CARE AND TREATMENT OF CHRONIC HBV AND HCV€¦ · PROFESSOR OF MEDICINE, TORONTO WESTERN AND...

CARE AND TREATMENT OF CHRONIC HBV AND HCV

GEORGE PAPATHEODORIDIS, MD

PROFESSOR IN MEDICINE AND GASTROENTEROLOGY ATHENS UNIVERSITY MEDICAL SCHOOL

HARRY JANSSEN, MD PROFESSOR OF MEDICINE, TORONTO WESTERN AND TORONTO GENERAL HOSPITAL,

UNIVERSITY HEALTH NETWORK, TORONTO, CANADA

ANGELOS HATZAKIS, MD PROFESSOR OF EPIDEMIOLOGY AND PREVENTIVE MEDICINE

ATHENS UNIVERSITY MEDICAL SCHOOL

Contents

Care and Treatment of Chronic Hepatitis B

Care and Treatment of Chronic Hepatitis C

Gaps and Barriers of Prevention, Care and Treatment

CARE AND TREATMENT OF CHRONIC HEPATITIS B

Chronic HBV and HCV are treatable or curable

HBV Treatment HCV Treatment

Interferon alfa-2b Interferon-alfa-2a/2b ± ribavirin

Lamivudine Peginterferon alfa-2b ± ribavirin + ribavirin

Adefovir Boceprevir / Telaprevir

Peginterferon alfa-2b Sofosbuvir

Peginterferon alfa-2a Simeprevir,

Entecavir Daclatasvir

Telbivudine Ledipasvir/Sofosbuvir

Tenofovir Paritaprevir/ritonavir/Ombitasvir , Dasabuvir

Hatzakis A et al. JVH 2011; 18, S1

EFFICACY OF 48-WEEKS OF PEG-IFNa IN CHB: End of therapy (EOT) & Sustained off-therapy responses

Pts, %

Lau G et al, NEJM 2005; Marcellin P et al, NEJM 2004

HBeAg(+)CHB HBeAg(-)CHB

EOT 6-mos FUP EOT 6-mos FUP HBeAg to anti-HBe seroconversion HBV DNA <400 cp/ml

Pati

ents

wit

h r

esis

tan

ce (

%)

25

48

60

66 68

0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 3 6

18

4

11 16

19

Years 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 6 1 2 3 4 1 2 3 4 5 6 7 8

LAM ADV ETV TBV TDF

Papatheodoridis et al. Hepatology 2002,36:219-26; Hadziyannis et al. Gastroenterology 2006,131:1743-51; Liaw YF et al. Gastroenterology 2009,136:486-95; Wang Y et al. AASLD 2009, Abstr. 482;

Tenney D et al. APASL 2008, Abstr. PL02; Marcellin P et al. AASLD 2014

29

HBeAg- HBeAg- HBeAg-

First-line

Resistance to oral antiviral agents in naive CHB patients Data from different studies with different patients characteristics and methodology

Han S et al. AASLD 2008. Shouval et al. AASLD 2008.

Pat

ien

ts w

ith

HB

V D

NA

<3

00

cp

/mL

(%)

55%

Year 1

83%

Year 2

89%

Year 3

67%

n/ N

236/ 354

Year 4

91%

80/ 146

116/ 140

116/ 131

98/ 108

Year 5

88/ 94

94%

Year 1

ETV-022

0

20

40

60

80

100

ETV-901

Long-term ETV therapy in naive HBeAg(+)/(-) CHB

HBeAg(+) HBeAg(-)

Year 1

91%

Year 2 95%

Year 3

94%

93/99 84/90

67/74 54/57

93%

Year 1

ETV-027

0

20

40

60

80

100

ETV-901

Marcellin P et al. AASLD 2011, 2012

HBeAg(-): 5 year - 6 years

ΙΤΤ: 83%- 81%

Per protocol*: 99%- 100%

HBeAg(+): 5 years - 6 years

ΙΤΤ: 65%- 62%

Per protocol*: 97%- 99%

Patients with HBV DNA <400 cp/mL at 5-6 years under TDF

*missing = exclusion

Resistance to ETV or TDF in CHB with LAM resistance P

atie

nts

wit

h r

esi

stan

ce (

%)

6 0 0 0 0

Years 1 2 3 4 5 6 1 2 3 4

Entecavir (ETV) Tenofovir (TDF)

These trials included different populations, different exclusion criteria and different endpoints

15

31

47 51

Although licensed, ETV (1.0 mg) is not recommended for patients with LAM resistance by almost all guidelines

57

Tenney D et al. EASL 2009, Abstr. 20; Van Bommel F et al. Hepatology 2010, 51: 73-80

Ishak Fibrosis Scores

Pe

rce

nta

ge o

f p

atie

nts

0

10

20

30

40

50

60

70

80

90

100

Baseline Year 1 Year 5

39%

38%

12%

P < 0.001

P < 0.001

63%

0

10

20

30

40

50

60

70

80

90

100

Baseline Year 1 Year 5

39%

38%

12%

P < 0.001

P < 0.001

63%

6

5

4

3

2

1

0

6

5

4

3

2

1

0

Patients with cirrhosis (Ishak score ≥5): 28% at baseline, 8% at year 5

Fibrosis Is ReversibleLiver Fibrosis Regression over 5 Yrs of Tenofovir Therapy

Marcellin P et al. Lancet 2013

348 patients with paired biopsies at baseline & year 5

HCC in CHB patients under LAM

Patients with HCC,

%

LAM Untreated

Patients n: 779 534

HBeAg(-) 49% 54%

Comp. Ci: 29% 39%

FUP (mos): 32-90 32-108

• Liaw et al, NEJM 2004

• Papatheodoridis et al, HEP 2005

• Yuen et al, AVT 2007

P=0.003

P=0.015

P=0.016

All VR BR/BTH Untreated pts LAM treated pts N 779 353 426 534

Papatheodoridis GV et al. J Hepatol 2010;53:348-56

Patients with HCC,

%

No cirrhosis

Cirrhosis

Virological remission

No virological remission

Patients NA naive LAM resistance NA naive LAM resistance

No 2233 / 1054 241 / 170 982 / 852 320 / 91

P<0.001 P<0.001 P<0.001 P=NS

HCC incidence in CHB patients under NA(s) for a median of 4 years


0,5%

1,0%

0,7%

0,1%

0,5%

0,0%

0,5%

1,0%

1,5%

2,0%

Tx-naive Tx-naive and/or tx-experienced Tx-naive

Papathe- odoridis N=212

Yang N=202

Wong N=984

Wong N=813

Yang N=314

Hosaka N=237

Lampe- rtico

N=213

Arends N=580

Ann

ual H

CC

Inci

denc

e

Lim N=878

Cho N=933

Wu N=18748

Lampe- rtico

N=243

Papathe- odoridis N=1231

ETV TDF ETV or TDF

Yamada N=402

Prior exposure

NR

Tx-naive and/or tx-experienced

Asians Caucasians

ETV or TDF for non-cirrhotic CHB patients

HCC rates per year


1,4%

2,8%

5,4%

2,0%

4,1%

3,3%

0,9%

5,4%

2,6%

5,1%

2,2%

4,5%

3,9%

0,0%

1,0%

2,0%

3,0%

4,0%

5,0%

6,0%

Yang N=121

Wong N=482

Wong

N=247

Hosaka N=79

Chen

N=239

Kim

N=324

Yang

N=152

Chen N=143

Papa theo- dori dis

N=69

Lamp- etico

N=155

Are- nds

N=164

Koklü N=77

2,8%

4,2%

1,8%

3,3%

2,5%

5,2%

1,5%

0,0%

1,0%

2,0%

3,0%

4,0%

5,0%

6,0%

Lim N=860

Cho

N=445

Su N=666

Wu N=2847

Lamp- ertico

N=131

Papa theo- dori dis

N=1231

Koklü N=72

Yama- da

N=94

ETV or TDF for cirrhotic CHB patients HCC rates per year

ETV TDF ETV or TDF

Tx-naive Tx-naive and/or tx-experienced Tx-naive

Prior exposure

NR

Tx-naive and/or tx-experienced

Asians Caucasians


Main advantages and disadvantages of Peg-IFN & nucleos(t)ide analogues (NAs) in CHB

Peg-IFN NAs

Advantages Finite duration

Higher rates of anti-HBe &

anti-HBs seroconversion

with 12 mos of therapy

Absence of resistance

Potent antiviral effect

Good tolerance

Oral administration

Disadvantages Moderate antiviral effect

Inferior tolerability

Risk of adverse events

Subcutaneous injections

Long-term (indefinite?) duration

Unknown long-term safety

Risk of resistance

EASL HBV CPGs. J Hepatol 2012

HBV treatment modifies the outcome of the disease

Sustained response after pegIFN or long-term ETV/TDF monotherapy

Improvement/Stabilization of liver disease in practically all patients

Often regression of histological cirrhosis

Improvement/Disappearance of portal hypertension and liver decompensation

No need for liver transplantation due to liver failure

Reduction but not elimination of HCC risk

Improved survival

CARE AND TREATMENT OF CHRONIC HEPATITIS C

1992 1996 1998 2001 2011 2013 2014

SVR, %

>

Standard IFNa

RBV

PegIFNa

BOC/TPV

New DAAs

Evolution in efficacy of CHC treatment

IFN: interferon-alfa, R: ribavirin, PR: pegylated IFN+R, PI: protease inhibitor, BOC:boceprevir, TPV: telaprevir, DAA(s): direcr acting antiviral(s)

2002-2011: Optimizing Peg-IFNa+RBV Response guided therapy

HCV genotype

Baseline HCV RNA levels

Rapid virological response (RVR) - at 4 weeks of therapy

undetectable HCV RNA (<50 IU/mL)

Early virological response (EVR) – at 12 weeks of therapy

complete: undetectable HCV RNA (<600 IU/mL)

partial: detectable HCV RNA but ≥2 log decrease from baseline

PEG-IFN+RBV in CΗC: HCV Genotype & SVR

PEG-ΙFN-2b (1.5μg/Kg/wk) + RBV 0.8g

PEG-ΙFN-2a (180μg/wk) + RBV 1-1.2g

x 48 weeks

SVR

, %

Manns et al. Lancet 2001 Fried et al . Ν Engl J Med 2002

2/3 1 2/3 1

HCV genotype HCV genotype

• 22 studies, 2891 G4 patients (12-308 patients per study)

PEG-IFN+RBV in CHC-G4

SVR, %

Khattab MA et al. J Hepatol 2011;54:1250-62

All patients F3-F4 patients

Unresolved issues with Peg-IFNa+RBV

Treatment contraindications

(all patients needed treatment most)

Low SVR rates mostly in G1 (& G4) patients

Poor chance of SVR in treatment failures

Side effects – Poor quality of life

Adherence problems

SOVALDI®

Sofosbuvir NS5B polymerase

Inhibitor Gilead

OLYSIO® Simeprevir

NS3/4A protease Inhibitor Janssen

DAKLINZA® Daclatasvir

NS5A Inhibitor

BMS

400 mg/24h

Genotypes 1-6

High genetic barrier

150 mg/24h with food

Genotypes 1,4

Low genetic barrier

60 mg/24h

Genotypes 1,2,3,4

Low genetic barrier

January 17, 2014 May 16, 2014 August 28, 2014 November 18, 2014

90+400 mg/24h

Genotypes 1,3,4

High genetic barrier

HARVONI® Ledipasvir

NS5A inhibitor +Sofosbuvir

NS5B polymerase Inhibitor Gilead

Anti-HCV agents approved by ΕMA in 2014

VIEKIRAX® Ombitasvir

NS5A inhibitor +Paritaprevir

NS3/4A protease inhibitor/ Ritonavir

EXVIERA® Dasabuvir

Non-nucleos(t)ide NS5B polymerase

inhibitor

[75/50+12.5 mg] x2 /24h with food

Genotypes 1, 4

Genetic barrier dependent on genotype

250 mg/12h

Genotype 1

Low genetic barrier

January 16, 2015

Anti-HCV agents approved by ΕMA in 2015

Abbvie

Simeprevir

Ribavirin

IFNa-containing combinations – Main strategies

+

+

PegIFNa

Ribavirin

+

PegIFNa

+

Ribavirin

+

PegIFNa

+

Ribavirin

+

PegIFNa

Boceprevir

Telaprevir

Sofosbuvir Daclatasvir

Nucleotide inhibitor of NS5B polymerase

NS3/4 protease inhibitor

NS5A inhibitor

?

Sofosbuvir

Simeprevir Daclatasvir

Paritaprevir /ritonavir

Dasabuvir Ribavirin

IFNa-Free combinations – Main strategies

Sofosbuvir

Ribavirin

+ + Ombitasvir

Ribavirin

±

±

± ±

Ledipasvir

Sofosbuvir

Ribavirin

±

Sofosbuvir

Ribavirin

+

Nucleotide inhibitor of NS5B polymerase

Non-nucleos(t)ide inhibitor of NS5B polymerase

NS3/4 protease inhibitor

NS5A inhibitor

PEG-IFNa + Ribavirin +Sofosbuvir

PEG-IFNa + Ribavirin + Simeprevir

Sofosbuvir + Ribavirin

Sofosbuvir + Simeprevir (±Ribavirin)

Sofosbuvir + Daclatasvir (±Ribavirin)

IFNa based

IFNa free

Possible treatment options for genotype 1

Sofosbuvir/Ledipasvir (±Ribavirin)

Paritaprevir/r/Ombitasvir ±Dasabuvir (±Ribavirin)

PEG-IFNa + Ribavirin

PEG-IFNa + Ribavirin + Daclatasvir

Jacobson I et al. Lancet 2014;384:403-13 & Manns M et al. Lancet 2014;384:414-26

18/ 31

n/N = 5/ 17

188/ 229

60/ 113

82

53 58

29

100

80

60

40

20

0 No cirrhosis Cirrhosis

n/N = 419/ 521

133/ 264

138/ 165

36/ 83

49/ 84

23/ 44

228/ 267

70/ 133

100

80

60

40

20

0

SVR

(%

)

Simeprevir + P/R Placebo + P/R

80

50

84

43

58 52

85

53

Total GT1a without

Q80K

GT1a with Q80K

GT1b

Simeprevir (SMV) + P/R in naive patients with GT1

QUEST-11 & QUEST-22 Pooled analysis

SMV (150 mg/24h) + PR x12 weeks followed by PR x12–36 weeks

PR: pegylated interferon + ribavirin

(88% of pts: 24 wks)

ASPIRE: Simeprevir (SMV) + PR in treatment experienced patients with GT1

Zeuzem S et al. Gastroenterology 2014;146:430–41

Pbo + PR SMV 100 mg*

+ PR

SMV 150 mg*

+ PR


+ PR

SMV 150 mg*

+ PR


+ PR

SMV 150 mg*

+ PR

SVR

24

(%

)

Relapsers Partial responders Null responders

67/79 67/79 10/27 39/68 52/69 2/23 23/50 26/51 3/16

SMV (100/150 mg/24h) x12/24/48 weeks + PR x48 weeks

NEUTRINO: Sofosbuvir + P/R for 12 weeks in naive patients with genotype 1/4/5/6

Lawitz E et al. N Engl J Med 2013;368:1878-1887

Total

SVR

12

(%

)

89 96

100

100

80

60

40

20

0 GT1 GT4 GT5,6

261/292 27/28 7/7 n/N =

90

295/327

Sofosbuvir + RBV for 24 wks in patients with genotype 1

Lalezari JP et al. EASL 2013, S346.

QUANTUM Sofosbuvir + RBV

for 24 wks

Total 65%

Genotype 1a 69%

Genotype 1b 53%

Non-cirrhotics 68%

Cirrhotics 36%

Cohort 1 (F0-F2 Nulls) Cohort 2 (F3-F4 Naives/Nulls)

SMV/SOF ± RBV

SVR12 (%)

SMV/SOF + RBV

SMV/SOF+ RBV

SMV/SOF SMV/SOF

24 Wks 12 Wks Overall

4/ 4

7/ 7

8/ 9

3/ 3

7/ 7

3/ 3

6/ 6

12/ 12

8/ 9

4/ 4

4/ 4

5/ 6

100 100 93

88

95 100 100

88

100 96

SMV/SOF ± RBV

SMV/SOF + RBV

SMV/SOF + RBV

SMV/SOF SMV/SOF

24 Wks 12 Wks Overall

6/ 6

11/ 11

11/ 11

4/ 4

7/ 7

4/ 4

5/ 5

13/ 14

7/ 8

3/ 3

7/ 8

3/ 3

18/ 18

38/ 40

25/ 26

100 100 100 100 100

100

80

60

40

20

0

100 100

89

100 100 100 100 100

89

100 100

83

100 100

89

GT1b GT1a without Q80K GT1a with Q80K

30/30

17/ 17

24/27

COSMOS: Simeprevir + Sofosbuvir ± RBV

in patients with genotype 1 (Phase ΙIa study)

Sulkowski M et al. EASL 2014, Abstract O7. Lawitz E et al. EASL 2014, Abstract O165.

Lawitz E et al. Lancet 2014.

OPTIMIST-1: SΜV+SOF x8-12 weeks in HCV GT-1 non-cirrhotics SV

R1

2 (

%)

112/115

Treatment-naive Treatment-experienced

97% (94.0;100)

88/103 38/40 40/52

85% (78.1;92.7)

95% (87.0;100)

77% (64.5;89.3)

Kwo P et al. EASL 2015, LB-Poster14

SMV+SOF 12 weeks SMV+SOF 8 weeks

OPTIMIST-2: SΜV+SOF x12 weeks in HCV GT-1 cirrhotics SV

R1

2 (

%)

44/50

Treatment-naive Treatment-experienceda

88 (95% CI: 78.0; 98.0)

42/53

79 (95% CI: 67.4; 91.1)

Lawitz E et al. EASL 2015, LB-Poster 04

CI, confidence interval; aTreatment-experienced patients included prior relapsers, prior non-responders, IFN-intolerant and other patients

SVR

12

(%

)

60/72

GT1a GT1a with Q80K

GT1a without Q80K

GT1b

25/34 35/38 26/31

83 (95% CI: 74.0; 92.6)

74 (95% CI: 57.2; 89.8)

92 (95% CI: 82.2; 100)

84 (95% CI: 69.3; 98.4)

Lawitz E et al. EASL 2015, LB-Poster 04

OPTIMIST-2: SΜV+SOF x12 weeks in HCV GT-1 cirrhotics

Sofosbuvir + Daclatasvir +/- RBV for G1 patients (phase IIb study)

100

80

60

40

20

0

SVR12 (%)

100

29/ 29

100

14/ 15

S/D S/D/R

24 wks

100

21/ 21

S/D

19/ 20

95

S/D/R

24 wks

100

41/ 41

95

39/ 41

12 wks S/D S/D/R

Naive Prior PI (BOC/TPV) failures

• 20% cirrhotics • Almost all cured – 12 weeks adequate, RBV unnecessary

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

HEPATHER: SOF+DCV ±RBV x12 or 24 wks in GT1 pts

SVR4, %

SOF+DCV SOF+DCV+RBV SOF+DCV SOF+DCV+RBV x12 wks x12 wks x24 wks x24 wks

S Pol et al. EASL 2015, Abstr. LB 03

409 patients, 318 cirrhotics, 306 failures to PR±TPV/BOC

No cirrhosis Cirrhosis

SVR

12

(%

)

n N

141 142

143 143

143 143

211 212

66 66

211 211

67 67

212 214

66 68

Overall GT1a GT1b

141 141

215 215

71 71

Subgroup results do not include patients who withdrew consent or who were lost to follow-up.

Error bars: 95% CI.

ION-1: SOF/LDV ± RBV in GT1 treatment-naive patients – SVR12

Afdhal N et al. New Engl J Med 2014;70:1889-98.

ION-1: SVR rates* in GT1 treatment-naive cirrhotic patients (subgroup analysis)

* Subgroup results do not include patients who withdrew consent or were lost to follow-up.


179 179

32 33

178 178

33 33

181 182

31 32

179 179

36 36

n N

SVR

12

(%

)


One patient achieved SVR12, but was not subgenotyped.

Error bars: 95% CI.

SVR

12

(%

)

n N

159 171

159 172

163 172

202 215

42 43

201 216

42 44

206 216

43 44

Overall GT1a GT1b

ION-3: Phase III SOF/LDV ± RBV in GT1 naive, non-cirrhotic patients – SVR12

Kowdley KV et al. New Engl J Med 2014;370:1879-88.

Predictors of relapse in ION-3 trial: SOF/LDV±RBV for 8 vs 12 wks in GT1 naive, non-cirrhotic patients

Patients with

relapse*, %

*Patients lost to follow-up or who withdraw

consent excluded CC non-CC <6 ≥6 MIU/ml IL28B genotype Baseline HCV RNA n/N 2/56 0/57 0/54 9/157 9/153 3/157 2/121 3/136 2/128 9/92 6/74 1/83

SOF/LDV x8wks SOF/LDV+RBV x8wks SOF/LDV x12wks

P=0.034

P=0.088

P=0.141

Kowdley KV et al. New Engl J Med 2014;370:1879-88.

SVR

12

(%

)

n N

82 86

84 88

84 85

102 109

20 23

107 111

23 23

108 109

24 24

Overall GT1a GT1b

87 88

110 111

23 23

Error bars: 95% CI.

One patient achieved SVR12, but was not subgenotyped.

ION-2: SOF/LDV ± RBV in GT1 treatment-experienced patients


ION-2: SVR rates in GT1 treatment-experienced cirrhotic patients (subgroup analysis)


83 87

19 22

89 89

18 22

86 87

22 22

88 89

22 22

n N

Error bars: 95% CI.

SVR

12

(%

)


LDV/SOF Efficacy in Cirrhotics According to Treatment Experience, Duration, RBV

100

80

60

40

20

0

Total Treatment Naive

92 96 98 100

SV

R12

(%

)

118 204 133 58

96 98 97

47 45 33 36

100

Treatment Experienced

90

96 98

71 159 100 22

100

12 wks of LDV/SOF 12 wks of LDV/SOF + RBV

24 wks of LDV/SOF 24 wks of LDV/SOF + RBV

n =

Bourlière M et al. AASLD 2014, Abstr. 82

Wyles DL et al. AASLD 2014. Abstr. 235

*25 pts (49%) SOF + pegIFN/RBV, 20 (39%) SOF ± RBV, 5 (10%) SOF-placebo +

pegIFN/RBV or GS-0938 μονοθεραπεία, 1 (2%) SOF monotherapy

SVR12, %

98

LDV/SOF + RBV x12 wks in GT1 HCV pts with previous failure on sofosbuvir regimens

GT1 HCV with previous SOF

failure (29% cirrhotic)*

(N = 51)

LDV/SOF + RBV

12 Wks

Phase II trial

LDV/SOF x24 wks for GT1 pts who failed after LDV/SOF x8 or 12 wks

E Lawitz et al. EASL 2015, Abstr. O5

SAPPHIRE-I: GT1 naive, non-cirrhotic patients — SVR12 rates by HCV GT1 subtype

•

SVR

12

(%

)

n N

455 473

307 322

148 151

Treatment-naive

Error bars: 95% CI.

Feld JJ et al. N Engl J Med 2014;370:1594-603.

Paritaprevir/r/Ombitasvir + Dasabuvir + RBV x12 wks

PEARL-III: SVR rates with 3D ± RBV in GT1b naive, non-cirrhotic patients

Error bars: 95% CI. Ferenci P et al. N Engl J Med 2014;370:1983-92.

Paritaprevir/r/Ombitasvir + Dasabuvir ± RBV x12 wks

209/210 207/209

SVR

12

(%

)

RBV No RBV

PEARL-IV: GT1a naive, non-cirrhotic patients

SVR

12

(%

)

97 100

185 205


Treatment discontinuations 0 2 (1%)

Ferenci P et al. N Engl J Med 2014;370:1983-92.

SAPPHIRE-II: GT1 treatment-experienced non-cirrhotic patients

SVR

12

(%

)

n N

286 297

166 173

119 123

One patient achieved SVR12, but was unable to be subgenotyped.

Error bars: 95% CI.

Zeuzem S et al. N Engl J Med 2014;370:1604-14.

Paritaprevir/r/Ombitasvir + Dasabuvir + RBV x12 wks

PEARL-II: HCV GT1b treatment-experienced non-cirrhotic patients

P Andreone et al. Gastroenterology 2014; 147:359-365

SVR

12

(%

)

n N

91 91

85 88

35% null-responders, 29% partial responders, 36% relapsers


TURQUOISE-II: SVR12 rates in GT1 treatment-naive and experienced cirrhotic patients

SVR

12

(%

)

12 Weeks 3D + RBV

91.8

191/208

95.9

165/172

24 Weeks 3D + RBV

P=0.089

Paritaprevir/r/Ombitasvir + Dasabuvir (3D) + RBV x12 wks

Poordad F et al. N Engl J Med 2014;370:1973-82

TURQUOISE-II: SVR12 rates in GT1 treatment-naive and experienced cirrhotic patients by HCV subgenotype

88.6

12-week arm

24-week arm

98.5 94.2 100

GT 1a GT 1b

3D + RBV

SVR

12

(%

)

124/140 67/68 114/121 51/51

Poordad F et al. N Engl J Med 2014;370:1973-82

Paritaprevir/r/Ombitasvir + Dasabuvir (3D) + RBV x12 wks

Treatment options for genotype 1 AASLD 12/14

EASL 04/15

EMA

PegIFNa+RBV (PR) No No x24/48/72wks

PR+SMV¶ – PR No x12-12wks in naive/RR, x12/36wks in PR/NR

PR+SOF No x12wks x12wks

PR+DCV - PR DCV not licensed No No

SOF + RBV No x24wks only if no other option

SOF +SMV* ±RBV x12wks (Ci: 24wks)

x12wks (Ci: +RBV or x24wks)

x12wks

SOF +DCV DCV not licensed x12wks (Ci: +RBV or x24wks)

x12wks, x24wks in Exp. or Ci & neg predictors

(+RBV)

SOF/LDV x12#wks, x24wks or +RBV x12wks in Exp. Ci

x12#wks (Ci: +RBV or x24wks)

x12# (24)wks in non-Ci, x24(12)wks in Ci

PRV*/r/OBV +DSV (+RBV for G1a or Ci)

x12wks, x24wks in G1a-Ci



¶Not in G1a with Q80K, *Not in PI failures, #Perhaps x8wks in naive non-Ci (HCV RNA<6 MIU/ml)

Sofosbuvir + RBV

PEG-IFNa + RBV + Sofosbuvir

Possible new treatment options for genotype 2

IFNa based

IFNa free

PEG-IFNa + Ribavirin (RBV)

Sofosbuvir + Daclatasvir ±RBV

HCV G2 Patients

Lawitz E et al, NEJM 2013,368:1878-87. Jacobson IM et al, NEJM 2013,368:1867-77.

Zeuzem S et al, AASLD 2013, Abstr. #1085.

VALENCE

SOF + RBV

12 wk

FISSION

SOF + RBV

12 wk

VALENCE

SOF + RBV

12 wk

SVR

12

(%

)

Treatment-Naive Treatment-Experienced

FUSION

SOF + RBV

12 wk

POSITRON

SOF + RBV

12 wk

97% 100%

29/30 2/2 0%

20%

40%

60%

80%

100% 98%

31/36

91%

30/33

78%

100%

23/23 7/9

91% 88%

30/33 7/8

92%

85/92

94%

16/17

Noncirrhotic Cirrhotic

60%

96%

25/26 6/10

FUSION

SOF + RBV

16 wk

BOSON: SOF +RBV ±Peg-IFNa in GT2 treatment experienced patients with cirrhosis

G Foster et al. EASL 2015, Abstr. LB 05

SVR12, %

13/15 17/17 15/16

Sulkowski M et al. New Engl J Med 2014;370:211-21

Daclatasvir + Sofosbuvir ± RBV x24 wks

in naive patients with genotype 2 Pa

tien

ts w

ith

SV

R1

2 (%

)

N=26

Treatment options for genotype 2

AASLD 12/14

EASL 04/15

EMA

PegIFNa+RBV (PR) No No x16/24wks

PR+SOF No x12wks in Ci ± Exp. No

SOF + RBV x12wks, x16wks in Ci

x12wks, x16-20wks in Ci

especially Exp.

x12wks, perhaps x24wks if ≥1 unfavorable factor(s) of SVR

SOF+DCV DCV not licensed

x12wks in Ci ± Exp.

?


PEG-IFNa + Ribavirin + Sofosbuvir

Possible new treatment options for genotype 3


IFNa based

IFNa free




HCV G3 Patients

Treatment-Naive Treatment-Experienced

Noncirrhotic Cirrhotic

19%

87%

60%

SVR

12 (

%)

89/145 86/92

FUSION

SOF +RBV 12 wk

VALENCE SOF + RBV 24 wk

87/100 5/26

92% 94%

12/13 14/38

37%

27/45

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

61%

FUSION

SOF +RBV 16 wk

14/23 25/40

63%

Lawitz E et al, NEJM 2013,368:1878-87. Jacobson IM et al, NEJM 2013,368:1867-77.

Zeuzem S et al, AASLD 2013, Abstr. #1085.

ALLY-3: SVR12 With SOF + DCV x12 wks in GT3

11 of 16 relapsers had cirrhosis

RAVs emerging at relapse: NS5A Y93H emerged in 9 of 16 pts

SVR

12

(%

)

Treatment-Naive Pts

Treatment-Experienced Pts

Overall Treatment-Naive Pts

Treatment-Experienced Pts


SVR

12

(%

)

100

80

60

40

20

0

90 86

100

80

60

40

20

0

96

63

97

58

94 69

105/ 109

20/ 32

73/ 75

11/ 19

32/ 34

9/ 13

91/ 101

44/ 51

Nelson DR et al. AASLD 2014, Abstract LB-3; Hepatology 2015 [Epub ahead of print].

ELECTRON-2: LDV/SOF + RBV x12 weeks in GT3

SVR12, %

Naive Experienced

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

Ci: 5 No Ci Ci

16/25 26/26 25/28 16/22

Gane E et al. AASLD 2014, LB11

SOF + RBV 16 weeks SOF + RBV 24 weeks SOF + PEG/RBV 12 weeks

58 70

65 72

68 71

12 21

26 34

17 36

30 35

44 54

49 52

41 54

SVR

12

(%

)

Treatment Naive Treatment Experienced

No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis

BOSON: SOF +RBV ±Peg-IFNa in GT3

G Foster et al. EASL 2015, Abstr. LB 05

18 22

21 23

Treatment options for genotype 3

AASLD 12/14

EASL 04/15

EMA

PegIFNa+RBV (PR) No No x16/24wks

PR+SOF x12wks x12wks (particularly SOF+RBV failures)

x12wks

PR+DCV - PR DCV not licensed No No

SOF + RBV x24wks x24wks x24wks

SOF+DCV ±RBV DCV not licensed x12wks in non-Ci, x24wks +RBV in Ci

(+RBV) x24wks in Ci ± Exp.

SOF/LDV +RBV

No No x24wks in Ci ± Exp.

PEG-IFNa + Ribavirin +Sofosbuvir

PEG-IFNa + Ribavirin + Simeprevir


Sofosbuvir + Simeprevir (±Ribavirin)


IFNa based

IFNa free

Possible treatment options for genotype 4


Paritaprevir/r/Ombitasvir (±Ribavirin)



Relapsers Partial responders

Naïve Σύνολο Null responders

Moreno et al. EASL 2014, Poster 1319

Simeprevir + PR in patients with genotype 4

NEUTRINO: Sofosbuvir + P/R for 12 weeks in naive patients with genotype 1/4/5/6

Lawitz E et al. N Engl J Med 2013;368:1878-1887

Total

SVR

12

(%

)

89 96

100

100

80

60

40

20

0 GT1 GT4 GT5,6

261/292 27/28 7/7 n/N =

90

295/327

Ruane PJ et al. Hepatology 2015, Epud ahead of print

Virologic ResponseSOF + RBV in Treatment of GT4 Patients of Egyptian Ancestry

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

Treatment-naive Treatment-experienced

SYNERGY Trial: LDV/SOF for 12 wks in patients with G4

• Single-center, open-label phase 2a trial

• 38% of patients were TE; all were naive to DAAs; 33% had cirrhosis

• No deaths, SAEs, or grade 4 laboratory events; 1 D/C

GT4 HCV (N=21)

SOF/LDV

12 wks SVR12, %

95

Kapoor R et al. AASLD 2014, Abstract #240

French cohort

GT4 HCV (N=44)

SOF/LDV

12 wks SVR12, %

93

Abergel A et al. EASL 2015, Abstr. O56

Experienced: 22 (50%), Cirrhosis: 10 (23%)

PEARL-I: Paritaprevir/r/Ombitasvir ± RBV x12 wks in non-cirrhotic naive/experienced patients with G4

SVR

(%

)

Hezode C et al. Lancet 2015; Epud ahead of print

No RBV +RBV +RBV (N=44) (N=42) (N=49)

SVR4

SVR12

P=0.086

Treatment options for genotype 4 AASLD 12/14

EASL 04/15

EMA

PegIFNa+RBV(PR) No No x24/48wks

PR+SMV – PR No x12-12wks in naive/RR, x12/36wks in PR/NR

PR+SOF x12wks x12wks x12wks

PR+DCV - PR DCV not licensed No x24–0/24wks

SOF +RBV x24wks No x24wks

SOF +SMV ±RBV x12wks x12wks in non-Ci, +RBV or x24wks in Ci

x12wks

SOF +DCV ±RBV DCV not licensed x12wks in non-Ci, +RBV or x24wks in Ci

x12wks, x24wks in Exp. or Ci & neg predictors

(+R)

SOF/LDV x12wks x12wks in non-Ci, +RBV or x24wks in Ci

x12(24)wks in non-Ci, x24(12)wks in Ci

PRV/r/OBV +RBV x12wks x12wks in non-Ci, x24wks in Ci

x12wks in non-Ci, x24wks in Ci

Sofosbuvir

Simeprevir (Not for Child C cirrhosis)

Daclatasvir

Sofosbuvir/Ledipasvir

Paritaprevir/r/Ombitasvir ± Dasabuvir (Not for Child C cirrhosis)

HCV decompensated cirrhosis & liver transplant pts

Drug-Drug interactions

None

Not with CsA

None

None

Increase of TAC>CsA levels TAC: 0.5 mg/wk or 0.2 mg/72h,

CsA: 20% of previous dose

Slower virologic response to SOF+RBV in patients with Child B than Child A cirrhosis & portal hypertension

HC

V R

NA

< L

LOQ

(%

)

Clinical Events, n

Ascites Hepatic Encephalopathy

SOF + RBV (n = 25)

Observation (n = 25)

SOF + RBV (n = 25)

Observation (n = 25)

Baseline 6 9 5 2

Wk 12 5 8 3 3

Wk 24 0 7 0 4

100

80

60

40

20

0 Wk 2 Wk 4 Wk 8 Wk 12

56

100 94

Wk 24

CTP A CTP B

44

75

100 100 100 94 93

Afdhal N et al. EASL 2014, Abstr. 68

SOLAR-1: SVR12 and safety according to CTP score in decompensated cirrhosis

Flamm SL et al. AASLD 2014, Abstr. 239

100

80

60

40

20

0

SVR

12

(%

)

Overall CTP B CTP C

LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks

87 89

45/52 42/47

87 89 86 90

26/30 24/27 19/22 18/20

3 relapses 1 death 1 relapse

2 deaths

1 relapse 1 death 1 LTFU 1 relapse

1 death

Patients n (%)

CTP B CTP C

12 Wks (n=30)

24 Wks (n=29)

12 Wks (n=23)

24 Wks (n=26)

AE 29 (97) 27 (93) 23 (100) 26 (100)

SAE 3 (10) 10 (34) 6 (26) 11 (42)

Treatment-emergent, -related SAEs

2 (7) 0 0 2 (8)

Treatment D/C due to AEs 0 1 (3) 0 2 (8)

SOLAR-2: SOF/LDV+RBV in HCV decompensated cirrhotics and transplant patients

M Manns et al. EASL 2015, Abstr. G02

SOLAR-2: SOF/LDV+RBV in HCV decompensated cirrhotics and transplant patients

M Manns et al. EASL 2015, Abstr. G02

MELD score change from baseline to follow-up week-4

US and EU registry: TARGET cohort in GT-1 patients with decompensated cirrhosis

1 HCV-TARGET, a consortium of >50 academic and community medical centers in the U.S., Canada, and Germany; Interim report.

Reddy KR, et al. EASL 2015, Abstr 7

55 71

13 16

HCV TARGET*1

Total n = 277 MELD score ≥10 GT-1 n = 199

17% MELD score ≥16

Safety: DC due to AE, 8 (3%)

SOF + SMV SOF + SMV + RBV

*Interim analysis

ALLY-1: Advanced cirrhosis cohort

Total: n = 60; any GT; Baseline MELD score range 8–27 GT-1: n=45; GT-1/CP-B: 53%, GT-1/CP-C: 22%

Safety: DC due to AEs, n = 1

SVR rates with SOF+DCV+RBV x12 weeks in HCV GT1 patients with advanced cirrhosis

Poordad F et al. EASL 2015, Abstract LB 08

All G1a G1b CP-A CP-B CP-C

SVR12, %

N=45 N=34 N=11 N=11 N=24 N=10

aBased on all treated patients who have reached PT Week 12 b1 HCV RNA > LLOQ but discontinuation before week 12.

Welzel T et al. EASL 2015 Abstr P772

EU multicentre Compassionate Use Program

Total n = 482 72% GT-1; CP-A: 57%, CP-B: 36%, CP-C: 6%

Safety: DC due to AE: 28 (6%)

DCV + SOF ± RBV, 24 weeks

Interim resultsa - DCV + SOF ± RBV in GT1 patients with decompensated cirrhosis in early access programme

52

55 95

100 147 155

21b

22 27 27

48b 49

Drug-Drug interactions (Liver transplantation & HIV drugs excluded) Co-administration is NOT recommended

Sofosbuvir (Caution: amiodarone)

P-glycoprotein inducers (carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifampicin, St. John's wort), modafinil

Simeprevir (Caution: digoxin, amiodarone, disopyramide, flecainide, mexiletine, propafenone, quinidine, warfarin, calcium channel blockers)

Inhibitors or inducers of CYP3A4 (erythromycin, clarithromycin, antifungals, dexamethasone, cicapride, milk thistle, astemizole, terfenadine)

P-glycoprotein inducers

Daclatasvir (Caution: erythromycin, dabigatran, digoxin, calcium channel blockers, rosuvastatin)

Strong inducers of CYP3A4/P-glycoprotein

(Moderate inducers of CYP3A4: DCV 90 mg/24h)

(Inhibitors of CYP3A4: DCV 30 mg/24h)

Ledipasvir/Sofosbuvir (Caution: amiodarone, antacids, PPIs, digoxin, dabigatran, pravastatin, statins)

P-glycoprotein inducers, rosuvastatin, simeprevir, modafinil

Paritaprevir/r/Ombitasvir ± Dasabuvir (Caution: digoxin, warfarin, calcium channel blockers)

P-glycoprotein inducers, gemfibrozil, lovastatin, simvastatin, oral midazolam, triazolam, pimozide, ethinyl estradiol-containing oral contraceptives, sildenafil for pulmonary hypertension

Sofosbuvir

Simeprevir

Daclatasvir

Sofosbuvir/Ledipasvir

Paritaprevir/r/Ombitasvir ± Dasabuvir

HCV & HIV coinfection IFNa-free regimens similar efficacy to HCV monoinfected patients

Drug-Drug interactions with HIV drugs

None

Not with cobicistat*, efavirenz, delavirdine, etravirine, nevirapine, ritonavir & any HIV

protease inhibitor

Not with darunavir, lopinavir, etravirine ή nevirapine - DCV 30 mg with atazanavir/r,

DCV 90 mg with efavirenz.

Not with cobicistat*, tripanavir/r

Not with efavirenz, rilpivirine ή lopinavir

*cobicistat: elvitegravir + cobicistat + emtricitabine + tenofovir

New DAAs - Conclusions

Increasing number of licensed agents for patients with HCV

-Availability and accessibility vary among countries

Shortening of treatment duration to 8 weeks is possible in some non-cirrhotic

patients, with no loss of efficacy

Treatment options available irrespective of cirrhosis status

The proportion of patients failing to respond to DAAs is small and re-

treatment options are available for most patients

-NS5A inhibitor failures remain a treatment challenge

The availability of DAAs means that HCV cure is now a reality for most

patients

GAPS AND BARRIERS OF PREVENTION, CARE AND TREATMENT

Pre

vale

nt

case

s

HBV- or HCV- Infected

Incident cases

MTCT

IDU

SEX HCVH MTCT: Mother to child transmission IHE: Incidental household exposure IDU: Injecting drug use HCVH: Health care associated hepatitis SEX: Sexual contact

Nu

mb

er

of

ind

ivid

ual

s IHE

Screening

Secondary prevention

Care and treatment

Primary prevention

Stage of HBV or HCV Prevention, Care and Treatment Hatzakis A et al, 2012

Pre

vale

nt

case

s

HBV- or HCV- Infected

Incident cases

MTCT

IDU

SEX HCVH N

um

be

r o

f in

div

idu

als

IHE

Screening


Care and treatment

Primary prevention

Stage of HBV or HCV Prevention, Care and Treatment

MTCT: Mother to child transmission IHE: Incidental household exposure IDU: Injecting drug use HCVH: Health care associated hepatitis SEX: Sexual contact

Hatzakis A et al, 2012

Pre

vale

nt

case

s

HBV- or HCV-

Infected

Incident cases

MTCT

IDU

SEX HCVH N

um

be

r o

f in

div

idu

als

IHE

Screening


Care and treatment

Primary prevention

Stage of HBV or HCV Prevention, Care and Treatment

MTCT: Mother to child transmission IHE: Incidental household exposure IDU: Injecting drug use HCVH: Health care associated hepatitis SEX: Sexual contact


Estimated proportions of HCV patients who remain undiagnosed

Poland: 98%

Germany: 90%

Northern Spain: 84%

Greece: >70%

United Kingdom: 69%

US: >50%

France: 44%

Gordon FD. Am J Med 1999;107:36S-40S. 2.

Culver DH et al. Transfusion 2000;40:1176-1181. 3.Eurasian Harm Reduction Network. October 2007.

Rates of no treatment among diagnosed anti-HCV+ patients in European countries: A systematic review

Untreated among

diagnosed anti-HCV+ patients,

%

N=177 N=1251 N=299 N=608 N=4626 N=1146

Papatheodoridis et al. Liver Intern 2014;34:1452-63

14% 10%

76%

Untreated chronic HCV PDUs Untreated chronic HCV patients

N= 4760 N= 320

29%

20%

51%

N= 561

Untreated HCV/HIV patients

Treatment contraindication Patient refusal Unknown/Other

12%

21%

67%

Reasons of no treatment among diagnosed anti-HCV+patients in European countries

Systematic review

Papatheodoridis et al. Liver Intern 2014;34:1452-63

Gaps and barriers in the prevention, care and treatment (1)

Patient-related barriers

Awareness how hepatitis transmitted, diagnosed, prevented and treated especially in high risk groups.

Language especially for migrants.

Cultural values and beliefs.

Social stigma.

Comorbidities (e.g. psychiatric)



Health care provider-related barriers Awareness of hepatitis risk groups and low hepatitis prevented and

treated.

Specialty us primary care provider.

Consensus and recommendations for screening and treatment.



Health care system barriers

Insurance and access to health care.

Referral system.

Awareness of how health care system works.

Health care facilities

Guidance and recommendations.


Gross domestic product (GDP) and overall resources for health

Membership of the EU. Countries in the EU are bound to a reference pricing system for

medicines, which imposes high drug prices on recent EU entrants relative to GDP.

Speed of reimbursement approval for new medicines

National treatment guidelines

Expanded access arrangements organized by pharmaceutical companies

Prices negotiated with pharmaceutical companies relative to volumes

Differential pricing policies of pharmaceutical companies

A Hatzakis et al. JVH 2013

Factors influencing treatment access at national level

Current management of hepatitis

C – Realistic approach

Whom to treat - Treatment priorities

Optimal – Most cost-effective (new) regimens

Treatment cost! The real challenge in 2015

Highest priority for treatment owing to highest risk for severe complications

F3-F4

Organ transplant recipients

Severe extrahepatic manifestations (type 2/3 essential mixed cryoglobulinemia with end-organ manifestations, proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis) High priority for treatment owing to high risk for complications

F2

HIV-1, HBV coinfection

NASH, Debilitating fatigue, Type 2 Diabetes (insulin resist.), Porphyria cutanea tarda

High HCV transmission risk

MSM with high-risk sexual practices

Active injection drug users

Incarcerated persons

Persons on long-term hemodialysis

AASLD/IDSA 2014

HCV treatment indications in the DAAs ERA – Priorities

Cohen C et al. JVH, 2011;18:377

Kramer JR et al. J Hepatol, 2012;56:320

Treatment efficacy vs. treatment effectiveness in the US

Disease Efficacy Effectiveness

Chronic HCV 40-80% 3.5%

Chronic HBV 60-90% 4-5%

HIV/AIDS ~ 80% 19%

Kramer JR et al. J Hepatol, 2012;56:520 Cohen C et al. JVH, 2011; 18:377

Gardner EM et al. Clin Inf Dis, 2011; 52: 793

CARE AND TREATMENT OF CHRONIC HBV AND HCV€¦ · PROFESSOR OF MEDICINE, TORONTO WESTERN AND...

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