Simpósio Satélite Janssen - RD Consultoria e Eventos

Simpósio Satélite Janssen
Carlos Eduardo Brandão-Mello
Professor Associado de Medicina –
Escola de Medicina e Cirurgia do RJ - UNIRIO
Faculdade de Medicina – UFRJ
Doutor e Livre Docente em Clínica Médica
Co-infecção HCV e HIV
CoFundamentos Teóricos
• Interação HCV
HCV--HIV ocorre em 30
30%
% dos casos HIV +
• Prevalência da co
co--infecção é maior quando a via de
aquisição é parenteral (hemofílicos e viciados em
drogas ilícitas)
• Hepatite crônica com rápida progressão para cirrose
e falência hepática
• Importante causa de morbidade / mortalidade
• Esquema HAART e Hepatotoxicidade
• Tratamento
Tratamento:: Interferon Peguilado + Ribavirina
• Novas Drogas (DAAs
DAAs))
Prevalência Global da CoCo-infecção
HIV–
HIV
–HCV
170 milhões
pacientes HCV1
40 milhões
pacientes HIV2
12 milhões
pacientes co-infectados
1. World Health Organization. Hepatitis C Fact Sheet No. 164,
Outubro 2000 2. UNAIDS, AIDS Epidemic Update 2004
Prevalência de HCV / HIV no Brasil
HCV/HIV –
16%
UDE – 83,7%
Unirio – Hemofilicos (82%)
UNIFESP – 17,5%
SP-Casa da Aids – 17,7%
Campinas – 53,8%
Santos – 36,2%
Santos – 84,8%
HCV/HIV – 53,8%
UDE – 88,2%
Brasil – 433.000 AIDS
HCV/HIV – 21%
1. Monteiro MR., et al., Rev Soc Bras Med Trop. 2004
2. Mendes-Correa., et al., Rev Inst Med Trop SP. 2000
3 Pavan MH. et al., Braz J Infect Dis. 2004
4. Segurado AC. et al., AIDS Patient Care STDS. 2004
5. Vogler IH. Et al., Rev Inst Med Trop SP. 2004
6. Treitinger A. et al., Braz J Infect Dis. 2000
7. Brandão-Mello, CE et al., Hepatology, 1994.
Co--infecção HCVCo
HCV-HIV - Tratamento
• Porque Tratar ?
• Quem tratar ?
• Quando tratar ?
• Como tratar ?
- Terapêutica passada
- Terapêutica atual
- Novas perspectivas
- Não
Não--Respondedor
C.E.Brandão,, 2014
C.E.Brandão
Mortalidade por hepatopatia em HCV/HIV
HCV/HIV
60
Mortalidade (%)
Pre-HAART era
50
50%
45%
HAART era
40
35%
30
20
13%
10
12%
5%
0
Itália (Brescia)*
* 55% tinham HIV controlado
Espanha (Madrid)
EUA (Boston)
Bica et al. Clin Infect Dis 2001. Puoti et al. JAIDS 2000. Soriano et al. Eur J
Epidemiol 1999. Martin-Carbonero et al. AIDS Res Human Retrovirus 2001.
Efeito da coco-infecção HCVHCV-HIV na
Progressão da Fibrose
4
Grau de
Fibrose
(Metavir)
3
2
HIV+ (n=122)
Controles (n=122)
Controles Simulados (n=122)
1
0
0
10
20
30
40
Duração da Infecção pelo vírus C (anos)
Com CD4 < 200/mm3, Álcool, Idade, IP
Fatores Preditivos Independentes
de Morte Relacionada a Doença Hepática em HIV+
Latest CD4 Cell Count (cells/µL)
16.06
<50
11.54
50-99
7.14
100-199
3.95
200-349
1.67
350-499
>500
2.01
HIV Acquisition via IDU
Hepatitis C Status
Negative
6.66
Positive
Hepatitis B Status
Negative
3.73
Positive
Multivariate analysis.
Not shown: Age per 5 years (1.32).
0.2
Weber R, et al. Arch Intern Med. 2006;166:1632-1641.
1.0
10
Risco Relativo de Morte
100
Change in Causes of Death in
Patients with HIV
• Swiss HIV Cohort Study (SHCS)
– 446 deaths between 2005 and 2009
– Causes of death
• #1 NonNon-AIDS defining cancers (n=85, 19.1%)
including HCC (n=13, 2.8%)
• #2 AIDS (n=73, 16.4%)
• #3 Liver Diseases (n=67, 15%)
When deaths due to HCC are included among liver-related
Deaths (instead of non-AIDS defining cancers)
Liver Diseases = #1 Cause of Death (17.9%)
Ruppik M. et al. Changing patterns of causes of death in the SHCS 2005-2009. CROI 2011.
Poster # 789. Available at: http://www.retroconference.org/2011/PDFs/789.pdf.
Co--infecção HCVCo
HCV-HIV - Tratamento
(Quem Tratar ?)
• Todos os coco-infectados são potenciais candidatos
• Infecção estável pelo HIV (CD4 > 350 céls./mm
céls./mm3 )
• ALT persistentemente elevada (> 1,5 x o LSN)
• ALT normal* – Decisão deve ser baseada na Biópsia
• Atividade inflamatória moderada e fibrose (F1(F1-F4)
• Fibrose F0 – Monitorar e repetir biópsia a cada 3 anos
• Doença hepática compensada
* 25 a 40% com fibrose significativa
C.E.Brandão,, 2014
C.E.Brandão
Co--infecção HCVCo
HCV-HIV - Tratamento
(Quem Tratar ?)
• Cirróticos
Cirróticos:: tratamento pode lentificar a progressão
para insuficiência hepática
hepática..
• Quando existir hepatotoxicidade recorrente a TARV.
• Infecção estável pelo HIV (CD4 > 200 - < 350 céls
céls../mm3):
A decisão deve ser baseada na biópsia, genótipo,
carga viral e tempo estimado de infecção
• Infecção pelo HIV (CD4 < 200 céls
céls../mm3 ) – tratar a
infecção pelo HIV e postergar o tratamento da hepatite
C.E.Brandão,, 2014
C.E.Brandão
Co--infecção HCVCo
HCV-HIV - Tratamento
• Porque Tratar ?
• Quem tratar ?
• Quando tratar ?
• Como tratar ?
- Terapêutica passada
- Terapêutica atual
- Novas perspectivas
- Não
Não--Respondedor
C.E.Brandão,, 2014
C.E.Brandão
Tratamento da CoCo-infecção HCV
HCV--HIV
Resposta Virológica Sustentada
HIV--neg
HIV
HIV--pos
HIV
IFN Monoterapia
20%
<10%
IFN + ribavirina
45%
12--21%
12
Peg--IFN + ribavirina
Peg
55%
27--55%
27
RVS com PEGPEG-IFN na HCV/
HCV/HIV
80
73
A5071
70
62
RIBAVIC
(%) RVS
60
53
46
50
20
55
44
38
40
30
APRICOT
71
Crespo
44
40
29
27 27
14
17
10
0
Genótipo 1 ou 4
Genótipo não 1
Barcelona
RVS
Impacto da Resposta Virológica Sustentada na
Evolução a Longo Prazo da Coinfecção HIV/HCV
Long-Term
Term Outcome Rate
(per 100 person/years)
GESIDA 3603 Cohort
4.33
(3.16,5.8)
Achieved SVR
Did not achieve SVR
3.12
(2.16,4.37)
1.65
(0.98,2.16)
1.02
0.83
0.93
(0.50,1.82)
(0.44,1.70)
(0.38,1.58)
0.46*
(0.06,1.65)
0.23†
(0.01,1.27))
(0.01,1.27
0.23‡
0
0§
(0.01,1.27)
(0,0.84)
(0,0.84)
Liver
Overall Liver-Related
Mortality
Mortality Decompensation
0.23
(0.01,1.27)
HepatoLiver
carcinoma Transplantation
New AIDS
Conditions
*P=0.003, †P=0.028, ‡P<0.001, and §P=0.034 versus not attaining a sustained virologic response.
n=711 HIV/HCV-coinfected patients receiving interferon (peg or conventional) + ribavirin.
Berenguer J. et al. Hepatology 2009.
Erradicação da Hepatite C Reduz Descompensação Hepática
Progressão do HIV e Morte em Coinfectados HIV/HCV
com Fibrose Hepática não Avançada
J. Berenguer1, F. X. Zamora2, C. Díez1, M. Crespo3, M. A. Von Wichmann4, J. López-Aldeguer5, M. J. Galindo6, I. Santos
7, H. Esteban8, C. Barros9, J. J. Jusdado10, C. Tural11, T. Aldámiz1, J. M. Bellón1, and J. González-García2,
for the GESIDA HIV/HCV Cohort Study Group 53rd ICAAC 2013 September 10-13, Denver, CO
Superioridade do Peg IFNIFN-Ribavirina
(Resposta Virológica Sustentada
Sustentada))
Tipo IFN
n.
IFN
IFN
/RBV
PEG IFN
IFN/RBV
ACTG
2a
133
12%
27%
APRICOT
2a
868
12%
40%
RIBAVIC
2b
400
19%
27%
Laguno
2b
95
21%
44%
Crespo
2b
121
26%
55%
Berenguer
2a/2b
315/242
33%
31%
Laguno
2a/2b
96/86
46%
42%
Superioridade do Peg IFNIFN-Ribavirina
(RVS) em Pacientes Genótipo 1
IFN
IFN
/RBV
PEG IFN
IFN/RBV
ACTG
G1 (78%)
6%
14%
APRICOT
G1 (60%)
7%
29%
RIBAVIC
G1 (65%)
6%
17%*
Laguno
G1 (63%)
7%
38%**
Crespo
G1 (48%)
18%
46%**
Laguno
G1 (45%)
28% (2b)
32% (2a) #
Berenguer G1 (50%)
31% (2b)
33% (2a) ¥
*p<0.01; **p<0.002 # p=0.677
Desenho do Estudo e
Randomização
Randomiza
ção dos Pacientes
PRESCO
0
Peg-IFN
IFN alfa
alfa-2a + RBV
1000-1200
1200 mg/dia
n=389
G1,4
Follow-up
N=192
G1,4
G2,3
Follow-up
G2,3
12
24
Follow-up
N=45
N=96
Follow-up
60
48
36
Semanas de Estudo
N=56
72
84
96
Somente pacientes que obtiveram RVP ( >2 log no HCV-RNA na sem. 12) continuaram tratamento
PRESCO
APRICOT
(RVS Global 40%)
PRESCO
FRIED
(RVS Global 50%)
(RVS Global 56%)
76%
72%
62%
Pacientes (%)
50
46%
40
36%
30
29%
20
10
0
Geno 1
n=176
Geno 3
n=95
Geno 1
Geno 3
Geno 1
Geno 3
n=191
n=152
n=298
n=140
48 semanas de terapia
24, 48 ou 72 semanas terapia
48 semanas terapia
HIV +  dose RBV
HIV + dose RBV baseada PC
HIV - dose RBV baseada PC
n=180
0
Desenho do Estudo e
Randomização
Randomiza
ção dos Pacientes
Peg-IFN
IFN alfa
alfa-2a + RBV
1000-1200
1200 mg/dia
ML18473
G1
N=90
Follow-up
Follow-up
G1
12
24
60
48
36
Semanas de Estudo
72
84
N=90
96
Desenho do Estudo
Estudo de fase IV, aberto, randomizado (1:1), multicêntrico
(17 centros, todos no Brasil), de grupos paralelos
Grupo 48 semanas: n=90
Alfapeginterferona-2a (40KD)
180 µg/semana + ribavirina*
Seguimento
Grupo 72 semanas: n=90
Alfapeginterferona-2a (40KD) 180 µg/semana + ribavirina*
0
48
Semanas
* Dose de ribavirina: 1.000 mg/dia (<75 kg de peso ) ou 1.200 mg/dia (≥75 kg de peso)
Seguimento
72
96
Características Basais (ITT)
Grupo 48 semanas
(n=80)
Grupo 72 semanas
(n=85)
42
42
49 (61)
59 (69)
Caucasiano/Branco
28 (35)
35 (41)
Outros
52 (65)
50 (59)
Média de peso, kg
68
69
Média do HCV RNA, log10 UI/mL
6.6
6.6
HCV RNA ≥800 000 UI/mL, n (%)
60 (77)
61(73)
Cirróticos (F3/F4), n (%)
11 (14)
16 (20)
Razão de ALT, n (%)
>1–2
>2–5
39 (51)
19 (25)
38 (48)
22 (28)
1 (1)
2 (3)
HIV-RNA indetectável, n (%)
64 (79)
60 (70)
CD4 >350 cels/mm3, n (%)
61 (78)
57 (70)
TARV na linha de base, n (%)
69 (86)
63 (74)
Média de idade
Masculino, n (%)
Raça, n (%)
>5
Características Basais – Estudo Co-infecção ML18743
Características
Idade (Anos)
Sexo (masculino/feminino) (%)
Pêso Corporal
Droga intra venosa n (%)
48 Semanas
(N=80)
42.3
49/31 (61)
68.0
34 (42.5)
72 Semanas
(n= 85)
42.2
59/26 (69)
68.7
28 (32.9)
Raça: Caucasiana (branca) (%)
28 (35)
35 (41)
60 (77)
61 (73)
Carga Viral > 800 000 IU/ml. (%)
Quociente de ALT n (%)
> 11- 2
39 (51)
38 (48)
> 22- 5
19 (25)
22 (27.8)
> 55- 10
1 (1.3)
2 (2.5)
11 (13.9)
16 (19.7)
Contagem CD4 (> 350 cel.mm3)
61(78.2%)
57(70.3%)
HIV RNA < 50 cópias/mL n (%)
64 (79)
60 (69.7)
Tratamento antiretroviral n (%)
69 (86.2)
63 (74%)
Cirrose n (%)
Taxa de resposta virológica (HCV RNA <50 UI/mL)
24 semanas após o final do tratamento (RVS)
População ITT
População Por Protocolo
Diferença entre tratamentos: 16%
(IC 95%: 0.00–28.9); p=0.0374
Diferença entre tratamentos: 10%
(IC 95% : 0.01–26.6); p=0.0536
50
33
40
30
23
20
10
0
n=18/80
48 semanas
n=28/85
72 semanas
% Pacientes com RVS*
% Pacientes com RVS*
50
39
40
30
23
20
10
0
n=18/77
48 semanas
n=31/79
72 semanas
*RVS = resposta virológica sustentada, definida com HCV RNA indetectável (<50 IU/mL) conforme medido pelo Teste Roche COBAS
AMPLICOR HCV 24 semanas após completar o período de tratamento.
Cheinquer, AASLD, 2010
ML18473: Taxas de Recidiva
Pacientes com HCVHCV-RNA Indetectável (< 50 UI/ml)
no Final de Tratamento sem RVS – Análise por ITT
• Pacientes com Genótipo 1 (n=165)
48 sem.
n=38
(50.7%)
Com RVS:
n=18
47.4%
Sem RVS: n=20
RNA-HCV
indetectável no
Final de Tratamento
N= 75
72 sem.
(52.6%)
n=37
(49.3%)
Com RVS: n=28
(75.7%)
Sem RVS: n=09
24.3%
Brandão-Mello, et al. Hepatology, 2010
ML18473: Taxas de Recidiva
Pacientes com HCVHCV-RNA Indetectável (< 50 UI/ml)
no Final de Tratamento sem RVS – Análise por PP
• Pacientes com Genótipo 1 (n=156)
48 sem.
n=37
(50.7%)
Com RVS:
n=18
48.6%
Sem RVS: n=19
RNA-HCV
indetectável no
Final de Tratamento
N= 73
72 sem.
(51.4%)
n=36
(49.3%)
Com RVS: n=28
(77.8%)
Sem RVS: n=08
22.2%
Brandão-Mello, et al., Hepatology, 2010
Tratamento da CoCo-infecção HCVHCV-HIV
Novo algoritmo
S4
S12
G2/3
HCV-RNA
neg
S48
S24
24 semanas
terapia *
G1/4
> 2 log 
no HCV-RNA
HCV-RNA
pos
HCV-RNA
neg
HCV-RNA
pos
< 2 log 
no HCV-RNA
S72
G2/3
G1/4
48 semanas
terapia
72 semanas
terapia
Parar
Parar
* Pacientes com baixa carga viral basal e fibrose hepática minima.
APRICOT: semana 4 – genótipo 1
RNA--HCV indetectável
RNA
• Pacientes com Genótipo 1 (n=176)
Sim
n=22
(13%)
Com RVS:
n=18
VPP=82%
Sem RVS: n=4
(18%)
RNA-HCV
indetectável
Não
n=154
(87%)
Com RVS: n=33
(21%)
Sem RVS:
n=121
VPN=79%
Torriani F, et al. 45th ICAAC 2005; Abstract 1024
Taxa de RVS (%)
Tipo IL28B é preditivo de RVS
na co-infecção HCV-HIV
100
p<0.0001
p=0.68
P=0.001
86%
80
75%
81%
65%
60
40
38%
38
30%
20
CT/TT CC
0
CT/TT
CC
Todos
HCV-1
N=164
N=95
CT/TT CC
HCV - 3
N=51
Rallon et al., AIDS, 2010
AIDS 2010
SVR
86%
81%
p<0.0001
75%
p=0.684
p=0.001
p=0.087
65%
67%
38%
30%
25%
CC CT/TT
CC CT/TT
CC CT/TT
CC CT/TT
75 89
34 61
HCV-1
35 16
HCV-3
6 12
HCV-4
95
51
18
All
164
IL28B-CC (rs 12979860) é potente fator preditivo
pré-tratamento de RVS na co-infecção HCV-HIV
Odds
Ratio
95% Confidence
Interval
p-value
CC IL28B vs não-CC
3.7
1.6
8.4
<0.002
VL ≤ 600,000 IU/mL
11.9
3.8
37.4
<0.001
METAVIR F0- F2
3.5
1.4
8.9
<0.0009
GENÓTIPO 3
8.0
3.1
21.0
<0.001
Rallon et al., AIDS, 2010
Futuro II: Novas Drogas antianti-
HCV
33
O Futuro - Novas drogas: ANTIVIRAIS
Ribozymes
Nucleotideos anti-sense
Inibidores de
Entrada
Inibidores de protease
-
Inibidores de Polimerase
Inibidores de Glucosidase
Adaptado de: Pawlotsky et al., Antivir Ther 2006
Ação da protease
Quebra
P7
NS2
NS3/4A
Protease
NS4B
E2
NS5A
E1
NS5B
C
35
Kwong A, et al. Beyond interferon and ribavirin: Antiviral therapies for hepatitis C virus.
Drug Discovery Today: Therapeutic Strategies. 2006;3:211-220.
35
Futuro: novos antivirais contra o HCV
STAT-C - Specifically Targeted
Antiviral Therapies for Hepatitis C
Poliproteína do HCV
capsid
C
envelope proteins
E1
E2
p7
protease/helicase
NS2
NS3
Structural
Proteins
NS3 protease
NS4A
NS4B
NS5B
NS5A
Nonstructural Proteins
NS3 helicase
Full-length NS3
... Asvir
… PREVIR
Telaprevir, Boceprevir
Telaprevir,
Simeprevir,, Faldaprevir
Simeprevir
Asunaprevir,, Vaniprevir
Asunaprevir
polymerase
NS5A
Daclatasvir
Ledipasvir,
Ombitasvir
NS5B RNA polymerase
... Buvir
Sofosbuvir
Deleobuvir
Tegobuvir
Resposta virológica sustentada
Terapia Tripla : Taxas de RVS Elevadas
em pacientes experimentados
100
REALIZE
RESPOND-2/PROVIDE*
(+/- Lead-in) TVR 12 sem. + PEG2a + Riba
48 semanas
Lead-in (+/-RGT) BOC + PEG2b + Riba
36 / 48 semanas
100
86%
80
80
57%
60
40
40
15%
20
52%
60
31%
24%
75%
36%*
29%
20
7%
5%
0
TVR
SOC
REL
TVR
SOC
P-Não R
TVR
SOC
NULL
0
BOC
SOC
REL
BOC
SOC
P-NR
NULL
Relapser (REL): negativo ao final do tratamento mas recidiva após
Parcial Não-Respondedor (P-NR): ≥2log sem.12 mas HCV RNA positivo sem. 24
Null-Responder (NULL): <2log sem. 12
Zeuzem et al., NEJM 2011
Bacon et al., NEJM 2011
*PROVIDE study, Vierling et al., AASLD 2011
Terapia Tripla : Taxas de RVS 24 Elevadas
(61% – 75%)
HCV RNA negativo sem. 24
 Co-infecção HIV-HCV Genótipo 1, naive
Boceprevir (n=98)
Telaprevir (n=60)
100
86%
12 TVR Tripla + 36 sem. SOC
75%
80
60
75%
67%
71%
80
60
50%
40
Lead-in - BOC Tripla 48 sem.
100
38%
33%
20
15%
20
BOC
0
TVR
SOC
Sem HAART
34%
40
TVR
SOC
TVR
HAART
SOC
HAART
EFV/TDF/FTC ATVr/TDF/FTC
 eRVR global 63% vs. 5%
 Elevação de Bilirubinas com ATVr
 TVR 1125mg TID em combinação com EFV
Sulkowski et al., AASLD 2011
SOC
BOC
SOC
0
Semana 8
Semana 24
 HAART: PI Sem booster, Raltegravir, CCR-5
antagonistas, sem NNRTI, NRTI sem ATZ,
d4T, ddI
Sulkowski et al., AASLD 2011
Novas Drogas antianti-HCV
a
DAAs de 1 Geração
Inibidores da NS3
 Boceprevir
 Telaprevir
39
Resposta virológica sustentada
Terapia Tripla : Taxas de RVS Elevadas (Naïve)
80
75%
ADVANCE
SPRINT-2
RGT, TVR 12 vs. 8 sem.
Lead-in(LI), RGT vs. não-RGT
69%
80
70
70
60
44%
50
60
40
30
30
20
20
10
10
TVR
TVR
Resposta
Resposta
guiada
guiada
TVR 12 sem TVR 8 sem
+ PEG2a
+ PEG2a
+ Riba
+ Riba
SOC
PEG2a
+ Riba
(48sem.)
Jacobson et al. NEJM 2011
38%
50
40
0
63%
66%
0
BOC
Resposta
guiada
LI BOC
+ PEG2b
+ Riba
BOC
LI BOC
+ PEG2b
+ Riba
(48 sem.)
SOC
PEG2b
+ Riba
(48sem.)
Poordad et al. NEJM 2011
Desenho do Estudo Boceprevir
Weeks
72PEG2b
Arm
1
Arm
2
+RBV
4 sem.
PEG2b
+RBV
4 sem.
12
24
28
Placebo + PEG2b + RBV
44 semanas
48
Follow-up
SVR-24 sem
Boceprevir + PEG2b + RBV Follow-up
44 semanas
SVR-24 sem
Futility Rules
•
•
•
Two-arm study, doubleTwodouble-blinded for BOC, openopen-label for PEG2b/RBV
– 2:1 randomization (experimental: control)
– Boceprevir dose 800 mg TID
4-week leadlead-in with PEG2b/RBV for all patients
– PEG
PEG--2b 1.5 µg/kg QW; RBV 600600-1400 mg/day divided BID
Control arm patients with HCVHCV-RNA ≥ LLOQ at TW 24 were offered
open--label PEG2b/RBV+BOC via a crossover arm
open
Características Demográficas
PR
B/PR
(N=34)
(N=64)
Idade (anos), mediana (SD)
45 (9.8)
43 (8.3)
Masculino, n (%)
22 (65)
46 (72)
28 (82)
6 (18)
52 (81)
12 (19)
Indice de Massa Corpórea, mediana
(SD)
26 (4)
25 (4)
Cirrose n (%)
1 (3)
4 (6)
22 (65)
10 (29)
42 (66)
15 (23)
HCV RNA carga >800,000 IU/mL, n (%)
30 (88)
56 (88)
HIV RNA <50 cópias/mL, n (%)
33 (97)
62 (97)
586 (187-1258)
577 (230-1539)
Raça, n (%)
Branca
Não-branca
HCV genotipo e subtipo, n (%)*
1a
1b
CD4 contagem cels/mm3), mediana
(variação)
% HCV RNA Indetectável
Resposta Virológica ao Longo do Tempo†
100
PR
B/PR
80
73.4
65.6
60.7
59.4
60
42.2
40
32.4
23.5
20
0
29.4
14.7
8.8
4.7
3/34
3/64
4
5/34
27/64
8
8/34
38/64
12
11/34 47/64
10/34 42/64
24
EOT
Treatment Week
†
26.5
Three patients undetectable at FW4 have not yet reached FW12 and were not included in SVR12 analysis.
9/34
37/61
SVR12
Taxas de RVS 12 Com BOC + P/R vs
Peg-IFN/R em Coinfectados HCV-HIV
RVS12 (%)
RVS 12 de
acordo com
TARV %
BOC +
PegIFN/RBV
(n = 61)
PegIFN/
RBV
(n = 34)
100
ATV/RTV
67
62
80
LPV/RTV
67
0
DRV/RTV
67
0
Outros PI/RTV*
57
0
Raltegravir
43
33
Outros†
0
0
60.7
60
40
26.5
20
0
n/N =
9/34
P/R
37/61
BOC + P/R
*SQV, FPV, TPV.,
†MVC, EFV.
 Rebote virológico do HIV-1 RNA
observado em 7 pacientes
– BOC + P/R: n = 3 (todos com Pis +
RTV)
– Placebo + P/R: n = 4

Dados preliminares (3 pacs
pacs.. no braço
braço
BOC ainda não chegaram na semana
FU 12)
Sumário de Segurança
PR
(N=34)
B/PR
(N=64)
34 (100)
63 (98)
7 (21)
11 (17)
0
0
34 (100)
61 (95)
Descontinuação do Estudo devido à EAs
3 (9)
13 (20)
Qualquer Modificação de Droga devido à
EAs
8 (24)
18 (28)
Qualquer Evento Adverso (EA)
EA Sério
Morte
EAs relacionados ao tratamento
.
Eventos Adversos Hematológicos
PR
B/PR
(N=34)
(n=64)
Anemia
Eventos Adversos Sérios (EAS)
6%
3%
EAS conduzindo a descontinuação
3%
2%
WHO, Grau 1-4 (<11.0 g/dL)
53%
63%
3%
5%
Uso de Eritropoietina
21%
38%
Transfusão
6%
6%
74%
86%
12%
27%
Grau 3-4 (<8.0 g/dL)
Neutropenia
WHO, Grau 1-4 (≤1.5x109/L)
Grau 3-4 (<0.75x109/L)
Rebote Virológico do HIV em Grupos B/PR
 No geral, 7 pacientes tiveram rebote virológico do HIV (>50 cópias HIV-RNA
em 2 visitas consecutivas): 3/64 randomizados para B/PR e 4/34 para PR
HIV RNA (cópias/mL)
Regime
BL
TW4 TW12 TW24 TW36 EOT
ATV/r
<50
<50
---
659
---
53
2990
†LPV/r
<50
<50
<50
55
59
67
68
ATV/r
<50
<50
<50
<50
243
---
7870
ATV/r, atazanavir/ritonavir; LPV/r, lopinavir/ritonavir
†The only subject to change ART. LPV/r changed to ATV/r at TW42; ATV/r to DRV/r at FW24.
FW4
Dados Preliminares em coinfectados HIV/HCV
Genótipo 1 Tratados com Telaprevir
Wk 12
Part A: No Current ART
HIV/HCV-coinfected patients;
CD4+ ≥ 500 cells/mm³;
HIV-1 RNA ≤ 100,000 c/mL
(N = 13)
Part B: Stable ART
HIV/HCV-coinfected patients
on stable ART, EFV/TDF/FTC
or TDF + (FTC or 3TC) +
ATV/RTV; CD4+ ≥ 300
cells/mm³; HIV-1 RNA ≤ 50 c/mL
(N = 47)
Telaprevir
750 mg q8h + PR†
(n = 7)
Current Analysis: Wk
24
Wk 48
Wk 72
PR†
(n = 7)
Follow-up
Placebo + PR†
(n = 6)
PR†
(n = 6)
Telaprevir*
750 mg q8h + PR†
(n = 31)
PR†
(n = 31)
Follow-up
Placebo + PR†
(n = 16)
PR†
(n = 16)
*Telaprevir dose increased to 1125 mg q8h with efavirenz.
alfa-2a 180 μg/wk; RBV 800 mg/day or weight based in France and Germany (1000 mg/day if weight < 75 kg; 1200 mg/day
if weight ≥ 75 kg).
†PegIFN
Sherman KE, et al. AASLD 2011. Abstract LB-8.
Study 110: Interim Data on Telaprevir in
HIV/HCV Genotype 1–
1–Coinfected Patients
Wk 12
Part A: No Current ART
HIV/HCV-coinfected patients;
CD4+ ≥ 500 cells/mm³;
HIV-1 RNA ≤ 100,000 c/mL
(N = 13)
Part B: Stable ART
HIV/HCV-coinfected patients
on stable ART, EFV/TDF/FTC
or TDF + (FTC or 3TC) +
ATV/RTV; CD4+ ≥ 300
cells/mm³; HIV-1 RNA ≤ 50 c/mL
(N = 47)
Telaprevir
750 mg q8h + PR†
(n = 7)
Current Analysis: Wk
24
Wk 48
Wk 72
PR†
(n = 7)
Follow-up
Placebo + PR†
(n = 6)
PR†
(n = 6)
Telaprevir*
750 mg q8h + PR†
(n = 31)
PR†
(n = 31)
Follow-up
Placebo + PR†
(n = 16)
PR†
(n = 16)
*Telaprevir dose increased to 1125 mg q8h with efavirenz.
alfa-2a 180 μg/wk; RBV 800 mg/day or weight based in France and Germany (1000 mg/day if weight < 75 kg; 1200 mg/day
if weight ≥ 75 kg).
†PegIFN
Sherman KE, et al. AASLD 2011. Abstract LB-8.
Resposta Virológica durante o tratamento
com Telaprevir em coinfectados HCV
HCV--HIV
•
•
Higher response rates with TVRTVR-based triple therapy vs pegIFN
pegIFN/RBV
/RBV through Wk
24
Bilirubin adverse events more common in patients receiving ATV/RTVATV/RTV-based
antiretroviral therapy with TVR + pegIFN
pegIFN/RBV
/RBV (27%; 4/15) vs pegIFN
pegIFN/RBV
/RBV (0%; 0/8)
–
–
•
Hyperbilirubinemia related to ATV exposure, primarily unconjugated in nature
3 discontinuations due to AEs, all in patients receiving TVR + ATV/RTV
Pharmacokinetic interactions with ATV or EFV not clinically significant
Undetectable HCV RNA, Wk 24 (ITT)
Patients (%)
100
86
75
80
75
71
67
60
55
50
33
40
20
0
n/N=
Telaprevir + PR
6/7
11/16 10/15
27/38
Sherman KE, et al. AASLD 2011. Abstract LB-8.
PR
2/6
4/8
6/8
12/22
No antiretroviral therapy
EFV/TDF/FTC
ATV/RTV + TDF/FTC
Total
Taxas de RVS12 Com Telaprevir + P/R
vs Peg-IFN/R em Coinfectados HIV/HCV
Sem Terapia ARV
Pacientes com RVS12 (%)
100
Terapia ARV baseada em EFV
80
80
71
Terapia ARV baseada em ATZ
69
60
40
50
50
4/8
4/8
33
20
n/N =
5/7 11/16 12/15
2/6
0
TVR + P/R
Placebo + P/R
 Rebote do HIV-RNA não foi observado em qualquer paciente
Dieterich DT, et al. CROI 2012. Abstract 46.
Efeitos Farmacocinéticos do BOC e TVR
sobre os IPs do HIV com booster de RTV
ATV/RTV
Mudança na Concentração
HIV PI Cmin,% (90% CI)
100
LPV/RTV
DRV/RTV
TVR[2]
85
(40 to 144)
80
60
40
14
(-4 to 36)
20
0
-20
-40
-60
-80
-49
(-39 to -56)
BOC[1]
-43
(-35 to -51)
-42
(-37 to -48)
-59
(-55 to -62)
-100
1. Hulskotte EGJ, et al. CROI 2012. Abstract 771LB. 2. van Heeswijk R, et al. CROI 2011. Abstract 119.
Efeitos Farmacocinéticos dos Inibidores
de Protease do HIV+RTV sobre BOC e TVR
 Similar reductions in BOC and TVR exposures observed with coadministration of
ATV/RTV, DRV/RTV, and LPV/RTV
 Prescribing information for TVR does not recommend coadministering TVR with
DRV/RTV, FPV/RTV, or LPV/RTV; prescribing information for BOC does not
recommend coadministering BOC with any HIV PI
Mudança na Concentração
HCV PI Cmin, % (90% CI)
BOC[1]
TVR[2]
0
-20
-40
-60
-15
(-2 to -25)
-18
(-2 to -32)
-35
(-24 to -44)
-57
(-47 to -64)
ATV/RTV
DRV/RTV
LPV/RTV
-32
(-26 to -37)
-52
(-44 to -60)
-80
-100
1. Hulskotte EGJ, et al. CROI 2012. Abstract 771LB. 2. van Heeswijk R, et al. CROI 2011. Abstract 119.
Estudo Insight – Telaprevir + PR para coinfectados HCV-HIV-
Montes, ML et al., AASLD, 2013
Estudo Insight – Telaprevir + PR para coinfectados HCV-HIV
Estudo Insight – Telaprevir + PR para coinfectados HCV-HIV
Estudo Insight – Telaprevir + PR para coinfectados HCV-HIV
Estudo Mono versus Coinfectados
Características dos Pacientes
Co-infected
(N = 33)
Monoinfected
(N = 117)
P-value
Median age (IQR)
57 (52-59)
56 (51-61)
0.82*
Male (% of total)
26 (78.8%)
79 (67.5%)
0.21§
Race (% of total)
White
Black
Other
Prior treatment response (% of total)
Naive
Relapser
Non responder/Intolerant
16 (48.5%)
14 (42.4%)
3 (9.1%)
65 (55.6%)
19 (16.2%)
34 (28.2%)
<0.01§
0.02§
3 (9.1%)
5 (15.2%)
25 (75.8%)
36 (30.8%)
23 (19.7%)
58 (49.6%)
Bridging fibrosis/cirrhosis (% of total)
16 (48.5%)
40/113
(35.4%)
0.17§
Baseline HCV viral load log10 IU/mL
(IQR)
6.46
(5.92-7.00)
6.46
(5.91-6.73)
0.42†
Sulkowski & Dieterich, 2014
Resposta Virológica Terapia Tripla em Mono
versus Coinfectado HCVHCV-HIV
Trend for better virologic responses in co-infected patient is potentially explained
by a selection bias
Novas Drogas antianti-HCV
a
DAAs de 2 Geração
Inibidores da NS3
 Simeprevir
60
QUEST-1: Resposta Virológica ao Tratamento com
Simeprevir + P/R
RVS12 por RGT
Desfechos Virológicos
SMV + P/R
P/R
85% dos pcs no braço SMV atingiram critérios RGT
80
100
80
60
50
40
20
0
91
80
80
n/
202/
N = 254
12
Sem. 4
RVS12 (%)
HCV RNA Indetectavel (%)
100
60
40
21
20
210/ 65/
264 130
RVS12
Jacobson I, et al. EASL 2013. Abstract 1425.
0
n/
N=
203/224
6/28
24 Sem
48 Sem
Braço SMV : Duração do RGT
QUEST-1: RVS12 por Nível de Fibrose,
Subtipo e Resistência
100
100
SMV + P/R
P/R
82
80
RVS12 (%)
RVS12 (%)
80
60
90
58
53
40
29
71
60
52
49
40
20
20
n/N = 188/229 60/113
18/31
5/17
105/147 36/74
105/117
29/56
0
0
Sem Cirrose
GT 1a
Cirrose
GT 1b
Differences in SVR12 by Subgroup (95% CIs)
SMV (n) Pbo (n)
147
74
GT 1a/other HCV
28.2 (13.4-42.9)
60
74
- With baseline Q80K vs Pbo
4.7 (-14.6 to 24.1)
86
74
- Without baseline Q80K vs Pbo
40.3 (25.8-54.8)
117
56
GT 1b HCV
42.1 (26.5-57.6)
-100
Jacobson I, et al. EASL 2013. Abstract 1425.
-50
Favors Placebo
0
50
Favors SMV
100
QUEST-2: Resposta Virológica ao
Tratamento com Simeprevir + P/R
SMV + P/R
P/R
100
81
86
RVS12 (%)
80
60
91% dos pcs no braço
SMV atingiram
critérios de RGT
50
40
32
20
n/N =
209/257
67/134
202/235
7/22
0
Global
24 sem
48 sem
Braço SMV:
Duração da RGT
Manns M, et al. EASL 2013. Abstract 1413
QUEST-2: RVS12 por Subtipo
e Grau de Fibrose
 Altas taxas de RVS12 com SMV, independente do genótipo HCV ou
cirrose
 Mutação Q80K (Baseline) não foi preditiva de resposta ( do QUEST-1)
SMV + P/R
P/R
100
RVS12 (%)
80
82
82
80
65
60
46
53
51
40
40
20
n/N =
0
86/
107
26/
57
GT 1a
Manns M, et al. EASL 2013. Abstract 1413.
123/ 41/
150 77
GT 1b
189/ 61/
231 119
Sem Cirrose
11/
17
6/
15
Cirrose
C212 study design: Phase III, openopen-label, singlesingle-arm,
international trial
24
12
36
Primary analysis
60
48
72
Week
SMV
• HCV treatment-naïve
• Prior relapse+
RGT*
150 mg/PR
SMV
150 mg/PR
• Partial response
• Null response
• Cirrhotic patients (F4)
SMV
150 mg/PR
PR
Follow-up
PR
Follow-up
PR
Follow-up
Primary endpoints: SVR12, safety and tolerability
Secondary endpoints: virologic response at other time points, meeting RGT criteria* for
shortened treatment to 24 weeks, onon-treatment failure and relapse rates
Primary analysis:
All patients included in the analysis (N=106) had completed 24 weeks of treatment, or had
reached the time point of the primary efficacy endpoint SVR12 (Week 60), or discontinued prior
to that point (for those on 48 weeks of treatment)
PR, peginterferon-α2a + ribavirin;
RGT, response-guided treatment;
SMV, simeprevir; SVR12, sustained virologic response
12 weeks’ after end of treatment
+After
PR treatment;
*RGT criteria: HCV RNA <25 IU/mL (detectable or undetectable)
at Week 4 and undetectable at Week 12
(measured using Roche COBAS TaqMan HCV/HPS assay, v.2)
C212: SMP + PR - RVS12 de acôrdo com o tipo
de resposta prévia ao tratamento
 Altas taxas de RVS12 com SMV + PR, independente do tipo de resposta.
 87% dos pacs. virgens e relapsers atingiram critérios para RGT por 24 sem.
 Em TARV: 99% com NRTI, 87% Raltegravir e 15% com Rilpivirina
100
74
79
87
70
RVS12 (%)
80
57
60
40
20
n/N =
78/106
42/53
Global
Virgens
13/15
7/10
Relapsers
Parcial
16/28
0
Dieterich et al. 2013. EACS.
Nulo
SVR12 (%)
C212: RVS12 ― Endpoint Primário
78/106
42/53
13/15
SVR12, sustained virologic response 12 weeks’ after end of treatment
7/10
16/28
C212: RVS12 por Subtipo do Genótipo 1
e presença de Polimorfismo da NS3 Q80K
 Altas taxas de RVS12 com SMV, independente do genótipo HCV ou mutação
Q80K (Baseline)
 87% dos pacs. virgens e relapsers atingiram critérios para RGT por 24 sem.
100
89
RVS12 (%)
80
72
71
67
60
40
20
n/N =
16/18
62/88
GT 1b
GT 1a
20/30
42/58
0
Dieterich et al. 2013. EACS.
G 1a c/ Q80K
G 1a s/ Q80K
C212: RVS12 por Escore de Fibrose METAVIR
Proportion of patients, % (n/N)
METAVIR
score
Overall
Naïve
Relapser
Partial
Null
F0–F2
80 (36/45)
89 (24/27)
78 (7/9)
50 (1/2)
57 (4/7)
F3–F4
64 (14/22)
57 (4/7)
100 (2/2)
67 (2/3)
60 (6/10)
SVR12, sustained virologic response 12 weeks’ after end of treatment
Introduction to faldaprevir
•
Faldaprevir is a potent and selective
inhibitor of the HCV NS3/A4 protease
– The pharmacokinetics of FDV allow
oral once daily administration
•
Phase IIb data demonstrated potent
antiviral activity against HCV GTGT-1 for:
– Faldaprevir combined with pegIFN/RBV
– An IFNIFN-free combination of faldaprevir
Faldaprevir: Interaction with
NS3/4A protease
Green = hydrophobic
Blue = mildly polar
Purple = H bonding
GT, genotype; HCV, hepatitis C virus;
IFN, interferon alpha; RBV, ribavirin;
BI 207127, a non-nucleoside inhibitor of HCV RNA polymerase
with BI 207127 and RBV
•
Phase III trials are ongoing for the iFree
and iBased faldaprevir clinical
development programs
Llinàs-Brunet M, et al. J Med Chem 2010;53:6466–6476;
Lemke CT, et al. J Biol Chem 2011;286:11434–11443;
Sulkowski MS, et al. Hepatology 2013 Jan 28 [Epub ahead of print];
Zeuzem S, et al. AASLD Congress November 9–13, 2012 [Abstract No. 232].
STARTVerso1: RVS12 de acordo com ETS,
Genótipo e Grau de Fibrose
FDV 120 mg
100
87 89
84
80
SVR12 (%)
Pacientes (%)
60
40
Placebo
100
86 89
80
69
67
60
60
40
81
56
36
20
20
0
FDV 240 mg
n/ 226/ 233/
N = 259 261
194/ 208/
226 233
Alcançaram
ETS
RVS12 in
pcs ETS
0
60/ 16/
87 45
143/ 52/
171 86
172/
212
30/
45
9/
16
GT 1a
GT 1b
< F3
≥ F3
F4
ETS definido como HCV RNA < 25 IU/mL na sem. 4 e HCV RNA < 25 IU/mL, TND na sem.8.
 23% dos pcs com GT 1a HCV tinham mutação Q80K (baseline); não preditiva de RVS12
Ferenci P, et al. EASL 2013. Abstract 1416.
STARTVerso 4:
High rates of early virologic response in HCV
genotype 1/HIV1/HIV-co
co--infected patients treated
with faldaprevir plus pegIFN and RBV
• Douglas Dieterich,
Dieterich,1 Vicente Soriano,2 Mark Nelson,3
Jürgen Kurt Rockstroh,4 Keikawus Arastéh,5 Sanjay Bhagani,6
Andrew Talal,7 Cristina Tural,8 Richard Vinisko,9 and Jens Kort
9
1Mount
Sinai School of Medicine, New York, NY, USA; 2Hospital Carlos III, Madrid, Spain; 3Chelsea and Westminster
Hospital, London, UK; 4University of Bonn, Bonn, Germany; 5EPIMED, Vivantes Auguste-Viktoria Hospital, Berlin,
Germany; 6Royal Free Hospital, London, UK; 7State University of New York, Buffalo, NY, USA; 8Hospital Universitari
Germans Trias i Pujol, Barcelona, Spain; 9Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
20th Conference on Retroviruses and Opportunistic Infections, March 3–6, 2013
STARTVerso 4: Study design (1)
Phase III open-label, sponsor-blinded study in treatment-naïve and relapser
patients with chronic HCV GT-1 and HIV infection
Interim data
Primary endpoint: SVR12
Faldaprevir 240 mg QD
+ pegIFN/RBV
Faldaprevir 240 mg QD
+ pegIFN/RBV
pegIFN/RBV
pegIFN/RBV
Randomization 1:1
pegIFN/RBV
Faldaprevir 120 mg QD
+ pegIFN/RBV
Day 1
Week 12
Week 24
Week 48
Patients with HCV RNA below LLoQ, at Week 4, and HCV RNA below LLoQ target not detected at Week 8 (=ETS)
will be re-randomized 1:1 at week 24 to stop treatment or continue pegIFN/RBV through week 48
Patients who did not achieve ETS will continue pegIFN/RBV through week 48
LLoQ, lower limit of quantification <25 IU/mL HCV RNA; pegIFN: pegylated interferon alfa-2a 180 µg once weekly; QD, once daily; SVR, sustained
virologic response at 12 weeks after end of treatment.; ETS, early treatment success
RBV: ribavirin 1000 or 1200 mg daily dose for body weight <75 kg or ≥75 kg, respectively
STARTVerso 4: Baseline characteristics
Treatment-naïve
(N=239)
Relapser
(N=69)
Total
(N=308)
47
47
47
184 (77)
64 (93)
80
179 (75)
39 (16)
21 (9)
63 (91)
2 (3)
4 (6)
79
13
8
67 (28)
60 (25)
105 (44)
7 (3)
17 (25)
7 (10)
41 (59)
4 (6)
84 (27)
67 (22)
146 (47)
11 (4)
Mean baseline CD4+ T cell count, cells/µL
544
549
545
Baseline HCV RNA ≥800 000 IU/mL, n (%)
197 (82)
49 (71)
246 (80)
HCV Genotype-1a, n (%)
184 (77)
55 (80)
239 (78)
Cirrhosis F4 or FibroScan >13 kPa, n (%)
40 (17)
11 (16)
51 (17)
Age, years (mean)
Male, n (%)
Race, n (%)
White
Black or African American
Othera
ART, n (%)
EFV-based
ATZ/r- or DRV/r-based
Ral-based and otherb
No ART (ARV-naïve), n (%)
aIncludes
bIncludes
Asian, Native Hawaiian or other Pacific Islander, American Indian or Alaska Native, and missing data.
1 patient taking maraviroc plus emtricitabine/tenofovir disoproxil fumarate, 1 patient taking emtricitabine/tenofovir disoproxil fumarate only.
Ral, raltegravir
STARTVerso 4: Patient disposition
(Week 12 interim data)
Screened
(N=453)
Screen failure
(N=143)
Allocated/
Randomized
(N=153/N=157)
HCV treatmentnaïve
(N=239)
Faldaprevir (120 or 240
mg QD) + pegIFN/RBV
(N=308)
Not available (N=18)
Discontinued (N=45)
15 Due to AE
12 Lack of efficacya
18 Other reasonb
Completed 12 weeks of
treatment
(N=176)
aIncludes:
Not treated
(N=2)
Relapser
(N=69)
Not available (N=4)
Discontinued (N=7)
3 Due to AE
1 Lack of efficacya
3 Other reasonb
Completed 12 weeks of
treatment
(N=58)
viral rebound ≥1 log10 HCV RNA from previous undetected level; lack of HCV RNA reduction from baseline by ≥ 2 log10 at Week 12;
lack of viral response at Week 24. bIncludes: protocol violation, withdrawal by subject, or other reasons
AE, adverse event; ATZ, atazanavir; DRV, darunavir; EFV, efavirenz; r, ritonavir
Early virologic response in HIV/HCV co-infected patients:
comparison with HCV mono-infected patients
Treatment-naïve <LLoQ TND
Relapser <LLoQ
Relapser <LLoQ TND
Proportion of patients (%)
Treatment-naïve <LLoQ
Treatment-naïve <LLoQ TND
*
191/
239
143/
239
63/
69
51/
69
Week 4
aSILEN-C1
Mono-infected patients, SILEN-C1 study:
108/
142
206/
239
195/
239
64/
69
63/
69
132/
142
Week 12
study arm of 240mg QD FDV plus pegIFN/RBV in HCV GT1 treatment-naïve monoinfected patients without cirrhosis; data on file
Response guided therapy criteria (ETS) in
STARTVerso 4
Relapser
Proportion of patients (%)
Treatment-naïve
aData
missing for 4 patients.
ETS, early treatment success
ETS criteria:
Wk 4 HCV RNA <LLoQ,
+ Wk 8 <LLOQ, TND
a
YES
184/
239
61/
69
50% Stop treatment at week 24
50% continue with pegIFN/RBV
through week 48
Proportion of patients with SVR4 (%)
RVS4 Global
89/123
66/84
72/86
140/185
a
aIncludes
additional patients from 240 mg treatment group who discontinued prior to week 12.
229/308
StartVerso 4 : RVS 12 de acordo com HCV Genótipo, IL28B e
Presença ou não de cirrose e tipo de resposta prévia
HCV/HIV tratados com FDV+ PegIFN + RBV x 24 semanas
100
89
HCV RNA <LLOQ (%)
74
77
90
74
80
67
67
70
60
50
40
30
20
10
178/242
51/66
89/100
101/151
34/51
229/308
GT 1a
GT 1b
IL28 CC
IL28 CT
IL 28 TT
Global
SVR12 (%)
0
100
90
80
70
60
50
40
30
20
10
0
Rockstroh et al. EACS 2013; AASLD, 2013
87
74
76
71
194/261
34/45
169/239
60/69
Virgens
Relapser
s/ Cirrose
c/ Cirrose
Acknowledgments
•
Patients, and study investigators and site staff at 67 study centers:
Brazil
Hans Jäger
Arastéh Keikawus
Josep Mallolas
Chloe Orkin
Alison Uriel
Carlos Eduardo Brandão
Juan Antonio Pineda
Mello
United States
Raymundo Ferreira Filho
Hartwig Klinker
Daniel Podzamczer
Paulo Ferreira
Jürgen Kurt Rockstroh
Cristina Tural
John Baxter
Italy
Juvencio Furtado
Jorge Vergas
Maurizio Bonacini
Switzerland
Beatriz Grinsztejn
Giacchino Angarano,
Cynthia Brinson
Jose Madruga
France
Marc Bourliere
Laurent Cotte
Pierre-Marie Girard
Andrea Antinori
Giovanni Di Perri
Gaetano Filice
Francesco Mazzotta
Paola Nasta
Manuel Battegay
Enos Bernasconi
Jan Fehr
Andri Rauch
United Kingdom
Caroline Lascoux-Combe
Marc-Antoine Valantin
Germany
Massimo Puoti
Spain
Kosh Agarwal
Sanjay Bhagani
Martin Fisher
Ranjababu
Kulasegaram
Clifford Leen
Mark Nelson
•
Johannes Bogner
Francisco Blanco
Manuel Crespo,
Christian Hoffmann
Patrick Ingiliz
Josep Guardiola
Juan Carlos Lopez
Marina Nunez
Gerald Pierone
Michael Saag
Michael Somero
Richard Sterling
Mark Sulkowski
Douglas Dieterich Andrew Talal
Richard Elion Kristen Marks
Jerome Ernst
Douglas G. Fish
Federico
Hinestrosa
Mamta Jain
Anthony LaMarca
Eric Lawitz
Cheryl McDonald
Karam Mounzer
Ronald Nahass
Boehringer Ingelheim for sponsoring the study and the Boehringer Ingelheim 1220.19 team
The external Data Monitoring Committee
Novas Drogas antianti-HCV
Inibidores da NS5a e NS5b
Sofosbuvir
81
Study Design & Duration
Wk 4
Wk 24
Wk 12
DCV + P/R
Wk 48
Wk 72
Follow Up
Yes
VR
(4 & 12)
No
P/R
Follow Up
Response Guided Treatment (RGT)
•
Subjects who achieve Virologic Response (VR) at Wks 4 and 12 will complete 24 weeks of triple
therapy
–
48 weeks follow up after treatment
•
Subjects not achieving VR at Wks 4 and 12 will receive 48 weeks total duration of therapy
(additional 24 weeks P/R)
24 weeks follow up after treatment
–
Therefore, the maximum duration of study for any subject completing treatment will be 72w
82
Study Overview
Single-arm study
Population
500 Subjects
Enrolled
Sites
Countries
DCV plus P/R
Previously untreated genotype 1 HCV coinfected with
HIV
• 300 treated (at least 40% screen fail projected)
~250 subjects on highly active antiretroviral therapy
(HAART)
– Up to 50 subjects not on HAART
–
~ 90 sites in 12 countries
•
•
•
•
Argentina
Australia
Belgium
Brazil
•
•
•
•
Canada
France
Germany
Italy
•
•
•
•
Russia
Spain
UK
US
Topline Summary of Sofosbuvir Trials
Trial
NEUTRINO[1]
FISSION[2]
FUSION[3]
POSITRON[4]
Patient Population
n
Regimen
Duration, Wks
SVR12, %
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
Tx-naive GT 2
70
SOF + RBV
12
97
Tx-naive GT 3
183
SOF + RBV
12
56
Tx-experienced GT 2
36
SOF + RBV
12
86
Tx-experienced GT 3
64
SOF + RBV
12
30
Tx-experienced GT 2
32
SOF + RBV
16
94
Tx-experienced GT 3
63
SOF + RBV
16
62
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.
Study 1910 Virologic Response and SVR12
Pacientes com HCV RNA <LLOQ (%)
Treatment--Naïve HCV/HIV CoTreatment
Co-infected Patients SOF + PegIFN + RBV x 12 weeks
10 0
100
100
91
90
80
70
60
50
40
30
20
10
23/23
23/23
21/23
Week 4
EOT
SVR12
0
 There was no on-treatment HCV or HIV virologic breakthrough
 Relapse occurred in 1 patient and accounted for the only virologic failure
 Two patients discontinued treatment early due to adverse events
• one patient discontinued at week 6 and was lost to follow-up
• one patient achieved SVR12 after 8 weeks of SOF + RBV therapy
Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714
SVR in HCV Mono-infected and HCV/HIV Co-infected
Short Duration of SOF + PegIFN + RBV x 12 Weeks
100
91
91
SVR12 (%)
80
60
40
20
296/327
21/23
0
NEUTRINO
(HCV Mono-infected)
Study 1910
(HIV/HCV Co-infected)
Similar response rates in HCV/HIV co-infected patients
compared to HCV mono-infected patients
Lawitz E, et al. APASL 2013. Singapore. Oral #LB-02
Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714
Phase 2 Study 1910 Design
Treatment-Naïve HCV/HIV Co-infected Patients
SOF + PegIFN + RBV x 12 weeks
•
Open-label trial in treatmentOpentreatment-naïve, nonnon-cirrhotic chronic HCV patients cocoinfected with HIV
0
Week
12
16
24
36
SVR4
SVR12
Primary endpoint
SVR24
HCV GT 1–4
Treatment-naïve,
on stable HIV ARV
N=23
SOF 400 mg +
PegIFN + RBV 1000‒1200 mg
No response guided therapy
•
Primary endpoints
– Efficacy: proportion of patients with SVR12
– Safety and tolerability of treatment, including effects on HIV RNA and
CD4 TT-cell %
Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714
Study 1910 SVR12 According to HCV GT and HIV ARV
Treatment--Naïve HCV/HIV CoTreatment
Co-infected Patients SOF + PegIFN + RBV x 12 weeks
100
100
100
100
89
87
17/19
13/15
4/4
1/1
2/2
1/1
GT 1
GT 1a
GT 1b
GT 2
GT 3
GT 4
90
HCV RNA <LLOQ (%)
100
80
70
60
50
40
30
20
10
SVR12 (%)
0
100
90
80
70
60
50
40
30
20
10
0
100
89
88
8/9
7/8
6/6
FTC/TDF +
Protease Inhibitor
FTC/TDF
+ NNRTI
FTC/TDF +
Raltegravir
Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714
NNRTI, non-nucleoside reverse transcriptase inhibitor
Sofosbuvir and Peginterferon AlfaAlfa-2a/Ribavirin
for TreatmentTreatment-Naïve Genotype 11-4 HCVHCVInfected Patients Who Are Coinfected With HIV
Maribel Rodriguez-Torres,1 Jose Rodriguez-Orengo,2 Anuj Gaggar,3 Gong Shen,3 Bill Symonds,3 John McHutchison,3 Milagros
Gonzalez1 IDWeek 2013, October 2-6, 2013, San Francisco, CA
Phase 3 PHOTON-1 Study Design
All-Oral Therapy of SOF + RBV in HCV/HIV Co-infection
GT 1 TN
n=114
SOF 400mg + RBV 1000-1200 mg
GT 2,3 TN
n=68
SOF 400mg + RBV 1000-1200mg
GT 2,3 TE
n=41
SOF 400mg + RBV 1000-1200 mg
Study Week
0
SVR12
SVR12
SVR12
12
24
No response guided therapy
 Broad inclusion criteria
– Cirrhosis permitted with no platelet cutoff
– Hemoglobin: ≥12 mg/dL (males); ≥11 mg/dL (females)
 Wide range of ART regimens allowed
– Undetectable HIV RNA for >8 weeks on stable ART regimen
 Baseline CD4 count
– ART treated: CD4 T-cell count >200 cells/mm3 and HIV RNA < 50 c/mL
– ART untreated: CD4 T-cell count >500 cells/mm3
Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212
36
PHOTON-1 Baseline Characteristics
PHOTONGT 1, 2, 3 HCV TreatmentTreatment-Naïve, HCV/HIV CoCo-infection
GT 1 TN
SOF + RBV
24 Weeks
(n=114)
GT 2 TN
SOF + RBV
12 Weeks
(n=26)
GT 3 TN
SOF + RBV
12 Weeks
(n=42)
49 (24-71)
48 (28-71)
48 (25-70)
Male, n (%)
93 (82)
21 (81)
34 (81)
Black, n (%)
37 (33)
6 (23)
2 (5)
Hispanic, n (%)
25 (22)
8 (31)
11 (26)
27 (19-46)
27 (21-32)
28 (20-44)
30 (27)
10 (39)
15 (36)
6.6 (1.4-7.7)
6.5 (5.0-7.3)
6.2 (5.0-7.4)
Cirrhosis, n (%)
5 (4)
1 (4)
6 (14)
On ART, n (%)
112 (98)
22 (85)
39 (93)
636 (251)
627 (278)
559 (224)
Mean age, y (range)
Mean BMI, kg/m2 (range)
IL28B CC, n (%)
Mean baseline HCV RNA,
log10 IU/mL (range)
CD4 T-cell count (cells/μL), mean (SD)
Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212
HCV RNA < 25 IU/mL (%)
PHOTON-1 SVR12
All-Oral Therapy of SOF + RBV in GT1, 2, 3 HCV Treatment-Naive and GT 3
Treatment-Experienced/HIV Co-infection
100
90
80
70
60
50
40
30
20
10
0
SOF + RBV
x24 weeks
GT1 TN1
100
SOF + RBV
x12 weeks
GT2 TN1
100
SOF + RBV
x12 weeks
GT3 TN1
100
SOF + RBV
x24 weeks
GT3 TE2
92
88
80
76
67
60
60
60
40
40
40
20
20
23/26
87/114
0
20
28/42
87/114
SVR12
80
80
0
SVR12
12/13
0
SVR12
SVR12
 An all-oral regimen of SOF + RBV for 12–24 weeks resulted in high SVR12 rates in TN GT 1, 2 and 3 and TE
GT 3 CHC with HIV coinfection – with SVR12 rates similar to mono-infection
 No HCV resistance (S282T) was observed in virologic failures via deep sequencing
 Two patients had HCV breakthrough; both had documented non-adherence to SOF
 Two other patients had transient HIV breakthrough; both had documented non-adherence to ART
1. Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212;
2. SOVALDI™ [PI]. Gilead Sciences, Inc. Foster City, CA December 2013
‡
SVR in HCV Mono-infected and HCV/HIV Co-infected
All-Oral SOF+RBV x 12 or 24 weeks
GT 2
SOF + RBV
12 weeks
100
100
60
40
0
100
60
40
87/114
SPARE1
HCV
PHOTON-12
HCV/HIV
0
85
60
56
40
68/73
VALENCE3
HCV
23/26
PHOTON-12
HCV/HIV
0
92
80
67
20
20
17/25
100
80
80
20
GT 3
SOF + RBV
24 weeks
88
SVR12 (%)
68
76
SVR12 (%)
SVR12 (%)
80
93
GT 3
SOF + RBV
12 weeks
SVR12 (%)
GT 1
SOF + RBV
24 weeks
60
40
20
102/183
FISSION4
HCV
28/42
PHOTON-12
HCV/HIV
0
212/250
12/13
VALENCE3 PHOTON-15
HCV
HCV/HIV
Similar response rates in HCV/HIV coinfected patients compared to HCV
monoinfected patients
1. Osinusi A, et al. JAMA. 2013;310(8):804-811. 2. Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212. 3. Zeuzem S, et al.
AASLD 2013. Washington, DC. #1085. 4. Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87. 5. SOVALDI™ [PI]. Gilead
Sciences, Inc. Foster City, CA December 2013
Drug Interactions with GSGS-7977 and HIV
Antiretrovirals in Healthy Volunteers
Effect of Co-Administration of
GS-7977 on HIV ARVs
AUC tau
Cmax
Ctau
GMR% (90% CI)
Combination/Alone
200
150
143%
100
70%
50
Kirby B, et al. AASLD 2012; Boston. #1877.
L
A
R
TV
R
V
R
D
PV
R
V
EF
C
FT
TF
V
0
Novas Drogas antianti-HCV
DAAs de 2a Geração Inibidores
da NS3/4, NS5a e NS5b (IFN Free)
 MK5172 + MK 7842
 Sofosbuvir +Ledipasvir
96
RVS 12 com regimes de DAAs IFN Free em
Coinfectados Virgens e Experimentados HCV/HIV
100
100
92
97
92
88
HCV RNA <LLOQ (%)
90
80
76
67
70
60
50
naive
42
40
30
experimentado
20
10
114
24
37
59
26
17
0
Photon 1
Sofo +RBV
Sofo +
Ledi
GT 1
C-Worthy
MK5172 +
MK8742  RBV
Photon 1
GT 3
Photon 1
GT 2
Sofo +RBV
Sulkowski, M et al. AASLD, 2013; Osinuzi, A. et al. EASL 2014, Sulkowski, M et al. EASL 2014
Taxas de RVS com os Novos Agentes DAAs para pacientes
virgens de tratamento mono e coinfectados HCV-HIV
Estudos de Fase II/III - DAAs  PegIFN/RBV
Not head-to-head comparisons
> 90
100
71-75
RVS (%)
80
68-85
65-85 75-80 61-84
> 95
> 95
42-83
63-75
60
40
20
0
BOC or
TVR [1,2]
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
3. Sulkowski M, et al. EASL 2011. Abstract 60. 4. Terrault N, et al. AASLD 2011. Abstract 79. 5. Vierling JM, et al. AASLD 2011.
Abstract LB-17. 6. Fried M, et al. AASLD 2011. Abstract LB-5. 7. Manns MP, et al. AASLD 2010. Abstract 82.
8. Jacobson I, et al. EASL 2010. Abstract 2088. 9. Lawitz E, et al. EASL 2011. Abstract 445. 10. Pol S. ICAAC 2011.
Abstract HI-376. 11. Flisiak R, et al. EASL 2011. Abstract 4.
Progression of SVR in HCV treatment in HIV
Fixed dose ribavirin
Weight-based
ribavirin
Direct-acting antiviral
agents
AASLD & IDSA Guidelines
GT 1, 2, 3 TreatmentTreatment-Naïve, Experienced HCV/HIV CoCo-infection
GT 1
GT 2
Treatment Naïve and Prior PR relapsers
IFN eligible
SOF +
PegIFN/RBV
12 Weeks
SOF + RBV
12 Weeks
Treatment Naïve and Prior PR relapsers
IFN ineligible
SOF + RBV
24 Weeks
SOF + RBV
12 Weeks
SOF + RBV
24 weeks
Treatment Naïve and Prior PR relapsers
IFN ineligible (alternative)
SOF + SMP
RBV
12 Weeks
SOF + RBV
12 weeks
SOF + DCL*
RBV
12/24 weeks
Treatment experienced and PR non-response
SOF + SMP
RBV
12 Weeks
SOF + RBV
12 Weeks
16 weeks for
cirrhotic
SOF + RBV
24 Weeks
24 weeks for
cirrhotic
Treatment experienced and TPV/BOC nonresponse
SOF x 12
weeks +
PegIFN/RBV
12/24 Weeks
NA
NA
AASLD & IDSA Guidelines, 2014
GT 3
SOF + RBV
24 weeks
* EASL Guidelines & Recommendations April 2014
Interação Medicamentosa entre DAAS e TARV
Droga
Telaprevir
Boceprevir
Simeprevir
Faldaprevir
Daclatasvir
Sofosbuvir
Atazanavir
Monitorar
bilirrubinemia
Individualizar
Não recomendada
Recomendada
120 mg/dia
Recomendada
30 mg/dia
Recomendada
Darunavir
Não recomendada
Não recomendada
Não recomendada
Recomendada
120 mg/dia
NA
Recomendada
Efavirenz
1125 mg 3 x/dia
Não recomendada
Não recomendada
Recomendada
240 mg/dia
Recomendada
90 mg/dia
Recomendada
Rilpivirina
Cautela com intervalo QT
Recomendada
Recomendada
NA
NA
Recomendada
Etravirina
Recomendada
Individualizar
NA
NA
NA
NA
Raltegravir
Recomendada
Recomendada
Recomendada
Recomendada
NA
Recomendada
Adaptado de Bhagani, EASL, 2014
Hepatite C - HIV - Resumo
• Ocorre em 25
25--30
30%
% dos pacientes com infecção pelo HIV
HIV..
• Mais freqüente em usuários de drogas ilícitas e hemofíicos
hemofíicos..
• Hepatite C é importante causa de morbi
morbi--mortalidade em doentes HIV
HIV..
• Terapia com Peg
Peg--interferon e Ribavirina com eficácia de 27 – 55
55%
%
(Geral), de 14 – 46
46%
% nos pacientes com Gen
Gen.. 1 e 43 – 73
73%
% Gen
Gen.. 2-3.
• Terapia combinada de Peg
Peg--interferon e Ribavirina e 1ª geração de
DAAs (Telaprevir e Boceprevir
Boceprevir)) com taxas de RVS  61
61%
% a 75
75%
%.
• Terapia combinada de 2ª geração de DAAs (Simeprevir
Simeprevir,, Faldaprevir
Faldaprevir))
e de inibidores da NS
NS5
5a/NS
a/NS5
5b IFN
IFN--Free com taxas de RVS  80
80--90
90%
%.
• Atenção a interação medicamentosa entre os novos DAAs e a TARV
TARV..
Recomendações
 Tratamento de Escolha
Escolha:: Peg
Peg--Interferon + Ribavirina com doses
otimizadas (1000
1000--1200 mg
mg)) e DAA (inibidores de Protease)
Protease)..
 Aguarda
Aguarda--se os resultados dos ensaios com novas moléculas
(Boehringer
Boehringer,,
Bristol))
Bristol
para
pacientes
virgens
e
para
os
recidivantes e não
não--respondedores
 Independente do genótipo a duração deve ser de 48 semanas
semanas..
 Avaliar resposta virológica rápida (na 4a) e precoce (12a)
semana.. Valor preditivo positivo (>
semana
(>80
80%
%) e negativo altos (98
98%
%)
 Atenção com a interação do esquema HAART e DAA (IP)
(IP)..
OBRIGADO...
Phase I
Gilead
Vertex
Phase II
SCY635
(Scynexis)
ANA598
(Anadys)
HTAs
DAA: NS5A
inhibitor
DAA: Nucpolymerase
inhibitors
Phase III
MK7009
(MSD)
RG7128 (Roche/
Pharmasset)
PSI-7977
(Pharmasset)
Filed
BMS650032
(BSM)
DAA: Protease
inhibitors
DAA: Non nucpolymerase
inhibitors
(BI Pharma)
Alisporivir
(Novartis)
BMS-791325
(Nuc/non-nuc BMS)
Boceprevir Telaprevir
(MSD) (J&J/Vertex)
BI201335
(BI)
GS9256 & GS9451
(Gilead)
Tegobuvir
(Gilead)
IDX-184
(Idenix)
IDX-375
(Idenix)
BMS790052
(BMS)
VX-222
(Vertex)
ACH-0141625
(Achillion)
BI207127
(BI)
TMC435
(Tibotec/Medivir)
RG7128 (Genentech/
Pharmasset)
ABT-333 & ABT-072
(Abbott)
ITMN-191/RG7227
(Roche/Interume)
NS=non-structural; nuc=nucleoside;
HTA=host-targeting antiviral; DAA=direct-acting antiviral
ABT-450
(Abbott)
Data correct as of March 2011