15. Mundo Brasil
Prevalência 170 - 200 milhões 2 - 3 milhões
Incidência/ano 3 - 4 milhões 10 mil
Mortalidade/ano 0.3 milhão ?
Barbosa AN, 2014
> 10%
2,5-10%
1-2,5%
Prevalência
ND
WHO, 2012
Inquérito Nacional das Hepatites Virais, MS-Brasil, 2010
18. Barbosa AN, 2014
VHB VHC
Parceiros Sexuais de VHB + Transfusões antes de 1994
Múltiplos Parceiros, Violência Sexual Usuários de Drogas
DSTs (HIV, VHC, Lues, HPV, etc) Hemofílicos, Hemodiálise
HSHs HSHs
Usuários de Drogas Acidentes Ocupacionais
Convívio Domiciliar com VHB + Seringas e Agulhas Não Descartáveis
Acidentes Ocupacionais Acupuntura, Piercing ou Tatuagem
Hemodiálise Parceiros Sexuais de VHC +
Institucionalizados Convívio Domiciliar com VHC +
Viajantes para Áreas Endêmicas DSTs (HIV, VHC, Lues, HPV, etc)
Filhos de Mães VHB + Filhos de Mães VHC +
Sinais de Hepatopatia Sinais de Hepatopatia
31. Barbosa AN, 2014
Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
PCR VHC
(-)
PCR VHC (-) Sem 4:
Resposta Virológica Rápida
RVS: 90%
32. Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
Barbosa AN, 2014
Fluxograma de Tratamento (PEG-IFN + RBV)
G2/3
G1
Tto: 24 semanas
Tto: 48 semanas
PCR VHC
(-)
PCR VHC (-) Sem 4:
Resposta Virológica Rápida
RVS: 90%
33. Barbosa AN, 2014
Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
PCR VHC (-) Sem 12:
Resposta Virológica
Precoce Completa
PCR VHC RVS: 66%
(+)
PCR VHC
(-)
34. Barbosa AN, 2014
Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
PCR VHC
(+)
G2/3
G1
Tto: 24 semanas
Tto: 48 semanas
PCR VHC
(-)
G2/3
G1
PCR VHC
(-)
PCR VHC (-) Sem 12:
Resposta Virológica
Precoce Completa
RVS: 66%
35. Barbosa AN, 2014
Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
Queda de
2 logs
PCR VHC
(+)
Queda de 2 logs Sem 12:
Resposta Virológica
Precoce Parcial
RVS: 45%
36. Barbosa AN, 2014
Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
PCR VHC
(+)
G2/3
G1
Tto: 24 semanas
Tto: 48 semanas
PCR VHC
(-)
G2/3
G1
PCR VHC
(-)
Queda de 2 logs Sem 12:
Resposta Virológica
Precoce Parcial
RVS: 45%
Queda de
2 logs
G1
Tto: 72 semanas
G2/3
37. Barbosa AN, 2014
Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
PCR VHC
(+)
PCR VHC
(-)
Queda de
2 logs
Sem queda
De 2 logs
Sem Queda de 2 logs
Sem 12: Resposta Nula
RVS: 2 %
38. Sem Queda de 2 logs
Sem 12: Resposta
Barbosa AN, 2014
Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
PCR VHC
(+)
G2/3
G1
Tto: 24 semanas
Tto: 48 semanas
PCR VHC
(-)
G2/3
G1
PCR VHC
(-)
Queda de
2 logs
G1
Tto: 72 semanas
Sem queda
De 2 logs
G1/2/3
Nula
Tto: Suspenso
G2/3
39. Barbosa AN, 2014
Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
PCR VHC
(+)
G2/3
G1
Tto: 24 semanas
Tto: 48 semanas
PCR VHC
(-)
G2/3
G1
PCR VHC
(-)
Queda de
2 logs
G2/3
G1
Tto: 72 semanas
Sem queda
De 2 logs
G1/2/3
PCR VHC Tto: Suspenso
(+)
40. Barbosa AN, 2014
Desafios
- Efeitos Adversos
- Interações Medicamentosas (HIV)
- Recidivantes e Não Respondedores (50%)
- Diagnóstico Tardio, Alcoolismo, Fibrose Avançada
52. Recommendation: Noncirrhotic patients can be considered for
response-guided therapy with TVR
TVR + PegIFN + RBV
PegIFN + RBV eRVR; stop at Wk 24, f/u 24 wks
0 4 12 24 48
TVR + PegIFN + RBV
0 4 12 24 48
Telaprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
PegIFN + RBV
HCV RNA
Undetectable Undetectable
Detectable
(≤ 1000 IU/mL)
Undetectable or
detectable (≤ 1000 IU/mL)
No eRVR; extend pegIFN + RBV to Wk 48; f/u 24 wks
HCV RNA
Barbosa AN, 2014
53. ILLUMINATE: Response-Guided TVR
+ PegIFN/RBV in
Treatment-Naive Genotype 1
65% of patients eligible for
shortened therapy[1]
92 88
T12PR24 T12PR48
SVR in Pts Achieving eRVR
100
(%)
80
60
40
20
0
149/
162
140/
160
n/
N=
ADVANCE: TVR + PegIFN/RBV in
Treatment-Naive Genotype 1
58% of patients eligible for
shortened therapy[2]
89
100
1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
2. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024.
97
T12PR24 T12PR48
SVR in Pts Achieving eRVR
(%)
80
60
40
20
0
189/
212
28/
29
n/
N=
Barbosa AN, 2014
54. BOC[1,2]
Time Point Criteria Action
Wk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapy
Wk 24 HCV RNA detectable Discontinue all therapy
TVR[1,3]
Time Point Criteria Action
Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy
Wk 24 HCV RNA detectable Discontinue pegIFN/RBV
Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA
detection of approximately 10-15 IU/mL.
1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
3. Telaprevir [package insert]. May 2011.
Barbosa AN, 2014
55. Recommendation: BOC approved for previous relapsers, partial, and null responders[1]
– AASLD guidelines say BOC “recommended” for previous relapsers and partial responders;
advise caution in null responders given lack of definitive information from phase III studies[2]
BOC + PegIFN + RBV
Previous relapse
100
80
60
40
20
0
PegIFN + RBV
n/N = 2/29 15/51 23/57 72/105 30/58 77/103
PegIFN
+ RBV
1. Boceprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
3. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
40
69
BOC RGT
52
75
BOC/PR48
7
29
PR48
SVR (%)[3]
Previous partial response
F/u
24 wks
BOC + PegIFN + RBV
0 4 8 12 24
28 36
48
Early response;
stop at Wk 36; f/u 24 wks
Barbosa AN, 2014
56. Recommendation: Response-guided therapy can be considered for
previous relapsers, may be considered for previous partial
responders, but not for previous null responders
BOC + PegIFN + RBV
PegIFN
+ RBV
0 4 8 12 24 28 36
48
PegIFN
+ RBV
BOC + PegIFN + RBV
Boceprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
Early response; stop at
Wk 36; f/u 24 wks
HCV RNA
Undetectable Undetectable
PegIFN + RBV
0 4 8 12 24
28 36
48
HCV RNA
Detectable Undetectable Slow response; PR to
Wk 48; f/u 24 wks
< 100 IU/mL
< 100 IU/mL
Barbosa AN, 2014
57. Recommendation: TVR approved for previous relapsers, partial, and null responders[1]
– AASLD guidelines say TVR “recommended” for previous relapsers and partial responders;
“may be considered” for previous null responders[2]
Previous relapsers*[1,2] (same as naives)
TVR + PegIFN + RBV
eRVR; stop at Wk 24, f/u 24 wks
PegIFN + RBV F/u
24 wks
0 4 12 24 48
Previous partial responders† and null responders[1,2]
1. Telaprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
F/u
24 wks
TVR + PegIFN + RBV
No eRVR; PegIFN + RBV
PegIFN + RBV
0 4 12 24 48
*Response-guided therapy not studied in relapsers in registration trials.
†AASLD guidelines say RGT “may be considered” for prior partial responders[2] but package insert
recommends 48 weeks of therapy[1]
Barbosa AN, 2014
58. REALIZE: TVR + PegIFN/RBV in G1 Previous Relapsers and Partial/Null Responders
Lead-in examined but found not to influence response and not included in TVR label
100
60
20
0
SVR (%)
80
40
PR48 T12/PR48 LI T12/PR48
Previous Relapsers Previous Partial
Responders
n/N=
Previous Null
Responders
24
*P < .001 vs PR48.
83*
88*
121/145 124/141
16/68
59*
54*
29/49 26/48
15
4/27
29*
33*
21/72 25/75
5
2/37
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
Barbosa AN, 2014
59. Recommendation: Response-guided therapy recommended for previous
relapsers, but not for previous partial or null responders*[1]
HCV RNA
Undetectable Undetectable
TVR + PegIFN + RBV
PegIFN + RBV eRVR; stop at Wk 24, f/u 24 wks
0 4 12 24 48
HCV RNA
Detectable
(≤ 1000 IU/mL)
Undetectable/detectable
(≤ 1000 IU/mL)
TVR + PegIFN + RBV
No eRVR; extend pegIFN + RBV to Week 48; f/u 24 wks
PegIFN + RBV
0 4 12 24 48
*AASLD guidelines say RGT “may be considered” for previous partial responders[2] but package insert
recommends 48 wks of therapy.[1]
1. Telaprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
Barbosa AN, 2014
60. Recommendation: All therapy should be discontinued in
patients with the following:
BOC[1,2]
Time Point Criteria Action
Wk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapy
Wk 24 HCV RNA detectable Discontinue all therapy
TVR[1,3]
Time Point Criteria Action
Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy
Wk 24 HCV RNA detectable Discontinue pegIFN/RBV
Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA
detection of approximately 10-15 IU/mL.
1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
3. Telaprevir [package insert]. May 2011.
Barbosa AN, 2014
64. Recommendation: All cirrhotic patients receiving TVR + PR may
PR48
T12PR
T8PR
benefit from 48 weeks of therapy[1,2]
78
100
80
60
40
20
1. Telaprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
3. Jacobson IM, et al. AASLD 2010. Abstract 211. 4. Jacobson IM, et al. NEJM. 2011;364:2405-2416.
62
73
53
47
33
0
No, Minimal, or Portal Fibrosis Bridging Fibrosis or Cirrhosis
SVR (%)[3,4]
134/
288
n/
N =
226/
290
205/
279
24/
73
45/
73
45/
85
Barbosa AN, 2014
65. Recommendation: IL28B genotype testing may be considered prior to
therapy if more information about probability of response or treatment
duration desired
IL28B Genotype Predicts Likelihood of SVR With Triple Therapy
SPRINT-2: BOC + PR48[1]
SVR (%)
80
44/
55
71
82/
115
59
26/
44
CC CT TT
100
80
60
40
20
0
n/
N =
1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.
ADVANCE: T12PR48*[2]
SVR (%)
90
45/
50
48/
68
16/
22
CC CT TT
100
80
60
40
20
0
71 73
n/
N =
*IL28B testing in ADVANCE was in whites only.
Barbosa AN, 2014
66. Recommendation: IL28B genotype testing may be considered prior to
therapy if more information about probability of response or treatment
duration desired
IL28B Genotype Predicts Likelihood of Short-Duration Therapy
SPRINT-2: BOC + PR[1]
Eligibility for RGT (%)
89
118/
132
52
158/
304
CC CT/TT
100
80
60
40
20
0
1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.
ADVANCE: T12PR*[2]
Eligibility for RGT (%)
39/
50
39/
68
10/
22
78
100
80
60
40
20
0
57
45
n/
N =
*IL28B testing in ADVANCE was in whites only.
CC CT TT
n/
N =
Barbosa AN, 2014
67. Data from T12PR arm only
71
152/
213
79
118/
149
100
50
0
1b 1a
Genotype
78
74
< 800,000 ≥ 800,000
HCV RNA (IU/mL)
62
78
F0-2 F3-F4
Fibrosis
SVR (%)
75
25
207/
281
64/
82
45/
73
226/
290
n/
N =
Marcellin P, et al. EASL 2011. Abstract 451.
Barbosa AN, 2014
69. Significantly higher rates of anemia, neutropenia, and
dysgeusia in BOC arms vs control
Adverse Event, % PR48
(n = 467)
BOC + PR RGT/48
(n = 1225)
Anemia* 30 50
Neutropenia 19 25
Dysgeusia 16 35
*Anemia was managed with RBV reduction and/or epoetin alfa
(43% of BOC + PR and 24% of PR).
Barbosa AN, 2014
70. Higher rates of rash, anemia, and anorectal signs/symptoms in TVR
arms vs control
Adverse Event, % PR48
(n = 493)
TVR + PR RGT/48*
(n = 1797)
Rash 34 56
Anemia† 17 36
Anorectal events 7 29
*Pooled results from TVR arms.
†Anemia was managed with RBV dose modification; epoetin alfa was not permitted.
In most subjects, rash was mild to moderate
– Severe rash in 4%; discontinuation due to rash in 6% of subjects
– Occurred early, usually first 4 wks, but can occur at any time during TVR
exposure
– < 1% had SJS or DRESS (11 cases DRESS and 3 cases SJS)
Telaprevir [package insert]. May 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/
Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf
Barbosa AN, 2014
71. Recommendation: Anemia should be managed initially
by reducing the RBV dose[1]
Dose reduction of RBV is acceptable
Dose reduction of DAA is not acceptable
Do not discontinue pegIFN/RBV and continue DAA
DAA should not be stopped and then restarted
Monitor closely if Hb falls < 10 g/dL
ESA agents are unlabeled for HCV anemia and should
not be used if Hb > 12 g/dL
1. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
Barbosa AN, 2014
72. Rash management
– Mild to moderate rash can be treated with oral
antihistamines, topical steroids
– Systemic steroids are not recommended
– Stop all 3 drugs for severe rash, DRESS, or SJS
– Important to have “go-to” dermatologist; vigilance with rash
is key
Anorectal symptom management
– Fiber, loperamide, hydrocortisone, and pramoxine topical
cream
Telaprevir [package insert]. May 2011.
Barbosa AN, 2014
73. Contraindications for BOC and TVR therapy
– Patients with previous SAEs leading to premature pegIFN/RBV discontinuation
– Pregnant women or men whose female partners are pregnant
– Coadministration with other drugs highly dependent on CYP3A4/5 for clearance
– Coadministration with potent CYP3A4/5 inducers that may significantly reduce
BOC or TVR plasma concentrations, leading to reduced efficacy
Safety and pharmacokinetics have not been studied in patients with
decompensated cirrhosis or in liver transplant recipients, patients coinfected
with HBV or HIV, or persons younger than 18 yrs of age
Assess carefully for all drug-drug interactions prior to commencing therapy
Boceprevir [package insert]. May 2011. Telaprevir [package insert]. May 2011.
Ghany MG, et al. Hepatology. 2011;54:1433-1444.
Barbosa AN, 2014