Transcript Related Guidelines

New 2-Drug Regimens to Treat HIV

David A. Wohl, MD · University of North Carolina


August 23, 2021

Editor’s Note: The US Food and Drug Administration (FDA) has approved the injectable form of the combination of the integrase inhibitor cabotegravir and reverse transcriptase inhibitor rilpivirine for the treatment of HIV-1 infection in adults.[1]

In addition, results of the phase 3 SALSA trial have been presented and reveal that two-drug fixed dose tablet antiretroviral (ART) therapy with dolutegravir/lamivudine shows noninferiority in viral suppression among people with HIV-1 who switch from any type of three- or four-drug antiretroviral ART regimens.[2]

This transcript has been edited for clarity.

It's really interesting to me, who’s been involved in HIV therapy now for a couple of decades, to see the pendulum swing back to trying to use fewer and fewer medicines, rather than more and more medicines. So, we talked about HAART—highly active antiretroviral therapy—with cocktails, then mega-HAART. And now we're going back to whether less is more and how we can do better—or at least the same—but with less medicines. And I think the interest driving using less medicine to achieve the same outcomes is to reduce potential toxicity, even as our medicines have gotten more and more tolerable.[3,4] But also, I think, really to reduce cost. And while there's sort of a feel-good aspect of, well, I'm only on two medicines instead of three medicines, and thus, I think maybe I don't have the exposure to side effects, really, I think a driver for this for many people, especially people who pay for medicines, is cost. 

We should also think about this in terms of when we use 2-drug therapy to treat HIV—again, a new paradigm. We have to think about it as far as induction and maintenance. And those are terms that we don't readily apply to HIV. We think of those more in oncology and, maybe in the olden days, when we would treat people with ganciclovir for CMV retinitis. But this induction-maintenance idea, I think, is helpful for breaking down where certain 2-drug regimens fit and where they don't. And again, we could talk about specific regimens. 

So, the SWORD studies that came out a number of years ago looked at rilpivirine and dolutegravir orally, and this was as maintenance therapy.[5] People who are living with HIV, who are on standard regimens, either switched or stayed on their regimen, and then switched to just two medicines, which is now co-formulated into one pill. This was considered, again, somewhat avant-garde—a little bit risky, and it worked if you chose the right people, people who clearly would not have any resistance to the rilpirivine or dolutegravir, of course, and who switched to two active drugs. And these two active drugs are pretty good. You don't really need a third drug, is what we learned from the SWORD studies, in people who don't have resistance to these drugs, who you are able to switch to and get them to take it. So, that was great. People liked it. Satisfaction scores were higher for people who got the 2-drug therapy versus those who stayed on their regimen. I think that that was very exciting. It hasn't really been necessarily adopted widely, because of maybe some of the limitations of that particular regimen. But it showed us that 2-drug regimens can work really well for maintenance. 

On the heels of that, we've had other data—the LATTE studies, of course.[6] They looked at cabotegravir— another integrase inhibitor—and also rilpirivine and NNRTI, orally at first, and then looked at it as an injection. And then it was followed up by the trials called ATLAS and FLARE.[6] And more recently, some extensions of those studies that showed the long-acting injectable integrase inhibitor and rilpirivine. Again, cabotegravir and rilpirivine can be really effective. 

Now, remember, when we talk about induction maintenance and we talk about the long-acting injectables, it gets a little wonky, because the long-acting injectables are given to people who are already suppressed. So if a person comes in and has never been on HIV therapy, you need a lead-in period with oral medicines. And that could be, of course, a standard regimen. And then you expose these folks to oral versions of the cabotegravir and rilpirivine, to make sure there's no serious toxicity, and then switch them over to the injection. So, in a way, the long-acting injectables are always maintenance, even in people who had never been on medicine before, because you need this oral therapy lead-in to get their viral load suppressed. So it's a little bit of semantics. But you know, again, I think the studies show that this is really well tolerated. And while 100% of people, practically, get an injection-site reaction with some soreness where they get the injection, it's an IM injection that's given on the side of the buttock, a side of the hip, in the gluteus medius. Most people say they don't mind it, and satisfaction scores again for simplified therapy beat out continued therapy with oral therapy. That's in the context of studies where people are volunteering, because they know they might get an injection. But hopefully, in clinic, that's exactly who we give these medicines to. 

So, I think 2-drug therapy is really exciting. I think 2-drug therapy orally is something that's available right now. I think 2-drug therapy with injectables is going to catch on. We're awaiting FDA approval in the United States for long-acting cabotegravir/rilpirivine. This will be given once a week, once every 4 weeks, once a month in the beginning. And then, hopefully, with longer-term data from another study—ATLAS 2M—we’ll be able to see that maybe 2-month intervals will work really well. There are still some things that have to be figured out that we don't completely understand. What do you do exactly when people come off of the 2-drug injectable and what kind of tail do you have to cover? Is it important to cover the tail? Things like that. I think some of the logistics that we have to figure out. But I think we will.

Lastly, I just want to mention another oral 2-drug regimen that I think is really important to talk about, and that's dolutegravir/3TC. And again, we talked about this as induction or we talk about it as maintenance; it's really interesting. So, there are a couple of studies that we should talk about—the GEMINI studies,[7] which is a combination of 2 studies, both identical, and TANGO.[8] In GEMINI, treatment-naïve folks were given dolutegravir/3TC alone as starting therapy—induction therapy—versus dolutegravir/FTC/TDF. And what was found, over time, was that this worked just as well as the triple- drug therapy. I think this was a surprise to a lot of people. Again, these were folks who didn't have any evidence of resistance, who were treatment-naïve, had no hepatitis B infection (of course the dolutegravir 3TC would not cover hepatitis B). But given those caveats aside, I think in that kind of population, the 2-drug therapy did really well, and these were very well-powered studies. Similarly, in TANGO, which I think is more apropos to the patients that we're seeing nowadays, people switched. So, these were adults who were suppressed; their viral load was undetectable for a while. They are on stable therapy; no previous virologic failure; again, no hepatitis B; and they either switch to dolutegravir/3TC or continued their regimen. All the people who switched were on a TAF-based regimen, or people who were randomized in the study were on a TAF-based regimen. So, you know, continuing on a really good regimen versus switching to dolutegravir/3TC, there was no difference in virologic suppression. 

So, this is a really provocative approach: Can we get away with less medicines? Do we need to? Is there a real motive here to do that? Longer-term and in real-life situations, people point out, well, maybe it's going to be messier. And maybe we'll see people really stress on the 2-drug therapy. That's really a point of conversation and even some controversy that I think we'll hear more about. But what we could say right now is that we do know that two drugs work. The whole idea that you need three drugs or even more to suppress HIV and keep it suppressed—that's no longer operative. It depends upon which two drugs you're talking about. And if you have the right two drugs, we now have evidence that it could work in the right patient.


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