Nouveaux traitements contre l’hépatite C - Nephroblog · Anti-HCV drug development pipeline...
Transcript of Nouveaux traitements contre l’hépatite C - Nephroblog · Anti-HCV drug development pipeline...
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Francesco Negro Hôpitaux Universitaires de Genève
Nouveaux traitements contre l’hépatite C
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HCV infects >185 million people worldwide
HAJARIZADEH et al. Nat Rev Gastroenterol Hepatol 2013;10:553-562 NEGRO and ALBERTI. Liver Int 2011;31 Suppl 2:1-3
HANAFIAH et al. Hepatology 2013;57:1333-1342
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Hepatitis C: a chronic inflammatory liver disease leading to cirrhosis and
HCC F1
F3F4
F2
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Proportion of cirrhosis or HCC cases attributable to HCV (Europe)
PERZ et al, J Hepatol 2006;45:529-38
%
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Chronic HCV increases mortality from hepatic and non-hepatic diseases
▪ 23 820 adults in Taiwan prospectively followed since 1991/2 ▪ 1095 were anti-HCV positive; 69.4% had detectable HCV RNA
The REVEAL HCV Cohort Study
20
18
16
14
12
10
8
6
4
2
0
20
18
16
14
12
10
8
6
4
2
00 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20
Follow-up (years) Follow-up (years)
Cum
ulat
ive
mor
talit
y (%
)
Cum
ulat
ive
mor
talit
y (%
)
Hepatic diseases Extrahepatic diseasesAnti-HCV seropositives, HCV RNA detectableAnti-HCV seropositives, HCV RNA undetectableAnti-HCV seronegatives
Anti-HCV seropositives, HCV RNA detectableAnti-HCV seropositives, HCV RNA undetectableAnti-HCV seronegatives
p<0.001 for comparison among three groupsp<0.001 for HCV RNA detectable vs undetectable
p<0.001 for comparison among three groupsp=0.002 for HCV RNA detectable vs undetectable
12.8%
1.6%0.7%
19.8%
12.2%11.0%
LEE et al, J Infect Dis 2012;206:469–477
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The growing burden of mortality associated with viral hepatitis in the US, 1999-2007 (CDC)
LY et al, Ann Intern Med 2012;156:271-8
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How many die of …. ?
Deaths in 2010
HCV 57,000
HBV 31,000
HIV 8,000
Global Burden Disease Study 2010 (COWIE et al, EASL 2014, oral presentation #86)
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In Switzerland, HCV prevalence peaked in 2003, but HCV-associated healthcare costs (excluding treatment costs) will peak in 2030
BRUGGMANN et al, EASL 2014, poster 1285
2013 2030
Viremic cases 82,700 (37,200 – 93,400) 63,200 (25,900 – 71,800)
HCV-related costs (excluding treatment
89.6M (43.3M – 191.1M) 118.7M (43.9M – 282.9M)
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Treatment indications
• All treatment-naive and -experienced patients with compensated liver disease due to HCV should be considered for therapy
• Treatment should be prioritized for patients with advanced fibrosis (Metavir score F3 or F4)
• Treatment is justified in patients with Metavir score F2
• Indication for and timing of therapy should be individualized for patients with no or mild liver disease (Metavir scores F0 or F1)
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Endpoint of treatment
• The goal of treatment is to eradicate HCV infection to prevent cirrhosis, decompensated liver disease, HCC and death
• The endpoint is undetectable HCV RNA in serum 12 or 24 weeks after the end of treatment
• SVR corresponds to cure in 99% of patients, and is associated with improved clinical outcomes and survival
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Like any dogma, liver fibrosis is
reversible
D’AMBROSIO et al, Hepatology 2012;56:532-43
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SVR is associated with a reduction in liver-related mortality and risk of HCC
N=530 N=530
VAN DER MEER et al, JAMA 2012;308:2584-2593
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1 .MCHUTCHISON et al, N Engl J Med 1998;339:1485–92; 2. FRIED et al, N Engl J Med 2002;347:975–82;
3. MANNS et al, Lancet 2001;358:958–65; 4. HADZIYANNIS et al, Ann Intern Med 2004;140:346–55;
5. JACOBSON et al, N Engl J Med 2011;364:2405-2416; 6 . SHERMAN et al, N Engl J Med 2011;364:1014-1024;
7. POORDAD et al, N Engl J Med 2011;364:1195-1206
100
80
60
40
20
0
SVR
(%)
Sustained virologic response (SVR) after treatment of therapy-naïve HCV-1
2–7% IFN-α1
Early 1990’s
16–28% IFN-α
+ RBV1
1998
42–54%
PEG-IFN-α +
RBV2–4
2001
64–75%
PEG-IFN-α +
RBV +
PI5-7
2011
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...previr...buvir
...asvir
CORNBERG & MANNS, Lancet Infect Dis 2013;13:378-9
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Anti-HCV drug development pipeline
Danoprevir Roche
Ora
l A
nti
vira ls
Telaprevir Janssen
Boceprevir MSD
Simeprevir Janssen
Alisporivir Novartis
NS5B Nuc. Polymerase Inhibitors
NS3 Protease Inhibitors
Cyclophilin inhibitorsNS5B Non-nuc. Polymerase Inhibitors
NS5A inhibitors
2011 2012 2013 2014 2015 >20192016 2017 2018
NOT EXHAUSTIVE
Sofosbuvir Gilead
ABT450 AbbVie
ABT267 AbbVie
Mericitabine Roche
Faldaprevir Boehringer Ingelheim
1st wave
2nd wave
ABT333 AbbVie
Daclatasvir BMS
Ledipasvir Gilead
??
?
Asunaprevir BMS
MK-5172 Merck
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IFN-free combination options*NI PI NS5A NNI RBV Genotype
Nucleotide analogue-based Gilead Sofosbuvir GS-9451 Ledipasvir ± 1-4
Roche Mericitabine
Danoprevir/r Setrobuvir ± 1, 4
Nucleos(t)ide-free triple combo AbbVie ABT-450/r ABT-267 ABT-333 ± 1
BMS Asunaprevir Daclatasvir BMS791325 ± 1, 4
Janssen/GSK
Simeprevir GSK2336805
TMC647055 ± 1
Nucleos(t)ide-free second generation double combo Merck MK-5172 MK-8742 ± 1, 2, 4-6
Achillion ACH-2684 ACH-3102 ± 1
Off-label options (na) Sofosbuvir Simeprevir - 1
(na) Sofosbuvir Daclatasvir - 1-3
*VX-135 and deleobuvir are not shown since currently on hold
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Approvals expected in 2014
Sofosbuvir (SovaldiTM) Nucleotide polymerase inhibitor
400 mg qd, all genotypes High barrier to resistance
Simeprevir (OlysioTM) NS3/NS4A serine protease inhibitor
150 mg qd, genotypes 1 and 4 Low barrier to resistance
Daclatasvir (DaklinzaTM) NS5A inhibitor
60 mg qd, all genotypes Low barrier to resistance
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The new options for 2014
Sofosbuvir + Ribavirin
Sofosbuvir + Simeprevir (± Ribavirin)
Sofosbuvir + Daclatasvir (± Ribavirin)
Pegylated IFNα + Ribavirin + Sofosbuvir
Pegylated IFNα + Ribavirin + Simeprevir
Pegylated IFNα + Ribavirin + Daclatasvir
12 weeks
12 weeks
12-24 weeks
12-24 weeks
12 weeks + RGT 12/36
12 weeks + RGT 12
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LAWITZ et al, N Eng J Med 2013
P + R + sofosbuvir (NEUTRINO study) (HCV genotypes 1, 4-6; treatment-naive)
100
80
60
40
20
0
SVR1
2 (%
)
89%
HCV-1
100%
HCV-5, -6
261/292
100
80
60
40
20
0
SVR1
2 (%
)
92%
No cirrhosis
80%
Cirrhosis
252/273 43/54
96%
HCV-4
27/28 7/7
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JACOBSON et al, AASLD 2013; CHOE et al, AASLD 2013 FOSTER et al, EASL 2014; FDA AVDAC, October 24, 2013
P + R + simeprevir (QUEST-1/2 studies) HCV-1: role of subtype and Q80K substitution
100
80
60
40
20
0
SVR2
4 (%
)
58%
1a Q80K
84%
1a no Q80K
85%
1b
n=84 n=155 n=267
Prevalence of Q80K in the US: 1a, 32.5; 1b, 0.1%
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What about therapy-experienced HCV-1?
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Sofosbuvir in treatment-experienced HCV-1
• Phase II ELECTRON1: 1/10 (10%) reached SVR • No data from the NEUTRINO2 study, but....
100
80
60
40
20
0
SVR
(%)
90
NEUTRINO
1. GANE et al, N Engl J Med 2013;368:34-44 2. LAWITZ et al, N Engl J Med 2013;368:1878-87
50% would have reached SVR with PR
40% wouldn’t.... meaning that SOF + P + R for 12 weeks allows reaching SVR in ~80% of prior failures to P + R
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FORNS et al, EASL 2014 (abstract 13)
Retreatment of HCV-1 PR relapsers with simeprevir + PR
(PROMISE phase III study, SIM + P + R for 24-48 weeks)
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REDDY et al, APASL 2014
SVR1
2 (%
)
0
25
50
75
100
Prior null responders Prior partial responders
69
47
70
44
TVR + PRSMV + PR
102/234 110/238 101/145 100/146
Adjusted difference -2.8 95% CI: –11.3, 5.8*
Adjusted difference 1.5 95% CI: –9.0, 12.0*
HCV-1 prior therapy failures: simeprevir + PR (ATTAIN, non-inferiority phase III study)
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What about IFN-intolerant HCV-1?
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SMV + SOF ± RBV in treatment-naive and prior null responders, HCV-1 (COSMOS phase II study)
100
80
60
40
20
0
SVR
(%)
93
No ribavirin
93
79
96100
93 93 93
Ribavirin No ribavirin RibavirinWeeks
SULKOWSKI et al, EASL 2014; LAWITZ et al, EASL 2014
12 24 12 24 24 1212 24
COHORT 1 NR, F0-F2 (n=80)
SVR12
COHORT 2 Treatment-naive + NR, F3-F4 (n=84)
SVR12
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Sofosbuvir + Daclatasvir ± Ribavirin in HCV-1 (126 naive + 41 PI-experienced; 26 cirrhotics; AI444040 phase II study)
SULKOWSKI et al, N Engl J Med 2014 Jan 16 [ePub ahead of print]
100
80
60
40
20
0
SVR2
4 (%
)
93*
S7 + SD23
100 10095* 93*
100**95**
SDR24 SDR12 SD24n 15 14 15 41 2141 20
Treatment-naive PI-experienced
SD24 SD12 SDR24
*Considering 4 SVR36 and 1 reinfection, true SVR = 99% (125/126) **SVR12 available only; considering 1 SVR24, true SVR = 100%
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2014: the different options for HCV-2
1. MANGIA et al, N Engl J Med 2005;352:2609-17; 2. FOSTER et al, Gastroenterology 2011;141:881-9
3. LAWITZ et al, N Engl J Med 2013;368:1878-87; 4. JACOBSON et al, N Engl J Med 2013;368:1867-77
100
80
60
40
20
0
SVR
(%)
89
PR1 24
100
TPR2 2/24Weeks
(RVR)
87
PR1 12
(RVR)
SOF + R4 12
SOF + R4 12
SOF + R4 16
9198
949296
60
100
78
SOF + R3 12
F4F4F4F4
(therapy-naive)
F4
82
62
PR3 24
PR3 24
(IFN-ineligible)(therapy-experienced)
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LAWITZ et al, AASLD 2013
P + R + sofosbuvir (LONESTAR-2 study) Phase 2, 12 weeks, HCV-2, treatment experienced
100
80
60
40
20
0
SVR2
4 (%
)
100%
No cirrhosis
94%
Cirrhosis
n=9 n=14
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2014: the different options for HCV-3
1. MANGIA et al, N Engl J Med 2005;352:2609-17; 2. LAWITZ et al, N Engl J Med 2013;368:1878-87
3. JACOBSON et al, N Engl J Med 2013;368:1867-77; 4. ZEUZEM et al, N Engl J Med 2014
100
80
60
40
20
0
SVR
(%)
100
PR1 24Weeks
(RVR)
77
PR1 12
(RVR)
SOF + R3 12
SOF + R3 12
SOF + R3 16
34
61
21
68
37
19
63 61
SOF + R2 12
F4F4F4F4
(therapy-naive)
F4
71
30
PR2 24
PR2 24
(IFN-ineligible) (therapy-experienced)
SOF + R4 24
87
60
F4
SOF + R4 24
94 92
F4
(therapy-naive)
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LAWITZ et al, AASLD 2013
P + R + sofosbuvir (LONESTAR-2 study) Phase 2, 12 weeks, HCV-3, treatment experienced
100
80
60
40
20
0
SVR2
4 (%
)83%
No cirrhosis
83%
Cirrhosis
n=12 n=12
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In 2014, all SOF-based options for treatment-naive HCV-4 to 6 will still contain PR
1. ANTAKI et al, Liver Int 2010;30:342-55 2. LAWITZ et al, N Engl J Med 2013;368:1878-87
100
80
60
40
20
0
SVR
(%)
PR1 48
96
SOF + PR2 12Weeks
G-4 G-5 G-6
43-70 60
60-85
100
SOF + PR2 12
100
SOF + PR2 12
PR1 48
PR1 48
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MORENO et al, EASL 2014, late breaking poster 1319
P + R + Simeprevir (treatment-naive or -experienced HCV-4: Phase III RESTORE
trial)
100
80
60
40
20
0
SVR2
4 (%
)
83%
Naive
86%
40%
NRn=35 n=22 n=40
60%
n=10
PRRR
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Patients with an indication for liver transplantation
• Patients with compensated cirrhosis and HCC should be treated with sofosbuvir + ribavirin until liver transplantation
• IFN-free combinations (sofosbuvir + simeprevir or sofosbuvir + daclatasvir) should be preferred
• Finite (12 weeks) therapy with sofosbuvir, pegylated IFNα and ribavirin is also acceptable (if tolerated)
• Patients with cirrhosis should undergo surveillance for HCC independently of SVR
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Impaired renal function
• These patients should receive an IFN-free (and possibly ribavirin-free) regimen
• No safety and efficacy data is available in this population, and the need for dose adjustments for sofosbuvir, simeprevir and daclatasvir is unknown
• Sofosbuvir and simeprevir should not be administered to patients with eGFR <30 mL/min/1.73 m2 or with end-stage renal disease until more data is available
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Sofosbuvir in ESRD
• Renal clearance of major metabolite GS-331007 • Trial ongoing in ESRD, no interim data available • Relative to patients with normal kidney function, exposure to
SOF was 61%, 107% and 171% higher in mild, moderate and severe renal impairment
• SOF exposure is increased by 28% when given 1 h before HD, and by 60% when dosed 1 h after HD
• Hemodialysis can efficiently remove GS-331007 (53% extraction ratio)
• SOF not recommended when eGFR <30 ml/min
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Simeprevir in ESRD
• Exposure increased in ESRD even if most metabolism is hepatic
• Removal of SIM by HD is unlikely due to significant protein binding
• SIM contraindicated when eGFR <30 ml/min
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Determine stage of chronic kidney disease
Stage 1 and 2 (≥60 eGFR)
PEG-IFN-α + RBV (titrate dose
according to tolerability)
Stage 3 to 5 PEG-IFN-α alone
(titrate dose according
to kidney function)
Stage 5D and maintenance
hemodialysis IFN-α or PEG-IFN-α adjust dose for GFR <15 ml/min/1.73 m2
If SVR, re-test for serum HCV RNA every 6 months and continue surveillance for HCC in cirrhotics
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Therapy of Hepatitis C in HD Patients
• All HD patients with compensated hepatitis C are candidates to IFN-α therapy
• Combination with ribavirin should be limited to clinical trials
• Patients with non-significant fibrosis (F0-F2) should also be placed on a kidney transplant waiting list
• Patients with advanced fibrosis should be treated and placed on kidney transplant waiting list if SVR
• Consider simultaneous liver/kidney transplant in patients with decompensated liver disease
BERENGUER, Hepatology 2008;48:1690-9
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2015
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Sofosbuvir/ledipasvir (single pill, once a day) ± RBV Results of phase III studies
Study Population Treatment Duration SVR12
ION-1HCV-1
treatment-naive (incl. 136/865 or
15.7% with cirrhosis)
SOF/LDV 12 weeks 99%SOF/LDV + RBV 12 weeks 97%
SOF/LDV 24 weeks 98%SOF/LDV + RBV 24 weeks 99%
ION-2HCV-1
treatment-experienced
(including 88/440 or 20% with cirrhosis)*
SOF/LDV 12 weeks 94%SOF/LDV + RBV 12 weeks 96%
SOF/LDV 24 weeks 99%SOF/LDV + RBV 24 weeks 99%
ION-3HCV-1
treatment-naive (all non-cirrhotics)
SOF/LDV 8 weeks 94%SOF/LDV + RBV 8 weeks 93%
SOF/LDV 12 weeks 95%*Includes patients treated with PI-containing regimens
AFDAHL et al, N Engl J Med 2014; AFDAHL et al, N Engl J Med 2014
KOWDLEY et al, EASL 2014
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All non-cirrhotics !
8-9 pills a day…
FELD et al, EASL 2014
ABT-450/r/ombitasvir qd + dasabuvir bid + R bid, 12 weeks
(SAPPHIRE-1 phase 3 study, HCV-1, n = 631 treatment-naive)
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ABT-450/r/ombitasvir qd + dasabuvir bid + R bid, 12 weeks
(SAPPHIRE-2 phase 3 study, HCV-1, n = 394 treatment-experienced)
ZEUZEM et al, EASL 2014
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POORDAD et al, EASL 2014
119 cirrhotics
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POORDAD et al, EASL 2014
263 cirrhotics
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IFN-free treatments: a summary
• Highly effective (>90% SVR) • Virtually no side effects • Simplified treatment schedules
– Short duration, only a few pills – No more response-guided treatment – Baseline features have less
influence on response (exceptions: cirrhosis, HCV-3)
• Negligible resistance
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HCV treatment: the next challenges
• Impact on long-term public health burden may require increased treatment uptake via increased diagnosis via ample screening strategies and proper linkage to care
• Treatment as prevention may become a reality (PWID, HIV+ MSM, heavy injectors)
• Treatment capacity will be constrained • [cost per treatment] x [volume] will explode
in the absence of agreements with the industry
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HCV treatment: the next challenges
• Impact on long-term public health burden may require increased treatment uptake via increased diagnosis via ample screening strategies and proper linkage to care
• Treatment as prevention may become a reality (PWID, HIV+ MSM, heavy injectors)
• Treatment capacity will be constrained • [cost per treatment] x [volume] will explode
in the absence of agreements with the industry
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Increasing SVR to 90-95% by 2016 will decrease HCV-related HCC cases and liver-related mortality by 10% in
2030
380
650
580400
740
670
• Increasing SVR while maintaining an annual treatment uptake of 1,100 patients will decrease HCC and liver-related mortality by 10% by 2030
• Total viremic infections will decrease by 7% vs base case
BRUGGMANN et al, EASL 2014, poster 1285
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Only increasing SVR to 90-95% by 2016 and treating 3,940 patients by 2018 will decrease HCV liver-related mortality by 80%
650
400
• The proposed scenario would require the diagnosis of 4,740 new viremic infections annually by 2020 (as compared with 1,050 in 2013)
• Expanding treatment access to ≥F0 patients would require treatment of 6,320 annually by 2018 to achieve the same reduction in HCC cases and liver-related mortality
• An estimated CHF 735 M and CHF 742 M in healthcare cost savings (excluding scenario and treatment costs) was projected for the scenario treating 3,940 ≥ F2 patients and 6,320 ≥ F0 patients, respectively
380
130
740
160
150 120
BRUGGMANN et al, EASL 2014, poster 1285
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Risk-based screening?• Risk screening in all those >20 yrs could have
identified 82% of all HCV infections, but in fact has failed to do so
TOMASZEWSKI et al, Am J Public Health 2012;102:e101-6
!• Despite risk-based screening policies, 25-50%
of patients are unaware of their infection !
• General population screening?
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Baby boomer generation: “Rock’n’roll, drugs, sexual liberation,
shaggy hair and.... HCV”*
• Persons born between 1945 and 1964 (baby boomers) account for 27% of the US population and 76% of all HCV infections
• Testing (and treating) baby boomers for HCV irrespective of risk factors would avert 47,189 more HCC, and 15,484 more liver transplant than risk-based screening
MMWR Recomm Rep 2012 Aug 17;61(4):1-32
*Jon Cohen, Science, 24 August 2012
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HCV treatment: the next challenges
• Impact on long-term public health burden may require increased treatment uptake via increased diagnosis via ample screening strategies and proper linkage to care
• Treatment as prevention may become a reality (PWID, HIV+ MSM, heavy injectors)
• Treatment capacity will be constrained • [cost per treatment] x [volume] will explode
in the absence of agreements with the industry
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Reducing the HCV prevalence among PWIDModeling the impact of antiviral therapy, opiate substitution
(OST) and needle/syringe exchange programs (HCNSP) scale-up
MARTIN et al, Clin Infect Dis 2013;57(suppl 22):S39-45
Treating with
peg/riba
Treating with
IFN-free DAA
Lines indicate the relative reduction in HCV prevalence at 10 years
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BRUGGMANN P. Hepatology 2013;58:1523-5
• Treat irrespective of the risk of reinfection (people at risk of reinfection are the most likely to spread HCV)
• Decriminalize drug use • Lower the cost of drugs (or face the consequences
of patent flexibility policies)
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Sexual transmission of HCV among HIV+ MSM
• Incidence of HCV among HIV-positive MSM has increased significantly after 19961: – 0.23 per 100 py (1998)2 – 4.09 per 100 py (2011)2
• Risk factors predisposing to HCV seroconversion: – History of inconsistent condom use2 – Past syphilis2 – Unprotected anal intercourse with multiple partners3
• Reinfection after eradication is possible3
1VAN DE LAAR et al, Gastroenterology 2009;136:1609-17
2WANDELER et al, Clin Infect Dis 2012;55:1408-16 3COTTE et al, Gastroenterol Clin Biol 2009;33:977-80
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HCV transmission via medical injections involve a core group of « heavy injectors »
The hypermedicalized 5% of the population receives >50% of all injections: they are the first ones to be infected and the first ones to transmit
Zwyat Razin, 2002, n=4020
BREBAN et al, EASL 2013
Should they be the first to be treated to prevent further spread?
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HCV treatment: the next challenges
• Impact on long-term public health burden may require increased treatment uptake via increased diagnosis via ample screening strategies and proper linkage to care
• Treatment as prevention may become a reality (PWID, HIV+ MSM, heavy injectors)
• Treatment capacity will be constrained • [cost per treatment] x [volume] will explode
in the absence of agreements with the industry
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ARONSOHN & JENSEN, Hepatology 2013 June 20 [ePub ahead of print]
• Complex, individualized care is not the solution for the control of the HCV epidemic
• Future regimens will be simple, allowing to expand the access to treatment by task shifting (as successfully adopted for HIV by the WHO)
• Recruit and train mid-level providers and primary care physicians as new treaters
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HCV treatment: the next challenges
• Impact on long-term public health burden may require increased treatment uptake via increased diagnosis via ample screening strategies and proper linkage to care
• Treatment as prevention may become a reality (PWID, HIV+ MSM, heavy injectors)
• Treatment capacity will be constrained • [cost per treatment] x [volume] will explode
in the absence of agreements with the industry