4. Prevalência Mundial (2,2%): 170 a 200 milhões
Incidência: 3 a 4 milhões/ano; 300 mil óbitos/ano
Anti-VHC: 2,7 milhões (1,38%)
PCR-VHC: 1,3 milhões (0,67%)
WHO, 2012
Casos Notificados: 70 mil Inquérito Nacional das Hepatites Virais, MS-Brasil, 2010
Barbosa AN, 2012
6. Nearly 100% of patients who achieve SVR remain undetectable
during long-term follow-up[1-4]
99[1] 99[2] 100[3] 100[4]
100
Patients With SVR
80
60
(%)
40
20
0
3.9 yrs 3.4 yrs 3.3 yrs 5.4 yrs
(mean) (median) (median) (median)
Duration of Follow-up
1. Swain MG, et al. Gastroenterology. 2010;139:1593-1601. 2. Giannini EG, et al. Aliment Pharmacol Ther. 2010;31:502-508. 3. Maylin S, et al. Gastroenterology.
2008;135:821-829. 4. George SL, et al. Hepatology. 2009;49:729-738.
Barbosa AN, 2012
7. 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%
Barbosa AN, 2012
8. Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
G2/3 Tto: 24 semanas
PCR VHC
(-) G1 Tto: 48 semanas
PCR VHC (-) Sem 4:
Resposta Virológica Rápida
RVS: 90%
Barbosa AN, 2012
9. Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
PCR VHC (-) Sem 12:
Resposta Virológica
PCR VHC
(-)
Precoce Completa
PCR VHC
(+)
RVS: 66%
Barbosa AN, 2012
10. Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
G2/3 Tto: 24 semanas
PCR VHC
(-) G1 Tto: 48 semanas
PCR VHC G2/3
(-) G1
PCR VHC PCR VHC (-) Sem 12:
(+) Resposta Virológica
Precoce Completa
RVS: 66%
Barbosa AN, 2012
11. Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
Queda de 2 logs Sem 12:
Resposta Virológica
PCR VHC
(-)
Precoce Parcial
PCR VHC
(+)
RVS: 45%
Queda de
2 logs
Barbosa AN, 2012
12. Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
G2/3 Tto: 24 semanas
PCR VHC
(-) G1 Tto: 48 semanas
PCR VHC Tto: 72 semanas
G2/3
(-)
PCR VHC G1
(+) Queda de
Queda de 2 logs Sem 12:
2 logs G1
Resposta Virológica
Precoce Parcial
RVS: 45%
Barbosa AN, 2012
13. Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
PCR VHC Sem Queda de 2 logs
(-)
PCR VHC Sem 12: Resposta Nula
(+) Queda de RVS: 2 %
2 logs
Sem queda
De 2 logs
Barbosa AN, 2012
14. Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
G2/3 Tto: 24 semanas
PCR VHC
(-) G1 Tto: 48 semanas
Tto: 72 semanas
PCR VHC G2/3
(-) G1
PCR VHC
(+) Queda de Sem Queda de 2 logs
G1
2 logs Sem 12: Resposta
Nula
Sem queda
G1
De 2 logs
Tto: Suspenso
Barbosa AN, 2012
15. Fluxograma de Tratamento (PEG-IFN + RBV)
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72
G2/3 Tto: 24 semanas
PCR VHC
(-) G1 Tto: 48 semanas
Tto: 72 semanas
PCR VHC G2/3
(-) G1
PCR VHC
(+) Queda de
G1
2 logs
Sem queda
G1
De 2 logs
PCR VHC Tto: Suspenso
(+)
Barbosa AN, 2012
16. 100
PegIFN/
80 ribavirin
(6-12 mos)[6,7]
Interferon/
50-60
SVR (%)
60 ribavirin PegIFN
(6-12 mos)[3,4] monotherapy
Standard 38-43 (6-12 mos)[5,6]
40 Standard interferon
(12-18 mos)[2,3] 25-30
interferon
(6 mos)[1] 15-20
20
8-12
0
1991 1995 1998 2001
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.
Barbosa AN, 2012
36. Recommendation: Noncirrhotic patients can be considered for
response-guided therapy with TVR
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 Undetectable or
(≤ 1000 IU/mL) detectable (≤ 1000 IU/mL)
No eRVR; extend pegIFN + RBV to Wk 48; f/u 24 wks
TVR + PegIFN + RBV PegIFN + RBV
0 4 12 24 48
Telaprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
Barbosa AN, 2012
37. ILLUMINATE: Response-Guided TVR
ADVANCE: TVR + PegIFN/RBV in + PegIFN/RBV in
Treatment-Naive Genotype 1 Treatment-Naive Genotype 1
58% of patients eligible for 65% of patients eligible for
shortened therapy[2] shortened therapy[1]
SVR in Pts Achieving eRVR
97
SVR in Pts Achieving eRVR
100 89 100 92 88
80 80
60 60
(%)
(%)
40 40
20 20
n/ 189/ 28/ n/ 149/ 140/
0 N= 212 29 0 N= 162 160
T12PR24 T12PR48 T12PR24 T12PR48
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.
Barbosa AN, 2012
38. 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, 2012
39. 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]
Early response;
PegIFN BOC + PegIFN + RBV stop at Wk 36; f/u 24 wks
+ RBV BOC + PegIFN + RBV PegIFN + RBV F/u
24 wks
0 4 8 12 24 28 36 48
100 Previous partial response
80 Previous relapse 75
69
SVR (%)[3]
60 52
40
40 29
20
7
n/N = 2/29 15/51 23/57 72/105 30/58 77/103
0
PR48 BOC RGT BOC/PR48
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.
Barbosa AN, 2012
40. Recommendation: Response-guided therapy can be considered for
previous relapsers, may be considered for previous partial
responders, but not for previous null responders
HCV RNA
Undetectable < 100 IU/mL Undetectable
PegIFN Early response; stop at
+ RBV BOC + PegIFN + RBV
Wk 36; f/u 24 wks
0 4 8 12 24 28 36 48
HCV RNA
Detectable < 100 IU/mL Undetectable Slow response; PR to
Wk 48; f/u 24 wks
PegIFN
BOC + PegIFN + RBV PegIFN + RBV
+ RBV
0 4 8 12 24 28 36 48
Boceprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
Barbosa AN, 2012
41. 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)
eRVR; stop at Wk 24, f/u 24 wks
TVR + PegIFN + RBV PegIFN + RBV F/u
No eRVR; PegIFN + RBV
24 wks
0 4 12 24 48
Previous partial responders† and null responders[1,2]
TVR + PegIFN + RBV PegIFN + RBV F/u
24 wks
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]
1. Telaprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
Barbosa AN, 2012
42. 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
PR48 T12/PR48 LI T12/PR48
Previous Relapsers Previous Partial Previous Null
100 Responders Responders
88*
83*
80
SVR (%)
59*
60 54*
40 33*
29*
24
20 15 5
n/N= 16/68 121/145 124/141 4/27 29/49 26/48 2/37 21/72 25/75
0
*P < .001 vs PR48.
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
Barbosa AN, 2012
43. 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 Undetectable/detectable
(≤ 1000 IU/mL) (≤ 1000 IU/mL)
No eRVR; extend pegIFN + RBV to Week 48; f/u 24 wks
TVR + PegIFN + RBV 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, 2012
44. 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, 2012
48. Recommendation: All cirrhotic patients receiving TVR + PR may
benefit from 48 weeks of therapy[1,2]
100 PR48
T12PR
78 T8PR
80 73
62
SVR (%)[3,4]
60 53
47
40 33
20
n/ 134/ 226/ 205/ 24/ 45/ 45/
N= 288 290 279 73 73 85
0
No, Minimal, or Portal Fibrosis Bridging Fibrosis or Cirrhosis
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.
Barbosa AN, 2012
49. 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] ADVANCE: T12PR48*[2]
100 100 90
80
80 71 80 71 73
59
SVR (%)
SVR (%)
60 60
40 40
20 20
n/ 44/ 82/ 26/ n/ 45/ 48/ 16/
N= 55 115 44 N= 50 68 22
0 0
CC CT TT CC CT TT
*IL28B testing in ADVANCE was in whites only.
1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.
Barbosa AN, 2012
50. 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] ADVANCE: T12PR*[2]
100 100
89
78
Eligibility for RGT (%)
Eligibility for RGT (%)
80 80
60 60 57
52
45
40 40
20 20
n/ 118/ 158/ n/ 39/ 39/ 10/
N= 132 304 N= 50 68 22
0 0
CC CT/TT CC CT TT
*IL28B testing in ADVANCE was in whites only.
1. Poordad F, et al. EASL 2011. Abstract 12. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.
Barbosa AN, 2012
51. Data from T12PR arm only
100
79 78 78
74
75 71
62
SVR (%)
50
25
n/ 118/ 152/ 64/ 207/ 226/ 45/
N = 149 213 82 281 290 73
0
1b 1a < 800,000 ≥ 800,000 F0-2 F3-F4
Genotype HCV RNA (IU/mL) Fibrosis
Marcellin P, et al. EASL 2011. Abstract 451.
Barbosa AN, 2012
53. Significantly higher rates of anemia, neutropenia, and
dysgeusia in BOC arms vs control
Adverse Event, % PR48 BOC + PR RGT/48
(n = 467) (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, 2012
54. Higher rates of rash, anemia, and anorectal signs/symptoms in TVR
arms vs control
Adverse Event, % PR48 TVR + PR RGT/48*
(n = 493) (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, 2012
55. 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, 2012
56. 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, 2012
57. 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, 2012
58. Drug Class Contraindicated With BOC[1] Contraindicated With TVR[2]
Alpha 1-adrenoreceptor Alfuzosin Alfuzosin
antagonist
Anticonvulsants Carbamazepine, phenobarbital, N/A
phenytoin
Antimycobacterials Rifampin Rifampin
Ergot derivatives Dihydroergotamine, ergonovine, Dihydroergotamine, ergonovine,
ergotamine, methylergonovine ergotamine, methylergonovine
GI motility agents Cisapride Cisapride
Herbal products Hypericum perforatum (St John’s wort) Hypericum perforatum
HMG CoA reductase Lovastatin, simvastatin Atorvastatin, lovastatin, simvastatin
inhibitors
Oral contraceptives Drospirenone N/A
Neuroleptic Pimozide Pimozide
PDE5 inhibitor Sildenafil or tadalafil when used for tx of Sildenafil or tadalafil when used for tx
pulmonary arterial hypertension of pulmonary arterial hypertension
Sedatives/hypnotics Triazolam; orally administered Orally administered midazolam,
midazolam triazolam
*Studies of drug-drug interactions incomplete.
1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011.
Barbosa AN, 2012
61. - ↑ RVS naïves e experimentados - Preço (R$ 60 – 70 mil)
- Menor tempo de tratamento - SUS ainda não cobre
- Maior chance de RVS para não - Resistência aos IPs
respondedores prévios - Efeitos Adversos
- Maior chance de RVS para - Interações medicamentosas
F3/F4
- Nº de comprimidos
- Maior chance de resposta IL28B
CT e TT - Boas opções no futuro
Barbosa AN, 2012
62. NS3/4A NS5B Polymerase Inhibitors NS5A Cyclophilin A
Protease Nucleos(t)ide Non- Inhibitors Inhibitors
Inhibitors Analogue nucleos(t)ide
High efficacy Mimic natural Bind to several NS5A has role Supports HCV-
Low genetic substrates of the different in assembly of specific RNA
barrier to polymerase allosteric replication replication,
resistance Incorporated into enzyme sites; complex protein
RNA chain results in Mechanism of expression
Macrocyclic conformational
or linear causing chain inhibition Interacts with
termination change under study NS2, NS5A,
Phase III: Resistance NS5B
BI 201335, Broad genotypic Phase III:
coverage more frequent Daclatasvir May regulate
TMC435 than nucs
High genetic (BMS-790052) polypeptide
barrier to Several agents processing,
resistance in phase II viral assembly
Phase III: Phase III:
PSI-7977 Alisporivir
Barbosa AN, 2012
64. Combination Therapy for Null Responders
Daclatasvir (BMS-790052) QD (NS5A inhibitor) + asunaprevir (BMS-650032)
BID (NS3 protease inhibitor) ± pegIFN/RBV for 24 wks
US Study[1] Japan Study[2]
100 Daclatasvir + Asunaprevir
90 90*
Daclatasvir + Asunaprevir + PR
80
SVR24 (%)
60
40 36
20
N/A
0
1. Lok A, et al. EASL 2011. Abstract 1356.
*all genotype 1b patients.
2. Chayama K, et al. AASLD 2011. Abstract LB-4.
Barbosa AN, 2012
65. - Experimentados SOC, F2-F4 - Naïve, F0-F2, CC
- Naïve, F3-F4, IL28B CT, TT - Experimentado F0-F1
- F3-F4: Telaprevir - Uso de medicamentos com
- Respondedor Nulo: Telaprevir interação com IP
- Contra-Indicação: IFN-Peg,
RBV ou IP
Barbosa AN, 2012