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%)
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