Emerging Two-Drug Regimens in HIV Infection

MAY 18, 2018
MD Magazine Staff

Joseph Eron, MD: Let’s talk about novel and emerging therapies. New drugs are coming. One of the things that’s being talked about a lot, even for initial therapy, is the use of 2-drug therapies. Eric, what’s going on there?

Eric Daar, MD: There has been some rethinking of, do we really need 3 drugs? We are now considering the potential benefits of the 2-drug regimen. We have pretty robust datasets for first-line therapy with lopinavir, ritonavir, and 3TC. The GARDEL study really sort of laid the foundation for this. For everything that followed, it showed that it really worked well. It worked as well as 2 nukes [nucleosides] and lopinavir/ritonavir. That was even true even in people with high viral loads and low T-cell counts. The limitation was that it was lopinavir/ritonavir.

Now, we’re seeing data with darunavir/ritonavir/3TC, which makes a little more sense. It’s one of the preferred boosted protease inhibitors. That data are still relatively small. They do all of these studies very carefully. They did a lead-in to make sure things looked good before they expanded the population. The lead-in looked good, so they’re expanding the population so there will be a fully powered study. But, we don’t have it yet.

The other area that’s being pursued is dolutegravir with 3TC. Again, this was initially addressed very carefully. There were 20 patients in the PADDLE study. It was actually 10, right? They made sure that everything was alright, and then expanded it to 20 patients. It was only done in people with CD4s of over 200 and viral loads of less than 100,000. This was done to make sure that we didn’t make a big mistake. It looked like it worked. Then, the ACTG [AIDS Clinical Trials Group] did a study where they expanded that to about 125 people. They assured that 25% of the population would have viral loads of 100,000 to 500,000—this is sort of the next step. It, too, looked very promising. Notably, there was 1 individual who selected for integrase resistance. Normally, out of 125 patients, we’d say, “OK, 1 patient.” But, considering that dolutegravir with 2 nukes is at 0, still….

Now, there are 2 large fully powered randomized control trials that are enrolled. We’ll be seeing the results from those studies pretty soon.

The other 2-drug regimen that’s actually in the guidelines is a boosted protease inhibitor with raltegravir. In that study, the primary endpoint showed noninferiority. But, in the population of people who had viral loads of over 100,000 and CD4s of less than 200, it did not work as well as 2 nukes in the boosted protease inhibitor. So, people have not rushed to that either, unless there’s an extremely good reason to do so—like in an individual with a relatively low viral load.

Daniel Kuritzkes, MD: In the era where that study was done, there was still a lot of concern about the use of TDF [tenofovir disoproxil fumarate], or abacavir, as an alternative. And so, it made sense—the nucleoside-sparing regimen. It’s really hard to determine what type of patient would be a candidate for an integrase inhibitor with a boosted protease inhibitor as a first-line regimen. It works within the parameters you described, but I just don’t see why I’d ever….

Eric Daar, MD: I think you’re right. Yes.

Joseph Eron, MD: We talked about nuke-sparing a lot. Now, we don’t talk about nuke-sparing so much. Colleen, there are also some long-acting alternatives. What do we know about those?

Colleen Kelley, MD: That’s kind of the next frontier in HIV therapy, for people who don’t want to take 1 pill every day. There are some long-acting injectable agents being studied. The first one is an injectable cabotegravir, which is an integrase inhibitor with rilpivirine. Hopefully, we will get to a point, someday, where people will not have to take a pill every day. They could get injectable therapy every few months, or, potentially, even longer.

Joseph Eron, MD: We have some preliminary data, in several hundred people, of the injectable cabotegravir, either monthly or every 2 months out to 96 weeks. There are 2 fully powered phase III trials, right?

Eric Daar, MD: Yes, for the monthly therapies. They’re just starting to study every-other-month versus once-a-month therapy. So, we’ll eventually see. But, this is all maintenance therapy.

Joseph Eron, MD: Right. People have to be suppressors.

Eric Daar, MD: Yes. That’s really important.

Daniel Kuritzkes, MD: Yes. In other therapeutic areas, there are going to be some patients for whom this is a great option. Other people are going to say, “Wait a minute, I was only seeing you once or twice a year. Now, I need to come in every month, or every other month, to get shots in my butt. Why would I want to do that?” So, it’ll depend. It’ll be patient preference, I think.

Joseph Eron, MD: People might choose to use an injectable during a certain period of their life, like when they’re traveling or when they’re in a setting where they don’t feel like they can have pills in their possession. In some way, it might become stigmatizing. So, I think it’s possible. And obviously, the longer the interval, the more attractive it becomes, along with the intervals between.

Eric Daar, MD: In LATTE-2, one of the intriguing observations, although it was actually informative, was how acceptable people found it to be.

Joseph Eron, MD: It was really remarkable.

Eric Daar, MD: Yes. The people who were randomized to the injectable arms found it to be much more acceptable than the people who were randomized to remain on the oral regimen. This tells us that for people who want it, it’s very well tolerated. When people ask, “So, who is this for,” it’s going to be for the people who want it.

Joseph Eron, MD: Right. That makes really good sense.

Transcript edited for clarity.

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