This is part one of a two-part article. For part two, New Antiretroviral Options: Emerging Data From Recently Approved Agents or Agents Available in Expanded Access, click here.

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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
• 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.

This is part one of a two-part article. For part two, New Antiretroviral Options: Emerging Data From Recently Approved Agents or Agents Available in Expanded Access, click here.