Lipodystrophy syndrome in HIV-infected patients – a cohort study in Lower Silesia, Poland

Abstract

Introduction: Human immunodeficiency virus (HIV)-associated lipodystrophy syndrome (LS) is defined as a redistribution of adipose tissue, metabolic and endocrine abnormalities, resulting from combined antiretroviral therapy (cART). Aim of this study was to evaluate LS in HIV-infected patients from Lower Silesia, Poland.
Material and methods: One hundred and ten HIV-infected patients on cART for at leat 2 years were included. Two subgroups of patients were established: patients with no or slight symptoms of lipodystrophy – LS1; and patients with moderate and severe changes – LS2. The patients were also divided according to the type of LS: lipoatrophy, lipoaccumulation, both lipoatrophy and lipohypertrophy.
Results: LS2 subgroup was significantly older, had much lower body weight, lower WHR, more advanced atherosclerotic changes. Patients with advanced lipodystrophy syndrome had very high pack-year values. LS1 group had hypertension much more frequently than controls. Comparing with controls, LS2 had significantly lower low-density lipoprotein (LDL) cholesterol, higher triglyceride levels, longer time of HIV infection, longer time of cART and cumulative time on cART (including PIs and NRTIs). A higher current CD4+ T-lymphocyte count and more frequent HCV infection in patients with more severe adipose tissue changes were of little statistical significance. Fat loss of face, limbs, buttocks and together with lipoaccumulation of abdomen were most common.
Conclusions: Lipodystrophy syndrome is still observed in the vast majority of HIV-positive patients receiving antiretroviral therapy, especially those older and with longer time of cumulative NRTI and PI treatment. A great concern is needed to evaluate body composition and risk factors for metabolic changes to prevent their progression and healthy consequences.

Full text

HIV & AIDS Review 2017/Volume 16/Number 1 HIV & AIDS Review 2017/Volume 16/Number 1
Lipodystrophy syndrome in HIV-infected
patients – a cohort study in Lower Silesia,
Poland
Justyna Drelichowska1,2, Wiesława Kwiatkowska1,2, Brygida Knysz1,3, Katarzyna Arczyńska1,
Marcin Czarnecki1,3, Jacek Gąsiorowski1,3, Maciej Karczewski1, Wojciech Witkiewicz1,2
1
Wrovasc – Integrated Cardiovascular Centre, Regional Specialist Hospital, Research and Development Center in Wroclaw,
Wroclaw, Poland
2
Department ofAngiology, Regional Specialist Hospital in Wroclaw, Research and Development Center in Wroclaw,
Wroclaw, Poland
3
Department ofInfectious Diseases, Wroclaw Medical University, Wroclaw, Poland
Abstract
Introduction: Human immunodeciency virus (HIV)-associated lipodystrophy syndrome (LS) is
dened as aredistribution ofadipose tissue, metabolic and endocrine abnormalities, resulting from
combined antiretroviral therapy (cART). Aim ofthis study was to evaluate LS in HIV-infected patients
from Lower Silesia, Poland.
Material and methods: One hundred and ten HIV-infected patients on cART for at leat 2 years were
included. Two subgroups ofpatients were established: patients with no or slight symptoms oflipodys-
trophy – LS1; and patients with moderate and severe changes – LS2. epatients were also divided
according to thetype ofLS: lipoatrophy, lipoaccumulation, both lipoatrophy and lipohypertrophy.
Results: LS2 subgroup was signicantly older, had much lower body weight, lower WHR, more ad-
vanced atherosclerotic changes. Patients with advanced lipodystrophy syndrome had very high pack-
year values. LS1 group had hypertension much more frequently than controls. Comparing with con-
trols, LS2 had signicantly lower low-density lipoprotein (LDL) cholesterol, higher triglyceride levels,
longer time ofHIV infection, longer time ofcART and cumulative time on cART (including PIs and
NRTIs). A higher current CD4+ T-lymphocyte count and more frequent HCV infection in patients
with more severe adipose tissue changes were oflittle statistical signicance. Fat loss offace, limbs,
buttocks and together with lipoaccumulation ofabdomen were most common.
Conclusions: Lipodystrophy syndrome is still observed in thevast majority ofHIV-positive patients
receiving antiretroviral therapy, especially those older and with longer time ofcumulative NRTI and
PI treatment. A great concern is needed to evaluate body composition and risk factors formetabolic
changes to prevent their progression and healthy consequences.
HIV AIDS Rev 2017; 16: 40-49
DOI: https://doi.org/10.5114/hivar.2017.65114
Key words: HIV, antiretroviral therapy, lipodystrophy syndrome, metabolic abnormalities.
Address for correspondence: Brygida Knysz,
Department of Infectious Diseases, Wroclaw Medical University,
5 Koszarowa St., 51-149 Wroclaw, Poland,
e-mail: brygida.knysz@gmail.com
Article history
Received: 11.07.2016
Received in revised form: 20.10.2016
Accepted: 31.10.2016
Available online: 20.01.2017
RESEARCH PAPER

Lipodystrophy syndrome in HIV-infected patients 41
HIV & AIDS Review 2017/Volume 16/Number 1
Table 1. Virological and immunological characteristics ofpatients on antiretroviral therapy
Infection data Results
Mode oftransmission HET/IDU/MSM, n [%] 31/51/28 (28.2/46.4/25.5)
Time ofHIV infection [years]* 8 (3.4-12.0)
AIDS, n [%] 32 (29.1)
HCV infection, n [%] 59 (53.6)
HBV infection, n [%] 26 (23.6)
CD4+ T-lymphocytes [cells/μl]* 515 (388-693)
CD4+ T-lymphocyte nadir [cells/μl]* 200 (66-280)
Log10 HIV RNA at themoment oftest [copies/ml]* 1.7 (1.6-1.7)
HIV RNA below thesensitivity ofthemethod, n [%] 93 (84.5%)
Log10 HIV RNA zenith, copies/ml, n =84* 4.7 (3.6-5.3)
cART Results
Time ofARV treatment [years]* 4 (2-8)
Cumulative time on PI [years]* 3.79 (0.71-7.37)
Cumulative time on NNRTI [years]* 0 (0-1.6)
Cumulative time on NRTI [years]* 8.79 (4.03-13.98)
Cumulative time on cART [years]* 16.6 (8.13-24.97)
*Median, IQR, n (%) – absolute number (percentage), other data – arithmetic mean
HET – heterosexual contacts, IDU – intravenous drug users, MSM – men who have sex with men
Introduction
Human immunodeciency virus (HIV)-associated lipo-
dystrophy syndrome (LS) is dened as aredistribution ofad-
ipose tissue accompanied by metabolic and endocrine ab-
normalities, resulting from combined antiretroviral therapy
(cART) [1-5].
e term was rst used in 1998 by Andrew Carr et al.
to describe morphological and metabolic abnormalities
observed in HIV-infected patients treated with protease in-
hibitors (PIs) [2]. However, further studies also discovered
the inuence of other antiretroviral drugs, mostly nucleo-
side reverse transcriptase inhibitors (NRTIs), and of HIV
infection itself [6-11]. Most authors emphasize thesigni-
cant role ofadipose tissue in pathogenesis ofthis condition;
therole ofthe immune system, proinammatory cytokines
such as TNF-α and interleukin (IL)-6 and genetic predispo-
sition are also mentioned [2, 3, 8, 12, 13].
e morphological abnormalities observed in clinical
presentation of patients with LS include: lipoatrophy (loss
of subcutaneous adipose tissue in the face, limbs, and but-
tocks), isolated or accompanied by lipoaccumulation (growth
of adipose tissue in the abdomen, waist, neck and growth
ofvisceral adipose tissue) [14-19].
Lipoatrophy should be distinguished from cachexia
and malnutrition observed in advanced stages ofAIDS and
chronic infections accompanying HIV infection. erapy
with PI is considered by many authors as an independent risk
factor for the development of insulin resistance, abnormal
glucose tolerance and diabetes mellitus type 2 [20-24]. Other
metabolic abnormalities include: increased triglyceride concen-
tration, low-density lipoprotein (LDL) and very-low-density
lipoprotein (VLDL) cholesterol and apolipoproteins B and E
levels, lower high-density lipoprotein (HDL) cholesterol level
[25-27].
e aim ofthis study was to evaluate thelipodystrophy
syndrome in HIV-infected patients living in Lower Silesia,
Poland.
Material and methods
Material
One hundred and ten HIV-infected patients, treated
in the Acquired Immunodeciency Syndrome Outpatient
Clinic in Wroclaw were included in theobservational study.
e same study population was analyzed in our previous
publications [28]. epreliminary inclusion criteria were:
documented HIV infection and antiretroviral therapy, of no
less than 2 years. eexclusion criteria were: AIDS diag-
nosis, acute medical condition (fever, severe infection, in-
ammation), serum creatinine level over 2 mg% and over
vefold increase in the alanine aminotransferase level, body
mass index (BMI) > 30 kg/m2, age over 65 years old, diabe-
tes, treatment with such drugs as metphormin. efollow-
ing patient data were known at thebeginning ofthestudy:
current virological and immune status, history of the in-
fection and information about coinfection with hepatitis B
and/or hepatitis C virus (Table 1).
All patients were on antiretroviral treatment for 2-8
years, 4 years on average. etime ofcumulative antiretrovi-
ral treatment with medications from all antiretroviral classes

Justyna Drelichowska, Wiesława Kwiatkowska, Brygida Knysz et al.42
HIV & AIDS Review 2017/Volume 16/Number 1
was from about 8 to 25 years, 16.6 years on average; thelon-
gest cumulative time oftreatment concerned NRTI. We did
not analyze contribution ofcertain antiretroviral drugs and
their classes in the LS. Before the beginning of this study
there were changes in thecART in many patients because
ofdrug toxicity and viral failure.
e control group included 42 healthy individuals living
in Lower Silesia, matched for age and sex with thepatients,
with negative medical history ofchronic diseases and car-
diovascular disease events (Table 2).
Characteristics ofthe study group (SG) and control group
(CG) are presented in Table 2.
Methods
e study protocol included collecting anamnesis and
data from medical documentation, especially information
about HIV infection and antiretroviral treatment (in years
and cumulative treatment with NNRTI, NRTI, PI). Physical
examination was performed with particular emphasis on an-
thropometric measurements – weight, height, waist and hip
circumferences, BMI and waist-hip ratio (WHR). eevalu-
ation ofclinical features ofLS was carried out using theme-
thodology of HIV Outpatient Study (HOPS), a multi-site
clinical study of over 4800 patients receiving ambulatory
care in theUSA in 1992-1998 [18].
Table 2. Characteristics of the study group (SG) and control group (CG)
Feature SG, n = 110 CG, n = 42 p-value
Age [years] (a, sd) 39.8 ± 9.3 (20-62) 41 ± 11.5 (20-58) 0.48
Sex (male), n [%] 70 (63.6) 26 (61.9) 0.99
BMI* 22.86 (21-25) 25.6 (24-27) 0.0001
Waist [cm]* 82.75 (76.5-91.0) 86.75 (75-95) –
Hips [cm]* 94 (88-98) 100 (95-105) –
WHR* 0.9 (0.84-0.96) 0.89 (0.78-0.94) 0.055
Smokers, n [%] 46 (84.6) 28 (47.6) 0.0001
Pack-years* 18 (8.875-27.125) 13.375 (4-27.5) 0.33
cIMT [mm]* 0.66 (0.58-0.78) 0.54 (0.46-0.62) 0.0001
cIMT mean-max [mm]* 0.99 (0.84-1.18) 0.81 (0.67-0.99) 0.0001
Atherosclerotic plaques, n [%] 35 (31.8) 7 (16.7) 0.12
Hypertension, n [%] 49 (44.5) 10 (23.8) 0.039
TC [mg/dl] (a,sd) 195.3 ± 45.4 212.67 ± 38.7 0.03
Non-HDL [mg/dl] 139.2 ± 42.4 150.41 ± 35.7 0.13
LDL [mg/dl] (a,sd) 110.13 ± 38.1 126.34 ± 31.7 0.016
HDL [mg/dl]* 51 (40-64) 58.5 (47-71) 0.012
TG [mg/dl]* 131.5 (93-189) 100.5 (68-137) 0.0077
Fasting glucose [mg%]* 91 (86.0-96.5) 93.5 (87-101) 0.11
Insulin [UI/ml]* 7.15 (5.2-10.4) 7 (4.4-10.9) 0.64
HOMA-IR*,** 1.63 (1.1-2.23) 1.48 (0.98-2.67) 0.9
Insulin resistance, n [%] 21 (19.4) 11 (27.5) 0.55
CRP [mg/l]* 0.62 (0.19-1.53) 0.72 (0.19-1.52) 0.89
Fibrinogen [g/l]* 2.7 (2.3-3.2) 2.9 (2.6-3.3) 0.037
D-dimers [ng/ml]* 216.6 (169-319) 245.7 (170-349) 0.78
Positive family history, n [%] 35 (31.8) 5 (11.9) 0.022
Metabolic syndrome, n [%] 22 (20) 5 (11.9) 0.35
Diabetes, n [%] 3 (2.7) 0 (0) 0.66
Obesity/overweight/underweight, n [%] 6/21/7 (5.5/19.1/6.3) 5/23/0 (12/54.8/0) 0.0001
Cardiovascular disease risk factors, n [%] 3 (2.7) – –
CV – ATP III risk*,*** 2 (1-6) 2 (1-5) 0.38
*Median, IQR, n (%) – absolute number (percentage), other data – arithmetic mean
**Homeostatic Model Assessment of Insulin Resistance
***Cardio-vascular risk according Adult Treatment Panel III

Lipodystrophy syndrome in HIV-infected patients 43
HIV & AIDS Review 2017/Volume 16/Number 1
eLS features were evaluated by two physicians – re-
searchers, taking into consideration patients’ opinions.
e physical examination included evaluation of upper
and lower limbs, buttocks, hips and face regarding fat loss
and ofvisceral regions, trunk and neck with regard to fat
accumulation. eresearchers graded all thechanges from
0 points (absent) to 3 points (the most severe). emaxi-
mum possible score was 15 points.
equantitative parameter for lipodystrophy was used
for analyzing dependencies between lipodystrophy and
atherosclerosis. All changes were classied in afour-degree
scale reecting theseverity oflipodystrophy syndrome: no
LS symptoms, subtle changes – noticeable only if specically
looked for, with no change in clothing t (up to 3 points),
moderate changes – easily noted by the patient or physician,
oen requiring achange in clothing size (3-7 points), severe
changes obvious to thecasual observer, requiring achange
in clothing size (over 7 points) (Figure 1).
Following the HOPS method, two main subgroups
ofpatients were established:
1) patients with no or slight symptoms oflipodystrophy
(57 individuals) – LS1,
2) patients with moderate and severe changes (53 indi-
viduals) – LS2.
e purpose of this division was to compare their vi-
rological, immunological and clinical state and to evaluate
thedata concerning cART in both subgroups. epatients
were also divided according to thetype of lipodystrophic
changes, into thefollowing subgroups: lipoatrophy (n = 34),
lipoaccumulation (n = 14), mixed forms – features ofboth
lipoatrophic and lipohypertrophic changes (n = 46). In
thecontrol group, no features oflipoatrophic or mixed lipo-
dystrophic changes were observed; 15 controls had symp-
toms ofvisceral obesity.
In all patients, aduplex ultrasound ofcarotid was per-
formed in order to evaluate subclinical atherosclerosis
by means of computer-measured cIMT. Carotid ultra-
sound was performed using a high-resolution ultrasound
GE LOGIQ 7 GE with broadband linear probe 6-12 MHz.
emain parameters for each patient were cIMT (the aver-
age IMT value obtained for all theseries) and IMT mean-
max (dened as theaverage of12 maximal IMT measure-
ments from each projection) [29].
Statistical analysis
Quantitative variables were presented as an arithmetic
mean, geometric mean or median, depending on normal-
ity of distribution. To achieve normality, the logarithmic
transform was applied to thevariable elements. For each
estimator, 95% condence intervals were calculated. Qual-
itative variables are presented as thenumber ofpatients in
each group. Dierences in quantitative features between
groups were analyzed by Student’s t-test, the Mann-Whit-
ney test or Kruskal-Wallis wit post-hoc analysis. Dierences
in thequalitative features were analyzed using theχ2 test or
Fisher’s exact test (for small groups). e eect of clinical
features on lipodystrophy was assessed using logistic regres-
sion. eanalysis was made using R and MedCalc statistical
packages. All results with asignicance level p < 0.05 were
found signicant.
e study was conducted with theapproval oftheBio-
ethics Committee. All participants provided their written
informed consent to participate in thestudy, according to
theHelsinki Declaration.
Results
At thebeginning ofthestudy, thepatients were classied
according to theseverity of lipodystrophy syndrome, from
no LS symptoms to severe changes in adipose tissue distri-
bution. e subgroups with subtle and moderate changes
were themost numerous (Figure 1).
Table 3 presents and compares thecharacteristics ofboth
subgroups. e patients from LS2 subgroup were signi-
cantly older, had much lower body weight and smaller hip
circumference and, as aresult, lower WHR.
Patients from LS2 subgroup had noticeably more ad-
vanced atherosclerotic changes, expressed by higher cIMT
values. Both LS1 and LS2 patients had signicantly high-
er IMT mean-max values in comparison with thecontrol
group. Among traditional risk factors, there was anotice-
able dierence concerning smoking. Patients with advanced
lipo dystrophy syndrome had very high pack-year values.
Aer further post-hoc analysis ofsubgroups and the control
group, it was discovered that LS1 had hypertension much
more frequently than controls (0.033). In comparison with
the control group, LS2 had signicantly lower LDL choles-
terol and higher triglyceride values (p = 0.015, p = 0.028
respectively). No other statistically signicant dierences in
basic laboratory parameters or concerning cardiovascular
disease risk factors were observed (Table 3).
Patients in LS2 subgroup had noticeably longer doc-
umented time ofHIV infection (Table 4). General time
ofcART and cumulative time on antiretroviral drugs, in-
cluding cumulative time on PIs and cumulative time on
Figure 1. Classification of patients according to the severity
of lipodystrophy syndrome
45
40
35
30
25
20
15
10
5
0
Number ofpatients
Severity oflipodystrophy syndrome
1 2 3 4

Justyna Drelichowska, Wiesława Kwiatkowska, Brygida Knysz et al.44
HIV & AIDS Review 2017/Volume 16/Number 1
NRTIs, were significantly longer in LS2. Some interesting
findings oflittle statistical significance indicate ahigher
current CD4+ T-lymphocyte count and more frequent
HCV infection in patients with more severe adipose tissue
changes.
Various combinations of fat distribution abnormalities
were observed in LS patients. emost common one was
cumulative fat loss in areas ofthe face, limbs, waist and hips
(lipo atrophy); another frequent pattern was lipoatrophy
combined with lipoaccumulation in the visceral area (mixed
lipodystrophy). epercentages ofparticular combinations
are presented in Figure 2.
Within thewhole group, all types ofdystrophic chang-
es were observed: lipoatrophy (30.9%), lipoaccumulation
(12.7%) and, most frequently, mixed forms (41.7%). Figure 3
shows numbers ofpatients in specic subgroups, according
to various dystrophic changes.
Table 5 presents statistically signicant dierences ob-
served in patients with dierent types of lipodystrophy.
ere were signicant dierences between thesubgroups,
concerning anthropometric measurements: BMI and waist
circumference were noticeably higher in lipoaccumula-
tion and mixed subgroups than in the lipoatrophy group;
hip circumference was signicantly lower in the atrophy
Table 3. Clinical and laboratory characteristics of patients from subgroups LS1 and LS2
Feature LS1, n = 57 LS2, n = 53 p-value
Age [years] (a,sd) 39 (31.75-43) 42 (35-48) 0.048
Sex (male), n [%] 33 (57.9) 37 (69.8) 0.38
BMI* 23.9 (21.6-25.7) 22 (20.6-24.0) 0.015
Waist [cm]* 81 (75.6-90.0) 84 (79.0-91.5) 0.29
Hips [cm]* 95 (90-100) 90.5 (87-95) 0.014
WHR* 0.88 (0.80-0.94) 0.93 (0.88-1.00) 0.0024
cIMT [mm]* 0.64 (0.56-0.76) 0.71 (0.61-0.82) 0.026
cIMT mean-max [mm]* 0.93 (0.83-1.12) 1.06 (0.90-1.21) 0.076
Atherosclerotic plaques, n [%] 15 (26.3) 20 (37.7) 0.28
Smokers, n [%] 45 (79.0) 48 (90.6) 0.18
Pack-years* 12 (5.75-21.50) 23.375 (13.3-29.5) 0.0017
Hypertension, n [%] 28 (50.9) 20 (37.7) 0.23
TC [mg/dl] (a, sd) 204 (164-226) 187 (156-223) 0.82
Non HDL-C [mg/dl] 143 (105-168.75) 128 (100.75-166) 0.71
LDL-C [mg/dl] (a, sd) 114 (82.75-145.75) 101.8 (80.00-124.5) 0.36
HDL-C [mg/dl]* 53 (40-62) 49 (40.5-68.0) 0.75
TG [mg/dl]* 131 (95.25-183.25) 132 (91.50-196.75) 0.75
Fasting glucose [mg%]* 91 (86.00-97.53) 91 (85.75-96.00) 0.71
Insulin [IU/ml]* 6.7 (5.45-8.93) 7.8 (4.80-11.43) 0.15
HOMA-IR*,** 1.46 (1.14-1.91) 1.91 (1.08-2.59) 0.13
Insulin resistance, n [%] 7 (12.7) 14 (26.4) 0.18
CRP [mg/l]* 0.47 (0.18-1.40) 0.89 (0.2-2) 0.13
Fibrinogen [g/l]* 2.61 (2.3-3.1) 2.71 (2.28-3.40) 0.47
D-dimers [ng/ml]* 201.8 (169.0-316.0) 253.2 (171.9-331.0) 0.18
Positive family history, n [%] 18 (31.6) 17 (32.1) 0.89
Metabolic syndrome, n [%] 12 (21.1) 10 (18.9) 0.96
Diabetes, n [%] 1 (1.8) 2 (3.8) 0.94
Obesity/overweight/underweight, n [%] 5/11/5 (8.8/19.3/8.8) 1/10/4 (1.9/18.9/7.5) 0.43
Cardiovascular disease risk factors, n [%] 0 (0) 3 (5.7) 0.23
CV – ATP III risk*, *** 2 (1-6) 2 (1-8) 0.45
*Median, IQR, n (%) – absolute number (percentage), other data – arithmetic mean
**Homeostatic Model Assessment of Insulin Resistance
***Cardio-vascular risk according Adult Treatment Panel III

Lipodystrophy syndrome in HIV-infected patients 45
HIV & AIDS Review 2017/Volume 16/Number 1
group, compared with accumulation and mixed subgroups;
it was thehighest in the accumulation subgroup in com-
parison to mixed and no-LS groups. WHR was noticeably
higher in the mixed subgroup than in no-LS and atrophy
groups. Patients with mixed changes were signicantly old-
er and had more advanced atherosclerotic changes (cIMT
mean-max), compared with no-LS group. cIMT values and
pack-years were oflittle statistical signicance. Metabolic
syndrome was observed among thepatients with adipose
tissue accumulation and with mixed forms. esubgroups
ofpatients with various dystrophic changes did not dier
in: occurrence of atherosclerotic plaques, results oflabo-
Table 4. Infection characteristics in subgroups LS1 and LS2
Infection data LS1 LS2 p-value
Mode of transmission HET/IDU/MSM**, n [%] 16/24/17
(28.1/42.1/29.8)
15/27/11
(28.3/50.9/20.8) 0.51
Time of HIV infection [years]* 4.5 (2.5-9.0) 11 (5.75-17.00) 0.0003
AIDS, n [%] 15 (26.3) 17 (32.1) 0.65
HCV infection, n [%] 25 (43.9) 34 (64.2) 0.071
HBV infection, n [%] 11 (19.3) 15 (28.3) 0.37
CD4+ T-lymphocytes [cells/µl]* 488 (386.5-632.25) 609 (400.75-760.25) 0.053
CD4+ T-lymphocyte nadir [cells/µl]* 200 (49.00-267.75) 198 (77.25-293.00) 0.68
Log10 HIV RNA at the moment of test [copies/ml]* 1.69 (1.6-1.7) 1.6 (1.6-1.7) 0.28
HIV RNA below the sensitivity of the method, n [%] 45 (78.9) 48 (90.6) 0.21
Log10 HIV RNA zenith, copies/ml* (n = 84) 4.27 (3.31-5.13) 4.93 (4.06-5.38) 0.14
cART LS1 LS2 p-value
Time of cART [years]* 3 (1-7) 6 (3-10) 0.0007
Cumulative time on PI [years]* 2.25 (0.10-5.67) 5.27 (2.14-8.44) 0.01
Cumulative time on NNRTI [years]* 0 (0-1.3) 0 (0-2.65) 0.42
Cumulative time on NRTI [years]* 6.22 (2.3-11.7) 10.59 (6.00-14.50) 0.0049
Cumulative time on cART [years]* 12.43 (4.7-21.2) 19.92 (12.40-28.00) 0.0021
*Median, IQR, n (%) – absolute number (percentage), other data – arithmetic mean
HET – heterosexual contacts, IDU – intravenous drug users, MSM – men who have sex with men
Figure 3. Numbers of patients with various dystrophic changes
50
45
40
35
30
25
20
15
10
5
0
Number ofpatients
Type oflipodystrophy syndrome
No LD Atrophy Accumulation Mixed
Lipoatrophy ofthe face, limbs and buttocks
Lipoatrophy ofthe face, limbs and buttocks + lipoaccumulation ofabdomen
Lipoaccumulation ofabdomen
Lipoatrophy ofthe face and limbs
Lipoatrophy ofthe face and lipoaccumulation ofabdomen
Lipoatrophy ofthe face, limbs and buttocks + lipoaccumulation ofabdomen
and neck
Lipoaccumulation ofabdomen and neck
Lipoatrophy ofthe face and limbs + lipoaccumulation ofabdomen and neck
Lipoatrophy ofthe face and limbs + lipoaccumulation ofabdomen
Lipoatrophy ofthe face
Other combinations
Figure 2. Combinations of dystrophic changes in lipodystrophy
syndrome patients
23%
21%
11%
7%
5%
5%
4%
3%
3%
3% 16%

Justyna Drelichowska, Wiesława Kwiatkowska, Brygida Knysz et al.46
HIV & AIDS Review 2017/Volume 16/Number 1
ratory tests (lipid prole, glucose, insulin, CRP, brinogen,
D-dimers), and in such risk factors as: cardiovascular dis-
ease risk factors, hypertension, diabetes or positive family
hi s tory.
e time ofHIV infection, cumulative time ofNRTIs and
cumulative time on cART were signicantly longer in the
mixed subgroup than in no-LS group (Table 5). No signi-
cant dierences were discovered in the mode ofHIV trans-
mission and immunological or virological state. e time
ofantiretroviral treatment and total time ofPIs and NNRTIs
treatment were similar.
In further analysis of logistic regression cumulative
cART and smoking had an inuence on theseverity oflipo-
dystrophy syndrome (Table 6). In subsequent models, aer
disregarding cumulative cART and including cumulative
NRTIs and PIs treatment, and then NNRTIs treatment, it was
discovered that cumulative NRTIs treatment and smoking
had an independent inuence on severity oflipodystrophy
syndrome (p = 0.004 and p = 0.0152, respectively) (Table 6).
Adding the current number of CD4+ T-lymphocytes to
themodel did not change theresult and had no impact on
theseverity ofLS.
Discussion
Prevalence of LS in HIV-infected patients varies from
8% to 84% in dierent studies; it is usually correlated to
thecharacteristics ofthe research project, inclusion criteria
and observation time [1, 10, 18, 19, 22, 30-32].
In this study, 94 out of110 patients were diagnosed with
LS, which represents 85% ofthe study group. is is not an
isolated case ofsuch a high percentage ofLS diagnosis. Sim-
ilar results were observed by Rozenbaum et al. (84%) and by
Carr et al. (83%) [14, 19].
However, some studies indicate amuch lower prevalence
ofLS, e.g. Martinez et al. diagnosed it in 17% of patients,
Mercie et al. – in 26% ofpatients [25, 27].
All types of dystrophic changes were observed in our
study, with themajority ofmixed forms (41.7%), lipoatro-
phy (30.9%) and, least frequently, lipoaccumulation (12.7%).
ese results are consistent with the ndings of the HIV
Outpatient Study, where LS was diagnosed in 49% of pa-
tients, mixed forms were most frequent (22.7%) and preva-
lence oflipoatrophy (13.3%) and lipoaccumulation (13.2%)
were similar [18]. Dierent ndings were presented by ie-
baut et al. in aFrench cohort, where mixed forms were least
Table 5. Statistically significant differences in subgroups depending on LS type
Feature
(0)
No LS
n=16
(1)
Atrophy
n=34
(2)
Accumulation
n=14
(3)
Mixed
n=46
p-value Post hoc
Age
(years) (a,sd) 33 (26.5-42.0) 40 (31.0-48.0) 33.5 (32.0-41.0) 41.5 (38.0-47.0) 0.015 0 vs. 3, p = 0.052
BMI* 23.6 (20.9-25) 21.1 (19.4-23.0) 25.4 (24.2-28.1) 23.4 (21.6-25.3) 0.0001 1 vs. 2, p = 0.0001
1 vs. 3, p = 0.006
Waist (cm)* 78 (73.5-85.5) 78.5 (74.0-86.0) 86 (81.0-101.0) 85 (80.5-95.0) 0.0001
0 vs. 3, p = 0.023
1 vs. 3, p = 0.003
1 vs. 2, p = 0.042
Hips (cm)* 94.5 (88.5-1.0) 90 (84.0-94.0) 100.5 (98.0-103.0) 94 (88.0-98.0) 0.0001
1 vs. 2, p = 0.0001
2 vs. 3, p = 0.003
1 vs. 3, p = 0.056
0 vs. 2, p = 0.054
WHR* 0.846 (0.79-0.91) 0.882 (0.84-0.94) 0.886 (0.8-0.93) 0.944 (0.88-1.01) 0.001 0 vs. 3, p = 0.002
1 vs. 3, p = 0.033
Smokers, n (%) 15 (93.7) 32 (94.1) 12 (85.7) 34 (73.9) 0.06
cIMT (mm)* 0.613 (0.54-0.75) 0.657 (0.57-0.81) 0.631 (0.54-0.82) 0.7 (0.61-0.81) 0.099
cIMT mean-
max (mm)* 0.859 (0.75-1.8) 0.96 (0.84-1.26) 0.968 (0.83-1.26) 1.062 (0.91-1.19) 0.039 0 vs. 3, p = 0.029
Metabolic
syndrome, n (%) 2 (12.5) 0 (0) 5 (35.7) 15 (32.6) 0.001 1 vs. 2, p = 0.002
1 vs. 3, p = 0.002
Time of HIV
infection, years* 4 (2.050-8.0) 7 (3.0-12.0) 3 (1.0-9.0) 11 (5.0-17.0) 0.006 0 vs. 3, p = 0.027
Cumulative
NRTI (years)* 2.49 (0.2-12.40) 8.54 (4.9-12.7) 4.41 (3.2-10.7) 11.04 (5.7-14.2) 0.03 0 vs. 3, p = 0.05
Cumulative
cART (years)* 6.75 (2.3-21.3) 17.15 (9.6-21.9) 9.28 (6.4-22.5) 20.2 (11.2-27.9) 0.045 0 vs. 3, p = 0.073
*Median, IQR, n (%) – absolute number (percentage), other data – arithmetic mean, post-hoc analysis

Lipodystrophy syndrome in HIV-infected patients 47
HIV & AIDS Review 2017/Volume 16/Number 1
frequent (10%), lipoatrophy was most common (16%) and
isolated lipoaccumulation was observed in 12% out of38%
ofpatients diagnosed with LS [26].
Trevisol et al. observed high frequencies of lipoaccu-
mulation (46%) and lipoatrophy (53.2%) in agroup where
53.2% ofHIV-infected patients were diagnosed with LS [33].
In the presented cohort, signicant dierences in an-
thropometric measurements were observed, depending on
the type and severity of LS. Patients with more advanced
LS had lower BMI and higher WHR. ehigher WHR was
aconsequence ofa signicantly lower hip circumference, re-
sulting from adipose tissue loss in this region.
A higher BMI and waist circumference was observed
in patients with lipoaccumulation and with mixed forms.
Patients with lipoatrophy had a noticeably lower hip cir-
cumference. Patients with mixed forms had signicantly
higher WHR in comparison to no-LS and atrophy sub-
groups. e relation between dystrophic changes and an-
thropometric measurements was studied by iebaut et al.
Among patients receiving cART, theprevalence oflipoatrophy
grew with age and was higher in males and in patients with
BMI ≤ 25. Lipoaccumulation was correlated to higher BMI and
WHR; no signicant relationship between lipoaccumulation
and age has been discovered. epercentage ofmixed forms
was correlated to older age and higher WHR [26]. However,
Alencastro et al. observed a dierent correlation between dys-
trophic changes and age or BMI. In their research, patients on
antiretroviral therapy were older and had signicantly higher
BMI. Lipodystrophy and lipohypertrophy were correlated to
age and BMI, whereas lipoatrophy was only correlated to BMI,
without any signicant inuence ofage [6]. Mercie et al. ob-
served signicantly older age ofpatients diagnosed with LS and
noticeably lower BMI and CD4+ T-lymphocyte count in com-
parison with cART-using patients with no LS [25]. In thema-
jority ofndings, LS features are found in patients treated
with antiretroviral therapy [6, 7].
One ofthemain inclusion criteria for thepresent study
was antiretroviral treatment. Its signicant inuence was ob-
served especially in thesubgroup ofpatients with severe LS.
einuence ofboth total and cumulative time ofcART on
LS types and severity has been discovered. Cumulative pro-
tease inhibitors treatment was related to LS severity, but not
to LS types. NRTIs medications were correlated to LS devel-
opment. Cumulative time ofNRTIs treatment had inuence
on severity oflipodystrophy and occurrence ofmixed forms.
e inuence of time of cART on LS and its relationship
with various types oflipodystrophy have been observed in
numerous clinical studies [1, 7, 11, 18, 26, 27].
However, iebaut et al. did not observe asignicant re-
lationship between LS and particular antiretroviral medica-
tions, except for theinuence oftime on cART on LS types
and severity ofsymptoms [26].
In many clinical studies, theinuence ofvarious classes
of antiretroviral drugs and of specic antiretroviral drugs
on LS in HIV-infected patients was observed. Since thein-
troduction ofantiretroviral treatment, PIs has been therst
class whose side eects have been described as lipodystro-
phy syndrome. einuence of this class of medications,
specic drugs and time ofPI treatment on LS development
and severity have been widely described [1, 2, 6, 11, 14, 27].
In one ofthe rst LS studies in 1999, Carr et al., aer
an over twenty-month long observation, discovered fat dis-
tribution disorders in PI-treated patients in comparison to
HIV-infected, untreated patients [14]. PIs were closely as-
sociated with visceral adipose tissue growth and adverse
changes in patients’ metabolic prole. Since LS was also
observed in patients never treated with PIs, further studies
proved the negative inuence of other classes of antiret-
Table 6. Influence of various factors on severity of lipodystrophy
Variable OR 95% CI pVariable OR 95% CI p
MODEL 1 MODEL 2
Age 1.0479 0.9912-1.1078 0.099 Age 1.0518 0.9936-1.1134 0.08
Sex 1.4816 0.5399-4.0658 0.45 Sex 1.6447 0.5851-4.6234 0.35
Pack-years 1.0245 0.9908-1.0594 0.16 Pack-years 1.0247 0.9910-1.0595 0.15
Hypertension 2.0866 0.7542-5.7732 0.16 Hypertension 1.9614 0.7019-5.4810 0.2
HOMA-IR* 1.4392 0.9025-2.2952 0.13 HOMA-IR* 1.3715 0.8629-2.1799 0.18
HCV 0.4784 0.1806-1.2678 0.14 HCV 0.4993 0.1868-1.3344 0.17
Cumulative cART 1.0571 1.0128-1.1033 0.011 Cumulative NRTI 1.0856 1.0027-1.1754 0.0428
Cumulative PI 1.094 0.9653-1.2398 0.16
Stepwise
Variable OR 95% CI pVariable OR 95% CI p
Pack-years 1.0373 1.0066-1.0689 0.0168 Pack-years 1.0377 1.0072-1.0693 0.0152
Cumulative cART 1.0628 1.0198-1.1076 0.0039 Cumulative NRTI 1.1148 1.0353-1.2003 0.004
Logistic regression
*Homeostatic Model Assessment of Insulin Resistance

Justyna Drelichowska, Wiesława Kwiatkowska, Brygida Knysz et al.48
HIV & AIDS Review 2017/Volume 16/Number 1
roviral drugs on LS development [7, 8, 11, 31]. Peripheral
lipo atrophy is mostly associated with some NRTIs [5, 8,
11, 34]. Mallal et al. also found independent inuence of
NRTIs on LS; moreover, they discovered acorrelation be-
tween thetime ofNRTIs treatment, theuse oftwo dierent
medications ofthis class and theincreased risk oflipoatro-
phy. In their study of an Australian cohort ofHIV-infect-
ed patients, evident inuence ofPIs on faster development
ofNRTI-induced atrophic changes, even in comparison to
treatment with two dierent NRTI drugs, without PI, was
observed. ey discovered a slow development oflipoatro-
phy in NRTI-treated patients and progression of atrophic
changes when combination therapy ofNRTIs and PIs was
used [11]. einuence ofcART on LS prevalence was also
studied by van der Valk et al. In their research, LS was more
frequently diagnosed in patients on PIs and NRTIs treat-
ment than in patients on PIs treatment alone [7]. In thepres-
ent study, more severe LS and mixed forms were observed in
patients with a signicantly longer documented time ofHIV
infection. ese patients were also older. ese observations
are consistent with most publications. ecorrelation be-
tween the time of HIV infection, its severity, patients’ age
and prevalence and severity ofdystrophic changes is undis-
putable [6, 18, 27]. Mercie et al. discovered avisibly lower
CD4+ T-lymphocyte count in agroup ofsignicantly old-
er patients with LS than in ano-LS group [25]. In thestudy
of1240 patients, Alencastro et al. observed acorrelation be-
tween LS and cART treatment with longer time since HIV
diagnosis, older age and CD4+ T-lymphocyte count below
350 cells/µl [6]. But we did not nd any signicant correla-
tion between CD4 Tcell count (nadir and present) and LS
severity, probably because ofthe low number of patients.
e lipid prole ofthe study group diered signicantly
from theprole ofthe control group. In thestudy group, total
cholesterol, LDL and HDL levels were signicantly lower, and
triglyceride concentration was signicantly higher. In compar-
ison with the control group, the LDL cholesterol level was no-
ticeably lower and TG concentration was signicantly higher
in patients with severe lipodystrophy (LS2). evast majority
ofauthors describing lipid dysfunction in HIV-infected patients
also observe hypertriglyceridemia [1, 25, 26, 30, 35-37]. Mercie
et al. also discovered asignicantly higher TG concentration in
LS patients than in no-LS subgroup [25]. Moreover, Hsue et al.
observed arelationship between ahigh TG concentration and
PI treatment [38]. Another metabolic dysfunction frequently
observed in HIV-infected patients is ahigher total cholesterol
level, contrary to thendings ofthis study [25, 26, 30].
Mercie et al. conrmed therelation between ahigh TC
level and LS diagnosis [25]. Hsue et al. did not observe sig-
nicant dierences in TC levels between HIV-patients and
healthy controls. ey have, however, discovered a notice-
ably lower HDL level in comparison to the control group,
which was also observed in other studies and in theresearch
presented here [25, 38]. Mercie et al. demonstrated high to-
tal cholesterol and LDL levels, apart from thelow HDL level,
which is interpreted as arisk factor for atherosclerosis and
cardiovascular diseases, especially in patients with LS [25].
Conclusions
Lipodystrophy syndrome is still observed in thevast ma-
jority ofHIV-positive patients receiving antiretroviral ther-
apy, especially those older and with longer time ofcumula-
tive NRTI and PI treatment. Smoking is an independent risk
factor of the severity of adipose tissue redistribution. Agreat
concern is needed to evaluate body composition and risk
factors formetabolic changes to prevent their progression
and healthy consequences.
Acknowledgment
is publication is a part oftheProject “Wrovasc – Inte-
grated Cardiovascular Centre”, co-nanced by the European
Regional Development Fund, within Innovative Economy Op-
erational Program, 2007-2013, realized in the Regional Special-
ist Hospital, Research and Development Center in Wroclaw.
Conict of interest
e author’s declared no potential conicts ofinterest
with respect to theresearch, authorship, and/or publication
ofthis article.
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