Global medical affairs, hepatology

paradigm to establish 8 weeks of treatment for TN NC, across all genotypes
G/P: integrated analyses have demonstrated high efficacy across different patient types, regardless of baseline patient or viral characteristics
LDV/SOF: RWE data continues to support the potential expanded use in GT1 patients irrespective of HCV RNA baseline viral load
SOF/VEL/VOX: integrated analyses have identified multiple baseline predictors associated with lower SVR rates in GT1a patients
From the data presented at EASL 2017, two regimens are expected to dominate the retreatment landscape: 16 weeks of G/P (MAGELLAN-1 Part 2) and 12 weeks of SOF/VEL/VOX (POLARIS integrated analyses)
EASL 2017 saw the release of data for many patient groups considered once difficult to treat, including patients with CKD, PWID, HIV/HCV coinfection and post-liver/renal transplant; these data bring into question whether special patient populations still exist with highly efficacious next-generation DAAs
EASL 2017 saw the release of a wealth of RWE data, including first reports of the use of SOF/VEL and EBR/GZR I real-life clinical practice; RWE continues to confirm the results of clinical trials across the currently approved regimens (OBV/PTV/r + DSV, LDV/SOF, SOF/VEL, EBR/GZR)

TN NC, treatment-naive, non-cirrhotic; RWE, real-world evidence; CKD, chronic kidney disease; PWID, persons who inject drugs.

TN NC, across all genotypes, including GT3 patients
G/P demonstrates consistently high efficacy across different patient types regardless of baseline patient or viral characteristics
Limited RW data suggests that LDV/SOF use for GT1 patients may be expanded based on RWE data suggesting a HCV RNA baseline viral load >6 million IU/mL has no impact on SVR
Multiple baseline predictors were associated with lower SVR rates in GT1a patients treated for 8 weeks with SOF/VEL/VOX
Studies continue to pursue mix and match regimens (DCV + SOF, EBR/GZR + SOF) for 8 weeks in TN NC patients; this could be a feasible option for select markets

+ DCV in Treatment-Naive HCV GT3-Infected Patients without Cirrhosis

BT, breakthrough; d/c, discontinuation; IDU, injection drug use; ND, not determined; non-VF, non-virologic failure; RAS, resistance-associated substitution.
* NS3 sequences not determined; † One patient with VF had poor adherence and both NS3 + NS5A baseline RASs.

Treatment-naive, GT3-infected patients without cirrhosis were randomized 2:1 to receive 12 weeks of either G/P or SOF + DCV, or were assigned to an 8-week G/P arm

149
157

111
115

222
233

12 weeks

12 weeks

8 weeks

1 BT
3 relapse
7 non-VF

0 BT
1 relapse
3 non-VF

1 BT
5 relapse
2 non-VF

Non-inferior to
12-week SOF + DCV

Non-inferior to
12-week G/P

n
N

Pangenotypic G/P: Integrated Efficacy Analysis of Genotype 1–6 Patients without Cirrhosis (1)

mITT, excludes patients with non-virologic failure. * All GT3 patients were treatment-naive; † GT1: n = 1; GT3: n = 1; ‡ GT3: n = 1; § GT2: n = 2; GT3: n = 5; ║ GT3: n = 3; ¶ N adjusted for patients with missing data and excludes non-virologic failure.

Integrated efficacy analysis of 8 or 12 weeks’ G/P treatment in non-cirrhotic patients with GT1–6 infection across seven phase 2 or 3 clinical trials

Logistic regression analysis showed presence of baseline NS3 155, 156, or 168 RASs combined with NS5A RASs had a statistically significant impact on SVR12 (P<0.0001) in this analysis
<1% of patients had the combination of RASs and most achieved SVR12 (78%; 7/9)

Pangenotypic G/P: Integrated Efficacy Analysis of Genotype 1–6 Patients without Cirrhosis (2)

TE, treatment-experienced; Tx, treatment compliant; OST, opioid substitute therapy.

Integrated efficacy analysis of 8 or 12 weeks’ G/P treatment in non-cirrhotic patients with GT1–6 infection across seven phase 2 or 3 clinical trials

409 416

571 575

87 87

155 155

150 152

178 178

40 40

65 65

168 171

274 274

15 15

18 18

197 201

219 221

665 668

856 859

54 56

86 87

85 89

117 117

135 138

189 192

59 59

123 123

61 61

58 59

87 88

91 91

Infection: An Integrated Analysis

d/c, discontinuation; GGT, gamma-glutamyl transferase; PI, protease inhibitor; PRS, pegIFN/RBV or SOF + RBV ± pegIFN. * NS5A- and/or PI experienced; † Of the total eight patients, three experienced a total of nine DAA-related AEs leading to study drug d/c, including abdominal pain, diarrhoea, dyspepsia, nausea, fatigue, malaise, dizziness, headache, and transient ischaemic attack; ‡ Four (0.2%) patients experienced any DAA related AE with ≥ grade 3, including upper abdominal pain, asthenia, migraine, and increased ALT, AST, and GGT; § Causes of death were pneumonia, accidental overdose, adenocarcinoma, hepatic cancer metastatic, cerebral haemorrhage, alcohol poisoning and toxicity to various agents (none were considered to be related to treatment); ¶ Increased grade from baseline result; # One patient experienced grade 3 and above ALT (>5 × ULN) elevations concomitant with total bilirubin (>2 × ULN) elevations 1 day post-treatment. Lab abnormalities were consistent with an obstructive pattern, most likely due to transient passage of a biliary stone; $ Most elevations were predominantly indirect bilirubin without associated ALT increase in patients with indirect Gilbert’s syndrome.

Patients received G/P for 8 weeks (non-cirrhotic; n = 828), 12 weeks (n = 1317; 225 [17%] with compensated cirrhosis) or 16 weeks (n = 120; 63 [53%] with compensated cirrhosis)

The frequency and severity of AEs were similar between non-cirrhotic patients and cirrhotic patients

Chronic HCV GT1, 2, 4, 5 or 6 Infection in Adults with Compensated Cirrhosis

d/c, discontinuation; PTW, post-treatment Week; RAS, resistance-associated substitution.
* SOF + RBV ± pegIFN.

Patient with history of hemophilia died due to cerebral hemorrhage (not related to study drug)

Baseline RAS prevalence
NS3, 2/133 (2%); NS5A, 53/133 (40%); NS3 + NS5A, 2/133 (2%)

GT1–6 HCV Infection and Compensated Cirrhosis: An Integrated Analysis

CC, compensated cirrhosis; CP, Child-Pugh; DILI, drug-induced liver injury; d/c, discontinuation; RI, renal impairment; PK, pharmacokinetics. * Baseline fibrosis stage was defined for subjects with non-missing liver biopsy scores, FibroScan scores, or FibroTest scores; cirrhosis status was determined as collected in EDC; † 1 patient had a CP score of 7; ‡ Both deaths due to AE (cerebral hemorrhage) and not deemed related to treatment.

An integrated safety and PK analysis of HCV GT1–6-infected patients with compensated cirrhosis treated with G/P for 12 or 16 weeks from four phase 2 and 3 clinical trials (EXPEDITION-1 and 4, SURVEYOR-II, and MAGELLAN-1)

Patients received G/P for 12 weeks (n = 245, including 20 patients with severe renal impairment [baseline eGFR of < 30 mL/min/1.73 m2]) or 16 weeks (n = 63)

Patient with a history of esophageal varices experienced an AE (esophageal variceal bleeding) with a sign of hepatic decompensation; event was not deemed related to study drug

There were no grade 3 ALT increases and no cases consistent with DILI

GLE exposures in patients with compensated cirrhosis were 2.2-fold higher than in non-cirrhotics; PIB exposures were similar

G/P in Phase 2 and 3 Clinical Trials

RAS, resistance-associated substitution; TE, treatment-experienced; VF, virologic failure. * Using next-generation sequencing (2% and 15% thresholds); † Includes polymorphisms at amino acid positions 155, 156, 168 in NS3, and 24, 28, 30, 31, 58, 92, 93 in NS5A relative to the subtype specific reference sequence: ‡ A30x is A30L/M/R/S/T/V.

A pooled resistance analysis* was conducted in HCV GT1–6-infected patients with or without compensated cirrhosis (N = 2256) treated with G/P for 8, 12, or 16 weeks from eight phase 2 and 3 clinical trials

High incidence of baseline NS5A RASs in GT2, GT4 and GT6 was driven by detection of:
L/M31 (in GT2a and GT2b) and R30K (GT2c)
position 58 (GT4a, 4d, and 4f)
position 28 (GT6)

NS3

NS5A

‡

Baseline NS3 RASs did not impact SVR12 rates in GT3 patients

Baseline NS5A A30K and Y93H had minimal impact on efficacy, except in TE patients treated 12 weeks

There were 22 virologic failures (1%) (GT1a [n = 2], GT2a [n = 2], GT3a [n = 17], GT3b [n = 1])

Baseline RASs did not impact SVR in GT1 and GT2 patients and there were no virologic failures in GT4–6 patients

Baseline polymorphisms in GT3 patients

with Chronic Genotype 1 Hepatitis C Virus Infection with and without Cirrhosis

BL, baseline; C, cirrhosis; d/c, discontinuation; ITT, intent-to-treat; ITT-PS, ITT population excluding patients with the HCV Y93H polymorphism; LTFU, lost to follow-up; NC, no cirrhosis. * 15% cut off.

Phase 3 study evaluating the safety and efficacy of G/P for 8 or 12 weeks or OBV/PTV/r for 12 weeks in Japanese patients with HCV GT1-infection without cirrhosis (Arms A and B) or with compensated cirrhosis (Arm C)

Among non-cirrhotic patients treated with G/P for 8 wks, all patients with BL Y93H RAS (n = 23) achieved SVR

Chronic Genotype 2 Hepatitis C Virus Infection with and without Cirrhosis

C, cirrhosis; d/c, discontinuation; LTFU, lost to follow-up; mITT, excludes non-virologic failures; NC, no cirrhosis; RL, relapse.
* Nausea and vomiting; † Malaise; ‡ Drug eruption, characterised as purpuric rash and eczema.

Phase 3 study of the safety and efficacy of G/P for 8 (CERTAIN-2) or 12 (CERTAIN-1) weeks in Japanese patients with HCV GT2-infection without cirrhosis (Arms A and B) or with compensated cirrhosis (Arm C)

DAA-related AEs were significantly different between Arm A and Arm B (P<0.001)

8 weeks G/P achieved non-inferiority compared with 12 weeks SOF + RBV

1 LTFU 1 d/c

2 RL 1 d/c

Results in High SVR12 in Genotype 1–6 HCV-Infected Patients with Minimal Fibrosis: A Retrospective Analysis of the ASTRAL and POLARIS Clinical Studies

* HCV RNA < 6 million IU/mL.

GT1

GT1a

GT1b

GT2

GT3

GT4

GT5

GT6

F0–2

F3

F4

LDV/SOF all patients SVR12: GT1 95% (35/37), GT1a 94% (30/32), GT1b 100% (5/5)

85
87

LDV/SOF all patients SVR12: GT1 90% (35/39), GT1a 86% (25/29), GT1b 100% (9/9)

14
14

19
19

63
65

11
11

10
10

22
22

3
3

8
8

303
303

202
202

100
100

195
195

218
221

101
101

23
23

31
31

127
133

85
90

42
43

41
43

90
90

40
41

13
14

23
23

91
92

66
66

25
26

34
34

76
76

20
21

5
5

6
6

31
33

21
23

9
9

5
5

22
22

5
6

1
1

4
4

152
155

105
107

47
48

58
58

154
163

49
49

5
5

13
13

55
63

45
52

10
11

15
15

85
87

11
11

2
2

3
3

Trials analysed: ION-3; ASTRAL-1, -2, and -3; POLARIS-2 and -3; POLARIS-2 and -3
Data presented is the completer population: All patients who completed treatment, and had HCV RNA data at post-treatment week 12 or a later time point

12 Weeks in DAA-experienced Patients or for 8 weeks in DAA-Naive Patients: An Integrated Analysis of the POLARIS-1, POLARIS-2, POLARIS-3 and POLARIS-4 Studies

BT, breakthrough; DAA-E, direct-acting antiviral treatment-experienced; DAA-N, direct-acting antiviral treatment-naïve; OT, other; RL, relapse.

Retrospective analysis of HCV GT1–6 infected patients treated with SOF/VEL/VOX for 8 weeks (DAA-naive) or 12 weeks (DAA-experienced) in the phase 3 POLARIS studies

59
63

1 BT 2 RL
3 OT

1 OT

4 RL
2 OT

1 RL
1 OT

14 RL

2 RL

2 RL

2 RL
3 OT

2 RL
2 OT

1 RL

SVR12 rates were generally lower across subgroups in GT1a patients

SVR12 was lower in DAA-naive GT1a patients

SOF/VEL/VOX for 8 Weeks in DAA-Naive Patients: An Integrated Resistance Analysis of the POLARIS-2 and POLARIS-3 Studies

BL, baseline; NS3 and NS5A RASs, substitutions that confer >2.5 fold reduced susceptibility to any NS3 or NS5A inhibitor; RASs, resistance associated substitutions; TE, treatment emergent. * 15% cut-off.

SVR12 was 98% (41/42) in patients with BL NS5B RASs

Integrated resistance analysis of baseline* and treatment emergent NS3, NS5A and NS5B RASs in DAA-naive HCV GT1-6 patients treated with SOF/VEL/VOX for 8 weeks in the phase 3 POLARIS-2 and -3 studies (RASs detected at 15% cut-off)

n
N

106
110

94
103

23
26

27
27

1
1

33
35

149
151

5
5

32
32

22
23

21
22

65
66

NS3

NS5A

80 any

155 any

156 any

168 any

28 any

30 any

31 any

93 any

66
74

1
1

16
17

0
0

41
41

28
30

39
42

27
27

SVR12 was 100% (24/24) in GT3 patients with BL Y93H RAS

SVR12 was 88% (51/58) in GT1a patients with BL NS3 Q80K RAS

12 Weeks in >1,000 Patients Treated in the POLARIS-1, POLARIS-2, POLARIS-3, and POLARIS-4 Studies: An Integrated Analysis

D/C, discontinuation; PTD, post-treatment Day; SAEs; serious adverse event. * Assessed as unrelated to treatment.

Retrospective safety analysis of 1056 HCV GT1–6 infected DAA-experienced (POLARIS-1 and -4) or DAA-naive (POLARIS-2 and -3) patients with or without compensated cirrhosis

POLARIS-1: SOF/VEL/VOX vs placebo (12 weeks)

POLARIS-4: SOF/VEL/VOX vs SOF/VEL (12 weeks)

POLARIS-2 and -3: SOF/VEL/VOX (8 weeks)
vs SOF/VEL (12 weeks)

DAA-naive

DAA-experienced

Most cases of diarrhea and nausea in the SOF/VEL/VOX group were grade 1; no grade 3/4 events

Older age, Asian race, cirrhosis and mild renal impairment did not impact incidence or severity of AEs in the SOF/VEL/VOX group

1 patient in the SOF/VEL/VOX group had a grade 3 elevation of ALT, while 1 patient had a grade 3 bilirubin elevation

Cirrhotic People with HCV GT3 Infection and Compensated Cirrhosis: SVR24 Results of the C-ISLE Study

BL, Baseline; DC/AE, discontinuation due to AE; FAS, Full set analysis; LTFU, lost to follow-up; RAS, resistance-associated substitution; RL, relapse;
VF, virologic failure; WC, withdrew consent.
*1 patient has Y93H, P58S & S62T RASs present at BL and P58S & S62T present at treatment-failure; 1 patient has no RAS present; † Y93H RAS was not present at
treatment failure in patient who did not achieve SVR; ‡ 1 case of each (lung infection, creatinine increased, chest pain, opiate overdose, and cellulitis); § 1 patient had a drug-related SAE of vomiting on Day 4 and subsequently d/c treatment on Day 7 due to cellulitis; || Lowest level was 8.9 g/dL.

52% (50/97) of patients had baseline NS5A RASs; 9 patients had Y93H RASs (1% level of detection)

C-ISLE: UK study of patients with HCV GT3 infection and compensated cirrhosis treated with EBR/GZR + SOF ± RBV for 8–16 weeks (N = 100)

2 RL*

n N

21 23

21 24

16 17

17 18

15 18

3 LTFU/WC

1 LTFU/WC

2 LTFU/WC
1 DC/AE

Treatment-naive

pegIFN/RBV treatment-experienced

Baseline NS5A RASs
98% SVR12 (49/50) in patients with baseline NS5A RASs
98% SVR12 (46/47) in patients without baseline NS5A RASs
89% SVR12 (8/9) in patients with Y93H RAS at BL†

Randomized 1:1 (n=47)

Randomized 1:1:1 (n=53)

1 LTFU/WC

29% Asian

47% treatment-naive

FAS population

Weeks in Treatment-Naive Non-Cirrhotic Patients with Chronic HCV GT3 Infection

BL, baseline; FS, FibroScan Score; TE, treatment-emergent.
* A30V (n = 1); S62L/Y93H (n = 1).

Ongoing, multicenter, open-label, single-arm pilot study evaluating the safety and efficacy of DCV + SOF for 8 weeks in treatment-naive patients with HCV GT3 infection without cirrhosis

4 relapses

No safety signal reported

Resistance analysis
BL S62L/Y93H NS5A RAS (n = 1); TE A30K/Y93H (n = 1); poor compliance (n = 1); data not available (n = 1)

Patients with Cirrhosis

CP, Child Pugh; D/C, discontinuation; IQR, interquartile range; LSM, liver stiffness measurement; TE, treatment-experienced; TN, treatment-naive. * LSM data available for 43 patients; † CP A vs CP B/C; ‡ IFN/RBV-experienced; § IFN/RBV/SOF-experienced.

Real-world study of DCV + SOF + RBV for 12 weeks in HCV GT3-infected patients with cirrhosis in Scotland

Quantifiable RNA at Week 4 was associated with numerically lower SVR12 vs unquantifiable RNA at Week 4 (75% [12/16] vs. 94% [33/35]; p=0.069)

SVR12 rates were similar to those in clinical trials

p = 0.76†

No D/C due to drug-related AEs

4
5

3
4

‡

§

population (~5–10%), however there continues to be data generated
The data reported for G/P established the 16 week regimen as a efficacious and safe retreatment option for the majority of GT1 DAA failures in 2018 and beyond
16 weeks of G/P in GT1 NS5A failures resulted in a 94% SVR12 rate
17/19 LDV/SOF failures achieved SVR12. LDV/SOF failures will represent the majority of DAA failures in the near future
12 weeks of G/P in GT1 NS3 failures resulted in a 100% SVR12 rate
Additional analyses reported for 12 weeks of SOF/VEL/VOX further support its use in the DAA failure population across all genotypes
The efficacy was ≥95% SVR12 irrespective of baseline characteristics
Two regimens are expected to dominate the retreatment landscape: 16 weeks of G/P and 12 weeks of SOF/VEL/VOX
G/P has a longer treatment duration, is restricted to GT1 but appears to have a cleaner safety profile

in Patients with Chronic HCV GT1 OR 4 and Prior Direct-Acting Antiviral Treatment Failure

BT, breakthrough; d/c, discontinuation; PI, protease inhibitor.

Randomized trial of G/P for 12 or 16 weeks in HCV GT1- or GT4-infected patients with prior DAA failure, without cirrhosis or with compensated cirrhosis

39
44

43
47

Treatment duration

1 BT
4 relapse

4 BT

SVR12 rate by prior DAA therapy

14
14

14
16

11
14

13
13

17
18

13
16

n
N

n
N

N = 19 patients had previously failed LDV/SOF
N = 10 had previously failed ≥2 DAA-containing regimens

Therapy in HCV-Infected Patients Who Had Failed Prior DAA Regimens Containing NS3/4A Protease and/or NS5A Inhibitors

NGS, next-generation sequencing; OTVF, on-treatment virologic failure; PI, protease inhibitor; RAS, resistance-associated substitution; wks, weeks.

NGS (detection threshold of 15%) was used to perform resistance analysis of HCV from DAA-experienced patients treated with 12- or 16-week G/P from the MAGELLAN-1 (Part 2) study

13
13

2
2

20
24

4
5

13
13

4
4

22
23

1
4

SVR12 rate by baseline RASs

1 OTVF
3 relapse

1 relapse

1 OTVF

3 OTVF

PI + NS5A- experienced (N = 30)

SVR12 % (n/N)

NS5A- experienced, PI-naive (N = 32)

PI-experienced, NS5A-naive (N = 26)

None

NS3 only

NS5A only
(single)

NS5A only
(multiple)

NS3 + NS5A

Prevalence (%)

n
N

Major HCV Genotypes

* Relative to GLE EC50s for the respective wild-type replicons in transient transfection assays: GT1a: 0.21 nM; GT1b: 0.47 nM; GT2a: 2.5 nM; GT2b: 3.1 nM; GT3a: 0.55 nM; GT4a: 0.67 nM; GT4d: 0.15 nM; GT6a: 0.15 nM; † Relative to GLE EC50s for the respective wild-type replicons in transient transfection assays: GT1a: 0.72 pM; GT1b: 1.9 pM; GT2a: 0.99 pM; GT2b: 1.2 pM; GT3a: 0.65 pM; GT4a: 0.78 pM; GT5a: 0.93 pM; GT6a: 1.0 pM.

The in vitro resistance profiles of GLE or PIB in major HCV genotypes were determined using drug-resistant replicon colony selection

Activity of GLE against common GT1–4 and 6 RASs

Activity of PIB against common GT1–6 RASs

GLE predominantly selected NS3 A156 substitutions in GTs 1–4 and D168 substitutions in GT6 in vitro
PIB selected few NS5A substitutions in vitro

12 Weeks in DAA-experienced Patients or for 8 weeks in DAA-Naive Patients: An Integrated Analysis of the POLARIS-1, POLARIS-2, POLARIS-3 and POLARIS-4 Studies

BT, breakthrough; DAA-E, direct-acting antiviral treatment-experienced; DAA-N, direct-acting antiviral treatment-naïve; OT, other; RL, relapse.

Retrospective analysis of HCV GT1–6 infected patients treated with SOF/VEL/VOX for 8 weeks (DAA-naive) or 12 weeks (DAA-experienced) in the phase 3 POLARIS studies

59
63

1 BT 2 RL
3 OT

1 OT

4 RL
2 OT

1 RL
1 OT

14 RL

2 RL

2 RL

2 RL
3 OT

2 RL
2 OT

1 RL

SOF/VEL/VOX for 12 Weeks in DAA-Experienced Patients: An Integrated Resistance Analysis of the POLARIS-1 and POLARIS-4 Studies

RASs, resistance associated substitutions * 15% cut-off; † VOX- or VEL-specific RASs that confer >2.5-fold change compared with GT-specific reference.

Integrated resistance analysis of baseline* and treatment-emergent NS3, NS5A and NS5B RASs in DAA-experienced HCV GT1–6 patients treated with SOF/VEL/VOX for 12 weeks in the phase 3 POLARIS-1 (NS5A inhibitor-experienced) and -4 (DAA-experienced) studies

GT3-infected patients: 93% (25/27) with Y93H NS5A RAS achieved SVR12

Of the 7 patients who relapsed (POLARIS-1, n = 6; POLARIS-4, n = 1), 1 (GT4d) had treatment-emergent NS5A Y93H RAS

VOX- or VEL-specific RASs did not impact SVR12

97% (32/33) of patients with NS5B RASs achieved SVR12

†

in HCV GT3 Patients ± Cirrhosis Treated with DCV + SOF or SOF/VEL ± Ribavirin According to Baseline Resistance Analysis

SOF + RBV failures*
N = 73

SOF + RBV Failures
n = 86

Resistance Analysis after SOF + RBV failure

SOF/VEL + RBV (n=1)

DCV + SOF ± RBV (n=9)

DCV + SOF ± RBV (n=14)

LDV/SOF + RBV (n=1)

SOF/VEL ± RBV (n=15)

Week 0

12

24

FU12

Retreatment with an NS5A-inhibitor (n=40)

Interim analysis: SVR 88% (n=21/24)

1 patient with VEL failure did not take RBV

Real-world data from treatment-experienced patients with HCV GT3 infection treated with DCV + SOF ± RBV for 12–24 weeks or SOF ± VEL/LDV ± RBV for 12–24 weeks

1

in n = 22 patients due to missing serum or failed sequence analysis.

PS-155, Vermehren; High SVR Rates in HCV GT3 Patients ± Cirrhosis Treated with DCV + SOF or SOF/VEL ± Ribavirin According to Baseline Resistance Analysis

DCV + SOF ± RBV failures*
N = 73

DCV + SOF ± RBV Failures
n = 80

Resistance Analysis after DCV + SOF ± RBV failure

Real-world data from treatment-experienced patients with HCV GT3 infection treated with DCV + SOF ± RBV for 12–24 weeks or SOF ± VEL/LDV ± RBV for 12–24 weeks

2

Retreatment of GT3 patients who failed a first course of DCV + SOF therapy

1 patient with VEL failure did not take RBV

Uprifosbuvir (MK-3682)/Grazoprevir/Ruzasvir in Cirrhotic or Non-cirrhotic Patients with HCV GT1 Infection Who Previously Failed a DAA regimen: C-SURGE

BL, baseline.
*1 patient withdrew from the study after taking 3 doses of study drug; † One participant in 24 week arm had unknown cirrhosis status
‡ RASs detected by next-generation sequencing with 15% sensitivity NS5A RAS = any change from wild-type at position 28, 30, 31 or 93;
NS3 RASs = any change from wild-type at positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170 or 175);;

A multicentre, open-label, randomized (1:1) study in n = 94 HCV GT1-infected patients who relapsed after receiving LDV/SOF or EBR/GZR

No DAA-related SAEs or d/c due to AEs

BL NS5A or NS3 RASs† had no impact on SVR12 and all patients with BL NS5A Y93 RAS achieved SVR

2, 3 Infection Following 16 Weeks of GZR/RZR/Uprifosbuvir (MK-3682) + RBV After Having Failed 8 Weeks of a Triple Drug Regimen (Part C of C-CREST-1 & -2)

* One GT2 withdrew after single dose with SAEs of vomiting and tachycardia; † >5-fold reduction in susceptibility to RZR in vitro.

83% (19/23) had RASs in both NS3 and NS5A High-impact RASs† were detected in: 77% (10/13) GT2 (L31M, F28C) 88% (7/8) GT3 (Y93H, A30K, L31M, S62L)

8 8

1 d/c*

Retreatment with GZR + RZR + UPR + RBV for 16 weeks in HCV GT1, 2, 3 non-cirrhotic patients that experienced relapse following 8 weeks of a 3-DAA regimen in Part A of C-CREST

of Direct-Acting Antivirals

Modelling
Natural history and disease progression were modelled using published meta-analyses and observational models
DAA treatment was modelled in different waves:
TVR, BOC launched in 2011
SOF/SMV, SOF+RBV±IFN in 2014
Multiple NS5A-inhibitors from 2015
F3–F4 patients assigned priority
SVR rates taken from published EU/US RW data
Non-cirrhotic NS5A treatment failures were not re-treated until 2018, after which they were eligible for re-treatment with new NS5As

Majority of treatment failures will occur in patients treated with NS5A inhibitors, or who are cirrhotic, or infected with HCV GT1a

and all CKD stages – irrespective of baseline characteristics
Only option for GT2–3 patients with severe CKD, including those on hemodialysis
Real world data are emerging for the use of SOF-based regimens in patients with severe CKD with attempts to establish safety and effectiveness
Conflicting data presented on impact of SOF on eGFR
First real-world data confirmed the effectiveness of EBR/GZR in patients across all stages of CKD
One analysis demonstrated the difficulty in capturing true renal function changes; no correlation was found between MDRD, cystatin-C and NGAL biomarkers with traditional biomarkers eGFR or Creatinine

HCV Infection GT1–6 as a Function of Chronic Kidney Disease Stage

CKD, chronic kidney disease; d/c, discontinuation; ITT, intent-to-treat; PK, pharmacokinetic. * DAA-related SAE was transient ischemic attack (patient d/c treatment and did not achieve SVR12); †Causes of death (all not related to study drug): CKD stage 1 (n=3) pneumonia, accidental overdose, alcohol poisoning and toxicity to various agents; CKD stage 2 (n=1) cerebral haemorrhage; CKD stage 3 (n=1) adenocarcinoma; CKD stage 4–5 (n=1) cerebral haemorrhage.

An integrated efficacy, safety, and PK analysis of HCV GT1–6-infected patients treated with G/P for 8 (n = 822), 12 (n = 1347), or 16 (n = 69) weeks from eight phase 2 and 3 clinical trials, as a function of CKD stage

Patients were stratified by CKD stage (eGFR [mL/min/1.73 m2] by MDRD) Stage 1, eGFR ≥90; stage 2, eGFR 60 to <90; stage 3, eGFR 30 to <60; stage 4, eGFR 15 to <30; stage 5 eGFR<15

SVR12 (ITT) rate was 98% overall, and high irrespective of CKD stage

Most total bilirubin elevations were primarily driven by indirect bilirubin and were not associated with ALT increase

Exposures of GLE and PIB were higher in patients with more advanced CKD, however PK changes were not clinically relevant

Overall, the mean change in eGFR (mL/min/1.73 m2) from baseline to final post-treatment visit was –2.5 ± 12.7

Tolerability and Safety of Largest ESRD Patient Cohort

ESRD, end-stage renal disease. * 1 patient discontinued due to severe nausea; 1 patient discontinued due to sepsis from pneumonia unrelated to treatment.

Analysis of chronic HCV GT1–3 infected patients with ESRD on dialysis or GFR <30 mL/min treated with full-dose (400 mg) SOF-based regimens (SOF + SMV, LDV/SOF, SOF + DCV, SOF/VEL) for 12 or 24 weeks

Most frequent AEs were: nausea (n = 4 [9%]), insomnia (n = 4 [9%], headache (n = 3 [7%]), pruritus (n = 1 [2%]), and anemia (n = 1 [2%])

The AE profile and rate of discontinuation were similar to those in the general HCV population

n
N

No hepatic decompensation events
No dose adjustments

7% (3/45) of patients were not on dialysis

to Moderate Renal Dysfunction Treated with SOF

CKD-EPI, chronic kidney disease epidemiology collaboration; eGFR, estimated glomerular filtration rate;
EOT, end of treatment; MDRD, modification of diet in renal disease; PTW12, post-treatment Week 12; SCr, serum creatinine.

Real-world retrospective study of the effect of SOF on renal function in patients with baseline eGFR <60 mL/min/1.73 m2 and chronic HCV infection in Hawaii

Serum creatinine
Overall average increase in SCr of 0.04 from baseline to EOT (p <0.01); there was no significant different in SCr between EOT and PTW12 (p = 0.26)
In patients ≥65 years old, SCr increased on average by 0.05 during therapy (p< 0.01); no significant difference was found between EOT and PTW12 (p = 0.45)
No significant difference in SCr between baseline, EOT, and PTW12 in patients with renal impairment (p = 0.61)

GFR: baseline to EOT
Laboratory GFR: no significant difference in any eGFR subgroup
Cockcroft–Gault formula: average decrease of 4.72 (p <0.01) among patients with GFR >60
MDRD formula: average decrease of 5.18 (p <0.01) among patients with GFR >60
CKD-EPI formula: average decrease of 5.18 (p <0.01) among patients with GFR >60

GFR: EOT to PTW12
No significant difference when GFR was calculated by any of the GFR equations

Cirrhosis Treated with DAA Agents

CC, compensated cirrhosis; DC, decompensated cirrhosis; eGFR, estimated glomerular filtration rate; EOT, end of treatment; MDRD, modification of diet in renal disease equation; NGAL, neutrophil gelatinase-associated lipocalin; PTW12, post treatment week 12.
* Renal risk factors include pre-existing renal impairment, diabetes mellitus, hypertension, and diuretics.

Assessing changes in renal function during DAA (mostly SOF) therapy in HCV-infected patients with compensated or decompensated cirrhosis using conventional markers (creatinine and eGFR using MDRD) and serum biomarkers (NGAL and cystatin C)

A poor correlation between NGAL or cystatin c and eGFR or creatinine existed

Impairment of renal function (detected by serum biomarkers) occurred during treatment in both groups and persisted beyond EOT

No difference in baseline creatinine or eGFR between CC and DC patients

No difference in eGFR between baseline and EOT

No significant changes in creatinine or eGFR

Kidney Disease: Real-World Experience from the TRIO Network

CKD, chronic kidney disease; PP, per-protocol (defined as patients that completed intended therapy and received SVR testing at 12 weeks); VF, virologic failure. * eGFR values were calculated using the CKD-EPI Creatinine equation; † Includes GT1 unknown, GT2, GT3, and GT unknown.

Data from the TRIO Network were used to evaluate the real-world effectiveness of EBR/GZR in patients with CKD* (baseline eGFR <90 mL/min/1.73 m2) in the United States

440 patients treated with EBR/GZR; 261 with CKD (24% stage 2, 20% stage 3, and 53% stage 4–5

EBR/GZR was used in 93% of patients with 7% receiving RBV. Most patients were treated for 12 wks.

1
1

34
36

27
27

11
11

68
68

142
144

CKD stage

PP population (n = 144)

2 VF

n
N

special patient populations still exist with highly efficacious next-generation DAAs
High SVR rates (>98%) were observed in special populations (HIV/HCV coinfected, post-transplant) treated with G/P with minimal drug-drug interactions anticipated to require additional patient monitoring requirements. No new safety signals were observed and the SVR rates were high regardless of patient or viral characteristics
HIV/HCV coinfected and patients post-transplant treated with G/P are not expected to require treatment durations that differ from TN NC or TN C patients
A pangenotypic regimen like G/P that can deliver high SVR rates with the shortest treatment durations available should provide additional benefits, especially for difficult to treat patient populations (i.e. GT3)
PWIDs achieved high SVR rates with DAAs despite challenges to adherence. These patients may benefit from shorter courses of treatment, as adherence was noted to decline with extended therapy duration

TN NC, treatment-naïve, non-cirrhotic; TN C, treatment-naïve with compensated cirrhosis.

Hepatitis C and Human Immunodeficiency Virus-1: The EXPEDITION-2 Study

BT, breakthrough; d/c, discontinuation; mITT, excludes non-virologic failure. * No GT5 were enrolled; † Patient achieved SVR4, but was lost to follow-up; ‡ Cerebrovascular accident and cerebral haemorrhage; both unrelated to G/P.

Phase 3, multicenter study evaluating G/P treatment in HCV/HIV-1 co-infected patients for 8 weeks (non-cirrhotic) or 12 weeks (cirrhotic) in HCV/HIV co-infected patients with HCV GT1–6 infection

SVR12 was 100% (136/136) in patients without cirrhosis treated for 8 weeks

SVR12 (mITT) was 93% (14/15) in patients with cirrhosis
1 patient with GT3a infection and cirrhosis had on-treatment failure at Week 8
No NS3 RASs at baseline; Y56H at failure
NS5A A30V at baseline; S24F, M28K at failure

Renal Transplant Adults with Chronic Hepatitis C Genotype 1–6 Infection

Phase 3 study to evaluate the efficacy and safety of G/P for 12 weeks in adults with chronic HCV GT1–6 infection without cirrhosis who have had liver (n = 80) or renal (n = 20) transplant

Grade 3 laboratory abnormalities were rare

Patient with mild liver transplant rejection unrelated to DDIs and did not lead to treatment interruption

GT: 1 (57%), 2 (13%), 3 (24%), 4–6 (6%) Fibrosis: F0–1 (80%), F2 (6%), F3 (14%)

BL immunosuppressant medication: tacrolimus (68%), mycophenolic acid (30%), cyclosporine (13%), prednisone (13%), prednisolone (11%), everolimus (8%), azathioprine (6%), and sirolimus (7%)

Inject Drugs

OAT = Outcomes, Adherence, Treatment; TAU = Individual self-administered treatment; DOT = directly observed treatment; * Reasons for treatment withdrawal include not interested in HCV treatment, and no longer in OAT; † Any drug use includes use of any drugs in 6 months, including opiates, cocaine and benzodiazepines; ‡ 3 patients did not achieve undetectable HCV RNA, 2 patients died, 4 patients with HCV RNA not detected at EOT.

PWIDs with HCV GT1 were randomized to one of three models of HCV care delivered on-site in an OAT program. Adherence measured by electronic blister pack

Adherence rates %

Study weeks

1–2

3–4

5–6

7–8

9–10

11–12

Overall adherence:
Individual: 74%
Group: 78%
DOT: 83%

Overall SVR12 rate was 94%‡
Individual: 90% (46/51)
Group: 94% (48/51)
DOT: 98% (50/51)

On-site DAA treatment as highly effective among PWIDs receiving OAT despite active drug use and comorbidities
Intensive care models led to higher rates of adherence

People with Chronic HCV Infection and Recent Injecting Drug Use

A phase 4, open-label, single arm, multicenter, international trial of SOF/VEL for 12 weeks in n = 103 patients with HCV infection and recent injection drug use.

* At study screening; † Missing data in n = 8 patients.

No cases of virologic failure, n = 1 virologic relapse/re-infection to date

3 LTFU
1 death

the comparison of DDIs for SOF/VEL/VOX. The addition of VOX to the regimen leads to increased drug-drug interactions
For certain classes of medications, G/P will have a more competitive DDI profile than SOF/VEL/VOX. In statins, for example, SOF/VEL/VOX may have a more challenging DDI profile
The actual number of DDIs will be confirmed in the pending label; the main classes of interactions are similar to GLE

atazanavir; EFV, efavirenz; FTC, emtricitabine; r, ritonavir; RIF, rifampin; TDF, tenofovir disoproxil fumarate.

The DDI profile of SOF/VEL/VOX with drug transporter and CYP probes, and commonly used concomitant medications was characterized using Phase 1 clinical data

SOF/VEL/VOX 400/100/100 mg (+ VOX 100 mg when evaluating perpetrator interactions to approximate systemic VOX exposures observed in HCV-infected patients) was administered to healthy volunteers

Strong OATP inhibitors increased VOX exposures
Inducers of P-gp, BCRP, and/or CYPs decreased SOF, VEL, and/or VOX exposures
Sensitive substrates of P-gp, BCRP, or OATP1B1/1B3 may require dose adjustment or use with caution and/or monitoring
Clinically significant interactions with HIV ARVs limited to EFV, ATV and lopinavir

the currently approved regimens (OBV/PTV/r + DSV, LDV/SOF, SOF/VEL, EBR/GZR)
First real-world data confirms the effectiveness of EBR/GZR in patients with and without chronic kidney disease
Advanced fibrosis and presence of cirrhosis continue to be a predictor of lower SVR rates
LDV/SOF use may be expanded based on RWE data suggesting HCV RNA BL VL >6 million has no impact on SVR
It will be important to show that the presence of baseline characteristics (especially patients with advanced liver fibrosis) have no impact on SVR rates in patients treated with G/P in the real world

with GT1 HCV: Real-world experience from the TRIO Network

PP, Per protocol; TE, treatment experienced; TN, Treatment-naive.

Real-world study to evaluate utilization of LDV/SOF (n = 1327) and SOF/VEL (n = 89) in HCV GT1-infected patients. Data were collected through Trio Health’s Innervation Platform in the US in 36 states and predominantly in community practices

PP SVR12 (%)

147 151

282 288

23 24

39 41

91 92

5 5

177 183

255 259

20 20

12 12

120 122

9 10

183 189

321 327

6 6

61 62

10 11

Baseline characteristics of patients were similar between 12 week LDV/SOF and 12 week SOF/VEL groups, with the exception of prior TE (17% [159/949] 12 weeks LDV/SOF vs. 31% [28/89] SOF/VEL, p <0.001) and platelets <100,000/mL (9% [72/803] 12 weeks LDV/SOF vs. 18% [14/78] SOF/VEL, p = 0.011)

19 19

n N

Overall SVR12 (PP)
LDV/SOF (8 weeks): 97% (189/195)
LDV/SOF (12 weeks): 98% (382/389)
SOF/VEL (12 weeks): 97% (29/30)

Among patients treated with LDV/SOF for 8 weeks, those treated in community settings were more likely to achieve SVR than those treated in academic settings
(p = 0.026; 98% vs 88%)

Treatment of HCV GT1–6: Results of the HCV-TARGET Study

*SVR presented for patients with available virological outcomes, excluding patients
who d/c early except for whom lack of efficacy was recorded.

Real-world efficacy and safety of SOF/VEL +/- RBV for 12 weeks in treatment-naive or -experienced HCV GT1-6 patients in the HCV-TARGET registry

Patients who did not achieve SVR were mainly treatment experienced and/or had advanced liver disease

SVR4/12*

the TRIO Network

PP, per-protocol (includes patients who completed treatment and excluded patients with non-virologic failure).

Real-world study of 1827 patients in the US HCV TRIO network to evaluate treatment utilization and compare outcomes between SOV/VEL ± RBV and existing DAA therapies in patients with GT2–6 chronic HCV

Prior to SOF/VEL approval in June 2016, the most commonly used regimens were SOF + RBV (77% in GT2), DCV + SOF ± RBV (86% for GT3), and LDV/SOF ± RBV (90% in GT4–6)

After approval, SOF/VEL ± RBV was used in 81% of GT2 patients, 74% of GT3 patients, and 36% of GT4–6 patients

66
68

10
11

238
252

266
267

PP population

SOF/VEL ± RBV

SOF + RBV

DCV + SOF ± RBV

LDV/SOF ± RBV

SVR rates were similar to those observed in clinical trials

n
N

Guide Treatment Duration with LDV/SOF in Patients With Chronic HCV GT1 Infection: Results from the German Hepatitis C-Registry (DHC-R)

TN, treatment naive; NC, non-cirrhotic; BL VL, baseline viral load. * Criteria for 8-week LDV/SOF ± RBV treatment.

*

DHC-R: A prospective, multicentre, real-world cohort study comprising ~10,000 HCV infected patients. This analysis includes HCV GT1-infected patients who received LDV/SOF ± RBV for 8 (N = 981) or 12 (N = 1939) weeks

All patients with BL VL > 6M treated for 8 weeks achieved SVR

42 relapsers
4/42 (10%) had a BL VL >6M IU/mL (all were treated for 12 weeks)
12/42 (29%) had been treated for 8 weeks and all had BLVL <6M IU/mL

BL VL < 6M

SVR12 (%)

LDV/SOF ± RBV
8 Weeks

LDV/SOF ± RBV
12 Weeks

793 807

23 23

1429 1463

209 214

n
N

BL VL < 6M IU/mL

BL VL > 6M IU/mL

carcinoma; TE, treatment-experienced; TN, treatment-naive.
* Reference group = treatment-naive patients

A real-world, retrospective, cohort study to evaluate the effectiveness of EBR/GZR in HCV-infected patients within the Veterans Health Administration

Patients who received RBV (OR 0.31 (95% CI, 0.20–0.49);
p < 0.0001) and treatment-experienced patients*
(OR 0.61 (95% CI, 0.40–0.92); p = 0.02) were less likely to achieve SVR12

FIB4 > 3.25 (OR 0.73 (95% CI, 0.41–1.29);
p = 0.28) demonstrated a trend towards being a negative predictor of SVR12

1924
2069

247
266

178
197

36
41

13
16

383
408

912
971

373
410

1850
1989

56
60

201
242

1559
1659

360
410

n
N

SVR12 (%)

Treatment of HCV GT1: Results of the HCV-TARGET Study

BL, baseline; C, cirrhosis; GT1 nos, not defined in abstract; NR, non-responder; PP, per protocol (excludes non-virologic failures); RL, relapse; TE, treatment-experienced; TN, treatment-naive.

Analysis of HCV GT1-infected patients treated with EBR/GZR ± RBV in the real-world HCV-TARGET study at academic and community medical centres in Europe and North America

RBV added in <10% of patients, and mainly limited to those with baseline RASs and those who are TE or cirrhotic

Anemia was reported in 2/200 treated with EBR/GZR alone and 1/16 treated with EBR/GZR + RBV

AEs leading to d/c:
Depression n = 1; Drug intolerance n = 1

Kidney Disease: Real-World Experience from the TRIO Network

CKD, chronic kidney disease; PP, per-protocol (defined as patients that completed intended therapy and received SVR testing at 12 weeks); VF, virologic failure. * eGFR values were calculated using the CKD-EPI Creatinine equation; † Includes GT1 unknown, GT2, GT3, and GT unknown.

Data from the TRIO Network were used to evaluate the real-world effectiveness of EBR/GZR in patients with CKD* (baseline eGFR <90 mL/min/1.73 m2) in the United States

440 patients treated with EBR/GZR; 261 with CKD (24% stage 2, 20% stage 3, and 53% stage 4–5

EBR/GZR was used in 93% of patients with 7% receiving RBV. Most patients were treated for 12 wks.

1
1

34
36

27
27

11
11

68
68

142
144

CKD stage

PP population (n = 144)

2 VF

n
N

Chronic Hepatitis C: Retrospective Data Analyses From the TRIO Network

BL VL, baseline viral load; CKD, chronic kidney disease; LTFU, lost to follow-up; PP, per protocol; RAS, resistance associated substitution; TE, treatment experienced; TN, treatment naive.
*GT2 n=2, GT3 n=1, GT unknown n=21; † Of the 4 TE F4 patients who did not achieve SVR, prior treatments were LDV/SOF, SMV + SOF, pegIFN + RBV and unknown.

Retrospective analysis of HCV-infected patients treated with EBR/GZR and a HCV GT1-infected comparator group treated with non-EBR/GZR regimens in the real-world TRIO Health Network

90% of the observed EBR/GZR use was for
12 weeks without RBV and mostly in
GT1-infected patients

PP population

HCV Care: Analyses of Treatment for 8,955 Patients From the TRIO Network

CKD, chronic kidney disease; ITT, intent to treat.; d/c, discontinuation; TE, treatment experienced; LTFU, lost to follow-up.

Retrospective analysis of HCV-infected patients in the real-world TRIO Health Network treated with DAA regimens October 2015–October 2016 (N = 8955)

1% died 7% LTFU 3% d/c

1% died 8% LTFU 5% d/c

1% died 5% LTFU 6% d/c

1% died 6% LTFU 1% d/c

SVR12 failures and d/c rates were higher with use of non-preferred therapies, for TE patients and patients with cirrhosis

N = 4491

N = 524

N = 480

N = 213

in Stage 4–5 Chronic Kidney Disease Patients in France

CKD, chronic kidney disease; LY, life years; QALY, quality-adjusted life years.

A decision-analytic model using both medical and economic criteria was used to estimate the cost-effectiveness of EBR/GZR vs no treatment (standard of care) in patients with HCV GT1 infection and CKD stage 4–5 (creatinine clearance <30 mL/min/1.73 m2, including hemodialysis patients)

The model was designed to identify the best strategy from an ‘all payers’ perspective

Sensitivity analysis shows that key drivers are:
Risk of CKD progression
Average annual cost of kidney transplant
Risk of death from HCV

Probabilistic sensitivity analysis suggests that EBR/GZR is increasingly more effective than standard of care in CKD patients, but also more expensive

100% of incremental cost-utility ratio simulations were < €31,500

Cirrhosis: Continued Improvement of Liver Function Parameters – Results From the German Hepatic C-Registry (DHC-R)

HCCs, hepatocellular carcinoma; PIs, protease inhibitors.
*Clinical events defined as defined by increase in MELD by ≥3 points, variceal bleeding, ascites,
encephalopathy, liver transplantation, de novo HCC, or death.

Analysis of DAA treatment in HCV-infected patients with advanced liver cirrhosis in the DHC-R – a large, multicenter, real-world cohort in Germany

121 (11%) patients reported SAEs
63 SAEs were liver-related; HCC (n = 17), variceal bleeding (n = 19), and ascites (n = 4)
14 deaths; 10 were liver-related

Child-Pugh B or C were associated with clinical events*

Liver function improved in the majority of patients during and after treatment

Neither use of HCV PIs nor RBV were associated clinical events*

Criteria for advanced liver cirrhosis included at least one of the following:
FibroScan >20 kPa, platelets <90,000/μL, albumin <35 g/L or clinical signs of liver decompensation

Liver function improvement – ALT and platelets

Liver function improvement – bilirubin and albumin

BL albumin 35.9 ± 8.5 g/L

BL bilirubin 1.1 ± 0.8 mg/dL

BL platelets 106.0 ± 56.7 x 103/µL

BL ALT 99.1 ± 69.8 U/L

4099 HCV GT1 Infected Adults: Real World Outcomes From HCV TARGET

d/c, discontinuation; IPW, inverse probability weighting.

Analysis of the incidence and predictors of virologic failure as well as re-treatment outcomes in HCV GT1-infected patients treated with ≥2 DAAs in the real-world HCV TARGET cohort

91
2241

IPW analysis
Compared to SMV + SOF ± RBV patients, LDV/SOF ± RBV (OR 2.63; p < 0.01) and OBV/PTV/r + DSV ± RBV (OR 1.92; p < 0.01) patients were more likely to achieve SVR

130
1107

38
751

To date, 19/22 (86%) DAA failures retreated with LDV/SOF ± RBV or OBV/PTV/r + DSV ± RBV achieved SVR

Of 4099 GT1-infected patients treated with ≥ 2 DAAs, 259 (6%) experienced treatment failure (primarily as relapse)

n
N

Cirrhosis, low albumin/platelet, high total bilirubin, and male sex were associated with treatment failure at the p < 0.001 level

42 d/c due to AEs

Treatment Failure: Real-Life Data From the Italian Platform for the Study of Viral Hepatitis Therapies (PITER)
HCC, hepatocellular carcinoma.

An analysis of DAA treatment failure and its clinical and economic burden using data from HCV-infected patients in the PITER study cohort

Of 3926 patients who underwent DAA treatment, 4% (n = 140) failed to achieve SVR12

Clinical burden of DAA failure
HCC occurred in 6 (5%) patients at end of treatment and in 10 patients (8%) after 6-months' follow-up
5 patients with cirrhosis underwent transplant
CP class changed from A to B in 15 (12%) patients and from B to C in 1 (1%) patient
24 patients experienced hepatic decompensation

Economic burden of DAA failure
Mean cost among non-hospitalized patients was €694/patient (main cost driver was laboratory tests)
Mean cost among hospitalized patients was €18607/patient (main cost driver was number of diagnostic procedures, after hospital admission costs)

Failure rate increased with higher degree of fibrosis at baseline

HCV

* GT2 results almost entirely DCV + SOF; – Not applicable.

Real-world evaluation of the efficacy and safety of legally imported generic DAAs (including SOF, LDV, DCV) across five treatment access programs in 88 countries worldwide

Aggregated results for the 4 cohorts. Cohort 1 final results & Cohorts 2–4 interim results

Cohort 2: N = 226; GT1, 2, 3, 4, 5
Cohort 3: N = 263; GT1, 2, 3, 4, 6
Cohort 4: N = 224; GT1b, 2, 3

REDEMPTION-1 The negative predictors significantly associated with SVR were cirrhosis (p = 0.01) and HCV RNA detectable after Day 24 (p = 0.02)

No new AEs reported

Cohorts include the Australian access program REDEMPTION-1, and a large cohort from London (Cohort 1)

SMV, in treatment naive patients with HCV infection with or without cirrhosis

VBT = Viral Breakthrough

Dose finding study:
Inclusion criteria:
Fibrosis stage F0–F3
GT1 or 3 infection
Treatment naive

3DAA vs 2DAA in GT1-infected patients

3DAA 8 vs 6 weeks in GT1-infected patients

3DAA in GT3-infected patients

SVR rate (%), 95% CI

SVR rate (%), 95% CI

SVR rate (%), 95% CI

AEs were mild and unspecific
1 d/c due to AE

4 Relapse

1 VBT

5 Relapse

1 VBT 2 Relapse

AL-335 + ODV ± SMV 6 or 8 weeks achieved high SVR in non-cirrhotic GT1 patients

– including patients with CKD 3b/4/5, HIV/HCV co-infection with & without compensated cirrhosis, and renal transplant
demonstrate improvement in perceived burden of disease and work productivity/activity
Reiterate that rates of hepatic decompensation and HCC in patients with advanced liver disease are similar to those seen in the literature
Treatment with 2D/3D demonstrates high SVR in patients with liver and renal transplant – with and without compensated cirrhosis
One death due to tacrolimus overdose [contraindicated in the USPI as of March 2017, and ‘not recommended’ in the EU label]
100% SVR12 [mITT] seen in first available pediatric data with 2D/3D ± RBV. The regimen was well tolerated by adolescents [12–17 yrs old] with no grade 3 or 4 laboratory abnormalities or treatment-emergent SAEs
Real world evidence of SOF-based regimens used in patients with severe CKD attempt to establish safety and effectiveness
Conflicting data presented on impact of SOF on eGFR

HCV GT1 or 4 with/without HIV-1 Co-Infection, Chronic Kidney Disease Stage IIIb/V and Dialysis in Spanish Clinical Practice – Vie-KinD Study

CKD, chronic kidney disease; EOT, end of treatment; PTW, post-treatment Week; VF, virologic failure. * Male patient with GT1b HCV infection and CKD Stage 5 experienced VF with 12 weeks of treatment with OBV/PTV/r + DSV + RBV. Patient did not reach SVR12.

A non-interventional, retrospective, multi-center, real-world study of OBV/PTV/r ± DSV ± RBV in n = 135 HCV GT1- or 4-infected (14/135 [10%] HIV/HCV co-infected patients) with CKD stages IIIb–V in 31 centers in Spain

125
126

n
N

11 (8%) patients had severe AEs Most AEs were mild or moderate in severity
5 (4%) patients withdrew treatment

Most patients (94% [33/35]) did not have a clinically significant decrease in CKD Stage IIIb and IV baseline eGFR levels at EOT or PTW12 in any CKD stage group

26% of GT1-infected patients received OBV/PTV/r + DSV + RBV
80% of GT4-infected patients received OBV/PTV/r + RBV

111
112

14
14

13
13

19
19

93
94

HIV/HCV co-infection

CKD stage

1 VF*

GT/Regimen

Renal transplant

115
116

10
10

76
77

49
49

DSV ± RBV in Adult Renal or Liver Transplant Recipients with HCV Infection

C, cirrhosis; d/c, discontinuation; LT, liver transplant; RAS, resistance-associated substitution; RT, renal transplant.

An ongoing, phase 2, open-label study evaluated OBV/PTV/R ± DSV ± RBV in HCV GT1-infected patients with liver or kidney transplant and HCV GT4-infected patients with liver transplant

6
6

Compensated cirrhosis

Non-cirrhotic

Death was due to tacrolimus overdose

n N

33
34

9
12

3
3

3 d/c due to AE

1 relapse

Patients were treatment-naive or IFN-experienced receiving tacrolimus or cyclosporine

HCV GT1

HCV GT4

Relapse patient had treatment-emergent RASs D168V in NS3 and Q30R in NS5A

There were 3 study drug related SAEs (nausea and vomiting, acute respiratory failure, and tacrolimus overdose), and led to d/c of study drug

Grade 3 laboratory abnormalities were rare, and there were no grade 4 events

± Cirrhosis

± RBV in Adolescents with GT1 or 4 HCV Infection

CV, coefficient of variation; d/c, discontinuation; EOT, end of treatment; PK, pharmacokinetics.* N = 11 for AUC and Ctrough of OBV and PTV; † AUC0–24 hours for OBV and PTV, AUC0–12 hours for DSV; ‡ as assessed by investigator.

An two-part, ongoing, open-label, phase 2/3 study assessed the PK of OBV/PTV/r + DSV ± RBV in GT1-infected adolescents without cirrhosis (Part 1) and the efficacy and safety of OBV/PTV/r ± DSV ± RBV in GT1- or GT4-infected adolescents with or without cirrhosis (Part 1 and 2)

Preliminary PK results: Geometric means from Part 1 (N = 12)*

No confirmed grade 3 or 4 laboratory
abnormalities were reported

38
38

n
N

DAA exposures were comparable to historical results seen in adults

with OBV/PTV/r ± DSV ± RBV Under Real-Life Conditions – Data from the German Observational Study LIFE-C

QoL, quality of life.

LIFE-C: German observational study assessing effectiveness, safety, and health-related QoL
in patients treated with OBV/PTV/r ± DSV ± RBV according to local label,
using several health-related QoL questionnaires (N = 472)

Study populations were: Core (excluded patients who had not begun treatment and those without confirmed on-label treatment) and Subgroup (excluded those who received 24-week therapy or began treatment after the cut-off date)

59
61

148
150

22
24

113 AEs occurred in 66 patients

Fatigue, pruritus, and rash were the most common AEs

96% (215/225) of treated patients in the subgroup population achieved adherence rates ≥ 95%

n
N

Core population

RBV in HCV GT1 in Patients with Advanced Fibrosis – Final Results of the REV1TAL Study

C, cirrhotic; CPA/B, Child-Pugh A/B; HCC hepatocellular carcinoma; NC, non-cirrhotic; NR, not reported.
* Variceal hemorrhage n = 4; hepatic encephalopathy n = 5; ascites n = 1; spontaneous bacterial peritonitis n = 1; unspecified cause n = 1; † 7 patients had CPA cirrhosis and 1 patient had CPB cirrhosis; 5 were de novo HCC; ‡ Hospital admission due to hepatic decompensation n = 7.

Real-world study of OBV/PTV/r + DSV ± RBV in HCV GT1-infected patients at 20 centers in Australia (N = 451)

SAEs occurred in 35% (12/34) of CPB patients and 12% (36/306) of CPA patients (p = 0.0005)

In multivariate analysis, CPB was a significant predictor of SAEs (OR 7.2 [95% CI, 1.5–33.9]; p = 0.012)

In multivariate analysis, baseline bilirubin (OR 0.96, p = 0.015) and early cessation (OR 0.04, p < 0.0001) were significant factors related to SVR

n=451

n=111

n=340

n=NR

n=NR

HCV GT1 and 4-Infected Hemodialysis Patients

CKD, chronic kidney disease; d/c. discontinuation; TN, treatment naive,
TE, treatment experienced; NC, non cirrhotic; C, cirrhotic .
* <15 mL/min/1.73 m2 by MDRD; ‡ Patient d/c study drugs at Week 4 and went on to achieve SVR12; § Deaths were due to myocardial infarction (n = 1) and sepsis-related complications (n = 1); both were considered unrelated to study drugs.

SOLID registry: an ongoing observational, cohort study, evaluating real-world safety and efficacy of OBV/PTV/r ± DSV ± RBV for 12 or 24 weeks in HCV GT1- or 4-infected patients with severe CKD* on hemodialysis

Patients receiving RBV were more likely to have higher hemoglobin levels, GT1a and be TE

with LDV/SOF or OBV/PTV/r + DSV Regimens Is Not Dependent on Baseline eGFR

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate estimated using the CKD-EPI equation; IQR, interquartile range. * Cirrhosis was calculated by FIB-4 score > 3.5.

The ERCHIVES cohort of HCV-infected US veterans was used to evaluate declines in eGFR during treatment with LDV/SOF ± RBV or OBV/PTV/r + DSV ± RBV by baseline kidney function

Percentage of patients with decline in eGFR of > 10 mL/min/1.73 m2

Small number of CKD 4–5 patients

Patients with ≥ 2 eGFR values 3 months apart prior to baseline and ≥ 1 eGFR value ≥ 12 weeks after baseline were included in the analysis

additional argument for initiating DAA therapy as early as possible

Patients with HCV Infection: Real-World Evidence from the United States

OptumTM Claims Data - ClinformaticsTM Data Mart dataset was used to evaluate the prevalence and incidence of 20 EHMs (including CKD, CVD, and metabolic- and immune-mediated diseases) in HCV-infected and non-HCV-infected patients in the United States

Two cohorts of adult patients with ≥5 years of post-index follow-up were matched 1:1 on age, sex, region, and years of follow-up: HCV and no-HCV (both N = 4032)

Cumulative incidence from 2nd to 5th year post-index for any EHM HCV: 65%
Non-HCV: 48%
(OR = 2.1; p < 0.05)

Prevalence of CKD among HCV versus no-HCV cohorts in the 5th year post-index HCV: 10.7%
Non-HCV: 4.4%
(OR = 2.6)

*P < 0.05

Cumulative prevalent and incident cases of any EHM from the 1st to the 5th year post-index

(HCV-CryoVas)

Open label study of SOF (400 mg/day) + DCV (60 mg/day) for 12 or 24 weeks

1

(HCV-CryoVas)

Open label study of SOF (400 mg/day) + DCV (60 mg/day) for 12 or 24 weeks

Outcome of kidney parameters

Immunological response kinetics of cryoglobulinemia and C4

DAAs improve mixed cryoglobulinemia however longer follow up is needed

Purpura, skin ulcers and arthralgia disappeared in all cases

Kidney involvement improved in 5/5
complete renal response in 4/5

Cryoglobulin level decreased from 0.56 ± 0.18 to 0.21 ± 0.14 g/L (W0 vs W36)
Cryoglobulin disappeared in 50%
C4 serum level increased from 0.08 ± 0.02 to 0.14 ± 0.02 g/L (W0 vs W36)

2

Patients with HCV Infection: RWE from the US

Predictors of MACE in patients with compensated HCV-related cirrhosis Multivariate Cox proportional hazards model

Patients enrolled/prospectively followed up from 2006–2012 with: a) biopsy-proven HCV cirrhosis; b) CP A; c) +ve viremia; d) no prior liver complication. All patients received HCV treatment after inclusion

At endpoint, a SVR was noted in 4 (6.9%) who did vs 302 (37.8%) pts who did not present a MACE (HR = 0.39 [0.13; 0.95], p =0.036)

MACE included stroke, myocardial infarction, ischemic heart disease, heart failure, peripheral arterial disease, cardiac arrest, and CV death
7% (62/878) of patients had total of 79 MACE after a median f/u of 57.5 months
Overall survival at 5 years was 60% vs 88% in those who did/did not have a MACE (p < 0.001)
Causes of death in patients who had a MACE mainly related to cardio-vascular disease in 32% (7/22) cases, liver failure 23% (n = 5) and HCC 14% (n = 3)

SVR12 was considered a time-dependent covariate and associated with reduced rate of cardiovascular events
There is insufficient data from DAA era to compare differences between IFN-based and IFN-free therapy

female infertility and adverse pregnancy outcomes: A real-world observation

US Insurance Claims Data from 2000-2015 was used to assess the relationship between HCV infection and female infertility and pregnancy outcomes in a large real-world population in the United States (US)

Rates of Adverse Pregnancy Outcomes

cost-effective relative to the current screening recommendations (either cohort based or risk based)
AbbVie needs to continue to reinforce the potential benefits of early screening and diagnosis and communicate the added costs associated with cohort or risked based screening approaches

Age-Based Hepatitis C Testing in the United States

Dx, diagnosis; ICER, incremental cost-effectiveness ratio; QALYs, quality adjusted life years; SoC, standard of care (one-time testing of persons born 1945–1965).
* All strategies assumed continued targeted testing of people who inject drugs.

Monte Carlo simulation of HCV testing and treatment with SOF/VEL was used to assess population-level outcomes and cost-effectiveness of expanding guidance for age-based HCV testing in the US with 4 strategies

Findings were robust in sensitivity analysis that assessed the impact of treatment on cost, utility, and mortality

The 4 strategies* were: 1) current SoC; 2) one-time testing adults ≥40 years old; 3) one-time testing adults ≥30 years old; and 4) one-time testing adults ≥18 years old

Expanded HCV testing increased the number of HCV cases identified, linkage to care, treatment uptake and numbers cured

by Treatment for All Americans Ages 18 and Older as Compared to Current Testing Recommendations in the United States

BC, birth cohort 1945–1965; RB, risked-based; QALYs, quality-adjusted life years; Tx, treatment.
* Annual probabilities of HCV testing: 0.05 risk-based, 0.212 birth-cohort, and 0.212 universal; for HCV GT1–4, SVR rates were weighted averages based on clinical trial and market share data; treatment costs were weighted averages based on listed wholesale acquisition costs and market share data; 3% annual discount rate was used;
† Compared with next most costly scenario; ‡ medical management costs; § Testing, treatment, and medical management costs.

Analysis of health outcomes and cost-effectiveness of no HCV testing or treatment, and 3 testing scenarios in the US: 1) risk-based (RB) testing; 2) birth-cohort (BC) testing (1945–1965) and RB testing; 3) universal testing of all adults aged ≥18 years in 2014

Simulation model*: health outcomes and costs for HCV RNA+ persons unaware of their infection status in 2018 and followed until death or age 100

Universal testing decreased liver-related morbidity and mortality

Universal testing would result in 1.2
million additional years lived compared
with the current US testing strategy

Implementing a one-time universal screening strategy at 18 years of age would lead to the largest benefit in terms of discounted incremental HCV-related costs and impact on QALYs

1956 and 1970 in Spain

ICER, incremental cost-effectiveness ratio; LYG, life-years gained; QALY, quality-adjusted life years.
* Prisoners, people who inject drugs, HIV/HCV co-infected. A 3% discount was used; † SVR rates obtained from clinical trials; ‡ Lifetime horizon was considered and a 3% discount rate was applied to costs and outcomes; § direct costs (2016 €) only were considered.

Study assessing the cost-effectiveness of HCV testing the Spanish population born 1956–1970 (birth cohort) versus screening only high-risk* individuals born 1956–1970 (current screening strategy)

A decision analysis model to establish the eligible population for screening and a Markov model to simulate disease progression from diagnosis were used; 82% of ≥F2 detected cases were assumed to be treated with DAAs†

At an efficiency threshold of €30,000 per QALY, screening of the Spanish population born 1956-1970 is cost effective vs current screening strategy

The screening strategy was applied to 5,915,645 people, with 1.9% diagnosed with chronic HCV

connection to care
Alternative screening strategies may help to reduce some of these challenges and connect more patients to care; however, it is important to understand the dynamics and roadblocks of each individual health care system
Regimens such as G/P that simplify treatment decisions may have a positive impact on the number of patients that can be successfully diagnosed and connected to care
In order to successfully achieve SVR, we also need to address other points of the HCV care cascade

Not Belonging in the Baby Boomer Birth Cohort

BBBC, baby boomer birth cohort.
* FIB-4 scores defined as Low (<1.45), Indeterminant (1.45–3.25), High (>3.25); † Abnormal ALT >45 in men and >30 in women

NHANES participants were stratified by FIB-4* score and ALT† levels and the prevalence of
HCV calculated for each stratum; 33,476 participants had complete laboratory data for FIB-4 calculation; 33,468 were tested for HCV

Evaluation of abnormal ALT and FIB-4 score as a trigger for HCV screening using data from the National Health and Nutrition Examination Survey (NHANES) 1999–2012

Prevalence of HCV infection was higher among BBBC than non-BBBC participants (3.3% vs 0.7%)

Among patients unaware of their HCV infection, 59% would be diagnosed if abnormal ALT or high FIB-4 scores were used as a trigger for screening; 35% of these individuals did not belong to the BBBC

Participants unaware of infection

Prevalence of positive HCV RNA (%)

Screening threshold

to a Specialist Hepatology Service in a Secondary Care Facility in the UK

PTW12, post-treatment Week 12. * DNA, did not attend.

Audit of HCV serology requests October 2015–September 2016 at York teaching hospital, UK, to determine if the launch of a specialist hepatology service improved screening, assessment, and treatment of HCV-infected patients

Screening to assessment pathway

HCV treatment has been started in 105 patients compared with 4 patients in 2013; 76 patients reached PTW12 and 95% achieved an SVR12

Individuals at High Risk for Chronic HCV Infection Among an Underserved Safety-Net Population

IV, inrtravenous. * Based on U.S. Preventative Services Task Force guidelines.

Prospective cohort study of HCV screening rates and awareness of prior HCV test results among high-risk individuals*

When offered HCV testing, > 80% of patients accepted, 64% of patients completed testing; All HCV positive patients were linked to care

HCV Screening and Awareness

Significant differences in acceptance of HCV testing by race (p<0.001), country of birth (p<0.01), BB cohort (p<0.05) and English speaking vs non-English speaking (p<0.01)

67% were high-risk for HCV (eligible for screening)

30% received prior HCV testing

30% were aware of prior testing

Enhance the Care Cascade

OST, opioid substitution therapy; PWID, persons who inject drugs.

Assessment of interventions required in Australia, a setting where all living persons with HCV have access to therapy, to reach WHO HCV elimination targets. A dynamic HCV transmission and liver disease progression model was used to test the following interventions:
1) scaling up primary care treatment delivery; 2) using biomarkers in place of liver stiffness measurement;
3) point-of-care HCV RNA testing; 4) testing of PWID on OST

Treatment scale-up alone was not enough to reach WHO elimination targets by 2030 as remaining infections were among PWID who were unaware of their infection, and could continue to transmit infection

Year

Required to achieve WHO HCV elimination targets
Increased testing of PWID
Annual HCV RNA testing as part of OST

Annual HCV incidence among PWID

Scaling up primary case treatment
+ using APRI to assess cirrhosis
+ point-of-care RNA testing
= $62 million in healthcare cost savings by 2030

to be clinically relevant
HBV/HCV coinfected patients require monitoring once they initiate HCV treatment although clinically significant reactivation is seen rarely
No need for prophylactic therapy
HBsAg- and HBcAg+ risk of reactivation is negligible

Chronic HCV/HBV Coinfection: A Phase 3 Study in Taiwan

* n = 1 patient changed HBsAg status between screening and baseline.

Taiwanese, open-label study to evaluate the efficacy and safety of LDV/SOF for 12 weeks in HCV/HBV coinfected patients with or without compensated cirrhosis. Patients were not receiving HBV treatment at enrolment

Efficacy

5% (5/111) of patients had concomitant increase in ALT
2% (2/111) of patients started HBV therapy

HBV DNA kinetics

Higher baseline HBV DNA and ALT were associated with up to 1 log10 increase in HBV DNA

LDV/SOF 12 weeks associated with asymptomatic HBV reactivation in 63% (70/111) of patients

No patient experienced clinical signs or symptoms of HBV reactivation

Evidence of Previous Hepatitis B Infection Receiving Anti-HCV Direct Acting Antivirals

ALT, alanine aminotransferase; ULN, upper limit of normal. * Patients with HIV coinfection or post solid organ transplant were excluded.

Retrospective analysis of HBV reactivation in 192 Veterans, receiving HCV DAA therapy at the Baltimore Veterans Affairs Medical Center, with evidence of previous HBV infection*

2 patients experienced ALT increase > ULN during treatment without HBV reactivation, both of which normalized without intervention

No HBV reactivation events were observed