inibitori delle proteasi di i generazione: sono una reale innovazione? - gastrolearning®
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Gastrolearning V lezione Inibitori delle proteasi di I generazione: sono una reale innovazione? - Prof. A. Craxì (Università di Palermo) www.gastrolearning.itTRANSCRIPT
Inibitori delle proteasi di HCV di I generazione: sono una
reale innovazione?
Antonio CraxìGastroenterologia & Epatologia,
Di.Bi.M.I.S.Università di [email protected]
18 Dicembre 2012
• 9 million chronic carriers
• 27,000 to 29,000 newly diagnosed cases per year
• 86,000 deaths per year
• Most affected age group: 25-44 year, followed by 15-24 year
• Clustered to sub-populations
Epidemiology of Hepatitis C in Europe
Van de Laar, Hepatitis Summit Conference, Brussels 2010
Time trends incidence
Map of estimated anti-HCV seroprevalence by GBD region, 2005
Hanafiah et al, Hepatology in press
Treatment of Hepatitis C: Evidence for Effectiveness in SVR Patients
1. Durable HCV-RNA eradication achievable
2. Histological reversal of cirrhosis documented
3. Reduced rates of decompensation and HCC
4. Reduced rates of liver-related mortality
Accessibility to Peg-IFN antiviral therapy in different European countries
Belgium France Germany Italy Spain UK
Pat
ien
ts t
reat
ed p
er 1
00
pre
vale
nt
case
s
HC
V p
reva
len
ce r
ate
(%)
HCV prevalence Treatment levels
0
1
2
3
4
0
2
4
6
8
10
12
14
16
There are substantial differences between European countries in terms of HCV prevalence and access to antiviral therapy
Deuffic-Burban S, et al. Gastroenterology 2012;[ePub ahead of print]Peg-IFN/RBV: peginterferon plus ribavirin
Effect of treatment strategy* according to fibrosis stage on HCV-related cirrhosis and deaths†
*With Peg-IFN + RBV; †All genotypes Deuffic-Burban S, et al. Gastroenterology 2012 [Epub ahead of print]
Cumulative HCV-related cirrhosis and deaths (95% CI)
Treatment scenario Cirrhosis Deaths
With treatment(baseline scenario)
330,700(313,200–342,000)
282,300(268,600–294,200)
Never treating patients with F0/F1
359,300(339,900–372,200)
295,000(280,700–307,700)
Not treating F0/F1 until F2 is reached
332,200(314,600–343,600)
282,700(269,000–294,600)
Not treating F0/F1until F3 is reached
342,400(324,100–354,300)
285,900(272,100–298,000)
• In comparison to the baseline scenario, delaying treatment in patients with F0/F1 is associated with an increase in HCV-related cirrhosis and deaths, regardless of the scenario
• Delaying treatment until F2 is reached appears to be efficient in terms of mortality but will necessitate efficient diagnostic testing of fibrosis to detect progression from F0/F1 to F2
Milestones in Therapy of Genotype 1 HCV
Adapted from US FDA Antiviral Drugs Advisory Committee Meeting; April 27-28, 2011; Silver Spring, MD.
SV
R (
%)
IFN
6 mos
PegIFN/ RBV 12 mos
IFN
12 mos
IFN/RBV
12 mos
PegIFN
12 mos
2001
1998
2011
Standardinterferon
Ribavirin
Peginterferon
1991
Direct-actingantivirals
PegIFN/RBV/DAA
IFN/RBV
6 mos
6
16
3442 39
55
70+
0
20
40
60
80
100
BoceprevirSVR increases from 38% to
63/66% ( + 25-28%)
Naive patients Increased SVR compared to Peg-IFN/RBV
TelaprevirSVR increases from 44% to
72/75%(+ 28-31%)
Poordad F et al. N Engl J Med 2011: 364: 1195-1206Sherman KE et al. Hepatology 2010; 52 (Suppl) : 401A.Jacobson IM et al. Hepatology 2010; 52 (Suppl) : 427A.
BoceprevirRelapsers
SVR increases from 29% to 75%
Partial-Responders SVR increases from 7% to 52%
Treatment-experienced patients Increased SVR compared to Peg-IFN/RBV
TelaprevirRelapsers
SVR increases from 24% to 83/88%
Partial-responders SVR increases from 15% to 54-59%
Null-respondersSVR increases from 5% to 29/33%
Bacon BR., et al. N Engl J Med 2011; 364:1207-1217. Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3
Patients Dual Triple Pts # SVR Pts # SVR
Previously untreated 1545 39% 1634
68.5%<2-fold
Relapsers/Partial Resp.
539 26% 719 73% 3-fold
Nonresponders 255 7.5% 386 44% 6-fold
Jurchis AR et al. EASL 2012, Poster 1123 (S442)
Chance for Cure in HCV 1. The Impact of Triple Therapy A Systematic Review
Number of Patients Ever Treated With PEG IFNs per 100 Prevalent HCV Cases until End of 2005
Lettmeier B et al, J Hepatol 2008;49:528-536
Pat
ient
s ev
er tr
eate
d w
ith P
eg-I
FN
s pe
r 10
0 pr
eval
ent c
ases
7000 patients HCV Gt 1 patients treated each year (2008-2011) with a 10% yearly trend to decrease (2010-2011):
– Spontaneous change due to disease epidemiology– Warehousing effect (triple therapy IFN-free)
¼ of Gt 1 patients treated yearly (2008-2010) were re-treatments. This figure has decreased markedly in 2011 (warehousing for triple therapy)
• Yearly expenditure (2011) for P/R: 165,000,000 Euros• Aging population of naives (mean age at tx 48 years) with 25-30% of
F3/F4 fibrosis• At least 20,000 patients with previous P/R failures (usually unclassified)
with a mean age > 55 years and at least 40% of F3/F4 fibrosis
Treatment of HCV genotype 1 in Italy:Treatment of HCV genotype 1 in Italy:the current situationthe current situation
HCV-AIFA Italian study: RVR and SRV to P/R in genotype 1 patients according to baseline factors
MALES
Variables N. of patients RVR SVR
No favorable factors 21/179 (11.7%) 1/19 (5.2%) 3/21 (14.3%)
1 favorable factor 82/179 (45.8%) 17/80 (21.2%) 25/82 (30.5%)
2 favorable factors 62/179 (34.6%) 25/58 (43.1%) 37/62 (59.6%)
3 favorable factors 14/179 (7.8%) 9/14 (64.3%) 12/14 (85.7%)
FEMALES
Variables N. of patients RVR SVR
No favorable factors 58/152 (38.1%) 8/57 (14.1%) 16/58 (27.6%)
1 favorable factor 75/152 (49.4%) 20/70 (28.6%) 26/75 (48.0%)
2 favorable factors 19/152 (12.5%) 12/17 (70.1%) 16/19 (84.2%)
Favorable factors: HCV-RNA < 400,000 UI/mlC/C genotype of rs12979860 SNPNo visceral obesity (VOB)
Favorable factors: Age < 50 years C/C genotype of rs12979860 SNP
First-generation protease inhibitors increase SVR rates in naive and treatment-experienced patients1,2 and may reduce liver-related morbidity and mortality in the long-term1,2
Potential for shorter treatment duration1,2
Not sufficiently tested in difficult patients (cirrhosis)
Modest potency with development of resistance2,3
Genotype 1 restricted
Complex regimens, with risk of poor adherence2
Increased adverse reactions and toxicity burden2
Increased risk of DDIs2
Costs
1. Ghany MG, et al. Hepatology 2011; 54: 1433–442. Ferenci P & Reddy KR. Antivir Ther 2011; 16: 1187–1201
3. Pawlotsky J-M. Hepatology 2011; 53: 1742–51
Advantages Disadvantages
The balance of triple therapy with boceprevir and telaprevir
Addition of BOC or TVR to PegIFN/RBV Improves SVR in Genotype 1 Patients BOC and TVR each indicated in combination with pegIFN/RBV for genotype 1 HCV
patients who are previously untreated or who have failed previous therapy
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 3. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 4. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 5. Bronowicki JP, et al. EASL 2012. Abstract 11.
0
20
40
60
80
100
SV
R (
%)
Relapsers[3,4] Partial Responders[3,4]
PegIFN + RBV
NullResponders[4,5]
BOC/TVR + pegIFN* + RBV
24-29
7-15
29-40
5
69-83
40-59
63-75
38-44
Treatment Naive[1,2]
*BOC was administered with pegIFN-α2b; TVR was administered with pegIFN-α2a in these trials.
Response-Guided Therapy
RGT Paradigm With BOC + PegIFN/RBV in Tx-Naive Patients Indicated for all noncirrhotic treatment-naive patients
BOC + PegIFN/RBV
480 28124
PegIFN/RBV
8 3624
Early response stop at Wk 28; f/u 24 wks
HCV RNA Undetectable Undetectable
480 28124
PegIFN/RBVPegIFN/RBV
8 36
BOC + PegIFN/RBV
24
Slow response extend triple therapy to Wk 36; PR to Wk 48; f/u 24 wks
< 100 IU/mL
< 100 IU/mL
Boceprevir [US package insert]. July 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Boceprevir [EU package insert]. July 2012.
HCV RNA
Detectable Undetectable
Response-Guided Therapy Paradigm With BOC + PegIFN/RBV in Tx-Exp Patients Indicated for noncirrhotic previous relapsers or partial responders*[1,2]
BOC + PegIFN/RBV
480 28124
PegIFN/ RBV
8 3624
HCV RNA Undetectable Undetectable
480 28124
PegIFN/RBVPegIFN/RBV
8 36
BOC + PegIFN/RBV
24
< 100 IU/mL
< 100 IU/mL
1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Boceprevir [EU package insert]. July 2012.
Early response stop at Wk 36; f/u 24 wks
Slow responsePR to Wk 48; f/u 24 wks
*RGT for this group indicated in US only; European prescribing information indicates that noncirrhotic previous relapsers or partial responders should receive 4 wks of pegIFN/RBV followed by 32 wks of BOC + pegIFN/RBV and then 12 wks of pegIFN/RBV, regardless of early response.[3]
HCV RNADetectable Undetectable
RGT With TVR + PegIFN/RBV in Tx-Naive Patients and Previous Relapsers
TVR + PegIFN/RBV
480 24124
eRVR stop at Wk 24, f/u 24 wksPegIFN/RBV
TVR + PegIFN/RBV
480 24124
PegIFN/RBV
HCV RNAUndetectable
Undetectable
Detectable (≤ 1000 IU/mL)
Undetectable or detectable (≤ 1000 IU/mL)
No eRVR extend pegIFN/ RBV to Wk 48; f/u 24 wks
HCV RNA
Indicated for all noncirrhotic treatment-naive pts and previous relapsers*[1,3]
1. Telaprevir [US package insert]. October 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [EU package insert]. March 2012.
Undetectable
Undetectable
*AASLD guidelines say RGT “may be considered” for previous partial responders[2] but package inserts recommend 48 wks of therapy.[1,3]
Futility Rules for BOC or TVR + PegIFN/RBV in Tx-Naive and Tx-Exp’d Pts All therapy should be discontinued in patients with the following:
1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Telaprevir [US package insert]. October 2012.
*Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA detection of approximately 10-15 IU/mL.
Boceprevir[1,2]
Time Point Criteria* Action
Wk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapy
Wk 24 HCV RNA detectable Discontinue all therapy
Telaprevir[2,3]
Time Point Criteria* Action
Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy
Wk 24 HCV RNA detectable Discontinue pegIFN/RBV
Use of HCV RNA Assays in Managing Patients Receiving BOC or TVR A quantitative assay with an LLOQ of ≤ 25 IU/mL and an
LLOD of approximately 10-15 IU/mL must be used
HCV RNA undetectable* (“target not detected”) required to qualify for RGT
– Detectable but < LLOQ is not equivalent to undetectable
– Carefully read HCV RNA assay report to ensure HCV RNA was undetected or “target not detected” before truncating therapy
*An assay with a LLOD of approximately 10-15 IU/mL must be used.
Adverse Events
BOC Plus PegIFN alfa-2b/RBV: Adverse Events Higher rates of anemia, neutropenia, and dysgeusia in
BOC arms vs control
Adverse Event, % PR48 (n = 467)
BOC + PR RGT/48*(n = 1225)
Anemia* 30 50
Neutropenia 19 25
Dysgeusia 16 35*Anemia was managed with RBV reduction and/or epoetin alfa (43% of BOC + PR and 24% of PR).
Boceprevir [US package insert]. July 2012.
TVR Plus PegIFN alfa-2a/RBV: Adverse Events Higher rates of rash, anemia, and anorectal signs and
symptoms in TVR arms vs control
Adverse Event, % PR48 (n = 493)
TVR + PR RGT/48*
(n = 1797)
Rash 34 56
Anemia‡ 17 36
Anorectal events 7 29*Pooled results from TVR arms. †Anemia was managed with RBV dose modification; epoetin alfa was not permitted.
Telaprevir [US package insert]. October 2012.
In most subjects, rash was mild to moderate– Severe rash in 4%; discontinuation due to rash in 6% of
subjects
Cirrhotic Patients
Treatment regimen
Peg-IFN α-2a + RBVTVR + Peg-IFN α-2a + RBV Follow-up
484 160 128Weeks
72
SVR assessment
BOC + Peg-IFN α-2b + RBV Follow-upPeg-IFN + RBV
36
http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdfhttp://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf
BOC: 800 mg/8h; Peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day
TVR: 750 mg/8h; Peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day
Interim analysis
Telaprevir: baseline characteristicsTelaprevir
n=292
Male, n (%) 197 (68)
Mean age, range (years) 57.2 (27-83) 54
Mean BMI, SD (kg/m2) 26.5 (4.1)
Genotype 1b / 1a / other (%) 54 / 34 / 12
HCV RNA >800,000 IU/mL, n (%) 181 (62)
Mean Neutrophils, range (109/mm3) 3.3 (0.8-9.7)
Mean Hemoglobin, range (g/dl) 14.6 (9.0-19.7) 15,6
Mean Platelets, range (/mm3) 152,000 (18,000-604,000) 167000
Telaprevirn=292
Mean Prothrombin Time, range (ratio) 86.3 (27-100)
Mean Total Bilirubin, range (µmol/L) 15.4 (4.0-73.5)
Mean Albumin, range (g/dL) 40.1 (20.7-52.0)
Child-Pugh A / B (%) 98 / 2
Mean MELD score, SD 8.1 (2.8)
MELD score <10 / 10 - <13 / ≥13 (%) 81 / 13 / 6
Esophageal varices (%) 33
Realize / Respond-2 exclusion criteria (%) 33 / 46
Telaprevir: baseline characteristics
Patients, n (% patients with at least one event) Telaprevir n=292
Serious adverse events (SAEs)* 132 (45.2%)
Premature discontinuationDue to SAEs
66 (22.6%)43 (14.7%)
DeathSepticemia, Septic shock, Pneumopathy, Endocarditis, Oesophageal varices Bleeding,
5 (2.6%)
Infection (Grade 3/4) 19 (6.5%)
Hepatic decompensation (Grade 3/4) 6 (2.0%)
Asthenia (Grade 3/4) 16 (5.5%)
Rash Grade 3/SCAR 14 (4.8%)
Renal failure 5 (1.7%)
*334 SAEs in 132 patients; SCAR: severe cutaneous adverse reaction
Telaprevir: week 16 safety findings
Patients, n (% patients with at least one event) Telaprevir n=292
Anemia
Grade 2 (8.0 – <9.0 g/dL?)
Grade 3/4 (<8,0 g/dL)
EPO use
Blood transfusion
RBV dose reduction
55 (18.8%)
34 (11.6%)
157 (53.8%)
47 (16.1%)
38 (13.0%)
Neutropenia
Grade 3 (500 – <750/mm3)
Grade 4 (<500/mm3)
G-CSF use
6 (2.0%)
2 (0.7%)
7 (2.4%)
Thrombopenia
Grade 3 (20 000 – <50 000/mm3)
Grade 4 (<20 000/mm3)
Thrombopoïetin Use
28 (9.6%)
9 (3.1%)
4 (1.4%)
EPO: Erythropoïetin; G-CSF: granulocyte-colony stimulating factor
Telaprevir: week 16 safety findings
Boceprevir: baseline characteristicsBoceprevir
n=205
Male, n (%) 140 (68)
Mean age, range (years) 56.9 (34-81)
Mean BMI, SD (kg/m2) 26.2 (4.1)
Genotype 1b / 1a / other (%) 50 / 40 / 10
HCV RNA >800,000 IU/mL, n (%) 131 (64)
Mean Neutrophils, range (109/mm3) 3.3 (0.5-8.5)
Mean Hemoglobin, range (g/dl) 14.8 (9.7-18.4)
Mean Platelets, range (/mm3) 146,000 (33,900-346,000)
Boceprevirn=205
Mean Prothrombin Time, range (ratio) 87.3 (23-100)
Mean Total Bilirubin, range (µmol/L) 15.0 (4.0-78.0)
Mean Albumin, range (g/dL) 40.4 (27.0-50.3)
Child-Pugh A / B (%) 99 / 1
Mean MELD score, SD 8.1 (3.0)
MELD score <10 / 10 - <13 / ≥13 (%) 83 / 12 / 5
Esophageal varices (%) 40
Realize / Respond-2 exclusion criteria (%) 29 / 40
Boceprevir: baseline characteristics
Patients, n (% patients with at least one event) Boceprevir n=205
Serious adverse events (SAEs)* 67 (32.7%)
Premature discontinuationDue to SAEs
54 (26.3%)15 (7.3%)
DeathPneumopathy
1 (0.5%)
Infection (Grade 3/4) 5 (2.4%)
Hepatic decompensation (Grade 3/4) 6 (2.9%)
Asthenia (Grade 3/4) 12 (5.8%)
Rash Grade 3/SCAR 0
Renal failure 0
*159 SAEs in 67 patients; SCAR: severe cutaneous adverse reaction
Boceprevir: week 16 safety findings
Patients, n (% patients with at least one event) Boceprevir n=205
Anemia
Grade 2 (8.0 – <9.0 g/dL)
Grade 3/4 (<8,0 g/dL)
EPO use
Blood transfusion
RBV dose reduction
48 (23.4%)
9 (4.4%)
95 (46.3%)
13 (6.3%)
22 (10.7%)
Neutropenia
Grade 3 (500 – <750/mm3)
Grade 4 (<500/mm3)
G-CSF use
2 (1.0%)
7 (3.4%)
9 (4.4%)
Thrombopenia
Grade 3 (20 000 – <50 000/mm3)
Grade 4 (<20 000/mm3)
Thrombopoïetin Use
10 (4.9%)
3 (1.5%)
2 (1.0%)EPO: Erythropoïetin; G-CSF: granulocyte-colony stimulating factor
Boceprevir: week 16 safety findings
Multivariate analysis: baseline predictors of severe complications*
* Death, severe infection and hepatic decompensation, n=32
Predictors OR 95%CI p-value
Prothrombin Time
(per unit decrease)
1.03 1.01-1.06 0.038
Age(per year increase)
1.05 1.01-1.11 0.025
Platelet count≤100,000/ mm3
3.19 1.32-7.73 0.0098
Albumin level<35 g/L
4.95 2.04-12.01 0.0004
Multivariate analysis: predictors of anemia <8g/dL or blood transfusion *
Predictors OR 95%CI p-value
Age(per year increase)
1.06 1.026-1.09 0.0003
Gender(Female)
2.32 1.10-4.35 0.023
No lead-in phase 2.33 1.22-4.35 0.01
Hemoglobin level≤12 g/dL for female ≤13 g/dL for male
5.85 2.83-12.08 <0.0001
* n=71
Telaprevir: week 16 efficacy dataPer protocol
0
10
20
30
40
50
60
70
80
90
100
Week 4 Week 8 Week 12 Week 16
ITT
58%55%
92%
80%
93%
79%
92%
67%
Pat
ien
ts w
ith
un
det
ecta
ble
HC
V R
NA
(%
)
161/276 161/292 236/257 236/292 230/247 230/292 196/212 196/292
Telaprevir: Week 16 efficacy according to prior treatment response (ITT)
NullResponse
Partial Response
Relapse0
10
20
30
40
50
60
70
80
Pat
ien
ts w
ith
un
det
ecta
ble
HC
V R
NA
(%
)
46%
66%
75%
11/24 90/136 92/123
P=0.005
Boceprevir: week 16 efficacy data
0
10
20
30
40
50
60
70
80
90Per protocol
ITT
Pat
ien
ts w
ith
un
det
ecta
ble
HC
V R
NA
(%
)
Week 4 Week 8 Week 12 Week 16
3% 2%
42%38%
64%
55%
77%
58%
5/194 5/205 77/181 77/205 112/174 112/205 118/154 118/205
Boceprevir: Week 16 efficacy according to prior treatment response (ITT)
0
10
20
30
40
50
60
70
80
NullResponse
Partial Response
Relapse
22%
50%
69%P=0.001
2/9 45/90 69/100
Rationale for Prompt Treatment of HCV
HCV is a progressive disease, associated with persistence of viral replication and ongoing necroinflammation and fibrosis
Remission (SVR) is associated with loss of active viral replication and improvement in hepatic fibrosis
Important questions
– Does that equate to a need to treat all patients?
– Can we avoid losing time for patients destined to progress?
– How do we avoid unnecessary or detrimental treatment when there are improved treatments pending?
Indications for Treatment of Chronic HCV Infection All patients, regardless of the degree of fibrosis, are
potential candidates for treatment
IFN-based therapy is current standard of care
Patients with mild disease may not require immediate treatment
For those who require treatment
– Patients should be fit for the regimen
– Patients should have the ability to adhere to treatment goals and monitoring
There is a complex ongoing debate regarding opportune timing for treatment given the therapeutic landscape
Pts Who Want TxWant to be cured of disease
Personal or social reasons
Plans for pregnancy
Social support
Eligible for reimbursement now
Pts Who Are Eligible for Tx
Eligible for pegIFN/ RBV
Fit for regimen
No contraindications
Disease stage
Pts Who Are Motivated and Understand . . .
Likelihood of response
Risks/benefits of treatment
Risk of resistance
Possibility of shortened therapy
What is “coming down the line” for their genotype
Who Should Be Treated Now?
Severity of Disease Increases Need for HCV Therapy but Also Impairs Response
May not need immediate treatment
BUT Easier to treat High likelihood of
response
Advanced disease/ cirrhosis
Mild disease
Greater need for treatment BUT
Response may be impaired Perhaps more effective options in
future, but efficacy of some investigational agents may be unclear due to trial eligibility criteria
What Are the Chances of Being Cured With Current Therapy?
Black Cirrhosis Genotype 1
(1a worse than 1b) IFN nonresponsive IL28B TT
Favorable prognostic factors
Less favorable prognostic factors
White No fibrosis Genotype 2/3 IFN responsive (eg,
RVR/EVR or response to lead-in)
Previous relapser IL28B CC
Limitations of Current Regimens and Prospects for Future Regimens
Current
Must be eligible for pegIFN/ RBV
Large pill burden, TID dosing of PIs (at present); parenteral IFN
Challenging adverse events
High likelihood of resistance with treatment failure
Current PIs only effective for genotype 1
Possibility of resistance with poor adherence
Future
Perhaps IFN free
Lower pill burden, less than TID dosing; perhaps all oral
May be better tolerated
May not generate resistance
Pangenotypic or at least more
Higher barrier to resistance with some classes
Challenging Patients for Whom Treatment With Current Options Less Than Optimal
Cirrhosis (all genotypes)
Decompensated cirrhosis
Null responders
Pretransplantation
Posttransplantation
Renal failure
– Impaired renal function
– Dialysis
– Renal transplantation recipients
Injection-drug users
– Methadone substitution
Thalassemics
Children
IFN contraindicated
IFN intolerant
Those on “edge” of society
Psychiatric comorbidity
No SVR
SVR100
Pat
ien
ts W
ith
Liv
er
Co
mp
licat
ion
s (%
) 80
60
40
20
01680 24 48 72 96 120 144
Mos
759 124
702119
634116
527108
34570
20741
3412
Cumulative Incidence of Liver-Related Complications Following SVR in Cirrhosis
Bruno S, et al. Hepatology. 2007;45:579-587.
Pts at Risk, n
SVR to Telaprevir in Treatment-Naive Pts With GT1 HCV and Compensated Cirrhosis
Kauffman RS, et al. HepDart 2011. Abstract 52.
79
46
92 90
66
7471
38
61
92
50 51
0
20
40
60
80
100
T12PR PR48 T12PR24 T12PR48 T12PR48 T12PR
AllCirrhosis
ADVANCE ILLUMINATE
eRVR+* eRVR-* Overall
n/N= 285/363
15/21
166/361
SV
R (
%)
8/21
149/162
144/160
78/118
398/540
11/18
11/12
6/12
31/61
*eRVR+ randomized: 60% (322/540); eRVR-: 22% (118/540).
CUPIC: Efficacy of TVR in Cirrhotics
~ 80% of patients treated with TVR-based therapy had undetectable HCV RNA at end of 16 wks of triple therapy
Hezode C, et al. AASLD 2012. Abstract 51.
0
20
40
80
100
Un
det
ecta
ble
HC
V R
NA
(%
)
60
145/276
53
Wk 4 Wk 8 Wk 12 Wk 16
145/285
224/265
224/282
219/254
219/281
177/205
177/251
51
8579
8678
86
71
Per protocolITT
n/N =
CUPIC: Efficacy of Boceprevir in Cirrhotics ~ 60% of patients treated with BOC-based therapy had
undetectable HCV RNA at Wk 16 of ongoing therapy
2/155
1
Wk 4 Wk 8 Wk 12 Wk 16
2/155
55/149
55/150
88/144
88/151
89/126
89/146
1
37 37
61 58
71
61
Un
det
ecta
ble
HC
V R
NA
(%
)
n/N =
Per protocolITT
0
20
40
80
100
60
Hezode C, et al. AASLD 2012. Abstract 51.
The First-Generation Protease Inhibitors: Where Are We Now? Telaprevir and boceprevir are harbingers of important treatment
advance
Improved SVR rates in both naive and experienced patients
Certain patients (advanced disease) require therapy imminently and should be treated now
Others may be motivated to be treated now—opportunities for cure, candidates for shortened therapy, and/or personal reasons
For many, the choice is not clear
The advent of triple therapy changes the way treatment discussed with patients
– Clinicians must educate and advocate for patients to choose the correct course of treatment
Factors That Influence Outcomes With HCV Therapy
SPRINT-2: Influence of Baseline Patient and Virus Factors on SVR With BOC
BOC + pegIFN-α2b/RBV RGTBOC + pegIFN-α2b/RBV 48 wks
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Poordad F, et al. Gastroenterology. 2012;143:608-618.
93/133
89/134
100
0
50
1b 1aGenotype[1]
70 66
≤ 800,000 > 800,000 HCV RNA (IU/mL)[1]
85
76
F0-2 F3/F4Fibrosis[1]
6767
SV
R (
%)
75
25
41/54
45/53
213/319
211/313
n/N =n/N =
63 5963 61
41
52
118/187
106/179
14/34
22/42
192/314
197/313
44/55
82/115
26/44
CC CT TT
80
71
59
IL28B[2]
1b 1aGenotype[1]
< 800,000 ≥ 800,000HCV RNA (IU/mL)[1]
F0-2 F3/F4Fibrosis[1]
ADVANCE: Influence of Baseline Patient and Virus Factors on SVR With TVR Data from TVR12 + pegIFN-α2a/RBV arm only
1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.
CC CT TT
IL28B*[2]
152/213
118/149
100
0
50
7971
7874
62
78
SV
R (
%)
75
25
207/281
64/82
45/73
226/290
n/N =n/N =
45/50
48/68
16/22
90
71 73
*IL28B testing was in whites only.
IL28B Genotype Predicts Likelihood of Eligibility for Shortened Therapy
1. Poordad F, et al. Gastroenterology. 2012;143:608-618. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.
SPRINT-2: BOC + PegIFN-α2b/RBV [1]
Eli
gib
ilit
y fo
r R
GT
(%
)
117/132
158/304
CC CT/TT
89100
80
60
40
20
0
52
ADVANCE: T12 + PegIFN-α2a/RBV *[2]
Eli
gib
ilit
y fo
r R
GT
(%
)
39/50
39/68
10/22
78
100
80
60
40
20
0
57
45
n/N =
*IL28B testing in ADVANCE was in whites only.
CC CT TT
n/N =
IL28B Genotype Should Not Be Used to Exclude Patients From Therapy If patients have favorable CC genotype
– Likelihood of SVR is high with pegIFN/RBV alone, but triple therapy may allow shorter therapy and, in one TVR study, higher SVR rates[1]
If patients have unfavorable CT/TT genotype
– Likelihood of SVR is higher with triple therapy than with pegIFN/RBV
– 59% to 71% in SPRINT-2[2]
– 71% to 73% in ADVANCE*[1]
Limited value of IL28B genotyping in treatment-experienced patients
– Most have unfavorable TT or CT genotype
1. Jacobson IM, et al. EASL 2011. Abstract 1369. 2. Poordad F, et al. Gastroenterology. 2012;143:608-618.
*IL28B testing in ADVANCE was in white Americans only.
Lead-in Strategies
Lead-in Strategy Can Help Determine Whom to Treat 4 wks of pegIFN/RBV lead-in before BOC (or TVR)
– Lowers HCV RNA burden
– May identify rapid responders who may not need DAA
– Allows assessment of IFN responsiveness
– Provides useful information regarding likelihood of SVR with addition of DAA
– Provides insight into tolerability of pegIFN/RBV backbone
– Elucidates hematologic response to pegIFN/RBV, especially in “marginal” patients; make needed dose adjustments before addition of DAA
Early IFN Response (Lead-in) Further Defines Likelihood of SVR for Non-CC Pts A > 1 log10 decrease in HCV RNA at Wk 4 of therapy is the strongest
predictor of SVR
0/2
2/3
2/4
56/75
83/102
58/72
1/27 19/
5120/45
37/117
83/111
109/133
1/20 6/
2510/25
13/26
23/28
26/34
CC CT TT
≥ 1 log ≥ 1 log ≥ 1 log
SV
R (
%)
SPRINT-2 and RESPOND-2 Combined100
80
60
40
20
0
67
50
7581 81
4
3744
32
7582
5
24
40
50
8276
PegIFN-α2b/RBV*
BOC + pegIFN-α2b/RBV RGT*
BOC + pegIFN-α2b/RBV 48 wks*
< 1 log < 1 log < 1 log
n/N=
Poordad F, et al. Gastroenterology. 2012;143:608-618.*BOC was administered with pegIFN-α2b in these trials.
Preparing for Treatment:Possibilities of
Drug–Drug Interactions
TVR
– Substrate of CYP3A
– Inhibitor of CYP3A
– Substrate and inhibitor of P-gp
Both BOC and TVR Have Potential for Many Drug–Drug Interactions BOC
– Strong inhibitor of CYP3A4/5
– Partly metabolized by CYP3A4/5
– Potential inhibitor of and substrate for P-gp
Most drug–drug interactions can be overcome by careful survey of the patient’s medications and judicious substitutions during HCV therapy (or just during the period of PI-based triple therapy)
Medicines That Are Contraindicated With BOC and TVR
1. Boceprevir [package insert]. July 2012. 2. Telaprevir [package insert]. October 2012.
Drug Class* Contraindicated With BOC[1] Contraindicated With TVR[2]
Alpha 1-adrenoreceptor antagonist
Alfuzosin Alfuzosin
Anticonvulsants Carbamazepine, phenobarbital, phenytoin
N/A
Antimycobacterials Rifampin Rifampin
Antiretrovirals EFV, all RTV-boosted PIs DRV/RTV, FPV/RTV, LPV/RTV
Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine
Dihydroergotamine, ergonovine, ergotamine, methylergonovine
GI motility agents Cisapride Cisapride
Herbal products Hypericum perforatum (St John’s wort) Hypericum perforatum
HMG CoA reductase inhibitors
Lovastatin, simvastatin Lovastatin, simvastatin
Oral contraceptives Drospirenone N/A
Neuroleptic Pimozide Pimozide
PDE5 inhibitor Sildenafil or tadalafil when used for treatment of pulmonary arterial HTN
Sildenafil or tadalafil when used for treatment of pulmonary arterial HTN
Sedatives/hypnotics Triazolam; orally administered midazolam
Orally administered midazolam, triazolam
*Studies of drug–drug interactions incomplete.
Preparing for Treatment:Management of Adverse Events
Adverse Effect Management: Anemia
Recommendation: anemia should be managed initially by reducing the RBV dose[1]
Do not dose reduce DAA or stop and then restart
Do not discontinue pegIFN/RBV and continue DAA
Monitor closely if Hb falls < 10 g/dL
ESA agents are unlabeled for HCV anemia
– May be effective as a secondary anemia management strategy
1. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
EPO and RBV Dose Reduction for Anemia Lead to Similar SVR Rates in BOC Patients Nested study within randomized trial of genotype 1 HCV therapy-naive patients
receiving 4 wks of lead-in with pegIFN-α2b/RBV and then either 44 wks of triple therapy or RGT (24-44 wks)
Poordad F, et al. EASL 2012. Abstract 1419.
0
20
40
80
100S
VR
(%
)
RBV DR EPO
∆ -0.7% (95% CI: -8.6 to 7.2)*
71 71
178/249 178/251n/N =
*Stratum-adjusted difference in SVR rates, adjusted for stratification factors and protocol cohort.
60
82% of RBV dose reduction group vs 62% in EPO group did not require secondary anemia intervention
Predictive Value of Anemia for SVR With BOC or TVR
1. Sulkowski MS, et al. Hepatology. 2012;[Epub ahead of print]. 2. Poordad F, et al. DDW 2011. Abstract 626.
5858
7272 7373 7474
SV
R (
%)
SV
R (
%)
SPRINT-2*[1]SPRINT-2*[1]
Hb ≥ 10 g/dLHb ≥ 10 g/dLHb < 10 g/dLHb < 10 g/dL
n/N =n/N =0
20
40
60
80
100
212/363 263/363 n/N =n/N =0
20
40
60
80
100
267/361384/524
ADVANCE and ILLUMINATE†[2]ADVANCE and ILLUMINATE†[2]
†Data from T12/PR arm only.†Data from T12/PR arm only.*Data from BOC/48 and BOC RGT arms.*Data from BOC/48 and BOC RGT arms.
In phase III trials, anemia positive predictor of SVR with BOC[1] but not TVR[2]
EOTR, relapse, and SVR comparable between RBV DR and EPO arms in treatment-naive patients who developed anemia during BOC/PR therapy[1]
Adverse Effect Management: Rash and Anorectal Symptoms Rash management
– Mild to moderate rash can be treated with oral antihistamines, topical steroids
– Systemic steroids are not recommended
– For severe rash, many practitioners will stop TVR alone and follow for 1 wk to see if the rash improves
– If not, stop all 3 drugs
– Important to have “go-to” dermatologist; vigilance with rash is key
Anorectal symptom management
– Fiber, loperamide, hydrocortisone, pramoxine topical cream, topical lidocaine
Managing Major Adverse Effects of PegIFN
Depression
– Assess mood, sleep, suicidal thoughts
– Consider SSRI to treat baseline or new depression
– Refer to mental health services to follow high-risk patients during treatment
Influenzalike symptoms
– Acetaminophen, hydration
– Reduce dose of IFN if necessary
Neutropenia, thrombocytopenia: monitor CBC frequently
Others: GI upset, hair loss, insomnia, injection-site reactions
Helping Patients Adhere to Complex Regimens PegIFN/RBV + BOC or TVR = very complex regimen
– BOC 800 mg TID: 12 pills/day with food
– TVR 750 mg TID: 6 pills/day with high-fat meal
– RBV (2-6 pills/day) and weekly pegIFN injection
Adherence enhanced by a combination of
– Patient education and motivation
– Reducing pill burden when possible
– Shortening therapy when appropriate
– Prompt adverse effect management
Optimizing Current HCV Therapy With PIs Plus PegIFN/RBV
Strategies to Enhance Current Therapy With PegIFN/RBV Plus PI for GT1 Pts Shorter therapy may be possible for certain patients
– Investigational T12/PR12 regimens for IL28B CC patients
PR alone for IL28B CC patients?
– Being evaluated in phase III trial vs BOC + pegIFN-α2a/RBV
Potential for BID dosing of TVR
– OPTIMIZE[1]: TVR 1125 mg BID noninferior to TVR 750 mg every 8 hrs (both with pegIFN-α2a/RBV) in treatment-naive GT1 patients
– SVR12 in 74% vs 72% of patients, respectively
– No increase in adverse events
1. Buti M, et al. AASLD 2012. Abstract LB-8.
NAIVES: RESULTS (SVR)
• BOC-RGT
• TVR-RGT
Universal treatment
• BOC-RVR
• TVR-IL28
Selective treatment
SVR % ICER ( )€
74.5
67.0
72.1
79.0
118,000
85,000
56,000
74,000
NAIVES: RESULTS (LYG)
• BOC-RGT
• TVR-RGT
Universal treatment
• BOC-RVR
• TVR-IL28
Selective treatment
LYG (yrs) ICER ( )€
4.18
3.75
4.04
4.42
19,200
13,400
8,300
11,400
ICER/LYG different clinical settings
ICER = < 12.000 € triple therapy for naives
ICER = 60.000 € erlotinib pancreatic cancer
ICER = 15.000 € Heart transplantation
ICER = 74.000 € sorafenib HCC
Naives: key points
Triple therapy with first-generation PIs in naïve Gt 1 CHC patients:
• is optimised by allocating patients according to IL28B and/or RVR based strategies
• improves survival by about 4 years
• is cost-effective, with an ICER per LYG below € 12,000
• is strongly influenced by the IL28B CC prevalence and the ensuing likelihood of RVR and SVR, but also by the pricing of BOC and TVR
- An individualized treatment strategy can avoid triple therapy in 25-33% of naive HCV G1 patients
FULL PAPERS
ABSTRACTS
Re-treatment with P/R of treatment-experienced patients
Overall SVR rate after retreatment: 16.1% (CI 6-33%)
Cammà C, et al. J Hepatol. 2009 Oct;51(4):675-81.
EASL and AASLD Guidelines recommend that G1 HCV patients failing to eradicate HCV on P/R should not be retreated with P/R alone
Phase 3 RCTs (BOC: RESPOND-2, PROVIDE: TVR: REALIZE) show that TT achieves SVR in about 30%-75% of experienced G1 CHC patients, with SVR rates progressively decreasing from :
• Relapse (RR) • Partial responders (PAR) (HCV-RNA drop >2 log at week 12, but never not detectable)• Null responders (NR) (HCV-RNA drop < 2 log at week 12).
Re-treatment with P/R plus a 1st generation PI
of treatment-experienced patients
Competing strategies
• BOC LEAD IN
• TVR LEAD IN
• BOC-POOR§
• BOC-GOOD*
• TVR-POOR §
Response to previous P/R
• TVR NO LEAD IN
• TVR-GOOD*
Strategy
*>1Log drop at week 4 of DT§<1Log drop at week 4 of DT
Responseto lead-in
• RR
• PAR
• NR
Cammà C, et al. J Hepatol, in press
Cost-effectiveness of Boceprevir or Telaprevir for previously treated
patients with Gt 1 CHC
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
F3-F4RR
F3-F4PAR
F3-F4NR
CHCRR
CHCGOOD
CHCPAR
CHCPOOR
CHCNR
ICER
for L
YGICERs According to Profile of Previous
Response and Severity of Liver Fibrosis
TVR
BOC
Cammà C, et al. J Hepatol, in press
CAVEATS
• Efficacy data from registration trials
• Inconclusive data on cirrhosis
• Aggregate rather than individual patient data
• Analysis limited to direct medical costs
• Time horizon = 20 years
• Local disease epidemiology and cost issues do not allow universal use of triple therapy (TT) in Italy
• Patients with F3/F4 fibrosis deserve priority for TT• Selected patients with F0/F2 fibrosis may benefit from TT• Some non-responders should not be retreated with currently
available therapies• Boceprevir and telaprevir are equally effective• Only Centers who meet specific requirements are allowed to
prescribe TT• HCV monoinfected and HCV/HIV coinfected patients should both
receive access to TT• TT after OLT can only be used off-label (law 648/96)
Approval of triple therapy for reimbursement in Italy:Approval of triple therapy for reimbursement in Italy:basic principles (presumably) followed by AIFAbasic principles (presumably) followed by AIFA
• IL28b status and virological features (baseline viral load and HCV subtype) are weak predictors at the individual level of RVR and SVR and cannot be used to pre-assign to TT or P/R
• Response to a lead-in phase (P/R alone for 4 weeks>1 log drop in HCV RNA from baseline) is the strongest predictor of SVR*, and its absence of appearance of RAVs, hence a lead-in period is enforced for both boceprevir and telaprevir to:– Rule-in naïve patients in need of TT– Rule-out treatment experienced patients with a low likelihood of
response to TT
Approval of triple therapy for reimbursement in Italy:Approval of triple therapy for reimbursement in Italy:basic principles (presumably) followed by AIFAbasic principles (presumably) followed by AIFA
* Proven for boceprevir, assumed for telaprevir
Approval of triple therapy for reimbursement in Italy:Approval of triple therapy for reimbursement in Italy:AIFA criteria for naive Gt 1 patientsAIFA criteria for naive Gt 1 patients
Fibrosis stage
Triple therapy (P/R with Boc or Tpv)
Dual therapy (P/R)
Comments
F0, F1, F2 RVR* negative RVR* positive
F3, F4 All patients None
Lead-in not needed for telaprevir
* RVR: at least 1 log10 drop after 4 weeks of P/R
Approval of triple therapy for reimbursement in Italy:Approval of triple therapy for reimbursement in Italy: AIFA criteria for treatment exp. Gt 1 patients AIFA criteria for treatment exp. Gt 1 patients
Fibrosis stage Triple therapy (P/R with Boc or Tpv)
Dual therapy
(P/R)
Comments
F0, F1, F2
RR: allPR: all
NR: only if RVR* positiveUK: only if RVR* positive
None
F3, F4 All patients NoneLead-in not needed for telaprevir
* RVR: at least 1 log10 drop after 4 weeks of P/R
RR: relapsers; PR: partial responders; NR: null responders; UK: unknown pattern
• AIFA criteria are partly hypothetical:• Lead-in largely unproven for telaprevir• No statements about indications for treatment (Do all patients with
F0/F2 fibrosis deserve therapy? What policy for informed deferral)?• Assimilating an unknown response to null response may be
unsound• Unclear diagnostic criteria for fibrosis• Efficacy in terms of cost reduction may be insufficient
• 20% of naïve patients• 30-40% of treament experienced patients
• Selection of Centers for treatment is delegated to regional Health Authorities, who are also empowered to impose further restrictions
Approval of triple therapy for reimbursement in Italy:Approval of triple therapy for reimbursement in Italy:potential critical issuepotential critical issue
The Future of HCV Therapy
Investigational Agents for HCV
Interferons Antiviral agents
Therapeuticvaccines
Hosttarget
Replication, polyprotein processing and/or assembly
Entry
NS5Bpolymerase inhibitors
NS3protease inhibitors
NS5Areplication complex inhibitors
miRNA-122 Cyclophilin
Cyp
inhibitors
Drugs in the HCV pipeline (November 2012)
Approved
Boceprevir
Telaprevir
Protease Inh (PI)Polym Inh (nuc)Polym Inh (nn)NS5A (RCI) InhOther (misc mechs)
Former IDs:1 ACH-1625 2. RG7227 (ITMN-191) 3 SH9005182 4 RG-7128; RO5024048 5 GS-9190 6 RG77907 BMS-0032 8 MK-7009 9 BMS 790052 10 Deb02511 BI-201335
BI-207127
RBV
Peg-IFNα-2B
Peg-IFNα-2a
Phase 2
Danoprevir2
GS 9256
GS 9451
Narlaprevir3
Mericitabine4
INX-189
VX-222
BI 207127
IDX-375
miR-122 a-s*
BMS 791325
Sovaprevir1
ABT 072
GS-9254
GS-9669
GSK 2336805
IDX 719
GS-5885
ABT-267
Silymarin (IV)
CT-011 mAb*
GS6624 mAb*
Celgosivir
GS-9620 TLR7
GI-2005
Ad3NSmut*
Setrobuvir6
Tegobuvir5
BMS 824393 *
Phase 3
Simeprevir
Alisporivir10
ABT-333
Daclatasvir9
Peg-IFNλ-3
Asunaprevir7
ABT-450/r
Vaniprevir8
Faldaprevir11
IDX-184X
X
Sofosbuvir
*
*
*
*ALS 2200
Characteristics of HCV DAA classesCharacteristic Protease
inhibitorsNucleos(t)ide polymerase inhibitors
Non-nucleoside polymerase inhibitors
NS5a inhibitors
Potency High, variable among HCV
geno/subtypes
Moderate-high, consistent across geno/subtypes
Variable, variable across
geno/subtypes
High, multiple HCV genotypes
Barrier to resistance
Low1a < 1b
High1a = 1b
Very low1a < 1b
Low1a < 1b
DDI potential High Low Variable Low-moderate
Toxicity RashAnemia
Bilirubin
Mitochondrial nucleos(t)ide
interactions (ART, RBV)
Variable Variable
Pharmacokinetics Variable: QD to TID
QD Variable: QD to TID
QD
Comments 2nd generation Pis: better barrier, pangenotypic
Single target active site
Allosteric inhibition, many
targets
Multiple mode of action
Kieffer T, et al. J Antimicrob Chemother 2010;65:202–12Gao M, et al. Nature 2010;465:96–100; Lagrace L, et al. Hepatology 2010;52(4 Suppl):1205A
Lenz O, et al. Hepatology 2010;52(4 Suppl):709A; Zeuzem S, et al. Hepatology 2010;52(4 Suppl):400A
R: resistant (>4-fold increase in EC50)S: susceptible (<4-fold change in EC50)
No cross resistance between classes: a combination of DAAs can eliminate RAVs
HCV therapy: hopes and hypes….• Interferon-free• >90% SVR• Once daily• High tolerability with low adverse event• Few drug-drug interactions• Short, fixed duration (12-24 weeks)• Pan-genotypic• High barrier to resistance or lack of cross
resistance• Affordable
IL28B genotype has been associated with viral kinetics during IFN-free therapy
INFORM-1 : Mericitabine (NI) + danoprevir (PI), 14 days, n = 15
Chu, Gastro , 2012
•Regimens With 1 DAA + PegIFN alfa/RBV
•Regimens With 2 DAAs
+ PegIFN alfa/RBV•IFN-Free Regimens
Faldaprevir* (BI 201335, PI)
Daclatasvir* (BMS-790052, NS5A)
Sofosbuvir* (GS-7977, NI)
Simeprevir* (TMC435, PI)
Alisporivir* (CYP) On Hold
Vaniprevir (MK-7009, PI)
Daclatasvir + asunaprevir* Sofosbuvir + RBV
Sofosbuvir + GS-5885 (FDC) ± RBV
Daclatasvir + asunaprevir
ABT-450/RTV + ABT-267 ± ABT-333 ± RBV
Investigational HCV Regimensin Phase III Clinical Trials
•New Interferons
PegIFN lambda-1a + RBV
PegIFN lambda-1a + daclatasvir + RBV
ClinicalTrials.gov.
•Alternative Dosing
TVR BID* (approved PI)
*Studied with pegIFN-α2a. Studied with both pegIFN-α2a and pegIFN-α2b.
Interferon Plus DAA-Based Regimens
ASPIRE: Simeprevir (TMC435) 150 mg for 12, 24, 48 Wks + PR in Tx-Exp’d GT1 Pts SVR24 rates according to previous response category[1]
High rates of efficacy in patients with METAVIR F3/F4 fibrosis [2]
` Relapsers: 65%; partial responders: 67%; null responders: 33%
Simeprevir 150 mg* + pegIFN-α2a/RBV 48 wks
Placebo + pegIFN-α2a/RBV 48 wks
*Pooled.
80
SV
R24
(%
)
0
40
60
100
20
Relapsers Partial Responders
Null Responders
37
85
9
76
19
51
1. Jacobson I, et al. IDSA 2012. Abstract 1287. 2. Poordad F, et al. AASLD 2012. Abstract 83.
10/27
67/79 2/23
52/69
26/51
3/16
n/N =
ATOMIC: Sofosbuvir (GS-7977) Plus PR in Treatment-Naive GT1 Patients Interim analysis of randomized, open-label phase II study
Kowdley KV, et al. EASL 2012. Abstract 1. Hassanein T, et al. AASLD 2012. Abstract 230.
Treatment-naive,
noncirrhotic patients*(N = 332)
Sofosbuvir + PegIFN-α2a/RBV
(n = 52)
Sofosbuvir + PegIFN-α2a/RBV(n = 125)
Sofosbuvir + PegIFN-α2a/RBV
(n = 155)
Wk 24Wk 12
Sofosbuvir (n = 75)
Sofosbuvir + RBV(n = 75)
*All infected with genotype 1 HCV, except for 16 patients with GT4 or 6 HCV who were eligible for 24-wk arm of sofosbuvir plus PR.
SVR12,%
90
92 overall
82 GT4
100 GT6
91
Interferon-Free Regimens
ELECTRON: Sofosbuvir and RBV in Naive and Experienced GT1 Patients
Wk 12Wk 12
Gane EJ, et al. AASLD 2012. Abstract 229.
Sofosbuvir + RBV 1000/1200 mg (GT1; naive) (n = 25)
Sofosbuvir + RBV 1000/1200 mg (GT1; null responders) (n = 10)
SVR12
10
Wk 8Wk 8
84
Sofosbuvir + GS-5885 + RBV 1000/1200 mg (GT1; naive) (n = 25)
SVR4
100
Viral Response, %
Sofosbuvir + GS-5885 + RBV 1000/1200 mg (GT1; nulls) (n = 9) 100*
*Data reported for 3 pts only. Data collection ongoing.
NIH SPARE: Interim Data on Sofosbuvir and RBV in Difficult-to-Treat GT1 Patients Patients with poor prognostic indicators: GT1a (70%), male (63%), black (83%), IL28B CT/TT (80%), advanced liver disease (22%)
Median BMI: 28; median HCV RNA: 6.4 logs
Wk 24Wk 24 SVR4
Osinusi A, et al. AASLD 2012. Abstract LB-4.
Sofosbuvir + RBV 1000/1200 mg (n = 10)
Sofosbuvir + RBV 1000/1200 mg (n = 25)
Sofosbuvir + RBV 600 mg (n = 25)
Part 1 (early-stage fibrosis) SVR12
90*
Part 2 (all stages of fibrosis)
56†
72*
EOT
90*
88†
96*
Viral Response, %
*1 dropout at Wk 3. †3 dropouts by Wk 8.
90*
Daclatasvir Plus Sofosbuvir ± RBV in Treatment-Naive GT1 or 2/3 Patients No impact of RBV on viral response
Treatment-naive, noncirrhotic
patients
GT1a or 1b (n = 44)
GT2 or 3 (n = 44)
Daclatasvir + SofosbuvirSofosbuvir
Daclatasvir + Sofosbuvir
Daclatasvir + Sofosbuvir + RBV
Wk 1 Wk 24
Sobosbuvir dosed 400 mg QD. Daclatasvir dosed 60 mg QD. RBV dosed by body weight for GT1 patients (1000-1200 mg/day); 800 mg/day for GT2/3 patients.
Sulkowski MS, et al. AASLD 2012. Abstract LB-2.
GT1
93
100
100
GT2/3
88
100
93
SVR24, %
AVIATOR: IFN-Free Regimens With ABT-450/RTV, ABT-267, ABT-333, and RBV
Cohort 1:Treatment-naive pts, GT1 HCV
ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV
(n = 80)
ABT-450/RTV 100/100 mg + ABT-267 + ABT-333 + RBV
ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV
ABT-450/RTV 100/100 mg + ABT-267 + ABT-333 + RBV
ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV
Kowdley KV, et al. AASLD 2012. Abstract LB-1.
Phase II trial with 2 cohorts SVR12, %
87.5
97.5
Wks 0 8 12 24
NR
Cohort 2:Tx-exp’d pts, GT1 HCV, with previous
null response
ABT-450/RTV 100/100 mg + ABT-267 + ABT-333 + RBV
ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV
ABT-450/RTV 100/100 mg + ABT-267 + ABT-333 + RBV
ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV
93.3
NR
(n = 79)
(n = 80)
(n = 43)
(n = 45)
Future Role of Interferon
What role may interferon play in future regimens?
– Preventing resistance?
For which sets of patients may IFN play a role?
– Patients with cirrhosis?
– Treatment-experienced patients?
– Patients with resistance to DAAs?
Will newer IFNs replace currently available agents?
– EMERGE: IFN lambda may have comparable efficacy but fewer hematologic AEs vs pegIFN alfa[1]
1. Muir AJ, et al. AASLD 2012. Abstract 214.
HCV: 2013-2020
PI+PEG+RBV PI2+PEG+RBV
DAA1 + DAA2 + RBV (or)DAA1 + DAA2 + DAA3 + RBV
QUAD: PEG/RBV/DAA1/DAA2 (???)
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020
PEG/RBV 0
10
20
30
40
50
60
70
80
90
100
% o
f Pati
ents