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ICAAC 2007: Chicago, Illinois; September 17-20, 2007

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The Body Covers: The 47th Interscience Conference on Antimicrobial Agents and Chemotherapy
ICAAC 2007 Study Summaries: An Interview With Roy Gulick, M.D., M.P.H.

September 18, 2007

Roy Gulick, M.D., M.P.H.
Listen (5MB MP3, 12.5 min.)
Welcome. This is Bonnie Goldman, Editorial Director of The Body PRO. I'm in Chicago at ICAAC 2007, one of the year's HIV conferences. Right now, I'm in the poster session where researchers are standing in front of their posters. There's nothing like hearing the results of research directly from those who actually conducted the research. It is these women and men who are transforming HIV treatment and care. In this podcast, the researchers will introduce themselves and then summarize their study. After their summary, I'll ask a few questions.

I'm Roy Gulick from Cornell in New York City. And this is a poster1 about vicriviroc [also known as: SCH 417690, SCH-D], which is an investigational CCR5 inhibitor. The prelude to this poster is that we did a randomized trial2 in the ACTG [AIDS Clinical Trials Group]. Heavily treatment-experienced patients. All were documented to have R5 virus. Then we randomized them to receive either placebo or one of three doses of vicriviroc, in combination with an optimized background regimen. At the time the study was done, many of the newer drugs were not available for the optimized background. So, while nucleosides, protease inhibitors, and T-20 [generic name: enfuvirtide; brand name: Fuzeon] were available, darunavir [brand name: Prezista; also known as TMC114], tipranavir [brand name: Aptivus; also known as TPV], and integrase inhibitors [like raltegravir (also known as: MK-0518)] were not available.

We randomized people and followed them along. The two highest doses did the best in terms of suppressing virus over time. We stopped the lowest dose early because of suboptimal antiviral activity.

At the end of 12 months, that study was completed, and that's where this study picks up. So, this was a single-arm study. All patients were changed to 15 mg of vicriviroc, which is the highest dose tested. This allowed continued access to this investigational drug over the course of an additional year and a half. This is a single-arm study for all of those patients who were able to complete 48 weeks of the ACTG study and continue on.

The purpose here was to look at the long-term durability, both the viral load effect and the CD4 effect, to continue to assess changes in tropism, and to look at safety. What we see here is that patients who were taking a vicriviroc regimen for up to another year and a half had nice suppression of their viral load levels -- 2¼ to 2½ log decreases that were durable over 18 months. CD4 cell increases were also durable. We see about 100-cell durable increase over the course of the next year and a half.

We did see six patients who had changes in tropism from R5 to dual/mixed. Patients were allowed to continue the drug, even if they had a tropism switch, if their clinicians felt that they were benefiting. That is, they continued to have virologic suppression and CD4 increases. Five out of the six continued to do well, despite switches in tropism.

In terms of safety, there has been concern from this study about malignancies. We saw, over the next year and a half, two additional malignancies, both of which were skin cancers. So no other lymphomas or other visceral malignancies were reported.

Our conclusion is that in this small number of patients, vicriviroc in combination with other agents in treatment-experienced patients provides durable virologic and CD4 activity, and appears to be generally safe and well tolerated.

Are the malignancies thought to be a result of the treatment-advanced nature of this patient population?

We described diverse malignancies, including four lymphomas, on this study in a small number of patients. It was only 118 patients exposed. That raised concerns early on as to whether this could be related to the drug. The drug binds an immune receptor, so there was biological plausibility that if you are binding an immune receptor, potentially you could increase the risk of tumors developing. But it was a small number of patients, and they were treatment advanced.

We reviewed this with an independent committee who concluded that we really couldn't tell causality from the information that we had. But that raised a red flag, and so all CCR5 inhibitor studies have been looking at malignancies in trying to assess whether they occur more frequently over time.

The other drug, maraviroc [brand name: Selzentry, Celsentri; also known as: MVC], which was just approved, saw no increased malignancies in its large phase 3 studies. So the malignancies we saw ... probably the best guess is that they were related more to the patient's stage of immune suppression, rather than to the drug itself, but we have to keep an open mind.

How does this drug differ from maraviroc?

In a couple of ways. One is that it's once daily, and maraviroc is approved twice daily. The second is more of a metabolic issue, that maraviroc is a substrate for the Pgp [P-glycoprotein], like a protein pump, which pumps drugs out of cells. Vicriviroc is not a substrate for that. Otherwise, hard to tell big differences.

Were there any plans to study this in treatment-naive people?

There was a treatment-naive study of this, which was two nukes versus three doses of vicriviroc, and the control arm was two nukes and efavirenz [brand name: Sustiva, Stocrin; also known as: EFV]. That study was stopped early because of suboptimal antiviral effects in the vicriviroc arms, particularly the lowest two doses. And so that study was stopped.

I should also say that another study has increased the dose of vicriviroc. The current dose that's going forward in the phase 3 studies is actually 30 mg a day, with ritonavir [brand name: Norvir; also known as: RTV] boosting. So that's greater than what we used in this study, which was 15 mg.

There are no notes here about the study population and their characteristics. Was this an older group of people?

No, not particularly older. The reason that it's not spelled out here is that this is a continuation from a published study, which is available in the Journal of Infectious Diseases,2 published in July of this year.

Is there any understanding of why tropism changes?

Yes. The feeling is that most people are infected with two different kinds of HIV: one that's tropic or binds to R5 receptors, and the other that's tropic or binds to X4 receptors. Probably most people have a combined population. Some viruses combine to both receptors, so we call those dual-tropic. If you have R5 and X4 members of a big population, you're called mixed-tropic. If you use an R5 receptor inhibitor, you're only going to affect viruses that bind to the R5 receptor. If you have a mixed population and you get rid of the R5, you're left with the X4.

Is there a moment that someone would switch? They would start R5? Why would that population grow at that moment ... because of failure?

Part of this is an effect of the test that we have to look at tropism. That can only detect down to 10% levels. So if a person has 91% R5 and 9% X4, the current test that's used, the Trofile assay, will say that they have R5-only virus. So they'll miss up to 10% of minority species. If you eliminate all of the R5 virus, then you're left with the X4 virus. It looks like the most common mechanism of failure with these drugs is actually the emergence of X4 virus.

Do you think that, regarding the CCR5 inhibitors, a lot of physicians will be able to handle the new tropism assay and all of the things that go with it? It's just a whole new kind of ballgame, in terms of treating people with HIV.

Right. It's a brand new class of drugs. The 23rd antiretroviral approved was maraviroc, the first CCR5 inhibitor. It's the first one to target the host, rather than the virus. So it does present new challenges. Clinicians will have to learn about tropism: what it means, how to test for it, what the limitations of the test are. Then we really have to think about resistance to these compounds in a different way. We're not talking about the virus changing, in a sense, but we could be talking about changes in the host cell receptors, or changes in the virus's ability to recognize those receptors. Fortunately, HIV docs are used to dealing with lots of new concepts, but this whole class of drugs brings up a lot of new things to know.

Is there a lot of resistance data on this drug yet?

No, nor on maraviroc. We're still really learning what resistance means. As I said, the most common way that these drugs appear to lose efficacy is a switch in tropism, which is really just emergence of a preexisting X4 population.

How frequently will a tropism test have to be preformed when somebody is taking a CCR5 inhibitor?

We don't know, clinically. Certainly, you'd want to screen any patient who is eligible for an R5 inhibitor to show that they had R5-only virus. We do have clinical trial data to show that if someone is dual/mixed, you would not want to use an R5 inhibitor in that person from the beginning because it doesn't have an antiviral effect. Once a person's on [an R5 inhibitor] -- your hope with designing a regimen is not just using the R5 inhibitor, but at least one or preferably two fully active drugs, and then suppressing someone to the level where you can't test for tropism.

What you want to do, your ultimate goal, is to get people below detection and keep them there. That should prevent failure of the drugs.

So as long as there's no failure, there's no need for a tropism assay?


Right now ... so far.

That's it. If you're suppressed, then you can't actually amplify the virus to study, to see if there's a tropism switch. So you assume that they haven't switched.

So if there is virologic failure, would you do a tropism assay? Or, you don't even need to, because you would guess ...

That's a debate in the field right now -- what you just said. Should you do one and show that they are dual tropic? Or should you just assume that they are dual tropic and that there's no value to doing the test? We don't have any data to tell us what to do.

Are there any studies out there to look at that?

I should say our study actually did follow people longer term, and sees what happens after you switch to dual/mixed virus. And again, in those cases, the five patients shown there [on the poster], people continued to do well despite having dual/mixed virus. Again, that may just be that we have eliminated all the R5, and the X4 is now detected. But it looks like people continue to do well, but we need more than just these cases to be able to conclude that.

Because it's only five people.

Right. Maraviroc studies have also looked at the same question, and really shown that even after failure, people continue to express CD4 increases. So what does that really mean? I don't know. It's going to take more study.

Thank you very much, Dr. Gulick!


  1. Gulick R, Haas D, Collier AC, Lennox J, Parker C, Greaves W. Two-year follow-up of treatment-experienced patients on vicriviroc (VCV). In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago, Ill. Abstract H-1030.
  2. Gulick RM, Su Z, Flexner C, et al, and AIDS Clinical Trials Group 5211 Team. Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-infected, treatment-experienced patients: AIDS Clinical Trials Group 5211. J Infect Dis. July 15, 2007;196(2):304-312.

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