24 Enero 2015
Dr. Javier de la Cabada Bauche
Hotel Riu
NUEVAS ESTRATEGIAS EN EL MANEJO DE HEPATITIS C
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Virus de Hepatitis C
1989 se identifica Virus
Familia Flaviviridae
Virus muy heterogéneo con diversidad genética
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Heterogéneo Virus
6 genotipos identificados:
– Los mas comunes: 1a, 1b, 2a, and 2b
GT 1
GT 1
GT 3
GT 3
GT 5
GT 6
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clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
Evaluación Pts con historia de exposición
– Basal- Ac Anti-HCV, RNA VHC, transaminasas
– 4 semanas post exposición: RNA VHC y transaminasas
– 3 meses post exposición: Ac Anti-VHC, RNA VHC y
Transaminasas
– 6 meses: Ac Anti-VHC
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Incidencia
La prevalencia es de 1.4%.
Norte (2.0%) Sur (1.5%) y las entidades del centro (1.1%) del país.
La incidencia se estima en 19 300 nuevos casos por año
2005, la cirrosis hepática (complicación tardía de la hepatitis C) fue la tercera causa de mortalidad en hombres
Salud Pública Méx 2011; Vol. 53(1):61-67
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Metas en el Tratamiento Antiviral
Erradicar RNA VHC
– SVR (Respuesta Virológica Sostenida) 24 semanas post tx.
– SVR se asocia a 97-100% CV negativa= CURA
– 1-4% recaída en SVR
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clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
Liang TJ, Ghany MG. N Engl J Med 2013;368:1907-1917
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
Liang TJ, Ghany MG. N Engl J Med 2013;368:1907-1917
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
Tratamiento para Hepatitis C
1991 20010
20
40
60
80
100
8-12
SV
R (
%)
15-20
38-43
25-30
50-60
1995 1998
Standard interferon
(6 m)[1]
interferonestándar(12-18 )[2,3]
Interferon/ribavirina(6-12 m)[3,4] PegIFN
monoterapia(6-12 m)[5,6]
PegIFN/ribavirin(6-12 m)[6,7]
2011
70-75
PI + PegIFN/RBV(6-12 m)[8-10]
1. Carithers RL Jr., et al. Hepatology. 1997;26(3 suppl 1):83S-88S. 2. Zeuzem S, et al. N Engl J Med. 2000;343:1666-1672. 3. Poynard T, et al. Lancet. 1998;352:1426-1432. 4. McHutchison JG, et al. N Engl J Med. 1998;339:1485-1492. 5. Lindsay KL, et al. Hepatology. 2001;34:395-403. 6. Fried MW, et al. N Engl J Med. 2002;347:975-982. 7. Manns MP, et al. Lancet. 2001;358:958-965. 8. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 9. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 10. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024.
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Historia de Tratamiento
Interferon (1) Citocinas
– Alpha interferon (formerly known as leukocyte interferon)
– Interferon alfa-2b (pegilado= polietinelglicol)
– Interferon alfa-2a
– Beta interferon (formerly known as fibroblast interferon)
– Gamma interferon (formerly known as immune interferon)
– Therapy of hepatitis C: meta-analysis of interferon alfa-2b trials. Hepatology. 1997;26(3 Suppl 1):83S.
(1) Am J Gastroenterol. 1999;94(3):581.
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Historia de Tratamiento
Ribavirina
(Combo J Hepatol. 1995;23 Suppl 2:8. / Gastroenterology. 1996;111(5):1307.)
– Análogo nucleosido con actividad antiviral amplio espectro
– Disminuye VHC dosis dependiente.
Nature. 2004;432(7019):922.
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Interferon
Poca respuesta en pacientes con cirrosis
IDEAL pegINF alfa -2a vs alfa-2b
Tasa curación:
–GT 1 Fibrosis F3/F4 24%
–GT 1 Fibrosis F1/F2 44%
– INF + RIB 44%
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clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
`
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clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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Tasa de RVS global en el estudio SPRINT-2 BOC+PegIFN+RBV en Pts sin tx previo
20
Adaptado de Poordad y cols., 2011.
Aumento de ~1.7 veces en la RVS
TGR BOC
242/366
137/363
233/368 242/366
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Tasas de RVS global en el estudio RESPOND-2 Pts en Recaída o Respondedores parciales
21
Bacon y cols., 2011.
Aumento de ~3 veces en la RVS
TGR BOC
17/80
95/162107/161
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PROVIDE: Terapia triple con Boceprevir en pacientes tratados previamente
En RESPOND-2 no incluyeron respondedores nulos.
Un brazo único, multicentrico en pacientes bien caracterizados de estudios previos que recibieron el brazo pegIFN/RBV en estudios fase II/III con BOC
– Se incluyeron respondedores nulos deRESPOND-2 y SPRINT-2: < 2 log decline in HCV RNA después de12 semanas de tx con pegIFN/RBV (N = 52)
– 4-semanas de pegIFN/RBV lead-in seguido por 44 semanas con triple terapia
Bronowicki J, et al. EASL 2012. Abstracto 11.
SVR de acuerdo a respuesta previa 100
80
60
40
20
0
40 (19/47)
68 (53/78)
56 (5/9)
Nulos Parciales Recaída
Pac
ient
es (
%)
Respuesta previa
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100
0
60
RV
S(%
)
80
40
RVS en pacientes con tratamiento previoRecaída, Respondedores Parciales, Respondedores Nulos
Se evaluó la terpapia de Inducción (Lead-in) pero no demostró influencia por lo que no se incluyo en la recomedación de la marca para TRV
Recaídas Previas Respondedores Parciales
n/N=
Respondedores Nulos
*P < .001 vs PR48.
REALIZE: TVR + PegIFN/RBV en G1: Recaída, Respondedores Parciales/Nulos
20
121/145 124/141
83*88*
16/68
24
29/49 26/48
59*54*
4/27
15
21/72 25/75
29*33*
2/37
5
T12/PR48PR48 LI T12/PR48
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
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REGLAS DE TRATAMIENTO CON BOCEPREVIR+ PegIFN+RIBA
TIPO DE PACIENTES TRATAMIENTO
CIRROTICOS LEAD IN 4 SEMANASTRIPLE TERAPIA 44 SEMANAS
RESPONDEDORES NULOS EN TRATAMIENTO PREVIO
LEAD IN 4 SEMANASTRIPLE TERAPIA 44 SEMANAS
PACIENTES VIRGENES CON DISMINUCION EL HCV RNA <1 LOG EN LA FASE DE INDUCCION
LEAD IN 4 SEMANASTRIPLE TERAPIA 44 SEMANAS
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Problemas con inhibidores de proteasas de primera generacion MULTIPLES EFECTOS COLATERALES :
ANEMIA(BOC), COMPLICACIONES DERMATOLOGICAS (TPV)
MULTIPLES DOSIS : DIFICULTAD EN EL APEGO, INGESTA CON ALIMENTOS
MULTIPLES INTERACCIONES MEDICAMENTOSAS
COMPLICACIONES GRAVES E INCREMENTO EN LA MORTALIDAD EN PACIENTES CON CIRROSIS HEPATICA
DIFICULTAD PARA SER UTILIZADO EN OTROS GRUPOS DE RIESGO: PACIENTES TRASPLANTADOS DE HIGADO Y CON HIV.
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CUPIC: Telaprevir or Boceprevir + P/R en cirróticos GT 1 previamente tratados
Experiencia Francesa de un programa de uso compasivo para acceso temprano de TVR y BOC antes de su aprovación.
Fontaine H, et al. EASL 2013. Abstract 60..
n/N =118/295
79/190
61/116
43/85
43/135
32/80
8/28 1/9
100
80
60
40
20
0
SV
R12
(%
)
Todos los grupos Recaídas Respuestas parciales
Respondedores nulos
40 41
53 51
3240
29
11
Telaprevir + P/RBoceprevir + P/R
Respuesta previa a P/R
clinicaloptions.com24th Annual CCO HIV and Hepatitis C SymposiumCUPIC: Seguridad del uso de TPV y BOC en cirróticos
Hezode C, et al. EASL 2012. Abstract 8.
Seguridad, % Triple terapia con Boceprevir /TPV (n = 159)
Eventos adversos serios 38.4
Abandono prematuro del tratamiento 23.9 Secundario a efectos adversos serios 7.4
Muerte Infecciòn broncopulmonar y sepsis
Efectos adversos graves no hematológicos
Infección 2.5 Rash 0 Descompesación hepática 4.4
Efectos advesos hematológicos
Anemia
• Grado 2 22.6
• Grado 3/4 10.1
• Uso de eritropoyetina 66.0
• Transfusiones 10.7 Trombocitopenia
• Grado 3/4 6.9
• Uso de trombopoyetina 1.9 Neutropenia
• Grado 3/4 5.0
• Uso de filgastrim 3.850% de riesgo de complicaciones graves y sepsis cuando se utiliza triple terapia en pacientes con Plaquetas <100,000Albúmina menor a 3.5 gr/dlGradiente presión >10 mm/Hg
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Telaprevir y Boceprevir
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phase III NEUTRINO trial reported the highest SVR rate (89%) for an IFN-containing regimen (sofosbuvir [400 mg daily]) in combination with PEG-IFN 2a (180 μg by subcutaneous injection weekly) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) in HCV genotype 1 infection and limited exposure to IFN to just 12 weeks, the safety and tolerability profile limits its usefulness in the setting of FDA-approved, highly efficacious oral DAA combinations. (Lawitz, 2013a)
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Tratamiento disponible VHC Genotipo 1, 4, 5, y 6
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2013
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Antiviral Therapies for Genotype 1 Currently AvailableRegimen DAA Class
PegIFN + RBV None
PegIFN + RBV + boceprevir Protease inhibitor
PegIFN + RBV + telaprevir Protease inhibitor
PegIFN + RBV + simeprevir Protease inhibitor
PegIFN+ RBV + sofosbuvir Nucleotide analogue NS5B polymerase inhibitor
RBV + sofosbuvir*(Extended duration)
Nucleotide analogue NS5B polymerase inhibitor
Sofosbuvir + simeprevir NUC + PI (off-label)
*Sofosbuvir + ribavirin for 24 wks can be considered in patients with genotype 1 HCV who are ineligible for interferon.
AASLD/IDSA treatment recommendations. Available at: http://www.hcvguidelines.org. Accessed June 16, 2014.
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Sofosbuvir + PegIFN/RBV:NEUTRINO Phase III Study Design
Open label
– Sofosbuvir 400 mg QD + pegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day for 12 wks (no response-guided therapy)
Treatment-naive, genotype 1 89% , 4, 5, and 6 HCV-infected patients
17% of patients with cirrhosis
SVR12Sofosbuvir + PegIFN/RBV
(N = 327)
Wk 0 12 24
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
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NEUTRINO Study: Virologic Response
n = 327 n = 291 54
SV
R (
%)
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
100
80
60
40
20
0ITT SVR12 GT1 Cirrhosis
Sofosbuvir + PegIFN/RBV x 12 Wks
90 8980
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NIH SPARE Study (No Interferon): Sofosbuvir + RBV in HCV GT1–Infected Pts 24 wks sofosbuvir + WB or low-dose (600 mg) RBV in treatment-naive subjects
Primarily GT1a (70%), male (66%), black (83%), IL28B CT/TT (81%)
Advanced liver disease 23%
Osinusi A, et al. JAMA. 2013;310:804-811.
Part 1
(Stage F0-F2)Part 2
(All Stages)
Pat
ien
ts (
%)
N = 10 N = 50
100
80
60
40
20
0Sofosbuvir +
WB RBVSofosbuvir +
Low-Dose RBVSofosbuvir +
WB RBV
90 90 88
48
96
68
EOTSVR24
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FISSION: Sofosbuvir/RBV Noninferior to P/R in Tx-Naive GT 2/3 HCV Patients
Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med.
2013;368:34-44.
249/250 158/236 242/244 207/224
Semana 4 Semana 24
HC
V R
NA
< L
LOQ
(%
)
188/190NA
Semana 12
170/253 162/243n/N =
Sofosbuvir + RBV PegIFN + RBV
100
80
60
40
20
0
99
67
99 9992
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FISSION: SVR12 por Genotipo y Grado de Fibrosis
Gane E, et al. EASL 2013. Abstract 5. Reproduced with permission.
Genotipo 2 Genotipo 3
SV
R12
(%
)
No Cirrosis No CirrosisCirrosis Cirrosis
58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37n/N =
100
80
60
40
20
0
98
8291
62 6171
34 30
Sofosbuvir + RBV PegIFN + RBV
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Resumen de estudios con SOFOSBUVIRESTUDIO Pacientes n Regimen Duración
semanas SVR12, %
NEUTRINO[1]
Tx-naive GT 1 292 SOF + P/R 12 89
Tx-naive GT 4 28 SOF + P/R 12 96
Tx-naive GT 5/6 7 SOF + P/R 12 100
FISSION[2]Tx-naive GT 2 70 SOF + RBV 12 97
Tx-naive GT 3 183 SOF + RBV 12 56
FUSION[3]
Tx-previo GT 2 36 SOF + RBV 12 86
Tx-previo GT 3 64 SOF + RBV 12 30
Tx-previo GT 2 32 SOF + RBV 16 94
Tx-previo GT 3 63 SOF + RBV 16 62
POSITRON[4]IFN-UII GT 2 109 SOF + RBV 12 93
IFN-UII GT 3 98 SOF + RBV 12 61
1. Lawitz E, et al. EASL 2013. Abstract 1411. 2. Gane E, et al. EASL 2013. Abstract 5.3. Nelson D, et al. EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61.
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Sofosbuvir + RBV ± PegIFN Post Trasplante hepático:
69% con RVS 4; 56% RVS12
– 2/36 recayeron
– 1/36 no respondieron
– 8/36 murieron
64% con mejoría de la descompensación
11% se estabilizaron
Forns X, et al. AASLD 2013. Abstract 1084.
Todos SOF + RBV SOF +PegIFN/RBV
SV
R4
(%)
100
80
60
40
20
0
6974
56
25/36 20/27 5/9n/N =
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CO-INFECTADOS TX CON SOFOSBUVIR Y RIBA
SOF + RBV efectivo con diferentes tratamamiento anti retrovirales
Estudio piloto: 91% RVS con SOF + P/R por 12 semanas en HCV GT1-4[2]
STARTverso4: FDV + P/R en GT1[3]
– Evaluatdo con múltiples dosis usando RGT en 24-48 semanas
– SVR4 y EA SIMILARES a pts monoifectados con VHC tratados con FDV + P/R
C212: SMV + P/R en GT1[4,5]
– SMV 150 mg QD + P/R por 12 semanas
– SVR and AEs similar a pts monoinfectedos
EFECTOS ADVERSOS MUCHO MENORES QUE CON AVD DE PRIMERA GENERACION
n/N =
1. Sulkowski M, et al. AASLD 2013. Abstract 212. 2. Rodriguez-Torres M, et al. IDSA 2013. Abstract 714. 3. Rockstroh JK, et al. AASLD 2013. Abstract 1099. 4. Dieterich D, et al. EACS 2013. Abstract LBPS9/5. 5. Jacobson I, et al. EASL 2013. Abstract 1425.
100
80
60
20
0
40
SV
R12
(%
)
GT1: SOF+ RBV por 24 semanasGT2: SOF + RBV por 12 semanas GT3: SOF + RBV por 12 semanas
76
88
67
87/114
23/26
28/42
PHOTON-1[1]
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Simeprevir + P/R in GT1, Tx-Naive Patients: QUEST-1/2 Phase III Trial Design
RGT in simeprevir arm: if HCV RNA < 25 IU/mL at Wk 4 and undetectable at Wk 12, complete treatment at Wk 24; otherwise, continue treatment to Wk 48
Stopping rules
– If HCV RNA > 1000 IU/mL Wk 4, stop SMV/placebo
– If HCV RNA < 2 log10 IU/mL reduction at Wk 12, or confirmed > 25 IU/mL at Wk 24 or 36, stop all treatment
*QUEST-1: n = 264; QUEST-2: n = 257.†QUEST-1: n = 130; QUEST-2: n = 134.
Response-Guided Treatment
SMV 150 mgQD + P/R P/R
P/RN = 521*
Placebo + P/R
P/R P/RN = 264†
0 12 24 48 72Wk
Jacobson I, et al. EASL 2013. Abstract 1425. Manns M, et al. EASL 2013. Abstract 1413.
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Simeprevir + P/R: Phase III QUEST-1: Impact of Subtype & Fibrosis Stage in GT1
SVR: GT1b > GT1a
SVR is lowest for patients with GT1a and baseline Q80K mutation
SVR: F0-F2 > F4
SV
R (
%)
80
50
71
49
90
52
Jacobson I, et al. EASL 2013. Abstract 1425.
83 78
58 60
26 29
100
80
60
40
20
0
100
80
60
40
20
0Simeprevir P/R Simeprevir P/R
Overall GT1a GT1b F0-F2 F3 F4
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Simeprevir en pacientes previamente tratados Estudios fase II
100
80
60
40
20
0
SV
R24
(%
)
85
37
45/53
10/27
70
32/46
9
2/23
Recaídas Respondedor Parcial
Simeprevir FDA Hearing. October 24, 2013.
FDA incluyo la indicación para repondedores parciales y nulos
45
15/33
19
3/16
Respondedor Nulo
SMV + P/R x 12 sem+ P/R 36 semP/R x 48 sem
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COSMOS: Simeprevir + Sofosbuvir ± RBV in GT1 HCV: Phase IIa Study Design
Cohort 1: previous null responders (METAVIR F0-F2)
Cohort 2: treatment naive and previous null responders (METAVIR F3-F4)
SMV 150 mg QD + SOF 400 mg QD ± RBV 1000/1200 mg/day
SMV + SOF + RBV Posttreatment follow-up
0 4 12 24 36 48
Arm 1
Wk
SMV + SOF
SMV + SOF + RBV
SMV + SOF
Posttreatment follow-up
Posttreatment follow-up
Posttreatment follow-up
Arm 2
Arm 3
Arm 4
Enrolment ratio 2:1:2:1
Jacobson I, et al. AASLD 2013. Abstract LB-3. Lawitz, et al. EASL 2014. Abstract 165.
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COSMOS: SVR12 en Cohortes 1 y 2 de acuerdo al subgenotipo de VHC y del polimorfismo basal Q80K
Cohort 1 (F0-F2 Nulos)*[1] Cohort 2 (F3-F4 vírgenes y nulos)*[2]
1. Sulkowski M, et al. EASL 2014. Abstract O7. 2. Lawitz E, et al. EASL 2014. Abstract O165.
SMV/SOF ±RBV
SVR12 (%)
SMV/SOF +RBV
SMV/SOF+RBV
SMV/SOF SMV/SOF
24 semanas 12 semanas Todos
4/4
7/7
8/9
3/3
7/7
3/3
6/6
12/12
8/9
4/4
4/4
5/6
*Excluyeron pacientes que suspendieron tratamiento por razones no virológicas.
100 10093
8895
100 100
88
10096
SMV/SOF ±RBV
SMV/SOF +RBV
SMV/SOF +RBV
SMV/SOF SMV/SOF
24 semanas 12 semanas Todos
6/6
11/11
11/11
4/4
7/7
4/4
5/5
13/14
7/8
3/3
7/8
3/3
18/18
38/40
25/26
100 100 100 100 100100
80
60
40
20
0
100 100
89
100100 100 100 100
89
100 100
83
100 100
89
GT1b GT1a sin Q80K GT1a con Q80K
30/30
7/17
24/27
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Adverse Effects of New Therapies
PegIFN/RBV: well-established AE profiles
Sofosbuvir[1-3]
– Mild fatigue
– Mild headache
Simeprevir[4,5]
– Mild, reversible hyperbilirubinemia
– Due to transporter inhibition and not associated with hepatotoxicity
– Mild photosensitivity
1. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. 2. Jacobson I, et al. AASLD 2013. Abstract LB-3. 3. Sofosbuvir [package insert]. 4. Fried MW, et al. Hepatology. 2013;58:1918-1929. 5. Simeprevir [package insert].
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Multiple Classes of Direct-Acting Antiviral Agents
3’UTR5’UTR Core E1 E2 NS2 NS4B NS3 NS5A NS5Bp7
TelaprevirBoceprevirSimeprevirAsunaprevirABT-450MK-5172FaldaprevirSovaprevirACH-2684
DaclatasvirLedipasvirOmbitasvirMK-8742GS-5885GS-5816ACH-3102PPI-668GSK2336805Samatasvir
Sofosbuvir
VX-135
IDX21437
ACH-3422
Dasabuvir
BMS-791325
PPI-383
GS-9669
TMC647055
NS5BNUC Inhibitors
NS3Protease Inhibitors
NS5AReplication
Complex InhibitorsRibavirin
NS5BNon-NUC Inhibitors
*Representative list; may not be fully inclusive.
PolymeraseProtease
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THE CURRENT COST OF A 12-WEEKREGIMEN OF SOFOSBUVIR ALONE IS $84,000, OR $1,000 PER TABLET
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2013
2014
Medicamentos Próximamente Disponibles
Genotipes 1, 4, 5, and 6
HARVONIIon-1-2
Viekira PakISapphire1-2Turquoise
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1. Mangia A, et al. EASL 2014. Abstract O164. 2. Afdhal N, et al. N Engl J Med. 2014;370:1889-1983. 3. Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.
SOF/LDV + RBV (n = 111)
SOF/LDV (n = 109)
Wk 24
ION-2[3]
Treatment-experienced
HCV GT1; 20% cirrhotics(N = 440)
SOF/LDV + RBV (n = 111)
SOF/LDV (n = 109)
Wk 12
ION-1,2: No difference in outcomes according to cirrhosis status, type of treatment failure
SOF/LDV + RBV (n = 217)
SOF/LDV (n = 214)
Wk 24
ION-1[1,2]
Treatment-naiveHCV GT1;
cirrhosis in 15% to 17% per arm
(N = 865)SOF/LDV + RBV (n = 217)
SOF/LDV (n = 217)
Wk 12SVR12, %
99
97
98
99
94
96
99
99
Phase III Studies of SOF/LDV(LEDIPASVIR) FDC ± RBV for 12 or 24 Wks in GT1 Patients
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Kowdley KV, et al. N Engl J Med. 2014;3701879-1888.
SOF/LDV + RBV (n = 216)
SOF/LDV (n = 215)
Wk 12
Treatment-naive, noncirrhotic pts with HCV GT1
(N = 647) SOF/LDV (n = 216)
Wk 8SVR12, %
94
93
95
ION-3: Phase III Study of SOF/LDV FDC ± RBV for 8-12 Wks in Tx-Naive Noncirrhotic GT1 Patients
clinicaloptions.com24th Annual CCO HIV and Hepatitis C SymposiumION 1:
efectos adversos
Efectos adversos, n (%)
12 semanas 24 semanas
SOF/LDV(n = 214)
SOF/LDV + RBV
(n = 217)
SOF/LDV(n = 217)
SOF/LDV + RBV
(n = 217)
EA total 169 (79) 185 (85) 178 (82) 200 (92)
Grado 3/4 4 (2) 14 (6) 21 (10) 12 (6)
EA significativos 1 (< 1) 7 (3) 18 (8) 7 (3)
EA que llevaron a DC tx 0 1 (< 1) 4 (2) 6 (3)
Alteraciones labGrado 3/4 10 (5) 21 (10) 22 (10) 27 (12)
Hemoglobina < 10 g/dL 0 20 (9) 0 16 (7)
Hemoglobina < 8.5 g/dL 0 1 (< 1) 0 0
Mangia A, et al. EASL 2014. Abstract 164. Afdhal N, et al. N Engl J Med. 2014;[Epub ahead of print].
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ERADICATE: SOF/LDV en pacientes co-infectados HCV/HIV con/sin tx anti-retroviral
SOF/LDV FDC
Semana 12
Osinusi A, et al. EASL 2014. Abstract O14
Sofosbuvir/ledipasvir 400/90 mg (una tableta diaria)
Pts co-infectados con HCV GT1 y HIV (N = 50)
• Estudio fase II (Un brazo)• ARV en 37 pts tratados ARV: efavirenz (41%), raltegravir (27%), rilpivirine (21%),
rilpivirine and raltegravir (8%), efavirenz/raltegravir (3%).
• Cuenta basal de CD4: tratados con ARV 576 cells/mm3 (113-1612). Pacientes sin tx ARV 687 cells/mm3 (319-1287)
• SVR12 en pts tratados: 100%• No se observaron cambios significativos en HIV-1 RNA o en cuenta de CD4+
• SOF/LDV bien tolerado, no se suspendió tx en ningún paciente ni se observaros EA grado 4 AE
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SAPPHIRE I & II: Phase III Studies of ABT-450/RTV/Ombitasvir (NS5A) + Dasabuvir (NNI) + RBV in Noncirrhotic GT1 Pts
SAPPHIRE: no difference in outcomes according to 1a/1b subtype, type of treatment failure
Placebo (n = 158)*
ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 473)
Wk 12
1. Feld JJ, et al. EASL 2014. Abstract O60. Reproduced with permission. 2. Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. 3. Zeuzem S, et al. EASL 2014. Abstract O1. 4. Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614.
*Placebo recipients crossed over to active treatment regimen at Wk 12.
SAPPHIRE-ITreatment-naive
noncirrhotic pts with HCV GT1[1,2]
(N = 631)
SAPPHIRE-IITreatment-experienced noncirrhotic pts with
HCV GT1[3,4]
(N = 394)Placebo (n = 97)
ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 297)
SVR12, %
96
96
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TURQUOISE II: Phase III Study of ABT-450/RTV/Ombitasvir (NS5A) + Dasabuvir (NNI) + RBV in Cirrhotic GT1 Patients
No significant difference in 12 vs 24 wks; high SVR in all subgroups analyzed
ABT450/RTV/Ombitasvir + Dasabuvir + RBV(n = 172)
ABT450/RTV/Ombitasvir + Dasabuvir + RBV
(n = 208)
Wk 24
Poordad F, et al. N Engl J Med. 2014;370:1973-1982.
DAA-naive cirrhotic pts with HCV GT1; 58% of
patients were treatment experienced, and 36%
were previous null responders (N = 380)
Wk 12
SVR12, %
92
96
ABT-450/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily; RBV 1000-1200 mg/day.
Viekira Pak
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TURQUOISE II: RVS 12 3 AVD + RBV en Cirroticos
12 Sem24 Sem 100 100
Vírgenes Recaída
100 100 85.7100 100 100
Parcial Nula
GT1b
Poordad F, et al. EASL 2014. Abstract 163
SV
R12
(%
)
Virgenes Recaída Parcial Nula
GT1a
59/64
14/15
52/56
13/13
11/11
40/50
10/10
39/42
Falla Virológica en 17/380 (4.5%); recaídas más frecuentes en 12-sem vs 24-sem (12 vs 1 pt), 7/12 recaídas a las 12 sem fueron en respondedores nulos con GT1a
100
80
60
40
20
0
92.292.9 93.3100 100 100
80.0
92.9100
80
60
40
20
0
22/22
25/25
18/18
20/20
6/7 14/14
3/3 10/10
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Ribavirin-Free Therapy in GT1b
GT1b Tx Naive
99
99
PEARL-III[2]
1. Andreone P, et al. Gastroenterology. 2014;[Epub ahead of print]. 2. Ferenci P, et al. N Engl J Med. 2014. 22;370:1983-1992.
ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 91)
ABT450/RTV/Ombitasvir + Dasabuvir (n = 95)
GT1b Tx Experienced
Wk 12
100
97
SVR12, %
PEARL-II[1]
GT1a Tx Naive
90
97
PEARL-IV[2]
ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 210)
ABT450/RTV/Ombitasvir + Dasabuvir (n = 209)
ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 100)
ABT450/RTV/Ombitasvir + Dasabuvir (n = 205)
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HALLMARK-DUAL: Daclatasvir + Asunaprevir in Pts con vhc GT1b HCV
AI447-028: Estudio aleatorizado doble ciego fase III
Manns M, et al. EASL 2014. Abstract O166.
Daclatasvir 60 mg/día; asunaprevir 100 mg dos veces al día.
*Pts en placebo recibierón tx en otro estudio después de 12 semanas.
Placebo* (n = 102)
Daclatasvir + Asunaprevir (n = 203)
Daclatasvir + Asunaprevir (n = 235)
Daclatasvir + Asunaprevir (n = 205)
Semana 24
Vírgenes a tratamiento (N = 305)
Respondedores nulos o parciales (N = 205)
Intolerantes/no elegibles a Interferon(N = 235)
Semana 12
VHC GT1b
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HALLMARK-DUAL: RVS12 con Daclatasvir + Asunaprevir en VHC GT1b
Resurgimiento viral: 9 (4%) en vírgenes a tx, 26 (13%) no respondedores,
20 (9%) Intolerantes/no elegibles a IFN
Recaída: 5 (3%) en vírgenes 7 (4%) no respondedores, 12 (6%) Intolerantes/no elegibles a IFN
RVS 12 en 28 / 73 patients con NS5A-L31 y/o variante Y93 al inicio de tx
Manns M, et al. EASL 2014. Abstract O166.
SVR12, % (n/N) Daclatasvir + Asunaprevir
Vírgenes a tratamiento90
(182/203)
Respondedores nulos82
(98/119)
Respondedores parciales81
(68/84)
Intolerantes/no elegibles a IFN 82
(192/235)
Fibrosis/cirrosis con trombocitopenia73
(56/77)
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FISSION, POSITRON, and VALENCE. (Lawitz, 2013a); (Jacobson, 2013c); (Zeuzem, 2013c) PROTON, ELECTRON
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ALLY-3: SOF + DCV x 12 Wks in Tx-Naive and Tx-Experienced Pts With GT3 HCV
N = 152 pts with GT3 HCV
– 66% tx naive, 34% experienced
– 19% of tx-naive pts and 25% of tx-experienced pts had cirrhosis
– 61% of tx-experienced pts relapsed on previous therapy, 14% had null response
1 SAE, grade 3/4 lab abnormalities in 2% of pts
Nelson DR, et al. AASLD 2014. Abstract LB-3.
SV
R12
(%
)
No cirrhosisCirrhosis
Overall Tx Naive Tx Experienced
100
80
60
40
20
0
96
63
97
58
9469
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Treatment-naive patients with GT1 HCV and cirrhosis
(N = 123)
MK-5172 + MK-8742 + RBV (n = 31)
MK-5172 + MK-8742 (n = 29)
MK-5172 + MK-8742 + RBV (n = 32)
Wk 12
MK-5172 100 mg once daily; MK-8742 50 mg once daily, RBV 1000-1200 mg divided twice daily.
C-WORTHY: MK-5172 + MK-8742 ± RBV in GT1 Patients With Cirrhosis and in Null Responders
Lawitz E, et al. EASL 2014. Abstract O61.
Patients with GT1 HCV and null response to pegIFN/RBV
(N = 130)
MK-5172 + MK-8742 + RBV (n = 31)
MK-5172 + MK-8742 (n = 33)
Wk 18
MK-5172 + MK-8742 (n = 31)
MK-5172 + MK-8742 + RBV (n = 33)
MK-5172 + MK-8742 (n = 32)
90
97
97
97
94
91
100
97
SVR4/8, %
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RVS > 90%
Baja toxicidad
Tolerabilidad
Debe de tener
Corta duración
Barrera alta a resistencias Helpful
Requerimientos de una terapia ideal para virus de hepatitis C
Sin interacción con otras drogas
Pocas pastillas
Nicebonus
Tratamiento pangenotípico
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Historically “Hard-to-Treat” Pts and Special Populations Cirrhosis pts
– Compensated
– Decompensated
– Cirrhosis with HCC
Treatment failure pts with GT3 HCV (pegIFN/RBV ± DAA)
Posttransplant HCV
HCV/HIV-coinfected individuals
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Conclusiones
Existen alternativas orales nuevas disponibles en los próximos meses (años)
Esquemas duales o triples 90%+ RVS
Dudas sobre papel de Ribavirina y duración tx en subtipos de VHC
Duración de Tratamiento 12 semanas vs 8 sem.
– Bien tolerado.
– Poco efecto secundario.
– Beneficio población con cirrosis establecida COSMOS II
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