CARE AND TREATMENT OF CHRONIC HBV AND HCV - Hepatitis B … · 2017. 3. 22. · Treatment...
Transcript of CARE AND TREATMENT OF CHRONIC HBV AND HCV - Hepatitis B … · 2017. 3. 22. · Treatment...
CARE AND TREATMENT
OF CHRONIC HBV AND HCV - D e c e m b e r 20 1 6 -
GEORGE PAPATHEODORIDIS, MD
PROFESSOR IN MEDICINE AND GASTROENTEROLOGY ATHENS UNIVERSITY MEDICAL SCHOOL
HARRY JANSSEN, MD PROFESSOR OF MEDICINE, TORONTO WESTERN AND TORONTO GENERAL HOSPITAL,
UNIVERSITY HEALTH NETWORK, TORONTO, CANADA
ANGELOS HATZAKIS, MD PROFESSOR OF EPIDEMIOLOGY AND PREVENTIVE MEDICINE
ATHENS UNIVERSITY MEDICAL SCHOOL
Contents
Care and Treatment of Chronic Hepatitis B
Care and Treatment of Chronic Hepatitis C
CARE AND TREATMENT OF CHRONIC HEPATITIS B
Chronic HBV and HCV are treatable or curable
HBV Treatment HCV Treatment
Interferon alfa-2b Interferon-alfa-2a/2b ± ribavirin
Lamivudine Peginterferon alfa-2b ± ribavirin
Adefovir Boceprevir / Telaprevir
Peginterferon alfa-2b Sofosbuvir
Peginterferon alfa-2a Simeprevir
Entecavir Daclatasvir
Telbivudine Ledipasvir/Sofosbuvir
Tenofovir Paritaprevir/ritonavir/Ombitasvir ± Dasabuvir
Velpatasvir/Sofosbuvir
Elbasvir/Grazoprevir
Hatzakis A et al. JVH 2011; 18, S1
Indications for treatment
• Patients should be considered for treatment if
– HBV DNA >2,000 IU/ml and
– ALT >ULN and
– At least moderate necroinflammation and/or at least moderate
fibrosis by liver biopsy (or non-invasive markers once validated in
HBV-infected patients) (A1)
• If the criteria for HBV DNA and histological severity are fulfilled,
treatment may be initiated even if ALT levels are normal (A1)
• Indications for treatment may also take into account
age, health status, comorbidities, family history of HCC or cirrhosis and
extrahepatic manifestations
EASL HBV CPGs. J Hepatol 2012
Treatment indications in HBeAg-pos. CHB patients
EASL 2012
ALT >ULN & HBV DNA >2,000 & Biopsy ≥A2/F2
A. Immunotolerant phase: Persistently ALT ≤ULN
• No Biopsy – No therapy – Follow-up if age ≤30
• Biopsy if age >30 or family history of HCC, cirrhosis
B. Obviously active CHB: ALT >2xULN & HBV DNA >20,000 IU/ml
• Therapy – Biopsy optional
EASL HBV CPGs. J Hepatol 2012
ALT >ULN & HBV DNA >2,000 & Biopsy ≥A2/F2
A. HBeAg-ve patients with persistently ALT ≤ULN
(ALT every 3 months for at least 12 months) &
HBV DNA 2,000-20,000 IU/ml & no evidence of liver disease
• No Biopsy – No therapy – Follow-up (close for 3 years)
B. Obviously active CHB: ALT >2xULN & HBV DNA >20,000 IU/ml
• Therapy – Biopsy optional
Treatment indications in HBeAg-neg. CHB patients EASL 2012
EASL HBV CPGs. J Hepatol 2012
HBeAg-negative patient with normal ALT at baseline
ALT every 3–4 months for one year +serum HBV DNA determination
ALT >ULN and/or HBV DNA >20,000
(Liver biopsy) Therapy
Persistently ALT<ULN and HBV DNA <2,000 IU/mL
ALT every 6 months (& HBV DNA?)
Persistently ALT <ULN and HBV DNA 2,000-20,000
ALT every 3–4 months and HBV DNA every year for two more years (FibroScan?) ALT <ULN and HBV DNA 2,000–20,000 IU/mL
ALT every 6 months and HBV DNA every year
ALT >ULN and/or
HBV DNA >20,000
Liver biopsy Papatheodoridis GV et al. J Hepatol 2012;57:196–202
No need for liver biopsy
• Patients with compensated cirrhosis
must be considered for treatment
if detectable HBV DNA, even with normal ALT (B1)
• Patients with decompensated cirrhosis
urgent antiviral treatment with NA(s)
if detectable HBV DNA (A1)
EASL HBV CPGs. J Hepatol 2012
• Sustained HBsAg loss (± seroconversion to anti-HBs).
Ideal - Associated with a complete and definitive remission of the
activity of CHB and an improved long-term outcome (A1).
• Sustained off-treatment virological response (HBV DNA <2,000 IU/mL)
for both HBeAg+ve/-ve patients combined with durable anti-HBe
seroconversion in HBeAg+ve patients.
Associated with improved prognosis (A1).
• Maintained undetectable HBV DNA by a sensitive PCR assay on
treatment with NAs in HBeAg+ve patients who do not achieve anti-HBe
seroconversion and in HBeAg-ve patients.
Next most desirable end-point (A1).
End-points of therapy
EASL HBV CPGs. J Hepatol 2012
EFFICACY OF 48-WEEKS OF PEG-IFNa IN CHB: End of therapy (EOT) & Sustained off-therapy responses
Pts, %
Lau G et al, NEJM 2005; Marcellin P et al, NEJM 2004
HBeAg(+)CHB HBeAg(-)CHB
EOT 6-mos FUP EOT 6-mos FUP HBeAg to anti-HBe seroconversion HBV DNA <400 cp/ml
Pati
ents
wit
h r
esis
tan
ce (
%)
25
48
60
66 68
0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 3 6
18
4
11 16
19
Years 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 6 1 2 3 4 1 2 3 4 5 6 7 8
LAM ADV ETV TBV TDF
Papatheodoridis et al. Hepatology 2002,36:219-26; Hadziyannis et al. Gastroenterology 2006,131:1743-51; Liaw YF et al. Gastroenterology 2009,136:486-95; Wang Y et al. AASLD 2009, Abstr. 482;
Tenney D et al. APASL 2008, Abstr. PL02; Marcellin P et al. AASLD 2014
29
HBeAg- HBeAg- HBeAg-
First-line
Resistance to oral antiviral agents in naive CHB patients Data from different studies with different patients characteristics and methodology
Han S et al. AASLD 2008. Shouval et al. AASLD 2008.
Pat
ien
ts w
ith
HB
V D
NA
<3
00
cp
/mL
(%)
55%
Year 1
83%
Year 2
89%
Year 3
67%
n/ N
236/ 354
Year 4
91%
80/ 146
116/ 140
116/ 131
98/ 108
Year 5
88/ 94
94%
Year 1
ETV-022
0
20
40
60
80
100
ETV-901
Long-term ETV therapy in naive HBeAg(+)/(-) CHB
HBeAg(+) HBeAg(-)
Year 1
91%
Year 2 95%
Year 3
94%
93/99 84/90
67/74 54/57
93%
Year 1
ETV-027
0
20
40
60
80
100
ETV-901
Marcellin P et al. AASLD 2011, 2012
HBeAg(-): 5 year - 6 years
ΙΤΤ: 83%- 81%
Per protocol*: 99%- 100%
HBeAg(+): 5 years - 6 years
ΙΤΤ: 65%- 62%
Per protocol*: 97%- 99%
Patients with HBV DNA <400 cp/mL at 5-6 years under TDF
*missing = exclusion
Resistance to ETV or TDF in CHB with LAM resistance P
atie
nts
wit
h r
esi
stan
ce (
%)
6 0 0 0 0
Years 1 2 3 4 5 6 1 2 3 4
Entecavir (ETV) Tenofovir (TDF)
These trials included different populations, different exclusion criteria and different endpoints
15
31
47 51
Although licensed, ETV (1.0 mg) is not recommended for patients with LAM resistance by almost all guidelines
57
Tenney D et al. EASL 2009, Abstr. 20; Van Bommel F et al. Hepatology 2010, 51: 73-80
Ishak Fibrosis Scores
Pe
rce
nta
ge o
f p
atie
nts
0
10
20
30
40
50
60
70
80
90
100
Baseline Year 1 Year 5
39%
38%
12%
P < 0.001
P < 0.001
63%
0
10
20
30
40
50
60
70
80
90
100
Baseline Year 1 Year 5
39%
38%
12%
P < 0.001
P < 0.001
63%
6
5
4
3
2
1
0
6
5
4
3
2
1
0
Patients with cirrhosis (Ishak score ≥5): 28% at baseline, 8% at year 5
Fibrosis Is Reversible Liver Fibrosis Regression over 5 Yrs of Tenofovir Therapy
Marcellin P et al. Lancet 2013
348 patients with paired biopsies at baseline & year 5
HCC in CHB patients under LAM
Patients with HCC,
%
LAM Untreated
Patients n: 779 534
HBeAg(-) 49% 54%
Comp. Ci: 29% 39%
FUP (mos): 32-90 32-108
• Liaw et al, NEJM 2004
• Papatheodoridis et al, HEP 2005
• Yuen et al, AVT 2007
P=0.003
P=0.015
P=0.016
All VR BR/BTH Untreated pts LAM treated pts N 779 353 426 534
Papatheodoridis GV et al. J Hepatol 2010;53:348-56
Patients with HCC,
%
No cirrhosis
Cirrhosis
Virological remission
No virological remission
Patients NA naive LAM resistance NA naive LAM resistance
No 2233 / 1054 241 / 170 982 / 852 320 / 91
P<0.001 P<0.001 P<0.001 P=NS
HCC incidence in CHB patients under NA(s) for a median of 4 years
Papatheodoridis GV et al. J Hepatol 2010;53:348-56
0,5%
1,0%
0,7%
0,1%
0,5%
0,0%
0,5%
1,0%
1,5%
2,0%
Tx-naive Tx-naive and/or tx-experienced Tx-naive
Papathe- odoridis N=212
Yang N=202
Wong N=984
Wong N=813
Yang N=314
Hosaka N=237
Lampe- rtico
N=213
Arends N=580
An
nu
al H
CC
In
cid
en
ce
Lim N=878
Cho N=933
Wu N=18748
Lampe- rtico
N=243
Papathe- odoridis N=1231
ETV TDF ETV or TDF
Yamada N=402
Prior exposure
NR
Tx-naive and/or tx-experienced
Asians Caucasians
ETV or TDF for non-cirrhotic CHB patients
HCC rates per year
Papatheodoridis GV et al. J Hepatol 2015;62:956-67
1,4%
2,8%
5,4%
2,0%
4,1%
3,3%
0,9%
5,4%
2,6%
5,1%
2,2%
4,5%
3,9%
0,0%
1,0%
2,0%
3,0%
4,0%
5,0%
6,0%
Yang N=121
Wong N=482
Wong
N=247
Hosaka N=79
Chen
N=239
Kim
N=324
Yang
N=152
Chen N=143
Papa theo- dori dis
N=69
Lamp- etico
N=155
Are- nds
N=164
Koklü N=77
2,8%
4,2%
1,8%
3,3%
2,5%
5,2%
1,5%
0,0%
1,0%
2,0%
3,0%
4,0%
5,0%
6,0%
Lim N=860
Cho
N=445
Su N=666
Wu N=2847
Lamp- ertico
N=131
Papa theo- dori dis
N=1231
Koklü N=72
Yama- da
N=94
ETV or TDF for cirrhotic CHB patients HCC rates per year
ETV TDF ETV or TDF
Tx-naive Tx-naive and/or tx-experienced Tx-naive
Prior exposure
NR
Tx-naive and/or tx-experienced
Asians Caucasians
Papatheodoridis GV et al. J Hepatol 2015;62:956-67
PAGE-B represents a simple to use HCC risk score for the first 5 years of ETV/TDF in Caucasian CHB patients
Construction of the PAGE-B risk score for HCC
Age (years) Gender Platelets
(/mm3)
16–29: 0 Female:
0 ≥200,000: 0
30–39: 2 Male: 6 100,000–
199,999: 6
40–49: 4 <100,000: 9
50–59: 6
60–69: 8
≥70: 10
Papatheodoridis GV et al. J Hepatol 2016;64:800-6
Patients with
durable HBeAg
serocon- version,
%
At 6 12 24 months after NA(s) discontinuation
GV Papatheodoridis et al. Hepatology 2016; 63:1481-92.
Rates of durable HBeAg seroconversion after NAs discontinuation Systematic review: 6 studies, 289 initially HBeAg+ patients
Patients with
HBV DNA <20,000 IU/mL,
%
At 6 12 24 36 months after NA(s) discontinuation
Rates of virological remission after NAs discontinuation 14 studies, 733 initially HBeAg+ patients
Pooled HBsAg loss: 1%; Durable biochemical remission: 76%
GV Papatheodoridis et al. Hepatology 2016; 63:1481-92.
Patients with
HBV DNA <20,000 IU/mL,
%
At 6 12 24 36 months after NA(s) discontinuation
Rates of virological remission after NAs discontinuation 17 studies, 967 HBeAg- patients
Pooled HBsAg loss: 1.7%; Durable biochemical remission: 57%
GV Papatheodoridis et al. Hepatology 2016; 63:1481-92.
Patients with VR
at 12 mos after NAs
discontin., %
Rates of virological remission at 12 mos after NAs discontinuation in HBeAg-neg. CHB patients in relation to several factors
VR: virological remission
HBV DNA (IU/mL) <200 <2,000 <20,000 <12 12-24 >24 mos
VR definition Duration of on-NAs VR
P=0.513 P=0.017
GV Papatheodoridis et al. Hepatology 2016; 63:1481-92.
Main advantages and disadvantages of Peg-IFN & nucleos(t)ide analogues (NAs) in CHB
Peg-IFN NAs
Advantages Finite duration
Higher rates of anti-HBe &
anti-HBs seroconversion
with 12 mos of therapy
Absence of resistance
Potent antiviral effect
Good tolerance
Oral administration
Disadvantages Moderate antiviral effect
Inferior tolerability
Risk of adverse events
Subcutaneous injections
Long-term (indefinite?) duration
Unknown long-term safety
Risk of resistance
EASL HBV CPGs. J Hepatol 2012
HBV treatment modifies the outcome of the disease
Sustained response after pegIFN or long-term ETV/TDF monotherapy
Improvement/Stabilization of liver disease in practically all patients
Often regression of histological cirrhosis
Improvement/Disappearance of portal hypertension and liver decompensation
No need for liver transplantation due to liver failure
Reduction but not elimination of HCC risk
Improved survival
CARE AND TREATMENT OF CHRONIC HEPATITIS C
1992 1996 1998 2001 2011 2013 2014
SVR, %
>
Standard IFNa
RBV
PegIFNa
BOC/TPV
New DAAs
Evolution in efficacy of CHC treatment
IFN: interferon-alfa, R: ribavirin, PR: pegylated IFN+R, PI: protease inhibitor, BOC:boceprevir, TPV: telaprevir, DAA(s): direcr acting antiviral(s)
2002-2011: Optimizing Peg-IFNa+RBV Response guided therapy
HCV genotype
Baseline HCV RNA levels
Rapid virological response (RVR) - at 4 weeks of therapy
undetectable HCV RNA (<50 IU/mL)
Early virological response (EVR) – at 12 weeks of therapy
complete: undetectable HCV RNA (<600 IU/mL)
partial: detectable HCV RNA but ≥2 log decrease from baseline
PEG-IFN+RBV in CΗC: HCV Genotype & SVR
PEG-ΙFN-2b (1.5μg/Kg/wk) + RBV 0.8g
PEG-ΙFN-2a (180μg/wk) + RBV 1-1.2g
x 48 weeks
SVR
, %
Manns et al. Lancet 2001 Fried et al . Ν Engl J Med 2002
2/3 1 2/3 1
HCV genotype HCV genotype
• 22 studies, 2891 G4 patients (12-308 patients per study)
PEG-IFN+RBV in CHC-G4
SVR, %
Khattab MA et al. J Hepatol 2011;54:1250-62
All patients F3-F4 patients
Unresolved issues with Peg-IFNa+RBV
Treatment contraindications
(all patients needed treatment most)
Low SVR rates mostly in G1 (& G4) patients
Poor chance of SVR in treatment failures
Side effects – Poor quality of life
Adherence problems
SOVALDI®
Sofosbuvir NS5B polymerase
Inhibitor Gilead
OLYSIO® Simeprevir
NS3/4A protease Inhibitor Janssen
DAKLINZA® Daclatasvir
NS5A Inhibitor
BMS
400 mg/24h
Genotypes 1-6
High genetic barrier
150 mg/24h with food
Genotypes 1,4
Low genetic barrier
60 mg/24h
Genotypes 1,2,3,4
Low genetic barrier
January 17, 2014 May 16, 2014 August 28, 2014 November 18, 2014
90+400 mg/24h
Genotypes 1,3,4
High genetic barrier
HARVONI® Ledipasvir
NS5A inhibitor +Sofosbuvir
NS5B polymerase Inhibitor Gilead
Anti-HCV agents approved by ΕMA in 2014
VIEKIRAX® Ombitasvir
NS5A inhibitor +Paritaprevir
NS3/4A protease inhibitor/ Ritonavir
EXVIERA® Dasabuvir
Non-nucleos(t)ide NS5B polymerase
inhibitor
[75/50+12.5 mg] x2 /24h with food
Genotypes 1, 4
Genetic barrier dependent on genotype
250 mg/12h
Genotype 1
Low genetic barrier
January 16, 2015
Anti-HCV agents approved by ΕMA in 2015
Abbvie
EPCLUSA® Velpatasvir
NS5A inhibitor +Sofosbuvir
NS5B polymerase Inhibitor Gilead
100+400 mg/24h
Genotypes 1-6
High genetic barrier
July 8, 2016
ZEPATIER®
Elbasvir NS5A inhibitor +Grazoprevir
NS3/4A protease inhibitor
MSD
50+100 mg /24h
Genotypes 1, 4
Genetic barrier dependent on genotype
July 28, 2016
Anti-HCV agents approved by ΕMA in 2016
Simeprevir
Ribavirin
IFNa-containing combinations – Main strategies Not recommended by most current guidelines
+
+
PegIFNa
Ribavirin
+
PegIFNa
+
Ribavirin
+
PegIFNa
+
Ribavirin
+
PegIFNa
Boceprevir
Telaprevir
Sofosbuvir Daclatasvir
Nucleotide inhibitor of NS5B polymerase
NS3/4 protease inhibitor
NS5A inhibitor
?
PegIFNa +Ribavirin is still used in
several countries for easy to treat
patients without access to
IFNa-free regimens
PegIFNa +Ribavirin +Sofosbuvir
bay be still used for genotype 2 or 3
patients in some countries
without access to all current DAAs
Sofosbuvir
Simeprevir Daclatasvir
Paritaprevir/ritonavir
Dasabuvir Ribavirin
IFNa-Free combinations – Main strategies
Sofosbuvir
Ribavirin
+ + Ombitasvir
Ribavirin
±
±
± ±
Ledipasvir
Sofosbuvir
Ribavirin
±
Sofosbuvir
Ribavirin
+
Nucleotide inhibitor of NS5B polymerase
Non-nucleos(t)ide inhibitor of NS5B polymerase
NS3/4 protease inhibitor
NS5A inhibitor
Velpatasvir
Sofosbuvir
Ribavirin
±
Elbasvir
Grazoprevir
Ribavirin
±
Sofosbuvir + Simeprevir (±Ribavirin)
Sofosbuvir + Daclatasvir (±Ribavirin)
IFNa-free regimens for genotype 1
Sofosbuvir/Ledipasvir (±Ribavirin)
Paritaprevir/r/Ombitasvir ±Dasabuvir (±Ribavirin)
Sofosbuvir/Velpatasvir
Grazoprevir/Elbasvir (±Ribavirin)
OPTIMIST-1: SΜV+SOF x8-12 weeks in HCV GT-1 non-cirrhotics SV
R1
2 (
%)
112/115
Treatment-naive Treatment-experienced
97% (94.0;100)
88/103 38/40 40/52
85% (78.1;92.7)
95% (87.0;100)
77% (64.5;89.3)
SMV+SOF 12 weeks SMV+SOF 8 weeks
Kwo P et al. Hepatology 2016;64:370-80.
OPTIMIST-2: SΜV+SOF x12 weeks in HCV GT-1 cirrhotics SV
R1
2 (
%)
44/50
Treatment-naive Treatment-experienceda
88 (95% CI: 78.0; 98.0)
42/53
79 (95% CI: 67.4; 91.1)
CI, confidence interval; aTreatment-experienced patients included prior relapsers, prior non-responders, IFN-intolerant and other patients Lawitz E et al. Hepatology 2016;64:360-9
SVR
12
(%
)
60/72
GT1a GT1a with Q80K
GT1a without Q80K
GT1b
25/34 35/38 26/31
83 (95% CI: 74.0; 92.6)
74 (95% CI: 57.2; 89.8)
92 (95% CI: 82.2; 100)
84 (95% CI: 69.3; 98.4)
Lawitz E et al. EASL 2015, LB-Poster 04
OPTIMIST-2: SΜV+SOF x12 weeks in HCV GT-1 cirrhotics
Sofosbuvir + Daclatasvir +/- RBV for G1 patients (phase IIb study)
100
80
60
40
20
0
SVR12 (%)
100
29/ 29
100
14/ 15
S/D S/D/R
24 wks
100
21/ 21
S/D
19/ 20
95
S/D/R
24 wks
100
41/ 41
95
39/ 41
12 wks S/D S/D/R
Naive Prior PI (BOC/TPV) failures
• 20% cirrhotics • Almost all cured – 12 weeks adequate, RBV unnecessary
Sulkowski M et al. N Engl J Med 2014;370:211-21
ALLY-1: Advanced cirrhosis cohort
Total: n = 60; any GT; Baseline MELD score range 8–27 GT-1: n=45; GT-1/CP-B: 53%, GT-1/CP-C: 22%
Safety: Discontinuations due to adverse events, n = 1
SVR rates with SOF+DCV+RBV x12 weeks in HCV GT1 patients with advanced cirrhosis
Poordad F et al. Hepatology 2016;63:1493-505.
8291
76
92100
50
0
20
40
60
80
100
N=45 N=34 N=11 N=11 N=24 N=10
All GT1a GT1b CP-A CP-B CP-C
SVR12, %
CP: Child-Pugh
HEPATHER: SOF+DCV ±RBV x12 or 24 wks in GT1 pts
SVR4, %
SOF+DCV SOF+DCV+RBV SOF+DCV SOF+DCV+RBV x12 wks x12 wks x24 wks x24 wks
409 patients, 318 cirrhotics, 306 failures to PR±TPV/BOC
No cirrhosis Cirrhosis
S Pol et al. EASL 2015, Abstr. LB 03
SVR
12
(%
)
n N
141 142
143 143
143 143
211 212
66 66
211 211
67 67
212 214
66 68
Overall GT1a GT1b
141 141
215 215
71 71
Subgroup results do not include patients who withdrew consent or who were lost to follow-up.
Error bars: 95% CI.
ION-1: SOF/LDV ± RBV in GT1 treatment-naive patients – SVR12
Afdhal N et al. New Engl J Med 2014;70:1889-98.
ION-1: SVR rates* in GT1 treatment-naive cirrhotic patients (subgroup analysis)
* Subgroup results do not include patients who withdrew consent or were lost to follow-up.
No cirrhosis Cirrhosis
179 179
32 33
178 178
33 33
181 182
31 32
179 179
36 36
n N
SVR
12
(%
)
Afdhal N et al. New Engl J Med 2014;70:1889-98.
One patient achieved SVR12, but was not subgenotyped.
Error bars: 95% CI.
SVR
12
(%
)
n N
159 171
159 172
163 172
202 215
42 43
201 216
42 44
206 216
43 44
Overall GT1a GT1b
ION-3: Phase III SOF/LDV ± RBV in GT1 naive, non-cirrhotic patients – SVR12
Kowdley KV et al. New Engl J Med 2014;370:1879-88.
Predictors of relapse in ION-3 trial: SOF/LDV±RBV for 8 vs 12 wks in GT1 naive, non-cirrhotic patients
Patients with
relapse*, %
*Patients lost to follow-up or who withdraw
consent excluded CC non-CC <6 ≥6 MIU/ml IL28B genotype Baseline HCV RNA n/N 2/56 0/57 0/54 9/157 9/153 3/157 2/121 3/136 2/128 9/92 6/74 1/83
SOF/LDV x8wks SOF/LDV+RBV x8wks SOF/LDV x12wks
P=0.034
P=0.088
P=0.141
Kowdley KV et al. New Engl J Med 2014;370:1879-88.
SVR
12
(%
)
n N
82 86
84 88
84 85
102 109
20 23
107 111
23 23
108 109
24 24
Overall GT1a GT1b
87 88
110 111
23 23
Error bars: 95% CI.
One patient achieved SVR12, but was not subgenotyped.
ION-2: SOF/LDV ± RBV in GT1 treatment-experienced patients
Afdhal N et al. New Engl J Med 2014;370:1483-93.
ION-2: SVR rates in GT1 treatment-experienced cirrhotic patients (subgroup analysis)
No cirrhosis Cirrhosis
83 87
19 22
89 89
18 22
86 87
22 22
88 89
22 22
n N
Error bars: 95% CI.
SVR
12
(%
)
Afdhal N et al. New Engl J Med 2014;370:1483-93.
LDV/SOF Efficacy in Cirrhotics According to Treatment Experience, Duration, RBV
100
80
60
40
20
0
Total Treatment Naive
92 96 98 100
SV
R1
2 (
%)
118 204 133 58
96 98 97
47 45 33 36
100
Treatment Experienced
90
96 98
71 159 100 22
100
12 wks of LDV/SOF
12 wks of LDV/SOF + RBV
24 wks of LDV/SOF
24 wks of LDV/SOF + RBV
n =
Reddy KR et al. Hepatology 2015;62:79-86.
SAPPHIRE-I: GT1 naive, non-cirrhotic patients — SVR12 rates by HCV GT1 subtype
•
SVR
12
(%
)
n N
455 473
307 322
148 151
Treatment-naive
Error bars: 95% CI.
Feld JJ et al. N Engl J Med 2014;370:1594-603.
Paritaprevir/r/Ombitasvir + Dasabuvir + RBV x12 wks
PEARL-III: SVR rates with 3D ± RBV in GT1b naive, non-cirrhotic patients
Error bars: 95% CI. Ferenci P et al. N Engl J Med 2014;370:1983-92.
Paritaprevir/r/Ombitasvir + Dasabuvir ± RBV x12 wks
209/210 207/209
SVR
12
(%
)
RBV No RBV
PEARL-IV: GT1a naive, non-cirrhotic patients
SVR
12
(%
)
97 100
185 205
Paritaprevir/r/Ombitasvir + Dasabuvir ± RBV x12 wks
Treatment discontinuations 0 2 (1%)
Ferenci P et al. N Engl J Med 2014;370:1983-92.
SAPPHIRE-II: GT1 treatment-experienced non-cirrhotic patients
SVR
12
(%
)
n N
286 297
166 173
119 123
One patient achieved SVR12, but was unable to be subgenotyped.
Error bars: 95% CI.
Zeuzem S et al. N Engl J Med 2014;370:1604-14.
Paritaprevir/r/Ombitasvir + Dasabuvir + RBV x12 wks
PEARL-II: HCV GT1b treatment-experienced non-cirrhotic patients
P Andreone et al. Gastroenterology 2014; 147:359-365
SVR
12
(%
)
n N
91 91
85 88
35% null-responders, 29% partial responders, 36% relapsers
Paritaprevir/r/Ombitasvir + Dasabuvir ± RBV x12 wks
Welzel T et al. EASL Special Conference September 23–24 2016. Poster presentation #163.
GARNET: Efficacy of 8-Week Paritaprevir/r/Ombitasvir+Dasabuvir (PRV/OBV+DSV) in Treatment-Naïve Non-cirrhotic GT1b Patients
162 166
160 162
2 relapses, 1 discontinuation
160 163
ITT: all patients who received at least one dose of study drug; mITT-GT: ITT modified to exclude 3 patients without GT1b (1a, 1d, 6); mITT-GT-VF: mITT-GT modified to exclude non-virologic failures (1 patient discontinued prematurely due to noncompliance).
Fibrosis was the only significant predictor of SVR12 identified:
(F3 86.7% [13/15] vs F0–F2 99.3% [147/148])
TURQUOISE-II: SVR12 rates in GT1 treatment-naive and experienced cirrhotic patients
SVR
12
(%
)
12 Weeks 3D + RBV
91.8
191/208
95.9
165/172
24 Weeks 3D + RBV
P=0.089
Paritaprevir/r/Ombitasvir + Dasabuvir (3D) + RBV x12 wks
Poordad F et al. N Engl J Med 2014;370:1973-82
TURQUOISE-II: SVR12 rates in GT1 treatment-naive and experienced cirrhotic patients by HCV subgenotype
88.6
12-week arm
24-week arm
98.5 94.2 100
GT 1a GT 1b
3D + RBV
SVR
12
(%
)
124/140 67/68 114/121 51/51
Poordad F et al. N Engl J Med 2014;370:1973-82
Paritaprevir/r/Ombitasvir + Dasabuvir (3D) + RBV x12 wks
• EOTR = end-of-treatment response. * Prior pegIFN/RBV failures.
Feld JJ et al. J Hepatol 2016; 64:301–7.
• Phase 3b, multicenter, single-arm, open-label study
TURQUOISE-III: Paritaprevir/r/Ombitasvir+Dasabuvir (PRV/OBV+DSV) for HCV GT1b-infected, Cirrhotic Patients
Study weeks
PRV/OBV+DSV
0 24 12
HCV GT1b, treatment-naive
or -experienced*, cirrhotic (N=60)
36
SVR12
60 60
100% of patients achieved
SVR12 with 12-week
treatment
Pat
ien
ts (
%)
60 60
60 60
60 60
Characteristic Median (range)
pegIFN/RBV experienced Non-responder Relapser/breakthrough Other
33 (55.0) 18 (30.0)
5 (8.3) 10 (16.7)
Albumin, g/dL 4.0 (2.8–4.5)
Platelet count, 109/L 132 (54–514)
Alpha fetoprotein, ng/mL 11.9 (2.7–247.0)
Total bilirubin, mg/dL 0.8 (0.3–2.5)
nN
ASTRAL-1: SOF/VEL STR for 12 Weeks in GT1 Patients
Feld JJ et al. N Engl J Med. 2015;373:2599-607.
323/328 206/210 117/118
SVR12, %
SV
R1
2 (
%)
299/316 144/157 129/131 n/N =
Overall GT1a GT1b
95 92 99 100
75
50
25
0
SV
R1
2 (
%)
356/370 89/94 92/92 n/N =
Overall 12 weeks 16 weeks + RBV
96 95 100 100
75
50
25
0
Naive
Treatment experienced
Elbasvir/Grazoprevir for GT1 patients
Zeuzem Z et al. Ann Intern Med 2015;163:1-13. Kwo P et al. Gastroenterology 2016.
Naive or PegIFNa±RBV experienced, non cirrhotics with GT1a
AASLD (09/2016)
EASL (09/2016)
PegIFNa+RBV (PR) NO NO
PR+SMV – PR NO 24/48 (12-12/36)wks in naive-RR/PR-NR (No in Q80K+)
PR+SOF NO 12wks
SOF +SMV 12wks NO
SOF +DCV 12wks
12wks in naive, 12wks+RBV or 24wks in experienced
SOF/LDV 12wks 8 or 12wks in naive, 12wks+RBV ή 24wks in experienced
PRV/r/OBV +DSV 12wks +RBV
12wks +RBV
SOF/VEL 12wks 12wks
EBR/GZR 12wks σε RASs*-,
16wks +RBV in RASs*+
12wks in HCVRNA ≤800,000 IU/ml (or RASs*-), 16wks +RBV in HCVRNA >800,000 IU/ml (&
RASs*+)
*NS5A RASs (resistance associated variants) at position/s 28,30,31 and/or 93
AASLD (09/2016)
EASL (09/2016)
PegIFNa+RBV (PR) NO NO
PR+SMV – PR NO 48 (12-36)wks (No in Q80K+)
PR+SOF NO 12wks
SOF +SMV 24wks ±RBV (No in Q80K+)
NO
SOF +DCV 24wks ±RBV 12wks in naive, 12wks+RBV or 24wks in experienced
SOF/LDV 12wks in naive, 12wks +RBV or24wks
in experienced
12wks in naive, 12wks+RBV or 24wks in experienced
PRV/r/OBV +DSV 24wks +RBV
24wks +RBV
SOF/VEL 12wks 12wks
EBR/GZR 12wks in RASs*-,
16wks +RBV in RASs*+ 12wks in HCVRNA ≤800,000 IU/ml (or RASs*-),
16wks +RBV in HCVRNA >800,000 IU/ml (& RASs*+)
Naive or PegIFNa±RBV experienced, cirrhotics with GT1a
*NS5A RASs (resistance associated variants) at position/s 28,30,31 and/or 93
AASLD (09/2016)
EASL (09/2016)
PegIFNa+RBV (PR) NO NO
PR+SMV – PR NO 24/48 (12-12/36)wks in naive-RR/PR-NR
PR+SOF NO 12wks
SOF +SMV 12wks NO
SOF +DCV 12wks
12wks
SOF/LDV 12wks 12wks (perhaps 8wks in naive)
PRV/r/OBV +DSV 12wks 12wks (perhaps 8wks in naive)
SOF/VEL 12wks 12wks
EBR/GZR 12wks 12wks
Naive or PegIFNa±RBV experienced, non cirrhotics with GT1b
AASLD (09/2016)
EASL (09/2016)
PegIFNa+RBV (PR) NO NO
PR+SMV – PR NO 48 (12-36)wks
PR+SOF NO 12wks
SOF +SMV 24wks ±RBV NO
SOF +DCV
24wks ±RBV 12wks
SOF/LDV 12wks in naive, 12wks +RBV or24wks in experienced
12wks
PRV/r/OBV +DSV 12wks 12wks
SOF/VEL 12wks 12wks
EBR/GZR 12wks 12wks
Naive or PegIFNa±RBV experienced, cirrhotics with GT1b
Sofosbuvir + RBV
IFNa free regimens for genotype 2
Sofosbuvir + Daclatasvir
Sofosbuvir /Velpatasvir
SOF + RBV in GT2 Patients
Lawitz E et al, NEJM 2013,368:1878-87. Jacobson IM et al, NEJM 2013,368:1867-77.
Zeuzem S et al, AASLD 2013, Abstr. #1085.
VALENCE
SOF + RBV
12 wk
FISSION
SOF + RBV
12 wk
VALENCE
SOF + RBV
12 wk
SVR
12
(%
)
Treatment-Naive Treatment-Experienced
FUSION
SOF + RBV
12 wk
POSITRON
SOF + RBV
12 wk
97% 100%
29/30 2/2 0%
20%
40%
60%
80%
100% 98%
31/36
91%
30/33
78%
100%
23/23 7/9
91% 88%
30/33 7/8
92%
85/92
94%
16/17
Noncirrhotic Cirrhotic
60%
96%
25/26 6/10
FUSION
SOF + RBV
16 wk
BOSON: SOF +RBV ±Peg-IFNa in GT2 treatment experienced patients with cirrhosis
G Foster et al. EASL 2015, Abstr. LB 05
SVR12, %
13/15 17/17 15/16
Sulkowski M et al. New Engl J Med 2014;370:211-21
Daclatasvir + Sofosbuvir ± RBV x24 wks
in naive patients with genotype 2 Pa
tien
ts w
ith
SV
R1
2 (%
)
N=26
ASTRAL-2: SOF/VEL STR for 12 Weeks in GT2 Patients
133/134 124/132
SOF/VEL SOF + RBV P=0.018*
Foster GR et al. N Engl J Med 2015;373:2608-17.
104/104
Feld JJ et al. N Engl J Med. 2015;373:2599-607.
AASLD (09/2016)
EASL (09/2016)
PegIFNa+RBV (PR) NO OXI
PR+SOF NO 12wks
SOF +RBV NO OXI
SOF +DCV
12wks, 16-24wks in cirrhosis
12wks
SOF/VEL 12wks
12wks
Naive or PegIFNa±RBV experienced, (non-)cirrhotics with GT2
IFNa free regimens for genotype 3
Sofosbuvir + RBV
Sofosbuvir + Daclatasvir (±Ribavirin)
Sofosbuvir /Velpatasvir (±Ribavirin)
HCV GT3 Patients
Treatment-Naive Treatment-Experienced
Noncirrhotic Cirrhotic
19%
87%
60%
SVR
12 (
%)
89/145 86/92
FUSION
SOF +RBV 12 wk
VALENCE SOF + RBV 24 wk
87/100 5/26
92% 94%
12/13 14/38
37%
27/45
68%
21%
61%
34%
0%
20%
40%
60%
80%
100%
FISSION SOF + RBV 12 wk
VALENCE SOF + RBV 24 wk
13/38
POSITRON SOF + RBV 12 wk
57/84 3/14
61%
FUSION
SOF +RBV 16 wk
14/23 25/40
63%
Lawitz E et al, NEJM 2013,368:1878-87. Jacobson IM et al, NEJM 2013,368:1867-77.
Zeuzem S et al, AASLD 2013, Abstr. #1085.
ALLY-3: SVR12 With SOF + DCV x12 wks in GT3
11 of 16 relapsers had cirrhosis
RASs emerging at relapse: NS5A Y93H emerged in 9 of 16 pts
SVR
12
(%
)
Treatment-Naive Pts
Treatment-Experienced Pts
Overall Treatment-Naive Pts
Treatment-Experienced Pts
No cirrhosis Cirrhosis
SVR
12
(%
)
100
80
60
40
20
0
90 86
100
80
60
40
20
0
96
63
97
58
94 69
105/ 109
20/ 32
73/ 75
11/ 19
32/ 34
9/ 13
91/ 101
44/ 51
Nelson DR et al. Hepatology 2015;61:1127-35.
SOF + RBV 16 weeks SOF + RBV 24 weeks SOF + PEG/RBV 12 weeks
58 70
65 72
68 71
12 21
26 34
17 36
30 35
44 54
49 52
41 54
SVR
12
(%
)
Treatment Naive Treatment Experienced
No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis
BOSON: SOF +RBV ±Peg-IFNa in GT3
G Foster et al. EASL 2015, Abstr. LB 05
18 22
21 23
• No virological breakthrough or discontinuation due to adverse events
Leroy V et al. AASLD 2015, Abstract LB-3.
All Pts Advanced Fibrosis
(F3)
Cirrhosis + Treatment
Experienced
SVR
12
(%
)
12-wk DCV + SOF + RBV 16-wk DCV + SOF + RBV
Cirrhosis
88 92 100 100 83 89 88 86
21/ 24
24/ 26
6/ 6
8/ 8
15/ 18
16/ 18
14/ 16
12/ 14
80
100
60
40
20
0
n/N =
ALLY-3+: SVR12 with SOF + DCV + RBV x12 wks in GT3
SVR
12
(%
)
264/277 221/275
P<0.001*
12 Weeks 24 Weeks
ASTRAL-3: Open-Label Trial - SVR12, Safety With Sofosbuvir/Velpatasvir in GT3 HCV
Foster GR et al. N Engl J Med 2015;373:2608-17.
100
ASTRAL-3: Open-Label Trial - SVR12, Safety With Sofosbuvir/Velpatasvir in GT3 HCV
Foster GR et al. N Engl J Med 2015;373:2608-17.
n/N =
SVR
12
(%
)
80
60
40
20
0
264/277
221/275
191/197
163/187
73/ 80
55/ 83
200/ 206
176/ 204
64/ 71
45/ 71
95
80
63
90 97 97 87
91
66
86
All Pts No Yes Naive Experienced
Cirrhosis
P < .001 (superiority)
SOF/VEL 12 wks
SOF + RBV 24 wks
Treatment History
AASLD (09/2016)
EASL (09/2016)
PegIFNa+RBV (PR) NO NO
PR+SOF NO 12wks
SOF +RBV NO NO
SOF +DCV
12wks 12wks in naive, 12wks +RBV in RAS*+ or 24wks in
experienced
SOF/VEL 12wks 12wks in naive, 12wks +RBV in RAS*+ or 24wks in
experienced
*NS5A RAS Y93H
Naive or PegIFNa±RBV experienced, non-cirrhotics with GT3
AASLD (09/2016)
EASL (09/2016)
KEEΛΠΝΟ (04/2016)
PegIFNa+RBV (PR)
OΧΙ OΧΙ OΧΙ
PR+SOF OΧΙ 12wks 12wks
SOF +RBV OΧΙ OΧΙ 24wks σε naive, OΧΙ σε αποτυχ.
SOF +DCV
24wks (+RBV σε RAS*+) naive, 24wks +RBV σε αποτυχ.
24wks +RBV 12-24wks +RBV
SOF/LDV OΧΙ OΧΙ 12wks +RBV (περιορισμένα δεδομένα)
SOF/VEL 12wks (+RBV σε RAS*+) naive, 24wks +RBV σε αποτυχ.
12wks (+RBV σε RAS*+) ή 24wks
-
*NS5A RAS Y93H
Naive or PegIFNa±RBV experienced, non-cirrhotics with GT3
Sofosbuvir + Simeprevir (±Ribavirin)
Sofosbuvir + Daclatasvir (±Ribavirin)
IFNa-free regimens for genotype 4
Sofosbuvir/Ledipasvir (±Ribavirin)
Paritaprevir/r/Ombitasvir ±Dasabuvir (±Ribavirin)
Sofosbuvir/Velpatasvir
Grazoprevir/Elbasvir (±Ribavirin)
Ruane PJ et al. Hepatology 2015, Epud ahead of print
Virologic ResponseSOF + RBV in Treatment of GT4 Patients of Egyptian Ancestry
11/14 11/14 14/14 10/17 10/17 14/15
Treatment-naive Treatment-experienced
SYNERGY Trial: LDV/SOF for 12 wks in patients with G4
• Single-center, open-label phase 2a trial
• 38% of patients were TE; all were naive to DAAs; 33% had cirrhosis
• No deaths, SAEs, or grade 4 laboratory events; 1 D/C
GT4 HCV (N=21)
SOF/LDV
12 wks SVR12, %
95
Kapoor R et al. AASLD 2014, Abstract #240
French cohort
GT4 HCV (N=44)
SOF/LDV
12 wks SVR12, %
93
Abergel A et al. EASL 2015, Abstr. O56
Experienced: 22 (50%), Cirrhosis: 10 (23%)
PEARL-I: Paritaprevir/r/Ombitasvir ± RBV x12 wks in non-cirrhotic naive/experienced patients with GT4
SVR
(%
)
Hezode C et al. Lancet 2015; 385:2502-9.
No RBV +RBV +RBV (N=44) (N=42) (N=49)
SVR4
SVR12
P=0.086
Error bars indicate 95% confidence intervals.
Arm A: 12 weeks (N = 59)
Arm B: 16 weeks (N = 61)
Non-responses, n (%) 2 (3) 1 (2)
Virologic failure 1 (2) 0
Relapse 0 0
Premature study drug D/C 1 (2) 0
Missing SVR12 data 0 1 (2)
1 2 w e e k 1 6 w e e k
0
2 5
5 0
7 5
1 0 0V
iro
log
ic R
es
po
ns
e,
% P
ati
en
ts
5 9
5 7
5 8
5 7
6 0
6 0
9 8 1 0 09 7 9 8
O B V / P T V / r + R B V T r e a t m e n t D u r a t io n
6 1
6 0
S V R 1 2 (s e n s it iv ity a n a ly s is )
SVR12 Rates by Treatment Arm (Sensitivity Analysis)
The sensitivity analysis excluded patients who prematurely discontinued study drug (with no on-treatment virologic failure) or who were missing follow-up data in the SVR12 window
AGATE-I: Paritaprevir/r/Ombitasvir + RBV x12 wks in cirrhotic naive/experienced patients with GT4
Asselah T et al. DDW 2016
SV
R1
2 (
%)
18/18 n/N =
GT 4
100% 100
75
50
25
0
SV
R1
2 (
%)
32/37 7/9 8/8 n/N =
Overall 12 weeks 16 weeks + RBV
87 79 100 100
75
50
25
0
Elbasvir/Grazoprevir for GT4 patients
Zeuzem Z et al. Ann Intern Med 2015;163:1-13. Kwo P et al. Gastroenterology 2016.
Naive
Treatment experienced
ASTRAL-1: SOF/VEL STR for 12 Weeks in GT4, GT5, GT6 Patients
Feld JJ et al. N Engl J Med. 2015;373:2599-607.
116/116 34/35 41/41
SVR12, %
AASLD (09/2016)
EASL (09/2016)
PegIFNa+RBV (PR) NO NO
PR+SMV – PR NO 24 (12-12)wks in naive/RR, 48 (12-36)wks in PR/NR
PR+SOF NO 12wks
SOF+RBV NO NO
SOF +SMV NO 12wks in naive, 12wks +RBV or 24wks in experienced
SOF +DCV NO 12wks in naive, 12wks +RBV or 24wks in experienced
SOF/LDV 12wks 12wks in naive, 12wks +RBV or 24wks in experienced
PRV/r/OBV 12wks +RBV 12wks +RBV
SOF/VEL 12wks 12wks
EBR/GZR 12wks σε naive/RR, 16wks +RBV σε PR/NR
12wks in naïve or in experienced with HCVRNA ≤800,000 IU/ml,
16wks +RBV in experienced with HCVRNA >800,000 IU/ml
Naive or PegIFNa±RBV experienced, non-cirrhotics with GT4
AASLD (09/2016)
EASL (09/2016)
PegIFNa+RBV (PR) NO NO
PR+SMV – PR NO 48 (12-36)wks
PR+SOF NO 12wks
SOF+RBV NO NO
SOF +SMV NO 12wks in naive, 12wks +RBV or 24wks in experienced
SOF +DCV
NO 12wks in naive, 12wks +RBV or 24wks in experienced
SOF/LDV 12wks in naive, 12wks +RBV or 24wks in experienced
12wks in naive, 12wks +RBV or 24wks in experienced
PRV/r/OBV 12wks +RBV 12wks +RBV
SOF/VEL 12wks 12wks
EBR/GZR 12wks in naive/RR, 16wks +RBV σε PR/NR
12wks in naïve or in experienced with HCVRNA ≤800,000 IU/ml,
16wks +RBV in experienced with HCVRNA >800,000 IU/ml
Naive or PegIFNa±RBV experienced, cirrhotics with GT4
AASLD (09/2016)
EASL (09/2016)
PegIFNa+RBV (PR) NO NO
PR+SOF NO 12wks
SOF +RBV NO NO
SOF +DCV NO 12wks in naive, 12wks +RBV or 24wks in experienced
SOF/LDV 12wks 12wks in naive, 12wks +RBV or 24wks in experienced
SOF/VEL 12wks 12wks
Naive or PegIFNa±RBV experienced, (non-)cirrhotics with GT5/6
SOLAR-1: SVR12 and safety according to CTP score in decompensated cirrhosis
100
80
60
40
20
0
SVR
12
(%
)
Overall CTP B CTP C
LDV/SOF + RBV 12 wks LDV/SOF + RBV 24 wks
87 89
45/52 42/47
87 89 86 90
26/30 24/27 19/22 18/20
3 relapses 1 death 1 relapse
2 deaths
1 relapse 1 death 1 LTFU 1 relapse
1 death
Patients n (%)
CTP B CTP C
12 Wks
(n=30)
24 Wks
(n=29)
12 Wks
(n=23)
24 Wks
(n=26)
AE 29 (97) 27 (93) 23 (100) 26 (100)
SAE 3 (10) 10 (34) 6 (26) 11 (42)
Treatment-emergent, -related
SAEs 2 (7) 0 0 2 (8)
Treatment D/C due to AEs 0 1 (3) 0 2 (8)
Charlton M et al. Gastroenterology 2015;149:649-59.
SOLAR-2: SOF/LDV+RBV in HCV decompensated cirrhotics and transplant patients
M Manns et al. Lancet Infect Dis 2016;16:685-97.
SOLAR-2: SOF/LDV+RBV in HCV decompensated cirrhotics and transplant patients
MELD score change from baseline to follow-up week-4
M Manns et al. Lancet Infect Dis 2016;16:685-97.
aBased on all treated patients who have reached PT Week 12 b1 HCV RNA > LLOQ but discontinuation before week 12.
Welzel T et al. EASL 2015 Abstr P772
EU multicentre Compassionate Use Program
Total n = 482 72% GT-1; CP-A: 57%, CP-B: 36%, CP-C: 6%
Safety: DC due to AE: 28 (6%)
DCV + SOF ± RBV, 24 weeks
Interim resultsa - DCV + SOF ± RBV in GT1 patients with decompensated cirrhosis in early access programme
52
55 95
100 147 155
21b
22 27 27
48b 49
ASTRAL-4: SOF/VEL ± RBV in HCV Patients with Decompensated Liver Disease
75/90 82/87 77/90 60/68 65/68 65/71 7/14 11/13 6/12 GT2 4/4 GT4 4/4
GT2 4/4 GT4 2/2
GT2 3/4 GT4 2/2 GT6 1/1
Curry MP et al. N Engl J Med 2015;373:2618-28.
Decompensated cirrhosis
AASLD (09/2016)
EASL (09/2016)
Treatment indication Expert’s assessment Indication for liver transplantation (LT): MELD <18-20 or ΜΕLD ≥18-20 & waiting time for LT >6 months Indication for LT: Child-Pugh score ≤12
Protease inihibitors (SMV, PRV, GZR)
NO NO
AASLD (09/2016)
EASL (09/2016)
SOF +RBV NO NO
SOF +DCV GT1/4: 12wks +RBV*
or 24wks (contraindication for RBV)
GT2/3: 12wks +RBV*
GT1/2/4/5/6: 12wks +RBV*
or 24wks (contraindication for RBV)
GT3: 24wks +RBV*
SOF/LDV GT1/4: 12wks +RBV*
or 24wks (contraindication for RBV)
or 24wks +RBV (SOF failures)
GT1/4/5/6: 12wks +RBV*
or 24wks (contraindication for RBV)
SOF/VEL
GT1/4: 12wks +RBV
or 24wks (contraindication for RBV)
or 24wks +RBV (SOF failures)
GT2/3: 12wks +RBV
GT1/2/4/5/6: 12wks +RBV*
or 24wks (contraindication for RBV)
GT3: 24wks +RBV*
*RBV: 600 mg/24h as initial dose – gradual dosage increase to 1000/1200 mg/24h
Decompensated cirrhosis
Sofosbuvir
Simeprevir
Daclatasvir
Sofosbuvir/Ledipasvir
Paritaprevir/r/Ombitasvir ± Dasabuvir
Drug-Drug interactions
None
Not with CsA
None
None
Increase of TACR>CsA levels TAC: 0.5 mg/wk or 0.2 mg/72h,
CsA: 20% of previous dose
Not with everolimus
None
Not with CsA (increases GZR plasma levels: ALT flares?)
- Close monitoring TACR levels
Sofosbuvir/Velpatasvir
Grazoprevir/Elbasvir
HCV transplant patients
Drug-Drug interactions (Liver transplantation & HIV drugs excluded) Co-administration is NOT recommended
Sofosbuvir P-glycoprotein inducers (carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifampicin, St. John's wort), modafinil, amiodarone
Simeprevir (Caution: digoxin, amiodarone, disopyramide, flecainide, mexiletine, propafenone, quinidine, warfarin, calcium channel blockers)
Inhibitors or inducers of CYP3A4 (erythromycin, clarithromycin, antifungals, dexamethasone, cicapride, milk thistle, astemizole, terfenadine)
P-glycoprotein inducers
Daclatasvir (Caution: erythromycin, dabigatran, digoxin, calcium channel blockers, rosuvastatin)
Strong inducers of CYP3A4/P-glycoprotein , amiodarone
(Moderate inducers of CYP3A4: DCV 90 mg/24h)
(Inhibitors of CYP3A4: DCV 30 mg/24h)
Ledipasvir/Sofosbuvir (Caution: amiodarone, antacids, PPIs, digoxin, dabigatran, pravastatin, statins)
P-glycoprotein inducers, rosuvastatin, simeprevir, modafinil , amiodarone
Paritaprevir/r/Ombitasvir ± Dasabuvir (Caution: digoxin, warfarin, calcium channel blockers)
P-glycoprotein inducers, gemfibrozil, lovastatin, simvastatin, oral midazolam, triazolam, pimozide, ethinyl estradiol-containing oral contraceptives, sildenafil for pulmonary hypertension, amiodarone
Drug-Drug interactions (Liver transplantation & HIV drugs excluded) Co-administration is NOT recommended
Velpatasvir/Sofosbuvir (Caution: antacids, H2RAs, PPIs)
P-glycoprotein inducers (carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifampicin, St.
John’s wart), amiodarone
Elbasvir/Grazoprevir (Caution: amiodarone, cyclosporine)
OATP1B1/3 inhibitors, Potent CYP3A4 inducers (carbamazepine, phenytoin, rifampicin, St. John’s wart)
Drug-Drug interactions with HIV drugs
None
Not with cobicistat*, efavirenz, delavirdine, etravirine, nevirapine, ritonavir & any HIV protease inhibitor
Not with darunavir, lopinavir, etravirine ή nevirapine - DCV 30 mg with atazanavir/r, DCV 90 mg with efavirenz
Not with cobicistat*, tripanavir/r
Not with efavirenz, rilpivirine ή lopinavir
Not with efavirenz (closer follow-up for TDF AEs)
Not with efavirenz (closer ALT fup with atazanavir, darunavir, lopinavir, saquinavir, tripanavir)
*cobicistat: elvitegravir + cobicistat + emtricitabine + tenofovir
Sofosbuvir
Simeprevir
Daclatasvir
Sofosbuvir/Ledipasvir
Paritaprevir/r/Ombitasvir ± Dasabuvir
Sofosbuvir/Velpatasvir
Grazoprevir/Elbasvir
HCV & HIV coinfection IFNa-free regimens similar efficacy to HCV monoinfected patients
Sofosbuvir
Simeprevir
Daclatasvir
Sofosbuvir/Ledipasvir
Paritaprevir/r/Ombitasvir, Dasabuvir
HCV in patients with renal impairment Drug doses in reduced Creatinine
Clearance (CrCl)
Peg-IFNa-2a 135 μg/wk – ClCr <50 ml/min Peg-IFNa-2b 25%/50% - ClCr 30-50/15-29
200/400 mg /24/24h - ClCr 30-50 ml/min 200 mg /24h - ClCr <30 ml/min
No change for CrCl ≥30 ml/min Contraindicated for CrCl <30 ml/min
No change
No change
No change for CrCl ≥30 ml/min Contraindicated for CrCl <30 ml/min
No change
No change for CrCl ≥30 ml/min Contraindicated for CrCl <30 ml/min
No change
Peg-IFNa
Ribavirin
Sofosbuvir/Velpatasvir
Grazoprevir/Elbasvir
New DAAs - Conclusions
Increasing number of licensed agents for patients with HCV
-Availability and accessibility vary among countries
Shortening of treatment duration to 8 weeks is possible in some non-cirrhotic
patients, with no loss of efficacy
Treatment options available irrespective of cirrhosis status
The proportion of patients failing to respond to DAAs is small and re-
treatment options are available for most patients
-NS5A inhibitor failures remain a treatment challenge
The availability of DAAs means that HCV cure is now a reality for most patients