Current HCV Treatment by Genotype

Empire Liver Foundation

Ira M. Jacobson, MD Chairman, Department of Medicine

Mount Sinai Beth Israel

Professor of Medicine

Co-Director, Liver Institute

Icahn School of Medicine at Mount Sinai

New York, New York

Objectives

• To understand the prevalence of HCV and

distribution of HCV genotypes

• Describe the HCV lifecycle and how specific drugs

target the HCV polypeptide sequence

• Explain circumstances where it is important to test for

possible drug resistance

• Understand the landscape in regards to advances

made in the evolution of treating HCV over the past

20+ years

• Understand the HCV genotypes and the drug

regimens that work to eradicate HCV on each

genotype

• Approximately 3.5 million people in the United States are chronically

infected with HCV (1.3%)

– Including populations excluded from NHANES (e.g., the incarcerated,

homeless, institutionalized, and those living on Native American

reservations) brings the total estimate to 4.6 million2

• Seroprevalence is higher in

– 1945-1965 birth cohort (3.5%)

– Non-Hispanic blacks (2.2%)

– Males (1.9%) vs females (1.1%)

• Many diagnosed patients remain

untreated3

• Birth cohort screeing introduced

HCV: A Major Public Health Problem

NHANES=National Health and Nutrition Examination Survey. aNHANES data as of 2010; bNHANES data, 2001-2008.

1. Ditah I, et al. J Hepatol. 2014;60:691-698

2. Edlin BR, et al. Hepatology. 2015;62:1353-1363

3. Yehia BR, et al. PLoS ONE. 2014;9:1-7.

50% Undiagnosed

50% Diagnosed

Distribution of Hepatitis C Genotypes

Epidemiology of Infectious Diseases. Available at: http://ocw.jhsph.edu. Copyright © John Hopkins Bloomberg School of Public Health. Creative Commons BY-NC-SA.

The HCV Life Cycle

HCV Polypeptide Sequence

T. Asselah.

The HCV Polymerase (NS5B)

The active site of the HCV polymerase is highly conserved…

Explains why sofosbuvir is the backbone of several regimens

What’s Special About the Active Site of the HCV Polymerase?

Feature Therapeutic Implication

Highly conserved across genotypes Pangenotypic efficacy of

potent inhibitors

Low replicative fitness conferred by

amino acid substitutions High resistance barrier

Resistance Considerations

• Most pts with failure of current DAAs have emergent resistance-

associated variants (RAVs), especially to the NS5A class

– NS5A RAVs persist much longer than PI RAVs

• 15% of pts have baseline NS5A RAVs with variable effects on

GT1a response

• Second-generation drugs are designed to cover RAVs

Which classes are

prone to resistance?

Protease, NS5A,

and nonnucleotide

NS5B inhibitors

Barrier to PI and

NS5A resistance

Higher for GT1b

vs GT1a

Where HCV Therapy Stands Now

• Interferon is gone in the U.S.; ribavirin…not quite

• SVR in over 95% of patients

• “Difficult to treat” populations no longer difficult

– African-Americans

– HIV coinfected

– Cirrhosis

– Older age

– Renal failure and transplant

– Liver transplant

– Persons who use IV drugs (PWID)

• Confidence that SVR12 = cure

• Cost and access issues persist, but improving

Rising Cure Rates for Chronic HCV (GT1)

16%

35%

44%

70-80%

80-90% >95%

0%

20%

40%

60%

80%

100%

1991 1998 2001 2011 2013 2014+

IFN

IFN/RBV

PegIFN/RBV

Telaprevir or Boceprevir + PegIFN/RBV

PR/SMV PR/SOF

IFN-Free DAA Combination

Regimens

Cu

re R

ate

*

Year

The Evolution of HCV Therapy

Curability of HCV

without IFN

Frequent curability of diverse

populations without IFN

Simeprevir, sofosbuvir with IFN (GT1)

2015 2011 2012 2013 2014

Telaprevir and

boceprevir

Daclatasvir: DCV+ASV

(Japan) DCV+SOF (Europe)

Ledipasvir +

sofosbuvir (GT1)

Paritaprevir/r-

ombitasvir/ dasabuvir

± RBV (GT1)

Simeprevir +

sofosbuvir (GT1)

First approved IFN-free therapy: sofosbuvir + RBV (GT2,3)

DCV + SOF (GT3)

(GT1 2016)

Interferon Era 2016

Grazoprevir+

Elbasvir

(GT1,4

1991-

Sofosbuvir +

velpatasvir

(all genotypes)

DAA: direct-acting antiviral; GT: genotype;

IFN: interferon; PI: protease inhibitor; NI: nucleoside/nucleotide inhibitor; RBV: ribavirin; r: ritonavir.

Structural domain Nonstructural domain

Approved Direct-Acting Antiviral Agents from Multiple Classes: Combination Regimens for HCV in 2016

3’UTR 5’UTR Core E1 E2 NS2 NS4B NS3 NS5A NS5B P

7

Ribavirin

Polymerase

Daclatasvir (DCV)

Ledipasvir (LDV)

Ombitasvir (OMV)

Elbasvir (EBV)

Velpatasvir

Sofosbuvir

(SOF)

Dasabuvir

(DSV)

NS5B

NUC

Inhibitors

NS5A

Replication

Complex

Inhibitors

NS5B

Non-NUC

Inhibitors (NNI)

Simeprevir (SMV)

Paritaprevir/ritonavir

(PTV/r)

Grazoprevir (GZR)

NS3

Protease

Inhibitors

Protease

4A

(RBV)

“previr” = protease inhibitor; “asvir” = NS5A inhibitor; “uvir ”= polymerase inhibitor Courtesy of Albert Min MD.

SVR and All-Cause Mortality in CHC

Patients with Advanced Fibrosis

530 patients with all genotypes followed for a median of 8.4 years

Baseline factors

significantly associated

with all-cause mortality:

– Older age

– Genotype 3 (2-fold

increase in mortality

and HCC)

– Higher Ishak

fibrosis score

– Diabetes

– Severe alcohol use

SVR patients Non-SVR patients

10

-Year

Cu

mu

lati

ve

Occu

rren

ce R

ate

(%

)

8.9

26.0

1.9

27.4

5.1

21.8

2.1

29.9

25

20

15

10

5

0

30

All-Cause Mortality

Liver-Related Mortality or

Liver Transplant

HCC Liver Failure

Van der Meer A, et al. JAMA. 2012; 308:2584‒2593.

Cirrhosis Regression and Fibrosis Reduction Following SVR (any genotype)

Fibrosis Reduction

• After treatment, the area of fibrosis decreased in 34/38 (89%) of patients

• Post-treatment liver biopsies showed a significantly reduced area of fibrosis, with a

median individual decrease of 71.8%

Sample Liver Biopsy

Pre-treatment (F4) Post-treatment (F3)

7

14 38

15

0%

20%

40%

60%

80%

100%

Pre-treatment Post-treatment

F1 F2 F3 F4

2

Cirrhosis Regression in 61% of Patients

Prospective study of patients with pre-treatment cirrhosis and an SVR with IFN-based therapy (enrolled in 2009-2010) to assess the

impact of SVR on the full spectrum of histopathologic features of HCV-related cirrhosis. N=38, median f/u 67 months (range, 54-110 months).

Adapted from D’Ambrosio R, et al. Hepatology. 2012;56:532-543.

Evolution of Portal Pressure After DAA Therapy

∆HVPG Absolute ∆: -2.63 ± 0.38 mmHg; p<0.001

Relative ∆: -23 ± 2.9%

0

6

10 12

16

20

30

HV

PG

(m

mH

g)

BL BL FU FU 13.1 ± 0.7 mmHg 10.4 ± 0.79 mmHg

Earlier portal hypertension is more

reversible than advanced PHT

Subclinical portal hypertension at BL

Resolved 63% No progression

HVPG 10–15 mmHg at BL Resolved 14% Regression 29% No progression

Pronounced portal hypertension at BL

No resolution Regression 5% Increase 20%

Mandorfer M, et al. EASL. 2016. Barcelona. #PS005.

Extra-hepatic Manifestations of

HCV Infection

Cacoub P, et al. Dig Liver Dis 2014; 46(Suppl 5):S165–S173; Negro F, et al. Gastroenterology 2015; 149:1345–1360; Englert Y, et al. Fertil Steril 2007; 88:607–11; Samuel DG & Rees IW. Frontline Gastroenterol 2013; 4:249–254.

Renal

impairment

Thyroid dysfunction

Peripheral neuropathy

Cardiovascular/

metabolic diseases

Mixed

cryoglobulinemia

Hematological disorders/

malignancies

Neuropsychiatric

manifestations

Type II

diabetes

Treatment of HCV Is Associated with Reduced

Risk for Type 2 Diabetes Mellitus

1.. Arase Y, et al. Hepatology 2009; 49:739–744; 2. Romero-Gomez M, et al. J Hepatol 2008; 47:721–727

Japanese retrospective study: 2842 patients treated with IFN ± RBV were

followed for a mean of 6.4 years1

SVR was associated with a

66% reduction in the development of T2DM

Spanish HCV chronic HCV cohort study:

1059 patients treated with IFN + RBV for

24/48 weeks2

SVR reduces the risk of IFG and/or T2DM

development

P=0.0003

Follow up (years)

50

30

20

10

0

40

0 10 20

Cu

mu

lati

ve d

evelo

pm

en

t

rate

of

T2D

M p<0.001

SVR

(n = 1175)

Non-SVR

(n = 1667)

Pati

en

ts w

ith

ou

t IF

G a

nd

/or

T2D

M

Follow-up (months)

SVR

NR Censored

Censored

0 24 48 72 96

1.0

0.8

0.6

0.4

0.2

0.0

Treatment of HCV Is Associated with Reduced

Risk for Cardiovascular Complications

• ACS, acute coronary syndrome. • Hsu YC, et al. Gut 2015; 64:495–503.

Antiviral treatment was

associated with a 38% lower risk

for ischemic stroke

Antiviral treatment was

associated with a 23% lower risk

for ACS

Large Taiwanese chronic HCV cohort study: 12,384 patients treated with

pegIFN/RBV and 24,768 untreated matched controls were followed up for a

mean of 3.3 years and 3.2 years, respectively

Follow-up (years)

2

1

0

1.5

0.5

0 1 2 3 4 5 6 7 8

Cu

mu

lati

ve i

ncid

en

ce (

%) Untreated

cohort Treated cohort

Ischemic stroke, p=0.001

Follow-up (years)

3

1

0

2

0 1 2 3 4 5 6 7 8

Cu

mu

lati

ve i

ncid

en

ce (

%) Untreated cohort

Treated cohort

Acute coronary syndrome,

p=0.027

Treatment of HCV Is Associated with Reduced

Risk for End Stage Renal Disease

Hsu YC, et al. Gut 2015; 64:495–503;

Large Taiwanese prospective chronic HCV cohort study: 12,384 patients treated

with pegIFN/RBV and 24,768 untreated matched controls were followed up for a

mean of 3.3 years and 3.2 years, respectively

Follow-up

(years)

1.5

0.9

0.6

0.3

0

1.2

0 1 2 3 4 5 6 7 8

Cu

mu

lati

ve i

ncid

en

ce (

%)

Untreated cohort

Treated cohort

End-stage renal disease,

p<0.001

Pre-Treatment Evaluation

• Quantitative PCR for HCV RNA

• Genotype

• Exclusion of other liver diseases (HBV, NAFLD)

• Ensuring HAV, HBV immunity

• Medications

• Comorbidity assessment

• Assessment of level of fibrosis remains essential

– Liver biopsy is OUT

– Noninvasive tests are IN

• Blood tests (APRI, FIB-4, Fibrosure, Hepascore, etc)

• Elastography (e.g. Fibroscan, ARFI, MRI)

• HCC screening w/advanced fibrosis/cirrhosis

• Varices screening for cirrhotics

Genotype 1 Regimens

AASLD/IDSA Guidelines

Updated October 2016

hcvguidelines.org

AASLD/IDSA: Recommended and Alternative Regimens for GT1 Without Cirrhosis

No Distinction Between Naïve & Experienced

Nucleotide No nucleotide

“Recommended” “Alternative”

Population LDV/SOF SOF

+ VEL

DCV

+ SOF

SMV

+ SOF GZR/EBR OBV/PTV/RTV

+ DSV

GT1a

12 wks (8 wks if

HCV RNA<6M

IU/ml, non-AA,

no HIV)

12 wks 12 wks 12 wks

12 wks

16 wks +

RBV†

12 wks + RBV

GT1b

12 wks (8 wks if

HCV RNA<6M

IU/ml, non-AA,

no HIV)

12 wks 12 wks 12 wks 12 wks 12 wks

†If NS5A RAVs present (GT1a only)

AASLD/IDSA. hcvguidelines.org. Apirl 2017.

AASLD/IDSA: Recommended and Alternative Regimens for GT1 with Compensated Cirrhosis

Nucleotide No nucleotide

“Recommended” “Alternative”

Population LDV/SOF SOF

+ VEL

DCV

+ SOF

SMV

+ SOF GZR/EBR OBV/PTV/RTV

+ DSV

GT1a

- Naive

- PR exp

12 wks

12 wks

+ RBV

or

24 wks

w/o RBV

12 wks

12 wks

24 wks

± RBV

24 wks

± RBV

24 wks

± RBV*

24 wks

± RBV*

12 wks

16 wks

+ RBV†

12 wks

16 wks

+ RBV†

24 wks + RBV

24 wks + RBV

*Not w/Q80K

†If NS5A RAVs present.

AASLD/IDSA. hcvguidelines.org. Apirl 2017.

AASLD/IDSA: Recommended and Alternative Regimens for GT1 with Compensated Cirrhosis

Nucleotide No nucleotide

“Recommended” “Alternative”

Population LDV/SOF SOF

+ VEL

DCV

+ SOF

SMV

+ SOF GZR/EBR OBV/PTV/RTV

+ DSV

GT1b

- Naive

- PR exp

12 wks

12 wks

+ RBV

or

24 wks

12 wks

12 wks

24 wks

± RBV

24 wks

± RBV

24 wks

± RBV*

24 wks

± RBV*

12 wks

12 wks

12 wks

12 wks

*Not w/Q80K

†If NS5A RAVs present.

AASLD/IDSA. hcvguidelines.org. April 2017.

The Most Recently Approved Regimen

in the US (June 2016)

Sofosbuvir/Velpatasvir

ASTRAL-1: SOF/VEL FDC for 12 Weeks in G1, 2, 4, 5, 6

Patients with and Without Cirrhosis: ASTRAL-1 Study

• Velpatasvir (VEL, GS-5816) is a pangenotypic HCV NS5A inhibitor

• GT3 pts evaluated in separate study

• 19% cirrhosis, 32% treatment-experienced

SV

R12*

(%)

99 98 99 100 100 97 100

0

25

50

75

100

Overall G1a G1b G2 G4 G5 G6

618/

624

206/

210

117/

118

104/

104

116/

116

34/

35

41/

41

*HCV RNA <15 IU/mL

Feld JJ, Jacobson IM, Hezode C, et al. N Engl J Med. 2015. Dec 31;373(27):2608-17.

Genotype 2

ASTRAL-2: SOF/VEL FDC for 12 Weeks Compared to SOF + RBV for 12 Weeks in GT2 Patients

• 266 patients with G2 HCV infection in

the US were randomized and treated

– 134 with SOF/VEL

– 132 with SOF + RBV

• 59% male

• 88% white

• 38% IL28B CC

• 15% prior treatment failure

• 14% cirrhosis

Wk 0 Wk 12 Wk 24

SVR12 SOF/VEL

SVR12 SOF + RBV

99 94

0

20

40

60

80

100

SOF/VEL SOF + RBV

SV

R1

2 (

%)

133/134 124/132

p=0.018

1 LTFU 6 relapses

2 LTFU

SVR12

Sulkowski M, et al. AASLD. 2015. San Francisco. #205; Foster GR, Afdhal N, Roberts SK, et al. N Engl J Med. 2015 Dec 31;373(27):2608-17.

ASTRAL-2: SOF/VEL FDC for 12 Weeks Compared to SOF + RBV for 12 Weeks in GT2 Patients

• 266 patients with G2 HCV infection in

the US were randomized and treated

– 134 with SOF/VEL

– 132 with SOF + RBV

• 59% male

• 88% white

• 38% IL28B CC

• 15% prior treatment failure

• 14% cirrhosis

Wk 0 Wk 12 Wk 24

SVR12 SOF/VEL

SVR12 SOF + RBV

99 94

0

20

40

60

80

100

SOF/VEL SOF + RBV

SV

R1

2 (

%)

133/134 124/132

p=0.018

1 LTFU 6 relapses

2 LTFU

SVR12

SOFOSBUVIR + RIBAVIRIN SHOULD NOT BE USED FOR GT2

Sulkowski M, et al. AASLD. 2015. San Francisco. #205; Foster GR, Afdhal N, Roberts SK, et al. N Engl J Med. 2015 Dec 31;373(27):2608-17.

Genotype 3

ASTRAL-3: SOF/VEL FDC for 12 Weeks Compared to SOF + RBV for 24 Weeks in G3 HCV Infected Patients

98 93 91 89 90

73 71

58

0

20

40

60

80

100

160 163

40 43

31* 34

33 37

141 156

33 45

22 31

22 38

Cirrhosis No Yes

Treatment-Naive Treatment-Experienced

No Yes

SOF/VEL SOF + RBV

84% No BL

NS5A RAVs n=231

16% BL NS5A RAVs

n=43

n=274 97%

SVR12

225/

231

88%

SVR12

38/

43

Resistance Analysis

*

*One reinfection: 94% without this patient

Mangia A, et al. AASLD. 2015. San Francisco. #249; Foster GR, Afdhal N, Roberts SK, et al. N Engl J Med. 2015;373:2608-17.

Management of Patients with Genotype 3

Trt

Experience Cirrhosis? Y93H RAV?

Recommended

Regimens

Naive No Testing not

recommended

Naive Yes No

Naive Yes Yes

PegIFN/RBV No No

PegIFN/RBV No Yes

PegIFN/RBV Yes --

AASLD/IDSA. HCV Guidance. April 2017.

Management of Patients with Genotype 3

Trt

Experience Cirrhosis?

Y93H

RAV? Recommended Regimens

Naive No -- • 12 wks DCV + SOF

Naive Yes No • 24 wks DCV + SOF ± RBV

Naive Yes Yes • 24 wks DCV + SOF + RBV

PegIFN/RBV No No • 12 wks DCV + SOF

PegIFN/RBV No Yes • 12 wks DCV + SOF + RBV

PegIFN/RBV Yes -- • 24 wks DCV + SOF + RBV

AASLD/IDSA. HCV Guidance. April 2017.

Management of Patients with Genotype 3

Trt

Experience Cirrhosis?

Y93H

RAV? Recommended Regimens

Naive No -- • 12 wks SOF/VEL

Naive Yes No • 12 wks SOF/VEL

Naive Yes Yes • 12 wks SOF/VEL + RBV

PegIFN/RBV No No • 12 wks SOF/VEL

PegIFN/RBV No Yes • 12 wks SOF/VEL + RBV

PegIFN/RBV Yes -- • 12 wks SOF/VEL + RBV

AASLD/IDSA. HCV Guidance at hcvguidelines.org April 2017.

Decompensated Cirrhosis

SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhotics: Genotypes 1 and 4, Childs-Pugh B and C

87 87 86 89 89 90

0

20

40

60

80

100

SV

R12 (

%)

LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks

CPT B CPT C Overall

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

Charlton M, et al. Gastroenterology. 2015;149:649-659.

Ledipasvir + Sofosbuvir + Ribavirin in Decompensated

Cirrhotics: Genotypes 1 and 4, Childs-Pugh B and C

Changes in MELD Score

-6

-4

-2

0

2

4

-6

-4

-2

0

2

4

n=5 n=5 n=2 n=3

(-8)

(+10)

CPT B CPT C

12 wk (n=30) 24 wk (n=29) 12 wk (n=23) 24 wk (n=26)

Flamm SL, et al. AASLD. 2014. Boston. #239.

SOF/VEL FDC for Treatment of HCV in Patients with Decompensated Liver Disease: Phase 3 ASTRAL-4 Study

• 267 treatment naive or experienced G1–6 with Child B cirrhosis

Wk 0 Wk 12 Wk 24 Wk 36

SVR12

SOF/VEL n=90

SVR12

SOF/VEL n=90

SVR12

SOF/VEL + RBV n=87

Charlton MR, et al. AASLD. 2015. San Francisco. #LB-13; O’Leary J, et al. EASL. 2016. Barcelona. #SAT-169.

ASTRAL-4: SOF/VEL FDC for Treatment of HCV in Patients with Decompensated Liver Disease

Safety

• d/c due to AE 3%; death 3% (9)

• AE more frequent with RBV

• Fatigue (29%); nausea (23%); HA (22%);

anemia (13%; 31% in RBV arm)

• RBV dose: Hb <10 = 23%; Hb <8.5 = 7%

• RBV decreased in 37% and d/c in 17%

• Bili <3 x ULN

83 88

50

100 94 96

85

100

88 94

50

86

0

20

40

60

80

100

Overall G1 G3 G2, 4, 6

SVR24 rates (%)

75/

90

82/

87

79/

90

60/

68

65/

68

67/

71

7/

14

11/

13

6/

12

G2:

4/4

G4:

4/4

G2:

4/4

G4:

2/2

G2:

4/4

G4:

2/2

G6:

1/1

- 1 1 - - - 6 1 4 - - - - - - - - - 1 - 1 - - 1

BT - 1 1 - - - Relapse 1

1 2 7 5 1 3

LTFU 1 - 1 1 - 1 Death 3 2 2 2 2 -

Charlton MR, et al. AASLD. 2015. San Francisco. #LB-13; O’Leary J, et al. EASL. 2016. Barcelona. #SAT-169.

What Therapy Should Be Used for Decompensated Cirrhotics?

1http://www.fda.gov/Drugs/DrugSafety/ucm468634.htm; 2hcvguidelines.org. Feb 24; 32016. EASL Recommendations. J Hepatol. 2016.

1. Only regimens containing an NS5A inhibitor and polymerase inhibitor

should be used for decompensated cirrhotic patients

2. Protease inhibitors should not be used in decompensated cirrhotics

because they accumulate to potentially toxic levels

3. Decompensated cirrhotics should be treated at a transplant

center or in close coordination with a transplant center

Renal Failure

C-SURFER Study: CKD Stage 4/5

Grazoprevir + Elbasvir N=122

Placebo N=101

12 weeks

Active treatment

• 55% on dialysis

• 55% with diabetes

• 52% GT1a, 48% GT1b

• 6% cirrhosis

Roth D, et al. Lancet. 2015. Oct 17;386(10003):1537-45.

66%

90%

100% 100% 99%

60%

95% 100% 99% 98%

0%

20%

40%

60%

80%

100%

TW2 TW4 TW12 FW4 FW12(SVR12)

Immediatetreatment group

Deferredtreatment group

C-SURFER: On Treatment Virologic Response Immediate and Deferred Treatment Arms

*Efficacy is presented for the modified full analysis set population (mFAS).

Roth D, et al. Lancet. 2015. Oct 17;386(10003):1537-45.

81

/122

109

/121

119

/119

118

/118

115

/116

61

/101

96

/101

101

/101

100

/101

97

/99

LDV/SOF for 12 or 24 Weeks in Kidney Transplant Recipients with Chronic G1 or 4 HCV Infection

100 100 100 96 96 100

0

20

40

60

80

100

G1 G4

SV

R12 (

%)

51/

51 6/6 4/4

Overall

51/

53* 57/

57

55/

57*

*2 lost to follow-up: NO VIROLOGIC FAILURES

Colombo M, et al. EASL. 2016. Barcelona. #GS13.

New Paradigm of HCV Therapy for Renal Failure Patients

Past:

– Difficult to use interferon + ribavirin in renal failure

– Renal transplantation historically withheld for HCV+ patients with

hepatic fibrosis (“we won’t transplant till HCV cured”)

• Concern about progression of fibrosis post-transplant

New Paradigm of HCV Therapy for Renal Failure Patients

Past:

– Difficult to use interferon + ribavirin in renal failure

– Renal transplantation historically withheld for HCV+ patients with

hepatic fibrosis (“we won’t transplant till HCV cured”)

• Concern about progression of fibrosis post-transplant

Present

– Effective and safe DAA therapy available for renal failure

patients

– Non-renal transplant candidates should be offered treatment

– If wait list is much shorter for an HCV+ kidney, may be better to

proceed with transplant and treat the HCV after transplant

New Paradigm of HCV Therapy for Renal Failure Patients

Past:

– Difficult to use interferon + ribavirin in renal failure

– Renal transplantation historically withheld for HCV+ patients with

hepatic fibrosis (“we won’t transplant till HCV cured”)

• Concern about progression of fibrosis post-transplant

Present

– Effective and safe DAA therapy available for renal failure

patients

– Non-renal transplant candidates should be offered treatment

– If wait list is much shorter for an HCV+ kidney, may be better to

proceed with transplant and treat the HCV after transplant

Future

– Transplant HCV- patients with HCV+ kidneys? Being studied

HCV Therapy: Almost at the Summit… But Still Climbing

The Quest: Pangenotypic regimens that cover resistant variants

associated with first generation NS5A and protease inhibitors

HCV Therapy: Almost at the Summit… But Still Climbing

The Quest: Pangenotypic regimens that cover resistant variants

associated with first generation NS5A and protease inhibitors

Second Generation Regimens

Protease

Inhibitor

NS5A

Inhibitor

Nucleotide

Polymerase

Inhibitor

Glecaprevir Pibrentasvir

GS-9857 Velpatasvir Sofosbuvir

Grazoprevir Ruzasvir Uprifosbuvir

+

+

+

+

+

Phase 3 Trial of SOF/VEL/VOX for 8 Weeks vs SOF/VEL for 12 Weeks in DAA-Naive GT1–6: POLARIS-2 Study

SOF/VEL/VOX n=501

SOF/VEL n=440

0 8 12 Wk

SVR12

SVR12

20 24

Jacobson IM, et al. AASLD. 2016. Boston. #LB-12.

POLARIS-2: Efficacy

95 98

0

20

40

60

80

100

SVR12, %

476/501

SOF/VEL/VOX

8 Weeks

21 relapses 4 LTFU

SOF/VEL

12 Weeks

432/440

3 relapses 1 DC due to AE

4 LTFU

Failed to meet

non-inferiority endpoint

Only 1/21 relapsers had treatment-

emergent resistant variants

Proportional difference -3.4 (-6.2% to -0.6%) noninferiority not met; error bars represent 95% confidence intervals.

Jacobson IM, et al. AASLD. LB-12.

POLARIS-2: SVR12 by Genotype (GT 1)

95 93

92 97 98 98 99 97

0

20

40

60

80

100

Overall 1 1a 1b

SV

R1

2, %

SOF/VEL/VOX 8 weeks, n=501 SOF/VEL 12 weeks, n=440

Overall GT 1a GT 1b GT 1

476

501

155

169

61

63

432

440

170

172

57

59

217

233

228

232

21

relapses

4 LTFU

3

relapses

1 W/C

1 LTFU

14

relapses

1 relapse

1 LTFU

2 relapses

1

LTFU

16

relapses

1

relapse

2 LTFU

2 of 2 patients (100%) with GT 1 Other achieved SVR12 (1 each in SOV/VEL/VOX and SOF/VEL arm); Error bars represent 95% confidence intervals.

POLARIS-2: SVR12 by Cirrhosis Status

Error bars represent 95% confidence intervals.

96 98

0

20

40

60

80

100

No Cirrhosis

N=767

394/411

SOF/VEL/VOX

8 Weeks

14 relapses 3 LTFU

SOF/VEL

12 Weeks

349/356

2 relapses 4 LTFU

1 DC due to AE

91 99

0

20

40

60

80

100

Cirrhosis

N=174

82/ 90

SOF/VEL/VOX

8 Weeks

7 relapses 1 LTFU

SOF/VEL

12 Weeks

83/ 84

1 relapse

POLARIS-2: AEs in >10% of Patients

Patients, n (%)

SOF/VEL/VOX

8 weeks

n=501

SOF/VEL

12 weeks

n=440

Headache 134 (27) 99 (23)

Fatigue 106 (21) 90 (20)

Diarrhea 88 (18) 32 (7)

Nausea 80 (16) 40 (9)

SOF/VEL/VOX 12 Weeks in NS5A Inhibitor-Experienced GT1–6 patients: Phase 3 POLARIS-1 Study

Placebo

SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC

0 4 8 12

1:1

Time (weeks)

SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC

G2–6 (n=152)

NS5A inhibitor-

experienced

G1 (n=262)

NS5A inhibitor-

experienced

46% cirrhosis

Bourlière M, et al. AASLD. 2016. Boston. #194.

SOF/VEL/VOX 12 Weeks in NS5A Inhibitor-Experienced GT1–6 patients: Phase 3 POLARIS-1 Study

Placebo

SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC

0 4 8 12

1:1

Time (weeks)

SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC

G2–6 (n=152)

NS5A inhibitor-

experienced

G1 (n=262)

NS5A inhibitor-

experienced

96

0

20

40

60

80

100

SV

R12,

%

253/263

6 relapses 1 on-tx failure

2 withdrew consent 1 LTFU

46% cirrhosis

Bourlière M, et al. AASLD. 2016. Boston. #194.

SOF/VEL/VOX 12 Weeks in NS5A Inhibitor-Experienced GT1–6 patients: Phase 3 POLARIS-1 Study

Placebo

SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC

0 4 8 12

1:1

Time (weeks)

SOF/VEL/VOX (400 mg/100 mg/100 mg QD) FDC

G2–6 (n=152)

NS5A inhibitor-

experienced

G1 (n=262)

NS5A inhibitor-

experienced

96

0

20

40

60

80

100

SV

R12,

%

253/263

6 relapses 1 on-tx failure

2 withdrew consent 1 LTFU

99 93

0

20

40

60

80

100

No Cirrhosis Cirrhosis

SV

R12,

%

140/142 113/121

1 withdrew consent 1 LTFU

6 relapses 1 on-tx failure

1 withdrew consent

46% cirrhosis

Bourlière M, et al. AASLD. 2016. Boston. #194.

POLARIS-3: Phase 3 Trial of SOF/VEL/VOX for 8 Weeks and

SOF/VEL for 12 Weeks for GT3 HCV Infection and Cirrhosis

SOF/VEL/VOX n=110 G3

Cirrhosis SOF/VEL n=109

0 8 12 Week

SVR12

SVR12

20 24

96 96

0

20

40

60

80

100

SVR12

106 110

SOF/VEL/VOX

8 Weeks

2 relapses 1 withdrew consent

1 death

SOF/VEL

12 Weeks

105 109

1 on-treatment failure 1 relapse

1 discontinued due to AE 1 LTFU

Foster GR, et al. AASLD. 2016. Boston. #258.

TakeAway Points From POLARIS Studies

• Triplet regimen very effective when given for 8 weeks but

probably will not replace current 12 week regimens

(failed to meet noninferiority vs SOF/VEL for 12 weeks)

• Triplet regimen for 12 weeks very promising as “rescue”

for DAA failure patients

• Very effective regimen for GT3

ENDURANCE-1, 2, 4 Studies: Efficacy of

GLE/PIB for Treating GT1, 2, 4, 5, 6 HCV

1. Zeuzem S, et al. AASLD 2016. Abstract 253.

2. Kowdley KV, et al. AASLD 2016. Abstract 73.

3. Asselah T, et al. AASLD 2016. Abstract 114.

100

80

60

40

20

0

SV

R1

2 (

%)

99.1

*

99.7

* 99

332/

335

331/

332

195/

196

8 Wks 12 Wks

120/

121

12 Wks

ENDURANCE-1

(GT1)[1]

ENDURANCE-2

(GT2)[2]

ENDURANCE-4

(GT4-6)[3]

99

12 Wks

No cirrhosis

ENDURANCE-3: Glecaprevir/Pibrentasvir 8

or 12 Wksin GT3 HCV Without Cirrhosis

Foster GR, et al. EASL 2017. Abstract GS-007.

95 95 97

0

20

40

60

80

100

G/P 8 wks G/P 12 wks DCV/SOF 12 wks

149/157 222/223 111/115

Arms A and B not inferior to C

EXPEDITION-1: Glecaprevir/Pibrentasvir in

GT1, 2, 4, 5, or 6 HCV and Compensated

Cirrhosis, 12 Weeks

Forns X, et al. EASL 2017. Abstract GS-006. ClinicalTrials.gov. NCT02642432.

10

0

80

60

40

20

0

SV

R12

(%

)

All Pts

1

145/

146

89/

90

31/

31

7/

7

99 99 1000 100

2/

2

2 4 5 6

Genotype

100 100

16/

16

Glecaprevir + Pibrentasvir for Prior DAA Failures, n=50: Genotype 1, 12 Weeks

95 95

0

20

40

60

80

100

Arm A Arm B Arm CABT-493 (mg) 200 300 300

ABT-530 (mg) 80 120 120

SV

R12

(%)

mIT

T

100

Poordad F, et al. EASL. 2016. GS-11.

6/6 20/21 19/20

Management of Patients After SVR

• Follow patients till SVR48

• HCC screening continues in F3 or F4

• Fibroscan, serum markers may improve but not reliable

for decisions re: d/c of HCC screening

• Can d/c variceal screening if no varices prior to

treatment

• Continue surveillance, treatment as needed in patients

who received primary prophylaxis for varices or

previously bled

• No alcohol consumption with advanced fibrosis/cirrhosis

Summary

• We are now in an era of highly effective interferon free

treatment

• Historically “difficult to treat patients” are no longer

considered difficult to treat

• HIV coinfected patients have similar efficacy, must

be mindful of drug-drug interactions

• PWID should be treated with appropriate avaliable

expertise in addiction medicine w/harm reduction

• There is significant fibrosis regression, reduction in

liver complications, and all-cause mortality post-SVR

• There is no justification for withholding treatment from

HCV infected patients regardless of degree of fibrosis

• Post-SVR patients with advanced fibrosis or cirrhosis

must be monitored for liver cancer