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Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Why liver fibrosis staging in 2011 ?
Vincent Soriano
Department of Infectious Diseases
Hospital Carlos III
Madrid, Spain
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Liver damage in HIV infection
• Viral hepatitis (B, C, D)
• Drug-related hepatotoxicity (ARVs & other meds)
• Metabolic abnormalities – NASH
• Alcohol abuse
• Liver involvement in AIDS-related infections
(ie, TB) or cancers (ie, lymphoma)
Nunez M. Hepatology 2010
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Deaths in a cohort of 23,441 HIV patients
on antiretrovirals
Weber et al. Liver-related deaths in persons infected with HIV: the D:A:D study.
Arch Intern Med 2006;166:1632-41.
• Hep B, C, D
• Drug-related toxicity
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Why we need liver fibrosis assessment in HIV
and what distinctions are relevant?
No fibrosis
Significant fibrosis
Advanced
or cirrhosis
Do nothing, wait
Consider interventions:
treatment or drug removal
• Screen for esoph varices
• Screen for HCC
• Adjust meds dosing
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Methods to measure liver fibrosis
• Invasive: Liver biopsy
• Non-invasive:
• Serum fibrosis indexes: FIB-4, Forns, APRI
• Imaging techniques: elastometry (FibroScan)
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Comparison of non-invasive markers
for the diagnosis of HCV-related liver cirrhosis
0
10
20
30
40
50
60
70
80
90
100
%
Plat INR APRI Forns HA YKL PIIINP FS
Nunes et al. JAIDS 2005
HIV negative
0
10
20
30
40
50
60
70
80
90
100
%
Plat INR APRI Forns HA YKL PIIINP FS
Sens
Spec
HIV positive
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Test Parameters
Fibrotest Age, sex, α2-macroglobulin, apolipoprot. A1,
haptoglobin, bilirubin, GGT
Forns Age, GGT, cholesterol, platelets
ELF Age, hyaluronic acid, procollagen III, TIMP-1
APRI AST / platelets
SHASTA Hyaluronic acid, ALT, albumin
FIB-4 Age, platelets, AST, INR
Fibrospect Platelets, cholesterol, GGT, α2-macroglob.
JHI AST, platelets, albumin, alcohol intake
Serum Fibrosis Indexes (Biomarkers)
Yellow: may be altered in HIV-infected patients on ARVs
Underlined: not routine parameters
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Correlation of liver fibrosis assessed by
FibroScan® and liver biopsy in
HIV-HCV co-infected patients
De Ledinghen et al. JAIDS 2005
Fibrosis score (METAVIR)
4321
Liv
er
stiff
ne
ss v
alu
e (
Ln
kP
a)
4,5
4,0
3,5
3,0
2,5
2,0
1,5
1,0
,5
1 - Specificity
1,0,8,5,30,0
Se
nsitiv
ity
1,0
,8
,5
,3
0,0
Cirrhosis AUROC 0.97
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Clinical studies using non-invasive methods
to assess liver fibrosis in HIV
• Liver damage & antiretroviral therapy.
• HCV:
– Comparison with HCV-monoinfected pts.
– Impact of IL28B SNPs on liver fibrosis.
– Regression of liver fibrosis following HCV eradication.
• HBV:
– Impact of long-term nuc therapy in HIV-HBV coinfection.
• Recognition of «hidden», compensated liver cirrhosis.
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Impact of HAART on survival in HIV/HCV patients
Qurishi et al. Lancet 2003:362:1708-13
0 2000 4000 6000 0.3
0.5
0.9
1.1
0.7
Global mortality
0 2000 4000 6000 0.3
0.5
0.9
1.1
0.7
Liver mortality
Patients on HAART
Patients with ART
Patients without ART
Patients on HAART
Patients on ART
Patients without ART
Time on follow-up (days)
P<0.0001 P<0.018
Time on follow-up (days)
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
36%
83%
0%
26%
40%
9%
35%
47%
19%
ARV
naive
ARVs
for <6 years ARVs
for >6 years
Patients
with ALF All patients (n=671)
HCV-RNA positive
HCV-RNA negative
14 6 8 262 146 116 405 237 168
Blanco et al. J Viral Hepat 2011; 18: 11-16
No.
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
The problem
• Hep C progress more rapidly to
cirrhosis in coinfected patients
with low CD4 counts.
• HAART reverses HIV-associated
CD4 depletion.
• Then, HAART should prevent
indirectly rapid progression of
HCV-related liver disease in HIV.
• ARVs may cause liver toxicity.
• Hepatotoxicity of ARVs is
more frequent in HCV/HIV co-
infected patients.
• Then, earlier treatment of
hepatitis C should improve the
tolerance of HAART
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Time Dependent Effect of HAART on Liver Fibrosis In HIV/HCV patients
HIV-RNA
CD4 count
•Immune recovery
•HIV suppression
•Long-term liver toxicity
•Mitochondrial
•Metabolic syndrome
HAART
Verma et al. 3.3 & 3.9 yrs
Brau et al. 3.6 yrs
Pineda et al. 1.8 & 5.7 yrs
HCIII cohort 6.8 yrs
Time (years)
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Progression of HCV-related liver fibrosis in HIV patients
No HAART
HIV-neg
Uncontrolled HIV replication
Low CD4 counts HAART
Metabolic abnormalities
Hepatotoxicity of meds
years
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Impact of HAART on liver fibrosis
in HCV-HIV coinfected patients –
the double sword effect
When possible treat
Hepatitis C in advance !
Benefit
Worsening
CD4 gain
PIs – dislipidemia & insulin resistance
NRTIs – mitochondrial toxicity
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
HIV positive HIV negative p
No. of patients 141 103
Mean age (years) 415 5015 <0.001
Male sex (%) 73
AST (IU/L) 8664 7360 ns
ALT (IU/L) 10274 11582 ns
Platelets 16362 23169 <0.001
HCV load (logIU/L) 6.80.9 5.90.6 <0.001
HCV genotype (%) 1 2 3 4
68 2 21 9
58 16 12 14
Mean liver stiffness (kPa) 13.510.7 8.97.4 <0.001
Metavir score (%) F0-F1 F2 F3 F4
28 21 16 35
53 21 9
17
Under HAART (%) 90 -- --
HIV load <50 copies/mL (%) 76 -- --
Mean HIV load (log copies/mL) 4.30.5 -- --
Mean CD4 count (cells/L) 512277 -- --
Characteristics of IFN-naive patients with chronic hepatitis C
and elevated ALT assessed by FibroScan
Barreiro et al. CID 2007
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Factors associated with liver fibrosis in HIV/HCV coinfected patients
Barreiro et al. Clin Infect Dis 2006
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Liver fibrosis assessed by FibroScan after HCV
therapy in 256 HIV-HCV coinfected patients
(mean 4 years follow-up)
0%
20%
40%
60%
80%
100%
SVR Non-SVR
F4 (>12 KPa)
F3 (9.5-12 KPa)
F2 (7.1-9.4 KPa)
F0-F1 (<7.1 KPa)
Barreiro et al. AVT 2007
86 170
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Odds ratio (95% confidence interval)
HCV-RNA <600,000 IU/ml
HCV genotype 3
rs12979860 CC genotype
Liver fibrosis stage F0-F2
0 5 10 15 20 25 30 35 40
11.9
8.0
3.7
3.5
p<0.001
p<0.001
p=0.002
p=0.009
Rallon et al. AIDS 2010
IL28B polymorphisms in HIV-HCV coinfection
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Prometheus index
• HCV genotype
• Fibrosis stage (KPa)
• Serum HCV-RNA
• IL28B SNPs
http://ideasydesarrollo.com/fundacio
n/prometheusindex.php
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
http://ideasydesarrollo.com/fundacion/prometheusindex.php
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Predictors of liver cirrhosis in 304 HIV/HCV pts
Variables Multivariate (OR [95% CI] p)
Age (per year) 1.05 [0.99 – 1.12] 0.08
Male gender 1.20 [0.42 – 3.44] 0.73
Prior alcohol intake >60 g/day 1.97 [0.95 – 4.06] 0.07
HOMA index (per unit) 0.99 [0.76 – 1.30] 0.97
ALT (per IU/L) 0.99 [0.94-1.06] 0.93
Nadir CD4 count (per cell/µL) 0.98 [0.99 – 1.01] 0.63
Under HAART 2.04 [0.42 – 9.93] 0.38
IL28B CC vs CT/TT 2.32 [1.22 – 4.41] 0.01
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Proportion of HIV/HCV-coinfected patients
with liver cirrhosis according to IL28B SNPs
and HCV genotypes
24%
28%
22%
18%
13%15%
6%
15%
0
5
10
15
20
25
30
All HCV-1 HCV-3 HCV-4
CCCT/TT
IL28B genotype:
HCV-genotypepatients
p=0.01
p=0.04
p=0.04
p=0.23
Pro
port
ion
of
cirrh
otics (
%)
170 96 38304
Barreiro et al. JID 2011
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Risk for developing cirrhosis over time in
HIV/HCV-coinfected patients according to
the IL28B SNPs
Cum
ula
tive p
roport
ion o
f
com
pensate
d liv
er
cirrh
osis
(%
)
0
20
40
60
80
100
0 10 20 30 40
length of infection (years)
IL-28B genotype:CC
CT/TT
HR= 3.02 (95% CI, 1.24 - 7.39), p= 0.015
Barreiro et al. JID 2011
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Summary
• Liver events account for a large number of complications
and deaths in HIV+ individuals.
• Assessment of liver fibrosis by non-invasive tools allows to
split out confidently null, moderate and advanced
(cirrhosis) liver fibrosis staging in this population.
• Elastometry may be more accurate than biomarker
indexes in most situations.
• Longitudinal periodic assessments and widespread use of
these tools provide a unique opportunity to monitor liver
fibrosis changes (progression or regression) under
different conditions (Heps, NASH) and interventions
(therapies).
Presented at the Pre-workshop Educational Course, Milan, Italy, 1 June 2011
Acknowledgments
Clinic Laboratory
Pablo Barreiro Norma Rallon
Pablo Labarga Ana Treviño
Luz Martin-Carbonero Carmen de Mendoza
Eugenia Vispo Eva Poveda
Jose Medrano Sonia Rodriguez-Novoa
Jose V Fernandez Jose Miguel Benito
Fernanda Rick Tamara Bar-Magen