One-on-One with Joe Eron, M.D.
An update on Isentress (raltegravir) data, including some unexpected results
Interview by Jeff Berry
Jeff Berry: I wanted to go over the Isentress studies presented at this year’s CROI, including the cancer data.
Joe Eron: The results of the 96 weeks of BENCHMRK are very encouraging. What we saw is that for the proportion of individuals whose viral loads were suppressed to less than 50 at 48 weeks, that proportion persisted quite well through 96 weeks. Given the high level of resistance that many of these patients had, many of us were concerned that the suppression wouldn’t be sustained. Many of the things we learned from the 48-week data were reinforced; for example, people who had two additional active drugs had the highest level of suppression and that high level of suppression was sustained. The other worthwhile point is there were no really surprising new toxicities that emerged between week 48 and week 96.
There was also a poster here presented by Jeff Lennox, on the STARTMRK data, that looked at multiple different sub-analyses of the 48-week data. STARTMRK is the study that looked at raltegravir compared to efavirenz [Sustiva], both with Truvada in treatment-naïve patients. Again, I think that study’s very easy to summarize—they looked at many, many different baseline characteristics such as age, race, gender, and area of the world, and really showed that there were very, very similar results regardless of how you stratified the data. They also included stratifications for baseline CD4 cell count and baseline viral load, and in all of the analyses the proportion that suppressed on the raltegravir arm was very, very similar compared to efavirenz.
You mentioned the cancer study. Originally, when the results of the BENCHMRK study came out, there was a suggestion of numerically more cancers in those patients treated with raltegravir. The cancers occurred relatively early, which would make you think it was a little bit harder to figure out anything causal. We also observed diverse cancer types, and if you talked to oncologists, all those different cancers have different mechanisms, so you would think that the relationship probably wasn’t due to the drug. But there were numerically more and people were concerned.
Now that Merck has even more data from BENCHMRK, now they have all the data from STARTMRK, and they have long-term follow-up from their Phase 2 study of raltegravir in treatment-experienced patients, I think now they have very convincing data that raltegravir is not associated with malignancies.
The SWITCHMRK study is actually two identical studies, just like BENCHMRK. I think that’s the harder one to discuss and explain because it doesn’t have a simple answer and in part because, literally, we just got the data right before Christmas on one of the two studies, and we didn’t get the data on the second study until between Christmas and the presentation.
Each SWITCHMRK study had about 350 patients, so a total of 700 patients, and they were randomized, double-blind, placebo-controlled studies where patients who were stable on a lopinavir/ritonavir [Kaletra]-containing regimen and [nucleoside] reverse transcriptase inhibitors [NRTIs], were randomized—remember, in a blinded fashion—to either stay on their lopinavir/ritonavir plus [NRTIs], or switch to raltegravir while obviously continuing [NRTIs]. So the only substitution that was made was raltegravir for lopinavir/ritonavir in a randomized way.
If we cut to the chase, the patients who switched to raltegravir had an improvement in multiple different lipid values: total cholesterol, non-HDL cholesterol, and triglycerides. This was one of the primary end points at 12 weeks and this was good.
On the other hand, if one looked at the proportion of individuals who had their viral load suppressed at week 24, which was the second primary end point, fewer patients were suppressed at week 24 on the raltegravir arm. The numbers were slightly different between the two studies—in the one study that was done mostly in Europe and the U.S., it was 87% remaining suppressed on the lopinavir/ritonavir arm vs. 81% on the raltegravir arm, so a difference of about 6%. In the other study, it was 94% remaining suppressed on lopinavir/ritonavir vs. 88% on raltegravir, so again about 6% difference.
The numbers are slightly rounded, but on average, it was about a 6% difference in suppression and what we can say, if you look at the two studies independently, is that raltegravir was not non-inferior to lopinavir/ritonavir in that setting and, as was pointed out during the questioning, if you actually put the studies together, then the difference approaches superiority for lopinavir/ritonavir. So that prompted us to ask, “Well, why is that?”
We thought we had so much positive data about raltegravir and it turns out that, if you look carefully at the study design, it’s very different from previous switch studies. The study design was such that patients could’ve had multiple previous treatment regimens, they could’ve even had multiple previous virologic failures. In fact, some of the patients had been on treatment on the order of 16-20 years, so we know those patients had received single and dual nucleosides because we didn’t have HAART 20 years ago. So when we looked at the patients who had virologic failure on the raltegravir arm, we found that for 84% (or 27 out of the 32 failures combined on the two studies), the Kaletra regimen they were on at the start of the study was not their first regimen. So then, if you look at those 27 where it wasn’t their first regimen, two-thirds of those patients actually had documented previous virologic failure on previous regimens, obviously not on lopinavir/ritonavir, but on previous regimens. Now, the analysis suggests that the reason we saw more virologic failure on the raltegravir arm is because these patients with previous virologic failure were likely to have nucleoside resistance.
JB: What does it show you as far as it not being a good idea to just substitute one drug for another?
JE: I think what it tells you is that if you’re going to substitute one drug for another, especially if you’re taking a drug that has a very high genetic barrier, like the protease inhibitors, and you have another drug that you know is very potent, but may not have as high a genetic barrier, you want to be sure that the rest of the regimen is very active.
So, for example, there were other studies presented here and at ICAAC [in October], and at the AIDS meeting last summer where raltegravir was substituted for T-20 and those studies all show a very good result. In fact, there was a randomized study presented here by the French ANRS group showing an excellent result with people randomized to either stay on T-20 or switch to raltegravir. I think the reason for that is that if T-20 is working—and on average, those patients were on T-20 for 2-2.2 years—if T-20 has been working for somebody for 2.2 years, probably the rest of the drugs in that regimen are contributing something, so switching the T-20, the enfuvirtide, for raltegravir maintains suppression.
If I had to guess, and I’m trying to be helpful clinically here, I’m not speaking for Merck or the study or anything but as a clinician—I think if a patient is on their first regimen, and you know, for example, that the nucleosides are fully active because you have a baseline resistance test when the patient has been suppressed, I think it’s likely that substituting raltegravir would be fine. Anecdotally, many of the investigators on these studies have come up to me and said, “Well, at our site we only looked at people who were on their first regimen and it’s our experience that the patients have done very well.”
That’s a little bit biased, right? Because 88% of the patients on raltegravir did fine, so if you only have 10 patients at your site, your impression is going to be that both raltegravir and lopinavir/ritonavir over time did well, so I think you have to be a little bit careful about that bias.
In general, I think if you have uncertainty about the strength of the partner drugs, that you shouldn’t be switching out one drug. The other lesson, I think, is that these were people who were very stable on lopinavir/ritonavir. They didn’t have hyperlipidemia, they couldn’t be on statins or other lipid-lowering agents. 83% of the patients had been on the lopinavir/ritonavir therapy for a year or more, so these people were tolerating the regimen really well and didn’t really have any major toxicities from the regimen.
So, again, I think one has to balance what you’re doing—if something’s working pretty well and it doesn’t have a lot of side effects, the impetus for change should be less. On the other hand, if you have a patient on their first regimen of boosted PI and their triglycerides are sky high and they are having GI trouble or diarrhea or something, then that’s probably a different situation.
JB: So the basic premise is not that switching from a drug that had a high barrier to resistance to one that had a lower one was the issue.
JE: No. There have been studies where people have switched boosted PIs to nevirapine [Viramune]. Nevirapine has a very low genetic barrier, much lower than raltegravir, and those studies, many of them published, have been successful. Or there’ve been switch studies, like the SWAN study for example, where individuals on a boosted PI have been switched to atazanavir [Reyataz] unboosted, clearly going from a higher genetic barrier to a lower genetic barrier, but in those studies, the partners, the other drugs in the regimen were likely to be very active. Most of the drugs that we use are pretty potent drugs, but the key is combining potent drugs. The one exception to that rule is the boosted PI, where we know you can give boosted PI monotherapy and get 75% of people suppressed. That’s different than any other drug. I think they are special drugs, and the boosted PI is a special combination. It has downsides, so you have to weigh the upsides and downsides.
Joe Eron is a Professor of Medicine at the University of North Carolina at Chapel Hill. He has been the Director of the UNC AIDS Clinical Trials Unit for 4 years and was the Associate Director for seven years prior to becoming the Director. He is also the Director of the UNC Center for AIDS Research Clinical Core and the Associate Director of the General Clinical Research Center at UNC.
