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Semelhante a Palestra Inibidores de Protease na Prática Clínica - Dr. Fernando Gonçales
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Palestra Inibidores de Protease na Prática Clínica - Dr. Fernando Gonçales
- 1. Inibidores de protease na prática clínica Fernando L Gonçales Jr Prof Livre Docente em Infectologia FCM-UNICAMP
- 3. http://www.who.int/ith/es/index.html. > 10% 2.5% to 10.0% 1.0% to 2.5% Prevalência NA • Cerca de 3 milhões de brasileiros infectados • 1/3 das causas de cirrose; 1/4 das causas de CHC • Mortalidade anual – 15-30% CH descompensada; 80-90% CHC Prevalência Global da HVC
- 4. VHC = virus da hepatite C 1. Viral Hepatitis C. Johns Hopkins Gastroenterology and Hepatology Web site. http://www.hopkins-gi.org/GDL_Disease.aspx?CurrentUDV=31&GDL_Disease_ID=F90D3628-F21C-41B8-873E-FFFD82A8AF4C&GDL_DC_ID=9AA60584-3607-4D15-BD3F67A3A4A7. Accessed February 20, 2011. Variabilidade Genética do VHC
- 5. Ônus da infecção pelo VHC na América Latina
- 8. Tratamento padrão com alfaPegInterferona (PegIFN) e Ribavirina (RBV) Estudo IDEAL e a Nova Portaria do MS / Brasil ( Protocolo Clínico e Diretrizes Terapêuticas para Hepatite Viral C – MS 2011)
- 9. Evolução da resposta virológica sustentada
- 10. Taxas de RVS (ITT) em pacientes HCV Genótipo 1 Esquemas de tratamento – estudo IDEAL
- 12. Protocolo Clínico e Diretrizes Terapêuticas para Hepatite Viral C – MS 2011 e Coinfecções
- 14. Polimorfismo Genético do IL28-B / rela ção com SNP rs12979860 prediz RVS em diferentes grupos étnicos Ge et al.Nature 2009. Figure 1 | Percentage of SVR by genotypes of rs12979860. Data are percentages + s.e.m.
- 15. Polimorfismo do Gene IL28B como preditor de RVS ( Genótipos CC>CT>TT ) Ge D, et al. Nature. 2009;461:399-401.
- 16. Respostas virológicas potenciais ao tratamento RFT = resposta ao fim do tratamento; RVP = resposta precoce; RVR = resposta virológica rápida; RVS = resposta sustentada. Adaptado de Ghany MG et al. Hepatology . 2009;49(4):1335–1374.
- 17. Inibidores de Entrada Ribozymes Nucleotideos anti-sense Inibidores de protease Inibidores de Polimerase Inibidores de Glucosidase Adaptado de: Pawlotsky et al., Antivir Ther 2006 A protease viral NS3/4 (serina) é a mais bem caracterizada das enzimas do HCV Contém 3 residuos altamente conservados compreendendo uma triade catalitica É fundamental para a síntese da poliproteína Viral. A monoterapia inevitavelmente leva ao desenvolvimento de cepas resistentes O Futuro - Novas drogas: ANTIVIRAIS
- 18. NS3/4A Protease NS4B NS5A NS5B NS2 P7 E2 E1 C Quebra Protease NS3/4A Kwong A, et al. Beyond interferon and ribavirin: Antiviral therapies for hepatitis C virus. Drug Discovery Today: Therapeutic Strategies . 2006;3:211-220.
- 21. Peginterferon (P) SC 1.5 μg/kg por semana mais ribavirina (R) na dose de 600-1400 mg/dia Boceprevir = 800 mg , tres vezes ao dia SPRINT 2: desenho do estudo (n=1097)
- 22. Peginterferon (P) SC 1.5 μg/kg por semana mais ribavirina (R) na dose de 600-1400 mg/dia Boceprevir = 800 mg , tres vezes ao dia SPRINT 2: desenho do estudo (n=1097)
- 23. Regra de parada: pacietnes com HCV-RNA detectável na semana 24 tiveram tratamento interrompido por futilidade. Peginterferon (P) administrado via subcutânea na dose semanal de 1.5 μg/kg, com ribavirina diária (R) na dose por kg de peso: 600-1400 mg/dia em doses divididas. BOC administrado 3x 800 mg por dia. Desenho do estudo SPRINT-2 Pacientes nunca antes tratados
- 24. SPRINT-2: RVS em todos os grupos
- 25. SPRINT-2 Resposta de acordo com a raça Poordad F, et al. AASLD 2010. Abstract LB-4.
- 26. RVS de acordo com queda da carga viral pós lead-in de PR na sem 4 (não-negros) * Variantes associadas à resistência ao Boceprevir determinados por sequenciamento P+R 48 P+R P+R B+P+R TGR B+P+R 48
- 27. Dinamica do RNA-VHC na semana 4 (lead-in) Grupo PEG-IFN + RBV Controle TGR PR+BOC RNA-VHC Semana 4 11% 89% negativo positivo queda < 1 log queda > 1 log RVS 92% RVS 52% RVS 5% de acordo com IDEAL de acordo com SPRINT 2 72% (64%) 28% (25%) PR PR PR
- 28. RVS de acordo com queda da carga viral pós lead-in de PR na sem 4 (não-negros) * Variantes associadas à resistência ao Boceprevir determinados por sequenciamento P+R 48 B+P+R TGR B+P+R 48
- 29. Dinamica do RNA-VHC na semana 4 GRUPOS PEG-IFN + RBV+ BOC Controle TGR PR+BOC RNA-VHC Semana 4 11% 89% negativo positivo queda < 1 log queda > 1 log RVS 92% acordo com IDEAL de acordo com SPRINT 2 72% (64%) 28% (25%) RVS 52% RVS 5% RVS 82% RVS 34% (29-39%) PR PR PR
- 30. Dinamica do RNA-VHC na semana 8 PEG-IFN + RBV+ BOC Controle TGR PR+BOC 18% RVS 86% RVS 89% RVS 91 % 60% 59% RNA-VHC negativo na semana 8 % de RNA-VHC (-) com BOC foi 3 vezes > comparado aos controles Sem 4 PR PR PR+BOC PR PR PR+BOC
- 31. RVS entre pacientes brancos com DNA-VHB (-) entre as semanas 8-24 TGR 47 % RVS 96% RVS 97 % 48 % RNA-VHC negativo entre semanas 8 e 24 47 % dos pacientes brancos do braço TGR foram randomizados para tratar com P+R+B por + 24 semanas PR+BOC PR+BOC PR PR PR+BOC
- 32. Eventos adversos relacionados ao tratamento Evento adverso Braço 1 (PR48); n=363 (%) Braço 2 (RGT); n=368 (%) Braço 3 (BOC/PR48); n=366 (%) Fadiga 59 52 57 Cefaléia 42 45 43 Náuseas 40 46 42 Anemia 29 49 49 Disgeusia 18 37 43 Calafrios 28 36 33 Pirexia 32 33 30 Insonia 32 31 32 Alopécia 27 20 28 Anorexia 25 26 24 Prurido 26 23 25 Neutropenia 21 25 25 Influenza Like 25 23 22 Mialgia 26 21 24 Rash 22 24 23 Irritabilidade 24 22 22 Depressão 21 23 19 Diarréia 19 19 23 Pele seca 18 18 22 Dispnéia 16 18 22 Tonturas 15 21 17
- 34. Boceprevir :momentos de controle
- 35. Para pacientes negativos nas semanas 4/8 , o BOC pode ser utilizado por 24 semanas e a duração total de P+R pode ser de 28 semanas RVS = 89% Pacientes que negativam entre as semanas 8-24 devem receber 24 semanas de BOC, mas devem completar 48 semanas de P+R (RGT) Poordad F.Curr Gastroenterol Rep, 2010 Conclusões do SPRINT 2
- 36. Alta taxa de Resposta Virológica Sustentada entre pacientes infectados pelo genótipo 1-VHC não respondedores ou recidivantes à PEG-IFN mais ribavirina quando retratados com Boceprevir mais PEGINTRON (Peginterferon alfa-2b) mais ribavirina Bruce R. Bacon , Stuart C. Gordon, Eric Lawitz, Patrick Marcellin, John M. Vierling, Stefan Zeuzem, Fred Poordad, Navdeep Boparai, Margaret Burroughs, Clifford A. Brass, Janice K. Albrecht & Rafael Esteban HCV RESPOND-2 Resultados finais
- 37. Braços do estudo e doses (N=403) Teste de HCV-RNA = Cobas TaqMan (Roche). Se HCV-RNA (LLD=9.3 IU/mL) na sem 12 = falha. Peginterferon (P) SC, 1.5 μg/kg/sem + Ribavirin (R) ,de 600-1400 mg/dia Boceprevir = 800 mg tres vezes /dia
- 38. Braços do estudo e doses (N=403) Teste de HCV-RNA = Cobas TaqMan (Roche). Se HCV-RNA (LLD=9.3 IU/mL) na sem 12 = falha Peginterferon (P) SC, 1.5 μg/kg/sem + Ribavirin (R) ,de 600-1400 mg/dia Boceprevir = 800 mg tres vezes /dia
- 39. Desenho estudo RESPOND-2 Pacientes experientes com falha terapêutica prévia Regra de parada: pacietnes com HCV-RNA detectável na semana 24 tiveram tratamento interrompido por futilidade. Peginterferon (P) administrado via subcutânea na dose semanal de 1.5 μg/kg, com ribavirina diária (R) na dose por kg de peso: 600-1400 mg/dia em doses divididas. BOC administrado 3x 800 mg por dia.
- 40. Características basais Braço 1: 48 P/R N = 80 Braço 2: BOC RGT N = 162 Braço 3: BOC/PR48 N = 161 Idade média (anos) 52.9 52.9 52.3 Sexo masculino (%) 73 60 70 Negros (%) 15 11 12 Região (%) América do Norte 64 71 75 Europa 36 28 26 América Latina 0 1 0 BMI – média (SD) 28 (4) 29 (5) 28 (5) HCV subtipo (%)* 1a 48 46 48 1b 45 46 42 Nível HCV RNA > 800.000 UI/ml (%) 81 91 88 METAVIR F3/F4 (%) 19 20 19 Não-respondedor (%) 36 35 36 Recidivante (%) 64 65 64
- 41. RESPOND-2 RVS e recidivas Intention to treat RVS para braços 1, 2 e 3 foram 21% (17/80), 58% (94/162) e 66% (106/161), respectivamente.
- 42. RVS de acordo com a resposta virológica na semana 4 ( lead-in) (n=393)
- 43. RVS de acordo com RNA-VHC na semana 8 Intention to Treat
- 44. 1. Bacon BR, et al. AASLD 2010. Abstract 216. RESPOND-2: Taxas de RVS de acordo com o braço de tratamento e resposta prévia à PR
- 45. IPs: RVS gen 1b > gen 1a ! Brass et al. EASL 2011.
- 48. Hemoglobina sérica média vs. tempo em estudos chave BOC=boceprevir; PR=peginterferon -2b + ribavirin. Sulkowsky at EASL 2011
- 49. Sumário de eventos relatados como anemia Tabela: proporção de pacientes relatando AEs associados aos termos preferidos anemia e anemia hemolítica. Individuos podem ter apresentado mais de um AE. PI=produto investigacional † Mortes contabilizadas como evento adverso sério. § Exclui pacientes que interromperam o tratamento devido a eventos adversos. Sulkowsky at EASL 2011 Evento adverso sério (AE) † Evento adverso Modificação de dose devido a AE § (qualque PI) Modificação de dose devido a AE (BOC/Placebo) Transfusão Interrupção do PI devido a AE Todos voluntários 1 (<1) 158 (29) 71 (13) 0 2 (<1) 4 (1) PR N=547 n (%) 14 (1) 758 (49) 406 (26) 28 (2) 39 (3) 23 (1) BOC/PR N=1548 n (%)
- 50. Manejo da anemia em pacientes com Hemoglobina <10 g/dL PR=peginterferon -2b + ribavirin; BOC=boceprevir; Hgb=hemoglobina; RBV=ribavirin; EPO=eritropoetina Sulkowsky at EASL 2011 Pacientes com Hgb <10 g/dL Apenas Redução Dose RBV Apenas EPO EPO e Redução Dose RBV Nenhuma Qualquer Redução Dose RBV Qualquer EPO 153 (28) 15 (3) 57 (10) 49 (9) 32 (6) 64 (12) 106 (19) PR N=547 n (%) 744 (48) 54 (3) 247 (16) 340 (22) 103 (7) 394 (25) 587 (38) BOC/PR N=1548 n (%)
- 53. Victrelis Bula do Produto
- 54. Boceprevir em Virgens de Tratamento Bula do Produto Bula do Produto
- 56. Boceprevir em re-tratamento Bula do Produto
- 58. Obrigado!
Notas do Editor
- HCV is an RNA virus whose exact structure is yet to be established. The particles are about 40 to 70 nm in diameter. Two envelope proteins, E1 and E2, are thought to be anchored to a lipid envelope that surrounds a nucleocapsid composed of multiple copies of the core protein and the genomic RNA. 1 The HCV genome consists of a single-stranded positive-sense RNA with noncoding 5 ’ region containing an internal ribosome entry site (IRES), an open reading frame that encodes 3 structural and 7 nonstructural proteins (NS), and a 3’ noncoding region. 1 The structural proteins include E1, E2, and the core protein. The nonstructural proteins include the p7 ion channel, the NS2-3 protease, the NS3 serine protease and RNA helicase, the NS4A polypeptide, the NS4B and NS5A proteins, and the NS5B RNA-dependent RNA polymerase. 1 Both the structural and nonstructural proteins play a key role in the HCV infection process, enabling the virus to enter the host cell, replicate, infect other cells, and persist. 1. Moradpour D et al. Nat Rev Microbiol . 2007;5:453-463. Moradpour p453A,B; p455A Moradpour p455A Moradpour p453A Moradpour p453B
- HCV has significant genetic variability due to its rapid and error-prone replication. HCV isolates can be classified into 6 major genotypes that differ in their nucleotide sequences by 30 to 35%. The genotypes can be further classified into subtypes, designated by a, b, c, etc. The subtypes differ in their nucleotide sequence by 20 to 25%. 1 These differences in sequences have clinical implications in that HCV genotype 1 is less responsive to standard interferon treatment than genotypes 2 and 3. 1 Genotypes 5 and 6 are relatively easy to treat with standard treatment while genotype 4 has intermediate susceptibility to treatment. 2 The prevalence of each genotype varies according to geographic location. 3 Genotypes 1, 2, and 3 are distributed worldwide, whereas genotypes 4, 5, and 6 tend to occur in certain areas and populations. 3 HCV = hepatitis C virus. 1. Moradpour D et al. Nat Rev Microbiol . 2007;5:453–463. 2. Antaki N et al. Liver Int. 2010;30:342–355. 3. Mukherjee S et al. Hepatitis C. http://emedicine.medscape.com/article/177792-print. Accessed September 29, 2010.
- This slide provides an overview of the substantial global burden of HCV disease. Of note is that at least 70% of newly infected persons will develop chronic infection, which will require regular monitoring for signs of liver disease progression. In terms of severity, 25% of these chronically infected persons will develop cirrhosis. 1 Of these, 1% to 5% will progress to hepatocellular carcinoma. 2 As noted earlier, the WHO estimates that globally, approximately 300,000 persons die annually from liver cancer or liver disease related to HCV. 3 1. Lavanchy D. Liver Intl . 2009;29(s1):74-81. 2. World Health Organization. Hepatitis C. 2002. http://www.who.int/csr/disease/hepatitis/Hepc.pdf. 3. Lavanchy D. Presentation at 3 rd Paris Hepatitis Conference--the International Conference on the Management of Patients with Viral Hepatitis. 2009. http://www.colloquium.eu/congres/09APHC/slides/lundi_19/AFTERNOON/Daniel_Lavanchy/alancer.pdf.
- Some recommendations for screening at-risk populations are shown on this slide. These recommendations were adapted from the 2004 practice guidelines of the American Association for the Study of Liver Diseases (AASLD) by European infectious disease and hepatology specialists in Italy, Germany, and Switzerland. 1 These guidelines expand on the similar WHO recommendations of 2002 for screening at-risk persons. 2 Routine testing is also recommended for patients with HIV infection and those with unexplained elevated aminotransferase levels. The more recent 2009 AASLD guidelines continue to support these recommendations. 3 Patients suspected of having HCV infection should be tested for HCV antibodies and those with detectable HCV antibodies should undergo HCV RNA testing with use of a highly sensitive assay such as reverse transcription-polymerase chain reaction. 1 Although sexual transmission of HCV is not clearly understood, certain high-risk sexual behaviors have been associated with HCV transmission, such as anal sex, sex with trauma, sex in the presence of a sexually transmitted disease, and sex without a condom. For this reason, patients who engage in these high-risk sexual practices should be tested. 1 Although the prevalence of infection is low in partners of HCV-infected persons, a negative test result in the partner can provide reassurance, making testing of sexual partners beneficial in clinical practice. 1 WHO = World Health Organization. 1. Santantonio T, et al. J Hepatol. 2008;49:625–633. 2. World Health Organization. Hepatitis C. 2002. http://www.who.int/csr/disease/hepatitis/Hepc.pdf. 3. Ghany M, et al. Hepatology . 2009;49(4):1335–1374.
- Stander
- When patients are treated with combination therapy, a spectrum of potential responses can occur. How quickly HCV RNA becomes undetectable is the single most important determinant of sustained virologic response. 1 Definitions of responses to therapy are listed here 2 : Rapid virologic response (RVR) is defined as undetectable HCV RNA after 4 weeks of therapy Early VR (EVR) or Complete EVR (cEVR) is defined as undetectable HCV RNA from baseline after 12 weeks of therapy Partial EVR can be characterized by decline of ≥ 2 log 10 IU/mL from baseline after 12 weeks of therapy Non-response is defined as failure to clear HCV RNA from serum after 24 weeks of therapy Null response, which is also considered non-response, is defined as an HCV RNA decline <2 log 10 IU/mL by Week 12 Partial response, which is also considered non-response, is a ≥ 2 log 10 IU/mL decline in HCV RNA but remains HCV RNA detectable at Week 24 End-of-treatment response (ETR) is undetectable HCV RNA at end of treatment (24 or 48 weeks depending on genotype) Sustained virologic response (SVR), the current definition of success in HCV treatment, is continued undetectable HCV RNA 24 weeks after completion of therapy HCV = hepatitis C virus; RNA = ribonucleic acid. 1. Shiffman ML. Curr Gastroenterol Rep. 2010;12:70–75. 2. Ghany MG et al. Hepatology . 2009;49(4):1335–1374.
- BOC, boceprevir; PR, peginterferon/ribavirin; SVR, sustained virologic response. The results of SPRINT-2 are shown on this slide. The overall SVR rates were 63% in the response-guided arm and 66% in the standard duration arm—a difference that is not statistically different. However, SVR rates in both boceprevir arms were statistically higher than the 38% SVR rate in the control arm (P < .0001) . For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/AASLD%202010/Tracks/HCV%20Treatment/Capsules/LB4.aspx
- BOC, boceprevir; EPO, erythropoietin; PR, peginterferon/ribavirin. This slide shows the adverse events and discontinuations that were observed with boceprevir in the treatment-naive trials. Anemia and dysgeusia were reported more frequently in the boceprevir arms than in the control arm in the SPRINT-2 trial. Indeed, 49% of patients who received response-guided therapy and 49% of those who received standard duration therapy developed anemia, vs 29% in the control arm. Erythropoietin was used in 43% of patients in both of these arms vs in 24% of patients in the control arm. Dysgeusia occurred in 37% and 43% of patients in the response-guided and standard-duration boceprevir arms, respectively, vs 18% in the control arm. Discontinuations due to adverse events were seen in 12% of patients in the response-guided therapy arm and 16% of patients in standard-duration therapy arm vs 16% in the control arm. Discontinuations were due to anemia in 2% of cases in the boceprevir-containing arms and 1% in the control arm. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/AASLD%202010/Tracks/HCV%20Treatment/Capsules/LB4.aspx