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?
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