UO Epatologia

“Centro di Riferimento Regionale per “la Diagnosi e il Trattamento delleEpatopatie Croniche e del Tumore di Fegato”

Azienda Ospedaliero UniversitariaPisana

Pisa, 16-11-2015

Hepatitis C Virus (HCV): the discovery

Michael Houghton

Science 1989

Genotype classification and definition

Six genotypes (1-6) and subtypes (a, b,c)

Genotypes differ at 31-34% of nucleotide positions of complete genomic sequences with approximately 30% amino acid sequence divergence

Simmonds P. J. Gen Virol (2001)

5’ NC Region variability

5-10% : genotypes

2-5% : subtypes

< 2% : isolates

Hepatitis C Envelope proteins have high variability to escape immune response

Why is so difficult to make HCV vaccine?

Viral Load

Target Cells

InfectedCells

Infected CellLoss

Free virion clearance

Two compartments model of chronic viral infection: viral replication maintains chronicity

Block of viral production efficacy:

IFN (0-99.9%)

RBV (5-10%)

DAAs (90-99.99%)

Hepatitis C Virus (HCV): next steps

Schematic Representation of the HCV Lifecycle

Reprinted by permission from Macmillan Publishers Ltd: NATURE Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. 36:933-938, copyright 2005. www.nature.com

Receptor bindingand endocytosis

Fusion and uncoating

Transportand release

(+) RNA

Translation andpolyprotein processing

RNAreplication

Virionassembly

Membranousweb

ER lumen

LD

LD

ER lumen

LD

Milestones in therapy of HCV infection

IFN6 mos

PegIFN/ RBV 12

mos

IFN12 mos

IFN/RBV12 mos

PegIFN12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN/RBV/DAA

IFN/RBV6 mos

6

16

34

4239

55

70+

0

20

40

60

80

100

DAAs8/12 weeks

>90

2014

HCV prevalence in Italian general population

Rosina F, XVII Congresso Nazionale delle Malattie Digestive, 2011

D’Amelio R at al, Am J Epidemiol 1992Stroffolini T et al, Ital J Gastroenterol 1995Stroffolini T et al, Ital J Gastroenterol 1997

Maio G et al, J Hepatol 2000Di Stefano R et al, J Med Virol 2002

3,9%

3,2%

8,4%

12,6%

16,2%

10,4%

26,0%

3,2%

Personalized management

of CHC patients:

• accurate selection

of patients to be

treated

• right timing

• tailoring of

antiviral treatment

Exposure(Acute phase)

Resolved Chronic

CirrhosisStable

SlowlyProgressive

HCCTransplant

Death

20% (17)

15% (15) 85% (85)

25% (4)

80% (68)

75% (13)

Natural History of HCV Infection

Alter, 1998

which factors favour disease progression ?

0

10

20

30

40

50

60

10 20 30 40

Years after infection

F3F4

The Natural History of Chronic Hepatitis C Fibrosis: a Non-Linear process

HCV-CLD

From M Pinzani

200

180

160

140

100

120

60

80

40

o

o

o

o

Me

an A

LT d

uri

ng

follo

w-u

p

Grades of fibrosis progression

0 1 2 3

Fibrosis Progression Correlates withMean ALT During Follow-up

©A. Alberti, 2003

Steatosis

Insulin Resistance

Oxidative Stress

Hepatic Iron storage

Several co-factors may contribute to a faster progression of liver

disease

Cofactors of liver damage

Alcohol

HCV

Hepatic Insulin resistance

Extrahepatic Insulin resistance

(post-insulin-receptor interaction) (mediated by soluble factors)

20-34% 66-80%

Whole body Insulin resistance

Vanni E., Hepatology 2009; Milner K Gastroenterology 2010

Prevalence of Type 2 diabetes in HCV + vs HCV - according to different classes of age

The third NHANES Survey, 1988-1994

Metha et al, Ann, Internal Med 2000

Effects of HCV infection beyond the liver

Renal(e.g. glomerulo-

nephritis)

Pulmonary(e.g. idiopathic

pulmonary fibrosis)

Neurological (e.g. cognitive impairment)

Cardiovascular (e.g. CAD, stroke)

Metabolic (e.g. diabetes)

Lymphoproliferative (e.g. B-cell

malignancies)

Autoimmune(e.g. mixed

cryoglobulinemia)Dermatological (e.g. porphyria cutanea tarda)

Excess extrahepatic mortality associated with HCVThe REVEAL HCV Cohort Study

• 19,636 HBsAg-seronegative adults, aged 30-65 yrs

• 1,095 anti-HCV+ [5.6%]

• 2,394 deaths after an average FU of 16.2 years

LEE et al, J Infect Dis 2012;206:469-77

Causes of death Multivariate-adjusted HR (95% CI)

All causes 1.89 (1.66 – 2.15)

All liver-related 12.48 (9.34 – 16.66)

HCC 21.63 (14.83 – 31.54)

All extrahepatic diseases 1.35 (1.15 – 1.57)

All cancers, except HCC 1.32 (1.00 – 1.74)

Diabetes 1.49 (0.91 – 2.42)

Cardiovascular diseases 1.50 (1.10 – 2.03)

Nephritis/nephrosis 2.77 (1.49 – 5.15)

Chronic HCV increases mortality from hepatic and non-

hepatic diseases

23 820 adults in Taiwan prospectively followed since 1991/2

1095 were anti-HCV positive; 69.4% had detectable HCV RNA

The REVEAL HCV Cohort Study

20

18

16

14

12

10

8

6

4

2

0

20

18

16

14

12

10

8

6

4

2

00 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20

Follow-up (years) Follow-up (years)

Cu

mu

lative

mo

rta

lity (

%)

Cu

mu

lative

mo

rta

lity (

%)

Hepatic diseases Extrahepatic diseases

Anti-HCV seropositives, HCV RNA detectable

Anti-HCV seropositives, HCV RNA undetectable

Anti-HCV seronegatives

Anti-HCV seropositives, HCV RNA detectable

Anti-HCV seropositives, HCV RNA undetectable

Anti-HCV seronegatives

p<0.001 for comparison among three groups

p<0.001 for HCV RNA detectable vs undetectable

p<0.001 for comparison among three groups

p=0.002 for HCV RNA detectable

vs undetectable

12.8%

1.6%0.7%

19.8%

12.2%

11.0%

Lee et al, J Infect Dis 2012;206:469–477

NS3/4A

inhibitors (PI)

NS5A

inhibitor

Daclatasvir

Nucleotide NS5B

inhibitor

HCV treatments nowadays and in the near future

Ledipasvir Sofosbuvir

Simeprevir Sofosbuvir

Paritaprevir/R Ombitasvir Dasabuvir

…Grazoprevir + Elbasvir (MK2 MSD) [+ MK-3682 (MK3 MSD)]

Characteristics of the Different Classes of Antiviral Drugs

Characteristic

Protease

Inhibitor

1st gen

Protease

Inhibitor

2nd gen

NS5A

Inhibitor

Nuc

Polymeras

e Inhibitor

Non-Nuc

Polymer.

Inhibitor

Resistance

profile

Antiviral

potency

Pangenot.

Effivacy

Adverse

events

Good profileAverage profileUnfavorable profile

BoceprevirTelaprevir Simeprevir

DaclatasvirLedipasvirOmbitasvir

Sofosbuvir Dasabuvir

Pazienti oggi

eleggibili al

trattamento:

Categoria I

Categoria II

Categoria VII

Categoria III

Categoria V

Categoria IV

Categoria VI

HCV GT1

- Sofosbuvir + Simeprevir +/- RBV - per 12 settimane + RBV o 24 senza RBV

- subottimale in cirrosi Child B per insufficienti dati di sicurezza (Categoria AIFA I)

- nella recidiva dopo OLT da HCV GT1b anche senza RBV; RBV consigliabile nel danno avanzato (Categoria II); qui e nell’EC in trapianto non di fegato (Categoria VII) attenzione alle interazioni

- per 12 settimane senza RBV nell’EC F3; se experienced con RBV (Categorie III e IV)

- Sofosbuvir + Ledipasvir +/- RBV- per 12 settimane + RBV o 24 settimane se senza RBV e pz difficili (es. experienced )

- per 12 settimane senza RBV in EC F3; con RBV se experienced (Categoria IV)

- nei trapiantati (Categorie II e VI) valutare interazioni farmacologiche

- Sofosbuvir + Daclatasvir +/- RBV-per 12 settimane + RBV o 24 settimane se senza RBV e pz difficili (es. GT 1a ed experienced)

-per 24 settimane nei trapiantati con forme colestatiche (Categoria II)

-12 settimane senza RBV in EC F3 (Categoria IV), con RBV in experienced

- ABT-450/r+ ABT-267+ ABT-333 +/- RBV- per 12 settimane + RBV o 24 settimane senza RBV e HCV GT 1a

- in EC F3 per 12 settimane senza RBV in HCV GT1b e con RBV in GT1a

- controindicato nel pz con cirrosi Child B (Categoria I)

- attualmente l’unico schema rimborsato nel trapiantato con epatite ricorrente F0-F1 (Categorie II);

- attenzione alle interazioni farmacologiche nel trapiantato (Categoria AIFA II e VI)

RACCOMANDAZIONI AISF MAGGIO 2015

Terapie anti-HCV consigliate come ottimali

HCV-TARGET: Adjusted SVR4 in GT1 HCV Pts

Receiving SOF + SMV ± RBV

• SVR4/SVR12 concordance was 97.2%

• In multivariate analysis, likelihood of achieving SVR4 was associated with baseline

albumin, HCV genotype, previous decompensation, and history of triple therapy failure

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

100

80

60

40

20

0Overall Cirrhotic Noncirrhotic GT1a

(n = 180)GT1b

(n = 93)Naive Experienced

SOF + SMV SOF + SMV + RBV

86 87 85 8389 90

84 8292 93 89 87 85 86

Pts

(%

)

784 228 440 137 344 91 318 82 465 144N

LDV/SOF

LDV/SOF+RBV

Afdhal et al 2014

865 treatment-naive including cirrhosis (16%) patientsno difference in SVR based on:

- use of RBV- length of treatment- HCV genotype 1 subtype- presence of cirrhosis

[ION-1]

Error bars represent 95% confidence intervals

Afdhal N, EASL, 2014, O109

Afdhal N, et al. N Engl J Med 2014;370:1483-1493

Failed PegIFN+RBV Failed Protease Inhibitor + PegIFN+RBV

SV

R12 (

%)

40/43 62/66 45/47 62/64 58/58 49/50 58/59 51/51

12 Weeks 24 Weeks

LDV/SOF + RBV LDV/SOF + RBVLDV/SOF LDV/SOF

Afdhal et al 2014

100% 100% 100% 100% 95%

0

20

40

60

80

100a

ALIb SOF,

DCV+ SOF

HDCV

+ SOF+ RBV

CDCV

+ SOF

E DCV

+ SOF+ RBV

GDCV

+ SOF

24 weeks

HC

V R

NA

<LL

OQ

Pati

ents

, %

AI444-040 study: SVR12 primary endpoint (mITT) for treatment-naive patients

• SVR12 rates were 98% in GT1a and 100% in GT1b

• SVR24 rates ranged from 93–100% in GT1, and 88–100% in GT2/3c

1515

1414

4141

3941

1515

12 weeks

aOne patient had missing data at post treatment week 12 but achieved SVR24, and one who was lost to follow-up after achieving SVR4bLI (lead in) with SOF was not included in subsequent trialsc93% and 88% were the percentage for the lead in arm.

HC

V R

NA

<LL

OQ

Pati

ents

, %

92% 89%

0

20

40

60

80

100

2426

1618

DCV + SOF ±RBV

24 weeks

DCV + SOF ±RBV

a

LI, lead in; LLOQ = lower limit of quantitation (25 IU/mL), mITT, modified intent to treat

GT1 GT2 GT3

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

JDCV + SOF

+ RBV

100% 95%

0

20

40

60

80

100

AI444-040 study: SVR12 primary endpoint (mITT) for GT1 patients who have experienced PI failure

aOne patient with missing data at post treatment week 12, who achieved SVR24

IDCV + SOF

2121

1920

24 weeks

a

HC

V R

NA

<LL

OQ

Pati

ents

, %

• End of treatment (EOT) responses were 100%, with or without RBV

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

Original Article

ABT-450/r–Ombitasvir and Dasabuvir with Ribavirin for Hepatitis C with Cirrhosis (TURQOUISE-II)

Fred Poordad, et al.

N Engl J MedVolume 370(21):1973-1982

May 22, 2014

Sustained Virologic Response at Post-Treatment Week 12 in Each Treatment Group, Overall and According to Subgroups.

- 380 C-P A cirrhosis

- 12w. Vs 24w. (NS)

- 1a vs 1b

The overall efficacy of 12-week and 24-week treatment did not differ significantly (91.8% and 95.9%, respectively).

HCV GT2

- Sofosbuvir + RBV per 12 w-16 w nei pz. con cirrosi (Categoria I), con recidiva post-OLT >F3 e con forma

colestatica (Cat. II)

-nei pz con cirrosi CP B stretto monitoraggio

Sofosbuvir + Daclatasvir per 3 mesi (intolleranti Ribavirina) in attesa di approvazione?

HCV GT3

- Sofosbuvir + Daclatasvir +/- RBV - 24 w con RBV (pz. tolleranti) in cirrosi (Categoria I); stretto monitoraggio in CP B

- trapiantati post-OLT (Categoria II) 12-24 w con RBV= 24 w nei pz F4 o experienced)

- in EC F3 (Categoria IV) 12 w senza RBV per il momento

- Sofosbuvir + RBV per 24 w- indicata in EC F3 soprattutto se naive

VALENCE

SOF + RBV

12 wk

LONESTAR-2

SOF + PegIFN + RBV

12 wk

FISSION

SOF + RBV

12 wk

VALENCE

SOF + RBV

12 wk

SV

R12 (

%)

SVR12 Rates Across SOF-Based Studies

HCV GT 2 Patients

Treatment-Naïve Treatment-Experienced

Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87. Zeuzem S, et al. AASLD 2013. Washington, DC. #1085.Jacobson IM, et al. N Engl J Med. 2013 May 16;368(20):1867-77.

FUSION

SOF + RBV

12 wk

POSITRON

SOF + RBV

12 wk

97% 100%

29/30 2/20%

20%

40%

60%

80%

100%98%

58/59

91%

10/11

60%

96%

25/26 6/10

91% 88%

30/33 7/8

92%

85/92

94%

16/17

100%

9/9

93%

13/14

Non-cirrhotic Cirrhotic

Treatment with SOF + RBV ± PegIFN for 12 weeks resulted in similarly high SVR rates across all

HCV GT 2 patients regardless of presence of cirrhosis or treatment experience

NAIVE SVR12= 91-100% EXPER SVR12= 91-96%Cirr.= 60-93%

SVR12 Rates Across SOF-Based Studies

HCV GT 3 Patients

Treatment-Naïve Treatment-Experienced

Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87. Zeuzem S, et al. AASLD 2013. Washington, DC. #1085.Jacobson IM, et al. N Engl J Med. 2013 May 16;368(20):1867-77. Lawitz E, et al. AASLD 2013. Washington, DC. Oral #LB-4.

Non-cirrhotic Cirrhotic

61%

87%

60%

SV

R12

(%)

89/145 86/92

FUSION

SOF RBV

16 wk

VALENCE

SOF + RBV24 wk

LONESTAR-2

SOF + PegIFN + RBV

12 wk

87/10014/23

83%

10/12

92%94%

12/13 25/40

63%

27/45

83%

10/12

68%

21%

61%

34%

0%

20%

40%

60%

80%

100%

FISSION

SOF + RBV 12 wk

VALENCE

SOF + RBV 24 wk

13/38

POSITRON

SOF + RBV 12 wk

57/84 3/14

HCV GT 3 patients treated with SOF + RBV for 24 weeks or SOF + PegIFN + RBV for 12 weeks

achieved high SVR rates regardless of presence of cirrhosis or treatment experience

NAIVE SVR12= 12w 61-68% (Cirr.21-34%)24w 94%(Cirr.92%)

EXP. SVR12= 16w 63% (Cirr.61%)

24w 87%(Cirr.60%)

SVR

12

, %a

DCV plus SOF once daily for 12 weeks.- 101 pts treatment naıve - 51 pts treatment experienced

SVR12 by Genotype and Regime in decompensated HCV cirrhosis

0

10

20

30

40

50

60

70

80

90

100

All G1 G3 Others

SVR

12

rat

e %

(IT

T)

Sof/LDV/RBV Sof/LDV Sof/DCV/RBV Sof/DCV

61 7 114 7 27 13 3

59 43 70 71 %

89 85 100 %

SVR12 defined as HCV RNA at 12 weeks post-treatment < 30 IU/ml Foster G e al, English EAP program

N 252 28 172 15 164 21 45 5

p< 0.05

Schema pratico delle indicazioni secondo Linee Guida Italiane

Genotipo 1

1a

1b

RBV No RBV Exper. P/R OLT

Cirrosi

F3

Cirrosi

F3

SOF+LDV 12w 24w 24w RBV 12w RBVSOF+DCV 12w 24w 24w RBV 24w RBV *SOF+SIM 12w 24w 24w RBV 12w RBV*PAR/R+OMB+DAS 24w ---- 24w RBV suboptimal

SOF+LDV 12w 24w 24w RBV 12w RBVSOF+DCV 12w 24w 24w RBV 12-24w RBV *SOF+SIM 12w 24w 24w RBV 12w RBV*PAR/R+OMB+DAS 12w 12w (?) 12w RBV suboptimal

SOF+LDV ---- 12w 12w RBV 12w RBVSOF+DCV ---- 12w 12w RBV 12w RBV SOF+SIM ---- 12w 12w RBV 12w RBVPAR/R+OMB+DAS 12w ---- 12w RBV suboptimal

* NO Child B

* NO Child B

SOF+LDV ---- 12w 12w RBV 12w RBVSOF+DCV ---- 12w 12w RBV 12w RBV SOF+SIM ---- 12w 12w RBV 12w RBVPAR/R+OMB+DAS ---- 12w 12w suboptimal

Schema pratico delle indicazioni secondo Linee Guida Italiane

Genotipo

2

3

Cirrosi

Cirrosi

F3

SOF+RBV 16w ----- 16w 16w

SOF+DCV 24w 24w 24w RBV 12-24w RBV

SOF+DCV ---- 12w 12w (RBV?) 12-24w RBV SOF+RBV 24w ----- suboptimal suboptimal

RBV No RBV Exper. P/R OLT

F3 SOF+RBV 12w ----- 12w 16w

Schema pratico delle indicazioni secondo Linee Guida Italiane

Genotipo 4

RBV No RBV Exper. P/R OLT

Cirrosi

F3

SOF+LDV 12w 24w 12w RBV 12w RBVSOF+DCV 12w 24w 12w RBV 12w RBV *SOF+SIM 12w 24w 12w RBV 12w RBV*PAR/R+OMB 24w ---- 24w RBV suboptimal

SOF+LDV ---- 12w 12w RBV 12w RBVSOF+DCV 12w 12w 12w RBV 12w RBV SOF+SIM 12w 12w 12w RBV 12w RBVPAR/R+OMB 12w ---- 12w RBV suboptimal

* NO Child B

Concetti chiave nei regimi IFN free

Genotipi 1a e 3 rimangono i più difficili da trattare

Cirrosi avanzata comporta maggior rischio di NON eradicazione e di tossicità

Il precedente fallimento di terapie con Peg/Riba non riduce la possibilità di SVR

Se si scelgono schemi brevi (12w) è indicato associare la RBV

In generale, seguendo le LG, non si dovrebbe avere un rate di SVR <90%

Questioni aperte

Come si andranno a trattare i pazienti con recidiva agli schemi IFN free?

Come andranno seguiti i pz “eradicati” con cirrosi avanzata (rischio HCC)

Quando saranno disponibili farmaci a costi sostenibili per il trattamento dei pz

con Fibrosi F0-F2?

Grazie per l’attenzione