what to start: treatment naïve – pegifn or nucleos(t)ide analogues
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What to Start: Treatment naïve – PegIFN or Nucleos(t)ide Analogues. Case. 28 yo man accountant from the US Acquired HBV in college during period of “experimentation” Not previously vaccinated - PowerPoint PPT PresentationTRANSCRIPT
What to Start:Treatment
naïve – PegIFN or Nucleos(t)ide
Analogues
Case
• 28 yo man accountant from the US– Acquired HBV in college during period of
“experimentation”– Not previously vaccinated
– History of mild depression several years ago but no recent problems except “stress” with work and 2 small children
• No symptoms
• No current medications
Case
• Evaluation:– AFP = 9 ng/mL
– HBeAg +
– ALT = 124 (< 40 U/L)
– HBV DNA = 8.8 million c/mL
– HBV genotype not done
– Liver CT scan = “normal appearance to the liver without hypervascular lesion”
Case
• Liver biopsy not recommended – He meets guidelines for therapy
• He returns with his wife to discuss treatment options– He currently feels well and is not anxious
to take medications long-term
– His wife has been concerned about his “stress” level, particularly at home
Debate
1. Peginterferon alfa: Short and to the point (seroconversion)
2. Oral nucleoside or nucleotide analogues: Durable, dependable,and cost-effective
Peginterferon Alfa:Short and to the point
(seroconversion)
HBV Treatment in theUnited States: 2009
1957Interferon
discovered
1991Interferon alfa-2b
approved for HBV
1998Lamivudine (3TC) approved as first
nucleoside analogue for HBV
1991 3TC anti-HBV and anti-HIV activity
discovered
1990 PMEA anti-HBV
activity discovered
2002Adefovir dipivoxil (PMEA prodrug)
approved for HBV
1998 Entecavir anti-HBV activity discovered
2005Entecavir and
peginterferon alfa-2a approved for HBV
2006Telbivudine
approved for HBV
2001 Telbivudine anti-HBV activity discovered
2008Tenofovir approved
for HBV
Duration of HBV Treatment
• HBeAg positive– 6-12 months after HBeAg seroconversion to
minimize relapse rate
– Long-term therapy may be required
• HBeAg negative– Relapse common after cessation of therapy
– Long-term treatment currently recommended
• Cirrhosis– Long-term therapy may be required
Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.
HBV Genotypes as Predictorsof Response to Interferon-Alfa:
Multivariate Analysis
OR(95% CI)
P value
HBV genotype
A vs. D3.620
(2.316-5.657)0.0001
B vs. D2.621
(1.618-4.245)0.0001
C vs. D3.184
(2.054-4.936)0.0001
ALT >5 vs. ≤5 xULN1.432
(1.056-1.940)0.02
HBeAg neg. vs. pos.2.124
(1.527-2.966)0.0001
Conclusion: Multivariate analysis adjusted for treatment identified genotype D, HBeAg negative status and normal ALT level as independent predictors for failing to achieve SVR
% S
VR
0
20
40
60
Genotype A
10
30
50
Genotype B
Genotype C
Overall SVR
HBeAg pos SVR
HBeAg neg SVR
Genotype D
Independent Predictors for SVRSVR by Genotype and HBeAg Status
Erhardt A, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 883.
Lau GK, et al. NEJM. 2005;352(26):2682-2695.
Peginterferon-2a and/or Lamivudine in Patients with HBeAg-Positive Chronic HBV
Patients with HBeAg-positive chronic hepatitis B
(N = 814)
Peginterferon alfa-2a 180 µg/week+ Oral placebo once daily
(n = 271)
Peginterferon alfa-2a 180 µg/week+ Lamivudine 100 mg/day
(n = 271)
Lamivudine 100 mg/day
(n = 272)
Week 48
24 weeksfollow-up
Randomized 1:1:1
Patients stratified according to geographic
region and ALT level
Peginterferon-2a and/or Lamivudine in Patients withHBeAg-Positive Chronic HBV
Responses at End of Follow-Up (week 72)
0
10
20
30
40
50
60
70
80
90
100
Pa
tie
nts
(%
)
32%
PegIFN-2a (n=271)
PegIFN-2a + lamivudine (n=271)
Lamivudine (n=272)
27%
19%
32%34%
22%
14%
5%
41% 39%
29%
14%
HBV DNA<400 copies/mL
HBeAgSeroconversion
HBV DNA<105 Copies/mL
Normalized ALT
PegIFN-2a statistically significantly better than lamivudine monotherapy for all measures.
Lau GK, et al. N Engl J Med 2005;352:2682-2695.
Peginterferon-2a and/or Lamivudine in Patients withHBeAg-Negative Chronic HBV
• Observational study: 4-yr follow-up of randomized phase III trial
Marcellin P, et al. AASLD 2008. Abstract 919.
*PegIFN-treated patients eligible for participation in long-term follow-up.
Patients with HBeAg-negative, HBsAg-positive
chronic HBV infection
(N = 537)
PegIFN alfa-2a 180 μg/wk + Placebo(n = 177)*
PegIFN alfa-2a 180 μg/wk + LAM 100 mg/day
(n = 179)*
LAM 100 mg/day(n = 181)
Wk 48
4-yr follow-up
Peginterferon-2a and/or Lamivudine in Patients withHBeAg-Negative Chronic HBV
Responses at End of Follow-Up (week 72)
0
10
20
30
40
50
60
70
80
90
100
Pat
ien
ts (
%)
43%
PegIFN-2a (n=177)
PegIFN-2a + lamivudine (n=130)
Lamivudine (n=130)
43%
29%
19% 20%
59% 60%
44%
7%
HBV DNA<400 copies/mL
HBV DNA<20,000 Copies/mL
Normalized ALT
PegIFN-2a statistically significantly better than lamivudine monotherapy for all measures.
Marcellin P, et al. N Engl J Med. 2004;351:1206-1217.
* Marcellin et al. N Engl J Med 2004** 4-year analysis of patients from initial study who entered long-term follow-up
Long-term Follow-up Studyin HBeAg-negative CHB:
Study Design
Lamivudine 100 mg qd
PEGASYS 180 μg qw + 100 mg lam qd
PEGASYS 180 μg qw + placebo qd
48 weeks
Initial study*
EOT(week 48)
6 monthspost-EOT
Long-term study
4 yearspost-EOT**
HBsAg Clearance Increases After End of Treatment with
PEG-IFNα-2a +/- LAM
1
3
5
7
9
11
Pa
tie
nts
wit
hH
Bs
Ag
cle
ara
nc
e (
%)
N=230
3%
6%
8%
11%
1 2 3 4Years after EOT
HBsAg Level as Predictor of Long-term Durability
of PegIFN Response• Higher response rates at 6 mos associated with Wk 12 HBsAg
≤ 1500 IU/mL vs > 1500 IU/mL in all patients
Marcellin P, et al. AASLD 2008. Abstract 919.
6-Mo Post-treatmentResponse Rates, %
Overall(N = 250)
Wk 12 HBsAg ≤
1500 IU/mL (n = 78)
Wk 12 HBsAg >
1500 IU/mL (n = 172)
P Value(HBsAg ≤ vs > 1500 IU/mL)
HBV DNA≤ 2000 IU/mL
36 55 27 < .001
HBV DNA≤ 80 IU/mL
17 36 9 < .001
HBsAg clearance 3 6 2 .112
Long-term Follow-up After Interferon Therapy:
NIH Experience• 103 patients received
interferon between 1984-1991– 30% were responders
(lost HBeAg and HBV DNA [by bDNA assay])
• Analysis reviewed long-term outcomesin responders and nonresponders– Mean follow-up time:
6.2 years (range: 1-11)
Lau DT, et al. Gastroenterology. 1997:113;1660-1667.
*P value not provided
Responders Nonresponders
Outcomes at Long-term Follow-up
P < .001
Per
cen
tag
e
0
20
40
60
80
100
NormalALT
HBV DNANegative
(PCR)
HBeAgNegative
HBsAgNegative
86
72
100
65
86
11
53*
8
P = .0001
P = .0001
Side effects in HBV patients are lower than HCV
1. Hadziyannis S, et al. Ann Intern Med. 2004;140:346-355. 2. Fried M, et al. N Engl J Med. 2002;347:975-982. 3. Zeuzem S, et al. Gastroenterol. 2004;127:1724-1732. 4. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217.
0 20 40 60 80 100
D/C
Dose Reduction
Fever
Fatigue
Myalgias
Rigors
Depression
HBV[4]
HCV[3]
HCV[2]
HCV[1]
PegIFN: Summary
• High rate of seroconversion with carefully selected patients– High ALT
– Favorable genotype
• Finite course of therapy
• No resistance (ever)
• Side effects are better with HBV– No Ribavirin
– Different patient group
Oral Nucleos(t)ide Analogues:
Durable and Dependable
Anti-viral Agents: Safety, Tolerability, Cost and
Risk:Benefit
LAM ADV Entecavir Telbivudine Tenofovir
Dosing QD QD QD QD QD
TolerabilityWell
tolerated
Well tolerated,
Watch serum Cr
Well tolerated
Well tolerated,
Watch CPK
Well tolerated,
Watch serum Cr
Pregnancy C C C B B
Approximate cost for 1 year
2,500 6,500 8,700 6,000 6,000
Potency Moderate Modest High High High
Resistance High Moderate Low High Low
Dienstag JL. New Eng J Med 2008;359:1486-500
HBeAg-positive Chronic HBVHBV DNA Suppression and HBeAg
Seroconversion at End of 1 year
44
21
6760
80
2112
21 22 21
0
10
20
30
40
50
60
70
80
90
LAM ADV ETV TBV TDF
HBV Undetectable HBeAg seroconversion
Dienstag JL. New Engl J Med. 2008
HBeAg-negative Chronic HBVHBV DNA Suppression at
End of 1 Year
7364
90 8895
0102030405060708090
100
LAM ADV ETV TBV TDF
HBV Undetectable
Dienstag, JL
Cumulative Incidence of HBV Resistance
24
0 0.24
0
38
30.5
22
0
49
11
1.2
67
18
1.2
70
29
1.20
20
40
60
80
LAM ADV ETV LdT TDF
%
Year 1 Year 2 Year 3 Year 4 Year 5
EASL Clinical Practice Guidelines. J Hepatol. 50(2009),doi:10.1016/j.jhep.2008.10.001; Dienstag JL. N Engl J Med;359:1486
Tenofovir
• Potent, predictable response
• Easy once per day regimen
• No food effect
• Long-term data (HBV and HIV)
• No issues with LAM resistance
• Category B in Pregnancy (in case his wife decides to get pregnant)
• Randomized, Double-Blind, Comparison of TDF vs. ADV for HBeAg(+) Chronic Hepatitis B
• HBV DNA >106 c/mL and ALT ≥2x and <10xULN• Knodell Necroinflammatory score ≥3
• Nucleos(t)ide Naïve• Week 48 Phase 3 data showed TDF superior to ADV:
– HBV DNA <400 copies/mL: 76% TDF vs. 13% ADV (p<0.001)• 96 week data presented
Study 103: Two Year TDFTreatment and ADV Switch Data
in HBeAg(+) with CHB
Heathcote E, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 158.
RA
ND
OM
IZA
TIO
N
1:1
Tenofovir 300 mg (n = 250)
Adefovir 10 mg
(n=125)
Double Blind
TDF 300 mg
TDF 300 mg
Open-Label
Week 240Liver Biopsy
Week 48Liver Biopsy
Pre-treatment Liver Biopsy
Week 96 End of Study
HBV DNA ≥400 copies/mL option to add emtricitabine (FTC) to TDF in a fixed dose tablet
Week 72
Study 103: HBV DNA <400 copies/mL
• TDF demonstrated durable, potent antiviral activity through Week 96:
• 82% of pts viremic on ADV at wk 48 were <400 c/mL on TDF at wk 96
• No resistance to TDF detected after 2 years on TDF monotherapy
Heathcote E, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 158.
Perc
enta
ge (%
)
0
10
20
30
40
50
60
70
80
90
100
960
20
50
100
08 16 24 32 40 48 56 64 72 80 88
Weeks on Study
P=0.801
78%
78%
17690
16586
17489
17088
17288
17190
16889
16487
TDF-TDF n=ADV-TDF n=
ITT AnalysisRandomized Double Blind Open Label
On Treatment AnalysisRandomized Double Blind
Perc
enta
ge (%
)
0
10
20
30
40
50
60
70
80
90
100
960
20
50
100
08 16 24 32 40 48 56 64 72 80 88
Weeks on Study
Open Label
P=0.374
89%85%
17690
14279
17388
16585
16684
16085
14883
14481
TDF-TDF n=ADV-TDF n=
No Evidence of TDF Resistance at Two Years
• Genotypic changes observed at Week 96/last on TDF among HBeAg- and HBeAg+ TDF treated patients
Snow-Lampart A, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 977.
1
0
10
20
30
40
50
60
70
80
90
100HB eAg - (n =2)HB eAg + (n =12)
(1) (1)
(2)
(0)
(8)
(2)
Patie
nt P
erce
nt
Patients with HBV DNA ≥400 copies/mL
No Polymorphic Site Conserved SiteChange Changes Changes
0
10
20
30
40
50
60
70
80
90
00HB e Ag - (n =4)
HB e Ag + (n =3)(3)(2)
(1)(1)
(0)(0)
Patients Experiencing Virologic Breakthrough
No Polymorphic Site Conserved SiteChange Changes Changes
HBsAg Loss is observed with oral antivirals
• Loss of HSbAg has not been commonly seen with oral anti-HBV therapies
• Approximately 0.5% of HBsAg carriers will spontaneously clear HBsAg yearly
• TDF achieved HBsAg loss of 3.2% at week 48 and 5% at week 64
Snow-Lampart A, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 977.
Rates of HBsAg Loss in Approved Antiviral Therapies Among Treatment-
Naïve Patients with HBeAg+ CHB*
Loss of HBsAg
Standard IFN-
5 MU qd or 10 MU tiw 12-24 wk 7.8%
PegIFN 180 mcg qw
Wk 483%
PegIFN + Lamivudine
180 mcg qw + 100 mg 48 wk 3%
Lamivudine100 mg qd
48-52 wk<1%
Adefovir10 mg qd
48 wk0
Entecavir0.5 mg qd
48 wk2%
Telbivudine600 mg qd
52 wk0%
* Adapted from AASLD Guidelines, 2007.
Entecavir
• Potent predictable effect
• Easy once per day regimen
• Must take 2 hours away from food
• Long term data
• Likely to have resistance issues because of previous LAM exposure
• No data on pregnancy in female partners
Studies ETV-022/-901: Entecavir Therapy in HBeAg(+) CHB
Study DesignStudy Design
Han S, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 893.
ETVN=354
Responders [R]HBV DNA <0.7 MEq/mL by bDNA and HBeAg loss
Virologic Responders [VR]HBV DNA <0.7 MEq/mL by bDNA and HBeAg(+)
Non-responders [NR]HBV DNA ≥0.7 MEq/mL by bDNA
NR=19
VR=247
R=74
Week 48
21 Non-respondersAt Week 48 or who became non-responders during Year 2
151 Virologic RespondersAt Week 96
11 RespondersAt Week 48 or who became responders during Year 2 who relapsed during off-treatment follow-up
Week 144Week 96 5 Years
NR=8
VR=198
R=37
243
ETV-022 ETV-901
Studies ETV-022/-901: Proportion with HBV DNA <300 c/mL
Through 5 Years
Han S, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 893.
HBeAg(+) ETV Long-term Cohort (ETV-022→ETV-901)
94%91%89%83%
55%
67%
0
20
40
60
80
100
236/354 80/146 116/140 116/131 98/1 88/94
Year 1 Year 1 Year 2 Year 3 Year 4 Year 5
Ishak Fibrosis Score
Fibrosis Regression with continuous ETV
0
10
20
30
40
50
60
Baseline Week 48 Long-term
1
2
3
4
5
6
Missing
0
Pat
ien
ts (
n)
• 96% of patients in the Long-term Histology Cohort who received continuous treatment with ETV achieved histologic improvement
• All patients with advanced fibrosis/cirrhosis at baseline (Ishak fibrosis score ≥4) demonstrated an improvement in fibrosis
Liaw Y-F, et al. 59th AASLD; San Francisco, CA; October 31-November 4, 2008; Abst. 894.
Distribution of Ishak FibrosisScores at Baseline, Year 1, and Years 3–7
Viral suppression leads to improved clinical outcomes: HCC and ESLD
YF Liaw et al. N Engl J Med. 2004;351:1521-1531.
Time After Randomization (Months)
0
5
10
15
20
25
0 6 12 18 24 30 36
% W
ith D
isea
se P
rogr
ess
ion
Placebo (n=215)
YMDDm (n=209) (49%)
Wild Type (n=221)
YMDDm
Placebo
5%
13%
21%
WT
Oral agents: Summary
• Potent, once daily therapy
• High genetic barrier with carefully selected agents – TDF, ETV
• Very few side effects (particularly compared to PegIFN)
• Proven liver disease regression and prevention of ESLD/HCC
Discussion