hcv, un problema di salute globale
TRANSCRIPT
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XI Workshop SEIEVAIl Sistema Epidemiologico Integrato dell’Epatite Virale Acuta (SEIEVA) a 30 anni
dal suo avvio: riflessioni sullo stato dell’arte e prospettive futureISS ‐ Giovedì 17 dicembre 2015
HCV, un problema di Salute Globale
Stefano Vella
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TOLERABIL ITY
EFFICACY
IFN
IFN/RBV
PEG‐IFN/RBV
PEG‐IFN/RBV/TVRPEG‐IFN/RBV/BOC
PEG‐IFN/RBV/SMV
PEG‐IFN/RBV/SOF
48 WEEKS
24‐48 WEEKS
24 WEEKS
12 WEEKS
Dore GJ & Feld J. CID 2015
20 years
3 years
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• Several highly effective IFN-free DAA regimens for different genotypes
• No impact of HIV on HCV treatment outcomes
• HCV resistance testing of limited clinical relevance
• Some treatment individualization required (e.g. cirrhosis)
• Decompensated cirrhosis reversible, but not always
• Shorter duration (6-8 wks) pangenotypic regimens in development
HCV: recent developments in IFN-free therapy
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0
10
20
30
40
50
60
70
80
90
100
SOF/LDV PTV/OBV/DSV/RBV ASV/BCV/DCV GZR/EBR SOF/SMV
Naïve (12 wks)
Exp (12 wks)
Naïve (8 wks)
IFN-free DAA therapy: GT1 regimens
SVR12%
Zeuzem, NEJM 2014; Afdhal, NEJM 2014; Kowdley, NEJM 2014; Feld, NEJM 2014; Poordad, AASLD 2014; Zeuzum, ILC 2015; Kwo, ILC 2015
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0
10
20
30
40
50
60
70
80
90
100
SOF/LDV PTV/OBV/DSV/RBV SOF/DCV* GZR/EBR
HCVHIV/HCV
IFN-free DAA therapy: HCV vs HIV/HCV
SVR12%
Afdhal, NEJM2014; Naggie, CROI2015; Feld, NEJM2014; Rockstroh, WAC2014; Wyles, CROI2015; Zeuzem, ILC2015; Rockstroh, ILC2015; Poordad, ILC2015
GT1, treatment naïve, F0-4; 12 weeks duration
*HCV mono in post-transplant
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0
10
20
30
40
50
60
70
80
90
100
SOF/RBV SOF/DCV SOF/GS-5816
SVR12%
68/70 20/21
Lawitz E, et al. NEJM 2013; Everson G et al. ILC 2014; Wyles D et al. CROI 2015; Poordad F et al. ILC 2015
17/18
Treatment naïve and exp., 12 wks
IFN-free DAA therapy: GT2 regimens
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0
10
20
30
40
50
60
70
80
90
100
SOF/RBV SOF/DCV SOF/GS-5816
TN
TE
103/183 50/54 50/53
IFN-free DAA therapy: GT3 regimens
Lawitz E, NEJM 2013; Nelson DR, Hepatology 2015; Everson G, ILC2014; Pianko S, AASLD 2014
91/101 44/51
Treatment naïve and exp., 12 wks
SVR12%
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grazoprevir/elbasvir: Integrated Analysis for Patients with Cirrhosis
*Death (coronary artery disease)mFAS (modified full analysis set) excludes patients who discontinued treatment for reasons unrelated to study medication
88,991,4 93,9
100
No RBV +RBV No RBV +RBV12 Weeks 16 or 18
Weeks
Treatment Experienced
97,8 96,1 100 100
0
25
50
75
100
Patie
nts,
(%)
LTFU/EarlyDiscon. 1* 1* 0 0
SVR12 (mFAS†) 98.5% (135/137)
97% (73/75)
100% (56/56)
100%(6/6)
BreakthroughRelapse
11
11
00
00
135138
7376
5656
66
4854
7481
4649
4949
2* 1* 0 092.3% 92.5% 93.9% 100.0%(48/52) (74/80) (46/49) (49/49)
0 0 0 00 0 2 04 6 1 0
Jacobson I, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-22.
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GRAZOPREVIR/ELBASVIR for Treatment-naive Patients with HCV/HIV Co-infection and HCV GT1, 4 or 6
SVR24: Full Analysis Set
93,1% 93,1% 93,2% 92.9%
0%
25%
50%
75%
100%
All Patients GT1a GT1b GT4
Patie
nts,
%
All GT GT1a GT1b GT4Relapse, n (%) 5 (2.4) 4 (2.8) 0 (0) 1 (3.6)Other Failure Criteria, n (%) 10 (4.6) 6 (4.2) 3 (6.8) 1 (3.6)
Reinfection, n 2 1 1 0LTFU or discontinuedunrelated to VF, n
8 5 2 1
203/218
134/144
41/44
26/28
Rockstroh J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 210.
Open-label, Single-arm, Multicenter Study Across Europe, United States and Australia Treatment-naive Patients with HCV GT1, 4 Or 6 HCV/HIV Co-infection
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Future DAA combinations (2016-17)
Elbasvir(MK 8742)
2nd generationNS5A inh
Pangenotypic (± Gt3)
Grazoprevir(MK 5172)
2nd generationprotease inh.
Fixed dose combination of two or three DAAs
ABT 450/RProtease inh.
Daclatasvir
NS5A inh.
BeclabuvirPolymerase
Inh.Pangenotypic
MK 3682 (IDX 21437)Polymerase
Inh.
Sovaprevir(ACH-1625
Protease inh.
ACH-3102
NS5A inh.
ACH‐3422Polymerase
Inh.Pangenotypic (?)
‐ Ultra‐short therapy (4‐6 wks)‐ >95% SVR for all pts.‐Pangenotypic‐One‐pill regimen, no RBV
GS 5816
2nd generationNS5A inh.
Pangenotypic
Sofosbuvir
Nucleotidepolymerase inh.
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The development of interferon-free
HCV therapy is one of the major
advances in clinical medicine in
recent decades
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Key Attributes
• Extremely high efficacy (>95%)
• Well tolerated
• Once daily dosing
• Pangenotypic
• Short duration (6-8 weeks)
HCV treatment: in pursuit of “perfectovir”
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Key Attributes
• Extremely high efficacy (>95%)
• Well tolerated
• Once daily dosing
• Pangenotypic
• Short duration (6-8 weeks)
• Affordable
HCV treatment: in pursuit of “perfectovir”
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Sofosbuvir Medicaid restrictions in US
Barua S, et al. Ann Intern Med 2015
Liver disease stage
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Sofosbuvir Medicaid restrictions in US
Barua S, et al. Ann Intern Med 2015
Illicit drug use
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Prevalenza dell’infezione da HCV nel mondo
* Estimated number of chronically infected individuals (2010)
• Lavanchy D. Clin Microbiol Infect 2011; 17:107–115;CDC: http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter‐3‐infectious‐diseases‐related‐to‐travel/hepatitis‐c.htm.
Prevalence of HCV >10%5–10%2–5%
<1%No data
Africa28 M*
Americas14 M*
Europe18 M*
130–170 million people world wide are infected with HCV
Middle East16 M*
1–2%
China30 M
S. Korea 0.8 M
Japan3 M
N. Korea0.2 M
Australia0.2 M
India18 M
Indonesia9 M
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Prevalenza dell’infezione da HCV in Europa
Central Europe > 2.9 million
Western Europe > 10 million
East Europe > 6.2 million
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HIV/AIDS as a model of Global Health:
the battle towards universalaccess to antiretroviral drugs
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AIDS: A heavy toll so far…
Crisismanagement
StrategicResponse
75 million people infected with HIV
35 million people living with HIV
39 million AIDS‐related deaths
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HIV/AIDS: dramatic impact on life expectancy
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World AIDS ConferenceDURBAN, 2000
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At the country‐level, the HIV response is already having a dramatic impact on life expectancy
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• Pharmaceutical industry competition
• Discounting, risk‐sharing arrangements, volume taxation
• Compulsory licenses
• Advocacy/Activism
• Voluntary licenses (Gilead + Generic companies in 113 LMICs)
HCV treatment: drug price reform
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• IFN‐free therapy is enormous advance on IFN‐containing therapy
• Even advanced liver disease may be partially reversible
• Cost of starting treatment only at later stages: ongoing monitoring and care for residual liver disease after HCV eradication, potentially for decades
• Hopefully, drug price curve will continue downwards
• Potential for HCV treatment as prevention (at least in some settings)
CONCLUSION: interferon-free therapy access for all
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Incidence and Predictors of Hepatocellular Carcinoma Following SVR
Incidence of HCC with SVR 3.27/1000 PY (0.327% PY) and with no SVR 13.2/1000 PY (1.32% PY) [HR 0.358]
Age, DM, cirrhosis and G3 risk factors post SVR
VA Study Cohort
10,638 without HCC and 100 with HCC
10,865 without HCC and 425 with HCC
22,197 with HCV RNA tests available to determine SVR12
10,817 with SVR 11,380 without SVR
HCC Incidence Following SVR: By Cirrhosis
010%20%30%40%50%60%70%80%90%
100%
Cum
ulat
ive
inci
denc
eof
HC
C
0 1 2 3 4 5 6 7 8
Years After SVR
Cirrhosis
No Cirrhosis
El-Serag H, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 90.
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• IFN‐free therapy is enormous advance on IFN‐containing therapy
• Even advanced liver disease may be partially reversible
• Cost of starting treatment only at later stages: ongoing monitoring and care for residual liver disease and progression after HCV eradication, potentially for decades
• Hopefully, drug price curve will continue downwards
• Potential for HCV treatment as prevention (at least in some settings)
CONCLUSION: interferon-free therapy access for all