New Approaches to HIV Prevention, Management of Patients With HIV

In this podcast, Charles Flexner, MD, speaks about the current state of long-acting agents for the management of patients with HIV, HIV prevention and vaccines, and HIV pathogenesis and cure. Dr Flexner also participated in a panel discussion on these topics at ID Week 2022 titled "HIV: State of the ART."

This podcast was recorded ahead of IDWeek 2022. 

Additional Resource:

• Flexner C, Barouch D, Caskey M. HIV: state of the art. Talk presented at: IDWeek 2022; October 19-23, 2022; Washington DC. Accessed October 19, 2022. 

Charles Flexner, MD, is a professor of international health at the Bloomberg School of Public Health and a professor of infectious diseases and clinical pharmacology at the Johns Hopkins University School of Medicine (Baltimore, MD).

TRANSCRIPTION:

Jessica Bard: Hello everyone and welcome to another installment of Podcast 360, your go-to resource for medical news and clinical updates. I'm your moderator, Jessica Bard, with Consultant 360, a multidisciplinary medical information network. The World Health Organization has released additional guidelines for the use of pre-exposure prophylaxis for HIV. Dr. Charles Flexner is here to speak with us today about a panel discussion in which he is participated at ID Week 2022, titled HIV: State of the Art. Dr. Flexner is a professor of international health at the Bloomberg School for Public Health and a professor of infectious diseases and clinical pharmacology at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Thank you for joining us today, Dr. Flexner. Could you please provide us with an overview of this discussion?

Dr Charles Flexner: This symposium, which will take place on Thursday, is entitled HIV: State of the Art. And there will be three presentations in that session. One will be a presentation on the current state of long-acting agents for the treatment of HIV, and I will be delivering that session. There will be two other presentations in that session, one on HIV prevention and vaccines and one on HIV pathogenesis and cure.

Jessica Bard: What would you say are the new strategies in the pipeline working toward a cure for HIV?

Dr Charles Flexner: Most of the strategies being pursued right now are attempting to, if you will, kick HIV out of its latent reservoir and cause the virus to start replicating so that it can be targeted by antiretroviral drugs and other drugs that will eliminate cells that have been harboring HIV for very, very long periods of time. I should state that, at least until today, the only way to cure a patient infected with HIV has been a bone marrow transplant. And that's a rather extreme intervention to try to eradicate HIV. But at least so far, it's been the only thing that has worked.

Some of these other approaches, the so-called kick-and-kill approach, that is kick HIV out of its latent reservoir and then kill it with antiretrovirals and other drugs, I think there's been a glimmer of hope in those studies, but so far nothing that has looked like it's consistently able to reduce the HIV-latent reservoir to the extent that would be necessary to try to achieve either a sterilizing cure or a functional cure.

Jessica Bard: What would you say are the new biomedical approaches to HIV prevention?

Dr Charles Flexner: We'll hear at this symposium about the use of broadly neutralizing anti-HIV monoclonal antibodies to prevent HIV infection. There was one very large study, the AMP study, sponsored by the HIV Prevention Trials Network, that was published in the New England Journal of Medicine last year. And that study used only a single monoclonal antibody given every month, but it did appear to prevent HIV infection in people in areas where the circulating virus was sensitive to the antibody, even though the overall benefit of that antibody did not materialize.

So, I think we learned a lot from that trial. One thing we learned is if we're going to use broadly neutralizing monoclonal antibodies for prevention, we're almost certainly going to have to use more than one, possibly three or four at a time, in order to cover all of the virus that might be circulating in an area where the at-risk individual lives. So, it's going to be a little more complicated to develop these agents, but they have terrific pharmacokinetic properties now with long-acting modifications, allowing these antibodies to be given every three to six months. And it is possible pharmacologically to combine multiple antibodies into a single injection. So even though there would be three or possibly four antibodies involved, that would be invisible to the patient. They would be receiving a single injection or infusion of the antibody, whether it was one antibody or whether it was several.

Jessica Bard: Could you speak more about the medication that was also approved for the prevention of HIV?

Dr Charles Flexner: Yes. You're talking about long-acting cabotegravir, which was originally developed for HIV treatment. And that is a drug that I'm going to talk about in my talk on long-acting formulations. Cabotegravir is an integrase inhibitor, closely related to dolutegravir, that is formulated for very slow release from an intramuscular depot. And in HIV prevention studies sponsored by the National Institutes of Health, in randomized double-blind placebo-controlled prospective studies, compared to the standard of care, which is tenofovir disoproxil fumarate plus emtricitabine, injectable cabotegravir, given initially once a month and then once every other month, every eight weeks, was substantially more effective at preventing new HIV infections in both MSM and transgender women in the HPTN 083 study, and in cisgender women in the HPTN, HIV Prevention Trials Network, 084 study.

And the magnitude of the difference in benefit was remarkable. In the case of MSM, there was about a two-thirds reduction in new HIV cases as compared to the control group. And in cisgender women, there was a nearly 90% reduction in new infections compared to the control group. This is by far the most effective form of PrEP that has ever been developed, and it's quite an exciting advance in HIV prevention.

Jessica Bard: A great segue into my next question on new approaches to HIV treatment. Can you speak to those new approaches?

Dr Charles Flexner: The most exciting new approaches involve long-acting parenteral or injectable antiretroviral formulations. And the only such formulation currently approved, the combination of long-acting cabotegravir, which is an integrase inhibitor, with long-acting rilpivirine, which is a non-nucleoside reverse transcriptase inhibitor, for HIV treatment.

Now, it's important to point out to that this combination, which is known as Cabenuva, is only approved for the treatment of individuals who have had their viral load suppressed by daily oral therapy for more than six months. So that may set a bar too high, if you will, for broader use of these exciting new formulations. But that's the way the studies were done.

There are, I think, ongoing studies to look at the ability to use these drugs in individuals who are not fully suppressed. There, I think, is reason to believe that one could develop strategies with these long-acting injectable agents that would allow them to be used in individuals who do not have a suppressed viral load. But those are studies that are underway.

I do think it's important to point out that in randomized prospective clinical trials, the monthly administration of Cabenuva or the every-eight-week administration of Cabenuva was non-inferior to daily oral standard of care. And so, I think this offers a new option for HIV-infected patients who don't want to keep taking pills every day. And from surveys and from experience in our own clinic, that's an awful lot of patients who are tired of taking daily oral pills and would love to switch over to an intermittent injection.

Jessica Bard: Yeah, it's certainly an exciting time. What would you say are the overall take-home messages from this session?

Dr Charles Flexner: Well, the pipeline of long-acting injectable drugs is quite rich. In addition to Cabenuva, which I mentioned, lenacapavir, which is a subcutaneously-administered HIV capsid inhibitor being given every six months, has shown great promise in its early clinical trials in both heavily treatment-experienced patients with multi-class resistance and in treatment-naive patients. And that is a drug that is now in phase three, and there is an application to the FDA for approval of that drug for people with multi-class resistance.

There also are implants in development; for example, implants that release tenofovir alafenamide, a drug we're all familiar with, over a period of several weeks to several months. And there's even transdermal delivery of HIV with so-called microarray patches or microneedles that can create the same kind of reservoir for slow release, of drugs like cabotegravir, under the skin instead of in the muscle. And those patches, in theory, could be applied by the patient rather than having to be applied by a trained clinical care provider.

And so, I think there's a lot happening in a drug and formulation development that's very exciting. I think in the next five to 10 years, the treatment landscape and the prevention landscape for HIV are going to change radically. We're going to be using a lot of formulations in drugs 10 years from now that we're not using today.

I think we will continue to learn more about how to move towards an HIV cure. I'm personally not optimistic it's going to be easy. Nor do I think we're going to come up with a way to cure HIV, either through sterilizing eradication of the virus or through so-called functional cure; that is, the virus is there, but it's not causing disease. I don't think we're going to be able to do that in the majority of individuals anytime soon. But we're certainly learning a lot, and I think that's been very exciting.

Finally, HIV vaccines will be touched on in this symposium. There is some progress in the vaccine field. There are some trials that have shown surprising benefit, although it's still incomplete benefit of an HIV vaccine. And we are working on novel approaches to HIV vaccination that may begin to bear fruit in the near future. So all in all, I think the take-home message from this symposium is there's lots going on, lots to be excited about, lots for the practitioner to keep up with because your patients are going to be coming into the office and asking you about these treatments that you may not be familiar with. And so, it's important to keep an eye on where the field is moving and where we might be going in the next few years.

Jessica Bard: Certainly a lot to cover at ID Week 2022, so we look forward to that. Thank you so much for your time, Dr. Flexner. We appreciate you being on the podcast.

Dr Charles Flexner: Thanks, Jessica. It was great to be here.