Changing Epidemiology of HCV Mortality

and Morbidity in HIV patients

10th International Workshop on HIV & Hepatitis Co-infection, Paris,

France, Thursday 12th June, 2014

Jrgen K. Rockstroh
Department of Internal Medicine I
University Hospital Bonn
Germany

Conflict of interest
I have received honoraria for speaking at educational
events or consulting from:
Abbott, Abbvie, Bionor, BMS, Boehringer, Gilead,
Janssen, Merck, Novartis, Pfizer, Roche, Tibotec,
Tobira and ViiV

Changing Epidemiology of HCV Mortality and

Morbidity in HIV Patients

Why is the natural history of HCV different in

HIV?

Which impact has successful HIV therapy on the

further course of HCV associated liver disease and
how does it change the liver disease burden of HCV
in HIV?

Can HCV therapy induced SVR or cure of HCV

change the outcome of clinical endpoints in
HIV/HCV coinfection?

New HCV /HIV epidemiological data.

Center for Disease Analysis 2013

Background
HIV accelerates the natural course of hepatitis particularly
with declining CD4 counts1
Liver disease associated with HCV infection has become
a leading cause of morbidity and mortality among
HIV-infected patients

1. Rockstroh J, et al. Am J Gastroenterol 1996;91:25632568;

2. Weber R, et al. Arch Intern Med 2006;166:163241

% of Patients Without Liver Failure

Morbidity and Mortality in Patients

with HIV and HCV
100

Group B-D
(n=191)
p < 0.001

90

80
Group A (n=49)

70

30

40

50
Time (months)

60

Rockstroh JK et al., Am J Gastroenterology 1996;91:2563-2568

70

Mechanism of the effect of HIV on the

progression of hepatitis C
HIV may increase HCV replication and fibrogenesis via TGF 11.
Enhanced intrahepatic inflammatory cytokine response could be
the main cause of accelerated progression2.
Increases in profibrogenic cytokine expression and secretion,
generation of enhanced oxidative stress, and increases in
hepaotcyte apoptosis which may be further augmented in the
presence of increased microbial translocation in the setting of
HIV.
Impaired IL-2 secretion of CD4+ T cells resulting in an ineffective
stimulation of anti-fibrotic NK cell function4.
Altered levels of matrix metalloproteinases; HIV-associated gut
depletion of CD45
1Lin

W, et al. Gastroenterology 2008; 134: 803-811

T, et al. AIDS 2008;22: 203-210.
Lin W et al., J Infect Dis 2013;207:S13-18
4Glssner et al., J Hepatol 2013;59: 427-433
5Mastroianni Cm et al., Int J Mol Sci 2014;15:9184-9208
2Kuntzen

Changing Epidemiology of HCV Mortality and

Morbidity in HIV Patients

Why is the natural history of HCV different in

HIV?

Which impact has successful HIV therapy on the

further course of HCV associated liver disease and
how does it change the liver disease burden of HCV
in HIV?

Can HCV therapy induced SVR or cure of HCV

change the outcome of clinical endpoints in
HIV/HCV coinfection?

Cumulative Proportion of Patients With Cirrhosis by

PI Exposure: MultivirC Group

Benhamou Y, et al. Hepatology. 2001;34:283-287.

Patients With Cirrhosis

60

Cumulative Proportion (%)

Retrospective cohort study

182 HIV/HCV-coinfected
patients
At liver biopsy
PI-based HAART (n=63)
Never treated with PI-based
HAART (n=119)
PI exposure versus no PI exposure
Lower liver fibrosis stage
(P=0.03)
Cirrhosis rates (P=0.0006)
5-year: 2% versus 5%
15-year: 5% versus 18%
25-year: 9% versus 27%

P=0.0006

50

No PI Exposure

40
30
20

PI Exposure

10
0

10

15

20

25

Estimated HCV Infection

Duration (y)

30

Qurishi N, et al. Lancet. 2003:362:1708-1713.

Cumulative Survival

Bonn cohort (1990-2002)

285 HIV/HCV coinfected
patients
Liver-related mortality rates
per 100 person-years
HAART: 0.45
ART: 0.69
No therapy: 1.70
Predictors for liver-related
mortality
No HAART
Low CD4 cell count
Increasing age

Cumulative Survival

Impact of ART on Overall Liver Mortality

in HIV/HCV-Coinfected Patients
Overall Mortality

HAART*
0,8
0,6

ART
0,4

*P<0.001
0,2

1000

2000

No therapy
3000 4000
Days

6000

Liver-Related Mortality

HAART*
ART

0,8

No therapy

0,6
0,4
0,2

5000

*P=0.018
0

1000

2000

3000 4000
Days

5000

6000

Impact of HIV RNA, CD4, or Both on Liver

Fibrosis Progression Rate
Estimated Time From HCV
Infection to Cirrhosis (years)

60
50

P=0.005

P=0.004

P=0.005

50

49

49

41

40

39

37

31

30
20
10
0

P=0.05

P=0.04

<400

400-99K

>100k

>350

<350

<400

>400

(n=141)

(n=117)

(n=16)

(n=124)

(n=150)

(n=100)

(n=88)

HIV RNA

CD4

(copies/mL)

(cells/mm3)

Time to cirrhosis estimated using liver fibrosis progression

rate based on Ishak Fibrosis units/year.

HIV RNA (copies/mL) +

<500 CD4 cells/mm3

Brau N, et al. J Hepatol. 2006;44:47-55

Effect of HAART on liver fibrosis

progression: Sequential studies.
Factors independently asociated with fibrosis progression
Adjusted Odds Ratio (95% CI)
1.26
Year 1st LBx (p=0.58)
0.9
ART between LBx (p=0.8)
0.29
3.23

Undetectable HIV-RNA (p=0.017)

High necroinflamatory activity (p=0.008)

0.26

Response to HCV Rx (p=0.018)

0.01

0.1

0.125

0.17

0.25

0.5

Macas J, et al. Hepatology 2009; 50:1056-1063

10

ART and SVR to HCV therapy are associated with slower

liver fibrosis progression in HIV-HCV-coinfected patients:
study from the ANRS CO 13 HEPAVIH cohort.
Methods:
HIV-HCV-coinfected adults enrolled in the ANRS CO 13
HEPAVIH cohort, for whom two results of LS, evaluated over
24 months, were available.
Results:
In multivariate linear and logistic analyses, excessive alcohol
intake ( coefficient 6.8; P=0.0006) and high HCV viral load
(OR 1.7, 95% CI 1.1, 2.5; P=0.01) were independently
associated with an increase in LS, whereas time on
ART>114.5 months (OR 0.5, 95% CI 0.3, 0.9; P=0.03) and
achievement of sustained virological response (OR 0.1, 95%
CI 0.01, 0.9; P=0.04) were independently associated with no
increase in LS.
Loko MA, et al; ANRS CO 13 HEPAVIH Study Group. Antivir Ther. 2012;17:1335-43.

Antiretroviral Therapy Reduces the

Rate of Hepatic Decompensation
Among HIV- and Hepatitis C Virus
Coinfected Veterans
Objective: To evaluate 10 090 HIV/HCV-coinfected males
from the Veterans Aging Cohort Study Virtual Cohort,
who had not initiated ART at entry, for incident hepatic
decompensation between 1996 and 2010.
Results: Initiation of ART significantly reduced the rate
of hepatic decompensation by 28%41% on average.

Anderson JP, et al. Clin Infect Dis. 2014 Mar;58(5):719-27.

Study design: Retrospective cohort study from

the Veterans Aging Cohort Study Virtual Cohort
12 mo
In VA

HIV/HCV
on ART
Baseline

Follow-up

Start of
Follow-up

Study Endpoint
Death
HCV Therapy

12 mo
in VA

Last Visit Before Sept.

30, 2010

HCV
Baseline

Follow-up

Start of
Follow-up

Study aim: To compare the incidence of hepatic decompensation between ARTtreated HIV/HCV-coinfected and HCV-monoinfected pts
Hepatic decompensation was defined as a hospital diagnosis indicated by ICD9 code or two or more outpatient diagnoses of ascites, spontaneous bacterial
peritonitis, or esophageal variceal hemorrhage
Lo Re V, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. WEAB0102.

Standardized Cumulative Incidence of

Hepatic Decompensation*
* Based

on
competing risk
regression
analysis.

ART-Treated
HIV/HCV-Coinfected

HCV-Monoinfected

Log-rank
p<0.001

HD risk was 83% higher in the coinfected group (aHR 1.83, 95% confidence interval [CI] 1.54 to 2.18)
Lo Re V, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. WEAB0102.

HIV Suppression Is Associated with Less

Hepatic Necroinflammatory Activity
10
9

Activity Score

*
*

7
6
5
4
3
2
1
0

Viral Load
Undetectable
Mehta SH et al. Hepatology 2005

Viral Load
Detectable

Probability of remaining free of developing

a hepatic decompensation

Pineda JA et al., Hepatology 2007;46:622-630

HAART induces recovery of specific T-cell

response to HCV core proteins
P=0.003

% patients with detectable ELISpot

response

ART

49

P=0.002

50

40
33
30
24
19

20
13
10

0
-41

-2

n=16

n=64

n=50

33

n=64

74

n=37

Median time (months)

from ART starting

Median (IQR) log HCV-RNA (IU/mL)

ART
P for
trend=0.02

8
7,5
7
6,5
6
5,5
5
-41

n=20

-2

n=51

n=51

33

74

n=66

n=35

Rohrbach J, et al. CROI 2009. Abstract 105, Rohrbach J, et al. GUT 2010;59:1252-1258

Median time (months)

from ART starting

Any additional benefits or impact of

ART?

1Mohan

The changing pattern of glomerular disease in HIV

and hepatitis C co-infected patients in the era of
HAART1
ART is associated with lower post-IFN HCV-RNA
levels; that change is linked to reduced hepatic
interferon stimulating gene (ISG) expression; these
data support recommendations to provide ART
prior to IFN-based treatment of HCV

S et al., Clin Nephrol 2013;79:285-291

Balagopal A et al., Hepatology 2014; April 5th Epub ahead of print

Has the outcome of liver disease in HIV/HCV-coinfected

patients become similar to that in HCV monoinfection?
Metanalysis of 26 studies
No HAART

HAART
(b)

Deng L, et al. World J Gastroenterol 2009; 15: 996-1003

EACS Guidelines: When to Start

Initiation of ART

ART is always recommended if CD4 count <350 cells/mm3

Condition

Current CD4 + lymphocyte count

350500

>500

HBV requiring anti-HBV treatment

HBV not requiring anti-HBV treatment

R
C

HCV for which anti-HCV treatment is being considered or given

HCV for which anti-HCV treatment not feasible

R
R

C
C

C = CONSIDER; D = DEFER; R = RECOMMENDED

EACS treatment guidelines, Version 7.0, Nov 2013. Available at:

http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed November
2013

Changes in death causes over time

1999-2000
N=255

2009-2011
N=548

3,802 deaths in 49,734 HIV positive individuals followed for 304,695 person-years
Death rate fell from 17.4 deaths per 1000 py in 1999-2000 to 8.3 deaths in 2009-2011
Weber R, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. THAB03104.

Changing Epidemiology of HCV Mortality and

Morbidity in HIV Patients

Why is the natural history of HCV different in

HIV?

Which impact ha successful HIV therapy on the

further course of HCV associated liver disease and
how does it change the liver disease burden of HCV
in HIV?

Can HCV therapy induced SVR or cure of HCV

change the outcome of clinical endpoints in
HIV/HCV coinfection?

HCV infection can be cured

Clinical events after HCV treatment for 493 patients with no SVR and 218 patients with SVR3

Overall
mortality

Liver
decompensation

SVR, sustained virologic response

Treatment of chronic infection: SVR is possible1, durable2, and prevents

death3
1. Torriani FJ, et al. New Engl J Med 2004; 351:438450; 2. Soriano V, et al. Antivir Ther 2004; 9:987992;
3. Berenguer J, et al. Hepatology 2009; 50:40713.

Patients included in the study

1,600
1,400

1,599

1,200
1,000
800
600
400

695

200
0

274 (35%)

Patients in the database

Patients with F0,F1,F2

Berenguer J, et al. ICAAC 2013, Denver, Session 204 - Abstract # H-1527

Patients with SVR

Kaplan Meier estimates of events

Median FU (IQR): No SVR: 59.3 mo (40.679.2); SVR: 59.5 mo (42.881.8)

Berenguer J, et al. ICAAC 2013, Denver, Session 204 - Abstract # H-1527

Effects of ART on the liver in HIV/HCVcoinfected patients: Conclusions

The short- and mid-term effects of ART on the
progression of HCV-related liver disease largely
outweigh the potential risks for long-term toxicity.
This supports an earlier starting of ART in patients with
HIV/HCV-coinfection.
However, surveillance of possible new side effects, as
well as of changes in the natural history of hepatitis C
infection in patients on HAART is required.
SVR does not only decrease liver disease associated
morbidity and mortality but also overall survival and this
for all fibrosis stages