HIV Long-Acting Injectable Therapies in Development

Joseph Eron, MD: OK, so novel and emerging drugs. We have to talk about long-acting therapies. We’ve gotten some teaser information about long-acting therapies. Ian, what do we know?

Ian Frank, MD: Well, the drugs that are furthest along with long-acting strategies are injectable cabotegravir and rilpivirine. We have some studies that are mostly using these drugs as maintenance therapies in individuals with virological suppression, testing the ability of these agents, which can be administered perhaps every 4 weeks—no more frequent than every 4 weeks—and maybe every 8 weeks with a couple of shots in the gluteus medius. The studies have shown that the combinations in comparison to continuing oral regimens are just as effective in maintaining virological suppression. Individuals develop injection-site reactions. It’s a little bit more than getting a shot of benzathine penicillin or a couple of shots of benzathine penicillin. There is some discomfort that can last for a couple of days, but it’s rare in these studies for individuals to drop out because of the injections. And they tend to tolerate the injections better and better as they continue in the studies over time.

W. David Hardy, MD: I would say they tolerate them better than benzathine penicillin because benzathine penicillin is very thick, and it’s very uncomfortable when it’s injected, from what I’m told. And cabotegravir and rilpivirine are liquid, and they go in very easily. But they do cause some irritation at the injection site. You’re right.

Joseph Eron, MD: I think, unlike those of you out there who may have used enfuvirtide, or Fuzeon, there aren’t nodules that persist.

Paul Sax, MD: No.

Joseph Eron, MD: But there’s pain.

Paul Sax, MD: And it’s not self-administered.

Joseph Eron, MD: And it’s not self-administered, right. Really important point.

Ian Frank, MD: The goal here is to create therapies that don’t require daily pill taking and may promote adherence. Although I would say that they will create other adherence challenges because these are potentially long-acting drugs. They don’t disappear when individuals have reached that 8-week time point; they persist. And so if individuals are late in coming in for their next injection—and these aren’t easy injections to give. They’re not going to be things that people can self-administer, so they’ll need to be administered by a friend or a family member. Or people will need to come into the office in order to receive the injection, or the office is going to need to go to them to administer the injection. And so individuals are at risk for developing resistance as the drug concentrations wane if they’ve missed a dose. So they will solve an adherence problem and create other adherence problems. Also, these are being tested for prevention, long-acting cabotegravir. And individuals who get long-acting cabotegravir can have a drug level that’s measurable for over a year after their last administration.

Paul Sax, MD: One thing I have to ask, because it’s going to be fascinating to see how this is rolled out when it happens. What percentage, what proportion of patients who are stably on ART [antiretroviral treatment] right now do you think are going to want to switch to an injection every 4 weeks?

Joseph Eron, MD: I think 5%, maybe.

W. David Hardy, MD: It’s going to also depend on how it’s presented to them.

Paul Sax, MD: Well, no, just…

W. David Hardy, MD: What’s going to be.

Joseph Eron, MD: Just what do you think?

W. David Hardy, MD: I think there will be individuals who will say, you mean I can just show up at the pharmacy and have a pharmacist or someone like a nurse practitioner give me this shot? I don’t have to worry about any more prescriptions. All I have to do is show up, and my pharmacy can do that in multiple cities.

Paul Sax, MD: So Joe said, Dr. Eron said, 1 of 20.

W. David Hardy, MD: I would say more than that. I’d say probably 15%, 20% at first. But this is going to be driven, I think, by people telling their friends. Guess what I’m doing differently now?

Eric S. Daar, MD: And also the dynamic may change a lot if every 8 weeks works.

Paul Sax, MD: Let’s start with every 4 weeks.

Eric S. Daar, MD: My fantasy is that I’ll be able to tell those newly diagnosed people that not only will they be able to live forever with HIV and not have to worry about transmitting to anybody, but they’ll only have to think about their HIV 6 days a year, when they’re going to show up at their local pharmacy for an injection.

Joseph Eron, MD: Yeah.

Eric S. Daar, MD: And if that’s true, if my fantasy comes true, I think it may end up being a lot higher.

Joseph Eron, MD: Yeah. It depends.

Paul Sax, MD: I would have been more in the 1 of 10, 1 of 20 as well. What do you think, Ian?

Ian Frank, MD: If it was me, it would be low because I’d rather just take 1 pill a day and be done with it. But when I talk about this issue, I always ask the audience how many people in the audience would rather take 1 pill a day or get 2 shots in the butt every 8 weeks, and it’s usually about 50-50.

Joseph Eron, MD: Well, I think every 8 weeks is different. And also people don’t quite get that you have to be in a health care setting.

Paul Sax, MD: They might imagine an insulin shot. They’re imagining an insulin shot or something.

W. David Hardy, MD: The other thing I think you have to ask, you have to ask people who are HIV positive, not doctors who are HIV negative.

Ian Frank, MD: Right, that’s true.

Joseph Eron, MD: We have to take care of our own biases and get rid of them. I have a bias against shots, personally.

Ian Frank, MD: A lot of our patients have comorbidities. A lot of my patients are on other medications, and just adding 1 extra pill doesn’t eliminate the need to take medications every day.

W. David Hardy, MD: It does eliminate the stigma of having to think about being HIV positive and hiding that pill from everyone in your house.

Joseph Eron, MD: No, no, I think that’s a very big issue: the stigma. The other thing is much as you were talking about PrEP [pre-exposure prophylaxis] before, someone could go on injectables for a year and then go back to oral therapy. It’s not as if you’re making a life-forever choice. There may be people who are traveling for a time, as you mentioned. If it actually is done in pharmacies, they may be able to get them in different places across the country.

W. David Hardy, MD: Sure, like antipsychotics.

Joseph Eron, MD: They may be in a new living situation.

W. David Hardy, MD: Yeah.

Ian Frank, MD: Options are good. It’s good to have options.

Joseph Eron, MD: Options are good.

Eric S. Daar, MD: And the tolerability data from the phase IIb study are really remarkable for those who wanted this at the beginning.

Joseph Eron, MD: Wanted it, right—people who signed up for it.

Eric S. Daar, MD: And anecdotally—and my experience is probably less than some of the others in the room in the clinical trials—it really is amazing how the discomfort goes away with each injection.

Joseph Eron, MD: Yeah, it’s definitely less. And we now have people on their third and fourth year of getting these injections in our clinic as part of the LATTE-2 study. It will definitely have a following, I’m quite sure, and it will be interesting to see if it increases over time and how that works.

Paul Sax, MD: I thought it was interesting. The survey that was published in OFID [Open Forum Infectious Diseases], actually.

Joseph Eron, MD: Who’s the editor of that?

Paul Sax, MD: Basically, OFID asked people with HIV, hypothetically, which would you rather do: Would it be 2 injections every month, an implant in the arm twice a year, or a pill once a week? And the pill once a week was the winner.

Joseph Eron, MD: Pill once a week. Well, that could be coming, actually.