- the way forward Dr Iain Brew GPSI Hepatitis C HMP Leeds - - PowerPoint PPT Presentation

Hepatitis C in Primary Care:

• the way forward

Dr Iain Brew GPSI Hepatitis C HMP Leeds

Hepatitis C in Primary Care:

• the way forward

I have received speaker and consultancy fees from:-

• AbVie and Janssen

Twist or Stick?

• Todays drugs
• What is emerging
• How do we get people onto therapy?

Twist or Stick?

• Todays drugs
• What is emerging
• How do we get people onto therapy?

A bit of history…

Genotype 1 – Good Drugs on the market PegIFN / Ribavirin and Protease inhibitors

T12PR

659/903

PR48

158/361 n/N =

72–75*

Sherman KE, et al. Hepatology 2010;52(Suppl.):401A Jacobson IM, et al. N Engl J Med 2011;364:2405-16; Sherman KE, et al. CROI 2011. Abstract 957 *p<0.001 vs PR48 in ADVANCE (75% versus 44%)

Telaprevir SVR rates by fibrosis stage in treatment-naïve patients

SVR, considered virologic cure, was defined as HCV RNA undetectable 24 weeks after last planned dose

Marcellin P, et al. J Hepatol 2011;54(Suppl 1):S183

SVR (%)

PR48 67/147 n/N= T12PR 109/134 PR48 67/141 T12PR 117/156

F0–F1 F3

PR48 17/52 T12PR 32/52

F4

T12PR 13/21 PR48 7/21

F2

Telaprevir SVR rates by fibrosis stage in treatment-naïve patients

SVR, considered virologic cure, was defined as HCV RNA undetectable 24 weeks after last planned dose

Marcellin P, et al. J Hepatol 2011;54(Suppl 1):S183

SVR (%)

PR48 67/147 n/N= T12PR 109/134 PR48 67/141 T12PR 117/156

F0–F1 F3

PR48 17/52 T12PR 32/52

F4

T12PR 13/21 PR48 7/21

F2

OPTIMIZE: telaprevir bid was non- inferior to q8h in terms of SVR

ITT analysis CI: confidence interval Buti M, et al. AASLD 2012:LB-8

SVR12 (%)

270/371 274/369

T12(q8h)/PR T12(bid)/PR Difference 1.5% (95% CI: –4.9%, 12.0%)

SPRINT-2: SVR rates with boceprevir-based therapy versus PR alone

BOC RGT

233/368

BOC44/PR48

242/366

PR48

137/363 n/N =

Adapted from Poordad F, et al. N Engl J Med 2011;364:1195–206 *p<0.001 for both boceprevir arms versus PR48

* *

Boceprevir Response is Predictable

At 4 weeks:-

• < 1 log decline – low probability of response
• > 1 log decline – high probability of response

Current Drugs - Problems

• SIDE EFFECTS
• Anaemia, skin rashes, odd tastes
• Long duration of therapy

CUPIC Week 60 analysis: safety

• verview

Hézode C, et al. Unpublished data Updated 26 September 2013

Outcomes, % TVR CUPIC N=299 BOC CUPIC N=212 Serious adverse event 53.8 44.3 Premature discontinuations due to serious adverse events 23.8 17.5 Death, n (%) 8 (2.7) 3 (1.4) Infections (grade 3/4) 9.7 2.4 Hepatic decompensation 4.7 4.2 EPO use 56.5 56.1 Transfusion 17.7 11.8 RBV dose reduction 27.8 23.6

Adverse events in cirrhotic patients with Peg and Riba

CPT: carnitine palmitoyltransferase; IFN: interferon Fernández-Rodríguez CM, et al. Am J Gastroenterol 2010;105:2164–2172

26 centres in Spain; 568 treatment-naïve patients with cirrhosis Treated with PR Adverse event, n (%) All patients (N=508) Ascites / encephalopathy / CPT 2 59 (11.6) Variceal hemorrhage 19 (3.74) Development of HCC 31 (6.1) Any adverse event 89 (17.5) Liver-related mortality 29 (5.7) IFN safety in advanced liver disease is poor

Current Drugs - not perfect

For G1 – reasonable efficacy, high side effects For G2/3 – good efficacy, moderate side effects In cirrhosis efficacy falls, side effects rise

So

DO NOT LET YOUR PATIENT GET CIRRHOSIS

Twist or Stick?

• Todays drugs
• What is emerging
• How do we get people onto therapy?

Specific targets for HCV treatment: protease, polymerase and NS5A inhibition

C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B

Polymerase Protease NS5A

Kwong A, et al. Drug Discovery Today: Therapeutic Strategies 2006;3:211–220 Schmitz U, Tan SL. Recent Pat Antiinfect Drug Discov 2008;3:77–92

New Protease Inhibitors

Simeprevir Faldaprevir

Results are for separate trials for each compound, not head-to-head studies, in treatment-naïve patients also receiving PegIFN/RBV Hatched regions indicate ranges of results

• 1. Incivo EU SmPC 2011; 2. Victrelis EU SmPC 2011;
• 3. Poordad F, et al. N Engl J Med 2011;364:1195–1206;
• 4. Sulkowski MS, et al. Manuscript in preparation;
• 5. Fried M, et al. AASLD 2011. Abstract LB-5

QD, once daily; RGT, response-guided therapy; SVR, sustained virological response; TID, three times daily

Duration of RGT (wk) 24 28 24 24 Eligible for RGT Overall SVR

Patients (%)

58 79 44 63–66 84 87 79–86 81–86 Telaprevir 750 mg TID1 Boceprevir 800 mg TID2,3 Faldaprevir 240 mg QD4 Simeprevir 150 mg QD5 Eligible for RGT Overall SVR Eligible for RGT Overall SVR Eligible for RGT Overall SVR

New Protease Inhibitors (With Peg + Riba)

Results are for separate trials for each compound, not head-to-head studies, in treatment-naïve patients also receiving PegIFN/RBV Hatched regions indicate ranges of results

• 1. Incivo EU SmPC 2011; 2. Victrelis EU SmPC 2011;
• 3. Poordad F, et al. N Engl J Med 2011;364:1195–1206;
• 4. Sulkowski MS, et al. Manuscript in preparation;
• 5. Fried M, et al. AASLD 2011. Abstract LB-5

QD, once daily; RGT, response-guided therapy; SVR, sustained virological response; TID, three times daily

Duration of RGT (wk) 24 28 24 24 Eligible for RGT Overall SVR

Patients (%)

58 79 44 63–66 84 87 79–86 81–86 Telaprevir 750 mg TID1 Boceprevir 800 mg TID2,3 Faldaprevir 240 mg QD4 Simeprevir 150 mg QD5 Eligible for RGT Overall SVR Eligible for RGT Overall SVR Eligible for RGT Overall SVR

New Protease Inhibitors (With Peg + Riba)

Results are for separate trials for each compound, not head-to-head studies, in treatment-naïve patients also receiving PegIFN/RBV Hatched regions indicate ranges of results

• 1. Incivo EU SmPC 2011; 2. Victrelis EU SmPC 2011;
• 3. Poordad F, et al. N Engl J Med 2011;364:1195–1206;
• 4. Sulkowski MS, et al. Manuscript in preparation;
• 5. Fried M, et al. AASLD 2011. Abstract LB-5

QD, once daily; RGT, response-guided therapy; SVR, sustained virological response; TID, three times daily

Duration of RGT (wk) 24 28 24 24 Eligible for RGT Overall SVR

Patients (%)

58 79 44 63–66 84 87 79–86 81–86 Telaprevir 750 mg TID1 Boceprevir 800 mg TID2,3 Faldaprevir 240 mg QD4 Simeprevir 150 mg QD5 Eligible for RGT Overall SVR Eligible for RGT Overall SVR Eligible for RGT Overall SVR

New Protease Inhibitors (With Peg + Riba)

New Protease Inhibitors (With Peg + Riba)

• Once a day regimes
• Far fewer drug:drug interactions
• ‘User friendly’ – less anaemia, less side

effects

New protease inhibitors

Restricted to the US viral strains Early data in HIV encouraging Fewer DDIs (Not as good as they pretend they are)

NS5A Inhibitors

Daclatasvir Ledipasvir

Daclatasvir + PR

PDR <LLOQ Wk4 + <LOD Wk 12

G1a G1b % of patients

PR48 DCV 20/PR DCV 60/PR

DCV arms RGT criterion

Hézode et al, AASLD 2012 (SVR 12 analysis), abstract 755; TVR EU SmPC

63/ 106 66/ 113 21/ 56 5/16 32/ 41 27/ 31 105 147 105 146

SVR: 75-87% SVR

PDR: protocol defined response

NS5A Inhibitors

Quirky Large variation in efficacy Good to work with

NS5B – Non Nucleotides

Very unpredictable Generally G1 specific

R 7128 (Roche) MK 0608 (Merck) VCH 759 (ViroChem) GSK 625433 (GSK) HCV 796 (Wyeth) …and others

Nucleotides

Sofosbuvir

Sofosbuvir with PEG-IFN + RBV

• NEUTRINO Phase III trial

– Sofosbuvir plus PEG-IFN + RBV* for 12 weeks – Treatment naïve, GT1 (89%), 4, 5 or 6 (N=327)

• 17% had compensated cirrhosis

– Primary endpoint: SVR12

91 99 99 90 20 40 60 80 100

Week 2 Week 4 Last† SVR12

Patients achieving SVR (%) *Dose administered according to body weight

†Last observed measurement

Lawitz et al. N Eng J Med 2013;368:1878–87

Sofosbuvir with PEG-IFN + RBV

NEUTRINO Phase III trial

• Genotype 1a SVR = 92%
• Genotype 1b SVR = 82%
• Peg/Riba/Telap
• Genotype 1b = 79%

*Dose administered according to body weight

†Last observed measurement

Lawitz et al. N Eng J Med 2013;368:1878–87

Nucleotides

Fast Effective Cures all strains Side effect free (Too good to be true?)

Interferon Regimes

6-12 months

• PI + Peg Riba
• + Old PI (dirty, but cheap)
• + New PI (clean, but expensive, ‘quirky’)

3 months

• Sofosbuvir - + Peg Riba (expensive)

What about interferon free?

Interferon is horrid… …so …can we go to interferon free?

Playing Tag (I)

Protease Inhibitor + Non – Nuc/NS5A

BI BMS

+ +

Co-Pilot: Virologic Outcomes

• SVR12 in 94% of treatment-naive and 47% of treatment-experienced

pts – Responses independent of IL28B genotype

Poordad F, et al. EASL 2012. Abstract 1399. Patients (%) 40 60 80 100 20 ABT-450/r 250/100 mg QD + ABT-333 + RBV Treatment naive (n = 19) ABT-450/r 150/100 mg QD + ABT-333 + RBV Treatment naive (n = 14) ABT-450/r 150/100 mg QD + ABT-333 + RBV Nonresponders (n = 17) RVR eRVR SVR4 SVR12 90 90 95 95 79 79 93 93 77 59 47 47

Co-Pilot: Virologic Outcomes

• SVR12 in 94% of treatment-naive and 47% of treatment-experienced

pts – Responses independent of IL28B genotype

Poordad F, et al. EASL 2012. Abstract 1399. Patients (%) 40 60 80 100 20 ABT-450/r 250/100 mg QD + ABT-333 + RBV Treatment naive (n = 19) ABT-450/r 150/100 mg QD + ABT-333 + RBV Treatment naive (n = 14) ABT-450/r 150/100 mg QD + ABT-333 + RBV Nonresponders (n = 17) RVR eRVR SVR4 SVR12 90 90 95 95 79 79 93 93 77 59 47 47

Two drugs (PI + X) is good

• But not good enough – send in the boys!

AVIATOR: SVR12 Rates With ABT-450/RTV, ABT-267, ABT-333, and RBV

• SVR12 rates higher in pts with HCV GT1b, but also high in pts with HCV GT1a

– 12-wk regimen with all 3 DAAs + RBV produced highest SVR12 rates

• No drug-related SAEs reported; 2 pts discontinued tx due to drug-related AEs

8 weeks 12 weeks 12 weeks

82 86

20 40 60 80 100 SVR12, %

96 100 100 100 100 100 84 96 56 24 79 100 29 12 85 100 52 27 83 96 52 25 96 100 54 25 81 100 26 18 89 100 28 17

Observed data (above bar) ITT (within bar)

n = 81 98 88 88 100 89

1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b

ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV

Treatment-Naive Patients Null Responders Kowdley K, et al. AASLD 2012. Abstract LB-1.

AVIATOR: SVR12 Rates With ABT-450/RTV, ABT-267, ABT-333, and RBV

• SVR12 rates higher in pts with HCV GT1b, but also high in pts with HCV GT1a

– 12-wk regimen with all 3 DAAs + RBV produced highest SVR12 rates

• No drug-related SAEs reported; 2 pts discontinued tx due to drug-related AEs

8 weeks 12 weeks 12 weeks

82 86

20 40 60 80 100 SVR12, %

96 100 100 100 100 100 84 96 56 24 79 100 29 12 85 100 52 27 83 96 52 25 96 100 54 25 81 100 26 18 89 100 28 17

Observed data (above bar) ITT (within bar)

n = 81 98 88 88 100 89

1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b

ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV

Treatment-Naive Patients Null Responders Kowdley K, et al. AASLD 2012. Abstract LB-1.

What about the alternatives?

Sofosbuvir + Ribavirin 24 weeks Cures 68% of tough patients (Kottilil – JAMA 2013)

Does Superman need a friend

Sofosbuvir +DCV for 24 weeks

*1 patient required addition of peg-IFN/RBV, 1 patient with relapse at Week4 **2 patients lost to follow-up (following Week 12 and 24 visits)

Patients with HCV RNA <LOD (%) GT1 TN GT2/3 TN N=15 N=15 N=16 N=14 N=14 N=14 * **

= < LLOQ and detectable

Sulkowski M, et al. AASLD 2012, LB-2

wo R wo R with R

COSMOS: Simeprevir + Sofosbuvir ± RBV in GT1 HCV Pts

• Planned interim analysis of phase IIa randomized study
• 2 cohorts with same study design; evaluating impact of duration and RBV
• Primary endpoint: SVR12

Simeprevir 150 mg QD; Sofosbuvir 400 mg QD; RBV 1000 or 1200 mg/day BID.

Pts with GT1 HCV Cohort 1: Previous null responders, F0- F2 (N = 80) Cohort 2: Naives and previous null responders, F3-F4 (N = 87) Simeprevir + Sofosbuvir + RBV Simeprevir + Sofosbuvir Wk 12 Wk 24 Simeprevir + Sofosbuvir Simeprevir + Sofosbuvir + RBV* Jacobson I, et al. AASLD 2013. Abstract LB-3. Randomized 2:1:2:1

COSMOS: SVR12 in F0-F2 Pts (All Arms) and SVR4 in F3-F4 Pts (12-Wk Arms Only)

• AEs (anemia and indirect bilirubin increases) largely confined to RBV arms

SVR12, % Cohort 1 (F0-F2 Nulls ): SVR12 (N = 80, all arms)

100 80 60 40 20 24-Wk Arms 79.2 93.3 96.3 92.9

Cohort 2 (F3-F4 Naives 7 Nulls): SVR4 (N = 41, 12-wk arms)

100 80 60 40 20 100 100 100 93 12-Wk Arms

SVR4, %

Naives Null Responders

19/24 26/27 13/14 12/12 7/7 14/15 7/7

Jacobson I, et al. AASLD 2013. Abstract LB-3. SMV + SOF + RBV SMV + SOF

14/15

Sofosbuvir +

• Sofosbuvir + ‘anything potent’ for 12

weeks looks wonderful

• Sofosbuvir + Ledipasvir (NS5A) = ~100%
• Sofosbuvir + Simeprevir (NS3) = ~100%

Sofosbuvir +

• Sofosbuvir + ‘anything potent’ for 12

weeks looks wonderful

• Sofosbuvir + Ledipasvir (NS5A) = ~100%
• Sofosbuvir + Simeprevir (NS3) = ~100%
• Can we shorten further?

SYNERGY: Sofosbuvir/Ledipasvir FDC ± GS-9669 (Non Nuc) or GS-9541 (PI) in GT1 HCV Pts

• NIAID nonrandomized parallel-arm phase II trial
• Primary endpoint: SVR12

Treatment naive, F0-F4 (n = 20)

SOF/LDV FDC + GS-9669 SOF/LDV FDC

Treatment-experienced, F0-F3 (n = 20)

SOF/LDV FDC + GS-9451

Wk 12 Kohli A, et al. AASLD 2013. Abstract LB-8. Sofosbuvir 400 mg QD; ledipasvir 90 mg QD; GS-9669 500 mg QD; GS-9451 80 mg QD. Wk 6 Treatment naive, F0-F3 (n = 20) Pts with GT1 HCV

SYNERGY: High Response Rates With 6-Week Triple-Drug Regimens

SOF/LDV FDC + GS-9669, 6 wks SOF/LDV FDC, 12 wks SOF/LDV FDC + GS-9451, 6 wks

100 100

HCV RNA < LLOQ (%) 100 80 60 40 20 EOT SVR4 SVR12

90 100 100 100 100

Kohli A, et al. AASLD 2013. Abstract LB-8.

20/20 20/20 20/20 20/20 20/20 20/20 18/20

Genotype 1 Interferon Free

• Sofosbuvir containing regimes look very, very good
• 12 weeks is the standard

but triple therapy may allow shorter therapies

• AbVie have a fantastic triple 12 week regime

Genotype 2

NAIVE EXPERIENCED G2 G2 12 WEEKS G2 16 WEEKS

Non Cirrhosis Cirrhosis Non Cirrhosis Cirrhosis Non Cirrhosis Cirrhosis

92% 94% 96% 60% 100% 78%

Jacobson NEJM 2013

Genotype 2

NAIVE EXPERIENCED G2 G2 12 WEEKS G2 16 WEEKS

Non Cirrhosis Cirrhosis Non Cirrhosis Cirrhosis Non Cirrhosis Cirrhosis

92% 94% 96% 60% 100% 78%

Jacobson NEJM 2013

Genotype 2

NAIVE EXPERIENCED G2 G2 12 WEEKS G2 16 WEEKS

Non Cirrhosis Cirrhosis Non Cirrhosis Cirrhosis Non Cirrhosis Cirrhosis

92% 94% 96% 60% 100% 78%

Jacobson NEJM 2013

G2 - Current Therapy

• Interferon therapy for G2 is over:
• FISSION trial

SVR >90% for Sofos+Ribavirin

(Lawitz NEJM 2013)

• PHOTON trial (HIV co-infected)

SVR 81%

Genotype 3

G3 (NAÏVE) IFN Intolerant G3 12 WEEKS G3 16 WEEKS

Non Cirrhosis Cirrhosis Non Cirrhosis Cirrhosis Non Cirrhosis Cirrhosis

68% 21% 37% 19% 63% 61%

Jacobson NEJM 2013

IFN Intolerant and IFN treated G3

G3 (NAÏVE) G3 12 WEEKS G3 16 WEEKS

Non Cirrhosis Cirrhosis Non Cirrhosis Cirrhosis Non Cirrhosis Cirrhosis

68% 21% 37% 19% 63% 61%

Jacobson NEJM 2013

IFN Intolerant and IFN treated G2 and G3

G3 (NAÏVE) G3 12 WEEKS G3 16 WEEKS

Non Cirrhosis Cirrhosis Non Cirrhosis Cirrhosis Non Cirrhosis Cirrhosis

68% 21% 37%

19%

63%

61%

Jacobson NEJM 2013

Nucleotide struggles with G3

Zeuzem S, et al. AASLD 2013. Washington, DC. #1085

SVR12 in GT 3 Patients Treated for 24 Weeks

An all oral regimen of SOF + RBV for 24 weeks for GT3 significantly increased SVR rates compared to both FISSION and FUSION trials

94 92 87 60

86/92 12/13 27/45 87/100 Naïve, Noncirrhotic Experienced, Noncirrhotic Naïve, Cirrhotic Experienced, Cirrhotic

85

Overall

SVR12 (%)

20 40 60 80 100

VALENCE – 24 weeks therapy for Genotype 3

LONESTAR Study Design

SOF 400 mg once daily, PEG 180 µg once weekly, RBV 1000-1200 mg divided daily

SOF + PEG/RBV

SVR12 GT 2/3 (N=47)

 Study population

– HCV GT 2 or 3 – Failed treatment with pegylated interferon and ribavirin – Approximately 50% with compensated cirrhosis – HIV and HBV coinfected patients excluded

Wk 0 Wk 12 Wk 24 Wk 36

59

Results: SVR12 by Cirrhosis Status

100 83 93 83 20 40 60 80 100 GT 2 GT 3

No Cirrhosis Cirrhosis

SVR12 (%)

9/9 13/14 10/12 10/12

60 Error bars represent 95% confidence intervals.

We are nearly there...

We are nearly there...

Genotype 1

• Powerful drugs with Peg+ Riba (PIs, Nucs)
• Multiple PI drug regimes without Peg

G1b = PI + 1, G1a = PI + 2 (Abbott, Nuc+NS5A)

• Sofosbuvir + AN Other – almost perfect!

We are nearly there....

Genotype 2

• Nuc + Ribavirin – Game over

Genotype 3

• Struggling
• We need a partner for the nuc

Twist or Stick?

• Todays drugs
• What is emerging
• How do we get people onto therapy?

The HCV Challenge

Find them, get them on therapy

Who do we need to target?

• Immigrants
• Drug users – now and past

Who do we need to target?

• BME groups
• Drug users – now and past

BME and Viral Hepatitis

• Eastern Europe, SE Asia, Egypt, Far East
• Clearly large numbers, BUT –
• Pattern of infection unpredictable

(‘healthy migrant’ effect)

• Access can be difficult
• Not everyone wants to be associated with

these viruses

Accessing BME populations

• This will not be as easy as you think!
• We are working with local community

groups to resolve some of the issues (Chinese speaking doctors, community delivered therapy, easy access clinics with extended opening times)

• Outreach to Mosques in Bradford

Who do we need to target?

• Immigrants
• Drug users – now and past

IDUs

• Current injectors are ‘low hanging fruit’

– Known – In services – Accessing methadone

• So easy to find, but how easy to treat?

Prison Pathways

• Opt-out BBV screening in reception
• Pathways in every prison
• Communication with outside providers
• Centralised Specialist Commissioning

Treatment outcomes

Over all Current-injection drug users % Ex-injection drug users % Total 152 77 51 75 49 Compliant with treatment 118 61 79 57 76 End of treatment response (ETR) 105 54 70 51 68 Sustained viral response (SVR) 83 45 58 38 51 Non-responders 38 18 23 20 27 Relapsed after successful treatment 18 9 12 9 12 Partial response to treatment 1 1 1 Lost to follow up or

• utcome unknown

12 4 5 8 10 Reinfection 1 1 1 Death 5 3 4 2 3

Treatment outcomes

Genotype Number (50) Completion (%) ETR (%) SVR 24 (%) 1 19 (38) 10 (52.6)* 14 (73.7) 13 (68.4) 2 8 (16) 8 (100) 8 (100) 6 (75)† 3 23 (46) 21 (91.3) 21 (91.3) 16 (69.6)‡

3 released & did not complete; 5 ADRs although 4 achieved SVR anyway † 1 retreated 24 weeks after failure after 12 weeks ‡1 deceased, 3 lost to follow up, 2 pts now +ve genotype 1

HCV in Injectors

• Therapy CAN be given
• People can be cured (and stay cured)

Treating Current Injectors

• Effective
• Easy to access pathways are safe
• Only a small proportion access therapy
• How many do we need to treat?

Modelling HCV in treated injectors – what can therapy achieve?

Martin et al – J Hep 2011

Treating Current Injectors

• Effective
• Easy to access pathways are safe
• Only a small proportion access therapy
• How many do we need to treat?

–Surprisingly few

HCV Therapy

• We are close to a cure for all
• Now we need to find the patients
• Eradicating HCV is within our grasp

Thank you for your attention

• Any questions / comments?

Resources

http://www.hcvadvocate.org/hepatitis/hepC/Quick_Ref_Guide.pdf British Association for the Study of the Liver (BASL) http://www.hcvaction.org.uk http://www.hepctrust.org.uk http://www.hpa.org.uk

Dr Iain Brew

iainbrew@nhs.net With thanks to Professor Graham Foster