How Will Long-Acting HIV Antiretrovirals Work in the Real World?

Anton Pozniak at the 90-90-90 Targets Workshop, an AIDS 2018 preconference meeting, in Amsterdam, the Netherlands.
Terri Wilder

While there has been considerable buzz within the HIV workforce about the promise of long-acting antiretrovirals to transform both HIV prevention and treatment, a critical question hangs in the air: Once viable long-acting options have reached the market, what will be their true impact? Will they really help move us toward an HIV-free world?

Our correspondent Terri Wilder, M.S.W., got a glimpse of what that future might look like while attending the 90-90-90 Targets Workshop, a preconference hosted by the International Association of Providers of AIDS Care (IAPAC) from July 21-22 in advance of the International AIDS Conference (AIDS 2018) in Amsterdam, the Netherlands. Anton Pozniak, M.D., the HIV service director at the Chelsea and Westminster Hospital in London and the president-elect of the International AIDS Society, gave a presentation entitled "Looking Ahead -- Long-Acting Antiretrovirals for HIV Treatment and Prevention." Wilder spoke with him shortly after the talk.

Terri Wilder: Obviously, there's lots of chatter about what is next in antivirals. In terms of injectables for HIV, for people who have HIV, what do you think is kind of the most exciting thing that's coming down the pike?

Anton Pozniak: Well, in pretty advanced development, injections of cabotegravir and rilpivirine. They'll probably be every month. And I think that, for those people who have got pill fatigue, can't take pills, had real problems with pill taking, they offer an alternative for them.

One of the advantages of the long-acting [antiretrovirals] is that you don't have to keep pills at home. As long as you turn up for your appointment, you don't need to worry about whether or not you're going to miss a dose. So it takes a lot of pressure off a certain group of people.

There are downsides to injectables. They can hurt, obviously, having an injection in your buttock. For some people it's fine. We do a lot of injections for syphilis, etc., so people do understand what they feel like. But very few people in the trial, when they did this experiment with cabotegravir and rilpivirine, actually dropped out because of that. You have to warn patients that it might cause a bit of skin reaction or a bit of a lump, but that's transient usually. So it's not for everyone.

I think a lot of people say, "I'll just take a pill every day." But for a certain group of people, I think it's a real advantage.

TW: Who are the key institutions that are really looking at this?

AP: So basically the trials have been organized by ViiV, with collaboration from Janssen. Then it's been global. So it's been an effort from [the U.S.], Europe, Africa, etc. There have been lots of different groups trialing this out. It hasn't just been in one center.

TW: One of the things that you talked about was resistance. Do we need to be concerned about resistance in a long-acting injectable?

AP: For treatment, yes, we do. One of the issues is that, obviously, if you've got wild-type virus and you become undetectable -- because you have to take pills first in case you get an allergy to the injection -- if you're fine and undetectable, you go on the injections. If you don't come regularly for the injections, the problem is that the drug levels start to decrease over time. And as they decrease over time, there will become a time when you might get some viral escape; and those viruses could then become resistant.

We have seen them in the trials: We have seen patients who have developed resistance to drugs in this manner. So we have to be concerned about resistance. But the clinical trials have been small numbers, so we need the bigger trials, of course. Doctors always say that: Let's have bigger trials and get more information.

So, yes: We do have to be concerned. When somebody decides they want to go on injectables, there's a couple of things, really. One is to turn up regularly. I think although people have said to me, "Isn't it great? We could give this to poorly adherent people," maybe that's not a good thing, because it's the poorly adherents that may not come up for their injections.

The second thing is that, probably, patients should have some of the oral therapy at home, in case they can't make it to the clinic for a couple of weeks, something disastrous happens, or they go on holiday and they can't take injections with them. We have got to have some flexibility. I think maybe someone says, "I've had enough of it. I want to go on pills," [and] a year later goes, "Hey, I'd like to get back on the injectables, please." I think this flexibility we have should be useful.

TW: There are conversations happening here [at AIDS 2018]. There's a pre-conference on U=U [undetectable equals untransmittable] and a lot of excitement globally around this kind of U=U messaging. Not only does it help combat stigma, but it's a really important clinical issue for clinicians to be aware of. And so, when we think about these long-acting injectables in the future, how could that impact things like treatment as prevention?

AP: Using the injectables as PrEP [pre-exposure prophylaxis] is really an idea worth pursuing, and it is being pursued. They've been [testing] cabotegravir as PrEP in the [United] States. They've set up several trials, which are being used globally, actually. But anyway, aside from that, the great thing about it is that if you have one of these injections or some other device that can last several weeks or months, you're protected during all that time. So, even though you've got on-demand PrEP, which I think is with Truvada [emtricitabine/tenofovir disoproxil fumarate], which is a great innovation, if you suddenly decide you're going to have sex and you don't have the pills on you, but you had the injection, then it's fine, you know? You're going to be protected.

So I think that some people will be happy taking PrEP, one pill a day. Others will do it on demand. But actually, there will be a lot of people who say, "Right. This is great. I'll come every four to six weeks, have an injection. I'm fine during my sexually active phase." Or if they're going somewhere, and where they know they're going to have sex for several days on end, they don't want to take pills, or they might. And there [are] a lot of people who take chemsex and other stuff during this, and they may forget pills. So this is a bit of a safety mechanism for them.

TW: We have lots of messaging that clinicians give to their patients about PrEP, like you have to take it a certain amount of time for it to get to the cellular level. That would obviously be something that we would have to look at for injectables for PrEP.

AP: It's vital that we know about the running period before, as I say. But maybe you take pills for a few days and then after that you just go on the injection, because the levels will be up -- just like they've seen in the studies.

TW: I guess I'm thinking of the client that it sounds like you were describing. Like, "I know I'm going to the beach and I'm going to have sex." Making sure that they understand that we have no idea what the data is going to say, but it's probably going to be unlikely -- maybe, maybe not -- that you can take an injection on Friday and get on your plane or train on Saturday.

AP: And it may be different between men and women, like it is with oral PrEP. I think it's vital that we look at all of these things. But, like a lot with HIV, we're really good at sorting these things out.

The other thing is, as I said in my talk, that the involvement of the community, in terms of where they believe it all fits in, is absolutely essential. Because it's no good that the doctor's going, "Hey, we've got this great thing here, and this is a way you can take it and deal with it," and then someone comes from the community and goes, "Yeah, but actually what's happening is this." How do we actually get that issue sorted out?

And, like you say, we need to know how quickly this is going to react, rather than a doctor saying, "Oh, this is a great protection for a few weeks." It might be that -- imagine if you've got to wait five days before it reaches adequate levels. Then you've got to tell people, "Well, actually, you've got to go on pills first."

TW: Right. I'm glad you brought this up. One of the things that you said [in your talk] was, "This really needs to be in the hands of the activists to demand this."

AP: I said that because, first of all, it may be -- I don't think it should be; it may be -- expensive [at] first. But people should demand that the cost of it is not big if we find the utility is great. There's a lot of ifs. But if it's a really good method of PrEP for a population that wants it, they've really got to say, "We want this. Why are you not making it available?"

I mean, look at the whole hassle we've had over oral PrEP in many countries -- I mean, my own country, the UK [United Kingdom], where we did one of the pivotal trials, the PROUD trial. Yet the government wanted an implementation project. And we've got one of the best STD [sexually transmitted disease] networks in the world, right? So we could have implemented it from our STD clinics tomorrow, is my firm belief.

If injectable PrEP comes and the utility is good, then we should be able to have it and people should be able to use it. We should not have barriers. Well, cost is always a barrier, but it shouldn't be [such] an extortionate cost that we can't use it. And we should have people being able to access it where it's available.

TW: There are a lot of activists now that believe PrEP as an oral pill is not accessible to everyone, that it is way too expensive, and that it is getting in the way of us ending HIV epidemics across our globe. There was a New York Times article< by James Krellenstein, [Aaron Lorde,] and Peter Staley this past week kind of speaking to that point.

AP: Well, the issue for me is that without prevention, whichever form works -- circumcision, PrEP pills, if we get PrEP injections -- without those, you're not going to finish this epidemic off. So we have to have a huge prevention [push]. And everybody's moving to this, to link prevention in with TasP. And it makes sense.

So, you have to have it available. But that's on lots of elements. So, number one, health care systems saying we can't afford it: Well, it should be affordable. Generic companies can make it extremely cheap and make it available. Every country where you can get a pill for HIV, you should be able to get PrEP in the same way.

Then there are countries where there's so much stigma around HIV and AIDS that getting penetration of PrEP into those countries is challenging. Because if you're found with the pills, you're suddenly branded as being of a certain sexuality, or you're a sex worker, or whatever. And that can be a criminal offense in those countries. So people are very secretive.

But there is some good news about what's happening with PrEP in my own region, in Europe, many countries now. Holland is going to say that PrEP's going to become available while we're here in Amsterdam. So I think, like a lot of things, once all the cards start falling down, at least in some regions, you'll see everybody joining in. Because why shouldn't they be?

The biggest issue for me is the drug cost barriers. It's interesting that Truvada, say, for PrEP, costs much different in France [than] Belgium -- and they are neighbors. You cross the border, and suddenly you're paying a very different price. That drug cost inequality should disappear.

TW: Your presentation was given in the 90-90-90 Targets Workshop. Somebody asked you: What do you think the timeline is on injectables for people who have HIV and injectables for prevention? Are we going to see it within the context of trying to meet our goals for 90-90-90 [90% diagnosis rate among all people living with HIV; 90% on-treatment rate among all diagnosed people; 90% viral suppression rate among all people on treatment]?

AP: Nope. I think by 2020 we'll have some more data, especially on the treatment side. But obviously, after trial readout comes a lot of implementation work. That's why I said that a lot of the studies probably buoy in the [2020s]. I think we'll be in good shape by the mid-'20s. If you want to call 95-95-95, that's 2030; I think we'll be ready for that then. But I don't think we're going to get a lot more movement by 2020.

TW: So basically the message is: Stay tuned.

AP: Stay tuned. We've got oral PrEP. We've got circumcision. There's other methods of preventing HIV; lots of stuff that goes on. And you see some cities that are doing it really well, like New York. So, yeah: Stay tuned. I think that the world will be a different place in 10 years' time. I hope.