10_Rockstroh

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Changing Epidemiology of HCV Mortality

and Morbidity in HIV patients

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

France, Thursday 12th June, 2014

Jürgen K. Rockstroh

Department of Internal Medicine I

University Hospital Bonn

Germany


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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


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Changing Epidemiology of HCV Mortality and

Morbidity in HIV Patients

• Why is the natural history of HCV different inHIV?

• Which impact has successful HIV therapy on thefurther 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 HCVchange the outcome of clinical endpoints in

HIV/HCV coinfection?


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New HCV /HIV epidemiological data.

Center for Disease Analysis 2013


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Background

1. Rockstroh J, et al. Am J Gastroenterol 1996;91:2563–2568;

2. Weber R, et al. Arch Intern Med 2006;166:1632–41

• 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 amongHIV-infected patients²


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Morbidity and Mortality in Patients

with HIV and HCV

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

100

90

80

70

30 40 50 60 70

Time (months)

% o

f P a t i e n

t s W i t h o u

t L i v e

r F a

i l u r e Group B-D

(n=191)

Group A (n=49)

p < 0.001


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Mechanism of the effect of HIV on the

progression of hepatitis C

1Lin W, et al. Gastroenterology 2008; 134: 803-8112Kuntzen T, et al . AIDS 2008;22: 203-210.

³Lin W et al., J Infect Dis 2013;207:S13-184Glässner et al., J Hepatol 2013;59: 427-4335Mastroianni Cm et al., Int J Mol Sci 2014;15:9184-9208

• HIV may increase HCV replication and fibrogenesis via TGF β11.

• 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 inhepaotcyte apoptosis which may be further augmented in the

presence of increased microbial translocation in the setting of

HIV.³

• 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


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• Which impact has successful HIV therapy on thefurther course of HCV associated liver disease and


in HIV?




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Cumulative Proportion of Patients With Cirrhosis by

PI Exposure: MultivirC Group

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

Patients With Cirrhosis

0

10

20

30

40

50

60

C u m u

l a t i v e

P r o p o r t

i o n

( % )

0 5 10 15 20 25 30

Estimated HCV InfectionDuration (y)

• 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%



P=0.0006

PI Exposure

No PI Exposure


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Impact of ART on Overall Liver Mortality

in HIV/HCV-Coinfected Patients

• 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

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

0,2

0,4

0,6

0,8

1

Days

Overall Mortality

C u m u

l a t i v e

S u r v

i v a

l

0 1000 2000 3000 4000 5000 6000

ART

HAART*

0,2

0,4

0,6

0,8

1

Days

Liver-Related Mortality

C u m u

l a t i v e

S u

r v i v a

l

0 1000 2000 3000 4000 5000 6000

HAART*

No therapy

ART

No therapy

*P=0.018

*P


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Impact of HIV RNA, CD4, or Both on Liver

Fibrosis Progression Rate

0

10

20

30

40

50

60

HIV RNA(copies/mL)

E

s t i m a

t e d T i m e

F r o m

H C V

I n f

e c

t i o n

t o C i r r h o s

i s ( y e a r s

)

P=0.05 P=0.04

P=0.005 P=0.004 P=0.005

350(n=124)


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High necroinflamatory activity (p=0.008)

Adjusted Odds Ratio (95% CI)

2 4 6 8 100.01 0.1 0.125 0.17 0.25 0.5

Year 1st LBx (p=0.58)

Undetectable HIV-RNA (p=0.017)

Response to HCV Rx (p=0.018)

0.29

0.26

3.23

1.26

0.9

ART between LBx (p=0.8)

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

Factors independently asociated with fibrosis progression

Effect of HAART on liver fibrosis

progression: Sequential studies.


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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 (β 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) andachievement 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.


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Antiretroviral Therapy Reduces the

Rate of Hepatic Decompensation

Among HIV- and Hepatitis C Virus–Coinfected Veterans

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

• Objective: To evaluate 10 090 HIV/HCV-coinfected malesfrom 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.


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Study design: Retrospective cohort study fromthe Veterans Aging Cohort Study Virtual Cohort

Study Endpoint

Death

HCV Therapy

Last Visit Before Sept.

30, 2010

HIV/HCV

on ART

HCV

12 mo

In VA

Baseline

12 mo

in VA

Baseline

Follow-up

Follow-up

Start of

Follow-up

Start of

Follow-up

Lo Re V, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. WEAB0102.

• Study aim: To compare the incidence of hepatic decompensation between ART-

treated HIV/HCV-coinfected and HCV-monoinfected pts

• Hepatic decompensation was defined as a hospital diagnosis indicated by ICD-

9 code or two or more outpatient diagnoses of ascites, spontaneous bacterial

peritonitis, or esophageal variceal hemorrhage


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Standardized Cumulative Incidence ofHepatic Decompensation*

ART-Treated

HIV/HCV-Coinfected

HCV-MonoinfectedLog-rank

p


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0

12

3

4

5

6

7

8

9

10

HIV Suppression Is Associated with Less

Hepatic Necroinflammatory Activity

Mehta SH et al. Hepatology 2005

A c

t i v

i t y

S c o

r e

Viral Load

Undetectable

Viral Load

Detectable

*

*


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

Probability of remaining free of developing

a hepatic decompensation


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HAART induces recovery of specific T-cell

response to HCV core proteins

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

ART

n=20 n=51 n=51 n=66 n=35

P for

trend=0.02

5

5,5

6

6,5

7

7,5

8

-41 -2 0 7 33 74

M e

d i a n

( I Q R ) l o g

H C V - R

N A ( I U / m L )

Median time (months)

from ART startingn=16 n=64 n=50 n=64 n=37

ART

P=0.003

P=0.002

13

19

24

33

49

0

10

20

30

40

50

-41 -2 0 7 33 74

% p a

t i e n

t s w

i t h d e

t e c

t a b l e E L I S p

o t

r e s p o n s e

Median time (months)

from ART starting


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Any additional benefits or impact of

ART?

• The changing pattern of glomerular disease in HIVand hepatitis C co-infected patients in the era of

HAART

1

• ART is associated with lower post-IFN HCV-RNAlevels; that change is linked to reduced hepatic

interferon stimulating gene (ISG) expression²; these

data support recommendations to provide ART

prior to IFN-based treatment of HCV

1Mohan S et al., Clin Nephrol 2013;79:285-291

²Balagopal A et al., Hepatology 2014; April 5th Epub ahead of print


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(b)

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

patients become similar to that in HCV monoinfection?

Metanalysis of 26 studies

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

No HAART HAART


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EACS Guidelines: When to Start

• Initiation of ART

– ART is always recommended if CD4 count 500

HBV requiring anti-HBV treatment R R

HBV not requiring anti-HBV treatment RC

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

HCV for which anti-HCV treatment not feasible R 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


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Changes in death causes over time

1999-2000

N=255

2009-2011

N=548

Weber R, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. THAB03104.

• 3,802 deaths in 49,734 HIV positive individuals fol lowed 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


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• Which impact ha successful HIV therapy on thefurther course of HCV associated liver disease and


in HIV?




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HCV infection can be cured

1. Torriani FJ, et al. New Engl J Med 2004; 351:438–450; 2. Sor iano V, et al. Antivi r Ther 2004; 9:987–992;

3. Berenguer J , et al. Hepatology 2009; 50:407–13.

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


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0

200

400

600

800

1,000

1,200

1,400

1,600

Patients in the database Patients with F0,F1,F2 Patients with SVR

1,599

695

274 (35%)

Patients included in the study

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


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Kaplan Meier estimates of events

Median FU (IQR): No SVR: 59.3 mo (40.6 –79.2); SVR: 59.5 mo (42.8 –81.8)

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


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Effects of ART on the liver in HIV/HCV-

coinfected 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 withHIV/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

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