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Dr. Alexandre Naime Barbosa MD, PhD
       Infectologista Assistente
        barbosa.an@ymail.com


           SAE de Infectologia
          “Domingos Alves Meira”
Eventos Científicos:    Abbott, Bristol-Myers Squibb, Glaxo Smith Kline,
                        Merck Sharp Dome, Pfizer, Roche, Schering Plough,
                        United Medical
Patrocínio de Eventos   Boehringer Ingelheim, Jansen e Merck
Apoio à Pesquisa:       Abbott, CNPq, Fapesp, Roche
Palestrante:            Abbott, Boehringer Ingelheim , Bristol-Myers-
                        Squibb, Glaxo Smith Kline
Textos:                 Bristol-Myers-Squibb, Roche
Vínculos:               HC Unesp, Roche Pharma - Virologia,
                        SAE/HD DAM - FMB Unesp
Bolsa Pesquisa:         CNPq - DTI - Upeclin - FMB Unesp,
                        Fundep DN DST/Aids e Hepatites Virais
                                                                Barbosa AN, 2012
Barbosa AN, 2012
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
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]
                                              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
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
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
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
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
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
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
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
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
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
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
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/day
McHutchison JG, et al. N Engl J Med. 2009;361:580-593.


                                                                                                   Barbosa AN, 2012
Barbosa AN, 2012
Barbosa AN, 2012
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                                    2011
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. 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. Sherman
KE, et al. N Engl J Med. 2011;365:1014-1024.

                                                                                                                                                           Barbosa AN, 2012
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                                         Drugs
Interferons                                   Peginterferon lambda-1a
Cyclophilin inhibitor                         Alisporivir
Nucleos(t)ide analogue polymerase inhibitor   GS-7977
                                              Mericitabine
Nonnucleoside polymerase inhibitor            ABT-072
                                              ABT-333
                                              BI 207127
                                              Tegobuvir
Protease inhibitor                            ABT-450
                                              Asunaprevir
                                              BI 201335
                                              Danoprevir
                                              GS-9451
                                              Simeprevir (TMC435)
NS5A inhibitor                                Daclatasvir
                                              GS-5885


                                                                        Barbosa AN, 2012
Barbosa AN, 2012
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 care
1. Boceprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
3. Telaprevir [package insert]. 2011.


                                                                                                                        Barbosa AN, 2012
 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
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
SPRINT-2

                                   P < .001                                                 P = .004

       100             P < .001                                         100           P = .04

           80                                          68                   80
                                            67
Patients




                                                                 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
ADVANCE[1]                                 Pooled Analysis From ADVANCE
                                                                      and ILLUMINATE[2]
                                                                                 Nonblack
      100                                              100                       Black
                           P < .001
          80                           75                  80                     75
                                                                                       61
SVR (%)




                                                 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          T12PR
1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
2. Dusheiko GM, et al. EASL 2011. Abstract 1788.
                                                                                       Barbosa AN, 2012
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                      48

Boceprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444.



                                                                                                                                 Barbosa AN, 2012
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 Wks
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.



                                                                                                   Barbosa AN, 2012
 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
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
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
      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
 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
      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
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
    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
 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
Barbosa AN, 2012
Barbosa AN, 2012
 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             F3/4

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.


                                                                                                                                 Barbosa AN, 2012
 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
      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
      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
 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
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)                         Fibrosis
Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Reddy KR, et al. EASL 2011. Abstract 466.


                                                                                                                                Barbosa AN, 2012
 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
 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
 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
 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
      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
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
Barbosa AN, 2012
Barbosa AN, 2012
- ↑ 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
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
Barbosa AN, 2012
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
- 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
SAE de Infectologia
“Domingos Alves Meira”

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Nova Era no Tratamento do Vírus da Hepatite C

  • 1. Dr. Alexandre Naime Barbosa MD, PhD Infectologista Assistente  barbosa.an@ymail.com SAE de Infectologia “Domingos Alves Meira”
  • 2. Eventos Científicos: Abbott, Bristol-Myers Squibb, Glaxo Smith Kline, Merck Sharp Dome, Pfizer, Roche, Schering Plough, United Medical Patrocínio de Eventos Boehringer Ingelheim, Jansen e Merck Apoio à Pesquisa: Abbott, CNPq, Fapesp, Roche Palestrante: Abbott, Boehringer Ingelheim , Bristol-Myers- Squibb, Glaxo Smith Kline Textos: Bristol-Myers-Squibb, Roche Vínculos: HC Unesp, Roche Pharma - Virologia, SAE/HD DAM - FMB Unesp Bolsa Pesquisa: CNPq - DTI - Upeclin - FMB Unesp, Fundep DN DST/Aids e Hepatites Virais Barbosa AN, 2012
  • 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
  • 5. Conceitos de Resposta ao Tratamento Completo 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
  • 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/day McHutchison JG, et al. N Engl J Med. 2009;361:580-593. Barbosa AN, 2012
  • 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 2011 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. 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. Sherman KE, et al. N Engl J Med. 2011;365:1014-1024. Barbosa AN, 2012
  • 22. Illustration courtesy of Alison Jazwinski, MD. Barbosa AN, 2012
  • 27. Class Drugs Interferons Peginterferon lambda-1a Cyclophilin inhibitor Alisporivir Nucleos(t)ide analogue polymerase inhibitor GS-7977 Mericitabine Nonnucleoside polymerase inhibitor ABT-072 ABT-333 BI 207127 Tegobuvir Protease inhibitor ABT-450 Asunaprevir BI 201335 Danoprevir GS-9451 Simeprevir (TMC435) NS5A inhibitor Daclatasvir GS-5885 Barbosa AN, 2012
  • 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 care 1. Boceprevir [package insert]. 2011. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [package insert]. 2011. Barbosa AN, 2012
  • 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. 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. SPRINT-2 P < .001 P = .004 100 P < .001 100 P = .04 80 68 80 67 Patients 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. ADVANCE[1] Pooled Analysis From ADVANCE and ILLUMINATE[2] Nonblack 100 100 Black P < .001 80 75 80 75 61 SVR (%) 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 T12PR 1. 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. 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 48 Boceprevir [package insert]. May 2011. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Barbosa AN, 2012
  • 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 Wks Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 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
  • 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 F3/4 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. 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
  • 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) Fibrosis Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Reddy KR, et al. EASL 2011. Abstract 466. 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