HCV Disease Pathway Acute infection Spontaneous cure Chronic Hepatitis Cirrhosis Hepatocellular...

HCV The Beginning of the end

Dr John F Dillon

HCV Disease Pathway

Acute infection Spontaneous cure

Chronic Hepatitis

Cirrhosis Hepatocellular carcinoma

20-30%

70-80%

1- 4%/annum

20-100%!!!

??

Modelled prevalent number of HCV infected IDUs in Scotland

according to stage of HCV disease, 1960-2030

1960 1980 2000 2020

0

10

20

30

40

50

60

Liv

ing

IDU

s (t

ho

us

an

ds

)

2008

Calendar year

Mild disease

Moderate disease

Cirrhosis

Recovered from HCV

Cleared HCV from treatment

Hutchinson et al. Hepatology 2005

Strategic aims of the Scottish Hepatitis C Action Plan

• Prevent liver failure and HCC

• Treat patients with cirrhosis

• However, the treatment is less effective

• Treat enough patients early in infection

• Find them

Compensated

cirrhosisCirrhosis prevented

from antiviral therapy*

Liv

ing

ID

Us w

ith

cir

rhosis

2010 2020 2030

01

,00

02

,00

03

,00

0

2010 2020 2030

01

,00

02

,00

03

,00

0

2010 2020 2030

01

,00

02

,00

03

,00

0

Decompensat

ed cirrhosisHCC

Uptake of therapy

by 225 IDUs per year

Uptake of therapy

by 1,000 IDUs per year

Uptake of therapy by

(up to) 2,000 IDUs per year

Modelled number of IDUs with cirrhosis in Scotland by different uptake rates of HCV antiviral therapy, 2008-2030

* Excludes those prevented from antiviral therapy prior to 2008 Hutchinson, SJ. et al 2008 J Hepatol. 48 (Suppl 2):S297

In Scotland, 2002-2012: (a) the number of chronic HCV persons commencing a course

of therapy each year, and (b) the cumulative number of patients attaining SVR

Key points: •1052 patients treated in 2012/13 (marginally below the national target of 1,150)•In the last three years, more than 1,000 patients per year commencing treatment in Scotland•The number of persons known to have attained a SVR, now exceeds 3000

UPTAKE OF TREATMENT

0

1000

2000

3000

4000

200

400

600

800

1000

Num

ber

trea

ted

.

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

No persons commencing treatment

Cumulative number of known SVR

Cum

ulat

ive

SV

R

McDonald et al. J Viral Hep; in press

Proportion attending a specialist clinic within 12 months of diagnosis, by calendar period, in Scotland.

(1a) ATTENDANCE AT SPECIALIST SERVICES (1b) UPTAKE OF TREATMENT

Proportion commencing treatment within 12 months of attendance, by calendar

period, in Scotland.

0

10

20

30

40

50

96-98 99-01 02-04 05-07 08-09

0

10

20

30

40

50

96-98 02-04 05-07 08-0999-01

Pre phase II

% A

tten

ded

% T

reat

ed

Phase II

PERIOD OF DIAGNOSIS PERIOD OF ATTENDANCE


Liver deaths and instances of first time liver failure among person with Hepatitis C in Scotland, 1998-2011

0

50

100

150

98 00 02 04 06 08 10

Num

ber

of d

eath

s

Year Death

0

50

100

150

98 00 02 04 06 08 10

Year AdmissionN

umbe

r of

adm

issi

ons

(I) LIVER DEATHS (II) FIRST-TIME ADMISSION FOR LIVER FAILURE

(4) IMPACT OF SVR


Estimated uptake of HCV antiviral therapy, by selected

country

Estimated number living with chronic

HCV(N)

Annual number initiated on HCV

therapy(Rx)

Annual treatment uptake (Rx/N)

Scotland (2012) 38,000 1,052 2.8%

France (2000-2005)1 ~500,000 ~13,500 ~2.7%

USA (2008-2012)2 ~3,200,000 65,000 ~2.6%

Australia (2006)3 202,400 2900 ~1.4%

1Lettmeier et al. J Hepatol. 2008;49(4)528-36

2Volk et al. Hepatology. 2009; 50:1750-1755

3Gidding et al. J Gastroenterol Hepatol. 2009; 24(10)1648-54

Excess risk of a liver and an alcohol related hospital episode post

treatment (in SVR & non-SVR patients) AND post diagnosis (in

spontaneously resolved patients), compared to the general population

Innes et al. Hepatology, 2011.* Age, sex & year standardised

0.5

1.0

5.0

10.0

50.0

Ex

ces

s ri

sk* Liver

Alcohol

Non-SVR (N=638)

SVR (N=560)

Non-cirrhotic SVR (N=503)

Spontaneous resolved (N=3,690)

53.2

10.5

5.9

26.8

4.5

2.01.3

7.4

HCV treatment the state of the art Feb 2014

Interferon Based

Tailored to Genotype

Duration 24-48 weeks

Scotland Genotype 1&3

SVR G1 70%, G3 75%

Boceprevir regimen in G1 HCV-infected patients

*This regimen has only been tested in patients who have failed previous therapy who were late responders Boceprevir EU SmPC

Non-cirrhotic treatment-naïve with detectable HCV RNA at Week 8 but undetectable at Week 24*

Non-cirrhotic relapsers and partial responders

0 48284 8 24 3612 28

Null responders Patients with cirrhosis

Weeks

PRlead-in BOC + PR*BOC + PR PR

STOP

BOC + PR

Treatment-naïve without cirrhosis who achieve undetectable HCV RNA at Weeks 8 and 24

HCV RNA If ≥100 IU/mLdiscontinue all

drugs

If detectablediscontinue all

drugs

Boceprevir dose must not be reduced or restarted once stopped

Telaprevir regimen in G1 HCV-infected patients

eRVR: extended rapid virologic response Telaprevir EU SmPC

If >1000 IU/mL at Week 4 or 12:discontinue all drugs

If detectable at Week 24 or 36:discontinue PR

240 4812 364Weeks

STOP

PR

Telaprevir+ PR

PR

Non-cirrhotic naïves and relapsers achieving undetectable HCV RNA at Week 4 and 12 (eRVR)

Non-cirrhotic naïves and relapsers without eRVR Partial and null responders Patients with cirrhosis

HCV RNA

Telaprevir dose must not be reduced or restarted once stopped

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

0

20

40

60

80

100

38

63 66

SV

R (

%)

BOC RGT

233/368

BOC44/PR48

242/366

PR48

137/363n/N =

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

* *

ADVANCE and ILLUMINATE: SVR rates with telaprevir therapy versus PR alone

0

20

40

60

80

100

44

SV

R (

%)

T12PR

659/903

PR48

158/361n/N =

72–75*

Sherman KE, et al. Hepatology 2010;52(Suppl.):401AJacobson 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%)

Treating PWID: who do we mean?

• Last injected this morning or last injected 35 years ago!

No Contact/harm reduction

Methadone/

opiate substitutio

n

Needle

exchange

On or off opiate substitution therapy?

Has changed drug habit to get HCV treatment

What is the best pathway to SVR in PWID patients?

• Therapy will be required to have• SVR rate similar to RCTs to maintain cost-effectiveness• Re-infection low enough not to reduce cost-effectiveness• Wide enough access to make a difference to overall

prevalence

• Options for patients to enter treatment• Enter maintenance programme, treat quickly• Stabilize drug issues first, then treat• Enhancing delivery

• Contingency management

• Treat the HCV, ignore the drug habitRCTs: randomized control trials

PWID: not a barrier to SVR in OST therapy

*ex-IDU vs active IDU; P=0.02 Jafferbhoy H, et al. J Viral Hepat. 2012:19(2):112–9

Non-IDU Ex-IDU Active IDU

80

70

60

50

40

30

20

10

0

G1 Non-G1

SV

R a

ch

iev

ed

(%

)

19/36 12/39 11/31 56/86 33/43* 33/43*

The Future

http://www.google.co.uk/url?sa=i&rct=j&q=hcv+drug+targets&source=images&cd=&cad=rja&docid=Otsw27USMESOVM&tbnid=jKdXgmcOnOwhxM:&ved=0CAUQjRw&url=http://natap.org/2013/HCV/010813_02.htm&ei=HVaXUYqzA4v70gXFlYHYDg&bvm=bv.46751780,d.d2k&psig=AFQjCNG4Qp8SgbBsQ7s4alNbVnLiYWKgkg&ust=1368958841869573

HCV Antivirals in Development

Other HCV Compounds

NS5As

PhIIa

PhIIb

PhIII

PhI

ITMN-191/R7227

BI-201335

MK-7009

VBY376

Boceprevir

R7128

MK3281

BMS

PF868554

GS 9190

ANA598

Albuferon

Locteron CR

Nitazoxanide

Debio025

IF's

PEG-IL-29

Non-nucpolymerases

IDX-184

Nucpolymerases

PIs

IDX-102

BMS 790052

PSI-7851

VCH 916IFN-alpha-2b-XL

TMC435350

Telaprevir

VX-813

Sources: GBI Analysis (August 4, 2010), Pipeline Sources, Company Press Releases, Reuters Knowledge Analyst Reports

VCH-222

BIT-225

PHX-1766

ABT-333

ITCA-638

AZD-7295

Celgosivir

SCH 900518

sr-IFN-alpha (LG Life Sciences)

ABT 450

BI-207127

Belerofon

ABT-072

IDX-136 and IDX-316

ACH-1095

HDV-IFN (Hepasome)

SCY-635

Miglustat

NA-808

SPC-3649

CF-102

AVL-181

IFN alpha, Medgenics(Biopump SR)

NIM-811

Taribavirin

ANA773

PF 4878691

VCH 759

BMS-791325

ITX 5061

IMO-2125

MK-1220

Golotimod (SCV 07) sc

ACH-1625

PSI-879

PPI-461

IPH 1101

PRO 206

Interferon-alpha (buccal lozenge, Amarillo)

BMS-650032

IFN-alpha-2b-medtronics

Suspended / Discontinued

CYT-107

P-1101

Nov-205

BMS-824393

ATI-0180

IDX-189

MK5172 IDX-375

GS 9256

VX-985

CB-5300

GS9190+GS9256

CombinationProducts

VCH-222+ Telaprevir

RG7227+RG7128

BMS-790052 + BMS-650032BI-201335+BI20127

AZD 2795

EDP-239

PSI-938

PSI-7977

RG 7348

GI-5005

Changed/additional info

IDX-320

TaigGen Bio

ACH 2928

Clemizole

FGI 103723

IDX184+IDX320

22

‡

Race (Non-Black vs. Black)

SOF Phase 3 Analysis in Patients with Traditional Negative FactorsVirologic Response: SVR12 in NEUTRINO GT 1,4,5,6

Mangia A, et al. AASLD 2013. Washington, DC. #1115

Non-Black Black

9187

0

20

40

60

80

100

248/273 47/54

Obesity (BMI < vs. ≥ 35 kg/m2)

< 35 kg/m2 ≥ 35 kg/m2

90 91

0

20

40

60

80

100

254/282 41/45

SV

R12

(%

)

IL28B GT (Non-TT vs. TT)

Non-TT TT

0

9186

20

40

60

80

100

251/276 44/51

Sulkowski M, et al. J Hepatol 2012; 56: S1422

NUC NS5B inhibitor sofosbuvir & Daclatasvir ± Ribavirin (geno 1, n =45)

79%

93% 93%100% 100%

67%77%

100%100% 100%

0%

20%

40%

60%

80%

100%

2 weeksOn Rx

4 weeksOn Rx

12 weeksOn Rx

24 weeksEnd of Rx

12 weekspost-Rx

% u

ndet

ecta

ble

HC

V R

NA

GS7977/daclatasvir GS7977/daclatasvir/RBV

QUEST-1: Phase 3 trial of Simeprevir + PR in G1 treatment-naive patients

24Jacobson IM et al, EASL 2013, Amsterdam, #1425

A NS3a PI a replacement for Boceprevir or telaprevir

Response Guided Therapycriteria met by 85%SVR in 91% of RGT patientsNo incremental rash/anemiaHyperbilrubinemia

AbbVie Phase III Clinical Program Results fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg), dosed once daily, and ABT-333 (250mg) twice daily

Study Patients Treatment Regimen SVR12

PEARL-II(12 weeks)

GT1b treatment-experienced(N=179)

AbbVie regimen + RBV (n=88)

97%(85/88)

AbbVie regimen only (n=91)

100%(91/91)

PEARL-III(12 weeks)

GT1b treatment-naive(N=419)


99%(209/210)


99%(207/209)

PEARL-IV(12 weeks)

GT1a treatment-naive (N=305)


97%(97/100)


90%(185/205)

TURQUOISE-II(12 & 24 weeks)

GT1 treatment-naive and treatment-experienced with compensated cirrhosis(N=380)

AbbVie regimen + RBV, 12 weeks (n=208)

92% (191/208)

AbbVie regimen + RBV, 24 weeks (n=172)

96%(165/172)

SAPPHIRE-I(12 weeks)

GT1 treatment-naive(N=631)


96%(455/473)

SAPPHIRE-II(12 weeks)

GT1 treatment-experienced(N=394)


96%(286/297)

Strategic aims of the Scottish Hepatitis C Action Plan

• Prevent liver failure and HCC

• Treat patients with cirrhosis

• However, the treatment is less effective

• Treat enough patients early in infection

• Find them

• Prevent infection

•Treatment as prevention

• In developed country settings, people who inject drugs (PWID) contribute to the majority (>80%) of HCV transmission

• Pooled UK evidence for impact of harm reduction on HCV incidence1

• Opiate substitution therapy (OST) or high coverage needle and syringe programmes (NSP) alone reduces an individual’s HCV risk by ~50%

• In combination, reduces HCV risk by ~80%

• Modelling indicates OST and NSP likely important in preventing very high HCV prevalences in UK, BUT insufficient to reduce HCV to very low levels2

[1] Turner K et al. Addiction 2011; 106:1978-88[2] Vickerman P et al. Addiction 2012;107:1984-1995.

CURRENT HCV PREVENTION INTERVENTIONS

How much treatment for prevention?

Bars indicate the mean relative prevalence reductions; whiskers represent the 95% credibility interval for the simualtions Martin NK, et al. J Hepatol 2011;54:1137–44

No scale-up

Scale-up to 10/1,000 PWID



Annually


Rel

ati

ve

pre

vale

nce

re

du

ctio

n (

%)

at 1

5 ye

ars

(20

27)

100

0

10

30

40

50

60

70

80

90

20

Edinburgh25% baseline

chronic prevalence

Melbourne50% baseline

chronic prevalence

Vancouver65% baseline

chronic prevalence

DYNAMIC HCV TRANSMISSION MODEL

Non-SVR infected PWID

Chronically infected PWID

UninfectedPWID

Antiviral treatment

Allow for re-infection

NewPWID

Cease/dieAcutely infected

PWID Infection

Spontaneous clearance

ADDITIONAL RISK HETEROGENEITY

High risk, Off OST

High risk, On OST

Low risk, Off OST

Low risk, On OST

Martin NK, Vickerman P, Grebely J, Hellard M, Hutchinson SJ, Lima VD, Foster GR, Dillon J, Goldberg DJ, Dore G, and Hickman M. HCV treatment for prevention among people who inject drugs: modeling treatment scale-up in the age of direct acting antivirals. Hepatology 2013

• PWID cycle through various risk and intervention states, associated with different risks of HCV acquisition

• Allows for examination of targeting strategies

RESULTS: EDINBURGH

IFN-free DAAs


SENSITIVITY ANALYSIS

• Delaying initiation of IFN-free DAA scale-up by 4 yrs reduces impact by over 20%

• Less impact seen with shorter injecting duration

• Impact not sensitive to changes in assumptions regarding population heterogeneity and treatment targeting (low risk or on OST) because of movement/cycling between risk states


UK POOLED EVIDENCE FOR IMPACT OF HARM REDUCTION ON HCV INCIDENCE

• Survey data pooled from England, Wales and Scotland

• Looked at impact of OST and/or exchanging more syringes than you inject (100%NSP) on an individual’s risk of recent infection

Turner K et al. Addiction 2011; 106:1978-88

Effect Estimates AOR1 95% CI>100%NSP 0.48 0.3 0.9OST 0.41 0.2 0.8OST and >100%NSP 0.21 0.1 0.51 adjusted for: gender, crack, homeless, injecting duration100%NSP is defined as exchanging more syringes than you inject

HCV free survival in needle exchanage

NECESSARY DAA TREATMENT RATES TO HALVE CHRONIC PREVALENCE IN 10 YRS WITH HARM REDUCTION

Martin NK, et al.. CID 2013

The drug using population in Tayside

2,500–3,000 in total

• 2,200 in methadone program

• HCV prevalence: 38%

• Risk episodes less than 5 per year

• 7–800 in needle exchange

• HCV prevalence: 29%

• Harm reduction vs sharp needles

• Risk episodes: 30–300 per year

• 20% seroconversion at 1 year

• 300–900 using without service contact

• Risk episodes? prevalence? most high risk

Tayside

How do you find them• Conventional testing

with elution step• HCV ab, HIV ab• HCV-PCR & HBsAg• Works where

venepuncture difficult

Eradicate HCV• Treat 20–40 very active PWIDs per year• Recruit from Needle exchange

• Bring a friend, mine the vein • Contingency management• Low threshold methadone

• End-points• Year 2: numbers in treatment and SVR• Year 5, 7 and 10: HCV prevalence

• NESI, Needle exchange, entering methadone

NESI: Needle Exchange Surveillance Initiative

Eradicate HCV project: an update

• 28 patients initiated on to treatment

• 3 drop-outs

• Adherence good• Contingency management – most popular

• Protein drinks and food vouchers

• Side-effects appear less than conventional treatment pathways• One rash not on DAA

• 5/6 SVR

6 months into project

1985 20yrs 2004

Success of HCV Therapy

0%

25%

50%

75%

100%C

ure

rate

IFN-α48 weeks

9%

IFN-α24 weeks

4%

IFN/RBV 48 weeks

27%

PEG/RBV 48 weeks

45%

Triple RxProtease inhibitor

+ PEG/RBV24 weeks

75%

2011

Combo DAANuc

+ 2nd DAA12 wksNo IFNNo RGT

95-100%

2013

HCV a disease that need not kill anyoneHCV a disease we can kill in our life time

HCV Disease Pathway Acute infection Spontaneous cure Chronic Hepatitis Cirrhosis Hepatocellular...

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