1

in partnership

with

Medical Centre for Infectious Diseases

Berlin (MIB), Germany

Dr Patrick Ingiliz

Pre-conference Clinical Course

in partnership

with

COMPETING INTEREST OF FINANCIAL VALUE > £1,000

Statement

I have done educational presentations and advisory boards for

Abbvie, BMS, Gilead, and MSD

Date: December 2015

Medical Centre for Infectious Diseases

Berlin (MIB), Germany

Dr Patrick Ingiliz

Pre-conference Clinical Course

2

Treatment of Hepatitis C: Who?When?How?

Patrick Ingiliz, Berlin

FIVE NATIONS CONFERENCE

on

HIV and Hepatitis

8–9 December 2014

Queen Elizabeth II Conference Centre

LONDON · UK

HCV is a Progressive Disease with Serious Sequelae

Adapted from Chen SL, Morgan TR. Int J Med Sci 2006;3:47–52

*20–30% of individuals are symptomatic; HCC: hepatocellular carcinoma

Permission is granted to use this figure; original source:

Chen SL, Morgan TR. The Natural History of Hepatitis C Virus (HCV) Infection.

Int J Med Sci 2006; 3(2):47-52. http://www.medsci.org/v03p0047.htm

Acute

infection*

Chronic

infection

75–85%

Clearance of

HCV RNA

15–25%

Extrahepatic manifestations

Cirrhosis

10–20%

over 20 years

HCC

1–4% per year

Decompensated

cirrhosis

5-year survival rate 50%

Risk of decompensation increases

from 5% (1 year) to 30% (10 years)

from the diagnosis of cirrhosis

3

Effective treatment of HIV infection reduces fibrosis risk in HIV/HCV-coinfected patients

Created from Macias J, et al. Hepatology 2009;50:1056–63.

Predictive factors of fibrosis progression (≥1 stage) (multivariate analysis)

RR (95% CI)=relative risk (95% confidence interval); ETR=end-of-treatment response; HAART=highly active antiretroviral therapy; *Undetectable HIV RNA in ≥70% determinations during the follow up.

Age, years

HAART during the follow-up

Undetectable HIV viraemia*

CD4 cell counts change

Genotype 3

Baseline ALT, IU/mL

Baseline necroinflammatory activity

Time between liver biopsies

Response to anti-HCV treatment

0.90

0.72

0.028

0.87

0.72

0.58

0.009

0.011

0.023

Relative risk (95% CI)

0.5 1.0 1.5 2.0 2.5 3.0

p multivariate

Data collected from 135 coinfected patients with 2 liver biopsies >1 year apart.

Specimens were centrally read and scored blindly by 2 independent pathologists using the Scheuer classification.

(≥37 vs <37)

(Yes vs No)

(Yes vs No)

(Per 25 cell increase)

(Yes vs No)

(≥66 vs <66)

(L2–4 vs L0–1)

(Per 1 year increase)

(ETR vs no ETR)

ART and hepatic decompensation in HCV/HIV vs. HCV alone

Lo Re III, V, et al. Ann Intern Med 2014; 160: 369

4

SVR is associated with a reduction of liver-related mortality and HCC

van der Meer AJ, et al. JAMA. 2012; 308(24):2584-2593.

retrospective multicenter study, n=530, HCV mono

SVR is associated with a reduction of overall mortality: meta-analysis of 129 studies, n=29,269

Hill et al., AASLD 2014

5

Estimated prevalence of liver cirrhosis

Wedemeyer et al., JVH 2014

Estimation: SVR rate 90%, treatment rate doubled

Rx as Prevention - Modelling treatment impact in IDU populations - seven UK cities with scale-up with DAAs

Martin NK, et al. C-Hep, Berlin 2014.

Baseline in 2014

2024, no scale-up, ITT SVR with PEG-IFN + RBV

2024, scale-up to 26/1000 annually with IFN-free DAAs (all genotypes) in 2016

HC

V c

hro

nic

pre

vale

nce a

mo

ng

PW

ID (

%)

0

10

20

30

40

50

60

70

80

90

100

Bristol East

London

ManchesterNottingham Plymouth Dundee North

Wales

6

Reinfection – an alarming reality!

Ingiliz et al., EASL 2014

553 patients from 7 NEAT centers

with cured acute HCV since 6/2001

141 with at least one reinfection (25.5%)

1509 patient-years of FU, median 2.1 years

Incidence rate: 7.82/100 patient-years

Treated patients: 7.9/100 patient years

Spontaneous clearers: 3.3/100 patient-

years

0

20

40

60

80

100

IFN

6 mo

IFN

12 mo

IFN+RBV

6 mo

IFN+RBV

12 mo

PEG

12 mo

PEG+RBV

12 mo

PI+PEG

+RBV

6-12 mo

LDV/SOF/RBV

AbbVie 3D

5172/8472

12 weeks

68-75

54-56

3942

34

16

6

90

1986 1998 20022001 2011 2013

SV

R R

ate

(%

)

*Year of data presentation at EASL 2014 and publication in NEJM

Adapted from Strader DB, et al. Hepatology 2004;39:1147-71. INCIVEK [PI]. Cambridge, MA: Vertex Pharmaceuticals; 2013. VICTRELIS [PI]. Whitehouse Station, NJ: Merck & Co; 2014. Jacobson I, et al. EASL 2013. Amsterdam. The Netherlands. Poster #1425. Manns M, et al. EASL 2013. Amsterdam. The Netherlands. Oral #1413. Lawitz E, et al. APASL 2013. Singapore. Oral #LB-02; Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 ; Kowdley K, et al. N Engl J Med 2014; 2014 Apr 11

SMV+PEG

+RBV

6-12 mo

80-81

2014*

SOF+PEG

+RBV

3 mo

94-99

HCV Genotype 1 Treatment-Naïve Patients – improving SVRs

7

EASL recommendations on treatment of hepatitis C

EASL recommendations April /easl-recommendations-on-treatment-of-hepatitis-c-summary.pdf2014 http://files.easl.eu

Newly diagnosed chronic

HCV infection

F2F3aF0F1a F4a

In general, treatment can be

deferred. Treatment with Peg/RBV and

DAA or 2/3 DAA +/- r based

regimen.

Treatment with Peg/RBV

and DAA if compensated

disease or 2/3 DAA +/- r

based regimen

Treatment should be

undergone in specialised

centres.

Management of newly diagnosed HIV-HCV coinfected

genotype-1 patients

Perform transient elastography and/or

serum marker and/or liver biopsy

aMetavir fibrosis score: F0=no fibrosis; F1= portal fibrosis, no septae;

F2= portal fibrosis, few septae, F3=bridging fibrosis, F4=cirrhosis.

Management of HIV/HCV Co-infected Patients (EACS 2014)

8

3’UTR5’UTR Core E1 E2 NS2 NS4BNS3 NS5A NS5Bp7

Telaprevir

Boceprevir

Simeprevir

Asunaprevir

Paritaprevir

Grazoprevir

Daclatasvir

Ledipasvir

Ombitasvir

Elbasvir

GS-5816

Sofosbuvir

VX-135

IDX21437

ACH-3422

Dasabuvir

Beclabuvir

NS5B

NUC Inhibitors

NS3

Protease

Inhibitors

NS5A

Replication

Complex

Inhibitors

Ribavirin

NS5B

Non-NUC

Inhibitors

*Representative list modified from CCO.

PolymeraseProtease

Which drugs beyond PegRIBA?

3’UTR5’UTR Core E1 E2 NS2 NS4BNS3 NS5A NS5Bp7

Telaprevir

Boceprevir

Simeprevir

Asunaprevir

Paritaprevir

Grazoprevir

Daclatasvir

Ledipasvir

Ombitasvir

Elbasvir

GS-5816

Sofosbuvir

VX-135

IDX21437

ACH-3422

Dasabuvir

Beclabuvir

NS5B

NUC Inhibitors

NS3

Protease

Inhibitors

NS5A

Replication

Complex

Inhibitors

Ribavirin

NS5B

Non-NUC

Inhibitors

*Representative list modified from CCO.

PolymeraseProtease

....previr (PI)

....asvir (NS5A)

....buvir (Pol)

Which drugs beyond PegRIBA?

9

HCV drug pipeline

Jan 2014

Sofosbuvir

May 2014

Simeprevir

Aug 2014

Daclatasvir

Nov 2014

STR Gilead

Sofosbuvir

Ledipasvir

Jan 2015

3D Abbvie

Ombitasvir

Paritaprevir

Dasabuvir

2016?SOF/GS-5816

2016?MSD-Worthy

Grazoprevir

Elbasvir

....buvir

2015?BMS-Unity

Daclatasvir

Asunaprevir

Beclabuvir

DAA combinations in 2015/2016

Gilead STR

(ION-1)1

3D Abbvie

(SAPPHIRE-I)2

BMS Unity3 DCV + SOF4 MSD

(C-WORTHY)5

1. Afdhal N, et al. NEJM 2014; Epub ahead of print. 2. Feld J, et al. EASL 2014, Abstract O60. 3. Everson GT, et al. CROI 2014,

Abstract 25. Available at: http://croi2014.org/sites/default/files/uploads/CROI2014_Final_Abstracts.pdf (Accessed May 2014).

4. Sulkowski M, et al. NEJM 2014;370:211–21. 5. Hezode C, et al. EASL 2014, Abstract O10. EASL abstracts available at:

http://www.ilc-congress.eu/#&panel1-1 (Accessed May 2014).

455/473 71/77 41/41 25/25211/214

SVR rates from different regimens in Phase II-III studies (genotype 1,

treatment naive, 12 weeks)

10

Indications for HCV treatment in HIV/HCV co-infected patients are identical to those in HCV mono-infection (A1)

Same treatment regimens can be used in HIV/HCV patients as in patients without HIV infection, as the virological results of therapy are identical (A1)

EASL recommendations April 2014 http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-c-summary.pdf

HCV/HIV co-infection: pegIFNα-free regimens GT-1

1. Molina J, et al. AIDS 2014, MOAB0105LB2. 2. Sulkowski M, et al. AASLD

2014. 3. Osinusi A, et al. EASL 2014, O14. 4. Sulkowski M, et al. AIDS 2014,

MOAB0104LB.

11

SOF/LDV: GT1 and 4: 12 weeks (8-24) +/-RBV

GT 3: 24 weeks+ RBV (TE, F4)

22

SVR12 from VALENCE includes pooled analysis from all patients (treatment-naïve and –experienced) by genotype and duration of therapy*GT1 SVR24 of 75%; GT3 TE SVR24 of 88%

100

28/42

SV

R12 (%

)

90 89

0

20

40

60

80

100

NEUTRINO1

HCV

19102

HCV/HIV

GT 1

SOF + RBV + PegIFN

12 weeks

GT 1

SOF + RBV

24 weeks

68

76*

0

20

40

60

80

100

SPARE3

HCV

PHOTON-14

HCV/HIV

87/11417/25 95/112

85

PHOTON-26

HCV/HIV

GT 3

SOF + RBV

24 weeks

85

94*

0

20

40

60

80

100

VALENCE5

HCV

PHOTON-14

HCV/HIV

16/17212/250

PHOTON-26

HCV/HIV

89

94/106

GT 2

SOF + RBV

12 weeks

9388

0

20

40

60

80

VALENCE5

HCV

PHOTON-14

HCV/HIV

68/73 23/26

88

22/25

PHOTON-26

HCV/HIV

262/292 17/19

Photon 1 & 2: SOF + RBV Comparison HCV monoinfection and HIV/HCV coinfection trials

1. Lawitz E, et al. APASL 2013. Singapore. Oral #LB-02. 2. Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster 714. 3. Osinusi A, et al. JAMA. 2013;310(8):804-811. 4. Naggie S, et al.

CROI 2014. Boston, MA. Oral #26. 5. Zeuzem S, et al. AASLD 2013. Washington, DC. #1085. 6. Molina JM, et al. IAS Melbourne Abstract MOAB0105LB

12

Any remaining question on HCV treatment?

• How will study data translate into real-life?

• HCV non-genotype 1/HCV genotype 3?

• Ribavirin?

• Cirrhotics beyond CHILD A

• ESLD/LTX/ESRD?

• DDIs?

SOF/P/R

N=384

SOF/RBV

N=667

SOF/SMV

N=784

SOF/SMV/RBV

N=228

Safety and Efficacy of SOF-Containing Regimens for HCV

HCV-TARGET

Jensen, AASLD, 2014, Oral #45

Genotype 3

SOF/PegIFN/RBV

8.5%

SOF/RBV

91.5%

Genotype 2

SOF/PegIFN/RBV

0.9%

SOF/RBV

99.1%

Genotype 1

SOF/SMV/RBV

14.9%

SOF/PegIFN/RBV

23.1%

SOF/RBV

8.8%

SOF/SMV

53.1%

Real-world observational study of 2,063 patients treated with DAAs at academic (n=38) and community medical centers (n=15) in North America and Europe

Started Therapy HCV-TARGET 2.0

N=2063

13

HCV-TARGET

n (%)

SOF+PegIFN+

RBV

n=384

SOF+SMV

±RBV

n=228

SOF+SMV

n=784

SOF+RBV

n=667

Total

n=2063

Completed treatment 332 (86.5) 189 (82.9) 663 (84.6) 429 (64.3) 1613 (78.2)

Ongoing treatment 41 (10.7) 32 (14.0) 101 (12.9) 205 (30.7) 379 (18.4)

D/C Prematurely* 11 (2.9) 7 (3.1) 20 (2.6) 33 (4.9) 71 (3.4)

AE 6 (1.6) 5 (2.2) 16 (2.0) 17 (2.5) 44 (2.1)

Death 1 (0.3) 2 (0.9) 6 (0.8) 3 (0.4) 12 (0.6)

140/164 269/303 44/54 168/187

GT 1 GT 2

12 Wk Regimens

SVR4/SVR12 Concordance: 94.4–98.2% PPV

Jensen, AASLD, 2014, Oral #45*Not all premature D/C are summarized. Full list available in final slides.

Safety and Efficacy of SOF-Containing Regimens for HCV

SOF-DAC for 12 weeks in GT 3

a Cirrhosis status determined in 141 patients by liver biopsy (METAVIR F4), FibroScan (> 14.6 kPa), or FibroTest score ≥

0.75 and APRI (aspartate aminotransferase to platelet ratio index) > 2.b Cirrhosis status for 11 patients was inconclusive (FibroTest score > 0.48 to < 0.75 or APRI > 1 to ≤ 2).

■ Among patients with cirrhosis, 34% (11/32) had baseline platelet counts <100,000/mm3

SV

R1

2,

%

PresentAbsent PresentAbsent PresentAbsent

Treatment-naive Treatment-experiencedOverall

Cirrhosisa,b

14

Sofosbuvir / GS5816 +/- Ribavirin 12 weeks genotype 3

Pianko et al., AASLD 2014

3D: Paritaprevir/r/ombitasvir (150/100/25 mg QD) plus dasabuvir (250 mg BID)

RBV: 1000 or 1200 mg daily in 2 divided doses according to body weight

(<75 kg and ≥75 kg, respectively)

Day 0 Week 12 Week 24

Open-Label Treatment

SVR12

All patients followed

through

48 weeks post-treatment3D + RBV

(N = 208)

3D + RBV

(N = 172)

SVR12

Week 36

TURQUOISE-II: Study Design380 Patients with Cirrhosis, genotype 1

15

SV

R1

2,

% P

ati

en

ts

12-Week 24-Week

0

20

40

60

80

100

96.591.8

191

208

166

172

TURQUOISE-II: Overall SVR12 Rates

LDV/SOF + RBV for HCV Patients with Decompensated Cirrhosis

108 patients randomized 1:1 to 12 or 24 weeks of treatment

Stratified by CTP class B [7-9] or C [score 10–12]*

Broad inclusion criteria:

No history of major organ transplant, including liver

No hepatocellular carcinoma (HCC)

Total bilirubin ≤10 mg/dL, Hemoglobin ≥ 10 g/dL

CrCl≥ 40 mL/min, Platelets > 30,000

RBV dosing: dose escalation, 600–1200 mg/d

SOLAR-1

Prospective, multicenter study of 12 or 24 weeks of LDV/SOF + RBV in TN and TE HCV GT 1 and 4 patients with CTP B (N=59) or CTP C (N=49) clinically decompensated cirrhosis

Wk 0 Wk 12 Wk 36Wk 24

SVR12N=53

SVR12N=55 LDV/SOF + RBV

LDV/SOF + RBV

*Patients with CTP scores 13-15 were excludedFlamm, AASLD, 2014, Oral #239

16

Results: SVR12

SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhosis

CTP B CTP C

SV

R12 (

%)

26/30 19/22 18/2024/27

Error bars represent 90% confidence intervals.

LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks

SVR rates were similar with 12 or 24 weeks of LDV/SOF + RBV

Flamm, AASLD, 2014, Oral #239

ABT450rSubstrate for CYP 3A4, PgP,

OATP1B1/3

Weak inhibitor PgP/BCRP (gut),

?OATP1B1/3

MK-5172Substrate for CYP 3A4, PgP, ?

OATP1B1

Inhibits CYP 2C8, weak inhibitor

of UGT1A1, ? BCRPModerate

Simeprevir Substrate for CYP 3A4, PgPInhibits OATP1B1, MRP2

Mild inhibitor gut CYP 3A4, PgPModerate

MK-8742Substrate for CYP 3A4, PgP,

?OATP1B1weak inhibitor of UGT1A1 Moderate

Sofosbuvircathepsin A, esterases, kinases

PgP & BCRP substrate (parent)

Weak inhibitor of gut PgP &

BCRPLow

Daclatasvir Substrate for CYP 3A4, PgP Inhibits OATP1B1/3 & PgP Moderate

VICTIM of DDI PERPETRATOR of DDIDDI

potential

Dasabuvir(ABT-333)

Substrate of CYP 2C8 > 3A4 >

2D6,

Substrate of PgP, BCRP

Weak inhibitor of UGT1A1

Ombitasvir(ABT-267)

Substrate for PgP, BCRP

(CYP 3A4 )Weak inhibitor of UGT1A1

Moderate to

Significant

(RTV)

LedipasvirPrimarily excreted unchanged

(>98% faeces), PgP / BCRP

substrate

Weak inhibitor of PgP/BCRP,

?OATP1B1/3?Low

TLPTeleprevir Substrate for CYP 3A4, PgP

Inhibits CYP 3A4, PgP,

OATP1B1/2

? Protein binding

Significant

BoceprevirSubstrate for

aldoketoreductase,

CYP 3A4, PgP, BCRP

Inhibits CYP 3A4, PgP, OCT 1&2Significant

Slide courtesy of S Khoo, 2014

17

DCV SOF SMV LDV

NRTIs

Lamivudi

ne

Emtricita

bine

Abacavir

Tenofovir

NNRTIs

Nevirapi

ne

Efavirenz 90

Etravirin

e

Rilpivirin

e

DCV SOF SMV LDV

HIV Protease Inhibitors

Lopinavir/r 30

Fosamprenavi

r/r 30

Atazanavir/r 30

Atazanavir 60

Darunavir/r 30

Integrase strand Inhibitors

Raltegravir

Dolutegrav

ir

Elvitegravi

r/C

Entry Inhibitors

Maraviroc

Drug-Drug Interactions

No clinically relevant interaction

No data or risk of potential interaction

Concomitant use contraindicated or not recommended

18

Conclusions

As highly effective treatments with few side effectsfor most HCV cases are now available:

• Most national guidelines demand prioritisation for higherfibrosis stages (Treat the sickest)

• HCV may be an eradicable disease (Treat all)

• In the future, treatment uptake will mainly be driven bythe cost debate (Treat who the payers are willing to pay)

19

Acknowledgements:

Sanjay Baghani

Christoph Boesecke

in partnership

with