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A Closer Look at Raltegravir: An Interview With David Wohl, M.D.

October 23, 2007

Listen to full interview (16 min., 6.3MB MP3)
On Oct. 12, the U.S. Food and Drug Administration approved raltegravir, which was known throughout much of its development as MK-0518, and is now known by its generic name raltegravir, brand name Isentress. Raltegravir is the first approved member of a new class of antiretrovirals known as integrase inhibitors.

David Wohl, M.D., associate professor of medicine at the University of North Carolina-Chapel Hill, and co-director of HIV services for the North Carolina Department of Corrections.

To learn more about raltegravir and its potential impact on the treatment of HIV-infected patients, I spoke by phone 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. In the interest of disclosure, I should note that Dr. Wohl has participated in research on raltegravir, and has also received research funding from Merck & Company, which developed raltegravir.

Background

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Tell me about raltegravir. How does it work, and why is it so exciting?

I think most people will appreciate that raltegravir is a drug that is in a completely new and novel class of antiretrovirals. This is an integrase inhibitor, so it prevents -- or inhibits -- the ability of viral DNA to integrate into the host genome, and that's a very crucial step. It's been a target of investigation for quite some time, yet until now we hadn't really seen a compound that could achieve the feat of preventing viral DNA from integrating into host DNA without nasty side effects. I think now that we have a compound that is effective and well tolerated, it's exciting.

It's also nice because whenever we get a new drug in a new class, we're excited. The first thing we think about is all those people who've been exposed to drugs of other classes who've run out of options. The appropriate response is to consider the drug in treatment-experienced patients, and that's exactly how raltegravir has been studied, and how it's been approved -- that's its indication. I think it gives a new lease on treatment life to many of our patients who have exhausted many of their options. This is exciting, and I think there are many properties of the drug that are exciting and novel, and that may allow us to be even more creative in our treatment of HIV.

Adverse Effects

Have studies so far indicated anything about adverse effects, drug-drug interactions -- any kind of red flags at all?

I think that the studies to date indicate several things. One is that raltegravir is a pretty potent agent; I think that we're learning, as we've learned for every single drug we've studied in a salvage situation, that it can't do it alone -- that, when combined with other drugs that are active or semi-active against a patient's virus, that it performs better. We've seen this time and time again, whether it's with darunavir [TMC114, Prezista], whether it's with tipranavir [Aptivus], whether it's with enfuvirtide [T-20, Fuzeon]. When you have a critical mass of active agents, duh, the virus is suppressed.

Same thing with raltegravir. The BENCHMRK1,2 studies: We saw that when raltegravir was taken with darunavir, it did better; when it was taken with Fuzeon, it did better. If all three were taken, it did even better.

I think that this is really good news; I think it fits in with the pieces of the puzzle that have been emerging for awhile: When you have more active agents, therapy's effective. Now we have another agent we can use, to reach for, when crafting a potent regimen to which the virus should be susceptible. No one should have a lot of integrase inhibitor resistance.

This is a very exciting development that we now have an entire new class of medicines to reach for when trying to make combinations that a person can use to suppress their virus, even if they've developed resistance to most of the existing drugs in different classes. So I think that's exciting.

As far as side effects, it seems to be a very well-tolerated drug. The drug has been studied most extensively in treatment-experienced patients -- quite extensively treatment-experienced patients -- who are more ill than your average treatment-naive subject. So you've got a mess of drugs in people who are not as well, so you're going to see a lot of background side effects and toxicities and adverse events.

To date, the signal that we're seeing is maybe some GI [gastrointestinal] intolerance, and that goes with every HIV medicine. There's been CPK [creatine phosphokinase] elevations seen, so that's another thing we'll just have to keep an eye on in post-marketing surveillance. Some suggestion that there may be increases in malignancies; again, hard to tease out from background instances of neoplasms in this population. So I think the post-marketing period's going to be pretty important for this compound, as it is for all these compounds that have limited clinical trial data, and then it will be widely used.

Drug-Drug Interactions

The drug-drug interactions are going to have to be worked out better, too. We know that Norvir [ritonavir] can increase the level of raltegravir, but it doesn't require Norvir at all, so I think that's a very positive aspect of raltegravir as well: It's not a drug that will need to be boosted. I think that freedom from Norvir pharmacological boosting is another positive aspect of this medication.

Overall, I think that there are some interesting things about this medication. It seems to have fewer drug interactions than maybe some of the other drugs we've seen. Proton-pump inhibitors and such, that's not known to be a problem with this medication. I think we'll learn more about that, but boy, I think at this point, if you're a person who's HIV infected and running out of options, this is good news.

First-Line Therapy Potential

It's good news for those running out of options, but how about treatment-naive patients? I know there was a study presented at IAS 2007 in Sydney,3 which wasn't a head-to-head comparison, exactly, of efavirenz [Sustiva] and raltegravir, but it did seem to show that -- virologically, at least -- raltegravir had a quicker viral suppression rate than efavirenz did. What does that potentially mean for first-line therapy?

What we saw in Sydney were more data from a study that we've seen data from previously. It's a relatively smaller study, in which raltegravir was administered to patients who were treatment naive at various doses, compared to efavirenz. You're right; early on there was more rapid viral decay with raltegravir than with efavirenz. But after a few weeks, it all caught up and was about the same. So I think that's an exciting observation, one that would have to be borne out by further study, to make sure that: a) it's real, and b) it has any ramifications for clinical care.

Some people are really interested in looking at what does that mean, in terms of viral reservoirs, and is there something going on with raltegravir that's different than other drugs in that regard. But you're right, it did go toe-to-toe with efavirenz, which is not an easy thing to do, and it came out looking good. Now, this is not a large -- 700-, 800-person -- clinical trial; it's a smaller study. But it's a good indication that the drug may be potent enough to use early on, in that situation.

I think we'll see much better data coming out over the next year or so, looking at people who are treatment naive or nearly so, and those are going to be exciting studies. I totally agree that we'll probably see migration of this medication from a strictly salvage position to earlier and earlier therapy vis-à-vis what we saw with other drugs, such as lopinavir/ritonavir (Kaletra), and what we may be starting to see already with darunavir. I think it's going to be natural, especially given the advantages of the medication, that it doesn't require ritonavir. There are just some people who can't or won't take ritonavir. This may be an excellent option for them.

The other thing, of course, is that we really need more drugs in that sort of second-line position. Right now, when people fail Atripla [efavirenz/tenofovir/FTC], we're not really sure what to do. You may have a 184 mutation, you likely could have a 103 mutation, and it's not very clear what to do in that next slot. This may fill a niche there. It requires further study, but I know that HIV providers are a very clever lot of clinicians and it doesn't take long for them to start applying HIV medications in creative ways.

Drug Resistance

Speaking of sequencing and resistance, how does the resistance profile of raltegravir look?

Again, a lot of it's very early and we're all looking at the same limited data. It does seem like in vitro, resistance can be cultivated, of course, and it doesn't seem like the drug suffers from as low a genetic barrier as the non-nucleosides, but it doesn't seem to be as resistant to resistance as boosted protease inhibitors. So maybe it falls somewhere in between.

Again, I think there'll have to be more data to look at this, for us to understand this better. So probably, if you feel comfortable using efavirenz, you won't have much trouble with the genetic barrier that raltegravir has. I think most of us are comfortable with the genetic barrier trade-offs of efavirenz, given its other features. I think that that is one aspect of raltegravir that is a quantity that will have to be better understood, but that I think we can accept, even if that turns out to be the case.

If you do get resistance to raltegravir, there could be cross-resistance to elvitegravir [GS 9137], another integrase inhibitor that's being developed, so that could lead to issues of sequencing. I think that has to be worked out as well. Apparently, there are different pathways of resistance for integrase inhibitors, and depending upon which way the virus goes, you may or may not have cross-resistance to other drugs in development in the class. Again, I think that has to be worked out a little bit better.

Utilizing Raltegravir in Clinical Practice

Are there any other looming questions about raltegravir that you personally would like to see addressed in the near future?

Like you mentioned before, I think seeing the drug performed earlier in therapy is going to be key. I'm excited about the possibility of this ritonavir-free compound being used with other drugs, and seeing if there could be some synergy with combinations that may be very novel and different than the way we've approached HIV therapy before. As I mentioned before, is there a role of something like raltegravir in second-line therapy after non-nucleoside failure? Where does this fit in as far as sequencing?

I think right now, we're just going to see the linearity of sequencing is going to change. We're not going to be always thinking of, "First this drug, then that drug, then that drug." We're going to see a lot more branch points, wherein you start with one thing, and if that doesn't work or that fails, you don't have just one path to go down, you have several paths to go down, and they're almost equally attractive.

That can cause us some angst, because, "Oh my god, we're not knowing exactly what to do. I have to make a decision." That's OK; I think we have to get comfortable that the field has become more crowded, there are more options, and that can only be a good thing if we don't become intimidated by the choices.

So I think it won't be clear cut, and the people who like cookie-cutter and like guidelines get very nervous when we don't know what to do next. I think it's hard to do a clinical trial for every situation, and there will be times when we'll have to decide, "Do I put them on a boosted protease inhibitor? Do I put them on raltegravir?" I think we have to figure out what other drugs we're going to use with raltegravir. This may be an opportunity to break free of the whole notion of two nukes plus a third anchor drug, and people are really actively thinking a lot about this.

In the beginning though, of course, just as we saw with other drugs such as lopinavir/ritonavir and we're seeing with darunavir, we're going to use this in treatment-experienced patients and see how it goes. After we get comfortable, then I think you'll start seeing us using the drug in different circumstances, fed by clinical data that I know are going to come out.

While we're in this "uncomfortable" phase, what would be your advice to a clinician who's seen the approval of darunavir, maraviroc [Selzentry in the United States and Celsentri elsewhere], and now raltegravir just over the course of the past couple of years, and might be jittery about trying to determine the best way to combine all these drugs in a salvage regimen?

Well, with salvage, my approach is, you have less and less to lose. You've got a very dangerous virus that's not suppressed, and people are often symptomatic from that or will be, if you don't do something about it. So I think I'm more aggressive in trying to combine these drugs.

Again, the data we see is that when we combine drugs that have activity against the virus, the success rate goes up tremendously and fantastically in the BENCHMRK studies. So I have not too much concern about combining some of these medicines. In BENCHMRK alone, we did see enfuvirtide and darunavir and raltegravir used together in a small group of people who did wonderfully, so I'm not too worried about it.

The whole maraviroc thing, that might be a whole separate podcast, to discuss that medication, and how that's going to be factored into this. I think that's a complicated discussion, but I think that in most of our patients, we feel comfortable -- when they really are pushed up against a wall, with low CD4 counts and unchecked viremia -- that we may have to be somewhat creative. But I don't think we're in a vacuum; I think we have data that consistently show us that when we combine regimens, as long as there's no obvious pharmacological interactions of concern, that we can get good results.

Dr. Wohl, thank you so much.

It's my pleasure, thank you.

References

  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.
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