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 Siena4. Niguarda Hospital, Milan; 5. University of Latina, Rome; 6. San Gerardo Hospital, Monza; 7. University College, London

8. University of Milan

• 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

BACKGROUND

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).

PATIENTS & METHODS

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.

Incidence rate was calculated as number of major liver events or liver-related death divided by person year follow-up (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)

STATISTICAL ANALYSES

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(%) 2549 73.3 Age, median (IQR) 39 33-45 Mode of HIV transmission, n(%) Heterosexual contacts 1483 42.7 Homosexual contacts 974 28.0 IVDU 800 23.0 Other/unknown 218 6.3 Time from HIV diagnosis, years, median (IQR) 1.0 0.1-5.5 Log10 HIV-RNA, median (IQR) 4.9 4.3-5.4 CDC C stage, n(%) 576 16.6 CD4, cell/mmc, median (IQR) 260 119-378 HCV Ab positive, n(%) 944 27.2 Blood glucose mg/dL, median (IQR) 87 80-94 Cholesterol, mg/dL, median (IQR) 158 134-187 HDL cholesterol, mg/dL, median (IQR) 38 31-47 LDL cholesterol, mg/dL, median (IQR) 96 73-117 FIB4 index <1.45 2291 65.9 1.45-3.25 917 26.4 >3.25 267 7.7 Calendar year of cART start, n(%) 1997-2000 1336 38.5 2001-2004 499 14.4 2005-2008 447 12.9 2009-2013 1193 34.3

0.1

00.

20.

30.

40.

5

267 111 40 11FIB4>3.25917 401 159 411.45<=FIB4<=3.25

2291 1000 429 90FIB4<1.45Number at risk

0 5 10 15Years from cART start

FIB4<1.45 1.45<=FIB4<=3.25FIB4>3.25

Kaplan-Meier curve stratified by baseline FIB4 index

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)

Overall IR 2.2 (1.6-3.0) per 1000 PYFU

P at log-rank test<0.001

Description of 41 eventsMajor liver events, n 25

Decompensated chirrosis 15

Hepatic encephalopathy 5

Gastrointestinal bleeding 2

HCC 2

hepato-renal syndrome 1

Liver-related deaths, n 16

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

HCV positive subjects

Association of variables with major liver event/liver-related death. Univariable Cox regression.

HR 95% CI P Male gender vs female 1.25 0.61 2.55 0.542

Mode of HIV transmission: Heterosexual contacts 1.00 Homosexual contacts 0.34 0.04 2.92 0.326 IVDU 10.95 4.28 28.03 <0.001 Other/unknown 1.44 0.17 12.34 0.739

Time from HIV diagnosis (per 1 yr more) 1.13 1.08 1.18 <0.001 CDC stage C vs A/B 0.66 0.26 1.68 0.381 HCVAb positive vs negative 12.65 5.31 30.09 0.000 FIB4 at baseline: <1.45 1.00 1.45-3.25 6.39 2.48 16.48 <0.001 >3.25 30.62 12.29 76.28 <0.001 Score difference between current fib4 and baseline fib4 (per 1 point higher) 1.02 1.00 1.08 0.013 Calendar year of cART start: 1997-2000 1.00 2001-2004 0.83 0.38 1.83 0.643 2005-2008 0.52 0.15 1.75 0.290 2009-2013 0.17 0.02 1.33 0.092 Alchool consumption: No 1.00 yes daily 3.81 1.56 9.27 0.003 yes occasionally 0.91 0.36 2.33 0.845 Blood glucose at baseline: <126 mg/dL 1.00 >=126 mg/dL 1.82 0.25 13.27 0.553 Current CD4 (per 100 cell/mmc higher) 0.69 0.59 0.80 <0.001 Current log10 HIV-RNA (per 1 log cp/mL higher) 1.56 1.24 1.96 <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)

N events/PYFU

Incidence Ratio 95% CI AHR* 95% CI P

HCV Ab negative 6/12,770 0.5 0.2-1.0 1.0 HCV Ab positive 35/5,892 5.9 4.3-8.3 2.09 0.49 8.86 0.318 FIB4 at baseline <1.45 6/12,406 0.5 0.2-1.1 1.00 1.45-3.25 15/4,885 3.1 1.8-5.1 5.07 1.64 15.71 0.005 >3.25 20/1,370 14.6 9.4-22.6 14.66 4.64 46.32 <0.001

Score difference between current fib4 and baseline fib4 (per 1 point higher) 1.02 1.01 1.04 0.003 Alcohol consumption No 1.00 yes daily 2.03 0.78 5.28 0.145 yes occasionally 0.84 0.31 2.28 0.737 Blood glucose at baseline <126 mg/dL 1.00 >=126 mg/dL 4.35 0.82 23.17 0.085 Current CD4 (per 100 cell/mmc higher) 0.73 0.61 0.88 0.001 Current log10 HIV-RNA (per 1 log cp/mL higher) 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,

In HIV-positive individuals, FIB4 at baseline and its modification after cART initiation are predictive of major liver events or liver-associated death independently of infection with HCV and could be used as surrogate markers of severe clinical eventsFIB4 could be used as a simple marker to prioritize HCV treatments in the HIV+ population

CONCLUSIONS

ICONA Foundation Study GroupBOARD OF DIRECTORSM 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 VialeSCIENTIFIC SECRETARYA d’Arminio Monforte, A Antinori, A Castagna, F Ceccherini-Silberstein, A Cozzi-Lepri, E Girardi, S Lo Caputo, C Mussini, M PuotiSTEERING 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 RusconiSTATISTICAL AND MONITORING TEAMA.Cozzi-Lepri, P. Cicconi, I. Fanti, T. Formenti, L. Galli, P. LorenziniPARTICIPATING PHYSICIANS AND CENTERSItaly 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).