September 30, 2006
|Listen (7.6MB MP3, 22 min.)|
Ben Young, M.D., Denver ID Consultants, Denver, Colo.
The symposium on acute infection, I think, was one of the highlights of my attendance at this year's meeting. I think Susan Little really captured this question in very nice detail. I think we are moving in a direction that is beginning to reassert the idea of offering therapy for patients who are willing and able to be adherent to medications. It's not a slam dunk. I don't think the data are conclusive. But, as I understand it, both Dr. Little's recommendations and the interpretation of the AIEDRP [Acute Infection and Early Disease Research Program] cohort, the sense is that there's a sustained .5 to .6 log viral load benefit that's translated to actual outcome benefits in the long term.
Part of what also stimulates this is the very detailed presentation from that cohort of patients [AIEDRP], that looked at, I believe, 1,600 patients who were identified during acute seroconversion and followed over time without treatment. What they showed was, that the time to which half the patients achieved CD4 counts of 350 -- in other words the level in which they should be offered treatment -- was only 1.8 years. So, in fact, the notion that starting people on early treatment might be giving them many, many years of treatment that they might not otherwise need may not be entirely true, since half the patients needed treatment in less than two years anyway. If we could do something that could offset that and minimize the risk of complications, that may in the end be a good thing.
As medications get better and better, easier to tolerate and easier to take, I think the costs of treatment become less. So, the pendulum is beginning to swing back towards an opinion, not [entirely] back, but towards an opinion that there is a benefit to earlier treatment.
Now, I want to ask you about first-line therapy. Do you think we are moving towards initiating therapy at a CD4 count of 350, instead of the somewhat nebulous "before it falls to 200"?
I think very much so. Current treatment guidelines give us this gray zone between 200 and 350. I don't think there's any disagreement that treatment should be offered and started in patients whose CD4 counts are less than 200. There is a growing data set that says that there's a benefit, both in complications and in terms of mortality, in starting patients [on treatment] earlier.
As I mentioned previously, as medications become better tolerated, easier to take and hopefully easier to adhere to, the risks of treatment have gone down [at least] since the beginning days of HAART therapies. While it's understandable that people don't want to be on therapies that they shouldn't be on, I believe that [treatment may provide] measurable benefits to patients insofar as protecting their long-term health.
In our practice [Denver ID Consultants] it's commonplace to offer patients therapy at [a CD4 count of] 350. In fact, some proactive patients are beginning to look at this as a soft guideline and, in fact, are wanting to start therapy with CD4 counts that are even higher. So, yes, I think starting therapy earlier makes sense. If it was me making the decision today for myself I would probably not want to wait until 200. I would certainly be considering starting treatment earlier.
Do you have a favorite first-line regimen? And, if so, why?
This is a moving target. We'll probably make commercial sponsors unhappy or nervous, but in our practice I offer patients the spectrum of treatment opportunities and options. I certainly think that fixed-dose combination nucleosides make the most sense because they reduce pill-burden and [insurance] co-payments and so on.
Which nucleosides do we use? We use either of the two once-daily fixed dose combos -- that's either a fixed dose combination of abacavir/3TC, otherwise know as Epzicom or Kivexa, or the combination of tenofovir/FTC, otherwise known as Truvada. Which one is my favorite? I actually don't have a favorite. It really depends on the background of the [individual's] disease state, racial background and so on of the patients, what kinds of health risks they may have long before HIV comes along and how do we minimize the risks of complications from those medications. Again, we are fortunate that we have a number of options. Those are the two that we probably most frequently use in our practice.
In terms of the so-called third agent, the big debate for a long time has been whether to use a non-nucleoside- [NNRTI] based regimen, namely efavirenz [EFV] or Sustiva or Stocrin, or to use a boosted protease inhibitor. Here the pendulum has been fluctuating back and forth.
There's considerable evidence that either of the two approaches will likely result in excellent virological results, [and] excellent immunological results. At this point, it comes down to issues related to pill burden, potential side effect profiles, [and] trying to mitigate side effect profiles. One of the areas of concern that has resonated with our patients has been the kinds of resistance patterns that emerge after treatment failure of those first-line therapies. There, there are some differences that are important -- [namely] where boosted protease-inhibitors have less treatment emergent resistance after treatment failure compared to non-nucleoside based regimens. That notion of preserving future treatment options has resonated with our patients and certainly resonates with me.
Conversely, there's also data that suggests that the use of protease inhibitors is associated with an increased risk of cardiovascular complications and lipid abnormalities and those should not be dismissed either. Recent data from the ACTG [AIDS Clinical Trial Group]-5142 study at the very least suggests that that the two regimens are comparable but actually may tip the balance towards non-nuke based regimens. [To read more about this study, click here]. I think the jury is out. We can afford to have a number of options and we can tailor the particular regimen to patients' needs and patients' backgrounds. Really, I don't have one favorite regimen. [Choosing just one] is like saying that all patients fit into one shoe and therefore there's only one regimen that one uses.
Moving on to multidrug resistant patients, do you think that getting multidrug resistant patients to undetectable levels has become a reasonable goal? And if so, what should people do and how should people do it?
[That's a] very complicated question. First of all, the number of multidrug resistant patients is decreasing as we go along. Or rather, the number of multi-drug resistant patients who we can't suppress is getting fewer and fewer. This is based on two factors. Number one, first-line therapies are becoming increasingly successful. We are seeing fewer and fewer first-line failures and therefore fewer and fewer second-line failures. I haven't seen virological failure among first-line patients in my practice for a number of years. That's a stark contrast to the situation just five years ago. So, that's an important observation that needs to be shared with patients who are considering starting treatment today.
Unfortunately, of course, we do have a smaller, but certainly important, population of patients who have been failed by conventional first- and second-line therapies, who have multidrug resistance, some of who are still having difficulty getting virological suppression. A number of those patients have been suppressed recently with the approvals of enfuvirtide [T-20], or Fuzeon, in combination with some of the newer protease inhibitors. I think that already begins to tip the balance in favor of suppression. Now, we have some of the new arrivals like darunavir [TMC114], or Prezista, and the available expanded access programs for the Merck integrase inhibitor [MK-0518], for the CCR5 inhibitor Maraviroc [UK-427857] and for the second-generation non-nucleoside TMC-125 [Etravirine]. I think we really can begin to cobble together fully potent, fully suppressive drug regimens for patients even who have been failed by all the previously available drugs. I do believe that in the near future, if not in the current time, many of these patients can experience the promise of undetectable viral loads, restored immune health and so on.
I know a lot of patients take an unstructured treatment interruption without telling their physicians. How safe do you think a structured treatment interruption is?
I think this is another area where the jury is still out. I think a lot depends on why the structured treatment interruption is being proposed. If it's being offered in the context of someone who is having significant side effects with drugs or someone who is having significant issues with adherence, then the issue is not simply the risks and benefits of the treatment interruption per say, but also the need to stop medication for those reasons.
Treatment interruptions were actually not infrequently used in our patients who had very high CD4 counts a couple of years ago. For example, a patient with a CD4 count of a thousand who had been on treatment for four or five years and was simply tired of taking medicines, those are patients that with close clinical monitoring, were actually electing to go off of treatment. In our clinical practice, that [the treatment interruptions of these patients] had not come with significant issues or complications.
On the other hand, it's also fair to say that large clinical studies, including studies in the United States and studies in Europe and Africa, have suggested that there's significantly increased risk of having complications and some of those risks are quite serious in the context of stopping therapies. [For coverage of these studies, click here]. Some of this is based on the [patient's] CD4 count at the time of stopping the therapy and [the patient's] nadir CD4 count prior to the initiation of therapy. Individual patients may fall somewhat differently into these categories. Nonetheless, I think it would be unwise to ignore the data that suggests there's increased risk. The way that this translates into my counseling to my patients is that unless there's a [good] reason for stopping therapy right now, with the [currently] available data, I don't recommend stopping until more information gives us guidance on this.
I know the Staccato data were recently presented at the International AIDS Conference. Did that impress you and convince you that that's a counter-balance to SMART?
Absolutely. The Staccato study did say that in fact the risks are not significant in patients with higher CD4 counts. So, we have two well-designed clinical studies that offer competing visions on whether there's risk. But given that the patients who stay on therapies have limited risk, until I know there isn't risk and there's confirmation of that I would rather offer the patients both sets of information and offer a conservative view of whether it's safe or not, because if it's not safe and we were wrong, we've given increased risk to people.
At this conference there was a lot of exciting news about new drugs in development. What are your thoughts about the new drugs and how they're going to change HIV management?
I'll restrict my comments to the two drugs that are closest to FDA [U.S. Food and Drug Administration] review and those are Maraviroc, a CCR5 inhibitor, and MK-0518, the Merck integrase inhibitor. Maraviroc has continued to show very promising results and a safety profile that, in my view, is surprisingly good. On the other hand, there is some information that suggests that there are yet unknown, unanswered questions related to co-receptor switch and issues related to increased risks of complications in patients. There was signal related to risk of West Nile virus infection in a cohort of patients from the U.S. west who have CCR5 deletions, which suggests there may be some important immunological role for this co-receptor. [For more on this issue, click here.]
I'm cautious about the product, but again so far, so good. In patients who desperately need a new class of drugs, certainly it's a drug that's going to have a lot of importance. The issue with it, however, is that as patients' CD4 counts decline, more and more of them have viruses that are either dual tropic or not CCR5 tropic. So, the use of the drugs will probably be limited in those patients, [i.e.,] the very patients who would probably benefit from it, in salvage therapy or later rounds of therapy. Again, I'm encouraged but cautious.
I'd say the emotion at this meeting and at the Toronto meeting in terms of the Merck inhibitor has been, if anything, exuberant. The data have been very impressive for patients with three drug-class resistance. The data have also been equally impressive in patients who were therapy na?ve. Note that this is the first time that we have seen a drug take on efavirenz and actually have at least some measures which are not just equivalent to efavirenz, the industry standard comparator, but has actually surpassed efavirenz with regard to early viral load suppression, with regard to lipid profiles and so on.
I think these two drugs are clearly going to be important. How they are going to be incorporated into our treatment decision-making in the months and years to come remains to be seen. They will both certainly be important new drugs for salvage patients. [To know] whether they will make it into earlier rounds of therapy we'll need more information, more experience, more time. But I'm much more optimistic than pessimistic about how these drugs will be factored into our treatments in the future.
Although there's been a lot of research on these complications it seems like we are no closer to figuring out what causes these complications and, more importantly, how to reverse them. What are your thoughts? Do you think there was anything new from this meeting and the lipodystrophy meeting that took place this week?
I didn't go to the lipodystrophy workshop, so I can't comment on that. I'm looking forward to seeing other people's reviews of that study. There was a study presented from the London group looking at a number interventions for lipodystrophy, again really mostly reiterating what we previously had known about various rosiglitazones and so on. I'm not sure we've made a lot of progress in either the biological understanding or the treatment and prevention of various lipodystrophy syndromes. The metabolic syndromes of hyperlipidemia have, I think, garnered a lot of due center stage, particularly as our patients live longer. The D:A:D study that has been presented multiple times by the EuroSIDA group and, in part, here by Jens Lundgren continues to emphasize the risk of cardiovascular disease in our patients. [For a review of this study, click here.]
It's important to put that into a context of other risk factors for cardiovascular disease. Both HIV, HIV therapies and a number of other cardiovascular risk factors we have known about for years, smoking, diabetes, hypertension and so on, all influence an individual's risk. Those are factors that are often not well discussed in the context of HIV disease. We are really focusing on the virus and the antiretrovirals. I approach those in my patients by hopefully trying to understand and balance all those risk factors, trying to figure out which one is going to give us the maximum benefit for the intervention we have proposed.
Another feared complication of HIV is cardiovascular disease. Do you think the risk is HAART, HIV, a combination of the two, or something else all together?
I think it is actually a combination of the two and then some, as we just mentioned. It's clear, for example, that people with HIV have abnormalities in their lipid profiles even before antiretroviral therapy is initiated. These are [conclusions drawn from] data that predate the HAART-era. It's also clear that antiretroviral therapy moderates or changes, sometimes in a beneficial way, but most often negatively, the lipid profiles in patients. Those changes do increase the risk of cardiovascular disease. Again, in the D:A:D study the increased risk per year is something like 16 percent per year of treatment of HIV. Much of that risk is attributable to protease inhibitors, though again much of the data is from years ago with earlier, more toxic protease inhibitors. That [information] should be balanced with knowledge that factors like diabetes and [cigarette] smoking increase relative risk by an order of magnitude greater than antiretroviral therapies. So, depending on what modifiable risk factors are present and the underlying risk of cardiovascular disease, we have to develop an approach that includes HIV and antiretroviral therapy but also addresses all these other needs.
The overall risk of cardiovascular disease is not going to go down in our population, which in a sense is a fortunate thing because it means our patients are getting older. As populations of people get older, their risk of cardiovascular disease inherently goes up. So, this will be an area of increasing concern, but, in part, because of a good thing, because our patients are living longer, living to an age where cardiovascular disease significantly affects people.
My final question is what do you think has been the most unexpected piece of news that has come out in the past year? Is there anything that comes to mind that has particularly surprised you?
I think there's been a lot of interesting information that's emerged in the last year. If I were to, in a moment's notice, pick a couple, I think the information on treatment interruptions has changed one's willingness to offer treatment interruptions. Though, again, I think the data is by no means conclusive. I expected we would see data that would say treatment interruptions are actually safe to do. To me, it came as a surprise that there are warning signals about treatment interruptions.
The data on Merck's integrase inhibitors was both welcome and surprisingly good. I think we have to balance that enthusiasm about the drug with the understanding that it is a new drug, a new class of drugs. It's been tested in a handful of patients for a relatively short period of time. But whenever we see a new class of drug, it's exciting. In fact, it sort of harkens back to the early days when we saw unexpectedly good results with a set of drugs now called nucleosides and before that with a new class of drugs now called protease inhibitors. So, the data that we've seen so far not just with the Merck integrase inhibitor, but the preliminary data from the Gilead inhibitor have been very affirmative. It's too early to be sure, but we're certainly looking forward to seeing what this data set looks like in the months to come.
Thank you, Ben Young, for your time.