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PrEParing for the Future: Upping Our Game in HIV Prevention
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Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™

European Learners: 0.25 hours EBAC® effective education time

Released: December 06, 2024

Expiration: December 05, 2025

Dinah Bons
Dinah Bons
Yvonne Gilleece
Yvonne Gilleece, MB, BCh, BAO, FRCP
Justyna Kowalska
Justyna Kowalska, MD, PhD
Angelina Namiba
Angelina Namiba, BAHons
Jürgen K. Rockstroh
Jürgen K. Rockstroh, MD
Sophie Strachan
Sophie Strachan

Dr. Rockstroh:

PrEParing for the Future

All right. So obviously there is a need to expand PrEP options.

[00:43:08]

Expanding PrEP Options: Today and in Near Future

If what we look today we have our oral formulations FTC/TDF, FTC/TAF. But already with the oral formulations we have restrictions. FTC/TAF is not available in Europe. We're all pretty much bound to the cheaper generic version. And that already raises questions, at least for people with kidney impairments.

Long-acting cabotegravir has been registered but is not commercially available or only very limited in Europe. There's some programs like in Ukraine, which I learned through the wonderful webinar Justyna set up, where colleagues from Ukraine actually shared their experience. And I was impressed to hear that they had 1000 people on—on cabotegravir for that reason.

And then we know that it's also available in North America already. So something which will be coming. We already heard a little bit about the—the vaginal ring, which comes with a lower protection level. But there are also developments in place to maybe improve that way of protection.

And then for the future, I think we've seen really exciting news on longer acting injectable this years. And then there still are ongoing efforts of trying to find something which does not require an injection. So that would be an oral pill, preferably once weekly or even once monthly. And then there are also, you know, future things around implants and other devices and—and treatment modalities. So I think there's quite an exciting development portfolio.

[00:44:36]

Why Do We Need Long-Acting HIV Prevention?

And I think when we ask yourself the question, why do we need long-acting HIV prevention? I think the most important message really is that daily oral PrEP is effective if you take it, but it's not really working well in all populations. And we have seen quite some studies which actually failed with oral PrEP, mostly because people were not taking it. But that tells us that there are other needs in populations, and if we want to have successful PrEP interventions, we'll have to sort of tailor our interventions according to these populations.

And they may also help for unwanted or unexpected sex acts. That's something we should also forget that you don't necessarily always know that you're going to have sex in 2 hours. Hopefully, yes, but who knows? Alcohol and drug use, it can have an impact which also will directly affect adherence. And then there are also stigma challenges associated with daily medication, something we also know from the treatment arena with long-actings. And then there is travel with frequent time zone changes not remembering when to take. And—and then it's also predominantly also about offering choices.

[00:45:38]

HPTN 083 and 084: LA IM CAB Every 2 Mo vs Daily Oral FTC/TDF for PrEP

Now I think excitement started really when we saw the first results of the first long-acting, which was intramuscular cabotegravir every 2 months versus daily oral FTC/TDF for PrEP. And there were 2 large studies, HPTN 083, which was done in a very large sample of men who have sex with men and transgender women. And then there was HTPN 084, which was done in cisgender women.

And the amazing thing here was that we saw a very low incidence infection rate in HTPN 083 and zero infections with on-time CAB injections in HTPN 084. Clearly, highlighting that this was superior to daily oral FTC/TDF, 66% in the one trial and 88% risk reduction in HPTN 084. And so that really paved the way to say we really need something different and long-acting may be the way forward.

[00:46:33]

PURPOSE 1: Twice-Yearly LEN Injections vs Daily Oral FTC/TDF or FTC/TAF as PrEP in Cisgender Women

Now, for those of you who attended the IAS Munich conference, I think we all will never forget that presentation for Linda-Gail Bekker, because it really led to spontaneous clapping and—and—and quite some emotional reactions just because people have been waiting so long for these changes. And the story here is that a capsid inhibitor was studied in the context of PrEP as a twice yearly subcutaneous injection, and that was compared to daily oral FTC/TDF or FTC/TAF as PrEP in cisgender women. This was conducted in South Africa and Uganda in sexually active women, which were all pretty young.

And the—the amazing thing here was that they looked at a large group and determined the background HIV incidence. And then for those who were negative upon screening and baseline, were then randomized either to the twice yearly lenacapavir subcutaneous injection or FTC/TDF or FTC/TAF. And note that the randomization was 2-to-1 to 2, so the group with FTC/TDF was the lowest group studied in this PURPOSE-1 trial.

[00:47:45]

PURPOSE 2: Twice-Yearly LEN Injections vs Daily Oral FTC/TDF as PrEP in Men Who Have Sex With Men

And then you may have also noted that just a couple of weeks ago, the results of PURPOSE-2, which is similar design again comparing subcutaneous lenacapavir versus FTC/TDF was studied in men who have sex with men. So we have 2 large studies addressing this long-acting new drug in the setting of PrEP.

[00:48:07]

PURPOSE 1 and 2: HIV Incidence at Interim Analyses

And you can see here the HIV incidence at the interim analysis. And you can see there were zero infections in the large cisgender woman trial in South Africa and Uganda. And then you can see that there was very few, only 2 infections in the cismen, trans men and women study in PURPOSE-2, whereas the background was pretty similar 2.4 and 2.37. And you can see that the oral therapies didn't work as well, did very poorly, actually, in cisgender women, which is very much in line with previous studies showing that it's just difficult to get a good adherence. And there were adherence sub-analysis showing that most of the not working was really related to not taking the drug. And I think really paving the way to a new way of performing PrEP in—in—in these groups.

[00:48:55]

PURPOSE 1 and 2: Primary and Secondary Analyses of LEN Efficacy

And this shows you the primary and secondary analysis of lenacapavir efficacy, which was just simply striking. And the difference is so large that obviously this offers quite some—some positive feelings. And—and—and you can see that the overall reduction was by 100%. And this is gender women's study in 96%. So this was just simply amazing.

And clearly the question now is more about how can we implement these advances? Because I think that's the big question. Or the elephant in the room, how can we really make access happen in these countries as fast as possible?

[00:49:31]

PURPOSE 1 and 2: LEN Injection-Site Reactions (ISRs)

Now one of the remaining questions, though, is what about injection site reactions? Obviously, any kind of long-acting which is administered intramuscularly or subcutaneously may come with some injection site reactions. So that—I think that is a very fair question. These subcutaneous injections can lead to the emergence of nodules. And the question is, how are people going to tolerate these nodules? Is that going to play a role over extended periods of time? And I think that's one of the limitations, because the studies were all stopped prematurely because of the big efficacy.

But remember, if you—if you're going to remain sexually active more than 2 years. So this is a question over time, are there going to be more? How is that going to be? Reassuringly, in these PURPOSE trials, you can see that the more advanced nodules grade 2 actually became less. So it doesn't really look as if it's getting worse from injection to injection. So I think that's good news. But I think there still is at least some question out there, how is this going to perform over time. And clearly we're going to need more follow up on the injection site reactions.

[00:50:31]

Earlier Phase Investigational Approaches Aimed at Offering a Wider Range of Options

Now, reassuringly, in this whole context of long-acting developments in the PrEP arena, we've also seen other news from other compounds. And remember that there was a drug which worked—developed for PrEP, which was then stopped because of the occurrence of lymphopenia, islatravir. And now there is a backup substance, MK-8527, which has a very favorable half-life profile, and this will be targeted to be developed for monthly oral use. So that would be a tablet once per month, which is obviously also big coverage and wouldn't come with some of the adverse events which come with an injection. So I think that also may have some promising aspects.

There's also an initiative to develop an ultra-long acting cabotegravir with a slower absorption. So that would be something which potentially could also be given maybe at—at a longer interval. There's also efforts to improve the dapivirine vaginal ring, which would need to be changed every 3 months. And then there is also efforts to combine oral PrEP with contraceptive pills, making it maybe more attractive to adhere to that kind of oral intervention.

And then there still are a lot of noise around other modalities, including transdermal patches and implants. And we've seen some data at some conferences. But obviously this portfolio is getting bigger and bigger, and we'll have to see where that all fits in. And particularly I think the question remains, how is this all going to be implemented once it's registered and—and licensed?

[00:52:09]

Expert Discussion: PrEParing for the Future

So—so with that in mind, let me ask Sophie, you know, so all these new things that are developing are—is—I mean do we need them? I mean, some people in Europe sort of say, well, if we have generic TDF/FTC, we're sort of fine. Or do you think we really need a more individualized, tailored approach with many different choices?

Sophie Strachan: The latter, without a doubt. You know, many of us need—need choice. And in—in the context of women, who were not able to experience the benefits of accessing PrEP when it was a once daily oral pill. As you said, the PURPOSE-1 study—although activists have been saying for a very long time, women need choice. I think everybody needs choice. But I'm going to sit here and talk about women. Women need choice, and you only have to look at contraception to—to realize how much, you know, we benefit from that.

I think the—the historical and unfortunately some still current narrative around women in terms of the whole adherence issue has been quite blaming. I don't know about you, but I struggle to take a course of antibiotics. I think everybody can struggle with adherence at times. So I think where these option comes in, these options, you know, are now landing. Hopefully the narrative will change.

The PURPOSE-1 study was and is and will be, you know, I think revolutionary for—for women and that's needed. I think it came as a surprise. But to be honest, for us that understood and realized that it was just about providing women with a choice. It was just, yes, you know, this is finally landed. And, you know, it's exciting to—to see what will emerge, you know, in the—in the future.

And I think, you know, women's lives are diverse. Not every woman has, like, caring responsibilities. There are—there are many factors that contribute to the feasibility of one particular option for a woman. And I think that, you know, the twice yearly injections really support that.

Dr. Rockstroh: Yeah. I mean, I think it's fair to say that it's not only about adherence when oral therapy fails, because it's important to remember that, oral PrEP in the context of TDF/FTC for women, only works in continuous delivery of PrEP, whereas in—in—in men you can also use on-demand PrEP. So it takes more time to have adequate protection and levels which are protective in the various tissues, which means that you don't have all these choices, so you have to continuously do—the adherence quest is much higher than—than for males.

So I think there's per se a biological difference in how oral therapy works. So I think that's one—one of the other issues. So I think it's—it’s more than just adherence. But clearly if you don't take it then and you don't have the drug that—it's not—it's not going to work.

So I think these—these new modalities are really going to help. And I think you really emphasized the issue of—of how important it is to have choices, you know. And I—I think that's something we also see on the treatment perspective that we always, in the European way, say we'd love to have choices because every person is different. And to reflect on that, not just to say one thing is the right thing for everybody.

[00:55:39]

SEARCH Randomized Prevention Trials in Kenya and Uganda

And—and I think one of the really impressive trials which was done in that context was the SEARCH prevention trial in Kenya and Uganda, which really looked sort of at the standard of care, which was oral PrEP versus a dynamic choice of HIV prevention intervention. So people were able to switch between different PrEP options or stop PrEP or do PrEP. So there was a more dynamic choice.

And in—in that first phase, and that was before the introduction of long-acting cabotegravir, there was a 30% to 40% increase in prevention coverage with the dynamic choice versus standard of care. And then in the extension phase where long-acting cabotegravir was included, there was even a further increase in prevention coverage.

So having choice actually made more people sign up to use PrEP. And—and—and I think that's just underlines beautifully what you said about how important choices in—in that particular setting.

[00:56:48]

SEARCH Randomized Prevention Trials in Kenya and Uganda: More Choices = More Usage

And the question then was obviously, did this uptake just come into place because long-acting became available so that people were not interested in oral PrEP? But that was not what we found. It was really more that half of the participants used long-acting, half continue to use oral PrEP, but it was really about having choices. And—and that increased the total number of people who use PrEP. So I think that study very nicely shows it's really important to have an armamentarium and get people on board by also having them choose actively what—what they want as their personal prevention intervention.