Upload
others
View
2
Download
0
Embed Size (px)
Citation preview
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.
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)
Toyoda H et al, Open Forum Infect Dis. 2019 Apr 15;6(5):ofz185.
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
Takehara T, Sakamoto N et al.. J Gastroenterol 2019; 54:87-95.
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
Takehara T, Sakamoto N et al.. J Gastroenterol 2019; 54:87-95.
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