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Novel Mechanisms of Action in HIV Treatment

MAY 16, 2017 | PANELISTS: PETER L. SALGO, MD; IAN FRANK, MD; PAUL E. SAX, MD; JOSEPH ERON; ERIC S. DAAR, MD


Transcript (slightly modified for clarity)

Peter L. Salgo, MD: In your practice, what proportion of patients require targeting HIV by a drug that works by a different mechanism than those that are currently available?

Eric S. Daar, MD: This used to be a big issue—people with multidrug-resistant virus, lots of transmitted resistance, lots of cross-resistance within classes. And most of them are the ones Joe was talking about, the people we started on treatment 20 years ago that transmitted resistance from vertical transmission. So there’s a subset of them. They’re pretty rare. Even in an inner city population like mine, they’re pretty rare because most of the failures aren’t taking their drugs at all.

Paul E. Sax, MD: We have one patient who’s in the ibalizumab/fostemsavir clinical program.

Eric S. Daar, MD: But they exist. And we, I think, are very pleased when companies are willing to go out there and try to create new drugs for a niche population who’s in great need.

Joseph Eron, MD: It’s a big challenge because it is a need. But it’s a small need.

Paul E. Sax, MD: A niche.

Joseph Eron, MD: So, really, the challenge is to both the FDA and the developers. How do you create studies where you want to study 300 people and each center has one person? You have to have 300 centers, and that costs a lot of money to do that sort of thing. Again, in the early 2000s, the people who failed with lots of drug resistance, who actually are very adherent people, somehow stayed alive when they took AZT (azidothymidine), then D14, and then indinavir. So, in some of those studies, like the BENCHMRK study and the POWER study, patients actually did really well because they were really adherent people. Even though they had lots of resistance, they had lots of resistance because they were adherent. Now, it’s the other way around. Now, for these people that have multidrug-resistant virus, some of them are people that have a really hard time adhering to therapy.

Paul E. Sax, MD: A lot of them have congenitally acquired HIV.

Joseph Eron, MD: Right. For example, these adolescents that have been through poor formulations.

Eric S. Daar, MD: The other challenge is incentivizing companies to invest in developing these drugs for a small patient population.

Peter L. Salgo, MD: The one that I was poking around at was fostemsavir. I looked at it not as an ID person and not as an HIV person. This entirely new mechanism, which in my own filtered way, seems to say, “If it’s a different mechanism, it has a chance for these multidrug-resistant people.”

Joseph Eron, MD: Yes. That’s what saved the lives of so many people, was the new mechanism, integrase. That was what really got these men and women through the mid-2000s. And the problem with fostemsavir is that unlike dolutegravir, which is 1 pill once a day (it’s great if you have resistance, but it’s also great up front), fostemsavir is not. It has, kind of, modest antiviral activity. It definitely has antiviral activity, but it’s a little bit modest. It’s an attachment inhibitor, so it attaches to the most variable part of the virus—that’s the envelope. So, attacking the most variable part of the virus is not the best strategy because the virus is going to become resistant more easily. So, really, it’s unfortunately just kind of modest antiviral activity, and it probably will need to be given twice a day, which makes it a little bit tougher. But we need it. There will be people that need it, but it won’t be that many.

Ian Frank, MD: We need more than 1 new drug in 1 new class because a lot of these people have resistance to the protease inhibitors, have resistance to the NNRTIs (non-nucleoside reverse transcriptase inhibitors), and the integrase inhibitors. So, it’s not just about having 1 new drug. You have to combine that with some other drugs that have some activity. But, again, this can be a challenge.

Peter L. Salgo, MD: This is a drug that attacks the virus, not the cell or the replication inside the cell. That’s why it’s a different class.

Joseph Eron, MD: It blocks attachment. Obviously, HIV has to bind to the CD4 molecule, then touch one of the chemokine receptors and get inside the cell. By binding to the virus, it actually blocks binding to the CD4 molecule.
We have another drug that blocks entry, maraviroc, that actually binds to the cell and prevents the virus from entering. So, it’s an important drug. There’s no question that it is a different mechanism. The patients who are resistant to our protease inhibitors, INSTIs (integrase strand transfer inhibitors), and NNRTIs likely won’t be resistant to this. Though some people are naturally resistant, it’s only a small percentage because it binds to that envelope. So, it’s unequivocally useful, and the phase III studies are ongoing. In fact, it’s past its primary endpoint. It likely will show activity. We’ll find out, probably this summer, whether it has much toxicity. The study’s ongoing; It hasn’t been stopped; it will be available. The issue is whether it will be available for small subsets of people.

Eric S. Daar, MD: And then there’s this other drug, ibalizumab, which actually targets the CD4—the cell. Another blocks entry—a completely different mechanism. And that’s also in fairly advanced stages of development. So we do have 2 new drugs.

Peter L. Salgo, MD: They basically have 2 different pathways.

Eric S. Daar, MD: In all likelihood, to meet some of the needs Ian was talking about, where we can’t just add one drug to people who have a lot of other resistance, they’re going to need 2.

Joseph Eron, MD: Yes, but ibalizumab is an infusion. It’s not a pill, so that makes it challenging. They’re working on formulating it so maybe it can be an injection, but right now it’s an infusion.

Peter L. Salgo, MD: So here we go with compliance again.

Joseph Eron, MD: Oh, yes. Absolutely.

Peter L. Salgo, MD: It occurs to me that what we’re looking at are drugs for multiple-resistant or heavily resistant patients. You’ve been telling me that most of these drugs, for most of the patients, work really well.

Paul E. Sax, MD: This is a very small subset of the people with HIV in the United States, but it’s a needy subset.

Peter L. Salgo, MD: In that subset, they’re running out of time. They’re running out of drugs, right?

Joseph Eron, MD: Absolutely.

Eric S. Daar, MD: The clock is ticking on these people.

Joseph Eron, MD: I have a guy who’s been on ibalizumab now for 6 years, with tipranavir (a drug we never use) and maraviroc (another drug we almost never use). And he’s hoping this drug will get approved. What is he going to do if it doesn’t get approved?

Peter L. Salgo, MD: Tell me about the potential here. It’s very small, but it occurs to me that as we treat more and more people with more and more drugs, we’re going to see more and more resistance.

Paul E. Sax, MD: Actually, not true.

Peter L. Salgo, MD: Not true? Why not?

Paul E. Sax, MD: Because it turns out that the antidote to resistance is virologic suppression. And with the more successful regimens that we have, the more it is virologically suppressed, the lower the incidence of resistance. But very smart people predicted exactly what you were saying.

Peter L. Salgo, MD: Thank you. I’m relieved at the moment.

Paul E. Sax, MD: It turned out not to be the case, thank goodness.

Joseph Eron, MD: In the setting of monitored. Now, in Sub-Saharan Africa and other primitive settings where they don’t monitor (so they don’t detect failure earlier), you certainly see accumulation of resistance—absolutely. Usually its seen with nucleoside and NNRTI resistance, which fortunately [we’ll] likely be able to be overcome. But monitoring is an important part of it. So we talked about spacing out monitoring, but we would never get rid of viral load monitoring.

Paul E. Sax, MD: True.
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