Long-Acting Formulations Emerging in HIV Treatment

Transcript (slightly modified for clarity)

Peter L. Salgo, MD: There are some other emerging agents, too, such as long-acting cabotegravir. Is that what you were referring to, the long-acting drugs?

Joseph Eron, MD: Yes. I’m talking about the issue that we’ve all kind of danced around and talked about—adherence. You get different opinions from different people, but there’s certainly a subset of people that would probably do better if they had a therapy that could be administered infrequently and, perhaps, under observation. And we’re moving toward that. Cabotegravir and rilpivirine are 2 long-acting agents that can be given intramuscularly by shot. The original hope was that maybe they would be given as infrequently as once every 3 months. The reality, now, is it’s given once a month. There’s the potential for very long-acting formulations that can be implanted and perhaps can last as long as 3 or 6 months.

Again, also for prevention, there may actually be a bigger role in prevention because, for treatment, you’re probably going to need 2 drugs that have a similar half-life (which is twice the challenge). On the other hand, for prevention, if you had a shot that lasted 3 months or an implantable medication that lasted 6 months, the potential for prevention is improved.

Eric S. Daar, MD: When we talked about PrEP (pre-exposure prophylaxis), we really didn’t talk about the big limitation of PrEP being the ability of people to take the pill, even 1 pill a day, consistently. So, a long-acting agent could have a huge advance. And I think the long-acting agents, cabotegravir and rilpivirine, were sort of suggested on the precipice that we’re in the midst of a registrational trial that, based on the phase IIb study, has a very high chance of success and may have a niche population.

Paul E. Sax, MD: Yes. And I think it will succeed in the study. I’m concerned about implementation because the injections are fairly big and cannot be self-administered—at least not as currently formulated.

Peter L. Salgo, MD: There were these other studies people have heard about—the SWORD-1, SWORD-2 studies. What are they?

Eric S. Daar, MD: SWORD-1 and SWORD-2 is sort of a byproduct of the desire to develop the long-acting formulations where they found out that you can use these 2 drugs, an integrase inhibitor and a NNRTI (non-nucleoside reverse transcriptase inhibitor), rilpivirine, and they could maintain viral suppression in somebody who’s already suppressed. And then with that information, they said, “Great, now let’s move on with the long-acting combination. But by the way, we do have a pretty darn good 1-pill-a-day integrase and we have this rilpivirine, and the 2 of them together add up to 75 mg of total drug.”

Joseph Eron, MD: So, it’s a small pill and is likely very well tolerated. It won’t matter if you have renal failure or not, necessarily. Some people do have a problem with pill size. It does make a difference to some people. It’s a potential. We always thought if you were going to use 2 drugs that one of them should be a boosted protease inhibitor. The SWORD study, I think, will or has demonstrated that it doesn’t really have to be that way.

Paul E. Sax, MD: The downside of rilpivirine, as I alluded to earlier, is this interaction with acid-reducing therapies and a requirement that you take it with food for proper absorption.

Eric S. Daar, MD: And clearly an advantage here, especially since nucleosides aren’t as big a problem as they used to be with the availability of TAF (tenofovir alafenamide fumarate), I think the big advance here is going to be the pill size. It would be, by far, the smallest pill.

Peter L. Salgo, MD: Before we leave, I want to ask something that I think our viewers would like to know. There are a lot of folks out there that are going to be HIV-positive that are not going to have access to any of you guys. Where does, or can, the primary care physician fit into this? Can a primary care doctor start this therapy, monitor this therapy, follow on for years? Or is this something that really is “inside baseball” for you guys? What do you think?

Paul E. Sax, MD: This has become a specialty area, and I don’t want to completely lose it, but I also think it’s become sufficiently effective, simple, and well tolerated that with good advice from a specialist, even if given over the telephone, or by e-mail, or by advanced telecommunications, a primary care doctor could do it. A primary care doctor who’s interested could definitely do this.

Eric S. Daar, MD: They would have to really be invested in it and have the desire to work with somebody else, because I still find the biggest mistakes I see referred to me are the switch patients—where people really didn’t spend a lot of time thinking about what they were doing. You simply switched somebody to the wrong regimen, and had they just simply called someone and said, “My patient wants this” or “I want to give them that, is that okay?” they’d have been able to do it.

Paul E. Sax, MD: But wouldn’t you agree, for initial therapy, it’s easier to treat the HIV than it is to treat diabetes or hypertension?

Eric S. Daar, MD: Not just to start, but to be successful.

Joseph Eron, MD: I think one drug that’s on this list of new agents, bictegravir, is very similar (initially looking so, even though we don’t have phase III data) to dolutegravir. But the issue is that it will get co-formulated. In fact, it’s going to start co-formulated with TAF and FTC (emtricitabine). So, it won’t be 2 pills, it will be 1 pill. It will be a relatively small pill. I don’t know the size of it, but it will be a relatively small pill. It won’t have any of the boosting problems that a current TAF-containing integrase inhibitor has (so that’s elvitegravir/cobicistat, which is the blocker TAF/FTC), so it’s possible that it won’t have a hepatitis B issue, it won’t have an HLA-B57 issue (which we didn’t even mention), and probably won’t have a cardiovascular issue. So that, potentially, could be a therapy that virtually anybody with HIV, with the exception of someone that has a creatinine clearance of 20, could start. And that is the vast majority. So you could have, for the primary practitioner that’s invested and wants to do it, like Eric said, one starting therapy that you could literally give to everybody.

Eric S. Daar, MD: And even if it’s 2 or 3, if they wanted to do it, they could do it.

Peter L. Salgo, MD: Diabetes is complicated. Diabetes is hard.

Paul E. Sax, MD: Managed by primary care doctors.

Peter L. Salgo, MD: It is, that’s my point. Doctors can do this.

Ian Frank, MD: Not always very well.

Paul E. Sax, MD: I’m married to a primary care doctor, and she is smarter than I am.

Ian Frank, MD: The HIV experts at this table, I think, would agree with me. We would all rather have HIV infection than diabetes.

Joseph Eron, MD: Oh, yes, without a doubt.

Ian Frank, MD: Because HIV is easier to manage and much easier to comply to regimen.

Joseph Eron, MD: And if you take all your pills, you don’t get complications. Like diabetes, you can do everything right and still lose your foot.

Ian Frank, MD: Exactly.

Eric S. Daar, MD: Stigma issues are real. Medically, it’s much easier.

Paul E. Sax, MD: Medically, it’s easier.

Peter L. Salgo, MD: I just want to say, because we’re going to wrap this up, that is the single most startling, most encouraging, and most bright and shining example of medicine that I’ve heard in the past 20 years. It’s astounding that we are sitting here today discussing this.

Paul E. Sax, MD: We feel incredibly lucky that we’ve been part of it.