Hi everyone. Welcome to Febrile, a cultured podcast about all things infectious disease. We use consult questions to dive into ID clinical reasoning, diagnostics and antimicrobial management. I'm Sara Dong, your host and a Med Peds ID doc. I'll first introduce Dr. Anshel Kenkare. Anshel is a second year internal medicine resident at the Montefiore Primary Care and Social Internal Medicine Program. He's interested in a career in ID focused on public health and environmental stewardship.
Also, joining us today is Dr. Mike Reid. Mike is an Associate Professor at University of California, San Francisco. He currently serves as the Chief Science Officer for PEPFAR in the Bureau of Global Health Security and Diplomacy in the US State Department. He also serves as Associate Director of the Center for Global Health Diplomacy, Delivery, and Economics at UCSF. All right. So as everyone's favorite cultured podcast, we ask our guests to share a little piece of culture.
So it's really just something non-medical that makes you happy. Um, so what are you guys bringing today?? Oh, I can start. Yeah. Yeah. A long time listener, first time caller. So excited. Um, I think for me, I did a tour of the Southwest National Parks recently. Ooh. and I had a lot of hype around Zion and the Grand Canyon, which were incredible. But I loved Arches the National Park, uh, and I just found it so peaceful and beautiful that I will highly recommend it to everybody. Very cool.
That's awesome. So, um, on an outdoors theme, I recently walked the Camino de Santiago in northern Spain. So two weeks ago I was in Northern Spain walking the, the pilgrimage to Santiago. Long days of walking, conversations with strangers from all over the world. It was really restorative. Also a humbling, um, realization of how, uh, how at least I need to feel grounded, um, Hmm. could choose a quiet path. And, um, Spanish tapas, uh, were, were, were very restorative.
Um, you can't pour from an empty cup rate, and this was a Yeah. my cup refilled. It was great. Yeah. Oh, that's lovely. Now I wanna go take a walk outside. Um, so, Anshel had reached out with this great idea to have an episode and luckily we had some awesome timing because hot off the press, we have heard about the FDA approval of HIV prevention option lenacapavir. And so we're gonna talk about that today, but I will go ahead and hand it off to Anshel to take us forward. Yeah. Thank you so much.
I, I really just wanted to talk to Dr. Reid today a little bit about lenacapavir. So just to start, what is lenacapavir and how well does it work? Yeah, so lenacapavir, um, is a first in class HIV capsid inhibitor. It's a, a novel antiretroviral that targets multiple stages in the HIV lifecycle, including capsid assembly, disassembly, viral release. Um, and for the context of this podcast, it's actually marketed as two different products.
There's lenacapavir for treatment, which I think is called Sunlenca in the US. And then, as you alluded to hot off the press, the, the formulation for prevention, which is called Yeztugo, is now available. Um, it's available as an oral tablet. More importantly, as a twice yearly subcutaneous injection.
Um, I don't think I'll speak too much about treatment with you today, Anshel, but, um, I'm happy to share more details about the science that has recently emerged around prevention and the use of LEN. Yeah, I think that would be great. Just thinking about how this would potentially apply to a patient. Let's say we have a patient here I'm practicing in the Bronx, uh, who is interested in transitioning from an oral PrEP regimen to lenacapavir after seeing the news. How easily can we switch her?
What's, what's the general availability of lenacapavir currently?. Yeah. Maybe I can start by just reviewing the clinical research that has been published that sort of supports its use and then I can answer your questions around its clinical role in a place like the Bronx. Um, so. Uh, late last year, at the end of 2024, the scientists who were working on LEN published two papers: PURPOSE 1 and PURPOSE 2, both published in New England Journal.
PURPOSE 1 looked at the role of LEN as a prevention tool for cisgender women in Sub-Saharan Africa. They, they evaluated LEN in a setting of very high HIV incidence in, uh, Uganda and South Africa. And they basically randomized participants to either getting injectable LEN every six months or oral Truvada (emtricitabine-tenofovir disoproxil fumarate), which as you know, is the gold standard for biomedical prevention. Um, and they looked at, uh, outcomes over a 12 month period.
And in that study, and this is one, one of the most groundbreaking pieces of science, I think, published in many, many years. They found zero HIV infections in the LEN arm. So an HIV incidence that was statistically indistinguishable from zero, which has never been found before in a, in a prevention trial. For, for the purposes of of your question, I think it's worth just highlighting PURPOSE 2 though.
So PURPOSE 2, very similar study design, but this was in men and gender diverse people, mostly in the US I think 60 research sites in the US and then about 30 research sites across Brazil, Thailand, South Africa, Peru, Argentina. Uh, I think there may have been one other country. And again, they randomized individuals in that trial to LEN every 6 months or, oral Truvada. And what they found there, again, was incredibly impressive results.
Essentially two infections in the LEN group, um, among 2100 participants. And, and that represented a 96% reduction in HIV risk compared to background incidence. So much higher superiority, uh, as compared to the oral option, uh, Truvada. I think key takeaways, which again, relevant to your patient in the Bronx. Near perfect prevention in in PURPOSE 1, um, a hundred percent efficacy and 96% efficacy and statistical superiority in PURPOSE 2 over daily oral PrEP.
Um, this is unheard of in, in HIV research. I think the other thing to, to highlight that is, again, relevant to your patient, um, and, and also validated by a fair amount of other research though, is that Truvada, whilst an effective agent is only as good as it is when people take it, um, and in PURPOSE 1, um, many people just didn't take it or they didn't take it continuously during the, the research period.
And I think that speaks to the potential value of LEN as something where adherence really isn't the same challenge because you're just getting an injection every six months, and that injection offers sustained protection. I think the other insight that, again, is relevant is just that this is very well tolerated. There were mild injection site reactions, some inflammation, a little bit of pain. But overall almost everybody continued the LEN throughout the research period.
So for your patient, in the Bronx, and I will say I was a resident in the Bronx. I totally appreciate that, that that client context. Um, yeah, I think the potential to use this drug is very high. I think this could have a, a really transformative impact for, for folks who are at greatest risk of HIV acquisition. And, and not only those that have a harder time taking pills, everybody, the research shows everybody benefited. Two, two things I'll say.
And then I'll let you ask your next question Anshel, um. PURPOSE 1 and PURPOSE 2 are just two trials in a family of trials that the drug company have sponsored. Um, three, four, and five. PURPOSE 3, 4, and 5 will explore the role of LEN in cisgendered people in the US. I think that's three. Um, PURPOSE 4 is looking at LEN in people who inject injection drugs And PURPOSE 5 is looking at LEN in Europe and the UK.
So there are still some important unknowns about its potential impact in those populations. Look, I would imagine that it will be very efficacious in those contexts too. But, but we will wait on those data that some of which will be published pretty soon to confirm that. The other answer to your question though, about is it a good option for somebody in the Bronx, is, um, is it available? Right? And, and I think this is the really exciting thing.
So on June 18th, the FDA approved LEN for, for prevention, um, under the brand name, Yeztugo. Um, I dunno how they come up with these names for new drugs, but it is what it is. And I think people have started to prescribe, I think the first drug prescription was soon thereafter. Nonetheless, I think a major challenge is, is ensuring that insurance companies and, and patient assistance programs make the drug available. I understand that Gilead have, have committed to broad access.
They have like an advance access program to reduce costs for, for clients. Um, but I imagine that it'll be a few months before it's actually available and on insurance schemes, et cetera. The last thing I'll say, and I'm I'm not an expert on, on drug pricing in the US, but think it will be quite expensive to begin with. The reports I've read are that in the US, Yeztugo will, will be priced annually at between $28,000 and $42,000.
And so that may be prohibitive for, for some, although I understand that they, they priced it at that, um, level with the expectation that insurance companies will be able to, to cover that for many people. So there's a long answer to your short question. Happy to revisit any of the pieces that weren't clear. No, I think that was extremely clear.
I think, it really is amazing, uh, that we have this FDA approval now, and I, I think the cost overall is something that everybody seems to be questioning, but as people start to prescribe, I think we're gonna see, see where it lands and, and kind of advocate from there. I think a similar question, just because you referenced the PURPOSE 1 trial was conducted in Sub-Saharan Africa. If we were in a clinic in rural Uganda, what kind of access to lenacapavir would potentially be seen?
And then on top of that, uh, can be a little bit contentious, but how has the PEPFAR freeze and subsequent defunding affected the ability to roll out a drug like lenacapavir, which has been so incredibly effective? Yeah, it's, it's a great question. Well, both, both of those are great questions. I think, um, up until recently there was, there was great optimism that LEN would be widely available in Sub-Saharan Africa, in, in the imminent future, contingent on FDA approval.
I think there is still optimism that lenacapavir will be available in Sub-Saharan Africa in the imminent future. But I, I think it's fair to say that the incoming administration have taken a different approach to global health than past administrations, Democratic and Republican. Um, and as you alluded to Anshel, they instituted a, a pause on foreign assistance early in January after President Trump, uh, returned to power.
And that pause on foreign assistance has had quite substantial impacts on the program that I'm involved with, PEPFAR, the, the President's Emergency Plan for AIDS relief and specifically, um, we initially saw a pause of all programming, and then quickly thereafter a resumption of life sustaining activities.
So, within a few days of that initial pause after January 21st, we were able to resume much of the activity that had been undertaken before that, as long as it was related to care and treatment and other life sustaining activities. However, there was a pause on all prevention activities that were sustained. And that has had an impact on our capacity to support biomedical prevention programming in high burden countries that PEPFAR had previously supported.
I'll also say that to execute the programs that we fund has been concomitantly challenged by the dissolution of US AID as one of our implementing agencies. And so whilst some of our programming that has been funded through other US agencies like the CDC has resumed, some of the programmatic activities undertaken by USAID, particularly related to prevention have, have not been resumed. So all of those things have had a big impact.
Perhaps we can include in the links to this podcast, some of the great science that has been done to try and evaluate that. Um, there have been 10 or 20, maybe 30 really great modeling papers that have been produced that have tried to assess the impact on the pause in foreign assistance on HIV outcomes, mortality, incidence, as well as on other diseases including tuberculosis, malaria. Um, I just draw your attention to one.
There's a great paper that's published in Lancet HIV by Debra ten Brink, at al about three months ago that estimated if that pause was continued after January in perpetuity, then there would be 3 million additional deaths by 2026, um, from HIV, but there are a number of other papers out there that have similarly kind of evaluated either a country level or across Sub-Saharan Africa, the impact of the pause on, on programs. There's even a website you can go to.
There's the PEPFAR Impact Counter website, which is produced by colleagues at Boston University that tries to track in real time the, the impact of these pauses on, on clinical programs. And I, again, I think we might be able to share the link to that in the notes to the podcast. Um, so that all brings me back to, to your question around the, the person in Uganda, um, who, who would be interested in LEN. And I think the question is no, right now, there is no ability to make LEN available.
Um, uh, for a couple of reasons. One is that we're still in this place where the current administration haven't determined what their policy is vis-a-vis, um, supporting prevention programming. And two, because the drug is not yet available in Sub-Saharan Africa and, and at a point where it is, the question remains as to whether it'll be affordable for, for ministries of health to procure with their own resources.
Maybe I'll just reflect on, on, on some other data that has been published that speaks to the excitement and I think, desire of, of, of recipients of care in Sub-Saharan Africa to, to access long-acting agents. So there's a, a research group, um, actually from the University of California, San Francisco, the SEARCH (Sustainable East Africa Research in Community Health) group that work in Kenya and Uganda.
And they have looked at willingness of individuals to switch from Truvada to Cabotegravir, which is another long-acting agent, and, and found that in that setting almost everybody, the vast majority of people when given the choice moved from oral to injectable. And one would anticipate that the same is true for LEN. That if available it will be willingly and excitedly pursued by individuals who would benefit from it.
And we can spend a little bit of time, uh, dwelling on this next reflection if it's useful. But I think one of the key issues for Sub-Saharan Africa is, is not so much related to the efficacy. We know based off of PURPOSE 1, that this is incredibly efficacious drug for prevention, but really the cost effectiveness and the cost effectiveness will be determined by what price LEN is available at and, and the volumes that are, are procured to ensure that that price is affordable.
And then also the incidence. So there is a fair amount of modeling that's also been done to try and anticipate where LEN will have the greatest impact in high burden settings. I think initial rollout modeling suggests that if we were able to roll out between one and 6 million person years of LEN over a three year period, then that could avert up to a hundred thousand infections in Sub-Saharan Africa.
That's actually a, a relatively small fraction of the global incidence, but it's a vital step towards sort of a broader adoption. The places where LEN will be most cost effective are the places of highest incidence. So in Sub-Saharan Africa, that really will mean um, South Africa, which has the highest HIV incidence in Sub-Saharan Africa. And there, there are a number of districts with very high incidence where we, you know, ideally LEN would be targeted.
And then there are other smaller pockets in many other countries in Sub-Saharan Africa where if targeted to the right priority populations, it would again be, be cost effective. Um. then similarly in the Philippines, you may know that there's a sort of a, a really rapidly unfolding HIV epidemic in the Philippines right now. And that would be a place where there would be a likelihood of high impact in the near term.
The other thing to say is that, that impact will, will, right, will diminish over time, right? So that as incidence goes down, the cost will go up. That is a sort of a paradox that we would have to deal with. But nonetheless, the key message is that, yes, effective. Yes, cost effective in the right, right settings, and it all comes down to what the price is. And I haven't spoken to the price. I'm happy to. Um, the cost savings potentials exist when the price for LEN is around 40 to $60 per year.
LEN would be cost saving in those highest burden settings. Um, and that's compared to, so when they do these assessments of cost effectiveness, they compare it to the, the lifetime cost of antiretroviral therapy, right? So. Because of the amazing work of PEPFAR over the last 20 years, antiretroviral therapy, um, in high burden, low income settings is really cheap. A year's supply of TLD, um, which is tenofovir, lamivudine, dolutegravir costs $40 a year.
So it's actually not that expensive an intervention. So if you want a prevention intervention that is more cost effective than ART, then it has to be cheaper than the, you know, 20 years of TLD. And so what that means is cost of, of closer to, to 40 to $60 per year. I have two more reflections and then I'll answer your next question if there is one, Anshel.
But, there is some really exciting data that has been shared but not peer reviewed, including a paper that is currently under review with Lancet HIV suggesting that generic drug companies could develop lenacapavir at a cost of less than $25 per person per year, um, in the near future. So what that means is that the cost of the goods, the cost of manufacturing could be reduced substantially from the cost that the originator Gilead are making it at to a really affordable price.
$25 a year and $25 a year would be very affordable in many high burden countries. The caveat there is that for the generic drug companies to make it available at that affordable price, they have to be sufficient volumes. Um, they're not gonna make it at $25 per prevention year if only a hundred thousand people in Sub-Saharan Africa are on it. They'll, they'll be able to make it at those cost effective prices when the volumes are really, really high.
So when there are more than 10 million people on prevention per year. And so they, we end up in a kind of a chicken egg you know, conundrum where you, you need that early adoption of LEN, probably from procurement of the Gilead formulation, the originator formulation, to start to drive the market so that generics know that there is an appetite for this drug. So they then go out and develop more and do so at a price that is, is affordable.
To their credit, Gilead have said we want this drug to be widely available Sub-Saharan Africa, and we are gonna make the, the license available to several different generic drug manufacturers. So I think they've made their license available to six generic drug companies right now who in theory, are gonna be able to run with it, figure out how to make it as, as effectively and cheaply as possible. But those generic companies need a market, right?
And they're not gonna jump in unless they know that there is a market for this drug, which brings us back to this challenge that. Who's gonna pay for LEN in the first place. And historically, that has been the US government through PEPFAR, um, as well as the Global Fund, which is a, a multilateral donor initiative that includes funding from the US government, also from many other high income countries.
Global Fund have said yes, we are very interested in investing in LEN and they are going to procure it and make it available. Um. I am very hopeful that this US administration sees the value of LEN as a prevention tool that that, um, will help us control the epidemic in Sub-Saharan Africa and is worth investing in, but that, that remains to be seen at this time.
If they do, I think, um, the investments from the US Government and Global Fund could be really catalytic in driving down the prices to a point at which they become more affordable. But ultimately, and this is my last reflection, we, we are moving into a different time in global health, where the role of donors like the US government, like Global Fund is, is, is evolving.
And there is increasing consensus that many countries, particularly middle income countries, should be funding their own HIV response. Um, and in that context, um, there are, there are many countries in Sub-Saharan Africa with a high HIV burden that that will and should invest more in the, the, the prevention programming that is ongoing in their countries rather than relying on, on donors to support that.
And for those countries, I think there is a real challenge here in, in, in terms of persuading them that LEN makes sense, particularly when you are comparing LEN to Truvada, which is less than $40 a year, or to condoms which are very effective and even more affordable, right. Um, and so this is the calculus that ministers of health and ministers of finance have to have to deal with. I'll just say one last thing.
Even for those politicians though, the dividend of LEN in, in particular high incidence priority populations is, is very compelling. So if you can target LEN to those pockets of highest incidence, whether those are people who inject drugs, men who have sex with men, professional sex workers, um, and then some, some communities of adolescent girls and young women with high HIV incidence, then you could still have a very impactful and cost effective intervention.
The challenge there is to sort of identify those pockets and then with precision, allocate the LEN in, in ways that ensure that you are getting not only clinical bang for your buck, but also, financial bang for your buck. And I, I think there's some really interesting science that we need to, to do there around predictive tools, maybe the role of AI, um, et cetera, in determining how we allocate a drug like LEN.
Um. Finally, finally, um, in Sub-Saharan Africa, we have a generalized epidemic, right? It's quite different from the US where we have a, a, an epidemic that is really concentrated in small pockets and in that generalized epidemic in, in Sub-Saharan Africa, the, the risk of HIV acquisition is fairly heterogeneous. Um, and so that makes it harder to determine who, who is gonna benefit most from it.
Certainly in priority populations, we know that LEN will have value, but in that, in that heterogeneous context, it's more like finding a needle in a haystack. You do have to scale interventions large to see that benefit when that risk is so heterogeneous. So, which, which again adds to this paradox of where LEN will have the greatest value. That was a really long-winded way of answering your short question, so I hope that got some of the answer that you were after. No, not at all.
I, I think that was truly fantastic and I appreciate a lot of the insights you provided. I, I did wanna also highlight specifically, the removal of a hundred thousand people from the pipeline of screening, diagnosis and treatment. So really like taking them entirely out of that pipeline, even though it may seem like a smaller number of people, it goes a long way at curtailing the overall epidemic.
I also wanted to highlight some international advocacy organizations that, that really helped push for the generic manufacturing of lenacapavir. Uh, I put a link to the People's Medicine Alliance, uh, and I think that, uh, a lot of countries in Sub-Saharan Africa where this drug was tested, um, had community-based organizations come together and advocate for themselves and, and, and really strongly push for this, as you said, lifesaving drug. And, and we, we talk about it being lifesaving.
I do wanna ask if you have any concerns about the use of lenacapavir? We've really highlighted the pros, uh, and, and I think for very good reason. Uh, but anything in the implementation that we need to be conscious of, aside from the cost effectiveness? Yeah, that's a great question. There are a couple of things that are worth highlighting. From a biomedical point of view, I think a potential concern relates to resistance, right?
Um, so as a first in class capsid inhibitor, LEN represents a novel mechanism, which also means that, uh, we have limited real world data on resistance patterns, and particularly in settings of imperfect adherence or delayed HIV diagnosis. It remains to be seen, um, whether we need to be concerned about the potential of LEN resistance. I will just add to that a caveat that in Sub-Saharan Africa LEN's not available for treatment.
In the near term, if it's available, it will only be available for, for prevention. So, so the. The issue of resistance may not be such a big issue in those settings, but I can imagine that in a place like the US where LEN is going to be used as part of treatment and prevention, then be important to consider, um, the potential development of resistance. And you can mitigate that challenge by ensuring that as it's scaled, it's scaled with safeguards, right?
So that that means reliable HIV testing before initiation and then monitoring on, on LEN, um, and, as with anybody's who's on oral Truvada or, or Cabotegravir, they, they need to continue to get tested whilst taking that prevention modality to ensure they haven't developed HIV whilst on the drug and therefore at risk for resistance. I am not so worried about resistance in Sub-Saharan Africa, though.
I think that the, the biggest concern for me is really about how do we, how do we get to scale and do so affordably, affordably so that ministries of health are able to procure it. That's the biggest challenge that we probably face in the near term for places where I work. Thank you so much Dr. Reid. I, I just wanted to ask for people who are listening, how did you get into this role and can you describe a little bit more about PEPFAR in general?
Sure. I finished residency at arguably the best residency program in the country at, uh, Montefiore Primary Care Social Medicine Program. I'll just throw that out there. Um, and actually knew then that I wanted to do global health. I, I was really interested in issues of justice and equity, um, preferential care for the poor and underserved and, and immediately after residency worked in a PEPFAR program, um, Oh, cool.
Africa, first, first living in New York then, moving to and living in, in Botswana. Uh, I'll just mention what PEPFAR is and I'll come back to it again. So, PEPFAR is the President's Emergency Plan for AIDS Relief. It's the US Government's flagship program for assistance for HIV established in 2003 by G.W. Bush and has had an unprecedented impact on the HIV epidemic. More than 25 million people's lives have been saved.
More than 20 million people are on treatment right now through PEPFAR and over $110 billion of of aid has gone to partner countries during that period. And. At the time that I did residency, PEPFAR was a very morally compelling program that I wanted to be all in on.
And so out of residency, I, I worked in a, a funded program in Manhattan at Columbia University, and then moved to Botswana and, and lived there for, for four years where I worked as a an HIV physician and you know, it was great, like on the one hand, I was able to, to see how care was delivered.
I was providing HIV care in rural Botswana, but on the other hand, it was fairly jarring to be in a setting where, um, me as a UK trained, American paid physician was delivering care, while I was surrounded by people who were far better clinicians than me, but didn't have the resources. Um, and it really got me thinking about how do we improve the health systems in these countries so that they're able to respond to HIV.
Um, so I did that for five years and, and realized actually I wanted to do more training and I was very interested in how do you optimize health systems in high HIV burden settings and then ended up doing fellowship after five years away. Um, did ID fellowship. By the time I'd finished ID fellowship, I was deep in the weeds on how do you optimize health systems? And, and that led to my subsequent career doing health policy research in the HIV space.
Fast forward, uh, 10 years and, and now I work as the Chief Science Officer for PEPFAR. Really trying, trying to deliver on my own ambition to support and improve health systems, um, Yeah. in those countries. Yeah. I just wanted to open up to just a last question for you, Dr. Reid, anything that you can recommend for folks who are interested in global health in the future and folks who are interested in advocating for lenacapavir's implementation broadly going forward. Yeah, brilliant question.
I love that question. So, let me zoom out and say I think global health is at an inflection point right now. We're at a point where there is a change of political priorities around the importance of global health. I think political attention is waning.
And some of that moral ambition that led to PEPFAR being established is waning in places like the US and, and there is a really important responsibility on people that care about these issues to, to make a loud effective noise in support of initiatives like PEPFAR. PEPFAR has had an incredible impact over the last 20 years. Um, but to sustain that impact, I think does require an ongoing political investment from our leadership.
And I, I think this is a, a really critical time for people interested in global health to exercise their advocacy and protesting capabilities to ensure that we continue to prioritize global health in settings like the US which historically has been the funder of substantial global health programming . And so I think there is a considerable value in, in folks like you Anshel telling your congresspeople and, and senators about the importance of PEPFAR.
You know, as to the role of lenacapavir, again, there is no doubt that LEN is incredibly efficacious clinically, but but unless we're able to show that it's cost effective, then that that clinical efficacy won't be realized on the ground in the places that need it most.
And in order for us to get to that point where it's cost effective, again, I think there is, there is real need for advocacy and ambition to ensure that we procure the volumes necessary in the first instance from Gilead to make it available. Mm. And that motivates the generics to, to, to invest. So the price comes down to a point at which partner governments can afford it. So for all of those reasons, I think there is a role for, for folks like you, advocating for LEN.
I'll just say one last thing. Some of these things I write about on my substack, you can find Yeah. about my opinions on this and many other things at reimagineglobalhealth. substack.com. Thanks so much to Anshel and Mike for joining us today. You can find more info on our website, febrilepodcast.com, where we house the Consult Notes, which are written supplements of the episodes with links to references, our library of ID infographics, and a link to our merch store.
Febrile is produced with support from the Infectious Diseases Society of America. Please reach out if you have any suggestions for future shows or wanna be more involved with Febrile. Thanks for listening. Stay safe and I'll see you next time.