INFEZIONE DA HCV - Peperosso Srlwin.peperosso.tv/public/presentazioni/Dr.ssa Menzaghi - Il...

INFEZIONE DA HCV:

FACCIAMO IL PUNTO DOPO UN ANNO DALL’INIZIO DELLE NUOVE TERAPIE

Barbara Menzaghi

Dall’infezione alla patologia epatica

1. Adapted from Metzner KJ. Future Virol. 2006;1:377-91

Infezione

acuta1

Infezione

cronica1

15 - 50 Years

Terapia ideale per HCV: ci stiamo arrivando ?

All oral

All genotypes

High barrier

to Resistance

Optimal tolerabIlity

COst reductioN

Availability: Cirrhosis, HIV–HCV,

etc.

Short treatment

Duration

Potent Efficacyacross all patient

populations

PharmaCokinetic

(low pill burden)

Minimal

drug inTeraction

Ideal HCV treatment

GOAL = ERADICATION

0

20

40

60

80

100

IFN

6 or

12 mo

IFN+RBV

6 mo

IFN+RBV

12 mo

PEG

2a/b+RBV

12 mo

TVR+PEG

+RBV

6-12 mo

LDV/SOF

2-6 mo

62-63

19-2823

20

0

87

20112011 2013 2013

SV

R R

ate

(%

)

1 – pooled data from ION-1, ION-2, and ION-3

Jeffers L, et al. Hepatology 2004; 39: 1702-1708; Conjeevaram H, et al. Gastroenterology 2006; 131: 470-477; Muir A, et al. N Engl J Med 2004; 350: 2265-71; McHutchison J, et al. Gastroenterology 2000; 119: 1317-1323; Poordad F, et al. N Engl J Med 2011; 364: 1195-206; Bacon B, et al. N Engl J Med 2011; 364: 1207-17; Jacobson I, et al. N Engl J Med 2011; 364: 2405-16; Zeuzem S, et al. N Engl J Med 2011; 364: 2417-28; Manns M, et al. Lancet 2014; 384: 414-426; Jacobson I, et al. Lancet 2014; 384: 403-413; Lawitz E, et al. N Engl J Med 2013; 368:1878-87; Afdhal N, et al. N Engl J Med 2014; 370: 1889-98; Afdhal N, et al. N Engl J Med 2014; 370: 1483-1493; Kowdley K, et al. N Engl J Med 2014; 370: 1879-88.

SMV+PEG

+RBV

6-12 mo

63

2014

SOF+PEG

+RBV

3 mo

951

SVR Rates for Approved Therapies in HCV GT 1 TN or TE

Years are not to scale

42-61

BOC+PEG

+RBV

6-12 mo

20041998 1998

2015

J Hepatol. 2015 Apr 21. pii: S0168-8278(15)00208.

http://www.easl.eu/research/our-contributions/clinical-practice-guidelines

1) Pazienti con cirrosi in classe di Child A o B e/o con epatocarcinoma con

risposta completa a terapie resettive chirurgiche o loco-regionali non

candidabili a trapianto epatico nei quali la malattia epatica sia determinante

per la prognosi

2) Recidiva di epatite dopo trapianto di fegato con fibrosi METAVIR1 ≥2 (o

corrispondente Ishack) o fibrosante colestatica

3) Epatite cronica con gravi manifestazioni extra-epatiche HCV-correlate

(sindrome crioglobulinemica con danno d'organo, sindromi linfoproliferative

a cellule B)

4) Epatite cronica con fibrosi METAVIR ≥3 (o corrispondente Ishack)

5) In lista per trapianto di fegato con cirrosi MELD <25 e/o con HCC all'interno

dei criteri di Milano con la possibilità di una attesa in lista di almeno 2 mesi

6) Epatite cronica dopo trapianto di organo solido (non fegato) o di midollo

con fibrosi METAVIR ≥2 (o corrispondente Ishack).

7) Pazienti con epatite cronica con fibrosi METAVIR F0-F2 (o corrispondente

Ishak)

Categorie di pazienti affetti da epatite C cronica ammesse alla rimborsabilità in Italia

SVR:

Clinical

Outcomes

Prevent Decompensation

Delay Liver-Related Death

Delay/prevent HCC

Prevent Viral Recurrence After OLT

Cirrhosis regression

Slowing progression of PH

HCV Cirrhosis Natural History: can we modify it ?

Clinical

Outcomes



“Regressione” cirrosi in pazienti HCV che ottengono SVR

0

10

20

30

40

50

60

70

80

90

100

Prima di SVR Dopo SVR

Nu

mb

er

of

Pati

en

ts (

%)

Metavir

Score*

F4

F3

F2

F1

Hepatology. 2012;56:532-543.

*Median interval between pre and post-treatment liver biopsies was 79 months

«Regressione» cirrosi: in oltre il 60%

Hepatology. 2012;56:532-543.

Cumulative incidence of esophageal varices in 149 IFN ± RBV-treated patients with compensated HCV-

induced (stage 1) cirrhosis according to response to therapy

Bruno S, et al. Hepatology 2010

The impact of SVR on Esophageal Varices

Clinical

Outcomes



Impact of SVR on long-term outcome in 848 patients with HCV-related histologically-

proven cirrhosis (stage 1) treated with IFN MT

0 24 48 72 96 120 144 168

0

20

40

60

80

100

months

% w

ith

liv

er

co

mp

lica

tio

ns

SVR 124 119 116 108 70 41 12

no SVR 759 702 634 527 345 207 34

Patients at risk

SVR

no SVR

liver-related complications Liver-related mortality

Bruno S, et al. Hepatology 2007

(p: 0.001 by log-rank test)

(p: 0.001 by log-rank test)

0 24 48 72 96 120 144 168

0

20

40

60

80

100

months

% s

urv

iva

l to

liv

er-

rela

ted

de

ath

SVR 120 115 112 105 66 38 11

no SVR 728 680 629 541 369 234 47

Patients at risk

SVR

no SVR

The impact of SVR on long-term Outcome

Clinical

Outcomes

Delay/prevent HCC

SVR è associata ad una riduzione della mortalità correlata alle malattie del fegato e all’epatocarcinoma

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

N=530 N=530

EpatocarcinomaMortalità correlata a malattia epatica

e trapianto di fegato

Clinical

Outcomes


Post-Transplant HCV Recurrence in patients in whom HCV RNA was non detectable for 28 days prior to transplant

0 30 60 90 120 150 180 210 240 270 300 330 360 390

Days with HCV RNA Continuously TND Prior to Liver Transplant

No Recurrence (69%) Recurrence (31%)

No recurrence in 24/25 (96%) of

patients who maintained HCV RNA

TND >28 days

*Wilcoxon rank sum test.

2828

Curry AASLD 2013

NB: stop therapy at OLT !!!

OLT transforms a “suboptimal”

treatment for HCV cirrhosis in

“excellent” strategy !!

SVR:

Clinical

Outcomes



Delay/prevent HCC




HCV Cirrhosis Natural History: can we modify it ?

Fino a tutt’oggi:

Valutazione SE trattare

HCV

Lieve / Assente

Malattia Epatica

Effetti collaterali

% risposta

Vantaggi ??

Trattamento “infezione”

% risposta

SI

NOEffetti collaterali

% risposta

Vantaggi ??Trattamento “infezione”

% risposta

SI

NO

Evoluta/Scompenso

FUTURO ??

Valutazione QUANDO trattare

HCV

Lieve / Assente

Costi !•% risposta

•Tollerabilità

•Paziente !!

•Eradicazione HCV

SI

NO

• ??•Malattia “evolutiva”

•% risposta

•Tollerabilità

SINO

NON evoluta / Evoluta/Scompenso

Malattia epatica

F0

F0 24

F1 27

F2 36

F3 10

F4 7

23 % 26 %

35 %

10% 7%

Evoluzione fibrosi: F0

49 %

17%

NB: Tempo 1-2 biopsia:

23 anni


6 anni

Curarsi subito o aspettare ?

F1

F0 0

F1 34

F2 40

F3 23

F4 11

0

32 %

37%

21%

10%


31 %32% NB:

Tempo 1-2 biopsia:

> 15-20 anniNB:

Tempo 1-2 biopsia:

< 5-10 anni



F2

F0 0

F1 0

F2 8

F3 16

F4 35

0% 0%14 %

27 %

59%

86 %


> 10-15 anni


HBV HCV

Trattamento antivirale

HBV-DNA (-)

HBsAg (+)

HCV-RNA (-)

antiHCV (+)

Soppresso Eradicato !

HCV and Liver Disease

Liver

Chronic HCV Infection Also Causes Extrahepatic Manifestations

Endocrine

Thyroid disease

Diabetes mellitus

Hematologic

Mixed cryoglobulinemia

Lymphoproliferative disorders

Thrombocytopenia

Renal

Membranoproliferative

glomerulonephritis

Ocular

Corneal ulcers

Sjögren syndrome

Vascular

Systemic vasculitis

Dermatologic

Lichen planus

Porphyria cutanea tarda

Musculoskeletal

Arthralgia

Myalgia

Peripheral neuropathy

Inflammatory polyarthritis

130─160 Million Chronic HCV Carriers Are at Risk of Developing Cirrhosis and/or HCC1,2

Within 20 years

1. World Health Organization. Media Centre: Hepatitis C. April 2014. http://www.who.int/mediacentre/factsheets/fs164/en/. Accessed May 20, 2014.

2. World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. April 2014. 2002.

http://www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/. Accessed May 20, 2014.

Acute

infection

Spontaneous

clearance

(15%-45%)

Chronic

infection

(55%-85%)

Mild fibrosis

Moderate to

severe

fibrosis

Cirrhosis

(15%-30%)

Decompensated cirrhosis

Hepatocellular carcinoma

(2%-4% per year in cirrhosis)

HCV Host

Therapy

0

1

2

3

4

5

6

7

8

Lee et Al. J Infect Dis 2012; 206: 469-477

Is HCV more than a liver disease?Increased mortality “beyond” the liver

The REVEAL cohort study

All causes Extrahepatic Circulatory Nephritic Oesophageal Prostate Thyroiddiseases diseases Nephrotic cancer cancer cancer

Ad

just

edH

azar

dR

atio

fo

r D

eath

2.201.90-2.55

(p=0.0001)1.47

1.47-1.77(p=0.0002)

1.531.53-2.33

(p=0.0026)

2.981.43-6.22

(p=0.0032)

5.861.98-17.35(p=0.0014)

5.831.64-20.77(p=0.0065)

7.0710.73-68.35

(p=0.09)

Hazard ratio reference value:

1 for HCV negative in each disease cathegory

Factors Associated With Increased Risk Of Secondary Outcomes In Patients With HCV

McCombs, JAMA Intern Med 2014;174:204–212

Characteristic Cirrhosis HCCLiver related

Hospitalization

(n=123,988) (n=128,481)

Male gender 1.35 (1.21–1.50) 3.41 (2.39–4.88) 1.09 (1.01-1.17)

Age 1.02 (1.02–1.02) 1.07 (1.07–1.07) 0.99 (0.99-0.99)

Race White

Black

Other

1 (reference)

0.54 (0.52–0.56)

0.73 (0.70–0.76)

1 (reference)

0.73 (0.68–0.78)

0.80 (0.74–0.87)

1 (reference)

0.74 (0.72-0.76)

0.58 (0.56-0.60)

HCV genotype

1

2

3

Other

1 (reference)

0.64 (0.61–0.68)

1.24 (1.18–1.31)

0.87 (0.75–1.00)

1 (reference)

0.52 (0.46–0.58)

1.63 (1.47–1.79)

0.77 (0.57–1.04)

1 (reference)

0.80 (0.76-0.83)

1.10 (1.05-1.15)

0.89 (0.79-0.99)

Diabetes 1.38 (1.32–1.44) 1.31 (1.21–1.42) 1.19 (1.15-1.24)

Undetectable

HCV-RNA0.62 (0.54–0.73) 0.62 (0.42–0.81) 0.71 (0.63-0.80)

Cum

ulat

ive r

ates

of inc

idenc

eof

lym

phom

a(%

)

0

1

3

0 5 10 15

Years

Persistent Infection (n=2161)SVR (n=1048)

HCV Elimination Reduces The Incidence of Malignant Lymphoma

Follow-up duration (years)

2

4

0.36%

1.49%

0%0%

2.56%

0%

Log-rank test p=0.0159

Kawamura Y, et al. Am J Med 2007;120:1034-1041

Cumulative incidence of ischemic stroke, ESRD and acute coronary event in three study cohorts of diabetic

patients

Modified log rank test with death adjusted as a competing risk event.

Hsu YC et al. HEPATOLOGY 2014;59:1293-1302

Antiviral therapy for concomitant HCV

infection is associatedwith improved renal and cardiovascular outcomes

in patients with DM

ESRDISCHEMIC

STROKE

ACUTE CORONARY

EVENT

Italy

2015 ?? ?? ??

SOF..

SIM..

NOW late 2015 end 2015/2016

USA

DAA classes and subclasses: antiviral potency and resistance barrier according to HCV genotype

Drug Class Subclass1 b 1a 2 3 4

Protease inhibitors

1st Generation first wave i.e.

Telaprevir/Boceprevir

1st Generation 2nd wave i.e.

Simeprevir Paritaprevir/r

2nd Generation

Grazoprevir ABT 493

NS5a Inhibitor

1st Generation

Ledipasvir Ombitasvir Elbasvir

Daclatasvir 2nd Generation

Valpatasvir ABT 530

NN Polymerase

Inhibitors

Dasabuvir

Nucleos/tides

Polymerase

inhibitors

2nd Generation : Sofosbuvir

High Moderate Low Very low

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5

Summary of SVR rates to IFN free regimens in HCV G1 HIV- and HIV+ Naives non Cirrhotics

SIM/SOF study Cosmos, cohorts: TRIO, TARGET

SOF/LED studies ION-1 ION-3

3D: studies PEARL SAPPHIRE

SOFO + R: SPC Sovaldi

SOF/SMV

+R

X 12-24s

SOF/DAC

+R

X 12-24s

SOF/LEDI

+R

X 12-24s

3D +R

X 12-24s

94% 99% 98% 96%

214 126 729 1380

SOFO +R

X 24s

148

68%

A

B

C

D

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4

Summary of SVR rates to IFN free regimens in HCV G1 HIV- Experienced non Cirrhotics


SOF/LED studies ION-1 ION-3

3D: studies PEARL SAPPHIRE

SOFO + R: SPC Sovaldi

SOF/SMV

+R

X 12-24s

SOF/DAC

+R

X 12-24s

SOF/LEDI

+R

X 12-24s

3D +R

X 12-24s

87% 100% 98% 96%

144 41 350 472

A

B

C

D

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4

Summary of SVR rates to IFN free regimens in HCV G1 HIV- Naives Cirrhotics


SOF/LED study meta analysis AASLD 2014

3D: studies Turquoise II

SOF/SMV

+R

X 12-24 w

SOF/LEDI

+R

X 12-24 w

3D +R

X 12-24 w

87% 98% 94%

246 161 160

A

B

C

D

SOF + R

X 124 w

11

36%

0

10

20

30

40

50

60

70

80

90

100

1 2 3

Summary of SVR rates to IFN free regimens in HCV G1 HIV- Experienced Cirrhotics


SOF/LED study meta analysis AASLD 2014

3D: studies Turquoise II

SOF/SMV

+R

X 12-24 w

SOF/LEDI

+R

X 12-24 w

3D +R

X 12-24 w

85% 95% 90%

158 352 141

A

B

C

D

SOF/LDV ± RBV in compensated cirrhotics: SVR12 by Treatment Regimen

Bourlière et al., AASLD 2014, abstract# 82 (oral)

SVR12 by treatment regimen TotalTreatment

naïveTreatment

experienced

Overall SVR12 96% 98% 95%

Duration12 wk 95% 97% 94%

24 wk 98% 99% 98%

RegimenLDV/SOF 95% 96% 95%

LDV/SOF + RBV 97% 99% 96%

Duration/

± RBV

LDV/SOF 12 wk 92% 96% 90%

LDV/SOF + RBV 12 wk 96% 98% 96%

LDV/SOF 24 wk 98% 97% 98%

LDV/SOF + RBV 24 wk 100% 100% 100%

SVR12 %

3D: SVR12 rates in treatment-naïve andP/R-experienced cirrhotic patients with GT1a HCV

41

100

80

60

40

20

0

SVR

12

(% p

atie

nts

)

92%

HCV subtype 1a

93%93%100% 100%100%

80%

93%

5964

1415

5356

1313

1111

4050

3942

1010

ombitasvir/paritaprevir/ritonavir Summary of product characteristics. dasabuvir Summary of product characteristics. .

TURQUOISE-II

Prior partialresponse

24 wks

Prior nullresponse

Naïve

12 wks24 wks12 wks 24 wks12 wks24 wks12 wks

Prior relapse

3D:SVR12 rates in treatment-naïve andP/R-experienced cirrhotic patients with GT1b HCV

42

100

80

60

40

20

0

SVR

12

(% p

atie

nts

)

100%

Prior partialresponse

24 wks

Prior nullresponse

HCV subtype 1b

100% 100% 100%85.7%

2222

1414

1818

1010

67

2525

2020

33

100% 100%100%

1. ombitasvir/paritaprevir/ritonavir Summary of product characteristics.2. dasabuvir Summary of product characteristics.

Naïve Prior relapse

12 wks24 wks12 wks 24 wks12 wks24 wks12 wks

TURQUOISE-II

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12

Summary of SVR rates in HCV G4 HIV- & HIV+

Registrative studies;RESTORE III Neutrino,PEARL –I Osinusi et al AASlD 2014, Gamal E et al AASLD 2014

PR/SIME

X 24-48 w

86% 100%

2393 55 41

A

B

C

D

PR SOFO

X 12 w

33

SOF+R

X 24 w

Naïve Exp

Non Cirrhosis

89% 44%

86 32

SOF+R

X 24 w

8

Cirrhosis

NaïveExp

SOFO/

LEDI

X 12 w

14

2D

Abbvie

X 12 w

100% 93%

PR/SIME

X 24-48 w

50

SOF+R

X 24 w

94%

2D

Abbvie

X 12 w

SOFO/

LEDI

X 12 w

SOF+R

+ LEDI

X 24 w

100% 100% 91% 80%

1081

84%

PR

DAC

X 24 w

IFN-Free Options, Gen 1a

SOF/LDV 3D SOF + SIM SOF + DCV

No cirrhosis8-12 wk

without RBV12 wk

with RBV12 wk

without RBV12 wk

without RBV

Compensated cirrhosis (CPT-A)

12 wk with RBV, or 24 wk

without RBV*

24 wk with RBV


without RBV*


without RBV*

Decompensated cirrhosis (CPT-B and CPT-C)


without RBV*

No No


without RBV*

*Patients with negative predictors of response can be treated 24 weeks with ribavirin (negative

predictors: treatment-experienced, platelet <75x103/uL)

IFN-Free Options, Gen 1b


No cirrhosis8-12 wk

without RBV12 wk

without RBV12 wk

without RBV12 wk

without RBV



without RBV*

12 wk with RBV


without RBV*


without RBV*



without RBV*

No No


without RBV*



IFN-Free Options, Gen 4


No cirrhosis12 wk

without RBV12 wk

with RBV12 wk

without RBV12 wk

without RBV



without RBV*

24 wk with RBV


without RBV*


without RBV*



without RBV*

No No


without RBV*



0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7

Summary of SVR rates in HCV G2 HIV-

Registrative studies: Fusion, Fission Positron, Valence, Lonestar,

cohorts: TRIO, TARGET

SOF+R

X 12 w

94% 81% 90%

415 282 14

A

B

C

D

PR §X 24 w

81

SOF+R

X 12 w

Naïve Exp

Non Cirrhosis

89%

SOF+R

X 12 w

87%

109

PR §X 24 w

13

SOF+R

X 12 w

62% 74%

SOF+PR

X 12 w

58

Cirrhosis

Naïve Exp


SOF + RBV SOF + DCV

No cirrhosis 12 wk12 wk

without RBV


16-20 wk12 wk

without RBV

Decompensated cirrhosis (CPT-B and -C)

16-20 wk12 wk

with RBV

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7

Summary of SVR rates in HCV G3 non cirrhosisHIV-& HIV+

Registrative studies: Fusion, Fission Positron, Valence, Lonestar, Ally 3, Gane et al AASLD 2014

SOF+R

X 24 w

92% 97%

146 45 75

A

B

C

D

PR SOFO

X 12 w

39

Naives

93%

SOF/DAC

X 12 w

88%

SOFO/R

X 24 w

137

PR SOFO

X 12 w

83% 97%

SOF/DAC

X 12 w

12

Experienced

SOF/LEDI

X 12 w

28

89%

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6

Summary of SVR rates in HCV G3 cirrhosisHIV-& HIV+

SOF+R

X 24 w

94% 59%

16 19 13

A

B

C

D

Naives

SOF/DAC

X 12 w

68%

109

SOFO/R

X 24 w

74

PR SOFO

X 12 w

83% 69%

SOF/DAC

X 12 w

12

Experienced

22

SOF/LEDI

X 12 w

72%

Registrative studies: Fusion, Fission Positron, Valence, Lonestar, Ally 3, Gane et al AASLD 2014


SOF + RBV SOF + DCV

No cirrhosis 24 wk12 wk

without RBV


No24 wk

with RBV

Decompensated cirrhosis (CPT-B and -C)

No24 wk

with RBV

Terapia ideale per HCV: ci stiamo arrivando ?

All oral

All genotypes

High barrier

to Resistance

Optimal tolerabIlity

COst reductioN

Availability: Cirrhosis, HIV–HCV,

etc.

Short treatment

Duration

Potent Efficacyacross all patient

populations

PharmaCokinetic

(low pill burden)

Minimal

drug inTeraction

Ideal HCV treatment

GOAL = ERADICATION

The price you pay

Drug US Price $ Estimated

Price for Italian

NHS €

Sofosbuvir 84-168.000 37.000

Daclatasvir 18.000

Simeprevir 54.000 10.000

Harvoni 94-188.000 40.000

Viekirax

Exviera

83-166.000 23.000

Il trattamento dell’epatite C: stato dell’arte

• Basi virologiche del trattamento

• Strategie di terapia

• Terapia anti HCV : AD 2015

• Terapia anti HCV: il futuro prossimo

ASTRAL studies :Sofosbuvir + Velpatasvir FDC in HCV G1, 4, 5, 6

stratified according to liver disease stage

323/

328

116/

116

34/

35

41/

41

Gilead sciences Inc: http://www.businesswire.com/news/home/20150921005402/en/

ASTRAL studies :Sofosbuvir + Velpatasvir FDC in HCV G 2 & 3 stratified

according to liver disease stage

237/

238

264/

277

Gilead sciences Inc: http://www.businesswire.com/news/home/20150921005402/en/

EFFICACY AND SAFETY OF GRAZOPREVIR/ELBASVIR +/- RBV FOR 12 OR 16 WEEKS IN PATIENTS WITH HCV G1, G4 OR G6

INFECTION WHO PREVIOUSLY FAILED PEGINTERFERON/RBV: C-EDGE TREATMENT-EXPERIENCED

Kwo P et al EASL 2015

EFFICACY OF AN 8-WEEK REGIMEN OF GRAZOPREVIR PLUS ELBASVIR WITHAND WITHOUT RIBAVIRIN IN TREATMENT-NAIVE, NONCIRRHOTIC HCV

GENOTYPE 1B INFECTION

Vierling JM et al EASL 2015

INFEZIONE DA HCV - Peperosso Srlwin.peperosso.tv/public/presentazioni/Dr.ssa Menzaghi - Il...

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