Observational Study
Copyright ©The Author(s) 2017.
World J Virol. May 12, 2017; 6(2): 36-45
Published online May 12, 2017. doi: 10.5501/wjv.v6.i2.36
Table 1 Demographic, clinical and laboratory characteristics of the patients, according to the existence or not of significant liver fibrosis (≥ F2)
All patients (n = 158)No fibrosis (n = 124)Fibrosis (n = 34)P value
Demography, epidemiology, anthropometry and habits
Age (yr)44.56 (43.20-45.92)44.50 (42.93-46.07)44.79 (41.96-47.63)0.9
Male, n (%)104 (65.8)78 (62.9)26 (76.5)0.14
Weight (kg)65.17 (62.88-67.46)64.46 (61.72-67.20)67.76 (64.03-71.50)0.24
Height (cm)164.4 (160.6-168.2)163.4 (158.5-168.2)168.2 (166.2-170.2)0.3
Body mass index (kg/m2)23.58 (23.10-24.05)23.48 (22.95-24.01)23.90 (22.75-25.0.6)0.5
Tobacco smokers, n (%)105 (66.5)78 (62.9)27 (79.4)0.07
Cannabis use, n (%)38 (24.1)22 (17.7)16 (47.1)0.0004
Alcohol intake, n (%)155 (35.0)43 (34.7)12 (36.4)0.9
IDU, n (%)58 (36.9)29 (23.6)29 (85.6)< 0.0001
Men who have sex with men, n (%)28 (17.8)27 (22.0)1 (2.9)0.01
Heterosexual, n (%)67 (42.7)63 (51.2)4 (11.8)< 0.0001
Transfusion, n (%)4 (2.5)4 (3.3)0 (0.0)0.3
HIV-related parameters
Current CD4 counts (cells/μL)581.5 (533.0-630.1)612.3 (555.8-668.8)469.6 (383.7-555.4)0.017
Nadir CD4 counts (cells/μL)201.8 (176.5-227.1)213.4 (183.4-243.4)159.7 (116.7-202.6)0.04
CD4 gain (cells/μL)379.7 (334.4-425.0)399.0 (345.4-452.6)309.9 (231.4-388.4)0.11
Undetectable HIV viral load, n (%)135 (85.4)109 (87.9)26 (76.5)0.09
HIV viral load (log copies/mL)22.996 (2.556-3.434)2.991 (2.407-3.575)3.006 (2.173-3.840)0.97
Years of HIV infection11.93 (11.12-12.73)11.31 (10.39-12.22)14.19 (12.70-15.68)0.003
Months on antiretroviral therapy114.3 (106.8-121.8)109.9 (101.3-118.5)130.2 (115.0-145.3)0.03
CDC clinical stage, n (%)
A84 (53.5)65 (52.8)19 (55.9)0.07
B23 (14.6)22 (17.9)1 (2.9)
C50 (31.8)36 (29.3)14 (41.2)
HCV-related parameters
HCV infection, n (%)57 (36.1)25 (20.2)32 (94.1)< 0.0001
HCV viral load (log copies/mL)5.745 (5.504-5.985)5.524 (5.085-5.964)5.915 (5.649-6.181)0.11
Years of HCV infection22.46 (20.71-24.21)21.84 (18.96-24.72)22.94 (20.65-25.23)0.5
HCV genotype, n (%)
131 (54.4)14 (56.0)17 (53.1)0.7
22 (1.3)1 (4.0)1 (3.1)
315 (23.6)5 (20.0)10 (31.3)
49 (15.8)5 (20.0)4 (12.5)
Liver fibrosis parameters
Transient elastometry (kPa)7.53 (5.99-9.06)4.65 (4.45-4.85)18.02 (11.93-24.10)< 0.0001
APRI0.633 (0.511-0.756)0.385 (0.346-0.423)1.541 (1.093-1.989)< 0.0001
Forns4.412 (4.116-4.707)3.990 (3.734-4.246)5.949 (5.095-6.802)0.0001
FIB-41.475 (1.249-1.700)1.088 (0.985-1.191)2.884 (2.031-3.736)0.0002
YFPI30.584 (0.416-0.752)0.281 (0.222-0.340)0.821 (0.548-1.095)0.0004
Degree of liver fibrosis, n (%)
F0-F1124 (78.5)124 (100)0 (0.0)< 0.0001
F215 (9.5)0 (0.0)15 (44.1)
F310 (6.3)0 (0.0)10 (29.4)
F49 (5.7)0 (0.0)9 (26.5)
Laboratory parameters
Platelet count (/μL)222570 (211690-233450)236750 (225410-248090)169270 (147220-191330)< 0.0001
Glucose (mg/dL)98.54 (95.25-101.84)98.00 (94.62-101.38)100.66 (90.92-110.39)0.5
Total cholesterol (mg/dL)195.01 (188.51-201.51)201.0 (193.8-208.3)173.0 (160.6-185.4)0.0004
HDL cholesterol (mg/dL)49.33 (46.88-51.78)49.42 (46.95-52.29)48.25 (42.02-54.48)0.7
LDL cholesterol (mg/dL)110.73 (104.68-116.77)116.97 (110.22-123.72)87.53 (76.91-98.16)0.0001
Triglycerides (mg/dL)199.79 (170.08-229.50)189.0 (157.5-220.5)241.7 (161.4-322.0)0.22
AST (UI/mL)40.89 (36.01-45.78)30.72 (28.30-33.13)78.00 (62.01-93.99)< 0.0001
ALT (UI/mL)47.82 (40.54-55.09)36.91 (32.03-41.79)87.59 (62.16-113.02)0.0003
AST/ALT ratio1.011 (0.949-1.074)0.993 (0.927-1.059)1.079 (0.913-1.246)0.3
GGT (UI/mL)83.95 (66.61-101.29)59.73 (48.40-71.07)174.21 (110.61-237.81)0.001
Alkaline phosphatase (UI/mL)91.87 (85.09-98.65)90.72 (83.22-98.23)98.31 (81.46-115.17)0.4
MMP-2 (ng/mL)0.538 (0.442-0.654)0.482 (0.387-0.600)0.867 (0.579-1.300)0.02
MMP-3 (ng/mL)15.00 (13.24-17.01)14.36 (12.47-16.54)17.77 (14.45-23.49)0.18
MMP-8 (ng/mL)0.031 (0.023-0.041)0.029 (0.021-0.039)0.040 (0.020-0.078)0.4
MMP-9 (ng/mL)22.49 (18.81-26.90)23.19 (19.00-28.31)19.94 (13.01-30.58)0.5
MMP-10 (ng/mL)2.50 (1.66-3.75)2.163 (1.487-3.145)5.077 (0.938-27.469)0.12
TIMP-1 (ng/mL)50.56 (45.58-56.08)50.84 (45.43-56.88)49.49 (37.71-64.94)0.8
TIMP-2 (ng/mL)8.23 (7.16-9.46)7.62 (6.59-8.80)11.15 (7.55-16.45)0.03
TIMP-4 (ng/mL)0.040 (0.030-0.054)0.037 (0.027-0.051)0.054 (0.026-0.110)0. 3
1Less than 50 g/d;
2Only if detectable;
3YFPI: Yearly fibrosis progression index (only in HCV-infected patients), calculated as transient elastometry value divided into the years of estimated HCV infection. Values are expressed as mean (95%CI) or n (%) as appropriate. IDU: Intravenous drug use. MMP: Matrix metalloprotease; HCV: Hepatitis C virus; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; APRI: AST to Platelet Ratio Index; FIB-4: Fibrosis-4 index; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; GGT: Gamma-glutamyl transpeptidase; TIMP: Tissue inhibitor of metalloprotease.
Table 2 Genotypic frequencies of different single nucleotide polymorphisms according to liver fibrosis ≥ F2 and hepatitis C virus status
SNPGenotypeNo fibrosis n (%)Fibrosis n (%)P valueHIV mono-infected n (%)HIV/HCV coinfected n (%)P value
MMP-1 -1607 1G/2G1G1G14 (20.3)4 (16.7)0.99 (16.1)9 (24.3)0.6
1G2G13 (18.8)5 (20.8)12 (21.4)6 (16.2)
2G2G42 (60.9)15 (62.5)35 (62.5)22 (59.5)
MMP-8 -799C/TCC30 (27.0)6 (22.2)0.625 (26.3)11 (25.5)1
CT47 (42.4)10 (37.0)39 (41.1)18 (41.9)
TT34 (30.6)11 (40.8)31 (32.6)14 (32.6)
MMP-9 -1562 C/TCC78 (81.2)28 (84.8)0.661 (83.6)45 (80.4)0.6
CT18 (18.8)5 (15.2)12 (16.4)11 (19.6)
TT0 (0.0)0 (0.0)0 (0.0)0 (0.0)
MMP-13 -77A/GAA89 (74.8)21 (61.8)0.1470 (72.9)40 (70.2)0.7
AG30 (25.2)13 (38.2)26 (27.1)17 (29.8)
GG0 (0.0)0 (0.0)0 (0.0)0 (0.0)
TNF-α -308 G/AAA11 (11.3)4 (11.8)0.57 (9.5)8 (14.0)0.7
AG62 (63.9)18 (52.9)46 (62.1)34 (59.6)
GG24 (24.7)12 (35.3)21 (28.4)15 (26.3)
CCR5-Δ32wt/wt96 (80.0)30 (88.2)0.2777 (79.4)49 (86.0)0.3
wt/Δ3224 (20.0)4 (11.8)20 (20.6)8 (14.0)
Δ32/Δ320 (0.0)0 (0.0)0 (0.0)0 (0.0)
SNP: Single nucleotide polymorphisms; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; MMP: Matrix metalloprotease.
Table 3 Liver fibrosis indexes according to the single nucleotide polymorphisms genotypes
SNPGenotypeTransient elastometryYFPI1APRIFornsFIB-4
MMP-1 -1607 1G/2G1G1G5.583 (4.600-6.567)0.346 (0.215-0.477)0.693 (0.192-1.195)3.719 (2.860-4.579)1.317 (0.723-1.911)
1G2G5.911 (4.649-7.174)0.470 (0.250-0.691)0.488 (0.307-0.670)4.253 (3.430-5.077)1.092 (0.859-1.324)
2G2G8.781 (5.585-11.977)0.689 (0.378-1.001)0.675 (0.453-0.897)4.390 (3.914-4.867)1.479 (1.097-1.862)
P value0.30.30.70.40.5
MMP-8 -799C/TCC6.644 (3.736-9.553)0.633 (0.074-1.193)0.615 (0.411-0.819)4.510 (3.920-5.099)1.461 (1.058-1.864)
CT5.628 (5.060-6.196)0.357 (0.275-0.439)0.453 (0.347-0.559)4.126 (3.701-4.551)1.145 (1.014-1.277)
TT7.729 (4.540-10.918)0.671 (0.376-0.965)0.768 (0.447-1.088)4.407 (3.825-4.989)1.603 (1.081-2.125)
P value0.40.190.10.50.15
MMP-9 -1562 C/TCC7.540 (5.810-9.269)0.527 (0.361-0.694)0.612 (0.475-0.749)4.370 (4.024-4.717)1.404 (1.163-1.645)
CT11.178 (4.093-18.264)0.833 (0.229-1.437)0.867 (0.412-1.323)5.083 (4.024-6.142)2.043 (1.044-3.041)
TT-----
P value0.140.160.160.110.065
MMP-13 -77A/GAA7.217 (5.654-8.780)0.535 (0.358-0.712)0.623 (0.480-0.766)4.352 (3.993-4.711)1.462 (1.185-1.738)
AG8.721 (4.646-12.798)0.700 (0.291-1.109)0.698 (0.426-0.970)4.588 (3.998-5.177)1.553 (1.109-1.998)
GG-----
P value0.40.40.60.50.7
TNF-α -308 G/AAA10.073 (1.300-18.849)0.656 (0.132-1.180)0.693 (0.135-1.250)4.331 (3.280-5.383)1.584 (0.693-2.475)
AG8.086 (5.779-10.394)0.552 (0.336-0.767)0.675 (0.495-0.855)4.603 (4.174-5.033)1.575 (1.210-1.940)
GG7.514 (4.623-10.404)0.620 (0.228-1.012)0.701 (0.405-0.997)4.221 (3.513-4.929)1.466 (1.021-1.910)
P value0.70.90.990.60.9
CCR5-Δ32wt/wt7.852 (5.998-9.707)0.590 (0.399-0.783)0.664 (0.525-0.803)4.439 (4.102-4.775)1.513 (1.264-1.762)
wt/Δ326.521 (4.109-8.934)0.545 (0.232-0.858)0.539 (0.230-0.847)4.391 (3.684-5.098)1.335 (0.699-1.971)
Δ32/Δ32-----
P value0.50.90.40.90.6
1YFPI: Yearly fibrosis progression index (only for HCV-infected patients); SNP: Single nucleotide polymorphisms; MMP: Matrix metalloprotease. Values are expressed as mean (95%CI) in ng/mL; APRI: AST to Platelet Ratio Index; FIB-4: Fibrosis-4 index.
Table 4 Metalloproteases and their tissue inhibitors according to the single nucleotide polymorphisms genotypes
SNPGenotypeMMP-2MMP-3MMP-8MMP-9MMP-10TIMP-1TIMP-2TIMP-4
MMP-1 -16071G/2G1G1G0.379 (0.195-0.736)16.69 (11.00-25.33)0.035 (0.013-0.095)19.93 (11.59-34.28)1.782 (0.350-9.071)41.73 (30.87-56.42)6.79 (4.52-10.21)0.031 (0.010-0.091)
1G2G0.803 (0.409-1.575)19.87 (15.13-26.10)0.041 (0.012-0.134)22.35 (13.37-37.36)1.451 (0.417-5.047)54.07 (39.44-74.14)7.30 (4.49-11.87)0.047 (0.020-0.113)
2G2G0.609 (0.449-0.826)14.72 (11.57-18.73)0.027 (0.017-0.042)23.65 (17.07-32.76)3.345 (1.512-7.399)50.34 (42.16-60.10)8.39 (6.54-10.76)0.032 (0.019-0.053)
P value0.180.40.70.90.50.40.60.7
MMP-8 799C/TCC0.655 (0.473-0.908)15.96 (12.94-19.68)0.048 (0.025-0.090)29.93 (19.94-44.94)4.650 (1.354-15.97)61.60 (49.94-75.99)11.67 (8.59-15.85)0.041 (0.023-0.073)
CT0.568 (0.409-0.787)13.05 (10.22-16.65)0.031 (0.018-0.054)21.30 (15.50-29.28)2.179 (1.201-3.953)47.17 (38.80-57.34)6.71 (5.50-8.18)0.035 (0.021-0.058)
TT0.432 (0.280-0.668)16.66 (13.35-20.81)0.020 (0.015-0.027)18.86 (14.03-25.37)1.623 (0.938-2.808)47.75 (40.75-55.94)8.12 (5.89-11.20)0.050 (0.030-0.084)
P value0.30.30.090.170.170.110.010.6
MMP-9 1562 C/TCC0.495 (0.385-0.637)15.42 (13.11-18.14)0.034 (0.024-0.049)22.39 (17.79-28.19)2.405 (1.462-3.957)52.23 (46.17-59.07)8.39 (7.18-9.80)0.037 (0.026-0.053)
CT1.031 (0.853-1.246)18.15 (13.99-23.54)0.020 (0.008-0.047)22.97 (14.77-35.71)5.960 (0.666-53.34)46.55 (33.82-64.07)8.18 (4.40-15.21)0.058 (0.025-0.137)
TT--------
P value0.020.30.20.90.20.40.90.3
MMP-13 77A/GAA0.522 (0.419-0.650)15.62 (13.47-18.13)0.030 (0.022-0.041)23.06 (18.64-28.54)2.337 (1.380-3.957)53.30 (47.05-60.38)8.54 (7.21-10.12)0.050 (0.036-0.069)
AG0.683 (0.458-1.017)14.37 (11.10-18.59)0.037 (0.019-0.071)22.96 (16.01-32.93)2.685 (1.215-5.931)48.10 (39.30-58.88)8.07 (6.09-10.68)0.031 (0.016-0.058)
GG--------
P value0.220.60.60.980.80.40.70.14
TNF-α 308 G/AAA0.730 (0.325-1.639)21.40 (14.72-31.13)0.039 (0.010-0.156)17.42 (8.16-37.21)0.804 (0.369-1.755)57.25 (37.28-87.92)13.14 (8.72-19.80)0.111 (0.054-0.227)
AG0.558 (0.429-0.727)14.65 (11.96-17.95)0.031 (0.020-0.050)23.41 (17.78-30.83)4.460 (2.097-9.486)51.62 (43.92-60.66)8.39 (6.71-10.48)0.043 (0.028-0.064)
GG0.453 (0.281-0.732)16.54 (13.36-20.47)0.027 (0.018-0.040)23.62 (17.25-32.34)1.998 (0.879-4.542)46.63 (39.84-54.59)7.04 (5.36-9.26)0.023 (0.012-0.045)
P value0.40.240.80.70.0650.60.10.02
CCR5-Δ32wt/wt0.601 (0.484-0.747)15.75 (13.71-18.09)0.031 (0.022-0.043)21.55 (17.50-26.53)2.441 (1.482-4.020)50.72 (44.83-57.38)8.10 (6.95-9.45)0.041 (0.029-0.057)
wt/Δ320.431 (0.286-0.652)13.64 (9.87-18.85))0.032 (0.020-0.051)27.15 (18.55-39.73)2.662 (1.222-5.801)52.01 (42.66-63.42)9.44 (6.49-13.72)0.043 (0.021-0.088)
Δ32/Δ32--------
P value0.150.40.90.30.90.90.40.9
SNP: Single nucleotide polymorphisms; MMP: Matrix metalloprotease. Values are expressed as mean (95%CI) in ng/mL. APRI: AST to Platelet Ratio Index; FIB-4: Fibrosis-4 index; TIMP: Tissue inhibitor of metalloprotease.
Table 5 Correlations among metalloproteases, their tissue inhibitors and liver fibrosis parameters
MMP-3MMP-8MMP-9MMP-10TIMP-1TIMP-2TIMP-4TEYFPIAPRIFornsFIB-4
MMP-20.19 (0.04)0.21 (0.02)0.21 (0.02)0.20 (0.09)0.29 (0.002)0.29 (0.002)0.35 (0.0002)0.23 (0.016)0.30 (0.058)0.20 (0.03)0.19 (0.04)0.20 (0.03)
MMP-30.29 (0.0006)0.30 (0.0006)0.15 (0.19)0.33 (0.0001)0.27 (0.002)0.38 (< 0.0001)0.09 (0.3)0.001 (0.99)0.16 (0.06)0.16 (0.06)0.10 (0.24)
MMP-80.69 (< 0.0001)0.25 (0.02)0.71 (< 0.0001)0.40 (< 0.0001)0.24 (0.005)-0.02 (0.8)-0.15 (0.3)-0.01 (0.9)0.03 (0.8)-0.03 (0.7)
MMP-90.21 (0.06)0.71 (< 0.0001)0.16 (0.06)0.21 (0.01)-0.21 (0.01)-0.32 (0.02)-0.17 (0.047)-0.11 (0.2)-0.20 (0.02)
MMP-100.12 (0.3)0.22 (0.051)0.11 (0.3)0.01 (0.9)-0.09 (0.7)0.12 (0.3)-0.08 (0.5)-0.03 (0.8)
TIMP-10.40 (< 0.0001)0.39 (< 0.0001)0.02 (0.8)-0.04 (0.8)-0.02 (0.8)0.07 (0.4)0.01 (0.9)
TIMP-20.33 (0.0001)0.28 (0.0009)0.25 (0.08)0.35 (< 0.0001)0.20 (0.018)0.36 (< 0.0001)
TIMP-40.11 (0.2)0.03 (0.8)0.14 (0.12)0.06 (0.5)0.19 (0.03)
TE0.94 (< 0.0001)0.75 (< 0.0001)0.59 (< 0.0001)0.82 (< 0.0001)
YFPI0.63 (< 0.0001)0.51 (0.0001)0.74 (< 0.0001)
APRI0.55 (< 0.0001)0.90 (< 0.0001)
Forns0.67 (< 0.0001)
Values are expressed as r (P value). MMP: Matrix metalloprotease; HCV: Hepatitis C virus; TE: Transient elastometry; YFPI: Yearly fibrosis progression index (only for HCV-infected patients); TIMP: Tissue inhibitor of metalloprotease.
Table 6 Independent predictors of different fibrosis indexes
TEAPRIFornsFIB-4YFPI
Higher MMP-2 levels0.0010.00010.030.00090.004
Higher TIMP-2 levels0.0160.00010.0240.0002-
Lower MMP-9 levels0.0230.016-0.030.043
Lower current CD4 counts-0.0320.0370.043-
Older age--0.0040.05-
% of the index accounted for by the model20.00%35.30%23.30%33.50%20.70%
Numbers represent P values. HCV: Hepatitis C virus; MMP: Matrix metalloprotease; TE: Transient elastometry; YFPI: Yearly fibrosis progression index (only for HCV-infected patients); APRI: AST to Platelet Ratio Index; TIMP: Tissue inhibitor of metalloprotease.