Body habitus changes, metabolic abnormalities,
osteopenia and cardiovascular risk in patients treated
for human immunodeficiency virus infection
Augusto Cirelli, Gloria Cirelli, Giorgio Balsamo, Raffaele Masciangelo*, Alessandro Stasolla**, Mario Marini**
The aim of this study was to evaluate the influence of three variables – protease inhibitors,
stavudine, and the length of combined therapy – on body habitus changes, metabolic effects and
bone mineral density in HIV patients treated with highly active antiretroviral therapy (HAART).
The onset of possible cardiovascular involvement was considered.
Forty HIV patients (29 men and 11 women, mean age 39.13 ± 7.82 years, range 28-61 years) treated with HAART for 12-43 months were evaluated for fat, lean, bone tissues, immunohematological
and cardiovascular alterations.
The differences in fat/lean tissues and bone mineral density were evaluated at dual-energy X-ray
absorptiometry (DEXA). Serum lipids and the CD4/CD8 T-cell counts were recorded. ECGs were
taken every 6 months; color Doppler echocardiography and color Doppler ultrasounds of the carotid
vessels were performed in close chronological sequence with the second DEXA. Statistical analyses included: Student’s t-test, Wilcoxon test, and single-multiple regression analysis.
Thirteen patients presented with fat loss, 7 fat accumulation, and 20 a combined form of both.
The changes in the single body districts showed that the decrease in the limb fat is to be attributed to protease inhibitors, while none of the three variables was responsible for the decrease in
the upper limb fat. The trunk weight increase was not significant. The decrease in the lean mass
of the upper limbs is to be attributed to protease inhibitors, while none of the three variables was
responsible for the increase in the lean mass of the upper and lower limbs. The decrease in bone
mineral density was not significant. No treatment-related cardiovascular lesions were observed.
In HIV patients treated with HAART for 12-43 months, the decrease in lower limb fat was due
to protease inhibitors. Neither osteopenia nor cardiovascular diseases were observed during follow-up.
(Ann Ital Med Int 2003; 18: 238-245)
Key words: Cardiovascular risk; Highly active antiretroviral therapy; Lipodystrophy; Osteopenia.
The HAART-associated lipodystrophy syndrome has a
multifactorial etiology: genetic factors, age, gender, viral
load, immunological reconstitution, lifestyle, and length
of therapy11-16.
In a previous study which ended in February 1997, we
examined 23 HIV stable patients treated with one or two
NRTI but without d4T and PI. Evaluations with dualenergy X-ray absorptiometry (DEXA) in both the study
group and controls showed that the only somatic-morphologic difference between the two groups was a subtle
but significant loss in limb fat in the study group17.
We therefore enrolled 40 patients – 9 of whom had
already been included in the previous study – treated with
PI and d4T for at least 12 months with the aim of evaluating the possible influence of three independent variables: PI, d4T, and the number of months between two successive DEXA examinations (MD). The bone mineral
density was also measured to investigate the development of osteoporosis and osteopenia after the treatment.
Two DEXA examinations, performed at least 12 months
apart, were the referring points of observation. During the
Introduction
After approximately 1 year following the introduction,
in clinical practice, of protease inhibitors (PI) for the
treatment of HIV-infected patients with highly active
antiretroviral therapy (HAART), this class of drugs was
temporarily associated with the first descriptions of the
“lipodystrophy syndrome”1-4.
A more accurate study, however, highlighted that even
nucleoside reverse transcriptase inhibitors (NRTI), especially stavudine (d4T), were responsible for at least the
upper and lower limb lipoatrophy, without visceral fat
accumulation or metabolic changes but with mitochondrial
toxicity associated with an increased risk of hyperlactatemia5-10.
S.S. Chemioantibioticoterapia Monitorizzata/AIDS (Responsabile:
Prof. Augusto Cirelli), Dipartimento di Malattie Infettive e
Tropicali; *Dipartimento di Medicina Sperimentale e Patologia
(Direttore: Prof. Mario Piccoli); **Dipartimento di Radiologia
(Direttore: Prof. Mario Marini), Università degli Studi “La
Sapienza”, Policlinico Umberto I di Roma
This work was partially supported by a grant from the University
“La Sapienza” (ex quota 60%) for a study on the “endocrinemetabolic alterations associated with HIV infection”.
© 2003 CEPI Srl
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Augusto Cirelli et al.
same period, the patients’ biochemical parameters were
also evaluated, together with their CD4/CD8 T-cell counts.
The onset of possible cardiovascular diseases was also
monitored.
Two years after the last DEXA examination, 38/40
patients were again evaluated for any changes in body habitus.
Cardiovascular evaluation was performed in all the
patients and included an ECG every 6 months and a color
Doppler echocardiography plus a color Doppler ultrasound of the carotid vessels (AU5-EPI Esaote SpA, 75
MHz probes) carried out in close chronological sequence
with the second DEXA. Male patients with breast enlargement were also submitted to breast ultrasound. Two years
after the last DEXA examination, 38/40 patients are still
under observation, while one patient died of a liver carcinoma and another one was lost to follow-up.
Seven female patients are still under treatment with PI
+ d4T, 3 are being treated with PI but not d4T, and 1 with
d4T but not PI; 19 males are under treatment with both PI
+ d4T, 2 are being treated with PI but not d4T, 5 with d4T
but not PI, and 1 is not being treated with either of these
drugs.
Methods
From November 1996 until June 2000, 40 patients (29
men and 11 women, mean age 39.13 ± 7.82 years, range
28-61 years) – 25 of whom were intravenous drug users
and 6 homosexual – were enrolled by our Service in the
Department of Infectious Diseases of the University of
Rome “La Sapienza” while receiving routine care for
their documented HIV infection. All of them were clinically stable, without any concomitant active AIDS-related disorders or opportunistic infections.
Anabolic/steroid drugs were not administered and fasting blood samples were collected from each patient for the
CD4/CD8 T-cell count, total cholesterol, HDL cholesterol,
triglycerides, amylase and hemoglobin. The total fat, the
lean body mass (LBM) of the limbs and the trunk, and the
bone mineral density were assessed by means of two
DEXA analyses of the body composition and expressed
in grams.
Measurements were performed by means of total body
scanners (QDR-1000 and QDR-2000, Hologic Inc.,
Waltham, MA, USA); with this technique it is possible to
exactly quantify the tissues in peripheral regions. However,
since the abdominal subcutaneous and visceral fat compartments may change in opposite directions in the same
patient, a single computed tomography cut at L4 is preferable to DEXA examinations18.
All the patients received HAART including PI: indinavir
in 35 cases, ritonavir in 3, and nelfinavir in 2. The first
NRTI used was d4T in 35 cases and zidovudine in 5; the
second NRTI used was lamivudine in 32 patients, didanosine in 7, and zalcitabine in 1 case. During the observation period, 3 patients switched from didanosine to lamivudine.
Before the introduction of d4T, all the patients were treated with zidovudine, but only 5 of them continued this drug;
we therefore considered, for our analysis, a first group
(Group 1) which included all the 40 patients – 5 of whom
were never treated with d4T but with zidovudine – and a
second group (Group 2) of 35 patients who were treated
with both PI and d4T.
The total treatment duration between the first and the second DEXA was not the same for all the patients (Table I).
Statistical analysis
The statistical analysis (Statgraphics Plus-Manugistics
Inc., Rockville, MD, USA) was performed using the
Student’s t-test for paired differences, the Wilcoxon test,
and simple and multiple linear regression analysis. This last
analysis was carried out to evaluate the relationship of
the changes in fat mass or LBM – expressed as percentage
differences (PD) with the first DEXA examination – and
the duration (months) of treatment with PI, d4T and MD.
Results
Immunohematological tests
In the overall evaluation of our 40 patients (Group 1)
there was a significant increase in total cholesterol, a
non-significant increase in triglycerides, and a decrease in
HDL cholesterol. This last finding was less evident in
Group 2. The serum levels of amylase decreased slightly. Hyperglycemia was recorded in 1 case only. There was
a marked increase in hemoglobin levels.
TABLE I. Total treatment duration in Groups 1 and 2.
Group 1
(n = 40)
Age (years)
MD (months)
PI
d4T
39.13 ± 7.82 (28-61)
25.05 ± 12.87 (12-45)
30.65 ± 7.02 (12-43)
–
Group 2
(n = 35)
38.97 ± 8.00 (28-61)
25.69 ± 13.10 (12-45)
31.11 ± 6.79 (12-43)
29.51 ± 7.77 (12-44)
Data are expressed as mean ± SD (range values in brackets).
d4T = stavudine; MD = months between the first and the second dualenergy X-ray absorptiometry; PI = protease inhibitors.
239
Ann Ital Med Int Vol 18, N 4 Ottobre-Dicembre 2003
There was an evident increase in the number of CD4 Tcells but this was less evident for the CD8 T-cell count
(Table II).
Lower limb fat
In Group 1 the mean PD was -14.98 ± 35.87. Multiple
regression analysis was used to assess the influence of two
independent variables (PI and MD) on the PD expressed
in grams. Since the MD was not significant, it was removed
from the model; the fitted model equation, therefore, was:
PD of the lower limb fat 53.09 - 2.22 * PI.
In Group 2 the mean PD was -16.40 ± 38.05. Multiple
regression analysis aimed at evaluating the influence of
three independent variables (PI, d4T, and MD) provided
Fat and lean tissues
The fat and lean weight variations of each body region
are reported in table III.
The peripheral fat tissue was expressed as the sum of the
fat in each of the four limbs. Figure 1 shows our results:
13 patients presented with fat loss, 7 with fat accumulation, and 20 with a combination of both.
TABLE II. Descriptive statistics and paired differences in Groups 1 and 2.
Variables
Group 1 (n = 40)
Group 2 (n = 35)
Mean
t
df
CD4 (cells/mm3)
Time I
Time II
257.75 ± 172.15
423.83 ± 209.39
5.875
39
CD8 (cells/mm3)
Time I
Time II
786.73 ± 405.59
879.43 ± 359.71
1.421
Total cholesterol (mg/dL)
Time I
Time II
183.95 ± 53.62
203.83 ± 51.41
HDL cholesterol (mg/dL)
Time I
Time II
Mean
t
df
< 0.001
248.23 ± 169.81
427.86 ± 215.92
6.082
34
< 0.001
39
0.163
774.43 ± 399.80
884.54 ± 351.88
1.532
34
0.135
2.758
39
0.009
186.26 ± 56.03
206.37 ± 51.99
2.572
34
0.015
40.91 ± 11.22
36.30 ± 10.22
-2.246
39
0.030
39.67 ± 10.02
36.71 ± 10.74
-1.452
34
0.156
Triglycerides (mg/dL)
Time I
Time II
197.85 ± 145.77
211.53 ± 142.38
0.510
39
0.613
211.26 ± 151.07
224.46 ± 146.62
0.431
34
0.669
Amylase (U/L)
Time I
Time II
169.05 ± 75.37
158.58 ± 62.84
-1.225
39
0.228
174.48 ± 77.53
159.57 ± 64.89
-1.597
34
0.119
13.71 ± 1.62
14.33 ± 1.62
2.931
39
0.006
13.82 ± 1.62
14.47 ± 1.59
2.970
34
0.005
Hemoglobin (g/dL)
Time I
Time II
p
p
TABLE III. Differences between the first and the second dual-energy X-ray absorptiometry.
Variables
Group 1 (n = 40)
Mean
Lower limb fat
Upper limb fat
Trunk fat
Lower limb LBM
Upper limb LBM
Trunk LBM
- 683.33
- 138
483.68
424.43
- 265.23
858.33
Group 2 (n = 35)
t
p
- 3.275
- 1.624
1.830
2.76
- 2.21
3.66
0.0022
0.1100
0.0740
0.0088
0.033
0.00075
LBM = lean body mass.
240
Mean
t
-746.71
-143.6
543.89
468.89
-325.74
868.51
-3.17
-1.48
1.93
2.84
-2.8
3.53
p
0.003
0.150
0.060
0.0075
0.0082
0.0012
Augusto Cirelli et al.
FIGURE 1. Patients’ fat modifications.
LL = lower limbs; UL = upper limbs.
the following fitted model: PD the of the lower limb fat
52.2271 - 2.97928 * PI + 1.05816 * d4T - 0.278834 * MD.
This results in a confirmation of both the influence of
PI – the angular coefficient of which is negatively more
emphasized as compared with Group 1 – and the lesser
influences of MD and d4T, which, in fact, were not significant (p > 0.05).
In Group 2 (without the 5 cases in whom d4T was not
administered), the mean fat mass decreased to an even
greater degree, although, paradoxically, d4T tended to
slightly restore the fat mass of the lower limbs; the influence of MD was still irrelevant.
In conclusion, since d4T and MD were both not significant, they were removed from the model. The final
equation, therefore, was PD of the lower limb fat 63.5203
- 2.56868 * PI, a very similar equation to that obtained for
the 40 patients.
Finally, considering the response variability of the
patients, we have limited the analysis to the 23 patients who
presented a decrease in the lower limb fat and were treated with both PI and d4T (Table IV).
Multiple regression analysis confirmed that PI is the only
significant variable; the simple linear regression with this
variable, therefore, was the following: PD of the lower limb
fat 12.0837 - 1.53298 * PI.
Upper limb fat
The differences in the decrease of upper limb fat expressed
in grams – less evident as compared with the lower limb fat
– were not significant in both groups (Table III).
In the 23 patients with a fat decrease treated with both
PI and d4T, the mean of the upper limb fat difference was
-304.96, t = -2.55, p = 0.018. Multiple and simple linear
regression percent difference analyses did not reveal any
significance of the three variables (PI, d4T, MD).
Trunk fat
The analysis identified a slight increase, both absolute
(Table III) and in percentage, of the trunk fat, but it should
be stressed that DEXA is unable to reliably distinguish
between the subcutaneous and visceral fat of the thorax and
abdomen; both anatomical regions were therefore considered as “trunk”19,20.
The mean of the weight differences of the trunk fat
was not significant in both Groups 1 and 2 (Table III).
Lean body mass
Table III shows the mean LBM weight differences in the
various body districts.
Multiple regression analysis of the LBM performed in
the 35 cases in whom both d4T and PI were administered
did not reveal any significant influence of d4T. The analysis was therefore carried out on all the 40 cases, with the
following PD:
• PD of the lower limb LBM mean 2.93 ± 6.74;
• PD of the upper limb LBM mean -2.87 ± 12.35;
• PD of the trunk LBM mean 3.64 ± 6.27.
Multiple regression analysis yielded significant results
only for the PD of the upper limb LBM. These were related to the duration of PI treatment. The equation of the fitted model was: PD of the upper limb LBM -26.9609 +
0.785984 * PI.
TABLE IV. Descriptive analysis of 23 patients.
Variables
Mean ± SD
Minimum
Maximum
PD of LF*
PI
d4T
MD
- 40.28 ± 19.01
32.70 ± 6.79
29.65 ± 8.28
28.35 ± 13.12
-71.64
16
12
12
- 4.98
43
44
45
d4T = stavudine; LF = lower limb fat; MD = months between the first
and the second dual-energy X-ray absorptiometry examinations; PD =
percentage difference; PI = protease inhibitors.
* PD of the fat tissue evaluated between the first and the second dualenergy X-ray absorptiometry.
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Ann Ital Med Int Vol 18, N 4 Ottobre-Dicembre 2003
in all the patients studied. Hyperglycemia was recorded in
only 1 patient with a trend towards diabetic. The increase
in the hemoglobin and CD4 T-cell count and the decrease
in HIV-RNA were both significant findings. The viral load
was < 400 cps/mL in nearly all the patients (data not
shown).
The modifications in the adipose tissue of the various
body districts were not homogeneous; according to the
Marrakech classification, our 40 patients could be included in the first three categories: 13 were type 1 (fat loss),
7 were type 2 (fat accumulation), and the remaining 20
were type 3 (combined form).
Multiple regression analysis indicated that the absolute
and percentage decrease of the lower limb fat was due to
PI, while the influence of d4T and MD seems irrelevant.
As an unusual finding13,23,26-31, a slight, although not significant, tendency of d4T to restore the lower limb fat was
noted in the second group of 35 patients.
It is however evident that the patients cannot be easily
evaluated by one single calculation: the variability of the
results, in fact, remarkably influenced the survey. In a more
homogeneous sample (23/26 patients treated with PI and
d4T, all of them with a decrease in the lower limb adipose
tissue), again the only significant variable factor was PI.
Similarly, the interpretation of the decrease of the upper limb
fat – as an absolute variation expressed in grams and PD –
was disappointing. The whole model was not satisfying and
the variability was considerable. In none of these three
groups of patients (40, 35, and 23 patients) was it in fact possible to appreciate any incisiveness of the variables.
The increase in the trunk volume, even when considering
the reservations due to the technique used, was not statistically significant in both groups, neither as an absolute
nor as a percentage value.
The LBM had increased in the lower limbs and the
trunk, but had decreased in the upper limbs; PI was the
active variable in relation to the duration of administration.
The reduced bone density recorded in HIV-infected
patients has been associated either with the dyslipidemia
secondary to the use of PI, or with the lactic acidemia secondary to the mitochondrial toxicity due to the use of
NRTI32. Vascular osteonecrosis has also been described33.
In our 40 patients, all of them treated with long-term
NRTI, the bone mineral density decreased, but the difference was not significant. In 3 male patients, physical
examination and ultrasound were suggestive of gynecomastia, i.e. bilateral enlargement of the breast tissue due
to hyperplasia of the mammary glands in the absence of
adipose tissue masses. It should however be noted that,
unlike other cases described in the literature34, we did not
administer ritonavir to our patients.
Bone mineral density
Bone mineral density of the 40 patients evaluated at L2,
L3, and L4 levels, was:
• first DEXA mean 0.99 ± 0.13 (g/cm2);
• second DEXA mean 0.97 ± 0.14 (g/cm2).
The Wilcoxon test, considering the distribution asymmetry, was not significant: mean bone mineral density differences - 0.024 ± 0.06, W = 1.77, p = 0.78.
Cardiovascular examination
None of our patients but one showed any abnormalities
suggestive of coronary heart disease at both electrocardiography and echocardiography. A Doppler ultrasound
of the epiaortic vessels performed in 32 cases matched with
the same exam of other patients treated with NRTI, of those
with or without NRTI, and of patients of the same age present in our database. There were no significant differences and the median of the carotid intima-media wall
thickness was ≤ 1.2 mm.
After 2 years of observation including clinical examinations and the patients’ self-reported questionnaires
(changes in the body morphology, such as thinning of the
limbs and buttocks, abdomen fat gain, sunken cheeks
and/or temples, breast enlargement in women), the following findings were found in 38/40 patients:
1) modest habitus changes in 8 men (5 d4T + PI, 1 d4T,
1 PI, 1 without d4T and PI) and in 2 women (1 d4T + PI,
1 PI);
2) marked body habitus changes (facial and lower limb fat
loss in particular) in 19 men (14 d4T + PI, 4 d4T, 1 PI) and
in 9 women (6 d4T + PI, 1 d4T, 2 PI).
Discussion
The body fat redistribution syndrome in HAART recipients was first described in 199721, but only in 1998 was
this finding more extensively studied22. Both PI and NRTI
(above all d4T) contribute to HIV-associated lipodystrophy syndrome23-27; the influence of these two classes of
drugs is however still under debate.
In the present study, we evaluated 40 HIV-infected
patients receiving HAART who were divided into two
groups: Group 1 which included all the 40 patients, 5
treated without d4T but with zidovudine, and Group 2
which included 35 patients, all treated with PI and d4T at
the same time. In all of them, the lipid abnormalities
observed were related to an increase in the total cholesterol values and a decrease in the HDL cholesterol values
(this latter finding was statistically significant in Group 1
only). The increase in triglyceride values was not significant in both groups. The levels of amylase were normal
242
Augusto Cirelli et al.
patients had a long NRTI exposure, especially zidovudine.
Finally, while estimates vary greatly (from 10 to 75% of
HAART patients develop a lipodystrophy approximately 10 months after the initiation of combined treatment),
our patients received HAART for at least 12 months and
had the same time interval between the first and the second DEXA examination.
After the first descriptions of premature coronary artery
disease in patients treated with PI35, an increase in the number of cases of coronary diseases, myocardial infarctions,
and of an augmented carotid intima-media wall thickness has been recorded during the last 3 years in HAART
patients and the length of the treatment36-39 was included
among the various risk factors.
Among our patients, only one had a myocardial infarction during treatment, but he had a positive family history and was a heavy smoker (> 40 cigarettes per day). In
the remaining 39 patients, all of them followed up by
means of electrocardiography, echocardiography, and
color Doppler ultrasound of the epiaortic vessels every 6
months, no significant cardiac anomalies were reported.
However, our observations were made during a shorter
period than is usually required for the development of serious cardiovascular diseases. Data from larger cohorts,
ideally prospectively collected, are clearly needed.
The influence of HAART on cardiovascular diseases
should be confirmed: approximately 500 000 individuals
in western countries are presently receiving antiretroviral
treatments without a higher incidence of coronary disease,
transient ischemic attack, RIND, or stroke40. We therefore
believe that not only these antiretroviral therapies but
also the family history and lifestyle (including smoking)
should be considered together with a longer follow-up for
the evaluation of the cardiovascular risk.
In 28/38 of our patients, after many years of treatment,
we found peripheral fat loss, especially of the face and
lower limbs, more severe in women, but the fact that
NRTI and PI may have independent and interacting effects
on the development of lipodystrophy does not necessarily mean that these drugs are the only factors responsible
for these changes. We believe that the subcutaneous adipose tissue loss, manifesting as sunken cheeks and lower
limb thinning, is an HIV-related phenomenon. In a previous
paper17, we had noted how 23/25 HIV-infected patients had
significant limb thinning even before treatment with d4T
and PI.
The present study is burdened by some biases which
must be taken into account: the first one is the small number of patients of different ages. The second point is that
it is a retrospective evaluation based on DEXA examinations. We should however stress that in November 1996,
when our DEXA studies started, this method was not
used for regional fat and LBM quantification in HIV
patients who, therefore, were studied by means of anthropometric measurements, bioimpedency analyses, and
sonography all operator-dependent techniques, lacking
in both precision and accuracy.
The third aspect to be considered is that d4T and PI were
not administered for the same length of time and that our
Riassunto
Scopo dello studio è stato valutare l’influenza di tre variabili – inibitori delle proteasi (PI), inibitori nucleosidici della transcriptasi inversa (stavudina) e periodo di terapia combinata – nell’indurre modificazioni della distribuzione somatica di tessuto adiposo e muscolare, diminuzione della densità minerale ossea, alterazioni metaboliche e malattie cardiovascolari in pazienti trattati con
terapia antiretrovirale (HAART) per l’infezione da virus
dell’immunodeficienza umana (HIV).
Quaranta pazienti (29 uomini, 11 donne, età media
39.13 ± 7.82 anni, range 28-61 anni) trattati con HAART
per un periodo di 12-43 mesi sono stati arruolati e monitorati per le variazioni di tessuto adiposo e muscolare, densità minerale ossea, modificazioni metaboliche e complicanze cardiovascolari. Le differenze ponderali dei tessuti grassi e magri, la densità minerale ossea sono state valutate con esame DEXA (dual energy X-ray absorptiometry) all’inizio e alla fine del periodo di terapia. Esami
elettrocardiografici ogni 6 mesi. Ecocardiogramma color
Doppler ed eco color Doppler dei vasi epiaortici praticati in concomitanza della seconda DEXA. Vengono riportati i parametri immunoematologici all’inizio e alla fine
dello studio.
Al termine dell’osservazione 13 pazienti mostravano globalmente perdite di tessuto adiposo, 7 accumulo e 20
quadri misti. All’esame distrettuale, la diminuzione significativa del tessuto adiposo degli arti inferiori era attribuibile a PI, nessuna delle tre variabili appariva collegata con quella degli arti superiori. La diminuzione modesta del tessuto muscolare degli arti superiori era secondaria all’impiego di PI. Non sono state dimostrate alterazioni cardiovascolari. Di scarso rilievo la diminuzione della densità minerale ossea.
In conclusione nei 40 pazienti studiati l’unica variazione significativa era la diminuzione del tessuto adiposo degli arti inferiori, attribuibile, secondo la nostra interpretazione, a PI. L’impiego della HAART, nel periodo di osservazione, non modificava significativamente la massa minerale ossea né induceva complicanze cardiovascolari.
Parole chiave: Lipodistrofia; Osteopenia; Rischio cardiovascolare; Terapia antiretrovirale.
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Ann Ital Med Int Vol 18, N 4 Ottobre-Dicembre 2003
[abstract]. In: Abstracts of the 13th International AIDS
Conference. Durban, South Africa: July 9-14, 2000.
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Manuscript received on 16.10.2003, accepted on 3.12.2003.
Address for correspondence:
Prof. Mario Marini, Dipartimento di Radiologia, Università degli Studi “La Sapienza”, Policlinico Umberto I, Viale del Policlinico 155, 00161
Roma. E-mail: [email protected]
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