Vincent Soriano Department of Infectious Diseases Hospital...

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


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


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


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


Methods to measure liver fibrosis

• Invasive: Liver biopsy

• Non-invasive:

• Serum fibrosis indexes: FIB-4, Forns, APRI

• Imaging techniques: elastometry (FibroScan)


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


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


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


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.


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)


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.


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


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)


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


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


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


Factors associated with liver fibrosis in HIV/HCV coinfected patients

Barreiro et al. Clin Infect Dis 2006


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


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


Prometheus index

• HCV genotype

• Fibrosis stage (KPa)

• Serum HCV-RNA

• IL28B SNPs

http://ideasydesarrollo.com/fundacio

n/prometheusindex.php


http://ideasydesarrollo.com/fundacion/prometheusindex.php


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


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


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


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).


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

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