Liver disease mortality among drug users, competing causes ... · 2'-5'-oligoadenylate synthetase 1 (OAS-1). Factor V Leiden genotype (Arg560Gln) Ferritin Serum hepcidin IL-10 (-1082)

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

Disclosures

• K.B. Kielland has given sponsored lectures for MSD and AbbVie

2

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)

3

Elastography

F1 F2 F3

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.

4

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–

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

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%

7

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.

8

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

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

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


HCVRNA– 195 161 122 77 5

HCVRNA+ 328 283 237 154 11

HCV RNA+

HCV RNA–

Log rank test: p= 0.16


Cu

m S

urv

ival

1.0

0.8

0.6

0.4

0.2

0.0

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


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)


Cu

m S

urv

ival

1.0

0.8

0.6

0.4

0.2

0.0

12

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–


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


HCV RNA– 195 169 130 89 5

HCV RNA+ 328 292 246 177 15

Mean age 50 years

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

13


Natural course of chronic hepatitis C (age by exposure 20–25 years)

14


ESLD, HCC, liver-tx, liver death

F4

F3

F2

F0–F1


HCV exposure

%

100

90

80

70

60

50

40

30

20

10

0


Natural course of chronic hepatitis C in PWID (age by exposure 20–25 years)

15


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


HCV exposure

Liver deaths

%

100

90

80

70

60

50

40

30

20

10

0

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


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

Cumulated causes of death among Norwegian PWID in 2012 in a cohort admitted for drug abuse treatment 1970-1984 at

mean age 22 years

17

Dead by other causes than liver

disease 45–50%


F0–F1

F3

ESLD, HCC, liver-tx

F2

F4

Among all HCV-exposed PWID


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

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

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


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%


F3

F2

F0-F1

Deaths from other causes than liver disease


%

0

10

20

30

40

50

60

70

80

90

100


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



21



F3

F2

F0-F1



%

0

10

20

30

40

50

60

70

80

90

100


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)?



22



F3

F2

F0-F1



%

0

10

20

30

40

50

60

70

80

90

100


HCV exposure

Liver deaths


Chronic hepatitis C


Natural course of chronic hepatitis C in people who inject drugs in the late era of direct-acting anti-virals (DAAs)?

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

23

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

24

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-

Liver disease mortality among drug users, competing causes ... · 2'-5'-oligoadenylate synthetase 1 (OAS-1). Factor V Leiden genotype (Arg560Gln) Ferritin Serum hepcidin IL-10 (-1082)

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