NATAP – www.natap.org
4th Intl Workshop on Adverse Drug Reactions and Lipodystrophy
Sept 22-25, 2002
San Diego, CA
This is one of two reports providing summary coverage and insights into the
Lipodystrophy Workshop from lipodystrophy researchers writing for NATAP.
Additional coverage by Jules Levin and an interesting summary of a talk on
Bone Loss and Protease Inhibitors written by Don Kotler, MD is archived at:
http://www.natap.org/2002/lipoWorkshop/ndxLipo.htm
Lipodystrophy, lactic acidosis/acidemia and mitochondrial toxicity issues at
the 4th International Workshop on Adverse Drug Reactions and Lipodsytrophy in
HIV
Written by Cecilia Shikuma, MD, University of Hawaii and ACTG lipodystrophy
researcher
Abstracts presented at this conference extended our understanding of the
mechanisms inducing lipodystrophy and related metabolic abnormalities.
Unfortunately, no new break throughs were reported in therapeutic
interventions for lipoatrophy.
TOPICS:
Leptin as a potential replacement therapy for lipoatrophy
Pathophysiologic Mechanisms: in cell, muscles and tissue
Mitochondrial dysfunction in the liver
Modalities for the assessment of lipodystrophy
Genetic polymorphisms and lipoatrophy
Switch Therapy for lipoatrophy
Mitochondrial DNA analysis in blood specimens: using blood vs tissue samples
Longitudinal assessment of body composition over time: ACTG 384 results
Clinical management of lipodystrophy
Reconstructive surgery options for facial lipoatrophy
Leptin as a potential replacement therapy for lipoatrophy
The Monday sessions started with a Keynote Lecture on "Leptin, lipodystrophy
and insulin resistance" given by Jeffrey Friedman and a Plenary Lecture by
Philip Gorden on "Treatment of non-HIV lipodystrophy with thiazolidinediones
and leptin". Leptin is a hormone produced by adipose tissue which acts as a
satiety signal to the brain and regulates appetite. Decreased levels are
seen as a response to starvation. In non-HIV infected individuals with
congenital and acquired forms of lipodystrophy, leptin has been noted to
reverse insulin resistance and decrease the elevated serum triglycerides and
free fatty acids associated with severe fat lipoatrophy. Leptin may
therefore have some efficacy in countering the diabetic tendencies and
hyperlipidemia associated with fat loss in HIV patients on HAART. While much
of leptin’s effect seems to be secondary to a central effect on the
hypothalamus, direct effects have been demonstrated on peripheral tissues
including T cells. The precise mechanism of action of leptin on fat is
unknown. Increased leptin may act to decrease levels of stearoyl-CoA
desaturase (SCD1). The decrease in SCD1 may not only block the production of
free fatty acids and triglycerides but also lead to increased metabolic
disposition of fat by indirectly increasing the activity of CPT1, the enzyme
that catalyzes the entry of saturated fatty acyl CoA into the mitochondria
for b oxidation.
Pathophysiologic Mechanisms
In tissue culture (test tube testing), adipocyte (fat cells)dysfunction
following indinavir may be related to impaired lamin A/C maturation, and
disruption of nuclear architecture [Abs 1]. Inhibitory effect on adipocyte
differentiation may involve inhibition of glycerol-3-phosphate dehydrogenase
activity due to increased levels of TNF-a and IL-6 [Abs 3]. In cultured
adipocytes, d4T and ddI did not alter cell differentiation although they
moderately impaired lipid accumulation and promoted apoptosis. Cell loss was
further increased when stavudine was used in combination with indinavir.
However d4T and ddI partly reversed the indinavir-induced alterations of cell
differentiation and insulin resistance, possibly by restoring the
intra-nuclear penetration of SREBP-1 [Abs 9]. Interpretation of
anti-retroviral medication effects in cell culture is difficult as results
are dependent on such variables as type of cell culture, and on the timing,
concentration and duration of administration of drugs. It appears clear
however that both NRTIs and PIs appear to have effects on adipocyte
metabolism and that various agents in each class may have unique and
different effects.
Lipoprotein lipase (LPL) mRNA expression is reduced in thigh subcutaneous
tissue from HIV-1 infected subjects with subcutaneous lipoatrophy [Abs 4],
suggesting a defect in triglyceride uptake by adipocytes in these
individuals.
An interesting modality for possibly assessing reduced oxidative enzyme
function by assessing the body’s ability to extract O2 for its use was
presented by WT Cade, SouthWest Texas State University [Abs 16]. Utilizing a
breathing apparatus, a maximal exercise threadmill test to exhaustion and
calculations based on a rearrangement of the indirect Fick equation (oxygen
consumption = cardiac output x difference between Arterial to Venous O2
level) the authors noted that the peak oxygen extraction was diminished in
subjects infected with HIV taking HAART compared with HIV-infected subjects
not taking HAART and non-infected controls, raising the intriguing question
as to whether this was due to decreases in mitochondrial function.
Using positron emission tomography (PET) [Abs 17], b-oxidation was studied in
skeletal muscle. No evidence of impaired b-oxidation was found in
individuals with lipodystrophy and it was suggested that the high free fatty
acids in the blood was the result of increased release of fatty acids rather
than the failure of skeletal muscle to metabolize and utilize this energy
source.
Two abstracts [Abs 32, 33] addressed the potential role of adiponectin in
lipodystrophy and associated metabolic dysfunction. Adiponectin is a newly
discovered hormone secreted by fat cells that appear to reverse the effects
of insulin resistance in non-HIV models of diabetes. O Tong et al [Abs 32]
reported that concentrations of this hormone were significantly reduced in
HIV infected subjects with lipodystrophy and was strongly correlated with
adipose tissue redistribution, hyperinsulinemia, insulin resistance and
dyslipidemia. They speculated that reduction in adiponectin might contribute
to the metabolic abnormalities in lipodystrophic individuals and that
replacement might be used as a therapeutic strategy.
In a retrospective cohort study and analysis of 137 repository plasma
samples, pretreatment leptin levels, but not BMI, predicted risk of
lipoatrophy [Abs 78].
Mitochondrial dysfunction in the liver
Bernard Fromenty gave a plenary lecture on "Mitochondrial dysfunction in the
liver: from drugs to NASH." b oxidation is a process whereby fatty acids are
metabolized. Effective mitochondrial b oxidation require the availability of
Coenzyme A and L carnitine, the ability to reoxidize NADH, and functional
integrity of the mitochondria. Drugs that inhibit b oxidation can be
classified as those that have a direct toxic effect on b oxidation with
enzymatic inhibition and/or sequestration of coenzyme A or carnitine, those
that accumulate in the mitochondria and interact and affect the OXPHOS
components of the mitochondria and those that have its effect on inhibition
of mtDNA. The fatty liver seen in the context of NRTI therapy may belong to
this last category. Interestingly excessive alcohol intake can affect b
oxidation by all three mechanisms. (editorial note: fatty liver, also called
steatosis, is a condition among some patients with HCV where fat accumulates
in the liver perhaps due to impaired liver function and may contribute to
accelerated liver disease. In HIV, elevated fats like cholesterol and
triglycerides may also contribute to fatty liver and HCV/HIV coinfected
patients may be more prone to fat accumulation and glucose abnormalities in
the liver due to liver impairment and elevated lipids).
Inability to metabolize fat by b oxidation leads to accumulation of fat
within cells. When examined at a cellular level, accumulation of fat can be
categorized as "macrovesicular" (the accumulation of fat in large droplet
form) or as "microvesicular" (in smaller droplet form). Macrovesicular fat
accumulation is considered a benign type of fatty liver that does not
progress. Microvesicular fat accumulation, on the other hand, is associated
with ATP depletion and fatty acid toxicity with risk to eventual liver
inflammation followed by cirrhosis and liver failure. A significant
component of this process may be secondary to the production of cytokines
such as TNF alpha which are produced when damaging effects of the byproducts
of fat (lipid peroxidation products) interact with reactive oxygen species
(ROS) produced in excess by a dysfunctional mitochondrial energy system.
(editorial note: it has been suggested that TNF alpha abnormalities may be
associated with body composition changes: see below).
Modalities for the assessment of lipodystrophy
Investigators from Washington University [Abs 29] found that MRI measurements
of abdomen and thigh fat area correlated well with DEXA measurements of trunk
and leg fat content in 56 HIV seropositive subjects and 18 controls. During
the question and answer period, it was commented that other researchers have
not had similar experiences in regards to truncal fat. Whether truncal fat
by DEXA (which measures both visceral and subcutaneous fat in the trunk)
could be used to estimate visceral fat specifically as can be done by MRI or
CT, probably remains to be demonstrated in larger cohort studies.
Genetic polymorphisms and lipoatrophy
In yet another indication of the strong influence that genetics could play in
the development of various human disorders, D Nolan from Perth, Australia
[Abs 26], reported that having a tumor necrosis factor alpha gene -238G/A
promoter polymorphism (found in 11.4% of their cohort all of white racial
origin), was a risk factor for the development of lipoatrophy. The risk was
modest and was independent of the usual well-recognized risks for the
development of lipoatrophy such as age and time on NRTI therapy.
Switch Therapy for lipoatrophy
Tyler Lonergan [Abs 21] presented the 48 wk data from the TARHEEL study
reporting continued beneficial effect and lack of recurrence of asymptomatic
and symptomatic hyperlactatemia when stavudine (d4T) is replaced by either
abacavir (ABC) or zidovudine (ZDV). A sustained normalization of lactate
levels and a decrease in liver function values were seen. Improvement in
lipoatrophy was also seen. At week 48 in the group as a whole, there was a
median increase of 35% (249g) of fat in the arms, 18% (949) median increase
of fat in the trunk and 12% (288g) in the legs. Interestingly, single slice
CT scan through L4 at baseline and at week 48 demonstrated a tendency for
visceral fat to decrease following switch while abdominal subcutaneous fat
increased. HIV-1 viral load remained well suppressed in these individuals.
These results indicating favorable response past 48 weeks are encouraging and
support the view that d4T substitution with either abacavir or zidovudine may
be a viable option for some individuals with lipoatrophy and/or
hyperlactatemia.
Mitochondrial DNA analysis in blood specimens
Much interest has been generated in assessing the mitochondrial DNA levels of
peripheral blood mononuclear cells (PBMCs) in individuals at risk of or
suffering from hyperlactatemia, lipoatrophy and other mitochondrial side
effects of NRTIs. Several abstracts were presented on the relevance and
technical aspects of such mitochondrial DNA assays in PBMCs. Investigators
from the International Antiviral Therapy Evaluation Center (ITEC) and
Primagen in the Netherlands serially assessed PBMC mtDNA and mtRNA levels
using the single tube duplex real-time NASBA method [Abs 25] in a subset of
36 subjects within the EASIER trial. Individuals in this trial were
randomized to receive either RTV/IND + EFV with or without d4T. They
reported that inclusion of d4T in the regimen was associated with a delayed
24% increase (rather than a decrease) in mtDNA after 24 weeks. A Cossarizza
from Milan, Italy [Abs 23] presented data stressing the importance of
platelet elimination before assaying PBMCs for mtDNA. Platelets contain
mtDNA but no nuclear DNA; therefore contamination can lead to falsely
elevated mtDNA levels. S. Lopez from Barcelona, Spain [Abs 24] presented
information on doing functional studies on mitochondria from PBMCs (by
assessing the enzyme activity of the mitochondria’s energy generating
system
(OXPHOS) and determining oxygen consumption) in addition to mtDNA analysis.
They found that functional assays were often normal even when mtDNA levels
were not. They urged caution in focusing too much relevance on mtDNA levels.
During the panel discussion that followed, several key points were made:
First that increases in mtDNA levels, such as seen in the EASIER trial, may
be seen as a response to mitochondrial injury and could not be interpreted as
lack of mitochondrial toxicity. Secondly, mitochondrial toxicity is
extremely tissue specific; therefore, lack of toxicity in blood lymphocytes
do not mean that no toxicity is occurring in the tissue of interest whether
it is fat or skeletal muscle. For clinical care, the relevance and role of
mtDNA levels in blood lymphocytes is not clear at the moment; therefore,
similar to the situation in plasma lactates, routine assessment of PBMC
mtDNA levels cannot be recommended at this time.
Longitudinal assessment of body composition over time
Longitudinal results of body composition from 2 reasonably large cohort
trials were reported. M. Dube of Indiana University [Abs 27] presented the
preliminary DEXA results in a cohort of 156 subjects up to week 80 in A5005s,
a metabolic substudy of ACTG 384. ACTG 384 was a large anti-retroviral trial
in ARV naïve subjects. Subjects received a backbone of either ZDV +3TC or
d4T + ddI. NFV and/or EFV were added to this backbone. Anti-retroviral
naïve subjects randomized to d4T + ddI lost a greater proportion of limb fat
than those receiving ZDV + 3TC at weeks 48 – 80. Subjects randomized to
nelfinavir lost a greater proportion of limb fat at week 80 than with
efavirenz. Although trunk fat increased across all group, regimen specific
differences in trunk fat changes were not detected. D. Nolan of Perth,
Australia [Abs 28] presented longitudinal DEXA study in 53 subjects in the
Western Australian HIV Cohort Study who had at least 2 sequential DEXA scans
while undergoing a first HAART triple therapy regimen containing either
stavudine or zidovudine. A new non-linear mixed effects model was proposed
to assess fat wasting as a continuous time-dependent variable rather than as
a dichotomous subjective outcome. The investigators reported that both
stavudine and zidovudine groups averaged approximately 22% leg fat at the
time they first began HAART. This percentage dropped exponentially to
approximately 13% after 2 years in patients on stavudine. In contrast, the
zidovudine treated group leveled off after 2 years to approximately 19% leg
fat. Interestingly, whether these individuals had started HAART as
completely anti-retroviral naïve or whether they had had 30 months of prior
ZDV, subjects on each NRTI group after 2 years drifted down and leveled off
to these same levels.
Clinical management of lipodystrophy
Several speakers gave an overview of the state of the art in the clinical
management of lipodystrophy. Treatment for metabolic abnormalities should
include therapy modalities commonly given to non-HIV infected individuals
including diet, exercise regimens and statins, fibrates and oral antidiabetic
agents as required. Treatment options for lipodystrophy are limited. Judith
Currier, UCLA, noted clinical trials of various agents including anabolic
agents such as growth hormone or anabolic steroids such as testosterone, and
insulin-sensitizing drugs such as thiazolidinediones and metformin.
Substitution or avoidance of certain NRTIs may be appropriate in some
individuals. Trials of possible preventive strategies to delay or eliminate
the onset of lipodystrophy may be in order.
Reconstructive surgery options for facial lipoatrophy
Derek Jones, UCLA, presented a review of reconstructive surgery options for
facial lipoatrophy. Non-permanent reconstructive options such as injections
of fat or collagen suffer from gradual resorption of the injected material.
Currently, more permanent reconstructive surgery options for facial soft
tissue molding are limited particularly for residents in the United States.
Medical grade liquid injectible silicone is legally marketed in the U.S. as
an FDA-approved medical device although not explicitly approved for building
soft tissue. Other products are available in Europe but not FDA approved for
use in the United States. Clinical trials of these products are needed.
Satisfactory results are often dependent on the skill and experience of the
technician. The costs of many of these products are high. Difficulties are
often encountered in seeking medical reimbursement for these procedures and
the point of view that these procedures cannot be considered as simple
"cosmetic surgery" was presented. (editorial note: my take on Jones talk was
there is potential small risk with all these procedures. Many of the benefits
that result can fade after 6 or 12 months and procedures may have to be
repeated}.
David Giunti email: DGiu…@aol.community
What is the question? Gertrude Stein’s last words
No one mouth is big enough to utter the whole thing. Alan Watts
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