Table of Contents
At the 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008), we continue to hear reassuring news and data that the progress we've made with new antivirals, as well as with new tools to use them, and use them well, has borne fruit.
In a study presented to us by a research group from Vancouver, Canada,1 the researchers have been able to monitor essentially all of their patients over time, and look at how well these patients have been doing virologically over the past decade of antiviral treatment. They looked at the results of 21,300 resistance tests that were ordered in several thousand patients over the past decade, to take a look at, first of all: How well are we doing at virologic suppression? And what are we seeing on resistance assays?
The results are pretty striking. A decade ago, there were lots of new cases of resistance observed with resistance testing. In 2007, there was a dramatic decline. Indeed, 2% or fewer of the patients who had resistance testing done showed evidence of drug resistance. We see, in fact, the least amount of resistance with the protease inhibitor drug class in the resistance tests that were ordered. Only eight new cases of protease resistance were reported by the research group.
Perhaps this is not surprising, since the researchers also reported that 85.8% of the patients achieved a viral load of less than 50 copies/mL in an outpatient setting in Vancouver -- a pretty optimistic outcome, and certainly better than the outcome just years ago. When HIV meds work, we don't see resistance. That the HIV meds are working can be attributed to the fact that we have very successful new regimens, and not just for those starting therapy, but also for people who are already on therapy.
Let's review some of the new drug classes, since we saw for the first time at this conference, data about a new CCR5 inhibitor called vicriviroc [SCH 417690, SCH-D]. This is a drug that's been in development for a few years. It's the second CCR5 inhibitor to have some phase 2 data -- the first being, of course, the already-approved maraviroc [MVC, Selzentry, Celsentri].
The vicriviroc study is called the VICTOR-E1 trial. The results of this phase 2b study were shown at this meeting.2,3 The study is of treatment-experienced patients who went on one of two doses of vicriviroc. It requires ritonavir [RTV, Norvir] boosting, so everybody was on at least 100 mg of ritonavir as part of their background regimen.
In this study, 116 people were randomized to one of three arms (about 40 people per study arm): vicriviroc at 30 mg a day, vicriviroc at 20 mg a day, or placebo. The goal was to see how well patients suppressed the virus after a year.
Just to give you some idea of the baseline characteristics of the study population, the mean CD4+ cell count was 210 cells/µL and the mean viral load was 4.5 log10, which is around 30,000 copies/mL or so. In terms of the background regimen, only about a third of the patients used darunavir [TMC114, Prezista] for the first time, and only about a quarter used enfuvirtide [T-20, Fuzeon]. So certainly, these background regimens were not necessarily all that powerful, and yet the results are reasonably impressive. Indeed, if we take a look at those patients who received vicriviroc -- stratified by the number of active drugs in their regimen -- we can see how well vicriviroc adds to the background regimen.
If a patient had no active drugs in his or her background regimen, we can see, in terms of the percentage who achieved less than 50 copies/mL, that 29% on the 30-mg dose of vicriviroc got to less than 50 copies/mL. If we contrast that with those patients who had two or more active drugs in their background regimen, plus vicriviroc, then about 80% of patients achieved a viral load of less than 50 copies/mL in this study -- an impressive finding for a new drug and a new drug class. That this drug is active and certainly does suppress the virus in these patients is, I think, pretty optimistic and reassuring data for the field of HIV research and treatment.
There wasn't much of a safety signal in this study. It looked reasonably well tolerated. We saw some reassuring data in terms of liver function tests, as well as about blood levels, to suggest that this drug certainly does achieve virologic suppression as part of a well-tolerated overall regimen.
Additional data for maraviroc was also presented at this conference. The MOTIVATE trials were updated out to week 48.4 For the most part, those patients who achieved virologic suppression at week 24 continued to do so to week 48. This is, again, not a surprise, but the assurance that we need when we use new drugs and new drug classes. Achieving a viral load of less than 50 copies/mL has typically been durable, but we can't assume that that will be the case with a new drug. We want to see it. We saw it here.
In this study, we also saw that there were some factors, other than background regimen, that predict response. They are the standard ones, like viral load and CD4+ cell count. The higher the viral load is at baseline, the less likely the patient is to achieve suppression. The lower the CD4+ cell count is, the less likely the patient is to reestablish virologic suppression, regardless of the regimen. Nevertheless, the addition of maraviroc increased the odds that we did get to viral loads less than 50 copies/mL.
Once again, we had some reassuring news about the safety of the drug. There wasn't much difference at week 48 versus what was reported to us at week 24 in prior meetings last year. Overall, the news about both of these drugs has been pretty good.
One of the challenges of the CCR5 inhibitor drug class, however, has been the need to assess viral tropism. The Trofile test has, on occasion, failed to identify some people who, while they appear to have R5 virus, when we further examine additional samples or conduct additional testing, in fact have a dual-tropic or X4 viral population, as well.5 Unfortunately, when a patient has an X4 viral population, in addition to R5, maraviroc offers little to no additional efficacy.
At this meeting, some initial data were presented on the enhanced sensitivity assay that's being developed by the same group that created the Trofile assay.6 The data are pretty reassuring. The research group was able to take samples from the vicriviroc studies that we have seen over the past couple of years, and do a comparison of a standard Trofile with this now enhanced Trofile. Some of the patients who had R5-tropic virus, as judged by a standard Trofile, turned out to have a dual-tropic virus when they were now tested using the enhanced Trofile assay.
This is the kind of result that will be needed in order to have greater confidence that this enhanced Trofile assay will be able to identify, with more precision than we have now, those for whom vicriviroc is likely to work, and in whom it is unlikely to work. I think we all look forward to having those data available to us, and, hopefully, the drug commercially available to us, as well.
There were also some data presented about another genotype test called SensiTrop and other assays that are trying to do what the Trofile test does, but faster or at less cost.7 Unfortunately, the data was not as compelling, in terms of sensitivity. These other tests, at least so far, seem to miss some of the dual tropism that is present in a population. So, unfortunately, it's not yet clear that we have an alternative assay to the Trofile, but perhaps we'll have a better Trofile sometime, hopefully, later this year.
We also saw some reassuring data about the integrase inhibitor raltegravir [MK-0518, Isentress], another drug that has been recently approved for HIV and is in a new drug class. The BENCHMRK studies that have had such a dramatic impact in our field, were now followed out to week 48.8,9 The week 48 data pretty much reinforced the earlier week 16 and week 24 data, that were presented last year.
Still, after 48 weeks, about a doubling of the response rate was seen. There are now two-thirds of the study participants, on average, who have a viral load of less than 50 copies/mL on a raltegravir-containing regimen versus a placebo-based regimen, with the expected improvements in CD4+ cell counts as a result of that enhanced suppression. The investigators noted about a 120-cell increase on raltegravir, compared to a 50-cell increase without it.
There's been a fair bit of interest in understanding the relationship between raltegravir and the background regimen. Because, while raltegravir is a relatively easy drug to use -- it's almost certainly active in a wide variety of patients -- the question has been not so much, "What do I need to know about raltegravir?" but, "What do I need to know about the regimen that goes with raltegravir so that I make sure this drug is durable?"
Historically, it's always been true that the more active drugs we add, the better. That was reinforced here. Those patients with a genotype score of their background regimen of 2 or more did better than those with a score of 0. But we saw some very, very interesting analyses about how active the background drugs have to be in order to offer some additional activity.
There are a couple of ways to evaluate that, here the researchers did an analysis using a phenotypic score. As readers may know, when we do a phenotype for most drugs, there's what's called a lower cut-off and an upper cut-off. When a drug is active, as judged by the lower cut-off, it should be fully active, or near fully active. When the drug's phenotype is above the upper cut-off, we expect it to have little activity. Then, of course, there's a range in the middle.
So, a year or two ago, when the researchers presented the data on raltegravir with a regimen in which the drugs were judged as having zero activity -- based on being above the lower cut-off -- what they said was that the regimen achieved suppression in about half the patients. However, many argued that this doesn't provide much clinical guidance since the study looked at the phenotype score above the lower cut-off, and the lower cut-off means that the drug may not be fully active.
What if the regimen is really inactive? What if the drugs, by the phenotype score, have so much resistance that by phenotype their fold change is above the upper cut-off? What if these drugs look really inactive as we understand them by resistance testing? Then how well does raltegravir do?
The astounding result presented here, at least, is that we see similar activity with raltegravir even with very compromised drugs, as judged by phenotype testing. So it was pretty impressive, certainly to me, that raltegravir obviously should be given with two, if not three, active antivirals in total. That continues to be the message. We always do better with a regimen of three active drugs. But how active those drugs have to be is a subject of some uncertainty. This particular analysis suggests that even if the drug has partial activity, it may be reasonable to use that drug if we don't have better choices. At least these data were reassuring that that gets us to a similar place.
In terms of safety, there were no new signals at this particular meeting. Everything worked out quite well. Perhaps one of the most impressive slides of the past year was the absence of a safety signal and the presence of high degrees of efficacy.
The presentation on the BENCHMRK trials ended with a very memorable slide demonstrating how well raltegravir did when it was paired with two of the most active drugs available during the studies -- the combination of enfuvirtide and darunavir. In this study, at week 48, of the patients who received raltegravir, enfuvirtide and darunavir, 89% had less than 50 copies/mL. This is an astounding result, certainly a result as good as any seen when a treatment-naive patient starts on his or her first regimen. So the reassurance we had from these studies was certainly reinforced here with some great data, even one year later.
What about the newer drugs in existing classes? We've got nucleosides, non-nucleosides and protease inhibitors. What progress are we making there? The newest non-nucleoside, etravirine [TMC125, Intelence], was recently approved by the U.S. Food and Drug Administration.10 At this meeting, we saw the 48-week results of the DUET trials, which look at the activity of etravirine.11,12 These double-blind, placebo-controlled, randomized trials reinforce what we've seen earlier, which is that if patients get to a viral load of less than 50 copies/mL at week 24, they seem to stay there for an additional 24 weeks. The week 48 data are very reassuring, with continued CD4 improvements.
For patients who have additional active drugs, like enfuvirtide, they'll do even better than people who don't use enfuvirtide. Those lessons are still there. Just like with the BENCHMRK trials, the makers of etravirine did an analysis to look at how active the background drugs have to be to establish suppression.
They took a look at the activity of darunavir, in part because everybody in this study was assigned to receive the protease inhibitor darunavir. When they looked at the activity of darunavir -- as judged by a fold change, or phenotype below 10-fold versus below 40-fold -- what was striking is that the results were pretty similar, in the overall rate of getting to a viral load of less than 50 copies/mL. This means that when darunavir is fully active, the fold change is less than 10. Certainly, when darunavir is fully active, with a good regimen, patients do the best. About 80% got to less than 50 copies/mL, with darunavir active, etravirine active, and at least one other drug.
The results are pretty reassuring that, while it's always great to have three fully active drugs, even when some of the drugs are compromised, we can still establish suppression in a remarkable majority of these patients.
Some additional information about darunavir was presented at this meeting, in part because some clinicians have been concerned about using darunavir earlier in the treatment sequence. Most of the concern has centered on the question of the cross-resistance implications of using darunavir early in the treatment sequence when there is detectable viremia and resistance.
TITAN is a very large study that was presented last year13 and already published.14 It focused on patients viremic on a prior regimen, but who were naive to both darunavir and lopinavir [LPV]. TITAN compared a darunavir-based regimen with a lopinavir/ritonavir [LPV/r, Kaletra]-based regimen. The result overall was that darunavir was found not to be inferior to lopinavir/ritonavir at reestablishing suppression and, indeed, if the lopinavir/ritonavir wasn't fully active -- meaning, if it was above 10-fold, in terms of phenotypic resistance -- then darunavir was, in fact, a superior option to reestablish suppression.
But we've already known that for a while. The focus of this study was: What if a patient uses darunavir and it doesn't get him or her to a viral load of less than 50 copies/mL? What do we see, and what are the implications?15 There were a few patients who used darunavir and there was viremia. There were a few people in whom there were some mutations that arose on the darunavir arm. The researchers compared the implications of those mutations to what was observed on lopinavir/ritonavir.
The good news here is that, again, while there were very few mutations in those on darunavir, there was also very little cross-resistance, meaning that after darunavir didn't work and didn't result in suppression, most patients still had essentially every protease inhibitor appear to be phenotypically fully active. Indeed, more so than what was observed on lopinavir/ritonavir, in which case after the use of lopinavir/ritonavir there was some cross-resistance observed in some patients to some of the protease inhibitors; not just to lopinavir, but some loss of activity to drugs like amprenavir [APV, Agenerase] and atazanavir [ATV, Reyataz]. That was not the case for those on darunavir.
This reasonably reassuring piece of news allows us to know that the earlier use of darunavir in the treatment sequence is safe to do. It certainly appears successful. If there is not incomplete suppression, the resistance implications are few, in terms of the activity of other protease inhibitors.
Overall, most of what was seen at this meeting reinforces what we've learned over the years. When we can find three active drugs, we can reestablish virologic suppression in the vast majority of patients. Indeed, in many of these studies, about 90% of those who get three active drugs have a viral load of below 50 copies/mL a year later. So the rules of the game are to find three active drugs, though I think at this meeting we saw some information to suggest that three active drugs -- even if the drugs are not fully active -- can actually do pretty well. That doesn't, however, mean that we should choose less than fully active drugs when given the choice. But it does mean that if the best we can do is three drugs, where one of them is not at full activity, we still have reasons to be optimistic that that regimen can get the viral load back to less than 50 copies/mL and keep it there for at least the first year, and hopefully for years to come.
This transcript has been edited for clarity.
- Lima V, Hudson E, Wynhoven B, et al. Drastically declining incidence of HIV drug resistance: the end of the beginning? In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 895.
- Zingman B, Suleiman J, DeJesus E, et al. Vicriviroc, a next generation CCR5 antagonist, exhibits potent, sustained suppression of viral replication in treatment-experienced adults: VICTOR-E1 48-week results. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 39LB.
View slides: [Download PowerPoint](https://img.thebody.com/confs/retro2008/slides/39LB Zingman VICTOR-E1 final slides.ppt)
- Zingman B, Suleiman J, DeJesus E, et al. Vicriviroc in combination therapy with an optimized ART regimen for treatment-experienced subjects: VICTOR-E1. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 795.
View poster: [Download PDF](https://img.thebody.com/confs/retro2008/slides/795 Zingman VICTOR-E1 public.pdf)
- Hardy D, Reynes J, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in treatment-experienced patients infected with CCR5-tropic HIV-1: 48-week combined analysis of the MOTIVATE studies. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 792.
View poster: [Download PDF](https://img.thebody.com/confs/retro2008/slides/792 Hardy poster.pdf)
- Stawiski E, Whitcomb J, Coakley E, et al. Co-receptor tropism predictions based on V3 loop sequence in antiretroviral-experienced patients are specific but insensitive for the detection of CXCR4-using variants. In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago, Ill. Abstract H-1028.
- Reeves J, Han D, Wilkin T, et al. An enhanced version of the trofile HIV co-receptor tropism assay predicts emergence of CXCR4 use in ACTG5211 vicriviroc trial samples. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 869.
View poster: [Download PDF](https://img.thebody.com/confs/retro2008/slides/869 Reeves poster.pdf)
- Tressler R, Valdez H, van der Ryst E, et al. Comparison of results from the SensiTrop vs Trofile Assays on 100 samples from the Maraviroc Expanded Access Program. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 920a.
- Cooper D, Gatell J, Rockstroh J, et al, and the BENCHMRK-1 Study Group. 48-week results from BENCHMRK-1, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV-1. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 788.
View poster: [Download PDF](https://img.thebody.com/confs/retro2008/slides/788 Cooper poster.pdf)
View slides: [Download PowerPoint](https://img.thebody.com/confs/retro2008/slides/788 Cooper slides.ppt)
- Steigbigel R, Kumar P, Eron J, et al, and the BENCHMRK-2 Study Group. 48-week results from BENCHMRK-2, a phase III study of raltegravir in patients failing ART with triple-class resistant HIV. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 789.
View poster: [Download PDF](https://img.thebody.com/confs/retro2008/slides/789 Steigbigel poster.pdf)
View slides: [Download PowerPoint](https://img.thebody.com/confs/retro2008/slides/789 Steigbigel slides.ppt)
- Intelence (TMC125, etravirine) approved by U.S. FDA. Rockville, Md.: U.S. Food and Drug Administration; January 19, 2008.
- Haubrich R, Cahn P, Grinsztejn B, et al, on behalf of the DUET-1 study group. DUET-1: week 48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 612 treatment-experienced HIV-1-infected patients. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 790.
View poster: [Download PDF](https://img.thebody.com/confs/retro2008/slides/790 Haubrich final.pdf)
- Johnson M, Campbell T, Clotet B, et al, on behalf of the DUET-2 study group. DUET-2: week-48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 591 treatment-experienced HIV-1-infected patients. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 791.
View poster: [Download PDF](https://img.thebody.com/confs/retro2008/slides/791 Johnson final.pdf)
- Hardy D, Berger D, De Paepe E, et al. Influence of baseline (BL) factors on virologic response to darunavir/ritonavir (DRV/r) vs lopinavir/r (LPV/r): week 48 outcome in TITAN. In: Program and abstracts of the 45th Annual Meeting of the Infectious Diseases Society of America; October 4-7, 2007; San Diego, Calif. Abstract 1209.
- Madruga JV, Berger D, McMurchie M, et al, on behalf of the TITAN study group. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet. July 7, 2007;370(9581):49-58.
- De Meyer S, Lathouwers E, Dierynck I, et al. Characterization of virologic failures on darunavir/ritonavir in the randomized, controlled, phase III TITAN trial in treatment-experienced patients. In: Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Mass. Abstract 874.
View poster: [Download PDF](https://img.thebody.com/confs/retro2008/slides/874 De Meyer.pdf)
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