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3rd Paris Hepatitis Conference Morning Session
on HBeAg-Neg CHB

WHY DO I TREAT MY PATIENTS WITH
PEGYLATED INTERFERON?
Bob Perrillo Baylor University Medical
Center Dallas, TX USA
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Problems Confronting Clinician with HBeAg
Negative Hepatitis B

• High rate of relapse to conventional strategies
• Diagnosis can be a bit challenging
• Patients tend to be older group than HBeAg ()
  with more severe disease
• Not much known about predictors of sustained
  virologic response to IFN

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Recent PEG IFN Developments that Impact on
Care of Patients with HBeAg (-) CHB

• Long-term follow up
• Durability
• HBsAg clearance
• On treatment prediction of SVR
• HBV DNA response
• HBsAg response
• Clarification of importance of genotype
• Better understanding of tolerability

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Antiviral Therapy A Matter of ChoiceCase
Features Should Determine Approach
Peginterferon Nucleoside Analog
Poor tolerability in elderly and those with comorbid illness Any age, minimal adverse events
Less effective for high level viremia Baseline viremia generally not an issue
Chance for SVR determined by baseline ALT ALT elevation not required for viral suppression
Response genotype dependent Viral suppression independent of genotype
Contraindicated with decompensated disease Can be used safely in decom- pensated disease
Limited usefulness in special populations Appropriate in certain settings
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Many Other Factors Go Into a Treatment Decision
Drug cost /cost of care Indirect costs
Tolerability Convenience Need for
monitoring
Finite treatment Diminished
infectivity Potential for long term
benefit (HBsAg loss) Durability off
treatment
Modified from Perrillo, Hepatology, 2006
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Initial and Long Term Follow Up from PEG IFN
alfa-2a Study in HBeAg-Neg CHB
Initial study Follow-up
study 6 mos after EOT
4years after EOT n 356
n 230
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Marcellin, EASL, 2008
Marcellin, NEJM 2005
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27
24
19
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ALT HBV DNA ALT
HBV DNA normal lt20,000
lt 400 normal lt 20,000 lt 400
w/wo LAM
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Follow up Data in PEG IFN-Treated
HBeAg-Neg CHB
Follow-up study 4 years after EOT n 230
Initial study 6 months after EOT n 356
3 increase annually in responders
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2 with lamivudine
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HBsAgclearance
ALTnormal
ALTnormal
HBV DNAlt 400 copies
HBV DNA lt 400 copies
HBsAgclearance
Marcellin, 2005, 2008
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Prolonged PCR Negativity Does not Allay Concerns
About Relapse
Virologic relapse
0.8

• 50 Chinese patients
• treated with LAM
• 37 treated for 2 yrs
• 27 neg. by PCR
• for 9 mos meet
• criteria for treatment
• withdrawal

Clinical relapse
0.6
0.4
0.2
Months to Relapse
0- 2 4 6 8
10 12 14 16 18
Fung, 2004
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Long Term Response in Adefovir-Treated Cohort
Negative for HBV DNA x 4-5 Years

• 33 patients neg for HBV DNA x 4-5 yrs on adefovir
• Followed for median duration 18 mos off treatment
• 67 continue with ALT NL
• HBV DNA becomes detectable in all (low, varying
  from BDL to 5 x 104 copies)
• HBV DNA declines with further ollow up
• 
  Hadziyannis et al, AASLD, 2006

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Worldwide Distribution of HBV Genotypes
Asia 1
Europe 1
Mediterranean 1
USA 2
1 Westland, Gastroenterology 2003 2 Chu,
Gastroenterology 2003
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Genotype and Virologic Response to IFN According
to HBeAg Status in 1229 Patients
Genotype A n174 Genotype B n245 Genotype C n464 Genotype D n346
HBeAg () n703 36.3 21.1 18.5 14.6
HBeAg (-)n526 34.0 32 50.4 21.4
Standard 298l PEG 491 with LAM 440
Erhardt , AASLD 2008, Absract 883
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Frequency of Depression-Related Events During
Treatment with PEG IFN alfa-2a
25
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Chronic hep B studies
22
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Chronic hep C studies
Events ()
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P 0.003
P lt 0.001
P 0.027
10
9
10
4
5
2
8/346
4/47
9/90
4/448 185/827
180/702
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ALL PATIENTS ASIANS
CAUCASIANS
Depression events 4 (B) vs 22 (C)
Marcellin et al, Liver International, 2007
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Side Effects HBeAg (-) CHB (n 177) vs CHC (n
791)
Drug Discon- tinuations B , C Discontinua- tion for Safety, B, C 1 or More Serious Adverse Events B, C Most Common Serious Event B, C
8, 17-33 7, 7-22 5 (n 9), 7-16 Infection (6), psychiatric

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Patients with Cirrhosis Respond Just as Well to
IFN As Those Without
Response rates
Cirrhosis
Non-Cirrhosis
HBeAg
P Value
Niederau 63 47 ns D Lau
59 24 0.01 van Zonneveld 50
29 0.034 Lin 39 35 ns Cooksley
Peg IFN?2a 48 35 ns Buster
Peg IFN?2b 33 14 0.02 Papatheodori
dis - 28 27 ns Brunetto -
26 18 ns Cooksley Peg IFN?2a - 40
45 ns
Dose reduction, early discontinuation, and SAEs
comparable for both groups (33 vs 34, 11 vs
8, 4 vs 5)
modified after Chu and Liaw Sem Liver Dis 2006
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Peginterferon for Delta Hepatitis

• Patients often HBeAg-negative
• Interferon only effective treatment
• Treatment required long-term
• Where possible, continue until loss of HBsAg
• (Farci, J Viral Hep 2007 14S58-63)

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3rd Paris Hepatitis Conference Session on
HBeAg-Neg CHB

• HBsAg Loss, HBsAg Monitoring,
• and Relationship of Treatment-
• Induced Changes in HBsAg
• Concentration to Virologic Response

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• Why Is HBsAg Clearance So Important?

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Qualitative Differences Between HBsAg and
Prolonged Viral Suppression

• Durability of virologic response
• Significantly lower levels of intracellular
  genomic template (cccDNA)
• Better long-term prognosis
• Lower rate of HCC
• Lower rate of progression to cirrhosis
• Less chance of viral reactivation
• Spontaneous
• Immune suppression

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HBsAg Levels with Peg IFN Alfa -2a and
Lamivudine in HBeAg (-) CHB

• 63 patients (42 IFN, 21 LAM) analyzed for HBsAg
  by ADVIA
• Centaur Bayer (92 geno D)
• Low BSL HBsAg level predictive of HBsAg clearance
  
• HBsAg decreased in both treatment groups
• - Sharp drop in most IFN treated patients
  sustained in VR
• - More gradual slope for LAM ETU of HBsAg is
  median of 10.6 yrs of treatment vs 5.4 yrs
  with IFN
• 
  
• 
  Manensis et al, Anitiviral Ther, 2007

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Measuring HBsAg in HBeAg (-) CHB with 60 Week
Extended Course of Peg IFN Alfa -2a
HBsAg ng/mL Baseline Treatment Week 12 Treatment Week 60 Follow up Week 12 Follow up Week 24
Resp 1 6,515 7,257 19 77 0
Resp 2 gt7692 gt7692 273 446 205
Resp 3 1,619 566 9 20 61
Resp 4 gt7,692 196 38 27 19
NR 1 1,212 1,056 NA 1,910 1,473
NR 2 6,881 gt7,692 6,088 6,823 5,219
NR 3 368 392 304 NA 189
NR 4 5,019 6,030 7,584 6,161 7,715
Response PCR negative at FU week 24
Gish, Lau, Schmid, Perrillo
Am J Gastro 2007
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HBV DNA SVRs vs Non-responders
NRs (n18)
Log copies/mL
SVRs (n12)
Treatment
FUP
Moucari et al, Hepatology, in press
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HBsAg LevelSVRs vs Non-Responders
NRs (n18)
Log IU/mL
SVRs (n12)
FUP
Treatment
Moucari et al, Hepatology, in press
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HBsAg Predictive Value for SVR by Wk 24 Decline
(1 Log IU/mL)
SVR ()
Week 24 ? HBsAg 1 Log IU/mL
PPV 92
n 11
n 12
n 1
SVR (-)
48 Patients
SVR ()
n 1
n 36
Week 24 ? HBsAg lt 1 Log IU/mL
NPV 97
n 35
SVR (-)
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HBsAg Decline at Wk 48 Predicts Outcomes at Year
3 After End of Rx
Predictive Value of qHBsAg at Wk 48 for Outcome NPV PPV Spec Sens
Sustained HBsAg Clearance at Yr 3
HBsAg lt 380 IU/mL at wk 48 100 25 100 74
HBsAg reduction gt 1.9 log10 at wk 48 98 44 92 75
HBV DNA 400 copies at 3 Yrs
HBsAg lt 19 IU/mL at wk 48 98 44 75 92
HBsAg reduction gt 0.46 log10 IU/mL at wk 48 95 30 66 81
Based on subset of 198 patients In initial
treatment cohort HBsAg (-) in 16 (8)
Brunettto et al, Hepatology, in press
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SUMMARY Why PEG IFN First for HBeAg-Negative
CHB?

• Useful as first line therapy in selected
  patients
• Age, comorbid illnesses, compensated liver
  disease
• Test for genotype (non geno
  D)
• Better tolerated than in hepatitis C
• Patients with stable cirrhosis can be treated
  safely
• Specific advantages
• Discrete interval of treatment
• Responses can be durable
• HBsAg loss
• Possibility of response directed therapy

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Summary Why PEG IFN FIrst? (2)

• Responses can be durable
• If treatment fails, no impact on success with NA
  or
• requirement for more complex therapy

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Managing Patients with Limited Access to Care
Potential Problem
Addressment
Identify those chronically infected Government or privately sponsored screening programs
Determine ease of, and need for treatment Liver biopsy may be optional High likelihood of response Obvious features of cirrhosis Treatment to prevent HCC?
Investigate treatment possibilities Government health care programs Pharmaceutical free/discounted drug
Only monitor what and when it is necessary More dependence on ALT Minimize HBV DNA testing intervals Monitor compliance Annual HBeAg assessment
Manage patient education Native language encourage family participation reasonable insight
Survey for confounding factors Social circumstances, HIV/HCV/delta, Compliance history