with Lipodystrophy Expert- Dr David Nolan
May 2005 HIV
related lipoatrophy (fat loss under the skin) is a clinical problem
that affects many people living with HIV. Lipoatrophy can cause
substantial loss of buttock tissue, veiny legs and arms, and facial
wasting. Lipoatrophy can happen alone or in combination with lipohypertrophy
(fat accumulation) in the visceral (organ) and dorsocervical (back
of the neck) area. These body changes with or without blood
level alterations of cholesterol, triglycerides, lactic acid,
glucose, and insulin is what is called HIV-related lipodystrophy
syndrome. Many of these body changes occur normally with
aging, but being HIV positive seems to accelerate this problem
at earlier ages. Many observational cohorts and studies
to determine the causes and potential treatments of lipodystrophy
have been performed since 1997, the first year when we realized
that living longer with HIV may be accompanied with side effects
like body changes. Even though there seems not to be a consensus
based case definition for lipodystrophy, there are many things
that we have learned since then. One of them is the potential
negative role of nucleoside analogs like Zerit (D4T, stavudine)
and AZT (zidovudine) on subcutaneous fat wasting. Studies
in which patients were switched from these drugs to Abacavir (Ziagen) or Tenofovir (Viread) have produced encouraging results
in reversing lipoatrophy, even if it is at a slow rate. Other
studies looking at using insulin sensitizers like rosiglitazone
(Avandia) have produced conflicting results in reversing lipoatrophy.
It seems that the use of Avandia in combination with Zerit or
AZT does not allow for regrowth of subcutaneous fat tissue. Fortunately,
good news came to patients with lipoatrophy in the US when the FDA approved Sculptra (polylactic acid)
injections in August 2004 for the treatment of HIV related facial
lipoatrophy. Although this option does not treat the root cause
of the problem, it can give patients hope to look healthy once
again. There are still many unanswered questions and misunderstandings
in the field of lipodystrophy and metabolic disorders in HIV.
That is why I am glad to have the pleasure to interview one of
the leading researchers in the field of metabolic disorders in
HIV. I have seen him in every conference that deals with lipodystrophy
and side effects and have always been impressed with his knowledge
and his strong stand on the effect of HIV medications on body
changes. David Nolan is a clinician and researcher based
at Royal Perth
Hospital in Western Australia, where he works at the Centre for Clinical Immunology
and Biomedical Statistics. He has a broad range of interests relating
to HIV and its treatment, with a particular emphasis on lipoatrophy
where he has explored associations between NRTI therapy, mitochondrial
toxicity and fat tissue pathology. He has published more than
30 research papers and reviews, covering the broad topic of lipodystrophy
as well as related topics including mitochondrial toxicity syndromes,
metabolic complications of HIV protease inhibitor therapy, hyperlactatemia
syndromes, genetic susceptibility to abacavir and nevirapine hypersensitivity
reactions, and the effects of HIV and treatment on bone density.
HIV itself cause lipoatrophy or mitochondrial dysfunction in treatment
naive patients? If so, can starting treatment with non-thymide
analogs like tenofovir or abacavir reverse it?
There is no evidence that HIV infection
itself can cause lipoatrophy. It has been known for some
time that severe immune deficiency and AIDS-defining illnesses
can be associated with ‘AIDS wasting’, but this is
quite different in terms of the effects on body composition.
Lipoatrophy specifically affects the fat tissue just under the
skin surface (subcutaneous fat), leading to fat loss that is particularly
noticeable over the legs, buttocks and face. It is also
notable that the lean body mass (i.e. muscle tissue predominantly)
is unaffected in the case of lipoatrophy, and indeed muscle
mass often improves in the presence of lipoatrophy. On
the other hand, AIDS wasting associated with untreated HIV predominantly
affects lean body mass while having less of an effect on fat tissue.
The only exception here is that women with advanced HIV disease
tend to lose fat as well as muscle, although again this has different
characteristics. Loss of fat in AIDS wasting in women tends to
be generalised (i.e. the same all over the body) as with any weight
loss, while part of the reason that lipoatrophy is so noticeable
in both men and women is the way in which fat loss is so ‘unevenly
spread’ over the body. For women in particular, the
preferential loss of fat over the legs and buttocks associate
with lipoatrophy is quite unusual.
lipoatrophy data on AZT shows about half the adipocyte (fat cell)
depletion that is caused by d4T. Do you think that depletion of
fat cells and mitochondrial DNA/function is enough to warrant
industrialized countries to minimize the use of AZT for first
This is a very interesting question, and one
where there is no definitive answer yet. The adipocyte depletion
findings tell some of the story, although the clinical data are
probably more important in showing how significant the effect
of AZT is in terms of lipoatrophy risk. Overall, the severity
of fat loss and the risk of clinical lipoatrophy is approximately
halved with zidovudine treatment compared to stavudine.
This means that in ball park terms, the risk of developing noticeable
fat loss is 15-20% after 3 to 5 years of zidovudine treatment.
My own view (and again there is no consensus opinion available
as yet) is that the impact of zidovudine treatment is not sufficient
to minimize its use for first line therapy in industrialized countries;
for a number of reasons:
fat loss associated with zidovudine treatment tends to be fairly
slowly progressive, typically beginning after the first year of
treatment with the greatest risk of fat loss between 12-36 months.
In this instance, if those taking AZT (and those clinicians treating
them) are aware of the risk of lipoatrophy and actively monitor
for early signs (i.e. fat loss that particularly affects the legs,
buttocks and/or face, and which is often not associated with any
loss of weight), then treatment can be altered if and when this
complication develops. We know from the results of ‘NRTI
switching’ studies involving the use of abacavir or tenofovir
that fat loss is at least halted, and often improves, when the
NRTI drugs are changed.
host and disease factors that also contribute to the risk of lipoatrophy
when AZT or d4T are used (although, as stated above, these risk
factors only operate when these drugs are used).
Therefore, the risk of lipoatrophy with AZT treatment is likely
to be substantially reduced in those who are younger than 35 years
of age, who are of non-white racial origin, and who start treatment
when the CD4+ T cell count is greater than 100-200.
I think that part of the reason that AZT has remained in continuous
clinical use since 1987 is that it has a favourable resistance
profile in terms of its interaction with other NRTI drugs (see
below). The available data for newer backbone NRTI drugs
such as tenofovir and abacavir is certainly very promising, but
there are still some questions regarding both their long-term
effectiveness and (to a lesser extent) the potential for tenofovir
to cause renal and/or bone toxicity.
those who want to start or remain in a non protease inhibitor
combo, AZT seems to have a protective role in the selection for
K65R and L74V/I in all nucleoside combos. How can those patients
or doctors balance this fact with the potential lipoatrophy effects
Again, a very interesting question. I think it is
fair to say that any triple NRTI drug regimen needs to include
AZT to have a good chance of success, given the poor outcomes
that have been associated with NRTI combinations such as tenofovir/abacavir/lamivudine
or tenofovir/didanosine/lamivudine (very poor efficacy), or stavudine/didanosine/abacavir
(poor efficacy and high toxicity) [reviewed in 1]. In these
regimens, it appears that these drugs all tend to favour the emergence
of a similar pattern of resistance mutations, so that there is
very little barrier to the emergence of K65R or L74V/I.
AZT appears to counteract this effect, as it pulls in another
direction, actually becoming more potent when these resistance
mutations start to emerge. This means that the virus has
more difficulty becoming broadly resistant to both AZT and the
other NRTIs (most commonly lamivudine and abacavir) within the
NRTI combination. As stated above, I think the risk
of lipoatrophy associated with AZT can be managed in a rational
way that minimises the chances of developing problematic fat loss,
and in this particular case (when triple NRTI therapy is desired)
there really is no effective alternative drug at present.
4- Do you
think the move in international and US guidelines for delayed
treatment at lower CD4 counts will increase the incidence/prevalence
of lipodystrophy in the HIV population?
I think there is strong evidence that delaying
treatment until CD4+ T cell counts fall below 200 increases
the risk of a number of drug-related toxicities, including lipoatrophy
(if using d4T or AZT) and neuropathy (which can be associated
with HIV itself as well as the use of stavudine, didanosine or
zalcitabine) [reviewed in 2]. There is also a concern
that low HDL-cholesterol levels associated with more advanced
HIV disease may predispose patients to metabolic complications
and the potential for a greater risk of cardiovascular disease
. I would argue that treatment should be initiated at
higher CD4+ counts (i.e. 200-350) and should be focused
each individual case on its merits. This means taking into
account the patients characteristics and finding the best match
in terms of HIV therapy. These considerations may include
the toxicity profiles of individual HIV drugs, as well as the
tolerability of the HAART regimen. The main goal is to provide
the best possible chance of achieving 100% adherence to therapy.
Assessing and monitoring those side-effects that are specifically
associated with HIV drugs that are being used, so that these complications
can be picked up early and managed appropriately.
TARHEEL study results seem to point to the intriguing fact that
even though mitochondrial DNA (mtDNA) levels rebounded after d4T
therapy was discontinued, mitochondrial function did not recover.
Do you think that there may be some permanent mitochondrial damage
even after patients switch from d4T or AZT to non-thymidines?
I think the mitochondrial toxicity at a cellular level
is reversible, as it is likely that the toxic of these drugs is
mediated specifically by their effects on mitochondrial DNA depletion.
The more worrying problem is that severe lipoatrophy represents
a profound loss of adipocytes (fat storing cells) within the fat
tissue through cell death (apoptosis). The TARHEEL study
showed very nicely that you can ‘turn off this process of
cell death by switching from d4T to a non-thymidine NRTI (i.e.
far fewer cells are killed), but you are then left with the problem
of having to replace the cells that have been lost. While
the non-thymidine NRTIs are obviously not toxic to fat tissue,
they do not actively encourage new cells to grow, and treatments
that may be anticipated to help this process of regeneration (such
as rosiglitazone) have not performed well to date. This
problem is further complicated by the fact that lipoatrophic fat
tissue contains a large number of macrophages, inflammatory cells
that are probably there to mop up the adipocytes and their stored
fat after cell death, and these may also inhibit the growth and
development of new fat cells.
is your opinion about the use of micronutrients (carnitine, coenzyme
Q-10, thiamine, riboflavin) or the use of Uridine to reverse or
prevent loss or mitochondrial DNA or function in the presence
of thymide analogs?
With regard to the micronutrients you mention here, there
is no evidence that they improve any clinical outcomes if used
as a preventive treatment. They have been used in the management
of lactic acidosis (usually in an intensive care setting) although
because these events are so rare the benefits are not really known.
Uridine treatment (in the form of a sugar cane extract called
Mitocnol or Nucleomaxx’) has shown a lot of promise as a
preventive treatment that may limit the toxicity associated with
either stavudine or zidovudine without compromising the effectiveness
of these drugs against HIV, but these results have been obtained
primarily from the laboratory. Clinical experience with this extract
is minimal at present and the cost of treatment is ~$100/month.
I'm sure more information will be available in the next year or
so, which will be watched with interest.
7- We have
seen several studies that show improvement in limb fat after switching
patients from AZT or d4T to abacavir or tenofovir. Unfortunately,
no one has really been able to quantify facial fat in those studies.
Do you think that patients with moderate to severe facial wasting
may see improvements after this switch? Some of your data show
loss of fat cells due to macrophage activation. Do you think people
may not have enough fat cells for facial lipoatrophy reversal?
This is an important area, but one where it has been difficult
to obtain good data. Facial lipoatrophy is obviously one
of the most stigmatizing aspects of lipodystrophy, and this is
an area where people really want to see improvement following
NRTI switching. We do see improved facial appearance associated
with NRTI switching, although in general the more severe the initial
lipoatrophy (prior to switching) the more limited the improvement.
This is a frustrating aspect of the syndrome, as it is a case
of first affected, last to improve. This means that less
affected areas (such as the arms and trunk) tend to improve before
more badly affected areas such as the face and legs. Also,
because the process of regrowing populations of fat cells seems
to be slow, improvements happen over years rather than months.
is your personal opinion about the fact that AZT and d4T are still
becoming the most popular HIV drugs for the treatment of HIV people
in the developing world?
My own opinion is that we need to put this issue on the
agenda and keep it there particularly in the case of stavudine,
where there is a substantial concern about toxicity issues.
There is a rationale that stavudine may be better tolerated in
non-white populations and certainly this is an anecdotal opinion
that is expressed by clinicians who look after mainly African
American patients. However, the potential toxicity of these
drugs needs to be assessed carefully and quickly in the developing
world, before the development of severe and widespread complications.
We have already seen the burden of disease associated with severe
lipoatrophy in our own communities this history should not be
reproduced in developing countries.
lipoatrophy, what other long term health implications do lower
mitochondrial DNA and function mean to someone with HIV?
In truth, probably very few. The effects of NRTI
drugs on mitochondrial function appear to be very tissue-specific,
so in the case of lipoatrophy it is very likely that the damage
is limited specifically to fat tissue. For example, it is
notable that stavudine treatment which has been consistently associated
with severe mitochondrial DNA depletion in adipocytes has no significant
effects on mitochondrial DNA in blood cells. Also, the mitochondrial
toxicity associated with NRTI appears to be readily reversible,
in the sense that mitochondrial DNA depletion goes away quickly
after ceasing/switching NRTI therapy.
10- Will we ever have data to show
whether or not ddI is implicated in lipoatrophy?
Some historical data exists suggesting that ddI treatment
is not associated with lipoatrophy. For example, an early
study of dual NRTI therapy by Thierry Saint-Marc (published in
1999) included a number of patients receiving didanosine in both
stavudine (d4T/ddI = 13/27, 48%) and zidovudine treatment groups
(AZT/ddI = 13/16, 81%) that were well-matched for NRTI therapy
duration. In this study, use of stavudine remained the most
significant risk factor for lipoatrophy (relative risk 1.95 compared
with zidovudine), while no significant didanosine effect could
be demonstrated . More recently, results from the FTC-301A
study also suggest that the once-daily NRTI drug emtricitabine
(FTC) compares favourably with stavudine (each combined with ddI-EC
and efavirenz) in terms of lipoatrophy risk over 72 weeks (n=571),
while maintaining equivalent efficacy and improved overall tolerability.
Average loss of fat was noted only in the stavudine group, despite
the fact that ddI was used in both study arms . More
long-term data are awaited in this study.
11- In your experience, does tenofovir
have the same or different benefits when it comes to lipoatrophy
reversal/prevention as abacavir? How about when it comes to lipids?
We have observed the same non-toxic effects on adipocytes
mitochondrial DNA levels for these drugs, and the study data certainly
suggest that tenofovir and abacavir are not associated with risk
of lipoatrophy (both with an incidence of <3% over 3 years).
In this respect, neither drug will have a particular advantage.
With regard to lipids, the lipid lowering effect of NRTI switching
appears to basically represent the effect of removing stavudine
from the HAART regimen (in NRTI switching strategies) or of removing
PI drugs such as indinavir, rather than any special attribute
of tenofovir or abacavir. There was some attempt to differentiate
the effects of abacavir and tenofovir on lipid/lipoatrophy outcomes
in presentations at this years CROI, but I think these will come
to nothing once other confounding factors are taken into account.
From the lipodystrophy point of view, including both metabolic
and lipoatrophy outcomes, these are both good drugs.
12- What makes subcutaneous fat so different from visceral
or dorsocervical fat? Why do nucleoside analogs not
affect visceral fat? Why does insulin resistance seem to expand
visceral and dorsocervical fat but not subcutaneous fat?
Probably the best way to conceive of the difference between
subcutaneous fat and these other fat depots is that subcutaneous
fat is the ideal storage site for dietary fat, while visceral
fat tends to function as an overflow system if the fat-storing
capacity of the subcutaneous fat tissue is exceeded.
This means that subcutaneous fat responds very effectively
to the insulin stimulus that is associated with eating a meal.
What happens in this transition from a fasting to a fed
state, therefore, is that:
stops breaking down its stores of triglycerides, (where it has
been used as an energy source during a period of fasting);
starts to take up dietary fatty acids very efficiently (so that
it stores energy in the form of triglyceride for later use while
the dietary sugars and protein provide an immediate source of
metabolic fuel). Overall, about 50% of a dietary intake of fat
gets stored in this manner.
The whole idea of this process is that fat stores are
created while there is food around, so that there is an energy
source available for a period of fasting (eg. overnight for those
who dont have late-night snacks!). As you can imagine, this is
a system that has evolved over thousands of years when fast food
hadn't been invented and the next meal wasn't always guaranteed!
In this context, visceral fat is different in that it
doesn't respond to insulin so strongly which means that it doesn't
generally compete with subcutaneous fat tissue for the storage
of dietary fat. It is also much more labile, in that fatty acids
are also released back into the circulation much more readily
from visceral fat than from subcutaneous fat. Its purpose
is probably to create a short-term store of fat that can be used
again quickly, without running the risk of letting excess fatty
acids build up in tissues such as muscle and liver where they
can be quite damaging. So from a metabolic point of view,
there are a couple of important points to make here. One is that
you can create excess visceral fat by eating more fat than your
subcutaneous stores can cope with. The second is that insulin
resistance which means that tissues (including subcutaneous fat
but also liver and muscle) don't react to the presence of insulin
appropriately reduces the ability of subcutaneous fat to store
fat in the most efficient way. This leads to the accumulation
of fatty acids in all the wrong places (muscle, liver) and also
creates a reservoir of fatty acids (from visceral fat) that is
released at all the wrong times (eg. even when you've just eaten
and there is already plenty of metabolic fuel available). How
does this relate to lipodystrophy?
Visceral fat accumulation is a part of the ‘Metabolic
Syndrome that includes insulin resistance and dyslipidemia, and
these three elements cluster together quite strongly;
Excessive dietary intake of saturated fats and sugars contributes
to the development of visceral obesity by exceeding the capacity
of the subcutaneous fat to store dietary fat in an appropriate
way, and lack of exercise also leads to fat not being burned as
a source of energy. This means that you don't have to have
HIV infection and/or PI therapy to get these problems and indeed
~30% of US adults are affected by this Metabolic Syndrome.
Once visceral obesity is established it makes it harder
to recover from insulin resistance, as there is always a source
of fat that must also be burned along with dietary fat before
the system can go back to efficient functioning.
One of the least understood areas is whether having lipoatrophy
also contributes to the risk of insulin resistance and visceral
obesity. This would make some sense, as having less and/or poorly
functioning subcutaneous fat would be likely to make it easier
to overload the capacity of this organ to store fat. Some
recent data from the Netherlands [van Wijk JP, et al J Clin Endocrinol
Metab. 2005 Mar 22; [Epub ahead of print] support this possibility,
indicating that more severe lipoatrophy increases the risk of
insulin resistance. I think this is an example of how we need
to think carefully about how to look after the health of those
who are affected by severe lipoatrophy into the future.
Getting back to the original question, it is not really
known why stavudine and zidovudine don't affect visceral fat in
the way that they cause lipoatrophy. One explanation may
be that visceral fat is intrinsically more resistant to mitochondrial
toxicity, because (1) it doesn't rely so much on energy-requiring
processes such as triglyceride synthesis, and (2) because it expresses
anti-apoptotic proteins (one is called cIAP) that make visceral
fat cells less susceptible to mitochondrial toxicity and subsequent
cell death. At this stage, no one has collected fat samples
from this fat depot in HIV-infected patients.
12- Besides serving as caloric
storage and may be protection against the elements, what other
function does subcutaneous fat have?
This is currently a ‘boom’
area in medical research, as it becomes increasingly recognized
that subcutaneous fat actually functions as an active metabolic
organ rather than as an inert storage site. There are many
examples of how this plays out, but the case of adiponectin might
be a good starting point. Adiponectin is basically a hormone
that is released only from subcutaneous fat, which profoundly
influences the way that fatty acid metabolism is regulated by
the body as a whole. When subcutaneous fat tissue is healthy (and
not affected by insulin resistance) it releases increased amounts
of adiponectin into the system, which acts as a signal for the
body to efficiently ‘burn’ the fat that is present
in muscle and liver. This means that adiponectin acts to
protect against insulin resistance. However, when subcutaneous
fat is not functioning properly, adiponectin levels go down and
this then becomes part of the problem of insulin resistance –
fat is allowed to build up in the wrong places and is not efficiently
burned. There is a lot more to this story, but to
summarise it is certainly true to say that subcutaneous fat is
an integral player in metabolism generally – and is likely
to be just as important to ‘metabolic health’ as muscle
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Keswani SC, Pardo CA, Cherry CL, Hoke A, McArthur JC. HIV-associated sensory neuropathies.
El-Sadr WM, Mullin CM, Carr A, Gibert C, Rappoport C, Visnegarwala
F, Grunfeld C, Raghavan SS. Effects of HIV disease on lipid, glucose
and insulin levels: results from a large antiretroviral-naive
cohort. HIV Med. 2005;6:114-21.4.
Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere
O, Lang JM, Gastaut JA, Touraine JL. A syndrome of peripheral
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analogue therapy. AIDS. 1999;13:1659-67. 5.
Saag MS, Cahn P, Raffi F, Wolff M, Pearce D, Molina JM,
Powderly W, Shaw AL, Mondou E, Hinkle J, Borroto-Esoda K, Quinn
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of emtricitabine vs stavudine in combination therapy in antiretroviral-naive
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with Dr. Lemperle about facial implants
I met Dr. Gottfried
Lemperle in San Diego for breakfast a month ago. He turned out
to be a very pleasant and passionate guy who knows a great amount
of information about facial implants. He is currently a cosmetic
surgery professor at UC- SD medical school. He moved to the US
3 years ago from Germany, where he holds patents with his son
on microspheres for facial implants. These are his answers to
WHAT IS THE CRITERIA FOR A GOOD IMPLANT FOR FACIAL LIPOATROPHY?
For facial lipoatrophy, there are solid and injectable implants
commercially available. The solid ones from polymerized silicone,
Teflon, hydroxyapatite, or polyethylene can be cut to suitable
shapes and implanted on the malar bone, maxillary sinus, and the
mandibular arch. The center of the cheek, the atrophied Bichat's
fat pad can be augmented with an oval shaped implant from soft
silicone (1), which was first choice before the era of permanent
soft tissue fillers.
The ideal injectable dermal filler substance must be biocompatible
and safe, stable at the implantation site, retain its volume and
remain soft and pliable, should not dislocate by gravity, and
evoke minimal foreign body reaction (2).
WHAT ARE THE RISKS?
The potential risks of temporary filler substances, such as collagen,
hyaluronic acids, polylactic acid or PMA beads, are fast absorption
within 3 to 6 months, allergic reactions and - not yet understood
- late granuloma formation.
Permanent filler substances, such as silicone fluid or gel, polyacrylamides,
silicone particles, or PMMA microspheres, carry the risk of technical
mistakes during implantation, allergic reactions, dislocation
by muscle movement or gravity, and late granuloma formation.
HOW CAN THE POTENTIAL RISKS/SIDE EFFECTS BE TREATED (GRANULOMA,
Dislocated implants or lumps can be diminished and softened effectively
by intralesional corticosteroid (Kenalog) injections (3). They
inhibit fibroblasts from producing collagen fibers, thereby reducing
the volume of the encapsulating host tissue by half. The rather
rare granulomas (1 in 10,000), which are an ongoing foreign body
reaction, can also be reduced to its former size by corticosteroids.
Since every patient reacts differently to these drugs, which may
cause temporary atrophy, when injected into the subcutaneous fat,
these strictly intralesional injections have to be repeated in
3-weeks intervals. Larger depositions of silicone gel or polyacrylamides
can be reduced by suction. Surgical excisions are never indicated
DO YOU KNOW OF ANY DATA ON CANCER DUE TO SOFT TISSUE AUGMENTATION
In rats, artificial substances such as solid polymers can cause
sarcoma formation on smooth surfaces and edges (Oppenheimer effect).
This effect, however, could never be demonstrated with the same
substances injected in powder form, e.g. as microparticles or
microspheres. In humans, no malignant tumor formation has been
reported on substances, which have been used for more than 50
years, such as paraffin, silicone, or PMMA-bone cement.
IN YOUR OPINION, WHAT ARE THE BEST AND MOST DURABLE OPTIONS
Since 20 years, I have a personal experience with all injectable
substances. I have injected all of them into the skin of my left
forearm to control persistence and histology. There is no question:
the risks of lumpiness and dislocation are less in temporary fillers
since both will be absorbed within a few months. On the other
hand, the costs of repeating these treatments every 6 months are
certainly much higher than one to three treatments with a permanent
Silicone fluid can be effective and durable, however, dislocation
by gravity in patients with loose connective tissue, and late
granuloma formation in some patients have banned its use in most
Polyacrylamides appear to be very biocompatible and do not cause
the formation of a capsule at all. Therefore, the deposit can
dislocate by gravity in certain patients and have to be removed
For me, tiny microspheres from any non-absorbable polymer are
the material of choice for tissue augmentation today. Their smooth
surface allows encapsulation instead of rejection, and permanent
fixation at the location, where they were injected.
DO YOU THINK THAT POLYLACTIC ACID IS EFFECTIVE TO FILL
CHEEKS ATROPHIED BY HIV LIPOATROPHY?
Since two years, we are trying to find a substance, which will
have a semi-permanent effect of about 2 years in the human tissue.
All efforts to change the formulation of polylactic acids have
failed, so far. NewFill® microspheres are absorbed within
3 - 6 months and therefore not worthy for the treatment of a lasting
condition such as facial lipoatrophy.
WHAT CAN YOU TELL US ABOUT ARTECOLL, THE NEXT PRODUCT
TO BE APPROVED IN THE US? I HAVE A FRIEND WHO GOT THIS DONE ONCE
IN CANADA AND DID NOT SEE ANY BENEFITS.
Artecoll has been used in Europe and ex-US countries for over
ten years in more than 200,000 patients worldwide. Each of the
6 million microspheres is encapsulated with the body's own connective
tissue, which makes up 80 % of the final implant. Until 1994,
the microspheres had tiny PMMA particles attached, which were
the cause of granuloma formation in some patients. These cases
are still mentioned on meetings but are history, fortunately.
The clinical trials in the US showed its lasting effectiveness
without any side effects worth mentioning. The FDA reveals the
application of approval and will make its decision by the end
To my 12-year experience with Artecoll, a medium lipoatrophy needs
at least 5 cc of filler material on each side to be treated successfully.
Therefore, one or even 2 cc injected too deeply will easily give
the impression of disappearance to the patient. Especially in
an atrophic skin, one has to be very carefully to deposit Artecoll
deep dermally and not into the residual subcutaneous fat ! Your
friend may have got a small amount injected.
WHAT IS YOUR OPINION ABOUT POLYACRYLAMIDE BASED PRODUCTS?
Polyacrylamides have been used extensively in Ukraine
for 20 years, however, no statistical data are available. Histologically,
it causes almost no reaction or capsule formation (2) and shows
similarities to inert fluid silicone. Since the patent expired
recently, at least 7 European companies produce filler substances
from this material. A high health official in China, however,
told me some months ago that polyacrylamides (Interfall®)
will be prohibited soon because of a high incidence of enlarged
lymphnodes, dislocation by gravity, and granuloma formation in
WHAT ARE THE MOST PROMISING PRODUCTS IN THE PIPELINE FOR
Since more than 20 years, there is only one product approved
for soft tissue augmentation in the US, and that is bovine collagen
(Zyderm® and Zyplast®). Hyaluronic acid products (Restylane®
and Hylaform®) are in clinical trials and may be approved
in 2003. Both are, however, not longer lasting than collagen,
have similar side effects and can cause late granulomas like collagen.
Polylactic acid microspheres (NewFill®) are in clinical trials
for facial lipoatrophy but are not longer lasting than collagen,
Scientifically, Artecoll® consisting of microspheres sieved
from bone cement (polymethylmethacrylate) and suspended in collagen
is the best and longest proven materials in aesthetic surgery,
and therefore my first choice for the treatment of wrinkles and
facial lipoatrophy. I would switch tomorrow to a better injectable
material, if there would be one.
WHAT DO YOU THINK THE HIV COMMUNITY SHOULD DO TO ENSURE
FASTER ACCESS TO THESE OPTIONS?
The HIV community should approach the companies of soft tissue
fillers and ask for clinical trials especially with facial lipodystrophy
patients. Later on, these companies should provide the material
at their lowest price exclusively for HIV patients. Since side
effects of drugs are real diseases, the FDA should categorize
these trials as urgent and renounce their usual long way of approval
process. The HMO's should recognize F.L. as a disease and discuss
a certain amount for the physician's reimbursement. If this does
not work out soon, it's common practice among pharmaceutical companies
to reimburse patients for the treatment of side effects caused
by their drugs.
ARE THE FEARS ABOUT SILICONE UNFOUNDED?
The fears about silicone gel being immunogenic, which have been
launched in the early nineties by some focused physicians, lawyers,
and breast implant patients, have been proven by many rheumatologists
and epidemiologists to be unfounded. Soon, gel filled breast implants
will be on the US market again. The only case I know of as an
expert witness, which tries to relate multiple sclerosis to injected
fluid silicone, is still not settled in London.
ANYTHING ELSE THAT YOU WOULD LIKE TO ADD?
I am well aware of the importance the stigma of facial
lipoatrophy means to its bearer. There is an easy applicable and
safe way of leveling this deformity in 3 to 5 ambulatory sessions
to its former appearance. The price per syringe is rather high
and must be reduced effectively to meet the needs of these real
patients. Furthermore, HMOs must realize the effect of such a
treatment on the working capacity of a whole important community.
1. Hasse FM, Lemperle G: Resection and augmentation of
Bichat's fat pad in facial contouring. Europ J Plast Surg 17:
2. Lemperle G, Romano JJ, Busso M: Soft tissue augmentation with
Artecoll: 10-year history, indications, technique, and potential
side effects. Dermatol. Surg.28:, 2002
3. Lemperle G, Morhenn VB, Pestonjamasp V, Charrier U, Gallo RL.
Histology, persistence, and migration studies of various injectable
filler substances for tissue augmentation. Plast Reconstr Surg