July 7, 2007
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Hi Bonnie. It's a pleasure to be here.
Dr. Berger is here to provide us with a sneak preview of some of the noteworthy studies that will be presented at IAS 2007. Dr. Berger, you've had a chance to review the conference program on the IAS Web site, and you've personally been involved with some of the studies that will be presented. What does it look like the big stories will be?
This conference in Sydney looks to be an exciting meeting because a lot of new information will be discussed and presented; I think more so than at previous IAS [International AIDS Society] meetings. In fact, today, July 7, The Lancet published the initial results of two very important studies, TITAN and DUET, but the IAS meeting will be the first time these results will be described during an oral platform presentation, with the results and implications being discussed openly in a dialogue between thought leaders, researchers and physicians.
The TITAN study was the very first randomized, controlled trial comparing ritonavir [RTV, Norvir]-boosted darunavir [TMC114, Prezista] -- the newest protease inhibitor [PI] on the block -- against an older PI, in this case lopinavir/ritonavir [LPV/r, Kaletra], or boosted lopinavir as we usually refer to it.
Boosted lopinavir is what many consider the gold standard in the industry, but darunavir has very much been responsible for creating a new paradigm shift recently in the highly treatment-experienced patient population. The POWER 24,5 study showed that darunavir use, despite a very experienced patient population with multi-class resistance, resulted in, more than ever before, higher numbers of patients achieving undetectability, which we all felt was unprecedented compared to say the RESIST6 trials or the TORO7 studies.
Getting back to TITAN, it was conducted in an early treatment-experienced patient group. It pitted darunavir against lopinavir with the physician-directed optimized background regimen. This was a study that looked for patients who were not as sick as some of those studied in trials of highly treatment-experienced patients. In that regard the treatment-experienced patients were individuals who had at least 12 weeks of HAART [highly active antiretroviral treatment] experience. Patients who had previous or current use of lopoinavir, darunavir, tipranavir [TPV, Aptivus] or enfuvirtide [T-20, Fuzeon] were excluded, again selecting for a less compromised study patient population.
So, according to what has been published in The Lancet, approximately 300 patients were randomized to each study arm. A good proportion, 18%, of patients were black, and 21% of patients were female, so there was a good heterogenous representation, more so than in many other studies, traditionally.
So a quick glance at the study's outcome: The results are nothing short of dramatic. I think that it's going to have important implications, 68% of the patients in the lopinavir group and 77% of patients in the darunavir arm achieved viral load suppression to less than 400 copies. Additionally, when looking at the number of patients achieving viral loads below 50 copies: significant results again. Sixty percent of patients achieved optimal suppression in the lopinavir arm, while significantly more, or 71%, achieved below 50 copies in the darunavir arm.
Similar CD4 count gains were observed in both groups: around 81 cells with lopinavir and 88 cells with darunavir. Various subanalyses were done showing favorable results as well, including subanalyses of individuals with viral loads greater than 100[,000] copies. Similar CD4 count gains were observed in both groups: around 81 cells with lopinavir and 88 cells with darunavir. Various subanalyses were done showing more favorable results in favor of the darunavir arm, including subanalyses of individuals with viral loads greater than 100[,000] copies. Further data evaluating patients' viral load responses in different CD4 count stratifications will also be shown. Another important subanalysis on resistance showed that of the subjects who experienced virologic failure, patients randomized to darunavir compared to those randomized to lopinavir, went on to develop less resistance mutations. In other words, darunavir failure, when it occurred, was associated with less emergence of resistance than lopinavir failure.
We are going to be discussing these again in more detail in a later podcast, but suffice it to say that darunavir looked very good in terms of this type of patient population. In fact, the TITAN study, by demonstrating that there are real differences between lopinavir and darunavir, it really helps us to distinguish between what is the best therapy for patients who failed their first regimen or their first PI. Darunavir has the potential to change sequencing strategies not just for patients with triple-class resistance, as demonstrated by the POWER studies, but also for patients who fail treatment early on. And as you all may recall, darunavir only just made its preview into our armamentarium catalog last year, so this is very dramatic.
DUET, the other important study that is also going to be presented at this conference, in late breakers, actually consists of two studies called DUET 1 and DUET 2. DUET 1 and DUET 2 were both conducted simultaneously in various areas around the world, from Europe to South America and the United States. For the purposes of my preview for this short podcast, I'm going to refer to the studies as just DUET and actually only present the data from DUET 1, but I will present and discuss the differences between DUET 1 and DUET 2 in a later podcast at the conference itself.
DUET evaluated the PI darunavir, but this time it was combined with the very first of the second-generation non-nukes [NNRTIs], TMC125, which is also called etravirine. This was a randomized, double blind, controlled study in patients with triple-class resistance -- the usual type of triple-class resistance trials where all patients in the study were administered darunavir.
Three hundred patients were randomized to receive the non-nuke TMC125 and approximately 300 patients the non-nuke placebo. And all the patients were administered an investigator-chosen optimized background regimen. The protocol also allowed for enfuvirtide use.
The results show that at baseline this was a very resistant population, with about 97% having at least three primary PI mutations at baseline and 66% having at least two NNRTI mutations at baseline and over 90% with at least one NNRTI mutation in the TMC125 group. Also, 54% were resistant to all available NRTIs. You can see that this is really a good representative of a very heavily pre-treated group. But despite that, at 24 weeks, results show that 56% of patients achieved optimal suppression of less than 50 copies compared to 39% in the placebo group.
The mean change in viral load from baseline was a 2.4-log drop on TMC125, compared to a 1.7-log drop with the placebo. Also, like other salvage protocols, a statistical benefit was seen in patients also being treated when on enfuvirtide was part of the TMC125 regimen. We will discuss the details of this in our podcast during the actual conference, but, overall, after 24 weeks of treatment, there was a significantly greater proportion of these treatment-experienced patients being administered TMC125 who achieved all kinds of other benefits that included increases in CD4 counts. Other details that will be discussed at IAS will include the prevalence of adverse events such as skin rash and neuropsychiatric side effects that was observed during the DUET studies.
The implications of these results relate to the fact that there are so many varieties of new agents that we can choose to construct a salvage regimen based on first or second generation agents from the NNRTI or PI class, or from entirely new drug classes such as the integrase inhibitors or CCR5s. But because there are so many choices, we really now need to decipher the specific differences between all these agents and need to further evaluate sequencing strategies. DUET is really the very first randomized controlled trial where two of these new agents are being used together, and I think it is going to add to the body of knowledge and guide physicians as to which types of patients would best benefit from darunavir and TMC125 together and whether integrase inhibitors or CCR5 inhibitors should be saved for a rainier day.
Other new agents that are also going to be discussed at IAS 2007 are the CCR5 inhibitors, which were very much in the news over the last year. We really expected one of them, maraviroc [UK-427,857; with the expected brand name of Selzentry], to have been available on the pharmacy shelves by now. But almost from the get-go, watching the development of this entire class has been like nothing short of sitting on a roller-coaster ride at Chicago's Six Flags Great America.
Initially, with the discontinuation of GSK [GlaxoSmithKline]'s aplaviroc [GSK873140] due to unexpected hepatic toxicities, and concerns about this potentially being a class effect, the future of CCR5s was put into question. Then came the concerns about a possible increased risk of malignancies with the use of vicriviroc [SCH 417690; SCH-D] seen in ACTG [AIDS Clinical Trials Group] 5211 -- that's the phase 2 trial. And then we heard other bad news about vicriviroc. In a study that combined that agent with Combivir [AZT/3TC, zidovudine/lamivudine] in antiretroviral-naive patients, patients failed therapy due to perhaps the overall combination or vicriviroc itself establishing a too-low barrier for resistance.
But now the malignancy issue seems to have been resolved. It was felt to be nothing more than a red herring. And regarding the failure issues, the dose has been readjusted, so the FDA [U.S. Food and Drug Administration] has actually allowed for development to proceed to phase 3 studying both 10 or 15 mg vicriviroc boosted with ritonavir. Results from ACTG 5211 will be discussed at IAS 2007.
Also, along with this now laundry list of unexpected hurdles with this class, the FDA committee unanimously voted (13 to 0) that maraviroc should be approved. Usually it's then a formality for the agency to officially bestow their blessings and approve the drug. Everyone in the industry expected for that to happen. But on June 20, instead of granting approval, the agency decided to send the drug company that makes maraviroc the cursed approvable letter, which is nothing short of FDA purgatory.
We don't really know what issues the FDA requires to further clarify their evaluation of maraviroc. So we don't really know when it's going to be on the market. I believe that it's going to make it to market, almost certainly. It's just a matter of when that's going to happen.
I think the Wall Street Journal noted that it was going to be in October, possibly.
Usually, Bonnie, when the FDA has put something on fast track, there's a rush, on the part of the drug company to get all the data together and get their application together very quickly. And there's pressure on the part of the agency to evaluate. But once the FDA sends them that approvable letter, then there's no more pressure; the FDA can take its time. And so it could be a week, it could be six weeks, it could be a few months. Any amount of time is a long time for a company to be sitting and waiting. But we just have to wait.
However, although it's bad news for the drug company that the drug isn't approved, it's good for patients that the agency consider safety and/or efficacy issues -- that they ensure patients should be able to be administered this medication 100%, with as much safety as possible. Also, maraviroc is on expanded access, and so patients can still get access to the drug, even though it's not approved.
One of the other important points about maraviroc not having been approved is that many clinical trials, especially trials of salvage regimens, have placed maraviroc within their trial design. So, by not having maraviroc approved at present, this may hold up the start of those clinical trials, and in fact, some sponsoring pharmaceutical companies may also want to redesign their protocols, and that might lead to further holdups.
One other drug that I think is very important and will be discussed at the conference is TMC278, which is a new NNRTI. At CROI 2007 [14th Conference on Retroviruses and Opportunistic Infections] they presented 48-week data from this phase 2 study.8
TMC278 is now called rilpivirine. But TMC278, in that study, was combined with Truvada [tenofovir/emtricitabine, TDF/FTC] or Combivir, and it showed very comparable efficacy to the gold standard non-nuke, efavirenz [EFV, Sustiva, Stocrin]. At CROI, it was very interesting, because the TMC278 compound showed less CNS [central nervous system] side effects and less rash than Sustiva. But metabolic parameters such as effects on lipids and body habitus changes -- which are becoming more relevant to daily practice as our patients live longer -- will be talked about at IAS 2007 in detail. And that will be very interesting to hear about.
So that's my summation, in terms of new drugs, during this Sydney conference.
I thought you were going to mention MK-0518 [raltegravir], of which there's one study, I believe.
Yes. There's one presentation. It will be a continuation of the initial presentation on MK-0518 that was presented at Toronto9 of a small cohort of patients who were naive to antiretroviral therapy and who were treated with this Merck integrase inhibitor MK-0518. At IAS 2007 we'll hear about the 48-week data. It's important to note that, while this is a small trial, Merck is actually conducting a very large phase 3 trial with MK-0518 in treatment-naive patients.
What was the other subject that you thought was interesting?
I think that there's going to be a new test that's going to be available to physicians, hopefully. It's called the HLA B5701. Abacavir [ABC, Ziagen] is associated with the development of severe hypersensitivity reactions, or for short, abacavir HSR. This usually manifests within the first six weeks of treatment, but most of the time we see this in patients after seven to nine days of treatment. Because of this, physicians have been reluctant or hesitant to prescribe abacavir.
For one of the first times in modern medicine, actually, we get to witness an emerging field of pharmacogenomics, where we use a marker within a patient's specific genome to actually predict the propensity of developing a problem -- in this case, abacavir HSR.
PREDICT will be presented as a late breaker. It's a very large prospective trial that was conducted in Europe. It's a double blind study where more than 1,700 patients were evaluated for HLA B5701 pre-therapy screening.
In other words, patients that were going to be started on treatment with abacavir either were randomized to having the screening of HLA B5701 done versus not having had it done. Among the people that were being screened, if they were found to be HLA B5701 positive, they were excluded from participating.
If the study shows a very high negative predictive value -- meaning that we can predict whether it's going to be safe for the patient to be on treatment and we can easily avoid the HSR -- then it may alter, or even reverse, many physicians' inhibitions about prescribing abacavir, and/or its coformulation, what we call Epzicom [abacavir/lamivudine, ABC/3TC, Kivexa].
The SHAPE study was conducted here in the United States. It was a retrospective study and it evaluated the presence of the allele, HLA B5701, with HSR. Being retrospective, they looked at the individuals, both white and black patients in the United States, that had a history of this HSR reaction. It also evaluated a skin patch test for its ability to confirm the immunological cause and association with the HSR symptoms.
So these are completely new tests, but while the patch test was a research tool, the HLA blood test is one that physicians could use to be empowered to ensure the safety of their patients, prior to putting them on abacavir or Epzicom. In modern medicine this hasn't really been seen before and I think this is very important.
Has the insurance coverage of HLA testing been worked out?
I think it will be covered by insurance because we do HLA typing before transplants. As a rheumatological disease marker, HLA typing is used. From what I have heard, there have been some investigations, looking at some of the major labs running the tests, the costs, and whether some of the carriers will be covering the tests. So far we won't know for sure, but the indicators are that the tests will be covered and will not be terribly expensive -- perhaps around $100 a test.
I noticed that some subanalysis of the SMART12 study will be presented at IAS 2007.
Bonnie, you picked really an excellent topic. One of the most important studies -- also, maybe winner of the most surprising results competition -- last year was the SMART study. As most of you will recall, SMART was a big randomized prospective trial of more than 5,000 patients; it began in 2002 and was conducted by CPCRA, or the Community Programs for Clinical Research on AIDS. It looked at patients with CD4 counts greater than 350 cells, to be on either continuous HAART versus episodic treatment. Meaning the episodic treatment subjects had treatment discontinued when their CD4 rose to 350 or greater, and reinstituted when their CD4 counts fell below 250.
One of the driving forces of this study was a very real world perspective: that is, patients live longer. It seems impractical to expect our patients to continue to consume mountain loads of pills daily, for years and years. Hence, they felt that it would be important to evaluate and construct a specific type of drug holiday in this way.
But, although the patient population was fairly healthy at baseline, the study was halted prematurely by the DSMB, or the Data Safety Monitoring Board. The study was stopped due to the unexpected observation that patients on episodic treatment had an increased risk of death and a greater number of opportunistic infections, as well as greater problems with cardiovascular, hepatic and renal-associated effects.
So we still have a lot of data to tease out about this SMART study. The subanalyses that are going to be presented at IAS 2007 are going to study or discuss opportunistic complications and mortality issues that were specific to patients that were coinfected with either hepatitis C and/or hepatitis B in the SMART study.
Also, another presentation, discussing high rates of required re-initiation of treatment during the SMART study among the patients that were hepatitis B coinfected, is also going to be talked about.
It will be very fascinating to find out the results of those two analyses.
I think so. I think it's important that the clinician who is faced more and more with hepatitis coinfection in practice learn how to manage those patients. And if there are greater chances of coinfected patients who go on a drug holiday having increased medical problems, we need to know about this.
You know, hepatitis coinfections continue to be on the rise, and we have been seeing and confronted with lots of questions and challenges. They include when to start patients on hepatitis C treatment and whether to start people on HIV treatment first or hep C treatment first. Patients with hepatitis C have decreased tolerability to antivirals, and they have also a higher risk of progression to endstage liver disease. So it's been very complicated. And actually, there's going to be an entire session at IAS 2007 devoted to hepatitis coinfection.
As I said, it's very important, because not only is the prevalence rate becoming high, especially in the men having sex with men population, or MSM population, but, due to factors since the advent of HAART, there's less regard for safe sex practices, which has also led to an upsurge in STDs [sexually transmitted diseases]. Additionally, crystal meth use among MSMs has also had a devastating effect on the HIV epidemic -- not just regarding the additional HIV seroconversions that we're seeing in younger patients, but also in hepatitis C coinfections.
In fact, in 2005 the Swiss COHORT study13 showed an increased incidence of hepatitis C coinfection from collected data of more than 1,500 MSMs that were HIV positive and who were initially hepatitis C negative and who didn't have any association to injection drug use.
Another trial that was also published around the same time period showed approximately more than 40% seroconverted to hep C among HIV MSMs. So physicians involved in the care of the HIV population and MSMs need to be vigilant for abnormal liver enzyme levels, perform regular hepatitis C virus and B virus screening, incorporate the screening during testing for STDs, and have a high index of suspicion if patients are using crystal meth.
In terms of taking drug holidays, like we talked about with the SMART study a moment ago, it needs to be reconsidered as to whether patients that are coinfected would be safe, in fact. Because, again, we saw a much higher rate of cardiovascular, renal and liver problems among all the patients [in the treatment interruption arm of the SMART trial]. We'll hear during the conference as to whether there were any specifics regarding this coinfected population.
That's a pretty surprising study, and will have implications in the clinic.
Unfortunately, patients using crystal methamphetamine don't openly admit it to their physicians. They are very expert on being able to hide their addiction. So if it's not part of routine testing, you are often not going to see it. As I said, it has really grave implications. And not just for liver problems, as we saw in the SMART study; but we don't know whether it could have been one of the reasons why there is an increase in heart disease problems, or cardiovascular disease. That's another thing that's going to be talked about during the conference.
One of the trials that will be presented -- since it's been so controversial as to whether there is, in fact, an increased risk of cardiovascular disease for patients on HAART, especially since we're seeing hyperlipidemia problems -- comes from Brazil, a Brazilian cohort. The title of the presentation is "Increased Risk of Cardiovascular Disease and Diabetes."
Then there's a presentation on endothelial dysfunction. Endothelial dysfunction is felt to be a marker. It's a prior event that occurs before atherosclerotic plaque develops. Endothelial function is actually easily measured through ultrasound. It's a noninvasive test looking at the flow dilatation in the brachial artery. We're going to hear about the effects of HAART and endothelial function. That's just another added attraction during the conference.
So I think that this conference is shaping up to be a very interesting meeting.
Well, I think you have given a great overview. We look forward to hearing from you daily at the conference, and hearing what you think of each daily presentation. Thank you very much, Dr. Berger.
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