CARE AND TREATMENT OF CHRONIC HBV AND HCV -December 2018- 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
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CARE AND TREATMENT OF CHRONIC HBV AND HCV€¦ · CARE AND TREATMENT OF CHRONIC HBV AND HCV -December 2018- GEORGE PAPATHEODORIDIS, MD PROFESSOR IN MEDICINE AND GASTROENTEROLOGY ATHENS
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CARE AND TREATMENT
OF CHRONIC HBV AND HCV - D e c e m b e r 20 1 8 -
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
Chronic HBV and HCV are treatable or curable
Current HBV treatment options Current HCV treatment options
achieved in most patients with long-term suppression of HBV
replication.
• HBsAg loss, with or without anti-HBs seroconversion:
optimal endpoint indicating profound suppression of HBV
replication and viral protein expression.
End-points of therapy
EASL 2017 CPG HBV, J Hepatol 2017;67:370-398.
Indications for treatment
• Patients should be considered for treatment if
– HBV DNA >2,000 IU/ml and
– ALT >ULN (40 IU/L) and/or
– At least moderate necroinflammation and/or at least moderate
fibrosis by liver biopsy [or liver stiffness >9 or >12 kPa if ALT ≤ULN or
>ULN (<5xULN)]
• Patients with compensated or decompensated cirrhosis need treatment, with any detectable HBV DNA level and regardless of ALT levels
• Indications for treatment may also take into account
age, health status, comorbidities, family history of HCC or cirrhosis and
extrahepatic manifestations
EASL 2017 CPG HBV, J Hepatol 2017;67:370-398.
Treatment indications/Management in HBeAg-pos. CHB patients
ALT >ULN & HBV DNA >2,000 & Biopsy ≥A2/F2
A. HBeAg-pos. chronic HBV infection (previously immunotolerant phase):
Persistently ALT ≤ULN
• No Biopsy – No therapy – Follow-up if age ≤30
• Treatment if age >30 or family history of HCC, cirrhosis, stiffness >9 kPa
B. Obviously active CHB: ALT >2xULN & HBV DNA >20,000 IU/ml
• Therapy – Biopsy optional
EASL 2017 CPG HBV, J Hepatol 2017;67:370-398.
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 <2000: No biopsy, No therapy, Follow-up
- HBV DNA 2,000-20,000 & no evidence of advanced liver disease:
No Biopsy, No therapy, Follow-up (close for another 2 years)
- HBV DNA >20,000 & no evidence of advanced liver disease: individualize
- HBV DNA >2000 & evidence of advanced liver disease
(including stiffness >9 kPa): therapy
B. Obviously active CHB: ALT >2xULN & HBV DNA >20,000
• Therapy – Biopsy optional
Treatment indications/Management in HBeAg-neg. CHB patients
EASL 2017 CPG HBV, J Hepatol 2017;67:370-398.
HBeAg-negative patient with normal ALT at baseline
ALT every 2-4 months for 12 months
ALT >ULN and/or Persistently ALT<ULN and Persistently ALT<ULN and HBV DNA >20,000 or HBV DNA >2,000 (≤20,000) HBV DNA <2,000 IU/mL signs of advanced disease or liver stiffness >12 kPa Elastography Liver stiffness >9 Stiffness ≤9 kPa ALT every 6 mos, periodical HBV DNA, & elastography Liver biopsy and/or ALT every 3-4 mos, Treatment HBV DNA every 12 mos for two years
ALT<ULN and HBV DNA 2,000-20,000 IU/mL ALT every 6 mos, periodical HBV DNA
ALT >ULN and/or
HBV DNA >20,000
Liver biopsy or Elastography
HBsAg<1000 ALT every 12 mos
Modified from
Vlachogiannakos & Papatheodoridis.
Liver Intern 2018;38(Suppl. 1):71-78.
Additional indications of treatment/prophylaxis
for chronic HBV patients
• Liver transplantation
• HBV-HIV co-infection
• HDV-HBV co-infection with ongoing HBV replication
• HBV-HCV co-infection during and for 12 weeks after DAAs
• Last trimester of pregnancy and up to 12 weeks after delivery if HBV DNA
>200,000 IU/ml or HBsAg >4 log10 IU/ml
• During and for 12 months after immunosuppressive therapy or
chemotherapy
• Healthcare workers performing exposure prone procedures with serum HBV
DNA >200 IU/ml
• Extrahepatic manifestations and replicative HBV infection
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
Indications for selecting ETV or TAF over TDF*
* TAF should be preferred to ETV in patients with previous exposure to nucleoside analogues.
** ETV dose needs to be adjusted if eGFR <50 ml/min; no dose adjustment of TAF is required in adults or adolescents (aged at least 12 years and of ≥35 kg body weight) with estimated creatinine clearance (CrCl) ≥15 ml/min or in patients with CrCl <15 ml/min receiving haemodialysis.
EASL 2017 CPG HBV, J Hepatol 2017;67:370-398.
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
Antiviral Efficacy of TAF and TDF at Week 96
Study 108 and 110: Phase 3 CHB Studies: TAF vs TDF
*Adjusted for baseline HBV DNA level and oral antiviral treatment status strata M=F: Missing =Failure
Agarwal K et al. J Hepatol 2018;68:672-81.
HBeAg+
Rates of Viral Suppression (ITT; M=F) HBV DNA <29 IU/mL
No resistance was detected through 96 weeks Similar HBV DNA suppression rates for TAF compared to TDF through
Week 96
HBeAg-
73%
75%
P=0.47*
90%
91%
P=0.84*
TAF
TDF
94%
93% 64%
67%
Changes in Renal Markers During Treatment with TAF or TDF
Study 108 and 110: Phase 3 CHB Studies: TAF vs TDF
Changes in Quantitative Proteinuria at Week 96
Significantly smaller changes in renal tubular markers with TAF vs TDF
UPCR, urine protein-to-creatinine ratio; UACR, urine albumin-to-creatinine ratio; RBP:Cr, retinol binding protein-to-creatinine ratio; B2M:Cr, β2 microglobulin-to-creatinine ratio * p-values from 2-sided Wilcoxon rank-sum test
Chuang, EASL 2017, SAT-171
Glomerular Proteinuria
Tubular Proteinuria
UPCR UACR
RBP:Cr β2m:Cr
Med
ian
% C
han
ge
(Q1
, Q3
) M
edia
n %
Ch
ange
(Q
1, Q
3)
100
50
0
-50
0 4 12 24 48 72 96
100
50
0
-50
100
50
0
-50
100
50
0
-50
0 4 12 24 48 72 96
0 4 12 24 48 72 96 0 4 12 24 48 72 96
P=0.07
P=0.20
P<0.001 P<0.001
Week Week
TAF
TDF
107
108.5 126.7 221.3 199.6 153.1
Monitoring of patients treated with ETV, TDF or TAF
1) All patients treated with NA should be followed with periodical assessments
including ALT (every 3-4 months during year 1 & then every 6 months) and
serum HBV DNA (every 3-4 months during year 1 & then every 6-12
months) (and HBeAg/anti-HBe every 6 months for HBeAg-pos. patients
EASL 2017 CPG HBV, J Hepatol 2017;67:370-398.
2) Patients at risk of renal disease treated with any NA should undergo
periodical* renal monitoring with eGFR and all patients regardless of
renal risk treated with TDF should undergo periodical* renal monitoring
with at least eGFR and serum phosphate levels.
(*periodical: every 3 months during year 1 & then every 6 months)
3) Patients on TDF at risk of development and/or with underlying renal or
bone disease should be considered for a switch to ETV or TAF, depending
on previous LAM exposure.
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
Long-term outcome during NA therapy
1) Patients under effective long-term NA therapy should
remain under surveillance for HCC.
(Evidence level II-2, grade of recommendation 1)
2) HCC surveillance is mandatory for all patients with
cirrhosis as well as those with moderate or high HCC
risk scores at the onset of NA therapy.
(Evidence level II-2, grade of recommendation 1)
EASL 2017 CPG HBV, J Hepatol 2017;67:370-398.
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
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
HCC risk in 1946 ETV/TDF treated CHB patients beyond year 5
GV Papatheodoridis et al. Hepatology 2017;66:1444-1453.
Ci
No Ci
All patients Patients with & without Ci
Yearly HCC incidence
1.22% 0.63%
P=0.086
Yearly HCC incidence
3.27% 1.07%
P=0.046
0.45% 0.51%
Cumu-
lative
HCC
incide-
nce,
%
Pts at risk-1946 1670 1088 498 169 56 No Ci-1346 1156 734 329 127 45
Ci-518 444 304 145 34 6
1) NAs should be discontinued after confirmed HBsAg loss, with or without anti-HBs seroconversion. (Evidence level II-2, grade of recommendation 1).
2) NAs can be discontinued in non-cirrhotic HBeAg positive CHB
patients who achieve stable HBeAg seroconversion and undetectable HBV DNA and who complete at least 12 months of consolidation therapy. Close post-NA monitoring is warranted. (Evidence level II-2, grade of recommendation 2)
3) Discontinuation of NAs in selected non-cirrhotic HBeAg-
negative patients who have achieved long-term (3 years) virological suppression under NA(s) may be considered if close post-NA monitoring can be guaranteed. (Evidence level II-2, grade of recommendation 2)
NA discontinuation
EASL 2017 CPG HBV, J Hepatol 2017;67:370-398.
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.
HBV treatment modifies the outcome of the disease
Sustained response after pegIFNa or long-term ETV/TDF/TAF 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
Sofosbuvir + Daclatasvir, Paritaprevir/r/Ombitasvir + Dasabuvir: not used in most countries; Sofosbuvir/Velpatasvir/Voxilaprevir: mostly used in DAA failures
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.
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%)
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, %
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, %
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.
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
SOF/VEL for 12 Weeks in GT 1, 2, 4, 5 and 6 HCV: SVR by Genotype
ASTRAL-1 (SOF/VEL x 12 weeks)
618/624
Total
206/210 117/118 104/104 116/116 34/35 41/41
GT 1a GT 1b GT 2 GT 4 GT 5 GT 6
Genotype LTFU=lost to follow up; WC=withdrew consent
1 death 1 relapse 1 relapse
2 LTFU 1 WC
Feld JJ, et al. N Engl J Med 2015;373:2599–2607.
ENDURANCE-1: 8- vs 12-week treatment with G/P in non-cirrhotic naive or PR/SOF experienced patients with GT1
(Primary Efficacy)
Zeuzem S, et al. NEJM 2018;378:354-369.
PR: Peginterferon+Ribavirin; SOF: sofosbuvir; VF, virologic failure; ITT, all patients receiving study drug.
331
332
332
335 332
332
8 weeks
12 weeks
1 LTFU
331
331
ITT population, excluding
HIV co-infected and SOF-
experienced patients
ITT-PS population excluding patients
with premature D/C or virologic failure
prior to week 8, and missing data in the
SVR12 window
1 d/c
1 VF
1 LTFU
ENDURANCE-4: 12-week G/P in naive or PR/SOF experienced HCV patients with GT4–6 (Efficacy)
mITT population is ITT population excluding patients who did not achieve SVR12 for non-virologic reasons.
120
121
75
76
26
26 19
19
120
120
75
75
26
26 19
19
The patient who did not achieve SVR12 discontinued on day 12 due to a SAE (transient ischemic attack with a reasonable possibility of being related to study drug)
1 D/C
Overall GT4 GT5 GT6
1 D/C
Asselah T, et al. Clin Gastroenterol Hepatol 2018;16:417-426
PR: Peginterferon+Ribavirin; SOF: sofosbuvir.
SURVEYOR-II (Part 4): 8-week G/P in Naive or PR/SOF-Experienced Patients with GT2, 4–6 without Cirrhosis (Efficacy – ITT)
LLOQ, lower limit of quantification; TE, treatment emergent; * All patients had HCV RNA <LLOQ at last visit; † Patient had a medical history of gastric bypass. Exposure of GLE on Day 1 and Week 4 was >75% lower than the mean in patients in the same treatment arm; exposure of PIB was comparable to the other patients in the cohort.
97% (196/203, ITT) of GT2, 4, 5, or 6-infected patients without cirrhosis
achieved SVR12 following 8 weeks of G/P
In DAA-naive patients with GT2 infection, 8-week treatment was non-inferior to the historical 95%
SVR12 rate achieved with 12 weeks SOF + RBV
2 relapses
2 D/C
3 missing
SVR12 data*
196
203
2 relapses
1 D/C
1 D/C
2 missing
SVR12 data
1 missing
SVR12 data
142
145
43
46
2
2
9
10
Sequence Analysis
Patient A† Non-cirrhotic
(relapse)
Patient B Non-cirrhotic
(relapse))
NS3 Baseline None None
TE substitutions at failure None None
NS5A Baseline L31M L31M
TE substitutions at failure None None
GT2-infected patients
Asselah T, et al. Clin Gastroenterol Hepatol 2018;16:417-426
EXPEDITION-I: 12-week G/P for of Chronic HCV GT1, 2, 4, 5 or 6 Infection in Adults with Compensated Cirrhosis (Efficacy)
Forns X, et al. Lancet ID 2017; 17:1062–1068.
d/c, discontinuation; PTW, post-treatment Week; RAS, resistance-associated substitution. * SVR12 ITT and mITT are the same.
145
146
89
90
31
31
16
16
2
2
7
7
1 GT1a patient
relapsed at PTW8
n
N
G/P treatment achieved high SVR rates regardless of baseline patient or viral characteristics
Sofosbuvir + Ribavirin (only for genotype 2)
IFNa free regimens for genotype 2, 3
Sofosbuvir + Daclatasvir ± Ribavirin
Sofosbuvir /Velpatasvir ± Ribavirin
Glecaprevir/Pibrentasvir*
Sofosbuvir + Ribavirin, Sofosbuvir + Daclatasvir: not used in most countries anymore; Sofosbuvir/Velpatasvir/Voxilaprevir in genotype 2: mostly used in DAA failures
Sofosbuvir/Velpatasvir/Voxilaprevir*
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.
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
SV
R1
2, %
29/32 72/75 76/77
SOF/VEL
12 weeks
SOF/VEL/VOX 8 weeks
34/35
Treatment-
Naive
Treatment-
Experienced
Treatment-
Naive
Treatment-
Experienced
SV
R1
2, %
POLARIS-3: SOF/VEL/VOX x8 wks or SOF/VEL x12 wks in DAA-Naive HCV GT3 Cirrhotics
Jacobson IM, et al. Gastroenterology 2017;153:113-122
ENDURANCE-3: 8- or 12-week G/P vs 12-week SOF+DCV in naive non-cirrhotic HCV patients with GT3 (Efficacy)