Alexandre Naime Barbosa MD, PhD 
Professor Assistente - Infectologista 
Preceptoria de Residência em Infectologia 
FMB - U...
Barbosa AN, 2014
Animação Virtual: http://youtu.be/Y8h2wzwdzZs Hodder Arnold - Use of Antibiotics 
Barbosa AN, 2014
Animação Virtual: http://youtu.be/Y8h2wzwdzZs Manns, M - Nature Reviews - 2013 
Barbosa AN, 2014
Manns, M - Nature Reviews - 2013 
Barbosa AN, 2014
Manns, M - Nature Reviews - 2013 
Barbosa AN, 2014
Barbosa AN, 2014
Slide cedido pelo Dr. Deílson de Elgui 
Barbosa AN, 2014
Barbosa AN, 2014
University of Washington - 2014 
Barbosa AN, 2014
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Dçs Cerebrovasculares 
17.08% 
Infarto Miocárdio 
13.66% 
Câncer 
12.42% 
Pneumonias 
9.47% 
Cirrose e Dçs 
Outras Dçs Isq...
Barbosa AN, 2014
Mundo Brasil 
Prevalência 170 - 200 milhões 2 - 3 milhões 
Incidência/ano 3 - 4 milhões 10 mil 
Mortalidade/ano 0.3 milhão...
Barbosa AN, 2014 
VHB 
VHC 
10 – 50 anos
Oliveira U. B., 2010 
Barbosa AN, 2014
Barbosa AN, 2014 
VHB VHC 
Parceiros Sexuais de VHB + Transfusões antes de 1994 
Múltiplos Parceiros, Violência Sexual Usu...
Slide cedido pelo Dr. Paulo Abraão 
Barbosa AN, 2014
Slide cedido pelo Dr. Paulo Abraão 
Barbosa AN, 2014
Slide cedido pelo Dr. Paulo Abraão 
Barbosa AN, 2014
Slide cedido pelo Dr. Paulo Abraão 
Barbosa AN, 2014
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Slide cedido pelo Dr. Paulo Abraão 
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Barbosa AN, 2014
Barbosa AN, 2014
Barbosa AN, 2014
Barbosa AN, 2014 
Fluxograma de Tratamento (PEG-IFN + RBV) 
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72 
PCR VHC 
(-) 
PCR VHC (-) S...
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 
...
Barbosa AN, 2014 
Fluxograma de Tratamento (PEG-IFN + RBV) 
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72 
PCR VHC (-) Sem 12: 
Respos...
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...
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 
...
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...
Barbosa AN, 2014 
Fluxograma de Tratamento (PEG-IFN + RBV) 
Sem 4 Sem 12 Sem 24 Sem 48 Sem 72 
PCR VHC 
(+) 
PCR VHC 
(-) ...
Sem Queda de 2 logs 
Sem 12: Resposta 
Barbosa AN, 2014 
Fluxograma de Tratamento (PEG-IFN + RBV) 
Sem 4 Sem 12 Sem 24 Sem...
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...
Barbosa AN, 2014 
Desafios 
- Efeitos Adversos 
- Interações Medicamentosas (HIV) 
- Recidivantes e Não Respondedores (50%...
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Protease Inhibitor Additional Regimen 
Components 
Considerations 
Boceprevir 800 mg TID (q7- 
9hrs)[1,2] 
PegIFN alfa 
+ ...
 Telaprevir 
– Treatment-naive 
– ADVANCE[1] 
– ILLUMINATE[2] 
– Treatment-experienced 
– REALIZE[3] 
 Boceprevir 
– Tre...
BOC + PegIFN + RBV 
PegIFN + RBV 
PegIFN 
+ RBV 
BOC + PegIFN + RBV 
0 4 8 12 24 
28 36 
48 
Early response*; stop at Wk 2...
P < .001 
P < .001 
Nonblack Patients 
P = .004 
P = .04 
Black Patients 
125/ 
311 
211/ 
316 
213/ 
311 
12/ 
52 
22/ 
5...
P < .001 
100 
SVR (%) 
80 
60 
40 
20 
0 
75 
271/ 
363 
44 
158/ 
361 
PR T12PR 
n/ 
N = 
100 
80 
60 
40 
20 
1. Jacobs...
BOC + PegIFN + RBV 
PegIFN 
+ RBV 
0 4 8 12 24 28 36 
48 
PegIFN 
+ RBV 
BOC + PegIFN + RBV 
Boceprevir [package insert]. ...
SPRINT-2: BOC + PegIFN/RBV in GT1 Treatment-Naive Patients 
HCV RNA undetectable 
at Weeks 8 and 24 
HCV RNA detectable at...
 Recommendation: Noncirrhotic patients can be considered for 
response-guided therapy with TVR 
TVR + PegIFN + RBV 
PegIF...
ILLUMINATE: Response-Guided TVR 
+ PegIFN/RBV in 
Treatment-Naive Genotype 1 
 65% of patients eligible for 
shortened th...
BOC[1,2] 
Time Point Criteria Action 
Wk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapy 
Wk 24 HCV RNA detectable Disconti...
 Recommendation: BOC approved for previous relapsers, partial, and null responders[1] 
– AASLD guidelines say BOC “recomm...
 Recommendation: Response-guided therapy can be considered for 
previous relapsers, may be considered for previous partia...
 Recommendation: TVR approved for previous relapsers, partial, and null responders[1] 
– AASLD guidelines say TVR “recomm...
REALIZE: TVR + PegIFN/RBV in G1 Previous Relapsers and Partial/Null Responders 
Lead-in examined but found not to influenc...
 Recommendation: Response-guided therapy recommended for previous 
relapsers, but not for previous partial or null respon...
 Recommendation: All therapy should be discontinued in 
patients with the following: 
BOC[1,2] 
Time Point Criteria Actio...
Barbosa AN, 2014
Barbosa AN, 2014
 Recommendation: All cirrhotic patients receiving BOC + PR should 
receive 48 weeks of therapy[1,2] 
Subgroup Analysis of...
 Recommendation: All cirrhotic patients receiving TVR + PR may 
PR48 
T12PR 
T8PR 
benefit from 48 weeks of therapy[1,2] ...
 Recommendation: IL28B genotype testing may be considered prior to 
therapy if more information about probability of resp...
 Recommendation: IL28B genotype testing may be considered prior to 
therapy if more information about probability of resp...
 Data from T12PR arm only 
71 
152/ 
213 
79 
118/ 
149 
100 
50 
0 
1b 1a 
Genotype 
78 
74 
< 800,000 ≥ 800,000 
HCV RN...
93/ 
133 
89/ 
134 
100 
50 
0 
118/ 
187 
106/ 
179 
1b 1a 
Genotype 
70 
66 
85 
76 
≤ 800,000 > 800,000 
HCV RNA (IU/mL...
 Significantly higher rates of anemia, neutropenia, and 
dysgeusia in BOC arms vs control 
Adverse Event, % PR48 
(n = 46...
 Higher rates of rash, anemia, and anorectal signs/symptoms in TVR 
arms vs control 
Adverse Event, % PR48 
(n = 493) 
TV...
 Recommendation: Anemia should be managed initially 
by reducing the RBV dose[1] 
 Dose reduction of RBV is acceptable 
...
 Rash management 
– Mild to moderate rash can be treated with oral 
antihistamines, topical steroids 
– Systemic steroids...
 Contraindications for BOC and TVR therapy 
– Patients with previous SAEs leading to premature pegIFN/RBV discontinuation...
Barbosa AN, 2012
Antirretroviral Boceprevir Telaprevir 
Tenofovir Dose Habitual Dose Habitual (↑ C min TDF, toxicidade?) 
Zidovudina Dose H...
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
Slide cedido pela Dra. Aline Vigani 
Barbosa AN, 2014
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Hepatite C - Tratamento Atual e Futuro 2014 (Versão Final)

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Hepatite C - Tratamento Atual e Futuro 2014 (Versão Final)

  1. 1. Alexandre Naime Barbosa MD, PhD Professor Assistente - Infectologista Preceptoria de Residência em Infectologia FMB - UNESP - Botucatu 2014
  2. 2. Barbosa AN, 2014
  3. 3. Animação Virtual: http://youtu.be/Y8h2wzwdzZs Hodder Arnold - Use of Antibiotics Barbosa AN, 2014
  4. 4. Animação Virtual: http://youtu.be/Y8h2wzwdzZs Manns, M - Nature Reviews - 2013 Barbosa AN, 2014
  5. 5. Manns, M - Nature Reviews - 2013 Barbosa AN, 2014
  6. 6. Manns, M - Nature Reviews - 2013 Barbosa AN, 2014
  7. 7. Barbosa AN, 2014
  8. 8. Slide cedido pelo Dr. Deílson de Elgui Barbosa AN, 2014
  9. 9. Barbosa AN, 2014
  10. 10. University of Washington - 2014 Barbosa AN, 2014
  11. 11. Barbosa AN, 2014
  12. 12. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  13. 13. Dçs Cerebrovasculares 17.08% Infarto Miocárdio 13.66% Câncer 12.42% Pneumonias 9.47% Cirrose e Dçs Outras Dçs Isq Coração 3.46% Sepse 2.25% Dçs Hipertensivas 7.66% Dçs Pulmonares Crônicas Diabete Mellitus 9.39% 8.88% Insuf. Cardíaca 4.72% Fígado 3.31% Miocardiopatia 2.29% Aids 2.08% Insuf. Renal 1.98% Demais Doenças Perinatais 1.35% Barbosa AN, 2014
  14. 14. Barbosa AN, 2014
  15. 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
  16. 16. Barbosa AN, 2014 VHB VHC 10 – 50 anos
  17. 17. Oliveira U. B., 2010 Barbosa AN, 2014
  18. 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
  19. 19. Slide cedido pelo Dr. Paulo Abraão Barbosa AN, 2014
  20. 20. Slide cedido pelo Dr. Paulo Abraão Barbosa AN, 2014
  21. 21. Slide cedido pelo Dr. Paulo Abraão Barbosa AN, 2014
  22. 22. Slide cedido pelo Dr. Paulo Abraão Barbosa AN, 2014
  23. 23. Barbosa AN, 2014
  24. 24. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  25. 25. Slide cedido pelo Dr. Paulo Abraão Barbosa AN, 2014
  26. 26. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  27. 27. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  28. 28. Barbosa AN, 2014
  29. 29. Barbosa AN, 2014
  30. 30. Barbosa AN, 2014
  31. 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. 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. 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. 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. 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. 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. 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. 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. 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. 40. Barbosa AN, 2014 Desafios - Efeitos Adversos - Interações Medicamentosas (HIV) - Recidivantes e Não Respondedores (50%) - Diagnóstico Tardio, Alcoolismo, Fibrose Avançada
  41. 41. Barbosa AN, 2014
  42. 42. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  43. 43. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  44. 44. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  45. 45. Protease Inhibitor Additional Regimen Components Considerations Boceprevir 800 mg TID (q7- 9hrs)[1,2] PegIFN alfa + weight-based RBV  Naive to previous therapy  Previous treatment failure  Compensated cirrhosis  RGT  Take with food Telaprevir 750 mg TID (q7-9hrs)[2,3] PegIFN alfa + weight-based RBV  Naive to previous therapy  Previous treatment failure  Compensated cirrhosis  RGT  Take with food (not low fat) For patients with genotype 2/3 infection, HCV therapy with pegIFN/RBV remains the standard of care 1. Boceprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. 2011. Barbosa AN, 2014
  46. 46.  Telaprevir – Treatment-naive – ADVANCE[1] – ILLUMINATE[2] – Treatment-experienced – REALIZE[3]  Boceprevir – Treatment-naive – SPRINT-2[4] – Treatment-experienced – RESPOND-2[5] 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. 3. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 4. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 5. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. Barbosa AN, 2014
  47. 47. BOC + PegIFN + RBV PegIFN + RBV PegIFN + RBV BOC + PegIFN + RBV 0 4 8 12 24 28 36 48 Early response*; stop at Wk 28; f/u 24 wks F/u 24 wks Boceprevir[1,2] Telaprevir[2,3] TVR + PegIFN + RBV eRVR†; stop at Wk 24, f/u 24 wks PegIFN + RBV F/u 24 wks 0 4 12 24 48 *Undetectable HCV RNA at Wk 8 of therapy (Wk 4 of triple therapy). †Undetectable HCV RNA at Wks 4 and 12 of triple therapy. 1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. May 2011. No eRVR †; PegIFN + RBV Barbosa AN, 2014
  48. 48. P < .001 P < .001 Nonblack Patients P = .004 P = .04 Black Patients 125/ 311 211/ 316 213/ 311 12/ 52 22/ 52 29/ 55 Patients (%) PR 48 BOC RGT 100 80 60 40 20 0 BOC/PR48 40 67 68 Patients (%) PR 48 BOC RGT 100 80 60 40 20 0 BOC/PR48 23 42 53 n/ N= n/ N= Poordad F, et al. N Engl J Med. 2011;364:1195-1206. SPRINT-2 Barbosa AN, 2014
  49. 49. P < .001 100 SVR (%) 80 60 40 20 0 75 271/ 363 44 158/ 361 PR T12PR n/ N = 100 80 60 40 20 1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Dusheiko GM, et al. EASL 2011. Abstract 1788. Pooled Analysis From ADVANCE and ILLUMINATE[2] ADVANCE[1] SVR (%) 0 PR T12PR n/ N = Nonblack Black 75 599/ 804 61 60/ 99 45 151/ 333 25 7/ 28 Barbosa AN, 2014
  50. 50. 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 28; f/u 24 wks HCV RNA Undetectable Undetectable PegIFN + RBV 0 4 12 28 48 8 24 36 HCV RNA Detectable Undetectable Slow response; extend triple therapy to Wk 36; PR to Wk 48; f/u 24 wks < 100 IU/mL < 100 IU/mL Barbosa AN, 2014
  51. 51. SPRINT-2: BOC + PegIFN/RBV in GT1 Treatment-Naive Patients HCV RNA undetectable at Weeks 8 and 24 HCV RNA detectable at Week 8, undetectable at Week 24 Nonblacks 100 80 60 40 20 0 PR48 BOC/PR RGT Poordad F, et al. N Engl J Med. 2011;364:1195-1206. BOC/PR 48 Wks 93 66 97 74 96 74 37/ 40 78/ 118 143/ 147 52/ 70 137/ 142 48/ 65 95 88 Blacks SVR (%) 100 80 60 40 20 0 PR48 BOC/PR RGT BOC/PR 48 Wks 100 62 87 58 n/ N = 3/ 3 8/ 13 13/ 15 7/ 12 18/ 19 7/ 8  57% of patients eligible for shorter therapy Barbosa AN, 2014
  52. 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. 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. 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. 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. 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. 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. 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. 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. 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
  61. 61. Barbosa AN, 2014
  62. 62. Barbosa AN, 2014
  63. 63.  Recommendation: All cirrhotic patients receiving BOC + PR should receive 48 weeks of therapy[1,2] Subgroup Analysis of SPRINT-2[3] PR48 BOC RGT BOC/PR48 41 14/ 34 F3/4 100 80 60 40 20 0 SVR (%) 38 67 213/ 319 F0/1/2 n/ N= 38 9/ 24 52 22/ 42 67 211/ 313 1. Boceprevir [package insert]. May 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Poordad F, et al. NEJM. 2011;364:1195-1206. 4. Bacon BR, et al. NEJM. 2011;364:1207-1217. Subgroup Analysis of RESPOND-2[4] F3/4 100 80 60 40 20 0 SVR (%) 23 66 77/ 117 F0/1/2 13 2/ 15 68 21/ 31 44 14/ 32 68 81/ 119 123/ 328 n/ N= 14/ 61 Barbosa AN, 2014
  64. 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. 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. 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. 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
  68. 68. 93/ 133 89/ 134 100 50 0 118/ 187 106/ 179 1b 1a Genotype 70 66 85 76 ≤ 800,000 > 800,000 HCV RNA (IU/mL) 67 67 BOC/PR48 F0-2 F3-F4 Fibrosis SVR (%) 75 25 41/ 54 45/ 53 213/ 319 211/ 313 n/ N = BOC/PR RGT 63 59 63 61 41 52 Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Reddy KR, et al. EASL 2011. Abstract 466. 14/ 34 22/ 42 192/ 314 197/ 313 Barbosa AN, 2014
  69. 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. 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. 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. 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. 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
  74. 74. Barbosa AN, 2012
  75. 75. Antirretroviral Boceprevir Telaprevir Tenofovir Dose Habitual Dose Habitual (↑ C min TDF, toxicidade?) Zidovudina Dose Habitual (↑ risco anemia) Dose Habitual (↑ risco anemia) Abacavir Dose Habitual Não recomendado (sem estudos) 3TC, ddI Dose Habitual Dose Habitual Atazanavir Não recomendado Dose Habitual DRV, FPV, LOP/r Não recomendado Não recomendado Efavirenz Não recomendado Dose: 1125mg 8/8h (↓ C min Telaprevir) Nevirapina Não recomendado (sem estudos) Não recomendado (sem estudos) Etravirina Dose Habitual (↓ C min ETV; Impacto?) Dose Habitual Raltegravir Dose Habitual Dose Habitual Maraviroque Dose Habitual (MVQ 150 mg 12/12h) Dose Habitual (MVQ 150 mg 12/12h) hep-druginteractions.org Barbosa AN, 2014
  76. 76. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  77. 77. Barbosa AN, 2014
  78. 78. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  79. 79. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  80. 80. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  81. 81. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  82. 82. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  83. 83. Barbosa AN, 2014
  84. 84. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  85. 85. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  86. 86. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  87. 87. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  88. 88. Slide cedido pela Dra. Aline Vigani Barbosa AN, 2014
  89. 89. www.slideshare.net/spitalex

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