The Bottom Line on Isentress: An Interview With David Wohl, M.D.

Executive Editor

This is Part I of an update on Isentress. For Part II, an explanation of how Isentress works, please click here.

On Oct. 12, the U.S. Food and Drug Administration approved Isentress, the first member of a new class of meds called integrase inhibitors. Isentress is also known generically as raltegravir, and during its early development was called MK-0518.

To find out more about Isentress and how it might impact treatment for HIV-positive people, I spoke with Dr. David Wohl, an associate professor of medicine at the University of North Carolina-Chapel Hill, and the co-director of HIV services for the North Carolina Department of Corrections. I should note that Dr. Wohl has participated in research on Isentress, and has also received research funding from Merck & Company, which developed Isentress.

Isentress: What is this drug all about, and why do HIV doctors seem to be so excited about it?

David Wohl, M.D., Associate Professor of Medicine at the University of North Carolina at Chapel Hill, and co-director of HIV services for the North Carolina Department of Corrections I think anytime that there is a new HIV medicine, there's certainly a buzz. But especially when there's a new HIV medicine that works completely differently than any of the previous HIV medicines we have. So here we have a new drug that also is in a different class of drugs than we have ever had before. Isentress works in a completely different way than any of the available HIV medicines we've had to date.

Is Isentress meant for people for whom other drugs have failed?

Typically what happens is that new drugs will come along and be tried in people who've failed other medications, or whose medications have failed them. "You might have been on something before; now here's a new medicine. Why don't you try this?" is the approach of studies of new HIV medicines.

It's pretty hard to start out as an HIV medication that would be used in first-line treatment. Part of that is because we have so many really good first-line medications -- those are medications we use initially to treat the virus infection -- that it's really challenging to come up with something that's even better than what we've got now. So the pharmaceutical companies, oftentimes, will try out a new medicine in people who are a little bit more needy for new medicines, people who've been through other medicines and don't have as many choices. That's exactly how Isentress has been studied to date.

How well does it seem to work in those people?

Isentress -- raltegravir -- works really well. That's why there's all the hoopla; that's why it was approved.

The medication has been studied in treatment-experienced patients.1,2 It's also been studied in a smaller way in people who've never been on therapy, so we do have some data on that.3 But the really big news has been how well this drug performed in people who had been on therapies before and did not have a lot of treatment options and that's a really tough group to see success in. The drug was well tolerated, it had great responses, and for people who don't have many choices, that's a tremendous finding, a great result and a boon to HIV therapy.

The study that was done -- there were a couple of really big studies done across the planet, looking at this drug -- what they found was that this drug doesn't work well alone. That's what we've seen with every HIV medication, basically: It could be powerful itself, but alone it's not going to do it. It's like a table with only one leg, instead of three or four to keep it stable. It just can't do all the heavy lifting by itself.

In these studies, it's shown that if you take another active drug -- another drug that should work against the virus that the patient has -- with this new drug, raltegravir, you see better success. Even better success is seen if you have three drugs altogether, i.e., Isentress plus two other drugs that have some activity against the virus. This is what we see with any HIV medicine.

We really need to combine this thoughtfully with other medications, and I think a very important thing -- and the reason why you're seeing this perfect storm of enthusiasm about this drug -- is that we have other new drugs that we can combine with this one to craft a very potent, effective regimen.

Is there any sign yet that specific drugs would be best combined with Isentress?

In the studies that have been done to date, it's really just a matter of the drugs that have been available. Certainly, if someone had never been on, let's say, Kaletra [generic name: lopinavir/ritonavir], and had susceptibility to Kaletra, taking Isentress with Kaletra and possibly another drug that the virus should respond to, that would be a good combo.

In the studies that were done, it was mostly darunavir (Prezista) [also known as TMC114], which was taken with Norvir [generic name: ritonavir], that had a good effect, as did Fuzeon [generic name: enfuvirtide; also known as T-20], an injectable drug that many people are familiar with. Certainly, if people took Fuzeon, Prezista, and also Isentress, they had great, great results. So I think if this drug came out, and there was nothing to combine it with, we'd see some trouble; we would see that it had limited applicability. But now that there are these other drugs that do work against resistant virus, it's exciting.

As you alluded to in your other question about when is it best to use this drug, I think part of the excitement is that this doesn't have to necessarily be a drug we think of as only being used in the salvage situation. That's the situation that we've studied the most -- that is, people who have been through other medications and don't have as many options left, and we "salvage" them with these combinations, these cocktails of potent HIV drugs. I think there's excitement because one could imagine that this could become a therapy that could be used even earlier in HIV care.

How far down the road do you think that might start to be the case?

I think what happens always is that a drug comes down and is used in one niche, and then migrates to another. We saw this with Kaletra. Kaletra came out and people were using it mostly in a salvage situation, in people who really have fewer choices. It was used to rescue them from virus that had become drug resistant. And slowly, but certainly, the drug became -- and really still is -- one of the most popular initial therapies we use. So it doesn't take long for clinicians to play with drugs and start to use them earlier.

It also helps a lot if there are more studies, well-powered studies, looking at the drug in those circumstances. Certainly the makers of Isentress appreciate this, and they have designed, and have already started presenting data from studies that look at the use of the drug in people who have limited or no HIV treatment experience. I think that once another nice, big study comes out, we'll be very tempted to use this earlier on.

You had mentioned a little bit earlier that in the studies on Isentress so far, it seemed to be very well tolerated. Can you talk a little about the side effects associated with it?

It's hard sometimes to tease out the side effects of the drug, especially in the kind of studies that it has been engaged in, because people are taking a bunch of other medicines at the same time. In the case of this particular drug and where it's been mostly studied, you have people who are involved in the study who have more advanced HIV and have more problems with their health.

There could be some nausea and diarrhea associated with this medication; again, there is the question of how much of that is the combined medication that people are taking in this situation. There could also be some elevations of some of the blood tests, including a muscle enzyme that people can have measured in their blood.

But generally, it was really well tolerated, and I think that's important. There have been reports of cancers developing in people on the drug; again, that's often hard to tease out from the background, because people living with HIV are more susceptible to cancers.

I think there's going to be a lot more investigation looking at what happens to people on the medication. This is fairly typical; I think it's this post-marketing surveillance that's very important in all drugs, especially HIV drugs. There's a big rush to get medications approved, and I think that's a good thing, but we may not have all the long-term safety data we need, so there's a real emphasis on trying to make sure we capture the safety data once the drug hits the proving ground after approval.

So I don't think we have the complete story, and I think once we see more data from treatment studies that involve people who have not been on HIV medicines before, you'll get a cleaner sense of what the side effects of the drug are. But so far, it seems to be remarkably well tolerated.

An important aspect of this drug is that it does not require Norvir to be coadministered. So many of our drugs, the protease inhibitors in particular, require Norvir to boost the level of the medication in the blood. Norvir is a protease inhibitor itself, but at low doses it can raise the level of other drugs in the blood, make those other drugs more potent, and make it so you don't have to take them as frequently. The problem is that even low doses of Norvir can be associated with intolerance, such as nausea, vomiting, diarrhea, and even some changes in cholesterol, triglycerides, and blood sugars in people's bodies. So it's not the most ideal HIV medicine that we have, and being free from Norvir, I think, is a positive aspect of Isentress.

Isentress is the first integrase inhibitor to be approved in the United States, but it's not the only one in development, right?

No, hot on its heels is another medication, elvitegravir [also known as TMC125]. This is another drug that does a similar sort of job of preventing the virus from integrating into our DNA. That drug is a little bit further behind in development; there have been some data regarding that drug, and again, it looks promising. That drug does need to be taken with Norvir, so that will be a little bit of a deficit with that particular compound.

I think it will be very important to see how these two drugs do head-to-head. I'm a big fan of comparative studies -- that is, studies that compare one drug versus another, rather than having to try to make some assumptions or inferences based on studies that were done separately. So you study drug A, and you study drug B, but not against each other, and you try to judge them against each other. It's really just best to put drug A and B in the same study and see how they do head-to-head. I think we'll see those kinds of studies in the not too-too distant future, but it's going to take a while. I think for a while it's going to be Isentress alone in this class of medications.

Is there any indication yet that, if a person takes Isentress and if Isentress doesn't work out, they have ruined their chances of taking elvitegravir or another integrase inhibitor down the line?

I can firmly say: maybe. We don't know. There is cross resistance between Isentress and this other integrase inhibitor drug being developed, elvitegravir, and there are different pathways of resistance. It's still very early in the game of trying to understand resistance, and understanding how much the resistance that is cultivated during treatment impacts other drugs. But yes, it's likely that if you have trouble with resistance to raltegravir, you may very well compromise other drugs in the class.

That's not unique to this class; we see that with all the classes of HIV medicines. You become resistant to one, you're basically going to knock out one or more of the other drugs in that class. The virus mutates and gets around the mechanism of one drug; if another drug shares that mechanism, it's not too surprising that you'd see some decreased activity of the other drug.

If a person wants to get their hands on Isentress, how easy will it be for them to do that, now that it's been approved?

I think it won't be too long before people will be popping Isentress. First, of course, your clinician would have to decide that it's the best approach for you. Again, generally crafting a new regimen around this medication is a good idea. We have a good sense that Isentress has some resistance to resistance, meaning it's not too easy to get resistant to it, but it's also not the most bulletproof of the HIV medicines we have, meaning that resistance can develop to this drug.

I think there has to be a good regimen, a good combination of medicines that are prescribed along with this medicine to increase its chance of working well and for a long time. Once that occurs, it's just a matter of when does it get to the stores. After FDA approval, there's usually a lag time before a drug can get transported to the various pharmacies. AIDS Drug Assistance Programs, or ADAPs, have to include the drug on the formulary and then get stocked. So it can take a few weeks from approval to availability in stores and on formularies and on insurance plans, but I would say within the next few weeks, certainly people will be able to get it. I hear that the drug is expected in stores within a week or so.

Stepping back and looking at the approval of Isentress from a larger perspective, what do you feel the overall impact of this drug's approval is, especially given that we have Selzentry [also known by the brand name: Celsentri; generic name: maraviroc], which came in a couple months ago. Is the approval of Isentress one small step for HIV treatment, or is it a giant leap?

I think it's a big hop. I really am encouraged by this. I like that this is a medication that works in a completely different way. I like that it's a medication that doesn't need pharmacological boosting with another drug -- meaning it doesn't require another drug to be as effective as it could be. It's likely that this drug will mix well with others. I think that, generally, this is a very, very exciting step.

We are bound historically by what drugs came out first. We use a lot of AZT [brand name: Retrovir; generic name: zidovudine] and like drugs, because they were the initial drugs. If they were to come out now, we might not be using them as much as we do. It's historic. That this drug comes out, it's in a new class -- were this to have come out 10 years ago, this might be something we'd be using all the time. We would be.

I think that this is a real, big advance and I am very encouraged by it. I think this is a bigger advance than having maraviroc, the new CCR5 inhibitor, come out. I think this is a novel, new class of drugs. This is going to be a workhorse of a drug in various situations. There's some exciting data, and some theories about how this integrase inhibitor Isentress works and what it can do to decrease the virus in different parts of the body. I think there's going to be a lot more work done with that.

So, I think overall, at this early point in its history, it's an exciting development. I'm looking forward to studies that examine this drug in different circumstances, including people with much less drug exposure in their past.

Dr. David Wohl, thank you very much.

It's my pleasure.

To read more about Isentress, browse through's collection of articles.


  1. Cooper D, Gatell J, Rockstroh J, et al, for the BENCHMRK-1 Study Group. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Oral 105aLB.
  2. Steigbigel R, Kumar P, Eron J, et al, for the BENCHMRK-2 Study Group. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Oral 105bLB.
  3. Markowitz M, Nguyen B-Y, Gotuzzo E, et al, and the Protocol 004 Part II Study Team. Rapid onset and durable antiretroviral effect of raltegravir (MK-0518), a novel HIV-1 integrase inhibitor, as part of combination ART in treatment HIV-1 infected patients: 48-week data. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB104.
    View slides: Download PowerPoint

Download the audio file