Doctor Views: Dr. Kathleen Mulligan

Please provide a little background on how you got into doing research on people with HIV and, in particular, lipoatrophy.

I have a Ph.D. in nutrition, and I started doing research in HIV infection back in the early '90s, back when wasting was the major metabolic and nutritional complication of HIV, and we were trying to figure out what was contributing to wasting, what the nature of weight loss was and what the metabolic consequences are of wasting.

When the protease inhibitor era began, we thought we were going to be out of business. We thought wasting was going to be a thing of the past, and we were going to have to look for other areas to do research, but, of course, the new treatments opened up a whole new set of metabolic complications, and so we switched our research focus from weight loss to morphologic alterations and also metabolic complications.

Focusing in particular on lipoatrophy, where do we stand now in terms of the research?

Well, I was thinking about this as I was driving across the Bay Bridge this morning. Here we are 10 years into the HAART [highly active antiretroviral therapy] era, and there are still a lot of things about lipoatrophy and fat distribution abnormalities in general that we really don't understand. I think it's become pretty clear that the nucleoside analogs, particularly the D-drugs [d4T (stavudine, Zerit), ddC (zalcitabine, Hivid), ddI (didanosine, Videx)], the thymidine analogs, are a major contributor to lipoatrophy, but there are still some studies, including an ACTG [AIDS Clinical Trials Group] study that I was involved with, suggesting that the addition of a protease inhibitor can accelerate lipoatrophy. It's still not clear what the contribution of protease inhibitors is to lipoatrophy or to fat accumulation. I think that's still something that deserves further research, but as far as treatments for lipoatrophy, I assume that's the main thing you want to get at.

But also, if you have some interesting ideas about what you think may cause it, and also the different mechanisms involved. It'd be great to have you talk some more about d4T, AZT (zidovudine, Retrovir), possibly ddI, and the protease inhibitor connection. And then, do you feel that it's settled, that it's a mitochondrial toxicity problem or that it actually could be other things?

Yes, all good questions. I'll attack the mitochondrial type of questions first. Then you'll probably need to remind me about the other parts of it. You know, the mitochondrial toxicity theory makes a lot of sense, and I think there are studies linking lipoatrophy with mitochondrial toxicity, but it's not clear to me whether that's the whole problem. Part of what I think we're going to learn from studies that are going on now and may be coming out in the next couple of years is to see whether treatments that specifically address mitochondrial functions, such as supplementation with uridine, whether those treatments can reverse lipoatrophy, and that, in my mind, would provide further evidence that there is mitochondrial involvement in lipoatrophy. The fact that there is an association between the use of protease inhibitors and apparently accelerated lipoatrophy suggests to me that there are other mechanisms working, as well. There have been some in vitro studies suggesting that when you add protease inhibitors to fat cells, they can increase the rate at which fat breaks down -- the rate of lipolysis -- and so that's a potential mechanism, as well, that may be operating completely independently of the effects of d4T and AZT and potentially ddI on mitochondrial replication. So it may be multiple factors that are either additive or synergistic that could be contributing to the fat loss.

For people who are under the impression that it's d4T or AZT and have switched off of those drugs, if it turns out to also be a protease inhibitor link and they're still taking that, what does that indicate? Correct me if I'm wrong, but a fair number of patients feel that they've seen lipoatrophy stop by going off those drugs.

Right.

Do you think that's true?

Yes, I think studies have shown that switching from d4T, AZT, to either abacavir [Ziagen] or, more recently, tenofovir [Viread], has reversed some of the lipoatrophy. Now, whether those drugs are fat friendly or fat neutral or just less toxic, it's not clear yet, but I think the evidence from the switch studies that have been performed to date shows that switching from those drugs can result in some improvement. [However] the improvement is slow. It takes years to evolve, and so whether there's going to be full restoration of pre-treatment fat levels is unclear yet, but . it doesn't surprise me that it takes a long time for these changes to reverse, because the changes occurred, to begin with, over years. You don't suddenly wake up one morning and find yourself lipoatrophic. It's not like turning a faucet on and off. These changes took quite a while to evolve, and so, as I said, it's logical to expect that it's going to take quite a while to reverse.

But you feel that the potential for reversal is definitely there?

At least partial reversal, based on the studies that I've seen to date, yes, I would say that.

That's good news. And what about the possibility of a cure?

Probably, if you're going to talk about [a] cure, removing the source of the problem is the best way to cure it. There might be other treatments that could overcome the problem, but to the extent that the nucleoside drugs, or certain of the nucleosides, are causing the problem, certainly removing them or substituting for them is the closest thing we're going to have to a cure.

Could you talk a little bit about the supplement uridine that's, I think, new to a lot of people?

Right, there's been quite a bit of interest in this and speculation. I guess the form in which uridine is being studied in people with HIV is in this supplement from Europe called NucleomaxX -- that's a sugar cane extract. The rationale behind using uridine is that one side effect of mitochondrial damage might be a reduction in nucleoside production, and by giving uridine, which is a nucleoside, you're kind of, in a way, overcoming that deficiency that's created secondary to mitochondrial toxicity, and by overcoming this deficiency, perhaps you could reverse some of the lipoatrophic effects of the nucleosides.

So that's the theory. You know, theory and practice are often widely separated. The only study that I'm aware of to date that's produced really well controlled data was a small study that was reported by Jussi Sutinen from Helsinki, and this was reported at the lipodystrophy meeting that was held in Dublin last fall, and it was a very small study, but it was well done, randomized, double-blind placebo-controlled. I think there were about 10 subjects per group, and they were randomized to get this supplement, NucleomaxX, or a placebo for three months. In that three-month period, the subjects who were randomized to receive NucleomaxX had an increase in limb fat, combined arm and leg fat, that totaled [about 900 grams]. That's [almost two pounds] of an increase in limb fat over three months, and that magnitude of increase is greater than what had been seen in so-called switch studies and also what's been seen in the studies using the so-called glitazones.

So it's very promising. A couple of big caveats: First of all, it was a very small study and obviously needs to be studied further in larger groups of subjects. The other thing is that in addition to an increase in limb fat, there was an increase in intra-abdominal fat, and so, in the patients who received NucleomaxX. So it's not clear whether the effect of this supplement was to just put on fat all over non-selectively or whether this will wind up being something that can specifically reverse lipoatrophy, the loss of subcutaneous fat, but I think it's intriguing and definitely warrants further study.

[Click here for recent research on NucleomaxX.]

I can imagine people wanting to go out and buy it immediately.

Yes.

Does it seem to be safe?

I would want to see more data on it. It's not cheap. I think it's available over the Internet, but it's not cheap. I think you have to mix it with juice and drink it, and there is -- some people have said that the flavor is not exactly delectable. Before I ran out and spent money on it, I would want to see more data. But you were asking me about what's on the horizon for research, and as a clinical researcher -- remember, I'm a Ph.D., I'm not a medical doctor -- I try to avoid practicing medicine and making recommendations. But as a seemingly stodgy, conservative researcher here, I'd want to see more data before I encourage people to go out and use the supplement. But I know -- I've been doing research on people with HIV infection for 16 years now, and I know that the mantra has been "Treat now. Ask questions later," and I can understand the wisdom of that, and I can understand why people who are looking for ways of solving a problem that's very troubling and very visible might want to jump the gun and try anything that they think at least will not harm them.

Yes, but in this case, as troubling as lipoatrophy is, it's not really a health danger.

Right.

So it's a good warning to wait for better data.

Yes, I think so, and you make a very good point that I try to harp on. We don't know what the long-term health consequences are going to be of lipoatrophy. I fully understand the concerns, particularly about facial wasting, and fully understand why people are very interested in getting facial implants or things like that, but we don't know what the overall health risk is of, the long-term health risk is, of not having as much fat on your arms and legs as most people. It seems that the metabolic -- to the extent that there are metabolic effects of lipoatrophy -- they're not as severe as are seen in certain rare cases of non-HIV lipodystrophy, where people have rampant diabetes and uncontrollable triglyceride levels. We're not seeing that so much in people with HIV lipoatrophy.

Yes, because the cause seems to be more direct. I mean, it's not organic.

Right.

So there aren't these additional factors.

Right.

What about the drugs that are being researched?

The main interest on the part of a lot of us for the last several years has been in the so-called glitazones, the thiazolidinediones, and --

How did that come about?

The first so-called glitazone that was approved by the FDA [U.S. Food and Drug Administration], troglitazone (Rezulin). This was a treatment for type II diabetes, and there were several studies in people with type II diabetes and also one study in people with non-HIV lipodystrophy who were given troglitazone, and these individuals lost fat in their bellies. They lost visceral fat, and at the same time, they gained subcutaneous fat in their arms and legs. So there was a lot of hope that if this class of drugs could have the same effects in people with HIV infection, this would be the ideal treatment for so-called HIV lipodystrophy.

Well, troglitazone was removed from the market by the Food and Drug Administration because of excess liver toxicity, and the second generation glitazones, rosiglitazone [Avandia] and pioglitazone [Actos], that are now approved, have been studied in a number of trials and people with HIV infection, and I think we can safely say that they don't have the same dramatic effects on visceral and subcutaneous fat that were seen with troglitazone.

None of these studies have really shown any consistent evidence of reductions in visceral fat, and the studies have been more or less inconsistent in terms of an effect on subcutaneous fat, I think, taken together. There was a study that came out of Australia a couple of years ago that was published in Lancet using rosiglitazone that declared that rosiglitazone had no positive effect on subcutaneous fat in people with HIV lipoatrophy.

Other studies have suggested that some patients who are taking this drug seem to benefit from it, and I want to say just a couple [of] things about that. I think there are enough studies now, enough data from enough studies, to convince us that there may be a subgroup of patients who could benefit from taking either rosiglitazone or pioglitazone in terms of its effects on subcutaneous fat, increasing subcutaneous fat. I think we need to do a little bit more research or data analysis to understand who might be most likely to benefit. Studies suggest that the people most likely to benefit are those who are not taking d4T, and that's unfortunate, because those are probably the people who need it most. So, and there's been some speculation about whether the people who have insulin resistance at baseline stand to benefit more. An ACTG study that I did with Steve Grinspoon didn't seem to suggest that that was the case. On the other hand, there was a study from a group in the Netherlands that was published last year in Annals of Internal Medicine that showed a correlation between baseline insulin resistance and improvement in subcutaneous fat, so I think we still need to understand that a little more.

I want to say one other thing, if I can, is that even in patients who are experiencing a benefit, say a group of subjects who are not on d4T, the increases in subcutaneous fat that have been seen thus far with the glitazones have been rather modest. There was a report at the Retrovirus meeting this year from a French study of pioglitazone, a randomized, double-blind, placebo-controlled study, where people got pioglitazone or placebo for a year, and there was a close to significant effect of pioglitazone, but overall, the increase in fat over a year was about three tenths of a kilogram, close to a pound, about three quarters of a pound.

If you think about, say, three sticks of butter spread out over four limbs in the course of a year, it's a messy thing to think about, but that's not a lot of fat increase, and it's not clear whether this is going to continue, whether it might accelerate over time, or whether it might, whether you might be able to optimize the use of this by doing it in people who've recently switched off of d4T to a less toxic drug. But the increases in fat with rosiglitazone and pioglitazone do seem to occur in some people, but overall I think they're fairly modest.

Yes, and there's no chance that the first generation glitazone, which proved to be liver toxic, is up for further research?

No. As you pointed out a couple [of] minutes ago, we don't know if there are any long-term health consequences of having a little less fat on your arms and legs, but troglitazone had some pretty obvious liver, bad liver, effects, and we don't want to trade one toxicity for another. Our mantra all along is "Do no harm," and given the increase in liver disease among people with HIV infection, I think it would be very imprudent to even consider reviving a drug that has known liver toxicity.

So it seems that, as wonderful a name as this class of drugs has, they're not really glittering so much.

Right. Well, you know, I think --

Maybe in a very specific group of people.

Right, or in combination with other approaches or over a longer period of time. I think Andrew Carr's study of abacavir substitution for d4T or AZT over the course of two years [demonstrated] over a kilogram increase in limb fat, and so that's getting there. It's still not fully restored, but I would say in people who have lipoatrophy and have options with their antiretroviral therapy, switching to a less toxic NRTI [nucleoside/tide reverse transcriptase inhibitor] would be the first thing that I would recommend trying, to the extent that I would make a recommendation.

Are there any other drugs that are being researched?

Not that I'm aware of at the moment. As I said, I think there needs to be and will be more studies using uridine, NucleomaxX. There was a kind of an incidental finding that was reported at the lipodystrophy meeting last fall, once again from our friends in Australia, from a study where they were giving a statin drug to people with high cholesterol levels and found as just an incidental secondary finding that there was an increase in subcutaneous fat in people who got the statin. I'm sure that's going to be followed up on, but those are the treatment approaches that I'm aware of right now.

Can I ask you a question about the corollary problems that people are having? Do you have a sense of the rates of additional complications that people who have lipoatrophy have in terms of other metabolic disorders, and are those things really related, or are they separate?

Yes, excellent question. You know, we look for a model to non-HIV lipodystrophy, and these are kind of a cluster of very rare, sometimes acquired, sometimes congenital conditions, and people with non-HIV lipodystrophy have severe metabolic complications. A lot of them have diabetes that is very resistant to treatment. A lot of them have triglyceride levels that are off the charts, over 1,000, and resistant to treatment, so a much more severe metabolic phenotype. In people with HIV, it's hard to sort out right now, and this is something our group has been trying to figure out. It's hard to sort out the effects of fat distribution abnormalities versus direct effects of the anti-HIV drugs.

We know that certain protease inhibitors induce insulin resistance. We know that certain protease inhibitors, particularly ritonavir [Norvir]-containing regimens, can increase lipids, triglycerides and cholesterol, and these are the same types of problems that can occur in association with fat distribution abnormalities. People who are obese tend to have high triglyceride levels and high cholesterol levels, so sorting out the independent contributions of fat distribution alterations in people with HIV infection to metabolic complications is really difficult. They seem to all kind of cluster together.

I will say, and this is a point I've been trying to make for several years, is that I think people should pay more attention to insulin resistance. Lipids get a lot of play, because they're easy to measure, easy to diagnose. It's a little more difficult to diagnose insulin resistance, but insulin resistance is an independent contributor to heart disease. People who have insulin resistance may well be on the road to developing full-blown diabetes, and with an assortment of complications of that, and I think it's been, in a way, overlooked in this, all the attention that's been focused on HIV-related metabolic complications.

Yes, and the longer the people are on the meds and living longer, getting older, the risk increases.

Right. Right. Absolutely. Absolutely. At the Retrovirus meeting in Denver in February, there was an updated report from this D:A:D study of cardiovascular disease that's been carried on for years now in thousands of people, and they reported that the people who were using protease inhibitor-containing regimens had an increased risk of cardiovascular disease, compared with people who weren't on protease inhibitors and that only a part of that effect could be attributed to increases in lipids. In other words, it seemed that there was something else about protease inhibitors that was independently contributing to increased risk of heart disease, and that could be insulin resistance. It could be other things, as well. It's speculation at this point, but I think it really deserves further attention.

Yes, that's very important and interesting. Thank you for pointing that out, that the drugs were not proving to be as promising as they had seemed at first, but --

Yes, but I do [think they are promising] -- maybe not as promising as they had seemed at first, but I'm not ready to take them off the table yet, and I think they're -- you know a couple years ago, people were writing the epitaph for glitazone in HIV, and I think recent research, including some that I've been involved with and studies from other people, have shown that there are effects of these drugs, positive effects, in certain groups of subjects, and it behooves us to figure out who is most likely to benefit from that and what place these drugs have in the overall armamentarium. As this discussion has revealed, there aren't a whole lot of really promising treatment options at this point for lipoatrophy, and so I'm not ready to take anything off the table until I can find something that is there to replace it that performs better and more consistently.

 

Click here to read an overview of recent research on lipoatrophy interventions.

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Kathleen Mulligan

About Kathleen Mulligan, Ph.D.

Dr. Mulligan helped organize the first International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, the only medical conference focused entirely on body-shape changes in people with HIV. She is one of the key researchers working on trying to understand and treat the disorder. After receiving a Ph.D. in nutritional sciences in the early 1990s, Dr. Mulligan became involved in HIV research, studying body composition and energy metabolism in efforts to control HIV-associated wasting. Now, as a member of the General Clinical Research Center at San Francisco General Hospital, she concentrates on the metabolic and morphologic effects of HIV therapy.

Dr. Mulligan's dedication and determination have led her to co-chair this year's International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV conference, as well as serve as chair or co-chair for multiple studies on body shape changes performed by the Adult and Pediatric AIDS Clinical Trials Group and the Adolescent Trials Network. Although the exact causes are still not understood and there is no effective treatment for lipoatrophy, Dr. Mulligan is hopeful about continuing research in this area.

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