liver disease mortality among drug users, competing causes ... · 2'-5'-oligoadenylate...
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Liver disease mortality among drug users, competing causes of deaths and age differences
Knut Boe Kielland, MD PhD Norwegian National Centre for Concurrent Substance Abuse
and Mental Health Disorder, Innlandet Hospital Trust
EMCDDA, September 30, Lisboa
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Disclosures
• K.B. Kielland has given sponsored lectures for MSD and AbbVie
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Normal liver F0
Shashidhar Venkatesh Murthy, Amar Paul Dhillon, UCL Medical School Royal Free
Campus, London
Cirrhosis F4
Classification of the progression of liver fibrosis in hepatitis C
Biopsies: Metavir stages F0–F4
F1 = portal fibrosis without septa F2 = portal fibrosis with few septa F3 = numerous septa without cirrhosis (septal or bridging fibrosis)
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Elastography
F1 F2 F3
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Mean duration of Metavir stages
A meta-analysis concluded with the following mean progression time through the Metavir stages
• F0–F1: 9 years • F1–F2: 12 years • F2–F3: 12 years • F3–F4: 8 years • F0–F4: 40 years Conclusions:
• For probable more than half the patients the progression is very slow (“non-fibrosing”)
• For at least 1/3 it is much more rapid.
Thein HH, Yi Q, Dore GJ, Krahn MD. Hepatology 2008; 48(2):418-431.
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Spontaneous clearance 25–30%
The natural course of liver disease in chronic hepatitis C
(age by exposure 20–25 years)
5
Chronic hepatitis C 70–75%
ESLD, HCC, liver-tx, liver death
F4
F3
F2
F0-F1
0 10 20 30 Years since HCV exposure
HCV exposure
%
100
90
80
70
60
50
40
30
20
10
0 Acute hepatitis C
HCV RNA+
Anti-HCV+/HCV RNA–
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Factors which may increase or reduce fibrosis progression
Male gender
High age by exposure
Co-infection HIV
Co-infection HBV
Schistosomiasis
Overweight
Steatosis
Insulin resistance (IR)/metabolic syndrome
Type 2 diabetes mellitus
Non-alcoholic steatohepatitis (NASH)
High inflammatory activity
Alanine aminotransferase (ALT)
2'-5'-oligoadenylate synthetase 1 (OAS-1).
Factor V Leiden genotype (Arg560Gln)
Ferritin
Serum hepcidin
IL-10 (-1082) AA genotype and the ATA/ATA and ACC/ACC homozygous haplotypes IL-10 (-1082) GG genotype
IL28B rs12979860 genotype CC
IL28B SNP rs8099917 genotype TT
MCP-1 (CCL-2)
Homocystein
Methylene-tetra-hydro-folate reductase (MTHFR) C677T polymorphism TT genotype Mixed cryoglobulinemia
Non-organ-specific autoantibodies 6
Host factors Male gender High age at exposure
Untreated co-infection HIV Untreated co-infection HBV
Overweight/steatosis/NASH Insulin resistence/ metabolic syndrome/DM2
Genetic and other factors
External factors Alcohol (Tobacco) (Cannabis) Coffee (reduced fibrosis?) Chocolate (reduced fibrosis?)
Viral factors Genotype 3 Genetic variability
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Cirrhosis
• Cirrhosis:
– Annual risk of liver cancer (HCC):1–5%
– Annual risk of hepatic failure (decompensation):
3–6% (variceal hemorrhage, ascites, encephalopathy)
• Decompensated cirrhosis:
– Risk of death the following year 15–20%
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Thein HH, Yi Q, Dore GJ, Krahn MD. Hepatology 2008;48:418–431.
Westbrook RH, Dusheiko G.. J Hepatol. 2014 Nov;61(1 Suppl):S58-68.
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Natural course of drug use Meta-analyses of mortality:
• People who inject drugs: Mortality rate: 2.3/100PY.
Standard mortality rate: 15
Main causes of deaths: Overdose and HIV
Mathers. Bull World Health Organ 2013
• Dependent users of heroin/other opioids: Mortality rate: 2.1/100PY Standard mortality rate: 15 Main cause of death: Overdose Degenhardt. Addiction 2011
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All-cause mortality among 523 anti-HCV positive PWID admitted for drug abuse treatment 1970–84 in Norway,
followed up until 2012
9
0 10 20 30 40 50 Years since admission
Number of patients at risk
523 444 359 231 16
CMR: 2.0/100PY
Kielland KB, unpublished data
CMR until age 50: 1.8/100PY
CMR after age 50: 3.6/100PY
Still alive at age 50: Males: 56% Females: 65% All: 59%
Cu
m S
urv
ival
1.0
0.8
0.6
0.4
0.2
0.0
Mean age 50 years
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All-cause mortality according to HCVRNA among anti-HCV positive PWID admitted for drug abuse treatment 1970–84 in
Norway followed up until 2012
10
0 10 20 30 40 50 Years since admission
Number of patients at risk
HCVRNA– 195 161 122 77 5
HCVRNA+ 328 283 237 154 11
HCV RNA+
HCV RNA–
Log rank test: p= 0.16
Kielland KB, unpublished data
Cu
m S
urv
ival
1.0
0.8
0.6
0.4
0.2
0.0
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Liver-related mortality according to HCV RNA among anti-HCV positive PWID admitted for drug abuse treatment 1970–84 in
Norway, followed up until 2012
11
0 10 20 30 40 50 Years since HCV exposure
Number of patients at risk
HCV RNA– 195 169 130 89 5
HCV RNA+ 328 292 246 177 15
HCV RNA+
HCV RNA–
Hepatitis B (two cases) Alcoholic liver disease (one case)
Kielland KB, unpublished data
Cu
m S
urv
ival
1.0
0.8
0.6
0.4
0.2
0.0
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HCV RNA+
Liver-related mortality according to HCV RNA among anti-HCV positive PWID admitted for drug abuse treatment 1970–84 in
Norway, followed up until 2012
HCV RNA–
Kielland KB, unpublished data
Cu
m S
urv
ival
1.0
0.8
0.6
0.4
0.2
0.0
0 10 20 30 40 50 Years since HCV exposure
Number of patients at risk
HCV RNA– 195 169 130 89 5
HCV RNA+ 328 292 246 177 15
Mean age 50 years
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4 6 10
11 1
5
9
2
2
2
5
6
5
4
6
4
1 20
21 19
11
0 %
10 %
20 %
30 %
40 %
50 %
60 %
70 %
80 %
90 %
100 %
Substance dependence
Suicide
Violent
HIV
Liver disease
Other disease
Death age <30 30-39 40-49 50+
Number of deaths 33 42 45 34
Causes of death among PWID with chronic hepatitis C according to death age
Kielland KB, unpublished information
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Spontaneous clearance 25–30%
Natural course of chronic hepatitis C (age by exposure 20–25 years)
14
Chronic hepatitis C 70–75%
ESLD, HCC, liver-tx, liver death
F4
F3
F2
F0–F1
0 10 20 30 Years since HCV exposure
HCV exposure
%
100
90
80
70
60
50
40
30
20
10
0
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Spontaneous clearance 25–30%
Natural course of chronic hepatitis C in PWID (age by exposure 20–25 years)
15
Chronic hepatitis C 70–75%
ESLD, HCC, liver-tx F4
F3
F2
F0-F1
Deaths by other causes than liver disease
Deaths by other causes than liver disease
%
100
90
80
70
60
50
40
30
20
10
0
0 10 20 30 Years since HCV exposure
HCV exposure
Liver deaths
%
100
90
80
70
60
50
40
30
20
10
0
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Estimated situation for anti-HCV positive PWID at age 50–60 years – about 30–35 years after HCV exposure
16
Dead by other causes than liver
disease 45–50%
Spontaneous clearance 15%
F0–F1
F3
ESLD, HCC, liver-tx
F2
F4
Among all HCV-exposed PWID
Spontaneous clearance 25–30%
F0–F1 30–35%
F3 -10%
ESLD, HCC, liver-tx 8%
F2 - 10%
F4 -12%
Among surviving HCV-exposed PWID
May be fewer because of re-infections
May be strongly influenced by antiviral treatment
Dead by liver disease
%
100
90
80
70
60
50
40
30
20
10
0
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Cumulated causes of death among Norwegian PWID in 2012 in a cohort admitted for drug abuse treatment 1970-1984 at
mean age 22 years
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Dead by other causes than liver
disease 45–50%
Spontaneous clearance 15%
F0–F1
F3
ESLD, HCC, liver-tx
F2
F4
Among all HCV-exposed PWID
Spontaneous clearance 25–30%
F0–F1 30–35%
F3 -10%
ESLD, HCC, liver-tx 8%
F2 - 10%
F4 -12%
Among surviving HCV-exposed PWID
Dead by liver disease
%
100
90
80
70
60
50
40
30
20
10
0
Substance dependence
45%
Suicide 8%
HIV 5%
Other disease 22%
Violent 10%
Liver 7%
Causes of death
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Extrahepatic manifestations
Certain associations with HCV: – Cryoglobulinemia
• >50% (mostly low levels without clinical consequences)
• Prevalence increases with age, and in Europe higher in the south than in the north
• Skin disease (<5%)
• Kidney disease (glomerulonephritis)
• Peripheral neuropathy
– Non-Hodgkin lymphoma, relative risk 2.0-2.5
18
Jan Peveling-Oberhag, Luca Arcaini,
Martin-Leo Hansmann, Stefan
Zeuzem. Journal of Hepatology 2013
vol. 59 j 169–177
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Extrahepatic manifestations
Possibly or probably associated with HCV:
– Diabetes mellitus type 2
– Some autoimmune diseases
– Fatigue, depression secondary to the chronic inflammation
– Vascular disease?
– Brain affection directly associated with virus replication in the brain?
• Impaired cognitive function? Depression? Fatigue?
19
Ruhl CE, Menke A, Cowie CC, Everhart JE. Hepatology. 2014 Oct; 60(4): 1139–1149.
Tang et al. Infectious Agents and Cancer (2016) 11:29
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Spontaneous clearance 30%
Natural course of chronic hepatitis C in people who inject drugs in the era of direct-acting anti-virals (DAAs)?
20
Chronic hepatitis C 70%
ESLD, HCC, liver-tx F4
F3
F2
F0-F1
Deaths from other causes than liver disease
Deaths from other causes than liver disease
%
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 Years since HCV exposure
HCV exposure
Liver deaths
Chronic hepatitis C
Natural course of chronic hepatitis C in people who inject drugs before the era of anti-viral treatment
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Spontaneous clearance 30%
Natural course of chronic hepatitis C in people who inject drugs in the era of direct-acting anti-virals (DAAs)?
21
Chronic hepatitis C 70%
ESLD, HCC, liver-tx F4
F3
F2
F0-F1
Deaths from other causes than liver disease
Deaths from other causes than liver disease
%
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 Years since HCV exposure
HCV exposure
Liver deaths
Clearance (SVR) after treatment
Chronic hepatitis C
Natural course of chronic hepatitis C in people who inject drugs in the first era of direct-acting anti-virals (DAAs)?
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Spontaneous clearance 30%
Natural course of chronic hepatitis C in people who inject drugs in the era of direct-acting anti-virals (DAAs)?
22
Chronic hepatitis C 70%
ESLD, HCC, liver-tx F4
F3
F2
F0-F1
Deaths from other causes than liver disease
Deaths from other causes than liver disease
%
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 Years since HCV exposure
HCV exposure
Liver deaths
Clearance (SVR) after treatment
Chronic hepatitis C
Clearance (SVR) after treatment
Natural course of chronic hepatitis C in people who inject drugs in the late era of direct-acting anti-virals (DAAs)?
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Conclusions
• 30–40% of PWID with CHC will develop advanced liver fibrosis/cirrhosis within 25–40 years
• After age 40–50 years, liver disease becomes an increasingly important cause of death
• Among PWID under 40–50 years of age, other causes of death dominate, mainly drug related
• Direct-acting antivirals may eliminate both the burden of liver disease and liver-related mortality
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Causes of death in cohort of Norwegian PWID 30-40 years after admission to drug abuse treatment 1970-1984,
mean age at that time was 22 years
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0,0 % 5,0 % 10,0 % 15,0 % 20,0 % 25,0 % 30,0 % 35,0 % 40,0 %
Intoxication opioids
Intoxication alcohol
Other intoxication
Drug dependence
Alcohol dependence
Suicide
Homicide
Accidents
Intox possible suicide
HIV
Liver disease
Endocarditis
Cancer
Cardiovascular disease
Respiratory disease
Other diseases
Unknown
HCVRNA+
HCVRNA-