Prognostic value of FIB4 in HIV positive
patients of the Icona cohort
co-infected or not with HCV.
C.Mussini1, P. Lorenzini2, A.De Luca3, M. Puoti4, M. Lichtner5, G.
Lapadula6, A. Cozzi-Lepri7 and, A. d’Arminio Monforte8 for the
Icona Foundation Study Group.
1 University of Modena and Reggio Emilia; 2. National Institte of Infectious Disease, Rome; 3. University of Siena
4. Niguarda Hospital, Milan; 5. University of Latina, Rome; 6. San Gerardo Hospital, Monza; 7. University College, London
8. University of Milan
BACKGROUND
• Liver-related death due to HCV, HBV or metabolic
complications still remains a main cause of death
among patients with HIV infection.
• FIB4 is a non-invasive serum fibrosis marker,
which has been validated in HCV positive
patients.
• Aim of the present study is to evaluate the
prognostic role of FIB4 at starting cART and
during treatment to predict major liver events or
liver-related death
PATIENTS & METHODS
Retrospective cohort study including all treatment-naive patients initiating
ART enrolled in ICONA
• with a known HCV serology
• negative for HBsAg
• with at least an available FIB4 index at cART start and during follow up
FIB4 was calculated as:
_Age (years) X AST (U/L)___________
Platelet count (109/L) X [ALT (U/L)]1/2
We analyzed FIB4 both as continuous variable and as divided in categories as
follows:
•FIB4 value >3.25 (as a proxy for cirrhosis),
•FIB4 value between 1.45 and 3.25 (in which cirrhosis status is considered
as undetermined),
•FIB4 value <1.45 (considered as absence of cirrhosis).
Time of starting cART was considered as “baseline” and patients were
followed to the date of the first major liver event or liver-related
death.
Major liver events were defined:
•variceal or gastrointestinal bleeding,
•ascites,
•hepatic encephalopathy,
•other signs of liver de-compensation including hepato-renal
syndrome
•hepatocellular carcinoma (HCC).
The follow-up was censored at last clinical visit, at the event or at
death for causes other than those liver-related.
STATISTICAL ANALYSES
Incidence rate was calculated as number of major liver
events or liver-related death divided by person year followup (PYFU).
Multivariable Cox regression model was used to determine
the association of FIB4 with the risk of major liver events or
liver-related death. FIB4 was used both as baseline and
time-updated co-variate (analyzing the change from
baseline to current FIB4)
RESULTS
Our analysis included 3,475 subjects who had
a known HCV serology, were HBsAg negative
and had a FIB4 index at baseline and at least
one FIB4 determination during follow up.
General characteristics of the study population at cART start (N=3475)
Male gender, n(%)
Age, median (IQR)
Mode of HIV transmission, n(%) Heterosexual contacts
Homosexual contacts
IVDU
Other/unknown
Time from HIV diagnosis, years, median (IQR)
Log10 HIV-RNA, median (IQR)
CDC C stage, n(%)
CD4, cell/mmc, median (IQR)
HCV Ab positive, n(%)
Blood glucose mg/dL, median (IQR)
Cholesterol, mg/dL, median (IQR)
HDL cholesterol, mg/dL, median (IQR)
LDL cholesterol, mg/dL, median (IQR)
FIB4 index
<1.45
1.45-3.25
>3.25
Calendar year of cART start, n(%) 1997-2000
2001-2004
2005-2008
2009-2013
2549
39
1483
974
800
218
1.0
4.9
576
260
944
87
158
38
96
2291
917
267
1336
499
447
1193
73.3
33-45
42.7
28.0
23.0
6.3
0.1-5.5
4.3-5.4
16.6
119-378
27.2
80-94
134-187
31-47
73-117
65.9
26.4
7.7
38.5
14.4
12.9
34.3
Cumulative proportion experiencing
a major liver event or liver-related death
after cART initiation according to baseline FIB4
(n=3,475; 41 events during 18,662 PYFU)
0.5
Kaplan-Meier curve stratified by baseline FIB4 index
15
Hepatic encephalopathy
5
Gastrointestinal bleeding
2
HCC
2
hepato-renal syndrome
1
Liver-related deaths, n
16
0.4
P at log-rank test<0.001
0
Decompensated chirrosis
0.3
25
0.2
Major liver events, n
Overall IR 2.2 (1.6-3.0) per 1000 PYFU
0.1
Description of 41 events
0
Number at risk
FIB4<1.45 2291
1.45<=FIB4<=3.25 917
FIB4>3.25 267
5
10
Years from cART start
1000
401
111
FIB4<1.45
FIB4>3.25
429
159
40
1.45<=FIB4<=3.25
15
90
41
11
Incidence rate of major liver events or liver related
death stratified by HCVAb serostatus and FIB4 index at
baseline
N events/PYFU=
IR per 1,000 PYFU
95%CI
HCV Ab negative
(N=2531)
6/12,770=0.5
0.2-1.0
HCV Ab positive
(N=944)
35/5,892=5.9
4.3-8.3
FIB4 index
<1.45
6/12,406=0.5
0.2-1.1
1.45-3.25
15/4,885=3.1
1.8-5.1
>3.25
20/1,370=14.6
9.4-22.6
HCV negative subjects
0.00 0.10 0.20 0.30 0.40 0.50
Kaplan-Meier failure estimates
0
2
4
6
Years from cART start
Number at risk
FIB4<1.45 1862
1.45<=FIB4<=3.25 562
FIB4>3.25 107
8
764
220
36
FIB4<1.45
FIB4>3.25
10
315
76
14
1.45<=FIB4<=3.25
HCV positive subjects
0.00 0.10 0.20 0.30 0.40 0.50
Kaplan-Meier failure estimates
0
2
4
6
Years from cART start
Number at risk
FIB4<1.45 429
1.45<=FIB4<=3.25 355
FIB4>3.25 160
8
236
181
75
FIB4<1.45
FIB4>3.25
10
114
83
26
1.45<=FIB4<=3.25
Association of variables with major liver event/liver-related death. Univariable Cox
regression.
Male gender vs female
Mode of HIV transmission: Heterosexual contacts
Homosexual contacts
IVDU
Other/unknown
Time from HIV diagnosis (per 1 yr more)
CDC stage C vs A/B
HCVAb positive vs negative
FIB4 at baseline: <1.45
1.45-3.25
>3.25
Score difference between current fib4 and baseline fib4
(per 1 point higher)
Calendar year of cART start: 1997-2000
2001-2004
2005-2008
2009-2013
Alchool consumption:
No
yes daily
yes occasionally
Blood glucose at baseline:
<126 mg/dL
>=126 mg/dL
Current CD4 (per 100 cell/mmc higher)
Current log10 HIV-RNA (per 1 log cp/mL higher)
HR
1.25
1.00
0.34
10.95
1.44
1.13
0.66
12.65
1.00
6.39
30.62
1.02
1.00
0.83
0.52
0.17
1.00
3.81
0.91
1.00
1.82
0.69
1.56
95% CI
0.61
2.55
P
0.542
0.04
4.28
0.17
1.08
0.26
5.31
2.92
28.03
12.34
1.18
1.68
30.09
0.326
<0.001
0.739
<0.001
0.381
0.000
2.48
12.29
16.48
76.28
<0.001
<0.001
1.00
1.08
0.013
0.38
0.15
0.02
1.83
1.75
1.33
0.643
0.290
0.092
1.56
0.36
9.27
2.33
0.003
0.845
0.25
0.59
1.24
13.27
0.80
1.96
0.553
<0.001
<0.001
Incidence ratio of major liver event/liver-related death according to HCV
serostatus and baseline FIB-4. Analysis of predictors (multivariable Cox regression)
HCV Ab negative
HCV Ab positive
FIB4 at baseline
<1.45
1.45-3.25
>3.25
Score difference between current
fib4 and baseline fib4
(per 1 point higher)
Alcohol consumption
No
yes daily
yes occasionally
Blood glucose at baseline
<126 mg/dL
>=126 mg/dL
Current CD4
(per 100 cell/mmc higher)
Current log10 HIV-RNA
(per 1 log cp/mL higher)
N
Incidence
events/PYFU
Ratio
6/12,770
0.5
35/5,892
5.9
6/12,406
15/4,885
20/1,370
0.5
3.1
14.6
95% CI
0.2-1.0
4.3-8.3
AHR*
1.0
2.09
95% CI
P
0.49 8.86
0.318
0.2-1.1
1.8-5.1
9.4-22.6
1.00
5.07
14.66
1.64 15.71
4.64 46.32
0.005
<0.001
1.02
1.01 1.04
0.003
1.00
2.03
0.84
0.78 5.28
0.31 2.28
0.145
0.737
1.00
4.35
0.82 23.17
0.085
0.73
0.61 0.88
0.001
1.10
0.85 1.43
0.456
*Also adjusted for age, sex, mode of transmission, time from diagnosis,
CDC stage at diagnosis, calendar year at cART initiation,
CONCLUSIONS
In HIV-positive individuals, FIB4 at baseline and
its modification after cART initiation are
predictive of major liver events or liverassociated death independently of infection
with HCV and could be used as surrogate
markers of severe clinical events
FIB4 could be used as a simple marker to
prioritize HCV treatments in the HIV+ population
ICONA Foundation Study Group
BOARD OF DIRECTORS
M Moroni (Chair), M Andreoni, G Angarano, A Antinori, A d’Arminio Monforte, F Castelli, R Cauda, G Di Perri, M Galli,
R Iardino, G Ippolito, A Lazzarin, CF Perno, F von Schloesser, P Viale
SCIENTIFIC SECRETARY
A d’Arminio Monforte, A Antinori, A Castagna, F Ceccherini-Silberstein, A Cozzi-Lepri, E Girardi, S Lo Caputo, C
Mussini, M Puoti
STEERING COMMITTEE
M Andreoni, A Ammassari, A Antinori, A d’Arminio Monforte, C Balotta, P Bonfanti, S Bonora, M Borderi, MR
Capobianchi, A Castagna, F Ceccherini-Silberstein, A Cingolani, P Cinque, A Cozzi-Lepri, A d’Arminio Monforte, A De
Luca, A Di Biagio, E Girardi, N Gianotti, A Gori, G Guaraldi, G Lapadula, M Lichtner, S Lo Caputo, G Madeddu, F
Maggiolo, G Marchetti, S Marcotullio, L Monno, C Mussini, M Puoti, E Quiros Roldan, S Rusconi
STATISTICAL AND MONITORING TEAM
A.Cozzi-Lepri, P. Cicconi, I. Fanti, T. Formenti, L. Galli, P. Lorenzini
PARTICIPATING PHYSICIANS AND CENTERS
Italy A Giacometti, A Costantini, S Mazzoccato (Ancona); G Angarano, L Monno, C Santoro (Bari); F Maggiolo, C
Suardi (Bergamo); P Viale, E Vanino, G Verucchi (Bologna); F Castelli, E Quiros Roldan, C Minardi (Brescia); T
Quirino, C Abeli (Busto Arsizio); PE Manconi, P Piano (Cagliari); J Vecchiet, K Falasca (Chieti); L Sighinolfi, D Segala
(Ferrara); F Mazzotta, S Lo Caputo (Firenze); G Cassola, C Viscoli, A Alessandrini, R Piscopo, G Mazzarello
(Genova); C Mastroianni, V Belvisi (Latina); P Bonfanti, I Caramma (Lecco); A Chiodera, AP Castelli (Macerata); M
Galli, A Lazzarin, G Rizzardini, M Puoti, A d’Arminio Monforte, AL Ridolfo, R Piolini, A Castagna, S Salpietro, L
Carenzi, MC Moioli, C Tincati, G. Marchetti (Milano); C Mussini, C Puzzolante (Modena); A Gori, G. Lapadula
(Monza); N Abrescia, A Chirianni, MG Guida, M Gargiulo (Napoli); F Baldelli, D Francisci (Perugia); G Parruti, T
Ursini (Pescara); G Magnani, MA Ursitti (Reggio Emilia); R Cauda, M. Andreoni, A Antinori, V Vullo, A. Cingolani, A
d’Avino, L Gallo, E Nicastri, R Acinapura, M Capozzi, R Libertone, G Tebano (Roma); A Cattelan, L Sasset (Rovigo);
MS Mura, G Madeddu (Sassari); A De Luca, B Rossetti (Siena); P Caramello, G Di Perri, GC Orofino, S Bonora, M
Sciandra (Torino); M Bassetti, A Londero (Udine); G Pellizzer, V Manfrin (Vicenza).