Disorders of body fat distribution in HIV-1-infected patients

Abstract

Body fat disorders are a common and relevant problem in HIV-1-infected patients that can be associated with metabolic alterations. Many controversies in their definition, pathogenesis, measurement, and management remain unclear. Several factors including HIV-1 infection itself and antiretroviral therapy have been associated with the development of these alterations. Most studies show that the action of drugs on the pathogenesis of lipoatrophy is undeniable. However, they also show that there are considerable differences not only between the different families of antiretroviral drugs, but also between the individual members of these families. The diagnosis of lipodystrophy is limited by the absence of an agreed definition and a reference for normality. Accurate diagnosis, especially in mild-moderate cases, is difficult, almost always subjective, not standardized, and cannot be carried out by a single method. In general, subjective evaluation by the physician and patient, together with simple techniques such as anthropometry, can provide highly valuable information, especially when used over time. Although there is no known therapy to completely reverse lipodystrophy once it becomes established, there is evidence that lipoatrophy can be partially improved by replacing thymidine analogs in certain cases. In addition, reparative surgery may prove useful in moderate or severe cases. Neither the interruption of antiretroviral therapy nor the use of metformin, glitazones or growth hormone analogs can be recommended due to their limited efficacy or associated complications.

Full text

AIDS Reviews. 2009;11
126
Disorders of Body Fat Distribution in HIV-1-Infected Patients
Santiago Moreno1, Celia Miralles2, Eugenia Negredo3, Pere Domingo4, Vicente Estrada5, Felix Gutiérrez6,
Fernando Lozano7 and Esteban Martínez8
1Hospital Ramón y Cajal, Madrid, Spain; 2Complejo Hospitalario Xeral de Vigo, Pontevedra, Spain; 3Hospital Universitari Germans Trias i
Pujol, Barcelona, Spain; 4Hospital de la Santa Creu i San Pau, Barcelona, Spain; 5Hospital Clínico Universitario, Madrid, Spain; 6Hospital
General Universitario de Elche, Alicante, Spain; 7Hospital Universitario de Valme, Seville, Spain; 8Hospital Clínic - Institut d’Investigaciones
Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
AIDS Rev. 2009;11:126-34
Correspondence to:
Esteban Martínez
Unidad de Enfermedades Infecciosas
Hospital Clínic, Universidad de Barcelona
Villarroel 170
08036 Barcelona, España
E-mail: esteban@fundsoriano.es
I
ntroduction
Body fat disorders are a common and relevant problem
in HIV-1-infected patients. Their clinical presentation in-
volves fat loss (lipoatrophy) and/or fat gain (lipohypertro-
phy) in different parts of the body. Lipoatrophy is usually
observed on the face, buttocks, and limbs, and lipohyper-
trophy generally presents as an accumulation of abdominal
visceral, dorsocervical, mammary, and/or suprapubic fat.
Disorders in the distribution of body fat associated with
HIV-1 infection must be differentiated from wasting syn-
drome and from the body changes associated with aging.
Wasting syndrome is characterized by a generalized loss
of body fat and lean mass. Aging may involve a reduction
in lean mass, and a redistribution of body fat with an in-
crease in the trunk and a reduction in the lower limbs1.
Anthropomorphic changes in HIV infection can be associ-
ated with various metabolic alterations, especially dyslipidemia
and insulin resistance, which are covered by the term “lipo-
dystrophy syndrome.” However, these conceptually different
processes can appear as clinically independent forms2.
These disorders are important because of the effect of
esthetic changes on a patient’s quality of life; the psychologi-
cal repercussions may affect the patient’s working and social
life and compromise adherence to therapy3. However, the
long-term consequences of cardiovascular risk stemming
from metabolic disorders must also be taken into account4.
Abstract
Body fat disorders are a common and relevant problem in HIV-1-infected patients that can be associated
with metabolic alterations. Many controversies in their definition, pathogenesis, measurement, and
management remain unclear. Several factors including HIV-1 infection itself and antiretroviral therapy
have been associated with the development of these alterations. Most studies show that the action of
drugs on the pathogenesis of lipoatrophy is undeniable. However, they also show that there are considerable
differences not only between the different families of antiretroviral drugs, but also between the individual
members of these families. The diagnosis of lipodystrophy is limited by the absence of an agreed definition
and a reference for normality. Accurate diagnosis, especially in mild-moderate cases, is difficult, almost
always subjective, not standardized, and cannot be carried out by a single method. In general, subjective
evaluation by the physician and patient, together with simple techniques such as anthropometry, can
provide highly valuable information, especially when used over time. Although there is no known
therapy to completely reverse lipodystrophy once it becomes established, there is evidence that lipoatrophy
can be partially improved by replacing thymidine analogs in certain cases. In addition, reparative
surgery may prove useful in moderate or severe cases. Neither the interruption of antiretroviral therapy
nor the use of metformin, glitazones or growth hormone analogs can be recommended due to their
limited efficacy or associated complications. (AIDS Rev. 2009;11:126-34)
Corresponding author: Esteban Martínez, esteban@fundsoriano.es
Key words
Lipoatrophy. Lipohypertrophy. HIV-1 infection. Antiretroviral therapy.
No part of this publication may be
reproduced or photocopying
without the prior written permission
of the publisher
© Permanyer Publications 2010

Santiago Moreno, et al.: Body Fat Disorders in HIV-1 Infection
127
Definition
Disorders of body fat distribution are difficult to define and
measure owing to the absence of “normality” references in
the general population, variability in clinical presentation, and
the lack of standardized, reproducible, and affordable meth-
ods of measuring regional fat. The current definition and
classification are based on the findings of a detailed physical
examination by the physician and the patient’s self-as-
sessment. In some cases, anthropometric measurements
and/or imaging may prove useful for follow-up.
Several attempts have been made to agree on an objective
case definition. A definition based on the following has been
put forward: demographic variables (sex, age), variables re-
lated to HIV-1 infection (duration and stage of infection), an-
thropometric variables (waist-hip index), biochemical variables
(anion gap, HDL cholesterol), and measurements by com-
puted tomography (CT) (ratio of visceral fat to subcutaneous
fat) and dual-energy x-ray absorptiometry (DXA) (ratio of trunk
fat to leg fat)5. This case definition is 80% accurate and more
sensitive than the usual clinical evaluation, both for diagnosis
and for assessment of the intensity of distribution disorders6.
In addition to being complex and requiring variables
from CT and DXA, this classification groups lipoatrophy
and lipohypertrophy under the common term “lipodystro-
phy.” Today, we know that the pathogenesis of each pro-
cess is different. In fact, there is consensus on classifying
body fat disorders into two clearly differentiated clinical
syndromes, i.e. fat loss or lipoatrophy, and fat accumula-
tion or lipohypertrophy2 (Table 1), although some patients
can present mixed conditions.
It may be useful to grade the intensity of clinical disorders
using a severity scale. The most well known is the Lipodystro-
phy Severity Grading Scale (LSGS) used in the HOPS (HIV
Outpatient Study)7 cohort, which, after observer- and patient-
based evaluation of the different areas, classifies lipodystro-
phy as mild, moderate, or severe. In order to clinically evalu-
ate facial lipoatrophy, Fontdevila, et al. have proposed a grade
classification based on the relief of facial bone and muscle
structures8. Starting from a normal situation in which the skin
in the malar region protrudes slightly from the orbit to the
nasogenial fold, grade I involves a flattening of malar relief,
grade II includes malar depression, and grade III is character-
ized by skeletization of the face with exposure of facial muscle,
especially the major zygomatic muscle. This classification has
been validated using CT, and has shown significant agree-
ment between different assessors on each of its grades9.
Pathogenesis
Lipoatrophy and lipohypertrophy have common risk fac-
tors2 and at least three are involved in their pathogenesis:
the patient, HIV-1 infection, and antiretroviral drugs.
The patient-related factors that have been associated with
the onset of lipoatrophy and lipohypertrophy are similar, if
not identical, and include age, sex, baseline body mass in-
dex (BMI), and ethnic group2. Furthermore, mutations in the
tumor necrosis factor (TNF) alpha-promoting gene and in
the interleukin 1 (IL) beta-promoting gene have been re-
ported to affect the incidence of lipoatrophic changes10,11.
However, the association of these mutations with the presence
of lipoatrophy has not been reproduced in the literature.
We have no direct evidence of the involvement of viral
factors in the pathogenesis of lipohypertrophy, although its
onset is similar to that of lipoatrophy in aspects of HIV-1 in-
fection such as CD4 levels, previous diagnosis of AIDS, and
the number of copies of HIV-1 RNA2. As for the action of the
virus on subcutaneous fat, reports on treatment-naive pa-
tients tell us that infection per se can increase expression of
anti-adipogenic and proinflammatory genes and reduce the
expression of pro-adipogenic genes and genes coding for
“trophic” adipocytokines (adiponectin and leptin)12.
Table 1. Classification of body fat distribution disorders associated with HIV-1 infection
Body fat distribution disorders classification
1. Fat loss (lipoatrophy) Face
Buttocks
Arms
Legs
2. Fat accumulation (lipohypertrophy) Abdominal obesity
Mammary hypertrophy
Accumulation of fat on the dorsal region of the neck
Accumulation of fat on the anterior region of the neck
Accumulation of fat on the side of the neck
Accumulation of fat on the suprapubic region
Localized or generalized lipoma
3. Mixed Alterations
No part of this publication may be
reproduced or photocopying
without the prior written permission
of the publisher
© Permanyer Publications 2010

AIDS Reviews. 2009;11
128
Most research into the pathogenesis of lipoatrophy and,
to a lesser extent, lipohypertrophy is based on in vitro or
ex vivo studies with patient fat samples. All these studies
show that the action of drugs on the pathogenesis of lipo-
atrophy is undeniable. However, they also show that there
are considerable differences not only between the different
families of antiretroviral drugs, but also between the indi-
vidual members of these families. Nucleoside reverse tran-
scriptase inhibitors (NRTI), especially thymidine analogs,
have been shown to act as mitochondrial toxins due to their
ability to inhibit DNA polymerase gamma, which is essential
for the replication and repair of mitochondrial DNA13. In
addition, NRTI have a negative effect on adipogenesis,
insulin sensitivity, and secretion of adipocytokines14,15. In
general, the same occurs with protease inhibitors (PI), al-
though with some differences: their effect is more intense
on adipocyte differentiation and less marked on mitochon-
drial function16. Furthermore, with the important exception
of atazanavir, PI have an effect on insulin sensitivity in which
GLUT4 glucose transporter channel inhibition plays a role16.
The confluence of the toxicity mechanisms of NRTI and of
PI could explain the additive, even synergistic, effects ob-
served in vivo when both classes are combined.
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
have traditionally been considered benign towards adipose
tissue. The recent results of a study involving efavirenz
(EFV) in the development of lipoatrophy17 have no solid
basis in experimental studies. Only one study shows the
anti-adipogenic effects of very high (greater than thera-
peutic) doses of EFV using a molecular mechanism simi-
lar to that reported for PI; that is, an effect by which there
is an alteration in the nuclear localization of sterol regula-
tory binding proteins18. There is no evidence of anti-adi-
pogenic effects of nevirapine on brown adipocytes19.
It is unknown whether fusion inhibitors have an effect on
adipocyte metabolism, and studies on the new antiretroviral
families have not yet been carried out. Nevertheless, integrase
inhibitors are not expected to have serious effects on the bio-
logical features of adipocytes due to the lack of similarity of
the cellular enzymes they act upon. The effect of CCR5
chemokine receptor agonists has not yet been investigated.
Knowledge of the pathogenesis of lipohypertrophy is limit-
ed. The exact mechanisms that lead to visceral adiposity are
mainly unknown, although antiretroviral drugs have been
shown to have characteristic effects on visceral and subcuta-
neous adipose tissue deposits20. Furthermore, in lipohypertro-
phy of dorsocervical tissue and in other areas of the body,
adipocytes have been observed to present a brown fat phe-
notype21. The analysis of gene expression in tissue samples
obtained from buffalo humps has revealed the absence of
traits of inflammation, whereas the low mitochondrial DNA
content and the presence of adipogenesis alteration markers
were similar to those observed in subcutaneous fat21. Further-
more, markers associated with a high state of proliferation
have been detected in the adipose tissue of buffalo humps.
Risk factors
Various studies have identified factors associated with
the development of body fat distribution disorders. These
factors are associated both with HIV-1 infection itself and
with the patient or antiretroviral therapy (Table 2).
As for those factors related to HIV-1 infection, only a few
studies have found an association between viral load and
a greater probability of developing lipodystrophy22,23. To a
great extent, it is unknown whether HIV-1 infection affects
development of this disorder, since the duration of HIV-infec-
tion is generally parallel to the duration of antiretroviral ther-
apy, and the effects of the two variables cannot be sepa-
rated. In the case-control study used for the case definition
of lipodystrophy, patients with this complication presented
a significantly greater duration of HIV-1 infection5.
As for patient-related factors, some authors have found
that age and CD4 count are significantly associated with the
development of body fat distribution disorders. Older age is
associated with the development of lipoatrophy and lipohy-
pertrophy, the lowest nadir of CD4 is associated with lipo-
atrophy, whereas the increase in CD4 count with therapy
has been associated with a greater risk of lipohypertrophy7.
There is no firm evidence that baseline nutritional status
has a significant effect on the onset of these changes,
although some studies have shown that patients with a great-
er BMI than normal (> 25 kg/m2) present a lower risk of li-
poatrophy and a greater risk of developing lipohypertrophy23.
Finally, although the existence of genetic factors is bio-
logically plausible, we do not yet know to what extent or
how these factors can affect the onset of the disorder10,11.
As for antiretroviral therapy, longer duration and prolonged
exposure to thymidine analogs, especially stavudine (d4T),
are associated with a greater risk of developing lipoatrophy
and lipohypertrophy2,24-28. The role of other antiretroviral
drugs is controversial, partly due to difficulties in establishing
causal relationships in combination regimens. In the nucleo-
side/nucleotide analog family, tenofovir (TDF) and abacavir
(ABC) have shown a beneficial effect on the recovery of
subcutaneous fat; therefore, they can be considered as hav-
ing low-risk for lipodystrophy. The importance of didanosine
(ddl) and lamivudine (3TC) or emtricitabine (FTC) in patho-
genesis is unknown, although it is generally considered low.
With regard to PI, prolonged therapy with indinavir or nelfi-
navir has been related to a greater probability of suffering
from lipoatrophy and lipohypertrophy, whereas preliminary
No part of this publication may be
reproduced or photocopying
without the prior written permission
of the publisher
© Permanyer Publications 2010

Santiago Moreno, et al.: Body Fat Disorders in HIV-1 Infection
129
data with PI boosted with low-dose ritonavir (saquinavir,
atazanavir, lopinavir, tipranavir, darunavir) seem to show
that they represent a lower risk of developing lipodystrophy.
As mentioned above, most studies with EFV and nevirapine
show that NNRTI have a neutral effect. It has even been
observed that prolonged use (> 1 year) of these drugs is
associated with a lower probability of developing lipo-
dystrophy29. In one study, the use of thymidine analogs
with EFV was associated with a greater incidence of lipo-
atrophy (defined as a limb fat loss of at least 20%) than the
same combination with lopinavir/ritonavir (LPV/r)17. How-
ever, this initial finding has been called into question due
to the arbitrariness of the definition of lipoatrophy used,
the lack of correlation between the definition and the clin-
ical diagnosis of lipoatrophy, and the role of several inde-
pendent risk factors in fat loss detected by DXA30. In
addition, one study of the specific effect on adipose tissue
of different antiretroviral drugs has confirmed that the
depletion of mitochondrial DNA and the pathological find-
ings of lipoatrophy are specifically associated with thymi-
dine analogs. No association was found with the non-an-
alogs (EFV) or protease inhibitors (LPV) evaluated31.
Diagnosis
The diagnosis of lipodystrophy is limited by the absence
of an agreed definition and a reference for normality. The
ideal method for evaluating body composition should be
accurate, user-friendly, cheap, fast, reproducible, and
harmless. Currently available methods (Table 3) fulfill only
a few of these requirements and, therefore, the choice of
one or the other will depend first on accessibility and
availability, and later on the information we want to obtain,
the type of study, and the number of patients.
Methods for the evaluation
of body composition
Anthropometry is widely used in clinical practice and
epidemiological studies. Skin fold thickness is measured
using standardized techniques. The tricipital fold alone
shows the best correlation with total fat in the general pop-
ulation. Fat mass can be calculated using different equa-
tions constructed from the sum of several folds that are
representative of fat thickness in different body segments.
The most widely used and validated is the Durnin-Womer-
sley equation, which includes the bicipital, tricipital, sub-
scapular, and suprailiac folds34,35. Anthropometry is sim-
ple, noninvasive, and affordable, but its greatest limitation
lies in the wide differences in the fat distribution pattern.
Some attempts have been made to validate ultrasound
for the assessment of subcutaneous adipose tissue (SAT)
in several localizations (abdomen, face, arms), but the
results have been disparate. Although attractive because
of its speed, innocuousness, low price, and convenience
for the patient, this technique requires the presence of an
experienced examiner37. Although it has not been widely
evaluated, some recent studies have shown acceptable
inter- and intra-observer variability and a good correlation
with CT when used for the evaluation of intraabdominal fat
and leg fat thickness, but not for the evaluation of subcu-
taneous abdominal, arm and facial fat38. Computed to-
mography and, to a lesser extent, magnetic resonance
imaging (MRI), have been used since the 1980s to mea-
sure abdominal fat by a slice at L4, with a considerable
predictive value in total adipose tissue39.
Bioelectric impedance analysis (BIA) brings together
many of the characteristics of the ideal method (ease of
use, innocuousness, and reproducibility), although it lacks
Table 2. Risk factors for the development of body fat distribution disorders in HIV-1-infected patients receiving antiretroviral therapy
Risk factors for the development of body fat distribution disorders
Patient-related factors Age
Sex
Body mass index
Ethnic group
Genetic factors
Factors related to HIV-1 infection Duration of infection
AIDS diagnosis
CD4+ lymphocyte count
Viral load
Factors related to antiretroviral therapy Duration of therapy
Treatment with thymidine analogs
Treatment with protease inhibitors
Treatment with non-nucleoside analogs (?)
Other factors Treatment with other drugs
No part of this publication may be
reproduced or photocopying
without the prior written permission
of the publisher
© Permanyer Publications 2010

AIDS Reviews. 2009;11
130
the accuracy of the reference methods. In addition, BIA
calculates total fat with no specific information on the dif-
ferent fat compartments. Furthermore, the redistribution of
fat itself affects the calculation of the total fat component.
Therefore, measurement of total fat by BIA is even less
accurate in the presence of lipodystrophy40.
One of the most novel diagnostic techniques is DXA,
which allows us to evaluate body composition by separating
the lean mass and fatty mass components of soft tissue. It
is very accurate in stable subjects (± 99%). Its main limita-
tions, aside from the high installation cost and the need for
specialized personnel, are the progressive increase in errors
with corpulence and the difficulty to detect sudden changes
in body composition (e.g. alterations to hydration). Despite
the fact that it is currently considered the gold standard for
evaluation of total fat, its limitations must be taken into ac-
count and further studies are necessary33,40. Unfortunately,
there is no simple correlation between the objective measure-
ment of body fat using techniques such as DXA and the
subjective diagnosis of lipoatrophy. This lack of agreement
was made obvious in a recent study in which lipoatrophy was
defined arbitrarily as a loss of at least 20% in limb fat and in
which this objective diagnosis showed very little correlation
with clinical lipoatrophy as perceived by the patient30. In
fact, further studies have shown that fat loss greater than
35% may be necessary to become clinically evident32.
None of the methods mentioned above for calculating
total fat can distinguish changes in each of the compart-
ments and, therefore, any evaluation of fat redistribution
requires the use of several complementary methods33.
Evaluation of central fat accumulation
or lipohypertrophy
Subjective evaluation by the patient and the physician
using a systematic questionnaire continues to be the most
useful method in clinical practice7,33,34. As for anthropom-
etry, the waist-hip index is the most widely accepted indi-
cator of anomalous fat distribution. Abdominal obesity is
defined as an index greater than 0.9 in men and 0.8 in
women. However, several aspects limit its accuracy: the
different measuring points used, the absence of a waist
measurement in obese subjects, and the size of abdomi-
nal organs and muscles. Measurement of isolated folds or
circumferences may be useful when used over time35,36.
Echography is a simple technique that has shown a good
correlation with other techniques, such as CT, for the mea-
surement of intraabdominal fat37,38. Nevertheless, the re-
sults depend on the expertise of the operator and can be
affected by the presence of intraluminal gas or in obese
patients37. Computed tomography is one of the best meth-
ods for measuring the components of abdominal fat. Only
one slice is used (at L4, approximately at the level of the
navel). Several studies have shown that this is the only slice
with a high correlation with multiple slices and lower radia-
tion and examination time. Its main limitations are cost,
radiation, the need for specialized personnel, and limited
availability33,40. Although MRI does not use ionizing radiation,
it is more expensive, examination time is longer, and it de-
limits visceral fat less accurately40. Although DXA is increas-
ingly used for the segmental study of fat, (i.e. to evaluate the
relationship between trunk fat and limb fat), there are few
validation studies. In addition, some limitations should be
taken into account: it is difficult to delimit soft tissue over
bone, with the result that its composition is extrapolated from
neighboring tissue, and it does not allow measurement of the
different abdominal fat components33,40.
Evaluation of lipoatrophy
Although the loss of facial fat is the most stigmatizing
external sign that most worries patients with lipodystrophy,
there is still no standardized accurate diagnosis. As is the
case with central accumulation, subjective evaluation by
the patient and physician using a systematic question-
naire continues to be the most useful method in clinical
practice for evaluating facial lipoatrophy7,33,34,41. The vari-
able results obtained with anthropometry and echography
reflect the lack of data in the general population and the
absence of a gold standard. Some researchers have ob-
served a good correlation between subcutaneous fat mea-
surement using echography and other methods of diag-
nosing lipoatrophy38,40, although these results have not
been uniform for other investigators41. In several studies,
single-slice CT and MRI have proven to be reproducible
and able to differentiate between patients with and without
lipoatrophy. They also have a high correlation with the loss
of subcutaneous fat evaluated by other standard meth-
ods40,42. Finally, novel techniques such as laser scan or
3-dimensional photography are cheap and easy to perform
Table 3. Useful diagnostic methods for measurement of
body composition and body fat disorders
Diagnostic methods
Anthropometric measurements
Echography
Bioelectric impedance analysis
Computed tomography
Magnetic resonance
Double-energy x-ray absorptiometry
Laser scan
No part of this publication may be
reproduced or photocopying
without the prior written permission
of the publisher
© Permanyer Publications 2010

Santiago Moreno, et al.: Body Fat Disorders in HIV-1 Infection
131
and are reasonably able to distinguish affected patients43.
However, experience is limited and large-scale validation
studies are necessary.
In conclusion, accurate diagnosis of lipodystrophy, espe-
cially in mild-moderate cases, is difficult, almost always sub-
jective, not standardized, and cannot be carried out by a
single method. For lipoatrophy, baseline evaluation is impor-
tant, as is early, even subclinical diagnosis. In general terms,
subjective evaluation by the physician and patient together
with simple techniques such as anthropometry can provide
highly valuable information, especially when used over
time. The use of more complex methods is limited to clinical
trials or studies for pathogenic and reversibility analyses for
which highly accurate techniques are necessary.
Prevention
Prevention of lipoatrophy
This strategy is very important for patients about to initiate
antiretroviral therapy as there is no known therapy to com-
pletely reverse this condition once it becomes established.
In recent years, the number of new cases of lipoatrophy has
fallen due to the choice of drugs, and, more specifically,
certain NRTI such as TDF and ABC, which are less harmful
for SAT. This choice is based on wide evidence that regimens
containing zidovudine (ZDV) or d4T induce lipoatrophy with
a greater frequency than those containing TDF or ABC.
Randomized clinical trials of initial regimens have clear-
ly shown the advantages of avoiding thymidine analogs.
Studies comparing TDF with d4T or AZT as initial therapy
have consistently shown a gain in limb fat content mea-
sured by DXA and scarce development of lipoatrophy in
patients taking TDF, in contrast with the limb fat loss ob-
served in those taking AZT or d4T44,45. These results are
supported by the metabolic subanalysis of a large clinical
trial with three treatment arms (EFV + two NRTI, LPV/r +
two NRTI, and EFV + LPV/r), in which lipoatrophy was
defined as a reduction of 20% or more in the adipose tis-
sue of the limbs measured by DXA17. Randomization was
stratified on the basis of the choice of NRTI, so a suitable
balance between the arms was reached. The frequency
of lipoatrophy at week 96 was considerably greater in
patients receiving d4T (42%) or ZDV (27%) than in those
taking TDF (9%). The frequency of lipoatrophy in the latter
was very similar to that of patients on the NRTI-sparing
EFV + LPV/r regimen (8%), yet another argument in favor
of the innocuousness of TDF with regard to peripheral
fat17. Similar data have been obtained in two clinical trials
comparing ABC with d4T. These studies, which used ob-
jective baseline values for measuring body fat, showed
that the patients treated with ABC gained limb fat, where-
as, once again, those treated with d4T lost fat46,47.
Protease inhibitors can also affect SAT, although there
is some variability between them. Clinical trials have pro-
vided different results. In study ACTG384, patients treated
with nelfinavir showed significant peripheral fat loss by
DXA (–13.1%) compared with those who took EFV
(+1.8%)48. Nevertheless, in a subanalysis of study BMS034,
in which sequential examinations with CT and DXA were
made, there were no significant changes in subcutaneous
body fat with atazanavir or EFV after one year of treatment49.
The NNRTI are not generally considered to be associ-
ated with peripheral lipoatrophy. This assessment is based
on clinician’s perception after long-term and widespread
use of NNRTI, as well as on results of several controlled
clinical trials and cohort studies. Recent data from the
aforementioned study ACTG5142 are therefore very
surprising. The prevalence of subclinical fat loss in that
study was greater in patients from the EFV + two NRTI
group than in those from the LPV/r + two NRTI group. The
DXA findings did, however, not correlate with clinically
observed lipo atrophy30. Other recent data from a study
evaluating an induction strategy with LPV/r + ZDV/3TC
followed by a maintenance regimen with LPV/r in mono-
therapy compared with a standard regimen of EFV +
ZDV/3TC are less meaningful to answer this question as
patients in the maintenance phase on LPV/r monotherapy
had no long-term exposure to ZDV, which as discussed
above is associated with lipoatrophy. The patients treated
with the ZDV-containing EFV regimen presented a sig-
nificantly lower limb fat content in the 96-week DXA than
those of the LPV/r group as a whole (triple therapy plus
monotherapy)50. In contrast, another recent long-term
study (extension of study CRPCRA016 up to five years) saw
no significant differences in body fat changes measured
by both anthropometry and bioelectrical impedance between
the three antiretroviral strategies compared (PI + two
NRTI, NNRTI + two NRTI, and PI + NNRTI)51.
In summary, an association between lipoatrophy and
thymidine analogs seems established, while non-thymi-
dine NRTI , PI, and NNRTI seem less so.
Prevention of lipohypertrophy
Contrary to the situation with lipoatrophy, and consistent
with the fact that it has not been possible to establish an
association between the development of trunk lipohyper-
trophy and certain drugs or drug classes, no therapeutic
strategy to prevent this condition is known. Furthermore,
although it is reasonable to think that suitable diet and
physical exercise can help to prevent lipohypertrophy, this
No part of this publication may be
reproduced or photocopying
without the prior written permission
of the publisher
© Permanyer Publications 2010

AIDS Reviews. 2009;11
132
has not yet been demonstrated in patients who already
have established disease and in whom abdominal fat con-
tent and hypertriglyceridemia fall slightly52.
Treatment
Medical treatment
Since the first descriptions of lipodystrophy, several strate-
gies based on the state of the art have been tried, with vary-
ing success rates. The first therapeutic strategy proposed,
based on the belief that PI were the only agents responsible
for the disease, was substitution of the PI with an NNRTI53-55.
Unfortunately, simply switching a PI for an analog did not
lead to significant improvement in morphological changes.
It was subsequently shown that NRTI were involved in the
pathogenesis of lipodystrophy through mitochondrial dys-
function. In vitro results showing a different affinity of analogs
for gamma polymerase led to clinical trials. The resultant
strategy was substitution of thymidine analogs (AZT or d4T),
which were associated with greater mitochondrial toxicity,
by other less toxic drugs. One of the first and most repre-
sentative studies, MITOX, showed a significant recovery of
subcutaneous limb fat after replacing the thymidine analog
with ABC56. Equally favorable results were published after
thymidine analogs were replaced by TDF57,58.
The same pathogenic mechanism was used as an argu-
ment in favor of withdrawing nucleosides and using nu-
cleoside-sparing regimens by combining a PI/r with a
NNRTI17,59,60 or PI/r in monotherapy (mainly LPV/r)61. Cur-
rent data suggest a favorable effect, although there are
few studies and the regimens used are frequently associ-
ated with dyslipidemia and problems of immediate or di-
gestive tolerance. There are no data to allow us to make
a recommendation on avoiding NNRTI or whether they
should be replaced. Finally, and contrary to expectations,
results from studies examining complete interruption of
therapy have been controversial, and interruptions are not
currently recommended under any circumstances62-64.
Parallel to this, insulin resistance and the subsequent
accumulation of central fat attributed to therapy with some
PI mean that co-adjuvant treatments have been proposed
to reverse lipohypertrophy. Insulin-sensitizing agents (thi-
azolidinediones) can correct PI-associated insulin resis-
tance and reverse visceral obesity as does metformin. Hor-
mone treatments, such as testosterone or growth hormone,
have been analyzed in several clinical trials with the same
objective. However, the limited results obtained in most
studies65, together with the not insignificant toxicity they are
often associated with66, do not speak in favor of generalized
use of these treatments to reverse lipodystrophy.
Lastly, promising preliminary results have been obtained
with investigational drugs such as uridine67, leptin68, or
growth hormone analog69. In addition to changes in
therapy, there is no doubt that changes to lifestyle and
diet can be included among the recommendations for the
patient with lipodystrophy. A healthy diet with calorie
restrictions plus exercise can help to reduce some grades
of lipohypertrophy52,70.
Surgical treatment
Despite the above observations, in recent years we
have had to turn to plastic surgery as an alternative to
palliate lipodystrophy in those cases where changes in
body fat are well established and have significantly re-
duced the patient’s quality of life. Therefore, different tech-
niques have been proposed, depending mainly on wheth-
er there is a loss or accumulation of body fat.
Ultrasonic liposuction is used to treat buffalo hump,
gynecomasty, increased abdominal contour, or lipomas
located in other areas. This technique provides more sat-
isfactory results than those of conventional liposuction,
with fewer local postoperative complications. Neverthe-
less, relapse has been reported in up to 15% of cases71.
Surgical resection and breast reduction could be indi-
cated when fat deposits are localized.
Fat loss in the buttocks can be repaired using silicone
gluteal prostheses, with satisfactory results, although im-
plantation requires admission to hospital, has a painful
postoperative period, and is not free from complications.
This technique is not recommended for most patients with
gluteal lipoatrophy, only in those who complain of diffi-
culty sitting down or who present trophic cutaneous dis-
orders. Lastly, facial atrophy, undoubtedly the most stig-
matizing sign, has been treated with several filling products
such as autologous fat or synthetic substances. Infiltration
of autologous fat can provide lasting results (at least more
than one year)72. Its advantages over synthetic materials
are the low risk of infection or rejection and the lower cost.
Its disadvantage is that a large proportion of patients with
lipoatrophy do not have sufficient fat to donate. It is not
advisable to use fat from the buffalo hump, since it can
lead to lipohypertrophy in the area where it is implanted73.
In addition to autologous fat, several synthetic products
are available as fillers. The main difference between them
is their durability, and, consequently, the greater or lesser
need for subsequent adjustments. The use of permanent
synthetic fillers should be recommended with caution:
their results can be unsatisfactory due to the natural mod-
ification of the facial contour with time, and any complica-
tion that arises may be very difficult to treat. The most
No part of this publication may be
reproduced or photocopying
without the prior written permission
of the publisher
© Permanyer Publications 2010

Santiago Moreno, et al.: Body Fat Disorders in HIV-1 Infection
133
widely used reabsorbable implants are polylactic acid and
hyaluronic acid, whereas the most widely used permanent
implants are polyacrylamides and polyalkylimides73-76.
To conclude, there is clear evidence that lipoatrophy
can be improved by replacing thymidine analogs in cer-
tain cases, although this improvement is slow and limited.
Similarly, lifestyle changes must be recommended to all
patients as they are easy, universally accessible, and bene-
ficial for the patient’s general health. Reparative surgery
may prove useful in moderate or severe cases where the
patient requests it. However, neither the interruption of
antiretroviral therapy nor the use of metformin, glitazones, or
growth hormone to treat lipodystrophy can be recommended
due to their limited efficacy or associated complications.
Furthermore, there is little information on the role of nucleo-
side-sparing regimens or the use of uridine, leptin, or growth
hormone analogs in the treatment of lipodystrophy.
Members of the “HIV Body Fat
Distribution Workgroup”
Aguirrebengoa K, Hospital de Cruces, Barakaldo (Biz-
kaia); Asensi V, Hospital Universitario Central de Asturias,
Oviedo; Blanco F, Hospital Carlos III, Madrid; Del Pozo M,
Hospital Clínico Universitario, Valladolid; Galindo P, Hos-
pital Clínico Universitario, Valencia; Knobel H, Hospital del
Mar, Barcelona; López Aldeguer J, Hospital Universitari
La Fe, Valencia; Palacios R, Hospital Universitario Virgen
de la Victoria, Málaga; Pedrol E, Hospital General de
Granollers, Granollers (Barcelona); Pérez-Elías Mª J, Hospital
Ramón y Cajal, Madrid; Podzamczer D, Hospital Univer-
sitario de Bellvitge, Barcelona; Ribera E, Hospital Universi-
tari Vall d’Hebrón, Barcelona; Rivero A, Hospital Reina
Sofía, Córdoba; Sanz J, Hospital Príncipe de Asturias,
Alcalá de Henares (Madrid); Suárez I, Hospital Infanta
Elena, Huelva; Viciana P, Hospital Universitario Virgen del
Rocío, Seville.
Acknowledgements
The organization of the meetings was supported by
Bristol-Myers Squibb.
Disclosures
Both, Dr. Esteban Martinez and Dr. Santiago Moreno
have been involved in speaking activities and/or have
received research grants from Abbott, Boehringer Ingelheim,
Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen
Cilag, Merck Sharp & Dohme, Roche, and Schering
Plough.
References
1. Schwartz R, Shuman W, Bradbury V, et al. Body fat distribution in healthy
young and older men. J Gerontol. 1990;45:181-5.
2. Lichtenstein K. Redefining lipodystrophy syndrome: risks and impact on
clinical decision making. J Acquir Immune Defic Syndr. 2005;39:395-400.
3. Marín A, Casado J, Aranzabal L, et al. Validation of a specific question-
naire on psychological and social repercussions of the lipodystrophy
syndrome in HIV-infected patients. Qual Life Res. 2006;15:767-75.
4. Friis-Møller N, Weber R, Reiss P, et al. Cardiovascular disease risk fac-
tors in HIV patients--association with antiretroviral therapy. Results from
the DAD study. AIDS. 2003;17:1179-93.
5. Carr A, Emery S, Law M, et al. An objective case definition of lipodystrophy
in HIV-infected adults: a case-control study. Lancet. 2003;361:726-35.
6. Law M, Puls R, Cheng AK, et al. Evaluation of the HIV lipodystrophy case
definition in a placebo-controlled, 144-week study in antiretroviral-naive
adults. Antivir Ther. 2006;11:179-86.
7. Lichtenstein K, Delaney K, Armon C, et al. Incidence of and risk factors
for lipoatrophy (abnormal fat loss) in ambulatory HIV-1-infected patients.
J Acquir Immune Defic Syndr. 2003;32:48-56.
8. Fontdevila J, Martínez E, Rubio-Murillo J, et al. A practical classification for
the surgical filling of facial lipoatrophy. Antiv Ther. 2005;10:28 [abstract].
9. Fontdevila J, Berenguer J, Prades E, et al. Validation of a simple clas-
sification for facial lipoatrophy in HIV-infected adults. In: Abstracts of the
9th International Workshop on Adverse Drug Reactions and Lipodystro-
phy in HIV; July 2007, Sydney, Australia [abstract P-18].
10. Nolan D, Moore C, Castley A, et al. Tumour necrosis factor-alpha gene
-238G/A promoter polymorphism associated with a more rapid onset of
lipodystrophy. AIDS. 2003;17:121-3.
11. Asensi V, Rego C, Montes A, et al. IL-1β (+3954C/T) polymorphism could
protect HIV-infected patients on HAART against lipodystrophic syn-
drome. Genet Med. 2008;10:215-23.
12.
Giralt M
,
Domingo P
,
Guallar J
,
et
al. HIV-1 infection alters gene
expression in adipose tissue, which contributes to HIV- 1/HAART-asso-
ciated lipodystrophy. Antivir Ther. 2006;11:729-40.
13.
Gerschenson M
,
Brinkman K
. Mitochondrial dysfunction in AIDS and
its treatment.
Mitochondrion. 2004;4:763-77.
14.
Jan V
,
Cervera P
,
Maachi M
, et al. Altered fat differentiation and
adipocytokine expression are inter-related and linked to morphological
changes and insulin resistance in HIV-1-infected lipodystrophic patients.
Antivir Ther. 2004;9:555-64.
15.
Ledru E
,
Christeff N
,
Patey O
, et al. Alteration of tumor necrosis
factor-alpha T-cell homeostasis following potent antiretroviral therapy:
contribution to the development of HIV-associated lipodystrophy syn-
drome.
Blood. 2000;95:3191-8.
16.
Noor M
,
Flint O
,
Maa J
, et al. Effects of atazanavir/ritonavir and lopi-
navir/ritonavir on glucose uptake and insulin sensitivity: demonstrable
differences in vitro and clinically.
AIDS. 2006;20:1813-21.
17. Haubrich R, Riddler S, DiRienzo G, et al
.
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
. 14th CROI. Los Angeles, 2007 [abstract 38].
18.
El Hadri K
,
Glorian M
,
Monsempes C
, et al. In vitro suppression of
the lipogenic pathway by the nonnucleoside reverse transcriptase in-
hibitor efavirenz in 3T3 and human preadipocytes or adipocytes.
J Biol
Chem. 2004;279:15130-41.
19. Rodríguez de la Concepción M, Iglesias R, Yubero P, et al. Uncoupling
protein and brown adipocyte mitochondrial as potential targets of re-
verse transcriptase inhibitor-induced lipodystrophy. Proceedings of the
XIV International AIDS Conference; 185-9.
20. Cianflone K, Zakarian R, Stanculescu C, et al.
Protease inhibitor effects
on triglyceride synthesis and adipokine secretion in human omental
and subcutaneous adipose tissue. Antivir Ther.
2006;
11
:681-91.
21. Guallar J, Gallego J, Domingo J, et al. Differential gene expression
analysis indicates that “buffalo hump” is a distinct adipose tissue distur-
bance in HIV-1/HAART-associated lipodystrophy. AIDS. 2008;22:575-84.
22. Arpadi S, Cuff P, Horlick M, et al. Lipodystrophy in HIV-infected children
is associated with high viral load and low CD4+ -lymphocyte count and
CD4+- lymphocyte percentage at baseline and use of protease inhibitors
and stavudine. J Acquir Immune Defic Syndr. 2001;27:30-4.
23. Nguyen A, Calmy A, Schiffer V, et al. Lipodystrophy and weight chang-
es: data from the Swiss HIV Cohort Study, 200-2006. HIV Med. 2008;
9:142-50.
24. Galli M, Cozzi-Lepri A, Ridolfo A, et al. Incidence of adipose tissue al-
terations in first-line antiretroviral therapy: the LipoICoNa Study. Arch
Intern Med. 2002;162:2621-8.
25. Mauss S, Corzillius M, Wolf E, et al. Risk factors for the HIV-associated
lipodystrophy syndrome in a closed cohort of patients after 3 years of
antiretroviral treatment. HIV Med. 2002;3:49-55.
26. Tsiodras S, Mantzoros C, Hammer S, et al. Effects of protease inhibitors
on hyperglycemia, hyperlipidemia, and lipodystrophy: A 5-year cohort
study. Arch Intern Med. 2000;160:2050-6.
No part of this publication may be
reproduced or photocopying
without the prior written permission
of the publisher
© Permanyer Publications 2010

AIDS Reviews. 2009;11
134
27. Seminari E, Tinelli C, Minoli L, et al. Evaluation of the risk factors associ-
ated with lipodystrophy development in a cohort of HIV-positive patients.
Antivir Ther. 2002;7:175-80.
28. Joly V, Flandre P, Meiffredy V, et al. Increased risk of lipoatrophy under
stavudine in HIV-1-infected patients: results of a substudy from a com-
parative trial. AIDS. 2002;16:2447-54.
29. Bacchetti P, Gripshover B, Grunfeld C, et al. Fat distribution in men with
HIV infection. J Acquir Immune Defic Syndr. 2005;40:121-31.
30. Haubrich R, Riddler S, DiRienzo G, et al. Clinical associations of extrem-
ity fat loss: ACTG 5142, a prospective, randomized, phase III trial of
NRTI-, PI-, and NNRTI-sparing regimens for ART of naive, HIV-1-infected
subjects. 15th CROI. Boston, 2008 [abstract 935].
31. Hammond E, McKinnon B, Pace C, et al. Influence of NRTI choice and
efavirenz vs lopinavir treatment options on lipoatrophy-associated adi-
pose tissue toxicity: a longitudinal study. 15th CROI. Boston, 2008 [ab-
stract 939].
32. Podzamczer D, Ferrer E, Martinez E, et al. How much fat loss is needed
for lipoatrophy to become clinically evident? 15th CROI. Boston, 2008
[abstract 941].
33. Carr A, Law M. An objective lipodystrophy severity grading scale derived
from the lipodystrophy case definition score. J Acquir Immune Defic
Syndr. 2003;33:571-6.
34. Kotler D, Rosenbaum K, Wang J, et al. Studies of body composition and
fat distribution in HIV-infected and control subjects. J Acquir Immune
Defic Syndr Hum Retrovirol. 1999;20:228-37.
35. AACTG Fat Redistribution Focus Group. Diagnostic criteria for abnor-
malities of fat distribution. In:
http://www.aactg.org/files/fatsum.pdf
.
Accessed January 23, 2008.
36. Palella F, Cole S, Chmiel J, et al. Anthropometrics and examiner-report-
ed body habitus abnormalities in the multicenter AIDS cohort study. Clin
Infect Dis. 2004;38:903-7.
37. Martínez E, Bianchi L, García-Viejo M, et al. Sonographic assessment of
regional fat in HIV-1-infected people. Lancet. 2000;356:1412-3.
38. Padilla S, Gallego J, Masiá M, et al. Ultrasonography and anthropometry
for measuring regional body fat in HIV-infected patients. Curr HIV Res.
2007;5:459-66.
39. Kotler D, Wang J, Pierson R. Body composition studies in patients with the
acquired immunodeficiency syndrome. Am J Clin Nutr. 1985;42:1255-65.
40. Wanke C, Polsky B, Kotler D. Guidelines for using body composition
measurement in patients with HIV infection. AIDS Patient Care STDS.
2002;16:375-88.
41. Carey D, Wand H, Martin A, et al. Evaluation of ultrasound for assessing
facial lipoatrophy in a randomized, placebo-controlled trial. AIDS.
2005;19:1325-7.
42. Padilla S, Gallego J, Masiá M, et al. Single-slice computed tomography
and anthropometric skinfold analysis for evaluation of facial lipoatrophy
in HIV-infected patients. Clin Infect Dis. 2004;39:1848-51.
43. Yang Y, Sitoh Y, Oo Tha N, et al. Facial fat volume in HIV-infected pa-
tients with lipoatrophy. Antivir Ther. 2005;10:575-81.
44. Gallant J, Staszewski S, Pozniak A, et al. Efficacy and safety of tenofovir
DF vs stavudine in combination therapy in antiretroviral- naïve patients:
a 3-year randomized trial. JAMA. 2004;292:191-201.
45. Pozniak A, Gallant J, DeJesus E, et al. Tenofovir disoproxil fumarate,
emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine
and efavirenz in antiretroviral-naïve patients. Virologic, immunologic, and
morphologic changes: a 96-week analysis. J Acquir Immune Defic
Syndr. 2006;43:535-40.
46. Podzamczer D, Ferrer E, Sanchez P, et al. Less lipoatrophy and better
lipid profile with abacavir as compared to stavudine. 96-week results of
a randomized study. J Acquir Immune Defic Syndr. 2007; 44:139-47.
47. Shlay J, Visnegarwala F, Bartsch G, et al. Body composition and meta-
bolic changes in antiretroviral-naive patients randomized to didanosine
and stavudine versus abacavir and lamivudine. J Acquir Immune Defic
Syndr. 2005;38:147-55.
48. Dubé M, Parker R, Tebas P, et al. Glucose metabolism, lipid, and body
fat changes in antiretroviral-naïve subjects randomized to nelfinavir or
efavirenz plus dual nucleosides. AIDS. 2005;19:1807-18.
49. Jemsek J, Arathoon E, Arlotti M, et al. Body fat and other metabolic
effects of atazanavir and efavirenz, each administered in combination
with zidovudine plus lamivudine, in antiretroviral-naive HIV-infected pa-
tients. Clin Infect Dis. 2006;42:273-80.
50. Cameron D, da Silva B, Arribas J, et al. Significant sparing of periph-
eral lipoatrophy by HIV treatment with LPV/r + ZDV/3TC induction fol-
lowed by LPV/r monotherapy compared with EFV + ZDV/3TC. Program
and abstracts of the 14th CROI 2007. Los Angeles [abstract 44].
51. Shlay J, Bartsch G, Peng G, et al. Long-term body composition and
metabolic changes in antiretroviral naïve persons randomized to pro-
tease inhibitor-, nonnucleoside reverse transcriptase inhibitor-, or pro-
tease inhibitor plus nonnucleoside reverse transcriptase inhibitor-based
strategy. J Acquir Immune Defic Syndr. 2007;44:506-16.
52. Jones S, Doran D, Leatt P. Short-term exercise training improves body
composition and hyperlipidemia in HIV-positive individuals with lip-
odystrophy. AIDS. 2001;15:2049-51.
53. Raffi F, Bonnet B, Ferre V, et al. Substitution of a nonnucleoside reverse
transcriptase inhibitor for a protease inhibitor in the treatment of pa-
tients with undetectable plasma HIV-1 RNA. Clin Infect Dis.
2000;31:1274-8.
54. Ruiz L, Negredo E, Domingo P, et al. Antiretroviral treatment
simplification with nevirapine in protease inhibitor-experienced
patients with HIV-associated lipodystrophy: 1-year prospective
follow-up of a multicenter, randomized, controlled study. J Acquir
Immune Defic Syndr. 2001;27:229-36.
55. Martinez E, Arnaiz J, Podzamczer D, et al. Nevirapine, Efavirenz, and
Abacavir (NEFA) Study Team. Substitution of nevirapine, efavirenz, or
abacavir for protease inhibitors in patients with HIV infection. N Engl J
Med. 2003;349:1036-46.
56. Carr A, Workman C, Smith D, et al. Abacavir substitution for nucleoside
analogs in patients with HIV lipodystrophy: a randomized trial. JAMA.
2002;288:207-15.
57. Moyle G, Sabin C, Cartledge J, et al. A randomized comparative trial of
tenofovir DF or abacavir as replacement for a thymidine analogue in
persons with lipoatrophy. AIDS. 2006;20:2043-50.
58. Moyle G, et al. Switching from Combivir to Truvada preserves limb fat:
Results of a DEXA sub-study of the 48 week randomized study. Proceed-
ings of the 15th CROI 2008. Boston [abstract 938].
59. Murphy R, Zhang J, Hafner R, et al. Peripheral and visceral fat changes
following a treatment switch to a nonthymidine analogue or nucleoside-
sparing regimen in patients with peripheral lipoatrophy: 48-week final
results of ACTG a5110, a prospective, randomized multicenter clinical
trial. 13th CROI 2006, Denver [abstract 755].
6 0. Viciana P, Lopez-Cortés L, Alarcón A, et al.
Facial lipoatrophy associated
with HAART: usefulness of cheek measure and factors associated.
Program and abstracts of the 14th CROI, 2007. Chicago [abstract 645].
61. Arribas J, Pulido F, Delgado R, et al. Lopinavir/ritonavir as single-drug
therapy for maintenance of HIV-1 viral suppression: 48-week results of
a randomized, controlled, open-label, proof-of-concept pilot clinical trial
(OK Study). J Acquir Immune Defic Syndr. 2005;40:280-7.
62. Hatano H, Miller KD, Yoder CP. Metabolic and anthropometric conse-
quences of interruption of highly active antiretroviral therapy. AIDS.
2000;14:1935-42.
63. Milinkovic A, Martínez E, Vidal S, et al. The effect of structured therapy
interruptions on the evolution of plasma lipids and body fat in patients
with primary HIV-1 infection. Abstract O-8. 3rd European Workshop on
Lipodystrophy and Metabolic Disorders. Marbella, Spain 2002.
64. The Strategies for Management of Antiretroviral Therapy (SMART) Study
Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl
J Med. 2006;355:2283-96.
65. Waters L, Nelson M. Long-term complications of antiretroviral therapy:
lipoatrophy. Int J Clin Pract. 2007;61:999-1014.
66. Nissen S, Wolski K. Effect of rosiglitazone on the risk of myocardial in-
farction and death from cardiovascular causes. N Engl J Med. 2007;
356:2457-71.
67. Walker U, Venhoff N, Koch E, et al.
Uridine abrogates mitochondrial
toxicity related to nucleoside analogue reverse transcriptase in-
hibitors in HepG2 cells. Antivir Ther.
2003
;8:463-70.
68. Mulliga K, Khatami H, Schwarz J, et al. Improvements in hepatic and
adipocyte insulin sensitivity, dyslipemia, and visceral fat during leptin
treatment in HIV-infected men with lipoatrophy and hypoleptinemia. 14th
CROI, 2007, Los Angeles [abstract 805].
69. Falutz J, Allas S, Kotler D, et al. A placebo-controlled, dose-ranging
study of a growth hormone-releasing factor in HIV-infected patients with
abdominal fat accumulation. AIDS. 2005;19:1279-87.
70. Engelson E, Agin D, Kenya S, et al. Body composition and metabolic
effects of a diet and exercise weight loss regimen on obese, HIV-infect-
ed women. Metabolism. 2006;55:1327-36.
71. Hultman C, McPhail L, Donaldson J, et al. Surgical management of HIV-
associated lipodystrophy: role of ultrasonic-assisted liposuction and
suction-assisted lipectomy in the treatment of lipohypertrophy. Ann Plast
Surg. 2007;58:255-63.
72. Fontdevila J, Berenguer J, Prados E, et al. Autologous fat grafts are safe
and durable in HIV-infected adults with facial lipoatrophy. 9th Interna-
tional Workshop on Adverse Drug Reactions and Lipodystrophy in HIV,
July 2007, Sydney, Australia [abstract P-25].
73. Guaraldi G, Orlando G, De Fazio D, et al. Comparison of three different
interventions for the correction of HIV-associated facial lipoatrophy: a
prospective study. Antivir Ther. 2005;10:753-9.
74. Serra-Renom J, Fontdevila J. Treatment of facial fat atrophy related to
treatment with protease inhibitors by autologous fat injection in patients
with HIV infection. Plastic Recons Surg. 2004;114:556-8.
75. Valantin M, AubronC, Ghosn J, et al. Polylactic acid implants (New-Fill)
to correct facial lipoatrophy in HIV-infected patients : results of the open
label study VEGA. AIDS. 2003;17:2471-7.
76. Negredo E, Higueras C, Adell X, et al. Reconstructive treatment for
antiretroviral-associated facial lipoatrophy: A prospective study compar-
ing autologous fat and synthetic substances. AIDS Patient Care STDS.
2006;20:829-7.
No part of this publication may be
reproduced or photocopying
without the prior written permission
of the publisher
© Permanyer Publications 2010