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Table of Contents

• Introduction
• Challenges of Current Antiretroviral Therapy
• Immune Discordance on HAART
• Lopinavir/Ritonavir Switch
• Rash and NNRTIs
• Tablet Formulation of Lopinavir/Ritonavir
• New Antiretroviral Options: Emerging Data From Recently Approved Agents or Agents Available in Expanded Access
• TITAN, a Detailed Analysis
• Enfuvirtide in Highly Treatment-Experienced Patients
• DUET Efficacy
• DUET Safety Data
• Maraviroc
• Conclusion
• Footnotes

Eric Daar is the chief of the Division of HIV Medicine at Harbor-UCLA Medical Center, and a professor of medicine at the David Geffen School of Medicine at UCLA.

Introduction

It's my pleasure to give you an update on some of the more important presentations that were provided at the 45th Annual Meeting of the Infectious Diseases Society of America [IDSA 2007], between Oct. 4 and 7, 2007, in San Diego, Calif.

The IDSA meeting comes shortly on the heels of several other very important meetings related to infectious diseases and HIV and AIDS, in particular, the International AIDS Society meeting in Sydney [in July 2007], as well as ICAAC [the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, which took place in September 2007 in Chicago, Ill.]. The purpose of IDSA has increasingly been to provide updated information for people in practice in the field, along with, to a lesser extent, I think, new science. What we saw here at this meeting is consistent with that, in that we saw some new analyses of cohort data and clinical trials, which are going to be extremely important in helping us make decisions about treatment, but not a lot of other brand new data.

What I'm going to do today is cover some of these issues, and particularly, talk about some of the challenges we have with current therapy, as well as discuss a little bit about what our new treatment options are, and what data is emerging from some of the trials that have been presented over just the last months related to some of these new drugs that have either recently been approved, recommended for approval, or available in expanded access.

Challenges of Current Antiretroviral Therapy

Immune Discordance on HAART

From the perspective of challenges of current therapy, one of the things that I seem to get asked about more than just about anything else is this so-called phenomenon of discordance, where we have patients who are on suppressive antiretroviral therapy, with completely undetectable levels of virus for prolonged periods of time, but who don't have robust increases in their CD4 count. There's always this concern as to how concerned we should be about these people developing complications of HIV and AIDS, and whether there is anything we should be doing differently with regards to their treatment.

There were two presentations at this meeting that started to touch on some of these issues. One of them was from the group at the Washington University in St. Louis, where they defined a population of patients in clinical care.¹ These were all people who had baseline CD4 counts of less than 350 cells/mm³, and viral suppression for a minimum of 52 weeks. They defined those who were either discordant or non-discordant with regards to their CD4 increase on therapy.

They arbitrarily defined those who were discordant -- meaning, good viral suppression without good CD4 increases -- as those whose CD4 change was less than 150 cells, versus the concordant group, where there was what was perceived as a more appropriate CD4 increase of greater than or equal to 150 cells.

They did a variety of analyses to try to define whether there are any baseline characteristics associated with being discordant versus concordant. They found, interestingly enough, that there was an increased risk, in a multivariate analysis, amongst: 1) Those who were male; 2) Those who had lower pre-antiretroviral therapy HIV-RNA viral loads; 3) Those who had used any unboosted indinavir [IDV, Crixivan] -- so, people who had been treated in the distant past -- and 4) [Those with] a greater number of antiretroviral-related side effects. All of these seemed to be associated with some level of discordance.

Even more interesting than this, really, is what are the consequences of being in the category of being "discordant?" They found that, overall, the outcomes in all of the groups were quite good, with no real significant difference in things like death. They also found that the long-term viral suppressed, immune-discordant [patient] was fairly common. They found, actually, 106 of these patients, but very little difference in the way of long-term outcomes.

They went further to try to look a little bit at what is going on immunologically with these people. They looked at the relationship between [cellular markers and] being discordant in a small subset of patients (20), comparing that to a small group of 25 who were concordant. What they found was that, in patients who were fully suppressed, but discordant, higher levels of memory CD4 cells were found, with reduced naive memory cells. They also found, interestingly enough, an increased level of CD4 T-cell activation amongst those with immune discordance.

We generally think of the level of activation as declining with the level of immune suppression, or virologic suppression. There has been a lot of interest in the potential role of immune activation on the pathogenesis of CD4 depletion in people with HIV. So this was an interesting observation, although, clinically, these are not markers that we are routinely using, nor do we really know what to do about it when it occurs.

I think, from this study, probably the most important thing for clinicians is that, overall, despite over 100 people being "discordant" and having lower CD4 responses, the outcomes were quite good.

It is worth noting, though, that despite the fact that these patients fell into the category of being discordant, [with regards to] the CD4s in this group, the highs were in the order of 392 cells, and the range didn't get down to the very low levels.

So I think there's some reassurance. It's an area, clearly, that needs additional research.

Lopinavir/Ritonavir Switch

While I think the kind of data that was presented by the group at Washington University is reassuring -- that for most of our patients who maintain good viral suppression regardless of their T-cell increase, they will probably remain healthy -- there are some individuals who we will want to talk to about potential alternative options. Again, frequently, we discuss this in the context of cases. Is there anything we can offer them? One of the things that is often proposed is the possibility of switching from an NNRTI [non-nucleoside reverse transcriptase inhibitor]- to a PI [protease inhibitor]-containing regimen.

The rationale for this is preliminarily based upon just some small case series showing maybe better CD4 responses in patients who are on PIs compared to those on NNRTIs. But a more robust data set was presented in the ACTG 5142 trial of patients who were randomly assigned at the time they were treatment-naive to nukes with either efavirenz [EFV, Sustiva, Stocrin] or a PI.² They found that there was actually a significantly higher increase in the CD4 elevation amongst those who received the PI compared to those who received the NNRTIs. The clinical relevance in that setting is not clear, but it's possible to at least think about extrapolating that to this unique population of so-called "discordant" patients.

There was a group that actually did this and presented their results at IDSA 2007.³ The researchers took a population of patients who were fully suppressed, and they defined some who were partial immune responders -- [these were patients who] had CD4 increases of greater than 50% and a change in what they defined as CD4 categories of greater than or equal to 1. So a group that either went from less than 100 that went to 100 to 200, or 100 to 200 that went to 200 to 350 ... and so on.

Then they had a group of immune nonresponders. These were people who had a CD4 increase of less than 50% and no change within these CD4 categories [mentioned above]. They identified, overall, 17 of these patients. Eight of them were randomly assigned to switch to a lopinavir/ritonavir [LPV/r, Kaletra]-containing regimen. The majority of them were on NNRTIs at the time. Nine patients were randomized to continue their therapy. The researchers simply followed these people for changes in CD4.

What they reported -- in, again, a relatively small data set -- was that CD4s generally went up at month 1 and 3 in both groups by about 50 cells. But they found that after month 3, between month 3 and 6, there was actually a dramatic increase in the group that received lopinavir/ritonavir -- it turned out that that was a highly significant increase, suggesting that maybe there is some benefit of a switch towards increasing CD4s, not necessarily that there is any true clinical benefit.

They suggested, based on an analysis of apoptosis markers on naive CD4 cells, that this may actually decrease in the people who got switched to lopinavir/ritonavir. They hypothesize that there is maybe some effect that is not related to viral control, since everybody maintained good viral suppression, [but is] associated with the use of lopinavir/ritonavir versus NNRTIs that resulted in this improvement in CD4 cells.

Again, a very small data set. Interestingly, for reasons that aren't completely explained, the benefit was really just seen at six months, and not seen at one month and three months. So I think, for now, these kinds of decisions are going to still be based upon a detailed discussion with our patients, since we have this small, incremental increase in the amount of data that might help this type of discussion in therapy in the future.

Rash and NNRTIs

Another challenge that confronts us in the clinic is: What to do with patients who experience rashes while on NNRTIs? Also, to what extent may that limit our ability to use other NNRTIs?

We'll be talking a little bit more about it [later with regards to] a more detailed presentation on a newer NNRTI, etravirine [TMC125], but let's [first discuss] efavirenz and nevirapine [NVP, Viramune], which are first-generation NNRTIs that are associated with a variable rate of rash in clinical trials and in clinical practice.

In a group from Chile, NNRTIs are one of the first-line therapeutics. Their guidelines suggest that if somebody develops a rash while taking one of the NNRTIs, that they should then switch to a boosted PI, presumably because of concerns about cross-reactions.

So, they actually looked at a subset of patients who initially started on NNRTIs and developed rashes, but chose not to follow guidelines and switch to a boosted PI.⁴ They were able to find about 35 patients who developed a rash on nevirapine who were given efavirenz after that.

We aren't told the nature of that rash, or whether it was a severe hypersensitivity rash. Presumably, it was not. Among the patients who were changed to efavirenz, the researchers found that of the 35, only two, or a little less than 6%, ultimately developed a rash. The rest of the patients did not have a rash, and tolerated efavirenz very well. This is reassuring. At least I would argue, for patients who don't have severe hypersensitivity rashes to nevirapine, many of them might be able to use efavirenz.

Only a few people developed rashes [while initially] on efavirenz, because that was not as commonly used. They had, overall, seven, of which two out of the seven who went on nevirapine, or about a quarter, developed a rash. But in general, these patients all maintained suppression. So I think, as long as it's not a severe reaction, this kind of data suggest that if there's a good reason to be thinking about switching to the other NNRTI, it can probably be done safely.

Tablet Formulation of Lopinavir/Ritonavir

Another common kind of side effect in patients on antiretroviral therapy is gastrointestinal [GI] symptoms. One of the more common protease inhibitors currently used is lopinavir/ritonavir. As you know, recently the tablet formulation has become available and the hope was that the tablets would be better tolerated than the softgel capsules, because they eliminated some of the products that were present in the capsules that may act as a laxative.

Particularly, it was thought that the tablet might be associated with less diarrhea. The tablets are now increasingly used in select countries, but not a lot of data is yet available on whether it really does improve tolerability.⁵ There are large, controlled trials that are underway.

There was a small observational study that was presented from the group at Emory [University], where they identified 74 patients who were on lopinavir/ritonavir softgel capsules, and then switched to tablets.⁶ They asked detailed questions and surveys about tolerability, using surveys or validated instruments to look at: bowel habits, global condition improvements, a system distress scale, tolerability, quality of life. They looked at lipids. They looked at viral suppression.

It turned out that, of these individuals, about 25 of them enrolled in the study prior to the switch. Then a larger group, about 49 patients, entered the study within eight weeks of the switch. The researchers collected the variety of information that I described. Overall, at four weeks, they found that more patients preferred the tablets to the softgel capsules; it was 74% versus 8%, in that type of simple assessment. That satisfaction with the tablet formulation was particularly true for things like improvement in bowel habits at four weeks that was maintained out to week 12.

In addition to finding improved GI tolerability, they also found a positive impact on the patient's overall well-being. They also, interestingly enough, saw a small improvement in triglycerides at the time of the switch, the clinical relevance of which isn't really clear.

There was also not a lot of information provided here as to how many of these people may have been receiving this as a twice-a-day, versus a once-a-day, drug. But at least it's some early data suggesting that, indeed, the tablets may be better tolerated than the softgel capsules, which will be helpful as we move forward and we await the larger, randomized controlled data that's pending.

New Antiretroviral Options: Emerging Data From Recently Approved Agents or Agents Available in Expanded Access

TITAN, a Detailed Analysis

In addition to learning how to best deal with some of the adverse effects associated with current therapy, we also need to think about how to manage patients who are experiencing virologic rebound and the emergence of resistance. There were several studies presented at this meeting that deal specifically with the treatment-experienced patient, both with existing drugs and newer drugs. The first of those that I'll talk about was one using existing drugs -- the TITAN trial. It was a head-to-head comparison in treatment-experienced patients who were lopinavir/ritonavir-naive who received darunavir [TMC114, Prezista]/ritonavir [RTV, Norvir] with an optimized background versus lopinavir/ritonavir with an optimized background.

The original data was presented⁷ and published⁸ over the summer. These patients were followed for 48 weeks for the primary outcome. The patient population that was enrolled consisted of people who were treatment-experienced, but were lopinavir/ritonavir-naive. Resistance testing was not performed routinely at baseline, although now all of the baseline resistance data is available.

They stratified [the data] based on viral loads of above and below 100,000, and the use of NNRTIs. The baseline characteristics, in reviewing this, demonstrated a few things that I think are important. One of which was that about 20% of the people were actually not on treatment at the time of enrollment. They were in the midst of a treatment interruption, for any one of a number of reasons. About 30% of them were actually PI-naive.

The other big imbalance between the two groups was that when the researchers ultimately did get resistance data, it proved that there was a larger number of people resistant to their assigned PI in the lopinavir/ritonavir arm (about 10%) versus the darunavir/ritonavir arm (about 2%).

The overall outcome of this study was that the researchers were able to show that the darunavir/ritonavir arm was both non-inferior, as well as superior, to lopinavir/ritonavir, for the overall population.

In the original analysis, they broke this down to try to better define how the imbalance in baseline resistance may have influenced the outcome. They found that even if you focused [only] on patients who had evidence of phenotypic susceptibility to lopinavir/ritonavir -- meaning less than 10-fold -- you still saw that for patients who had a virologic response of less than 50 copies/mL, darunavir/ritonavir was non-inferior. It didn't quite meet superiority when you broke it down that way.

Here at IDSA 2007, David Hardy presented a more detailed analysis looking at baseline characteristics and how that influenced outcome.⁹ This included a variety of univariate and multivariate analyses that incorporated many factors that included things like: baseline viral load and CD4, the number of active drugs in the optimized background, the level of PI resistance with prior PI experience.

In addition, for PI resistance, they broke it down, both based on those who had less than a 10-fold resistance to lopinavir/ritonavir at baseline, as well as the number of mutations from the International AIDS Society-USA profile.

What they found, in the multivariate analysis, was that the difference in response favoring darunavir/ritonavir was maintained even after adjusting for all of these various factors. They also found that when you broke it down based on the subset of patients who were susceptible to lopinavir/ritonavir (based on the phenotype being less than 10-fold), that in that population, as you accumulated more International AIDS Society-USA protease mutations, you actually saw an attenuation of the response.

I think that this further analysis reinforces the observations that darunavir/ritonavir in this patient population is highly effective. While there were some imbalances in the baseline characteristics -- even when accounting for many of these things -- darunavir/ritonavir appears to, at a minimum, be non-inferior to lopinavir/ritonavir, and may be trending towards better, with less virologic failures and less accrual of additional mutations. So it appears to be a very viable option for patients like this, and certainly for patients who are darunavir/ritonavir-naive.

Enfuvirtide in Highly Treatment-Experienced Patients

As we move from those patients who have an intermediate level of resistance to patients who have more advanced resistance, there were several presentations looking at existing drugs and how they complement newer drugs, and then more details on some of the newer drugs and how they may fit into managing this population.

There was a poster presented that summarized the data regarding the utility of enfuvirtide [T-20, Fuzeon] as a new agent from a variety of trials in highly treatment-experienced patients.¹⁰ Many of these studies have included that type of an analysis. Here, they looked at all of these studies and put them together in a single presentation.

The studies of interest that they looked at go back to: the RESIST trial,¹¹ with tipranavir [TPV, Aptivus]; the POWER trials,^12,13 with darunavir/ritonavir; the more recent MOTIVATE 1¹⁴ and 2¹⁵ trials, with maraviroc [MVC, Selzentry, Celsentri], a CCR5 antagonist; the BENCHMRK 1¹⁶ and 2¹⁷ trials, with raltegravir [MK-0518], an integrase inhibitor; as well as the phase 2B study with elvitegravir [GS 9137, JTK-303]¹⁸; and the recent DUET 1 and 2¹⁹ studies, with etravirine.

The researchers broke the analysis down for each of these different studies, based on patients who received enfuvirtide versus those who didn't.¹⁰ For the most part, they were really able to demonstrate, in this particular analysis, that enfuvirtide, particularly in people who have not been on enfuvirtide in the past, results in additional virologic suppression over the newer drug, whether it was a new protease inhibitor or a CCR5 antagonist, integrase, or NNRTI, in most of these trials.

The one [set of studies] in which it was most difficult to really demonstrate a difference -- although there was some increase, but it was modest -- was in the DUET 1 and DUET 2 trials.¹⁹ The addition of enfuvirtide in this situation didn't seem to markedly increase the virologic response.

We'll be talking about a more detailed analysis of DUET 1 and DUET 2 in a moment, but the explanation for this most likely relates to the fact that DUET 1 and 2 were unique, and that everybody in the intervention arm received a new drug, in this case etravirine, a second-generation NNRTI, for which many of them were likely to be susceptible. But they also all had darunavir/ritonavir as part of their optimized background regimen, with about 95% of them being darunavir/ritonavir-naive. We know from the POWER trials and the TITAN trial I just discussed that many of these people will have a virologic response.

So, in the DUET trials -- unlike some of the others where there was one new drug added, most people receive one new drug -- the people in the intervention arm received two new drugs: darunavir and the new NNRTI. It may be that adding a third active drug, in this case enfuvirtide, is going to have a smaller incremental increase in the level of viral suppression.

I think the take home from this type of data, and others, is that enfuvirtide continues to play a key role in the management of highly treatment-experienced patients, particularly if you need a second or perhaps third fully active drug in the regimen.

It also illustrates, in a variety of analyses, the importance of thinking about enfuvirtide based on whether the person has been on it in the past, because we know from studies that enfuvirtide resistance can occur quite quickly.²⁰ In all likelihood, if somebody's been on enfuvirtide with ongoing viremia, they are probably going to be resistant to it. That explains why, when they do these analyses with everybody on T-20, you don't see as much of an effect as when you focus on the people who are T-20-naive, where they are more likely to have susceptible virus.

DUET Efficacy

There were two presentations looking at further analyses from the DUET 1 and 2 trials. These are important studies. They are going to guide treatment with the new drug etravirine (the new NNRTI that's available on expanded access and likely to get approved in the coming months), and they may also provide some additional insight on how to manage these patients who are highly treatment-experienced in the future.

The DUET 1 and 2 trials were, again, two almost identical trials, carried out in different parts of the world, of highly treatment-experienced patients.¹⁹ They all had to have evidence of NNRTI resistance, documented either at the time they came into the study for screening or in the past on a documented, genotypic test. So they had to have proof that they actually had NNRTI resistance.

They came into the trial -- almost 1,200 of them -- and they got randomly assigned to receive an optimized background, which in all cases included darunavir/ritonavir, alone with placebo (importantly) versus etravirine, the new NNRTI. I think it is important, when we start talking about things like safety, to recognize that this was a placebo-controlled trial, which allows us to do that. The other important characteristic about this study that really did make it different than all of the others in highly treatment-experienced patients is the use of darunavir/ritonavir in a population of patients that, for the most part (about 95%), were darunavir/ritonavir-naive. So the optimized background, in this case, almost always included probably one fully active drug. Then we were adding to that. It sometimes included even more than that.

Patient baseline characteristics: The viral load was approaching 100,000, and the CD4 count median was about 100. When you looked at the patients in the study, about half of them received enfuvirtide. About 25% were actually enfuvirtide-naive.

In the primary analysis, using this time to loss of virologic response [TLOVR] for less than 50 copies/mL, it was 59% versus 41%, which was highly significantly different. Similarly, the level of viral suppression in the group that received etravirine was about 2.4 logs versus 1.7 logs in the control group -- which was highly significantly different. But notably, both groups did very well, including the placebo group, with regards to viral suppression and proportion undetectable.

Actually, the placebo group ended up with numbers that looked quite similar to those of the POWER^12,13 trials since, indeed, those are the people who were in POWER -- highly treatment-experienced patients in the intervention arm who received darunavir and ritonavir.

The mean change in CD4 count favored the etravirine group: an 86-cell increase versus 67 cells.²¹ When they broke it down based upon whether patients received new T-20 or not, as I mentioned before, there was a better response in those who received the etravirine with T-20 for the first time, than those who received T-20 for the first time without etravirine. It was 67% versus 62%. But the difference was not significant and, in all likelihood, this is a hint that [the benefit of] having two fully active drugs, such as darunavir/ritonavir and etravirine, isn't improved dramatically by the addition of a third active drug. This might provide some insight as to how many active drugs we need in these highly treatment-experienced patients, or what the incremental gain of adding a third, or a fourth, active drug is.

In fact, they further looked at this analysis based upon the phenotypic susceptibility score in those who had an optimized background regimen that had no active drug -- so they were even resistant to darunavir/ritonavir. The response rate, at less than 50 copies/mL, was only 8%, versus in those who received etravirine, where it was 45%.

Similarly, there was a difference in patients who had one active drug in the optimized background: 60% with etravirine, 30% with placebo. But when you had greater than or equal to two active drugs in the background, the difference was modest, at 74% versus 67%. So, again, this recurring theme.

What was commented on, and has been described in previous analyses, is that since this is a new drug in an existing class, there's going to be some level of cross-resistance in people who are NNRTI-experienced. In analyses from the data from DUET 1 and 2, they identified 13 key mutations that were associated with an attenuated response to therapy.

Interestingly, this did not include the K103N mutation since this drug was developed to have activity against the K103N-containing virus. They found -- as has been described before -- that there's a decrease in the response rate overall of the proportion of people who experienced a viral load drop to less than 50 based upon the number of etravirine-associated resistance mutations. If you had no etravirine-associated mutations, the response rate was about 75%. If there was one, it was 60%, and two, 58%. It was really only when you got to three that you saw a substantial drop-off, down to about 41%.

The observation that's been made before, and was described here, is that it turns out that, even in the placebo group, there was a relationship between the number of etravirine-associated mutations and response rate, with somewhat of a drop-off when you get to two or three mutations, suggesting that this is probably not just a marker for reduced response to etravirine, but may also be a marker for the extent of overall resistance within the regimen, since it influenced both groups.

I think, overall, it's very clear that this is going to be a very active new drug for highly treatment-experienced patients who have less than three of these etravirine-associated mutations, and that there is a hint from this study that there may not be a lot of additional gain by adding a third fully active drug to a regimen that already includes two fully active drugs, with other drugs in the background, such as nucleoside reverse transcriptase inhibitors [NRTIs].

DUET Safety Data

In addition to defining the efficacy of these new drugs, it is also important to completely understand the issues surrounding the safety of new drugs. I think one of the concerns with new drugs in existing classes is the level of overlapping toxicity that may exist. Since etravirine is an NNRTI, there are concerns about whether there would be overlapping toxicity -- such as rash, transaminase abnormalities and neuropsychiatric complications -- with existing NNRTIs.

At this meeting they presented a pooled analysis of the DUET 1 and 2 trials' safety and tolerability at 24 weeks. They were able to do this because this was, indeed, a placebo-controlled set of trials.²² So you could really define the differences in select adverse events between patients who received the etravirine with an optimized background, versus those who received the optimized background alone. Again, recognizing that everybody in both groups received darunavir/ritonavir.

One of the most notable things about the baseline characteristics is that about 40% of the patients admitted to having some type of neuropsychiatric problems in the past. About 10% had a history of an NNRTI-related rash. Now, presumably, these weren't hypersensitivity type rashes, but the patients did, indeed, have a rash coming into these studies.

If you looked at overall grade 3, 4 adverse events, there was really no difference overall between the arms. But when you looked at rash, there was indeed a higher frequency of rash amongst those who received etravirine: 17%, versus 9% in the control group, which was highly significant.

The researchers further characterized this. They described that there was only 1.3% of patients who had a grade 3 or 4 rash in the etravirine group, versus none in the placebo group. In the onset: the median time was about 12 days. The duration was about 11 days. Only 2.2% of the population had to discontinue because of rash. So it seems like the rash that exists occurs at a relatively low frequency, even in this highly treatment-experienced population. It generally is mild and only results in discontinuation in select cases. They said there were no constitutional symptoms, or systemic symptoms, associated with it, or any mucous membrane involvement suggestive of a Stevens-Johnson type syndrome.

Further, looking at the breakdown, they found that there was a somewhat higher frequency of rash amongst women than men, and they found in other potential complications or adverse events that there was really no difference with regards to central nervous system toxicities, psychiatric adverse events, or grade 3, 4 LFT [liver function test] abnormalities.

Similarly, there was no apparent difference in the levels of lipids over time between the two groups of patients. One observation where there was a significant difference was with regards to a higher rate of hospitalizations amongst those who received placebo versus etravirine: 16% versus 11%. This was significant, although the details about what these hospitalizations were for were not available at the time of this presentation.

Again, it's nice to collect additional safety data from a large number of people in a placebo-controlled trial with a drug that we're going to start using in clinical practice. This starts to get at the concern that some have about whether they can use this in people who have had a non-hypersensitivity type rash with other NNRTIs. It certainly appears to be a promising result.

Maraviroc

We'll close this CME with a presentation that was a late breaker. I think everybody is familiar with maraviroc, a new CCR5 antagonist that was recently approved by the FDA [U.S. Food and Drug Administration] for patients who have R5-only virus, meaning at the time of screening, using a tropism assay, they didn't have any detectable CXCR4-utilizing viruses.

One of the concerns about using this drug is the potential for selecting for CXCR4-utilizing viruses, and what the consequences of that might be, since there's natural history data suggesting an association between the presence of these viruses and CD4 decline in clinical progression.

There have been detailed analyses of patients treated with CCR5 antagonists who experience the emergence of this viral population and who have not shown any suggestion of CD4 declines, at least at 24 and 48 weeks.

Another study that was presented several months ago, at 24 weeks, was a study designed in part to address the issue of what would happen if you treated people who had CXCR4-utilizing virus.²³ This was the maraviroc study 1029, which took the individuals who would not have been eligible for the MOTIVATE trials because they had evidence of either dual/mixed-tropic virus or X4 virus, or [they were part of the] small number [for whom] the virus was simply not able to be typed by the assay. These patients were offered enrollment in this study.

This was a randomized, controlled trial of an optimized background with maraviroc, either once a day or twice a day, versus placebo. It included about 50 to 60 people in each arm, so it was a relatively small study to address both limited efficacy data and safety, to see whether enriching for a population of dual/mixed-tropic or X4 viruses would be associated with worse outcomes.

They followed these patients for 24 weeks, and although they had previously reported that data, I think it's really important that we have more long-term follow-up, particularly from a safety perspective. This was the 48-week data from this population of patients who came into the study with a median CD4 count of about 40 and a viral load of about 100,000.²⁴ About half of them received enfuvirtide, and less than two active drugs were present within these regimens for about 50% of the patients.

The investigators looked at the virologic change and they found that the difference in viral load suppression was essentially no different across the three different arms, consistent with what had been previously seen. When you looked at the proportion that got to less than 400 and less than 50 -- again, small numbers -- there was no significant difference between the groups.

It's based on this kind of data that most people believe that patients who have dual/mixed-tropic or X4 virus at baseline are not likely to derive virologic benefit from this drug, recognizing that the sample size is quite small. But [it, along with data from the big MOTIVATE trials, is] also why the current recommendations are that we'll be using this drug in treatment-experienced patients who don't have evidence of dual/mixed-tropic virus identified on a screening assay.

They reported the 48-week data on change in CD4 count, and, just as they had seen before, while we were worried that enriching for this population may be associated with CD4 decline and disease progression, it actually was associated with a better CD4 increase than what was seen in the placebo group. The reason for this isn't known yet, but there's a lot of speculation and I know there's some work going on to try to better define what is the effect of adding a CCR5 antagonist on select CD4 cell populations.

Adverse events were looked at carefully in this study, and there were no differences between the groups. There were no significant differences in the number of category C events. Previous studies with another CCR5 antagonist, vicriviroc [SCH 417690, SCH-D], raised some issues about the potential association with the emergence of malignancies. This has not been supported by further analysis from those trials, and certainly not from analysis of the MOTIVATE trials, nor this one.

Overall, there were about two malignancies in each of the three different groups, but no Hodgkin's lymphomas, no Kaposi's sarcomas. In general, it doesn't seem that there are any ill effects on CD4 counts or clinical progression after 48 weeks.

Adverse events: There was this continued increase in cough that was seen somewhat in the maraviroc groups, but no obvious evidence of increased things like pneumonia. There was no evidence of problems with transaminases, which came out of one of the earlier trials with CCR5 antagonists.

I think, in general, the 48-week data is completely consistent with the 24-week data and provides further reassurance that enriching for a population of dual/mixed-tropic virus won't be associated with a poor outcome in patients treated with CCR5 antagonists.

Conclusion

This is almost the last of a series of extremely important meetings that occurred during the course of this year. What's emerged is really unprecedented in the field -- with so much new data on how to optimally utilize existing drugs. But even more importantly, we've recently seen so much new data on how to better manage treatment-experienced patients with the emergence of several new drugs in new classes, as well as new drugs in existing classes. All of this has already had, and will certainly continue to have, a dramatic impact on the care of highly treatment-experienced patients.

I think that we're looking forward to an extremely exciting six months, as many of these new drugs reach the clinic and as more data emerge in the coming year, starting with the retrovirus conference in Boston in 2008.

Footnotes

1. Onen NF, Overton ET, Blair C, Mondy K. Immune discordance on highly active antiretroviral therapy (HAART) is not associated with increased morbidity or mortality. In: Program and abstracts of the 45th Annual Meeting of the Infectious Diseases Society of America; October 4-7, 2007; San Diego, Calif. Abstract 952.
   
2. Riddler SA, Haubrich R, DiRienzo G, et al, for the AIDS Clinical Trials Group 5142 Study Team. A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection -- ACTG 5142. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0204.
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3. Pitrak D, Novak RM, Estes R, Diaz-Linares M, Tschampa J. Beneficial effects of a switch to a lopinavir/rit (LPV/r)-containing regimen for patients with partial or no immune reconstitution with HAART despite complete viral suppression. In: Program and abstracts of the 45th Annual Meeting of the Infectious Diseases Society of America; October 4-7, 2007; San Diego, Calif. Abstract 955.
   View poster: Download PDF
4. Cortes CP, Wolff MJ, Beltrán C, and the Chilean AIDS Cohort Group. Cross allergy between non nucleoside transcriptase inhibitors (NNRTI): outcome with challenge to the other NNRTI. In: Program and abstracts of the 45th Annual Meeting of the Infectious Diseases Society of America; October 4-7, 2007; San Diego, Calif. Abstract 959.
   View poster: Download PDF
5. Zhu T, Chiu Y, Doan T, et al. New tablet formulation of lopinavir/ritonavir is bioequivalent to the capsule at a dose of 800/200 mg. In: Program and abstracts of the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2005; Washington, D.C. Abstract 1894.
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6. Ofotokun I, Chuck SK, Rivas MV, Rode RA. Switching from lopinavir/ritonavir (LPV/r) soft gel capsule (SGC) to tablet formulation improves tolerability in indigent AIDS clinic. In: Program and abstracts of the 45th Annual Meeting of the Infectious Diseases Society of America; October 4-7, 2007; San Diego, Calif. Abstract 962.
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7. Valdez-Madruga J, Berger DS, McMurchie M, et al. Comparison of 48-week efficacy and safety of darunavir/ritonavir (DRV/r) with lopinavir/ritonavir (LPV/r) in LPV/r-naive, treatment-experienced patients: a randomised, controlled phase III trial (TITAN). In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUAB101.
   View slides: Download PDF
8. 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.
9. 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.
   
10. Lalezari JP, Guittari CJ. Improved virologic response in triple-class-experienced patients with enfuvirtide (ENF) combined with new antiretroviral agents. In: Program and abstracts of the 45th Annual Meeting of the Infectious Diseases Society of America; October 4-7, 2007; San Diego, Calif. Abstract 964.
    View poster: Download PDF
11. Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet. August 5, 2006;368(9534):466-475.
12. Lazzarin A, Queiroz-Telles F, Frank I, et al. TMC114 provides durable viral load suppression in treatment-experienced patients: POWER 1 and 2 combined week 48 analysis. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUAB0104.
    View poster: Download PDF
13. Molina JM, Cohen C, Katlama C, et al. TMC114/r in treatment-experienced HIV patients in POWER 3: 24-week efficacy and safety analysis. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0060.
    View poster: Download PDF
14. Lalezari J, Goodrich J, DeJesus E, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of a phase 2b/3 study in the US and Canada. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 104bLB.
15. Nelson M, Fätkenheuer G, Konourina I, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-week results. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 104aLB.
16. Cooper D, Gatell J, Rockstroh J, et al, for the BENCHMRK-1 Study Group. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 105aLB.
17. Steigbigel R, Kumar P, Eron J, et al, for the BENCHMRK-2 Study Group. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 105bLB.
18. Zolopa AR, Mullen M, Berger D, et al. The HIV integrase inhibitor GS-9137 demonstrates potent antiretroviral activity in treatment-experienced patients. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 143LB.
    View slides: Download PDF
19. Cahn P, Haubrich R, Leider J, et al. Pooled 24-week results of DUET-1 and -2: TMC125 (etravirine; ETR) vs placebo in 1203 treatment-experienced HIV-1-infected patients. In: Program and abstracts of the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago, Ill. Abstract H-717.
    View slides: Download PowerPoint
20. Greenberg ML, Melby T, Sista P, et al. Baseline and on-treatment susceptibility to enfuvirtide seen in TORO 1 and TORO 2 to 24 weeks. In: Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston, Mass. Abstract 141.
21. Hicks C, Cahn P, Leider J, et al. Pooled 24-week results of DUET-1 and -2: efficacy of TMC125 in treatment-experienced HIV-1-infected patients. In: Program and abstracts of the 45th Annual Meeting of the Infectious Diseases Society of America; October 4-7, 2007; San Diego, Calif. Abstract 1207.
    View slides: Download PowerPoint
22. Haubrich R, Schechter M, Walmsley S, Peeters M, Janssens M, De Smedt G. TMC125 safety and tolerability in treatment-experienced, HIV infected patients -- pooled DUET trial data. In: Program and abstracts of the 45th Annual Meeting of the Infectious Diseases Society of America; October 4-7, 2007; San Diego, Calif. Abstract 1210.
    View slides: Download PowerPoint
23. Mayer H, van der Ryst E, Saag M, et al. Safety and efficacy of maraviroc (MVC), a novel CCR5 antagonist, when used in combination with optimized background therapy (OBT) for the treatment of antiretroviral-experienced subjects infected with dual/mixed-tropic HIV-1: 24-week results of a phase 2b exploratory trial. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0215.
24. Goodrich JM, Saag M, van der Ryst E, et al. 48-week safety and efficacy of maraviroc, a novel CCR5 antagonist, in combination with optimized background therapy (OBT) for the treatment of antiretroviral-experienced patients infected with dual/mixed-tropic HIV-1. In: Program and abstracts of the 45th Annual Meeting of the Infectious Diseases Society of America; October 4-7, 2007; San Diego, Calif. Abstract LB-2.
    View slides: Download PowerPoint