HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions Ruth J. Corbett, MSN, ARNP, CCRC Gastroenterology Advanced Practice Nurse, Specialty

HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions

Ruth J. Corbett, MSN, ARNP, CCRCGastroenterology Advanced Practice Nurse, Specialty CareDepartment of Veteran AffairsKansas City, Missouri

This program is supported by an educational grant from


clinicaloptions.com/hep

Program DirectorEmmet B. Keeffe, MD, MACPProfessor of MedicineCo-Director, Liver Transplant ProgramChief of HepatologyStanford University School of MedicinePalo Alto, California

FacultyRuth J. Corbett, MSN, ARNP, CCRC, has disclosed that she is a member of the speakers’ bureau for Roche and Schering-Plough.Emmet B. Keeffe, MD, MACP, has disclosed that he has received grants or research support from Roche. He has received consulting fees from Idenix, Roche, and Valeant. He has received fees for non-CME services from Roche and Schering-Plough.StaffJenny Schulz, PhD, has no significant financial relationships to disclose.Gordon Kelley has no significant financial relationships to disclose.Edward King, MA, has no significant financial relationships to disclose.

Faculty and Disclosures

FacultyRuth J. Corbett, MSN, ARNP, CCRCGastroenterology Advanced Practice Nurse, Specialty CareDepartment of Veteran AffairsKansas City, Missouri

Goals and Benefits of HCV Therapy



Nearly 4 million persons in United States infected

– Approximately 35,000 new cases yearly

– 85% of new cases become chronic

10,000-20,000 HCV-related deaths per year

– Number expected to triple in next 10-20 years

Leading cause of

– Chronic liver disease

– Cirrhosis

– Liver cancer

– Liver transplantation

CDC. MMWR Morb Mortal Wkly Rep. 1998;47;1-39. NIH Consensus Conference Statement. Available at: http://consensus.nih.gov/2002/2002HepatitisC2002116html.htm. Accessed September 25, 2006.

Hepatitis C Virus Infection:Magnitude of the Problem


clinicaloptions.com/hepLindsay KL. Hepatology. 2002;36(suppl 1):S114-S120.

Goals of HCV Therapy

Primary goal of treatment is to eradicate the virus

Additional goals

– Slow disease progression

– Minimize risk of hepatocellular carcinoma

– Improve liver histology

– Enhance quality of life

– Prevent transmission of virus

– Reduce extrahepatic manifestations



Drug Recommended Dosage

Pegylated interferons

Peginterferon alfa-2b

Peginterferon alfa-2a

1.5 µg/kg SQ once weekly combined with RBV; 1.0 µg/kg SQ once weekly monotherapy

180 µg SQ once weekly combined with ribavirin or as monotherapy

Interferon alfacon-1 9 µg SQ TIW; 15 µg TIW for nonresponders

Ribavirin 800-1400 mg PO daily depending on weight and genotype

PEG-IntronTM [package insert]. Kenilworth, NJ: Schering Corporation; 2003. Pegasys [package insert]. Nutley, NJ: Hoffmann-La Roche Inc; 2003. Modified from Strader DB et al. Hepatology 2004;39:1147-1171.

Overview of Current FDA-Approved Treatments for HCV



SVR Rates: Progress in the Treatment of Chronic Hepatitis C

McHutchison J, et al. N Engl J Med. 1998;339:1485-1492. Poynard T, et al. Lancet. 1998;352: 1426-1432.

100

80

60

40

20

0

19

43

6

IFN24 Weeks

IFN48 Weeks

IFN/RBV48 Weeks

SVR Rates With Standard Interferon

Pat

ien

ts (

%)



Peginterferon alfa-2b 1.5 µg/kg/wk + ribavirin 800 mg/d for 48 weeks

Peginterferon alfa-2a 180 µg/wk + weight-based ribavirin (1000 or 1200 mg/d) for 48 weeks

SVR Rates: Progress in the Treatment of Chronic Hepatitis C

Manns M, et al. Lancet. 2001;358:958-965. Fried MW, et al. N Engl J Med. 2002;347: 975-982.

46

76

56

Overall Genotype1

Genotype2/3

n = 298 n = 140n = 453

42

82

100

80

60

40

20

0

54

Overall Genotype1

Genotype2/3

Su

stai

ned

Vir

olo

gic

R

esp

on

se (

%)

n = 348 n = 163n = 511

Predicting Response to HCV Therapy


clinicaloptions.com/hepAlberti A, et al. J Hepatol. 1999;31(suppl 1):17-24.

Virus

Viral loadHCV genotypeQuasispecies

Environment

Alcohol or drugsHBV coinfectionHIV coinfection

SteatosisIron

NASH

Factors That May Influence the Outcome of Hepatitis C

Host

SexAge

RaceGenetics

Immune responseDuration of Infection



Baseline Factor Sustained Virologic Response Rates

PegIFN alfa-2a + RBV OR PegIFN alfa-2b + RBV

HCV RNA, %[1,2]

< 2 x 106 copies/mL > 2 x 106 copies/mL

62-7842-53

Genotype, %[1,2]

2 or 3 1

76-8242-46

Genotype 1 and high viral load, % 30-41

Liver histology, %[1,2]

Stage 0-2 Stage 3-4

55-5741-44

Age[1,2] Older age, lower SVR*

Weight[1,2] Higher weight, lower SVR*

Race, %[3,4]

Black White

5219-28*Logistic regression analysis, P ≤ .002.

1. Manns MP, et al. Lancet. 2001;358:958-965. 2. Fried MW, et al. N Engl J Med. 2002;347: 975-982. 3. Muir AJ, et al. N Engl J Med. 2004;350:2265-2271. 4. Conjeevaram HS, et al. 2006;131:470-477.

Predictors of Sustained Virologic Response: Fixed Factors


clinicaloptions.com/hepPawlotsky JM. Hepatology. 2002;36(suppl 1):S65-S73. Sethi A, et al. Clin Liver Dis. 2005;9:453-471.

Virologic Monitoring Markers and Definitions of Response to TreatmentRapid Virologic Response (RVR)

HCV RNA undetectable by Week 4

Early Virologic Response (EVR)

≥ 2 log decline in HCV RNA by Week 12

End of Treatment (EOT) Response

Undetectable HCV RNA at end of treatment

Partial Virologic Response

≥ 2 log decline in HCV RNA by Week 12, but HCV RNA detectable at Week 24

Sustained Virologic Response (SVR)

HCV RNA negativity 12-24 weeks after treatment end


clinicaloptions.com/hepPawlotsky JM. Hepatology. 2002;36(suppl 1):S65-S73.Sethi A, et al. Clin Liver Dis. 2005;9:453-471.

Virologic Monitoring Markers and Definitions of Response to TreatmentNull Response HCV RNA decline < 2 log10 IU/mL by Week 12

NonresponseFailure to achieve HCV RNA undetectability at any time point during therapy

Virologic Breakthrough

Decline in HCV RNA to undetectable levels followed by return of HCV RNA despite continued treatment

RelapseEnd of treatment response followed by return of HCV RNA after treatment discontinuation

Positive Predictive Value (PPV)

Given a positive response, what the chance is that an SVR will occur

Negative Predictive Value (NPV)

Given a negative response, what the chance is that an SVR will not occur



Days on Treatment

Patterns of Response to Initial Antiviral Therapy

1

2

3

4

5

6

7

0 1 2 3 7 14 21 28

Nonresponder

Flat-partial responder

Slow-partial responder

Rapid responder

Second phase

First phase

Limit of detection

HC

V R

NA



0

1

2

3

4

5

6

7

8

-6 0 6 12 18 24 30 36 42 48 54 60 66 72 78

Weeks

HC

V R

NA

(lo

g I

U/m

L)

2 log decline

Limit ofdetection

PegIFN/RBV

RelapseBreakthrough

Nonresponse

Treatment of Chronic HCV Infection:Nonresponse, Breakthrough, Relapse



Virologic monitoring to predict response can provide the following benefits to the patient and clinician

– Limits unnecessary exposure to therapy

– Identifies treatment failure

– Justifies early discontinuation in those responding poorly

– Limits treatment toxicity

– Limits cost for those unlikely to respond

– Identifies optimal duration of treatment

– Provides incentive to continue therapy

Benefits of a Thorough Virologic Monitoring Strategy

Sanchez-Tapias JM. AASLD 2004. Abstract 125. Jensen DM, et al. N Engl J Med. 2000;343:1673-1680. Davis GL, et al. Hepatology. 2003;38:645.

The Predictive Value of Week 12 and Week 4 HCV RNA



Davis GL. Hepatology. 2002;36(suppl 1):S145-S151. NIH Consens State Sci Statements. 2002;19:1-46. Fried MW, et al. N Engl J Med. 2002;34:7975-7982. Manns MP, et al. Lancet. 2001;358:958-965.

Week 12 Stopping Rule: Patients Without EVR Unlikely to Achieve SVR Week 12 viral kinetics predictor of SVR

– Only 1.6% of patients who fail to meet EVR criteria achieve SVR (NPV: 98.4%)

– 2 log cutoff at Week 12 optimal for predicting response

Poor PPV of Week 12 EVR (68%)

– Week 12 HCV RNA predictor of treatment failure but not predictor of success in achieving SVR

Week 12 stopping rule included in current guidelines

– ~ 20% of patients can stop early, lowering total treatment costs by 16% and decreasing unnecessary side effects



PPV of HCV RNAUndetectability Determining SVR

8680 76

0

20

40

60

80

100

Week 4 Week 12 Week 24

PP

V f

or

SV

R (

%)

Time to Undetectable HCV RNA

Davis GL. Hepatology. 2002;36(suppl 1):S145-S151. Fried MW, et al. N Engl J Med. 2002;34:7975-7982. Manns MP, et al. Lancet. 2001;358:958-965.

Pooled data from PegIFN alfa-2b/RBV and PegIFN alfa-2a/RBV phase III trials

Time to Undetectable HCV RNA Identified as Best Predictor of SVR



End-of-treatment response

SVR91 90 90

13

91

6048

20

20

40

60

80

100

Week 4Week 12Week 24

NegativeNegativeNegative

< 2 log dropNegativeNegative

< 2 log drop> 2 log drop

Negative

Any dropAny dropPositive

Pat

ien

ts (

%)

Ferenci P, et al. J Hepatol. 2005;43:425-433.

Relationship Between SVR and Time to HCV RNA Undetectability Retrospective analysis of genotype 1 patients receiving

48 weeks of PegIFN alfa-2a + RBV


clinicaloptions.com/hep1. Drusano GL, et al. J Infect Dis. 2004;189:964-970.2. Tang KH, et al. EASL 2005. Abstract 609.

Retrospective analysis of PegIFN alfa-2b/RBV dataset evaluated predictors of SVR in genotype 1[1]

– 32 weeks of HCV RNA negative: 80% chance of SVR

– 36 weeks of HCV RNA negative: 90% chance of SVR

Prospective study of viral kinetics and SVR evaluated in genotype 1 patients on PegIFN alfa-2a/RBV[2]

– Minimum time of HCV RNA negativity on therapy to achieve high SVR rates (80%) was 24 weeks

Longer Duration of Undetectability on Treatment Increases Chance for SVR



Wk 4Wk 0 Wk 12 Wk 24 Wk 48 (EOT)

HCV RNA undetectable for 44 weeks



Time to HCV RNA negativity

Rate of Viral Decline DeterminesPeriod of HCV RNA Negativity

Modified from figure by Michael Fried, MD.

Shorter Treatment Duration for Genotype 1 Patients

Reaching RVR


clinicaloptions.com/hepJensen DM, et al. Hepatology. 2006;43:954-960.

24 weeks 48 weeks

9788

93 91

0

20

40

60

80

100

EOT SVR

70

23

63

44

Outcomes in Patients With RVR According to Treatment Length

Pat

ien

ts (

%)

Retrospective analysis of multinational, randomized, phase III study: PegIFN alfa-2a + weight-based RBV (N = 740)

EOT SVR0

20

40

60

80

100

Pat

ien

ts (

%)

Outcomes in Patients Without RVR According to Treatment Length

Shorter Treatment Duration in Genotype 1 Patients With RVR


clinicaloptions.com/hepFerenci P, et al. EASL 2006. Abstract 8.

Patients with undetectable HCV RNA by Week 4 on PegIFN alfa-2a + RBV treated for total of 24 weeks– SVR rate for Week 4 responders (per-protocol analysis)

– Overall: 87% – Genotype 1: 84% – Genotype 4: 100%

Higher baseline, Week 4 viral load predictive of relapse

Baseline Viral Load (IU/mL)

Relapse Rate Based on Week 4 Viral Load (ITT Analysis)

7 51522

10

38

0

20

40

60

80

100

All Patients < 600,000 ≥ 600,000

Pat

ien

ts (

%)

< 10 IU/mL10-49 IU/mL

Week 4 HCV RNA

Week 4 Response as a Predictor of SVR



24 vs 48 weeks PegIFN alfa-2b + RBV in genotype 1 patients with low viral load (< 600,000 IU/mL)

– 24-week group received weight-based RBV

– 48-week group received 800 mg/day RBV (historical controls)

89

2517

50

8593

67 71

Week 4 Week 12 Week 24 Total

24 weeks48 weeks

SVR According to Time to First Negative HCV RNA

Pat

ien

ts W

ith

SV

R

Treatment Duration

Time to First Negative HCV RNAZeuzem S, et al. J. Hepatol. 2006;44:97-103.

0

20

40

60

80

100

Shorter Treatment for Genotype 1 and Low Baseline Viral Load

Extended Treatment Duration for Genotype 1



53 54

0

20

40

60

80

100

17

29

P = .04

Pat

ien

ts (

%)

n = 100 n = 106n = 230 n = 225

Overall SVRSVR Among Patients HCV RNA

Positive at Week 12

Week 48 Week 72

Berg T, et al. Gastroenterology. 2006;130:1086-1097.

48 vs 72 weeks of PegIFN alfa-2a + RBV 800 mg/day in genotype 1 patients

Longer Treatment Duration May Be Beneficial for Slow Responders

Week 48 Week 72

P = NS

0

20

40

60

80

100



32.0

48.0

4.8

45.0

13.0 18.0

0

20

40

60

80

100

SVR Relapse Discontinuation

48 weeks (n = 161) 72 weeks (n = 165)

Pat

ien

ts (

%)

Sanchez-Tapias J, et al. AASLD 2004. Abstract 126.

Patients who failed to achieve RVR randomized to 48 or 72 weeks of PegIFN alfa-2a + RBV 800 mg/day

Longer Treatment Duration May Be Beneficial for Slow Responders

P = .014 P = .005

Evaluating Shorter Treatment Duration in Genotype 2/3

Rapid Responders


clinicaloptions.com/hepDalgard O, et al. Hepatology. 2004;40:1260-1265.

90

10

56

26

0

20

40

60

80

100

SVR Relapse

RVR, received 14 weeks (n = 95)

No RVR, received 24 weeks (n = 27)

Pat

ien

ts (

%)

PegIFN alfa-2b + weight-based RBV

– 14 weeks for patients with RVR; 24 weeks for patients without RVR

Shorter Treatment in Genotype 2/3 Patients Achieving RVR



82

13

80

5

Von Wagner M, et al. Gastroenterology. 2005;129:522-527.

0

20

40

60

80

100

SVR Relapse

16 weeks (n = 71)

24 weeks (n = 71)

Patients with RVR received 16 or 24 weeks PegIFN alfa-2a + weight-based RBV


Pat

ien

ts (

%)



PegIFN alfa-2b + weight-based RBV– 12 weeks for patients with RVR; 24 weeks for patients

without RVR

No RVR, received 24 weeks (n = 80)85

10

64

6

Mangia A et al. N Engl J Med. 2005;352:2609-2617.

0

20

40

60

80

100

SVR Relapse

RVR, received 12 weeks (n = 133)


Pat

ien

ts (

%)


clinicaloptions.com/hepShiffman M, et al. EASL 2006. Abstract 734.

82

27

90

49

SVR Rates in Patients With or Without SVR: 16 vs 24 Weeks of Treatment

P < .001

P = .0007

0

20

40

60

80

100

Patients With RVR Patients Without RVR

16 weeks (n = 732)

24 weeks (n = 732)

Genotype 2/3 patients treated with PegIFN alfa-2a + RBV 800 mg/day for 16 vs 24 weeks

Poorer Responses With 16 vs 24 Weeks in Genotype 2/3 Patients

Pat

ien

ts (

%)



Summary of Shortened Treatment Duration for Genotypes 2 and 3 Mixed results on probability of SVR in patients with

24 weeks of therapy vs shorter durations

– Higher relapse rate with shorter duration

– Largest study suggests need for 24 weeks of therapy

Need more data on how shorter duration affects patients with cirrhosis, high HCV RNA levels at baseline

Summary: Using Virologic Monitoring in Your Practice



Week 4 RVR reached

Genotype 1 Genotype 2/3

Week 12 EVR not reached

Slow response (EVR, not HCV RNA undetectable until Week 24)

Reduction to 24 weeks total treatment time

may be possible

Data mixed: continue through Week 24 if

RVR achieved

Guidelines recommend treatment be stopped

Guidelines recommend treatment be stopped

Extension of treatment duration to 72 weeks

may improve SVR rates

Using Virologic Monitoring in Your Practice



Summary: Benefits of Virologic Monitoring In addition to host and environmental predictors of SVR,

frequent virologic monitoring has key impact on treatment decisions

By using Week 4 and Week 12 HCV RNA markers, treatment failures can be predicted early

Predictive negative value from Week 4 and Week 12 HCV RNA levels justify early discontinuation

Early virologic monitoring can limit unnecessary exposure, toxicity, and cost from treatment

Early responses can provide incentive to continue therapy



Virologic monitoring can identify optimal duration of treatment in genotype 1 and 4

– Week 12 HCV RNA showing a drop of ≤ 2 log10 now commonly used to identify those unlikely to respond

– Emerging data suggest that 24 weeks of therapy may be effective for genotype 1 patients who achieved an RVR

– Patients who do not achieve undetectable HCV RNA before Week 24 have ~ 50% chance of relapsing after 48 weeks of therapy

– Studies show that these slow responders may benefit from extended treatment

Summary: Virologic Monitoring in Genotype 1 and 4 Patients



Virologic monitoring can identify optimal duration of therapy in genotypes 2 and 3

– Mixed results on whether genotype 2/3 patients achieving RVR can reduce treatment duration to < 24 weeks

– Largest study to date suggests 24 weeks optimal duration

HCV on-treatment virologic monitoring can have a positive impact on treatment decisions and patient outcomes

Summary: Virologic Monitoring in Genotype 2 and 3 Patients

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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions Ruth J. Corbett, MSN, ARNP, CCRC Gastroenterology Advanced Practice Nurse, Specialty