode of prevention that we haven't talked much about 2:54:52.240,2:54:59.920 yet is vaginal rings — where you can have a slow release, you can insert a vaginal ring monthly, 2:54:59.920,2:55:06.560 say, and have a slow release that a woman, who wants to not be a risk of HIV, 2:55:06.560,2:55:13.600 has more control over if you have to get in some circumstances, than if she had to get 2:55:14.479,2:55:19.839 pills that were more visible to people in her household or her husband or something like that. 2:55:19.840,2:55:30.160 So there are a lot of different strategies here. When it comes to HIV, what's interesting to me is 2:55:30.160,2:55:37.519 that there are a few long lasting drugs that are being tested now, or are near the finish line now, 2:55:37.520,2:55:46.880 that use different approaches and yet achieve this kind of similar goal. The three that come 2:55:46.880,2:55:53.200 to mind for me are lenacapavir, which we've been talking about a lot, but then also cabotegravir, 2:55:53.200,2:55:59.840 which is already approved in some countries — in the US — which is this injection every two 2:55:59.840,2:56:06.479 months. And then also islatravir, and other follower drugs, that are being made by Merck, 2:56:06.479,2:56:12.160 that are oral drugs that you might be able to take once a month for prevention; 2:56:12.160,2:56:15.840 or for treatment, maybe you take once a week. There's a few different regimens 2:56:15.840,2:56:24.560 being tested. And my understanding of why islatravir sticks around for a month is- 2:56:24.560,2:56:26.080 Which one is islatravir? 2:56:26.080,2:56:29.024 Islatravir is a drug- 2:56:29.024,2:56:29.040 Is that Merck's? 2:56:29.040,2:56:37.439 Yes. Made by Merck. You know, imagine instead of taking daily oral PrEP, you take one pill once a 2:56:37.439,2:56:47.279 month say, and they've tested that regimen. What happens after you ingest that pill is, 2:56:49.680,2:56:56.800 the active ingredient sticks around intracellularly. So it's not- when you're 2:56:56.800,2:57:02.080 imagining lenacapavir, what you should imagine is: you've got a drug substance dissolved, in a liquid 2:57:02.080,2:57:09.439 that's 40% water; you are getting injected with that. The liquid's kind of dispersing, 2:57:09.439,2:57:14.879 and the drug is sticking around and forming a solid on the video just pointed at my arm, 2:57:14.880,2:57:20.880 but it's not in your arm, it's your stomach or in your butt. Then that active ingredient 2:57:20.880,2:57:28.000 is slowly dissolving, over the course of many months. Whereas, with islatravir, 2:57:28.000,2:57:34.479 you should imagine that the active ingredient is, in some way — and I wish I knew more about this, 2:57:34.479,2:57:40.319 I don't — is in some ways sticking around in your cell. So that if the HIV virus is entering 2:57:40.319,2:57:46.399 your cell, it's going to do its work, which is wonderful, but it's not some big depot or some 2:57:46.399,2:57:52.399 big lump. It's totally different and it might stick around for different biological reasons. 2:57:52.399,2:58:00.960 That is so interesting. I had no idea I was going to ask about this container or the package. Does 2:58:00.960,2:58:07.359 the package dissolve? Is the package, is that actually a separate molecule, or something 2:58:07.359,2:58:12.399 like that? But you answered my question. I guess that also varies with other drugs. 2:58:12.399,2:58:17.439 Yes, it does vary with other drugs, and the answer will differ for other drugs, 2:58:17.439,2:58:26.240 because there are different ways to achieve the goal. If you don't get a drug like lenacapavir 2:58:26.240,2:58:35.279 that has properties of slow degradation, then you might want to achieve the goal via packaging 2:58:35.279,2:58:40.319 your active ingredient differently. One thing that I think is, in a way, 2:58:40.319,2:58:48.399 fortunate about both lenacapavir and islatravir and cabotegravir — which is also an injection 2:58:48.399,2:58:56.240 that's a suspended solid that slowly degrades — is that you don't need a very complicated package. 2:58:56.240,2:59:05.920 Because a complicated package adds complexity, manufacturing cost, and makes me less optimistic 2:59:05.920,2:59:13.600 that in the near-term a drug will get used in lower resource settings. Whereas the simpler you 2:59:13.600,2:59:21.920 can make the package, the more likely you can use a drug in many settings. In this case, it's just 2:59:21.920,2:59:29.520 the drug itself — well, simplifying a little — but it's mostly the drug itself in a syrup solution. 2:59:29.520,2:59:34.241 And you know what? I could take a look at that. I might be able to one day inject myself with that. 2:59:34.800,2:59:38.880 This is so interesting. I mean, the other thing that reminded me was, I think what 2:59:38.880,2:59:45.680 I read about the fluorine atoms, is that those help it stick around in your fat. So you have 2:59:45.680,2:59:53.120 the injection either in your abdomen or your butt, and then I think the fluorine atoms keep 2:59:53.120,3:00:04.080 it around the fatty areas, but also they create this little lump underneath your skin, right? 3:00:04.080,3:00:10.160 Yes. Well, I mean, absolutely. And as I think about the lump, 3:00:10.160,3:00:13.200 I was just thinking about it spatially, and I would love someone who's worked on 3:00:13.200,3:00:18.319 injectables and on lenacapavir to correct me in the comments, if I'm thinking about 3:00:18.319,3:00:25.920 it spatially wrong, but. Is lenacapavir a one or two millilitre injection? Do you happen to recall? 3:00:25.920,3:00:28.000 Yes. Yeah, it is one to two. 3:00:28.000,3:00:35.760 Okay. So my memory of how millilitres work is that that's one cubic centimetre. Is that right? Okay, 3:00:35.760,3:00:41.359 so now I'm visualising we've got some liquid that's one by one by one centimetre. That's quite 3:00:41.359,3:00:48.799 a lot. And you get injected somewhere, and the liquid does disperse it. You've only got some of 3:00:48.800,3:00:54.080 it left, but a good amount of what you're getting injected with is this high concentration drug that 3:00:54.080,3:01:01.040 becomes solid. So sure enough, you should expect that to be a lump. You just got injected with a 3:01:01.040,3:01:05.920 decent volume of stuff and fair enough, some of it precipitates and becomes solid. If there 3:01:05.920,3:01:10.560 wasn't a lump, I'd almost be confused. I'd be like, where did it go? I thought it was meant 3:01:10.560,3:01:16.480 to stick around for six months, and anyway, so I think lumps form, definitely in different people. 3:01:17.120,3:01:24.559 I think what I read was also that the first injection typically leads to this lump forming, 3:01:24.560,3:01:32.880 but the subsequent doses don't. So that makes me think that maybe there's some bodily reaction to 3:01:32.880,3:01:39.200 the drug substance that creates the lump, and that the second or third time, your body gets used to 3:01:39.200,3:01:44.639 it in some way, or it just doesn't have the same reaction. But that was also really interesting. 3:01:45.920,3:01:54.720 It reminds me a little bit about when people had smallpox vaccines, you could see that from 3:01:55.439,3:02:05.200 the little mark on their shoulder. With this, you have this tangible little bump in your butt 3:02:05.200,3:02:13.519 or your stomach that typically shows you if the drug has formed this little depot. 3:02:13.520,3:02:19.520 I'm curious about these other long-acting injectable drugs 3:02:19.520,3:02:27.279 that you've read about. So how else do they differ from regular drugs that only last a 3:02:27.279,3:02:33.759 short amount of time? Are they more expensive? What's their safety like? What's all of that? 3:02:33.760,3:02:39.680 Great questions. And they, again, are going to have variable answers rather than an easy one. 3:02:40.479,3:02:47.519 It depends on what package you're including. On the safety front, you really want to have, 3:02:47.520,3:02:52.320 if anything, higher safety standards when you're doing something long lasting. Because 3:02:53.200,3:02:59.040 with a drug that washes out of your system within a day, there's only so bad it can be. 3:02:59.040,3:03:03.840 But with something that sticks around for a long time, you want to make sure it's harder 3:03:03.840,3:03:08.240 to get rid of, so you want to make sure that, before you get injected or before you take it, 3:03:08.240,3:03:15.200 there's not going to be toxicity or longer issues. I think that that is part of why, with lenacapavir 3:03:15.200,3:03:22.399 and with other drugs, you get an oral lead-in for two days before you get long injections, 3:03:22.399,3:03:30.639 just to check tolerability. It's interesting though, on efficacy as well, that you can 3:03:30.640,3:03:40.240 sometimes have the same underlying chemical, that is trying to achieve some medical goal, 3:03:40.240,3:03:47.200 but it can be higher efficacy in a long lasting injectable for a couple reasons. 3:03:47.200,3:03:55.840 One that we've mentioned is the real world and having- it's much more reliable if you just have 3:03:55.840,3:04:02.479 to get one injection or swallow one pill, than if you have to remember to do it all the time. But 3:04:02.479,3:04:08.559 another is more chemical or more to do with the body — which is that when you take daily pills, 3:04:08.560,3:04:16.560 you get this spike in how much of the drug you have, relatively soon after you take it, 3:04:16.560,3:04:23.520 operating in the bloodstream or elsewhere, that then decays relatively quickly. So you're kind of 3:04:23.520,3:04:29.920 doing this: spike and drop, spike and drop, spike and drop, for a daily drug. And that's not ideal. 3:04:30.880,3:04:37.279 Often you want to be in a therapeutic window that is not so spiky. With these long lasting 3:04:37.279,3:04:44.880 injectables, you have a lot more control, and you can tune that a lot more easily. You can predict, 3:04:44.880,3:04:49.680 okay, on a given day, how much am I going to have in my bloodstream, 3:04:49.680,3:04:55.520 based on how much I was initially injected with, and how much time it's been since then. You can 3:04:55.520,3:05:01.200 really hit that therapeutic window perfectly, so you can end up with a chemically more effective 3:05:01.200,3:05:07.439 drug. And you know, as I said, you want to check the safety a bit more though. 3:05:07.439,3:05:12.399 That totally makes sense. So the therapeutic window — that's the range of, 3:05:13.439,3:05:20.240 I guess, the volume or something of that drug in your system, and having that in the ideal range, 3:05:20.240,3:05:25.439 right? Yeah. And I guess the other thing I was thinking about was: 3:05:25.439,3:05:30.799 maybe it's not just about the predictability, it's also that there's less of a fluctuation. 3:05:30.800,3:05:40.399 Maybe some people react badly to these spikes, or the lack of- if the dosage suddenly drops, 3:05:40.399,3:05:46.559 does that mean the effectiveness is now not high enough? But if you can manage to get a stable 3:05:47.520,3:05:53.760 level of this drug for really long time, that is probably better in some respects. 3:05:53.760,3:06:00.640 Yep, absolutely. And my mind goes to: what other diseases for prevention or 3:06:00.640,3:06:10.960 for treatment — other than HIV — would you want those properties most? That's beyond the bounds 3:06:10.960,3:06:17.920 of this short podcast. But the ones that I can't wait to learn more about myself are... 3:06:17.920,3:06:25.920 So, malaria is one, where if you are under five and live in West Africa, 3:06:25.920,3:06:31.520 if you're a kid in West Africa, you will get preventive malaria drugs during the rainy season, 3:06:31.520,3:06:36.960 where you're most likely to get malaria; that's about four months long. Currently, 3:06:36.960,3:06:44.080 kids will get three-days-in-a-row worth of drugs, each month. So that's four times three. And the 3:06:44.080,3:06:51.439 drugs, they don't taste great, or kids don't always like 'em, and don't always take them all, 3:06:51.439,3:06:56.559 all three days in a row. If you're a busy parent and your kid is making a scene, 3:06:56.560,3:07:04.240 then you might not make sure to force all 12 of those doses. But if you could get a 3:07:04.240,3:07:13.040 long lasting injectable for a season, that could cover that season and make sure you had the right 3:07:13.040,3:07:17.120 amount of preventive drug in your system, if you got bit by a mosquito. My goodness, 3:07:17.120,3:07:24.240 that could be an enormous deal. I don't think, based on my knowledge of malaria drugs, 3:07:24.240,3:07:28.080 that we're close to rolling out something like that. But I do know that people are working on 3:07:28.080,3:07:34.479 that problem, and it's very interesting. I think that tuberculosis is another area; 3:07:34.479,3:07:39.759 Hepatitis C is another area, rheumatic heart disease is another area. So a few infectious 3:07:39.760,3:07:48.080 disease areas that I'm sort of — ooh, I'm getting excited about, but don't know in super depth. 3:07:48.080,3:07:53.680 And then, beyond infectious disease too, there's a bunch of potential applications. 3:07:54.479,3:07:59.679 I think there's a psychosis drug; there's a schizophrenia or bipolar disorder drug, 3:07:59.680,3:08:05.200 I think, that's also long-acting. What I was thinking about was: maybe it's useful 3:08:05.200,3:08:10.559 for things that are hard to predict when you're going to be infected by them, so you would prefer 3:08:10.560,3:08:17.279 to take something that lasts a long time, and so for various infectious diseases, that seems 3:08:17.279,3:08:23.120 useful. Maybe also for chronic diseases, where you have the condition for a really long time, 3:08:23.120,3:08:29.279 therefore it's useful to have this long acting treatment, instead of doing something 3:08:29.279,3:08:35.759 where you have to take it every day. But, I mean, that kind of covers most diseases... 3:08:36.319,3:08:41.359 There could be lot that fit that description and that you should also think about: 3:08:41.359,3:08:47.679 when do you want something to end? And I think, for a lot of those diseases, 3:08:47.680,3:08:53.920 you would not want a drug necessarily that lasted for life. If you could have one stick around- 3:08:53.920,3:08:54.640 That is very true. 3:08:55.840,3:09:01.760 For some drugs, for example, if you think, "Oh, there's a chance I want to get pregnant in the 3:09:01.760,3:09:07.279 next few years," then you might want more control over when the drug's out of your system, in case 3:09:07.279,3:09:13.840 that drug hasn't been tested as much in pregnancy, or has been tested and isn't as safe in pregnancy. 3:09:15.040,3:09:22.800 There's one thing that in the literature that I've found interesting to read is: the limitations, in 3:09:22.800,3:09:27.439 children, of long lasting drugs. I was wondering, oh, that's such a shame because of, for example, 3:09:27.439,3:09:35.200 the malaria thing. I was just talking about why is there a limitation? One reason is that the 3:09:35.200,3:09:43.519 dose that you get given, of different drugs, is relative to how big you are. And the correct dose 3:09:43.520,3:09:49.760 is often bigger, the bigger you are. The trouble is, with a child, that in six months, their size 3:09:49.760,3:09:54.479 is going to change a lot, and that means you might want to be dealing with a different 3:09:54.479,3:09:59.759 drug dose in six months time. So there's reasons like that, that you don't want to last forever. 3:09:59.760,3:10:08.240 That contrasts, usually, with vaccines where you actually wouldn't mind having as long a 3:10:08.240,3:10:18.080 lasting memory response as you can. And there are some vaccines that are known to be pretty 3:10:18.080,3:10:24.160 poor at generating long-lasting memories: flu vaccines are sort of a famous example; 3:10:24.160,3:10:30.639 the malaria vaccines so far aren't that durable, but are getting better. And then, 3:10:30.640,3:10:36.960 really, the best vaccine immunologists talk about is yellow fever vaccine, where you could live for 3:10:36.960,3:10:40.399 10,000 years and you wouldn't be getting yellow fever after you got that vaccine. 3:10:40.399,3:10:42.960 Wow, I didn't know that. 3:10:42.960,3:10:43.920 Yes. Well, that will- 3:10:43.920,3:10:46.800 I can live for 10,000 years? 3:10:46.800,3:10:49.200 That's what I've heard, but I don't know how they 3:10:49.200,3:10:53.120 extrapolated that. I think you can live for 10,000 years, and I think- 3:10:53.120,3:10:56.960 I mean, I kind of want to live for 10,000 years now, 3:10:56.960,3:11:01.359 just to see this vaccine lasting that long against it. 3:11:01.359,3:11:07.040 Imagine if you got a challenge with yellow fever at the end of 10,000 years to prove it, 3:11:07.040,3:11:12.399 and then it actually got you. Throwing up black bile and everything else. 3:11:12.399,3:11:18.319 The other thing I was thinking about, when you mentioned that on the size of the body, 3:11:18.319,3:11:25.840 was with lenacapavir: so, what I understood was, okay, the fluorine atoms keep lenacapavir in 3:11:25.840,3:11:30.399 fat tissue, but again, this is a problem for the same reason that you mentioned. If your 3:11:30.399,3:11:35.279 body size changes, that could affect how quickly it dissolves, I think, 3:11:35.279,3:11:44.160 or how much is remaining in this little depot. So imagine if you lost weight, for whatever reason, 3:11:44.160,3:11:49.760 you're on a diet or something, and somehow, suddenly, this drug becomes more potent or 3:11:49.760,3:11:55.200 effective in your body. I just thought that was a funny thing that I hadn't thought about. 3:11:55.200,3:11:59.599 No, totally. Another one is, that's hard to predict ahead of time is, 3:11:59.600,3:12:05.840 are you going to want to go on another drug, for another reason, that might have a negative 3:12:05.840,3:12:12.479 interaction with a long-lasting drug you're already on? My understanding of lenacapavir is, 3:12:12.479,3:12:16.319 they haven't discovered many drug interactions that are that concerning. 3:12:16.319,3:12:21.279 But that might apply to other long lasting drugs, so you got to think about that. 3:12:21.279,3:12:27.120 That's a really good point. The thing that reminds me of is grapefruit juice. 3:12:27.120,3:12:33.840 Have you read about this thing with- so, grapefruit juice has this chemical 3:12:33.840,3:12:40.800 that interferes with your liver's metabolism of lots of different drugs. And if you were- 3:12:40.800,3:12:43.200 I had grapefruit juice three days ago. I'm nervous. 3:12:43.200,3:12:44.720 Oh, did you? Yeah. 3:12:44.720,3:12:45.439 Well that explains- 3:12:45.439,3:12:50.799 Well, I mean, it's not all of the drugs, but it seems like it's quite a number of drugs 3:12:50.800,3:12:57.439 that are affected by this. And so, if you're drinking grapefruit juice, for whatever reason, 3:12:57.439,3:13:02.080 it sometimes makes various drugs last longer in your body, 3:13:02.080,3:13:05.680 because it interferes with their breakdown. This is true for, I think, 3:13:05.680,3:13:15.359 some other chemicals and drinks as well, but that's the most commonly-known in medicine. 3:13:15.359,3:13:18.719 So if you're getting towards the tail-end of 3:13:18.720,3:13:23.279 your six months of lenacapavir, just start doing shots of grapefruit juice? 3:13:23.279,3:13:29.120 I don't know if it interferes with lenacapavir specifically, but it seems to be a bunch of other 3:13:29.120,3:13:36.160 drugs. But I mean, it's just an interesting thing to think about, because now you're on this- okay, 3:13:36.160,3:13:42.080 you're on this six-monthly drug. What are the things that you now have to be thinking about, 3:13:42.080,3:13:48.880 to make sure that this drug is still working as expected? It's great to hear that it doesn't have 3:13:49.439,3:13:52.879 many drug interactions, but I think that's the other thing that, 3:13:53.600,3:13:56.960 if I was a drug developer, I would be thinking about. 3:13:56.960,3:14:00.479 And I'm sure there's more still to learn about drug interactions, 3:14:00.479,3:14:11.439 so we'll find out. The reversibility of some other preventive tools is a key part of why people want 3:14:11.439,3:14:18.559 to use them. For IUDs, for example, you can get an IUD removed and it will not affect your long-term 3:14:18.560,3:14:27.520 fertility. Whereas for lenacapavir, you got to wait it out. Once it's in there, it's in there. 3:14:28.080,3:14:34.399 I would find that exciting. But yeah, you're right. If there's something that could go wrong, 3:14:34.399,3:14:38.399 that is something that, this is why we need these long 3:14:38.960,3:14:44.640 clinical trials to make sure that this drug is safe, in the way that people take them, 3:14:44.640,3:14:53.342 in their daily lives. Maybe we should talk about the clinical trials and what they should- 3:14:53.342,3:14:57.439 I would love to, yes. I was wondering about the clinical trials. How did we 3:14:57.439,3:15:05.200 confirm that lenacapavir does actually work in the way we hoped, and that it is safe? 3:15:06.800,3:15:10.880 Where did we go once the scientists had done the experiments in the lab? 3:15:13.200,3:15:21.599 The period when lenacapavir was developed was the late 2010s. They did some molecular 3:15:21.600,3:15:28.479 studies to develop lenacapavir. They then did a phase one study — which is you're testing 3:15:28.479,3:15:35.919 the safety in a small number of participants, and you're checking basic things about the properties, 3:15:35.920,3:15:43.600 the pharmacokinetics, how long does it stay in the body, how effective is it in very specific ways, 3:15:43.600,3:15:49.360 in a small number of people — I think there's usually dozens or so. 3:15:50.160,3:15:57.760 Then after that, they moved on to phase two trials; this is a second part where it's a larger 3:15:57.760,3:16:03.120 number of people. Now, you're testing a little more about the safety, because now you have a 3:16:03.120,3:16:09.519 wider range of people with different backgrounds; they might be taking other drugs at the same time; 3:16:09.520,3:16:15.760 they have different behaviours and so on. So you can find out a little bit more about the safety. 3:16:15.760,3:16:23.360 But also, now with a larger sample, you can see how effective the drug is. They did this with 3:16:23.920,3:16:31.359 people who already had HIV and were taking other antiretroviral drugs, 3:16:32.000,3:16:37.840 and they saw how this combination of lenacapavir plus those other drugs worked. 3:16:37.840,3:16:47.439 Then, the breakthrough that really got me to notice this drug was their phase three trial; and 3:16:47.439,3:17:02.639 their phase three trial was- I think it started in 2021. They had two different trials. One was with, 3:17:02.640,3:17:10.319 I think, one was with men; the other one was with cisgender women — specifically adolescent girls 3:17:10.319,3:17:16.880 and young women. This quite important because the transmission, and the effect of these drugs, 3:17:16.880,3:17:23.680 can vary for women who are trans because the route of infection, their sexual activity, 3:17:24.560,3:17:30.720 how that actually works, is different. So they're focusing specifically on cisgender 3:17:30.720,3:17:40.239 women aged between 16 and 25; girls who were not using PrEP; they hadn't done HIV testing, or they 3:17:40.239,3:17:48.160 hadn't done it in the last three months. I think it was several thousand- it was around 8,000 women 3:17:48.160,3:17:58.559 in this trial across Uganda and South Africa. This is important because, if you're trying to test how 3:17:58.560,3:18:06.800 effective a drug is, you need enough, well- there need to be enough people, at least on the placebo, 3:18:06.800,3:18:14.080 who are getting infected, so that you can see what the difference would be with lenacapavir. 3:18:14.080,3:18:21.519 So they focused on these areas where HIV incidence rates were relatively high, 3:18:21.520,3:18:30.000 meaning that more than three or four people per hundred people were being infected per year. So 3:18:30.000,3:18:36.880 imagine 3% of the population of this age is being infected with HIV per year. That's, 3:18:37.520,3:18:43.840 to me, that's really high. This is quite common in some areas of South Africa and 3:18:43.840,3:18:52.000 Uganda. That means that it's much easier to tell if lenacapavir has an effect. 3:18:52.000,3:19:00.560 Because you'll detect in the other arm of the trial that there were HIV infections occurring. 3:19:00.560,3:19:05.920 Right. If you imagine, okay, if you were doing a trial in the UK or in the US, 3:19:05.920,3:19:14.080 where people are already taking PrEP or the rate of HIV is just so low to begin 3:19:14.800,3:19:21.279 with, then imagine no one in the placebo group gets HIV. How are 3:19:21.279,3:19:22.145 you going to tell if lenacapavir is better than that? There's nothing lower than zero. 3:19:22.145,3:19:28.880 You have to be able to distinguish, because happily, its transmission is 3:19:28.880,3:19:34.800 lower than it was twenty years ago or thirty. Yeah, it's interesting. It's a very clear case, 3:19:34.800,3:19:43.920 I guess, of trials in- well, I'm in the US, you're in the UK, but I may benefit from this drug, 3:19:43.920,3:19:51.279 living in the US, based on trials that occurred in other countries — because those trials were 3:19:53.359,3:20:00.559 in higher transmission settings. So you can get a statistical answer to the question; 3:20:00.560,3:20:08.160 that would've been harder if you were just doing the trials in the US. So that's a kind of selfish 3:20:08.160,3:20:16.479 benefit that the US, and people like me, get from the global nature of clinical trials. 3:20:16.479,3:20:22.080 That's what I think makes it really important to- we'll come to talk about this later on, but this 3:20:22.080,3:20:27.519 is what makes it really important to think about how to actually get it to be accessible. How to 3:20:27.520,3:20:35.200 scale up this drug, in the future, to the people who need it. This wasn't developed without the 3:20:35.200,3:20:41.599 help of all of these participants who agreed to be in this trial, who are living thousands of miles 3:20:41.600,3:20:49.439 away from us, and who are responsible for this breakthrough being tested, and the fact that we 3:20:49.439,3:20:54.399 know that it works, and so on. One of the other things that I found quite interesting about this 3:20:54.399,3:21:01.679 trial is: how trials actually work in terms of the healthcare and the screening involved. 3:21:02.560,3:21:10.720 So I think when people think of a trial, maybe they don't realise that you're not just receiving 3:21:10.720,3:21:17.712 the treatment itself, but people are doing other types of screening to monitor how you 3:21:17.712,3:21:24.960 are responding to the drug. They're also, in this case, doing tests and screening for other types of 3:21:24.960,3:21:33.520 related diseases. What they did in this trial was: they provided individual counselling to people; 3:21:33.520,3:21:39.439 they provided condoms, lubricants; they'd have support for reproductive health in 3:21:39.439,3:21:44.879 general. They also provided treatments for other sexually transmitted infections, 3:21:44.880,3:21:51.760 and they did routine tests for some common sexually transmitted infections, like chlamydia, 3:21:51.760,3:21:59.439 gonorrhoea, and syphilis there. Which means that, by participating in this trial, not only do you 3:21:59.439,3:22:05.200 get the potential of this drug and also the side potential side effects, or risks, of participating 3:22:05.200,3:22:12.080 in trial — but you also get the actual healthcare because of the clinical trial setting. 3:22:12.080,3:22:19.040 I think that's something that people might not realise: we have this system where we have these 3:22:19.040,3:22:23.279 clinics, or these hospitals, that are running these clinical trials; they're also providing 3:22:23.840,3:22:30.239 care to the people in the trial. When we think about how to actually set up these clinical 3:22:30.239,3:22:37.359 trials in countries in Africa, it's not just about doing the testing. The researchers, sometimes, 3:22:37.359,3:22:44.719 are involved in setting up new clinics, they're involved in recruiting staff to work on all of 3:22:44.720,3:22:51.760 this testing, and stuff like that, and that has various other benefits for the people in the area. 3:22:51.760,3:22:57.920 One thing that we've worked on at Open Philanthropy is — an area that's not HIV 3:22:57.920,3:23:08.239 but relates — is congenital syphilis. Syphilis is- nowhere is it incredibly 3:23:08.239,3:23:13.200 prevalent, but in some places, maybe one to three percent of people have syphilis. 3:23:15.279,3:23:21.200 That is not something you want for yourself, but it also is really bad if you're pregnant, 3:23:21.200,3:23:27.200 because you may have a birth complication basically, or a miscarriage, or being born 3:23:27.200,3:23:36.880 with congenital syphilis is very dangerous. One thing that HIV care has brought in many 3:23:36.880,3:23:45.760 countries is better antenatal screening, prenatal screening for HIV for many women. You'll get at 3:23:45.760,3:23:50.640 least one visit with a doctor, whereas in many areas before, if you were pregnant, you might 3:23:50.640,3:23:56.640 not have even had one visit with a doctor. So that infrastructure set up to screen for, 3:23:56.640,3:24:04.160 or to give you a touch point and some care while you're pregnant — mostly funded by the HIV world, 3:24:04.160,3:24:12.399 and by PEPFAR, and other donor countries — has enabled screening for syphilis as well. 3:24:12.399,3:24:18.960 There's now a dual test where — it's a rapid test; it costs just under a dollar — you can screen for 3:24:18.960,3:24:24.800 HIV and syphilis at the same time. And then, if you are positive for syphilis, you can get 3:24:24.800,3:24:32.560 relatively easy treatment on penicillin. That's such a clear example of the benefits of this 3:24:32.560,3:24:40.560 infrastructure, that were not initially planned from when HIV donors made those investments, 3:24:40.560,3:24:47.840 but that spill over. So it makes sense to me that, not only are there benefits from the 3:24:47.840,3:24:52.640 knowledge gained, of these lenacapavir trials, but people in the trials got better care too, 3:24:52.640,3:24:59.120 and there's now probably better trained doctors in the area and that kind of thing, yeah. 3:24:59.120,3:25:06.720 We have thousands of young women in this trial. First, they were tested for whether they already 3:25:06.720,3:25:13.279 had HIV at that point. This was useful, as I'll come back to later, this is useful to know: What 3:25:13.279,3:25:20.719 is the rate of HIV in the population? It turned out that it was about 2.5 per hundred people per 3:25:20.720,3:25:30.399 year, which is, so 2.5% of people in this age group are infected by HIV per year — which is, 3:25:30.399,3:25:38.559 to me, really difficult to think about. Those women would not necessarily benefit from this 3:25:38.560,3:25:42.800 treatment; that was not the purpose of this trial — it was to find out whether we could 3:25:42.800,3:25:50.479 prevent new infections. Those participants were not included in the rest of the study, I think. 3:25:50.479,3:25:53.200 So, you screen at the beginning for HIV; 3:25:53.200,3:25:56.960 if you're already positive, then this is not the trial for you. 3:25:56.960,3:26:05.840 Right. And the women who were HIV-negative were then randomly assigned to getting either this 3:26:05.840,3:26:12.880 lenacapavir injection, or- I think this is Descovy — it's the oral PrEP pill, 3:26:12.880,3:26:22.160 which is emtricitabine and tenofovir alafenamide. Or the third option was F/TDF, 3:26:22.160,3:26:24.369 I think there's another name for this, is that Truvada? 3:26:24.369,3:26:24.399 Truvada? That's Truvada, yeah. 3:26:24.399,3:26:32.799 That's Truvada; that's also an oral pill that people take daily; that is also emtricitabine, 3:26:32.800,3:26:40.479 but this time it's tenofovir disoproxil fumarate. And I think what they did was — because one of 3:26:40.479,3:26:47.919 them is an injection; the other two are oral pills — they actually gave fake version of the 3:26:47.920,3:26:51.520 opposites to all the participants, so that they don't know which one they're getting. 3:26:51.520,3:26:52.560 Oh, okay. Nice. 3:26:52.560,3:26:57.840 They're all getting an oral pill and they're also all getting an injection. 3:26:57.840,3:27:01.520 But some of the people who are getting the injection are getting lenacapavir, 3:27:01.520,3:27:05.840 the others are just getting a placebo — which is just some water or something like that. 3:27:05.840,3:27:11.359 Which, you know, I'm already curious about. Three things from what you said: number one is, 3:27:11.359,3:27:18.399 if I get the fake lenacapavir injection, does it form a depot? And can I tell that it's actually 3:27:19.040,3:27:25.680 fake, because it doesn't form a lump? But my other two reactions are maybe more fundamental. 3:27:25.680,3:27:30.720 So it sounds like there's no placebo here — in the sense of, there's no one who's getting no drugs, 3:27:30.720,3:27:36.720 because that would be unethical. We already have drugs that we know will reduce your 3:27:36.720,3:27:42.319 chance of acquiring HIV if you're on them. So the arms that you described 3:27:42.319,3:27:48.639 are the lenacapavir arm, descovy arm, truvada arm, and there's no zero arm. 3:27:48.640,3:27:55.600 Right, and in other clinical trials, you're not necessarily preventing people from getting 3:27:55.600,3:27:58.800 other treatments; they could be taking other treatments for the same disease, 3:27:58.800,3:28:04.479 at the same time. But, in this case, they wanted to see: How effective was this as 3:28:04.479,3:28:11.919 a prevention? And to get enough statistical power, you need everyone to be in the trial, 3:28:11.920,3:28:17.279 and you're having this situation where you don't want any of them to be taking PrEP 3:28:17.279,3:28:25.759 that you can't analyse in a consistent way. It's both ethical in the sense that they're 3:28:25.760,3:28:30.399 providing all of the participants with one of the three PrEP drugs, but it also 3:28:30.399,3:28:36.239 helps because it makes these comparisons simpler. They're not taking an additional 3:28:36.239,3:28:43.040 PrEP- some of them are not taking an additional PrEP drug that could complicate the analysis. 3:28:43.040,3:28:47.359 Okay. Got it. Makes sense. And then my third reaction was, it's interesting that Descovy 3:28:47.359,3:28:53.839 was in the mix because I thought that Descovy was not approved for use in cisgender women. 3:28:53.840,3:29:02.960 Yes, you're right, it hadn't been tested before in women. The company, Gilead had been criticised for 3:29:02.960,3:29:08.640 this, having this approved but not testing it beforehand. So this also functioned as, 3:29:08.640,3:29:14.960 not just the trial for lenacapavir, but it also tested how effective Truvada and Descovy are- 3:29:14.960,3:29:15.279 Great, okay. 3:29:15.279,3:29:19.040 -in the same population. So you get to have the answer to three questions. 3:29:19.040,3:29:25.040 You have the answer to how effective lenacapavir is, descovy, and truvada. 3:29:25.040,3:29:29.600 And then because of what you said, about the screening on the way in, can they compare it 3:29:29.600,3:29:34.319 to what they think the background rate, if you're on nothing, probably would be? 3:29:34.319,3:29:38.799 Yes, yes. So actually we have four things you can find out. 3:29:38.800,3:29:43.920 Well, that one's not measured. I guess that one's interpolated. 3:29:43.920,3:29:50.880 So you can now compare these three drugs, but you can also compare them all to not taking any drugs. 3:29:50.880,3:29:56.800 Okay. Well, I feel- I'm on the edge of my seat. So, what were the results? 3:29:56.800,3:30:04.160 What were the results? I'm going to show this chart. So this chart compares the outcomes in 3:30:04.160,3:30:08.319 each of these groups. The first bar is showing the background incidence; 3:30:08.319,3:30:14.319 these are the women who tested positive at the start of the trial, and around 2.4% of 3:30:14.319,3:30:27.587 them got infected with HIV per year in FTAF, which is Descovy? That had a rates of 2.02. 3:30:27.588,3:30:28.633 That's very similar to the background, right? 3:30:28.633,3:30:36.720 And in Truvada, it's around 1.69. These numbers are the point estimates, and that's our best 3:30:36.720,3:30:44.399 guess. But there's uncertainty around just what the number is; they all roughly fit 3:30:44.399,3:30:55.679 into the same range. So without drugs, Descovy, and Truvada have similar rates of HIV infection. 3:30:55.680,3:31:03.200 And I think the reason for this is because it's hard to take these on a consistent basis over 3:31:03.200,3:31:10.960 time — these are daily pills where the problem is: one, maybe remembering to take it every day; 3:31:10.960,3:31:16.720 second, having enough supplies with you every day; the stigma that we talked about; 3:31:16.720,3:31:21.760 maybe these issues around getting a refill on time. So there are all of these issues 3:31:21.760,3:31:29.120 that make it difficult to take these drugs in the long term, for women in Uganda and South Africa, 3:31:29.120,3:31:33.519 where this trial was done. What was interesting about the study is that 3:31:33.520,3:31:40.160 they could actually measure how regularly people were taking these drugs through blood testing. 3:31:40.160,3:31:42.479 Is that because they're taking samples? Wow. 3:31:42.479,3:31:50.160 They're taking dried blood spot samples from people and then they're testing the level of 3:31:50.160,3:31:56.479 tenofovir in their red blood cells. So this directly tells them what is a concentration 3:31:56.479,3:32:03.200 of this drug in this participant? With this, you can see how, over time, 3:32:03.200,3:32:11.120 the expected- how frequently people are taking them, that reduces over months of the study. 3:32:11.120,3:32:18.080 People, on average, are taking them quite often, but over time that adherence gets much lower, 3:32:18.080,3:32:24.800 so they're mostly taking them two or- one or two times per week, by the end of the trial. 3:32:26.319,3:32:35.439 And this gets back to this previous chart. So we've seen what happens with Descovy and Truvada, 3:32:35.439,3:32:46.639 what happens with lenacapavir? Zero women out of 2,134 get infected with HIV. That is 3:32:46.640,3:32:54.560 just an incredible result. And there is some uncertainty around that. The efficacy — so 3:32:54.560,3:33:01.760 how much lower the rate of HIV infection is, compared to the background rates — is 3:33:01.760,3:33:08.319 96 to a hundred percent. So it's somewhere- it's not completely effective, necessarily, 3:33:08.319,3:33:14.541 because there isn't a large enough sample to say that this is a hundred percent efficacy rate- 3:33:14.542,3:33:17.600 We can't rule out- -but it is more than 96% of a reduction. 3:33:17.600,3:33:24.880 That is so incredible. So incredible. That is so incredible. Zero cases. 3:33:24.880,3:33:32.239 Zero cases. I was reading about this, I think, on STAT news — the health and medicine 3:33:32.239,3:33:37.679 magazine — and they mentioned how these results were presented at this conference, and they just 3:33:37.680,3:33:44.080 got this standing ovation where people, I mean, unsurprisingly, this is just an incredible result. 3:33:44.080,3:33:45.439 Unbelievable. 3:33:45.439,3:33:51.599 One last thing about lenacapavir, truvada, and descovy is the side 3:33:51.600,3:33:55.680 effects. We talked about- okay, we have this long-lasting drug, 3:33:55.680,3:34:02.640 that means there's a risk of long-lasting side effects as well. What happened in this trial was, 3:34:02.640,3:34:07.840 they didn't find that much of a difference between the different groups. Most of the side effects 3:34:07.840,3:34:13.279 were similarly seen in the different groups, and those are mostly things like headaches, 3:34:13.279,3:34:20.880 fevers — but again, when we record side effects in a trial, we can't necessarily, conclusively, 3:34:20.880,3:34:25.120 say that these are because of drugs. People have headaches, fevers just anyway in a typical- 3:34:25.120,3:34:30.239 We don't have a clean placebo here, I guess. I mean it's interesting that, when I think 3:34:30.239,3:34:35.679 about what friends report as side effects of oral PrEP — because it's oral, there's often 3:34:35.680,3:34:42.399 digestive issues or stomach problems. I wonder if they tested for that, because I would guess 3:34:42.399,3:34:47.599 intuitively that lenacapavir would've fewer of those ones. But I dunno if they tested for that. 3:34:47.600,3:34:55.120 And you would be right! They did find lower rates of nausea and vomiting with lenacapavir, 3:34:55.120,3:35:01.040 and I guess this is because of the difference — where it's not an oral drug, it's an injectable, 3:35:01.040,3:35:05.279 so it's not passing through your digestive tract and your stomach. 3:35:05.279,3:35:09.840 We don't need to do trials. You can just quiz me on my guesses. 3:35:09.840,3:35:18.479 The other thing was the little bumps on people's skin, the depots of lenacapavir — so that was 3:35:18.479,3:35:24.639 quite common. About 70% of the people who got lenacapavir develop these little 3:35:24.640,3:35:34.960 bumps — nodules — under their skin, and those typically shrunk down to normal after a while, 3:35:34.960,3:35:41.120 but also, the next doses tended to not- you wouldn't tend to see those. 3:35:41.120,3:35:46.800 Yeah, I'd love to learn more about that. To me, it sounds like success: I want a little nodule, 3:35:46.800,3:35:51.760 I want to know that drug is there, and, sure enough, in six months, I want the nodule to be 3:35:51.760,3:35:58.880 gone because the drug is gone. But I guess there's more going on in the body than I'm projecting. 3:35:58.880,3:36:06.720 I was also surprised that 30% of people who get lenacapavir don't develop these nodules. What is 3:36:06.720,3:36:12.000 causing this difference? And I, sadly, don't know the answer to that, but it's quite interesting. 3:36:14.479,3:36:20.399 I was about to ask about other trials, outside of women, but is there anything else, 3:36:20.399,3:36:27.439 on this trial, that I should know first? I think, maybe, we should talk a little bit 3:36:27.439,3:36:35.759 about why was there almost no difference between Descovy and Truvada and the background rates, 3:36:35.760,3:36:41.279 and why is it that lenacapavir is so effective in these trials, or like, 3:36:41.279,3:36:48.719 in the real world? I think there's- so I would say that it's not entirely clear how effective 3:36:49.359,3:36:56.559 Descovy and Truvada are, compared to not taking any drugs. That's just because the uncertainty on 3:36:56.560,3:37:05.279 those is fairly moderate, so there isn't a very precise figure that we would have; it seems like 3:37:05.279,3:37:10.160 they're roughly similar, but there could still be some meaningful reduction that these are 3:37:10.160,3:37:16.720 providing. I guess the other reason is, if people are not taking it regularly — these oral pills 3:37:16.720,3:37:25.279 regularly — for whatever reason, in the long term, that reduces the efficacy. So even if someone 3:37:25.279,3:37:31.120 was taking it every day, it would be a higher level of effectiveness than in the real world, 3:37:31.120,3:37:38.000 where people are taking it less often. And I think this is why lenacapavir is so much more effective: 3:37:38.000,3:37:45.760 it's not just that it's highly effective on its own, but it's also really long lasting, and that 3:37:45.760,3:37:53.840 both of those contrast with Descovy and Truvada. Yeah, I guess it's proving the hypothesis with 3:37:53.840,3:37:59.359 data; that's what we were wondering, and we were hopeful that lenacapavir's 3:37:59.359,3:38:04.319 long-lasting properties would pay off, and it looks like they did. 3:38:04.319,3:38:12.960 They did. And they did another trial with men and gender-diverse people — this was in six countries: 3:38:12.960,3:38:18.640 the US, I think, some South American and central American countries as well. Again, 3:38:18.640,3:38:22.640 the reduction you would see — with lenacapavir, on how likely it is for 3:38:22.640,3:38:31.600 an infection — was massive. It was two people out of thousands who contracted HIV versus, 3:38:31.600,3:38:36.000 I think, more than a dozen, or a dozen, in the other groups. So again, 3:38:37.359,3:38:46.880 this time their estimate was that there was 82 to 99% efficacy for this drug. And again, 3:38:46.880,3:38:54.960 they saw that Descovy and Truvada had a very little impact compared to the background rate. 3:38:54.960,3:39:00.880 It's a big win. Okay, so there were two cases; so it wasn't zero. Two out 3:39:00.880,3:39:06.080 of a couple thousand, but the reduction in risk is enormous. 3:39:06.080,3:39:11.200 Is huge. I would say that, you shouldn't go away from 3:39:11.200,3:39:15.200 this thinking this completely prevents infections; 3:39:15.200,3:39:23.279 there is still a chance. But the reduction is so large that it's a really important breakthrough. 3:39:24.160,3:39:31.920 My hope, and I hate to be hopeful, but you can get non-linear population effects with transmission 3:39:31.920,3:39:41.120 reductions, where, if a transmission per event drops 90% at a background rate, the background 3:39:41.120,3:39:46.559 rate might start dropping too. I mean, it depends on interactions with treatment drugs and a lot of 3:39:46.560,3:39:52.800 other factors — but if you can imagine that, per event, your risk is going down and then, 3:39:52.800,3:39:59.680 over time, the background rate going down, that's actually a very large effect together. 3:40:00.560,3:40:05.520 That reminds me of this concept of the reproductive number, that a lot of people 3:40:05.520,3:40:12.960 would've heard about during the COVID pandemic- R nought. The R nought. So this is the number of 3:40:12.960,3:40:20.880 people, on average, that someone infects, if they've been infected. So if I was infected, 3:40:20.880,3:40:26.640 maybe I would infect three other people on average with the coronavirus, 3:40:26.640,3:40:32.479 in this case. The higher the number, the harder it is to control the disease, 3:40:32.479,3:40:40.000 but also the faster it spreads in the population. And if it gets below one — if I'm spreading it 3:40:40.000,3:40:47.760 to less than one person on average — eventually that disease will die out. 3:40:47.760,3:40:52.160 It's a dream that we can head towards now, maybe. Okay, that's PrEP. 3:40:52.880,3:41:00.479 Did lenacapavir get tested in trials for treatment as well, not just prevention? 3:41:00.479,3:41:07.759 Yes! It was actually tested and approved as a treatment drug before these preventive trials 3:41:07.760,3:41:14.800 and results. The first trial was as a treatment for drug-resistant HIV, where they're testing 3:41:14.800,3:41:21.840 lenacapavir plus the standard regimen that people are having, in people who have tried 3:41:21.840,3:41:30.880 many different treatments so far, and this is plan C or D. So it was effective in those trials; it 3:41:30.880,3:41:38.720 was approved as a treatment for drug-resistant HIV based on that. They also did a phase two trial, 3:41:38.720,3:41:46.000 where they tested it as a first line treatment — so that means that would be: How effective is it, 3:41:46.000,3:41:50.880 as the first treatment that someone receives if they have been diagnosed with HIV? So they 3:41:50.880,3:41:58.319 compared lenacapavir with other existing drugs. There are a bunch of other ongoing trials, 3:41:58.319,3:42:05.519 still. So I think there are more long-acting treatments, where they're 3:42:05.520,3:42:11.040 testing a combination of lenacapavir and islatravir, which you mentioned. 3:42:11.040,3:42:11.680 The Merck one. 3:42:11.680,3:42:17.279 That was the Merck oral pill, which are both long-acting, right? 3:42:17.279,3:42:18.479 Yeah. 3:42:18.479,3:42:22.799 And then, there were a bunch of other types of treatments: so they're doing 3:42:23.840,3:42:30.880 testing in children and adolescents; they're also testing whether it can 3:42:30.880,3:42:39.040 be used in people who have been receiving other types of antiretroviral drugs, but they still 3:42:39.040,3:42:46.720 have some HIV that's suppressed in their body. As we talked about, hours ago, one of the things 3:42:46.720,3:42:55.760 that you see with HIV is that these drugs can block the multiplication of HIV in your body. But 3:42:55.760,3:43:02.960 there are also particles that would stay in some parts of your body, hidden in silence, and these 3:43:02.960,3:43:10.720 reservoirs of HIV are difficult to get rid of. So is it possible to use lenacapavir to disrupt 3:43:10.720,3:43:16.080 these reservoirs? That is one of the questions that they're looking at in this other trial. 3:43:16.080,3:43:21.040 And then there are a bunch of others, so they think there's another one with lenacapavir plus 3:43:21.040,3:43:27.920 cabotegravir in people who have taken lots of other treatments. And these trials are 3:43:27.920,3:43:32.880 being conducted, essentially, almost like, all over the world — it's North America, 3:43:32.880,3:43:41.680 Europe, and Southern Africa; many different countries. It's basically quite a big process: 3:43:41.680,3:43:47.439 to do this lab testing, to develop these drugs, to then test them in some places, 3:43:47.439,3:43:53.519 in certain countries like the US or like Southern Africa, and then to scale it up, to these massive 3:43:53.520,3:44:03.600 trials — is quite interesting, but also, to me, quite impressive how fast this has happened. That 3:44:03.600,3:44:14.080 drug was only developed in 2018 and it's been — well, okay, it has been seven years since then. 3:44:14.080,3:44:20.160 I'm used to seeing timelines that are so long, and this was approved for the first time in 2022, 3:44:20.160,3:44:27.279 I think, as a treatment for drug-resistant HIV, which is only four years in trials. I think that, 3:44:27.279,3:44:35.439 I mean, on a personal level, I think that could still be sped up, but that is an impressive speed. 3:44:35.439,3:44:43.359 Yeah, it's a four year starting clock to finish line, not so bad. But we're not at the finish line 3:44:43.359,3:44:51.759 yet. The finish line is, is this really going to impact people's lives who are at risk of HIV? So 3:44:51.760,3:45:00.560 just summing up what we just covered: we have now looked at long-lasting drugs as a concept, 3:45:00.560,3:45:09.439 and other HIV long-lasting drugs, and long-lasting drugs in other areas that we're excited about, 3:45:09.439,3:45:14.399 but are still in development. And then, you just outlined with lenacapavir, 3:45:14.399,3:45:23.359 what was the clinical story to get here and who can benefit from lenacapavir? And it sounds like, 3:45:23.359,3:45:30.239 the people who've called this a miracle drug, to me, are basically right. In the clinical trial for 3:45:30.239,3:45:38.800 cisgender women, there were zero HIV infections among the 2,000 women who got this injection, and 3:45:38.800,3:45:46.880 there were tens of infections in the other arms, for women on other forms of PrEP; so this is a 3:45:46.880,3:45:54.479 totally different situation. And for men who have sex with men, and other trans people who are in 3:45:54.479,3:46:02.319 the other trial, the other phase three — there was also a massive drop of, say, 80, 90 more percent 3:46:02.319,3:46:11.040 in transmission. So, how do we get this drug to people, Saloni? That's what I want to know. 3:46:11.040,3:46:18.880 Maybe, also, just to think back to the whole timeline of drug development in this field. In 3:46:18.880,3:46:24.640 the 1980s, in the early 1980s, when the first case was reported — no drugs; people thought 3:46:24.640,3:46:31.199 this was an untreatable disease, or they wanted to treat it, but they had no idea how. In 1987, 3:46:31.199,3:46:39.519 the first HIV drug, azidothymidine. '95, the first protease inhibitor, and the start of combination 3:46:39.520,3:46:46.640 therapy that completely changed the survival for people with HIV. In 2012, is that right? 3:46:46.640,3:46:54.640 We have PrEP — truvada — introduced, and then, in 2022, we have lenacapavir, as this drug-resistant 3:46:54.640,3:47:03.760 treatment. Then, now, we have lenacapavir as a preventive drug, that is so long-lasting, 3:47:03.760,3:47:10.080 and both a breakthrough in terms of the effectiveness, in terms of how you take it, 3:47:10.080,3:47:15.600 how long it lasts in the body, but also, because it was a completely new type of 3:47:15.600,3:47:25.279 treatment. It works- it inhibits the capsid of the HIV virus; it's not just tweaking existing drugs, 3:47:25.279,3:47:30.239 it's this whole new type of treatment that now opens up the field of research 3:47:30.239,3:47:39.199 to developing more capsid drugs, I think, as well as more long-lasting drugs in the body. 3:47:39.199,3:47:42.160 All of that building on each other to get us to 3:47:42.160,3:47:46.880 this moment. The decades of science. I feel so grateful. 3:47:46.880,3:47:55.359 Decades of science. Let's talk about where we are now, in terms of, how are we going to scale this? 3:47:55.359,3:48:01.905 I mean, not us, specifically, but how are people going to scale up this drug? — you and me, back 3:48:01.905,3:48:07.040 of the van — getting them to everyone who- Like, just driving this van around in small villages. 3:48:07.040,3:48:10.720 I'm ready. Road trip? 3:48:10.720,3:48:20.560 So how is this going to be rolled out to people who need it, across the world? I think, 3:48:20.560,3:48:26.239 the most important continent here is Africa, and Southern Africa. Maybe we should talk a 3:48:26.239,3:48:33.120 little bit about: What has the situation been like until now? How does that process 3:48:33.120,3:48:39.279 work? How are people getting treatments across Africa, and how has that happened? 3:48:39.279,3:48:40.479 I love it. 3:48:40.479,3:48:48.719 Let's talk about HIV treatment and prevention around the world, how that's worked so far. 3:48:48.720,3:48:56.720 Where we are now, where we could go from here. I didn't know, until a few years ago, 3:48:56.720,3:49:06.960 how big the HIV treatment and prevention programs were worldwide. The biggest progra is PEPFAR, the 3:49:06.960,3:49:14.960 President's Emergency Plan for AIDS Relief, which was launched in 2003 by the Bush administration. 3:49:14.960,3:49:21.439 That was, at that point, the largest ever US global health initiative for a single 3:49:21.439,3:49:31.599 disease. It was 15 billion, as a commitment over five years, to fight HIV and AIDS in 3:49:31.600,3:49:38.319 affected countries — mostly in Southern Africa, but also other countries. I remember reading 3:49:38.319,3:49:45.840 about how this was formed, how the whole program came together, and it was super interesting and 3:49:45.840,3:49:52.960 inspiring — this idea that you could actually set up this huge program to treat millions of 3:49:52.960,3:50:02.800 people in the poorest parts of the world against this really deadly, scary disease. At that point, 3:50:02.800,3:50:08.720 there were effective combination drugs available, to people in the US and other richer countries, 3:50:08.720,3:50:15.040 but people in Africa were not, you know, they weren't able to access them, 3:50:16.560,3:50:22.960 which is quite scary. You have such a hugely unequal outcomes just based on where you live, 3:50:22.960,3:50:29.520 but also there is this drug that feels just out of reach that wasn't getting to people. 3:50:29.520,3:50:38.800 And what I read was that Bush wanted to do something big on HIV and AIDS and he asked 3:50:38.800,3:50:47.680 several people working with him on health in the US including Anthony Fauci and Dr. Mark 3:50:47.680,3:50:56.880 Dybul to figure out what was possible, and they looked at what was already being done in Africa. 3:50:57.840,3:51:02.720 Was there anyone who was receiving treatment at this time? How were they getting it? And 3:51:02.720,3:51:09.120 the main source that they found at the time was TASO, The AIDS Support Organisation and Doctors 3:51:09.120,3:51:16.640 Without Borders or Medicins Sans Frontieres — and they had been providing treatments to people, 3:51:18.479,3:51:24.479 I think it was in one- two countries, South Africa and Malawi. They were providing these 3:51:24.479,3:51:34.080 generic versions of antiretrovirals to them, on a voluntary basis. But what really stuck in my mind 3:51:34.080,3:51:39.439 was, when I was reading this interview of Mark Dybul — one of the people who worked on setting 3:51:39.439,3:51:46.160 up this program and planning it out — was that he mentioned that, at that point, TASO, the AIDS 3:51:46.160,3:51:52.639 support organisation, were actually transporting this in little, I think, fridges on their bags- 3:51:52.640,3:51:53.140 Wow. 3:51:54.239,3:51:59.920 -that they were carrying around on motorbikes around to remote villages, 3:51:59.920,3:52:07.760 to get these drugs to people who needed them. That was very inspiring. But the success of 3:52:07.760,3:52:14.239 Doctors Without Borders, in small scale- in providing treatment at a small scale, 3:52:14.239,3:52:19.279 showed that this was possible. Could it be scaled- 3:52:19.279,3:52:20.800 It's a proof of concept? 3:52:20.800,3:52:26.000 It's a proof of concept. So now what's needed is to set up these supply chains to do this at a much 3:52:26.000,3:52:34.239 bigger scale — to set up the drug development and manufacturing; set up the networks of clinics, 3:52:34.239,3:52:40.000 and the people who would be providing treatment to people in remote villages, 3:52:40.000,3:52:49.520 and so on. So Mark Dybul and Anthony Fauci put together these plans of: how much this would cost, 3:52:49.520,3:52:58.160 what it would look like to operate this, how it might look like at scale. The other reason this 3:52:58.160,3:53:04.479 is really interesting is because, at the time, people didn't think it was possible to do this. 3:53:04.479,3:53:11.279 They thought this was just some pipe dream. Several reasons: one is this is a really poor 3:53:11.279,3:53:18.000 region. Trying to set up something like this at scale requires a lot of work; you have to 3:53:18.000,3:53:24.960 work with community leaders, you need to hire people, train people to provide this treatment. 3:53:24.960,3:53:31.279 I think there was also this perception, that some people had, was that poor people 3:53:31.279,3:53:39.519 in Africa couldn't take daily pills; they couldn't follow these regimens. And I mean, 3:53:40.080,3:53:45.600 the fact that this program is so effective has, I think, has shown that that's not the 3:53:45.600,3:53:52.800 case. But it's also this idea that, just because something is difficult to take regularly doesn't 3:53:52.800,3:53:58.560 necessarily mean that we should stop there, and accept that as status quo. You could eventually 3:53:58.560,3:54:04.560 develop long-lasting drugs, you could find some way to make it easier for people to access these 3:54:04.560,3:54:11.360 treatments on a regular basis. And I think that kind of attitude shift is really important here. 3:54:14.560,3:54:18.720 You can do big things and sometimes they work, and at the turn of the century, 3:54:18.720,3:54:27.279 I feel like there was more optimism around big global health improvements and projects. And at 3:54:27.279,3:54:33.519 the same time as PEPFAR was getting started, or a similar time, the Global Fund was getting started, 3:54:33.520,3:54:40.800 which was not just a US program, but was a multilateral program that involved 3:54:40.800,3:54:47.279 many different donor countries. So higher income countries contributing into a pooled fund, 3:54:47.279,3:54:52.639 which would focus on HIV/AIDS, and malaria, and tuberculosis. Three 3:54:52.640,3:54:58.319 of the biggest infectious disease killers around the world, at the time and still now. 3:54:58.319,3:55:06.960 And since then, we have as a species, as a global society, made a huge amount of progress on all 3:55:06.960,3:55:16.479 three of those diseases. We should probably show a graph of HIV/AIDS incidence, but also AIDS deaths, 3:55:16.479,3:55:23.199 because the curve really bent down with these commitments from the Global Fund and from PEPFAR. 3:55:23.199,3:55:29.760 It was a problem that seemed to be spiralling out of control, and then lots of energy, focus, 3:55:29.760,3:55:36.319 attention, resources were put into it, on really scaling up proofs-of-concepts, and 3:55:36.319,3:55:42.319 really committing to it. Lo and behold, there were results. And that's inspiring to look back on, 3:55:42.319,3:55:47.359 and I wonder what it would've been like to be in the room when people thought it was impossible, 3:55:47.359,3:55:52.880 and you really thought, like Mark Dybul and others, but we gotta go for it. 3:55:52.880,3:56:02.720 It's also incredible to think about, from the perspective of people in Africa, how common HIV 3:56:02.720,3:56:09.920 was, at the time, is probably not obvious to some of us. But, in the year 2000, there were 3:56:09.920,3:56:20.479 several countries in Southern Africa where, some twenty, 15 to 30% of the adult population had HIV. 3:56:20.479,3:56:29.599 That is scary to think about, for such a deadly disease: how it affects the people themselves, 3:56:29.600,3:56:38.960 their families, the society as a whole. This was really effective and successful, both at changing 3:56:38.960,3:56:48.319 what life was like for people with HIV, but just also the culture around it, and it's continued 3:56:48.319,3:56:55.840 since 2003, so it's just an incredible program. It's one of the biggest global health programs. 3:56:55.840,3:57:03.840 But at the same time, it costs a very small fraction of our incomes here, or in the US, 3:57:03.840,3:57:11.439 to contribute to PEPFAR or the Global Fund, and it makes a massive impact on people around the world. 3:57:11.439,3:57:17.839 Well, it reminds me of the graph that you showed earlier in this episode, 3:57:17.840,3:57:23.040 when combination treatment first came out in the nineties, and you saw this totally 3:57:23.040,3:57:34.399 discontinuous drop in mortality rates. This was scaling that drop up to people who did not have 3:57:34.399,3:57:41.120 access to the drugs, until there was a global commitment behind them. That means that there 3:57:41.120,3:57:47.920 are many people — not just millions, but tens of millions of people — who are alive right now, 3:57:47.920,3:57:55.840 who are on drugs that control their infection, who would not have been alive. And it's so heady, 3:57:55.840,3:58:04.319 it's impossible to, at least for me, to get my head around that, but friends, so 3:58:04.319,3:58:13.199 many families. So it's mind blowing to think how different the world would be for so many people. 3:58:13.199,3:58:22.479 The scale of this is also incredible to me. The estimates are that there've been 25 million people 3:58:24.479,3:58:31.599 whose early deaths were prevented because of PEPFAR as a program. 25 million is such a, 3:58:32.560,3:58:37.920 in terms of the number of lives saved, it's just so huge to think about, it's like London's 3:58:37.920,3:58:47.920 population is what, 11, 12 million? That's two, more than two of the entire... Wow. It's just, 3:58:47.920,3:58:56.160 imagine that not existing; all those people not being alive. It's just a huge impact. 3:58:56.160,3:58:58.479 20 San Franciscos. 3:58:58.479,3:59:01.519 20 San Franciscos. 3:59:01.520,3:59:07.439 So what's happening now, then? It's all good news, by the sounds of things. 3:59:07.439,3:59:15.439 It's not good news, sadly. It's April when we're recording this and there's- in the 3:59:15.439,3:59:21.839 last few months, the picture around PEPFAR and various other global health programs has 3:59:21.840,3:59:30.720 completely changed. At the end of January, there was a foreign aid spending freeze. So, 3:59:30.720,3:59:37.199 all funding to various global health, humanitarian programs was frozen. Also, 3:59:37.199,3:59:47.120 staff who were working at the US aid agency, USAID, — some thousands of them were laid off. 3:59:47.120,3:59:52.880 The remaining ones were asked not to talk to the public, but also, they weren't able to keep 3:59:52.880,3:59:58.960 in contact with the programs in the field; they were just banned from communicating. 3:59:59.920,4:00:06.160 There was also this — because of all the layoffs — that also meant running the programs on the field 4:00:06.160,4:00:15.680 was difficult, for people who were working overseas. This freeze was meant to be — this 4:00:15.680,4:00:23.439 is the stated intention — which is that it was for a three-month-long review of these programs, 4:00:23.439,4:00:30.319 of all foreign aid programs, to see if they aligned with the Trump administration's interests, 4:00:30.319,4:00:36.719 such as national security and things like that. But a lot of them were, I mean, this just froze 4:00:36.720,4:00:43.279 all of them at once, rather than doing a review at the same time while they were ongoing. But also, 4:00:43.279,4:00:50.080 even after this freeze was ended, which was after- I think it was 39 or so, 4:00:50.080,4:01:01.279 35 business days, instead of three months, and some 80 to 90% of programs were just cancelled. 4:01:01.279,4:01:08.399 Because programs refers to specific recipients of funds, I think for specific purposes, that 4:01:08.399,4:01:18.319 doesn't mean that that PEPFAR was cut by 90% or so. For HIV and AIDS, I think it was around 23%, 4:01:18.319,4:01:24.239 if you roughly estimate based on the amount of funding those specific council programs received, 4:01:24.239,4:01:33.199 that were cut. And that seems like maybe just a fraction of this worst-case scenario, 4:01:34.000,4:01:39.359 of the whole thing being paused, but I think because so many thousands of staff were laid 4:01:39.359,4:01:44.960 off — and because of this uncertainty and this freeze — that actually had, 4:01:44.960,4:01:51.520 from what I can understand, quite a large impact. One reason for that is: clinics, or programs, 4:01:51.520,4:01:56.960 receiving the funding, some of them weren't able to survive more than a few months without 4:01:56.960,4:02:01.680 continued funding. Some of the funding was for stuff that they had already completed, 4:02:01.680,4:02:07.279 and they were just waiting to receive the payment for it, and that was cancelled as well. Some of 4:02:07.279,4:02:13.920 them were for continued work, and this was cancelled. If clinics are not able to survive 4:02:13.920,4:02:18.960 for more than a few weeks, or a few months, without this funding that they're expecting, they 4:02:18.960,4:02:28.880 might just shut down. So in the field, what people might have seen would be a physical clinic that's 4:02:28.880,4:02:34.160 there — sometimes the treatment is actually inside the clinic — but they can't access it, because the 4:02:34.160,4:02:42.239 clinic is shut down, and/or the staff is just not around. There aren't people working the clinics. 4:02:42.239,4:02:50.399 And thirdly, trying to get new supplies to these clinics was also disrupted, so they weren't able 4:02:50.399,4:02:56.559 to restock on a lot of the treatments. At the point where we are now, I think 4:02:56.560,4:03:03.920 there's been a lot of disruption, but there's a rough plan to merge all of these foreign aid 4:03:03.920,4:03:10.560 programs under USAID into the State Department of the US. I think this is still a little bit 4:03:10.560,4:03:16.560 up in the air, in terms of how that will actually work, how will it affect PEPFAR? 4:03:16.560,4:03:24.239 One thing I'm slightly worried about is what will they actually cut? What aligns 4:03:24.239,4:03:29.199 with the Trump administration's interests, and what doesn't? And I think you can get 4:03:29.199,4:03:37.120 a little bit of a clue from how they responded when this funding aid freeze began in January. 4:03:37.120,4:03:42.319 They initially said that there were certain parts of the program that would continue, 4:03:42.880,4:03:48.960 such as treatments for pregnant women. But from what I understand, that actually didn't 4:03:48.960,4:03:55.120 happen in practice, because of all of these layoffs, and the funding cuts, and so on. 4:03:55.120,4:04:02.880 But what I'm worried about is, what about prevention as a whole? We think about the critical 4:04:02.880,4:04:10.640 part of PEPFAR as being preventing mother-to-child transmission, but it's also the broader thing of: 4:04:10.640,4:04:17.600 how do we reduce the spread of HIV? How do we treat everyone who has HIV? This began as such 4:04:17.600,4:04:29.920 an ambitious and effective program that managed to treat some 20.5 million people last year, 4:04:29.920,4:04:37.359 and now that's massively been frozen and we don't know how much of it's going to remain. 4:04:37.359,4:04:45.839 It's so frustrating. It's so frustrating to see such a good use of money that, 4:04:45.840,4:04:52.160 in the grand scheme of things, is not that much money from the US government's perspective. 4:04:52.160,4:04:55.840 I mean, it's frustrating in the short term. I'm more nervous about treatment than prevention; 4:04:55.840,4:05:04.160 of what you're describing of clinics being closed. If you have HIV, you need to be on daily drugs, 4:05:04.160,4:05:12.559 and if you run out and can't get a refill, oh God, it must just be so scary. It must be so scary. And 4:05:12.560,4:05:19.840 then I totally agree. We're at this present, we at this wonderful moment of prevention and driving 4:05:19.840,4:05:26.640 down transmission is just becoming more and more possible with lenacapavir and with other drugs. 4:05:27.760,4:05:34.640 It's... I find it really heartbreaking because, until this point, until this year, I was so 4:05:34.640,4:05:41.520 excited about how would lenacapavir or other long-acting treatments change the picture? Like, 4:05:41.520,4:05:46.880 would we be able to effectively eliminate the transmission of HIV, in some of these 4:05:46.880,4:05:52.080 countries? And I think that's possible, and I think that's a little bit ambitious, just like 4:05:52.080,4:05:58.000 PEPFAR is. I think it's possible. But instead of going ahead, and kind of going big on this, 4:05:58.000,4:06:04.560 trying to really cut it down, and actually, then, not needing such a large program because you've 4:06:04.560,4:06:10.880 managed to reduce the number of people who are affected by this. Instead of doing that, 4:06:10.880,4:06:18.800 were on this road of a lot of uncertainty and disruption, and that it's come so suddenly that 4:06:18.800,4:06:26.479 people couldn't plan for it. They didn't expect that their treatment would suddenly disappear. I 4:06:26.479,4:06:33.839 think what the figures were showing, that I was reading, was- the program, PEPFAR is so big, 4:06:33.840,4:06:42.000 there's 20 and a half million people receiving treatment from PEPFAR per year. On a daily level, 4:06:42.000,4:06:50.800 that's 200,000 people who are getting their refills; 200,000 people who are realising 4:06:50.800,4:06:58.080 the clinics are shut, and they don't know how they're going to get their next supply. 4:06:58.080,4:07:05.519 Well, and that's 200,000 cases of higher risk of mutated viruses as well, presumably. 4:07:05.520,4:07:13.920 There's a risk of the resurgence of HIV, if people stop taking treatment for, I think, 4:07:13.920,4:07:20.319 it's a few months or so, and that has some quite nasty side effects in the initial period; 4:07:20.319,4:07:28.799 and then there's also of the complications that people would have with HIV as a disease itself. 4:07:28.800,4:07:33.600 Okay, so to summarise: the launch of PEPFAR, the launch of the Global Fund 4:07:33.600,4:07:40.399 were a particularly ambitious moment, and there were people around who thought maybe 4:07:40.399,4:07:43.679 they would not achieve their aims, because it never been done before. 4:07:43.680,4:07:49.359 And lo and behold, they achieved great things for tens of millions of people. 4:07:49.359,4:07:51.759 For over two decades. 4:07:51.760,4:07:59.439 Over two decades. And now we're not only, we've been talking, in this episode, 4:07:59.439,4:08:04.479 about great technical achievement. That could be a launch of a new ambitious program and really drive 4:08:04.479,4:08:10.959 down transmission, but really, we're at a state where, not only are the ambition levels lower, 4:08:10.960,4:08:20.560 but the basics are not, as we record, being provided for everyone who needs them. 4:08:20.560,4:08:25.920 Right. It brings me to this point that I often think about. So when I write this 4:08:25.920,4:08:33.120 Substack newsletter on medical innovation, and what is the use of new treatments if there's 4:08:33.120,4:08:41.840 no one to distribute them, or if there's no one that can access them. This is the whole point of 4:08:41.840,4:08:48.560 medical- or, these breakthroughs don't matter, if they're not getting to the people who need them. 4:08:48.560,4:08:54.479 Okay, so do we have any hope for the Global Fund? So listeners who are in the US, think about 4:08:54.479,4:09:02.719 PEPFAR. Listeners in other countries, think about your own health systems and think about the Global 4:09:02.720,4:09:08.640 Fund, which, I assume, is up for replenishment pretty soon, and is doing a lot of this work too. 4:09:08.640,4:09:15.439 Replenishment is when they get funding replenished from various countries. 4:09:15.439,4:09:16.000 Yes, exactly. 4:09:16.000,4:09:19.600 And those are decided by their foreign aid budgets. 4:09:19.600,4:09:30.160 Correct. So foreign aid in many higher-income and middle-income countries will contribute 4:09:30.160,4:09:37.359 some amount of tax revenues, or of government revenues, to foreign aid to other countries. 4:09:37.359,4:09:46.239 A good slice of that is global health; and HIV treatment and prevention is a reasonable portion 4:09:46.239,4:09:56.559 of that global health contribution, often via the Global Fund. And the UK is not in a particularly 4:09:56.560,4:10:03.600 ambitious moment either. At the time of recording, we are a month in, or possibly two months now, 4:10:03.600,4:10:13.040 into an announcement under the Labour government that, instead of returning to 0.7% of GNI, 4:10:13.040,4:10:20.800 basically GDP, being contributed to foreign aid — as was the case under the last Labour government 4:10:20.800,4:10:24.560 and the beginning of the last Conservative government — we are going to drop down 4:10:24.560,4:10:32.800 to 0.3. So under COVID, we dropped from 0.7 to 0.5 in what was termed a temporary measure for 4:10:32.800,4:10:42.714 COVID. And now instead of returning to 0.7, we're dropping down to 0.3 and we're going through- 4:10:42.714,4:10:43.760 0.3%, wow. 4:10:43.760,4:10:44.319 Yes. 4:10:44.319,4:10:50.399 So small. I mean, to me it seems so small as well, because I have read about some of 4:10:50.399,4:10:55.120 these other programs that our foreign aid has funded, and some of them are really impactful. 4:10:55.840,4:11:02.160 It's stuff like — oh my gosh — it's vaccination of millions of children against these deadly 4:11:02.160,4:11:10.239 diseases that don't really affect us very much in wealthier countries. It's stuff like trachoma, 4:11:10.239,4:11:16.559 which is this bacterial eye infection. The US and the UK, and some other philanthropic donors, 4:11:16.560,4:11:23.439 came together to fund this really ambitious program to supply antibiotic treatments, 4:11:23.439,4:11:28.879 better sanitation measures, and so on, to hundreds of millions of people across Africa, 4:11:28.880,4:11:34.319 and they've massively reduced this... really painful bacterial eye infection that can lead 4:11:34.319,4:11:41.679 to blindness in children. These are some huge successes that many people don't even know about. 4:11:41.680,4:11:47.600 Tuberculosis — way down from 20 years ago. Malaria, recently stalling, but has been 4:11:47.600,4:11:56.479 driven down a lot since 2000; mostly affects children. Progress is possible. Okay, well, 4:11:56.479,4:12:04.080 now that we've depressed ourselves sufficiently, there's both the financing that is not looking 4:12:04.080,4:12:10.800 so hot right now. The ambition not looking so hot right now. Another thing that you can do, 4:12:10.800,4:12:19.199 to try and get more people access to treatment and prevention, is to drive the cost down of 4:12:19.199,4:12:26.960 the actual drugs themselves. And maybe it's time we talk about that with respect to lenacapavir. 4:12:26.960,4:12:32.319 What do we know about the cost of lenacapavir right now? 4:12:32.319,4:12:39.199 Well, there's the cost of production and then there's the price that the company selling the 4:12:39.199,4:12:49.679 drug charges. The price that Gilead is charging, in the US, is $42,250 — is the last number I saw. 4:12:49.680,4:12:50.800 Per person? 4:12:50.800,4:12:57.199 Per person, per year. So that covers all the injections for the first year. That 4:12:57.199,4:13:05.359 is about double what cabotegravir — the Viiv injectable — is priced at in the US. 4:13:05.359,4:13:12.399 I was priced out of Cabotegravir; I assume I will be priced out of lenacapavir in the short term. 4:13:12.399,4:13:18.879 Why do they charge that much money? Well, a lot of the development that we talked about earlier 4:13:18.880,4:13:26.239 in the episode is done as a pure expense. So all of the scientists who are working at Gilead, 4:13:26.239,4:13:31.199 trying to iterate on the drugs to make them better, the funding for all the, or at least 4:13:31.199,4:13:36.080 most of the, clinical trials we discussed — that's all done as an expense. So they want to 4:13:36.080,4:13:42.319 charge more out the other end, to some patients, so that they can recoup some of that money. And 4:13:42.319,4:13:48.000 if they make any profit, hopefully some of it will get reinvested in more drug development, 4:13:48.000,4:13:53.520 not just distributed to shareholders. That, of course, raises questions: 4:13:53.520,4:13:58.640 well, do you think that someone in Botswana is going to pay $42,000? 4:13:59.600,4:14:05.920 My guess is no, and I'm not going to pay $42,000, so I'm with them. The price versus cost is very 4:14:05.920,4:14:11.680 different for patented medicines, often. There are estimates for how much it will 4:14:11.680,4:14:19.520 cost to produce a generic version of lenacapavir that are under a hundred dollars; I've seen as 4:14:19.520,4:14:24.479 low as $40. I haven't looked into the drivers of those estimates, or how much 4:14:24.479,4:14:30.959 Gilead has really revealed about the production methods in public — which would give you better 4:14:30.960,4:14:38.239 methods of coming up with estimates there. The good news, though, is that Gilead has 4:14:38.239,4:14:48.319 already signed agreements with six generic suppliers of lenacapavir for 120 countries; 4:14:48.319,4:14:54.080 so, plenty of low-income and middle-income countries in that mix. And you may recall there 4:14:54.080,4:14:59.680 are about 200 countries in the world, so there's a lot that are not covered there, but for those 120 4:14:59.680,4:15:08.640 countries, these suppliers will be able to provide versions of lenacapavir that have been shown to 4:15:08.640,4:15:17.199 be therapeutically-equivalent to the initial drug that Gilead used, in the clinical trials. 4:15:17.199,4:15:26.319 Though these new production runs will be made by different companies, that have been given the 4:15:26.319,4:15:36.080 rights and taught a bit by Gilead how to do it. Those generic companies will be manufacturing, 4:15:36.080,4:15:42.559 hopefully, eventually, enough supply for use in those 120 countries. What Gilead, 4:15:42.560,4:15:49.760 in their press release in October, has committed to is that they plan to provide 4:15:49.760,4:15:57.040 Gilead-supplied product at no profit to Gilead, until generic manufacturers are able to fully 4:15:57.040,4:16:05.279 support demand in high-incidence, resource-limited countries. So that's a great start, to be honest. 4:16:05.279,4:16:15.920 The questions that leaves me are, well, how quickly- what is the supply? How quickly could 4:16:15.920,4:16:21.199 demand be met? And, are we sure that they're going to ramp up quickly enough? I mean, number one. But 4:16:21.199,4:16:27.840 then, secondly, what about the other 80 countries? So there are plenty of countries in South America, 4:16:27.840,4:16:35.760 for example, that are not in the 120 covered by this generic agreement, and that have relatively 4:16:35.760,4:16:44.880 have medium HIV incidence — where a lot of people could be protected by this drug that now exists. 4:16:44.880,4:16:49.920 Some of them were part of the clinical trials for lenacapavir as well, 4:16:50.479,4:16:57.519 which is quite depressing. But, I think, what I've read is that they plan to provide it 4:16:58.399,4:17:05.120 to people in the trial. I'm not sure that that extends to the whole country. I mean, 4:17:05.120,4:17:09.840 could someone just make this drug themselves? Or, I mean, not like an individual. 4:17:15.840,4:17:21.120 There's something beyond that, which are: global intellectual property, and patents, 4:17:21.120,4:17:25.680 and enforcing those; then, there may also be some technical barriers. So 4:17:25.680,4:17:30.560 I'll talk about the patents and then the technical barriers. On the patents front, 4:17:30.560,4:17:38.960 there's a long history — with HIV specifically — of the tension of global pharmaceutical companies, 4:17:38.960,4:17:46.640 who want to enforce patents and high prices, and patients and activists and advocates, who want 4:17:46.640,4:17:54.319 medicines to be available for more people sooner. And there's two broad solutions to this problem. 4:17:54.319,4:18:01.120 One is, what I just described, with Gilead, which is voluntary licensing, where Gilead 4:18:02.319,4:18:08.000 arranges with other generic companies: 'Okay, you can do this and we will not sue you for 4:18:08.000,4:18:13.760 selling these drugs in these 120 countries. But if you sell them elsewhere, maybe we will sue 4:18:13.760,4:18:20.159 you.' That's voluntary [licensing]. Then there's compulsory licensing, 4:18:20.159,4:18:29.199 where a country may determine that they have a public health crisis, to the extent that they 4:18:29.199,4:18:35.519 are not going to- the normal patent rules are out the window. So this almost happened with HIV in 4:18:35.520,4:18:41.359 South Africa in the late '90s, early 2000s, and more recently, I believe, in Colombia, 4:18:41.359,4:18:48.319 where the government's like, 'Make drugs, that's okay, so long as people get the drugs.' I think 4:18:48.319,4:18:55.599 that is appropriate in some medical emergencies. It was a big topic of dispute and debate in COVID 4:18:55.600,4:19:00.560 as well, where I think the debate actually goes a bit of a different direction — probably 4:19:00.560,4:19:08.319 not worth getting into now, but vaccine manufacturing is quite different to generic 4:19:08.319,4:19:14.799 small molecule manufacturing. Small molecules are, in general, pretty commoditized: there are many, 4:19:14.800,4:19:19.600 many companies who can make them in many, many countries. And vaccines, 4:19:19.600,4:19:25.600 the product is the process to some degree — how you actually manufacture a given vaccine, 4:19:25.600,4:19:30.560 in a particular bioreactor, with particular cells, with particular growth medium, you got to kind 4:19:30.560,4:19:35.120 of get taught by the original manufacturer. It's harder to just scale up, and it's harder 4:19:35.120,4:19:41.760 to even infringe on a patent, if you wanted to. That brings me to the technical blockades here, 4:19:41.760,4:19:49.199 where, for a traditional generic drug, a small molecule, there are not many technical blockades; 4:19:49.199,4:19:55.199 you can just- even if a company has not revealed all the secrets of how they made something, 4:19:55.199,4:20:00.960 they have to file with a regulator, and give some information — some of which is then made public, 4:20:00.960,4:20:08.479 once a drug approval is given. They have to list certain information on a label for patients, 4:20:08.479,4:20:12.799 of what the heck is in this drug. And also, if you're a competitor, 4:20:12.800,4:20:18.399 you can simply buy their drug once it's on the market, and analyse what's in it. So you have 4:20:18.399,4:20:27.439 a lot of tools where you can basically enter as a competitor, from a technical point of view. Then, 4:20:27.439,4:20:36.479 the difficulty with some long-acting drugs is that they are more complicated to copy. If 4:20:36.479,4:20:44.799 you were dealing with a long-acting drug that had a liposome, or had a particular polymer- 4:20:44.800,4:20:46.159 What's a liposome? 4:20:46.159,4:20:50.159 You know, I don't want to answer that question because I'll get it wrong. 4:20:50.159,4:20:51.760 It's a fatty blob, right? 4:20:51.760,4:20:52.800 Say it again? 4:20:52.800,4:20:55.323 It's a fatty blob. 4:20:55.323,4:20:55.359 Exactly, thank you! "Lipo" means fat. 4:20:55.359,4:20:59.199 It's a fatty blob, I think it's probably a bilayer. I think, basically imagine a 4:20:59.199,4:21:04.239 fatty blob that encapsulates the thing you care about, but there are different fatty 4:21:04.239,4:21:08.800 blobs you might want to make, and there are companies trying to improve their fatty blobs, 4:21:08.800,4:21:13.840 and it's harder to copy the fatty blobs that are right at the frontier of fatty blob technology 4:21:13.840,4:21:18.720 than it is to copy the small molecule. Now, the good news about lenacapavir, 4:21:18.720,4:21:24.159 and the good news about cabotegravir, and the good news about islatravir — three of the long-lasting 4:21:24.159,4:21:30.239 drugs we've talked about for HIV — is that they don't seem to be right at the hardest end. We 4:21:30.239,4:21:36.080 don't have a liposome, for example, involved. We do, potentially, have some things that make 4:21:36.080,4:21:43.840 it a little harder than usual and — I'm a little bit beyond my knowledge about how it applies to 4:21:43.840,4:21:51.199 lenacapavir, and I would love to see how it goes — but, for example, I think you need a nano miller, 4:21:51.199,4:21:58.000 where you grind up your drugs! This is true for Cabotegravir and, I think, probably not true for 4:21:58.000,4:22:04.640 lenacapavir. You grind up your drug crystal, so they're tiny, tiny, tiny, tiny, so that when you 4:22:04.640,4:22:10.880 disperse them in a liquid, and then when you inject that liquid with the solids, you've got 4:22:10.880,4:22:20.319 solids that are high-surface-area-to-volume-ratio. So the question that comes to mind for me is: 4:22:20.319,4:22:26.799 Which generic companies own a nano miller, for example, and does that machine cost $8 million, 4:22:26.800,4:22:32.319 you know, how much? Those questions start rearing their head, and the next set of questions for me 4:22:32.319,4:22:41.359 is... there's a tried-and-true regulatory pathway at the FDA and other regulators, for generic 4:22:41.359,4:22:48.719 equivalents to small molecules: you have to prove only that they are equivalent in certain respects; 4:22:48.720,4:22:56.720 you do not have to redo everything else. Are we sure that those tests are going to 4:22:56.720,4:23:03.279 be good enough, for long-acting injectables, or for long-acting drugs in general? Or is there 4:23:03.279,4:23:08.880 some other reason why, towards the tail end of many months, there may be more deviation 4:23:08.880,4:23:13.520 than you got from just testing the batch chemically, and well- should we actually, 4:23:13.520,4:23:17.600 therefore, rerun a big clinical trial? And that would be cost-prohibitive; 4:23:17.600,4:23:22.319 then you really would not see much generic entry. I don't think that that's the way lenacapavir 4:23:22.319,4:23:29.759 will go. It certainly would get my hair up if people started worrying about it though. 4:23:29.760,4:23:36.159 I mean, I guess this also makes me think about Gilead producing it, probably, with multiple 4:23:36.159,4:23:42.720 manufacturing plants or so, and they would have to do this internal testing, presumably. Hopefully, 4:23:42.720,4:23:46.720 there's a way to do that in the same way — or they're producing it in a very similar way, 4:23:46.720,4:23:52.239 that they would be able to know early on, is this the equivalent; are these molecules equivalent 4:23:52.239,4:24:00.479 across these different sites? The other question that I had was, I had heard of this thing called 4:24:00.479,4:24:05.839 the Medicines Patent Pool? Is that something- have we already covered that, or what is that? 4:24:05.840,4:24:12.319 Well, conceptually, a little bit, but actually no. They are kind of an intermediary. They're 4:24:12.319,4:24:19.920 a UN-backed non-profit that tries to help match up originator companies — that are filing patents 4:24:19.920,4:24:24.399 on new medicines, taking those medicines through clinical trials, marketing them 4:24:24.399,4:24:33.279 in some countries — trying to match them up with generic companies, who might want to market the 4:24:33.279,4:24:40.559 drug in countries the originator company doesn't focus on as much, or doesn't care about as much, 4:24:40.560,4:24:47.920 in terms of making a profit, for example. Often, there's a match to be made there, 4:24:47.920,4:24:51.600 that both companies are very happy with. You know, especially if you're a smaller 4:24:51.600,4:24:58.239 originator company, who doesn't have any experience selling into Bangladesh, then 4:24:58.239,4:25:03.920 you might very well want your drug to be used by people in Bangladesh who want your drug... but you 4:25:03.920,4:25:09.359 just don't have the resources to get up to speed with the drug regulator in Bangladesh. You're 4:25:09.359,4:25:16.000 going to be on the hook if anyone sues you for side effects in Bangladesh; it's a big proposal. 4:25:16.000,4:25:21.760 But the Medicine Patents Pool, MPP, will sit in the middle and say, 'Look, we have relationships 4:25:21.760,4:25:27.760 with many generic manufacturers, many of whom have lots of experience in Bangladesh. If you just 4:25:28.479,4:25:33.359 sign on the dotted line here and say, you're not, basically, you're not going to sue them if they 4:25:33.359,4:25:40.719 sell in Bangladesh, then you can both be happy and patients get to benefit.' And they've had some 4:25:40.720,4:25:48.399 successes, in particular with HIV over the years. I think they were set up in 2010 so, for the more 4:25:48.399,4:25:55.439 recent round of voluntary licensing. But they worked on Cabotegravir, the initial long-lasting 4:25:55.439,4:26:02.719 injectable drug, and sort of sat between Viiv, the originator company, and, I believe, 4:26:02.720,4:26:08.960 three generic companies there, to help transition that- help get that out into more countries. 4:26:08.960,4:26:15.120 I didn't know much of that at all. That's really cool. I'm kind of thinking about, 4:26:15.120,4:26:20.800 okay, we heard a little bit about how PEPFAR was formed and that was set up, and yeah, 4:26:20.800,4:26:27.040 I'd very curious about that. The other thing I was thinking was, okay, given that we have 4:26:27.040,4:26:34.560 all of this — we have the Medicines Patent Pool, we have these licenses with generic manufacturers. 4:26:34.560,4:26:41.680 Also, Gilead, I think, they've said that they have the capacity to manufacture upto 4:26:41.680,4:26:49.199 10 million doses this year. I initially thought that was a big number, but if you think about it, 4:26:49.199,4:26:55.920 it's two doses per six months, so divide by four. Divide 10 million by four. That's 4:26:55.920,4:27:04.640 roughly 2.5 million people who would get this. And it's both a treatment for drug-resistant HIV, 4:27:04.640,4:27:11.920 and it's going to be used for prevention, so that's actually a small fraction. So 4:27:11.920,4:27:17.279 hopefully the generic manufacturers help to scale that up to some degree. 4:27:17.279,4:27:22.559 But aside from that, okay, if PEPFAR has this uncertain future right now, I think 4:27:22.560,4:27:29.920 we do know that the Global Fund is going to try and roll it out, but trying to scale that up is, 4:27:29.920,4:27:36.319 I think, maybe the next big thing to try to focus on — if people are listening and have 4:27:36.319,4:27:42.159 some way to convince their government that this is a really important thing to work on. 4:27:42.159,4:27:48.159 I think the Global Fund seems like it's going to be doing lots of the work, in terms of funding 4:27:48.159,4:27:55.760 these programs to roll it out and administering it worldwide. But I'm curious if there are 4:27:55.760,4:28:01.760 other things that come to mind, in terms of how you're thinking about the potential future here. 4:28:01.760,4:28:09.199 Those are the main ones to me. I think the time is now and the opportunity is here, and if you really 4:28:09.199,4:28:20.239 just take a step back, a whole 'nother level — what is happening in many countries most affected 4:28:20.239,4:28:33.359 by HIV? Well, a happy piece of news is that- I am cautious saying this in April 2025, where 4:28:33.359,4:28:38.239 trade relations are also a little bit up in the air, but the happy news from the last few decades 4:28:38.239,4:28:47.760 is that most lower- and middle-income countries have been growing economically, and that was not 4:28:47.760,4:28:57.279 true in the 1960s, for example. We, in fact, in most countries, have been seeing income growth for 4:28:57.279,4:29:04.559 people, and seeing the tax base of those countries also grow — meaning those countries can do more 4:29:04.560,4:29:15.279 public health interventions, too. And you know, that is really the future that will make a lot of 4:29:15.279,4:29:21.920 people with HIV have more sustainable healthcare- is that if you are in Nigeria, you should not have 4:29:21.920,4:29:27.920 to rely on the whims of the American public, and in the future you hopefully will not. 4:29:27.920,4:29:34.319 But that, unfortunately, is decades away. The tax base of many countries is not high enough 4:29:34.319,4:29:42.399 to provide lenacapavir to people who need it, and people are not individually rich enough to pay for 4:29:42.399,4:29:51.759 lenacapavir, if they need it. So now is a moment for people, especially voters, in richer countries 4:29:51.760,4:30:01.199 to kind of do our part. It's not a permanent humanitarian effort, I think it's a decadal- the 4:30:01.199,4:30:07.840 next few decades really matter. And we have these amazing new technologies that actually enable a 4:30:07.840,4:30:15.680 dent to be made. That would be where I would leave the topic of scale up is... now's the moment, 4:30:15.680,4:30:23.920 and I hope, I hope, that when you and I are 30 years older, this kind of topic doesn't exist 4:30:23.920,4:30:34.479 in the same way, because we don't have to think about external sources of financing quite as much. 4:30:34.479,4:30:40.159 No, I really hope so as well. I mean, I think, right now, where we are, this still 4:30:40.159,4:30:46.080 seems quite out of reach for a lot of people in the most-affected countries, in Southern Africa. 4:30:46.080,4:30:54.479 I think I was reading... the average spending on healthcare some $80 per person per year in 4:30:54.479,4:31:02.399 Southern Africa, whereas it's, what is it, like 80 times that or something in the US? And meanwhile, 4:31:02.399,4:31:08.960 I mean, that's not just for lenacapavir, which would be some $40 or so at a generic price, 4:31:08.960,4:31:16.000 it's also all the other treatments, preventions, testing, and so on. Right now, 4:31:16.000,4:31:25.199 it still feels quite out of reach, and I'm just- The Global Fund is going to be really important; 4:31:25.199,4:31:34.880 trying to keep PEPFAR running; but also trying to build up more capacity within these countries 4:31:34.880,4:31:43.680 to protect the people who are affected by HIV right now. That seems like a difficult problem. 4:31:43.680,4:31:50.319 It sounds like there's some uncertainty in the next decade then. So are there other tools that 4:31:50.319,4:31:58.080 are maybe not scientific, but more economic or financial, that we can apply to be more ambitious? 4:31:58.080,4:32:06.239 I think there are a few. I mean, it's not just lenacapavir. I think this is one really 4:32:06.239,4:32:11.279 important area that we want to scale up, but there are also these other potential 4:32:11.279,4:32:17.439 future drugs like islatravir, any other potential long-acting drugs that might work. 4:32:17.439,4:32:25.679 How do people get the funding model so that we're not having to be in the situation where 4:32:25.680,4:32:33.760 a pharmaceutical company is trying to recoup their costs at a very high price in richer countries, 4:32:33.760,4:32:42.080 and then hopefully, voluntarily, agreeing to these agreements, which may or may not be scaled up. One 4:32:42.080,4:32:50.319 idea that comes to mind for me is this idea of an Advance Market Commitments, or an AMC. And 4:32:50.319,4:32:59.040 I love the idea of AMCs. I've written about them a bunch, read a lot of stuff about them. I think, 4:32:59.040,4:33:07.199 the way to think about this is to contrast it with the regular approach to funding drugs or vaccines. 4:33:07.199,4:33:13.599 So we usually have this situation where a pharmaceutical company, or philanthropic funder, 4:33:13.600,4:33:20.160 or some government is trying to decide upfront which bets might work out — which companies 4:33:20.160,4:33:27.359 or which researchers might develop an effective drug — and they're funding those groups directly, 4:33:27.359,4:33:32.480 and then some of them will work out, some of them won't. In drug development, the success rate is 4:33:32.480,4:33:38.480 very low, and that means most of these bets are going to fail. There's going to be a lot of 4:33:38.480,4:33:47.759 wasted money on the funder's side. And secondly, there's this huge expense covered by individual 4:33:47.760,4:33:51.920 pharmaceutical companies, in developing the drug, that they now want to recoup, 4:33:51.920,4:33:59.039 so they charge these very high prices. It takes a while, usually, for a drug to go off-patent, 4:33:59.039,4:34:08.959 or for them to agree to these generic-licensing approaches, and that is a lot of time wasted; 4:34:08.959,4:34:13.520 it's a lot of people who are not getting the drugs or the vaccines that they need. 4:34:14.080,4:34:19.039 Is there another way to do it? And I think AMCs are one answer to that. 4:34:20.240,4:34:29.119 An AMC is kind of an inversion of this — where, instead of funding the groups directly, 4:34:29.119,4:34:36.160 you're funding the potential successful products at the end. So, you're setting up this pool of 4:34:36.160,4:34:43.680 funding — which might be some billions of dollars or so — if a company or a research group can 4:34:43.680,4:34:53.199 develop a drug or vaccine that meets certain standards. The amount that's given to these 4:34:53.199,4:35:00.719 companies, or manufacturers, depends on how much they're manufacturing. It's usually on a per-dose 4:35:00.719,4:35:07.439 basis — essentially, how many doses have you administered? You get more funding based on that. 4:35:07.439,4:35:13.919 I think this is a really cool idea for two reasons. One is, as a funder, 4:35:13.920,4:35:20.959 you don't have to know who is going to succeed. You have this pool of funding if something 4:35:20.959,4:35:27.439 succeeds. If nothing succeeds, you don't pay that money. So you are saving on that. And secondly, 4:35:28.240,4:35:34.719 you're also rewarding companies that scale up the drug faster and get it out to people who 4:35:34.719,4:35:42.080 need it. At the same time, you're only doing this for the successful drug. So you're giving 4:35:42.080,4:35:51.199 this stable potential future market to companies; they're going to have this commitment in advance, 4:35:51.199,4:35:55.439 often years in advance, of what the price is going to be, and they can plan 4:35:55.439,4:36:00.878 much more effectively based on that. This has been tried for pneumococcal 4:36:00.879,4:36:06.799 vaccines in the past. I think this was in the late 2000s, there was this advance market commitment 4:36:06.799,4:36:14.080 set up to try to speed up the production of pneumococcal vaccines. Pneumococcal disease 4:36:14.080,4:36:21.840 is a respiratory lung infection that affects people worldwide, and we already had effective 4:36:21.840,4:36:27.520 vaccines for it in richer countries, but in Africa, there were different strains of the 4:36:27.520,4:36:36.000 bacteria that weren't targeted for the vaccines. So this AMC was set up, knowing that it was 4:36:36.000,4:36:43.199 possible to develop a vaccine for these other strains. There was this pool of 1.5 4:36:43.199,4:36:49.920 billion dollars that was there for companies to receive, depending on how much they produced, 4:36:49.920,4:36:57.600 if they managed to get a vaccine through clinical trials to show safety and efficacy. And it was 4:36:57.600,4:37:02.000 very successful — so the scale-up of this pneumococcal vaccine in African countries was 4:37:02.000,4:37:09.840 very fast. I think three or four companies managed to produce effective vaccines including the Serum 4:37:09.840,4:37:15.680 institute and I think Pfizer was another one of them. It just shows this model, of how this can 4:37:15.680,4:37:22.000 work, and you don't even to have it for- you don't even need to believe that it's possible to develop 4:37:22.000,4:37:28.400 a drug or vaccine for it, because if it doesn't work out, you don't have to pay that funding out. 4:37:28.400,4:37:35.039 The people who do have to pay are, like, the pharmaceutical company themselves in the 4:37:35.039,4:37:40.799 early stages — they will still have to make the decision on whether this is a good bet for them. 4:37:40.799,4:37:47.600 Yeah, I think in that case, in the pneumococcal case, the Pfizer vaccine did — people reviewing 4:37:47.600,4:37:54.879 what effect did this really have — they think that did get rolled out quicker, maybe scale up years 4:37:54.879,4:37:59.439 quicker than it would've otherwise. I think the Serum one ended up coming through later, 4:37:59.439,4:38:05.919 and maybe being less affected. But the scale up is so important for actually getting drugs 4:38:05.920,4:38:11.199 to people who need them, not just inventing cool stuff. And when I think of applying this 4:38:11.199,4:38:20.560 across to lenacapavir, I think to this great piece that Kamal Nahas wrote in Asimov Press 4:38:20.561,4:38:27.279 about lenacapavir, and where he touched a bit on the voluntary agreements in 120 countries, 4:38:27.279,4:38:35.840 and what's happening outside of those countries. Maybe this is the shape of problem that, 4:38:35.840,4:38:44.000 for those 80 countries, where there's not in each country, enough demand, or there's too 4:38:44.000,4:38:53.520 much uncertainty around demand, for a company — Gilead or generic company — to enter that market, 4:38:53.520,4:38:59.920 and try and start selling to the public healthcare systems. If there were an AMC 4:38:59.920,4:39:08.959 that aggregated across those countries, and made the demand clearer, and had a price that was fair, 4:39:08.959,4:39:15.199 but also enough that money could be made to make it sustainable for the companies entering, 4:39:16.080,4:39:19.439 maybe that's a place for an AMC, I don't know. What do you think of that? 4:39:19.439,4:39:25.199 That's a great example of where it can be used. I actually also think it could be used in scaling 4:39:25.199,4:39:31.359 up a drug even once it's been approved, because this second part of what an AMC is used for, in 4:39:31.359,4:39:40.400 the scale up — having the amounts that companies receive be based on the amount they manufacture 4:39:40.400,4:39:47.279 means that you're incentivizing this large-scale manufacturing, and actually administering it to 4:39:47.279,4:39:56.000 people. That is something that could still be used even now. But one of the other applications 4:39:56.000,4:40:05.039 is as a way to pull funding towards some drug or vaccine or some product that hasn't yet been made, 4:40:05.039,4:40:10.959 so that would be another option. Can we develop a drug that's better than lenacapavir, 4:40:10.959,4:40:19.680 or easier to take, or so on, and fund it with this new model. And I think this reminds me as well, 4:40:19.680,4:40:26.160 I don't know if we mentioned it earlier, but as far as I know, Gilead is also trying to produce 4:40:26.160,4:40:33.279 improvements on lenacapavir that would be taken once per year instead of once per six months. 4:40:33.279,4:40:35.039 Imagine that, wow. 4:40:35.039,4:40:42.879 That would be very cool. I was wondering about why they were doing this. I mean, 4:40:42.879,4:40:50.080 if you were self-interested profit-making company, why not just stick with this already-amazing drug? 4:40:50.080,4:40:56.879 And it occurred to me, when you were talking about Merck's drug islatravir — that's this 4:40:56.879,4:41:02.639 oral pill that's once-per-month. If someone could choose between an oral pill once per month and 4:41:02.639,4:41:10.561 an injected drug once per six months, they might choose the pill. Not only the person themselves, 4:41:10.561,4:41:16.400 but the clinics might find it easier to distribute the drugs. It's just, you don't need a healthcare 4:41:16.400,4:41:22.798 worker, or a nurse, or someone to inject the drug if it's a pill. And that made me wonder, 4:41:22.799,4:41:26.959 maybe that was the incentive. That was the reason that they decided: 4:41:26.959,4:41:32.080 'Let's go even further, to make this thing that's even harder for Merck's 4:41:32.080,4:41:36.320 drug to beat.' I don't know if that's the case, but that's what I would guess. 4:41:36.320,4:41:41.920 And it just goes to show how much progress we've made with HIV. Because when you were 4:41:41.920,4:41:47.600 describing the first drugs around, they were not so good and there were no competitors, 4:41:47.600,4:41:54.639 and now we have great options for patients, and great options for people who 4:41:54.639,4:42:03.119 don't even have HIV yet who want to reduce their risk. So I'm glad to be alive today. 4:42:03.119,4:42:12.240 It's so much- I mean, the whole timeline is just incredible to think about. We talked about how, 4:42:12.240,4:42:20.160 in the early 1980s, how pessimistic or how scary it would've been to have HIV, 4:42:20.160,4:42:25.786 not have any treatments, have this- thought-of-as-this untreatable disease, 4:42:25.786,4:42:33.119 as just this behavioural problem; there's nothing that someone can really do medically to treat it. 4:42:34.879,4:42:41.279 Contrast that with where we are now. I think, personally, that process, that timeline could 4:42:41.279,4:42:49.039 have been sped up. Just reading about some of the details of early research in the 1980s, 4:42:49.039,4:42:54.240 but also, knowing about how long it takes to run a clinical trial, how long it takes to set 4:42:54.240,4:43:01.279 up the trial sites, or train the nurses and the healthcare workers, or to share this information 4:43:01.279,4:43:09.279 between different research groups and so on. But at the same time, it is just an incredible story. 4:43:09.279,4:43:18.959 Now is probably the time to step back on this story that we have told and conclude. I am sure 4:43:18.959,4:43:27.199 we missed out many subplots that are also ripe for discussion. But among what we have discussed, I'm 4:43:27.199,4:43:34.400 interested to hear: What were your main takeaways from this story over the last fifty years? 4:43:34.400,4:43:41.839 My takeaway... I mean, I had so many takeaways. One of them was just how many different ways 4:43:41.840,4:43:47.119 you can approach medical innovation. Like, what are the different things that you could 4:43:47.119,4:43:52.080 think are important here? I mean, partly it's 'Let's make a really effective drug', 4:43:52.080,4:43:59.279 but it's also 'How do we make a drug that's easier for people to take on a regular basis?' It's, 4:43:59.279,4:44:05.679 maybe, refining drugs that already exist — trying to improve on them, in terms of their safety, 4:44:05.680,4:44:12.480 efficacy, or again, how people take them. The other was the different types of 4:44:12.480,4:44:19.759 drug development. So we talked about this trial-and-error process with the first drug 4:44:19.760,4:44:28.400 azidothymidine, where they just looked at some 180 compounds: tried each of them in the lab, saw what 4:44:28.400,4:44:37.039 worked in cells in the lab, and then scaled up based on that. The other is, this is an example of 4:44:37.039,4:44:44.879 screening existing compounds, or just compounds in nature, that helps repurpose this previous 4:44:44.879,4:44:52.959 cancer therapeutic that didn't work, for HIV. Then we had some examples where this understanding 4:44:52.959,4:44:59.039 of the specifics of HIV, or how the enzymes work, what they look like, what will fit 4:44:59.039,4:45:08.719 into these little gaps between them — that was another option for developing a new drug. But, 4:45:08.719,4:45:14.080 at the same time, there was so much iteration and adjustment — that was tinkering — that was 4:45:14.080,4:45:21.039 important there. The move from this drug that was potentially promising, to one that actually met 4:45:21.039,4:45:27.680 several criteria that you would have, with the efficacy, the safety, how long lasting it was. 4:45:27.680,4:45:35.119 And then I guess, there are these other- improving on the drugs that already exist, 4:45:35.119,4:45:43.680 that is not just trying to use existing information. If there has been, already, 4:45:43.680,4:45:50.320 a protease inhibitor invented, can you now develop a new one based on that knowledge? Can you develop 4:45:50.320,4:45:59.039 a different type of nucleoside inhibitor, like AZT? Will people develop more capsid inhibitors, 4:45:59.039,4:46:05.039 based on the knowledge that they have from this? I mean, all of this, I think, is super interesting. 4:46:05.039,4:46:14.959 I totally agree on how much the tinkering and iteration stands out, as important. Basically, 4:46:14.959,4:46:19.680 at every level, there's.. so much of that's happening at the screening stage, 4:46:19.680,4:46:26.719 so much of that is happening, as you just said, at designing a capsid inhibitor that makes sense 4:46:26.719,4:46:32.879 for patients in a particular context. Another thing that stood out to me is 4:46:32.879,4:46:42.480 how hard science is to predict — in the sense of, thank goodness people in the last forty, 4:46:42.480,4:46:50.638 fifty years, scientists did not only work on vaccines. We don't have an HIV vaccine, 4:46:50.639,4:46:56.639 and we do have a HIV preventive drug that you can get injected with, 4:46:56.639,4:47:02.320 and kind of feels like a vaccine. I'm so grateful that people were exploring 4:47:02.320,4:47:09.759 different parts of the technology tree there. We don't have a cure either. We don't have 4:47:09.760,4:47:15.199 a cure for HIV and we don't have a vaccine, but guess what? We have game-changing tools, 4:47:15.199,4:47:22.560 and that came from a part of exploration you may not have been able to predict back in 1981. 4:47:22.561,4:47:30.799 Also, the fact that the treatments could be used as a prevention as preventive drugs was probably 4:47:30.799,4:47:37.199 not that obvious to scientists at the time. That itself was quite unpredictable, I think. 4:47:37.199,4:47:38.400 Absolutely. 4:47:38.400,4:47:43.839 The other thing that reminded me of was just how many different aspects, 4:47:43.840,4:47:49.359 or how many different types of science- or what is involved in developing a drug, 4:47:49.359,4:47:58.240 is not just one person tinkering with it in the lab. It's this whole network of clinical trials 4:47:58.240,4:48:05.840 that are running; there's the basic research, there's stuff like developing microscopes 4:48:05.840,4:48:10.719 with a high-enough resolution that you can really see what is happening inside the cell, 4:48:10.719,4:48:17.840 what this virus looks like, what the proteins look like. There's the DNA sequencing technologies, 4:48:17.840,4:48:25.359 there's the protein development. Like, all of this stuff comes together to develop these 4:48:25.359,4:48:30.320 drugs. And then there's the medicinal chemistry, and the pharmacology — which I think, probably, 4:48:30.320,4:48:37.439 I had kind of underrated before as just, okay, this seems like this last-minute thing; after 4:48:37.439,4:48:42.878 you've developed a drug, you now want to make sure that it's safe and effective. I previously 4:48:42.879,4:48:49.600 had this assumption that that was what medicinal chemistry was about, and now I'm thinking this 4:48:50.480,4:48:57.519 can make a huge difference on whether a drug is useful or effective at all in the real world. 4:48:57.520,4:49:03.039 Even right at the discovery stage of lenacapavir. So important, how stable it is and how it doesn't 4:49:03.039,4:49:09.600 break down very quickly. I totally agree with what you just said about interlocking parts of 4:49:09.600,4:49:20.240 the medical innovation system. It's amazing that we just about had recombinant DNA at the time when 4:49:20.240,4:49:28.879 HIV started becoming a crisis. So we could use recombinant DNA in the lab as a research tool 4:49:28.879,4:49:33.600 and that we did not have all of those other things we just mentioned. We didn't have PCR, we didn't 4:49:33.600,4:49:35.039 have electron microscopes- well, I dunno about that- we didn't have cryo-electron microscopes, 4:49:35.039,4:49:41.920 certainly. We, only in the last few years, have learned the capsid, which we are now inhibiting 4:49:41.920,4:49:48.639 with lenacapavir, in fact stays intact into the nucleus. There's so much more that we're still 4:49:48.639,4:49:55.520 going to learn over the next coming years that might open up new frontiers. And that's true not 4:49:55.520,4:50:02.240 just for HIV, I bet you that things that HIV researchers have learned will be useful for 4:50:02.240,4:50:09.519 hepatitis B, for other cancers, for this, that, and the other. And the final interlocking surprise 4:50:09.520,4:50:19.199 of science that I learned from you many hours ago was that it was only two years before 1981 4:50:19.199,4:50:26.240 that the first human retrovirus was discovered. Thank goodness for that. And it makes you wonder 4:50:26.240,4:50:33.359 what we don't yet understand, that will make solving and curing diseases in the future easier. 4:50:33.359,4:50:41.279 Yes! And, and, above all of that, the other interesting thing for me was learning about 4:50:41.279,4:50:47.119 how drug pricing works or how these patents work. How does manufacturing actually work 4:50:47.119,4:50:55.119 at large scale? What do the funding models- what they have to do with whether drugs are developed, 4:50:55.119,4:51:03.599 how fast they're rolled out, who's ready to pay for certain drugs? And it's every aspect 4:51:03.600,4:51:09.920 of this whole process: not just the lab, not just the clinical trials, but the funders, 4:51:09.920,4:51:15.760 the people who decide, who show support for foreign aid spending, for example. 4:51:15.760,4:51:22.799 Everything comes together when we're talking about any disease, but particularly for HIV, it's 4:51:22.799,4:51:30.561 so salient because of these huge programs that have transformed the lives of millions of people. 4:51:30.561,4:51:36.320 And going into the future. There's no point for all of this wonderful science unless we remain 4:51:36.320,4:51:43.439 ambitious. And unless we make sure that people who need these drugs can access them. It's possible, 4:51:43.439,4:51:55.839 we've done it before and into the future we go, with uncertainty and with resolve. 4:51:55.840,4:52:01.039 This episode was only possible from a lot of work done by a lot of people publishing in the 4:52:01.039,4:52:05.600 open — whose papers we read and whose reviews we read. I won't thank them all here, but we'll 4:52:05.600,4:52:10.400 leave, in the show notes, some of the research that we base this episode on. I, in particular, 4:52:10.400,4:52:17.359 would like to thank Anne de Bruyn Kops, who wrote a great review of long-lasting injectables for 4:52:17.359,4:52:23.279 many different diseases for Open Philanthropy, that I learned a lot from. I want to thank Sanela 4:52:23.279,4:52:31.679 Rankovic, who was the HIV researcher who knows all about PF-74. And then, of course, I'm sure 4:52:31.680,4:52:38.160 we both want to thank Douglas Chukwu, who joined us for our first ever phone-a-friend section. 4:52:38.959,4:52:45.359 Yes. And the team at our Works in Progress, Aria Babu, who helped 4:52:45.359,4:52:50.480 us really, actually, get this podcast to run Adrian Bradley, 4:52:50.480,4:52:57.279 who's here with us now producing and keeping us on track with this episode. Then, the team 4:52:57.279,4:53:04.080 at Works in Progress and Open Philanthropy, who were sponsoring this podcast. And then, 4:53:04.080,4:53:10.320 I would say, also, all of the scientists who were involved in developing all of these drugs, 4:53:10.320,4:53:14.799 all the people who were participating in all the clinical trials, all the healthcare workers 4:53:14.799,4:53:22.320 who worked in them, everyone involved in this massive program, PEPFAR, everything. It's just- 4:53:23.279,4:53:24.080 It's so cool. 4:53:24.080,4:53:25.600 It's very inspiring. 4:53:25.600,4:53:30.400 And with that, I will ask you as listeners, if you enjoyed this episode, 4:53:30.400,4:53:36.240 feel free to subscribe. We will be talking about other Hard Drugs in the future, 4:53:36.240,4:53:39.920 and check out the show notes for more details on this one. 4:53:39.920,4:53:43.359 Bye. Bye.

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