NUOVE OPPORTUNITÀ

TERAPEUTICHE

IN EPATITE DA HCV

FRANCESCO ARCADU U.O. MEDICINA GENERALE E GASTROENTEROLOGIA

P.O. “SAN FRANCESCO” ASL 3 - NUORO

THE DISEASE – Common, chronic, and potentially progressive

– Complications are becoming more common

– Liver failure, HCC

THE TREATMENT

– Viral cure, or SVR, is achievable

– SVR associated with histologic improvement and gradual regression of fibrosis

– SVR reduces risk for liver failure and HCC, improves survival

Why Treat Chronic Hepatitis C

Kanwal F et al. Gastroenterology 2011; 140:1182-88. Maylin et al. Gastroenterology 2008, 3:821-9

Asselah et al. Liver Int. 2015;35 S1:56-64

Martinot-Peignoux et al.. Hepatology 2010;51:1122-1126 Swain MG, et al. . Gastroenterology 2010;139:1593-1601.

SVR 24 = SVR 12 = Cure

– The primary goal of HCV therapy is to cure the infection

– A sustained virological response - SVR - is defined as undetectable HCV RNA 12 weeks (SVR12) or 24 weeks (SVR 24) after treatment completion

– The infection is cured in more than 99% of patients who achieve an SVR

Hill AM, et al. AASLD 2014. Abstract 44

SVR Associated With Reduced 5-Yr Risk of

Death and HCC in All Populations

Analysis included survival data from 34.563 pts followed for average of 5 yrs

SVR on IFN-based therapy was associated with substantial benefit vs no SVR – 62% to 84% reduction in all-cause mortality – 90% reduction in liver transplantatio – 68% to 79% reduction in HCC

5-Yr Risk of All Cause Death by SVR

5-Yr Risk of HCC by SVR SVR No SVR

RISPOSTA VIROLOGICA SOSTENUTA (SVR)

Risposta alla terapia anti HCV (fino al 2013)

Terapia basata su IFN/RBV e nel GT1 anche sui DAA

di 1^ generazione (Telaprevir/Boceprovir)

Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting,

IFN

6 mos

PegIFN/ RBV

12 mos IFN

12 mos

IFN/RBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standard IFN

RBV

PegIFN

1991

DAAs

PegIFN/ RBV/ DAA

IFN/RBV

6 mos

6

0

16

34

42 39

55

70+

20

40

60

80

100

DAA ± DAA

± RBV

± PegIFN

2014

April 27-28, 2011, Silver Spring, MD.

The evolution of CHC therapy Virologic eradication is the goal

SVR

%

Adapted from the US Foof and Drug Administration , Antiviral Drugs Advisory Cmmitee Meeting,

27-28 2011, Silver Spring, MD

HCV therapeutic timeline 70+

BF, maschio, 58 anni HCV prevalence, diagnosis and treatment

rates in 2013

Dore G et al. J Viral Hepatitis 2014

BF, maschio, 58 anni Gaps in the achievement of effectiveness of

HCV treatment in national VA practice

Kramer et al, Journal of Hepatology 2012; 56: 320-325

PWID have a high willingness to receive HCV

treatment

PWID LIVING WITH HCV INFECTION

PWID have a high willingness to receive HCV

treatment

PWID LIVING WITH HCV INFECTION

80% OF PWID ARE WILLING TO RECEIVE HCV TREATMENT

Doab A, Clinical Infectious Diseases 2005. Fischer B, et al. Presse Med 2005. Strathdee S, et al Clinical Infectious

Diseases 2005. Grebely J, et al. Drug and Alcohol Dependence 2008. Alavi M, et al. Clinical Infectious Diseases 2013.

Treatment uptake among PWID is still low….

PWID LIVING WITH HCV INFECTION

80% OF PWID ARE WILLING TO RECEIVE HCV TREATMENT

Grebely J. J Viral Hepatitis 2009. Mehta S. J Community Health 2008. Iversen J, J Viral Hepatitis. 2013. Alavi M. Liver International. 2014

1-2% are treated each year

The HCV Care Cascade Less than 10% of people with HCV have been cured

Yehia BR, Schranz AJ, Umscheid CA, Lo Re V III (2014) The Treatment Cascade for Chronic Hepatitis C Virus Infection in

the United States: A Systematic Review and Meta-Analysis. PLoS ONE 9(7): e101554. doi:10.1371/journal.pone.0101554

Should improve with IFN-free therapy but long way to go……

Diagnosi

Accesso

Terapia SVR

Thomas, DL Lancet 2010 Oct 30;376(9751):1441-2

SVR in individuals SVR in the population

Efficacious treatments do not work if not

given…..

Need for reinforcing HCV screening and access to therapy to amplify the control of the disease

– 63 out of 353 Centers throughout Italy parteciped

– 33,433 patients were involved, 56% genotype 1

Combining these figure with NHS registries of HCV disease identification (016) the predicted number of known HCV patients are:

250,000 Monoinfected attending liver centers

30,000 HIV co-infected attending ID centres

25,000 Inmates

70,000 Under the care of GPs and legal migrants

Overall 350,000

Quanti HCV cronicamente infetti in Italia?

* Documento GdL Epatite C - AIFA-MinSal- ISS-SIMIT-AISF-EPAC-CNT Aprile 2014

Scenario 2014….quanti pazienti da trattare?

15.000 - 20.000* urgenti

60.000* entro 18 mesi

* Documento GdL Epatite C - AIFA-MinSal- ISS-SIMIT-AISF-EPAC-CNT Aprile 2014

15.000 - 20.000* urgenti

60.000* entro 18 mesi

* Documento GdL Epatite C - AIFA-MinSal- ISS-SIMIT-AISF-EPAC-CNT Aprile 2014

Con quali costi?

EASL & AASLD-IDSA Recommendations

Indications to treatment

All treatment-naïve and -experienced patients with compensated disease due to HCV should be considered for therapy (A1)

Treatment is recommended for patients with chronic HCV infection (IA)

All Clinical Practice Guidelines emphasizes the potential benefits of — and recommends treatment for — all pts with HCV infection

URGENT TREATMENT INITIATION RECOMMENDED FOR:

– Advanced fibrosis (Metavir F3)

– Compensated cirrhosis (Metavir F4)

– Liver transplantation

– Severe extrahepatic HCV

Treatment Benefits All Pts

Treatment Benefits All Pts

REDUCED HCV TRANSMISSION EXPECTED WITH

TREATMENT OF:

– Women wishing to become pregnant

– Long-term hemodyalisis pts

– MSM with high-risk sexual practices

– Injection drug users

– Incarcerated persons

– Extremely high efficacy (>95%)

– Tolerability - IFN free

– Minimal toxicity

– High barrier to resistance

– Once daily oral dosing

– Pangenotypic

– No drug – drug interactions

– Short duration (4-6 weeks)

– Affordable

Requirements for HCV regimen

Farmaci che interferiscono su processi

specifici nel ciclo di replicazione del virus

attraverso una diretta interazione con una

proteina virale o acido nucleico

Direct-Acting Antivirals (DAA)

Protease Inhibitors

“….PREVIR”

Telaprevir Boceprevir Simeprevir Asunaprevir

ABT-450 - Ritonavir Paritaprevir Sovaprevir Ombitasvir

NS5A Inhibitors “….ASVIR”

Daclatasvir Ledipasvir ABT-267 GS-5816

ACH-3102 Samatasvir MK-8742

GSK-2336805

Polymerase Inhibitors “….UVIR”

Schinazi R, Halfon P, Marcellin P, Asselah T. Liver Int 2014; 34 S1:69-78

HCV genome and polyprotein potential drug

targets

Direct-Acting Antiviral Agents (DAAs) - Key

Characteristics

NS3 /4A Inhibitors (Protease inhibitor PI)

High potency

Limited genotypic coverage

Low barrier to resistance

NS5B Nucleos(t)ide Inhibitors (NI)

Intermediate potency

Pangenotypic coverage

High barrier to resistance

NS5A Inhibitors

High potency

Multi-genotypic coverage

Low barrier to resistance

NS5B Non Nucleoside Inhibitors (NNI)

Intermediate potency

Limited genotypic coverage

Low barrier to resistance

NS2 NS3 NS4A NS4B NS5A NS5B p7 E2 E1 C

Boc and Tel Simeprevir Paritaprevir

Sofosbuvir

Ledipasvir Ombitasvir Daclatasvir

Dasabuvir

NS= Nonstructural Proteins

Agents and Regimens

Jan Feb Mar Apr May Jun Jul Aug Sept Oct Nov Dec

EASL

guidelines

WHO

guidelines

EACS

guidelines

Sovaldi Olysio Daklinza Harvoni Viekirax

Exviera

EMA APPROVAL

FDA APPROVAL

AASLD recommendations 1

Sovaldi & Olysio

EASL recommendations

AASLD recommendations 2

Harvoni Viekira

Pack

HCV guidelines, recommendations & anti HCV drugs

approval by International agencies - 2014

Anti HCV drugs approval by International agencies

Sofosbuvir (Sovaldi®) 16/01/2014

Simeprevir (Olysio®) 14/05/2014

Daclatasvir (Daklinza®) 22/08/2014

Ledipasvir/Sofosbuvir (Harvoni®) 26/09/2014

Ombitasvir /Paritaprevir/Ritonavir (Viekirax®) 21/11/2014

Dasabuvir (Exviera®)

21/11/2014

European Medicines Agency (EMA) authorisations

Agenzia Italiana del Farmaco (AIFA) authorisations

– Sofosbuvir (Sovaldi®) 30/09/2014

– Simeprevir (Olysio®) 23/02/2015

Comunicato n. 423 27 febbraio 2015

Epatite C: accordo AIFA e Gilead Sciences per la rimborsabilità di Harvoni®

Ufficio Stampa Agenzia Italiana del Farmaco - Dott.ssa Arianna Gasparini Tel. 06 59784419 ufficiostampaaifa@aifa.gov.it – a.gasparini@aifa.gov.it

Pazienti con cirrosi in classe di Child A o B e/o con HCC con risposta completa a terapie resettive chirurgiche o locoregionali non candidabili a trapianto epatico nei quali la malattia epatica sia determinante per la prognosi

Criterio 1

Recidiva di epatite dopo trapianto di fegato con fibrosi METAVIR ≥2 (o corrispondente Ishack) o fibrosante colestatica

Criterio 2

Epatite cronica con gravi manifestazioni extra-epatiche HCV correlate (sindrome crioglobulinemica con danno d'organo, sindromi linfoproliferative a cellule B)

Criterio 3

Epatite cronica con fibrosi METAVIR F3 (o corrispondente Ishack) Criterio 4

In lista per trapianto di fegato con cirrosi MELD Criterio 5

Epatite cronica dopo trapianto di organo solido (non fegato) o di midollo con fibrosi METAVIR ≥2 (o corrispondente Ishack)

Criterio 6

Epatite cronica con fibrosi METAVIR F0-F2 (o corrispondente Ishack) (solo per Simeprevir)

Criterio 7

Priorità in base all'urgenza clinica 7 criteri di eleggibilità AIFA

Regimens with the best cost/benefit

* Si ritiene che il criterio 4 non comprenda pazienti con diagnosi clinica di cirrosi

Categorie Gt1 e 4 Gt2 Gt3

Cirrotici Child A/B – controind. a P/R

SIM + SOF ± RBV

SOF + RBV SOF + RBV (24 w) oppure

SOF + DACLA (compassionevole) – Non Responder

SIM + SOF ± RBV

SOF + RBV

Pazienti non cirrotici* appartenenti ai criteri

2,3,6

SOF + RBV + Peg-IFN

oppure SIM + SOF

± RBV

SOF + RBV SOF + RBV + Peg-IFN

FDA-Approved All-Oral Regimens for GT1

*Not recommended per AASLD/IDSA guidance. †8-wk course can be considered in pts without cirrhosis with pretreatment HCV RNA < 6 million IU/mL. ‡12-wk course may be considered for some patients based on previous treatment history.

*Up to 48 wks or until transplantation, whichever occurs first. †Not FDA approved but recommended in AASLD/IDSA guidance.

‡24 wks of SOF/LDV if anemia or RBV intolerance; 24 wks of SOF/LDV + RBV (600 mg/day with increasing dose if tolerated) if prior SOF failure.

www.hcvguidelines.org

All-Oral Regimens for Other Populations

SVR rates >90% in genotype 1

AASLD/IDSA HCV Guidelines

Sofosbuvir and Ribavirin in HCV Genotype 4 Egyptian Ancestry Trial: results

SVR 12 by Regimen Duration and Treatment Experience

Source: Ruane P, et al. 49th EASL. April 2014: Abstract P1243

Treatment Naive Treatment Experienced

11/14 10/17 14/14 13/15

SVR 12 by Regimen Duration and Treatment Experience

11/14 10/17 14/14 13/15

Liver Int. 2015 Jan;35 Suppl 1:27-34 Optimal therapy in genotype 4 chronic hepatitis C: finally cured? Abdel-Razek W, Waked I.

Optimal therapy for patients with hepatitis C virus (HCV) genotype 4 (HCV-4) infection is changing rapidly, and the possibility of a total cure is near.

IFN-free combinations with paritaprevir-ombitasvir, SOF-ledipasvir, or DCV-asunaprevir (ASV)-beclabuvir (BMS-791325) for 12 weeks or less with close to 100% cure rates will soon become the optimal therapy

I pazienti con cirrosi avevano significativamente meno probabilità di

raggiungere SVR rispetto ai pazienti non cirrotici per tutti i genotipi

studiati, e in particolare per il genotipo 3

GT3 GT2 GT1, 4-6

Mangia A. et al AASLD 2013 Abstract 1115

Treatment naïve Treatment naïve Treatment

experienced

Treatment

experienced

Genotype 3 HCV: still difficult to treat?

Sofosbuvir-Ledipasvir +/- Ribavirin in GT 1 & 3 ELECTRON 2: Results

SVR 12, by GT and Treatment Regimen

Gane EJ, et al. 49th EASL. 2014: Abstract O6

SOF-Experienced Treatment Naive CTP Class B

A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3 infected patients with cirrhosis is underway

HEPATOLOGY 2015;00:000-000

Afdhal N et al, EASL OC #68

Phase 2 clinical trials with IFN-free regimens including cirrhotic patients.

Patients With Compensated or Decompensated

Cirrhosis are Candidates for IFN-free Regimens

Afdhal N et al, EASL OC #68

Difficult to Treat Patients: Decompensated Cirrhosis

and portal hypertension

Phase 3 clinical trials with IFN-free regimens including cirrhotic patients.

Flamm SL, al. 65th AASLD. 2014: Abstract 239

Ledipasvir-Sofosbuvir + Ribavirin in HCV GT 1,4 SOLAR-1 (Decompensated Cirrhosis): Preliminary Study Results

42/47 45/52 24/27 26/30 18/20 19/22

Treatment Naïve and Treatment Experienced

Therapeutic approaches of HCV infection in

cirrhosis decompensated, in waiting list & after LT

Flamm SL, al. 65th AASLD. 2014: Abstract 239. Afdhal N, et al. ILC 2014, Abstract #O68

Feedback from the real-world: do HCV cure rates in real-life

patient cohorts hold what clinical trials promised?

HCV-TARGET & TRIO

Data from two large observational databases demonstrate that:

– IFN-free regimens dominate the treatment landscape

– SOF-based regimens are effective in “real-world” settings

– Safety demonstrated in non-cirrhotic and cirrhotic patients

Jensen D, et al. AASLD 2014. Abstract 45. Dieterich D, et al. AASLD 2014. Abstract 46

Source: Liver Int © 2014 Blackwell

….in summary, after 2015

Where do we go from here??

Mild Severe

Decomp

Currently treated

HCV chronic disease spectrum

Mild Severe

Decomp

The future treatment

HCV chronic disease spectrum

By enrolling new patients at the extreme of the spectrum

By enforcing need for mass screening for HCV

IFN-free DAA will expand the pool of

treatable patients

WHO. Guidelines on the screening, care and treatment of persons with hepatitis C infection. April 2014

We must strive to obtain appropriate and effective treatment for all patients