During the 14th Retrovirus Conference I had the opportunity to sit down with Dr. Joseph Eron, Associate Professor of Medicine at the University of North Carolina-Chapel Hill, and one of the investigators for BENCHMRK-2. Dr. Eron graciously took time out of his hectic conference schedule to talk in-depth with Positively Aware about raltegravir as well as some of the other new drugs that will soon become available, and what it all means in terms of new options for both treatment naïve and experienced patients.

Berry: Could you give us an overview and some of the highlights from BENCHMRK-1 and 2?

Eron: The overview and some of the big picture results are that in very highly treatment-experienced patients, Merck’s integrase inhibitor raltegravir—as it’s now called—added to other HIV drugs was significantly better than the background therapy of HIV drugs combined with placebo. These are 16-week results and, while it’s a planned analysis, it’s kind of an early analysis. Three-quarters of the people in both studies, however, got below 400 copies, compared with approximately 48% in the placebo arm. This is highly statistically significant. The other important thing to point out is how well tolerated raltegravir was compared to placebo. There is a very long list of potential adverse reactions, but there was a kind of similar response between placebo and raltegravir.

B: Wasn’t there one AST (liver enzyme) that was elevated in one group?

E: Yes. I think it wasn’t really consistent across the two studies. It was different in one study and kind of flipped around in the other study, so I think it was really generally stacking up as being very well tolerated. The other factor that we’re learning, or we keep relearning, is that when the integrase inhibitor was combined with more active agents, we saw an even better effect. This was broken down very nicely for us in this study.

B: These were people who were new to darunavir [Prezista] or enfuvirtide [Fuzeon]?

E: Yes. We did a subset analysis that looked at patients who were receiving enfuvirtide for the first time, receiving darunavir for the first time, and also got the Merck integrase inhibitor. Again [it’s] a subset analysis, so these are smaller numbers, but 98% of those people were less than 400 [copies/mL], which is really kind of remarkable. If you look at the numbers, it means just one person in that group of 44 people didn’t get less than 400. And that’s with a typical “missing equals failure” analysis where dropouts, or toxicity dropouts, would be included as failures, so I think it’s pretty encouraging. And then if you look at the breakdown, if they were naïve to enfuvirtide and got it and didn’t get darunavir but got the integrase, it was about 90% [below 400 copies/mL], and the same if you flipped it around. I think what it’s telling us is that as clinicians, we need to keep our eye on the ball and make sure if we’re changing therapies for our patients that we’re actually combining active drugs. It’s great to have an exciting new investigational agent that works by a new mechanism, but we need to pay attention and make sure the background is solid behind this drug.

I think that’s why people like Dr. Mellors are saying that we are in a different era.

B: Dr. John Mellors talked about these new drugs, including maraviroc, as marking a “milestone” in the treatment of HIV in resistant patients. Do you feel that way?

E: I think that’s the way that I think about it. If we got less than 400 copies just three or four years ago, even in treatment-naïve patients, we would be very pleased. I think that’s why people like Dr. Mellors are saying that we are in a different era. What these data show is that if you combine this drug with other active agents you see these very strong responses. And then you hear about maraviroc and etravirine [TMC-125] and TMC-278 [Tibotec’s other NNRTI], and while we don’t know for sure, one would anticipate that combining these drugs with raltegravir is going to get the same kind of good result.

B: So you’re “cautiously optimistic”?

E: I’m a little bit cautious, yes. I think we need to see longer-term data. We saw some of the continuation out to 24 weeks, but the whole population hadn’t made it there yet. The studies will extend to beyond 48 weeks as I understand it, so we’ll get the long-term data that we want to see.

Drugs that are easy to administer and are well-tolerated tend to move forward.

B: That was actually one of my questions, because you always hear “48 weeks—don’t get too excited until you get that 48-week data,” and a lot of this data is early. So do you have to keep that in mind?

E: You have to keep that in mind. We are a little bit unfortunate with the Phase 2 data because we are kind of in between meetings. At ICAAC we saw 24-week, Phase 2 data, and it’s a very similar design, though multiple doses, and obviously if there were 24-week data at ICAAC there are now 48-week data for that earlier study available. There just is no venue to present it at because the deadline for this meeting was months ago. So, I’m agreeing with you, I think that what we’ll see, maybe in Sydney in the summer, is some of the more extended data. I do think that if you look at the POWER studies, for example, or even some of the older TORO studies, you’ll see that for the most part, if people got below 400 [copies] or 50 in particular, at 24 weeks, you tended to see similar percentages. In fact, that was also published in the RESIST studies, so we can actually look at three now published studies, TORO, RESIST and POWER 1, where we kind of see that the proportion that is below 50 or 400 at 24 weeks is similar to what was then seen at 48. But I’m a cautious person—I don’t want to extrapolate too far. But you’re right, we want to see the durability of this drug—actually, all the new drugs that were presented.

B: Can you think of any other drug that demonstrated that kind of reduction in viral load in just two to four weeks?

E: Well, the reduction in viral load that was seen with raltegravir and certainly in the treatment of these patients was remarkable. No, I can’t think of another single drug like that. There is published data on etravarine from years ago but it’s hard to make cross study comparisons. I think that drop is really kind of remarkable. And again, it was a little easier to see in the Phase II naïve study; it wasn’t really highlighted in yesterday’s presentation, so I really don’t know how the rate of drop compares. We do know that by two weeks, 60% of the patients are less than 400. I would say that’s remarkable.

B: Pretty remarkable, especially in that there are really no interactions or side effects so far.

E: Right. The fact that the drug is glucoronidated is an advantage and it avoids the potential drug interactions with protease inhibitors, NNRTIs, anti-depressants, and statins. Also, it’s not going to be boosted by ritonavir. The flip side, however, is that it’s a twice-a-day drug. But I think the fact that it is glucoronidated will make it easier to combine with other drugs and we’ll have to worry somewhat less about PK interactions.

B: So, what do you feel is the significance of the fact that it was a highly treatment- experienced group in terms of how the drug will be used in the general population?

E: I can only speak for myself as a clinician. I think that initially we will use this drug in the treatment-experienced population. My experience has been that drugs that are well-tolerated tend to then move forward in the treatment cascade. Drugs that are hard to administer—multiple pills, side-effects, etc., tend to stay in the later salvage. Drugs that are easy to administer and are well-tolerated tend to move forward. So, I can’t predict the future but I think the fact that it is so well tolerated suggests that people might start experimenting with it. But again the data we have here is in a specific population.

B: What about those who have used both darunavir and enfuvirtide? Should they be adding raltegravir to their regimen, or should they be waiting for another active agent?

E: Yeah, I think the most difficult decision in clinical practice now is when to switch therapy in people who are treatment experienced. And I feel very strongly that it is a balance between clinical urgency and making sure you combine your new drug with other adequate drugs. My own opinion is that if someone is clinically stable, then it’s wiser to wait for stronger partner agents. And you could ask, “Do I have a CD4 cell count threshold that I would say, definitely switch?” I don’t think you can be that precise. Though I think if someone’s got a new opportunistic infection and their CD4 cell count is falling, then I think you’re forced to make tougher decisions. I think if someone has a good CD4 cell count, then it only makes sense to wait until you have other new agents in hand. I think that is sensible and the data from the BENCHMRK trials would support that—that it’s better to have other active drugs in the regimen for sure.

My own feeling is that you’re probably better off with more than two active drugs.

B: I’m sure you’ve probably heard from some providers that you need more than two active drugs, that you should have three if you’re failing therapy.

E: Well, I think that the BENCHMRK studies suggest pretty darn good activity with two active drugs, when it was enfuvirtide plus the integrase or darunavir plus the integrase. On the other hand, there are other agents in the background here: they’re getting nucleoside anologs. I think Andy Zolopa asked the question, “What was the average number of drugs in the background?” That’s a question we should ask Merck because I’m not sure those data were presented. My own feeling is that you’re probably better off with more than two active drugs. So I’d be more in the camp looking toward three active drugs, if you have that option. Then the T-20 [Fuzeon] sort of thing comes into play and patients have preferences about T-20. But, again 98% less than 400 with three active drugs makes it tough to argue. It will be great to see the durability in that population. I think if you have them and it’s convenient and it’s safe for the patient, then one should strongly consider using three active drugs. Because that’s what we say for naïve patients, right? We wouldn’t compromise in naïve patients. So, if you have that opportunity for treatment-experienced patients, then that would be one that I would take.

B: What about raltegravir resistance mutations and cross resistance to other agents?

E: What we know is that in this study, so far, there were 71 biologic failures and they were able to genotype 41—I think they just haven’t gotten to all 71 yet and that was part of the presentation. Of those 41, nine did not have integrase mutations. We don’t know if those people picked up a T-20 mutation or a darunavir mutation, we just don’t have the information on those nine. 31 developed integrase mutations and they tend to be on one of two pathways. So, I think what could have been stated more clearly in the presentation is that it’s not one mutation or another; there are typically groups of mutations. There is a 155 pathway and a 148 pathway. Typically what was seen were multiple mutations, suggesting a higher barrier to resistance. There was a presentation by another Merck scientist, John Wai. It was just in vitro work but, in that presentation, he suggested that if you have multiple integrase inhibitor mutations, there is likely to be cross-resistance amongst the two integrase inhibitors that are currently in clinical development. But I’m not a resistance maven, so I’m not completely sure.

B: Any serious adverse events? What should someone taking raltegravir look for or expect?

E: Well, I’ve treated 14 people now and it’s kind of trite to say it’s generally well tolerated, but I think it is very well tolerated. I can’t point to a symptom or a problem either looking at the study or looking at the patients I’ve had the opportunity to care for to be able to say, “Oh, you should expect this.”

B: So you haven’t had any problems with adherence?

E: My experiences with most of the people who have gotten to this super-highly resistant state are usually people who actually listen to their doctor. They’re people who took AZT and then 3TC [Epivir] and then added indinavir [Crixivan]. So my personal experience—outside of the study—is that most of my patients that have extensive triple-pass resistance are actually pretty adherent. My patients who are not very adherent tend to have less resistance; they tend to have NNRTI and 3TC resistance. So, in general, in any of the salvage studies that I’ve worked on, I haven’t had a big issue with adherence. If you look at the TORO studies, and obviously T-20 has a huge barrier to resistance, most of the people in that study who failed therapy had resistance mutations, meaning they were taking the drug. I think that people in highly treatment-experienced settings take the medications. We would have to ask Merck how much adherence data they collected in this study. I don’t remember. It would be good to know, but my sense is that adherence is quite good because tolerability is good. Almost all regimens that we have for these deeper salvage patients are twice daily. If you’re going to incorporate darunavir, tipranavir or enfuvirtide for that matter, all those are twice-daily regimens. We don’t really have a once-daily salvage regimen. Maybe that will come but we don’t have it yet.