Dr. Alexandre Naime Barbosa MD, PhD       Infectologista Assistente        barbosa.an@ymail.com           SAE de Infectol...
Eventos Científicos:    Abbott, Bristol-Myers Squibb, Glaxo Smith Kline,                        Merck Sharp Dome, Pfizer, ...
Barbosa AN, 2012
Prevalência Mundial (2,2%): 170 a 200 milhõesIncidência: 3 a 4 milhões/ano; 300 mil óbitos/ano            Anti-VHC: 2,7 mi...
Conceitos de Resposta ao Tratamento Completo                                               Barbosa AN, 2012
 Nearly 100% of patients who achieve SVR remain undetectable  during long-term follow-up[1-4]                            ...
Fluxograma de Tratamento (PEG-IFN + RBV)  Sem 4                Sem 12       Sem 24   Sem 48   Sem 72 PCR VHC   (-)        ...
Fluxograma de Tratamento (PEG-IFN + RBV)  Sem 4                 Sem 12       Sem 24           Sem 48         Sem 72       ...
Fluxograma de Tratamento (PEG-IFN + RBV)  Sem 4                Sem 12       Sem 24        Sem 48      Sem 72              ...
Fluxograma de Tratamento (PEG-IFN + RBV)  Sem 4                Sem 12        Sem 24           Sem 48          Sem 72      ...
Fluxograma de Tratamento (PEG-IFN + RBV)  Sem 4                Sem 12       Sem 24        Sem 48      Sem 72              ...
Fluxograma de Tratamento (PEG-IFN + RBV)  Sem 4                Sem 12         Sem 24           Sem 48             Sem 72  ...
Fluxograma de Tratamento (PEG-IFN + RBV)  Sem 4                Sem 12       Sem 24       Sem 48      Sem 72               ...
Fluxograma de Tratamento (PEG-IFN + RBV)  Sem 4                Sem 12          Sem 24           Sem 48              Sem 72...
Fluxograma de Tratamento (PEG-IFN + RBV)  Sem 4                Sem 12          Sem 24           Sem 48              Sem 72...
100                                                                                                                      P...
IDEAL Study: PegIFN alfa-2a vs alfa-2b in Treatment-                      Naive Genotype 1 HCV Patients             100   ...
Barbosa AN, 2012
Barbosa AN, 2012
PI + PegIFN/RBV              100                                                                                          ...
Barbosa AN, 2012
Illustration courtesy of Alison Jazwinski, MD.                         Barbosa AN, 2012
Barbosa AN, 2012
Barbosa AN, 2012
Barbosa AN, 2012
Barbosa AN, 2012
Class                                         DrugsInterferons                                   Peginterferon lambda-1aCy...
Barbosa AN, 2012
Protease Inhibitor                                          Additional Regimen                      Considerations        ...
 Telaprevir                                                                           Boceprevir               – Treatme...
Boceprevir[1,2]                                                                                               Early respon...
SPRINT-2                                   P < .001                                                 P = .004       100    ...
ADVANCE[1]                                 Pooled Analysis From ADVANCE                                                   ...
HCV RNA                Undetectable < 100 IU/mL                          Undetectable       PegIFN                        ...
SPRINT-2: BOC + PegIFN/RBV in GT1 Treatment-Naive Patients            57% of patients eligible for shorter therapy       ...
 Recommendation: Noncirrhotic patients can be considered for    response-guided therapy with TVR                         ...
ILLUMINATE: Response-Guided TVR                 ADVANCE: TVR + PegIFN/RBV in                                   + PegIFN/RB...
BOC[1,2]  Time Point                                                           Criteria                        Action  Wk ...
      Recommendation: BOC approved for previous relapsers, partial, and null responders[1]           –          AASLD gui...
 Recommendation: Response-guided therapy can be considered for      previous relapsers, may be considered for previous pa...
      Recommendation: TVR approved for previous relapsers, partial, and null responders[1]           –       AASLD guidel...
REALIZE: TVR + PegIFN/RBV in G1 Previous Relapsers and Partial/Null Responders       Lead-in examined but found not to inf...
    Recommendation: Response-guided therapy recommended for previous      relapsers, but not for previous partial or null...
 Recommendation: All therapy should be discontinued in    patients with the following:                                   ...
Barbosa AN, 2012
Barbosa AN, 2012
 Recommendation: All cirrhotic patients receiving BOC + PR should    receive 48 weeks of therapy[1,2]                 Sub...
 Recommendation: All cirrhotic patients receiving TVR + PR may    benefit from 48 weeks of therapy[1,2]                  ...
      Recommendation: IL28B genotype testing may be considered prior to         therapy if more information about probabi...
      Recommendation: IL28B genotype testing may be considered prior to         therapy if more information about probabi...
 Data from T12PR arm only                    100                                    79                    78             ...
BOC/PR48                   100                                                                                            ...
 Significantly higher rates of anemia, neutropenia, and  dysgeusia in BOC arms vs controlAdverse Event, %                ...
 Higher rates of rash, anemia, and anorectal signs/symptoms in TVR   arms vs control Adverse Event, %                    ...
 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 ...
      Contraindications for BOC and TVR therapy           – Patients with previous SAEs leading to premature pegIFN/RBV d...
Drug Class                                  Contraindicated With BOC[1]                   Contraindicated With TVR[2]  Alp...
Barbosa AN, 2012
Barbosa AN, 2012
- ↑ RVS naïves e experimentados    - Preço (R$ 60 – 70 mil)- Menor tempo de tratamento        - SUS ainda não cobre- Maior...
NS3/4A                NS5B Polymerase Inhibitors                 NS5A           Cyclophilin AProtease            Nucleos(t...
Barbosa AN, 2012
Combination Therapy for Null Responders                Daclatasvir (BMS-790052) QD (NS5A inhibitor) + asunaprevir (BMS-65...
- Experimentados SOC, F2-F4      - Naïve, F0-F2, CC- Naïve, F3-F4, IL28B CT, TT     - Experimentado F0-F1- F3-F4: Telaprev...
SAE de Infectologia“Domingos Alves Meira”
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Nova Era no Tratamento do Vírus da Hepatite C

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Revisão sobre o tratamento da hepatite C crônica

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Nova Era no Tratamento do Vírus da Hepatite C

  1. 1. Dr. Alexandre Naime Barbosa MD, PhD Infectologista Assistente  barbosa.an@ymail.com SAE de Infectologia “Domingos Alves Meira”
  2. 2. Eventos Científicos: Abbott, Bristol-Myers Squibb, Glaxo Smith Kline, Merck Sharp Dome, Pfizer, Roche, Schering Plough, United MedicalPatrocínio de Eventos Boehringer Ingelheim, Jansen e MerckApoio à Pesquisa: Abbott, CNPq, Fapesp, RochePalestrante: Abbott, Boehringer Ingelheim , Bristol-Myers- Squibb, Glaxo Smith KlineTextos: Bristol-Myers-Squibb, RocheVínculos: HC Unesp, Roche Pharma - Virologia, SAE/HD DAM - FMB UnespBolsa Pesquisa: CNPq - DTI - Upeclin - FMB Unesp, Fundep DN DST/Aids e Hepatites Virais Barbosa AN, 2012
  3. 3. Barbosa AN, 2012
  4. 4. Prevalência Mundial (2,2%): 170 a 200 milhõesIncidência: 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
  5. 5. Conceitos de Resposta ao Tratamento Completo Barbosa AN, 2012
  6. 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-up1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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 20011. 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
  17. 17. IDEAL Study: PegIFN alfa-2a vs alfa-2b in Treatment- Naive Genotype 1 HCV Patients 100 Intent-to-Treat Analysis (N = 3070) 80 SVR (%) 60 40 38 41 40 20 0 PegIFN alfa-2b PegIFN alfa-2b PegIFN alfa-2a 1.5 µg/kg/wk + 1.0 µg/kg/wk + 180 µg/wk + RBV 800-1400 mg/day RBV 800-1400 mg/day RBV 1000-1200 mg/dayMcHutchison JG, et al. N Engl J Med. 2009;361:580-593. Barbosa AN, 2012
  18. 18. Barbosa AN, 2012
  19. 19. Barbosa AN, 2012
  20. 20. PI + PegIFN/RBV 100 (6-12 mos)[8-10] 70-75 80 PegIFN/ribavirin (6-12 mos)[6,7] Interferon/ 50-60 SVR (%) 60 ribavirin PegIFN (6-12 mos)[3,4] monotherapy Standard 38-43 40 interferon (6-12 mos)[5,6] Standard (12-18 mos)[2,3] 25-30 interferon 15-20 20 (6 mos)[1] 8-12 0 1991 1995 1998 2001 20111. Carithers RL Jr., et al. Hepatology. 1997;26(3 suppl 1):83S-88S. 2. Zeuzem S, et al. N Engl J Med. 2000;343:1666-1672. 3. Poynard T, et al. Lancet. 1998;352:1426-1432.4. McHutchison JG, et al. N Engl J Med. 1998;339:1485-1492. 5. Lindsay KL, et al. Hepatology. 2001;34:395-403. 6. Fried MW, et al. N Engl J Med. 2002;347:975-982. 7.Manns MP, et al. Lancet. 2001;358:958-965. 8. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 9. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 10. ShermanKE, et al. N Engl J Med. 2011;365:1014-1024. Barbosa AN, 2012
  21. 21. Barbosa AN, 2012
  22. 22. Illustration courtesy of Alison Jazwinski, MD. Barbosa AN, 2012
  23. 23. Barbosa AN, 2012
  24. 24. Barbosa AN, 2012
  25. 25. Barbosa AN, 2012
  26. 26. Barbosa AN, 2012
  27. 27. Class DrugsInterferons Peginterferon lambda-1aCyclophilin inhibitor AlisporivirNucleos(t)ide analogue polymerase inhibitor GS-7977 MericitabineNonnucleoside polymerase inhibitor ABT-072 ABT-333 BI 207127 TegobuvirProtease inhibitor ABT-450 Asunaprevir BI 201335 Danoprevir GS-9451 Simeprevir (TMC435)NS5A inhibitor Daclatasvir GS-5885 Barbosa AN, 2012
  28. 28. Barbosa AN, 2012
  29. 29. Protease Inhibitor Additional Regimen Considerations Components Boceprevir 800 mg TID (q7- PegIFN alfa  Naive to previous therapy 9hrs)[1,2] +  Previous treatment failure weight-based RBV  Compensated cirrhosis  RGT  Take with food Telaprevir 750 mg TID PegIFN alfa  Naive to previous therapy (q7-9hrs)[2,3] +  Previous treatment failure weight-based RBV  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 care1. Boceprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Telaprevir [package insert]. 2011. Barbosa AN, 2012
  30. 30.  Telaprevir  Boceprevir – Treatment-naive – Treatment-naive – ADVANCE[1] – SPRINT-2[4] – ILLUMINATE[2] – Treatment-experienced – Treatment-experienced – RESPOND-2[5] – REALIZE[3]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, 2012
  31. 31. Boceprevir[1,2] Early response*; stop at Wk 28; f/u PegIFN BOC + PegIFN + RBV 24 wks + RBV F/u BOC + PegIFN + RBV PegIFN + RBV 24 wks 0 4 8 12 24 28 36 48 Telaprevir[2,3] 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 *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. Barbosa AN, 2012
  32. 32. SPRINT-2 P < .001 P = .004 100 P < .001 100 P = .04 80 68 80 67Patients Patients 60 60 53 (%) (%) 40 42 40 40 23 20 20 n/ 125/ 211/ 213/ n/ 12/ 22/ 29/ 0 N= 311 316 311 0 N= 52 52 55 PR 48 BOC RGT BOC/PR48 PR 48 BOC RGT BOC/PR48 Nonblack Patients Black Patients Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Barbosa AN, 2012
  33. 33. ADVANCE[1] Pooled Analysis From ADVANCE and ILLUMINATE[2] Nonblack 100 100 Black P < .001 80 75 80 75 61SVR (%) SVR (%) 60 60 44 45 40 40 25 20 20 n/ 158/ 271/ n/ 151/ 7/ 599/ 60/ N= 361 363 N= 333 28 804 99 0 0 PR T12PR PR T12PR1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.2. Dusheiko GM, et al. EASL 2011. Abstract 1788. Barbosa AN, 2012
  34. 34. HCV RNA Undetectable < 100 IU/mL Undetectable PegIFN Early response; stop at Wk 28; + RBV BOC + PegIFN + RBV f/u 24 wks 0 4 8 12 24 28 36 48 HCV RNA Detectable < 100 IU/mL Undetectable Slow response; extend triple therapy to Wk 36; PR to Wk 48; f/u 24 wks PegIFN BOC + PegIFN + RBV PegIFN + RBV + RBV 0 4 8 12 24 28 36 48Boceprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Barbosa AN, 2012
  35. 35. SPRINT-2: BOC + PegIFN/RBV in GT1 Treatment-Naive Patients  57% of patients eligible for shorter therapy HCV RNA undetectable HCV RNA detectable at Week 8, at Weeks 8 and 24 undetectable at Week 24 Nonblacks Blacks 97 96 100 95 88 100 93 100 87 80 74 74 80 66 62 58 SVR (%) 60 60 40 40 20 20 37/ 78/ 143/ 52/ 137/ 48/ n/ 3/ 8/ 13/ 7/ 18/ 7/ 0 40 118 147 70 142 65 0 N = 3 13 15 12 19 8 PR48 BOC/PR BOC/PR PR48 BOC/PR BOC/PR RGT 48 Wks RGT 48 WksPoordad F, et al. N Engl J Med. 2011;364:1195-1206. Barbosa AN, 2012
  36. 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 48Telaprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Barbosa AN, 2012
  37. 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 T12PR481. 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. 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. 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 wks0 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/PR481. 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. 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 48Boceprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Barbosa AN, 2012
  41. 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. 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. 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. 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
  45. 45. Barbosa AN, 2012
  46. 46. Barbosa AN, 2012
  47. 47.  Recommendation: All cirrhotic patients receiving BOC + PR should receive 48 weeks of therapy[1,2] Subgroup Analysis of SPRINT-2[3] Subgroup Analysis of RESPOND-2[4] 100 PR48 100 BOC RGT 80 BOC/PR48 80 68 68 67 67 66 52 SVR (%)SVR (%) 60 60 41 44 38 38 40 40 23 20 20 13 n/ 123/ 213/ 211/ 9/ 14/ 22/ n/ 14/ 77/ 81/ 2/ 14/ 21/ N= 328 319 313 24 34 42 N= 61 117 119 15 32 31 0 0 F0/1/2 F3/4 F0/1/2 F3/41. 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. Barbosa AN, 2012
  48. 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 Cirrhosis1. 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. 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. 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. 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) FibrosisMarcellin P, et al. EASL 2011. Abstract 451. Barbosa AN, 2012
  52. 52. BOC/PR48 100 BOC/PR RGT 85 70 76 75 66 67 67 63 63 61 59 SVR (%) 52 50 41 25 n/ 93/ 89/ 118/ 106/ 45/ 41/ 197/ 192/ 211/ 213/ 22/ 14/ N = 133 134 187 179 53 54 313 314 313 319 42 34 0 1b 1a ≤ 800,000 > 800,000 F0-2 F3-F4 Genotype HCV RNA (IU/mL) FibrosisPoordad F, et al. N Engl J Med. 2011;364:1195-1206. Reddy KR, et al. EASL 2011. Abstract 466. Barbosa AN, 2012
  53. 53.  Significantly higher rates of anemia, neutropenia, and dysgeusia in BOC arms vs controlAdverse Event, % PR48 BOC + PR RGT/48 (n = 467) (n = 1225)Anemia* 30 50Neutropenia 19 25Dysgeusia 16 35*Anemia was managed with RBV reduction and/or epoetin alfa(43% of BOC + PR and 24% of PR). Barbosa AN, 2012
  54. 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. 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/dL1. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Barbosa AN, 2012
  56. 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 creamTelaprevir [package insert]. May 2011. Barbosa AN, 2012
  57. 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 therapyBoceprevir [package insert]. May 2011. Telaprevir [package insert]. May 2011.Ghany MG, et al. Hepatology. 2011;54:1433-1444. Barbosa AN, 2012
  58. 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
  59. 59. Barbosa AN, 2012
  60. 60. Barbosa AN, 2012
  61. 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 IPsrespondedores prévios - Efeitos Adversos- Maior chance de RVS para - Interações medicamentosasF3/F4 - Nº de comprimidos- Maior chance de resposta IL28BCT e TT - Boas opções no futuro Barbosa AN, 2012
  62. 62. NS3/4A NS5B Polymerase Inhibitors NS5A Cyclophilin AProtease Nucleos(t)ide Non- Inhibitors InhibitorsInhibitors 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
  63. 63. Barbosa AN, 2012
  64. 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. 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
  66. 66. SAE de Infectologia“Domingos Alves Meira”

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