Transcript HCV On-Treatment Virologic Monitoring: Impact on Treatment

HCV On-Treatment Virologic
Monitoring: Impact on
Treatment Decisions
Ruth J. Corbett, MSN, ARNP, CCRC
Gastroenterology Advanced Practice Nurse,
Specialty Care
Department of Veteran Affairs
Kansas City, Missouri
This program is supported by an educational grant from
HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Faculty and Disclosures
Program Director
Emmet B. Keeffe, MD, MACP
Professor of Medicine
Co-Director, Liver Transplant Program
Chief of Hepatology
Stanford University School of Medicine
Palo Alto, California
Faculty
Ruth J. Corbett, MSN, ARNP, CCRC
Gastroenterology Advanced Practice
Nurse, Specialty Care
Department of Veteran Affairs
Kansas City, Missouri
Faculty
Ruth 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.
Staff
Jenny 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.
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Goals and Benefits of
HCV Therapy
HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Hepatitis C Virus Infection:
Magnitude of the Problem
 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.
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
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
Lindsay KL. Hepatology. 2002;36(suppl 1):S114-S120.
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Overview of Current FDA-Approved
Treatments for HCV
Drug
Pegylated interferons
Recommended Dosage
 Peginterferon alfa-2b
 1.5 µg/kg SQ once weekly combined with RBV;
1.0 µg/kg SQ once weekly monotherapy
 Peginterferon alfa-2a
 180 µg SQ once weekly combined with ribavirin or
as monotherapy
 9 µg SQ TIW; 15 µg TIW for nonresponders
 800-1400 mg PO daily depending on weight and
genotype
Interferon alfacon-1
Ribavirin
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.
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
SVR Rates: Progress in the Treatment
of Chronic Hepatitis C
SVR Rates With Standard Interferon
100
Patients (%)
80
60
43
40
20
0
19
6
IFN
24 Weeks
IFN
48 Weeks
IFN/RBV
48 Weeks
McHutchison J, et al. N Engl J Med. 1998;339:1485-1492. Poynard T, et al. Lancet. 1998;352: 14261432.
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
SVR Rates: Progress in the Treatment
of Chronic Hepatitis C
 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
Sustained Virologic
Response (%)
100
82
80
60
76
56
54
46
42
40
20
0
n = 511
n = 348
n = 163
n = 453
n = 298
n = 140
Overall
Genotype
1
Genotype
2/3
Overall
Genotype
1
Genotype
2/3
Manns M, et al. Lancet. 2001;358:958-965. Fried MW, et al. N Engl J Med. 2002;347: 975-982.
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Predicting Response
to HCV Therapy
HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Factors That May Influence the
Outcome of Hepatitis C
Host
Virus
Sex
Age
Race
Genetics
Immune response
Duration of Infection
Viral load
HCV genotype
Quasispecies
Environment
Alcohol or drugs
HBV coinfection
HIV coinfection
Steatosis
Iron
NASH
Alberti A, et al. J Hepatol. 1999;31(suppl 1):17-24.
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Predictors of Sustained Virologic
Response: Fixed Factors
Baseline Factor
HCV RNA, %[1,2]
 < 2 x 106 copies/mL
 > 2 x 106 copies/mL
Genotype, %[1,2]
 2 or 3
1
Genotype 1 and high viral load, %
Liver histology, %[1,2]
 Stage 0-2
 Stage 3-4
Age[1,2]
Weight[1,2]
Race, %[3,4]
 Black
 White
Sustained Virologic Response Rates
PegIFN alfa-2a + RBV OR PegIFN alfa-2b + RBV
62-78
42-53
76-82
42-46
30-41
55-57
41-44
Older age, lower SVR*
Higher weight, lower SVR*
52
19-28
*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.
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Virologic Monitoring Markers and
Definitions of Response to Treatment
Rapid 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
Pawlotsky JM. Hepatology. 2002;36(suppl 1):S65-S73.
Sethi A, et al. Clin Liver Dis. 2005;9:453-471.
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Virologic Monitoring Markers and
Definitions of Response to Treatment
Null Response
HCV RNA decline < 2 log10 IU/mL by Week 12
Nonresponse
Failure 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
Relapse
End 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
Pawlotsky JM. Hepatology. 2002;36(suppl 1):S65-S73.
Sethi A, et al. Clin Liver Dis. 2005;9:453-471.
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Patterns of Response to Initial
Antiviral Therapy
7
HCV RNA
6
Nonresponder
First phase
5
Flat-partial responder
4
Second phase
Slow-partial responder
3
Limit of
2 detection
Rapid responder
1
0123
7
14
21
28
Days on Treatment
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Treatment of Chronic HCV Infection:
Nonresponse, Breakthrough, Relapse
HCV RNA (log IU/mL)
8
7
PegIFN/RBV
Breakthrough
6
Relapse
5
Nonresponse
4
2 log decline
3
2
Limit of
detection
1
0
-6
0
6
12 18 24 30 36 42 48 54 60 66 72 78
Weeks
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Benefits of a Thorough Virologic
Monitoring Strategy
 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
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.
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The Predictive Value of Week 12
and Week 4 HCV RNA
HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
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
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.
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Time to Undetectable HCV RNA
Identified as Best Predictor of SVR
 Pooled data from PegIFN alfa-2b/RBV and PegIFN alfa2a/RBV phase III trials
PPV for SVR (%)
PPV of HCV RNA
Undetectability Determining SVR
100
80
86
80
76
60
40
20
0
Week 4
Week 12
Week 24
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.
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Relationship Between SVR and Time to
HCV RNA Undetectability
 Retrospective analysis of genotype 1 patients receiving
48 weeks of PegIFN alfa-2a + RBV
100
91 91
90
End-of-treatment response
SVR
90
Patients (%)
80
60
60
48
40
13
20
2
0
Week 4
Week 12
Week 24
Negative
Negative
Negative
Ferenci P, et al. J Hepatol. 2005;43:425-433.
< 2 log drop
Negative
Negative
< 2 log drop
> 2 log drop
Negative
Any drop
Any drop
Positive
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Longer Duration of Undetectability on
Treatment Increases Chance for SVR
 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
1. Drusano GL, et al. J Infect Dis. 2004;189:964-970.
2. Tang KH, et al. EASL 2005. Abstract 609.
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Rate of Viral Decline Determines
Period of HCV RNA Negativity
Wk 0 Wk 4
Wk 12
Wk 24
Wk 48 (EOT)
HCV RNA undetectable for 44 weeks
HCV RNA undetectable for 36 weeks
HCV RNA undetectable for 24 weeks
Time to HCV RNA negativity
Modified from figure by Michael Fried, MD.
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Shorter Treatment Duration
for Genotype 1 Patients
Reaching RVR
HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Shorter Treatment Duration in
Genotype 1 Patients With RVR
 Retrospective analysis of multinational, randomized, phase III
study: PegIFN alfa-2a + weight-based RBV (N = 740)
Outcomes in Patients With RVR
According to Treatment Length
Outcomes in Patients Without RVR
According to Treatment Length
24 weeks
97
93
88
100
91
80
80
Patients (%)
Patients (%)
100
48 weeks
60
40
20
0
EOT
SVR
Jensen DM, et al. Hepatology. 2006;43:954-960.
70
63
60
44
40
23
20
0
EOT
SVR
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Week 4 Response as a
Predictor of SVR
 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
Relapse Rate Based on Week 4
Viral Load (ITT Analysis)
Patients (%)
100
80
Week 4 HCV RNA
60
38
40
20
0
22
7
5
10
15
< 10 IU/mL
10-49 IU/mL
All Patients
< 600,000
≥ 600,000
Baseline Viral Load (IU/mL)
Ferenci P, et al. EASL 2006. Abstract 8.
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Shorter Treatment for Genotype 1 and
Low Baseline Viral Load
Patients With 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)
SVR According to Time to First Negative HCV RNA
93
100
89 85
71
80
67
Treatment Duration
60
50
40
25
20
0
24 weeks
48 weeks
17
Week 4
Week 12
Week 24
Total
Time to First Negative HCV RNA
Zeuzem S, et al. J. Hepatol. 2006;44:97-103.
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Extended Treatment Duration
for Genotype 1
HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Longer Treatment Duration May Be
Beneficial for Slow Responders
 48 vs 72 weeks of PegIFN alfa-2a + RBV 800 mg/day in
genotype 1 patients
SVR Among Patients HCV RNA
Positive at Week 12
Overall SVR
100
100
Patients (%)
80
60
80
P = NS
53
54
60
P = .04
40
40
20
20
17
0
n = 100
Week 48
0
n = 230
Week 48
n = 225
Week 72
Berg T, et al. Gastroenterology. 2006;130:1086-1097.
29
n = 106
Week 72
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Longer Treatment Duration May Be
Beneficial for Slow Responders
 Patients who failed to achieve RVR randomized to 48 or
72 weeks of PegIFN alfa-2a + RBV 800 mg/day
48 weeks (n = 161)
72 weeks (n = 165)
Patients (%)
100
80
P = .014
60
40
45.0
48.0
32.0
13.0
20
0
P = .005
SVR
Sanchez-Tapias J, et al. AASLD 2004. Abstract 126.
Relapse
18.0
4.8
Discontinuation
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Evaluating Shorter Treatment
Duration in Genotype 2/3
Rapid Responders
HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Shorter Treatment in Genotype 2/3
Patients Achieving RVR
 PegIFN alfa-2b + weight-based RBV
– 14 weeks for patients with RVR; 24 weeks for patients
without RVR
Patients (%)
100
RVR, received 14 weeks (n = 95)
No RVR, received 24 weeks (n = 27)
90
80
60
56
40
26
20
10
0
SVR
Dalgard O, et al. Hepatology. 2004;40:1260-1265.
Relapse
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Shorter Treatment in Genotype 2/3
Patients Achieving RVR
 Patients with RVR received 16 or 24 weeks PegIFN
alfa-2a + weight-based RBV
Patients (%)
100
80
82
16 weeks (n = 71)
24 weeks (n = 71)
80
60
40
20
13
5
0
SVR
Von Wagner M, et al. Gastroenterology. 2005;129:522-527.
Relapse
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Shorter Treatment in Genotype 2/3
Patients Achieving RVR
 PegIFN alfa-2b + weight-based RBV
– 12 weeks for patients with RVR; 24 weeks for patients
without RVR
Patients (%)
100
80
RVR, received 12 weeks (n = 133)
No RVR, received 24 weeks (n = 80)
85
64
60
40
20
10
6
0
SVR
Mangia A et al. N Engl J Med. 2005;352:2609-2617.
Relapse
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Poorer Responses With 16 vs
24 Weeks in Genotype 2/3 Patients
 Genotype 2/3 patients treated with PegIFN alfa-2a + RBV
800 mg/day for 16 vs 24 weeks
SVR Rates in Patients With or Without SVR:
16 vs 24 Weeks of Treatment
P = .0007
Patients (%)
100
82
16 weeks (n = 732)
90
80
24 weeks (n = 732)
P < .001
60
49
40
27
20
0
Patients With RVR
Shiffman M, et al. EASL 2006. Abstract 734.
Patients Without RVR
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
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
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Summary: Using Virologic
Monitoring in Your Practice
HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Using Virologic Monitoring in
Your Practice
Genotype 1
Genotype 2/3
Week 4 RVR
reached
Reduction to 24 weeks
total treatment time
may be possible
Data mixed: continue
through Week 24 if
RVR achieved
Week 12 EVR
not reached
Guidelines recommend
treatment be stopped
Guidelines recommend
treatment be stopped
Slow response
(EVR, not HCV
RNA undetectable
until Week 24)
Extension of treatment
duration to 72 weeks
may improve SVR rates
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
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
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Summary: Virologic Monitoring in
Genotype 1 and 4 Patients
 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
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HCV On-Treatment Virologic Monitoring: Impact on Treatment Decisions
Summary: Virologic Monitoring in
Genotype 2 and 3 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
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