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

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

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 among HIV-infected patients²

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 Pat

ient

s W

ithou

t Liv

er F

ailu

re Group B-D

(n=191)

Group A (n=49)

p < 0.001

Mechanism of the effect of HIV on the progression of hepatitis C

1Lin W, et al. Gastroenterology 2008; 134: 803-811 2Kuntzen T, et al. AIDS 2008;22: 203-210. ³Lin W et al., J Infect Dis 2013;207:S13-18 4Glässner et al., J Hepatol 2013;59: 427-433 5Mastroianni 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 in hepaotcyte 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

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

0

10

20

30

40

50

60

Cum

ulat

ive

Prop

ortio

n (%

)

0 5 10 15 20 25 30 Estimated HCV Infection

Duration (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% • 15-year: 5% versus 18% • 25-year: 9% versus 27%

P=0.0006

PI Exposure

No PI Exposure

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

Cum

ulat

ive

Surv

ival

0 1000 2000 3000 4000 5000 6000

ART

HAART*

0,2

0,4

0,6

0,8

1

Days

Liver-Related Mortality

Cum

ulat

ive

Surv

ival

0 1000 2000 3000 4000 5000 6000

HAART*

No therapy

ART

No therapy

*P=0.018

*P<0.001

Impact of HIV RNA, CD4, or Both on Liver Fibrosis Progression Rate

0

10

20

30

40

50

60

HIV RNA (copies/mL)

Estim

ated

Tim

e Fr

om H

CV

Infe

ctio

n to

Cirr

hosi

s (y

ears

)

P=0.05 P=0.04

P=0.005 P=0.004 P=0.005

<400 (n=141)

CD4 (cells/mm3)

HIV RNA (copies/mL) + <500 CD4 cells/mm3

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

49

400-99K (n=117)

>100k (n=16)

>350 (n=124)

<350 (n=150)

<400 (n=100)

>400 (n=88)

41

31

50

39

49

37

Time to cirrhosis estimated using liver fibrosis progression rate based on Ishak Fibrosis units/year.

High necroinflamatory activity (p=0.008)

Adjusted Odds Ratio (95% CI)

2 4 6 8 10 0.01 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.

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) 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

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

• 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.

Study design: Retrospective cohort study from the 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

Standardized Cumulative Incidence of Hepatic Decompensation*

ART-Treated HIV/HCV-Coinfected

HCV-Monoinfected Log-rank p<0.001

* Based on competing risk regression analysis.

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

HD risk was 83% higher in the coinfected group (aHR 1.83, 95% confidence interval [CI] 1.54 to 2.18)

0123456789

10

HIV Suppression Is Associated with Less Hepatic Necroinflammatory Activity

Mehta SH et al. Hepatology 2005

Activ

ity S

core

Viral Load Undetectable

Viral Load Detectable

* *

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

Probability of remaining free of developing a hepatic decompensation

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

Med

ian

(IQR

) log

HC

V-R

NA

(IU

/mL)

Median time (months) from ART starting n=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

atie

nts

with

det

ecta

ble

ELIS

pot

resp

onse

Median time (months) from ART starting

Any additional benefits or impact of ART?

• 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) 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

(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

EACS Guidelines: When to Start

• Initiation of ART – ART is always recommended if CD4 count <350 cells/mm3

Condition Current CD4 + lymphocyte count 350–500 >500

HBV requiring anti-HBV treatment R R

HBV not requiring anti-HBV treatment R C

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

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 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

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

1. Torriani FJ, et al. New Engl J Med 2004; 351:438–450; 2. Soriano V, et al. Antivir 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

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

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

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 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