New treatments for HIV associated lipodystrophy beyond Egrifta

Question from a person living with HIV:
May 2, 2012

I body build and work out, eat right, etc. The lipodystrophy I accumulated during my early use of Crixivan and others doesn't really go away that much. It's frustrating, depressing.

I do also appear to have some features of "muscle belly" where there is a space between my lower abs (possibly caused by strain). I've read about adbominoplasty.

Apart from egrifta, which my ID doc does not recommend, what other options are there now or on the horizon?

I want to get a CT scan of my gut to see just how pervasive it is. But to my knowledge, it's not just easy to go in to the organ area and remove the omentum, etc. That's all very risky.

Over the years I've gotten very depressed about it, even to the verge of eating disorders. I have 2 closets full of nice shirts that I can't/wont wear, as my gut protrudes. I'm otherwise very in shape and muscular.

What can I do? Is there any hope for this problem...

Answer from Nelson: New treatments for lipodystrophy beyond Egrifta

AIDS Activists Support the Approval of Egrifta- But With Some Conditions for Theratecnologies and Serono

17 May 2010

Paul Tran, BS Pharrn, RPh Advisors and Consultants Staff Center for Drug Evaluation and Research Food and Drug Administration 5630 Fishers Lane, HFD-21 Rockville, MD 20857

Dear Mr. Tran:

On behalf ofthe Drug Development Committee (DDC) ofthe AIDS Treatment Activists Coalition (ATAC), I am writing to urge members ofthe Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) to recommend approval of Egrifta (tesamorelin) for the treatment of HIV-associated lipohypertrophy (NDA 22-505). This letter of support is submitted free of influence, financial or otherwise, from the NDA's sponsor, Theratechnologies, or Egrifta's planned U.S. distributor, EMD Serono.

Though the exact prevalence of lipohypertrophy among HIV -positive patients is not well established-the prevalence of the broader lipodystrophy syndrome is believed to be between 18 and 81 percent of people living with HIV-it has been an established comorbidity in the HIV patient population since the mid-1990s. Indeed, it is one of the only clinically significant HIV-related manifestations for which there is no proven treatment modality approved for use.

After review of the published data, we firmly believe that Egrifta, with its moderate efficacy profile and minimal adverse effects, should receive an EMDAC approval recommendation and cleared for marketing by the Food and Drug Administration (FDA). However, we remain sensitive to the fact that there are lingering concerns and questions regarding Egrifta's long-term efficacy and safety. Thus, our support for approval hinges on the establishment of post-marketing safety and efficacy features, clearly written into the product's labeling, along with a commitment to conduct additional safety and efficacy evaluations.

ATAC. 611 Broadway, #308 . New York, NY 10012.646/284-3801. admin@atac-usa.org

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Interpretation of Efficacy Evaluations

Our initial optimism began with the successful completion of seven Phase II studies showing clear benefits-with minimal adverse events, notably a statistically significant increase in rates of glucose intolerance and diabetes mellitus-associated with 2 mg daily dosing of Egrifta.

The 26- and 52-week efficacy data from Theratechnologies' two Phase III studies, LIPO-Ol0 and CTR-l0lljCTR-l012, solidify our encouragement. The 15 percent and 11 percent reductions in visceral adipose tissue (VAT), respectively, after 26 weeks (and maintained reductions among patients treated for 52 weeks) and the differences in the intent-to-treat and per-protocol analyses with respect to the primary endpoint (a VAT reduction of ~8 percent) are proof-positive of Egrifta's potential for HIV-infected patients with lipohypertrophy. We are also heartened by Egrifta's secondary benefits, compared with placebo, including decreases in waist circumference, increases in lean body mass, preservation of subcutaneous adipose tissue (SAT) and significant improvements in triglyceride levels and other CVD-related biochemical indices.

It is disappointing that the Phase III studies lacked the design and resources needed to validate decreases in VAT as a surrogate marker for reduced cardiovascular disease (CVD) risk, in light of data indicating that VAT and increased waist circumference is a predictor of clinical and subclinical CVD in both HIV-positive and HIV-negative individuals. There is undoubtedly a need for observational and randomized, controlled studies exploring the effects of VAT -reducing agents, including Egrifta, on the absolute and relative risks of serious cardiovascular and cerebrovascular events, as well as other clinical manifestations such as sleep apnea and pancreatic, liver, pulmonary and vascular functioning.

There is, however, much to be said for patient reported outcomes of both studies. These data cannot be overstated given the disfiguring and stigmatizing effects of lipodystrophy. Increases in VAT have clearly been shown to be associated with psychological distress, impaired quality of life measurements, reduced willingness to commence antiretroviral (ARV) therapy and poorer adherence among those on ARV treatment.

As is clearly documented in the published data, Egrifta treatment is associated with significant improvements in patient ratings of belly and body appearance distress, along with improvements in physician ratings of belly profile. These comprehensive data are unmatched by any other lipohypertrophy-reversing strategy explored thus far.

ATAC. 611 Broadway, #308 . New York, NY 10012.646/284-3801. admin@atac-usa.org

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Interpretation of Safety Evaluations

Unlike the last hormonal agent (Serostim; recombinant human growth hormone) reviewed and ultimately rejected by the FDA for the treatment of lipohypertrophy, the 52-week data from Egrifta's two Phase III studies are encouraging with respect to safety. Indeed, they establish that Egrifta's moderate efficacy outweighs Egrifta's minimal adverse effects.

Rates of injection site reactions, including localized hypersensitivity, appear to be more common among Egrifta-treated patients compared with placebo recipients. These rates, however, are dwarfed by those associated with another injectable agent, Fuzeon (enfuvirtide), used by people living with HIV.

While there also appeared to be slightly larger rates of growth hormone-related adverse events, such as arthralgia and edema, among patients receiving Egrifta compared with placebo, the reported percentages do not compare with the high rates of growth hormone­related events seen in Phase III clinical trials of Serostim.

Phase II and Phase III studies have consistently documented that Egrifta has an extremely limited effect on glycemic measures and did not appear to significantly increase the risk of glucose intolerance or diabetes mellitus. In fact, as is documented in the available data, patients with diet-controlled diabetes can receive Egrifta without an increased risk of untoward effects. Though an increased risk of glucose intolerance or diabetes cannot be ruled out completely and should be studied further, the risk-at least over 52 weeks of treatment-is minimal when balanced against the drug's moderate efficacy.

Egrifta's highly variable effect on insulin-like growth factor 1 (IGF-l) in a significant number of patents is not without potential concern. While we understand that these variations have not been associated with any clinically meaningful adverse effects, we believe that additional, long-term data are necessary to confirm these initial findings.

Another concern is the development of anti-tesamorelin IgG antibodies in a sizeable number of study participants. Though we are aware of data concluding that antibody production to this peptide is not associated with any clinically meaningful decreases in efficacy or increased rates of adverse events, we have not yet seen research exploring whether anti-tesamorelin IgG antibodies have an effect on endogenous growth hormone production after drug cessation. We are also unaware of data exploring the potential of these antibodies to shunt treatment responses to Egrifta in the event the drug is stopped and then restarted. These data, if not already compiled and analyzed, are necessary.

As with virtually every agent that has been considered by the FDA for an HIV indication, we are not without concerns regarding the long-terms safety of Egrifta. Knowing that the drug

ATAC. 611 Broadway, #308 . New York, NY 10012.646/284-3801. admin@atac-usa.org

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will need to be continued-perhaps indefinitely-to maintain reductions in VAT, we firmly believe that the product's labeling should feature prominent safety-related instructions for clinicians and patients, notably the need for regular glycemic and IGF -1 testing, along with cancer screenings, with recommendations to terminate Egrifta therapy when appropriate.

We also believe that a recommendation for Egrifta's approval be met with a commitment from the sponsor to conduct a long-term post-marketing study-either observational or randomized in design, following patients for at least three to four years-to collect data regarding the long-term safety of Egrifta.

Further Recommendations

In addition to our request for long-term safety data via a post-marketing study, we advocate for the following:

1)     Phase IV evaluations of Egrifta-associated VAT reductions on the risk of CVD. Though Theratechnologies should not be required to evaluate Egrifta in studies employing myocardial infarction or ischemic stroke as endpoints as a condition for approval, we believe that post-marketing studies exploring associations between VAT reductions and softer measures ofCVD-such as vascular function-should be required.

2)     Required Phase IV studies exploring the effects of Egrifta-associated VAT reductions on other clinical outcomes, including fatigue, gallbladder disease, liver disease, osteoarthritis, pulmonary function and sleep apnea.

3)     Required Phase IV studies exploring Egrifta in combination with exercise and/or diet modification to determine if VAT can be synergistically decreased.

4)     A required Phase IV gender-balanced clinical trial evaluating the safety and efficacy of Egrifta in HIV-positive women with lipohypertrophy compared with men.

5) The approved labeling should spell out the indication for Egrifta treatment, along with indicators of effectiveness while receiving therapy, to ensure that the risk­benefit ratio is maintained for each patient. Though slice CT scans were used to measure VAT reductions in the Phase III clinical trials, these will not likely be practical in the clinical setting. Waist circumference, waist-to-hip ratio and basic psychological/body image assessments are much more feasible and should be employed by clinicians when considering patients for Egrifta and while monitoring their progress (or lack thereof), at regular time points, for as long as treatment is continued.

ATAC. 611 Broadway, #308 . New York, NY 10012.646/284-3801. admin@atac-usa.org

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6)     Approve Egrifta as a medical/reconstructive modality. We strongly urge against reviewing, approving, or labeling Egrifta as a cosmetic treatment. Though Egrifta­associated VAT reductions have not yet been established as a marker of reduced CVD risk, its effects on patients' body-image perceptions, sense of well being and quality of life is substantial. This is no different than breast reconstruction following a mastectomy-an unquestioned medical approach to minimize the negative psychological effects stemming from vital but disfiguring treatment.

In conclusion, we sincerely hope that EMDAC panelists will appreciate that the approval of Egrifta, with its favorable efficacy and safety profiles, is supported by this coalition of AIDS treatment activists that has closely followed the development of this agent, carefully scrutinized the published data and-perhaps most importantly-remains eager to see this option made available to address this long-standing unmet medical need.

Respectfully submitted,

Tim Horn Drug Development Committee AIDS Treatment Activists Coalition

cc:

Mary Parks, MD Director, Division of Metabolism and Endocrinology Products

Richard Klein Office of Special Health Concerns

Kimberly Struble, PharmD Division of Antiviral Drug Products

ATAC. 611 Broadway, #308 . New York, NY 10012.646/284-3801. admin@atac-usa.org

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Update on Body Shape Changes and HIV

This Month in HIV: 2009 Update on Body Shape Changes and HIV
A Conversation With Dr. Donald Kotler and Patient Activist Nelson Vergel

April 2009




From TheBody.com


Body shape changes are some of the most frustrating complications of HIV and HIV medications. Whether it's the loss of cheeks or the sudden swollen midsection, people with HIV have been mostly dealing silently with these issues since there are few treatments available. In This Month in HIV, HIV activist and long-time survivor Nelson Vergel leads a discussion with Donald Kotler, M.D., who is an expert on metabolic complications and HIV. They will fill us in on some of the latest updates on this issue.

Nelson Vergel: Hi, Bonnie. Thanks for having me here. And thanks to Dr. Kotler for joining us.

Dr. Kotler, I'd like to start with some basic questions, if you don't mind, to cover the basics about body changes and HIV.

In your opinion, how widespread are body changes in the HIV-positive population? Is there any way that somebody who was recently diagnosed with HIV can know how probable it is that he or she will experience body changes?

Dr. Donald Kotler: That's two questions.

The first one: How frequent are the body shape changes?

The answer is that it depends which shape you're talking about. Some people gain body fat, and others lose body fat. Of the people who gain body fat, for example in the belly, or behind the neck, it's about one-third of patients who have that kind of problem.

In terms of losing body fat and getting really skinny legs, or the skinny face that people notice that's so stigmatizing, in the old days it was almost everybody, and currently it's not many people.

With the change in the antivirals, specifically the stopping of the use of stavudine [d4T, Zerit] and limiting the use of zidovudine [AZT, Retrovir; this drug is also included in Combivir and Trizivir], many fewer people get really thin from lipodystrophy.

Now, the second question: Is there any way that somebody recently diagnosed can avoid these issues?

I gave part of the answer. You can avoid the loss of fat by the choice of medications. Very few people in the United States are taking the medications that will cause body fat loss.

A way of preventing body fat gain was shown about a year and a half ago at the international meeting in Sydney, Australia. Limiting the amount of weight that's gained as people start antivirals will limit the amount of fat that ends up in the belly.1

Nelson Vergel: How do we actually limit the amount of weight that people gain when they start HIV medications?

Dr. Donald Kotler: That's a good question. In the study, which was from Brazil, they use what's called the NCEP [National Cholesterol Education Program] diet. [NCEP was launched in November 1985 by the National Institutes of Health to help reduce illness and death from coronary heart disease in the United States.] It's a healthy diet for somebody with heart disease; it asks people to moderate carbohydrates, decrease fat and consume more fiber. So you tend not to eat things that are so rich and so dense in calories.

It's a standard type of diet for people with heart disease. At least in the study that was presented, people who started their first regimen, plus the diet, gained much less weight -- their cholesterol didn't go up nearly as much and their belly didn't get nearly as big as people who were allowed to eat whatever they wanted.

Nelson Vergel: Dr. Kotler, another issue is the actual word that we use for these changes. People have been using the word "lipodystrophy" for a long time. Is that still a correct word for what's happening in HIV?

Dr. Donald Kotler: Not really, though when you say it, everybody knows what you're talking about. So you could probably get away with it. But lipodystrophy, the classic lipodystrophy, really referred to genetic problems. It was something that people were born with that, as they developed, would show the wasting, would show the thinning of the skin in their face and arms and legs, etc.

The term lipodystrophy with respect to people who are HIV infected is used to mean anything -- fat loss or fat gain, which are not necessarily related, diabetes or high cholesterol, which, once again, may or may not be related to any of the other problems.

We would probably be better off if we were to call fat gain "lipohypertrophy," fat loss "lipoatrophy," and then talk about problems with sugar and fat separately, rather than try to make them all into the one thing.

Nelson Vergel: It is not one thing; they are different syndromes that may happen together or separately.

Dr. Donald Kotler: Right.

Nelson Vergel: You're saying that lipoatrophy -- which is fat loss under the skin in the extremities (e.g., legs), body and face -- is actually not occurring as much in the United States, because we're not using AZT or d4T. But how about fat gain? Is fat gain occurring as much as we used to see it in the '90s, for instance?

Dr. Donald Kotler: Fat gain is, I believe, as common now as it's ever been. I don't think that that's really changed. About one-third of the patients complain of fat gain.

Bonnie Goldman: Are most of the complaints about belly fat? Or are people still seeing fat gain in their neck? Is there one that's more likely?

Dr. Donald Kotler: Belly fat is much more likely. Belly fat is, like I said, a problem in about a third of the patients. Of the people who gain fat behind the neck, probably somewhere between 5 and 10 percent will have a big growth.

Interestingly enough, there are some obese people, who are not HIV infected and not otherwise ill, who actually have small humps. The humps are called buffalo humps, but in HIV, they seem to grow much, much larger.

Nelson Vergel: Dr. Kotler, how does somebody know if they're gaining more weight than normal because they're eating more, or whether it's something related to HIV, or HIV medications?

Some people complain about increased appetite once they start HIV medications. Is the fat gain related to their caloric intake (i.e., how much food people are actually taking in)? Or is there something else -- maybe the fact that their immune system may be getting better?

Dr. Donald Kotler: You know how much weight you can lose when you're sick and then, after you're done being sick, how much weight you can gain, and how fast you can gain weight just when you become healthy?

It turns out that when people start their antivirals, especially when the T cells are down around 200, they are sick. They may not know it. They may not realize it. But they're sick.

If you think about it, antivirals are not appetite stimulants. They're not anabolic agents. So how come people are gaining so much weight? I think the answer to that is that they were sick and had lost weight; so people were thinner than they would normally be and when they take antivirals, it brings them back to a normal weight -- "normal" in the United States is at risk of obesity.

Nelson Vergel: So it is actually better for somebody to start treatment when they're healthier, if they want to avoid any body changes? Is that it?

Dr. Donald Kotler: The literature would say yes. People have looked from the very start as to what makes people lose weight, what makes people gain weight. It turns out that it's a lot of things. Things related to the patient -- for example, family history.

Before you got HIV, if you were 280 pounds, you're probably a lot more likely, when all is said and done, to complain of a big belly than to complain of skinny legs. Whereas if you started out 5'10", 130 pounds, you are probably much more likely to complain that your face looks bad or the veins in your legs are really prominent, than complain of having a big belly.

If everybody in your family is obese, you're probably more likely to have problems on therapy by being obese rather than being skinny.

Nelson Vergel: Have you seen any differences whatsoever with respect to what people start with? Different types of HIV treatments? Are there any data out there that show whether people who start, for instance, on Atripla [efavirenz/tenofovir/FTC] versus Kaletra [lopinavir/ritonavir] or Truvada [tenofovir/FTC] have any differences in body changes?

Dr. Donald Kotler: There are not a lot of data on that, I must say. I don't know that I answered the last question well enough. But, there are many factors that will affect what happens to the patient. These factors can be related to the virus, they can be related to the HIV medication or they can be related to the patient himself, or herself.

For example, family history is related to the patient. Taking a drug like d4T is related to, obviously, the drug. Many people have several of these predisposing factors.

Nelson Vergel: Lipodystrophy (or what we used to call lipodystrophy and are now calling metabolic disorders) also includes increases in triglycerides and cholesterol, especially the bad cholesterol, and decreases in HDL [high-density lipoprotein], the good cholesterol.

Are people with increases in cholesterol and triglycerides more prone to having belly fat increases? Have you seen anything on that subject?

Dr. Donald Kotler: In general, people with a lot of belly fat tend to have increased levels of cholesterol. But there are some medications that, even if given to people who are very thin, will cause cholesterol levels to go up. And there are certain genetic tendencies in people that may make their cholesterol go up high, often when they take antivirals, whether or not they are obese. So you don't have everything or nothing. You can have a big belly and high cholesterol, but you don't necessarily have to have a big belly to have high cholesterol.

Bonnie Goldman: Dr. Kotler, can you specify which medications you are referring to in terms of raising the cholesterol, or raising the fats in the blood?

Dr. Donald Kotler: The one that does it more than any other is ritonavir [Norvir]. It turns out that it depends on how much you take. If you take, for example, the drug Reyataz [atazanavir], you only take one Norvir. If you're taking Kaletra, on the other hand, you take two Norvir. If you take the drug tipranavir [Aptivus], I believe you end up taking four Norvir in a day -- because that's what you need in order to get good drug levels to keep the virus under control. But it turns out that the more Norvir you take, the higher the fat levels are in the blood.

Bonnie Goldman: In Kaletra, you're taking the Norvir within the one pill that you're taking.

Dr. Donald Kotler: Right. You don't take a Norvir tablet. It's inside the Kaletra tablet.

Bonnie Goldman: Many people aren't aware that when they're taking Kaletra, they're also taking Norvir.

Nelson Vergel: Dr. Kotler, another assumption people make -- and I think even some clinicians out there -- is that if you treat high cholesterol with a cholesterol-lowering drug, or anything else that treats it, you will tend to decrease belly fat. Is that a right assumption? Are there any data to substantiate that?

Dr. Donald Kotler: No. It's the other way around. If you have a big belly and high cholesterol, and you make the belly small, the cholesterol will go down.

But if you have a big belly and high cholesterol, and you take a drug to lower the cholesterol, it may not do anything to your belly.

Nelson Vergel: Are there any treatments right now for the belly fat gain?

Dr. Donald Kotler: No. There are no treatments that are approved by the FDA [U.S. Food and Drug Administration]. Obviously, losing weight does something, although many people will say it doesn't do nearly as much as they want it to. You try to lose weight to lose your belly, but then you lose your butt, or your face looks worse and your belly doesn't change all that much.

Nelson Vergel: How about exercise?

Dr. Donald Kotler: Some people do that. Exercise will do it. The exercise that tends to do it is more resistance training exercise (i.e., lifting) than aerobics, surprisingly enough.

Nelson Vergel: Some people are actually afraid of aerobics because of fat loss.

Dr. Donald Kotler: Exactly. There are other people who have shown that some of the antidiabetic medicines, such as Glucophage [metformin], have been shown to decrease belly size.

There were several studies that looked at the drug growth hormone. Growth hormone did significantly lower belly size, but the FDA didn't approve it, likely because they were not happy with the side effect profile. They thought it was too toxic a drug.

Now, a month and a half ago, there was a meeting in London, the 10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. At that meeting, two other treatments were talked about. One was a drug called IGF-1 [insulin-like growth factor 1], or IGF-1 combined to a binding protein.

It's what growth hormone causes to happen. But here, rather than using growth hormone, they use the IGF-1. And rather than this worsening toxicity, worsening blood sugar, it actually made it better. It also caused an anabolic effect: lean mass went up and the amount of fat in the trunk went down. But it didn't really lower it as much as had been seen before with growth hormone. But it was a little, tiny study, just to show that it could work.

In addition, there's a drug called tesamorelin, which [acts as a] growth hormone-releasing factor. So when you give tesamorelin, you get a growth hormone-like effect and that also causes belly fat to go down. It doesn't cause glucose to get worse, like growth hormone does.

At this same meeting in London, Julian Falutz from Montréal looked at the two studies of this drug, tesamorelin, to see if it mattered what kind of antivirals are used.2 Does it matter if someone is taking protease inhibitors or the non-nucleosides? Does it matter whether someone is taking Kaletra or Sustiva [efavirenz, Stocrin]? It turns out that it doesn't matter. The drug tesamorelin will cause body fat to decrease. It will cause belly fat to decrease, no matter what your drug is.

Nelson Vergel: That drug is not approved yet?

Dr. Donald Kotler: The drug is not approved yet. But there have been several studies that have shown its benefit -- three, actually. I believe the FDA is looking at it now or, if not now, very, very soon. [Click here for more on tesamorelin.]

Nelson Vergel: If you were an HIV-positive patient, right now, in 2009, and you had problems with belly fat, what would you do? Just diet and exercise? Is that all we have?

Dr. Donald Kotler: Right now diet and exercise are the best hope. I would not treat with an antidiabetic medicine in the absence of diabetes.

Nelson Vergel: So you're not sure whether, for instance, Glucophage, which is an antidiabetic drug, would do anything for somebody who is experiencing belly fat gain.

Dr. Donald Kotler: Let's say you have to wear a size 40 pants, or keep your pants so low that your belly hangs over in a not very nice looking way, and you start taking Glucophage. Your waist will probably go from 40 to 39. You wouldn't go down to a 33, or a 32, or even a 34. The effect of Glucophage is really tiny.

When it was used at high doses, the effect of growth hormone was more like two or three inches. You'd go down to a 37 or a 36 waist. But it was real toxic and caused a lot of problems. Drugs like tesamorelin cause your waistline to decrease only an inch or so.

Nelson Vergel: The unfortunate thing, in my point of view, is that we haven't really seen combinations of therapy. For instance, researchers have not looked at exercise plus either the growth hormone-releasing factor or Glucophage. As an activist, I think I'm also a little frustrated that there are no real guidelines on the nutritional aspects of this problem. Like you said, nutrition and dieting. Where do we send people when they want information about what to eat? Do you recommend just a Mediterranean diet? Anything specific?

Dr. Donald Kotler: A Mediterranean diet would work well. People tend to do better with low-carbohydrate diets, as opposed to low-fat diets whether they are HIV positive or HIV negative. For people who don't know what a Mediterranean diet is, it is olive oil, nuts, very low in highly saturated fats, more fish and less meat. [Click here for more details on what a Mediterranean diet is.] But there has been very little data published on it, in terms of its effects in HIV.

Nelson Vergel: That brings me to the next question. If you had all the money in the world, what would be your main research project, when it comes to the area of body shape disorders in HIV?

I'm interested in your view since you both see patients and do research -- which is a good thing since many researchers don't actually see patients.

Dr. Donald Kotler: That's an easy question. If I had all the money in the world, I would study everything. But if I could only do one thing, what would I do? It would be a comprehensive program in which I wouldn't be looking for one treatment, but rather, I would use the combination.

It would be diet and it would be exercise and it would be medication. Our laboratory presented a study at the lipodystrophy meeting in London, in which we compared diet and exercise to diet and exercise plus the drug rosiglitazone [Avandia], or simply rosiglitazone alone. Rosiglitazone is an insulin-sensitizing agent; it's an antidiabetic agent.

The question we asked is: If we treat an HIV-positive person with big-belly lipodystrophy and an HIV-negative person who has a big-belly metabolic syndrome the same, would they respond the same?

If I got somebody who has HIV to lose 15 pounds and get into good shape, would his or her insulin resistance change the same as someone who is HIV negative?

Although we didn't have enough people in the study to be able to be absolutely confident of the results, it seemed that the two groups responded pretty much the same.

The average weight loss we got was about 15 pounds. The changes in an HIV-positive and in an HIV-negative person were really pretty much the same not only in the belly, but also in things like cholesterol and the special types of good cholesterol and bad cholesterol.

It looked like HIV didn't really influence it very much. So in the absence of any other information, I would treat an HIV-positive person the same as I would treat an HIV-negative person with metabolic syndrome. The best treatment is to treat it all -- not looking for one magic pill, but instead getting people to eat less, getting people to eat smarter and getting people to exercise more. If there is high cholesterol, bring it down. If the triglycerides and other types of fat are high, bring them down.

If the usual medicines don't work, well, then you try other things, like fish oil (omega-3 fatty acid) or niacin. There are a number of these new medicines that have been tried in HIV. They seem to work about as well in HIV as in non-HIV; it's not so different.

So I think that the optimal way to do it is a whole integrated program.

Bonnie Goldman: But don't you think that many patients around the country don't have a physician that they could turn to who may have this kind of very understanding point of view?

Dr. Donald Kotler: Maybe not a lot of private doctors, but there are a lot of clinics that are putting together metabolic clinics that are putting together expertise to look at having a cardiologist or an endocrinologist treating diabetes go into the HIV clinics to treat people.

You're right. It's not really fully integrated. But I think that would be the best.

Nelson Vergel: As an activist, I think the community also has to take an active role in advocating for things like this. In Houston, Texas, we have a non-profit where we provide exercise and dieticians looking at people's diets and trainers. Yet in the past five years, we haven't been able to duplicate these kinds of programs anywhere else because of money. Money and funding are really tight lately, especially in HIV. People sometimes don't even have the money to get the treatments, the HIV medications, which are basic. So it's a battle.

My next question -- which is really relating to this -- is: How do we get insurance companies or Medicare/Medicaid -- other systems that pay for medication -- how do we get them to accept that body changes in HIV are not a cosmetic issue, per se. It's something that not only affects people's self-esteem, anxiety and depression, and quality of life, but it may actually be something that also affects their survival, eventually.

That's where we have the most challenge right now. How do we shift from perceiving this as a cosmetic issue -- shifting third-party payers, insurance companies, to see it as a clinical problem?

Dr. Donald Kotler: It's not really a medical question. It's a question for activists. I think that the answer is activism. My suggestion would be to push it as a comprehensive care program, rather than a reimbursement for drug X. Because in fact some of the treatments are so costly that I don't know that I would be happy paying for the treatment in somebody who is not watching their diet or someone who would not consider doing exercise. Or even -- which is what's happened before and which is what I think limited it before -- you don't necessarily even look at the results of what you're doing; that it's really considered more of an entitlement to get the prescription, as opposed to having somebody measure you, work out your risk, give you some treatment and follow up. If you're not responding the way you should, look to find out why. Sometimes the medicine is not even being taken.

I think it's important to accept the fact that there's not a magic bullet, but there are a lot of things that you can do to help yourself. I think that the activists should really push on that.

Nelson Vergel: That's my main goal. I just wanted to summarize it, because some people may be so concerned about this discussion, and they're considering going on HIV medications for the first time.

The fact is that we're not experiencing as many problems metabolically right now, compared to 10 years ago. Is that a fair statement, in your point of view? Should people be really concerned before they start treatment?

Dr. Donald Kotler: The one thing that doesn't seem to have changed is that if people gain weight, they may get a big belly.

On the other hand, the diabetes that used to be seen, especially with Crixivan [indinavir], we don't see much of that anymore. There may be more diabetes that comes with Zerit or AZT, but for people taking the newer medicines, we don't tend to see that nearly as much.

The lipoatrophy -- the skinny face, the skinny butt and the really skinny legs -- if we see somebody now who has that, it's somebody who has been treated with HIV medications for a long time, and has had that for years.

With the new HIV medicines, it doesn't tend to happen that much anymore. The high triglycerides and high cholesterol: We still see some of it, although much of it occurs in people who are genetically predisposed to it.

The new medicines, like the integrase inhibitor Isentress [raltegravir, MK-0518], the CCR5 antagonist Selzentry [maraviroc, Celsentri] or the entry inhibitor Fuzeon [enfuvirtide, T-20], don't seem to cause any of these problems.

I think that people now are a lot less likely to develop these changes than they were in the past. It may be that if people are really careful about trying to prevent weight gain and eating very healthily at the time they start their antivirals, they may be much less likely to get it. On the other hand, if somebody weighed 280 before any of this happened and you make them healthy again, they are, as likely as not, going to go back to a weight of 280.

Nelson Vergel: Are some of these changes related to aging, or are they really accelerated aging by HIV and HIV medications?

Doctors are also saying to patients, "Well, don't complain. You really are healthy. It's just that you are getting older, too."

Dr. Donald Kotler: They are steady changes. But if you look at HIV-negative people, even though the changes are pretty continuous, when do people start really seeing the belly fat? And when do men start losing their butt, even if they're not HIV infected? It seems to be somewhere between ages 45 to 50. At that point, jeans fit differently. They are no longer tight in the thighs and loose in the waist; it's the other way around.

Nelson Vergel: There are also some hormonal changes, too, right?

Dr. Donald Kotler: Right. People's own growth hormones go down. People's own testosterone levels go down.

Nelson Vergel: Even thyroid. We're seeing some reports on thyroid dysfunction in some patients, too, right?

Dr. Donald Kotler: That's kind of an immune reconstitution problem, though. You'll get laboratory abnormalities. It really causes your thyroid to get so bad that you need hormone replacement.

Nelson Vergel: So it is good for patients who are experiencing some of these changes to at least get some of their hormones checked and talk to their doctors about it, right?

Dr. Donald Kotler: Absolutely. Women tend to have more problems with thyroid than men, so it's especially important in a woman, because she might develop a thyroid problem totally independent of HIV. Not everything that happens to people who are HIV positive is really HIV related.

Nelson Vergel: Dr. Kotler, one last question from my side. We're seeing some reports on decreases in bone density. Is that something that you see in your practice? I'm not even talking about research. I'm talking about your practice. You see a lot of patients in New York. You've been around since the '80s. I think you're probably one of the leaders in metabolic disorders.

In your practice, are you starting to see any bone-related fractures or any bone-related problems?

Dr. Donald Kotler: Yes, I've been seeing this for a long time. In fact, the bones that I've seen break most commonly, being in the middle of a city, are bones in the feet in people who run on treadmills. I don't see a whole lot of broken hips, broken ribs or crushed vertebrae. But I've seen people break bones in their feet, simply by the pounding.

At the meeting in London, there were a couple of interesting talks about bone. It's known that thin bones, brittle bones, are very common. Whereas most people blame antivirals, you can also see it in HIV-positive people who are untreated. So HIV-positive, treatment-naive people also may have thinned, decalcified bones. If that's the case, well, then it can't just be due to drugs!

There are two possibilities. Actually, the one possibility that many researchers are leaning towards is that when you're sick, you have inflammation. Inflammation tends to cause bone to break down.

Just like somebody who has chronic bronchitis from cigarette smoking and on that basis gets brittle bones, somebody can have a chronic infection with HIV and get brittle bones. It was felt that it was just the inflammation.

However, a group from Ireland exposed growing bone cells to HIV in serum -- either a low viral load or a high viral load or a negative viral load -- and showed that, when you exposed the cells to HIV, the bone cells tended to turn into fat cells. Bone cells and fat cells are related. So there may be something about HIV itself that tends to shut off the calcium being laid down in the bone. That was brand new information that hadn't been seen before.

There was another study, though, and this was really very hard to understand. It was related to the SMART study. You remember the SMART study?3 In that study, patients either stayed on therapy or, when their T cells went up, they stopped therapy, and then when their T cells went down, they started treatment again. It was a big study of a couple thousand people. [Click here to read more about the SMART study and treatment interruptions.]

Two hundred seventy-five of the people in the study actually had bone density studies done, either when they were on continuous therapy, or starting and stopping.

In fact, in that study, the people who stayed on therapy tended to have more bone problems than those who started and stopped. The author said that is not a reason to start and stop. So don't take that as a reason. But the people who were on therapy and didn't stop were more likely to have fractures and, when they were followed over, I believe, two years, they were more likely to lose calcium in their bones than the people who did start and stop.

That was a surprise finding, as almost everything out of the SMART study is. Nobody's really sure what to make of it, other than, as we move forward, we probably should be concentrating on bone density and making sure that we don't allow our patients to get to the point where they are likely to have fractures.

Nelson Vergel: That's definitely a problem I'm seeing. Very few doctors are prescribing bone scans, DXA [dual energy X-ray absorptiometry] scans, before therapy or once every few years to follow up on patients even if they don't think it's a problem; it's just that it's really not part of standard of care. That's another activist issue.

Dr. Donald Kotler: The activist issue is reimbursement.

Nelson Vergel: Those who stayed on continuous therapy in the SMART study also had fewer problems with heart attacks and cardiovascular disease, right?

Dr. Donald Kotler: Right ... as well as other endpoints. The people who started and stopped are more likely to have problems with liver disease and are more likely to have problems with tumors. Starting and stopping has turned out not to be healthy.

Nelson Vergel: Any other questions, Bonnie? I think Dr. Kotler has been extremely helpful in clarifying some of the questions the community has.

Bonnie Goldman: If you have bone density issues, is it related to fat accumulation or fat wasting? Or are they all kind of the same phenomena?

Dr. Donald Kotler: Sort of, because they tend to be found in the same people. But no, I don't know how they are necessarily related in terms of the cause.

Bonnie Goldman: It sounds like there are hints of a lack of calcium in patients. Would this mean that it's a good idea to take calcium supplements to prevent bone density loss?

Dr. Donald Kotler: I don't know. I don't know if taking calcium supplements prevents it. That's the problem.

Nelson Vergel: Or exercise.

Dr. Donald Kotler: You should avoid vitamin deficiency. You should avoid eating too little calcium. That's mainly a problem in people who have trouble with milk and dairy. If you're lactose intolerant, you tend to eat less calcium than if you are not lactose intolerant.

Somebody who is at risk for bone loss should make sure they are taking enough calcium in their diet, should make sure there's at least enough vitamin D in their diet. I don't know, though, that just by taking an extra two vitamins everything will be cool. I just don't know that. I think that you would be better off having your bone density checked.

Certainly, if your bone density is low and you take the regular bone density medicines, like the kind that you see on TV, they do work.

I'm not sure how well vitamin D and calcium work. But the kinds of drugs, what are called bisphosphonates, that you either take every day, every week or every month, they do cause bone density to rise.

Bonnie Goldman: Do you see a lot of people having metabolic complication myths? They think it's due to all the protease inhibitors, or they think it's due to all antiretrovirals. Are there myths that we need broken?

Dr. Donald Kotler: I don't know. Patients tend, if they believe the doctor, to believe what the doctor tells them. So if there's a myth, it's probably the myth of the doctor. This whole idea that protease inhibitors caused everything didn't come from the patients. It came from the doctors. We had it wrong. We tend to have it wrong a lot, unfortunately.

Bonnie Goldman: I think that's one of the reasons that these kinds of complications -- bone, metabolic complications and body shape changes -- are so difficult. Because it's an ongoing understanding. And we don't know that much about this.

Dr. Donald Kotler: There's another part of it, though. It's that we're looking so hard at T cells, or viral load, that we just tend to forget about the rest. We're working so hard to make sure that people don't get cytomegalovirus (CMV), or toxoplasmosis, and die. When they get better and they're not going to die of the AIDS things, we can either say that's fine or ask what else would it be. As HIV docs we're not built to be worried about people's prostates or breast self-exams. We were aiming towards fighting pneumocystis pneumonia [PCP], CMV and all the rest. So we have had to retrain ourselves to be primary care physicians, to look at things that would happen to somebody who doesn't have a killer disease.

What happens to people without a killer disease? You either get cancer or heart disease. Or you develop Alzheimer's disease, or bad kidney disease, or all the other stuff. We're just coming around as doctors to realize that. Patients also have to come around.

Probably the best example of where patients and doctors have been caught short has to do with cigarette smoking. I knew it. If I had a patient who was dying of AIDS in 1985, I didn't bother much about them smoking cigarettes. What for? Now, it turns out that lung cancer is really common in HIV, and has nothing to do with HIV, it seems, and has everything to do with cigarette smoking.

So only lately have doctors like myself said, "Look, you're not going to die of AIDS. Why would you go through all that and then allow yourself to die of lung cancer? How could you be so crazy?" We're just getting around to that now.

Bonnie Goldman: You need to have a historic point of view to understand this whole issue, and how we came to the point where we're now dealing with this.

Dr. Donald Kotler: There's nobody to blame, because it's success. But if we want real success, it's not only not allowing somebody to die of AIDS, it's not allowing anybody to die before their time of anything. Drug overdose, as well.

Bonnie Goldman: And also dealing with quality-of-life issues -- you may live a long life, but you might have this belly that embarrasses you.

Nelson Vergel: Or facial wasting, or fatigue, or many other issues. One more question that I just thought of related to this talk about HIV doctors training themselves to be primary care physicians and treating people that are aging with HIV and who are showing up with some of these metabolic problems: Are there any Web sites, any groups, where guidelines are posted for doctors when it comes to metabolic disorders? One place, one document? Anything that doctors who are starting to treat HIV nowadays can go to to train themselves?

Dr. Donald Kotler: If you google "HIV metabolic guidelines," there have been several from the International Association of Physicians in AIDS Care, and from the International AIDS Society-USA. I believe that the Europeans also have one. There are some guidelines that are written. The early guidelines were not great. They would say, "In the absence of information, you probably should treat diabetes in HIV like you treat diabetes in non-HIV." For high cholesterol, or high triglycerides, as well, you should consider the medications. After that, you should treat just like you would treat anybody else.

I think the major point is that you don't ignore something that's bad. In the past, we ignored cigarette smoking, because we were worried that people were going to die of CMV.

Now we shouldn't ignore cigarette smoking. We shouldn't ignore high cholesterol, and we shouldn't ignore diabetes. We shouldn't ignore excess weight gain. We shouldn't ignore any of it.

Bonnie Goldman: So, success has allowed us to focus on these other details.

Dr. Donald Kotler: Yes, and those who are successful have more work to do.

Nelson Vergel: I also remind patients that HIV medications may have some side effects, but the worst side effect is leaving HIV untreated. I always say that, because sometimes we lose perspective and forget that these medications have kept a lot of us alive for 20-plus years. Sometimes the new guys and girls that are coming through with treatment are so afraid. I remind them that leaving HIV untreated can cause more problems than any side effects they may have in the future that can be treated by a good doctor.

Dr. Donald Kotler: I was in clinic today and saw a 24-year-old girl with a CD4 of 5, who had herpes around the rectum and around the vagina, who was being treated for MAC [Mycobacterium avium complex] infection in the liver, who has a huge liver, and who also probably has CMV. She had lost 70 pounds. She doesn't leave the house. She feels miserable. There's no reason for it.

Nelson Vergel: She got to a good doctor, though.

Dr. Donald Kotler: She's at a good clinic.

Nelson Vergel: A good clinic, that's lifesaving. Anything else, Bonnie? Dr. Kotler has been great.

Bonnie Goldman: I think this is really great, and hopefully it explains some of the phenomena that people have been experiencing. Maybe it will motivate a lot of people to go on a diet, do some exercise and take charge of their health in that way, while waiting for other treatments or other understanding of metabolic complications.

Nelson Vergel: Hopefully, we'll bother Dr. Kotler in the future to give us more details about any progress in this field, too. So, thank you.

Bonnie Goldman: Thank you so much for taking the time to talk with us. Thank you, Nelson, for joining us and for leading the conversation. I really appreciate that.

Nelson Vergel: Thanks a lot for having us! We'll talk to each other soon, I hope.

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References
Lazzaretti R, Pinto-Ribeiro J, Kummer R, Polanczyk C, Sprinz E. Dietary intervention when starting HAART prevents the increase in lipids independently of drug regimen: a randomized trial. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEAB303.
Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. December 6, 2007;357(23):2359-2370.
Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. November 30, 2006;355(22):2283-2296.
For more information on facial wasting, check out our lipoatrophy resource center.

Click here to read Mark King's latest blog about treatment for facial wasting.




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HIV Lipodystrophy: Where are we after 10 years?

From Gay Men's Health Crisis

HIV Lipodystrophy: Where Are We After Ten Years?
By Nelson Vergel
July-December 2007

Note: The following article expresses the opinions and learned lessons of the writer, not of GMHC, Treatment Issues, or their staff. It is not intended as medical advice and should not be taken as such.

Ten years have passed since the first report of lipodystrophy at an HIV conference. The excitement and hope for a longer life that accompanied the arrival of Highly Active Anti-Retroviral Therapy (HAART) has been tempered by accounts of humps, bellies, and facial wasting. A decade on, many unanswered questions and misconceptions about HIV associated lipodystrophy persist with only a limited number of treatment options available. Frustrated and tired of waiting for answers from the medical community, many people living with lipodystrophy have turned to the internet for advice, treatment and support in hopes of reversing some of the devastating effects of this stigmatizing syndrome.
Lipodystrophy is a condition of abnormal fat redistribution that can lead to either lipohypertrophy (fat accumulation in specific areas of the body such as the neck, belly, upper torso, and breasts) or lipoatrophy (fat loss in the face, buttocks, arms and legs). An online survey of 695 people (predominantly white men, over the age of 40, living with HIV for over 10 years and with exposure to HAART for at least that long) found that 20% had considered suicide because of body shape changes associated with lipodystrophy. Almost 90% of respondents believed that their HIV medications caused lipodystrophy, and 20% had stopped taking their HIV medications altogether due to this concern. Further, over 60% of respondents reported being rejected by potential sexual partners because of the syndrome. A similar number of respondents indicated that they had stopped looking into the mirror because of crippling body dissatisfaction. Nearly all of the respondents attempted to curb the effects of lipodystrophy with diet and exercise or by using costly facial reconstruction procedures, supplements and hormones -- treatments not typically covered by insurance companies or drug assistance programs.


Lipoatrophy and HIV Medications

In 1999, the HIV drug Zerit was correlated with the development of lipoatrophy related fat loss under the skin.1 Since then, several studies have concluded that Zerit can affect the way our mitochondria (energy factories in our cells) work and multiply. Later studies also linked lipoatrophy to AZT, although at a lower rate than Zerit. Nucleoside reverse transcriptase inhibitors (NRTIs) like Zerit and AZT, keep HIV from altering the genetic material of healthy T-cells, thereby halting the reproduction of new virus cells. Additionally, NRTIs affect the mitochondria in fat cells under the skin, preventing them from multiplying and causing them to die. Also, those who have taken Zerit and Videx (another NRTI) together report more lipoatrophy than those taking Zerit alone. This combination is not recommended by guideline groups. It appears that Zerit and AZT make fat accumulation worse in the presence of protease inhibitors or non-nucleoside analogs (NNRTIs) like Sustiva, leading researchers to suspect that their negative effect may play a combined role. However, Sustiva taken with Viread (Tenofovir) and Epivir (3TC) seems to cause less lipoatrophy. Due to the high risk of developing lipoatrophy and neuropathy, the US Department of Health and Human Services guidelines committee dropped Zerit from the list of recommended drugs for first line therapy for people new to HAART.

Viread (Tenofovir) and Ziagen (Abacavir), two other NRTIs in the same drug class as Zerit and AZT, do not seem to strongly correlate with the development of lipoatrophy. Some people have even reported a slow reversal of the fat loss after switching from Zerit or AZT to either Ziagen or Viread. However, even after a number of years most patients do not experience re-accumulation of fat in their faces after going off AZT or Zerit. It is also important to note that puzzling new data from a recent study by the AIDS Clinical Trials Group2 showed that 20% of subcutaneous fat loss (loss in body fat closer to the skin's surface) occurred in a small percentage of patients starting HAART for the first time with a combination of Sustiva, Viread and Epivir. More studies are needed to determine why lipoatrophy still occurs in some patients in the absence of Zerit or AZT.

The sales of Zerit and AZT in the industrialized world have dropped considerably in the past years due to their effects on lipoatrophy. Unfortunately, these two drugs are among the primary HIV medications used in the developing world, so millions of people in poorer countries will continue to suffer with body changes.

Treatment Options for Lipoatrophy

In recent years many men have relied on an off-label injectable anabolic steroid called nandrolone decanoate (old trade name: Deca Durabolin), to "balance out" their bodies and add muscle to their thin extremities and buttocks affected by lipoatrophy. Even though Watson Laboratories ceased production of nandrolone in March of 2007, it is still available through prescription at compounding pharmacies for a low cost.3

Uridine (Nucleomaxx), a supplement made of sugar cane and available through a German supplier,4 may lessen lipoatrophy in patients taking Zerit, however it may also cause abdominal fat and high triglycerides. These side effects, along with high cost and bad taste, make Uridine an unpopular choice. However, for those who must take Zerit, Uridine may be a viable option to prevent or reverse lipoatrophy. Additionally, for those who are no longer taking Zerit, the diabetes drug Rosiglitazone (Avandia) works well for reversing lipoatrophy. There are side effects however, including weight gain and high triglycerides.

Since 2002 there have been a couple of non-permanent reconstruction procedures available to treat facial lipoatrophy. The face wasting reconstruction option, Sculptra (polylactic acid, old name: NewFill) entails an expensive series of multiple sessions, requiring additional touch ups that can be used to treat those moderately affected by lipoatrophy. Radiesse, another FDA approved option, seems to last a little bit longer but is also costly, requiring 3?5 sessions and yearly touch ups. Some patients treated with face wasting fillers experience side effects such as bruising and treatable granulomas (hardened pimple-like nodules). There are patient assistance programs available for both Sculptra and Radiesse.5

There are no FDA approved permanent solutions for facial lipoatrophy, yet many in the US seek tiny injections of silicone (Silikon 1000) from their doctors. Silikon 1000 can be used legally in an off-label manner for facial lipoatrophy. Silikon 1000 micro-injections can reconstruct patients' faces slowly over five sessions spaced one month apart. There is no patient assistance program for this option and sessions cost anywhere from $600 to $900. Here too, multiple sessions are required. Beware that very few US doctors are well trained in this procedure.
Another permanent product, Polymethylmethacrylate (PMMA), has been used in Brazil for eight years and in Mexico for three with relatively positive results, though more time is needed to determine the long term effects of this procedure. Usually 2?4 sessions are required and no yearly touch ups are needed. Short term, we have seen that PMMA can harden and be lumpy in certain patients, but many people seem pleased with the results. Artefill, a PMMA based product, is FDA approved for cosmetic purposes but not for HIV related lipoatrophy. Artefill is extremely expensive for the amount required to treat lipoatrophy, so some HIV positive people in the US go to Mexico or Brazil for the procedure, where costs can range from $2000 to $6000. PMMA is not removable.

BioAlcamid (poly-alkylamide gel), also permanent, is an injectable filler unavailable in the US (some patients travel to Mexico or Canada for injections). Unfortunately, BioAlcamid forms a "pocket" in the face and buttocks enabling bacteria to penetrate and posing a high risk of infection. As such, extreme caution is warranted before pursuing this option.
It is critical to remember that no long-term data on these experimental facial reconstruction treatments are available, so one must weigh the risks of injecting a foreign substance into one's body. Sadly, many people find that the emotional, psychological and social toll of living with lipoatrophy is so great as to justify these risks.

Understanding LipohypertrophyUnlike lipoatrophy, researchers have not been able to attribute lipohypertrophy (fat gain in the belly, back of neck and breasts) to any specific medication or drug class. Protease inhibitors were once thought to be the main culprits. However, researchers have recently discovered that fat gain in the belly may relate to inflammatory responses in the immune system when CD4 cells increase in number. This means that those who start HAART with a lower baseline CD4 count may see greater lipodystrophy. Moreover, recent data shows that patients with a CD4 count of over 250, who start a HAART regime with protease inhibitors boosted with Norvir plus Viread and Epivir, do not experience a gain in visceral fat (fat surrounding the internal organs). It is still too early to tell what happens to those on this particular regimen who start with lower CD4 counts. Some studies have shown that those who begin taking protease inhibitors in combination with Zerit, AZT or Zerit plus Videx seem to have more visceral and hump fat gain than those who start on protease inhibitors with other drugs. It may be that the same drugs that are linked to lipoatrophy may also make fat gain worse, especially in patients who start HAART with fewer CD4 cells.

A common misconception promoted by a few pharmaceutical companies and echoed by some doctors is that HIV medications that do not increase cholesterol, and that triglycerides do not cause fat gain. On the contrary, several studies have shown that people taking lipid friendly drugs like Reyataz with Viread also gain fat in the belly after starting HAART.

Dr. David Nolan, a clinician and researcher at Royal Perth Hospital in Western Australia and an expert on fat metabolism and HIV, was asked about why visceral fat does not get "burned off" by Zerit and AZT like subcutaneous fat does. Dr. Nolan hypothesized that fat cells in the organ cavity may not be as susceptible as subcutaneous fat cells to the mitochondrial toxicity caused by Zerit and AZT.

Fat gain may also be linked to insulin resistance. Insulin resistance can cause glucose intolerance, which has been associated with fat gain, increased triglycerides, and the development of diabetes. Insulin is a hormone produced by the pancreas to control blood sugar-glucose. HIV medications may block or slow down the process by which insulin converts glucose to energy. In laboratory studies, Crixivan and higher doses of Norvir and Zerit have been shown to impair the action of insulin in fat and muscle cells. In this scenario the pancreas will tend to produce more and more insulin to compensate for the decrease in function. High insulin levels may be present for years before type 2 diabetes develops. A glucose tolerance test (GTT) may reveal that problem easily but it is hardly used in clinical practices. Additionally, some people may have a genetic predisposition to insulin resistance. A sedentary lifestyle and a diet rich in sugars and animal fats may also compound this problem. In any case, insulin resistance may just be a part of the mystery of lipohypertrophy. There is no agreement among researchers whether or not monitoring insulin levels in HIV-positive people is justifiable or dependable as a tool to assess insulin resistance and fat gain.

The full body dual x-ray absorptiometry (DEXA) scan is the gold standard test in lipodystrophy. It is a highly valuable test that can provide information about body fat, muscle mass and bone density (low bone density has been associated with HIV in several studies.) Both Medicare and private insurance often cover this inexpensive test. While the scan cannot differentiate between fat accumulated in the belly on under the skin in the abdominal area, it can be useful as a baseline to assess body changes and to justify reimbursable therapies for fat, muscle, and bone mass.

Treatment Interventions for Lipohypertrophy

Some people have switched from protease inhibitors to Viramune or Sustiva to combat visceral fat gain, but this has not been shown to make a difference. It is not yet known what happens to belly fat when a patient switches from Zerit or AZT to Viread or Ziagen while taking protease inhibitors or non-nucleoside analogs like Sustiva or Viramune.

The recombinant human growth hormone Serostim is a daily injectable drug approved by the FDA for HIV associated wasting. At approximately $3000 a month, it is an expensive option for treating lipodystrophy. Serostim works well in lowering abdominal fat but has many side effects including joint pain, water retention, carpal tunnel syndrome, and irreversible diabetes. These side effects and the lack of proven long-term health benefits are why the FDA has not approved Serostim for the treatment of HIV related fat accumulation. Tesamorelin-TH9507, made by Theratecnologies, is a daily injectable growth hormone precursor that is in its last stages of FDA approval. Tesamorelin appears to have fewer side effects than Serostim, but may take a longer time to show benefits in patients. Disappointingly, fat gain returns after discontinuation of both Serostim and Tesamorelin.

Leptin, a hormone that produced by fat cells, is another new contender in the search to decrease visceral fat. Researchers have found that leptin levels in the blood are proportional to an individual's level of body fat. Leptin works in the part of the brain that controls appetite and other basic functions. High levels of leptin generally suppress the appetite and stimulate the burning of fat. Leptin does not appear to have a negative impact on glucose tolerance.

Nowadays, physicians are likely to prescribe testosterone gels, injections, and subcutaneous pellets. A testosterone gel applied to the belly can reduce the waist size in HIV-positive men. This decrease is usually as a result of a reduction in subcutaneous fat, not in visceral fat. In contrast, a small pilot study of Oxandrin (an oral anabolic steroid) has yielded encouraging results in decreasing visceral fat. Increases in the low density lipoprotein (the "bad" cholesterol) and decreases in the high density lipoprotein (the "good" cholesterol) correspond to a small decrease in subcutaneous fat. There are no data yet on a connection with the popular anabolic steroid, nandrolone decanoate, and visceral fat reductions.

Some individuals who have been looking elsewhere for fat burners have fallen prey to advertisements pushing growth hormone supplements or fat burners. These products do little but increase blood pressure and anxiety and are generally considered scams.

Metformin (trade name, Glucophage), is a generic diabetes drug that has been shown to improve glucose tolerance and lower visceral fat. Its effects may be enhanced by exercise. Metformin improves insulin sensitivity, triglycerides and fatty liver but can also cause diarrhea and weight loss. There have also been reports of low blood sugar and dizzy spells associated with this drug.

In addition to the aforementioned treatments many patients explore liposuction. Ultrasound-assisted liposuction can be used to successfully remove fat accumulated in buffalo humps and around the neck.

Some patients complain about the enlargement of salivary glands on each side of the face commonly referred to as the "chipmunk look." While only a few radiologists know how to use it for this purpose, low dose electron radiation has worked very effectively in treating the enlargement of salivary parotid glands. It is unknown whether the "chipmunk look" is related to lipodystrophy or caused by immune reconstitution.

Another under explored intervention is diet and exercise. A study at Tufts University revealed a trend towards less lipodystrophy in those who had higher consumption of soluble fiber (fruits and vegetables) and who exercised. However more research is needed with the use of diets lower in simple carbohydrates. These diets have been shown to improve insulin resistance and visceral fat in non-HIV studies. One observational cohort showed that people with HIV eat more saturated fats. A small pilot on a combination of cardiovascular and resistance exercise showed decreased triglycerides and visceral fat. However, adherence to exercise remains a challenge to many people, and exercise research in HIV generally remains in its infancy.

Increased Lipids: Low Density Lipoprotein (LDL) and Triglycerides

The most common lipid abnormalities in HIV are high triglycerides and LDL, "bad" cholesterol, and low High Density Lipoprotein (HDL), "good" cholesterol. Before HIV-positive people start HIV medication for the first time, both their high and low density lipoprotein may be lower than normal. However, after HIV drugs are started, low and high density lipoproteins and triglycerides increase in some people. Some studies have shown that LDL increases to "pre-HIV" levels while HDL never returns to normal levels. Increased triglycerides is the most strongly associated lipid change caused by HIV medications such as protease inhibitors, Zerit, AZT, or Sustiva. Among protease inhibitors, Reyataz seems to correlate with the lowest lipid increases.

Many people want to start supplements before they start lipid lowering medications. The only supplements with solid emerging data on lipids are omega-3 fatty acids (fish oils), and niacin (also available as Niaspan). Fish oils can decrease triglycerides but some patients' stomachs cannot tolerate them. Niacin is better than any lipid lowering drug in increasing the "good" cholesterol (HDL). It can cause flushing of the face and a hot sensation for a half an hour at a time, but most people get used to it. Non-flush versions are available but their effectiveness is unknown.

It is not clear if Raltegravir (Isentress, the first integrase inhibitor) or Maraviroc (Celsentry -- a CCR5 entry inhibitor) have any effect on body composition. So far, they appear to be lipid friendly when taken with Viread and Epivir. Fuzeon (an injectable entry inhibitor) also seems to be lipid friendly, but it is usually used with boosted protease inhibitors that can cause increases in lipids. It seems that there may be genetic factors that make some patients more prone to increased low density lipoprotein (bad) cholesterol and triglycerides.

Lipid lowering agents like statins (Lipitor, etc) or fibrates (Tricor, etc.) can work wonders in many, but even with their use, some patients never reach "normal" lipid levels. A combination of niacin, lower sugar and animal fat intake, exercise, fish oil supplements or an increase in fatty cold water fish consumption (salmon) and soluble fiber (fruits, vegetables, oats) are sometimes used to treat lipids. Some individuals have tried combining statins and fibrates, but this combo can lead to an increase in muscle related disorders in some patients.

Conclusion

We have learned a lot during the past 10 years about body changes associated with HIV, but many more questions remain. It is the hope that those new to HAART therapy will not have to suffer the devastating drug side effects that their predecessors have had to contend with in the past 20 years. As patients, it is our responsibility to stay educated and learn from others about emerging options that may make it possible one day to live fully without HIV related body changes and other side effects.

For more information visit: http://www.facialwasting.org/ or to subscribe to the largest internet HIV health discussion group send a blank email to pozhealth-subscribe@yahoogroups.com

Nelson Vergel is director of Program for Wellness Restoration.

A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, Gastaut JA, Touraine JL. AIDS. 1999 Sep 10;13(13):1659-67.
Metabolic Outcomes of ACTG 5142: A Prospective, Randomized, Phase III Trial of NRTI-, PI-, and NNRTI-sparing Regimens for Initial Treatment of HIV-1 Infection. Richard H. Haubrich, S Riddler, G DiRienzo et al.
More information is available at http://www.medibolics.com/.
More information is available at http://www.nucleomaxx.com/.
More information is available at http://www.facialwasting.org/.