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3rd Paris Hepatitis Conference: Morning Session on HBeAg-Neg CHB
WHY DO I TREAT MY PATIENTS WITH WHY DO I TREAT MY PATIENTS WITH PEGYLATED INTERFERON?PEGYLATED INTERFERON?
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
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
Antiviral Therapy: A Matter of ChoiceAntiviral Therapy: A Matter of ChoiceCase Features Should Determine ApproachCase Features Should Determine Approach
Antiviral Therapy: A Matter of ChoiceAntiviral Therapy: A Matter of ChoiceCase Features Should Determine ApproachCase Features Should Determine Approach
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
Peginterferon Nucleoside Analog
Finite treatment * Diminished infectivity Potential for long term benefit (HBsAg loss)* Durability off treatment
Drug cost /cost of care Indirect costs * Tolerability * Convenience * Need for monitoring *
Many Other Factors Go Into a Treatment Decision
Modified from Perrillo, Hepatology, 2006
Initial and Long Term Follow Up from PEG IFN alfa-2a Study in HBeAg-Neg CHB
0
10
20
30
40
50
60
70
60%
19%
27%
17%
ALT HBV DNA ALT HBV DNA normal <20,000 < 400 normal < 20,000 < 400
Initial study Follow-up study 6 mos after EOT 4years after EOT
n= 356* n = 230*
* w/wo LAM
Marcellin, EASL, 2008Marcellin, NEJM 2005
43%
24%
Follow up Data in PEG IFN-Treated HBeAg-Neg CHB
ALTnormal
ALTnormal
HBV DNA< 400 copies
HBV DNA < 400 copies
HBsAgclearance
HBsAgclearance
Initial study6 months after EOT
n =356
Follow-up study4 years after EOT
n = 230
0
10
20
30
40
50
60
70
3%
11%
~ 3%~ 3%increaseincreaseannually inannually inrespondersresponders
Marcellin, 2005, 2008
2% withlamivudine
0- 2 4 6 8 10 12 14 16 18
Virologic relapse
0.2
0.4
0.6
0.8
Fung, 2004
Months to Relapse
• 50 Chinese patients treated with LAM
• 37 treated for 2 yrs
• 27 neg. by PCR for ≥ 9 mos meet
criteria for treatment withdrawal
Prolonged PCR Negativity Does not Allay Concerns About Relapse
Clinical relapse
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 adefovir33 patients neg for HBV DNA x 4-5 yrs on adefovir
• Followed for median duration 18 mos off treatmentFollowed for median duration 18 mos off treatment
• 67% continue with ALT NL67% continue with ALT NL
• HBV DNA becomes detectable in all (“low,” varying from BDL to 5 HBV DNA becomes detectable in all (“low,” varying from BDL to 5 x 10x 1044 copies) copies)
• HBV DNA declines with further ollow upHBV DNA declines with further ollow up
Hadziyannis et al, AASLD, 2006Hadziyannis et al, AASLD, 2006
Worldwide Distribution of HBV GenotypesWorldwide Distribution of HBV Genotypes
Genotype A
Genotype B
Genotype C
Genotype D
Genotype E
Genotype F
Genotype G
1 Westland, Gastroenterology 2003; 2 Chu, Gastroenterology 2003
Asia 1
Europe 1
USA 2Mediterranean 1
42%
46%
9%83%
14%
35%40%
15% 22%
35%
31%
10%
Genotype A
n=174
Genotype B
n=245
Genotype C
n=464
Genotype D
n=346
HBeAg (+)
n=703
36.3% 21.1% 18.5% 14.6%
HBeAg
(-)n=526
34.0% 32% 50.4% 21.4%
Genotype and Virologic Response to IFNAccording to HBeAg Status in 1229 Patients
Erhardt , AASLD 2008, Absract 883Standard =298l PEG = 491; with LAM 440
0
5
10
15
20
25
ALL PATIENTS ASIANS CAUCASIANS
Chronic hep B studies
Chronic hep C studies
Eve
nts
(%
)Frequency of Depression-Related Events During Treatment with PEG IFN alfa-2a
Marcellin et al, Liver International, 2007
4%
22%
2%
9% 10%
23%
P < 0.001 P = 0.003 P = 0.027
Depression events 4% (B) vs 22% (C)
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
Patients with Cirrhosis Respond Just as Well to IFN As Those Without
modified after Chu and Liaw Sem Liver Dis 2006
Niederau + 63% 47% ns
D Lau + 59% 24% 0.01
van Zonneveld + 50% 29% 0.034
Lin + 39% 35% ns
Cooksley Peg IFN2a + 48% 35% ns
Buster Peg IFN2b + 33% 14% 0.02*
Papatheodoridis - 28% 27% ns
Brunetto - 26% 18% ns
Cooksley Peg IFN2a - 40% 45% ns
Cirrhosis Non-CirrhosisHBeAg P ValueResponse rates
* Dose reduction, early discontinuation, and SAEs comparable for both groups (33% vs 34%, 11% vs 8%, 4% vs 5%)
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; 14:S58-63)
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
Why Is HBsAg Clearance So Important?
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
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
HBsAg HBsAg ng/mLng/mL
BaselineBaseline TreatmentTreatment
Week 12Week 12
TreatmentTreatment
Week 60Week 60
Follow upFollow up
Week 12Week 12
Follow up Follow up
Week 24Week 24
Resp 1* 6,515 6,515 7,257 19 77 0
Resp 2 >7692>7692 >7692 273 446 205
Resp 3 1,6191,619 566 9 20 61
Resp 4 >7,692>7,692 196 38 27 19
NR 1NR 1 1,212 1,056 NA 1,910 1,473
NR 2 6,881 >7,692 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
Measuring HBsAg in HBeAg (-) CHB: with 60 Week Extended Course of Peg IFN Alfa -2a
Gish, Lau, Schmid, Perrillo Am J Gastro 2007* Response = PCR negative at FU week 24
HBV DNA SVRs vs Non-responders
0
1
2
3
4
5
6
7
8
BL W12 W24 W48 W72 W96
Lo
g c
op
ies/
mL
Treatment FUP
SVRs (n=12)
NRs (n=18)
Moucari et al, Hepatology, in press
HBsAg LevelSVRs vs Non-Responders
0
0.5
1
1.5
2
2.5
3
3.5
4
BL W12 W24 W48 W72 W96
Lo
g I
U/m
L
FUPTreatment
SVRs (n=12)
NRs (n=18)
Moucari et al, Hepatology, in press
HBsAg: Predictive Value for SVR by Wk 24 Decline (1 Log IU/mL)
48 Patients
n = 12
n = 36
n = 1
n = 35
n = 1
n = 11 PPV = 92 %
NPV = 97 %
Week 24 ↓ HBsAg ≥ 1 Log IU/mL
Week 24 ↓ HBsAg < 1 Log IU/mL
SVR (+)
SVR (-)
SVR (+)
SVR (-)
Predictive Value of qHBsAgPredictive Value of qHBsAg at Wk 48 for Outcome:at Wk 48 for Outcome:
NPVNPV PPVPPV SpecSpec SensSens
Sustained HBsAg Clearance at Yr 3
HBsAg < 380 IU/mL at wk 48 100 25 100
74
HBsAg reduction > 1.9 log10 at wk 48 98 44 92 75
HBV DNA ≤ 400 copies at 3 Yrs
HBsAg < 19 IU/mL at wk 48 98 44 75 92
HBsAg reduction > 0.46 log10 IU/mL at wk 48
95 30 66 81
HBsAg Decline at Wk 48 PredictsOutcomes at Year 3 After End of Rx*
Brunettto et al, Hepatology, in press* Based on subset of 198 patientsIn initial treatment cohort; HBsAg (-) in 16 (8%)
SUMMARY WhyWhy PEG IFN First for HBeAg-Negative CHB?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
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
Managing Patients with Limited Access to Care
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
Potential Problem Addressment
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