hcv treatment of patients with cirrhosis 2014 singapore
DESCRIPTION
HCV Treatment of Patients With Cirrhosis 2014 SingaporeTRANSCRIPT
Singapore Viral Hepatitis Meeting
June 2014
HCV: management of the patient with Cirrhosis: a focus on treatment
HCV and Cirrhosis
Robert G Gish MD
Professor Consultant– Stanford University
Vice Chair: – Executive Committee National Viral Hepatitis
Roundtable
Senior Medical Director – St Josephs Hospital and Medical Center– Phoenix Arizona
Disclosures
Dr Gish receives consulting fees from
BMS Gilead Merck Idenix AbbVie Genentech
All income is then expensed or donated to research and education
What is cirrhosis?
MELD over 6 CPT 7 and above Liver biopsy Elastography kPa value over 8-11 Spleen over 12 cm Portal vein over 12 mm Varices on EGD or abdominal imaging Large left lobe with physical finding of portal
hypertension Imaging with characteristic changes of liver
morphology and or portal hypertension
HCV Incremental All-Cause Health Care Costs by Liver Disease Severity (USD 2009)
Difference between HCV and non-HCV matched controls.Numbers in parentheses are +SD. Costs normalized to 2009 dollars using Consumer Price Index.
McAdam-Marx C, et al. J Manag Care Pharm. 2012;17:531-546.
Incr
emen
tal A
ll-C
ause
Co
sts
(per
-pat
ien
t-p
er-y
ear)
5879(157) 5330
(491)
27,845(965)
810(49)
974(194)
15,464(710)
1721(123) 1081
(275)
5818(292)
641(37) 93
(130)
4526(213)
2659(41)
3102(157) 1893
(123)
No liver disease (n=26,977)
Compensated cirrhosis (n=1521)
Decompensated cirrhosis (n=4249)
InpatientTotal HealthCare Costs
Outpatient PhysicianServices
PharmacyCostsPlace of Service
HCV Incremental All Cause Health Care Costs by Liver Disease Severity (USD 2009)
Difference between HCV and non-HCV matched controls.Numbers in parentheses are +SD. Costs normalized to 2009 dollars using Consumer Price Index.
McAdam-Marx C, et al. J Manag Care Pharm. 2012;17:531-546.
43,671(2588)
93,609(4482)
27,845(965)
60,143(3612)
17,197(194)15,464
(710)
5818(292)
Decompensated cirrhosis (n=4249)
Hepatocellular carcinoma (n=959)
Liver transplantation (n=891)
12,307(1069)
12,915(829)
4526(213)
9423(1188)
11,697(646)
1893(123)
4632(587)
8736(363)
Incr
emen
tal A
ll-C
ause
Co
sts
(per
-pat
ien
t-p
er-y
ear)
InpatientTotal HealthCare Costs
Outpatient PhysicianServices
PharmacyCostsPlace of Service
0
1000
2000
3000
4000
5000
6000
NCD CC ESLD NCD CC ESLD NCD CC ESLD
Treated
Untreated
1370
2389
1007
543591
3634
885
4656
3186
119312241023
729
5137
3547
1802
1369
P<0.001 P<0.001P<0.057P<0.001P<0.001P<0.826
Pre
dict
ed
cost
(20
10$U
SP
PP
M)
HCV-related costs Medical costs Total costs
225
P<0.001 P<0.001P<0.001
Mean follow-up per patient per month (PPPM) by treatment history and liver disease severity
35% lower
24% lower
31% lower
HCV Therapy Is Associated with Lower Healthcare Costs in Non-Cirrhotic and ESLD Patients
PPPM=per-patient-per-month; NCD=non-cirrhotic disease; CC=compensated cirrhosis; ESLD=end-stage liver diseaseCovariates adjusted for in the analysis included age, sex, geographical region, index year, baseline comorbidities, and baseline treatment for HCVGordon S.C., et al. Aliment Pharmacol Ther. 2013; 38:784-793.
REALIZE: SVR by Baseline Fibrosis Stage and Prior Response
Prior relapsers
Prior partial responders
Prior null responders
No, minimal or portal fibrosis
CirrhosisStage
Pooled T12/PR48
Pbo/PR48
Pat
ien
ts w
ith
SV
R (
%)
Bridgingfibrosis
No, minimal or portal fibrosis
CirrhosisBridgingfibrosis
No, minimal or portal fibrosis
CirrhosisBridgingfibrosis
2/15
n/N= 53/62
145/167
12/38
0/5
10/18
36/47
3/17
0/9
16/38
11/32
1/5
1/15
48/57
24/59
1/18
7/50
1/10
Presented at AASLD – November 6th, 2011
Telaprevir
Category, n (%)Cirrhotics (F4)
N=139Non-cirrhotics (F0–3)
N=391
Patients without SVR 73 (53) 107 (27)
On-treatment virologic failure*Prior relapsersPrior partial and null responders
44 (32)1 (1)
43 (31)
52 (13)2 (1)
50 (13)
Relapse‡
Prior relapsersPrior partial and null responders
17 (12)3 (2)
14 (10)
20 (5)5 (1)15 (4)
Other§
Prior relapsersPrior partial and null responders
12 (9)5 (4)7 (5)
35 (9)24 (6)11 (3)
REALIZE: Reasons for not Achieving an SVR in TVR-treated Patients
*Includes patients with viral breakthrough and/or patients who discontinued due to a virologic stopping rule‡Relapse rate calculated relative to total number of patients
§Includes patients with detectable HCV RNA at the end of treatment (for reasons other than virologic stopping rules) without viral breakthrough, or who had undetectable HCV RNA at the end of treatment but were subsequently lost to follow up before Week 72
Presented at AASLD – November 6th, 2011
REALIZE: AEs in ≥25% of TVR-treated Patients during Any Treatment Phase*
AE, n (%)Cirrhotics (F4)
N=139Non-cirrhotics (F0–3)
N=391
Rash SSC 93 (67) 206 (53)
Pruritus SSC 82 (59) 205 (52)
Fatigue 62 (45) 214 (55)
Headache 54 (39) 167 (43)
Anemia SSC† 59 (42) 134 (34)
Nausea 52 (37) 129 (33)
Influenza-like illness 55 (40) 124 (32)
Insomnia 39 (28) 113 (29)
Anorectal symptoms‡ 33 (24) 101 (26)
Diarrhea 33 (24) 102 (26)
Pyrexia 34 (25) 97 (25)
*Grouped special search category (SSC); †Anemia reported by the investigator as an adverse event; ‡ Grouped term including several different AEs in the anorectal area; AE = adverse event
CUPIC: French EAP: Baseline Demographics and Characteristics
CharacteristicTelaprevir
N=295Boceprevir
N=190
Child-Pugh score A/B, n (%)* 280 (95) / 6 (2) 177 (93) /1 (1)
MELD score, mean (range) 8.1 (6-22) 8.1 (6-28)
Prothrombin time ratio, mean % (range) 86 (27–100) 87 (23–100)
Serum albumin g/L, mean (range) 40.0 (20.7–53.2) 40.7 (27.0–50.3)
Total bilirubin μmol/L, mean (range) 15.5 (4.0–73.0) 15.2 (4.0–78.0)
Hb level g/dL, mean (range) 14.5 (9.0–19.7) 14.8 (10.8–18.4)
Neutrophils, mean (range) (109/mm3) 3.3 (0.8-8.5) 3.2 (0.5-8.5)
Platelet count, mean (range) (103/mm3) 151(18–604)
144(34–346)
Esophageal varices, n (%) 51/145 (35.2) 37/97 (38.1)
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
* Missing data : 21
CUPIC: Virological response (ITT)
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
TELAPREVIR BOCEPREVIR
0
10
20
30
40
50
60
70
80
90
100
49%
Pat
ien
ts w
ith
un
det
ecta
ble
HC
V R
NA
(P
erce
nta
ge
)
79% 81%
56%
W4 W8 W12 W24 W48 W60W16
77 %
68 %
146295
234295
239295
227295
200295
165295
118295
0
10
20
30
40
50
60
70
80
90
100
16%
51%
62%65%
67%
W4 W8 W12 W16 W24 W48 W60
31190
97190
118190
124190
128190
108190
57%
79190
40% 41%
CUPIC: SVR12 According to Prior Treatment Response
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
61/116 43/135 8/28
Relapsers Partial responders
Null responders
53%
32% 29%
P=0.004
P=0.001
P=0.03
TELAPREVIRTELAPREVIR
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
3119043/85 32/80 1/9
P=0.003
51%
40%
11%
BOCEPREVIR
Relapsers Partial responders
Null responders
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
CUPIC: Virological Failure
Non response
0102030405060708090
100
Vir
olo
gic
al
fail
ure
(
Per
cen
tag
e)
33/177 25/177*47/177
Premature discontinuationRelapse Breakthrough
19% 14%27%
72/177
41%
TELAPREVIR
01020304050607080
90100
Vir
olo
gic
al
fail
ure
(
Per
cen
tag
e)
40/111 12**/11130/111
Premature discontinuationRelapse Breakthrough
36%
11%
27%
29/111
26%
Non response
BOCEPREVIR*22 without failure
**10 without failure
CUPIC: SVR 12 According to HCV Subtype
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
Genotype 1a
Genotype 1b
Undeterminedgenotype 1
33/98 75/162 9/33
34%46%
27%
P=0.004
0
10
20
30
40
50
60
70
80
90
100
SV
R 1
2 (I
TT
) (
Pe
rcen
tag
e)
TELAPREVIR
Genotype 1a
Genotype 1b
Undeterminedgenotype 1
0
10
20
30
40
50
60
70
80
90
100
31190 6/16
P=0.03
31%
51%
37%
49/9624/77
BOCEPREVIR
SV
R 1
2 (I
TT
) (
Pe
rcen
tag
e)
CUPIC: SVR12 According to Initial Viremia
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
< 800000 IU/mL ≥ 800000 IU/mL
48/108 68/182
45%37%
TELAPREVIR
0
10
20
30
40
50
60
70
80
90
100
SV
R 1
2 (I
TT
) (
Pe
rcen
tag
e)
< 800000 IU/mL ≥ 800000 IU/mL0
10
20
30
40
50
60
70
80
90
100
51/122
41% 42%
BOCEPREVIR
27/65
SV
R 1
2 (I
TT
) (
Pe
rcen
tag
e)
CUPIC: SVR12 Safety Findings
Patients, n (% patients with at least one event) Telaprevir n=295 Boceprevir n=190
Serious adverse events (SAEs)*535 in 160 patients
(54.2%) 321 in 97 patients
(51.0%)
Premature discontinuation / due to SAEs
139 (47.1%) / 63 (21.3%)
80 (42.1%)/27 (14.2%)
Death 7 (2.4 %) 3 (1.6%)
Infection (Grade 3/4) 27 (9.1 %) 8 (4.2%)
Hepatic decompensation (Grade ¾ )
15 (5.1 %) 9 (4.7%)
Anemia (Grade ¾ : Hb < 8 g/dL) 38 (12.9 %) 19 (10%)
Rash (grade 3/SCAR) 16 (5.4 %)/ 2 (0.6 %) 2 (1.0%)/
EPO use / blood transfusion
168 (57 %) / 53 (18 %)
119 (62.6%) /26 (13.7%)
GCSF use 8 (2.7 %) 13 (6.8%)
TPO use 6 (2 %) 3 (1.6%)
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
SAEs in patientsSCAR: severe cutaneous adverse reaction
CUPIC:Predictors of Severe Anemia <8 g/dl
Predictors OR 95%CI p-value
Gender: Female 2.19 1.11-4.33 0.023
No lead-in phase 2.25 1.15-4.39 0.018
Age ≥65 years 3.04 1.54-6.02 0.0014
Hemoglobin level≤12 g/dL for female
≤13 g/dL for male
5.30 2.49-11.25 <0.0001
Multivariate analysis: baseline factors related to anaemia <8g/dl or blood transfusion
Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 51.
FactorsPlatelets count
>100,000/mm3
Platelets count
≤100,000/mm3
Albumin 35 g/L3.4 %
(10/298)
4.3 %
(3/69)
Albumin <35 g/L7.1 %
(2/28)
44.1 %
(15/34)
8%
CUPIC: Risk of Occurrence of Death or Severe Complications
Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 51.
French National Early Access Program: Interim Analysis of the CUPIC Cohort (Genotype 1)
Prospective cohort, HCV genotype 1, compensated cirrhosis– Relapse or prior partial responders to PR– No HBV or HIV
SVR12– Telaprevir: 40% (range: 29%-53%)– Boceprevir: 41% (range: 11%-51%)– SVR12 predictors: partial responders, 1b
Discontinuations: 47% Serious adverse events: 40%
– Early treatment discontinuation: 21.3%– Death: 2.0%– Anemia (<9.0 g/dL): 29.4%– Hepatic decompensation: 2.4%
Fontaine H, et al. J Hepatol. 2013;58(suppl 1):S27. Abstract 60.Hezode C, et al. Hepatology. 2012;56(suppl 4):217A-218A. Abstract 51.Hezode C, et al. J Hepatology. 2013;59:434-441.
AdjustedOdds Ratio
Platelet <100,000/mm3 3.1 (P=0.0105)
Serum albumin <35 g/dL 6.33 (P=0.0001)
Factors Associated WithDeath and Severe Complications (n=62)
Platelets (/mm3)
>100,000 <100,000
Albumin (g/dL) >35 (n=298/69) 3.4 4.3
<35 (n=28/34) 7.1 44.1
Risk of Death or Severe Complications (%)
Triple Therapy for HCV in Patients with Compensated Liver Cirrhosis: Real-World Experience
n=48 cirrhotic pts, 31% naïve, platelets 144 50% anemia <10 g/dl, 27<8.5 g/dl, dose reduction in 50% TVR 33 (69%), BOC 15 (31%)
Group APlatelets <110/nl
andChild-Pugh Score >5
n=7
Group BPlatelets <110/nl
orChild-Pugh Score >5
n=16
Group CPlatelets ≥110/nl
andChild-Pugh Score 5
n=20#
Treatment Failure 100% (n=7/7) 69% (n=11/16) 30% (n=6/14)
SAE 57% (n=4/7) 63% (n=10/16) 25% (n=5/20)
Either SAE or Treatment Failure 100% 94% 50%
Almost every patient (96%; n=22/23) with a Child-Pugh Score >5 and/or baseline platelets <110/nl (Group A/B) experienced either a treatment failure and or at least one SAE until EOT
Massoumy B, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 857.
Triple Therapy for HCV GT1 Difficult to Treat Patients: Real Word Experience
High rates of serious adverse events: 64% (BOC) and 53% (TVR)
Severe anemia (<9g/dl) occurred in 65%, blood tx 38% All pts >60 yrs and all cirrhotic patients received blood tx Discontinuation rate 33% (BOC) and 31% (TVR)
Baseline characteristics n = 143
Median age 55yrs30% > 60a
male 67%
Caucasian 90%
Genotype 1a / 1b 39% / 60%
Advanced fibrosis >F3 48%
F4 and platelets < 120/nl 23%
Tx naïve / pretreated 26% / 74%Non responder 50%Tx BOC / TVR 69 / 74
Patients at risk for development of SAE and treatment failure n = 83
Platelets <100.000 /ul and albumin <40g/l n=17
100% treatment failure and 100% SAE
Petersen J, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 891.
Patients, n (% patients with at least one event) Telaprevir n = 295
Serious adverse events (SAEs)* 535 in 160 patients (54.2%)
Premature discontinuation / due to SAEs 139 (47.1%) / 63 (21.3%)
Death 7 (2.4 %)
Infection (Grade 3/4) (3 septicemia, 1 variceal hemmoragia, 1 enkephalopthy, 1 pulmonary neoplasia, 1 pulmonary infection)
27 (9.1 %)
Hepatic decompensation (Grade 3/4) 15 (5.1 %)
Rash (grade 3/SCAR) 16 (5.4 %) / 2 (0.6 %)
Anemia (Grade 3/4 : Hb < 8 g/dL) 38 (12.9 %)
EPO use / blood transfusion 168 (57 %) / 53 (18 %)
GCSF use 8 (2.7 %)
TPO use 6 (2 %)* SAEs in patients; SCAR: severe cutaneous adverse reaction
Telaprevir : SVR12 safety findings
Patients, n (% patients with at least one event) Boceprevir n = 190
Serious adverse events (SAEs)* 321 in 97 patients (51.0%)
Premature discontinuation / due to SAEs 80 (42.1%) / 27 (14.2%)
Death (1 pulmonary infection, 1 anevrysmal beeding, 1 septicemia) 3 (1.6 %)
Infection (Grade 3/4) 8 (4.2 %)
Hepatic decompensation (Grade 3/4) 9 (4.7 %)
Rash (grade 3/SCAR) 2 (1.0 %)
Anemia (Grade 3/4: Hb < 8 g/dL) 19 (10.0 %)
EPO use / blood transfusion 119 (62.6 %) / 26 (13.7 %)
GCSF use 13 (6.8 %)
TPO use 3 (1.6 %)
* SAEs in patients; SCAR: severe cutaneous adverse reaction
Boceprevir : SVR12 safety findings
Evaluation of the true direct cost of treatment with PI+PR in unselected sequential population of patients (n=200) treated at a tertiary care center (BIDMC, Boston) for HCV
GT1
Real World Cost per SVR of HCV Triple Therapy with PIs
The mean cost per SVR was $172,889SVR rate of 49%
Yesn=82
No n=118
TNn=57
Rn=61
P/NRn=82
Yesn=109
No n=91
Yesn=33
Non=167
Yesn=39
No n=161
Prior Response Cirrhosis Anemia Thrombocytopenia Hospitalization
Sethi N, et al. AASLD 2013. Washington, DC. #1847TN: Treatment-naïve; R: Relapsers; P/NR: Partial or null responders
‡
PR + telaprevir or boceprevir or simeprevir Monotherapy with pegIFN, RBV, or a DAA Do not treat decompensated cirrhosis with pegIFN or simeprevir
AASLD and IDSA HCV Regimens: Failed Previous PR + Telaprevir or Boceprevir
Sofosbuvir 12 weeks + PR 24 weeks
PR: pegIFN + RBV.
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version January 29, 2014.
Genotype 1a
Sofosbuvir 12 weeks + PR 12-48 weeksGenotype 1b
Preferred Regimens
Sofosbuvir + RBV 24 weeksGenotype 1a
Sofosbuvir + RBV 24 weeksGenotype 1b
Alternative Regimens
Genotypes 1a or 1b
Regimens Not Recommended
HCV Treatment Considerationsfor Transplant Candidates
Achieving sustained virologic response– Possible in some well-selected patients with HCV and decompensated
cirrhosis Post-transplantation recurrence of HCV may be prevented if SVR is
achieved pretransplant Potential benefits of HCV therapy need to be balanced against the
risk of sepsis, hepatic failure, and death Child’s C cirrhotics
– Risks usually outweigh benefits Transplantation evaluation
– Complete before initiating HCV treatment begins (in case patient should decompensate)
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
Antiviral Therapy Before Liver Transplantation for HCV-Infected Recipients With Advanced Fibrosis and Cirrhosis
Lower SVR rates in cirrhotics– Child-Pugh class A versus C: 40% to 50% versus 7% to 26%
Suboptimal SVR rates by genotype 1/4 versus 2/3 – Advanced fibrosis: 51% versus 61%– Cirrhosis: 33% versus 57%
Marked step-wise reduction in SVR by fibrosis stage in genotype 1– No fibrosis verus cirrhosis: 70% verus 10% (P<0.0001)
RVR is the strongest on-treatment predictor of SVR, regardless of genotype
Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354.Fried MW, et al. N Engl J Med. 2002;347:975-982.Manns MP, et al. Lancet. 2001;358:958-965.Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355.Bruno S, et al. Hepatology. 2010;51:388-397.
Antiviral Therapy Before Liver Transplantation for HCV-Infected Recipients With Advanced Fibrosis and Cirrhosis
Challenges– Poor tolerance– Increased adverse events
• Risk of hepatic decompensation– Suboptimal SVR rates
HCV treatment in this patient population requires significant oversight and input in an experienced practice
Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354.Fried MW, et al. N Engl J Med. 2002;347:975-982.Manns MP, et al. Lancet. 2001;358:958-965.Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355.Bruno S, et al. Hepatology. 2010;51:388-397.
Pre-Transplant Antiviral Treatment Strategies for HCV-Infected Liver Transplant Recipients
Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354; Terrault N. Best Pract Res Clin Gastroenterol. 2012;26:531-548; Roche B, et al. Liver Int. 2011;32(suppl 1):120-128.
Standard Duration
Antiviral Treatment(24 to 48 weeks) Post-Transplant Follow-Up
Transplantation
Follow-Up
HCV Goal:SVR
Candidates: Compensated cirrhosis Mild decompensated cirrhosis (MELD <18)
Projected HCV outcome: Prevents HCV recurrence in 100% if SVR achieved pre-transplant
Short Duration
Antiviral Treatment(12 to 16 weeks)
Post-Transplant Follow-Up
Transplantation
HCV Goal:Undetectable
HCV RNAOn-Treatment
Candidates: Compensated cirrhosis Mild decompensated cirrhosis (MELD <18)
Projected HCV outcome: Prevents HCV recurrence in 30% if HCV RNA negative at time of transplantation; 50% if HCV RNA negative >16 weeks pre-transplant
HCV Treatment Before Liver Transplantationin Patients With Decompensated Cirrhosis
G1 (%)
Child-Pugh(%) Treatment
EOTRG1/non-G1 (%)
SVRG1/non-G1 (%)
HCV RNA Negative Post Transplant (%)
Crippin 2002(pilot study; n=15)
73 11.9 IFN + RBV 33(overall)
NA 0
Thomas 2003(single cohort; n=20)
67 10.0 IFN 60(overall)
NA 20
Everson 2005(single cohort; n=124)
70 7.4 IFN + RBV(LADR)
30/82 13/50 26
Forns 2003(single cohort; n=30)
70 A (50%);B (43%); C (7%)
IFN + RBV 30(overall)
NA 20
Carrion 2009(case controlled; n=51)
80 A (45%); B (43%); C (4%)
PR 20/100 NA 20
Everson 2013(randomized, controlled; n=79)
56 7.0 PR(LADR)
41/53 NA 25
Crippin JS, et al. Liver Transpl. 2002;8:350-355; Thomas RM, et al. Liver Transpl. 2003;9:905-915;Everson GT, et al. Hepatology. 2005;42:255-262; Forns X, et al. J Hepatol. 2003;39:389-396;Carrion JA, et al. J Hepatol. 2009;50:719-728; Everson GT, et al. Hepatology. 2013;57:1752-1762.
G: genotype; EOTR: end-of-treatment response (HCV RVA undetectable); PR: peg IFN + RBV; LADR: low accelerating dose regimen.
Adult-to-Adult Living DonorLiver Transplant Cohort Study (A2ALL)
First, randomized, controlled trial of pre-transplant PR (LADR) to prevent recurrent HCV post-transplant– HCC, MELD waiting list upgrade, stable
clinical status, MELD <20– >12 weeks to transplantation
Exclusion criteria– Prior null responders– Creatinine (>2.2 mg/dL); Hb (<10 g/dL); ANC
(<750/µL); platelets (<35K/µL) Randomized to either pegIFN + RBV
(LADR) or control (untreated) Primary endpoint
– Post-transplant HCV RNA undetectable at week 12
Everson GT, et al. Hepatology. 2013;57:1752-1762.
PR: pegIFN + RBV; LADR: low accelerating dose regimen.
Treatment(n=63)
Control(n=16)
Male (%) 73 81
Age (years) 56 56
Genotype (%) 1/4 or 6 2/3
47/424/25
88/120/0
HCV RNA (log10 IU/mL) 5.7 5.7
HCC upgrade (%) 54 94
MELD 12.0 12.0
CPT score 7.0 6.3
Hemoglobin (g/dL) 13.1 13.5
ANC (/µL) 794 531
Platelets (x103/µL) 92 93
Previous IFN treatment (%)
92 93
Baseline Characteristics
A2ALL Study:Virologic Response With PR
Trea
ted
Pat
ien
ts (
%)
Overall(n=44)
59%
25% 22%
2, 3(n=21)
Virologic Responseby Genotype
52%
HCV RNA Undetectable
At liver transplantation
Week 12 post-transplant
Everson GT, et al. Hepatology. 2013;57:1752-1762.
29%
67%
1, 4, 6(n=23)
HCV Genotype
Per protocol analysis. PR: pegIFN + RBV.
Trea
ted
Pat
ien
ts (
%)
<8(n=8)
25%
0%
18%
>16(n=14)
Virologic Responseby Treatment Duration
68%
HCV RNA Undetectable
At liver transplantation
Week 12 post-transplant
50%
64%
8 to 16(n=22)
PegIFN + RBV Duration (Weeks)
A2ALL Study:Predictors of Response and Safety
Predictors of undetectable HCV RNA 12 weeks post-transplant– Increased duration of treatment (P<0.01)– Nonsignificant trend
• Genotype 2 or 3, lower baseline HCV RNA, growth factors during treatment, achieved target doses of antiviral therapy
Serious adverse events– Similar incidence between treated and controls (68% versus 55%)– Higher number per patient in treated versus controls (2.7 versus 1.3; P=0.003)– No association with MELD score
Death– Pretransplant HCV treatment not associated with increased risk of death versus
controls (15% versus 10%)– Transplant recipients versus no transplant (7.0% versus 31.8%)
Everson GT, et al. Hepatology. 2013;57:1752-1762.
AASLD and IDSA Recommendations:HCV-Related Cirrhosis
Patients with decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C)– Should be referred to a medical practitioner with expertise in that
condition (ideally in a liver transplant center)
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version January 29, 2014.
Preferred Regimen Sofosbuvir + RBV for up to 48 weeks
(consider creatinine clearance and hemoglobin)Any Genotype
Any IFN-based therapy Monotherapy with pegIFN, RBV, or a DAA Telaprevir-, boceprevir-, or simeprevir-based regimens
Any Genotype
Regimens Not Recommended
Mangia A, et al. AASLD 2013. Washington, DC. #1115.
No Cirrhosis vs Cirrhosis: SVR12 Rates
No cirrhosis Cirrhosis
9892 96 100
91 94
60
78
FISSION POSITRON FUSION 12 FUSION 16
58/59 85/92 25/26 23/23
10/11 16/17 6/10 7/9
6168
37
63
34
21 19
61
FISSION POSITRON FUSION 12 FUSION 16
13/38 3/14 5/26 14/23
89/145 57/84 14/38 25/40252/273
43/54
GT 2 GT 3GT 1, 4, 5, 6
92
80
NEUTRINO0
20
40
60
80
100
SV
R12
(%
)Virologic Response: CirrhosisSOF Phase 3 Analysis in Patients with TraditionalNegative Factors
40/40 40/40 29/40 28/40 28/40
Virologic Response
Post-Liver Transplant Study (SOF+RBV)
Samuel D, EASL, 2014, P1232
LLOQ, lower limit of quantification (25 IU/mL)
Twenty-four weeks of SOF+RBV resulted in high SVR rates in this difficult-to-treat post-transplant population, including many cirrhotics and treatment-experienced patients
Relapse was not influenced by RBV dose or exposure SOF + RBV in patients with recurrent HCV after liver transplantation was safe and well
tolerated No TAC or CsA toxicities or drug interactions were observed - 4 patients increased TAC
dosing due to improved liver function
Pre-Liver Transplant Sofosbuvir + RBV:Prevention of Recurrent HCV
Open-label, phase 2 study conducted at 16 sites (n=61)– Deceased donor liver transplantation
candidates with HCV– HCC meeting MILAN criteria– MELD exception for HCC– CPT <7– Exclusion: decompensated cirrhosis, prior
solid organ transplantation, HBV or HIV coinfection, renal impairment
Up to 48 weeks of sofosbuvir 400 mg + RBV (1000-1200 mg) pre-transplant
Post-transplant, immunosuppressive regimen: tacrolimus + prednisone + mycophenolate mofetil.
Primary endpoint: SVR12 post-liver transplant
Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
Baseline CharacteristicsTreatment
(n=61)
Male (%) 80
Age (years) 59
BMI <30 kg/m2 (%) 43
Genotype (%) 1a/1b 2/3 4
39/3413/12
4
HCV RNA >6 log10 IU/mL (%) 41
IL28 B non-CC (%) 78
MELD 8
CPT score 5-7 (%) 95%
Prior HCV treatment (%) 75
Pre-Liver Transplant Sofosbuvir + RBV:Virologic Response in HCV Genotypes 1-4
HCV recurrence prevented in 64% of patients HCV RNA <LLOQ at time of transplantation
On treatment HCV RNA suppression was rapid (1 week)
Factors associated with HCV recurrence (multivariate exact odds ratio)– Days continuously TND prior to
transplantation: 1.04 (1.01, 1.08; P=0.0007)
TND: target not detected.
Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
Pat
ien
ts (
%)
Overall(n=44)
93%
Post-TransplantWeek 12
(n=39)
HCV RNA Undetectable
91%
64%
>12 WeeksTreatment
(n=33)
At Transplant
Pre-Liver Transplant Sofosbuvir + RBV:Target Not Detected and Safety in Genotypes 1-4
Median days TND– No HCV recurrence (n=28): 95 – HCV recurrence (n=10): 5.5
(P<0.001) Sofosbuvir + RBV was generally
well tolerated– Discontinuations due to adverse
events: 3% (none related to sofosbuvir)
– Selected adverse events• Fatigue: 38%• Anemia: 23%• Headache: 23%• Nausea: 16%• Rash: 15%
Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
TND: target not detected.
Ind
ivid
ual
Pat
ien
t D
ata
Days Continuously TND Before Liver Transplant and Preventing HCV Recurrence
HCV RNA Continuously TND (Days)
>30 days TND
HCV recurrence (n=10)
No HCV recurrence (n=28)
Cost Per Cure of Sofosbuvir vs PIs: Treatment-Naïve With and Without Cirrhosis Genotype 1
-$10,708 (-10%)
-$18,039 (-16%)
-$17,153 (-13%)
-$31,472 (-24%)
Tota
l C
ost
per
Su
cce
ssfu
lly
Trea
ted
Pat
ien
t
BOC + PR TVR + PR SOF + PR BOC + PR TVR + PR SOF + PR
‡
AMCP Dossier Data on file, Gilead Sciences December 2013
Cost Per SVR of Sofosbuvir vs Simeprevir: Treatment Naïve With and Without Cirrhosis Genotype 1
Tota
l C
ost
per
Su
cce
ssfu
lly
Trea
ted
Pat
ien
t
-$6,730 (-6%)
Without Cirrhosis (F0-F3) With Cirrhosis (F4)
-$33,573 (-20%)
‡
Gordon SC, et al. Hepatology. 2012;56(5):1651-60.Lawitz E, et al. N Engl J Med. 2013 May;368(20):1878-87.Lenz O, et al. AASLD 2011. San Francisco, CA, USA. Poster #1329Jacobson I, et al. EASL 2013. Amsterdam, the Netherlands. Poster #1525
Manns M, et al. EASL 2013. Amsterdam, the Netherlands. Poster #1525McAdam-Marx C, et al. J Manag Care Pharm. 2011;17(7):531-46.Zein NN, et al. Clin Microbiol Rev. 2000 Apr;13(2):223-35.
Risk of HCC Remains After SVR in HCV Patients With Advanced Hepatic Fibrosis
Meta-analysis (n=1000)– 10 cohorts, individual patient data– SVR with IFN-based therapy– Bridging fibrosis or cirrhosis– No HIV or HBV coinfection
51 events of HCC over 5.1 years of follow-up
Patients with HCV-induced cirrhosis who achieve SVR remain at risk for HCC
Risk increased with age, severity of liver disease, and presence of diabetes mellitus
van der Meer AJ, et al. Hepatology. 2013;58(suppl 1):280A. Abstract 143.
Rat
e (%
)
Cumulative HCC by Age Group
0 1 2 3 4 5 6 7 8 Years After SVR
P=0.006
12.2%
2.6%
9.7%
Age Group <45 years 45 to 60 years >60 years
Conclusion
Patients with HCV cirrhosis globally remain an enigma as to timing of treatment– Cirrhosis: when present, are those patients most in
need of treatment today– Treat with INF based therapy down to albumin of 3.5
and platelets of 100,000
With the advent of new therapies, all oral regimens– Cirrhosis treatment will evolve to be simple and
expedient – Prices will need to be aligned with GDP and health
care allocations per country