hepatitis c: boomers at risk diagnosis and treatment outcomes richard k. sterling, md, msc, facp,...
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Hepatitis C: Boomers at RiskDiagnosis and Treatment Outcomes
Richard K. Sterling, MD, MSc, FACP, FACGVCU Hepatology Professor of Medicine
Chief, Section of HepatologyFellowship Director, Transplant Hepatology
Virginia Commonwealth UniversityRichmond, 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
ChronicLiver disease cirrhosis
Liver failure
Other organsStop working
Livercancer
DEATH
LIVERTRANSPLANT~ 8-10 million
Americans affected
Global epidemiology of hepatitis C virus infection: New estimates of age specific antibody to HCV ‐seroprevalence
HepatologyVolume 57, Issue 4, pages 1333-1342, 4 FEB 2013 DOI: 10.1002/hep.26141http://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
56
46
16 1511 10
75
0
10
20
30
40
50
60
pe
rce
nt
Bajaj et al
N=104 cirrhotic subjects
Veterans and non-vets equally affected
MELD and HE drives caregiver burden
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 ofrisk factors (Edlin BR. Hepatology 2013;57:1644-1650)
Impact of timing and prioritzation for treatment on cost effectiveness of birth cohort screening
McEwan et al, Hepatology. 2013 Feb 6. doi: 10.1002/hep.26304.
Age
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 HCVHCV Ab +
HCV RNA and Genotype
Repeat HCV RNA
Resolved HCV
Liver EnzymesCBC with Plt
HBV sAg/sAb/cAbHAV IgG
HIVANA
Assess severity of disease(liver biopsy or non-invasive test)
Assess for treatment(May require referral)
Avoid alcoholCounsel on household and sex
Vaccinate for HAV and HBVAvoid raw shell fish
+ -
-
+
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)
NormalMinimal chronic hepatitisMild chronic hepatitisModerate chronic hepatitis
3547429
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
0
10
20
30
40
50
60
70
80
90
100
RVR cEVR pEVR LVR RVR EVR
GT 1 and 4 GT 2 and 3
% SVR
% Rx 10% 60%
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 POLYMORPHISMIMPACT ON SVR
0
20
40
60
80
100
TT TC CC
SV
R (
%)
D Ge et al.Nature 2009; 461:399-401.
IL28-B POLYMORPHISM AND SVRIMPACT OF RACE AND ETHNICITY
0
20
40
60
80
100
30 40 50 60 70 80 90 100
IL28B CC HAPLOTYPE (%)
SV
R (
%)
African Americans
Hispanics
Caucasians
Asians
D Ge et al.Nature 2009; 461:399-401.
HCV Polyprotein Processing and Viral Protein Function
McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12
ComplexInhibitor
Telaprevir in GT 1ADVANCE and REALIZE trials
0
10
20
30
40
50
60
70
80
90
Naïve Relapser PartialResponder
NulResponder
T + P + R
P + R
% SVR
Boceprevir in GT1SPRINT 2 and RESPOND 2
0
10
20
30
40
50
60
70
80
Naïve Relapser PartialResponder
B + P + R
P + R
%SVR
ADVANCE: Telaprevir with Response Guided Therapy in naïve HCV-1eRVR = HCV RNA(-) @W4,12: Yes 24W, No 48W
TPV 750 mg q8h; PEG-2a; WB RBV
0
20
40
60
80
100
SVR
(%)
44
6975
PegIFN/RBV +Placebo 48w (n=361)
TPV 8w+ PegIFN/RBV RGT (n=364)
TPV 12w+ PegIFN/RBV RGT (n=363)
P <0.0001 P < 0.0001
Jacobson I et al, NEJM 2011;364:2405-16
828 1/04
589
7/1.47
579
5/0.58
eRVR, %
Relapse, %
DC rash, T or Pl/all %
DC any AE,%
ILLUMINATE: Randomized trial of short vs. long duration Rx after eRVR
• met noninferiority criteria• A truncated PEG/RBV/TPV
regimen preserves high rates of SVR following eRVR
Sherman K et al, AASLD 2010; abstract LB-2
Peg2a /WB RBV/TPV x 12 wks
GT 1, Tx naive (N=540)
Wk 4, 12 HCV RNA (-)65.2% (n=352)
+12 wks P/R(n=162)
+36 wks P/R(n=160)
Randomize
SVR 87%
SVR 92%
HCV TREATMENT FOR NAIVEStandard of Care- Present
Genotype 1 (or 4) Genotype 2 or 3DAA +Peg IFN alfa 2a or 2b + ribavirin
(wt. based) for 48 wks Peg IFN alfa 2a or 2b + ribavirin
800 mg/qd for 24 wks
RGT or Futility Early d/c
SVR65-75%
SVR70-80%
Pooled SVR70-80%
Confirm HCV PresentDetermine VL and GenotypeEvaluate Severity (Histology)
Evaluate Contraindications to Rx
Response Guided Therapy with Boceprevirnon-cirrhotic
PR BOC + P + R
0 4 8 12 24 28 36 48
Undetectable < 100 IU/mL Undetectable
HCV RNA
eRVR, stop at week 28
PR BOC + P + R
0 4 8 12 24 28 36 48
Detectable < 100 IU/mL Undetectable
PR
No RVR
Lead in
Stop If HCV RNA > 100 IU/mL
Response Guided Therapy with Telaprevirnon-cirrhotic naïve or experienced relapsers
0 4 8 12 24 28 36 48
Undetectable Undetectable Undetectable
HCV RNA
eRVR, stop at week 24
0 4 8 12 24 28 36 48
Detectable < 1000 IU/mL Undetectable
PR
No RVR
T + P + R P+R
T + P + R
Stop If HCV RNA >1000 IU/mL
Treatment of Null Responders and Cirrhotics
PR BOC + P + R
Undetectable < 100 IU/mL Undetectable
HCV RNA
Lead in
0 4 8 12 24 36 48
0 4 8 12 24 28 36 48
Undetectable Undetectable Undetectable
HCV RNA
T + P + R P+R
Drugs that are contraindicatedTelaprevir 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
• Provider Related– Lack of experience– Lack of office infrastructure– Poor reimbursement– Lack of referral to experienced
provider
• Government Related– Restrictions to Tx– Funds to Tx– Lack of promotion
• Payer Related– Cost of meds– Restricting coverage or providers– Excessive paper work– Excessive requirements of testing
McGowan et al. Hepatology 2013;57:1325-1332
Caution in cirrhosisCUPIC
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
SVR 12
40 41
0102030405060708090
100
TVR BOC
Fontaine EASL 2013 #60
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 Non-
nuc Poly Inhib, Nuc+Nuc– With and without RBV
Preclinical
Phase I
Phase II
Phase III
Filed
Boceprevir(MSD)
Telaprevir(Vertex/JJ)
TMC-435(Tibotec/JJ)
MK7009(MSD)
ITMN191/R7227 (Roche/Intermune)
BI201335(BI)
BMS650032(BMS)
GS9256(Gilead)MK5172
(MSD)
ABT450(ABT)
ACH2684(Achillion)
BMS 790052(BMS)
AZD-7295(AZN)
BMS 824393(BMS)PPI-1301
EDP-239(Enanta)
GSK
Vertex
Idenix719MSD
Taribavirin(Valeant)
IFN λ(Zymogen/Novartis)
Debio025/ NIM811
(Novartis)
Nitazoxamide(Romark)
Silibinine
Vitamine D
BMS
BI
ROCHE
Gilead
R7128(Roche)
SofosubirGilead)
BIJapon Tonbacco
R0622 (Roche)Medivir (Tibotec)
GLS9393 (GSK)
BiocrystINX 189
(Inhibitrex)
BMS791325 (BMS)Filibuvir
(PFE)GS9190 (Gilead)
ANA598 (Anadys)BI201127
(BI)
Vx222 (Vertex)
ABT333ABT072 (ABT)
IDX 375 (Idenix)
IDX 184 (Idenix)
SCY-835
PPI-461
VBY-376
VX-985(Vertex)
VX-813(Vertex)
GS9451(Gilead)
RG7348(Roche)
TMC 647055 (Tibotec)
A837093(Abbott)
VX-916VX-759
CelgosivirBavituximab
HCV TREATMENT LANDSCAPEDAAs in development
AVL-181(Avila)
AVL-192(Avila)
ACH-2928(Acillion)
GS-5885
Vertex
Abbott
Pharmasset
Nucleoside NS5B
Polymerase Inhibitors
Nucleotide NS5B Polymerase Inhibitors
Non Nuc NS5BPolymerase inhibitors
NS3/4A Protease inhibitors
NS5A inhibitors
DAA Combinations
Others
Cyclophilin. I
IDX 077 (Idenix)
IDX 079 (Idenix)
ABT267(ABT)
Adapted from Bourliere M. HepDart 2011
NEUTRINOSofasbuvir (NS5B Poly Inhib) + Peg/RVN x 12 weeks
GT 1 (90%),4,5,6 Tx Naive
0
10
20
30
40
50
60
70
80
90
100
SVR 12
GT 1No CxCxCCnon-CC
%
Lawitz NEJM 2013 N=327
MK 5172 (PI) 12 w + Peg/RVN RGTGT1, Tx naïve, no Cx
0
10
20
30
40
50
60
70
80
90
100
MK 100 MK 200 MK 400 MK 800 BOC+P/R
SVR24RGT 24RGT 48
Manns EASL 2013
%
Faldaprevir + P/R vs. P/R RGTNS 3/4 PI (BI 201235)
0
10
20
30
40
50
60
70
80
90
SVR GT1A GT1B CC CT/TT
F(120)+P/RF(240)+P/RP/R
EASL 2013
Ledipasvir (GS 5885) + GS 9451NS5A Complex Inhibitor + Protease Inhibitor
GT 1 Tx Naïve, IL28B CC, no Cirrhosis
0102030405060708090
100
RVR SVR12 L/PI/P/R6w
L/PI/P/R12w
LDV + PI + P/R 6wLDV + PI + P/R 12 wP/R 24/48 w
%
EASL 2013
What about interferon free?
Holy Grail
SOFOSBUVIR (GS 7977 NS5B Nuc Pol Inhib)Genotypes 1/2,3
100 100 100 100
60
100
10
84
0102030405060708090
100
Gane et al., NEJM, 2013
Genotype 1Genotype 2/3
FISSIONSofosbuvir/RVN (12w) vs. PEG/RVN (24w)
GT2/3 Treatment Naive
Lawitz et al. NEJM 2013
FUSIONGT2/3 Tx Experienced
Sofosbuvir + RVN (12 vs. 16 weeks)
0102030405060708090
100
EOT SVR12 GT2 nocx
GT 2 cx GT3 nocx
GT 3 cx
Sofosbuvir+RVN 12Sofosbuvir+RVN 16
Jacobson NEJM 2013
%
POSITRONSofosbuvir + RVN x 12 weeks
GT 2/3 IFN intolerant/ineligible
0
10
20
30
40
50
60
70
80
90
100
SVR12 GT 2 no Cx GT 2 Cx GT 3 no Cx GT 3 Cx
%
Jacobson NEJM 2013 N=207
AI443-014 TRIAL
TREATMENT NAÏVE Genotype 1
• Randomized Triple Drug Regimen
• N= 32– Daclatasvir (NS5A) +
Asunaprevir (NS3/4)+ BMS-791325
– 12 vs. 24 weeks
• Results– Safe and well tolerated
SVR 4
Everson et al., HEPATOLOGY, LB-3
SOUND-C2TREATMENT NAÏVE Genotype 1Including cirrhotics
• 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
SVR 12- ITT
Zeuzem et al., HEPATOLOGY, Abs 232Faldaprevir NS3/4 PIBI 207127 NS5B NNI
AVIATORTREATMENT NAÏVE/EXPERIENCED Genotype 1 (PI/NS5A/Non-Nuc)
• 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
SVR 12- ITT
Kowdley et al., HEPATOLOGY, LB-1ABT450/r NS3/4 Boosted PI ABT333 NS5B NNIABT267 NS5A Inhibitor
AVIATOR (4 oral agents)SVR 24
0
10
20
30
40
50
60
70
80
90
100
Naïve Experienced
12 Week24 Week
%
Kowdley EASL 2013
Evolution Scenario HCV Therapy
PEG-IFN
+
Pol Inhibitor
+/-ribavirin
++
or
Prot Inhibitor
+
Pol Inhibitor
+
New Prot Inhibitor
+
ribavirin
All Oral
Therapy for Most
1989-1998 1998-2001 2001- 2011 2011-Present 2014-2016 2016+
All Oral for Some
10%
35%
42-50%
Estimated65-70%
Estimated85-95%
0
10
20
30
40
50
60
70
80
90
100
1st Stage 2nd Stage 3rd Stage 4th Stage 5th Stage 6th Stage
Sust
aine
d Vi
rolo
gic
Resp
onse
in G
1 (S
VR)
?100%
Increasing ComplexityOf HCV Management
PegRVN
DAA
Resistance
RGT
CostComplianceE-scribe
Genetic tests
EMR
NewDAAs
NewCombinations
Factors to Consider In Treatment Decisions
Treatment regimen
PEG-IFNRibavirinDAA
Host factors
Age, gender, race obesity, co-morbiditiesGenetic factors (IL28B and ITPA)
Disease features
Fibrosis, steatosis, co-infection (HBV, HIV)
Viral factors
Genotype / SubtypeQuasispecies / ResistanceViral load
Identifying Candidates For Triple Therapy 2013
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,
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 Reduces Mortality
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
PI+PEG+RBV PI2+PEG+RBV
DAA1 + DAA2 + RBV
QUAD: PEG-l/RBV/DAA1/DAA2 (???)
2011 2012 2013 2014 2015 2016 2017 2018 2019
PEG/RBV 0
10
20
30
40
50
60
70
80
90
100
%
Discovery Comes to the Prepared Mind
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
SVR4
Gane et al, HEPATOLOGY