Brainstorming with the Experts Practical Approaches to the Complex World of HCV Supported by an...

Brainstorming with the Experts

Practical Approaches tothe Complex World of HCV

Supported by an educational grant from

Reducing the Health BurdenReducing the Health Burdenof HCV: Moving from Efficacy of HCV: Moving from Efficacy

to Effectivenessto Effectiveness

Hashem B. El-Serag, MD, MPHHashem B. El-Serag, MD, MPHProfessor of MedicineProfessor of Medicine

Department of GastroenterologyDepartment of GastroenterologyBaylor College of Medicine Baylor College of Medicine

and Michael E. DeBakey VA Medical Center and Michael E. DeBakey VA Medical CenterHouston, TexasHouston, Texas

National Institutes of Health. Hepatology. 2002;36(5 suppl 1):S3-20.

Hepatitis C Infection FactsHepatitis C Infection FactsUnited StatesUnited States

HCV is a leading cause of liver diseaseHCV is a leading cause of liver disease HCV accounts for an estimated 1/3 of HCV accounts for an estimated 1/3 of

hepatocellular carcinoma (HCC) cases hepatocellular carcinoma (HCC) cases HCV is the #1 reason for liver transplantHCV is the #1 reason for liver transplant Approximately 10,000 to 12,000 deaths Approximately 10,000 to 12,000 deaths

are attributed to HCV infection annuallyare attributed to HCV infection annually– Based on death certificates; likely Based on death certificates; likely

underestimatesunderestimates

Burden of HCV DiseaseBurden of HCV Disease

FrequencyFrequency– Prevalence (pool of existing cases)Prevalence (pool of existing cases)

– Incidence (occurrence of new cases)Incidence (occurrence of new cases)

Impact on Impact on – Longevity (premature death)Longevity (premature death)

– Morbidity (in- and outpatient care, quality of life)Morbidity (in- and outpatient care, quality of life)

– Finance (direct and indirect costs to society)Finance (direct and indirect costs to society)

US Prevalence of HCV InfectionNational Health and Nutrition Examination Survey

(NHANES), 1999–2002

Armstrong GL, et al. Ann Intern Med. 2006;144:705-714. Graphic courtesy of Dr. H.B. El-Serag.

0 1 2 3 4 5

Genotype

HCV RNA

Anti-HCV

Million

4.1

3.2

G2/3: 22%G1: 74%

0%

1%

2%

1960 1970 1980 1990 2000 2010 2020 2030

0

50

100

150

1960 1970 1980 1990 2000 2010 2020 2030

Infected 20+ years

Overall prevalence

Past and Future (Estimated) US IncidencePast and Future (Estimated) US Incidenceand Prevalence of HCV Infectionand Prevalence of HCV Infection

Graphic courtesy of Centers for Disease Control and Prevention.

Decline among IDUs

Overall incidence

Seropositive Seropositive withwith

no prior no prior testing (14%)testing (14%)Seropositive and Seropositive and

prior testing (86%)prior testing (86%)

4000 random sample 4000 random sample from 3.2 million veterans from 3.2 million veterans seen at 145 VA facilities seen at 145 VA facilities with research programswith research programs

HCV serology obtained HCV serology obtained on 1288/4000on 1288/4000

52/1288 anti-HCV+52/1288 anti-HCV+ 39/52 HCV RNA+39/52 HCV RNA+

Unaware of Unaware of diagnosis diagnosis

(46%)(46%)Aware of Aware of

diagnosis (54%)diagnosis (54%)

Estimated Chronic HCV Patient Status Estimated Chronic HCV Patient Status in the US Veteran Populationin the US Veteran Population

Dominitz JA, et al. Hepatology. 2005;41:88.

HCV InfectionHCV Infection

Chronic Hepatitis

Cirrhosis

HCC 1%1%

(1%–3%/y)(1%–3%/y)

100%100%

25 y25 y

90%90%(60%–95%/y)(60%–95%/y)

15%15%(10%–30%/y)(10%–30%/y)

HCV to HCC PyramidHCV to HCC Pyramid

Graphic courtesy of Dr. H.B. El-Serag.

-2 -1.5 -1 -0.5 0 0.5 1 1.5 2

All Other Cancers (Average)

LiverThyroid

Esophagus

Lung & Bronchus (Female)

Testis

Corpus & Uterus, NOS

Trends in US Cancer Mortality RatesTrends in US Cancer Mortality Rates

Annual Percent Change (1994–2003)NOS = not otherwise specified.National Cancer Institute. Seer Summary Figures and Tables. Available at: http://seer.cancer.gov/csr/1975_2003/results_merged/topic_graph_trends.pdf. Accessed on October 17, 2008.

Liver Cancer Has the Fastest Growing Liver Cancer Has the Fastest Growing Death Rate in the United StatesDeath Rate in the United States

0.990

0.995

1.000

0 2 4 6 8Years of Follow -Up

HCV and Non-Hodgkin’s LymphomaHCV and Non-Hodgkin’s Lymphomain US Veteransin US Veterans

n = 1369

HR 1.28 (95%CI 1.12–1.45)a

HCV+

HCV-

Giordano TP, et al. JAMA. 2007;297:2010-2017. Graphic courtesy of Dr. H.B. El-Serag.

aHazard ratios adjusted for gender, age, race, era of military service, and VA visits.

• Retrospective cohort studyRetrospective cohort study• 146,394 HCV+ and HCV+ and 572,293 HCV- • US veterans using VA data (1997–2004)US veterans using VA data (1997–2004)

HCV and Intrahepatic HCV and Intrahepatic Cholangiocarcinoma in US VeteransCholangiocarcinoma in US Veterans

With permission from El-Serag HB, et al. Hepatology. 2008. In press.

HCV PrevalenceHCV Prevalence HCC MortalityHCC Mortality

US1960sLowLow

HighHigh

LowLow

HighHigh

Japanese

1920s

European1940s

Association Between HCV Prevalence Association Between HCV Prevalence and HCC Mortalityand HCC Mortality

Schematic ofSchematic of 3 Worldwide Patterns3 Worldwide Patterns

Tanaka Y, et al. Gastroenterology. 2006;130:703-714.

Davis GL, et al. Liver Transpl. 2003;9:331-338.

Estimated Future HCV Disease Burden Estimated Future HCV Disease Burden 2000–20302000–2030

Assuming No CureAssuming No Cure Cirrhosis cases will almost double Cirrhosis cases will almost double

(472,103 to 879,747)(472,103 to 879,747) Decompensated cirrhosis cases will more Decompensated cirrhosis cases will more

than double (65,294 to 146,408)than double (65,294 to 146,408) HCC cases will almost double HCC cases will almost double

(7271 to 13,390)(7271 to 13,390) Liver-related deaths will more than triple Liver-related deaths will more than triple

(13,000/year to 39,875/year)(13,000/year to 39,875/year)

Efficacy and EffectivenessEfficacy and Effectiveness

Efficacy = Efficacy = utility of a medical treatment (drug or utility of a medical treatment (drug or device) evaluated under optimal conditionsdevice) evaluated under optimal conditions

Highly selected patient populationHighly selected patient population Best trained physiciansBest trained physicians Academic centers of excellenceAcademic centers of excellence

Effectiveness = Effectiveness = utility of a medical treatment in utility of a medical treatment in routine clinical settings, ie, real liferoutine clinical settings, ie, real life

Unselected patient populationUnselected patient population All physiciansAll physicians Private practicePrivate practice

Efficacy x Access x Correct Efficacy x Access x Correct Diagnosis x Recommendation Diagnosis x Recommendation

x Acceptance x Adherencex Acceptance x Adherence

With permission from El-Serag HB. Gastroenterology. 2007;132:8.

Treatment of HCVTreatment of HCV

Efficacy in Clinical Trials and Research

Centers

Effectiveness in Community Practice

Efficacy and EffectivenessEfficacy and EffectivenessA Demonstration of the Multiplicative A Demonstration of the Multiplicative

Effect of FactorsEffect of Factors

Efficacy of Rx Efficacy of Rx “X”“X”

60%60%

AccessAccess x 80%x 80%

Correct Correct diagnosisdiagnosis

x 85%x 85%

RecommendRecommend x 85%x 85%

AcceptanceAcceptance x 85%x 85%

AdherenceAdherence x 70%x 70%

Effectiveness of Effectiveness of Rx “X”Rx “X”

= 21%= 21%

El-Serag HB. Gastroenterology. 2007;132:8.


80%80%



x 85%x 85%




Effectiveness of Effectiveness of Rx “Y”Rx “Y”

= 28%= 28%


60%60%



x 90%x 90%




Effectiveness of Effectiveness of Rx “X” modifiedRx “X” modified

= 32%= 32%

Example 1: Rx “X”

Example 2: Rx “Y”

Example 3: Rx “X” Modified

ConclusionsConclusions

Burden of HCV is increasingBurden of HCV is increasing Although HCV incidence has declined,Although HCV incidence has declined,

the prevalence remains highthe prevalence remains high HCC incidence is increasingHCC incidence is increasing

– Lymphoma, cholangiocarcinomaLymphoma, cholangiocarcinoma

Treatment efficacy in clinical trials and Treatment efficacy in clinical trials and research settings is relatively high, but research settings is relatively high, but effectiveness in community practiceeffectiveness in community practiceis lowis low

Why Is Standard of CareWhy Is Standard of CareFalling Short?Falling Short?

Zobair M. Younossi, MD, MPHZobair M. Younossi, MD, MPHExecutive Director of Research, Inova Health SystemExecutive Director of Research, Inova Health System

Executive Director, Center for Liver Diseases, Executive Director, Center for Liver Diseases,Inova Fairfax HospitalInova Fairfax Hospital

Professor of Medicine, VCU-Inova CampusProfessor of Medicine, VCU-Inova CampusAffiliate Professor of Biomedical SciencesAffiliate Professor of Biomedical Sciences

George Mason UniversityGeorge Mason University Falls Church, Virginia Falls Church, Virginia

Possible Reasons for NonresponsePossible Reasons for Nonresponse

• Dose reductionDose reduction

• Active psychiatric issuesActive psychiatric issues

• Side effectsSide effects

• Patient’s beliefs & social supportPatient’s beliefs & social support

• Provider experienceProvider experience

Treatment FactorsTreatment Factors

Host FactorsHost Factors

Virus FactorsVirus Factors

• CirrhosisCirrhosis

• Poor responsiveness to treatmentPoor responsiveness to treatment

• Racial and ethnic differencesRacial and ethnic differences

• Variability in immune responsesVariability in immune responses

• Obesity and insulin resistanceObesity and insulin resistance

• GenotypeGenotype

• Viral loadViral load

• Sequence variabilitySequence variability

Younossi ZM, et al. J Hepatol. 2008;48:S285.

Can We Predict Nonresponse with Can We Predict Nonresponse with Gene Expression Profiling?Gene Expression Profiling?

68 HCV-infected patients (30 treatment-naive) 68 HCV-infected patients (30 treatment-naive) treated with PEG IFN treated with PEG IFN -2a or -2a or -2b plus RBV-2b plus RBV

Blood samples collected prior to treatment and on Blood samples collected prior to treatment and on days 1, 7, 28, and 56 posttreatmentdays 1, 7, 28, and 56 posttreatment

Virologic response data collectedVirologic response data collected From the peripheral blood cells, total RNA From the peripheral blood cells, total RNA

extracted, quantified, and used for 1-step RT-PCR extracted, quantified, and used for 1-step RT-PCR to profile 154 mRNAsto profile 154 mRNAs

Multiple regression and stepwise selection Multiple regression and stepwise selection performedperformed– Differences in gene expression assessed at different Differences in gene expression assessed at different

time points and predictive performance evaluatedtime points and predictive performance evaluated

Gene Expression Models Predicting SVRGene Expression Models Predicting SVRin Treatment-Naive HCV- Genotype 1 Patients in Treatment-Naive HCV- Genotype 1 Patients

Younossi ZM, et al. J Hepatol. 2008;48:S285.

PPV = positive predictive value; NPV = negative predictive value; AUC = area under the curve;

HCV Genotype

Gene(s) in the Predictive

Model

ModelP-

value

Sensitivity %(95% CI)

Specificity %

(95% CI)

PPV %

NPV %

AUC

Pretreatment

Genotype 1

EP300, SOCS6 .00143285.7

(42.2–97.6)83.3

(51.6–97.4)75.0 90.9

0.881(0.651–0.980)

24 hours after initiation of treatment

Genotype 1

IL1B, ADAM9 .00908971.4

(29.3–95.5)81.8

(48.2–97.2)71.4 81.8

0.74(0.484–0.913)

7 days after initiation of treatment

Genotype 1

PRKRIR .009460100.0(58.9–100.0)

66.7(34.9–89.9)

63.6 100.00.786

(0.540–0.936)

This data suggests that SVR depends on the successful engagement of host-

specific response by IFN-based therapy

Immunity, Race, and NonresponseImmunity, Race, and Nonresponse HCV-infected African Americans (AA) have lower HCV-infected African Americans (AA) have lower

sustained virologic response (SVR) compared with sustained virologic response (SVR) compared with HCV-infected HCV-infected Caucasian American (CA): 28% vs. 52%28% vs. 52%11

Could lower SVR be related to differences in immune Could lower SVR be related to differences in immune response?response?– 187 Caucasian American (CA) and 187 African American (AA)

infected with HCV genotype 1 from Virahep-C study Virahep-C study

– Type 1 helper (Th1) response to HCV core protein and Type 1 helper (Th1) response to HCV core protein and combined HCV antigens were lower in AA compared with CAcombined HCV antigens were lower in AA compared with CA

– This difference in immunity remained significant after adjusting for gender, serum alanine aminotransferase, histologic severity and viral load22

– This suggests that AA may have weaker This suggests that AA may have weaker HCV-specific immunityHCV-specific immunity

1. Conjeevaram HS, et al. Gastroenterology. 2006;131:470-477 2. Rosen HR, et al. Hepatology. 2007;46:350-358

Obesity, Diabetes, Steatosis, and Nonresponse

DDiisseeaasse e

PPrrooggrreessssiioonn

Impact on progression

RReessppoonnsse e

tto o

TThheerraappyy

+

SVR

SVR

Impact on the efficacy of treatment

HCV graphic courtesy of David Brunelli, MD. http://www.med-ars.it/virus.htm.

0%

10%

20%

30%

40%

50%

60%

70%

0%

10%

20%

30%

40%

50%

60%

70%

Graphic courtesy of Dr. Zobair M. Younossi.

Author, Year Evidencea N SVR (%) Association with SVR

Kumar D, 20021 II-2 62 G1 (32), G3 (65)

For G3, SVR steatosis

Poynard T, 20032 II-2 1428 56 SVR with steatosis

Bressler B, 20033 II-2 253 42 SVR with BMI >30 kg/m2, G1, and cirrhosis

Sanyal A, 20034 II-2 110 NA Response in fatty liver disease

Thomopoulos K, 20055

II-2 116 52 SVR with steatosis, GGT, and G1/4

D’Souza R, 20056 II-1 59 56 SVR with Insulin resistance, fasting insulin, and Asian ethnicity

Harrison S, 20057 II-2 315 40 SVR with steatosis and steatohepatitis

Romero-Gomez M, 20058

II-2 159 53 SVR with insulin resistance, fibrosis, and GI

Camma C, 20069 II-2 291 NA SVR with steatosis, fibrosis, and age >50 y

Jian Wu Y, 200610 II-1 98 57 SVR with insulin resistance and fasting insulin

Tarantino G, 200611 II-2 80 NA SVR with waist circumference

Conjeeveram HS, 200712

II-1 399 NA SVR with insulin resistance

Westin J, 200713 II-1 272 G3: 89; nonG3: 56

SVR with steatosis in nonG3 only

Insulin Resistance, Obesity, Steatosis, and Nonresponse

Graphic courtesy of Dr. Zobair M. Younossi.aAASLD strength-of-evidence scale. Strader DB, et al. Hepatology. 2004;39:1147-1171.

Insulin Resistance and NonresponseInsulin Resistance and NonresponseGenotype 1 Patients Treated with PEG IFN + RBV for 48 weeksa

aTreatment: PEG IFN -2a 180 g/wk or PEG IFN -2b 1.5 g/kg/wk + RBV 800–1200/d.HOMA = Homeostasis Model of Assessment; an index of insulin resistance calculated as fasting insulin (mIU/L) x fasting glucose (mmol/L) 22.5.Romero-Gomez M, et al. Gastroenterology. 2005;128:636-641.

20%

40%

61%

0

10

20

30

40

50

60

70

HOMA <2 HOMA 2–4 HOMA >4

SVR (%)

n = 43 n = 45 n = 25

Patients with chronic hepatitis C treated with IFNPatients with chronic hepatitis C treated with IFNor IFN/RBV for 24 weeks (N = 89)or IFN/RBV for 24 weeks (N = 89)11

– Insulin resistance and beta cell function were measured by Insulin resistance and beta cell function were measured by HOMA-IR and HOMA-%B, respectivelyHOMA-IR and HOMA-%B, respectively

– SVR was associated with improvement of insulin resistance and SVR was associated with improvement of insulin resistance and beta cell function beta cell function

Non-genotype 3 patients (N=96) re-treated with PEG-Non-genotype 3 patients (N=96) re-treated with PEG-IFN+RBV for 24 weeks (HALT-C)IFN+RBV for 24 weeks (HALT-C)22

– Insulin resistance was measured by HOMA-IR Insulin resistance was measured by HOMA-IR – After 20 weeks of treatment, HOMA-IR declined in responders After 20 weeks of treatment, HOMA-IR declined in responders

(HCV RNA negative) as compared to partial responders ((HCV RNA negative) as compared to partial responders (>> 1 log 1 log decline but positive) or null responders (< 1 log decline)decline but positive) or null responders (< 1 log decline)

Change in HOMA-IR from baseline: -2.68 vs. -0.72 vs. +0.1, p=0.017Change in HOMA-IR from baseline: -2.68 vs. -0.72 vs. +0.1, p=0.017

1. Kawaguchi T, et al. Am J Gastroenterol. 2007;102:570-576.2. Delgado-Borrego A, et al. Hepatology 2008; 48 (no.3) Supplement: 271 (Abstract)

Impact of SVR on Insulin ResistanceImpact of SVR on Insulin Resistance

• IR seems to be associated with low SVR• Achieving SVR may improve IR• What are the mechanisms?

• Host-related• Virus-related

Mechanism—Host-related Metabolic Conditions Contributing to Nonresponse

LOWER

SVR

IR

Pro-inflammatory

adipocytokines

Lower interferon bioavailablity

+

Increase adipose tissue +

Biologicresponse

to IFN-

+ +

Oxidativestress

Graphic courtesy of Dr. Zobair M. Younossi.

Proteasomal degradation

of IRS-1(Insulin receptor

substrate 1)

STAT-1(Signal transducer

& activator of transcription-1)

Promotes

ImpairedIFN

signaling

Impairedinsulin

signaling

SOCS-3(Suppressor of

cytokine signalling-3)

Negative regulator

Up-regulatesexpression

LowerSVR

LowerSVR

Mechanism—Virus-Related Metabolic Conditions Contributing to Nonresponse

Graphic courtesy of Dr. Zobair M. Younossi.HCV graphic courtesy of David Brunelli, MD. http://www.med-ars.it/virus.htm


Nonresponse may be related to virus-, host-, or Nonresponse may be related to virus-, host-, or treatment-related factorstreatment-related factors– Virus—genotypes, viral loadVirus—genotypes, viral load– Host—early gene expression, immunity, metabolic Host—early gene expression, immunity, metabolic

conditionsconditions– Treatment—adherence to full regimen, Treatment—adherence to full regimen,

side-effect managementside-effect management Although some of these factors are fixed, others Although some of these factors are fixed, others

can be modified, potentially improving responsecan be modified, potentially improving response These strategies to improve response must be These strategies to improve response must be

tested in well designed clinical trialstested in well designed clinical trials

Challenges Posed by Nonresponders and Relapsers

Fred Poordad, MDChief, Hepatology and Liver Transplantation

Associate Professor of MedicineComprehensive Transplant Center

Cedars-Sinai Medical CenterLos Angeles, California

Re-treatmentRe-treatment

Should We Ever Re-treat a PEG IFN/RBV Should We Ever Re-treat a PEG IFN/RBV Nonresponder or Relapser?Nonresponder or Relapser?

EPIC-3 DIRECT

What Did We Learn from These Trials?

EPIC-3 = Evaluation of Peg-Intron in Control of Hepatitis C Cirrhosis.REPEAT = Retreatment with Pegasys in Patients Not Responding to Peg-Intron Therapy.DIRECT = Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy.

REPEAT

EPIC-3 Study DesignEPIC-3 Study Design2293 HCV-infected patients 2293 HCV-infected patients with advanced fibrosis whowith advanced fibrosis whofailed prior (PEG)IFN/RBVfailed prior (PEG)IFN/RBV

PEG IFN PEG IFN -2b 1.5 µg/kg/wk + RBV 800–1400 mg/d-2b 1.5 µg/kg/wk + RBV 800–1400 mg/d

HBV RNA at 12 wk

Continue Continue treatment through treatment through

wk 48wk 48

Follow-up Follow-up through wk 72through wk 72

Metavir fibrosis stage

PEG IFN PEG IFN -2b -2b 0.5 µg/kg/wk 0.5 µg/kg/wk vs control for vs control for

up to 3 y up to 3 y

PEG IFN PEG IFN -2b -2b 0.5 µg/kg/wk 0.5 µg/kg/wk vs control for vs control for

up to 5 yup to 5 y

PosPos NegNeg

F2–3F2–3 F4F4

Poynard T, et al. J Hepatol. 2008;48:S369.

SVR in Nonresponders by Prior SVR in Nonresponders by Prior Treatment and Genotype/Fibrosis ScoreTreatment and Genotype/Fibrosis Score

68

16

18

18

5640

8

3938

18

6

4

4

4

0 20 40 60 80

G2/3 F2

G2/3 F3

G2/3 F4

G1 F2

G1 F3

G1 F4

Overall

SVR

Prior PEGIFN/RBV (n = 476)

Prior IFN/RBV (n = 903)

SVR = sustained virologic response.Poynard T, et al. J Hepatol. 2008;48:S369.

76

28

42

43

51

32

21

18

26

59

67

62

61

32

0 20 40 60 80

G2/3 F2

G2/3 F3

G2/3 F4

G1 F2

G1 F3

G1 F4

Overall

SVR

Prior PEGIFN/RBV (n = 344)

Prior IFN/RBV (n = 300)


SVR in Relapsers by Prior Treatment SVR in Relapsers by Prior Treatment and Genotype/Fibrosis Scoreand Genotype/Fibrosis Score

Association of SVR withAssociation of SVR withHCV RNA at Week 12HCV RNA at Week 12

Nonresponders and RelapsersNonresponders and Relapsers

12

56

00

20

40

60

Pat

ien

ts w

ith

SV

R (

%)

HCV RNAHCV RNA

UndetectableUndetectable(n = 823)(n = 823)

Positive; Positive; ≥2-log decrease≥2-log decrease

(n = 188)(n = 188)

Positive; Positive; <2-log decrease<2-log decrease

(n = 66)(n = 66)


Follow-up

Wk 0Wk 0

Jensen DM, et al. Hepatology. 2007;46:291A.

REPEAT Study DesignREPEAT Study Design

Wk 48Wk 48Wk 24Wk 24 Wk 72Wk 72 Wk 96Wk 96

Follow-up

Follow-up

Follow-up

AA

BB

CC

DD

RBV 1000–1200 mg/d

RBV 1000–1200 mg/d

RBV 1000–1200 mg/d

RBV 1000–1200 mg/d

Wk 12Wk 12

PEG IFN -2a 180 µg/wk




360 µg/wk

360 µg/wk

No

nre

spo

nd

ers

to p

revi

ou

s N

on

resp

on

der

s to

pre

vio

us

PE

G I

FN

P

EG

IF

N

-2a/

RB

V (

N =

942

)-2

a/R

BV

(N

= 9

42)

SVR with PEG IFN SVR with PEG IFN -2a/RBV Re-treatment-2a/RBV Re-treatment+/- Higher-dose Induction, +/- Longer Duration+/- Higher-dose Induction, +/- Longer Duration

Jensen DM, et al. Hepatology. 2007;46:291A. ITT analysisITT analysis

aaAll arms 91% genotype 1.All arms 91% genotype 1.

72-wk induction arm (n = 317) 72-wk induction arm (n = 317)

48-wk induction arm (n = 156)48-wk induction arm (n = 156)

Treatment ArmTreatment Armaa

16161414

77 99

00

1010

2020

3030

4040

AA BB CC

SV

R (

%)

SV

R (

%)

DD

72-wk standard arm (n = 156)72-wk standard arm (n = 156)

48-wk standard arm (n = 313)48-wk standard arm (n = 313)

DIRECT Study—Consensus IFN DIRECT Study—Consensus IFN in PEG IFN/RBV Failuresin PEG IFN/RBV Failures

PEG IFN PEG IFN -2a or -2a or -2b + RBV-2b + RBV

<2-log decline HCV RNA<2-log decline HCV RNA HCV RNA positiveHCV RNA positive

12 wk12 wkaa 24 wk24 wk

Consensus IFN Consensus IFN 9 µg QD + RBV9 µg QD + RBVbb

48 wk (n = 170)48 wk (n = 170)

Consensus IFN Consensus IFN 15 µg QD + RBV15 µg QD + RBVbb

48 wk (n = 170)48 wk (n = 170)

No treatmentNo treatment24 wk (n = 170)24 wk (n = 170)

May be eligible for May be eligible for roll overroll over

Randomization (N = 510)

DIRECT Trial. Available at: http://www.directtrial.com/. Accessed on October 17, 2008.

aaPatients with <2-log drop in HCV RNA between week 12 and 24. bRBV 1000–1200 mg/d.

No

nre

spo

nd

ers

No

nre

spo

nd

ers

SVR with Consensus IFN Re-treatmentSVR with Consensus IFN Re-treatmentDIRECT Trial (N = 343)DIRECT Trial (N = 343)

OverallOverall

<2-log drop<2-log dropaa

55 66

00

1010

2020

3030

4040

OverallOverall

Consensus IFN 9 µg QD + RBVConsensus IFN 9 µg QD + RBV

SV

R (

%)

SV

R (

%)

4466

00

F0–F3F0–F3bb F4F4bb

1010 1111

OverallOverall

2200

F0–F3F0–F3bb F4F4bb

2929

Consensus IFN 15 µg QD + RBVConsensus IFN 15 µg QD + RBV

>2-log drop>2-log dropaa

OverallOverall

<2-log drop<2-log dropaa

>2-log drop>2-log dropaa

aHCV RNA response to previous therapy.bFibrosis score within 3 years of study entry.

Bacon B, et al. Hepatology. 2007;46:311A. ITT analysisITT analysis

Maintenance TherapyMaintenance Therapy

Does PEG IFN Prevent Histologic Does PEG IFN Prevent Histologic and Clinical Progression?and Clinical Progression?

HALT-C COPILOT

What Did We Learn from These Trials?

HALT-C = Hepatitis C Antiviral Long-term Treatment against Cirrhosis.COPILOT = Colchicine vs Peg-Intron Long-Term.

HALT-C Trial DesignHALT-C Trial Design

Re-treatment (“Lead-In”) Re-treatment (“Lead-In”) PhasePhase

Maintenance PhaseMaintenance Phase

11451145HCV-HCV-infected infected patients patients with with advanced advanced fibrosis fibrosis whowhofailed failed IFN-based IFN-based therapytherapy

PEG IFN PEG IFN -2a 180 -2a 180

µg/wk + RBV µg/wk + RBV 1000–1200 1000–1200

mg/d for 24–mg/d for 24–48 wk48 wk

Nonresponse at wk 24

(n = 662)

Relapse/breakthrough during or after

48 wk(n = 151)

PEG IFN PEG IFN -2a 90 -2a 90 µg/wkµg/wk

(n = 517)(n = 517)

Discontinue Discontinue treatmenttreatment(n = 533)(n = 533)

Ran

do

miz

atio

n

Express(n = 237)

Pro

gre

ssio

n o

f L

iver

Dis

ease

The HALT-C Trial. Available at: The HALT-C Trial. Available at: http://www.haltctrial.org/overview.html. Accessed on September 30, 2008.

3.5

y

4.64.6

13.213.2

3.23.2

31.931.9

6.6*6.6*

14.3*14.3*

2.8*2.8*

28.2*28.2*

00

1010

2020

3030

4040

DeathDeath DecompensationDecompensation HCCHCC

No treatment (n = 533)No treatment (n = 533)

PEG IFN PEG IFN -2a 90 µg/wk (n = 517)†-2a 90 µg/wk (n = 517)†

*P = NS †17% d/c at 1 y and 30% d/c at 3.5 y

Di Bisceglie AM, et al. Hepatology. 2007;46:290A.

Effect of Long-term PEG IFN Effect of Long-term PEG IFN HALT-C Data at 3.5 YearsHALT-C Data at 3.5 Years

% P

atie

nts

%

Pat

ien

ts

IncreaseIncreasein Fibrosisin Fibrosis

COPILOT Study DesignCOPILOT Study Design

Baseline Baseline

LB = liver biopsy; US = ultrasound.

Afdhal NH, et al. J Hepatol. 2008;48:S4.

24 Weeks24 Weeks12 Weeks12 Weeks 2 Years2 Years 4 Years4 Years

PEG IFN -2b 0.5 µg/kg/wk (n = 286)

Colchicine 0.6 mg BID (n = 269)

LB, US,LB, US,endoscopyendoscopy

Clinical Clinical evaluationevaluation

USUS Endoscopy, Endoscopy, LBLB

Endoscopy, Endoscopy, LBLB

IFN/RBV orPEG IFN/RBV

Nonresponders with Ishak stage 3–6

21.2

16.718.5

12.6

0

5

10

15

20

25

ITT PP

Clinical Endpoint (%)

PEG IFN PEG IFN -2b 0.5 µg/kg/wk (n = 286)-2b 0.5 µg/kg/wk (n = 286)

Colchicine 0.6 mg BID (n = 269)Colchicine 0.6 mg BID (n = 269)

Impact of Long-Term Colchicine vs PEG Impact of Long-Term Colchicine vs PEG IFN on Liver Disease ProgressionIFN on Liver Disease Progression

COPILOT Final Results

Afdhal NH, et al. J Hepatol. 2008;48:S4.ITT = intention-to-treat analysis; PP = per-protocol analysis.

Group Event-Free Survival— PEG IFN vs Colchicine

(P-value, logrank)

All .311

With portal hypertension .057

Without portal hypertension .345

ITT AnalysisITT Analysis

Group Event-Free Survival— PEG IFN vs Colchicine

(P-value, logrank)

All .146

With portal hypertension .038

Without portal hypertension .656

On-Drug AnalysisOn-Drug Analysis

Afdhal NH, et al. J Hepatol. 2008;48:S4.

COPILOT—Event-Free SurvivalCOPILOT—Event-Free SurvivalColchicine vs PEG IFN

Individualizing Therapy for Individualizing Therapy for Nonresponders and RelapsersNonresponders and Relapsers

Maintenance therapy has no significant beneficial effectsMaintenance therapy has no significant beneficial effects

Nonresponders or relapsers to prior

IFN +/- RBV

Consider re-treatment with PEG IFN/RBV

Nonresponders to prior PEG IFN/RBV

Do not re-treat with PEG IFN/RBV

Consider consensus IFN for nonresponders with >2-log

decline and no cirrhosis

Relapsers to prior PEG IFN/RBV

Consider re-treatment with PEG IFN/RBV


Response to re-treatment regimens Response to re-treatment regimens depends on initial responsedepends on initial response

Majority of patients do not warrant Majority of patients do not warrant re-treatment with current regimensre-treatment with current regimens

Future regimens with small molecules Future regimens with small molecules need to be further studied in these need to be further studied in these patient populations patient populations

Can We Do Better?Role of Emerging

STAT-C Drugs

Ira M. Jacobson, MDVincent Astor Professor of Clinical Medicine

Chief, Division of Gastroenterology and HepatologyMedical Director of the Center for the

Study of Hepatitis CWeill Cornell Medical College

New York, New York

Emerging Anti-HCV TherapiesEmerging Anti-HCV Therapies

Genome Sequence-Based

RNA interference

EnzymeInhibitors

Protease

Polymerase

Other

IFN and RBV modifications• Albumin IFN, omega IFN• Taribavirin (viramidine)

Immune approaches• Therapeutic vaccines• Toll-like receptor agonists• Yeast expressing HCV Ag

Targeting cellular factors• Cyclophilin antagonists• Nitazoxanide

STAT-CSTAT-C

Other EnzymeInhibitors

Ribozymes

Antisenseoligonucleotides

Graphic courtesy of Dr. I. M. Jacobson.Ag = antigen; IFN = interferon; RBV = ribavirin.

Increased SVR Resistance

Side effectsDecreased duration

Key Themes at the Dawn of a New EraKey Themes at the Dawn of a New Era

Graphic courtesy of Dr. I. M. Jacobson.

PROVE1: Telaprevir Phase IIPROVE1: Telaprevir Phase IIU.S., Genotype 1, Treatment NaiveU.S., Genotype 1, Treatment Naive

240 48 72Weeks 12 6036

Peg-IFN + RBV Follow-upTVR +

Peg-IFN + RBV T12/PR24

(n=79)

TVR + Peg-IFN + RBV Peg-IFN + RBV Follow-up

T12/PR48(n=79)

Follow-upPR48 (control)

(n=75)Peg-IFN + RBV Placebo +

Peg-IFN + RBV

Follow-upT12/PR12

(n=17)TVR +

Peg-IFN + RBV

McHutchison J et al, J Hepatol. 2008;48:S4.

Peg-IFN = Peg-IFN alfa-2a 180 ug/wkRBV = Ribavirin 1000-1200mg/dayTVR = Telaprevir 750mg q8h

PROVE 2 Study PROVE 2 Study European Phase 2: G1, NaïveEuropean Phase 2: G1, Naïve

Interim AnalysisInterim Analysis

Arm A

Arm B

Arm C

Arm D

Weeks

12 24 48

TVR+PEG+RBVTVR+PEG+RBV

TVR+PEGTVR+PEG

TVR+PEG+RBVTVR+PEG+RBV

PEG IFN alfa-2a 180 ug + RBV 1000-1200 mgPEG IFN alfa-2a 180 ug + RBV 1000-1200 mg

0

PEG+RBV

36

Dusheiko G et al, J Hepatol. 2008;48:S26.

N=82

N=81

N=82

N=78

PROVE2: SVR Rates PROVE2: SVR Rates

0

20

40

60

80

Control T/P/R24 T/P/R12 T/P12

48

68*

36

% HCV RNAneg 62**

Higher relapse ratewith 12 vs 24 weeks

Impaired response, more breakthrough

and more relapse w/out RBV

*p=0.01 vs control**p=0.08 vs control

(SVR-12)

Dusheiko G et al, J Hepatol. 2008;48:S26.

Boceprevir: SPRINT-1 Study Boceprevir: SPRINT-1 Study Inernational, Genotype 1, Treatment NaiveInernational, Genotype 1, Treatment Naive

PEG 1.5 µg/kg + RBV 800-1400 mg + boceprevir 800 mg TID for 48 weeksPEG 1.5 µg/kg + RBV 800-1400 mg + boceprevir 800 mg TID for 48 weeks


No Lead-inNo Lead-in Dosing Strategy Dosing Strategy


Low dose Low dose RBVRBV

Dosing Strategy Dosing Strategy

PEG 1.5 µg/kg +RBV 800-1400 mg for 48 weeks

PEG 1.5 µg/kg +RBV 800-1400 mg for 48 weeksControlControl

PEG 1.5 µg/kg + RBV 800-1400 mg + boceprevir 800 mgTID for 24 weeks

PEG 1.5 µg/kg + RBV 800-1400 mg + boceprevir 800 mgTID for 24 weeks


PEG-2b + PEG-2b + RBV 800-1400 mg RBV 800-1400 mg

x 4 weeksx 4 weeks


x 4 weeksx 4 weeks


x 4 weeksx 4 weeks


x 4 weeksx 4 weeksLead-inLead-in

Dosing Strategy Dosing Strategy

Follow-up Follow-up x 44 weeksx 44 weeksFollow-up Follow-up x 44 weeksx 44 weeks






Kwo et al., EASL 2008, p. 372; Oral Presentation; Kwo P, et al, Hepatology. 2008;48:1027A.

SPRINT-1—SVR-12 RatesSPRINT-1—SVR-12 RatesPEG IFN PEG IFN -2b + RBV-2b + RBV +/-+/- BoceprevirBoceprevir

0

20

40

60

80

100

SV

R (

%) 56 55

7466

PEG IFN -2b/RBV lead-in

No PEG IFN/RBV lead-in

SVR = sustained virologic response.Kwo P, et al, Hepatology. 2008;48:1027A. Graphic courtesy of Dr. I. M. Jacobson.

38

(SVR-12)(SVR-12)28 wk28 wk 48 wk48 wk

Control (PEG IFN/RBV)

48 wk48 wk(SVR-12)(SVR-12)

(58/

103)

(59/

107)

(76/

103)

(68/

103)

(39/

104)

STAT-C Agents STAT-C Agents in Nonrespondersin Nonresponders

“Functional Monotherapy”“Functional Monotherapy”Or Something More?Or Something More?

Virologic ResponseVirologic Response in PEG-Interferon + Ribavirin Non-Responders in PEG-Interferon + Ribavirin Non-Responders

(ITT, N=357)(ITT, N=357)Initial treatment armInitial treatment arm EOT EOT SVR SVR

Control Lead-in with PEG-IFN Control Lead-in with PEG-IFN αα-2b-2b + ribavirin + ribavirin

•PCR negativePCR negative →→ PEG-IFN PEG-IFN αα-2b-2b + ribavirin + ribavirin 8% (4/49)8% (4/49) 2% (1/49)2% (1/49)

•PCR positivePCR positive →→ P PEG-IFN EG-IFN αα-2b-2b + ribavirin + boceprevir + ribavirin + boceprevir 400 mg400 mg

32% 32% (14/44)*(14/44)* 7% (3/44)7% (3/44)

PEG-IFN PEG-IFN αα-2b-2b + boceprevir 100 mg + boceprevir 100 mg 6% (3/48)*6% (3/48)* 2% (1/48)2% (1/48)

PEG-IFN PEG-IFN αα-2b-2b + boceprevir 200 mg + boceprevir 200 mg 16% 16% (8/49)*(8/49)* 12% (6/49)12% (6/49)

PEG-IFN PEG-IFN αα-2b-2b + ribavirin + boceprevir 400 mg + ribavirin + boceprevir 400 mg 20% 20% (10/49)*(10/49)* 14% (7/49)14% (7/49)



Assay: TaqMan PCR assay LLD < 125 IU/ml (N/ITT)= number of subjects/Intent to Treat ( n=357 subjects)Assay: TaqMan PCR assay LLD < 125 IU/ml (N/ITT)= number of subjects/Intent to Treat ( n=357 subjects)*143 subjects rolled over PegInterferon + ribavirin + boceprevir 800 mg TID *143 subjects rolled over PegInterferon + ribavirin + boceprevir 800 mg TID

PROVE3: Prior Treatment FailuresPROVE3: Prior Treatment Failures

240 48 72Weeks 12 6036

(P) Peg-IFN = pegylated interferon alfa-2a 180 µg/wk; (R) RBV = ribavirin 1,000 or 1,200 mg/day;(T) TVR = telaprevir 750 mg q8h

Interim analysis

Peg-IFN + RBV

Follow-upT12/PR24TVR +

Peg-IFN + RBV

SVR

Follow-upPR48

(control) Peg-IFN + RBV Placebo +

Peg-IFN + RBV

SVR

Follow-upSVR

TVR + Peg-IFNT24/P24 (no RBV)

T24/PR48 Follow-upSVR

Peg-IFN + RBV TVR +

Peg-IFN + RBV

McHutchison JG, et al. 59th AASLD. October 31-November 4, 2008. Abstract 269.

PROVE3: Interim Results in Prior PROVE3: Interim Results in Prior NonrespondersNonresponders

PR48PR48

N=68N=68

T12/PR24T12/PR24

N=66N=66

T24/PR48T24/PR48

N=64N=64

T24/P24T24/P24

N=62N=62

Wk 4Wk 4 0% 50% 34% 32%

Wk 12Wk 12 3% 71% 55% 37%

EOTEOT NA 65% NA 34%

SVR-12SVR-12 NA 41% NA 11%


PROVE3: Interim Results in PriorPROVE3: Interim Results in PriorRelapsersRelapsers

PR48PR48

N=42N=42

T12/PR24T12/PR24

N=40N=40

T24/PR48T24/PR48

N=41N=41

T24/P24T24/P24

N=39N=39

Wk 4Wk 4 0% 80% 71% 72%

Wk 12Wk 12 17% 88% 78% 78%


SVR-12SVR-12 NA 72% NA 36%


PROVE3: Interim Results in PriorPROVE3: Interim Results in PriorBreakthroughsBreakthroughs

PR48PR48

N=3N=3

T12/PR24T12/PR24

N=9N=9

T24/PR48T24/PR48

N=8N=8

T24/P24T24/P24

N=10N=10

Wk 4Wk 4 0% 44% 75% 30%

Wk 12Wk 12 0% 44% 75% 50%


SVR-12SVR-12 NA 44% NA 20%


Telaprevir “Rollover” StudyTelaprevir “Rollover” Study

Open label telaprevirOpen label telaprevir Treatment failures in control arms of the three PROVE Treatment failures in control arms of the three PROVE

trialstrials Prior response patterns well characterizedPrior response patterns well characterized Telaprevir + PEG IFN 2a + RBV 12 weeks, then 12 or 36 Telaprevir + PEG IFN 2a + RBV 12 weeks, then 12 or 36

weeks of additional therapyweeks of additional therapy Stopping rules: Stopping rules:

– HCV RNA > 100 IU/ml at week 4HCV RNA > 100 IU/ml at week 4

– HCV RNA > 25 IU/ml at week 12HCV RNA > 25 IU/ml at week 12

Shiffman ML, et al. 59th AASLD, October 31-November 4, 2008. Abstract 1852; Shiffman ML, et al. J Hepatol. 2008;4:1135A.

Telaprevir “Rollover” StudyTelaprevir “Rollover” Study

0

20

40

60

80

100

Week 4 Week 12 Week 24

Null

Partial

Relapse4040

85859191

6161

90909494

4343

8282

7171

48 33 23 46 29 18 42 22 7

Shiffman ML, et al. 59th AASLD, October 31-November 4, 2008. Abstract 1852; Shiffman ML, et al. J Hepatol. 2008;4:1135A.

HC

V R

NA

<10

IU/m

l(%

)

Nucleoside Polymerase Inhibitor R7128Nucleoside Polymerase Inhibitor R7128 + PEG IFN + PEG IFN -2a + RBV-2a + RBV

28-Day Data in G1 Patients28-Day Data in G1 Patients11

0

20

40

60

80

100

10

30

85

1. Lalezari J, et al. J Hepatol. 2008;48:S29. 2. Gane EJ, et al. 59th AASLD. October 31–November 4, 2008. Abstract LB10. Graphic courtesy of Dr. I. M. Jacobson.

% P

CR

Neg

ativ

e

PEG IFN/RBV(n = 10)

PEG IFN +RBV +R7128

500 mg BID(n = 20)

PEG IFN/RBV + R7128

1500 mg BID(n = 20)

Ongoing studies in G2,3 as well as G1; RVR 90% in

G2,3 treatment failures2

Nitazoxanide in Genotype-4–Infected Nitazoxanide in Genotype-4–Infected Patients (Egypt)Patients (Egypt)

0

20

40

60

80

100

RVR ETR SVR

PEG IFN +RBV

NTZ + PEG IFN

NTZ + PEG IFN +RBV

Rossignol JF, et al. 59th AASLD. October 31-November 4, 2008. Abstract 1848. Graphic courtesy of Dr. I. M. Jacobson.

N = 96 treatment-naive patientsN = 96 treatment-naive patients

Control group PEG IFN + RBV (48 wk)Control group PEG IFN + RBV (48 wk)

Lead-in with 12 wk of nitazoxanideLead-in with 12 wk of nitazoxanide

–36 wk of additional therapy of PEG IFN or PEG IFN + RBV36 wk of additional therapy of PEG IFN or PEG IFN + RBV

7979

6161

5050

3838

54546464

75757171

8282

RVR = rapid virologic response; ETR = end-of-treatment response; SVR = sustained virologic response.

Drug 1 Drug 2Enhanced

Suppression

Resistance Studies

Decreased Emergence of de Novo Resistance

Suppression of Pre-existing

Resistant Variants

Boceprevir1 Valopicitabine Yes Yes Yes

Boceprevir2 HCV-796 Yes Yes Yes

ITMN-1913 R1479 Yes NA Yes

NM1074 ACH-806 Yes NA NA

Telaprevir4 ACH-806 Yes NA NA

Telaprevir5 R1479 NA Yes NA

Valopicitabine6 Various NA NA Yes

1. Ralston R, et al. J. Hepatol. 2007;46:S298. 2. Howe AY, et al. J. Hepatol. 2007;46:S165. 3. Seiwert SD, et al. J. Hepatol. 2007;46:S167. 4. Huang M, et al. J. Hepatol. 2007;46:S8. 5. McCowen M, et al. 14th International Symposium on Hepatitis C Virus and Related Viruses. September 9-13, 2007. Abstract P-265. 6. Bichko V, et al. J. Hepatol. 2007;46:S163.

The PromiseThe Promise of Combination Therapy of Combination TherapyIn Vitro Combinations StudiedIn Vitro Combinations Studied

The Goal of Future Combination RegimensThe Goal of Future Combination Regimens

•Different drugs may contribute variably to each of these goals•Not all components have to be STAT-C agents

Drug A Drug B Drug C

Profound suppression of broad range of

viral variants,including pre-existing

Prevention of emergent resistance

(pre-existing or de novo)

+ +

How Should the Prospect of Novel How Should the Prospect of Novel Treatments Factor into Your Decision-Treatments Factor into Your Decision-

Making?Making? Treatment-naive G1Treatment-naive G1

– Stage 0–1: watch and wait is acceptable in many patentsStage 0–1: watch and wait is acceptable in many patents– Stage 3–4: should treat nowStage 3–4: should treat now– Stage 2: proactivity with flexibilityStage 2: proactivity with flexibility

Where in stage 2 is patient?Where in stage 2 is patient? Mindset of patient; age of patient; duration of infectionMindset of patient; age of patient; duration of infection ContraindicationsContraindications

Treatment-naive G2,3Treatment-naive G2,3– Need good reason not to treatNeed good reason not to treat

NonrespondersNonresponders– Watch and wait appropriate for mostWatch and wait appropriate for most

RelapsersRelapsers– Consider longer course of retreatment, especially if advanced Consider longer course of retreatment, especially if advanced

fibrosisfibrosisYour local (or not so local) clinical investigator is happy to hear from you!Your local (or not so local) clinical investigator is happy to hear from you!

Brainstorming with the Experts Practical Approaches to the Complex World of HCV Supported by an...

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