CARE AND TREATMENT

OF CHRONIC HBV AND HCV - D e c e m b e r 20 1 6 -

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

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

Adefovir Boceprevir / Telaprevir

Peginterferon alfa-2b Sofosbuvir

Peginterferon alfa-2a Simeprevir

Entecavir Daclatasvir

Telbivudine Ledipasvir/Sofosbuvir

Tenofovir Paritaprevir/ritonavir/Ombitasvir ± Dasabuvir

Velpatasvir/Sofosbuvir

Elbasvir/Grazoprevir

Hatzakis A et al. JVH 2011; 18, S1

Indications for treatment

• Patients should be considered for treatment if

– HBV DNA >2,000 IU/ml and

– ALT >ULN and

– At least moderate necroinflammation and/or at least moderate

fibrosis by liver biopsy (or non-invasive markers once validated in

HBV-infected patients) (A1)

• If the criteria for HBV DNA and histological severity are fulfilled,

treatment may be initiated even if ALT levels are normal (A1)

• Indications for treatment may also take into account

age, health status, comorbidities, family history of HCC or cirrhosis and

extrahepatic manifestations

EASL HBV CPGs. J Hepatol 2012

Treatment indications in HBeAg-pos. CHB patients

EASL 2012

ALT >ULN & HBV DNA >2,000 & Biopsy ≥A2/F2

A. Immunotolerant phase: Persistently ALT ≤ULN

• No Biopsy – No therapy – Follow-up if age ≤30

• Biopsy if age >30 or family history of HCC, cirrhosis

B. Obviously active CHB: ALT >2xULN & HBV DNA >20,000 IU/ml

• Therapy – Biopsy optional

EASL HBV CPGs. J Hepatol 2012

ALT >ULN & HBV DNA >2,000 & Biopsy ≥A2/F2

A. HBeAg-ve patients with persistently ALT ≤ULN

(ALT every 3 months for at least 12 months) &

HBV DNA 2,000-20,000 IU/ml & no evidence of liver disease

• No Biopsy – No therapy – Follow-up (close for 3 years)

B. Obviously active CHB: ALT >2xULN & HBV DNA >20,000 IU/ml

• Therapy – Biopsy optional

Treatment indications in HBeAg-neg. CHB patients EASL 2012

EASL HBV CPGs. J Hepatol 2012

HBeAg-negative patient with normal ALT at baseline

ALT every 3–4 months for one year +serum HBV DNA determination

ALT >ULN and/or HBV DNA >20,000

(Liver biopsy) Therapy

Persistently ALT<ULN and HBV DNA <2,000 IU/mL

ALT every 6 months (& HBV DNA?)

Persistently ALT <ULN and HBV DNA 2,000-20,000

ALT every 3–4 months and HBV DNA every year for two more years (FibroScan?) ALT <ULN and HBV DNA 2,000–20,000 IU/mL

ALT every 6 months and HBV DNA every year

ALT >ULN and/or

HBV DNA >20,000

Liver biopsy Papatheodoridis GV et al. J Hepatol 2012;57:196–202

No need for liver biopsy

• Patients with compensated cirrhosis

must be considered for treatment

if detectable HBV DNA, even with normal ALT (B1)

• Patients with decompensated cirrhosis

urgent antiviral treatment with NA(s)

if detectable HBV DNA (A1)

EASL HBV CPGs. J Hepatol 2012

• Sustained HBsAg loss (± seroconversion to anti-HBs).

Ideal - Associated with a complete and definitive remission of the

activity of CHB and an improved long-term outcome (A1).

• Sustained off-treatment virological response (HBV DNA <2,000 IU/mL)

for both HBeAg+ve/-ve patients combined with durable anti-HBe

seroconversion in HBeAg+ve patients.

Associated with improved prognosis (A1).

• Maintained undetectable HBV DNA by a sensitive PCR assay on

treatment with NAs in HBeAg+ve patients who do not achieve anti-HBe

seroconversion and in HBeAg-ve patients.

Next most desirable end-point (A1).

End-points of therapy

EASL HBV CPGs. J Hepatol 2012

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 Reversible Liver 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

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

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

An

nu

al H

CC

In

cid

en

ce

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

Papatheodoridis GV et al. J Hepatol 2015;62:956-67

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

Papatheodoridis GV et al. J Hepatol 2015;62:956-67

PAGE-B represents a simple to use HCC risk score for the first 5 years of ETV/TDF in Caucasian CHB patients

Construction of the PAGE-B risk score for HCC

Age (years) Gender Platelets

(/mm3)

16–29: 0 Female:

0 ≥200,000: 0

30–39: 2 Male: 6 100,000–

199,999: 6

40–49: 4 <100,000: 9

50–59: 6

60–69: 8

≥70: 10

Papatheodoridis GV et al. J Hepatol 2016;64:800-6

Patients with

durable HBeAg

serocon- version,

%

At 6 12 24 months after NA(s) discontinuation

GV Papatheodoridis et al. Hepatology 2016; 63:1481-92.

Rates of durable HBeAg seroconversion after NAs discontinuation Systematic review: 6 studies, 289 initially HBeAg+ patients

Patients with

HBV DNA <20,000 IU/mL,

%

At 6 12 24 36 months after NA(s) discontinuation

Rates of virological remission after NAs discontinuation 14 studies, 733 initially HBeAg+ patients

Pooled HBsAg loss: 1%; Durable biochemical remission: 76%

GV Papatheodoridis et al. Hepatology 2016; 63:1481-92.

Patients with

HBV DNA <20,000 IU/mL,

%

At 6 12 24 36 months after NA(s) discontinuation

Rates of virological remission after NAs discontinuation 17 studies, 967 HBeAg- patients

Pooled HBsAg loss: 1.7%; Durable biochemical remission: 57%

GV Papatheodoridis et al. Hepatology 2016; 63:1481-92.

Patients with VR

at 12 mos after NAs

discontin., %

Rates of virological remission at 12 mos after NAs discontinuation in HBeAg-neg. CHB patients in relation to several factors

VR: virological remission

HBV DNA (IU/mL) <200 <2,000 <20,000 <12 12-24 >24 mos

VR definition Duration of on-NAs VR

P=0.513 P=0.017

GV Papatheodoridis et al. Hepatology 2016; 63:1481-92.

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

EPCLUSA® Velpatasvir

NS5A inhibitor +Sofosbuvir

NS5B polymerase Inhibitor Gilead

100+400 mg/24h

Genotypes 1-6

High genetic barrier

July 8, 2016

ZEPATIER®

Elbasvir NS5A inhibitor +Grazoprevir

NS3/4A protease inhibitor

MSD

50+100 mg /24h

Genotypes 1, 4

Genetic barrier dependent on genotype

July 28, 2016

Anti-HCV agents approved by ΕMA in 2016

Simeprevir

Ribavirin

IFNa-containing combinations – Main strategies Not recommended by most current guidelines

+

+

PegIFNa

Ribavirin

+

PegIFNa

+

Ribavirin

+

PegIFNa

+

Ribavirin

+

PegIFNa

Boceprevir

Telaprevir

Sofosbuvir Daclatasvir

Nucleotide inhibitor of NS5B polymerase

NS3/4 protease inhibitor

NS5A inhibitor

?

PegIFNa +Ribavirin is still used in

several countries for easy to treat

patients without access to

IFNa-free regimens

PegIFNa +Ribavirin +Sofosbuvir

bay be still used for genotype 2 or 3

patients in some countries

without access to all current DAAs

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

Velpatasvir

Sofosbuvir

Ribavirin

±

Elbasvir

Grazoprevir

Ribavirin

±

Sofosbuvir + Simeprevir (±Ribavirin)

Sofosbuvir + Daclatasvir (±Ribavirin)

IFNa-free regimens for genotype 1

Sofosbuvir/Ledipasvir (±Ribavirin)

Paritaprevir/r/Ombitasvir ±Dasabuvir (±Ribavirin)

Sofosbuvir/Velpatasvir

Grazoprevir/Elbasvir (±Ribavirin)

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)

SMV+SOF 12 weeks SMV+SOF 8 weeks

Kwo P et al. Hepatology 2016;64:370-80.

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)

CI, confidence interval; aTreatment-experienced patients included prior relapsers, prior non-responders, IFN-intolerant and other patients Lawitz E et al. Hepatology 2016;64:360-9

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

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: Discontinuations due to adverse events, n = 1

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

Poordad F et al. Hepatology 2016;63:1493-505.

8291

76

92100

50

0

20

40

60

80

100

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

All GT1a GT1b CP-A CP-B CP-C

SVR12, %

CP: Child-Pugh

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

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

No cirrhosis Cirrhosis

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

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.

No cirrhosis Cirrhosis

179 179

32 33

178 178

33 33

181 182

31 32

179 179

36 36

n N

SVR

12

(%

)

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

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

Afdhal N et al. New Engl J Med 2014;370:1483-93.

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

No cirrhosis Cirrhosis

83 87

19 22

89 89

18 22

86 87

22 22

88 89

22 22

n N

Error bars: 95% CI.

SVR

12

(%

)

Afdhal N et al. New Engl J Med 2014;370:1483-93.

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

R1

2 (

%)

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 =

Reddy KR et al. Hepatology 2015;62:79-86.

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

Paritaprevir/r/Ombitasvir + Dasabuvir ± RBV x12 wks

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

Paritaprevir/r/Ombitasvir + Dasabuvir ± RBV x12 wks

Welzel T et al. EASL Special Conference September 23–24 2016. Poster presentation #163.

GARNET: Efficacy of 8-Week Paritaprevir/r/Ombitasvir+Dasabuvir (PRV/OBV+DSV) in Treatment-Naïve Non-cirrhotic GT1b Patients

162 166

160 162

2 relapses, 1 discontinuation

160 163

ITT: all patients who received at least one dose of study drug; mITT-GT: ITT modified to exclude 3 patients without GT1b (1a, 1d, 6); mITT-GT-VF: mITT-GT modified to exclude non-virologic failures (1 patient discontinued prematurely due to noncompliance).

Fibrosis was the only significant predictor of SVR12 identified:

(F3 86.7% [13/15] vs F0–F2 99.3% [147/148])

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

• EOTR = end-of-treatment response. * Prior pegIFN/RBV failures.

Feld JJ et al. J Hepatol 2016; 64:301–7.

• Phase 3b, multicenter, single-arm, open-label study

TURQUOISE-III: Paritaprevir/r/Ombitasvir+Dasabuvir (PRV/OBV+DSV) for HCV GT1b-infected, Cirrhotic Patients

Study weeks

PRV/OBV+DSV

0 24 12

HCV GT1b, treatment-naive

or -experienced*, cirrhotic (N=60)

36

SVR12

60 60

100% of patients achieved

SVR12 with 12-week

treatment

Pat

ien

ts (

%)

60 60

60 60

60 60

Characteristic Median (range)

pegIFN/RBV experienced Non-responder Relapser/breakthrough Other

33 (55.0) 18 (30.0)

5 (8.3) 10 (16.7)

Albumin, g/dL 4.0 (2.8–4.5)

Platelet count, 109/L 132 (54–514)

Alpha fetoprotein, ng/mL 11.9 (2.7–247.0)

Total bilirubin, mg/dL 0.8 (0.3–2.5)

nN

ASTRAL-1: SOF/VEL STR for 12 Weeks in GT1 Patients

Feld JJ et al. N Engl J Med. 2015;373:2599-607.

323/328 206/210 117/118

SVR12, %

SV

R1

2 (

%)

299/316 144/157 129/131 n/N =

Overall GT1a GT1b

95 92 99 100

75

50

25

0

SV

R1

2 (

%)

356/370 89/94 92/92 n/N =

Overall 12 weeks 16 weeks + RBV

96 95 100 100

75

50

25

0

Naive

Treatment experienced

Elbasvir/Grazoprevir for GT1 patients

Zeuzem Z et al. Ann Intern Med 2015;163:1-13. Kwo P et al. Gastroenterology 2016.

Naive or PegIFNa±RBV experienced, non cirrhotics with GT1a

AASLD (09/2016)

EASL (09/2016)

PegIFNa+RBV (PR) NO NO

PR+SMV – PR NO 24/48 (12-12/36)wks in naive-RR/PR-NR (No in Q80K+)

PR+SOF NO 12wks

SOF +SMV 12wks NO

SOF +DCV 12wks

12wks in naive, 12wks+RBV or 24wks in experienced

SOF/LDV 12wks 8 or 12wks in naive, 12wks+RBV ή 24wks in experienced

PRV/r/OBV +DSV 12wks +RBV

12wks +RBV

SOF/VEL 12wks 12wks

EBR/GZR 12wks σε RASs*-,

16wks +RBV in RASs*+

12wks in HCVRNA ≤800,000 IU/ml (or RASs*-), 16wks +RBV in HCVRNA >800,000 IU/ml (&

RASs*+)

*NS5A RASs (resistance associated variants) at position/s 28,30,31 and/or 93

AASLD (09/2016)

EASL (09/2016)

PegIFNa+RBV (PR) NO NO

PR+SMV – PR NO 48 (12-36)wks (No in Q80K+)

PR+SOF NO 12wks

SOF +SMV 24wks ±RBV (No in Q80K+)

NO

SOF +DCV 24wks ±RBV 12wks in naive, 12wks+RBV or 24wks in experienced

SOF/LDV 12wks in naive, 12wks +RBV or24wks

in experienced

12wks in naive, 12wks+RBV or 24wks in experienced

PRV/r/OBV +DSV 24wks +RBV

24wks +RBV

SOF/VEL 12wks 12wks

EBR/GZR 12wks in RASs*-,

16wks +RBV in RASs*+ 12wks in HCVRNA ≤800,000 IU/ml (or RASs*-),

16wks +RBV in HCVRNA >800,000 IU/ml (& RASs*+)

Naive or PegIFNa±RBV experienced, cirrhotics with GT1a

*NS5A RASs (resistance associated variants) at position/s 28,30,31 and/or 93

AASLD (09/2016)

EASL (09/2016)

PegIFNa+RBV (PR) NO NO

PR+SMV – PR NO 24/48 (12-12/36)wks in naive-RR/PR-NR

PR+SOF NO 12wks

SOF +SMV 12wks NO

SOF +DCV 12wks

12wks

SOF/LDV 12wks 12wks (perhaps 8wks in naive)

PRV/r/OBV +DSV 12wks 12wks (perhaps 8wks in naive)

SOF/VEL 12wks 12wks

EBR/GZR 12wks 12wks

Naive or PegIFNa±RBV experienced, non cirrhotics with GT1b

AASLD (09/2016)

EASL (09/2016)

PegIFNa+RBV (PR) NO NO

PR+SMV – PR NO 48 (12-36)wks

PR+SOF NO 12wks

SOF +SMV 24wks ±RBV NO

SOF +DCV

24wks ±RBV 12wks

SOF/LDV 12wks in naive, 12wks +RBV or24wks in experienced

12wks

PRV/r/OBV +DSV 12wks 12wks

SOF/VEL 12wks 12wks

EBR/GZR 12wks 12wks

Naive or PegIFNa±RBV experienced, cirrhotics with GT1b

Sofosbuvir + RBV

IFNa free regimens for genotype 2

Sofosbuvir + Daclatasvir

Sofosbuvir /Velpatasvir

SOF + RBV in GT2 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

ASTRAL-2: SOF/VEL STR for 12 Weeks in GT2 Patients

133/134 124/132

SOF/VEL SOF + RBV P=0.018*

Foster GR et al. N Engl J Med 2015;373:2608-17.

104/104

Feld JJ et al. N Engl J Med. 2015;373:2599-607.

AASLD (09/2016)

EASL (09/2016)

PegIFNa+RBV (PR) NO OXI

PR+SOF NO 12wks

SOF +RBV NO OXI

SOF +DCV

12wks, 16-24wks in cirrhosis

12wks

SOF/VEL 12wks

12wks

Naive or PegIFNa±RBV experienced, (non-)cirrhotics with GT2

IFNa free regimens for genotype 3

Sofosbuvir + RBV

Sofosbuvir + Daclatasvir (±Ribavirin)

Sofosbuvir /Velpatasvir (±Ribavirin)

HCV GT3 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

RASs 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

No cirrhosis Cirrhosis

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. Hepatology 2015;61:1127-35.

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

• No virological breakthrough or discontinuation due to adverse events

Leroy V et al. AASLD 2015, Abstract LB-3.

All Pts Advanced Fibrosis

(F3)

Cirrhosis + Treatment

Experienced

SVR

12

(%

)

12-wk DCV + SOF + RBV 16-wk DCV + SOF + RBV

Cirrhosis

88 92 100 100 83 89 88 86

21/ 24

24/ 26

6/ 6

8/ 8

15/ 18

16/ 18

14/ 16

12/ 14

80

100

60

40

20

0

n/N =

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

SVR

12

(%

)

264/277 221/275

P<0.001*

12 Weeks 24 Weeks

ASTRAL-3: Open-Label Trial - SVR12, Safety With Sofosbuvir/Velpatasvir in GT3 HCV

Foster GR et al. N Engl J Med 2015;373:2608-17.

100

ASTRAL-3: Open-Label Trial - SVR12, Safety With Sofosbuvir/Velpatasvir in GT3 HCV

Foster GR et al. N Engl J Med 2015;373:2608-17.

n/N =

SVR

12

(%

)

80

60

40

20

0

264/277

221/275

191/197

163/187

73/ 80

55/ 83

200/ 206

176/ 204

64/ 71

45/ 71

95

80

63

90 97 97 87

91

66

86

All Pts No Yes Naive Experienced

Cirrhosis

P < .001 (superiority)

SOF/VEL 12 wks

SOF + RBV 24 wks

Treatment History

AASLD (09/2016)

EASL (09/2016)

PegIFNa+RBV (PR) NO NO

PR+SOF NO 12wks

SOF +RBV NO NO

SOF +DCV

12wks 12wks in naive, 12wks +RBV in RAS*+ or 24wks in

experienced

SOF/VEL 12wks 12wks in naive, 12wks +RBV in RAS*+ or 24wks in

experienced

*NS5A RAS Y93H

Naive or PegIFNa±RBV experienced, non-cirrhotics with GT3

AASLD (09/2016)

EASL (09/2016)

KEEΛΠΝΟ (04/2016)

PegIFNa+RBV (PR)

OΧΙ OΧΙ OΧΙ

PR+SOF OΧΙ 12wks 12wks

SOF +RBV OΧΙ OΧΙ 24wks σε naive, OΧΙ σε αποτυχ.

SOF +DCV

24wks (+RBV σε RAS*+) naive, 24wks +RBV σε αποτυχ.

24wks +RBV 12-24wks +RBV

SOF/LDV OΧΙ OΧΙ 12wks +RBV (περιορισμένα δεδομένα)

SOF/VEL 12wks (+RBV σε RAS*+) naive, 24wks +RBV σε αποτυχ.

12wks (+RBV σε RAS*+) ή 24wks

-

*NS5A RAS Y93H

Naive or PegIFNa±RBV experienced, non-cirrhotics with GT3

Sofosbuvir + Simeprevir (±Ribavirin)

Sofosbuvir + Daclatasvir (±Ribavirin)

IFNa-free regimens for genotype 4

Sofosbuvir/Ledipasvir (±Ribavirin)

Paritaprevir/r/Ombitasvir ±Dasabuvir (±Ribavirin)

Sofosbuvir/Velpatasvir

Grazoprevir/Elbasvir (±Ribavirin)

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 GT4

SVR

(%

)

Hezode C et al. Lancet 2015; 385:2502-9.

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

SVR4

SVR12

P=0.086

Error bars indicate 95% confidence intervals.

Arm A: 12 weeks (N = 59)

Arm B: 16 weeks (N = 61)

Non-responses, n (%) 2 (3) 1 (2)

Virologic failure 1 (2) 0

Relapse 0 0

Premature study drug D/C 1 (2) 0

Missing SVR12 data 0 1 (2)

1 2 w e e k 1 6 w e e k

0

2 5

5 0

7 5

1 0 0V

iro

log

ic R

es

po

ns

e,

% P

ati

en

ts

5 9

5 7

5 8

5 7

6 0

6 0

9 8 1 0 09 7 9 8

O B V / P T V / r + R B V T r e a t m e n t D u r a t io n

6 1

6 0

S V R 1 2 (s e n s it iv ity a n a ly s is )

SVR12 Rates by Treatment Arm (Sensitivity Analysis)

The sensitivity analysis excluded patients who prematurely discontinued study drug (with no on-treatment virologic failure) or who were missing follow-up data in the SVR12 window

AGATE-I: Paritaprevir/r/Ombitasvir + RBV x12 wks in cirrhotic naive/experienced patients with GT4

Asselah T et al. DDW 2016

SV

R1

2 (

%)

18/18 n/N =

GT 4

100% 100

75

50

25

0

SV

R1

2 (

%)

32/37 7/9 8/8 n/N =

Overall 12 weeks 16 weeks + RBV

87 79 100 100

75

50

25

0

Elbasvir/Grazoprevir for GT4 patients

Zeuzem Z et al. Ann Intern Med 2015;163:1-13. Kwo P et al. Gastroenterology 2016.

Naive

Treatment experienced

ASTRAL-1: SOF/VEL STR for 12 Weeks in GT4, GT5, GT6 Patients

Feld JJ et al. N Engl J Med. 2015;373:2599-607.

116/116 34/35 41/41

SVR12, %

AASLD (09/2016)

EASL (09/2016)

PegIFNa+RBV (PR) NO NO

PR+SMV – PR NO 24 (12-12)wks in naive/RR, 48 (12-36)wks in PR/NR

PR+SOF NO 12wks

SOF+RBV NO NO

SOF +SMV NO 12wks in naive, 12wks +RBV or 24wks in experienced

SOF +DCV NO 12wks in naive, 12wks +RBV or 24wks in experienced

SOF/LDV 12wks 12wks in naive, 12wks +RBV or 24wks in experienced

PRV/r/OBV 12wks +RBV 12wks +RBV

SOF/VEL 12wks 12wks

EBR/GZR 12wks σε naive/RR, 16wks +RBV σε PR/NR

12wks in naïve or in experienced with HCVRNA ≤800,000 IU/ml,

16wks +RBV in experienced with HCVRNA >800,000 IU/ml

Naive or PegIFNa±RBV experienced, non-cirrhotics with GT4

AASLD (09/2016)

EASL (09/2016)

PegIFNa+RBV (PR) NO NO

PR+SMV – PR NO 48 (12-36)wks

PR+SOF NO 12wks

SOF+RBV NO NO

SOF +SMV NO 12wks in naive, 12wks +RBV or 24wks in experienced

SOF +DCV

NO 12wks in naive, 12wks +RBV or 24wks in experienced

SOF/LDV 12wks in naive, 12wks +RBV or 24wks in experienced

12wks in naive, 12wks +RBV or 24wks in experienced

PRV/r/OBV 12wks +RBV 12wks +RBV

SOF/VEL 12wks 12wks

EBR/GZR 12wks in naive/RR, 16wks +RBV σε PR/NR

12wks in naïve or in experienced with HCVRNA ≤800,000 IU/ml,

16wks +RBV in experienced with HCVRNA >800,000 IU/ml

Naive or PegIFNa±RBV experienced, cirrhotics with GT4

AASLD (09/2016)

EASL (09/2016)

PegIFNa+RBV (PR) NO NO

PR+SOF NO 12wks

SOF +RBV NO NO

SOF +DCV NO 12wks in naive, 12wks +RBV or 24wks in experienced

SOF/LDV 12wks 12wks in naive, 12wks +RBV or 24wks in experienced

SOF/VEL 12wks 12wks

Naive or PegIFNa±RBV experienced, (non-)cirrhotics with GT5/6

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

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)

Charlton M et al. Gastroenterology 2015;149:649-59.

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

M Manns et al. Lancet Infect Dis 2016;16:685-97.

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

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

M Manns et al. Lancet Infect Dis 2016;16:685-97.

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

ASTRAL-4: SOF/VEL ± RBV in HCV Patients with Decompensated Liver Disease

75/90 82/87 77/90 60/68 65/68 65/71 7/14 11/13 6/12 GT2 4/4 GT4 4/4

GT2 4/4 GT4 2/2

GT2 3/4 GT4 2/2 GT6 1/1

Curry MP et al. N Engl J Med 2015;373:2618-28.

Decompensated cirrhosis

AASLD (09/2016)

EASL (09/2016)

Treatment indication Expert’s assessment Indication for liver transplantation (LT): MELD <18-20 or ΜΕLD ≥18-20 & waiting time for LT >6 months Indication for LT: Child-Pugh score ≤12

Protease inihibitors (SMV, PRV, GZR)

NO NO

AASLD (09/2016)

EASL (09/2016)

SOF +RBV NO NO

SOF +DCV GT1/4: 12wks +RBV*

or 24wks (contraindication for RBV)

GT2/3: 12wks +RBV*

GT1/2/4/5/6: 12wks +RBV*

or 24wks (contraindication for RBV)

GT3: 24wks +RBV*

SOF/LDV GT1/4: 12wks +RBV*

or 24wks (contraindication for RBV)

or 24wks +RBV (SOF failures)

GT1/4/5/6: 12wks +RBV*

or 24wks (contraindication for RBV)

SOF/VEL

GT1/4: 12wks +RBV

or 24wks (contraindication for RBV)

or 24wks +RBV (SOF failures)

GT2/3: 12wks +RBV

GT1/2/4/5/6: 12wks +RBV*

or 24wks (contraindication for RBV)

GT3: 24wks +RBV*

*RBV: 600 mg/24h as initial dose – gradual dosage increase to 1000/1200 mg/24h

Decompensated cirrhosis

Sofosbuvir

Simeprevir

Daclatasvir

Sofosbuvir/Ledipasvir

Paritaprevir/r/Ombitasvir ± Dasabuvir

Drug-Drug interactions

None

Not with CsA

None

None

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

CsA: 20% of previous dose

Not with everolimus

None

Not with CsA (increases GZR plasma levels: ALT flares?)

- Close monitoring TACR levels

Sofosbuvir/Velpatasvir

Grazoprevir/Elbasvir

HCV transplant patients

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

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

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 , amiodarone

(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 , amiodarone

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, amiodarone

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

Velpatasvir/Sofosbuvir (Caution: antacids, H2RAs, PPIs)

P-glycoprotein inducers (carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifampicin, St.

John’s wart), amiodarone

Elbasvir/Grazoprevir (Caution: amiodarone, cyclosporine)

OATP1B1/3 inhibitors, Potent CYP3A4 inducers (carbamazepine, phenytoin, rifampicin, St. John’s wart)

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

Not with efavirenz (closer follow-up for TDF AEs)

Not with efavirenz (closer ALT fup with atazanavir, darunavir, lopinavir, saquinavir, tripanavir)

*cobicistat: elvitegravir + cobicistat + emtricitabine + tenofovir

Sofosbuvir

Simeprevir

Daclatasvir

Sofosbuvir/Ledipasvir

Paritaprevir/r/Ombitasvir ± Dasabuvir

Sofosbuvir/Velpatasvir

Grazoprevir/Elbasvir

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

Sofosbuvir

Simeprevir

Daclatasvir

Sofosbuvir/Ledipasvir

Paritaprevir/r/Ombitasvir, Dasabuvir

HCV in patients with renal impairment Drug doses in reduced Creatinine

Clearance (CrCl)

Peg-IFNa-2a 135 μg/wk – ClCr <50 ml/min Peg-IFNa-2b 25%/50% - ClCr 30-50/15-29

200/400 mg /24/24h - ClCr 30-50 ml/min 200 mg /24h - ClCr <30 ml/min

No change for CrCl ≥30 ml/min Contraindicated for CrCl <30 ml/min

No change

No change

No change for CrCl ≥30 ml/min Contraindicated for CrCl <30 ml/min

No change

No change for CrCl ≥30 ml/min Contraindicated for CrCl <30 ml/min

No change

Peg-IFNa

Ribavirin

Sofosbuvir/Velpatasvir

Grazoprevir/Elbasvir

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