November 12, 2010
For years now, it has been clear that HIV-positive people are especially prone to developing unusual increases of fat in specific parts of their bodies. What has been less clear is exactly what a person with this type of fat gain, known as lipohypertrophy, can do about it.
On Nov. 10, a new option was approved by the U.S. Food and Drug Administration (FDA). Its name is Egrifta, known generically as tesamorelin. It is the first drug approved specifically for use by HIV-positive people with lipohypertrophy. Egrifta doesn't treat all kinds of fat gain -- it focuses on reducing fat gain in the belly area -- but its approval is historic nonetheless.
Daniel Berger, M.D., has been one of the HIV clinicians involved in studies of Egrifta prior to its approval. He is the medical director and founder of NorthStar Medical Center in Chicago, as well as a clinical associate professor at the University of Illinois-Chicago College of Medicine. In this interview, he'll walk us through how Egrifta works, who should take it, and what else we know to date about the treatment of lipohypertrophy.
[Editor's note: This interview does not include a discussion of the specific warnings and indications included in the drug's labeling; we'll follow up on that in a future article. In addition, in the interest of disclosure, please note that Dr. Berger was a lead investigator for both phase 3 studies of Egrifta and a co-author of several published studies on the drug. He has served as a speaker and consultant for Theratechnologies Inc., which developed Egrifta. He has also served as a speaker and consultant for Serono Laboratories Inc., which is marketing the drug. This interview represents Dr. Berger's personal opinion and not necessarily that of Theratechnologies or Serono.]
Let's start with the basics. What is Egrifta?
Egrifta -- previously it was known as tesamorelin or growth hormone-releasing factor -- is a medication that was studied in HIV-infected individuals with increased belly fat, in the form of visceral adiposity or fat accumulation. In other words, it was investigated in patients who had fat accumulation within the abdominal body cavity. We also use the term lipohypertrophy to denote the same thing.
The studies with Egrifta were designed to examine whether patients with visceral fat accumulation can take Egrifta safely, but specifically, using it as a strategy to obtain reductions of visceral abdominal fat. So this drug is important and is going to be used for HIV-infected patients who are developing or have had increases in abdominal, visceral fat.
About how many people are we talking about here? People with HIV who have this excess fat in their belly.
There's been a number of studies that looked at the prevalence in abdominal fat accumulation. I believe, of the three or four studies that I'm familiar with, it's anywhere between 25% to 35% of patients that are currently on antiretroviral therapy in whom we have observed abdominal fat accumulation.
Is there any particular person that's more likely to have it?
In the early days of the epidemic -- or the earlier days, I should say -- when certain medications that were more metabolically toxic were used, we observed lipohypertrophy, or fat accumulation, more often. So for example, a protease inhibitor known as Crixivan [indinavir] was a medication that was quite famous [for causing this] and, in fact, people often referred to the manifestation as "Crix belly."
But we are not using that medication currently, and some of the newer protease inhibitors, we feel, are less likely to cause the problem. There are other medications, such as nucleosides, that have also been found to have similar problems in terms of metabolic problems, including fat redistribution.
Which specific nucleosides are you talking about there?
I should back up a little bit and just say that it goes toward understanding the cause and mechanisms of this fat redistribution problem. We feel that medications that have mitochondrial toxicities play a greater role in being associated with the problem. Mitochondria are small organelles that are metabolic powerhouses in each cell. And fat tissue is actually very rich in mitochondria. Certain nucleosides such as Zerit [stavudine, d4T], ddI [Videx, didanosine] and AZT [Retrovir, zidovudine] have an inhibitory effect on mitochondrial DNA polymerase gamma, which is the principal enzyme responsible for mitochondrial DNA synthesis. And it can also have other negative effects on protein synthesis. Some of the nucleoside analogs pose a significant obstacle for normal metabolism and this leads to increased fat redistribution changes in HIV.
And it's worth noting that there's been development of newer agents, most being thought of as being less mitochondrial toxic, or in other words, being mitochondrial friendly. These medication toxicities, overall, have been observed much less than with the older agents that were used back in the day.
So is this drug most likely to be used by people who have been on treatment for a long period of time?
Yes, but there's strong evidence that both HIV infection as well as specific medications are associated with the problem. In fact, an early study showed that abdominal fat changes occurred in patients even before starting on treatment. Fat accumulation such as posterior or neck fat, or buffalo humps, have even been seen in people before they started on their medications.
We also know that there are a lot of host factors that are also associated with the problem and are probably independent of the type of medications that the person uses. So for example, if one is an older-aged individual, there are high rates of lipodystrophy. We often see more lipodystrophy in Caucasians as opposed to other races. Although both males and females can show either or any of the manifestations of lipodystrophy, females have a greater instance of having fat accumulation and men are more apt to have facial atrophy. And we also know that the lower CD4 counts and higher viral loads that patients have before they get started on treatment, in some studies, have also been shown to be a factor.
All in all, the fat changes in HIV are fairly common and its causes are multiple and complicated. Regardless of the fact that people are on certain types of medications, we believe that some individuals are still going to develop this problem. And since many people are also living longer and have been HIV positive for a very long time, most of the individuals already have the manifestations. So I believe that Egrifta's going to be used widely and hopefully provide benefit to a wide number of individuals that are HIV positive on treatment.
Alright, so let's get into the nitty a bit, if not the gritty as well. How well does Egrifta actually work against people with HIV who have developed this abdominal, visceral fat?
There were two studies that were designed to look at patients with HIV. Those studies basically looked at patients that were on stable antiviral therapy and had fat accumulation problems -- that was measured in waist circumference that was at least 95 centimeters, and a waist-to-hip ratio that was at least a certain measurement ratio of .94. And those patients could also have some mild type of diabetes. In other words, diabetes that didn't require medication treatment.
What was seen in the study was that patients that were on Egrifta were likely to get somewhere between a 17% and 18% reduction in visceral fat. In other words, there was a significant loss of visceral fat compared to the control arm or the placebo.
The way that the study was designed was very interesting in that for the first 24 weeks, patients were randomized with two to one being on Egrifta versus a placebo. But at 24 weeks, patients that were on placebo automatically were then put on Egrifta treatment. And the patients that were on the Egrifta treatment arm at the start of the study, they were re-randomized three to one to staying on Egrifta versus going to a placebo.
The visceral fat loss that was observed in the patients was seen, then persisted throughout the course of the study, as long as one was on [Egrifta]. Patients that went off of [Egrifta] and were re-randomized to the control arm, a placebo, then tended to show a reversal of those improvements.
So this is a drug that, once you start taking it, you need to keep taking it in order for it to be effective.
We believe that. However, studies haven't been done looking at the long-term usage of Egrifta. And this is one question or concern in clinicians' or physicians' minds, as to how long you need to keep your patients on Egrifta -- whether you can stop. Or can you put a patient on a lower-maintenance dose in order to maintain the benefits? But as I mentioned, these studies haven't been done. I'm hopeful that there will be more studies designed looking at these questions.
You said that the drug appeared to reduce excess abdominal fat by around 18%. What does that translate to in real terms? If people have that kind of fat gain and look at themselves in the mirror after having taken Egrifta for, let's say, a 26-week period, are they really going to notice that 18% difference?
Yes, it's actually a dramatic change. And actually, study patients who had more fat accumulation tended to do even better. Body image was also studied, with patients themselves having to answer questionnaires. Patients were able to say, or at least it was seen in the study, that body image, what's called "body image distress" or "belly profile," improved more with Egrifta use than with placebo.
Oh, so it's almost a mental health impact there.
Yes. When I saw patients after they experienced this drop in belly fat, it was very remarkable and sometimes often dramatic for me to see. And patients were extremely happy. It wasn't just noticeable, they were very happy with their results.
How often do people need to take the drug, and how is it taken?
Patients in the study were taking two milligrams of Egrifta by subcutaneous injection every day.
Where specifically did they inject?
They were injecting into their subcutaneous belly, or abdomen. In other words, they pinch their abdomen and just give themselves a small injection, not unlike an insulin shot.
Are there any particular concerns about the time of day you need to take it, whether it needs to be stored in a particular way, or whether it interacts with any other drugs?
I'm not sure much about drug interactions. There may have to be more studies looking at all the specific medications, but understand that growth hormone-releasing factor, or Egrifta, is mediated by insulin-like growth factor, or IGF-1, which is also not unlike Serostim. And that agent is being used widely without any concerns about drug interactions. I believe that this agent would also be safe to use with many medications and all the antiretroviral agents. From the study, patients were taking a wide variety of different varying antiretroviral regimens and it wasn't any problem in terms of what their regimens were.
This drug was specifically studied in people with excess abdominal fat. What's the extent of knowledge as far as how well or not well it will work for any other form of fat gain throughout the body?
Oh, there's been a lot of questions about people with different types of fat accumulation. Normal people that have, for example, subcutaneous fat as opposed to visceral fat -- obviously this drug has not been studied for that situation. But suffice it to say that the medication Egrifta, it showed a very specifically targeted effect on visceral fat with reductions. It didn't show any specific changes with limb fat that was significant in any way, nor in terms of subcutaneous fat.
You were referring to buffalo hump a little bit before. Is there any indication that it could help with that kind of complication?
In the study, and it hasn't been studied significantly, there have been some reports of one or two patients that have had fat accumulation such as buffalo hump that did get benefit when they were on the Egrifta. But again, this wasn't studied and it's hard to make any big conclusions from that.
True. And regardless, we're talking about a situation here where, if you have a very large belly, it doesn't sound like this drug is going to eliminate it completely. It just may make it better enough that it causes a significant improvement in your quality of life, from the sounds of it.
Absolutely. I think that patients often have depression and feelings of isolation when their body image has been altered to that degree. And it is my personal opinion that patients concerned about fat changes may have reasons not to take their antiviral medications. In my mind, in other words, lipodystrophy may be associated with poor adherence to medications.
So if there were medication or treatment that could combat the problem of fat accumulation or body image problems, then patients should have less depression, less feelings of isolation and better adherence to medications. I think that this was highlighted during the FDA meeting when several patients came forward and testified about how they felt about the fact that they were on Egrifta during the studies and what they got out of being on treatment.
What is the threshold then? How does a person with HIV, or a doctor who's treating a person who's HIV positive, know when a drug like Egrifta is worth trying?
We know that Egrifta causes, or has a potential to cause, a reduction in visceral fat accumulation. And we know that visceral fat accumulation is a part of the syndrome of lipodystrophy that has also been associated with increased cardiovascular risk. We know that, as they live longer and are aging, we're seeing higher rates of cardiovascular problems in this patient population.
So a physician that's seen patients with HIV infection, if he or she sees a patient who's developing the problem -- the patient's complaining about it or the patient's already noticing it, which is often how the problem emerges in the exam room -- I think it behooves the physician to consider what the patient is experiencing and to weigh out the benefits versus the downsides, which appear, at least from studies, to be minimal.
Patients who have the problem and are somewhat concerned about it and a little frustrated by it, any patient with visceral fat accumulation, can be a candidate for treatment with Egrifta -- and even patients that have mild diabetes problems can be a candidate. Although the study hasn't looked at specific patients with diabetes that require treatment, there is some foundation from which to believe that Egrifta or tesamorelin can be used to treat even those patients safely.
And you can't look away from the fact that Egrifta, by reducing visceral fat adiposity, may also have some benefits in terms of reducing the overall cardiovascular risks of patients -- but we cannot assuredly state this from the data, since the study wasn't designed to look at this. However, if one looks at the published articles of the studies, there were some reductions in triglycerides as well as cholesterol levels. So I believe that Egrifta will be useful in many patients with HIV infection who have visceral fat accumulation.
There were a couple of concerns. You had mentioned the minimal long-term risks of the drug. Those did come up a little bit during the FDA advisory committee meeting that met a couple of months prior to the approval of Egrifta. Although they did vote unanimously, it was 16 to nothing, that the drug should be approved, they did raise a couple of those potential long-term issues. Can you talk about them for just a moment?
Sure. There were some adverse effects that were observed during the studies, but in general, they seemed to be well tolerated and manageable. Patients taking Egrifta are more likely to get these effects because of how Egrifta works. It increases levels of insulin-like growth factor, or what's known as IGF-1. It's important to understand that some patients can experience events such as some joint aches, some mild swelling in their extremities such as their ankles, or get some mild stiffness in their joints, even some stiffness in their hands and feet, which I have found generally improves with some small exercises that tend to loosen the joints up. Some patients also had some injection-site reactions, some mild redness or tenderness at the injection site, which also clears up fairly quickly. It should be noted that there was a very small number of patients who appeared to have some allergic reactions such as one would expect -- the development of hives, etc.
But what you're referring to in terms of other concerns that came up at the FDA meeting, an important finding is that in the study, patients with mild diabetes did not show exacerbation of diabetes. But there were some small number of patients that experienced new diabetic symptoms. And in my opinion, this is a very small number.
It obviously is a concern. However, when looking at the total profile of the medication and the risks versus benefits, I believe that the committee felt that the benefits far outweighed the small number of patients that may have experienced new symptoms. And I believe that in terms of any other severe effects that would concern me, I'm not terribly concerned personally. I'm going to be monitoring my patients' blood sugars, as I believe other clinicians will be, especially people who are diabetic. From what I mentioned before, Egrifta's not really been studied in patients while on diabetes treatment, and this would be useful to investigate more closely, hopefully in phase 4, or post-marketing, studies.
There's also been a concern that because the mechanism for Egrifta increases IGF-1 levels, that being a growth factor, it may cause development of cancers. But there's been no evidence, at least with Egrifta treatment at present, of that occurring. But I think as patients use this more long term, it'll be very important to continue documenting and to continue monitoring our patients to learn more.
I think there was also something mentioned at some point during that advisory meeting about people developing antibodies to Egrifta and, as a result, having the drug become less effective over time.
Yes. Actually, in the studies, I believe somewhere around 50% of patients had developed IgG [immunoglobulin G] antibodies to Egrifta. However, despite that, most of the patients have continued to derive benefit.
There was a very small number of patients, I mentioned earlier, that had allergic reactions. And all those people that developed allergic reactions also had those antibodies to Egrifta. But it's not known whether the antibodies to Egrifta have any relevance to its efficacy.
Egrifta is the first drug that's been approved for this use: to treat any kind of fat gain, specifically in HIV-positive people, right?
Are there any other drugs out there, whether approved or in late development, that work similarly to Egrifta?
There have been a lot of medications that have been looked at to treat lipohypertrophy, or fat accumulation. But, as you say, currently there's been no other drug or medication that has ever been approved to treat visceral fat accumulation. So Egrifta is definitely the first.
In terms of what other things can be done for patients with fat accumulation: As I said earlier during this interview, certain antiviral agents can be metabolically unfriendly. Some studies have looked at switching therapy, in other words, switching to another effective regimen of medications. However, when these switch studies were done, the effects were modest and sometimes not consistent. Currently, we have the good fortune of having many new agents that were approved in recent years. And most of these therapies are felt to be patient-friendly treatment. So switching is now very limited use.
Other things, such as, for example, anabolic steroids were looked at. Low testosterone levels, for example, are seen in HIV-positive patients and are associated with visceral abdominal fat accumulation. But while we've sometimes used testosterone replacement in our patients, these individuals show increases in lean body mass or muscle tissue. It didn't really result in decreases in visceral abdominal fat in our patients.
Growth hormone, or Serostim, has been studied. Growth hormone resulted in significant decreases in visceral fat. However, Serostim did not get approved for use in this circumstance. And we believe that this is due to the severity of side effects that was associated with Serostim; that included significant development of diabetes, or changes that led to imbalance, or increased blood sugars.
Other treatments included other medications, such as some medications used to treat diabetes, like metformin. Metformin showed only a non-significant change. [Editor's note: "Non-significant" is a research term meaning that, although there was a change, it may simply have been due to chance.] Other diabetes medications, such as the insulin-sensitizing agents -- troglitazone, for example, was looked at, but that also didn't show significant improvement, and was eventually withdrawn from the market due to liver problems.
Other things that we try to do for our patients: One thing that I try to stress with my patients is that a change in diet can have some benefits. I've often advised my patients to reduce fat and some types of sugars, and begin with what's called a Mediterranean diet. Also, have smaller, more frequent meals as opposed to large meals. And combine this with exercise. Both diet and exercise have been independently shown to decrease abdominal visceral fat and improve lipids, such as cholesterol and triglycerides, and also benefit better glucose control.
All of this again leads to reduced cardiovascular risk, which I think is a big focus for our patients as they live longer now. But in terms of diet and exercise, it's sometimes difficult to get patients into the habit of making those kinds of changes.
That's the debate that seems to go on a fair bit among people who have a lot of fat gain and then decide to resort to liposuction, for instance, instead of a diet or nutrition or exercise change in order to resolve the problem.
But when we're talking about this particular type of fat gain, doesn't this tend to be something that people don't really have much control over?
Well, true, certainly if it's due to their HIV infection and due to medication, there is a certain amount of non-control in terms of fat accumulation developing. But I strongly believe that individuals who maintain exercise regimens, who subscribe to a diet such as the Mediterranean type of diet, have a lot less potential for developing the problem in general. They can develop lipoatrophy, in other words, loss of fat. But in terms of lipo-accumulation, I believe that they're less likely, or the severity of what they'll see will be much less than seen otherwise because from just the logical sense: If you're exercising normally, you're going to be burning body fat, oxidizing fatty acids. Your body's going to be working more metabolically efficiently and you'll be using your nutrients more efficiently. Your cells and mitochondria will be working more efficiently.
So then to take a step back, we're looking at a situation where we still have people developing or continuing to have this excess belly fat, this visceral adiposity that you had mentioned. And we suddenly have this new option on the table that can be used to potentially treat it, at least in part.
So for you, as an HIV doctor, what would you recommend for your HIV-positive patients who might be developing fat gain, or who might want to avoid it in the first place? Does it start with diet and nutrition? Is that what you focus on and only resort to Egrifta later on? Or is there a point at which you're like, "You know what? I know this person's been on treatment for 10 years. They've had this for a while. I should just start them on this immediately"?
I think it's going to be patient-specific, knowing your patients and taking them as individuals. So for a patient who has lousy eating habits and doesn't exercise, obviously you want to target them, you want to get them to get into better habits. And also, as I mentioned earlier, we're always looking at the overall benefit in terms of reducing cardiovascular risk for our patients. So that's very much consistent with that line of thinking.
As you said, say you have seen a patient for several years and you've already talked to him or her about a diet, or you know that the patient is not going to be good at that -- just by understanding the patient's personality and habits -- I think that it's then reasonable to try Egrifta. But again, I always believe that we should be counseling our patients in terms of diet and exercise wherever possible.
Also, in terms of reducing cardiovascular risk, if patients have elevated lipids, [then recommend they go] on a statin, for example; if they're a smoker, try to help them to try to quit. All of that is part of trying to reduce the long-term complications that are now being seen in people with HIV as they live longer.
I think that Egrifta is an option for patients that have visceral adiposity. You can use it as first line, or you can use it in combination with some dietary habits or for people that are not going to effectively change dietary habits. I think Egrifta is an option. And I think it's going to be widely used.
Yes, and we'll see how things pan out, particularly over the long term as people begin to use it more frequently.
Daniel Berger is the medical director and the founder of NorthStar Medical Center in Chicago. He's also a clinical associate professor at the College of Medicine at the University of Illinois at Chicago. Dr. Berger, thank you so much for taking the time to talk to us.
This transcript has been lightly edited for clarity.
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
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