hcv treatment at the dawn of the daa era · apasl stc pakistan 2014 hepatitis c: care and cure...

HCV Treatment at the Dawn of the DAA era

Dr Ashley Brown, Imperial College Healthcare NHS Trust

APASL STC PAKISTAN 2014

Hepatitis C: Care and Cure

Saturday October 18th 2014

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• Investigator, received grant income and acted as an advisor for or speaker on behalf of the following companies:

– Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharpe & Dohme, Novartis, Roche

Disclosures

Note: This presentation includes reference to investigational agents not currently approved for use in HCV by the EMA, or FDA

HCV burden and genotype

Global burden of HCV lies in the Asia-Pacific Region where all GT’s are represented.

• Messina JP, et al. Hepatol 2014; doi: 10.1002/hep.27259

• IFN has been the backbone of HCV therapy for over two decades

• PEG-IFN/RBV was standard of care for a decade

• But new DAAs will allow us to go beyond what was possible with IFN-based therapy

HCV – opportunities for cure have expanded beyond our wildest dreams

DAA: direct acting antiviral agents; PEG-IFN: pegylated interferon; RBV: ribavirin

Feeney ER & Chung RT. BMJ. 2014BMJ 2014; 349 doi: http://dx.doi.org/10.1136/bmj.g3308 (Published 07 July 2014)

• Intense research activity identified further classes of DAAs and new routes to cure, +/- IFN

The HCV life cycle offers new targets for DAAs

Graphic includes several investigational agents which are not approved for use in HCV by the EMA/FDA;

Agents approved by the FDA are highlighted in bold

1986

New DAAs are transforming the treatment landscape

IFN 6 m

6%

1986


1998

IFN 6 m

IFN + RBV 12 m

6%

42%

>5%

1986


1998

2001

IFN 6 m

IFN + RBV 12 m

PEG-IFN 12 m

6%

42%

39%

90% >5%

1986


1998

2001

IFN 6 m

IFN + RBV 12 m

PEG-IFN 12 m

PEG + RBV 48w

2002

6%

42%

39%

54–56%

90% >5%

54–56%

1986


1998

2001

IFN 6 m

IFN + RBV 12 m

PEG-IFN 12 m

PEG + RBV 48w

2002

6%

42%

39%

54–56%

63–79% PEG + RBV + PI 48w

>5%

54–56% 2012

1986


1998

2001

2014

IFN 6 m

IFN + RBV 12 m

PEG-IFN 12 m

PEG + RBV 48w

2002

6%

42%

39%

54–56%

63–79% PEG + RBV + PI 48w

PEG + RBV + SOF 12w

90% >5%

54–56% 2012

1986


1998

2001

2014

IFN 6 m

IFN + RBV 12 m

PEG-IFN 12 m

PEG + RBV 48w

2002

6%

42%

39%

54–56%

63–79% PEG + RBV + PI 48w

PEG + RBV + SOF 12w

90%

SVR rates 95% are now within reach

ALL ORAL DAA’s 6-8w

2015

>95%

Efficacy Genotype dependency

Barrier to resistance

NS3/4A protease inhibitors

+++ +++ ++

NS5A inhibitors +++ +++ ++

NS5B (NUC) inhibitors

+++ +++ +++

NS5B (non-NUC) inhibitors

++ + +

Properties of the DAA classes

Asselah T, Marcellin P. Liver Int 2013;33:93–104 NUC: nucleos(t)ide

• Some DAAs need to be used in combination with others to limit potential for resistance

• Ideal agent: would combine high pangenotypic efficacy and high barrier to resistance

What are we waiting for?

DAA + PR (2014)

SIMEPREVIR + PR

SOFOSBUVIR + PR

DACLATASVIR + PR

IFN-FREE (2014)

SIMEPREVIR + SOFOSBUVIR

SOFOSBUVIR + DACLATASVIR

SOFOSBUVIR + RIBAVIRIN

FUTURE IFN-FREE (2015–2016)

SOFOSBUVIR + LEDIPASVIR

PARATAPREVIR/r + OMBITASVIR + DASABUVIR

SOFOSBUVIR + GS-5816

MK5172 + MK8742

DACLATASVIR + ASUNAPREVIR + BMS-791325

SIMEPREVIR + TMC647055 +IDX719

FDC: fixed-dose combination

How are guidelines keeping pace with new DAA development?

• Unprecedented speed of drug development

• Recommendations on treatment regimens with agents that are available/anticipated to be available in 2014

– Sofosbuvir

– Simeprevir

– Daclatasvir

2014: Transformational change – the first EASL online recommendations

EASL Recommendations on Treatment of Hepatitis C 2014. http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C.pdf. Accessed September 2014

Various combinations ± PEG-IFN/RBV

EASL: Recommended treatment options for GT 1

PEG-IFN + RBV + sofosbuvir [12 weeks]

PEG-IFN + RBV + simeprevir [12 weeks + 12/36]

PEG-IFN + RBV + daclatasvir [12 weeks + 12]

Sofosbuvir + simeprevir (±RBV) [12 weeks]

Sofosbuvir + daclatasvir (±RBV) [12–24 weeks]

Sofosbuvir + RBV [12 –24 weeks]

IFN-based regimens*

IFN-intolerant or -ineligible patients

All-oral regimens

* In settings where none of these options is available, PEG-IFN + RBV remains acceptable


100 100 100 95

89 96

0

20

40

60

80

100

Cohort 1 (Null/F0–2) Cohort 2 (TN/Null/F3–4)

GT 1b

GT 1a no Q80K

GT 1a Q80K

SVR

12

(%

) COSMOS: SOF + SMV ± RBV for 12 or 24 weeks in GT 1 patients

TN: treatment-naïve

17/17 30/30 18/18 25/26 24/27 38/40

Similar SVR rates with and without RBV

.

Lawitz E, et al. EASL 2014; Oral 165; Sulkowski M, et al. EASL 2014; Oral 07; Sulkowski et al., N Engl J Med 2014;370:211–21

DCV + SOF ± RBV for 12 or 24 weeks in GT 1 patients

PI: protease inhibitor

Pro

po

rtio

n o

f p

atie

nts

(%

)

*DCV 60 mg once daily, SOF 400 mg once daily ± RBV 1000/1200 mg/day

GT 1 (82% GT 1a), Rx-naïve N=82: DCV + SOF ± RBV for 12 weeks*

GT 1 (80% GT 1a), prior PI non-responder N=41: DCV + SOF ± RBV for 24 weeks*

100 95

0

20

40

60

80

100

Category 1 Category 2

41/41 39/41

DCV + SOF DCV + SOF DCV + SOF + RBV DCV + SOF + RBV

Pro

po

rtio

n o

f p

atie

nts

(%

)

100 95

0

20

40

60

80

100

21/21 19/20

Sulkowski MS, et al. N Engl J Med 2014;370:211–21



Sofosbuvir + RBV [24 weeks]

Sofosbuvir + daclatasvir [12–24 weeks]

Sofosbuvir + RBV (24 weeks]

IFN-based regimens*


All-oral regimens



LONESTAR-2: 12W SOF+RBV in GT2/GT3 PR-Experienced Patients

FUSION: Impact of Cirrhosis and Duration on SVR in GT2 and GT3

VALENCE: Sofosbuvir + Ribavirin for 12W (GT2) or 24W (GT3)

BOSON: 24W vs 16W SOF+RBV vs 12W SOF+PEG+RBV in GT2/GT3

• 600 GT3 (naïve or experienced, non-cirrhotic or cirrhotic) and GT2 (experienced and cirrhotic)

• Study due to complete Jan 2015

PEG + RBV + SOF

SOF + RBV

SOF + RBV

0 12 16 24





PEG-IFN + RBV + simeprevir [12 weeks + 12/36]

PEG-IFN + RBV + daclatasvir [12 weeks + 12]

Sofosbuvir + simeprevir (±RBV) [12 weeks]

Sofosbuvir + daclatasvir (±RBV) [12–24 weeks]

Sofosbuvir + RBV [24 weeks]

IFN-based regimens*


All-oral regimens

Randomised, open-label, single-centre Phase 2 study conducted in the US of the safety and efficacy of all-oral SOF + RBV in patients with HCV GT 4

Egyptian Ancestry Study: SOF + RBV for 12 or 24 weeks in GT 4 patients

Ruane PJ, et al. EASL 2014. Poster#1243 BMI: body mass index

0 12 24 36 Study Week

SOF + RBV 1000-1200 mg, n=31

SOF + RBV 1000-1200 mg, n=29

48

SVR12 SVR24

SVR12 SVR24

Mean age: 53-55 years

Mean BMI:

29–30 kg/m2

Cirrhosis: 23–24%

IL28B non-CC:

79–87%

79

100

59

87

0

10

20

30

40

50

60

70

80

90

100

12 Week SOF+RBV 24 Week SOF+RBV 12 Week SOF+RBV 24 Week SOF+RBV

SV

R1

2 (%

)

Treatment-naïve Treatment-experienced

AASLD: Recommended treatment options for GT 1–6

Population Recommended IFN-Ineligible** Alternative

GT 1 TN* SOF + PEG-IFN + RBV (12 wks) SOF + RBV (24 wks) SOF + SMV (12 wks)

SMV + PEG-IFN + RBV (24 wks)

TE SOF + SMV (12 wks) SOF + RBV (24 wks) SOF + PEG-IFN + RBV (12 wks) SMV + PEG-IFN + RBV (24 wks)

PEG-IFN + RBV + PI Failure

SOF (12 wks) + PEG-IFN + RBV (12-24 wks)

SOF + RBV (24 wks)

GT 2 TN* SOF + RBV (12 wks)

TE SOF + RBV (12 wks) SOF + PEG-IFN + RBV (12 wks)

GT 3 TN* SOF + RBV (24 wks) SOF + PEG-IFN + RBV (12 wks)

TE SOF + RBV (24 wks) SOF + PEG-IFN + RBV (12 wks)

GT 4 TN* SOF + PEG-IFN + RBV (12 wks) SOF + RBV (24 wks) SMV x 12 wk + PEG-IFN + RBV x 24-48 wk

TE SOF + PEG-IFN + RBV (12 wks) SOF + RBV (24 wks)

GT 5 TN* SOF + PEG-IFN + RBV (12 wks) SOF + RBV (24 wks) PEG-IFN + RBV (48 wks)


GT 6 TN* SOF + PEG-IFN + RBV (12 wks) SOF + RBV (24 wks) PEG-IFN + RBV (48 wks)


*Treatment-naive patients with compensated cirrhosis, including those with hepatocellular carcinoma, should receive the same treatment as recommended

for patients without cirrhosis.

**Recommended or alternative regimens for IFN-ineligible patients.

TE: treatment experienced; TN: treatment naïve; wk: week

AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed September 2014

• Pangenotypic chain terminator (GT 1–6)

• Approved in December 2013 by the FDA for the treatment of CHC infection in adults as a component of a combination antiviral treatment regimen1

– Also approved in Egypt in July 20142

• High barrier to resistance

• Once-daily, oral, 400 mg tablet

• Limited potential for drug interactions

• Sofosbuvir (SOF)-based regimens achieve >90% SVR across all genotypes3,4

Sofosbuvir:NS5B nucleotide analogue polymerase inhibitor

1. Gilead Sciences US. SOVALDI (sofosbuvir), Prescribing Information, December 2013; 2. SOVALDI Egyptian registration certificate, 10 July 2014; 3. Lawitz E, et al. N Engl J Med 2013;368:1878–87; 4. Zeuzem S, et al. N Engl J Med 2014;370:1993–2001

Patient population* Treatment† Duration

Patients with GT 1, 4, 5 or 6 CHC

SOF + RBV + PEG-IFN

12 weeksa,b

SOF + RBV Only for use in patients ineligible or intolerant to

PEG-IFN

24 weeks

Patients with GT 2 CHC SOF + RBV 12 weeksb

Patients with GT 3 CHC

SOF + RBV + PEG-IFN

12 weeksb

SOF + RBV 24 weeks

Patients with CHC awaiting liver transplantation

SOF + RBV Until liver transplantationc

*Includes patients co-infected with human immunodeficiency virus (HIV) †The dose of RBV when used in combination with SOF is weight-based (<75 kg = 1000 mg and ≥75 kg = 1200 mg), administered orally in 2 divided doses with food a. For previously treated patients with HCV GT 1 infection, no data exists with the combination of SOF, RBV and PEG-IFN b. Consideration should be given to potentially extending the duration of therapy beyond 12 weeks and up to 24 weeks; especially for those subgroups who have

one or more factors historically associated with lower response rates to interferon based therapies (e.g. advanced fibrosis/cirrhosis, high baseline viral concentrations, Black race, IL28B non-CC genotype, prior null response to PEG-IFN and RBV therapy)

c. See Special patient populations – Patients awaiting liver transplantation

Recommended SOF-based treatment regimens (EU Label)

CHC: chronic hepatitis C Gilead Sciences Europe. SOVALDI (sofosbuvir), Summary of Product Characteristics, January 2014

• New compounds can cure >90% patients with HCV infection and are effective against GTs that were previously difficult-to-treat

• SOF + RBV ± PEG-IFN is recommended in GT 1, 2, 3 and 4 HCV infection vs PEG-IFN + RBV alone; SMV + PEG-IFN + RBV is recommended in GT 1

WHO Guidelines

BOC: boceprevir; PWIDs: people who inject drugs; SMV: simeprevir; SOF: sofosbuvir; TVR: telaprevir

GT Recommendation

1–4 SOF + RBV ± PEG-IFN preferred vs PEG-IFN + RBV [Strong recommendation, high quality of evidence]

1a (no Q80K) or 1b

SMV + PEG-IFN + RBV preferred vs PEG-IFN + RBV [Strong recommendation, high quality of evidence]

1 BOC or TVR + PEG-IFN + RBV preferred vs PEG-IFN + RBV [Conditional recommendation, moderate high quality of evidence]

World Health Organization Guidelines for HCV. Available at: http://www.who.int/hiv/pub/hepatitis/ hepatitis-c-guidelines/en/. Accessed September 2014

http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&docid=WS8iiTCQXRMXJM&tbnid=76gFuXFec0PpDM:&ved=0CAUQjRw&url=http://www.thecoachdiary.com/over-doing-it-and-who-is-to-blame/world-health-organisation-logo/&ei=NSSXU6mMFtKlyASp1oGIBQ&bvm=bv.68445247,d.ZWU&psig=AFQjCNG6nqy4xEPCc4vcjxZ6pgzuut8eWQ&ust=1402500510289535

Who should be treated first?

A need to prioritise?

1. Those with cirrhosis and advanced fibrosis

Future impact of HCV-related liver disease

Estimated number of people living with HCV-related cirrhosis or decompensated cirrhosis/HCC in England: 1995–2020 (95% credibility intervals are given in parentheses) Health Protection Agency. Hepatitis C in the UK, 2011 Report; Figure 15

18,000

16,000

14,000

12,000

10,000

8000

6000

4000

2000

0

Nu

mb

er

of

pe

op

le

1995 2000 2005 2010 2015 2020

Year

1960 (1490, 2510)

1960 (1490, 2510)

3290 (2520, 4190)

5090 (3600, 6430)

7240 (5600, 9160)

11,630 (9060, 14700)

590 (530, 640)

1020 (950, 1090)

1640 (1560, 1720)

2430 (2310, 2550)

3330 (3150, 3520)

4210 (3910, 4520)

Compensated cirrhosis

Decompensated cirrhosis and hepatocellular carcinoma

Effective treatment reduces the impact of cirrhosis

Adapted from van der Meer AJ et al. JAMA 2012;308:2584–93

International multicentre chart review of 530 patients with Ishak score 4–6 receiving INF-based therapy between 1990 & 2003

Cost of NOT treating HCV



2. Transmitters



2. Transmitters

– PWIDs and prisoners

Modelling HCV in treated injectors: what can therapy achieve?

Adapted from Martin NK et al. J Hepatol 2011;54:1137–440 IDU: intravenous drug users

Baseline chronic prevalence (%)

Re

lative

pre

va

len

ce

re

du

ctio

n

(%

) a

t 1

0 y

ea

rs

100

80

60

40

20

0 20 40 60

5 per 1000 IDUs annually




HCV in offender healthcare

• 70% of offenders report drug misuse prior to prison;

• 51% report drug dependency;

• 35% admit injecting behaviour;

• 36% report heavy drinking; and

• 16% are alcohol dependant

Drugs: Breaking the Cycle - Home Affairs Committee, www.parliament.uk

Eradication of HCV requires targeted programmes for patients at risk of transmitting

Grebely J, Dore GJ. Antiviral Research 2014;104:62–72 OST: opiate substitution therapy

• The considerable movements between PWID in the community, OST and prison settings provides a unique opportunity to capitalise on these settings as HCV treatment access points



2. Transmitters

– PWIDs and Prisoners

– High users of health services

47

HCV is at least 10 times more infectious than HIV

Rate per injection in HCV Rate per injection in HIV

3–10% 0.3% vs

HCV is a highly infectious virus



2. Transmitters


– High users of Health Service

– Women of childbearing age



2. Transmitters


– High users of Health Service


3. EVERYBODY!

Patients with chronic HCV feel unwell

Adapted from Foster GR et al. Hepatology 1998;27:209–12

0

10

20

30

40

50

60

70

80

90

100

Physical

functioning

Social

functioning

Role –

physical

Role –

emotional

Mental

health

Energy and

fatigue

Pain General health

perception

Controls

Mild disease

Severe disease

SF

36

sco

re

Study involved 72 unselected sequential patients with chronic HCV infection attending a London outpatient

clinic. Effect of chronic HCV infection on QoL measured using SF36 questionnaire

Change in QOL following INF therapy

Adapted from Bonkovsky HL et al. Hepatology 1999;29:264–70

*P<0.05 **P<0.01

Responder (n=41)

Non-responder (n=396)

*

**

**

* *

Ch

an

ge

fro

m b

ase

line

in

HR

Qo

L

(SF

-36

sca

le)

–5

0

5

10

15

20

25

30

35

Physical

function

Role

physical

Bodily

pain

General

health Vitality Social

function

Role

emotional

Mental

health

US multicentre randomised double-blind controlled study of 704 patients receiving 3µg interferon, 9µg consensus

interferon or 15µg interferon-alfa-2b 3 times a week for 24 weeks. Responder defined as undetectable HCV RNA

at end of treatment and 24 weeks’ post-treatment

HCV has an impact on patient life now: the indirect economic costs of HCV

• Data from the 2009 US National Health and Wellness Survey showed patients with HCV were significantly less likely

to be employed compared with controls (p<0.0001)1

• The presence of HCV in the EU population has been shown to significantly impact several domains of HRQL

(p<0.05)2

Pa

tie

nts

(%

)

Absenteeism Presenteeism Overall work impairment Activity impairment

20

30

10

0

Patients with HCV

Controls

1. Adapted from DiBonaventura M et al. J Med Econ 2011;14:253–61

2. DiBonaventura M et al. Eur J Gastroenterol Hepatol 2012;24:869–77



2. Transmittors

– PWIDs

– Prisoners


3. EVERYBODY!

– If we screen people we should be able to treat

– If we turn people away they may not come back!

When to Treat?

Reasons to defer treatment

HCC: hepatocellular carcinoma 1. Veldt BJ, et al. Hepatology 2008;47:1856–62

2. Wang CS, et al. Cancer Epidemiol Biomarkers Prev 2009;18:2054–60

It may take many years for my patients to

progress to cirrhosis

Future treatments appear equally effective

in cirrhotic as non-cirrhotic patients

Patient may decompensate on

interferon

We need to wait for the prices of the drugs to

come down before we start to use them

There’s not enough data in special patient groups

to use the new drugs Que sera sera!

Progression of fibrosis is unpredictable

Boccatto S, et al. J Viral Hepat 2006;13:297–302

79 patients with F1 fibrosis

n=28 35%

n=22 28%

n=16 20%

n=13 17%

Mean time to follow-up =

7.8 ± 1.5 years

F1 F2 F3 F4

51/79 patients (65%) showed fibrosis progression during the follow-up period

The need for cooperation

• Funding remains an issue in many parts of the world

• Pharmaceutical companies, governments and NGO’s need to work together to ensure access of these drugs to everyone living with HCV

• This CAN be achieved (look at HIV!)

Patient numbers WILL increase and

patients may progress while waiting

Planning for the Future

• Until we get an idea of the size of the problem, we cannot estimate what resources we will need for the future

• Widespread screening programmes are needed to plan the demand for future services

• It is important however to ensure that resources are available treatment to those identified through screening

Reasons to treat now

HCC: hepatocellular carcinoma

Patients liver disease will progress while we

wait

Ongoing extrahepatic manifestations affect

quality of life

Good chance of current treatment success today

The task ahead of us is enormous. The sooner

we get started the better

Timeframe for access to newer agents uncertain and may vary between

countries

In future resources mey be diverted elsewhere

Summary

• Who should we treat?

• What should we use?

• When should we do it?

Summary

• Who should we treat?

– EVERYBODY

• What should we use?

– THE BEST DRUGS AVAILABLE

• When should we do it?

– NOW!

• HCV – the only curable chronic viral infection to date

• A greater understanding of replication has provided new strategies for cure with IFN free regimens.

• This should allow treatment on a scale never before contemplated

• The challenges remain however in implementation

HCV: The Dawn of a New Era

HCV infection can be cured

hcv treatment at the dawn of the daa era · apasl stc pakistan 2014 hepatitis c: care and cure...

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