Challenges in the Era of Hepatitis C...

Challenges in the Era of Hepatitis C Cure

Naoya Sakamoto, MD, PhD

Department of Gastroenterology and Hepatology

Faculty of Medicine, Hokkaido University, Sapporo, Japan

28-Oct-2019 TOKYO HEP CLINICAL FORUM

Hokkaido University

Challenges in the Era of Hepatitis C Cure

1. Extrahepatic outcomes post SVR

2. Decompensated cirrhosis and portal hypertension

3. Post SVR HCC development

DAAs Available in Japan (Oct-2019)

E2 E1 C NS2 NS3 NS5A NS5B NS4B NS4AE1 E2

P7

Sakamoto, J Gastroenterol 2009;44:643

Protease Inhibitors

Asunaprevir

NS5A Inhibitors Polymerase Inhibitor

SofosbuvirLedipasvir

Velpatasvir

Grazoprevir

Glecaprevir

Daclatasvir

Elbasvir

Pibrentasvir

SVR12 Rates of Interferon-Free DAA Treatments

89,8%97,1% 95,7% 95,0%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Asunaprevir +Daclatasvir

Sofosbuvir +Ledipasvir

Pariaprevir +Ombitaasvir

Grazoprevir +Elbasvir

SV

R12

(%

)

N=322 N=485 N=57 N=58

Suda G, Sakamoto N, NORTE Study Group et al. J Gastroenterol 2016; 51:733-40Suda G, Sakamoto N, NORTE Study Group et al. Hepatol Res 2017; 47:1127-1136

Suda G, Sakamoto N, NORTE Study Group et al. J Clin Transl Hepatol 2016; 4:320-327Suda G, Sakamoto N, NORTE Study Group et al. J Gastroenterol 2018; 53:119-128

Suda G, Sakamoto N, NORTE Study Group et al. J Gastroenterol 2018; Epub ahead of printSuda G, Sakamoto N, NORTE Study Group et al. Hepatol Res 2018; Epub ahead of print

Sho T, Sakamoto N, NORTE Study Group et al. Hepatol Res 2018; Epub ahead of print

Trends and Efficacy of IFN-Free Therapy: A Real-World, Nationwide, Multicenter Study of 10,688 Patients in Japan

Regimen Naive Retreatment

Daclatasvir-asunaprevir 2441/2680 (91.1) —

Ledipasvir-sofosbuvir 3021/3082 (98.0) 89/119 (74.8)

Ombitasvir-paritaprevir-ritonavir 638/655 (97.4) 0/2 (0)

Elbasvir-grazoprevir 519/524 (99.1) 10/16 (62.5)

Daclatasvir-asunaprevir-beclabuvir 23/23 (100) 7/18 (38.9)

Sofosbuvir-ribavirin 2259/2344 (96.4) 0/1 (0)

Ombitasvir-paritaprevir-ritonavir-ribavirin 98/102 (96.1) 9/10 (90.0)

Glecaprevir-pibrentasvir 575/581 (99.0) 133/136 (97.8)

Percentages are given in parentheses.

Daclatasvir-asunaprevir, ledipasvir-sofosbuvir, ombitasvir-paritaprevir-ritonavir, elbasvirgrazoprevir, and daclatasvir-asunaprevir-beclabuvir regimens were used for patients with hepatitis C virus (HCV) genotype 1 infection. Sofosbuvir-ribavirin and ombitasvir-paritaprevirritonavir-ribavirin regimens were used for patients with HCV genotype 2 infection. The glecaprevir-pibrentasvir regimen was used for patients infected with any HCV genotype.

Toyoda H et al, Open Forum Infect Dis. 2019 Apr 15;6(5):ofz185.


Changes SVR Rate in Patients without History of DAA Therapy (n = 10,352)


Changes SVR Rate in Patients with History of Prior DAA Therapy (n = 336)

Long-term Benefits of DAA Treatment

Hepatic benefits

• Fibrosis regression

• Cirrhosis regression

• Portal hypertension reduction

• Decompensated cirrhosis regression

• Reduced cirrhosis complication (ascites, encephalopathy, varices)

• Removal from liver transplant waitlist

• Reduced HCC incidence

• Reduced HCC recurrence

• Liver-related mortality reduced

Extrahepatic benefits

• Insulin resistance and diabetes improve

• Reduced risk of cardiovascular diseases

• Cryoglobulinemic vasculitis improve

• Reduced risk of lymphoma

• Improved Patient-reported outcomes

• All cause mortality reduced

Ioannou GN and Feld JJ, Gastroenterology 2019;156:446–460

Extrahepatic Manifestation of HCV

World J Gastroenterol. Sep 21, 2014; 20(35): 12372-12380

HCV-Related Mixed Cryoglobulinaemia

• 80-90% of mixed cryoglobulinaemia (MC) patients are HCV‐positive

• 40-60% of HCV patients are positive for cryoglobulin

• 5‐30% of MC develop symptomatic MC vasculitis

JAAD Case Rep. 2018 Aug; 4(7): 684–687

IFN‐Free Therapy in HCV Mixed Cryoglobulinaemia

Gragnani L et al. Aliment Pharmacol Ther. 2018;48:440–450.

%Improved 81.7% 93.1% 96.7%

FCR: Full‐complete response, Disappearance of all baseline symptomsCR: Complete response, Improvement of all the baseline symptomsPR: Partial response, Disappearance or improvement of at least half of the baseline symptomsNR: Non‐response, Disappearance or improvement of fewer than half of the baseline symptoms

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

EOT SVR12 SVR24

FCR

CR

PR

NR

IFN-Free Therapy in Genotype 2 HCV Lichen Planus

Yoshikawa et al Clin J Gastroenterol 2017;10:270

Erosions on the

lip

SOF＋RBV

HC

V R

NA

(Lo

g I

U/m

ｌ)

0

week

6 weeks 12

weeks

0

2

4

6

8

HCV Elimination Reduces Incidence of Malignant Lymphoma

Kawamura Y et al. Am J Med (2007) 120, 1034-1041

• Untreated CHC (n=501) versus IFN-treated CHC (n=2,708)• Cumulative rates of malignant lymphoma development: 0.6%/5 yrs, 2.3%/10 yrs, 2.6% /15yes

HCV Clearance Decreases Hepatic and Extrahepatic Mortality (Taiwan cohort)

Lee MH et al, J Infect Dis 2012;206:469

Hepatic Mortality Extrahepatic Mortality

Overall Survivals of Cirrhosis Patients(Data from Japan Health Insurance Cohort)

Yatsuhashi H, 2015Ministry of Health, Labor and Welfare Scientific Research Project "Life prognosis of patients with liver cirrhosis"

0 1 2 3 4 （年）

100

90

80

70

60

50

（％）

Cum

ulative

Survival

100

80

60

40

20

（％）

0 1 2 3 4 （年）

All（N=267）

95.8%

91.8%87.3%

83.0%

＊：p＜0.0001†：p＜0.005

30.7%

71.0%

93.5%

CP-C（n=11）

CP-B（n=46）

CP-A（n=210）

Child-Pugh A, B & C

＊

†

＊

SOF/VEL±RBV for 12 weeks in HCV Decompensated Cirrhosis (Japanese Phase 3 Trial): Protocol

Study design:

• Cirrhosis patients of Child-Pugh stage B(6-10), C(11-12)

• All genotypes (20% non-GT1）

• Exclusion: HIV or HBV coinfection, HCC

• Primary endpoint: SVR12

CPT B or C

All GT

N=50

N=50

SOF/VEL

wk0 wk 12 wk 24

SVR12

SOF/VEL+RBV SVR12

Takehara T, Sakamoto N et al.. J Gastroenterol 2019; 54:87-95.

SOF/VEL±RBV for 12 weeks in HCV Decompensated Cirrhosis: SVR12

CP-A※2 CP-B CP-C[CPT ≤12]

（％）

SVR12

95.0％

80.0%

38/40 8/101/1

100

80

60

40

20

0Overall

（％）

SVR12

92.2%

47/51

100

80

60

40

20

0


0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

BL SVR12 SVR24

CPT C

CPT B

CPT A

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

BL SVR12 SVR24

CPT C

CPT B

CPT A

（n=76）（n=76）（n=75）（n=15）（n=15）（n=15）

CPT B at Baseline CPT C at Baseline

SOF/VEL±RBV for 12 weeks in HCV Decompensated Cirrhosis: Changes of CPT Stages


Impact of SVR on Portal Hypertension

• Study of 48 weeks of SOF+RBV for cirrhosis with portal hypertension (N = 50)

• SVR12: 72% (n/N = 33/46)

• Of 9 Patients with Baseline HVPG ≥ 12 mmHg and achieved SVR, 8 had >20% HVPG reduction.

Afdhal N, et al. J Viral Hepat. 2017;24:823-831.

-50-40-30-20

-100

-60-70

HV

PG

Ch

ange

(%

)

*n = 8 pts with > 20% decrease.

Baseline MELD< 10 ≥ 10

Progression of Portal Hypertension as a Function of Virological Response and Grades of Esophageal Varices

Even after viral suppression, patients with significant esophageal varices still have high risk of PHT progression.

Thabut D, Gastroenterology 2019;156:997–1009

Effects of Eradicating HCV in Cirrhosis Differ With Stage of Portal Hypertension (Italian Cohort)

Di Marco V et al. Gastroenterology 2016;151:130–139

Appearance of EV Progression of EV

• 444 HCV compensated cirrhosis patients were treated with PEG/RIBA in 2001-2009 and followed for a median of 7.6 years.

• SVR associated with decreased risk of EV development.

• SVR did not affect progression of preexisting EV.

EV: esophageal varices

SVR to IFN-free therapies ameliorates portal hypertension: paired HVPG

Mandorfer M et al. J Hepatol 2016; 65:692–699

• 104 HCV patients with portal hypertension (HVPG ≥ 6 mmHg) were enrolled.

• 60 patients underwent HVPG and transient elastography (TE) after antiviral therapy

All patients BL HVPG 6-9 mmHg BL HVPG 10-15 mmHg BL HVPG ≥ 16 mmHg

MOA Drug Phase

Angiotensin receptor blockers

Losartan Phase 3 and Phase 4

Candesartan Phase 1 and Phase 2

Irbesartan Phase 3

ASK1 inhibitors GS-4997 Phase 2 and Phase 3

PPAR-γ agonist GI262570 Phase 2

PPAR-δ agonist Elafibranor Phase 3

Caspase inhibitorEmricasan Phase 2

IDN-6556 Phase 2

ACC inhibitor GS-0976 Phase 1 and Phase 2

FXR agonist GS-9674DSP-1747LJN452

Phase 1 and Phase 2Phase 2Phase 2

FGF21 analogue BMS-986036 Phase 2

HSP47 inhibitor ND-L02-S0201 Phase 2

LXRα inhibitor Oltipraz Phase 2

Galectin Inhibitors GR-MD-02 Phase 2

Mineralocorticoid receptor antagonist (MRAs) MT-3995 Phase 2

CCR2/CCR5 antagonist Cenicriviroc Phase 2 and Phase 3

iNOS and eNOS modulation Simvastatin + Rifaximin Phase 2

AntioxidantSilybin Phase 3

Pentoxifylline Phase 2 and phase 3

Ongoing Clinical Trials for Liver Fibrosis

Rotman Y, Sanyal AJ. Gut 2017;66:180–190.

ビタミンA含有標的化剤

脂質成分

siRNA

脂質ナノ粒子

Vitamin A

HSP47-siRNA

Collagen

Activated HSC

Degradation of fibrosis

By collagenase

Production of collagen from

activated hepatic stellate cells

Retinol binding protein receptor

Vitamin A-liposome-HSP47-siRNA

Saito Y, Niitsu Y et al. Nature Biotech 2008

RBP recepter

Effects of VA-liposome-HSP47-siRNA on HCV/NASH Liver Fibrosis

0,000

0,200

0,400

0,600

0,800

1,000

1,200

1,400

1,600

1,800

2,000

0 5 10 15 20 25

% C

han

ge f

rom

Bas

elin

e

Visit Week

Fibroscan

Cohort1

Cohort2

Cohort3

Pre Wk 5 Pre Wk 5

Cohort 1 NASH F4 F2 A2 A1

NASH F3 F3 A2 A2

NASH F3 F3 A2 A2

Cohort 2 NASH F3 F3 A2 A2

HCV-SVR F3 F3 A2 A1

Alcohoilc F3 F2 A2 A1

Cohort 2 HCV-SVR F3 F3 A2 A2

NASH F3 F2 A1 A1

HCV-SVR F3 A2

Sakamoto et al. EASL 2018 #THU-257

Cumulative HCC incidence Post DAA Treatment（US Cohort, n=62,354)

Ioannou GN et al., J Hepatol 2018;60(1): 25-32

• Retrospective study• Data from US Veterans Affairs national healthcare system from 1999 to 2015• 35,871 IFN-only regimens, 4,535 DAA+IFN and 21,948 DAA-only• mean follow up of 6.1 years (range: 2-18); incident HCCs=3,271

All Treatments (n=62,354) IFN-Free DAA (n=21,948)

HCC Risk Post SVR（US Veteran Cohort、n=10,817）

El-Serag HB, Hepatology 2016;64:130-137

• Cumulative HCC occurrence post SVR: 0.33% / yr

• Risk factors: Age ≥ 65, cirrhosis , diabetes

Non cirrhosis cirrhosis P-value

N 315 79

Male 150 40 0.55

History of HCC 13(4.1%) 22(27.8%) <0.0001

Age 65.1±13.6 66.4±13.3 0.22

AST (IU/L) 48.3±32.7 69.4±43.9 <0.0001

ALT (IU/L) 51.8±43.3 59.6±43.6 0.16

γGTP (IU/L) 50.7±58.7 78.8±114.9 0.0027

Plt (×104/mL) 16.9±5.4 10.6±4.6 <0.0001

Alb (g/dL) 4.1±0.5 3.6±0.4 <0.0001

HA (ng/mL) 175.7±460.0 106.8±347.5 <0.0001

Fib4 3.11±2.33 7.61±9.77 <0.0001

Liver elasticity (kPa) 8.0±6.4 23.8±11.9 <0.0001

CAP (dB/m) 213.2±55.2 215.7±48.8 0.75

Analysis of Factors Associated with post SVR HCC

• Study of 394 CHC patients who achieved SVR by DAA regimen • non-cirrhosis:315, cirrhosis:79• Mean follow up period: 795.6±264.8 days• Primary endpoint: HCC development

Baseline Profiles of Patients

All cases

1yr:1.6％2yr:1.6％

1yr:2.3％2yr:3.0％

3yr:6.3％4yr:6.3％

3yr:3.3％ 4yr:3.3％

1yr:5.6％2yr:10.0％

3yr:20.9％

N=313

N=259 N=54

DaysDays

Days

Non-cirrhosis Cirrhosis

Cumulative HCC Development of SVR Patients

Incid

ence o

f H

CC

develo

pm

ent

Incid

ence o

f H

CC

develo

pm

ent

Incid

ence o

f H

CC

develo

pm

ent

No history of HCC With history of HCC

1yr:4.5％

2yr:9.9％

1yr:2.1％

2yr:2.5％ 3yr:2.5％ 4yr:2.5％

3yr:57.0％

N=291 N=22

日日

Cumulative HCC Development of SVR Patients

Incid

ence o

f H

CC

develo

pm

ent

Incid

ence o

f H

CC

develo

pm

ent

with HCC No HCC P-value

Cirrhosis 0.003

History of HCC 0.0004

Age 70.4±3.7 64.2±0.7 0.1

Sex 0.9

Plt 12.1±1.6 16.1±0.3 0.012

Alb 3.6±0.2 4.0±0.03 0.009

AFP 18.7±6.4 9.6±1.2 0.16

AST 52.8±9.9 51.3±1.9 0.9

ALT 18.7±12.2 53.0±2.3 0.7

Fib4 5.8±1.4 3.7±0.3 0.1

HA 348.8±125.5 212.4±24.6 0.3

Liver Elasticity 19.3±3.3 10.2±0.5 0.007

CAP 202.4±20.6 213.9±3.1 0.6

Relative Risk 95％CI

History of HCC 7.19 1.84-25.9

Cirrhosis 3.61 1.03-12.5

Factors Associated with HCC Development post SVR

Univariate analysis

Multivariate analysis

Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy

Reig M et al., J Hepatol 2016; 65:719–726

Negative Effect of DAA on Early HCC Recurrence (French Cohorts)

ANRS collaborative study group, J Hepatol 2016; 65:734–740

• Subject: French multicentre ANRS cohorts including >6,000 DAA treated patientsHCC patients who underwent curative procedures before DAA treatment

• Objective:To assess the rates of HCC recurrence according to DAA treatment

31 centers in North America304 Treated with DAAs489 Treatment naïve HCV

• Overall HCC recurrence (aHR: 0.90 95% CI: 0.90-1.17)• Early HCC recurrence (aHR: 0.96 95% CI: 0.69-1.33)

Singal AG et al. Gastroenterology 2019;156:1683–1692

DAA therapy Was Not Associated with an Increased Risk of HCC Recurrence

DAA Therapy Is Associated With Increased Survival in Patients With a History HCC

Singal AG et al. Gastroenterology 2019;157:1253–1263

• Retrospective study of 797 Patients with histories of HCV-related HCC recruited from 2013-2017

• 383 (48.1%) received DAA, 414 (51.9%) untreated

• DAA therapy was associated with a significant reduction in risk of death(HR=0.54; 95% CI, 0.33–0.90).

• Risk of death was reduced in patients with SVR but not in patients without SVR

Overall, HCC-free, and Decomp-free Survival According to DAA Treatment（US cohort)

Carrat F et al, Lancet 2019; 393:1453

HCC Decompensated cirrhosisAll-cause mortality

Multiv

ariable

-adju

sted

surv

ival (%

)

Challenges in the Era of Hepatitis C Cure: Messages

1. Extrahepatic Complications

• SVR improves hepatic and extrahepatic outcomes

• SVR reduces symptoms/risk of cryoglobulinemia, lichen

planus and lymphoma etc.

2. Decompensated cirrhosis and portal hypertension

• CPT stages improve post SVR

• Portal pressure decreases.

• Varices progression may occur.

• Development of fibrosis targeted therapy is ongoing

3. post SVR HCC

• Viral eradication reduces risk of HCC incidence

• HCC recurrence post SVR is not accelerated but high.

• SVR improves survival of patients with history of HCC

Acknowledgement

Dept. of Gastroenterology and Hepatology, Hokkaido University

Goki Suda Hiroshi Ogawa Kennichi Morikawa Masato Nakai Takuya Sho

Akihisa Nakamura Kazuharu Suzuki Taku Shigesawa Takashi Kitagataya

Participating hospitals

JCHO Hokushin General Hospital Sapporo Municipal General Hospital

NTT Sapporo General Hospital Sapporo Hokuyu General Hospital

Hokkaido Gastroenterology Hospital Hokkaido Medical Center

JCHO Hokkaido General Hospital Hakodate Municipal General Hospital

Hakodate Central General Hospital Obihiro-Kosei General Hospital

Iwamizawa Municipal General Hospital Wakkanai Municipal General Hospital

Kitami Red Cross General Hospital Abashiri-Kosei General Hospital

Hokkaido University

Challenges in the Era of Hepatitis C...

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