Yes, I was.
Do you remember what it was like when you were first beginning to see lipoatrophy?
Yes. This was one of those stories of drugs with promise, and then later, sort of the unfulfilled, or only partially fulfilled, promise of the drugs. For so long, we struggled to get any medications that would control HIV. In the mid-1990s, we finally were able to achieve that, and saw [a] reversal of disease and deaths among our patients. It was a real cause for celebration, despite many of the side effects of the medications. What came as a gigantic disappointment to those involved in HIV care -- both patients and medical providers -- was the later realization that some of these medications could cause serious toxicities. One of them, of course, as it turned out, is part of lipodystrophy and lipoatrophy. So it was this sense of taking away of the promise of completely normal lives, leaving many patients to say that "I would rather die than to suffer from those side effects." In fact, many patients elected in those days to avoid medications, often at the cost of severe disease and occasionally even death.
Do you think that that remains -- that that kind of stark decision remains an issue for people?
Well, in general terms, no. As medications have gotten better, better tolerated, easier to take, it's an unusual patient now that has to choose between side effects and life. That's not to say that drugs are perfect. But nor does it say that the medications are uniformly toxic. So that for the vast majority of patients -- and I would assert that for all patients on first- and second-line therapies -- we can find medication regimens that in fact are quite well tolerated, and many that cause no side effects.
Would you agree that lipoatrophy, in particular, is now a side effect of the past for people starting treatment these days?
Lipoatrophy clearly was more common in the past, and probably because of the fact that we used drugs, with good intentions, and without the full knowledge of the potential toxicity, in those days. Stavudine [d4T, Zerit] was a very commonly prescribed drug in the late 1990s because it was very well tolerated in the short term. We failed to recognize at the time -- because, in fact, we didn't have patients living long-term, so we didn't appreciate the long-term potential toxicity. As we stopped using Zerit, the frequency of new onset lipoatrophy in our practice has dropped dramatically, and frankly, it's a very unusual case now [to] see a new diagnosis of lipoatrophy. So I do think the medicines are better. New medications are better in their risk of causing lipoatrophy. All that said, it's also important to emphasize that not all lipodystrophy is caused solely by medications. In other words, HIV disease-related factors also play a significant role in the risk in the genesis of lipoatrophy.
Let's get down to naming names in terms of the drugs, as well as the other factors, that can cause lipoatrophy. I'd like to know what your view is, and if you think there's any kind of disagreement in the field about what the causes are.
Well, I think there is a general agreement that there are both medication-related factors and non-medication related factors. To that extent, there is some disagreement as to the relative contribution of specific drugs in their risk for causing the various syndromes of lipodystrophy. There is another sense of disagreement -- but, again, it's more a disagreement in detail -- [over] which HIV-related factors, or disease-related factors, also contribute to risk.
There are now a number of studies from across the world that show -- data without much debate -- the longer one waits to initiate therapy, that is to say, patients who wait to start therapy with the lowest CD4 counts, and often to avoid toxicity, paradoxically, are at greater risk of developing the very toxicity that they are trying to avoid. We know from multiple studies now, including our analysis [of] HOPS [HIV Outpatient Study], that patients with lower CD4 counts at time of treatment initiation are, in fact, at greater risk [of] developing lipoatrophy. [HOPS began in 2002. The study is taking place at nine sites in seven major U.S. cities and several thousand HIV-positive people are being followed.] That risk doesn't abate when their CD4 counts improve. So these data point to a biological phenomenon that's unrelated to drug, per se, that places patients with HIV and immunodeficiency at greater risk of having the complications.
For lipoatrophy, specifically?
Yes, for lipoatrophy. That's an obstacle, because patients generally want to wait to start medications, because they want to avoid and minimize the risk of toxicities and long-term complications.
I think the federal guidelines now say that treatment should be initiated at 350 CD4 cells. Is that accurate? What do you think?
The current treatment guidelines give patients and doctors some leeway in the decision as to when to start [treatment]. The guidelines suggest that patients consider treatment at CD4 counts of 350, but really don't make a mandated position, or mandated guideline, on this until CD4 counts are at 200. There's a very large difference between a patient with a CD4 count of 350 and one with a CD4 count of 200, with regard to their disease risk, in my view. It's that gray area that is the territory for this debate. Some doctors will simply wait until patients have CD4 counts of 200 prior to initiating therapy. Others will initiate therapy at 350, or even at counts above, but close to, 350. I tend to cast my vote on the side of earlier initiation, in large part to try to avoid the risk, the irreversible risk, of these kinds of complications, knowing that medications in 2006 are much better tolerated than the medications that we used in 1996.
So what medications, specifically, are implicated in lipoatrophy?
The primary drugs that are implicated in increasing risk of lipoatrophy are the deoxynucleosides, d4T and ddI [didanosine, Videx]. There is a debate over the relative contribution of the other thymidine drugs -- AZT [zidovudine, Retrovir] -- in causing lipoatrophy. Some studies have shown this, and others have not. But taken together, I think it's a certain class of nucleosides that are the more likely offenders with regard to increased risk of lipoatrophy.
They do that by what mechanism?
The mechanism is a point of debate, but I think the consensus, at the moment, is a mechanism that involves mitochondrial injury and probably some sort of injury to body fat cells, or adipocytes. So, therefore, drugs that cause a greater degree of mitochondrial injury are thought to be greater potential offenders in causing lipoatrophy. With that regard, it is probably not coincidental that d4T causes a certain degree of mitochondrial injury.
I think that some patients have a question about whether the fat that they are visibly losing is caused by fat cells that are actually dying and disappearing, or whether those fat cells are sort of just being made dysfunctional. And whether the fat cells will, when they go off the drugs, come back in some fashion, or other fat cells will come back. What's your view of that?
We actually don't know as much as we'd like to know about the actual mechanism of the fat loss. That is to say, whether it's a shrinkage of existing cells or death of normal sized cells -- or perhaps some mixture of both. We do know that there is a degree of reversibility of the fat loss and that suggests that the cells don't all die. That reversibility is seen primarily when the offending nucleoside drug is stopped. And again, the greatest amount of data on that comes from studies that take patients who have lipoatrophy, [are] receiving d4T, and [we] switch them to either abacavir [Ziagen] or to tenofovir [Viread] -- two drugs that do not seem to cause significant mitochondrial injury.
So even though those two drugs are nucleoside analogs, they don't seem to do the same thing. They are, in terms of this side effect, safe drugs.
I think that the existing data on the, let's say, the newer, more contemporary nucleosides is just that; they seem to have a much lower rate of causing lipodystrophy, lipoatrophy, and some of that may, in fact, be due to the absence of mitochondrial injury. There may be other factors involved that we are less aware of at the moment.
What proportion of your patients who have been on, say, d4T, or even ddI and AZT, have gotten lipoatrophy? Is it kind of a 100 percent guaranteed thing?
No. In fact, that's a very important point. Not everybody who receives even so-called "toxic" medications develops the side effects of the medication. However, in the earlier days, in first-line therapy nearly all patients got d4T. In that group of patients, about 50 percent of them developed some form of fat loss. With contemporary medications, it's not seen at any significant rate, at least in our practice, or in my memory -- so I think there are two important points here. One is that even in the old days, not everybody developed these toxicities. In fact, these are patients, some of whom still remain on d4T even today without lipoatrophy.
What we know from many studies is that lipoatrophy seems to select out a group of patients who are very susceptible to this, and they develop these symptoms relatively early after the initiation of therapy. There are other patients who appear not to be at risk of developing these complications, and despite years of exposure to those medications, still have not developed lipoatrophy. So I think that it means a management strategy, which is to avoid risk. But that risk is not one that's absolute. So some patients actually can tolerate the medications for a very long time.
There's even the possibility that, if you had a lot of drug resistance, and you had to try one of these medications, since the symptoms seem to develop early, especially in the case of d4T, you might be able to -- if you thought you were developing lipoatrophy and it was confirmed by your doctor -- switch off the drug and at least stop the lipoatrophy from developing beyond a minor case. Is that true?
Well, it's true insomuch [that if] the lipoatrophy is -- that what's observed -- is drug related. Again, the common misconception is that it's only the drugs that are responsible. So therefore, if you just switch out the drugs, everything will get better. Again, we have seen lipodystrophy and lipoatrophy develop in patients who have never been on medication. We have seen patients develop lipoatrophy on drugs that are not thought to be causing lipoatrophy. You can reverse the risk that's attributable to the drug, but you cannot necessarily reverse the risk of the lipoatrophy that is, let's say, attributable to having bad HIV disease.
So advanced HIV can also cause mitochondrial injury?
Among many other problems.
The important point is that recovery of mitochondria, and therefore the recovery of lipoatrophy, can take a very long time -- long after discontinuation of medications. In the studies that switched patients from d4T to tenofovir, or d4T to abacavir, the reconstitution of the fat, if you will, was very slow. It took months to really appreciate, even by sensitive x-ray measures.
So essentially when we speak of lipoatrophy reversing to the visible eye, it's going to take a long time before you're likely to see some results.
That's correct. This isn't like stopping a medication that causes nausea, and having nausea improve in a day or two. This is a circumstance where reversal of significant lipoatrophy may take months, if not years. These observations naturally lead to a strategy of avoiding drugs that cause lipoatrophy, since treatments for reversing lipoatrophy are not very effective. I think I would extend that statement, however, to include the concept of avoiding delayed initiation of therapy. If one of the reasons to treat HIV is to avoid lipoatrophy, per se, [then] again, I think an important misconception of the community is [to] wait [for a] CD4 count [of] 200 [before initiating therapy] to avoid developing lipoatrophy -- when, in fact, that's exactly the wrong thing to be doing if one wants to avoid increasing risk of lipoatrophy.
Especially now that we have quite a few other options for first-line therapy, and even for nucleoside analogs.
I wonder if that message is getting out there. What do you think?
I don't think it is, and it's not popular. It's popular to blame bad pharmaceutical companies and their bad products for all of the toxicities that we see. It's not very popular to assert that the patient, or the patient's disease, also plays a significant role in what we deem as drug toxicity. I believe strongly that patients who initiate therapy with healthier immune systems, arbitrarily defined [as] a CD4 count at or above 350, have a lower risk of developing some of these very significant complications. This may, in fact, be reflected in the somewhat decreased frequencies of lipoatrophy that we see in our practice.
I understand, and wouldn't want to minimize, the psychological effects of having lipoatrophy, but is it also physically dangerous for your body to have this kind of mitochondrial injury in your fat cells?
As far as we know, there really isn't any significant, let's say, internal, medical complications of lipoatrophy. For example, patients who have lost all of their peripheral body fat don't seem to be at greater risk of diabetes, or greater risk of heart disease, or greater risk of pancreatitis, per se. As such, I think that the approaches and treatments of lipoatrophy need to be balanced with [the] knowledge of what we think of what is largely a cosmetic -- and very serious cosmetic -- complication of HIV and HIV treatment. But directly to your question: It's not a life-threatening condition, by any stretch.
Right. Those other diseases, or complications that you mentioned, like pancreatitis, diabetes and peripheral neuropathy, those are also caused by damage to mitochondria. Is that true?
Some of those illnesses are -- not all of them. For example, we believe -- well, some believe -- that pancreatitis and peripheral neuropathy are related to mitochondrial injury, although I think that those data are subject to quite a bit of debate. What is clear is that some of the drugs that cause lipoatrophy also cause peripheral neuropathy and pancreatitis. Now [whether] the mechanism of injury in both organs systems [is] the same is an area of quite a bit of conjecture. It would be convenient if that were the case, but, in fact, the data does not fit neatly into that model.
Let me switch gears a little bit right now and just ask you, when you're talking to your patients about initiating treatment, do you find that lipoatrophy, or even lipodystrophy, comes up as a concern right away? Or are they just concerned about the general side effects of medications?
Yes. Now, appearance-related side effects, like facial lipoatrophy, are very serious concerns for many patients who got recently diagnosed with HIV, and more specifically, among patients who are soon to be initiating treatment for HIV. However, it's important both for patients and for doctors to remember a simple and important fact, which is that HIV and AIDS still kill people. And, again, it's a matter of balancing the knowledge of the risk of that fatal illness with the available treatment options for the disease.
With your patients who have developed lipoatrophy, what's been your strategy in terms of adjusting it -- switching off of the offending drug onto other things, if possible? What kind of reconstructive procedures would you recommend?
When we see patients who have lipoatrophy, we first try to address [the] multiple factors they have to deal with: Which antiretroviral medications they're taking? Are there medication switch options that are viable, and allow us to continue virologic suppression? It wouldn't be in the patient's best interest, for example, to switch someone off of d4T to a different drug if that new drug failed to suppress HIV. But assuming that those options exist, then, yes; we readily switch patients off of d4T, and have a lesser degree of urgency to switch patients off of other drugs, though those switches are also entertained.
We also make sure that patients have adequate access to food, access to nutrition -- because malnutrition alone can cause fat loss. We also talk about diet. But we also talk about exercise in those same patients, because increasing muscle bulk is one way to at least mitigate, or ameliorate, the severity of the appearance of fat wasting.
Now, once all of that is addressed and we still have significant issues [with] body appearance, then we can talk about other kinds of approaches with regard to lipoatrophy. What we're really talking about is a number of injectable filler materials, one of which is now approved by the FDA [U.S. Food and Drug Administration] for treatment of HIV. These medications have actually worked quite well in the patients who have had access to them. I think that latter point is an important one, because most insurance companies do not pay for these procedures. Medicare, Medicaid, Ryan White Fund, do not pay for these kinds of procedures. So it's really a story of the haves and have nots -- those who have access to reconstructive surgical approaches [versus] those who do not [and who] simply have to continue to deal with the lipoatrophy.
Do you feel comfortable in recommending, or discussing, the different options among the injectables?
It's not my area of expertise.
Who would you recommend a patient talk to?
Talk to a doctor who has experience with the various products. This is one of those things where it seems like a relatively new subject to HIV doctors, but the whole notion of plastic surgical fillers, in fact, has been around in the plastic surgery field for quite some time. Many of the products that we're now seeing [for] HIV lipoatrophy have been used by plastic surgeons, cosmetic surgeons, for the last decade. In essence, what I do is defer to our plastic surgical colleagues to make the decision about which product to use -- which ones they are the most comfortable with, which ones they have the greatest experience with -- and use that as a large component in the decision of which product to use.
In general, patients haven't been particularly successful in getting insurance to cover injectables. In some of the interviews we've done we have found that if patients appeal, and also have good documentation of the serious psychological problems that lipoatrophy can cause, can be useful in getting insurance to cover it. Have you been involved in any of those kinds of appeals?
Yes, we have. And the appeal process can be difficult, if not aggravating, at many levels. What insurance companies generally fail to appreciate is that this is a disease-related complication. And until insurance companies understand that, there will be a tendency to relegate facial fillers, for example, as a purely cosmetic procedure, and not one that takes care of, again, a disease complication. The analogy to this, in the ones where we have argued successfully, is to describe lipoatrophy as a disease complication, much like having a breast mastectomy as a complication of breast cancer. Clearly, insurance companies are comfortable and accept the idea of providing care for breast reconstruction surgery. Clearly, therefore, insurance companies should have little reticence in providing reconstructive surgery for patients with loss of [other] body parts -- meaning, body fat. That's not a logic that resonates with most insurance companies, and it requires extra work from the health care provider, and from the patient, to have a chance at making that reimbursement happen.
It seems like it would take a considerable amount of maybe even political pressure, or something like that, to get insurance companies to collectively change that ruling.
Yes, I think so. The insurance companies, the insurance industry itself, clearly won't be motivated to do that on their own. It is [a] place for effective lobbying, either from patient groups, or from medical provider groups. It is a difficult problem in an environment where we struggle to even get reimbursement [from] governmental funding to provide antiretroviral therapies. The dilemma that we all face is that there are states that have wait lists for antiretroviral medication. Frankly, in my view, while that situation is entirely abhorrent, we need to focus on making sure that we get lifesaving medications to people before we worry about the important appearance-related complications of HIV. But in my ideal world -- and part of that is the ideal world of having third party insurance companies -- we need to work within that framework to educate and lobby insurance companies [about] the point [that] lipoatrophy and lipo-accumulation, actually, are both AIDS-related complications that have significant, sometimes medical, and more often, psychological, implications [for] the quality of life of the patient. Therefore, it's an obligation of the insurance companies to provide appropriate medical remediation of those complications.
As I understand it, the reconstructive procedures are not -- I mean, everything is relative -- but they are not terribly expensive. For example, Sculptra (poly-L-lactic acid) -- both the product and the procedure itself -- can run up to maybe $10,000. That's a lot of money, but it's not like a lot of other things that insurance companies do cover.
Right. No disagreement there. I actually do think that the plastic surgical filler materials are awfully expensive for what they are. Nonetheless, that's not the focus of the discussion; the major issue is that we have disease-related complications, which have significant impact on quality of life. And we have available to us FDA-approved medications that can mitigate the severity of that disease. It seems like a pretty simple argument, that the clients of insurance companies should have access to those kinds of medical remediations if, in fact, they are disease related -- whether they cost $1 or they cost $10,000. It's the job of the company to make sure that these are serious and disease-related complications.
My final question is, for those people who have lipoatrophy but don't have the resources to pay out-of-pocket for any kind of reconstructive procedure: How do you work with them to deal with it? You mentioned some lifestyle changes, but beyond that, psychologically, is that something that you deal with, in terms of helping them?
Yes. We obviously try to help the whole patient; physical and emotional, of all of our patients, at all times. We're not always successful at that. It's important for patients, even those who have serious lipoatrophy, [to understand] that both the drug discovery process and the process of biomedical research will yield answers, both in terms of the causes of, and the better treatments of, lipoatrophy. I'd like my patients to always remember that as bad as these things are, number one, that they are -- to me -- better than the alternative of death from AIDS and its complications. I believe that in the years to come, we will have better strategies for taking care of this very serious complication, better strategies for reversing it, better strategies for preventing lipoatrophy, and so on. In the meanwhile, we'll try to provide the best access to strategies to support these patients, both physically and emotionally.
Thank you very much.
You're very welcome.
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