Download GIM Grd Rds 1 8 2013 - University of Colorado Denver

Advances in the Treatment of
Chronic Hepatitis C
Gregory T Everson, MD
Professor of Medicine
Director of Hepatology
University of Colorado Denver
Disclosures
Advisory Boards:
Consulting:
DSMB:
Stock/Ownership:
Management:
Research Grants:
Roche/Genentech, Merck, Vertex, BMS,
GlobeImmune, Abbott, Eisai, Novartis,
Pfizer, Gilead, Biotest, Tibotec/Janssen
Roche-Genentech, Novartis, BMS, Eisai,
Kadmon, Vertex, Abbott, Biotest,
Tibotec/Janssen
Centocor
Source, HepQuant LLC
HepQuant LLC
Roche/Genentech, Schering-Plough/Merck,
Vertex, GlobeImmune, Gilead, Novartis,
BMS, Pfizer, Source, Eisai, GSK, Pharmassett,
Ortho Biotech, Tibotec/Janssen, Amgen,
Medtronic, Abbott
Primer on HCV
Worldwide Prevalence of HCV
WHO, Wkly Epidemiol Rec, 2000
Genotype and Viral Load in US
4%
22%
Geno 2 & 3
Geno 1 HVL
> 800,000 IU/ml
Geno 1 LVL
50%
24%
Approximately 2/3 cases of GT1 infection in the US
are due to the GT1a subtype.
Natural History of HCV Infection
Acute HCV Infection
15%-45%
Recovery
55%-85%
Chronic HCV Infection
Chronic Hepatitis C
Mild
Moderate
Severe
Cirrhosis
End-Stage Liver Disease
Liver Transplantation
Hepatocellular Carcinoma
Death
There are an estimated 3 to 5 million cases of chronic hepatitis C in the US.
Hepatitis C Testing for Anyone Born During
1945-1965: New CDC Recommendations
If you were born during 19451965 (baby boomer), talk to
your doctor about getting
tested for Hepatitis C. The only
way to know if you have
Hepatitis C is to get tested.
Early detection can save lives.
Reasons for this recommendation:
1.
2.
3.
4.
Baby boomers – represent 75% of cases in US).
This one-time testing may prevent more than 120,000 deaths.
Most cases are undiagnosed - testing would find 800,000 new cases.
There have been recent advances in treatment.
Source: CDC. Recommendations for the identification of chronic hepatitis C virus infection among
persons born during 1945–1965. MMWR 2012;61(No. RR–4).
Recommendations for the Identification of Chronic
Hepatitis C Virus Infection Among Persons Born
during 1945–1965*
• Adults born during 1945–1965 should receive one-time testing for
HCV without prior ascertainment of HCV risk.
• All persons with identified HCV infection should receive a brief
alcohol screening and intervention as clinically indicated,
followed by referral to appropriate care and treatment
services for HCV infection and related conditions.
Source: CDC. Recommendations for the identification of chronic hepatitis C virus infection among
persons born during 1945–1965. MMWR 2012;61(No. RR–4).
Case
A baby boomer is screened for HCV and HCV-Ab is
positive. You order a polymerase-chain-reaction-based
test for HCV RNA quantification. What is the likelihood
that the HCV RNA will be positive?
1. 0%
2. ~ 25%
3. ~ 50%
4. ~ 75%
5. 100%
A baby boomer is screened for HCV and HCV-Ab is
positive. You order a polymerase-chain-reaction-based
test for HCV RNA quantification. What is the likelihood
that the HCV RNA will be positive?
1. 0%
2. ~ 25%
3. ~ 50%
4. ~ 75%
5. 100%
The HCV RNA is positive. Standard laboratory tests are
normal except for ALT 85 IU/mL. Further evaluation
reveals HCV genotype 1a, advanced fibrosis (F3), and
IL28B genotype CT. Given these factors, what would you
advise for treatment?
1. None
2. Silymarin (milk thistle)
3. Peginterferon alone
4. Peginterferon + Ribavirin
5. Peginterferon + Ribavirin + DAA
The HCV RNA is positive. Standard laboratory tests are
normal except for ALT 85 IU/mL. Further evaluation
reveals HCV genotype 1a, advanced fibrosis (F3), and
IL28B genotype CT. Given these factors, what would you
advise for treatment?
1. None
2. Silymarin (milk thistle)
3. Peginterferon alone
4. Peginterferon + Ribavirin
5. Peginterferon + Ribavirin + DAA
Treatment
The Goal of Treatment is SVR
Sustained Virologic Response
Undetectable HCV RNA - 3 months (SVR12) or
6 months (SVR24) after Treatment
The Primary Objective of
Therapy for Chronic Hepatitis C
SVR Equates with CURE
Swain MG, et al. Gastroenterology 2010;139:1593-1601.
Established Benefits of SVR
1.
Probably “Cured” of HCV infection – chance for late
relapse <1%.
2.
Halts progression of liver disease.
3.
Reduces risk for HCC – although patients with
bridging fibrosis or cirrhosis may develop HCC
after SVR and still need to be screened.
4.
HCV-related extrahepatic manifestations disappear or
are ameliorated
5.
Health-related (HCV) Quality of Life Improves
Past and Current Treatment for HCV GT2 & 3
% of Patients Achieving SVR
100
80
80
69
66
IFN/RBV 24
IFN/RBV 48
60
40
20
29
16
0
IFN 24
1991
IFN 48
Year of FDA Approval
PEG/RBV 24
2002
Triple Therapy
The Current Standard-of-Care for
HCV Genotype 1
First Generation Protease Inhibitors
Telaprevir
Boceprevir
with Peginterferon/Ribavirin
Past and Current Treatment for HCV GT1
% of Patients Achieving SVR
100
75
80
60
40
40
28
16
20
2
7
0
IFN 24
1991
IFN 48
IFN/RBV 24 IFN/RBV 48 PEG/RBV 48
Year of FDA Approval
2002
TT-TPV
2011
Predictors of SVR with TT in
Treatment Naïve Patients
 Interferon Sensitivity
 IL28B Polymorphism
 HCV RNA decline during Lead-In with
PEG/RBV
 On-treatment (TT) Response (eRVR)
 Stage of Fibrosis
IL28b Polymorphism
Telaprevir (TPV): Treatment-Naïve
SVR by IL28B Polymorphism
% SVR
100
90
80
∆ = 18%
73
71
64
60
∆ = 50%
40
25
23
CT
TT
20
CC
CC
CT
0
PR
TPV-based
TT
Boceprevir (BOC): Treatment-Naïve
SVR by IL28B Polymorphism
% SVR
100
80
∆ = 9 to 27%
82
78
80
71
65
59
55
60
∆ = 50%
40
28
27
CT
TT
20
CC
CC
CT
TT
CC
CT
0
PR
BOC-RGT
BOC-48
TT
IL28b Polymorphism in
Treatment-Naïve
1. Highly predictive when treatment is peginterferon
plus ribavirin (PR)
2. Less predictive when treatment has higher chance of
success in CT and TT polymorphisms – less predictive
when treatment is triple therapy.
Lead-In
Boceprevir Trial of Treatment-Naïve
(SPRINT-2)
Boceprevir (BOC): Treatment-Naïve
SVR by Log10 HCV RNA Decline during Lead-In with PR
% SVR
< 1 Log10 Decline
≥ 1 Log10 Decline
100
81
80
60
51
38
40
20
79
28
4
0
PR
BOC-RGT
SPRINT-2 Study. N Engl J Med 2011;364:1195-1206.
BOC-48
Lead-In in
Treatment-Naïve
1. Predicts likelihood of SVR with Boceprevir-based
triple therapy
2. SVR is still greater than 30% in the patients treated
with triple therapy who have < 1 Log10 decline in HCV
RNA during Lead-in - < 1 Log10 decline is NOT a Stop
Guideline
Extended Rapid Virologic Response
(eRVR)
Extended Rapid Virologic Response
eRVR Identifies the “Super” Responders who can Stop Early
 Two components of eRVR
 HCV RNA <10 IU/mL at Week 4 of Triple Therapy (RAPID)
 HCV RNA <10 IU/mL subsequently (EXTENDED)
 Telaprevir (T12/PR24)
 HCV RNA <10 IU/mL Weeks 4 through 12
 Stop treatment at Week 24 (58% & 65% of patients1)
 ILLUMINATE, randomized trial of eRVR, 24 vs 48 wks PR
 Boceprevir (LI PR4, B24/PR24)
 HCV RNA <10 IU/mL Weeks 8 through 24
 eRVR – Stop treatment at Week 28 (44% of patients2)
1 ADVANCE. N Engl J Med 2011;364:2405-2416. ILLUMINATE. N Engl J Med 2011;365:1014-1024.
2 SPRINT-2. N Engl J Med 2011;364:1195-1206.
eRVR and Treatment Duration
ILLUMINATE study of Telaprevir – 65% Achieved eRVR
% SVR
100
80
92
88
60
40
20
0
24 Weeks
48 Weeks
ILLUMINATE Study. N Engl J Med 2011;365:1014-1024.
Stage of Fibrosis
Impact of Stage of Fibrosis
Telaprevir and Boceprevir: Treatment-Naive
SVR (%)
100
80
*
F0-F2
F3-F4
*
60
40
20
0
ADVANCE T12 ADVANCE T8
ILLUMINATE
eRVR24
ILLUMINATE SPRINT-2 RGT
eRVR48
SPRINT-2 48
Jacobson IM, et al. ADVANCE trial. N Eng J Med 2011;364:2405-2416.
Sherman KE, et al. ILLUMINATE trial. N Engl J Med 2011;365:1014-1024.
Poordad F, et al. SPRINT-2 trial. N Engl J Med 2011; 364:1195-1206.
* Biggest Impact of reducing duration of TPV in ADVANCE, or PR in ILLUMINATE, was in F4 patients.
Case
The Patient Elects Treatment with Telaprevir-based Triple
Therapy. HCV RNA is undetectable from Weeks 1 through 8.
HCV RNA (IU/mL)
3000000
GT1a, F3, IL28b CT
No viral variants at baseline
2500000
2000000
1500000
1000000
Diverticulitis
500000
HCV RNA negative
0
Base
Wk 1
Wk 4
Wk 8
Post-Rx Post-Rx Post-Rx Post-Rx
Wk4
Wk12 Wk16
Yr2
The patient is admitted to the hospital with fever, LLQ
abdominal pain, and leucocytosis. CT confirms sigmoid
diverticulitis and blood cultures were positive for E. coli.
Best management includes antibiotic therapy and:
1. Continuation of TPV, PEG, and RBV
2. Continuation of PEG and RBV only
3. Continuation of PEG only
4. Discontinuation of TPV, PEG, and RBV
The patient is admitted to the hospital with fever, LLQ
abdominal pain, and leucocytosis. CT confirms sigmoid
diverticulitis and blood cultures were positive for E. coli.
Best management includes antibiotic therapy and:
1. Continuation of TPV, PEG, and RBV
2. Continuation of PEG and RBV only
3. Continuation of PEG only
4. Discontinuation of TPV, PEG, and RBV
Pitfalls of Current DAA Rx
•
•
•
•
•
•
•
•
Single DAA – low barrier to resistance
Only indicated for HCV GT1
Complex treatment algorithms
High pill burden
Rx duration of 24 to 48 weeks
Requires PEG/RBV – SEs, AEs, SAEs
Unique SEs, AEs, SAEs
Drug-Drug Interactions
Viral Resistance
Case
TPV, PEG, and RBV are discontinued and HCV RNA is monitored.
3000000
V36M
T54A
R155K
A156V
-
2500000
HCV RNA
Positive
30 IU/mL
2000000
1500000
Stopped all
Meds due to
Diverticulitis
1000000
500000
HCV RNA negative
0
Base
Wk 1
Wk 4
Wk 8
Post-Rx Post-Rx Post-Rx Post-Rx
Wk4
Wk12 Wk16
Yr2
After confirming relapse by repeat testing of HCV RNA, a blood
sample is analyzed for variants of HCV resistant to TPV.
3000000
V36M
T54A
R155K
A156V
-
+
-
2500000
HCV RNA
Positive
2000000
1500000
Stopped all
Meds due to
Diverticulitis
1000000
500000
R155K
Detected
HCV RNA negative
0
Base
Wk 1
Wk 4
Wk 8
Post-Rx Post-Rx Post-Rx Post-Rx
Wk4
Wk12 Wk16
Yr2
Complex Treatment Algorithms
Telaprevir: Treatment-Naïve Patients
Triple
Therapy
with
TPV+P+R
For
12 weeks
HCV RNA is quantified at
weeks 4, 8, 12 while the
patient is taking TPV – to
evaluate for viral response
and resistance.
TPV is stopped if there is
evidence of rebound in HCV
RNA.
eRVR
HCV RNA negative
At Weeks 4 & 12
NO eRVR
Slow Responder**
Additional
12 weeks of
P+R*
Additional
36 weeks of
P+R
Treatment is discontinued if HCV
RNA is >1000 IU/mL at week 4 or 12
or detectable at week 24
* FDA recommends extending P+R for 36 weeks in patients with cirrhosis.
** Slow responder is RNA positive at week 4 but RNA negative prior to or at week 24.
Boceprevir: Treatment-Naïve Patients
HCV RNA at Weeks 4, 8, 12, 24 while the patient is taking
BOC – to evaluate for viral response and resistance.
Lead-In
With
4 weeks
P+R
The drop in HCV RNA
predicts likelihood of
responding to subsequent
triple therapy with BOC.
Patients with <1log10
decrease (Poor response)
have SVR ~30%.
Triple
Therapy
with
BOC+P+R
For additional
24 weeks*
eRVR’
8 - 24 wk RNA neg
No
additional
Treatment*
(28 weeks total)
NO eRVR’
Slow Responder
All treatment is discontinued if
either HCV RNA >100 IU/mL at wk 12
or HCV RNA detectable at wk 24
Additional
8 weeks of
BOC+P+R and
12 weeks P+R
Treatment*
(48 weeks total)
* Cirrhotic patients and Poor Responders are treated for 44 weeks BOC+P+R, regardless of eRVR’.
** Slow responders are RNA positive at week 8 but RNA negative prior to or at week 24.
Unique Side Effects
Telaprevir and Rash
 Can be nasty (DRESS, S-J syndrome)!
 Occurs in over 50% of patients, mild in
most cases (hydroxyzine, topicals)
 Telaprevir discontinued in 5 - 10% due to
rash. Systemic steroids may be required.
All treatment stopped in 1-2% due to rash.
Ribavirin Rash
Telaprevir – Mild to Moderate Rash
Telaprevir – Moderate to Severe Rash
Black Box Warning – Severe Rash
December 19, 2012. The U.S. Food and Drug Administration (FDA) received
reports of serious skin reactions, some fatal, in patients taking the hepatitis
C drug Incivek (telaprevir) in combination with the drugs peginterferon alfa
and ribavirin (Incivek combination treatment). Significantly, some patients
died when they continued to receive Incivek combination treatment after
developing a worsening, or progressive rash and systemic symptoms
(symptoms affecting the entire body). As a result, FDA is adding a boxed
warning to the Incivek drug label stating that Incivek combination treatment
must be immediately stopped in patients experiencing a rash with systemic
symptoms or a progressive severe rash. Consideration should also be given
to stopping any other medications that may be associated with serious skin
reactions. Typical systemic symptoms and signs may include fever, nausea,
diarrhea, mouth sores or ulcers, facial swelling (edema), red or inflamed
eyes, or swelling or inflammation of the liver (hepatitis). All patients with
serious skin reactions should also receive urgent medical care.
Telaprevir and Anal Pain
 Ring of Fire! Aggravating.
 Occurs in about 20% of patients, mild in
most, occasionlly severe. Topical
lidocaine, steroid supporitories. May
respond to amitryptyline?
 Typically have not stopped treatment due
to this.
Anemia
Telaprevir and Boceprevir
Anemia during triple therapy with
Telaprevir or Boceprevir
15
Median Hemoglobin (g/dL)
CHC PegIFN+RBV
14
CHC PegIFN+RBV+ TPV
CHC PegIFN+RBV+BOC
13
12
11
10
9
8
0
4
8
12
16
20
24
Weeks
This Slide courtesy of X Forns, MD
Modified by GTE
Poordad F, et al. Hepatology 2010;52(Suppl.):402A
Bacon, B, et al. Hepatology 2010; 52(Suppl):430A
McHutchison JG et al, N Engl J Med. 2010
Management of Anemia
Step 1: RBV Dose Reduction
Step 2: EPA therapy
Step 3: Transfusion
Step 4: Discontinuation of TPV or BOC
Drug-Drug Interactions
(CNIs)
Impact of BOC or TPV on Drug X
Drug X
Oral
Drug X
IV
Intestine
X Int Lumen
P-gp →
X Metabolism
CYP3A4 →
Liver
X Bile
P-gp →
X Metabolism
CYP3A4 →
Kidney
X Urine
P-gp →
X Metabolism
CYP3A4 →
Drug X
Systemic
Exposure
Increases
IS Meds
Statins
Benzodiazepines
Antipsychotics?
E-mycins
Anticonvulsants
HIV PIs, NNIs
α-Adren Blkrs
Ca++-Ch Blkrs
Kiser J, et al. Review and Management of Drug Interactions with Boceprevir and Telaprevir. Hepatology 2012;55:1620-8
Tacrolimus
Garg V, et al. Effect of Telaprevir on the PK of CSA and TAC. Hepatology 2011;54:20-27.
Drug X AUC Ratio w/wo TPV
Ratio AUCs for Drug (w/wo TPV)
9
8
7
6
5
4
3
2
1
0
From tables in Prescribing Information for INCIVEK, May 2011
Kiser J, et al. Review and Management of DDIs with Boceprevir and Telaprevir. Hepatology 2012.
Management
• Dose Adjust DRUG X
• Adjust Duration between doses of DRUG X
• Monitor Closely
– Drug Levels
– Laboratory Parameters
– Clinical Assessment of the Patient
Resources for DDIs
• Outstanding – University of Liverpool (David
Back, Editorial Board, EASL reps); sponsored by
Janssen, MSD, Roche, Vertex:
– http://www.hep-druginteractions.org
• FDA:
– http://www.fda.gov/Drugs/DrugSafety/
• Other Online Resources –
–
–
–
–
http://www.drugs.com/drug-interactions/html
http://www.merckmedicus.com/pp/us/hep
Epocrates
Micromedex, Lexicomp and Others
Goals of Future Treatments




Improve rates of SVR to 100%
Activity against all HCV genotypes and subtypes
Simplify treatment algorithms
Extend treatment to the “difficult to treat”, “difficult to cure”
 Eliminate side effects
 Eliminate peginterferon
 Eliminate ribavirin
 Avoid rash, anemia, anal pain, and dysgeusia
 Reduce drug-drug interactions
 Reduce complexity and pill burden by avoiding  Injections (shots)
24, up to 48, total
 Ribavirin
up to 6/d
 Telaprevir
6/d x 3 months
 Boceprevir
12/d from 24 to 44 wks
 Reduce treatment duration
 Reduce costs
What’s on the Horizon?
HCV Proteins and their Functions
Charles M. Rice, PhD. Top Antivir Med 2011;19:117-120.
Timelines
PR
PR + 1st Gen DAA
PR + 2nd Gen DAA
IFN-Free
Regimens
QUAD or QUINT Rescue
2011
2013
2015
2017
Simiprevir
Inhibitor of NS3/4a Protease
Daclatasvir
Inhibitor of NS5a Protein
Sofusbivir
Inhibitor (Nuc) of NS5b Polymerase
Regimens of DAA + PEG/RBV
(Virologic Responses in Rx-Naïve Patients with HCV GT1)
% of Pts with HCV RNA (<10 IU/mL) weeks 4 - 12
100
80
60
60
78
79
DAC
DNV
82
87
92
100
65
50
40
20
0
BOC
MCB
TPV
SMV
FDP
SOF
ABT
Increased potency also reduces risk for emergence of resistant viral variants – e.g., MK-5172 is
active in vitro against common variants with resistance to TPV or BOC.
Case
Two years after triple therapy another blood sample is
analyzed for resistant variants of HCV.
3000000
V36M
T54A
R155K
A156V
-
+
-
-
WT
2500000
HCV RNA
Positive
2000000
1500000
Stopped all
Meds due to
Diverticulitis
1000000
500000
R155K
Detected
HCV RNA negative
0
Base
Wk 1
Wk 4
Wk 8
Post-Rx Post-Rx Post-Rx Post-Rx
Wk4
Wk12 Wk16
Yr2
Within a few weeks of discontinuing Triple Therapy, the
patient had relapsed and tested positive for R155K, an
HCV variant with resistance to TPV. On retesting, 2 years
after triple therapy, only wild-type and no variant of HCV
could be detected. Assuming all options listed below are
available, which re-treatment would be most successful in
achieving SVR?
1. Peginterferon/Ribavirin (PR)
2. Telaprevir + PR
3. Boceprevir + PR
4. Simeprevir + PR
5. Sofusbevir + PR
Within a few weeks of discontinuing Triple Therapy, the
patient had relapsed and tested positive for R155K, an
HCV variant with resistance to TPV. On retesting, 2 years
after triple therapy, only wild-type and no variant of HCV
could be detected. Assuming all options listed below are
available, which re-treatment would be most successful in
achieving SVR?
1. Peginterferon/Ribavirin (PR)
2. Telaprevir + PR
3. Boceprevir + PR
4. Simeprevir + PR
5. Sofusbevir + PR
IFN-Free Combinations
Dual DAA (Daclatasvir+Asunaprevir)
GT 1 Null Responders to PEG/RBV
DUAL DAA in GT1 Null Responders
Daclatasvir + Asunaprevir (n=11)
% HCV RNA <10 IU/mL
100
All breakthroughs
Occurred in
Patients with G1a
80
63.6
60
45.5
45.5
36.4
40
20
0
RVR
cEVR
EOT
SVR12
Lok A, et al. RVR/cEVR presented at AASLD 2010. SVR12 presented EASL 2011. N Engl J Med 2012;366:216-224 .
Daclatasvir 60 mg qd, Asunaprevir 600 mg bid, 24 weeks treatment.
QUAD (or QUINT) Therapy
When all else fails!
QUAD in the Treatment of G1 Null Responders
BMS-790052/BMS-650032 + PR (n=10), 24 Weeks of Rx
% HCV RNA <10 IU/mL
100
100
100
90
80
60
60
40
20
0
RVR
cEVR
EOT
Lok A, et al. N Engl J Med 2012;366:216-224.
790052 60 mg qd, 650032 600 mg bid; SVR at week24 post-Rx
SVR12
0
GT1 SOF 5885 R
12W
GT6 SOF PR 12W
GT4 SOF PR 12W
GT1 SOF PR 12W
GT1a FAL 127 R
16W
GT1b FAL 127 R
16W
GT1 Null DAC ASV
PR 24W
GT1b Null DAC
ASV 24W
GT1 Fib DNV MER
PR 24W
GT1 Null ABT450r
267 333 R 12W
GT1 ABT450r 267
333 R 12W
GT1 AA DtT SOF R
24W
GT1 DAC ASV
71325 12W
GT1 SOF DAC 12W
GT1 CC 5885 9451
PR 12W
GT1 CC 5885 9451
PR 6W
GT1a DAC ASV PR
24W
GT1b DAC ASV
24W
GT2/3 SOF DAC
12W
GT2/3 SOF R 12W
Optimistic Results in Phase 2 Trials
% SVR
100
80
60
40
20
Thompson A, et al. Six Weeks of an NS5A Inhibitor (GS-5885) and a Protease Inhibitor (GS-9451) Plus Peginterferon+Ribavirin Achieves High
SVR4 Rates in Genotype 1 IL28B CC Treatment-Naïve Hepatitis C Virus Patients: Interim Results of a Prospective, Randomized Trial. AASLD
2012.
Lok AS, et al. Preliminary Study of two antiviral agents for Hepatitis C Genotype 1. N Engl J Med 2012;366:216-224.
Chayama K, et al. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor,
asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology 2012;55:742-748.
Sulkowski M, et al. High Rate of Sustained Virologic Response With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir
(Nucleotide NS5B Inhibitor), With or Without Ribavirin, in Treatment-Naive Patients Chronically Infected With HCV GT 1, 2, or 3. AASLD 2012.
Everson GT, et al. An Interferon-Free, Ribavirin-Free 12-Week Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 Yielded
SVR4 of 94% in Treatment-Naïve Patients with Genotype (GT) 1 Chronic Hepatitis C Virus (HCV) Infection. AASLD 2012.
Osinusi A, et al. High Efficacy of GS-7977 in Combination with Low or Full dose Ribavirin for 24 weeks in Difficult to Treat HCV Infected
Genotype 1 Patients. AASLD 2012.
Kowdley KV, et al. A 12-week Interferon-free Treatment Regimen With ABT-450/r, ABT 267, ABT-333, and Ribavirin Achieves SVR12 Rates
(Observed Data) of 99% in Treatment-naïve Patients and 93% in Prior Null Responders With HCV Genotype 1 Infection. AASLD 2012.
Jacobson IM, et al. Safety and efficacy of ritonavir-boosted danoprevir (DNVr), peginterferon alfa-2a (40KD), and ribavirin with or without
mericitabine in HCV genotype 1-infected treatment-experienced patients with advanced hepatic fibrosis: the MATTERHORN study. AASLD
2012.
Lok AS, et al. Sustained Virologic Response in Chronic HCV Genotype (GT) 1-Infected Null Responders With Combination of Daclatasvir
(DCV; NS5A Inhibitor) and Asunaprevir (ASV; NS3 Inhibitor) With or Without Peginterferon Alfa-2a/Ribavirin (PEG/RBV) . AASLD 2012.
Zeuzem S, et al. Sustained Virologic Response in Chronic HCV Genotype (GT) 1-Infected Null Responders With Combination of Daclatasvir
(DCV; NS5A Inhibitor) and Asunaprevir (ASV; NS3 Inhibitor) With or Without Peginterferon Alfa-2a/Ribavirin (PEG/RBV) . AASLD 2012
Hassenein T, et al. Once Daily Sofosbuvir (GS-7977) plus PEG/RBV In Treatment-Naïve Patients With HCV Genotype 1, 4, and 6 Infection: The
ATOMIC Study. AASLD 2012.
Gane E, et al. 100 Percent Sustained Virologic Response Rate (SVR4) for an Interferon-Free Regimen of Sofosbuvir (GS-7977), GS-5885 and
Ribavirin in Treatment-Naïve Genotype 1 Hepatitis C Infected Patients. AASLD 2012.
The Promise of Future Treatments
1. Pan-genotypic coverage
2. IFN-Free Regimens (Gilead, Abbott, BMS,
Roche/Genentech, BI)
3. Greater Potency – higher rates of SVR
4. Shortened Duration of Treatment
5. Improved Tolerability and Safety
6. Less bone marrow suppression or hemolysis
Perspective
Future Treatment for HCV GT1
% of Patients with SVR
100
70
80
60
40
20
0
2
1991
7
16
28
85
92
98
100
40
Yr of FDA Approval
2011
2013
2015
Future Treatment for HCV GT2 & 3
% of Patients with SVR
100
80
60
40
20
0
69
16
1991
80
90
2002
2013
66
100
100
29
Yr of FDA Approval
2015
The Real Impact Could Be 1. Reduction in costs of care for HCV
2. Reduction in liver-related death
3. Reduction in Hepatocellular carcinoma
4. Reduction in need for liver transplantation
5. Reduction in autoimmune disorders
6. Reduction in adult-onset diabetes mellitus
7. Reduction in B-cell lymphoma