3rd Grampian Hepatitis C Stakeholders Meeting

Pittodrie Stadium16th June 2011

Grampian HCV PCR positive cases

Numbers starting treatment

Grampian Hepatitis B New Diagnoses

0102030405060708090

100

AcuteChronic

What you wanted to know about hepatitis but were too afraid to ask

Andrew Fraser – Consultant GastroenterologistClinical Lead Grampian HCV MCN

Pauline Dundas – Lead Hepatology Nurse NHS Grampian

Case 1

• 25 year old female with 3 month old baby• Referred from maternity found to have

genotype 3 hepatitis C infection• IDU from age 20, stopped on finding out

pregnant• Currently on 30 ml methadone• Does not drink alcohol• Boyfriend previously successfully treated

Case 2

• 50 year old man, works offshore• Drinks daily when onshore• Found to have deranged LFTs• Tested positive for genotype 1 Hepatitis C• Admits to dabbling IDU for a few months

in late teens, nil since• Wife not aware of previous IDU and

attends with him

Discussion points

• Who needs treatment?

• Are there any contraindications to treatment?

• Is this a good time for treatment?

• Any special precautions?

Case 1

• 25 year old female with 3 month old baby• Referred from maternity found to have

genotype 3 hepatitis C infection• IDU from age 20, stopped on finding out

pregnant• Currently on 30 ml methadone• Does not drink alcohol• Boyfriend previously successfully treated

Liver Fibrosis in HCVRisk factors for rapid progression

1

1.5

2

2.5

3

<10 10 to 20 20-30 30-40 >40

duration of infection (years)

fibrosis score (0-4)male gender

infection after age 40alcohol > 50g/day

male genderinfection after age 40

alcohol > 50g/day

female genderinfection before age 40

alcohol < 50g/day

female genderinfection before age 40

alcohol < 50g/day

Rate of progression of liver disease

Correctable– Alcohol

consumption (esp.

> 5 units per day)– Obesity– Smoking – Cannabis

Uncontrollable– Age at infection – Gender– Ethnicity– Co-infection HBV

and HIV– Immune deficiency

Case 1

• 25 year old female with 3 month old baby• Referred from maternity found to have

genotype 3 hepatitis C infection• IDU from age 20, stopped on finding out

pregnant• Currently on 30 ml methadone• Does not drink alcohol• Boyfriend previously successfully treated

“Standard” therapy

51

78

0

10

20

30

40

50

60

70

80

SVR

(%

)

Genotype 1 Genotype 2/3Hadziyannis SJ. Ann Int Med 2004Grampian HCV Database 2011 (n=296)

Case 1

• 25 year old female with 3 month old baby• Referred from maternity found to have

genotype 3 hepatitis C infection• IDU from age 20, stopped on finding out

pregnant• Currently on 30 ml methadone• Does not drink alcohol• Boyfriend previously successfully treated

Methadone 2001-10

0

10

20

30

40

50

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

% Methadone

Methadone and completion rates

0%

20%

40%

60%

80%

100%

No Meth Meth

Not CompletedCompleted

Effect on completing treatment- excluding non-responders

0%

20%

40%

60%

80%

100%

Completed Incomplete

No SVRUnknownSVR

Case 1

• 25 year old female with 3 month old baby• Referred from maternity found to have

genotype 3 hepatitis C infection• IDU from age 20, stopped on finding out

pregnant• Currently on 30 ml methadone• Does not drink alcohol• Boyfriend previously successfully treated

Case 2

• 50 year old man, works offshore• Drinks daily when onshore• Found to have deranged LFTs• Tested positive for genotype 1 Hepatitis C• Admits to dabbling IDU for a few months

in late teens, nil since• Wife not aware of previous IDU and

attends with him

Liver Fibrosis in HCVRisk factors for rapid progression

1

1.5

2

2.5

3

<10 10 to 20 20-30 30-40 >40

duration of infection (years)

fibrosis score (0-4)male gender

infection after age 40alcohol > 50g/day

male genderinfection after age 40

alcohol > 50g/day

female genderinfection before age 40

alcohol < 50g/day

female genderinfection before age 40

alcohol < 50g/day

Case 2

• 50 year old man, works offshore• Drinks daily when onshore• Found to have deranged LFTs• Tested positive for genotype 1 Hepatitis C• Admits to dabbling IDU for a few months

in late teens, nil since• Wife not aware of previous IDU and

attends with him

“Standard” therapy

51

78

0

10

20

30

40

50

60

70

80

SVR

(%

)

Genotype 1 Genotype 2/3Hadziyannis SJ. Ann Int Med 2004Grampian HCV Database 2011 (n=296)

Predictors of poor response

• Genotype 1 infection• Failure to complete therapy• Cirrhosis

• Male• Over 50• Obesity• Ongoing alcohol excess

Case 2

• 50 year old man, works offshore• Drinks daily when onshore• Found to have deranged LFTs• Tested positive for genotype 1 Hepatitis C• Admits to dabbling IDU for a few months

in late teens, nil since• Wife not aware of previous IDU and

attends with him

Contraindications to antiviral therapy

• Chaotic drug misuse– Alcohol, heroin, crack

• Untreated severe psychiatric disorder• Pregnancy / breast feeding• Severe epilepsy• Uncontrolled hypertension• Active malignancy• Renal failure (ribavirin)• Recent severe cardiac disease

Case 3

• 35 year old female originally from Indonesia. Married and moved to Aberdeen with 15 year old son and new husband.

• Currently pregnant and found to have chronic Hepatitis B infection on routine antenatal screening

• eAg negative, eAb positive, core IgM negative

• Works as a nurse in private nursing home

Discussion

• Why does she have infection• Why is there antenatal testing• Does she need further investigation• Does she need treatment• What about the rest of the family• What about her job

Case 3

• 35 year old female originally from Indonesia. Married and moved to Aberdeen with 15 year old son and new husband 5 years ago.

• Currently pregnant and found to have chronic Hepatitis B infection on routine antenatal screening

• eAg negative, eAb positive, core IgM negative

• Works as a nurse in private nursing home

HBV – Endemic Regions

• Up to 30% of population infected

• Vertical transmission at time of birth

• Chronic infection in >90%

• Fibrosis, cirrhosis and hepatoma

HBV – Nonendemic

• Infection usually in adulthood– IDU– Sexual transmission

• Up to 30% jaundiced especially IDU

• Virus cleared in 95%

Case 3

• 35 year old female originally from Indonesia. Married and moved to Aberdeen with 15 year old son and new husband.

• Currently pregnant and found to have chronic Hepatitis B infection on routine antenatal screening

• eAg negative, eAb positive, core IgM negative

• Works as a nurse in private nursing home

Stages of CHB disease

Normal/mild CH

HBeAg + CHB

Adapted from Fattovich. Sem Liver Dis 2003

Immune tolerance

HBV-DNA

109–1010 cp/mL

ALT

107–108 cp/mL

Immune clearance

HBeAg +

HBeAg + CHB

Inactive-carrier state

<105 cp/mL

Moderate/severe CH

Cirrhosis

Normal/mild CH

Inactive cirrhosis

Low replicative phase

HBeAg - HBeAg -

Reactivation phase

>105 cp/mL

Moderate/severe CH

Cirrhosis

HBeAg – CHB

HBeAg +

Case 3

• 35 year old female originally from Indonesia. Married and moved to Aberdeen with 15 year old son and new husband 5 years ago.

• Currently pregnant and found to have chronic Hepatitis B infection on routine antenatal screening

• eAg negative, eAb positive, core IgM negative

• Works as a nurse in private nursing home

subclinical

95% chronic carrier

Cirrhosis

HCC (up to 40%)

HBV INFECTION

Infant

HBV is preventable - Immunisation

• >95% protection from vertical transmission if immunised at birth– Consider addition of antiviral drugs in last

trimester in mother if viral load high

• >90% protection for adults in at risk categories

• WHO recommends universal HBV vaccination

• UK has adopted selective

80% subclinical

20% acute hepatitis

1% fulminant hepatitis

95% recovery

5% carriers

Cirrhosis

subclinical

95% chronic carrier

Cirrhosis

HCC (up to 40%)

HBV INFECTION

Infant

Adult

HCC (0.5%)

HBV - vaccination - Who?

• Babies of chronic carriers of HBV

• IDU• Multiple sexual

partners• Chronic liver disease

• Family contacts• Haemophiliacs• Chronic renal failure• Healthcare workers• Staff and residents in

mental handicap inst.• Emergency services• Prison staff and

inmates• Travellers to

endemic areas

HBV and EPP• EPP

– When part of the healthcare workers hands not fully visible and could come into contact with sharp object within patients body

• eAg +ve - EPP not allowed• eAg –ve

– HBV DNA > 1000 cp/ml • EPP not allowed

– HBV DNA 1000 – 100 000 cp/ml• EPP only allowed if < 1000 cp/ml on

treatment.

Hepatitis B and C in Scotland

Hepatitis C• Predominantly IDU• Indigenous• Curable• 6 to 12 months of therapy• High incidence of side

effects• Prevention

– Prevention of IDU– Safe injecting practices

Hepatitis B• Predominantly vertical• Immigrants• Treatable• Life-long therapy?• Low incidence of side

effects• Prevention

– Vaccination– Condoms

Stages of CHB disease

Normal/mild CH

HBeAg + CHB

Adapted from Fattovich. Sem Liver Dis 2003

Immune tolerance

HBV-DNA

109–1010 cp/mL

ALT

107–108 cp/mL

Immune clearance

HBeAg +

HBeAg + CHB

Inactive-carrier state

<105 cp/mL

Moderate/severe CH

Cirrhosis

Normal/mild CH

Inactive cirrhosis

Low replicative phase

HBeAg - HBeAg -

Reactivation phase

>105 cp/mL

Moderate/severe CH

Cirrhosis

HBeAg – CHB

HBeAg +

Predictors of poor response

• Genotype 1 infection• Failure to complete therapy• Cirrhosis

• Male• Over 50• Obesity• Ongoing alcohol excess

Discussion points

• Does she need treatment?

• Are there any contraindications to treatment?

• Is this a good time for treatment?

• Any special precautions?

• What are her chances of cure?

Liver Fibrosis in HCVRisk factors for rapid progression

1

1.5

2

2.5

3

<10 10 to 20 20-30 30-40 >40

duration of infection (years)

fibrosis score (0-4)male gender

infection after age 40alcohol > 50g/day

male genderinfection after age 40

alcohol > 50g/day

female genderinfection before age 40

alcohol < 50g/day

female genderinfection before age 40

alcohol < 50g/day

Discussion points

• Does she need treatment– Likely mild disease

• Young female, short duration of infection, no alcohol

• Are there any contraindications to treatment– Not obvious

• Is this a good time for treatment– Side effects– Small child, methadone– Teratogenicity of treatment

HCV Infection

Virus clearedNo liver disease

Ongoing viraemia

Minimalliver disease

cirrhosis

hepatomaLiver failure

Ongoing mildhepatitis

Liver fibrosis

15-20% 80-85%

Age at first positive HCV test

Available treatments

• Weekly subcutaneous injection of Pegylated interferon– Self-administered

plus• Daily Ribavirin tablets

– Between 4 and 7 tablets per day

• Treatment normally 6 or 12 months

Numbers starting treatment

Numbers starting treatment

Methadone 2001-10

0

10

20

30

40

50

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

% Methadone

What about treatment?

Progress in HCV Therapy

6

16

34

4239

55

0

10

20

30

40

50

60

SVR

%

IFN 6m IFN 12m IFN/RBV6m

IFN/RBV12m

PEG-IFN12m

PEG-IFN/RBV 12m

1986 2002

“Standard” therapy

51

78

0

10

20

30

40

50

60

70

80

SVR

(%

)

Genotype 1 Genotype 2/3Hadziyannis SJ. Ann Int Med 2004Grampian HCV Database 2011 (n=296)

Protease InhibitorsTreatment naïve Genotype 1

41

67

46

69

38

75

0

20

40

60

80

PROVE 1 PROVE 2 SPRINT 1*

SOC Combination

Protease InhibitorsPreviously treated Genotype 1

14

52

21

67

0

20

40

60

80

PROVE 3 RESPOND 2*

SOC for 48 weeks Combination

AEs Occurring in ≥25% of Patients During any Treatment PhasePatients, n (%)

T12/PR48 (N=266)

Pbo/PR48(N=132)

Fatigue 145 (55) 53 (40)

Pruritus 138 (52) 36 (27)

Headache 112 (42) 49 (37)

Rash 99 (37) 25 (19)

Nausea 94 (35) 31 (23)

Influenza-like illness 85 (32) 33 (25)

Anaemia 79 (30) 20 (15)

Anorectal symptoms 75 (28) 10 (8)

Insomnia 68 (26) 34 (26)

Diarrhoea 66 (25) 18 (14)

Pyrexia 60 (23) 36 (27)

Cough 62 (23) 26 (20)

Asthenia 51 (19) 38 (29)

Shading indicates AEs with an incidence >10% greater in the T12/PR48 arm compared with Pbo/PR48

Why do patients stop treatment

• Non-response• Disappear / Drug and alcohol use• Side-effects

– Anaemia• Erythropoeitin

– Reduced White Cells• GCSF

• Mental health issues– Antidepressants– Sleeping tablets

Adherence to planned treatment

0%

20%

40%

60%

80%

100%

IncompleteOn TreatmentComplete

Patients who come to clinic have a high chance

of starting antiviral therapy

80% of people completing prescribed course will cure their Hepatitis C infection

Hepatitis C conclusion

• There is a lot of it about (1%)• Majority are males of working age• Without treatment large percentage will

progress to cirrhosis• There is a cure• Treatment is arduous but time limited• Support through therapy

– Alteration of work pattern– Psychological– Financial

Hepatitis B

5% prevalence = 1600 cases of chronic HBV infection

Source of HBV infection 2004

Source of HBV infection 2010?

Stages of HBV infection

sAg sAb eAg eAb cAb cAbIgM

DNA ALT cccDNA

Acute infection + - + - + + +++ +++ present

Immunotolerant + - + - + - +++ N present

Immune reactive + - + - + - +++ +++ present

Low replicative + - - + + - +/- N present

Late reactivation + - - + + - ++ ++ present

Previous infection - + - + + - - N present

Hepatitis B does not cause the liver damage

• The Immune system does the damage

• The aim of treatment is to limit liver damage

• Timing of treatment is important• Aims of treatment need to be clear

Stages of HBV infection

sAg sAb eAg eAb cAb cAbIgM

DNA ALT cccDNA

Acute infection + - + - + + +++ +++ present

Immunotolerant + - + - + - +++ N present

Immune reactive + - + - + - +++ +++ present

Low replicative + - - + + - +/- N present

Late reactivation + - - + + - ++ ++ present

Previous infection - + - + + - - N present

Interferon• 48 weeks of Rx• Absence of resistance• Higher rates of HBV eAg

and sAg seroconversion

• Moderate antiviral effect• Poorly tolerated• Injection

NUC• Indefinite duration• Risk of resistance• Lower rates of eAg and

sAg seroconversion

• Potent antiviral effect• Well tolerated• Oral

Undetectable HBV DNA at 48 weeks

PEG-IFN

LAM ADV ETV LdT TDF0

102030405060708090

100

eAg +veeAg -ve

Treatment

• Around 20% of patients require treatment

• Some suitable for 1 year of interferon

• Lifelong treatment– Tenofovir, entecavir– Cost £3,000 per year

• Virus suppressed in >90%

Hepatitis B Summary

• Chronic HBV infection is becoming more common in Scotland (imported)

• Requires specialist referral to stage disease and assess for treatment

• Treatment is safe and effective

• HBV infection is preventable– Vaccination, Condoms, Universal

precautions, Sterile equipment

Healthy Liver

Cirrhosis

Viral Hepatitis

• Hepatitis A• Hepatitis B• Hepatitis C • Delta agent (Hepatitis D)• Hepatitis E• Other hepatotrphic viruses

– EBV, CMV

Viral Hepatitis

• Hepatitis A - Spread by the faecal-oral route• Hepatitis B• Hepatitis C • Delta agent (Hepatitis D)• Hepatitis E• Other viruses

– EBV, CMV

Viral Hepatitis

• Hepatitis A - Spread by the faecal-oral route• Hepatitis B - Spread by blood and secretions• Hepatitis C • Delta agent (Hepatitis D)• Hepatitis E• Other viruses

– EBV, CMV

Viral Hepatitis

• Hepatitis A - Spread by the faecal-oral route• Hepatitis B - Spread by blood and secretions• Hepatitis C - Spread by blood contact• Delta agent (Hepatitis D)• Hepatitis E• Other viruses

– EBV, CMV

Viral Hepatitis

• Hepatitis A - Spread by the faecal-oral route• Hepatitis B - Spread by blood and secretions• Hepatitis C - Spread by blood contact• Delta agent (Hepatitis D) – Incomplete virus• Hepatitis E• Other viruses

– EBV, CMV

Viral Hepatitis

• Hepatitis A - Spread by the faecal-oral route• Hepatitis B - Spread by blood and secretions• Hepatitis C • Delta agent (Hepatitis D) – Incomplete virus• Hepatitis E - Spread by the faecal-oral route• Other viruses

– EBV, CMV

Viral Hepatitis

• Hepatitis A - Spread by the faecal-oral route• Hepatitis B - Spread by blood and secretions• Hepatitis C - Spread by blood contact• Delta agent (Hepatitis D) – Incomplete virus• Hepatitis E - Spread by the faecal-oral route• Other viruses - Droplet spread mainly

– EBV, CMV

HCV infection can be curedMore than half treated are cured

You can’t be cured unless -you know you have the infection

-and receive antiviral therapy

Natural History

• Virus only identified 1989• 10% patients report acute jaundice• Rarely causes acute liver failure

• 80% chronic HCV infection• Most asymptomatic until cirrhotic• May have normal LFT’s

Transmission

• IDU

• Tattoos• Sexual • Unknown

• Blood products– UK blood donor screening since 1991– Heat treatment of plasma since mid 80s

Source of Infection(Of those attending HCV clinic in Grampian)

8%

3% 2% 1%

6%

80%

IDU

Unknown

Blood Transfusion

? Tattoo/piercing

HCV+ve partner

Vertical transmission

HCV Action PlanScotland - Target treatment figures

• 08/09 - 500• 09/10 - 1000• 10/11 - 1500• 11/12 - 2000*

* And every year for next 20 years

HCV Clinic

• Liver Nurse Specialists– Medical staff

• Substance Misuse Nurse• Dietician• Citizens Advice Bureau

• Outreach– Peterhead, Fraserburgh, Elgin,

Homeless practice, prisons

Customised Therapy

• Measure virus level (PCR)– Before Rx– 4, 12, 24, 48 (72, 96) weeks of treatment

• Genotype 1– 24 weeks for low viral load rapid responders– 72 weeks for slow responders

• Genotype 2 and 3– 16 weeks for rapid responders

Grampian Treatment 2001-08

• 274 started antiviral therapy– 198 (72%) completed planned treatment course

• 162 (59%) achieved SVR (cure)

• Success rates as good as clinical trials

80% subclinical

20% acute hepatitis

1% fulminant hepatitis

95% recovery

5% carriers

Cirrhosis

subclinical

95% chronic carrier

Cirrhosis

HCC (up to 40%)

HBV INFECTION

Infant

Adult

HCC (0.5%)