Hepatitis C - Special Populations10th Paris Hepatology Conference30-31 January, 2017

Stefan ZeuzemUniversity Hospital, Frankfurt, Germany

Less Special Populations in the DAA Era

Special Populations IFN era DAA era*

HCV/HIV coinfection + -

Compensated liver cirrhosis + -

Decompensated liver cirrhosis N/A (+)

Post-transplant (liver, kidney, etc.) + -

ESRD, hemodialysis + (+)

Cryoglobulinemia, vasculitis, etc. + -

Elderly patients + -

Children + -

PWID + -

Patients with psychiatric diseases + -

African American patients + -

etc. + -

* drug-drug interactions must still be considered

HCV and Chronic Kidney Disease

Stage GFR (mL/min/1.73m2)

CKD 1 >89 (normal)

CKD 2 60-89 (mild)

CKD 3 30-59 (moderate)

CKD 4 15-29 (severe)

CKD 5 <15 (end-stage)

HCV can cause CKD(mainly cryoglobulinemic

membranoproliferative glomerulonephritis)

CKD is a risk for HCV(blood transfusion, dialysis, renal transplant)

Clinical Trials in Patients with CDK

HCV-1 HCV-2 HCV-3 HCV-4 HCV-5 HCV-6

Sofosbuvir + Ledipasvir x x ? x x x

Sofosbuvir + Valpatasvir x x x x x x

Sofosbuvir + Daclatasvir x (x) x x x x

Sofosbuvir + Simeprevir x x x x x

Paritaprevir/r + Ombitasvir ± Dasabuvir ± RBV

x x

Grazoprevir + Elbasvir x x (x)

Glecaprevir + Pibrentasvir x x x x x x

Triple Therapies x x x x x x

RUBY I (20 pts.) & RUBY II (18 pts.)

C-SURFER (116 pts.)

EXPEDITION-IV (114 pts.)

RUBY-I: OBV/PTV/r + DSV ± RBV in Noncirrhotic

G1 Patients with Severe RI or ESRD

OBV/PTV/r + DSV ± RBV (200 mg QD in G1a) for 12 weeks

● G1a 65% (13); G1b 35% (7)● Black 70%● CKD-4: 30% (6); CKD-5: 70%

(14)● Median BL Hb 12.0 g/dL

– Treatment-emergent RAVs: – NS3 (D168V) & NS5A

(Q30R)

Pockros PJ, et al., Gastroenterology 2016;150:1590-98

Safety No early d/c; 4 SAEs (not related) AEs more frequent with RBV Anemia (69%); fatigue (35%);

diarrhea (25%); nausea (23%) ↓RBV dose: 69%; Hb <10 in 54%; Hb <8

in 8% ↑Bili <3 x ULN in 10%; no ↑ AST/ALT

95 10090 90

19/20

20/20

18/20

18/20

1 relapse1 death

Pts

(%

)

RUBY-II: Efficacy and Safety of RBV-free OBV/PTV/r

± DSV Regimen in Patients with Severe RI or ESRD

0 24Week

s

Arm AG1an=13

OBV/PTV/r + DSV

36

Arm BG4n=5

Treatment period

Post-treatment period

SVR12

SVR12

12

OBV/PTV/r

Overall G1a 3-DAA G4 2-DAA0

20

40

60

80

100 94 100

80

SV

R12

(%

pts

)

17/

18

13 /

13

4/5

Gane EJ, et al. AASLD 2016, Boston. #935

One G4 patient discontinued in wk 2 for elective renal tx

All patients 115/116

CirrhosisYesNo

 6/6

109/110HCV genotype

G1aG1b

61/6154/55

RaceWhiteAfrican American

58/5951/51

Previous txNaiveExperienced

96/9619/20

CKD stage45

22/2293/94

DiabetesYesNo

40/4175/75

HemodialysisYesNo

86/8729/29

C-SURFER: GZR + EBR in Tx-naive and -experienced Patients with HCV G1 Infection

and CKD

1 G1b, non-cirrhotic patient relapsed at FWk12

Virologic response (Immediate treatment group)

Pat

ient

s (H

CV

RN

A <

LLoQ

, %) 99

81/122

109/121

118/118

115/116

119/119

100908070SVR12 (95% CI)

SVR12 subgroup analyses

Roth D, et al, Lancet 2015; 385:1537-45

EXPEDITION-IV: Safety and Efficacy of G/P in G1–6 Adults with Renal Impairment

Patients with Stage 4/5 CKD (± HD), including cirrhosis and treatment experienced (PEG ± RBV ± SOF)

Genotype distribution:G1, 52%; G2, 16%; G3, 11%; G4, 19%; G5, 1%; G6, 1%

Gane EJ, et al. AASLD 2016, Boston. #LB-11

Day 1 Wk 12 PT Wk 24

n=104 GLE 300 mg + PIB 120 mg

Any AE 74 (71)

Serious AE25

(24)DAA-related SAEs 0

Treatment d/c due to AE 4 (4)Hb Gr ≥3 (<8.0 – 6.5 g/dL) 5 (5)AST Gr ≥2 (>5 ̶ 20 × ULN) 0ALT Gr ≥2 (>5 ̶ 20 × ULN) 0Bilirubin Gr ≥3 (>3 ̶ 10 × ULN)

1 (1)

0

20

40

60

80

100 98

102/104

Breakthrough 0Relapse 0

d/c 1LTFU 1

mITT=100%

SV

R12

(%

pt

s)

Clinical Trials in Patients with CDK

HCV-1 HCV-2 HCV-3 HCV-4 HCV-5 HCV-6

Sofosbuvir + Ledipasvir x x ? x x x

Sofosbuvir + Valpatasvir x x x x x x

Sofosbuvir + Daclatasvir x (x) x x x x

Sofosbuvir + Simeprevir x x x x x

Paritaprevir/r + Ombitasvir ± Dasabuvir ± RBV

x x

Grazoprevir + Elbasvir x x (x)

Glecaprevir + Pibrentasvir x x x x x x

Triple Therapies x x x x x x

RUBY I & RUBY II

C-SURFER

EXPEDITION-IV

Safety of SOF-based Regimens for HCV Treatment

of Patients with Mild or Moderate RI45 Phase 2/3 studies: 9141 patients with normal RF (>80 mL/min),

2239 with mild RI (50–80 mL/min), and 169 with moderate RI (30–49 mL/min)

eGFR stable during SOF

treatment regardless of RI

eGFR fluctuations only seen

in transplant recipients

Renal AEs increased by RBV

but not by baseline RI

Effect of SOF-based treatment on GFR

0

40

80

120

160

Me

an

(SD

) eG

FR

(m

L/m

in)

With RBV (n at BL)

W/o RBV (n at BL)

Normal RF (3062) (5704)

Mild RI (802) (1191)

Moderate RI

(49) (74)

Me

an

(SD

) eG

FR

(m

L/m

in)

With RBV (n at BL)

W/o RBV (n at BL)

Normal RF (100) (275)

Mild RI (63) (183)

Moderate RI

(6) (40)

0

40

80

120

160

BL 1 2 4 8 12 24 f/u 4

Decompensated liver disease

Compensated liver disease

Durrand F, et al. AASLD 2016, Boston. #867

Daily SOF 400 mg + RBV 200 mg for 24 Weeks in G1/3 Patients with Severe Renal Impairment

SOF and GS-331007 pharmacokinetics at Wk 12

Martin P et al. AASLD 2015, San Francisco. #1128Gane E, et al. AASLD 2014, Boston. #966

SOF 200 mg

SOF 400 mg

AEs, n

Any AE 10 9

Grade 3 AE 2 3

Serious AE 2 2

d/c due to AE

0 2

Death 0 0

Labs, n

Hb <10 7 9

Hb <8.5 4 3

Δ CrCl -3.1 mL/min

+6.3 mL/min

EchoBL 57.1 ± 2.9 56.4 ± 2.4

Week 24 58.1 ± 2.7 55.9 ± 3.8

Safety

No relationship observed between SOF, GS-331007 exposure (or RBV), and relapse

1000

10,000

100,000

100

1000

10,000

Severe RI

(400 mg)

Severe RI

(400 mg)

Historical(400 mg)

Historical(400 mg)

SOFGS-331007

SVR12Viral relapseG

S-3

310

07

AU

C

(ng•

h/m

L)

SO

F A

UC

( ng•h

/mL

)

6X 1.4X

eGFR ≤30 eGFR 31–45 eGFR 46–60 eGFR >600

20

40

60

80

100100

33

9381

100

80 8473

80 8091 87

100 10092

79

SVR12 (%)

HCV-TARGET: Efficacy of SOF-containing Regimens

in HCV Infected Pts with Reduced Renal Function

Saxena V, et al., Liver Int 2016;36:807-16

eGFR ≤30 ml/min

11 (58%)SOF/PEG/RBVSOF/RBVSOF/SMVSOF/SMV/RBV

Treatment regimen by baseline eGFR

5 (26%)

2 (11%)

1 (5%)

SVR12 by baseline eGFR and by treatment regimen*

*Among patients with known outcome

eGFR 31–45 ml/min

22 (51%)

15 (24%)

12 (19%)

4 (6%)eGFR 46–60 ml/min

79 (47%)

58 (35%)

16 (10%)

15 (9%)eGFR >60 ml/min

618 (38%)

525 (32%)

186(11%) 314

(19%)

1 4 10 2 3 10 25 9 14 45 68 13 232 400 552 171

HCV-TARGET: Safety of SOF-containing Regimens in HCV Infected Pts with Reduced

Renal Function

Saxena V, et al., Liver Int 2016;36:807-16

Dichotomous = n (%) Continuous = mean (range)

eGFR ≤ 30 ml/min (n=17)

eGFR 31─45 ml/min (n=56)

eGFR 46─60 ml/min (n=157)

eGFR >60 ml/min

(n=1559)Common AEs

Fatigue 3 (18) 19 (34) 56 (36) 543 (35)Headache 1 (6) 9 (16) 19 (12) 274 (18)Nausea 3 (18) 8 (14) 33 (21) 247 (16)

Anemia AE 6 (35) 16 (29) 37 (24) 246 (16)Required transfusion (s) 2 (12) 5 (9) 3 (2) 31 (2)Erythropoietin start on treatment

1 (6) 8 (14) 14 (9) 50 (3)

RBV

Reduction in RBV due to anemia

3 (38) 8 (30) 33 (42) 185 (19)

RBV discontinuation 0 (0) 4 (15) 1 (1) 12 (1)Worsening renal function 5 (29) 6 (11) 4 (3) 14 (1)Renal or urinary system AEs 5 (29) 6 (11) 13 (8) 84 (5)Any serious AEs 3 (18) 13 (23) 8 (5) 100 (6)Cardiac serious AEs 1 (6) 2 (4) 8 (5) 53 (3)Early treatment discontinuation 1 (6) 4 (6) 6 (4) 68 (4)Early treatment discontinuation AE

1 (6) 2 (3) 4 (2) 39 (3)

Death 1 (6) 0 (0) 2 (1) 10 (1)

Safety outcomes by baseline eGFR

SOF-based antiviral therapy in HCV patients with

severe renal failure– All patients with GFR <35

mL/min● 35 on hemodialysis● 17 with kidney transplant● 11 with liver transplant● 27 on waiting list for renal tx

– Antiviral regimen– SOF + RBV (n=7)– SOF + PR (n=2)– SOF + DCV ± RBV (n=30) – SOF + SMV ± RBV (n=11)– Treatment duration 12–24

weeks– SOF 400 mg qd or tiw in

dialysis pts

2 pts with relapse G3, severe fibrosis, no RBV No EPO use; no Hb <8 g/dL1 death on tx (liver failure), 1 at f/u mo 3 (unknown cause)1 treatment d/c (combined liver kidney transplant)No change in GFR for non-dialysis patients

Dumortier J, et al., Nephrol Dial Transplant 2016;epub

SOF-based therapy effective, and safe, in renal failure, including dialysis Need for reduced SOF dose not established because no apparent toxicity at either full or reduced dose

Wk 4 Wk 8 Wk 12 EOT SVR4 SVR120

25

50

75

100

64

94 100 10090 88

Pts

(%

)

49/49

50/50

47/50

32/50

44/49

38/43

Use of LDV/SOF in patients with advanced chronic kidney disease (eGFR ≤30mL/min): A case series

020406080

100100

18/18

SV

R12

(%

)

Full-dose LDV/SOF without RBV for 12 weeks (1 pt on HD received RBV 200 mg every other day)72% G1a, 22% G1b55% black, 33% white10 on hemodialysis67% cirrhosis50% diabetic4 had kidney transplant, 1 had liver transplant

Adverse events● Insomnia: 1● Nausea/vomiting: 1● Headache: 1● Chest pain (Hx CAD): 1● Anemia required transfusion or ESA: 2

(1 with RBV)

Sise M, et al. AASLD 2016, Boston. #1951

1 patient with cryo nephritis came off HD, at last report was on rituximab

Of pts with severe renal impairmentand post-tx f/u, 2 had increased eGFR and 4 had decreased eGFR

Cannot rule out an effect on renal function in CKD-4 patients

Clinical Trials in Patients with Decompensated Liver Cirrhosis

HCV-1 HCV-2 HCV-3 HCV-4 HCV-5 HCV-6

Sofosbuvir + Ledipasvir x x ? x x x

Sofosbuvir + Valpatasvir x x x x x x

Sofosbuvir + Daclatasvir x (x) x x x x

Sofosbuvir + Simeprevir x x x x x

Paritaprevir/r + Ombitasvir ± Dasabuvir ± RBV

x x

Grazoprevir + Elbasvir x x (x)

Glecaprevir + Pibrentasvir x x x x x x

Triple Therapies x x x x x x

NS3/4A protease Inhibitors and non-nucleosidic polymerase inhibitors

Contraindicatedin patients with decompensated liver cirrhosis

SOLAR-1 & -2

ASTRAL-4

ALLY-1

SOLAR-1 and SOLAR-2: LDV/SOF + RBV in GT 1 or 4 with Decompensated Cirrhosis

LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks

100

80

60

40

20

0

SV

R12

(%

)

CTP B CTP C

8796

20/23

22/23

8578

18/23

17/20

n/N =

SOLAR-2: GT 1SOLAR-1: GT 1 and 4

100

80

60

40

20

0

SV

R12

(%

)

CTP B CTP C

87 89 8690

26/ 30

24/ 27

19/ 22

18/ 20

n/N =

Comparable Efficacy (SVR12) Between SOLAR-1 and SOLAR-2 Studies

Charlton M, et al., Gastroenterology 2015;149:649-59Manns M, et al., Lancet Infect Dis 2016;16:685-97

0

20

40

60

80

100 96 9685

60

98 9683

67

F0–F3

53/55 22/26 15/18

CPT B

55/56 25/26 24/25 2/3

CPT A

3/5

CPT C

2 relapses

1 consentwithdrawn

1 death 1 death

1 relapse2 deaths

1 consent

withdrawn

3 deaths 2 relapses

1 relapse

SV

R12

(%

)

LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks**8 CPT B 24-week and 1 CPT C 24-week pts had not reached the Wk 12 post-Tx visit

LDV/SOF + RBV for the Treatment of HCV in Patients with Post-transplant Recurrence

(SOLAR-1)

G1 or 4, treatment-naive or -experienced

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

LDV/SOF + RBV

LDV/SOF + RBV

Week 0

Week 12

Week 24

SVR12

SVR12

Week 36

n=112

n=111

ALLY-1: DCV, SOF + RBV (600 mg) for HCV Patients with Advanced Cirrhosis or Post-LTX

Recurrence

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

Primary end point: SVR12 in GT1 82% (advanced cirrhosis) and 95% (post-transplant)

SVR12 by Child-Pugh class: Advanced cirrhosis cohort, all genotypes

9184

8997

75

56

100

73

0

20

40

60

80

100 92 94

56

A B C

Child-Pugh class

91 96

78 76

No Yes No Yes >3.52.8–3.5

<2.8

SV

R1

2 (%

)

<1.71.7─2.3

>2.3 <2.02.0─3.0

>3.0

Ascites HE Albuming/dL

INR Total bilirubin mg/dL

11/12

30/32

9/16

21/23

29/37

22/23

28/37

10/11

30/31

10/18

41/49

6/8

3/18

33/37

9/12

8/11

8388

50

10094 96

85

100

8894

50

86

ASTRAL-4: SOF/VEL for HCV in Patients with Decompensated Cirrhosis

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

SOF/VEL n=90

SOF/VEL + RBV n=87

SOF/VEL n=90

Wk 0 Wk 12 Wk 36Wk 24

SVR12

SVR12

SVR12S

VR

24 r

ates

(%

)

75/90

82/87

79/90

60/68

65/68

67/71

7/14

11/13

6/12

G2: 4/4G4:4/4

G2: 4/4G4:2/2

G2: 4/4G4:2/2G6:1/1

BT - 1 1 - - -Relapse 11 2 7 5 1 3

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

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

Baseline Clinical and Laboratory Parameters Associated with Clinical Benefits of SVR with SOF/VEL in Decompensated

Cirrhotic Patients

O’Leary J, et al. EASL 2016, Barcelona. #SAT-169

Patients, n/n (%) SVR12, n=127 SVR24, n=110BMI<30 kg/m2 80/133 (60) 76/129 (59)≥30 kg/m2 47/96 (49) 34/84 (40)

CPTA 8/14 (57) 6/13 (46)B 112/205 (55) 99/191 (52)C 7/10 (70) 5/9 (56)

MELD<15 105/203 (52) 92/188 (49)≥15 22/26 (85) 18/25 (72)

Ascites    None 27/48 (56) 24/42 (57)Mild/moderate

99/175 (57) 83/165 (50)

Severe 1/6 (17) 3/6 (50)Albumin ≤3 g/dL 63/105 (60) 57/93 (61)>3 g/dL 64/124 (52) 53/120 (44)

EncephalopathyNone 62/87 (71) 49/80 (61)Grades 1−2 65/142 (46) 61/133 (46)

Platelets<75 × 103/µL 61/96 (64) 54/91 (59)≥75 × 103/µL 66/133 (50) 56/122 (46)

n= 0 1 1 6 9 19 22 34 47 30 11 5 1 1 1 0Change

in MELD -12 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 7 10 11

n= 1 2 1 4 3 2 1 4 1 2 1 0 2 0 0 1Change

in MELD-12 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 7 10 11

Improvements in MELD score were driven largely by improvements in total bilirubin Lab improvements (albumin/bili) precede clinical improvements (ascites, encephalopathy)

0

1 13

5

1012

18

25

16

63

1 1 1

0

BL MELD <15

49% improved 26% worsened

4

8

4

16

12

8

4

16

4

8

4

0

8

0 0

4

BL MELD ≥15

72% improved 24% worsened

• SAE in 15/35 (43%) patients before (24 weeks) and in 12/35 (34%) patients during antiviral therapy, the majority in association with acute-on-chronic hepatic decompensation. Lactic acidosis occurred in 5/35 (14%) patients during therapy, while no event of lactic acidosis was observed prior to therapy. Lactic acidosis was severe (pH <7.3) in two patients.

• RBV in combination with SOF based antiviral therapy in patients with HCV associated advanced cirrhosis may be associated with the development of lactic acidosis. Impaired renal function, and higher MELD/Child-Pugh scores were identified as potential risk factors.

Welker et al., J Hepatol 2016;64:790-99

Safety of Combined SOF/RBV Treatment in Patients with Advanced Cirrhosis

Conclusions

• Few „special populations“ left in HCV• ESRD/hemodialysis

– Paritaprevir/r + Ombitasvir ± Dasabuvir (HCV-1,-4)– Grazoprevir + Elbasvir (HCV-1,-4)– Glecaprevir + Pibrentasvir (pangenotypic)

• Decomp. Cirrhosis: Sofosbuvir +NS5A-inhibitor• Safety of DAAs in these populations not yet fully defined –

thorough surveillance during therapy• No data in patients with ESRD and decompensated

cirrhosis