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L’infettivologia del terzo millennio: non solo AIDS Paestum 18-20 maggio 2006. Terapia dell’Epatite cronica HCV correlata: Peg-IFN/ribavirina e che altro?. T. Santantonio. Malattie Infettive Università degli Studi di Bari. Milestones in Therapy of Chronic Hepatitis C. 1986. 1998. - PowerPoint PPT Presentation
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Terapia dell’Epatite cronica HCV correlata:
Peg-IFN/ribavirina e che altro?
L’infettivologia del terzo millennio: non solo AIDSPaestum 18-20 maggio 2006
T. Santantonio
Malattie Infettive Università degli Studi di Bari
Milestones in Therapy of Chronic Hepatitis C
Strader et al Hepatology 2004
0
10
20
30
40
50
60
6
16
34
42 39
54-56
1986 1998 2001 2002
IFN6m
IFN12m
IFN/RBV6m
IFN/RBV12m
PEG12m
PEG/RBV12m
Sust
aine
d Vi
rolo
gic
Res
pons
e
Sustained Virologica Response according to genotype
0
20
40
60
80
100
PegIFNa2b + RBV PegIFNa2a + RBV
42%
82%
46%
76%
Manns et al Lancet 2001, Fried et al NEJM 2002
Genotype 1 Genotypes 2/3
% S
VR
Virological determinants of treatment outcomeSu
stai
ned
Viro
logi
c R
espo
nse
Difficult to treat
Easy to treat
0102030405060708090
100
HCV-2HCV-1
High viremia
HCV-3
High viremia
HCV-4HCV-1
Low viremia
HCV-3
Low viremia
30%
50%60%
70%80%
90%
Therapy of HCV - 2006
Whom to treat
All patients are potential candidates
Priority should be for:• Progressive/advanced disease• Highly motivated patients• Young patients• Easy-to-treat
Exclusions are:• Major contraindications• Decompensated liver disease
Therapy of HCV - 2006
How to treat
HCV-2/3 Peg-IFN/RBV 800-1000 mg x 6 mo
HCV-1/4 Peg-IFN/RBV 1000-1200 mg x 12 mo
Stopping rule for HCV-1 at 12-24 weeks
80/80/80 adherence rule important (particularly for HCV-1)
Attempts to optimize therapy
Some patients might be OVERTREATEDSome patients might be UNDERTREATED
Better Tailoring the Current Therapy
Development of New Therapies
DIFFICULT-TO-TREAT SUBGROUPS
Genotype 2 & 3
Shorter duration ?
• increase tolerability
• lower costs
Better Tailoring the Current Therapy
SVR in Patients HCV-2/3, 14 vs. 24 Weeks PEG-IFN -2b 1.5 g/kg QW + ribavirin 800-1,400 mg/day, N=122
82% 90%
56%
0%
20%
40%
60%
80%
100%
% o
f Pat
ient
s
Overall, (N=122) PCR Negative at week 4/8,14 weeks Tx., (n=95)
PCR Positive at week 4/8,24 weeks Tx., (n=27)
Dalgard O. et al. Hepatology 2004;40:1260 –1265.
78% of Patients were PCR Negative at Week 4/8.
SVR in HCV-2/3 Patients PCR neg at week 4/8 14 Week Tx.
PEG-IFN -2b 1.5 g/kg QW + ribavirin 800-1,400 mg/day
92%88%
98%
79%
0%
20%
40%
60%
80%
100%
% o
f Pat
ient
s
HCV 2 < 600 000 IU,
(n=13)
HCV 2 ≥ 600 000 IU,
(n=8)
HCV 3 < 600 000 IU,
(n=40)
HCV 3 ≥ 600 000 IU,
(n=33)
*
* p=0.019, G3a LVL vs HVL.Dalgard O. et al. Hepatology 2004;40:1260 –1265.
PEG-IFN 2b 1.0 g/Kg/week + RIBA 1000-1200 mg/day
STANDARD REGIMEN (70 pts)
VARIABLE REGIMEN (213 pts)
Week 4 HCV-RNA (Amplicor)
neg pos
12 wks 24 wks
week 4 neg 89% 87% HCV-2 76%
week 4 pos 50% 72%
week 4 neg 100% 77% HCV-3 76%
week 4 pos 43% 41%
24 wks
Mangia et al. NEJM 2005
S V R
Relapse Rates
-2%
-8%-10%*
-6%
-20%
-10%
0%
% o
f Pat
ient
s
PCR Neg. at week 4,24 weeks Tx., (n=42)
PCR Pos. at week 4,24 weeks Tx., (n=13)
PCR Neg. at week 4,12 weeks Tx., (n=126)
PCR Pos. at week 4,24 weeks Tx., (n=54)
*P=0.19, In patients PCR negative at week 4, 12 vs. 24 weeks Tx.
Mangia A. N Engl J Med 2005;352:2609-17.
Standard duration Variable duration
PEG-IFN 2a 180 g + RIBA 800-1200 mg/day (n=153)
Week 4 HCV-RNA (Monitor)
< 600 IU/mL (n=142)
16 wks (71) 24 wks (71)
> 600 IU/mL (n=11)
randomized
HCV-2 All 95% 95%HVL 93% 93% 1/1 100%LVL 100% 100%
HCV-3 All 76% 75%HVL 54% 67% 3/9 33%LVL 93% 84%
24 wks
S V R
Von Wagner et al, Gastroenterology 2005
- 20%
- 10% - 7% - 5%- 12% - 9%
(12 vs 24 wks) (16 vs 24 wks)
AE requiring dose reduction
Withdrawal
Mangia 2005(PEG-IFN 2b)
Von Wagner 2005(PEG-IFN 2a)
Overall Safety / Tolerability
ACCELERATE: study design
PEG-IFN -2a 180 g/wk plus RBV 800 mg/day Follow-up
Study week0 32168 24 40 48
n=1469
PEG-IFN -2a 180 g/wk plus RBV 800 mg/day
Follow-up
Randomisation. Treatment duration blinded until week 16
Shiffman M, et al. 41st EASL 2006; Abstract 734
732
731
THE ACCELERATE TRIAL
MAIN CONCLUSIONS
PEG-IFN Alfa-2a plus 800 mg Ribavirin• 24 wks better than 16 wks for HCV-2 and
HCV-3 due to higher relapse rates with shorter therapy
Shiffman et al EASL 2006
New Schedule of Treatment for Rapid Responders
HCV-2
Week 4 – HCV-RNA
Neg Pos
Treat for 12-16 wks Treat for 24 wks
Solid with full WBD ribavirin
Same for HCV-3 ?
Same for advanced disease ?
Genotype 1 & Rapid Virologic Response
Shorter duration ?
• increase tolerability
• lower costs
Better Tailoring the Current Therapy
Virologic Response Rates in HCV-1 (≤600,000 IU/mL), 24 vs. 48 Weeks
PEG-IFN -2b 1.5 g/kg QW + ribavirin 800-1400 mg/day
81%
50%
0%
20%
40%
60%
80%
100%
% o
f Pa t
i en t
s
EOT SVR
74% 71%
0%
20%
40%
60%
80%
100%
% o
f Pa t
i en t
s
EOT SVR
1. Zeuzem et al, J Hepatol 20062. Manns et al, Lancet 2001
24 Weeks Tx.1, N=235 48 Weeks Historical Control48 Weeks Historical Control2, 2, N=38N=38
SVR Rates by First Time to PCR Negativity in HCV-1 (≤600,000 IU/mL), 24 vs. 48 Weeks Tx.
PEG-IFN -2b 1.5 g/kg QW + ribavirin
89%
25%17%
0%
20%
40%
60%
80%
100%
% o
f Pa t
i en t
s
4, (n=110) 12, (n=61) 24, (n=24)
85%93%
67%
0%
20%
40%
60%
80%
100%
% o
f Pat
ient
s
4, (n=13) 12, (n=15) 24, (n=3)
24 Weeks Tx.1, N=235 48 Weeks Historical Control48 Weeks Historical Control2, 2, N=38N=38
1. Zeuzem et al, J Hepatol 20062. Manns et al, Lancet 2001
Discontinuation and Dose Reductions for Adverse Events HCV-1 (≤600,000 IU/mL), 24 vs. 48 Weeks Tx.
PEG-IFN -2b 1.5 g/kg QW + ribavirin
24 Weeks Tx., N=2351
48 Weeks Historical control, N=382
Discontinuation 3% 25%
Dose reductions 14% 49%
1. Zeuzem et al, J Hepatol 20062. Manns et al, Lancet 2001
89
16
73
35
0
20
40
60
SVR
(%)
Patients with an RVR at week 4
88 91
80
23
44
100
Patients without an RVR at week 4
n= 18 33 40 55 81 84 208 210
24-LD24-SD
48-LD48-SD
LD = RBV 800 mg/day; SD = RBV 1000–1200 mg/day; RVR = HCV RNA <50 IU/mL at week 4 Jensen D, et al. AASLD 2005
PEG IFN 2a + RBV: comparison of SVRs in Genotype 1 patients with and without RVR
(n=729)
Week 4 - qualitative HCV-RNA
Week 12 - quantitative HCV-RNA Week 12 - quantitative HCV-RNA
Negative PositivePositive
Treat for 24 wks
> 2 log
Treat for 48 wks
< 2 log
Stop(or shift to
suppressive therapy)
New Schedule for Rapid RespondersHCV-1
Applicable only to patients with LVL
and without cirrhosis
WHAT ABOUT SLOW RESPONDERS ?
0 12 24 48 72
HC
V R
NA
Fast RespondersSlow responders
Time HCV RNA negative
Level of detection
End of Treatment
Adapted from Bekkering F. et al, Hepatology, 2001, Buti M. et al, Hepatology, Vol. 35, No. 4, 2002
Time HCV RNA negative
Genotype 1 & Slow Virologic Response
Longer duration ?
• increase response rate
• decreased tolerability
• higher costs
Better Tailoring the Current Therapy
Extended treatment duration for HCV type 1: comparing 48 vs 72 weeks of PEG-IFN α-2a plus Ribavirin
Berg et al Gastroenterology 2006
Extended treatment duration for HCV type 1: comparing 48 vs 72 weeks of PEG-IFN α-2a plus Ribavirin
Berg et al Gastroenterology 2006
Follow-up
Follow-up
A prospective, randomised clinical trial in genotype 1 or 4 patients
Randomisation
0 72Week 4; RVR 24 48 96
No RVR AND EVR: Peg-iFN -2a 180 g/wk + RBV 1000-1200 mg/day
No RVR AND EVR: Peg-IFN -2a 180 g/wk (48wks) then 135 g/wk (24wks) + RBV 1000-1200mg/day
RVR: Peg-IFN -2a 180 g/wk +RBV1000-1200
Follow-up
Follow-up
Week 12; EVR
No RVR AND No EVR: Peg-IFN -2a 180 g/wk +RBV 1000-1200mg/day
n=26
7
n=104
Ferenci P, et al. EASL 2006
RVR = HCV RNA <50 IU/mL at week 4, EVR = HCV RNA <600 IU/ml or >2-log10 drop at week 12
Attempts to optimize therapy
Some patients might be OVERTREATEDSome patients might be UNDERTREATED
Better Tailoring the Current Therapy
Development of New Therapies
DIFFICULT-TO-TREAT SUBGROUPS
Potential targets and approaches in the next 5 years
Treatment of chronic hepatitis C
New IFNs
• Albumin-linked IFN alfa• Peg-Consensus IFN• Gene-shuffled IFN• “oral IFN inducers”
Potential targets and approaches in the next 5 years
Potential antiviral targets and approaches
New IFNs Ribavirin analogues
• Viramidine
Potential targets and approaches in the next 5 years
Potential antiviral targets and approaches
New IFNs Alternative “ribavirin-like” drugs
Specific HCV Inhibitors
• NS3 Protease Inhibitors• NS5B RNA Polymerase Inhibitors• IRES inhibitors (antisense oligonucleotides, ribozymes, siRNAs)• Other HCV inhibitors
Potential targets and approaches in the next 5 years
Treatment of chronic hepatitis C
New IFNs Immune Therapies
Alternative “ribavirin-like” drugs
Specific HCV Inhibitors
• Thymosin alfa-1• IL-10• Histamine• HC Ig• Therapeutic vaccine
Therapies in Development for HCV
Levovirin
Dev
elop
men
t Sta
ge
Phase II
On Market
Phase III
Phase I
Research
Preclinical
Thymosin
HCV Vaccines
Other IFNs
Many others includingAntisense
AntifibroticsImmune stimulants
Gene therapy
Ribozymes
E2 Vaccine
Ribavirin
Antisense
HCV Immunotherapy
Levovirin
Viramidine
Gamma IFN Histamine HCl
IL 10 & IL 12others
IMPDH inhibitors
Apoptosis Inhibitors
siRNA
IFN & PEG IFN
Polymerase inhibitors
Protease Inhibitors