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[Editor’s note: Donald Kotler, MD, a professor of medicine at Columbia University and chief of GI at St. Luke’s Roosevelt Hospital Center in New York City, answers questions about the problem of lipodystrophy, a potential treatment for it, and other issues related to the long-term adverse effects now associated with HIV disease and antiretroviral therapy. Kotler is involved with research into the use of somatropin (Serostim), a recombinant human growth hormone that appears to be of benefit to patients who have lipodystrophy, also called HIV-Associated Adipose Redistribution Syndrome. A Serostim clinical trial currently is recruiting 200 patients at trial sites across the United States.]
AIDS Alert: Are lipodystrophy and other adverse effects of antiretroviral medications, including heart disease, the biggest challenges that physicians face in treating HIV patients these days?
Kotler: The relationship to heart disease is not yet established. My own personal feeling is that that link will be made; it has not yet been made, and in my own mind that is perhaps the most significant downside of therapy. It is not the only one, and perhaps the other major downside of therapy would be osteopenia, bone loss, which has also come up over the past few years as being an important consideration. Both of these problems are serious enough in the adult HIV population but maybe even more problematic in the pediatric population.
AIDS Alert: Tell us a little more about that, please.
Kotler: One of the findings that’s been made in relationship to lipodystrophy or the potential bad outcomes that would come from lipodystrophy, such as heart disease, is that it’s a time-dependent phenomenon. People have not yet demonstrated clear evidence of increased risk of heart attacks because the follow-up is so short. The data presented at the 8th Conference on Retroviruses and Opportunistic Infections in Chicago, however, suggested that we will be seeing an increased risk of heart disease, but it may take several years of follow-up before that becomes manifest.
When you consider there is a time element, who has more time for bad outcomes to develop than little children? If we’re worried that adults may have a problem over the course of five to ten years, how about little children whose course of disease is a whole lifetime, maybe thirty to forty years? If there is going to be a problem, then it may be magnified in pediatric patients.
AIDS Alert: What is being done right now in the field of research and in treatments that are available to counteract this phenomenon?
Kotler: There is really one question that has to be asked, and that is: What is the phenomenon? What is lipodystrophy? There is a constellation of signs and symptoms that have developed, and they include changes in the body’s metabolism. Those changes are specifically high blood lipids and insulin resistance, a pre-diabetic condition, and a change in the body shape.
The change in the body’s shape includes both a loss of fat and a loss of fat especially from the fat under the skin. Much of the fat in the human body is located underneath the skin, as opposed to being deep inside. So it’s the fat under the skin that seems to be disappearing. Instead, fat deep inside the belly appears to be increasing in size. That’s a typical shape — the big belly, skinny arms and legs — of people who have diabetes and heart disease as an associated problem. To see that kind of shape coming up in an HIV-positive person is what originally made people worry about cardiac disease as a bad outcome.
AIDS Alert: What can be done about it now, and what do we need to do in the future?
Kotler: Nobody knows why it’s occurring. No one knows for certain whether it is a single phenomenon or a group of related phenomena, whether it has a single cause or whether it comes about for a variety of reasons.
We’re unsure which paradigm or model lipodystrophy really fits. Is lipodystrophy like tuberculosis, where if you are exposed to the TB bug you are bound to get it? Or is lipodystrophy more like a stroke or a heart attack, in which certain aspects will make it more likely or less likely, but nothing will determine that you absolutely will or will not get the disease?
Since we don’t know what lipodystrophy really is, we can’t really have a treatment for lipodystrophy, for all of it. It seems more and more that it’s not a single disease, but multiple diseases, and problems of high blood fats may be different from the ones that lead to fat loss. For that reason, people are looking more and more at trying to treat the individual problems. People are looking at therapies for high blood lipids. People are looking at therapies for food resistance. People are looking at different therapies for fat loss and different therapies for fat gain.
In fact, the Serostim trial is really directed at the fat gain associated with lipodystrophy. It’s to get rid of the excess fat. Most people think of the drug as an anabolic agent, a drug that puts on muscle and is a performance enhancer. But when you look at the studies that have been done, it really is quite a powerful fat burner, so that almost as much lean mass as is gained is actually lost in fat. So someone can take a drug like Serostim and have a huge change in the body’s composition and yet not really change body weight much at all. They may gain four to five pounds of lean mass and lose four to five pounds of fat, and body weight doesn’t change very much.
AIDS Alert: How are you and other researchers hoping Serostim will address the problem of lipodystrophy?
Kotler: One of the things that’s unusual about lipodystrophy is that it’s kind of familiar. It’s kind of familiar in the sense that people have been seen for a long time who have a kind of lipodystrophy-type of appearance. It’s a syndrome called the metabolic syndrome X, and this metabolic syndrome is one that is associated with fat accumulation in the belly, similar to where it accumulates in lipodystrophy patients; high blood lipids, insulin resistance, and a risk of heart disease or stroke.
You may have heard of a designation of women shaped like apples or pears. The importance of trying to distinguish between women shaped like apples and women shaped like pears is the fact that apples get diabetes, apples get heart attacks, and pears do not. The body shape is related to the outcome and to the metabolic phenomenon, like diabetes, heart attacks, etc., and that’s not HIV infection. That’s a phenomenon of the body itself. We’ve seen this before.
Interestingly enough, studies have been done that have suggested that people who have fat accumulation in the belly, of a kind that you would see similar to the HIV-positive people, appear to have some impairment in the secretion of growth hormone. In addition, people who are growth-hormone deficient have increased fat in the belly, and the metabolic profile is beginning to look more and more over time like someone is getting set to have a heart attack. If that’s not enough, treatment of such people with growth hormone therapy actually makes the fat in the belly less, and that’s all in non-HIV-infected people. Now, most recently, studies in HIV-infected people have shown essentially the same thing: that HIV-infected people with excess fat in the belly also have a decrease in the secretion of growth hormone. So perhaps it’s a similar phenomenon.
So the thought of replacing growth hormone in an attempt to decrease fat in the belly — and maybe, at the same time, to decrease cardiac risk — becomes a logical extension of what’s known in the non-HIV infected field.
There are other things to be studied for treatment of lipodystrophy. There are no real data for testosterone, but testosterone can burn fat just as it increases lean mass like Serostim.
AIDS Alert: Tell us a little about what the studies to this point have shown with regard to treatment of lipodystrophy.
Kotler: My lab, along with a community research group called Community Research Initiative on AIDS in New York City, performed a pilot study initially looking at 30 HIV-infected subjects, mostly men but some women as well, who were given the standard dose of Serostim, the same dose we would use for someone who was malnourished, wasting. We found a very positive effect in increasing lean mass and burning fat. We actually saw a stronger response than we’ve seen when Serostim was used just for wasting. In fact, associated with that was a decrease in the accumulated fat in the belly, but the amount of fat in the belly appeared to fall disproportionately. Whereas the total fat in the body fell by about 20%, the amount of fat under the skin fell by less than 10%, and the amount of fat in the belly fell by more than 40%. So it appeared to be there was a preferential loss of fat from the abdomen. The effect that was seen in the HIV-positive people with lipodystrophy was actually greater than the effect when it was studied for wasting.
It was not all good news. When the drug was stopped, the fat began to reaccumulate. So this was not a cure; it was a treatment. When you think about it, it was much the same as any hormonal treatment. As I mentioned, there is some data from another lab that suggests that there is a suppression of growth hormone secretion in patients with lipodystrophy. What this would suggest is that when the drug was given, a new steady state was set up, and when the drug was taken away, the drug reverts back to its prior steady state. It is not a cure, it’s just the physiology, the steady-state phenomenon.
We realized that we didn’t have a cure and that we were just altering a steady state. The drug appeared to be moderately toxic; there were a fair number of side effects to using the drug. So after the first study was finished, we had a second part of the study in which we gave a much lower dose of therapy. This showed that the lower dose of therapy had fewer side effects, and it still had some efficacy — less, but some.
Maybe the amount of growth hormone that’s given could be a much smaller amount than what we have been using for wasting, and that could be a great benefit, because one of the downsides to Serostim therapy is cost. If it’s true that it might even need a fraction of the doses that have been given, then perhaps that might be given at a fraction of the cost.
One of the aims of a new study is to reduce the amount of growth hormone used for treatment. In this study, we’re using much lower doses than what we were using before, based upon what we found in the pilot.
AIDS Alert: Would you please describe the study?
Kotler: It’s a double-blind, placebo-controlled trial looking at two doses, both lower than the dosage currently being used. After the initial 12 weeks, there is a prolonged open-label phase. It’s a re-randomization so people who were given no drug will be given a drug to take, and the opportunity for evaluating lower doses of drugs for much longer periods of time will be available.
AIDS Alert: Where can clinicians and HIV patients find more information about the study?
Kotler: For more information about the Serostim clinical trial, call (888) 566-5593 or visit Serono Inc.’s web site at www.seronostudies.com.