Conveners: S. Bruno, C.M. Mastroianni

Transcription

1 SESSIONE 2 Oral communications based on selected abstracts Conveners: S. Bruno, C.M. Mastroianni PNPLA3 variant is an independent predictor of severe steatosis in patients with chronic hepatitis C and HIV infection C. Sagnelli1, M. Merli2, C. Uberti-Foppa2, N. Coppola3, H. Hasson2,1, G. Cirillo4, A. Gradone4, S. Salpietro2, C. Minichini3, E. Miraglia Del Giudice4, A. Lazzarin2, E. Sagnelli3 1Department Experimental Medicine and Surgery "F. Magrassi e A. Lanzara", Second University of Naples, Naples, Italy; 2Department of Infectious Diseases, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy; 3Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy; 4Department of Pediatrics, Second University of Naples, Naples, Italy

2 Impact of Patatin-like Phospholipase-3 (PNPLA3) Variants on the Liver Histology of 168 Patients with HIV Infection and Chronic Hepatitis C C. Sagnelli, M. Merli, C. Uberti-Foppa, H. Hasson, G. Cirillo, A. Gradone, E. Miraglia Del Giudice, A. Lazzarin, E. Sagnelli, N. Coppola

3 Background A genome-wide association study has identified a non-synonymous sequence variation (rs C>G) encoding an isoleucine-to-methionine substitution at position 148 in adiponutrin/pnpla3 gene that appears to be the strongest determinant of human steatosis. The PNPLA3 I148M variant has been independently associated with liver steatosis and with disease progression in NAFLD, ALD and CHC.

4 The data on the impact of PNPLA3 on liver steatosis in patients with HIV infection and CHC are fragmentary and not conclusive. AIM This study analyzes the impact of PNPLA3 polymorphisms on 168 consecutive Caucasian anti-hiv positive subjects with biopsy proven CHC.

5 Methods 168 consecutive Caucasian HIV/HCV coinfected patients with asymptomatic chronic hepatitis for months were enrolled at the time they underwent their first liver biopsy from 1993 to Characteristics of patients: naive for anti-hcv treatment, 80% under ATR, no active alcohol abuse, nor statin assumption, HBsAg-negative, no autoimmune nor genetic liver disease, no US/serologic evidence of HCC.

6 Initial characteristics: according to PNPLA3 variants p.148 I/I p.148 I/M and p.148 M/M p-value N of patients Age (M ± SD), years 40.0 ± ± 6.7 ns Males, N (%) 65 (73.0) 57 (72.1) ns Alcohol abusers (>30g/die), N (%) IVDA, N (%) 63 (70.8) 41 (51.9) 0.01 BMI (M ± SD) kg/m ± ±3.4 ns Glucose (M ± SD) mg/dl 87.9 ± ± 21.3 ns Bilirubin (M ± SD), mg/dl 0.88± ± 0.73 ns AST (M± SD), IU/L ± ± 53.4 ns ALT (M± SD), IU/L ± ± 89.4 ns Cholesterol (M ± SD), mg/dl ± ± 39.7 ns Triglycerides (M ± SD) mg/dl ± ± ns GGT (M ± SD), IU/mL ± ± ns ALP (M ± SD) IU/mL ± ± ns HCV RNA (M ± SD), IU/mL 215,424±2,426,540 1,177,902 ± 1,639,3 ns Nadir of CD4 (M ± SD), cell/mmc 300.2± ± ns HIV RNA (M ± SD) cps/ml ± ± ns CD4 (M± SD), cell/mmc 571.2± ± ns Duration of ART (M± SD), years 8.7± ±4.6 ns ART, N (%): treated Untreated 70 (78.7) 19 (21.3) 63 (79.7) 16 (20.3) ns

7 Initial characteristics: according to PNPLA3 variants p.148 I/I p.148 I/M and p.148 M/M p-value N of patients HCV Genotype, N (%): Missing 34 (38.2) 5 (5.6) 38 (42.7) 10 (11.3) 2 29 (38.7) 3 (4.0) 30 (40.0) 13 (17.3) 4 HAI score (M± SD) 5.85± ±3.04 ns Degree of HAI, N (%): 0-8 score 67 (75.2) 63 (79.7) ns 9-18 score 22 (24.7) 16 (20.3) Fibrosis score (M ± SD) 2.2± ±1.6 ns Degree of fibrosis, N (%): (11.2) 28 (31.5) 17 (19.1) 21 (23.4) 3 (3.4) 5 (5.6) 5 (5.6) 3 (3.8) 22 (27.8) 19 (24.05) 17 (21.5) 8 (10.3) 3 (3.8) 7 (10.4) Steatosis score (M ± SD) 1.44± ± Degree of steatosis, N (%): (36) 12 (13.5) 23 (25.8) 18 (20.2) 4 (4.5) 16 (20.5) 10 (12.7) 19 (24.0) 28 (35.4) 6 (7.6) *0.01 *: patients with steatosis score 3-4 ns ns ns ns ns

8 Initial characteristics: according to the degree of liver steatosis Steatosis score 0-2 Steatosis score 3-4 p-value N of patients Age (M ± SD), years 40.3± ± 5.3 n.s. Males, N (%) 80 (22) 42 (10) n.s. IVDA, N (%) 73 (39) 28 (28) n.s. BMI (M ± SD) kg/m ± ± Glucose (M ± SD), mg/dl 87.9 ± ± 13.0 n.s. Bilirubin (M ± SD), mg/dll 0.87 ± ± AST (M± SD), IU/L 70.5 ± ± ALT (M ± SD), I U/L 95.3 ± ± Cholesterol (M ± SD), mg/dl ± ± Triglycerides (M ± SD), mg/dl ± ± n.s. GGT (M ± SD), IU/L ± ± ALP (M ± SD), IU/L ± ± 92.2 n.s. HCV RNA (M ± SD), IU/ml 1,354,722± 2,462,867 1,011,167 ± 1,309,754 n.s. Nadir of CD4 (M ± SD), cell/mmc ± ± n.s. HIV RNA (M ± SD), cps/ml 11,372 ± 37,686 24,655 ± 67,557 n.s. CD4 (M ± SD), cell/mmc ± ± Duration of ART (M ± SD), years 9.55 ± ± 13.8 n.s. ART, N (%): Treated Untreated 89 (79.5) 23 (20.5) 44 (78.6) 12 (21.4) n.s.

9 Initial characteristics: according to the degree of liver steatosis Steatosis score 0-2 Steatosis score 3-4 p-value N of patients HCV Genotype, N (%): (41.7) 5 (4.6) 38 (35.2) 20 (18.5) 18 (33.3) 3 (5.6) 30 (55.6) 3 (5.6) 0.01* Missing 4 2 PNPLA3 p.148i/i, N (%) PNPLA3 p.148i/m, N (%) PNPLA3 - p.148m/m, N (%) 67 (59.8) 38 (33.9) 7 (6.2) 22 (39.3) 29 (51.8) 5 (8.9) 0.01** HAI score (M ± SD) 5.5± ± Degree of HAI, N (%): (82.1) 37 (66.1) (17.8) 19 (33.9) Fibrosis score (M ± SD) 2.05± ± Degree of fibrosis, N (%): (88.4) 15 (13.4) 40 (71.4) 16 (28.8) 0.01 *: genotype 3 vs. non-3; ** p.148 I/I vs I/M or M/M

10 Multivariate logistic regression analysis to confirm the association between the PNAPL3 variants and severe steatosis, including: the PNAPL3 variants (I/M +M/M vs. I/I), HCV-genotype (3 vs. other genotypes), BMI and age, sex, CD4 cell count. The BMI (p=0.0165), HCV-genotype 3 (p=0.0075), CD4 cell count (p=0.0036) and PNPLA3-p.I148I/M and M/M polymorphism (p=0.0088) were independent predictors of severe steatosis.

11 Distribution of the patients according to the steatosis score, HCV-genotype and PNAPL3 variants p=0.002* N of patients Genotype 3 Genotype non-3 * patients with stearosis score 3 or 4

12 Multivariate logistic regression analysis was separately performed for patients with HCV-genotype 3 and for those with HCV-genotype non-3, including: the PNAPL3 variants (I/M +M/M vs. I/I), BMI, age, sex and CD4 cell count. In patients with HCV-genotype non-3 the PNAPL3 variants (I/M +M/M vs. I/I) (p=0.0126) and the CD4 cell count (p=0.0043) were the only predictors of severe steatosis.

13 Conclusion The PNPLA3 p.148 I/M and M/M variants, HCV-genotype 3, CD4+ cell count and the BMI were identified as independent predictors of severe steatosis in HIV/HCV coinfected patients, an association of clinical value deserving further investigation to define its role in clinical practice.

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