Injectable PrEP – an exciting tool, but no silver bullet for adherence
We talk to Giffin Daughtridge, CEO of medical diagnostics company, UrSure, about treatment adherence and the impact of long-acting cabotegravir as injectable PrEP.
Injectable pre-exposure prophylaxis (PrEP) has the potential to be an important and exciting new tool in our HIV prevention toolkit. Earlier this month, the success of the HPTN 083 trial was confirmed at AIDS 2020, which investigated the novel long-acting cabotegravir injected as PrEP among gay men and transgender women. It’s hoped that the same can be said for women later this year when its sister trial (HPTN 084) publishes its findings.
But is injectable PrEP for everyone? Giffin Daughtridge, M.D., CEO of UrSure, talks to Avert’s Caitlin Mahon about this exciting development, the adherence challenge and the future of PrEP.
Caitlin: Can you talk us through why injectable PrEP is a potential game-changer?
Giffin: When we think about PrEP effectiveness, I like to think of the three legs of a stool: there’s uptake, adherence, and retention. If you’re missing any one of those three legs, then the drug is not going to work in a public health population setting, nor at the individual level. So, the reason for the excitement around cabotegravir is, instead of having to take that daily oral pill, which we know has been a struggle for a lot of people and decreases the effectiveness of PrEP in the real world, we now have the opportunity for them to inject every two months. If you can get the individual in for those visits, you get two months of protection out of it. As opposed to giving somebody two or three months of medication and hoping they're going to take it on a daily basis.
Caitlin: Sounds great, so are there any drawbacks?
Giffin: As with any therapeutic intervention, there are going to be pros and cons. Different things are going to work for different people. Daily oral is going to be better for some people, and an injectable will be better for others. The beautiful thing about cabotegravir coming out, and the reason people are so excited, is that we now have options in the tool kit, and we can match those to individuals accordingly.
So, the drawbacks that I see are, you’re going to the doctor every two months instead of every three months for oral PrEP. We’ve talked a lot about decentralising PrEP – allowing people to get PrEP in the home, do their lab tests at home, have their medication sent to the home, and it not being so clinical – this now goes the other way. Cabotegravir is going to require you coming in to see your provider because you’re not able to administer these injections at home. So, it’s more a medicalisation of PrEP.
The second piece is around the patient acceptability of an injection versus a pill. The pill is painless, non-invasive – while an injection comes with some soreness and injection site reactions. It's been reported widely in the studies that it is happening, but people aren't saying that it’s a deal-breaker.
I think the biggest drawback is the long tail after discontinuing cabotegravir. If you decide you want to stop cabotegravir – perhaps you’ve just entered a monogamous relationship, or you don’t want to come in every two months, you don’t want injections, or you just don’t want to continue getting it – that’s fine, but you’re going to be dealing with this long tail. The research tells us it’s about 48 weeks. During this time, the level of cabotegravir in your blood is not enough to protect you but it is potentially enough to lead to viral resistance if you were to become HIV positive. The way you get around that is by taking oral PrEP for 48 weeks after that, and obviously adherence is critical during that time.
Caitlin: 48 weeks! That’s a long time
Giffin: Yeah, it is a long time. It could be less than that, but it looks to be as long as 48 weeks.
We saw similar concerns with oral PrEP, but it wasn't really an issue, because the drug gets to a therapeutic level, and then it goes back down so quickly… but it could be a risk with cabotegravir. If you start injectable PrEP with cabotegravir, it's not something you come on and off very quickly. You need a commitment to it.
Caitlin: Right, so it sounds like some sub-populations could definitely benefit from it. For example, if you're in a monogamous relationship with a partner who's living with HIV and you're HIV negative.
Giffin: Exactly, perfect example. People have been heralding cabotegravir as a game-changer for PrEP, seeing it as a solution to adherence. But when we think about the ideal populations for cabotegravir, it’s likely going to be people who are already pretty diligent about getting to the doctor every two months and people who stay on it for a long period of time. For people who are coming in and out of the healthcare system – they probably aren’t going to be as good a candidate. So, as many may conclude, long-acting PrEP is not necessarily a panacea for adherence… We need to identify the right candidates.
Caitlin: So, people who would be going into the clinic anyway for other things, such as for their contraception…
Giffin: Exactly right, if you're somebody who is already regularly coming in, then you're a great candidate for it – and we now will have something in the toolkit that is better for them. I think that's the way to be thinking about it. Each individual has certain lifestyle needs – and matching the formulation to what that individual needs, as opposed to thinking of it as, we've solved the adherence issue because we have long-acting injectable. I think that's the concern – that we think the work is done.
Caitlin: So if injectables serve to further medicalise PrEP for some populations, what’s next in the pipeline for drug development companies to think about? Maybe something that is self-administered?
Giffin: The next step for PrEP will be an implantable pump. Contraceptives are obviously a great model for this. We started out with the pill, then a long-acting injectable, the IUD, and an implantable pump. A PrEP implant still needs to be administered by a physician, because you have to place it under the skin. But this could potentially give you 12 months of coverage, and you don't deal with the long tail if somebody wanted it out – you could just take it out. So, it doesn't de-medicalise it in the same way, but it gives you longer coverage and takes out the tail. Exciting stuff, but probably a couple of years away.
Caitlin: And what about people’s perceptions between using injectable cabotegravir for PrEP versus for treatment of people living with HIV, which we know is pending FDA approval.
Giffin: If you're living with HIV and on treatment, you really don't have a choice to come on and off the medication, you're going to be taking it forever. So I would imagine people are going to be more willing to do the injectable for the treatment of HIV.
In PrEP, we think of seasons of risk, right? You enter a monogamous relationship. You don't necessarily need PrEP as much anymore. You decide to go off PrEP, or go to a lower frequency of PrEP – harder to do that with the injectable.
Caitlin: What other strategies are being explored to support PrEP adherence?
Giffin: So, a couple of things. One thing we’re looking at is oral PrEP formulations that are slower to release. So, maybe you take one pill per week instead of one pill per day. Then there are adherence tools – you have pill sensors, smart pill bottles, you have apps – all different things to track your adherence. You can also do adherence testing.
Caitlin: Right, so tell me about the adherence tool your company, UrSure, has developed. It’s a diagnostic that measures tenofovir levels in the blood or urine, so why is that important?
Giffin: Well, there’s a need for adherence information on PrEP, because in PrEP, you don't have a viral load, right? The only way we know if you're not taking your medication for PrEP is if you seroconvert, and we're like: Oh, they weren't taking their medication. So we wanted to come up with a marker that would show us non-adherence before that happened.
We've developed tests for tenofovir, in urine, as a short-term measure of adherence; and for tenofovir, in dried blood spot, as a longer-term measure of adherence. Both are already available as a lab test. We’ve also developed a point-of-care test, similar to a pregnancy test, a yes/no, very simple test that is already available as a research use test, which essentially means it works, it's in its final form – it just doesn't have its FDA clearance yet.
Caitlin: Wow – very exciting.
Giffin: We feel like it’s a very exciting time for adherence right now because you have cabotegravir coming out, both for prevention and the treatment of people living with HIV, soon. And then you also have the ability to monitor oral PrEP and ART adherence in real-time, so hopefully, we can close the loop on the adherence and retention struggles and optimise the real-world effect of these incredible medications.
Giffin holds an MD from the University of Pennsylvania and an MPA from the Harvard Kennedy School. He is the co-founder and CEO of UrSure, Inc. UrSure makes novel urine and blood tests that measure and improve adherence to HIV medications for prevention and treatment.