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Lipodystrophy
in HIV Disease
People with HIV are living longer lives, but they
often face new challenges to their health and self-esteem.
Learn about the condition called lipodystrophy. Transcript
>>
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Update
on Lipodystrophy in HIV
People taking HIV medications may experience a shift
in the distribution of their body fat. Listen to experts
discuss some important preliminary data showing that
some features of lipodystrophy may be reversible.
Transcript
>>
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Dealing
with Wasting in HIV Disease
Body changes such as loss of lean body mass and body
fat can occur in people with HIV. Some of these changes
occur because of what is called HIV wasting or cachexia.
This is different from body changes with conditions
known as lipoatrophy or lipodystrophy. Transcript
>>
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MEDICARE EXPANDS COVERAGE FOR TREATING FACIAL LIPODYSTROPHY SYNDROME IN PEOPLE LIVING WITH HIV
For Immediate release Contact: CMS Office of Media Relations March 23, 2010 (202) 690-6145
The Centers for Medicare & Medicaid Services (CMS) today announced its decision to cover facial injections for Medicare beneficiaries who experience symptoms of depression due to the stigmatizing appearance of severely hollowed cheeks resulting from the drug treatment for Human Immunodeficiency Virus (HIV). Today’s decision is effective immediately.
Facial lipodystrophy (LDS) is a localized loss of fat from the face, causing an excessively thin appearance in the cheeks. In some cases, facial LDS may be a side effect of certain kinds of medications (antiretroviral therapies) that individuals receive as part of an HIV infection treatment regimen.
The facial LDS can leave people living with HIV looking gaunt and seriously ill, which may stigmatize them as part of their HIV-infection status. Individuals who take these medications and experience facial LDS side effects may suffer psychological effects related to a negative self-image. These effects may lead people living with HIV to discontinue their antiretroviral therapies. The new decision allows for treatment of individuals who experience symptoms of depression due to the appearance changes from facial LDS.
The injections included in today’s coverage decision are “fillers” that have been approved by the U.S. Food & Drug Administration (FDA) to be injected under the skin in the face to help fill out its appearance specifically for treatment of facial LDS. Data show that these injections can improve patient self-image, relieve symptoms of depression, and may lead to improved compliance with anti-HIV treatment.
“Today’s decision marks an important milestone in Medicare’s coverage for HIV-infection therapies,” said Barry M. Straube, M.D., CMS Chief Medical Officer and Director of the Agency’s Office of Clinical Standards & Quality. “Helping people living with HIV improve their self-image and comply with anti-HIV treatment can lead to better quality of life and, ultimately, improve the quality of care that beneficiaries receive.”
The final decision is posted on the CMS Web site at http://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=234.
CODES TO BE USED BY PHYSICIANS TO GET MEDICARE TO PAY FOR PRODUCT AND PROCEDURE: http://www.wellcare.com/WCAssets/corporate/assets/HS134_Dermal_Injections_for_Facial_Lipodystrophy_Syndrome.pdf
HIV
Metabolic Complications Myths
Some misunderstandings about treatment
by
David Alain Wohl, M.D.
Introduction
One of the greatest drags on the success of potent antiretroviral
(ARV) therapy has been the fear of metabolic complications
associated with these medications. Disfiguring body shape
changes including the loss of fat in the face, as well
as unhealthy cholesterol and triglyceride levels and pre-diabetes
are troublesome counter-balances to the euphoria that
arose when these drugs arrived and people stopped dying.
Even as ARVs have become more user-friendly—less
pills, less frequent dosing, less diarrhea and nausea—the
specter of metabolic problems can still overshadow these
advances, leading those in need of therapy to hesitate
when ARVs are recommended. For those already on treatment,
metabolic disorders may prompt a change in therapy or
lead to the prescription of even more medication and can
raise the volume of the little voice that says it is okay
to skip doses.
A major frustration for people living with HIV and their
health care providers has been a lack of information regarding
the cause of metabolic problems during HIV infection and
ways to prevent and treat them. The field of metabolic
complications of HIV and its therapies is relatively young
and much has been learned during a short period of time
but some conclusions have been reached with little supportive
data. Below is a list of some of the most common of these
metabolic complications myths. Myths that emerged in a
data vacuum and that even people in the “HIV-know”
often still accept. Fortunately, over the past few years
a slew of studies has painted a clearer picture of these
changes and together suggest that some of our closely-held
beliefs about the risks for metabolic complications have
been wrong. Understanding that these assumptions are no
longer valid, and why, is essential if people living with
this infection and their health care providers are to
make informed decisions about their care.
Myth
#1: Protease inhibitors are responsible for the increases
in belly fat.
Like many myths, this one is based on a truth that has
been stretched to extremes. People taking protease inhibitors
can see an increase in their belly fat, both the deep
down fat that surrounds our internal organs and the surface,
pinch-an-inch fat so abundant in our land of amber waves
of grain. But protease inhibitors hold no monopoly on
an ability to expand trunk fat. Studies of efavirenz (Sustiva)
have shown that people taking this non-nucleoside also
tend to have increases in belly fat. In fact, increases
in waist size have been seen in studies of every HIV regimen
in which body shape has been objectively measured. For
example, in a federally funded AIDS Clinical Trials Group
(ACTG) clinical trial called study A5142 comparing the
popular HIV medications lopinavir/ritonavir (Kaletra)
and efavirenz, trunk fat was seen to increase in participants
regardless of which drug they were assigned. Similarly,
a Bristol-Myers Squibb sponsored head-to-head study of
efavirenz and another protease inhibitor, atazanavir (Reyataz),
in patients who were starting HIV therapy also found that
both drugs when combined with zidovudine and lamivudine
(Retrovir and Epivir, also Combivir) tended to increase
abdominal fat over time. Interestingly, a recent Abbott
Laboratories study that looked at using lopinavir/ritonavir
by itself (i.e. monotherapy) in patients started on this
protease inhibitor and zidovudine/lamivudine found that
these patients experienced increases in belly fat to the
same extent as a control group of patients who were maintained
on zidovudine/lamivuine and efavirenz. Therefore, it looks
like both protease inhibitors and, at least, the non-nucleoside
efavirenz can lead to gains in belly fat.
A problem for most all of these studies is that they rely
on a special type of scan called a DEXA to measure abdominal
fat. This scan, commonly used to also measure bone density,
cannot tell the difference between the deep and surface
fat. So, one therapy could be causing accumulation of
the deeper fat while another could be associated with
surface fat. CT and MRI scans, however, can differentiate
deep and surface fat. Unfortunately, we do not have much
data regarding the relative changes in fat in deep and
surface fat for most HIV regimens. Clearly, more studies
need to be done on other regimens, including those that
contain newer drugs, and should use CT scans when possible
but one thing is clear: when it comes to increasing belly
fat, protease inhibitors are not unique.
Myth #2: People who get bigger bellies on HIV
meds typically also lose fat in their arms and legs.
As if a big spare tire was not bad enough, some people
taking HIV medications also experience loss of fat of
the arms, legs, and face. The image of an apple-shaped
body with skinny limbs is a frightening one that further
turns many people off to HIV therapy. However, it has
become clear that most people on HIV medications do not
develop this body shape. In fact, a couple of studies
of people starting a variety of HIV regimens have found
that for most people limb and belly fat tend to increase
or decrease together. That is, if someone experiences
a gain in belly fat then they are more likely to also
experience a gain rather than a loss in limb fat. In one
study, only a quarter of people experienced a loss of
arm and leg fat while gaining abdominal fat.
Most studies suggest that overall fat gain is a major
problem for HIV-positive people. As in the general population,
being overweight and obese is common. In a study of HIV-infected
patients receiving care in Philadelphia, rates of being
overweight and obesity were more of a problem than weight
loss. As people with HIV infection look to decades of
living with their infection, the problem of obesity is
likely to take its toll since obesity increases the risk
of diabetes, heart disease and death.
![](images/ctscan.jpg)
Myth
#3: Loss of limb fat during HIV therapy only occurs when
stavudine (d4T) is included in the treatment regimen.
The profound loss of fat within the arms, legs and especially
the face among people on HIV medication cocktails that
was seen in the mid-1990s was quickly associated with
one drug, stavudine (Zerit). The link between such disfigurement
and this drug was so obvious that use of stavudine in
the U.S. and Europe quickly fell and is now rarely prescribed
(unfortunately, stavudine is still commonly used in developing
nations as it is easy to make and, thus, cheap).
The drop in stavudine use was followed by a dramatic reduction
in new cases of severe fat loss of the face and limbs.
However, over time some doctors and their patients noticed
a slower but undeniable depletion of fat in these same
areas of the body. But, as these changes were slow to
develop and DEXA, CT, and MRI scans are not routinely
performed in clinics to measure and follow body fat changes,
it was unclear whether these changes were real and, if
so, what caused them. What was clear was that these people
seemed to be losing limb and face fat but had never taken
stavudine.
Some answers came from clinical trials that incorporated
DEXA scans into their design. One study done several years
ago by the ACTG found that people starting HIV therapy
who took the protease inhibitor nelfinavir (Viracept)
were more likely to lose limb fat—as measured by
DEXA scans—than those taking efavirenz, even when
the other medication taken was limited to zidovudine/lamivudine
(Combivir). This meant that people on zidovudine/lamivudine
were experiencing fat loss and that this was accelerated
with nelfinavir use. Another study comparing zidovudine/lamivudine
with tenofovir/emtricitabine (Truvada) when both were
taken with efavirenz found that there was a progressive
loss of fat among those assigned to zidovudine/lamivudine
while those taking tenofovir/emtricitabine gained limb
fat over time.
The ACTG study A5142 looking at people new to HIV medications
also performed DEXA scans before HIV medications were
initiated and then at regular intervals after starting
the drugs. This was a large study of almost 750 people
who were assigned to one of three different study treatments:
a.) lopinavir/ritonavir plus two nucleosides, or b.) efavirenz
plus two nucleosides, or c.) lopinavir/ritonavir plus
efavirenz alone without nucleosides. Those taking nucleosides
could use only lamivudine plus either stavudine, zidovudine
or tenofovir (Viread). The study is very important as
efavirenz and lopinavir/ritonavir are two of the most
popular medications used to treat HIV infection yet, had
never been compared before. The results of this trial
have shaken the field of body shape changes during HIV
treatment. Those taking stavudine had, as expected, the
greatest loss of limb fat and those taking tenofovir had
the least. But, zidovudine fell in between. This alone
indicated that some people experienced limb fat loss even
when not receiving stavudine and that zidovudine was capable
of doing this to a greater extent than many had thought.
In addition, the study found that no matter what nucleoside
was used, efavirenz was more likely to cause significant
fat loss compared to lopinavir/ritonavir. That is, efavirenz
seemed to add to the fat loss that was associated with
the nucleosides. The good news is that few of those on
tenofovir lost significant amounts of limb fat at 96 weeks
of study, even when on efavirenz, so fear of fat loss
should not be a major concern for those who are taking
or considering use of tenofovir plus efavirenz (two of
the three medications in Atripla).
Taken together, these data indicate that fat loss of the
arms and legs is not limited to stavudine and that other
drugs can also produce these changes. Zidovudine appears
to be worse than tenofovir (or abacavir [Ziagen]), albeit
it is not as bad as stavudine. Additionally, efavirenz
seems to be able to dial-up the fat loss effect of nucleosides
to a greater extent than lopinavir/ritonavir. Unfortunately,
there is not much information regarding face fat from
any of these studies.
Myth #4: Sit-ups can spot reduce belly fat.
This myth falls into the same category as the belief that
going out with wet hair will increase your risk for a
death of a cold and that too much time spent self-pleasuring
can wreak havoc on your visual acuity. A remarkable number
of intelligent men and women arrive at their clinic visits
complaining of increases in belly fat, and are frustrated
that endless sit-ups have done nothing to reduce their
mid-body girth.
Sit-ups, when done properly, can increase strength in
the abdominal muscles. This leads to firmer muscles and
an increase in core strength but will not melt away fat
in that one area. Fat is lost when more energy is expended
than taken in. While sit-ups require energy, they do not
preferentially draw that energy from the deposit of fat
cells found in those love handles. A better approach is
to combine sit-ups with aerobic exercises that require
heavy breathing and sweating for prolonged periods of
time like running, cycling, stair climbing, rope jumping,
etc. Small studies have shown decreases in abdominal fat
when HIV-positive people followed a program of aerobic
exercise and weight lifting several times a week.
Diet can also play a role here and a smart approach would
be to limit simple sugars and the highly caloric fats
that make up most of the so-called comfort foods of our
society. For most people dietary modification need not
be very complicated and can be summed up with a recommendation
to greatly increase daily intake of fruits and vegetables,
the latter preferably raw or lightly steamed. These are
foods that are not packed with excess calories, contain
cholesterol-lowering fiber and are filling—leaving
less room for the fatty, super-size-me foods at the root
of many of our health problems.
In addition to eating like a Buddhist monk and joining
a gym there are other interventions that have been studied
to reduce excess fat. Unfortunately, few have panned out.
Growth hormone is an injectable agent that has been found
to reduce fat in the belly and buffalo hump and some people
have benefited from this therapy. However, this is an
expensive drug that is not usually covered by insurance
carriers for the treatment of excess fat. Also, at the
doses studied for the treatment of excess fat, growth
hormone has been plagued by a number of troublesome side
effects including worsening glucose levels, muscle and
joint aches, and feet swelling. Interestingly, exercise
is known to increase the body’s own production of
growth hormone.
Testosterone and other androgens (“male hormones”)
have also been studied as treatments for fat accumulation
in people with HIV infection. These hormones, like growth
hormone, can pop fat cells but in another ACTG study were
found to preferentially reduce the surface fat and not
the deep fat that made for most of the enlargement of
the belly. Androgens can also worsen limb and face fat
loss. Therefore, although beloved by many, the data suggest
that androgens may do little to reduce abdominal girth
and can aggravate loss of fat beyond the trunk.
A few drugs used for the treatment of diabetes have also
been studied for fat accumulation, including metformin,
rosiglitazone, and pioglitazone. Most of the data informing
the use of these drugs in people with HIV come from small
studies. Suffice to say that their effects, if present
at all, seem to be mostly limited to those with diabetes
or a pre-diabetes condition. The underwhelming study results
and the toxicities of these medications have diminished
any enthusiasm for dedicated use of these drugs to treat
fat changes in people with HIV infection.
Myth #5: People with HIV infection have higher
cholesterol levels than people without HIV.
Take a survey of people living with HIV or even their
docs and ask whether HIVers have higher cholesterol levels
than those without HIV. Chances are most would respond
that those who are HIV-positive would, on average, have
higher levels than those who are uninfected. Actually,
at least a couple of studies have found that people with
HIV infection tend to have lower levels of LDL cholesterol,
the “bad” cholesterol that has been strongly
linked to heart disease, than people in general; this
finding holds even when including those who are on HIV
medications.
This does not mean that those with HIV infection have
a better lipid profile than uninfected folks. A major
problem is that levels of the “good” cholesterol,
HDL cholesterol, are also lower in HIV-positive people.
HDL cholesterol has been found to offer protection from
heart disease and a low level is an independent risk factor
for cardiovascular problems. Exercise and modest alcohol
(not just red wine) intake can safely raise HDL cholesterol
in some people. In addition, a little appreciated fact
is that certain HIV medications also raise HDL cholesterol
levels. The non-nucleosides efavirenz and nevirapine [Viramune]
and the protease inhibitor atazanavir alone or in combination
with ritonavir [Norvir] and most all other protease inhibitors
that are boosted with ritonavir have all been found to
raise HDL cholesterol levels.
Triglyceride
levels, though, are a different story. Triglycerides are
broken down in the body from fat and can be found floating
free in the blood or in a complex with other lipids and
proteins in the form of cholesterol. The more triglycerides
in the cholesterol complex, the more dangerous it is in
terms of cardiovascular risk with LDL cholesterol having
more triglycerides than HDL cholesterol. Fasting triglyceride
levels are, on average, higher in people with HIV infection
and increases further with HIV therapy. While in some
people the level of triglycerides can skyrocket to very
concerning levels (greater than 500 mg/dL) most people
with HIV infection have levels that are high but not alarming.
In addition, by itself the level of triglycerides measured
in the blood is not considered as nearly big a risk for
cardiovascular disease as high LDL or low HDL cholesterol.
Most all HIV regimens can raise triglyceride levels. The
ritonavir-boosted protease inhibitors are a bit worse
in this regard than efavirenz, and most studies suggest
that lopinavir/ritonavir and fos-amprenavir/ritonavir
(Lexiva/Norvir) may raise triglyceride levels a bit more
than other commonly-used boosted protease inhibitors,
but the clinical significance of these modest differences
is not clear.
Overall, the data suggest that people with HIV may be
at greater risk of cardiovascular problems like heart
attacks due to their low HDL cholesterol levels and possibly
increases in LDL cholesterol and triglyceride levels during
HIV therapy. Additionally, there may be other factors
such as inflammation caused by the virus that can lead
to chemical changes in the body that can prompt clogging
of the arteries. However, it is almost certain that smoking
adds much more to the risk of cardiovascular disease than
these other HIV-related factors and that of all the things
a person with HIV infection could do to survive and thrive,
beyond taking HIV medications when necessary, the most
significant is to stop smoking.
Summary
Clinicians and their patients do not tolerate ambiguity
well. Gaps in knowledge of a disease demand to be filled
and when the research data come up short it is difficult
not to extrapolate. In the 25 years since the AIDS pandemic
ignited, much has been learned about HIV and the crowning
achievement of the scientists, clinicians, and advocates
dedicated to this disease has been the dramatic reversal
of the lethality of this disease. However, in HIV, as
in medicine in general, it has been difficult to not jump
to conclusions when data are conflicting or just plain
not in existence.
In the case of metabolic complications of HIV and its
treatments, we have learned to learn. New investigations
have revealed the accuracy and inaccuracy of previous
assumptions and allow us opportunities to better choose
among our options. The trick is we have to be willing
to let go of our old beliefs and embrace findings that
rigorously challenge these concepts. The old mantra that
knowledge=power still holds, but we have to accept that
better knowledge=even more power.
Dr.
Wohl is an Associate Professor of Infectious Diseases
and Co-Director of the AIDS Clinical Trials Unit at the
University of North Carolina. Metabolic complications
associated with HIV infection and the nexus between HIV
and incarceration are his major areas of research interest.
He can be reached via e-mail at wohl@med.unc.edu.
HIV
Lipodystrophy: Where
Are We After Ten Years?
By Nelson Vergel
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 Lipohypertrophy
Unlike 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: 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 www.medibolics.com.
More
information is available at www.nucleomaxx.com.
More
information is available at www.facialwasting.org.
Conference Report - Management
of HIV-Associated
Lipoatrophy: Emerging Data in Clinical Context
Andrew Carr, MBBS, MD,
FRACP, FRCPA
Of
all the toxicities linked to antiretroviral therapy (ART),
HIV lipodystrophy has
been perhaps the most important from the perspective of
patients. Lipodystrophy is
a combination of peripheral, subcutaneous lipoatrophy
with a lesser degree of
relative fat accumulation in the abdomen, breasts, and
upper trunk. This condition
is cosmetically distressing and stigmatizing for many
persons, and it is also
associated with reduced adherence to ART.[1] Furthermore,
it is associated with lipid
and glycemic abnormalities, such as higher levels of total
cholesterol and triglycerides,
lower levels of high-density lipoprotein cholesterol,
and insulin resistance and
type 2 diabetes mellitus. These abnormalities are strongly
linked to an increased risk
for myocardial infarction and other atherosclerotic disease.[2]
This report focuses on clinical management issues associated
with lipoatrophy.
Although published data are cited throughout, particular
attention is given to emerging
data from the 8th International Workshop on Adverse Drug
Reactions and Lipodystrophy
in HIV, which was held September 24-26, 2006, in San Francisco,
California. This
relatively small conference has become one of the most
important annual meetings
devoted to original research on morphologic and metabolic
disorders associated with
HIV and its treatment.
Treatment Issues
Since its identification, there has been substantial progress
in describing the phenotype,
risk factors, and natural history of lipodystrophy. There
are now 3 major treatment-related
issues specific to HIV lipoatrophy:
• how to prevent lipoatrophy;
•how
to predict lipoatrophy in those at risk; and
•what
to do about established lipoatrophy.
How to Prevent Lipoatrophy
Prospective, randomized trials have found that
antiretroviral treatment initiation with
regimens containing abacavir + lamivudine (ABC/3TC) or
tenofovir + emtricitabine (TDF/FTC)
results in less lipoatrophy than regimens that contain
stavudine (d4T) or zidovudine (AZT),
particularly regimens containing d4T + didanosine (ddI).[3,4]
Whether use of ABC/3TC or
TDF/FTC causes any lipoatrophy at all is unknown and requires
formal comparison with
nucleoside reverse transcriptase inhibitor
(NRTI)-sparing regimens; the body-composition
data from ACTG 5142 will be reported in early 2007 and
should shed some light on this
question. The contribution of protease inhibitors (PIs)
to lipoatrophy is unclear. Nelfinavir was
associated with more lipoatrophy than efavirenz, each
in combination with dual NRTIs, in the
ACTG 384 body-composition substudy.[5] In contrast, the
fat-friendly effects of ABC-3TC do
not seem to be diminished by coadministration of a PI,
and 3 PI switch studies found no
improvement in lipoatrophy (although reductions in visceral
adiposity were observed in one
study).[6-8] Again, ACTG 5142 should further help our
understanding of the relative contribution
of certain antiretrovirals or antiretroviral drug classes
to this adverse effect.
How to Predict Lipoatrophy
Risk factors for lipoatrophy have mostly been identified
from cross-sectional studies.[1]
Factors identified consistently include:
• NRTI use (both type and duration);
•PI
use and duration;
•prior
AIDS diagnosis; and
•low
CD4+ cell count.
(It is important to note that both prior AIDS diagnosis
and low CD4+ cell count are perhaps
surrogate markers for wasting and less baseline limb fat.)
In prospective studies, use of d4T,
AZT, or indinavir (IDV) was most commonly associated with
lipoatrophy risk. Unfortunately,
most studies have not defined lipoatrophy objectively
with body composition techniques such
as dual-energy x-ray absorptiometry (DEXA), and no study
has looked at whether any biomarker
might predict objectively defined lipoatrophy.
At this year's Lipodystrophy Workshop, Calmy and colleagues[9]
evaluated lipoatrophy objectively
in 54 patients (53 men) who initiated various first-line
ART regimens including 2 NRTIs (mostly d4T
and ddI) and who had serial body-composition studies over
2 years. The investigators evaluated
whether metabolic markers could predict long-term lipoatrophy
development; they looked for
associations between plasma markers and subsequent development
of lipoatrophy (change in limb
fat mass between weeks 24 and 96 by DEXA) and lipohypertrophy
(increase in visceral adipose
tissue [VAT] by abdominal CT through week 48). Using stored
samples from 2 prospective studies
that were collected at baseline and at weeks 12, 24, and
48, this group performed serial measurements
of plasma adipokines, cytokines, lipids, and glycemic
and acid-base parameters related to fat mass
and lipodystrophy.
There
were 2 findings of note from this study:
•
Higher
baseline body mass index and limb fat predicted greater
loss of limb fat at week 96. This finding
contrasts with cross-sectional studies that found lower
limb fat to be a risk factor for lipoatrophy (and
therefore, by inference, that starting earlier with higher
limb fat somehow protects against lipoatrophy).
The implication of these data is that lipoatrophy occurs
in all patients, but that fat loss is greater in those
with more fat at baseline.
•
Increases in leptin* levels at week 24 correlated with
greater fat loss at week 96, which suggests that
measuring leptin levels early in treatment might identify
those patients at greatest risk for lipoatrophy.
[*Editor's note: Leptin is a peptide hormone transmitter
produced only by fat cells and acts in muscle
to promote insulin sensitivity and in the central nervous
system to control appetite and, in turn, body
fat mass.]
What to Do About Established Lipoatrophy
Antiretroviral drug switches. The main
approach to improving or reducing the progression of
lipoatrophy is to switch NRTIs, generally from d4T or
AZT, to either ABC or TDF.[10,11] Switching
antiretroviral drugs is most commonly done for one drug
in a regimen for patients with complete viral
suppression. ABC and TDF appear to allow for similar improvements
in lipoatrophy, although the
improvements observed at 1-2 years after these switches
still are inadequate, with the mean gain in
limb fat of approximately 400 g per year. [Editor's note:
See Dr. Graeme Moyle's report in this program
for a graphic representation of these study data.] To
put this in perspective, this improvement is fairly
modest if one considers that men with severe lipoatrophy
have limb fat masses of about 3 kg and that
normal limb fat mass for men is about 8 kg. (Unfortunately,
there are minimal data for HIV-infected
women or children.) These data suggest, therefore, that
resolution of lipoatrophy might take 5 or even
10 years with this strategy alone.
ART cessation. The cessation of all ART
has not been well studied, although this is no longer
a
strategy for most patients because of negative results
that have been recently observed in a large
trial evaluating CD4-guided strategic treatment interruptions.
Kim and coworkers[12] evaluated adipose
gene expression in subcutaneous abdominal fat following
a 6-month interruption of all ART in 40 adults
with suppressed HIV replication, including 29 of whom
had available paired data:
•
NRTIs+ PI (n = 10); NRTIs without PI (n = 19)
•
d4T (n = 5) or AZT (n =
12); other NRTIs (n = 12)
The investigators evaluated adipose morphology, mitochondrial
DNA, and adipose tissue gene expression.
At 6 months, no subjective, clinical change in lipoatrophy
was observed, although objective body-composition
parameters were not measured. At 6 months, adipose fibrosis
did not change, but there was less adipose
inflammation such as fewer lipogranulomas and macrophages,
fewer TNF-alpha or IL-6-staining cells, and
less CD68 gene expression (CD68 is a macrophage-specific
gene). There were also improvements in the
expression of some mitochondrial genes (COX4 mRNA, and
increased mtDNA and COX2/COX4 ratio).
Unfortunately, this study was not randomized, and patients
were receiving very heterogenous ART regimens,
so the effects of specific antiretroviral drugs and drug
classes were not clear. The major weakness, however,
was the lack of body-composition data. Without these data,
it is not clear whether any of the tissue changes
might be associated with improvements in lipoatrophy,
and it is even less clear whether there is an association
with body-composition changes that are large enough to
be objectively measured and clinically useful.
Poly-L-lactic acid (PLA).
Injections of PLA are now licensed in the United States
and Europe for cosmetic
management of facial lipoatrophy. The drug appears to
be safe,[13,14] but its efficacy is less clear, as no
randomized trial of PLA with objective endpoints has been
performed to determine how much PLA is required
and for how long PLA maintains its benefit. The results
of a randomized trial with objective endpoint data should
be available in early 2007. PLA probably won't help the
problem if the underlying cause is not removed, as
lipoatrophy will continue to worsen in those taking drugs
such as AZT and d4T, so PLA injections probably
cannot take the place of d4T or AZT cessation. [Editor's
note: See Dr. Graeme Moyle's report on
surgical/cosmetic interventions for HIV lipoatrophy within
this program.]
Thiazolidinediones. The first drugs explored
for the treatment of HIV lipoatrophy were the thiazolidinediones,
which are drugs that can make fat cells grow and that
act by improving tissue insulin sensitivity. The best
studied
thiazolidinedione in patients with HIV is rosiglitazone.[15-17]
Four randomized, placebo-controlled trials of
rosiglitazone found improvements in insulin resistance
but relatively unexpected deteriorations in total cholesterol
and triglycerides.[1] Three of the studies found no significant
improvement in limb fat mass, although one found a
benefit at 6 months in those not receiving d4T or AZT
that was lost by 12 months. Pioglitazone was subsequently
reported as an effective treatment for HIV lipoatrophy
in a randomized, placebo-controlled study conducted by
the
ANRS in France and first presented at the 13th Conference
on Retroviruses and Opportunistic Infections (CROI) in
2006.[18] The mean improvement in limb fat mass over 48
weeks was about 0.3 kg, with the benefit largely
confined to those persons not receiving d4T. At this year's
Lipodystrophy Workshop, Maachi and associates[19]
presented additional metabolic data from this study. No
significant changes in plasma levels of leptin, resistin*,
and soluble TNF receptor I (sTNFRI)* were observed at
week 48 in the pioglitazone group as compared with the
placebo group. In contrast, plasma adiponectin* levels
increased by about 150% with pioglitazone relative to
placebo.
Of interest, this effect was observed both in patients
not receiving and receiving d4T. The change of limb fat
mass
between baseline and week 48 correlated with both plasma
pioglitazone concentration (r = 0.476, P < .001, n
= 51).
Given the availability of a higher dose of pioglitazone
(45 mg tablet given once daily) than was used in this
study (30
mg once daily), perhaps a higher dose warrants study and
might be more effective. Overall, the results of this
study
support the use of pioglitazone in the treatment of peripheral
lipoatrophy in HIV-infected adults, but the relatively
modest effect observed in fat gain means that pioglitazone
is no substitute for cessation of d4T or AZT.
[*Editor's note:
•
Resistin causes cells to be less sensitive to insulin.
•
TNF-alpha also downregulates insulin sensitivity (it antagonizes
leptin and adiponectin), and the level of its
soluble receptor in plasma is linked to insulin sensitivity.
•
Adiponectin is another adipocyte cytokine that, with leptin,
promotes insulin sensitivity in muscle and liver.
Low levels of adiponectin are associated with accelerated
cardiovascular disease.]
Uridine. In-vitro studies pioneered by
Ulrich Walker[20] have found that the mitochondrial toxicity
of AZT and d4T
could be prevented and reversed in fat cell culture by
uridine, even in the presence of ongoing AZT or d4T exposure.
Uridine is a substance required for the synthesis of pyrimidines,
which are building blocks of DNA and RNA. A small,
randomized, placebo-controlled study in 20 adults receiving
AZT or d4T showed that limb fat increased significantly
by a mean 700 g over only 12 weeks.[21] Provided that
these data can be replicated in larger and longer studies
currently in progress, the main question relating to uridine
will be whether it can still exert benefit in those who
are no
longer receiving d4T or AZT. This is very important given
that d4T is barely used in developed countries and AZT
use
is declining, particularly in light of the Gilead 934
study showing superiority of TDF over 48 weeks on an
intention-to-treat basis.[22] Unfortunately, uridine is
not licensed in North America, but can be imported at
considerable expense (about US$300 per month). This considerable
expense precludes use of the drug in
the developing world.
Pravastatin. One unexpected positive
therapeutic outcome for lipoatrophy has come in the form
of pravastatin, a
drug widely used for the treatment of high cholesterol
levels for the primary and secondary prevention of
ardiovascular disease. In a randomized, placebo-controlled,
12-week trial, pravastatin did not have much effect on
cholesterol levels in men receiving ART (mostly including
a ritonavir-boosted PI without d4T or AZT).[23] As with
uridine, however, limb fat mass increased significantly
(by about 500 g), again a far greater increase than seen
with
NRTI switch strategies over 48 weeks. Although the mechanism
of action is unknown, we know that the drug is safe
and, in particular, has few HIV drug interactions (with
the exception of darunavir). What we really need to know
is
whether this statin or other statins will show benefits
over longer periods.
Other interventions under study. No new
treatment intervention for lipoatrophy was reported at
this year's
Workshop. However, Boccara and colleagues[24] reported
on the effects of irbesartan in an in-vitro model of
ART-induced lipoatrophy (3T3-F442A murine adipocytes).
Irbesartan is an antihypertensive angiotensin II type
1
receptor blocker that recently was shown to activate peroxisome
proliferator-activated receptor gamma
(PPAR-gamma) in adipocytes and to reduce the incidence
of diabetes mellitus in hypertensive patients. PPAR-
gamma is a key adipocyte differentiating and maturation
factor, and its expression is reduced in HIV lipoatrophy.
The investigators found that irbesartan suppressed the
adverse effects of IDV and of ritonavir boosted-atazanavir
(ATV/r) on lipogenesis and lipid accumulation, but not
of ritonavir boosted-lopinavir (LPV/r). Irbesartan also
prevented
IDV and ATV/r-induced insulin resistance (normalizing
insulin-induced tyrosine phosphorylation [ie, activation]
of the
insulin receptor and insulin-mediated glucose transport),
as well as the expression of 2 major proteins, CCAAT-
enhancer-binding protein (C/EBP)-alpha and PPAR-gamma,
which are involved in adipogenesis and the insulin
response.
These data suggest that irbesartan may prevent or even
treat the lipoatrophy and insulin resistance induced by
some HIV PIs. The relevance of the dose used, however,
was not clear; a pilot study in humans seems justified.
The effects of NRTIs were not evaluated, which is unfortunate
as NRTIs clearly have more of a lipoatrophic effect
than PIs and because NRTIs also inhibit PPAR-gamma expression.
The effects of other angiotensin II type 1
receptor blockers also deserve investigation.
Another drug that has been of some interest in the management
of HIV lipoatrophy is leptin, an adipocytokine
(a key adipocyte-produced hormone). Leptin levels may
be low in HIV lipodystrophy, but because it is a fat cell
product rather than a fat cell stimulant whose plasma
levels are low in HIV lipodystrophy, it seems unlikely
that
leptin would improve lipoatrophy. However, it might well
improve the downstream insulin resistance and dyslipidemia
associated with the leptin deficiency that is seen in
congenital and other acquired lipodystrophies.
Khatami and colleagues[25] performed an open-label study
to determine whether leptin could produce similar
metabolic benefits in HIV-infected patients with lipoatrophy.
Eight men with HIV lipoatrophy, low plasma leptin levels
(< 3 ng/mL), dyslipidemia, and insulin resistance received
leptin for 6 months (0.01 mg/kg twice daily for 3 months,
followed by 0.03 mg/kg twice daily for 3 months). Hepatic
insulin sensitivity improved (reduce fasting insulin of
about
20%) as did endogenous glucose production, glycogenolysis,
and gluconeogenesis. However, there was no
significant change in peripheral glucose uptake in fat
or muscle, nor in limb fat mass, although lipolysis (breakdown)
of fat declined somewhat, which suggests an effect of
leptin on adipose tissue. Visceral fat decreased by about
30%
(183 to 129 cm2; P = .001); this improvement without a
decline in limb fat suggests that leptin may have a depot-
specific effect in adipose tissue.
Supported by an independent educational grant from Gilead.
Click here
for artical, with references in PDF format.
Expert Column -Cosmetic Interventions for HIV-Associated
Lipoatrophy
Graeme J. Moyle, MD, MBBS
Introduction
The development of facial changes associated with generalized
lipoatrophy during antiretroviral therapy is perceived
by patients as a highly stigmatizing manifestation of
their HIV infection. These facial changes may lead to
the
unmasking of HIV status to colleagues, affect social and
personal relationships, and suggest that an individual
who
is otherwise healthy is unwell.[1] It has been reported
not only to affect mood and quality of life, but also
to reduce
adherence to antiretroviral medication. Lipoatrophy in
other body areas may also lead to changes in personal
confidence and habits.
Lipoatrophy: Prevention Is the Best Policy
Lipoatrophy appears to be a preventable toxicity that
is largely restricted to individuals who have received
prolonged
therapy with thymidine analogue nucleoside reverse transcriptase
inhibitors (NRTIs). Use of thymidine analogs in
combination with (certain) protease inhibitors (PIs) may
accelerate the rate of fat loss. Prospective data from
studies
in which persons have begun regimens with thymidine-sparing
NRTI backbones (Table 1) --such as abacavir-
lamivudine, tenofovir-lamivudine, tenofovir-emtricitabine,
and didanosine-emtricitabine --have reported few instances
of
lipoatrophy, even over prolonged follow-up. These data
offer hope that in the future, the incidence of lipoatrophy
observed in clinical practice will decline relative to
the prevalence currently observed among HIV-infected persons
who
have a treatment history that includes a regimen containing
a thymidine analogue NRTI plus a PI.
Table 1. Nucleoside Reverse Transcriptase Inhibitors
(NRTIs) for the Treatment of HIV Infection
Thymidine analogue
NRTIs (single agents) |
Coformulated, fixed-dose NRTIs (containing
a thymidine analogue NRTI) |
Non-thymidine analogue NRTIs (single agents) |
Coformulated, fixed-dose NRTIs (not containing
a thymidine analogue NRTI) |
stavudine
zidovudine |
lamivudine +
zidovudine
abacavir +
lamivudine +
zidovudine |
abacavir
didanosine
emtricitabine
lamivudine
tenofovir DF
|
abacavir +
lamivudine
tenofovir DF +
emtricitabine
efavirenz* +
emtricitabine +
tenofovir DF |
*This coformulated tablet also contains efavirenz, an
NNRTI, in addition
to 2 NRTIs.
Pharmacologic strategies to manage lipoatrophy.
The only approach to management of lipoatrophy that has
demonstrated benefit in 2 or more controlled clinical
trials is switching therapy away from a thymidine analogue
NRTI.
Alternatives to thymidine analogue NRTIs include abacavir,
tenofovir, or NRTI-sparing antiretroviral regimens. While
recovery of peripheral fat mass can be detected by dual-energy
x-ray absorptiometry (DEXA) scanning, these studies
did not report impressive clinical recovery or subjective
improvements in fat gain The rate of limb fat recovery
appears
similar with each of these approaches, with comparative
data from the RAVE switch study[2] observing similar
recovery with switch from a thymidine analog to abacavir
or tenofovir DF (Figures 1 and 2). Of note, some individuals
experience little of no limb fat recovery over 48 weeks,
suggesting that for some individuals lipoatrophy may not
be
reversible (Figure 3). Laser facial imaging, reported
from a subset of patients in the RAVE study, indicated
that cheek
volumes also increased over 48 weeks (Figure 4).[3] Changes
in cheek volume were noted to correlate with limb fat
recovery.
Figure 1. Design of the RAVE switch study.[2]
Figure 2. Mean change in limb fat at
week 24 and week 48 in the RAVE
study.[2] (DEXA arm fat and total leg fat in grams: intent-to-treat,
missing = failure analysis).
Published with permission from Lippincott Williams &
Wilkins (http://lww.com)
Figure
3. Mean changes in limb fat after switch (±
interquartile range) at week 48 according to
baseline antiretroviral drugs and limb fat in the RAVE
study.[2] Published with permission from
Lippincott Williams & Wilkins (http://lww.com)
Figure 4. Median change in volume after
48 weeks in the RAVE facial
substudy measured by laser facial imaging.[3]
For those with established facial lipoatrophy who have
modified therapy and are waiting for clinically evident
fat
recovery to occur, the process is at best slow and has
an uncertain outcome. Prolonged treatment interruption
(longer than 6 months) does not yield clinically evident
improvements in lipoatrophy[4] and may risk disease
progression events.
More recently a large, randomized, placebo-controlled
study of pioglitazone 30 mg once daily has indicated a
similar
rate of limb fat recovery over 48 weeks to that observed
in switch studies. However, the benefit was restricted
to
persons not receiving stavudine.[5] Other agents under
investigation as lipoatrophy treatments include uridine
and
pravastatin.
Facial Fillers for Lipoatrophy
The slowness, and in some cases apparent absence, of clinical
recovery from lipoatrophy underscores the need for
cosmetic surgical interventions for people with facial
lipoatrophy. The agents used in these surgical approaches
are
known as implants or "facial fillers" (Tables
2 and 3). Evaluation of the potential of using fillers
to enhance the
buttocks or manage discomfort in feet has been very limited
and largely unsuccessful.
Facial fillers may be natural (such as transferred fat)
or synthetic, and they may be biodegradable (temporary)
or
nonbiodegradable (permanent). Of note, some "permanent"
fillers may be wholly or partially removable. Fillers
are
necessary because of the loss of tissue mass from the
lipoatrophy process. "Face lifts" cannot make
up for lost
tissue but merely tighten some of the skin that has become
looser following the loss of tissue mass.
[Editor's note: Because many clinicians who manage patients
with HIV may be unfamiliar with many of these fillers,
trade names and manufacturers are noted in Tables 2 and
3. In some cases in the text, trade names are used. This
is because some fillers that are the same or similar in
type/composition share a generic name, yet are sold under
different trade names. Some of the studies that the author
discusses were conducted with a particular branded
product.]
Biodegradable Agents
Biodegradable agents (Table 2) are attractive in a situation
in which there is the potential for recovery or partial
recovery of the underlying condition, as has been suggested
by the RAVE facial scan substudy.[3] The duration of
benefit varies among agents, and there may be a need for
"refilling" at a later time. Many of these agents
are
generally best suited to filling mild-to-moderate areas
of tissue loss.
Table 2. Management of HIV-Associated Facial Lipoatrophy:
Biodegradable Agents
Product/Technique |
Trade Name
(Manufacturer) |
Comment |
Poly-L-lactic acid |
•Sculptra
(Dermik)
•NewFill
(Ashford Aesthetics) |
•
FDA-approved for HIV-associated
lipoatrophy (Sculptra) •
Data from randomized studies •
Requires multiple injections/sessions
over many weeks •
Benefits observed up to 3 years •
Injections in buccal area show better results relative
to temporal area •
Nodule formation possible |
Hyaluronic acid |
•Restylane
(Q Med)
•Perlane
(Q Med)
•Hylaform
(Inamed) |
•Less
injection volume/more sustained
results relative to bovine collagen in
filling nasolabial folds •Benefits
observed up to 6 months in
HIV lipoatrophy |
Fat transfer |
|
•Expensive
•Patients
with lipoatrophy often have
inadequate fat to harvest and transfer •Transferred
fat can be rapidly lost •Fat
transferred from fat accumulation
sites (eg, dorsocervical humps) may
behave abnormally at the graft site •"Lumpy"
results have been observed |
Calcium
hydroxylapatite |
Radiesse
(Bioform) |
•In
a prospective trial in HIV lipoatrophy, all patients
showed
improvements through 1 year, and
most through 1.5 years.
•Mild
adverse effects |
Poly-L-lactic
acid (PLA). PLA is an injectable bioabsorbable
material for use in HIV-associated lipoatrophy. While
all agents or procedures discussed in this brief review
have been used off-label for management of lipoatrophy,
PLA is
the only agent that has a specific FDA indication for
this condition.
The substance stimulates dermal fibroblasts to produce
collagen, leading to thicker but natural-feeling skin.
It is
given as multiple subcutaneous or dermal injections. The
injected area requires frequent massage in the days
following injection to avoid nodule formation. Results
in the temporal area are generally less satisfactory than
those
in the buccal area. It is immunologically inert, with
inflammatory responses being very infrequent. PLA gradually
reabsorbs over a 2-to 3-year period, with benefits in
HIV lipoatrophy reported over this period. Treatment is
generally
given in 3-5 sessions separated by 2-6 weeks, leading
to a gradual change in facial appearance.
PLA has been evaluated in HIV lipoatrophy using a range
of endpoints, both objective and subjective. At the Chelsea
& Westminster Hospital in London, we randomized 30
persons with facial lipoatrophy to immediate and delayed
treatment with PLA. The immediate-treatment group received
3 bilateral injections of 4-5 mL administered 2 weeks
apart (weeks 0, 2, and 4) in the deep dermis overlying
the buccal fat pad; the delayed-treatment group received
injections at weeks 12, 14, and 16. Treatment was well
tolerated, with adverse events limited to transient bruising
in
1 patient and localized cellulitis in another. Assessments
were made by facial ultrasound, visual analogue scales
(VAS), and the Hospital and Anxiety Depression Scale at
weeks 0, 12, and 24. At week 12, patients in the
immediate-treatment group had significantly better VAS
scores, lower anxiety scores, and trends toward lower
depression scores compared with the control patients in
the delayed-treatment arm. Benefits persisted through
week
24, with the delayed-treatment group having similar benefits
measured at that time. Many patients did not achieve
complete resolution of their facial lipoatrophy.[6]
Longer term follow-up for a minimum of 18 months post
treatment indicated that improvements in VAS scores for
facial appearance (P < .05) and trends to lower anxiety
(P < .001) relative to baseline were sustained. One
case of
injection-site induration (after 24 weeks) and 9 cases
of injection-site nodules were noted.[7]
Various strategies have been suggested to decrease the
risks and avoid the potential complications associated
with
PLA.[8] These include:
•
higher volume dilution (8-12 mL/vial);
•
fewer vials used at each session;
•
injections placed in the subcutaneous plane without any
going into the dermis;
•
adequate time between injection sessions (at least 6 weeks);
and
•
postinjection patient massage.
Other larger but nonrandomized cohort studies have reported
similar benefits to those of the Chelsea and
Westminster study sustained through week 96, with a low
frequency of adverse events.[9-13]
Hyaluronic acid. Hyaluronic acid is a polysaccharide component
of mammalian soft tissue. These versions of
hyaluronic acid are FDA-approved for the treatment of
wrinkles. Comparative trial data in general cosmetic surgery
settings using treatment-blinded assessors have indicated
that hyaluronic acid requires less injection volume and
shows more sustained results relative to bovine collagen
in filling nasolabial folds; therefore, hyaluronic acid
may be
better for filling deeper cutaneous defects.[14]
Hyaluronic acid has been used successfully to treat HIV
facial lipoatrophy.[15] In general cosmetic practice,
the
benefits are expected to last about 6-12 months. In a
series of 5 individuals with HIV lipoatrophy given 5-6
mL into
the malar area, a good cosmetic result with sustained
benefits through 6 months has been reported. [16]
Fat transfer. Fat transfer is an expensive
and problematic approach as an intervention for HIV lipoatrophy.
Many
patients do not have fat elsewhere to transfer to facial
areas. To further complicate matters, if the pathologic
process
that led to the fat loss is ongoing, the transferred fat
can be rapidly lost. In contrast, fat transferred from
fat
accumulation sites such as dorsocervical humps may behave
abnormally at the graft site and lead to disfiguring
facial hypertrophy.[17] Cosmetically, lumpiness may be
a problem.
The most commonly used technique for fat transfer is known
as Coleman's method. Use of this technique has been
reported in several cohorts of patients with HIV-related
facial lipoatrophy. Durability for 6 months, and possibly
up to
24 months, may be achieved.[18,19] In a series of 33 patients,
independent assessors felt that only 12 (36%) of
individuals had improved, although self-assessment by
the participants showed that 14 (43%) were very satisfied
and
17 (50%) were somewhat satisfied, with 27 (81%) reporting
an improved quality of life.[20]
Calcium hydroxylapatite. Preparations
based on calcium hydroxylapatite (CaHA) microspheres suspended
in
carboxymethylcellulose gel were first FDA-approved for
vocal cord injections, for use in a range of orthopaedic
surgery approaches, and in radiology (CaHA is radiopaque).
However, this product has also been widely used for
treatment of wrinkles and lip augmentation. CaHA is bioabsorbable
over several years. Reported problems include
hardening and overcollagenization requiring steroid injections.
In an 18-month, prospective, open-label, multicenter clinical
trial of CaHA for facial lipoatrophy, all patients (N
= 100)
reported improvement in appearance at every time point
through 12 months, and improvements were observed in 91%
at 18 months. Skin thickness measurements at 12 months
remained significantly better than those at baseline.
Adverse events reported through 12 months were generally
mild (bruising, edema, erythema, pain, and pruritus).[21]
Nonbiodegradable Agents
Silicone. Several forms of liquid injectable
silicone are FDA-approved for ophthalmic, but not cosmetic,
uses. The
American Society for Aesthetic Plastic Surgery has warned
against the use of liquid injectable silicone for cosmetic
purposes pending further investigation. Unfortunately,
silicone oil injections can cause granulomas and long-term
inflammatory changes and can migrate.
Several series and anecdotes report the use of liquid
silicone for HIV-related lipoatrophy.[22-25] The use of
highly
purified 1000-cSt silicone oil injected by microdroplet
serial puncture technique has been evaluated for the treatment
of HIV-associated lipoatrophy. Data were reported on 77
individuals who were assessed as having achieved a
complete correction. The volume of silicone, number of
treatments, and time required to reach a complete correction
were directly related to initial severity of lipoatrophy
(P < .0001). Supple, even facial contours were restored,
with all
patients tolerating treatments well. No adverse events
were noted.[23] Although these data are encouraging, given
the potential risks of silicone relative to alternative
agents, and its permanence after injection, it is not
a preferred
treatment option.
Expanded polytetrafluoroethylene (ePTFE).
These FDA-approved implants are more typically used for
correction
of craniofacial abnormalities (such as in nasal reconstruction)
and after severe trauma, but can also be used for
localized tissue augmentation. They can be inserted using
a small incision while the patient is under local
anesthesia. However, there are potential problems with
lumpiness and physical obviousness of the implant. In
general, adverse events, including movement, infection,
swelling, induration, and uncommonly extrusion (emergence
of implant through the skin), have been reported with
cosmetic use of ePTFE implants.[26]
A case series on the use of ePTFE implants with or without
polyacrylamide gel has recently been published.[27] A
total of 90 consecutive persons with HIV-associated facial
lipoatrophy were treated using implants alone in 11 cases,
injections alone in 68 cases, and both implants and injections
in 11 cases. Mean follow-up was 17 months for
injections and 29 for implants. Adverse events included
3 cases of chronic inflammation and some lumpiness, which
usually resolved over few months.
Polymethylmethacrylate. Polymethylmethacrylate
(PMMA) in smooth microspheres suspended in bovine collagen
is FDA-approved, but has no specific indication for HIV
lipoatrophy. The bovine collagen in the implant is reabsorbed
over time, but the presence of the PMMA microspheres generates
new collagen production in that same site. It has
been used in Europe for close to a decade and is available
in other countries. A large series in Brazil described
its
use in HIV associated lipoatrophy, although clear systematic
collection of safety data was lacking. Side effects
reported included postinjection swelling and pain. Ultrasound
data indicated an increase of dermal thickness
sustained up to 5 years.[28]
Polyacrylamide and polyalkylimide gels.
These agents are not FDA-approved but have been used in
clinics in
Europe (where they are approved) and Latin America. Some
systematically collected data have been reported with
Bioalcamid and Eutrophill. The different products have
similar characteristics. They are relatively viscous and
are
injected subcutaneously. Following injection, the substances
encapsulate, enabling at least partial removal (such as
with a large-bore needle) at a later time. This characteristic
makes them of interest for a condition that may partially
resolve over time.
In a case series of 73 HIV-infected patients treated with
Bioalcamid with up to 3 years of follow-up, "excellent"
aesthetic results were reported with no episodes of implant
dislocation, migration, granuloma, or allergic reaction
recorded.[29] In a case series of 11 subjects with severe
facial lipodystrophy, bilateral injections of 15 and 30
mL
of a Bioalcamid gel into the buccal, malar, and temporal
areas of the face were used.[30] The authors reported
that
all 11 subjects received an immediately acceptable aesthetic
effect. Injections were generally well tolerated, with
only 3 adverse events (swelling and bruising) recorded.
Subjects, assessed at 3 and 18 months after treatment,
continued to show improvement.
A series of 249 individuals treated with Eutrophill with
up to 5-year follow-up reported good aesthetic outcomes,
with
13 individuals having persistent asymptomatic papules
at the injection sites and 2 patients reporting transient
inflammatory events.[31] Recently, cases of infection,
phlebitis, and ulceration around the sites of Bioalcamid
injections have been reported in persons with HIV, and
use of Bioalcamid in the buttock area has been associated
with implant migration.[32]
Table 3. Management of HIV-Associated Facial Lipoatrophy:
Nonbiodegradable Agents
Agent |
Trade Name
(Manufacturer) |
Comments |
Silicone oil |
|
•
Favorable
cosmetic data in
lipoatrophy •
Permanent •
Granulomas, long-term
inflammatory changes,
migration are possible •
American Society for Aesthetic
Plastic Surgery has warned
against liquid injectable silicone
for cosmetic purposes |
Expanded
polytetrafluoroethylene
(ePTFE) implants |
•
Gore-Tex subcutaneous
augmentation material
(S.A.M.) (W. L. Gore &
Associates) •
Advanta (Atrium
Medical) |
•More
extensive experience
in Europe and elsewhere •Incomplete
safety data in
lipoatrophy |
Polyacrylamide and
polyalkylimide gels |
•
Aquamid (Contura)
•
Bioalcamid (Polymekon) •
Eutrophill (Mediform) |
•
Not FDA-approved for HIV
lipoatrophy, but approved
in Europe and elsewhere for
general cosmetic use •
Case series data in lipoatrophy:
favorable aesthetic results,
minimal adverse effects •
Some reports of infection,
phlebitis, and ulceration around
the sites of polyalkylimide implants •
Buccal, malar, and temporal
restoration possible; implant
migration observed following
implantation in buttocks •
Partial removal possible |
Comparative
Data
Establishing endpoints is challenging for comparative
studies of facial fillers that work by different mechanisms.
Assessment by photographs may not lead to reproducible
results and is operator-dependent, and the continuation
of specific antiretroviral therapies may also influence
outcomes. Fortunately, some attempts at comparison have
been
made, and funding for additional comparative data is being
sought.
A 24-week comparative study of autologous fat transfer,
PLA, and polyacrylamide hydrogel as fillers for HIV-related
facial lipoatrophy has been reported.[33] The study was
semi-randomized; individuals with enough residual
subcutaneous fat in the abdomen or in the dorsocervical
region were offered fat transfer, while other individuals
were
randomly assigned to 2 different surgical teams who administered
either treatment with PLA or polyacrylamide
hydrogel injections every 4 weeks. The primary endpoint
used was the dermal plus subcutaneous thickness
measurement of Bichat's (malar) fat pad, as well as body
image evaluations, facial aesthetic satisfaction by VAS,
and aesthetic pre-and postpicture comparisons by independent
reviewers.
Twenty-four individuals received fat transfer, 20 PLA,
and 15 polyacrylamide hydrogel. The PLA and polyacrylamide
hydrogel groups received a mean of 5 and 6 injection sessions,
respectively. The mean change in dermal and
subcutaneous thickness was 3.3 ± 4.1 mm for fat
transfer, 3.5 ± 4.0 mm for PLA, and 2.1 ±
3.0 mm polyacrylamide
hydrogel (P = .687) (Table 4). Serious adverse events
occurred in 4 individuals in the fat transfer group, notably
fat
hypertrophy at the donor site.
Table 4. Results: Comparative Study of Fillers
for HIV-Related Facial Lipoatrophy
Intervention |
Mean Change in Dermal/Subcutaneous Thickness,
mm* |
Autologous fat transfer |
3.3 (± 4.1) |
PLA |
3.5 (± 4.0) |
Polyacrylamide hydrogel |
2.1 (± 3.0) |
*P
= .687
Comparative safety data are derived largely from the general
cosmetic surgery literature.[34] In an international
collaborative effort evaluating nodule formation and inflammatory
events with synthetic injectable fillers, biopsies were
contributed by various plastic surgeons from Europe and
Australia. (It is important to note that these data were
not
derived from persons treated for HIV-associated lipoatrophy.)
Data reported were based on:
•
5 biopsies from unreactive
tissue obtained at different times after injection
of polyacrylamide hydrogel (Aquamid);
•
28
biopsies from 20 individuals with intermediate or late
inflammatory nodules
after injection of polyacrylamide hydrogel (Artecoll);
•
2 cases of nodules following
hyaluronic acid-polyhydroxyethylmethacrylate/ethyl
methacrylate gel (Dermalive; Derma-Tech);
•
6 cases of nodules after
PLA use (NewFill); and
•
a review of the literature
on adverse reactions after injection with permanent fillers
Clinically unreactive tissues after injection with polyacrylamide
hydrogel showed modest or no host reaction.
Inflammatory nodules showed an increased foreign-body
reaction and a bacterial infection after injection with
polyacrylamide hydrogel, and a combination of moderate
foreign-body reaction, fibrosis, and in some cases also
bacterial infection after injection with Dermalive and
PLA (NewFill). Literature review suggested that inflammatory
nodules are rare beyond 1 year after injection with polyacrylamide
hydrogel, but may occur up to 6 years after
injection of combination gels (Artecoll), and up to 28
years after injection of silicone gel. The authors concluded
that
inflammatory nodules are likely to be caused by a low-grade
infection maintained within a biofilm surrounding
silicone gel and the combination gels.
Discussion
Case series and some limited controlled data indicate
that treatment of HIV-associated facial lipoatrophy with
facial
fillers leads to good cosmetic results, improved psychological
well-being, social functioning, and quality of life.
Biodegradable fillers such as PLA are the most well-studied
agents, but have the drawbacks of requiring multiple
treatment sessions and the eventual need for "top-ups"
in many patients. Permanent fillers are also of interest,
particularly those agents that have the potential for
partial removal. Fillers present a range of problems,
most
commonly postinjection pain and discomfort, and less commonly
local infection and scarring. Comparative and
systematically performed studies are needed to establish
the best fillers for HIV-associated lipoatrophy.
Supported by an independent educational grant from
Gilead.
Click
here for artical, with references in PDF format.
Treatment for lipoatrophy: facing the real costs; should
be reimbursed
EDITORIAL COMMENT
AIDS:Volume 21(13)20 August 2007p 1819-1820
Margolis, David M
From the University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina, USA.
Patients unlucky enough to suffer chronic
illnesses such as HIV infection, leprosy, tuberculosis,
or mental illness bear an additional burden: stigma. Indeed,
the fear of being identified as HIV infected or receiving
antiretroviral therapy may lead a significant number of
patients to avoid appropriate medical care. Nowhere is
this a more obvious problem than in individuals suffering
HIV-associated facial lipoatrophy.
The
causes of facial lipoatrophy and of HIV-associated metabolic
abnormalities in general, are yet to be fully defined
[1]. These conditions appear to be multifactorial, owing
in some part to metabolic changes induced by HIV infection,
but in large part to exposure to antiretrovirals. Specific
nucleoside reverse transcriptase inhibitors play a prominent
role, and studies have shown modest improvements in lipoatrophy
following the use of alternative antiretroviral regimens
[2,3]. Given the improved recognition of these disorders,
and the appreciation of antiretroviral regimens that are
less likely to result in lipoatrophy, one would hope to
soon see a decline in the prevalence of this troubling
disorder.
Despite
the efforts of many, medical approaches to treat lipoatrophy
once it is apparent have met with only modest success
[4]. In some studies, but not all, thiazolidinediones
have been shown to result in modest recovery in fat volume
[5]. The use of human growth hormone can improve visceral
adiposity, but may worsen facial or peripheral lipoatrophy
[6].
Given
the lack of effective medical therapy, patients have turned
to surgical alternatives. Facial fillers are currently
the only therapy that can result in prompt improvement
of lipoatrophy. A wide variety of biodegradable implants
using autologous fat transfer, collagen or cadaveric dermis
implants, poly-L-lactic acid, hyaluronic acid, or calcium
hydroxylapatite, have been used. Permanent materials such
as silicone, expanded polytetrafluoroethylene, polymethyl-methacrylate
implants or polyacrylamide and polyalkylimide gels. Few
well performed, fully powered studies have been done;
one comparative study has recently been reported [7].
In
this issue Loutfy and co-workers in Toronto compare the
effects observed in a group of patients with facial lipoatrophy
treated immediately with polyalkylimide gel, an injectable
product, or followed for 12 weeks prior to treatment [8].
Polyalkylimide gel is licensed in Canada and Europe, and
has been used there to treat HIV-associated facial lipoatrophy.
Loutfy and colleagues treated 31 patients, almost all
male. Most of the patients had mild to moderately severe
lipoatrophy, with few graded subjectively as having the
most severe disfigurement. Both patients and physicians
found that the immediately treated group improved significantly,
graded with a subjective scale. Obviously, all the patients
and probably most clinicians who were grading the response
knew which patients had received injections at week 12.
The improvement persisted to 48 weeks, however, and by
48 weeks the delayed treatment group had achieved equal,
sustained improvement. In this study group of modest size,
they note the absence of complications, particularly site
reactions and nodules noted with other products; however,
unsurprisingly, others have recently reported postoperative
complications after the use of polyalkylimide gel [9].
As
in few other studies of facial fillers, Loufty and coworkers
studied the effect of their intervention on mental health
and quality-of-life scores. While the immediately treated
group had improvements in these scores compared to the
untreated group at week 12, when re-evaluated at week
48 after both groups had been treated the picture changed
somewhat. Although mental health and quality-of-life scores
had improved somewhat from baseline to week 48 for both
groups, the extent of these changes was less uniform.
Only improvements in depression and anxiety scores achieved
statistical significance.
The
authors estimate that a course of therapy for an average
patient, taking into account the need for repeat injections
in some, might be between US$ 1750-4375 for a 10-15 ml
course (US$ 175 per ml), whereas in Europe the cost varies
in the range EU 200-425 per ml depending upon nation and
treatment centre. They conclude that polyalkylimide gel
might be a preferred intervention due to its permanence,
extractability in cases of adverse outcome, and the ability
to administer high volumes of product, and sadly, the
authors must conclude that treatment with polyalkylimide
gel may be restricted due to its cost.
While
this might be the case in the current healthcare environment,
perhaps we should ask the questions that take the next
logical step. While facial lipoatrophy is not fatal, it
is devastating for the lives of many. Do we know what
its attendant costs really are? Can facial fillers obviate
some of the need for antidepressants or counseling? Are
they more cost-effective? In the developed world, a treatment
course of polyalkylimide gel appears to be a fraction
of the annual cost of antiretroviral therapy. What is
the real cost of untreated facial lipoatrophy? Should
not healthcare systems provide treatment for a condition
that appears to be, for the lack of a kinder word, iatrogenic
('used to describe a symptom or illness brought on unintentionally
by something that a doctor does or says')?
AIDS:Volume
21(9)31 May 2007p 1147-1155
“Immediate versus delayed polyalkylimide gel injections
to correct facial lipoatrophy in HIV-positive patients”
Loutfy,
Mona Ra,b; Raboud, Janet Mb,c; Antoniou, Tonya,d; Kovacs,
Colina,b; Shen, Sandyc; Halpenny, Robertaa; Ellenor, Darlenea;
Ezekiel, Daviaa; Zhao, Alicea; Beninger, Francise
From the aMaple Leaf Medical Clinic, Canada
bDepartment of Medicine, University of Toronto
cDivision of Infectious Diseases, University Health Network,
Canada
dDepartment of Family and Community Medicine, St Michael's
Hospital, Canada
eDivision of Plastic Surgery, University of Toronto, Toronto,
Ontario, Canada.
Abstract
Objective: To evaluate the safety and efficacy of polyalkylimide
gel (PAIG) in the treatment of HIV-associated facial lipoatrophy.
Design:
A randomized, open-label, single-centre study.
Methods:
HIV-positive individuals with facial lipoatrophy (based
on physician assessment) were randomly assigned to immediate
(weeks 0 and 6) or delayed (weeks 12 and 18) PAIG injections
administered into the subcutaneous plane. Outcome measures
included a change in facial lipoatrophy severity scores
(five-point scale), adverse events, photographic assessment,
and changes in quality of life (QoL), depression and anxiety
using validated surveys.
Results:
Thirty-one patients (median age 48 years, 97% male) were
enrolled and completed 48 weeks of follow-up. Overall,
the median volume of product injected bilaterally was
16.0 ml. Adverse events, including swelling, redness,
bruising and pain, were mild, and resolved after a median
of 3 days. There were no cases of necrosis, nodules or
infection. Compared with patients randomly assigned to
delayed treatment, patients in the immediate therapy group
had significantly lower physician-rated facial lipoatrophy
scores (0 versus 2; P < 0.0001), improved QoL (P =
0.01), and lower anxiety (P = 0.02) at week 12. At week
48, median physician and patient facial lipoatrophy scores
were 0 and 1, respectively, for the entire cohort, and
were not significantly different between the groups. Significant
improvements in patient anxiety (P = 0.001) and depression
(P = 0.01) were observed from baseline to week 48.
Conclusion:
Treatment with PAIG was effective and safe and led to
improvements in facial lipoatrophy grading, QoL, anxiety
and depression scores in HIV-infected patients with facial
lipoatrophy.
Introduction
Facial lipoatrophy has emerged as perhaps the most distressing
and devastating manifestation of the antiretroviral therapy
(ART)-associated lipodystrophy syndrome for patients infected
with HIV. The profound depletion in both superficial and
buccal facial fat is highly stigmatizing for patients,
resulting in feelings of low self-esteem, social withdrawal
and forced disclosure of HIV status [1-3]. In addition,
the appearance of facial lipoatrophy may adversely affect
adherence to ART, and act as a deterrent to initiating
therapy in patients for whom ART would otherwise be indicated
[1,4]. Although some progress has been made in elucidating
the aetiology of and risk factors for facial lipoatrophy
[5], currently available medical treatments appear insufficient
for managing this adverse effect. In particular, intervening
with either recombinant human growth hormone or thiazolidinediones
has yielded negligible, if any, effect on facial lipoatrophy
[6-8]. Furthermore, although switching from a thymidine
analogue to either an abacavir, tenofovir or nucleoside-sparing-based
regimen has improved peripheral fat loss in randomized
controlled trials evaluating this approach, this option
is not always virologically feasible, and the clinical
significance of the observed fat recovery is questionable
[9,10]. Given the lack of improvement associated with
pharmacological approaches, interest has increased in
the surgical correction of lipoatrophy with facial fillers.
Poly-L-lactic
acid (PLA; New-Fill, Biotech Industry SA, Luxembourg)
is an aliphatic polyester that is the first filler to
be approved by the United States Food and Drug Administration
for the treatment of ART-associated facial lipoatrophy.
Approval of PLA was based on data from four open-label
studies documenting the safety and efficacy of this product
in 278 patients with facial lipoatrophy [11-14]. Long-term
follow-up of one cohort suggested that the benefits of
PLA persist for up to 96 weeks [11]. Although it is the
most extensively studied facial filler, PLA has several
potential drawbacks. As a biodegradable product, the effect
of PLA is temporary, and therefore re-treatment is eventually
necessary. Multiple treatment sessions are required to
administer PLA, necessitating repeat visits and injections
for the patient. Furthermore, subcutaneous nodules have
been reported after the injection of PLA [11-14]. Assessment
of alternative options for patients with facial lipoatrophy
is therefore important.
Polyalkylimide
gel (PAIG; Bio-Alcamid, Polymekon, Biotech Industrie,
Milan, Italy), a non-biodegradable, non-allergenic, non-toxic
polymer composed of 96% non-pyrogenic water and 4% polyalkylimide,
possesses several properties that make further study of
this compound in HIV-positive patients worthwhile [15].
In particular, once implanted, PAIG is unique among injectable
fillers in that a fine (0.02 mm) collagen capsule develops
around the gel, isolating it from host tissue [16]. As
a result of the encapsulation process, the implant can
be readily identified and, should the need arise, easily
removed by expressing the capsule and squeezing the material
out. Also, the cosmetic effects of PAIG are permanent,
obviating the need for further treatments [15]. The benefits
and safety of PAIG have been reported in a multicentre
study of 2000 otherwise healthy patients, who attained
excellent cosmetic results, with no evidence of implant
migration, dislocation, granuloma or allergic responses
noted. Although 12 patients developed postoperative staphylococcal
infections, these could be attributed to the implanted
material in only three cases [15]. These findings have
been replicated by several published case series of HIV-positive
patients with facial lipoatrophy, in whom restorative
treatment with PAIG was assessed as being safe and effective
[16,17]. Randomized trials of PAIG incorporating measures
of patient quality of life (QoL) have yet to be performed.
The
objectives of this study were to evaluate the efficacy,
safety and impact on QoL of PAIG given in a single session,
with an additional follow-up session as needed if the
level of correction was deemed less than optimal by the
treating surgeon (i.e. a 'touch up' session).
Materials
and methods
The study was an open-label, randomized, 24-week study
of immediate versus delayed treatment with PAIG injections
in HIV-infected patients with facial lipoatrophy. The
study design was modelled after a previous trial of immediate
versus delayed injections of PLA, with the intention of
assessing the temporal association between treatment and
improvements in both facial lipoatrophy score and patient
QoL [12].
Study
participants
HIV-positive individuals, 18 years of age or older who
self-identified as having facial lipoatrophy with confirmation
by their primary care physician were eligible for the
study. The severity of facial lipoatrophy was determined
using the validated Carruther's scale of facial lipoatrophy
which goes from grade 1 (mild lipoatrophy) to grade 4
(most severe lipoatrophy) (Fig. 1) [18]. Exclusion criteria
included pregnancy or intent for pregnancy, injectable
therapy for facial lipoatrophy within the past 9 months,
the presence of an inflammatory condition of the face
and the use of anticoagulation or non-steroidal inflammatory
agents in the 7 days before injection. The study protocol
was approved by our Research Ethics Board and all patients
provided written informed consent. Consent for the publication
of photographs was also obtained.
Study
injection technique
Patients received PAIG injections at their first treatment
visit by a single trained plastic surgeon into the subcutaneous
plane, avoiding the muscle or dermal planes (Fig. 2).
At this initial visit, patients received deposits of PAIG
in several injections because this product works on the
principle of applying a minimum of 0.3 ml, or preferably,
0.5 ml per aliquot, which encourages the encapsulation
process. Smaller aliquots do not encapsulate and are absorbed
by the body. A 16 gauge, 11/2 inch needle was used for
the baseline large aliquot injection. A 20 gauge, 11/2
inch needle was used when PAIG was transferred from a
5 ml syringe to a 1 ml syringe. Care was taken to ensure
not to go medial to the midpupilar line as this might
broaden the aspect of the nose and not to go above the
midline of the zygomatic bone because this may deepen
the orbital rim. When filling the cheeks, a minimum amount
of PAIG was always applied over the zygomatic bone to
blend in with the existing structures. To minimize pain,
1-2% lidocaine with or without epinephrine was injected
locally before the procedure. Patients were given a 5-day
course of antibiotic prophylaxis with oral cephalexin
500 mg four times per day, to be started one day before
the treatment. Levofloxacin 500 mg a day was used in cases
of penicillin allergy. The quantity of PAIG injected varied
with the severity of skin depression. At the end of the
initial injection, the cheeks were thoroughly and aggressively
massaged to smoothen out all the aliquots of PAIG, including
intra-oral massage techniques. A second session was organized
6 weeks after the initial injection if the surgeon judged
the level of correction to be less than optimal and not
fully corrected. In that case, the surgeon would provide
a 'touch up', defined as the necessary volume of PAIG
needed to optimize the aesthetic result. A 20 gauge, 11/2
inch needle was used for the small aliquot touch ups.
Additional touch-up injections could be arranged as required
to optimize treatment outcome at the discretion of the
plastic surgeon. Treatment was discontinued if any severe
or moderate reaction developed after injection.
Study
design and follow-up
Study participants were randomly assigned to immediate
treatment with injections of PAIG to the buccal area,
and in some cases, the temple region, on day 0 with a
touch up at week 6, or to delayed treatment with the injections
being done at week 12 with a touch up session at week
18. Randomization was performed by the sequential opening
of sealed opaque envelopes containing treatment assignments
as determined with a random number generator. At the baseline
visit, patients were evaluated by clinical examination,
fasting blood work (complete blood count, biochemistry,
liver function, lipids, glucose, lactate, viral load and
CD4 cell count), standardized facial photography and QoL,
anxiety and depression questionnaires. Clinical examination,
facial photography and the administration of all questionnaires
were repeated at weeks 2, 6, 12 and 24 of follow-up. Additional
visits are planned for weeks 48, 72 and 96. The clinical
examination and scoring were performed by two HIV specialists
and the injecting plastic surgeon at each facial lipoatrophy
grading visit using the Facial Lipoatrophy Severity Scale
(FLSS) (Fig. 1). Each patient was scored by the three
reviewers, the average of which was used to derive the
score for the analysis. Adverse events and safety reporting
were performed at each of the visits.
Study
endpoints
The primary endpoint of the study was the change from
baseline to week 12 in the facial lipoatrophy severity
score as assessed by the three physicians using the FLSS.
The FLSS is a validated four-point grading of facial lipoatrophy
from 1 (mild facial lipoatrophy) to 4 (severe facial lipoatrophy)
developed by Dr Carruther (Fig. 1). Grade 0 was used to
represent the condition of no facial lipoatrophy. The
secondary endpoints include the change in facial lipoatrophy
grading score as determined by the patient using the FLSS,
the nature and incidence of adverse events, and the change
in QoL and depression scores from baseline to weeks 12
and 48. QoL and depression were assessed using the Medical
Outcomes Study HIV Health Survey (MOS-HIV), the Hospital
Anxiety and Depression Scale (HADS) and the slightly modified
Dermatology Quality of Life Survey (sDQLS). The MOS-HIV
is the standard validated survey used to assess QoL in
HIV-positive patients, and includes functional, mental
health and QoL subscales [19]. The subscales are scored
out of 600, 700 and 100, respectively, with a higher number
indicating better health. The HADS is a validated survey
assessing both depression and anxiety that has been used
in the setting of facial lipoatrophy treatment [20]. Each
subscale is measured out of 21, with higher numbers representing
greater degrees of depression and anxiety. The sDQLS is
a survey that has been validated using the word 'skin'
and measures the impact of skin diseases on QoL [21].
For this study, the survey was slightly modified by changing
the word 'skin' to 'facial lipoatrophy'. The sDQLS is
scored out of 30, and the literature has identified that
the higher the score, the more a given individual's impaired
QoL is caused by appearance.
Statistical
analysis
The primary analysis was a comparison of the difference
in the change from baseline to week 12 in the FLSS score,
as graded by the three physicians between the immediate
and delayed groups using a Wilcoxon rank sum test. Wilcoxon
rank sum tests were also used to compare the change in
secondary outcomes from baseline to week 12 and primary
and secondary outcomes between the treatment groups at
week 48. The proportion of patients experiencing each
adverse event was tabulated by treatment group. Pain was
assessed by duration, peak severity on a scale of 0-10,
and current severity out of 10. Medians and interquartile
ranges (IQR) were used to summarize peak and current severity.
Wilcoxon signed rank tests were used to compare the patient
FLSS score and survey score between baseline and week
48 for the entire study group.
The
interrater agreement was assessed using the AC1 statistic
(K. Gwet, 2002, unpublished observation) instead of the
more widely used kappa. Kappa is low when the outcome
of many subjects falls into one category. In this study,
many subjects had an FLSS score of zero at the last visit.
As kappa measures the agreement over and above the 'agreement
by chance', it indicates a low level of agreement when
the agreement-by-chance is high. The AC1 statistic is
similar in nature to kappa, but accounts for the large
proportion of outcomes in one group; therefore it is a
more robust chance-corrected statistic.
Results
Thirty-one patients were enrolled between April and July
2005. The baseline characteristics of the cohort are summarized
in Table 1 by treatment group. Twenty-three patients (74%)
had moderate to severe facial lipoatrophy at baseline
with a median physician FLSS of 2 (IQR 1, 3). In addition
to facial lipoatrophy, 27 patients (90%) complained of
evidence of fat loss elsewhere in the body. All 31 patients
received PAIG injections, with 16 randomly assigned to
the immediate group and 15 to the delayed group. Week
12 data are available for 30 patients, as one participant
in the immediate group missed the week 12 visit. Similarly,
week 48 data are available for 30 patients as one patient
was lost to follow-up subsequent to the week 12 visit.
The two groups were similar with respect to baseline patient
and physician-graded FLSS score as well as QoL indices.
The median volume of PAIG injected in the immediate and
delayed group was 16.6 ml (IQR 14.8, 22.3) and 13.5 ml
(IQR 10.5, 18.0), respectively (P = 0.18). Overall, the
median total volume of PAIG injected by week 48 was 16.0
ml (IQR 12, 20), with the median volume for each grade
and arm presented in Table 2. The majority of patients
(58%) required either one injection of PAIG (n = 5; two
in the immediate group, three in the delayed group) or
one injection with one touch-up session 6 weeks later
(n = 13; five in the immediate group, eight in the delayed
group). Eight patients (six in the immediate group, two
in the delayed group) required three injections (baseline
with two touch-up injections), four patients (two in the
immediate group, two in the delayed group) received four
injections, whereas the remaining patient (immediate group)
received five injections. The number of patients requiring
touch-up injections of PAIG was not significantly different
between the two groups (P = 0.15).
The
median change in the physician FLSS score from baseline
to week 12 was -2 (IQR -3, -2) for the immediate group
and 0 (IQR 0, 0) for the delayed group (P < 0.0001;
Table 3). The interreviewer agreement for the three physicians
was 0.79 [95% confidence interval (CI) 0.64-0.94] at baseline
and 0.75 (95% CI 0.61-0.89) at 12 weeks' follow-up. The
median change in the patient FLSS score from baseline
to week 12 was -2 (IQR -2, -1) for the immediate group
and 0 (IQR 0, 0) for the delayed group (P = 0.002; Table
3). The interperson agreement between patient's self grade
and the median physician score was 0.44 (95% CI 0.20-0.68)
at baseline and 0.47 (95% CI 0.24-0.70) at 12 weeks' of
follow-up. High resolution digital photographs were taken
at baseline and at each follow-up visit, and a representative
selection are presented in Fig. 3. The median change in
MOS-HIV, HADS and sDQLS scores by week 12 is presented
in Table 3 by treatment group. All three subscales of
the MOS-HIV were improved for the immediate group compared
with the delayed group, although the QoL (P = 0.01) and
psychological subscales (P = 0.02) were more significantly
affected than the physical subscale. Statistically significant
improvements in the anxiety portion of the HADS and the
sDQLS were seen in the immediate groups compared with
the delayed group at week 12 (P = 0.02 and P = 0.001,
respectively).
Fig.
3. Pictures before and after injection of polyalkylimide
gel. (a) before and (b) after grade 1 FLA; (c) before
and (d) after grade 2 FLA; (e) before and (f) after grade
3 FLA; (g) before and (h) after grade 4 FLA. FLA, facial
lipoatrophy.
Adverse
events were mostly mild and transient, resolving after
a median of 3 days (IQR 2, 5). Swelling, pain, bruising
and erythema were the most common adverse effects, occurring
in 24 (77%), 21 (68%), 18 (58%) and 13 (42%) patients,
respectively. The median duration of swelling, pain, bruising
and erythema was 4 days (IQR 3, 7), one day (IQR 1, 3),
3 days (IQR 3, 5) and 3 days (IQR 2, 3), respectively.
The median peak degree of pain was 2 (IQR 1, 4) on a scale
of 0-10. There were no serious adverse events and no cases
of cellulitis or necrosis. No nodules or micronodules
were found up to week 48.
Although
the groups were different with regard to the endpoints
at week 12, no significant difference between groups was
evident in any endpoint by week 48 (Table 4). Subsequently,
the week 48 analysis was carried out for the entire group
as a single cohort. Relative to baseline, physician and
patient FLSS scores both changed by a median of -2 (IQR
-3, -1; P < 0.0001) and -2(IQR -2, -1; P < 0.0001),
respectively, such that the median physician and patient
FLSS scores at week 48 were 0 (IQR 0, 1) and 1 (IQR 0,
1), respectively. Whereas improvements in all domains
of the MOS-HIV were observed from baseline to week 48,
statistical significance was attained only for the mental
health summary score (P = 0.01). In terms of the sDQLS
from baseline to week 48, there was a statistically significant
change observed with a median change of -3 (IQR -7, -1;
P < 0.0001). Furthermore, statistically significant
improvements were noted in both the depression (-3, IQR
-5, 1; P = 0.01) and anxiety (-3, IQR -4, -1; P = 0.001)
portions of the HADS scale from baseline to week 48.
Discussion
The results of our study indicate that injections of PAIG
are associated with improvements in FLSS scores, as assessed
by both physicians and patients. Benefits persisted through
to week 48 of the study, with the delayed treatment group
attaining similar benefits at the end of the study. In
addition, treatment was associated with improved QoL and
physical scores using the MOS-HIV, attributable predominantly
to the mental health portion of the instrument. Similarly,
anxiety scores on the HADS questionnaire and the sDQOL
score were significantly reduced among patients receiving
immediate therapy with PAIG compared with patients receiving
deferred therapy, whereas the HADS depression score was
less affected. Improvements in the mental health portion
of the MOS-HIV, the sDQOL and the depression and anxiety
portions of the HADS were maintained to 48 weeks when
the cohort was analysed as a whole. Furthermore, treatment
with PAIG was safe, with local side effects of a mild
and transient nature being reported most often. Importantly,
no infections were noted, and palpable nodules or micronodules
were absent through the first 48 weeks of follow-up. As
facial lipoatrophy is not directly harmful to health,
the improvements noted in patient levels of anxiety and
depression and QoL are probably the most relevant clinical
indices of efficacy associated with the use of PAIG in
our study.
Our
study has several limitations, including the lack of assessment
of dermal thickness by objective methods and short-term
follow-up. Patients will continue to be followed in the
study from an efficacy and toxicity perspective for a
total of 96 weeks, thereby providing longer-term follow-up.
Furthermore, the lack of blinding at the time the FLSS
score was derived may have introduced bias into the study,
particularly in the week 48 evaluation of the persistence
of treatment effect. Blinding of the observers at the
time of FLSS scoring to patient treatment status or time
on-study, or the use of a control group would have remedied
this limitation of our study. Finally, our cohort was
composed almost exclusively of men, the majority of whom
had either grade 1 or 2 lipoatrophy. We are therefore
unable to draw conclusions about the safety, efficacy
and impact on QoL of this product in women with facial
lipoatrophy and patients with more severe facial lipoatrophy.
A
practical limitation of therapy with all facial fillers
for patients with facial lipoatrophy is the cost associated
with these products. At the time of writing, the cost
of PAIG in Canada was US$175.00 per millilitre, such that
patients requiring 10-25 ml of the product would have
to pay US$1750.00-4375.00 for a course of treatment. European
prices vary by nation and treatment centre, ranging from
200 to 425 Euros per millilitre. Controlled trials with
extended follow-up are required to determine whether improvements
in patient anxiety and depression associated with corrective
treatment of facial lipoatrophy offers a financial advantage
compared with the costs associated with the psychological
morbidity of this condition.
In
summary, PAIG is a safe and effective corrective option
for the correction of HIV-associated facial lipoatrophy,
resulting in clinically important improvements in patient
appearance, QoL, anxiety and depression. Extended follow-up
of patients is necessary to confirm that the benefits
of this product persist beyond the 48-week period of our
study.
Treatments for lipoatrophy. Are there improvements?
Are they noticeable?
Written by Donald P. Kotler, MD
St. Luke’s-Roosevelt Hospital Center
Introduction
Of all of the changes that are included in the umbrella-term,
‘lipodystrophy’, fat loss or lipoatrophy has
been the most difficult to manage. Treatment
options are limited; no therapy has received FDA approval.
Several studies
have suggested that factors which influence the development
of lipoatrophy, and
those that promote fat accumulation, are different.
The treatments proposed
for lipoatrophy and fat accumulation differ as well.
Treatments for fat
accumulation that have been reported in the literature
include diet and exercise,
growth hormone (Serostim), and metformin (Glucophage).
Treatments for
lipoatrophy that have been reported include antiretroviral
switches and treatment with
thiazolidinediones (glitazones). The published results
on these two therapies
will be reviewed.
What is normal?
In order to put the effects of therapy in context, it
helps to know what is
normal fat content and distribution, quantitatively.
Table 1 lists average DXA
results from two groups of healthy adults. The data
from control group C1
were published from our laboratory (1) and include both
men and women. The data
from control group C2 were taken from the initial publication
about
lipodystrophy by Carr and colleagues (2). Total
fat content is similar in men and
women but is higher as a percentage of weight in women
(30%) than in men (21%).
In contrast, fat-free mass is substantially higher in
men, as demonstrated
previously by others. There is a difference in the
percentage of fat that is
central (trunk) and peripheral (limb), with women having
more fat peripherally
than do men, a difference also shown by others.
The results in the men studied
by DXA in New York City and Sydney, Australia are very
similar. The average
man studied in New York has 36.7 pounds of fat, of which
19.4 pounds are in the
trunk and 15.6 pounds are in the limbs (6.2 pounds per
leg and 1.6 pounds per
arm).
Table 1: Fat-free mass, total body fat content
and its distribution in
healthy adults
Data in all Tables expressed as Kg (1 kg=2.2
lbs)
Fat-free mass
Total fat Trunk fat Limb fat
C1
female 39.4
17.7
8.3
9.1
C1
male 59.4
16.7
8.8
7.1
C2
male 59.6
17.9
9.4 7.2
Data as kg; C1=healthy male adults studied at St. Luke’s-Roosevelt
Hospital
Center (1), C1=healthy female adults studied at St. Luke’s-Roosevelt
Hospital
Center (1), C2=healthy male adults studied in Sydney,
Australia (2)
How different is body composition in subjects
with lipodystrophy?
Table 2 lists average DXA results, at baseline,
taken from subjects in
three published studies in which abacavir was switched
for zerit (3-5). Most or
all of the subjects studied were male. Average fat-free
mass, when reported,
was not substantially different from the controls.
Total and limb fat
averaged 2.5-5 kg lower in the lipodystrophy groups than
in the controls, while
trunk fat was slightly higher in subjects with lipodystrophy
than in the controls.
The ratio of trunk-to-limb fat was about 2.5 times higher
in subjects with
lipodystrophy than in controls. The absolute amount
of fat in the arms and
legs were about one half that of the controls.
Table 2: Baseline body composition in HIV-infected
subjects with lipoatrophy
Fat-free mass
Total fat Trunk fat
Limb fat
Carr (3) 58.6
12.6
9.1
3.5
John (4) -----
------
----
5.5
Moyle (5) 67.3
14.3
10.8 3.5
What is the effect of switching antiretrovirals?
Table 3 lists the absolute and
percentage changes in fat-free mass, total
fat, trunk fat, and limb fat, again estimated from the
published papers,
using the patients who switched from zerit to abacavir.
The switch did not affect
fat free mass in any study. In the study by Carr
et al (MITOX), total fat
mass rose by around 9%, while limb fat rose by 11% and
trunk fat rose by 15%
after 6 months (3). The change in limb fat was statistically
significant.
However, the subjects were unable to detect the change
in fat content. The data
were updated to a 2 year follow up, during the Fifth Workshop
on Lipodystrophy
(6). There was continued increase in limb fat totaling
a 36% increase from
baseline values. However, the changes continue to
be clinically inapparent in
many patients. In addition, the 36% rise represents
about one third of the
difference between the subjects at baseline, and controls.
In this study, measures
of visceral fat did not change, nor did the presence and
size of buffalo
humps.
John and colleagues from Perth, Australia
also studied subjects who
switched from zerit to abacavir to prevent or reverse
lipoatrophy, and noted an
increase in absolute limb fat of about 500 gm over 48
weeks (4). The change,
while statistically significant compared to those who
continued therapy, is the
equivalent of about 4 ounces of fat per limb. No
clinical correlations were
reported.
Moyle and colleagues from London performed
a complicated switch study,
and the results in 10 subjects who switched from zerit
to abacavir are lilsted
in the table (5). Total fat rose by 3.5 kg, or almost
25% after one year. The
increase was split relatively equally between trunk and
limbs. Because of
the loss of limb fat, the increase in limb fat after one
year, 1.7 kg,
represented almost one half of the difference between
baseline and control values.
Visceral fat content was unaffected by the switch.
Surprisingly, self-assessment
and quality of life scores did not change over 48 weeks.
One might question
the robustness of the measurement tool, though the group
size, at 10, is very
low for a subjective scale to show significant changes.
Table 3: Changes in fat-free mass, total body
fat, trunk and limb fat after
switching antiretrovirals
D fat-free
mass D total fat
D trunk fat D limb fat
Carr (3) -0.4 (0.07%)
1.1 (8.7%) 1.4 (15.4%)
0.4 (11.4%)
John (4) --------------
------------ ---------------
0.5
(9.1%)
Moyle (5) -0.7 (1.0%)
3.5 (24.5%) 1.8 (16.6%)
1.7 (48.5%)
(3) switch from zerit to abacavir, 24 weeks, 109/111 male,
(4) switch to
combivir/abacavir, 48 weeks, all male, (5) switch zerit
to abacavir, 48 weeks
(genders not specified)
To summarize, switching from zerit to abacavir
leads to a statistically
significant increase in limb fat with progressive rises
over periods up to 2
years. However, the degree of increase does not
return limb fat to normal. In
addition, there is a relative wide variation in individual
results.
What is the effect of therapy with thiazolidinediones?
Four studies have reported the effects of
therapy with
thiazolidinediones, three using rosiglitazone (Avandia)
and one using pioglitazone (Actos).
Jarvinen and colleagues from Helsinki performed
a placebo-controlled trial using
8 mg of rosiglitazone for 6 months, and was unable to
show a statistically
significant difference in either visceral (VAT) or subcutaneous
(SAT) adipose
tissue by whole body MRI (7). Gelato and colleagues
from Stony Brook performed
an open-label study in 8 subjects, and demonstrated a
23% increase in mean SAT
and a 21% fall in mean VAT by single slice CT scanning
(8). No clinical
correlations were reported. Calmy and colleagues
from Geneva reported on an
open-label trial of pioglitazone for 6 months and documented
significant increases
in total fat, trunk fat, and leg fat (9). They reported
that some subjects
noted improvement ranging from modest to substantial,
while others noted no
change, and some even reported progression of the changes.
Hadigan presented the
results of a randomized, placebo-controlled trial of rosiglitazone
at the
recent 5th Workshop on Lipodystrophy. Therapy was
placebo-controlled for 3
months, then followed by 3 months of open-label; therapy
(10). A 5% increase in
leg fat by DXA, which was not statistically significant,
was noted at 3 months.
However, an increase in abdominal subcutaneous fat of
8%at 3 months and 12%
at 6 months were found, and were statistically significant.
Trunk fat and VAT
did not change. No clinical correlates were reported.
Table 4: Effect of thiazolidinediones on body
fat content and distribution
TAT %D
TAT SAT %D SAT
VAT %D VAT
Jarvinen (7) 3050
2.9 1140
5.3 1920
1.6
Gelato (8) 264
-1.5 26
23 -30
-21
Calmy (9) ----
20.1 ----
28 ----
17.3
Hadigan (10) ----
---- ----
12 ----
-0-
(7) RCT, 24 weeks, whole body MRI , (8) Open-label,
6-12 weeks, single
slice CT, (9) Open-label, 6 months, DXA (SAT for
limb fat, VAT for trunk fat),
(10) RCT, 24 weeks, single slice CT
Discussion
Three points are worthy of discussion. The first
is that both antiretroviral
switching and thiazolidinedione therapy may lead to some
reversal of
lipoatrophy. The fact that these two completely
different approaches may have benefit
supports the contention that the development of lipoatrophy
is
multifactorial, or at least that treatment approaches
may be multi-pronged. Furthermore,
the results indicate that the process of lipoatrophy is
not irreversible.
A wide intra-individual variation in treatment effects
was seen in several of
the studies, which suggests that medications and other
factors variably
affect body fat content and distribution in different
subjects. In other words,
one or another antiretroviral may be the major cause of
lipoatrophy in some
subjects while other factors, e.g., a rigorous exercise
training program plus
anabolic steroids may be more important in others.
It is important to note that
no study reported complete reversal of lipoatrophy, though
it might have
occurred in some subjects. This author’s experience
is similar, in that many
patients show little change after switching or even discontinuing
antivirals, or
with thiazolidinedione therapy, while a few patients have
an excellent response.
An unanswered question is how much of a change is noticeable.
Several of the
studies did not report clinical correlations and others
remarked that the
increases in limb fat or SAT were unappreciated or labeled
as mild by the
subject. Subject perception was not a primary endpoint
in any study and most of the
studies were grossly underpowered for this question.
Prospective studies
using validated instruments in larger study groups will
be needed to determine if
the changes in limb fat/SAT after switching antiretrovirals
or treating with
thiazolidinediones are clinically relevant in addition
to being statistically
significant.
References
1. Engelson EE, Kotler DP, Tan YX, Wang J, Pierson RN,
Heymsfield SB. Fat
distribution in HIV-infected patients reporting truncal
enlargement quantified by
whole-body magnetic resonance imaging. Am J Clin Nutr.
1999;69:1162-9.
2. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral
lipodystrophy, hyperlipidaemia and insulin resistance
in patients receiving HIV protease
inhibitors. AIDS. 1998;12:F51-8.
3. Carr A, Workman C, Smith DE, Hoy J, Hudson J, Doong
N, Martin A, Amin J,
Freund J, Law M, Cooper DA; Mitochondrial Toxicity (MITOX)
Study Group.
Abacavir substitution for nucleoside analogs in patients
with HIV lipoatrophy: a
randomized trial. JAMA. 2002;288:207-15.
4. John M, McKinnon EJ, James IR, Nolan DA, Herrmann SE,
Moore CB, White AJ,
Mallal SA. Randomized, controlled, 48-week study of switching
stavudine and/or
protease inhibitors to combivir/abacavir to prevent or
reverse lipoatrophy in
HIV-infected patients. J Acquir Immune Defic Syndr. 2003;33:29-33.
5. Moyle GJ, Baldwin C, Langroudi B, Mandalia S, Gazzard
BG. A 48-week,
randomized, open-label comparison of three abacavir-based
substitution approaches
in the management of dyslipidemia and peripheral lipoatrophy.
J Acquir Immune
Defic Syndr. 2003;33:22-8.
6. Martin A, Carr A, Ringland C, Amin J, Workman C, Freund
J, Hoy J, Doong N,
Smith D, Cooper DA for the MITOX study. Long term changes
in lipodystrophy
after switching from nucleoside analogues to abacavir.
Program and abstracts,
Fifth International Workshop on Adverse Drug Reactions
and Lipodystrophy in HIV.
Paris, France, July 8-11, 2003, Abstract 16.
7. Yki-Jarvinen H, Sutinen J, Silveira A, Korsheninnikova
E, Fisher RM,
Kannisto K, Ehrenborg E, Eriksson P, Hamsten A. Regulation
of Plasma PAI-1
Concentrations in HAART-Associated Lipodystrophy During
Rosiglitazone Therapy.
Arterioscler Thromb Vasc Biol. 2003;23:688-94.
8. Gelato MC, Mynarcik DC, Quick JL, Steigbigel RT, Fuhrer
J, Brathwaite CE,
Brebbia JS, Wax MR, McNurlan MA. Improved insulin sensitivity
and body fat
distribution in HIV-infected patients treated with rosiglitazone:
a pilot study.
J Acquir Immune Defic Syndr. 2002;31:163-70.
9. Calmy A, Hirschel B, Hans D, Karsegard VL, Meier CA.
Glitazones in
lipodystrophy syndrome induced by highly active antiretroviral
therapy. AIDS.
2003;17:770-2.
10. Hadigan C, Yawetz S, Thomas A, Havers F, Sax P, Grinspoon
S. A
randomized, double-blind, placebo-controlled study of
rosiglitazone for patients with
HIV lipodystrophy. Program and abstracts, Fifth International
Workshop on
Adverse Drug Reactions and Lipodystrophy in HIV. Paris,
France, July 8-11, 2003,
Abstract 12.
___________________________________________________________________________
TREATMENT
OF ENLARGED PAROTID GLANDS IN HIV DISEASE
By Nelson Vergel- March 2006
I have been seeing many HIV positive men with enlarged
parotid glands in my 14 years of travels giving lectures
around the country. I am also one of those men with moderate
inflammation of the parotid glands. No one really knows
what causes this disfiguring inflammation. It could be
due to the HIV virus itself, inflammatory cytokines and
too many CD8 cells produced by immune reconstitution,
hormones, fat build up in the glands, etc. Some people
have this problem along with facial wasting, which makes
their faces look very abnormal. So even if you treat your
facial wasting with facial fillers, this problem needs
to be treated so that you can attain a more normal look
that resembles what you normally would look like without
the effects of HIV and its medications.
The parotid gland is the largest of the salivary glands
that produce saliva that is important in the digestion
of food. The gland lies under the angle of the jaw just
beneath the ear.
I have been searching for a long time for an answer. Not
a single HIV conference has had a presentation on this
problem that may affect around 20 percent of men with
HIV. It does not seem to affect as many women with HIV
for unknown reasons. I had heard about radiation treatments
in the past but they created severe side effects like
burning of the salivary glands, salivary production problems,
and eventual tooth decay. A few months ago my dear friend
Dr. Tony Mills from Los Angeles called me to tell me about
the great results he had seen in his patients referred
to Dr Patricia Gordon. I decided to call Dr. Gordon myself
to talk to her about her experiences. Dr. Gordon did her
undergrad at Harvard and her residency at UCLA. She is
a radiation oncologist and practices at Century City Hospital
in Los Angeles.
A very pleasant and seemingly dedicated doctor, she immediately
told me how happy she was with the excellent remission
rates she had been seen in her patients. Most noticed
complete resolution of the problem after a few sessions
of low dose electron-based radiation. She stressed the
fact that this protocol differs greatly from the ones
used in the past that created greater side effects because
of the nature of the radiation, Unlike the old method
that used photons that penetrate the skin more deeply,
she uses electrons that penetrate a very thin layer of
tissue instead, so they do not cause the burning and salivary
gland dysfunction seen in the past.
She has had over 200 male patients referred to her practice
(not one female has been referred). At baseline, all patients
get a CT scan of their parotid gland area for assessment.
They get a customized molded lead mask that only exposes
the area to be treated. They then receive 16 sessions
(once a day for five days a week, for five minutes each)
on both sides of the face. She said that most patients
see improvements after four sessions. However, she did
not have before and after pictures to share with me. All
procedures have been reimbursable by Medicare and insurance.
I decided to get my parotid glands treated and I am happy
to say that they got back to normal after 7 sessions.
It has been 4 years now (March 2006) and they are still
normal! I had no significant side effects besides redness
for a few days, no beard for a month (which I liked),
and a temporary loss of normal saliva production. All
returned to normal after a month or so. I am not sure,
but I think I had a slight decrease in CD4 cells (around
20) but this is hard to tell unless someone performs a
controlled study. My CD4 cells also returned baseline
after two months.
Dr. Gordon will publish a paper on her experiences soon.
Her phone number is 310-201-6739. Her email is pgordonmd@aol.com .She is happy to talk
to doctors or patients about this procedure.
PoWeR
Releases Groundbreaking Lipodystrophy Resources for HIV-Positive
People
Apr 8, 2008
HOUSTON, April 8 (AScribe Newswire) -- Program for Wellness
Restoration, PoWeR, released the results of the largest
online patient surveys performed to date on lipodystrophy
options and resources along with a free Spanish translation
of PoWeR's book, Built to Survive. The 776-person survey
summarizes the main therapeutic options used in the HIV
community along with a list and ratings of providers who
specialize in reconstructive procedures for HIV-related
body changes.
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). I am very happy that we have been able
to provide this key information to the HIV community,
said Nelson Vergel, founding director of PoWeR. People
have been wanting this important health resource for 10
years after the first report of lipodystrophy was reported
at an HIV conference,, added Vergel.
The
results of the survey can be found at: _Survey Results_
(http://www.surveymonkey.com/sr.aspx?sm=LYbzfgoEFlmgc1vkr3v_2bEWfscAbBPrjpRbaywPjqMqI_3d)
A
list of providers with comments from patients can be found
at : _Survey Results_ (http://www.surveymonkey.com/sr.aspx?sm=rc8hHUnWoT5VVui7aS9Q_2fsfxahbyw7goBCGlfANmm4A_3d)
A
free PDF copy of the Spanish translation of the book Built
to Survive can be downloaded from : _http://powerusa.org/pdf/Fortaleceteysobrevive1.pdf
Another
distressing and unaddressed issue related to HIV lipodystrophy
is buttock wasting. Currently, there is no research being
performed in the US or abroad on this debilitating problem
that can cause pain and discomfort in patients who have
to sit down for extended periods of time at work or school.
PoWeR gathered all available anecdotal and research information
on the subject and made it available in their new web
page: http://facialwasting.org/buttock_wasting.htm
PoWeR
is a national non-profit all-volunteer organization that
provides patient-friendly educational information to HIV-positive
people and their clinicians about ways to improve HIV
treatment response, side effects, and quality of life.
More information can be found at http://www.powerusa.org
.
For
an update on were we are after ten years of lipodystrophy,
please visit http://thebody.com/content/toparts/art45454.html
-
- - -
CONTACT:
Nelson Vergel, PoWeR Director, powertx@aol.com,
713-539-1978
CAN MEDICAL
EXPENSES SPENT ON FACIAL OR BUTTOCK RECONSTRUCTION BE
DEDUCTED FROM INCOME TAXES IN THE US?
Thanks
to the person who took the time to do this research! Great
email for all to save
Hi Nelson,
To
our friends in other countries - ignore this message!
It's about US tax.
As
is usual with tax, there's no simple yes/no answer to
your question. My answer boils down to - it SHOULD be
deductible, and it's worthwhile trying, but if you are
audited, there's a good chance that it will be reversed
and you will be billed for tax and interest, and possibly
penalty.
Deductibility
of medical expenses comes down to "medical necessity."
Internal Revenue Code section 213(a) says this:
"There
shall be allowed as a deduction the expenses paid during
the taxable year, not compensated for by insurance or
otherwise, for medical care of the taxpayer, his spouse,
or a dependent ..., to the extent that such expenses exceed
7.5 percent of adjusted gross income."
In
other words, you add up all your allowable medical expenses,
and if they are more than 7.5% of your adjusted gross
income (also called AGI - the last line of page 1 of your
Form 1040), then the excess is allowed as an itemized
deduction. If your AGI is $100,000, and your total medical
expenses are $10,000, your itemized deduction will be
$2,500. Your total itemized deductions have to exceed
your "standard deduction" to get any benefit.
The standard deduction for a single person in 2007 is
$5,350.
By
the way, as for medication, section 213(b) says "An
amount paid during the taxable year for medicine or a
drug shall be taken into account ... only if such medicine
or drug is a prescribed drug or is insulin."
So,
no deduction for aspiring or cough syrup.
Now,
in the tax code, you always have to look for the definition
of everything. Section 213(d)(1) says "The term 'medical
care' means amounts paid for the diagnosis, cure, mitigation,
treatment, or prevention of disease, or for the purposes
of affecting any structure or function of the body ..."
And then it goes on to also allow deductions for certain
medical-related travel expenses, for long-term care, and
for medical insurance premiums.
It
sounds from the above like facial and buttock reconstruction
would be covered - it mitigates disease (effect of the
treatment of a disease, which amounts to the same thing),
and does affect bodily structures.
However,
section 163(d)(9) says "(A) The term 'medical care'
does not include cosmetic surgery or other similar procedures,
unless the surgery or procedure is necessary to ameliorate
a deformity arising from, or directly related to, a congenital
abnormality, a personal injury resulting from an accident
or trauma, or disfiguring disease. (B) ... The term 'cosmetic
surgery' means any procedure which is directed at improving
the patient's appearance and does not meaningfully promote
the proper function of the body or prevent or treat illness
or disease."
We
have two problems, then. First, anything that can ALSO
be cosmetic, is very hard to prove as being medically
necessary - it's the same reason we have trouble getting
our insurance providers to cover the treatment. The IRS
is extremely skeptical of such deductions. In addition,
the IRS is very skeptical of any treatment that addresses
a mental/emotional problem, as opposed to a physical problem.
So if you have your butt fixed because it's painful to
sit, that's a physical issue. If you have your face fixed
because you can't even recognize yourself in the mirror
and it throws you into a deep depression - the IRS may
not be sympathetic.
This
is a heavily-contested subject - not lipoatrophy treatment,
but deduction of cosmetic treatment.
There
is no requirement that treatment be provided in the US,
and if you can show that it cost less because you had
it done elsewhere, that may help, although it also may
look to suspicious to examiner, particularly if it was
done in a place that is also a vacation spot (hmmm, Baja
Mexico, Brazil) ... and the regulations related to medical
travel expenses mention that a "vacation for to improve
general health" is not deductible so you'll need
to be ready to defend against that.
The
IRS has a publication on Medical Expenses called Publication
502. Here's what it says about cosmetic surgery:
"Generally,
you cannot include in medical expenses the amount you
pay for unnecessary cosmetic surgery. This includes any
procedure that is directed at improving the patient's
appearance and does not meaningfully promote the proper
function of the body or prevent or treat illness or disease.
You generally cannot include in medical expenses the amount
you pay for procedures such as face lifts, hair transplants,
hair removal (electrolysis), and liposuction.
"You
can include in medical expenses the amount you pay for
cosmetic surgery if it is necessary to improve a deformity
arising from, or directly related to, a congenital abnormality,
a personal injury resulting from an accident or trauma,
or a disfiguring disease."
Here's the link to the on-line version of Publication
502: http://www.irs.gov/publications/p502/index.html
If
you want to download it: http://www.irs.gov/pub/irs-pdf/p502.pdf
So, you need to be able to prove that you meet this definition.
A letter from a doctor will be a necessity here. Discuss
all this with your own tax provider. Large medical expenses
are a red flag for audit, so if you have other stuff in
your tax return you don't want them asking questions about,
then you'll want to think twice about taking this deduction.
I
hope this helps!
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