Transcript Diapositiva 1 - Fondazione ICONA

Progression of liver fibrosis among HIV-infected
patients under suppressive antiretroviral therapy:
role of untreated HCV and other unrelated factors
in the ICONA Foundation study cohort
P-250
Giuseppe Lapadula1, Alessandro Soria1, Patrizia Lorenzini2, Andrea De Luca3, Massimo Puoti4, Andrea Antinori2, Claudio Mastroianni5,
Giovanni Cassola6, Stefano Bonora7, Mirella Santoro8, Andrea Gori1, Antonella d'Arminio Monforte9 and the Icona Foundation Study
1San
Gerardo Hospital, Monza 2National Institute for Infectious Diseases IRCCS Lazzaro Spallanzani, Rome 3AOU Senese University, Siena 4AO Niguarda Ca' Granda,
Milan 5Sapienza University, Polo Pontino, Latina 6Galliera Hospital, Genova 7University of Torino, Turin 8University of Rome Tor Vergata, Rome 9University of Milan, Milan
Background
Objectives
• In several countries (including Italy), HCV treatment is currently available only for those with the
greatest need, that is patients with liver cirrhosis or significant fibrosis.
• HIV/HCV-coinfection has been associated with faster liver fibrosis progression than HCVmonoinfection.
• Although mitigated by suppressive antiretroviral therapy, this faster progression seems to persist
also when HIV viral replication is under control.
• Identifying predictors of faster liver fibrosis progression among HIV-infected subjects with no
significant fibrosis could be crucial for prioritizing interventions (including anti-HCV treatment) in
selected patients.
• We aimed at assessing the rate of progression to advanced liver fibrosis among HIV-infected
patients on suppressive antiretroviral therapy (ART), with or without HCV-coinfection, and
identifying its predictors, in a large Italian cohort of HIV-infected individuals.
Methods
• Patients from the ICONA cohort with two consecutive HIV-RNA<50 copies/ml after ART initiation • Patients were followed from the first of two consecutive HIV-RNA <50 copies/ml (baseline) up to
were enrolled if
the last available FIB-4, HIV-RNA rebound, or anti-HCV treatment introduction, whichever
• HCV-antibody (HCVAb) status was known,
occurred first
• ≥2 FIB-4 after HIV-RNA suppression were available and
• Time to development of advanced fibrosis, defined as the first of two consecutive FIB-4>3.25
• Baseline FIB-4 was <3.25.
(study outcome), was assessed using multivariable Cox regression, conducted among HCVAbpositive and HCVAb-negative patients separately.
• FIB-4 was calculated according to the following formula:
• The tested covariates were: gender, country of birth, injecting drug use (IDU) as HIV risk factor,
(age [years] × AST [IU/L]) / (platelets count [109/L] × ALT1/2 [IU/L])
CD4 nadir, baseline CD4, HDL-cholesterol, diabetes, duration of HIV infection, HCV-RNA, HCVgenotype, baseline FIB-4, first-line ART drugs.
Results
• 5,717 patients with a median follow-up of 4 (IQR 2.2-7.4) years, contributing to 30,299 patient-years of follow-up (PYFU), were included. The median number of FIB-4 measurements was 7 per
patient (IQR 4-14). Patients were predominantly males (75%), their median age was 40 years (IQR 34-46); 1,144 patients (20%) were HCVAb-positive. Median baseline FIB-4 was 1.09 (IQR 0.811.58) and 0.81 (IQR 0.59-1.12) among HCVAb-positive and HCVAb-negative patients, respectively (Table).
• During the follow-up, 272 patients progressed to advanced fibrosis. The rate of progression was higher among HCVAbpositive patients with positive or unknown HCV-RNA (2.94 [95%CI 2.43-3.55] and 3.10 [95%CI 2.51-3.83] per 100 PYFU,
Table. Baseline characteristics of patients under suppressive
ART, with or without HCV coinfection
Characteristics
HCV-Ab negative
HCV-Ab positive
P
3449 (75.4%)
832 (72.7%)
0.06
39 (33-47)
40 (36-45)
0.005
respectively) than among HCVAb-negative or HCVAb-positive/HCVRNA-negative patients (0.33 [95%CI 0.26-0.41] and
Male gender, n (%)
0.49 [95%CI 0.19-1.32] per 100 PYFU, respectively).
Italian nationality, n (%)
674 (14.7%)
53 (4.6%)
<0.001
IDU as HIV risk factor, n (%)
108 (2.4%)
806 (70.4%)
<0.001
0.81 (0.59-1.12)
1.09 (0.81-1.58)
<0.001
Risk factors for fibrosis progression among HCV-Ab positive patients
Age, years, median (IQR)
Baseline FIB-4, median (IQR)
• Univariate analysis, conducted among HCV-Ab positive patients, showed that male gender (HR 1.73; 95%CI 1.21-2.47),
history of IDU (HR 1.7; 95%CI 1.18-2.47), positive or unknown HCV-RNA (versus negative, HR 6.14; 95%CI 2.26-16.66
and HR 6.51; 95%CI 2.39-17.76), higher baseline FIB-4 (per unit increase, HR 3.86; 95%CI 3.22-4.62) and first ART
containing d4T or ddI (HR 1.46; 95%CI 1.08-1.97) were associated with a higher risk of progression. Conversely, CD4+
nadir >200/mmc (HR 0.74; 95%CI 0.55-0.97), HDL cholesterol >35 mg/dl (HR 0.6; 95%CI 0.44-0.82) and PI/r-based firstline ART (HR 0.65; 95%CI 0.43-0.99) resulted to be protective. No significant impact was exerted by HCV genotype.
HCV-RNA, n (%)
Negative
Positive
Unknown
N.A.
HCV genotype, n (%)
1a
1b
3a
4
Other/mixed infections
Unknown/unreported
N.A.
N.A.
145 (12.7%)
580 (50.7%)
419 (36.6%)
N.A.
201 (17.6%)
108 (9.4%)
225 (19.7%)
61 (5.3%)
111 (9.7%)
437 (38.2%)
1.9 (0.7-4.9)
9 (3.7-14.8)
<0.001
CD4 + at baseline, cell/mmc, median (IQR)
276 (152-378)
243 (120-343)
0.016
CD4+ nadir, cell/mmc, median (IQE)
463 (321-619)
442 (285-630)
<0.001
2010 (2004-2012)
2004 (2001-2008)
<0.001
Diabaetes, n (%)
176 (3.8%)
53 (4.6%)
0.226
HDL cholesterol, mg/dl, median (IQR)
44 (37-53)
44 (36-55)
0.502
95%CI 3.15-4.60, P<0.001) and didanosine
NVP-based first-line ART, n (%)
217 (4.7%)
79 (6.9%)
0.030
PI/r-based first-line ART, n (%)
1831 (40%)
267 (23.3%)
<0.001
or stavudine use (HR 1.38, 95%CI 1.01-
ddI/d4T containing first-line ART, n (%)
509 (11.1%)
261 (22.8%)
<0.001
• When multivariable survival analysis was
run,
after
adjustment
for
Figure. Risk factors for fibrosis progression (FIB-4 >3.25) among HCVAb
positive patients (multivariable Cox regression analysis)
HCV-RNA,
baseline FIB-4 (per unit increase, HR 3.81,
1.89, P=0.040) were confirmed to be
associated with a higher risk of fibrosis
HR (95%CI)
10
Calendar year, median (IQR)
Conclusions
1
progression, while HDL cholesterol (> vs
≤35 mg/dl, HR 0.65 95%CI 0.47-0.89,
P=0.008) was protective. (Figure)
HCV-RNA
Nadir CD4+
HDL-cholesterol
0.1
Risk factors for fibrosis progression among HCV-Ab negative patients
• Among HCVAb-negative patients, multivariable analysis showed that higher baseline FIB-4 (per unit increase, HR
3.88, 95%CI 2.86-5.26, P<0.001) and first-line ART containing didanosine or stavudine (HR 1.65, 95%CI 0.99-2.75,
P=0.054) were the only factors independently associated with fibrosis progression.
ICONA Foundation Study Group
Time since HIV infection, median (IQR)
• In our cohort, progression to advanced liver fibrosis was associated,
irrespectively of HCV sero-status, with d-drugs-containing ART.
• Although these regimens are no longer used, past exposure to them may
have caused irreversible iatrogenic damage, thus contributing to hasten
fibrosis progression due to other causes.
• In HCV-coinfected patients, HDL-cholesterol had a protective role on
fibrosis progression. Whether it is due to its role in regulating homeostasis
and counteracting inflammation and oxidative stress, or HDL levels are
rather a marker of severity of liver damage, warrants further investigation.
ACKNOWLEDGEMENTS This study was conducted thank to the invaluable efforts of all participants to the ICONA Foundation Study. The project was realized with the unconditional support of Gilead Sciences, Bristol-Meyers-Squibb and MSD.
BOARD OF DIRECTORS A d’Arminio Monforte (Vice-President), M Andreoni, G Angarano, A Antinori, 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, C Balotta, A Bandera, P Bonfanti, S Bonora, M Borderi, A Calcagno, L Calza, MR Capobianchi, A Castagna, F CeccheriniSilberstein, 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, S Nozza, M Puoti, E Quiros
Roldan, R Rossotti, S Rusconi, MM Santoro, A Saracino, M Zaccarelli. STATISTICAL AND MONITORING TEAM A Cozzi-Lepri, I Fanti, L Galli, P Lorenzini, A Rodano, M Shanyinde, A Tavelli. BIOLOGICAL BANK INMI F Carletti, S Carrara, A Di Caro, S Graziano, F Petrone, G Prota,
S Quartu, S Truffa. PARTICIPATING PHYSICIANS AND CENTERS A Giacometti, A Costantini, C Valeriani (Ancona); G Angarano, L Monno, C Santoro (Bari); F Maggiolo, C Suardi (Bergamo); P Viale, V Donati, G Verucchi (Bologna); F Castelli, E Quiros Roldan, C Minardi (Brescia); T
Quirino, C Abeli (Busto Arsizio); PE Manconi, P Piano (Cagliari); B Cacopardo, B Celesia (Catania); J Vecchiet, K Falasca (Chieti); L Sighinolfi, D Segala (Ferrara); F Mazzotta, F Vichi (Firenze); G Cassola, C Viscoli, A Alessandrini, N Bobbio, G Mazzarello (Genova); C Mastroianni, V
Belvisi (Latina); P Bonfanti, I Caramma (Lecco); A Chiodera, P Milini (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, G Borgia, R Orlando, F Di Martino, L Maddaloni, I Gentile, G Bonadies (Napoli); A Cascio, C Colomba (Palermo); F Baldelli, E Schiaroli (Perugia); G Parruti, T Ursini (Pescara); G Magnani, MA Ursitti (Reggio Emilia); R Cauda, M
Andreoni, A Antinori, V Vullo, A Cristaudo, A Cingolani, G Baldin, S Cicalini, L Gallo, E Nicastri, R Acinapura, M Capozzi, R Libertone, S Savinelli, A Latini, G Iaiani, L Fontanelli Sulekova (Roma); M Cecchetto, F Viviani (Rovigo); MS Mura, G Madeddu (Sassari); A De Luca, B Rossetti
(Siena); D Francisci, C Di Giuli (Terni); P Caramello, G Di Perri, GC Orofino, S Bonora, M Sciandra (Torino); M Bassetti, A Londero (Udine); G Pellizzer, V Manfrin (Vicenza).