The Safety & Efficacy of PrEP Containing Long-Acting Cabotegravir

In this podcast, Raphael Landovitz, MD, discusses the findings from his recent trial, HPTN 083, which indicates that long-acting cabotegravir injected once every 8 weeks is superior to daily oral TDF/FTC in the prevention of HIV among cisgender men and transgender women who have sex with men. These findings were presented at the 23rd International AIDS Conference (AIDS 2020: Virtual).

Reference:

• Landovitz RJ, Donnell D, Clement M, et al. Pre-exposure Prophylaxis containing long-acting injectable cabotegravir is safe and highly effective for cisgender men and transgender women who have sex with men. Paper presented at: 23rd International AIDS Conference (AIDS 2020: Virtual); July 7, 2020; Virtual. https://www.hptn.org/research/studies/hptn083 Accessed July 7, 2020

Raphael Landovitz, MD, is a professor of medicine in the Division of Infectious Disease at the UCLA Center for Clinical AIDS Research & Education.

TRANSCRIPT:

Christina Vogt: Hello everyone, and welcome back to another podcast. I’m Christina Vogt, associate editor of the Consultant360 Specialty Network. Today, I’m joined by Dr Raphael Landovitz, who is a professor of medicine in the Division of Infectious Disease at the UCLA Center for Clinical AIDS Research & Education. Thank you for joining me today, Dr Landovitz. Today, we will be discussing his recent study, “Pre-exposure Prophylaxis containing long-acting injectable cabotegravir is safe and highly effective for cisgender men and transgender women who have sex with men,” which was presented at the 23rd International AIDS Conference, or AIDS 2020: Virtual.

So first, in your trial, you and your colleagues found that long-acting injectable cabotegravir administered once every 8 weeks was superior to daily oral TDF/FTC among cisgender men and transgender women who have sex with men. Could you discuss what this long-acting injectable drug adds to the existing treatment landscape compared with a daily oral pill?

Dr Landovitz: Sure. Since 2010, we have understood that tenofovir disoproxil fumarate/emtriciabine (TDF/FTC), also currently marketed under the brand name Truvada, is highly effective for HIV prevention across a wide variety of populations, risks contexts, and circumstances if taken as prescribed. And, it's extremely potent for rectal protection of HIV and is quite forgiving of even missed doses for rectal protection. It's less forgiving in other contexts, particularly for vaginal protection, but it works extremely well if you take it. So, it set an extremely high bar for a biomedical HIV prevention strategy. But, what we've observed since its approval and global scale-up is that its really impressive and potent prevention activity hasn't translated to the public health benefit that you would hope that it would in all populations.

There have been some really dramatic demonstrations of population-level reduced HIV cases and incidence, but it's not been universally realized, and frustratingly, it's the same populations that are disproportionately affected by HIV who are struggling with realizing the benefits of TDF/FTC PrEP–so, younger individuals, particularly under age 30, underrepresented minority individuals, so black and African American gay men, Latinx gay men, and transgender women. So, the question is, what is it about those populations? And, it's likely a combination of racism, sexism, homophobia, transphobia, differential access to medical care, medical mistrust–all of those things in combination with the power of all of those forces to make it harder to take a daily oral tablet, a daily pill, and therefore realize the benefits of the daily oral PrEP.

So, in in our study, we were specifically thinking of the structural intervention of being able to offer somebody a shot that they would take every 2 months so they wouldn't have to carry around pills and potentially be seen with something that could be stigmatizing as part of any risk group or associated with HIV or HIV infection or HIV prevention in any way. It would remove the requirement for something that people had to remember and prioritize to do. It could have advantages, particularly in the most vulnerable populations. So, we went out specifically to enroll significant portions of our study in young individuals, in transgender women, among black or African American gay men in the United States, among Latinx populations, and really tough global reach, so that these findings, whatever they were, would be generalizable to the people who really haven't benefited as much from pill-based pre-exposure prophylaxis. So, the significance of it is, for people who can take a pill and do take a pill and have great protection from TDF/FTC right now, that's terrific. It's just another choice for them if they want different modality, and more choices is always better. But, for populations that have struggled with being able to really see the benefits of what could happen in terms of HIV prevention efficacy from a pill, but haven't been able for a myriad of reasons to realize those benefits, maybe this will make people say, “Maybe I can do this. Maybe I want to do this because it doesn't stigmatize, because it's easier, because I think I could show up in a clinic once every 2 months, even if I didn't think I could make myself take a pill every day.”

But then, you know, there's some people who aren't going to want an injection. So, it's not to solve all the problems. It's not going to solve medical mistrust. It's not going to solve our access to health care problems in the United States and globally, so it's not going to by itself end the HIV epidemic, but I think it's a big step forward in increasing our HIV prevention toolbox and hopefully bringing more people into the fold of having conversations about HIV prevention, and that we do have an expanding list of things that are shown to work to keep people HIV uninfected, and they're going to be different things that are right for different people, and different things that are right for the same person at different points in their lives.

Christina Vogt: Your findings indicated that cabotegravir was associated with a 66% reduction in incident HIV infections compared with TDF/FTC in the study population. Did you anticipate this finding, or was it surprising?

Dr Landovitz: I think we were delighted, but surprised, and the reason that we were surprised is, as I mentioned before, TDF/FTC set a remarkably high bar for HIV prevention, if taken as prescribed, in an 083-like study population. It's somewhere north of 95% protective. Some studies even suggest 99% protective. So, we asked ourselves, how do you do better than 99% protective? And the answer is, there's really only room to do better if it's hard for people to get that 99%, probably because it's difficult to get the pills in with a frequency, with a reliability that it takes to get that level of protection. So, it was a very high bar to meet, much less exceed. So, when the study was recommended to be stopped on May 14 by the independent Data and Safety Monitoring Board at the NIH, we were not only surprised because it's about 2 years earlier than the study was scheduled to finish, but knowing what an incredibly high bar we had to meet by the end of the study to stop at literally a quarter of the way through the study, the results had to be dramatically in favor of the cabotegravir for them to ask that the study be stopped. So, we were delighted, pleased, but also quite surprised.

Christina Vogt: How might the availability of a long-acting injectable treatment option in lieu of a daily pill help achieve national goals of ending the HIV epidemic by 2030? What steps need to be taken to ensure the drug is available to patients who want this option?

Dr Landovitz: So the first step, right, are going to be lots of regulatory approvals. Right. Nothing is going to be sort of widely available until it's gone through a very detailed and careful review by the FDA and then other nations’ and regions’ regulatory agencies to make sure that they concur with the safety and efficacy results that we've presented and observed. And then, there's the question of scale-up, and I think at this point, as I mentioned, there are certain people who believe in biomedical prevention, and we have to get more literacy for all communities about the power of some of these biomedical HIV prevention strategies to get people to want this.

And, I think we're not really good as a society at making people want things that are preventive strategies. They're not necessarily sexy. They're not on television and people's forefront. For example, the Apple company has done a miraculous job about making people need the latest Apple gadget. I mean, think to yourself, how many Apple products you or your friends have. It's sort of staggering. We haven't found out how to make people want an HIV prevention product. So, we need to do better about that, and part of that is increasing health literacy, HIV literacy, HIV prevention literacy, and reducing medical mistrust, and that requires an enormous investment of infrastructure and public health and work on racism, sexism, homophobia, transphobia, poverty, stigma, all the things I mentioned before. So, we've got a lot of work to do to really get this to the point where it's going to be able to let us end the HIV epidemic, and,I really think unless we do all of that work, there's no one chemical, product, or drug that's going to do it, but I do hope that if we do do all of that work, that having an additional option for choice, for people will engage more people in the conversation and get them to use it and hopefully get us closer to our goals of ending the HIV epidemic.

The questions about how it's going to be made most available and the costs around it–unfortunately, I don't have any insight to and I'm going to need to refer to my colleagues at ViiV Healthcare, who are the ones who are shepherding the regulatory submissions and will ultimately make all of the marketing decisions about how this is priced and made accessible, and I'm working with the HIV Prevention Trials Network Group that sponsored and ran the study that's independent from the ViiV Healthcare Group. So, I can't comment on that directly.

Christina Vogt: What areas of future research are needed going forward?

Dr Landovitz: The first thing that we desperately need, and hopefully we will have very soon, is, are these findings generalizable to cis gender women in Sub-Saharan Africa? So, I'm sure you're aware, we and your listeners probably are also, that there's a sister study to HPTN 083 called HPTN 084 that's about 11 months behind us in terms of its conduct. They started about a year after we did. It's being led by this really incredible powerhouse of a researcher from South Africa, Sinead Delaney-Moretlwe, and she is with the Wits Institute in Johannesburg, and her and her team’s study already has over 3200 participants enrolled out of a planned 3200, so they're about 95% enrolled, and they are collecting data, and we hope that these findings are replicated in women, such that we have a product that is generalizable to all populations for sexual exposures.

We still need work in transgender men and in people who are at risk for HIV through injection drug use, and then there's a family of studies, actually 2 of them, that are being done in adolescents that are really important as well because, of course, the most at-risk individuals globally are youth and adolescents. Currently, our study only enrolled people 18 and up, and so, that's true of 084 also, and that's true of the majority of drug development. It gets approval in adults first, but unless we have a product that is safe, effective, and tolerable and acceptable to use, we're really not going to be able to end the HIV epidemic.

And, Sybil Hosek and Linda Stranix are leading that family of studies that are just getting into the field to hopefully expand regulatory approvals, as was done for TDF/FTC down to a weight floor of 35 kg. So, there's no age bottom, if you will. People who are sexually active, long as they're over 35 kg ,TDF/FTC has approvals, and that would be the goal for this product as well from these adolescent what we call bridging studies.

Christina Vogt: What are the key takeaways that you hope to leave with infectious disease specialists and related providers who treat HIV?

Dr Landovitz: Thanks. It's a great question. We're still waiting on the drug concentration data and the resistance data from this study. We don't have that yet, so really, a full message, a full, nuanced understanding of these results really is predicated on having that information. So, at this point, based on the information we do have, I think it's clear that both TDF/FTC and cabotegravir are highly effective for HIV prevention in gay men and transgender women globally, and both are safe and generally well-tolerated, and that's terrific. So, we look forward to a more nuanced understanding of how best and in whom to recommend the use of these products and whether there are different groups who might benefit differentially one over the other.

With the final data, my suspicion of where we're going to end up is, as I mentioned at the beginning, that for people who are able to adhere to a daily oral pill or an event-based pill, this is just another choice, and it's great to have things to offer people. And for people who struggle with taking a pill or don't like taking pills or think that they would struggle taking a pill, it's really great to know that we have a shot-based option to offer them. And to me, this is just a renewed opportunity to engage people in the conversation about how to keep themselves HIV uninfected, and that is incredibly powerful.

Christina Vogt: Thanks again for joining me today, Dr Landovitz.

Dr Landovitz: Thanks so much for having me. It's been a pleasure, and I appreciate the insightful questions.