Transcript Hepatitis C: Boomers at Risk Diagnosis and Treatment Outcomes

Hepatitis C: Boomers at Risk
Diagnosis and Treatment Outcomes
Richard K. Sterling, MD, MSc, FACP, FACG
VCU Hepatology Professor of Medicine
Chief, Section of Hepatology
Fellowship Director, Transplant Hepatology
Virginia Commonwealth University
Richmond, VA
Conflicts of Interest in the last 12 months
• Advisory Board
– Roche/Genentech, Merck, Vertex, Bayer, Salix,
BMS, Abbott, Gilead
• Research support
– Roche/Genetech, Merck, Bayer, Gilead, Abbott,
Boehringer Ingelheim, Vertex, BMS
Goals of Discussion
• Epidemiology of HCV
• Populations to test (Boomers and those with
risks)
• Approach to patient (Diagnosis and testing)
• Treatment (past, present, future)
• Impact of treatment
• Future (at least as I see it)
Some basic facts about liver disease
Liver failure
Chronic
Liver disease
cirrhosis
Other organs
Stop working
DEATH
LIVER
TRANSPLANT
~ 8-10 million
Americans affected
Liver
cancer
Global epidemiology of hepatitis C virus infection: New estimates of age‐specific antibody to HCV
seroprevalence
Hepatology
Volume 57, Issue 4, pages 1333-1342, 4 FEB 2013 DOI: 10.1002/hep.26141
http://onlinelibrary.wiley.com/doi/10.1002/hep.26141/full#fig3
Hepatitis C
• HCV is the leading cause of end stage liver disease
and indication for liver transplant.
• HCV is an important risk factor for diabetes and also
increases the risk of heart disease.
• HCV is a potentially curable disease
• Risk factors:
– Birth cohort: Born between 1945-1965
– risk factors:
•
•
•
•
Blood and blood product transfusion
IVDA
Cocaine snorting
Multiple sex partners with unprotected sex
Time is critical
• The average age of an HCV-infected patient is
approximately 55 yrs
– Perhaps 40% have cirrhosis
• 10,000-15,000 die each year and is increasing
• Only 25-30% of HCV patients have been
diagnosed
• Only 11% have been treated
The growing burden of viral hepatitis in the
United States
Annals Int Med 2012
How much does viral hepatitis contribute to
cirrhosis and HCC
The burden of end-stage liver disease
60
56
N=104 cirrhotic subjects
50
46
Veterans and non-vets equally affected
40
percent
MELD and HE drives caregiver burden
30
20
16
15
11
10
10
7
5
ev
ict
ed
ba
nk
ru
pt
t
ou
ov
ed
m
fo
od
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s
bi
ll
on
e
ed
la
t
uc
at
io
n
de
bt
In
no
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o
pp
ed
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vi
n
g
0
Bajaj et al
Why is the situation particularly tragic ?
• Risk factors for viral hepatitis are well known
• A highly effective vaccine for hepatitis A and B exists
• Tests to diagnose the disease are available and are
being improved upon- and should allow point of care
testing
• Highly effective treatments for both hepatitis B and C
are available and getting better
How to prevent hepatitis C?
• Safe blood supply
• Intravenous drug users
• Iatrogenic spread (improve health care
associated outbreaks)
• ? Safe sex methods
What can we do?
• Detect early and prevent disease progression
• Identify those with clinically silent but serious
disease who are at greatest risk for morbidity
and mortality
Birth Cohort Screening
• Baby boomers: birth between 1945-65
• Risk factor based screening below that
•
•
•
•
•
Well known prevalence and risk factors
Contribution to burden of disease well established
Highly sensitive diagnostic tests available
Effective therapy is available
Treatment reduces mortality and morbidity
CDC guidelines 2012
Despite the USPSTF recommending that only high risk individuals be tested
(blood transfusion prior 1992, illicit drug use, increased ALT), most, if not all others
(AASLD, CDC, ACG, AGA, VAHA, NIH, ISDA, IOM) endorse birth cohort screening regardless of
risk factors (Edlin BR. Hepatology 2013;57:1644-1650)
Impact of timing and prioritzation for treatment on cost
effectiveness of birth cohort screening
Age
McEwan et al, Hepatology. 2013 Feb 6. doi: 10.1002/hep.26304.
More quality adjusted life years saved with
prioritization for Rx for more advanced disease
McEwan et al, Hepatology. 2013 Feb 6. doi: 10.1002/hep.26304.
Evaluation of HCV
HCV Ab +
HCV RNA and Genotype
+
-
Liver Enzymes
+
Repeat HCV RNA
CBC with Plt
HBV sAg/sAb/cAb
HAV IgG
Avoid alcohol
HIV
Resolved HCV
Counsel on household and sex
ANA
Vaccinate for HAV and HBV
Avoid raw shell fish
Assess severity of disease
(liver biopsy or non-invasive test)
Assess for treatment
(May require referral)
How to identify clinically silent but significant
disease in your clinic
• Know the epidemiology of disease in your area
• Evaluate risk factors:
– Alcohol history
– Body weight and type 2 diabetes
– High risk behavior for viral hepatitis
• Abnormal liver enzymes
• Use of simple methods to identify those with
fibrosis
Ability of abnormal ALT to detect chronic
hepatitis
Liver Biopsy
n
Patients with
abnormal ALT
(%) (95% CI)
Normal
Minimal chronic hepatitis
Mild chronic hepatitis
Moderate chronic hepatitis
35
47
42
9
0 [0-10]
64 [48-77]
59 [43-74]
89 [52-100]
Prati et al, Ann Intern Med, 2002; 137:1-9
Strategies to identify those with serious but
silent disease
•
•
•
•
AST: ALT > 1
Flip in AST: ALT ratio
Decreasing platelet count
Other non-invasive markers
– ELF score
– Fibrotest (Fibrosure)
– Fibroscan
– FIB4
– APRI
Past HCV Therapy (2001-2011)
PegIFN + RVN
100
90
80
70
60
% SVR
50
40
30
20
10
0
RVR
% Rx
cEVR
pEVR
10%
LVR
RVR
EVR
60%
GT 1 and 4
GT 2 and 3
Predictor of Response with PEG/R
• Favorable
–
–
–
–
–
–
–
–
–
Genotype 2 and 3
HCV RNA < 400,000 IU/ml
Mild fibrosis (F0-F2)
Non-African American
Age < 40
IL28B CC
Adherence
RVR
cEVR
• Unfavorable
–
–
–
–
–
–
–
–
–
–
–
Genotype 1
HCV RNA > 400,000 IU/ml
Advanced fibrosis (F3-F4)
African American
Age > 40
Steatosis
Insulin Resistance
Increased BMI
IL28B CT or TT
Dose reduction > 60%
Non-adherence
IL28-B POLYMORPHISM
IMPACT ON SVR
100
SVR (%)
80
60
40
20
0
TT
D Ge et al.
Nature 2009; 461:399-401.
TC
CC
IL28-B POLYMORPHISM AND SVR
IMPACT OF RACE AND ETHNICITY
100
Asians
SVR (%)
80
Caucasians
60
Hispanics
40
20
African Americans
0
30
40
50
60
70
80
IL28B CC HAPLOTYPE (%)
D Ge et al.
Nature 2009; 461:399-401.
90
100
HCV Polyprotein Processing
and Viral Protein Function
Complex
Inhibitor
McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12
Telaprevir in GT 1
ADVANCE and REALIZE trials
90
80
70
60
% SVR 50
T+P+R
P+R
40
30
20
10
0
Naïve
Relapser
Partial
Responder
Nul
Responder
Boceprevir in GT1
SPRINT 2 and RESPOND 2
80
70
60
50
%SVR 40
30
B+P+R
P+R
20
10
0
Naïve
Relapser
Partial
Responder
ADVANCE: Telaprevir with Response Guided Therapy in naïve
HCV-1
eRVR = HCV RNA(-) @W4,12: Yes 24W, No 48W
TPV 750 mg q8h; PEG-2a; WB RBV
P <0.0001
100
P < 0.0001
75
SVR (%)
80
69
60
44
40
20
0
PegIFN/RBV +
Placebo 48w
(n=361)
eRVR, %
Relapse, %
DC rash, T or Pl/all %
DC any AE,%
8
28
1/0
4
TPV 12w+
PegIFN/RBV RGT
(n=363)
58
9
7/1.4
7
TPV 8w+
PegIFN/RBV RGT
(n=364)
57
9
5/0.5
8
Jacobson I et al, NEJM 2011;364:2405-16
ILLUMINATE: Randomized trial of short vs. long
duration Rx after eRVR
GT 1, Tx naive
(N=540)
Peg2a /WB RBV/TPV x 12 wks
• met noninferiority criteria
• A truncated PEG/RBV/TPV
regimen preserves high
rates of SVR following
eRVR
Wk 4, 12 HCV RNA (-)
65.2% (n=352)
Randomize
+12 wks P/R
(n=162)
SVR
92%
+36 wks P/R
(n=160)
SVR
87%
Sherman K et al, AASLD 2010; abstract LB-2
HCV TREATMENT FOR NAIVE
Standard of Care- Present
Confirm HCV Present
Determine VL and Genotype
Evaluate Severity (Histology)
Evaluate Contraindications to Rx
Genotype 1 (or 4)
Genotype 2 or 3
DAA +Peg IFN alfa 2a or 2b + ribavirin
(wt. based) for 48 wks
RGT or Futility
Peg IFN alfa 2a or 2b + ribavirin
800 mg/qd for 24 wks
Early d/c
SVR
70-80%
SVR
65-75%
Pooled SVR
70-80%
Response Guided Therapy with Boceprevir
non-cirrhotic
HCV RNA
Undetectable
< 100 IU/mL
Undetectable
Lead in
BOC + P + R
PR
0
4
8
Detectable
12
eRVR, stop at week 28
24
< 100 IU/mL
28
36
48
Undetectable
No RVR
BOC + P + R
PR
0
4
8
12
Stop
PR
24
28
If HCV RNA > 100 IU/mL
36
48
Response Guided Therapy with Telaprevir
non-cirrhotic naïve or experienced relapsers
HCV RNA
Undetectable
Undetectable
T+P+R
0
Undetectable
P+R
4
8
Detectable
12
eRVR, stop at week 24
24
< 1000 IU/mL
28
36
48
Undetectable
No RVR
T+P+R
0
4
8
PR
12
Stop
24
28
If HCV RNA >1000 IU/mL
36
48
Treatment of Null Responders and
Cirrhotics
HCV RNA
Undetectable
< 100 IU/mL
Undetectable
Lead in
BOC + P + R
PR
0
4
8
12
24
36
48
HCV RNA
Undetectable
Undetectable
P+R
T+P+R
0
Undetectable
4
8
12
24
28
36
48
Drugs that are contraindicated
Telaprevir and Boceprevir
Effect
St. Johns Wort
May reduce virologic response
Rifampicin
May reduce virologic response
Ergot drug class
Potential for ergot toxicity
Lovastatin, simvastatin
Potential for myopathy
Sildinafil (in Tx of pulmonary HTN) Potential for PDE5 associated AE
Midazolam (oral)
Prolonged sedation
Triazolam
Prolonged sedation
Boceprevir
Phenobarbitol, Phenetoin,
Carbamezepine
May reduce virologic response
Oral contraceptives
(Drosperinone)
Potential for hyperkalemia
Monitoring HCV RNA
• Package inserts for TVR and BOC specific
different time points during therapy.
– TVR weeks 4, 12, and 24
– BOC weeks 8, 12 and 24
• Different labs use different assays.
• Different thresholds for using RGT.
– TVR week 4 1000 IU/mL
– BOC week 8 100 IU/mL
• Different thresholds for defining futility.
Stopping Rules
Telaprevir
Time point
HCV RNA
Action
Week 4 or 12
> 1000 IU/mL
Stop T/P/R
Week 24
Detectable
Stop P/R
Boceprevir
Time point
HCV RNA
Action
Week 8 or 12
> 100 IU/mL
Stop B/P/R
Week 24
Detectable
Stop P/R
Perceived Barriers to HCV Tx
• Patient Related
–
–
–
–
–
–
–
Side effects
Cost
Success rate
Duration
Stigmata of Tx
Experience of provider
Wants to wait for better Tx
• Government Related
– Restrictions to Tx
– Funds to Tx
– Lack of promotion
McGowan et al. Hepatology 2013;57:1325-1332
• Provider Related
–
–
–
–
Lack of experience
Lack of office infrastructure
Poor reimbursement
Lack of referral to experienced
provider
• Payer Related
–
–
–
–
Cost of meds
Restricting coverage or providers
Excessive paper work
Excessive requirements of testing
Caution in cirrhosis
CUPIC
TREATMENT EXPERIENCED Genotype
1- Cirrhotics
• National Registry-France
• N= 674 (295 TVR; 190 BOC)
• Patients treated with
DAA/PegIFN/riba by choice of
clinician
• All patients Child A
• Results
–
–
–
–
–
–
–
SAE 51-54%
Death 1.6% (BOC) 2.4% (TVR)
Infection 2.5-8.8%
Hepatic decompensation 5%
Epo use 57-62%
Transfusion 14-18%
Predictors of Poor Outcome
•
•
Alb<3.5
Plts < 100,000
Fontaine EASL 2013 #60
SVR 12
100
90
80
70
60
50
40
30
20
10
0
40
41
TVR
BOC
Issues Limiting Current
DAA/PegIFN/Ribavirin Treatment of HCV
•
•
•
•
•
•
Inexperience of treaters
Psychiatric complications
Anemia
Neutropenia
Thrombocytopenia
Dermatologic events
TREAT OR WAIT?
•
•
•
•
What is coming?
When?
Interferon Free or With Interferon?
What Will It Cost?
Two Parallel Paths in Development
• PEG-IFN/RBV + add-ons:
– Triple: PI, NS5A, Nuc, NNPI, CypA,
– Quad: PI+Nuc, PI+NS5A, PI+NNPI
– Interferon backbone difficult/intolerable
for some pts
• Interferon-free combination therapy:
– Strategies: PI+Nuc, PI+NS5A, PI+N5B Nonnuc Poly Inhib, Nuc+Nuc
– With and without RBV
HCV TREATMENT LANDSCAPE
DAAs in development
DAA Combinations
Preclinical
Gilead
Pharmasset
Others
Cyclophilin. I
BI
Phase I
Japon Tonbacco
R0622 (Roche)
Medivir (Tibotec)
Phase II
BI
Vitamine D
Vertex
Nitazoxamide
ROCHE
(Romark)
BMS
Abbott
Celgosivir
IFN λ
Bavituximab
(Zymogen/Novartis)
IDX 184
(Idenix)
Phase III
R7128
(Roche)
Filed
Debio025/ Taribavirin
NIM811
(Valeant)
(Novartis)
BMS 790052
Boceprevir
(BMS)
(MSD)
AZD-7295 ABT267
(ABT)
(AZN)
Sofosubir
Gilead)
Silibinine
SCY-835
ACH-2928
(Acillion)
PPI-461
MSD
Idenix719
NS5A inhibitors
Telaprevir
(Vertex/JJ)
GS-5885
TMC-435
(Tibotec/JJ)
BI201335
(BI)
Vertex
ITMN191/R7227
BMS 824393
MK7009(Roche/Intermune)
PPI-1301
(MSD)
(BMS)
GSK
ABT450
EDP-239
(ABT)
VBY-376
GS9256
(Enanta)
IDX 077
MK5172 (Gilead)
(Idenix)
VX-985 (MSD)
(Vertex)
IDX 079
VX-813
(Idenix) (Vertex)
AVL-181
(Avila)
Nucleotide NS5B
Polymerase
Inhibitors
GLS9393 (GSK)
INX 189
(Inhibitrex)
BMS791325
Filibuvir (BMS)
(PFE)
GS9190
(Gilead)
Vx222
ANA598 (Vertex)
AVL-192
(Avila)
NS3/4A Protease inhibitors
Biocryst
IDX 375
(Idenix)
RG7348
(Roche)
TMC 647055
(Tibotec)
A837093
(Abbott)
VX-916
BI201127 (Anadys)
(BI)
ABT333
ABT072
(ABT)
BMS650032
(BMS)
GS9451
(Gilead)
Nucleoside
NS5B
Polymerase
Inhibitors
ACH2684
(Achillion)
VX-759
Non Nuc NS5B
Polymerase inhibitors
Adapted from Bourliere M. HepDart 2011
NEUTRINO
Sofasbuvir (NS5B Poly Inhib) + Peg/RVN x 12 weeks
GT 1 (90%),4,5,6 Tx Naive
100
90
80
70
GT 1
No Cx
Cx
CC
non-CC
60
%
50
40
30
20
10
0
SVR 12
Lawitz NEJM 2013
N=327
MK 5172 (PI) 12 w + Peg/RVN RGT
GT1, Tx naïve, no Cx
100
90
80
70
60
%
SVR24
RGT 24
RGT 48
50
40
30
20
10
0
MK 100
Manns EASL 2013
MK 200
MK 400
MK 800
BOC+P/R
Faldaprevir + P/R vs. P/R RGT
NS 3/4 PI (BI 201235)
90
80
70
60
50
F(120)+P/R
F(240)+P/R
P/R
40
30
20
10
0
SVR
EASL 2013
GT1A
GT1B
CC
CT/TT
Ledipasvir (GS 5885) + GS 9451
NS5A Complex Inhibitor + Protease Inhibitor
GT 1 Tx Naïve, IL28B CC, no Cirrhosis
%
100
90
80
70
60
50
40
30
20
10
0
LDV + PI + P/R 6w
LDV + PI + P/R 12 w
P/R 24/48 w
RVR
EASL 2013
SVR12
L/PI/P/R
6w
L/PI/P/R
12w
What about interferon free?
Holy Grail
SOFOSBUVIR (GS 7977 NS5B Nuc Pol Inhib)
Genotypes 1/2,3
100
90
80
70
60
50
40
30
20
10
0
100
100
Gane et al., NEJM, 2013
Genotype 2/3
100
100
100
Genotype 1
84
60
10
FISSION
Sofosbuvir/RVN (12w) vs. PEG/RVN (24w)
GT2/3 Treatment Naive
Lawitz et al. NEJM 2013
FUSION
GT2/3 Tx Experienced
Sofosbuvir + RVN (12 vs. 16 weeks)
%
100
90
80
70
60
50
40
30
20
10
0
Sofosbuvir+RVN 12
Sofosbuvir+RVN 16
EOT
SVR12 GT2 no GT 2 cx GT3 no GT 3 cx
cx
cx
Jacobson NEJM 2013
POSITRON
Sofosbuvir + RVN x 12 weeks
GT 2/3 IFN intolerant/ineligible
100
90
80
70
%
60
50
40
30
20
10
0
SVR12
Jacobson NEJM 2013
GT 2 no Cx
GT 2 Cx
GT 3 no Cx
GT 3 Cx
N=207
AI443-014 TRIAL
TREATMENT NAÏVE Genotype 1
• Randomized Triple Drug
Regimen
• N= 32
– Daclatasvir (NS5A) +
Asunaprevir (NS3/4)+ BMS791325
– 12 vs. 24 weeks
• Results
– Safe and well tolerated
Everson et al., HEPATOLOGY, LB-3
SVR 4
SOUND-C2
TREATMENT NAÏVE Genotype 1
Including cirrhotics
SVR 12- ITT
• Randomized Phase IIb
• N= 362 in 5 arms
– 1 Faldaprevir +BI 207127 (tid) + R for
16 weeks
– 2 Faldaprevir + BI 207127 (tid) + R for
28 weeks
– 3 Faldaprevir + BI 207127 (tid) + R for
40 weeks
– 4 Fal + 127 (bid) + R 28 weeks
– 5 Fal + 127 (tid) 28 weeks (R free)
• Results
–
–
Bilirubin elevations frequent (13-41%)
Cirrhosis not a predictor of response
Zeuzem et al., HEPATOLOGY, Abs 232
Faldaprevir NS3/4 PI
BI 207127 NS5B NNI
AVIATOR
TREATMENT NAÏVE/EXPERIENCED
Genotype 1 (PI/NS5A/Non-Nuc)
SVR 12- ITT
• Randomized Phase IIb
– N= 358 Naïve- 6 Arms
– N= 90 Null Experienced- 3
Arms
– Duration 8, 12 (or 24 weeks n/s)
•
•
•
•
•
1ABT450/ritonavir/ABT267/ABT333/riba- 8
2ABT450/ritonavir/ABT333/riba-12
3ABT450/ritonavir/AVT267/riba-12
4ABT450/ritonavir/ABT267/ABT333-12
5ABT450/ritonavir/ABT267/ABT333/riba-12
– Previous Null Responders
•
•
6ABT450/ritonavir/AVT267/riba-12
7ABT450/ritonavir/ABT267/ABT333/riba-12
• Results
–
Generally safe/well tolerated
Kowdley et al., HEPATOLOGY, LB-1
ABT450/r NS3/4 Boosted PI
ABT267 NS5A Inhibitor
ABT333 NS5B NNI
AVIATOR (4 oral agents)
SVR 24
100
90
80
70
%
60
12 Week
24 Week
50
40
30
20
10
0
Naïve
Kowdley EASL 2013
Experienced
Evolution Scenario
Sustained Virologic Response in G1 (SVR)
HCV Therapy
Estimated
85-95%
100
90
Estimated
65-70%
80
70
+
Pol Inhibitor
?100%
All Oral
Therapy for Most
+
60
+
42-50%
50
Pol Inhibitor
35%
40
or
New Prot Inhibitor
+
ribavirin
30
20
10%
10
ribavirin
+
+
PEG-IFN
Prot Inhibitor
+/-
All Oral for Some
0
1st Stage
2nd Stage
3rd Stage
1989-1998
1998-2001
2001- 2011
4th Stage
2011-Present
5th Stage
2014-2016
6th Stage
2016+
New
Combinations
Peg
RVN
DAA
New
DAAs
Resistance
Genetic
tests
Increasing Complexity
Of HCV Management
RGT
EMR
E-scribe
Cost
Compliance
Identifying Candidates For Triple
Therapy 2013
Host factors
Treatment regimen
Age, gender, race obesity,
co-morbidities
Genetic factors
(IL28B and ITPA)
PEG-IFN
Ribavirin
DAA
Factors to Consider In
Treatment Decisions
Disease features
Viral factors
Fibrosis, steatosis,
co-infection
(HBV, HIV)
Genotype / Subtype
Quasispecies / Resistance
Viral load
SVR represents a cure and improves absolute
survival of infected individuals
• Impact of SVR on the health of the population:
– Koh et al: NIH experience, SVR from 1984 stable
in 100/103 subjects with no liver related mortality,
– Backus et al: > 21000 US veterans studied, SVR
improved absolute mortality,
SVR Reduces Mortality
Figure 1 Cumulative mortality for nonresponders (no SVR) and responders (SVR) with number at risk for all genotypes
Lisa I. Backus , Derek B. Boothroyd , Barbara R. Phillips , Pamela Belperio , James Halloran , Larry A. Mole
A Sustained Virologic Response Reduces Risk of All-Cause Mortality in Patients With Hepatitis C
Clinical Gastroenterology and Hepatology Volume 9, Issue 6 2011 509 - 516.e1
SVR decreases risk of type II diabetes mellitus
Romero Gomez et al, J Hepatol, 2008, 48:721-727
Treatment of HCV
• Past (2001-2010) PEG + RVN
– GT 1: 40% (48 weeks)
– GT 2/3: 70-80% (24 weeks)
• Present (2011-2013) PEG + RVN + TVP/BOC
– GT 1: 65-75% (24-48 weeks with RGT)
– GT2/3: 70-80% (24 weeks)
• Future (2014 and beyond) Multiple DAA +/-RVN
(?PEG)
– GT 1: 80-95%
– GT 2 > 3: 80-95%
Conclusions
• HCV is now more curable than ever (>80%)
• Standard dose ribavirin and PEG interferon will remain as
backbone of therapy for next few (2) years
• DAA
– Combining newer antiviral agents (NS 3/4A PI, NS5B NPI, NS5A)
Complex Inhibitor with few side effects and qd dosing
– Combining agents of different classes to avoid interferon and/or
ribavirin
– GT 3 may require more than type 2 to achieve similar SVR
• Frequent HCV RNA testing (monthly) to detect resistance
• SVR reduces morality and development of diabetes
The Future
0
PEG/RBV
10
PI+PEG+RBV
PI2+PEG+RBV
20
30
40
%
50
DAA1 + DAA2 + RBV
60
70
80
90
100
2011
2012
2013
2014
2015
2016
2017
2018
2019
Discovery Comes to the Prepared Mind
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ELECTRON
TREATMENT NAÏVE Genotype 1
• Sofosbuvir (GS-7977)
• N= 50
• 2 arms in TN G1
– SOF + RBV
– SOF + GS-5885 (NS5A Inhib.)
• Duration= 12 weeks
• Well tolerated
– AEs mainly due to known
ribavirin effects
Gane et al, HEPATOLOGY
SVR4