Simpósio Satélite Janssen - RD Consultoria e Eventos
Transcrição
Simpósio Satélite Janssen - RD Consultoria e Eventos
Simpósio Satélite Janssen Carlos Eduardo Brandão-Mello Professor Associado de Medicina – Escola de Medicina e Cirurgia do RJ - UNIRIO Faculdade de Medicina – UFRJ Doutor e Livre Docente em Clínica Médica Co-infecção HCV e HIV CoFundamentos Teóricos • Interação HCV HCV--HIV ocorre em 30 30% % dos casos HIV + • Prevalência da co co--infecção é maior quando a via de aquisição é parenteral (hemofílicos e viciados em drogas ilícitas) • Hepatite crônica com rápida progressão para cirrose e falência hepática • Importante causa de morbidade / mortalidade • Esquema HAART e Hepatotoxicidade • Tratamento Tratamento:: Interferon Peguilado + Ribavirina • Novas Drogas (DAAs DAAs)) Prevalência Global da CoCo-infecção HIV– HIV –HCV 170 milhões pacientes HCV1 40 milhões pacientes HIV2 12 milhões pacientes co-infectados 1. World Health Organization. Hepatitis C Fact Sheet No. 164, Outubro 2000 2. UNAIDS, AIDS Epidemic Update 2004 Prevalência de HCV / HIV no Brasil HCV/HIV – 16% UDE – 83,7% Unirio – Hemofilicos (82%) UNIFESP – 17,5% SP-Casa da Aids – 17,7% Campinas – 53,8% Santos – 36,2% Santos – 84,8% HCV/HIV – 53,8% UDE – 88,2% Brasil – 433.000 AIDS HCV/HIV – 21% 1. Monteiro MR., et al., Rev Soc Bras Med Trop. 2004 2. Mendes-Correa., et al., Rev Inst Med Trop SP. 2000 3 Pavan MH. et al., Braz J Infect Dis. 2004 4. Segurado AC. et al., AIDS Patient Care STDS. 2004 5. Vogler IH. Et al., Rev Inst Med Trop SP. 2004 6. Treitinger A. et al., Braz J Infect Dis. 2000 7. Brandão-Mello, CE et al., Hepatology, 1994. Co--infecção HCVCo HCV-HIV - Tratamento • Porque Tratar ? • Quem tratar ? • Quando tratar ? • Como tratar ? - Terapêutica passada - Terapêutica atual - Novas perspectivas - Não Não--Respondedor C.E.Brandão,, 2014 C.E.Brandão Mortalidade por hepatopatia em HCV/HIV HCV/HIV 60 Mortalidade (%) Pre-HAART era 50 50% 45% HAART era 40 35% 30 20 13% 10 12% 5% 0 Itália (Brescia)* * 55% tinham HIV controlado Espanha (Madrid) EUA (Boston) Bica et al. Clin Infect Dis 2001. Puoti et al. JAIDS 2000. Soriano et al. Eur J Epidemiol 1999. Martin-Carbonero et al. AIDS Res Human Retrovirus 2001. Efeito da coco-infecção HCVHCV-HIV na Progressão da Fibrose 4 Grau de Fibrose (Metavir) 3 2 HIV+ (n=122) Controles (n=122) Controles Simulados (n=122) 1 0 0 10 20 30 40 Duração da Infecção pelo vírus C (anos) Com CD4 < 200/mm3, Álcool, Idade, IP Fatores Preditivos Independentes de Morte Relacionada a Doença Hepática em HIV+ Latest CD4 Cell Count (cells/µL) 16.06 <50 11.54 50-99 7.14 100-199 3.95 200-349 1.67 350-499 >500 2.01 HIV Acquisition via IDU Hepatitis C Status Negative 6.66 Positive Hepatitis B Status Negative 3.73 Positive Multivariate analysis. Not shown: Age per 5 years (1.32). 0.2 Weber R, et al. Arch Intern Med. 2006;166:1632-1641. 1.0 10 Risco Relativo de Morte 100 Change in Causes of Death in Patients with HIV • Swiss HIV Cohort Study (SHCS) – 446 deaths between 2005 and 2009 – Causes of death • #1 NonNon-AIDS defining cancers (n=85, 19.1%) including HCC (n=13, 2.8%) • #2 AIDS (n=73, 16.4%) • #3 Liver Diseases (n=67, 15%) When deaths due to HCC are included among liver-related Deaths (instead of non-AIDS defining cancers) Liver Diseases = #1 Cause of Death (17.9%) Ruppik M. et al. Changing patterns of causes of death in the SHCS 2005-2009. CROI 2011. Poster # 789. Available at: http://www.retroconference.org/2011/PDFs/789.pdf. Co--infecção HCVCo HCV-HIV - Tratamento (Quem Tratar ?) • Todos os coco-infectados são potenciais candidatos • Infecção estável pelo HIV (CD4 > 350 céls./mm céls./mm3 ) • ALT persistentemente elevada (> 1,5 x o LSN) • ALT normal* – Decisão deve ser baseada na Biópsia • Atividade inflamatória moderada e fibrose (F1(F1-F4) • Fibrose F0 – Monitorar e repetir biópsia a cada 3 anos • Doença hepática compensada * 25 a 40% com fibrose significativa C.E.Brandão,, 2014 C.E.Brandão Co--infecção HCVCo HCV-HIV - Tratamento (Quem Tratar ?) • Cirróticos Cirróticos:: tratamento pode lentificar a progressão para insuficiência hepática hepática.. • Quando existir hepatotoxicidade recorrente a TARV. • Infecção estável pelo HIV (CD4 > 200 - < 350 céls céls../mm3): A decisão deve ser baseada na biópsia, genótipo, carga viral e tempo estimado de infecção • Infecção pelo HIV (CD4 < 200 céls céls../mm3 ) – tratar a infecção pelo HIV e postergar o tratamento da hepatite C.E.Brandão,, 2014 C.E.Brandão Co--infecção HCVCo HCV-HIV - Tratamento • Porque Tratar ? • Quem tratar ? • Quando tratar ? • Como tratar ? - Terapêutica passada - Terapêutica atual - Novas perspectivas - Não Não--Respondedor C.E.Brandão,, 2014 C.E.Brandão Tratamento da CoCo-infecção HCV HCV--HIV Resposta Virológica Sustentada HIV--neg HIV HIV--pos HIV IFN Monoterapia 20% <10% IFN + ribavirina 45% 12--21% 12 Peg--IFN + ribavirina Peg 55% 27--55% 27 RVS com PEGPEG-IFN na HCV/ HCV/HIV 80 73 A5071 70 62 RIBAVIC (%) RVS 60 53 46 50 20 55 44 38 40 30 APRICOT 71 Crespo 44 40 29 27 27 14 17 10 0 Genótipo 1 ou 4 Genótipo não 1 Barcelona RVS Impacto da Resposta Virológica Sustentada na Evolução a Longo Prazo da Coinfecção HIV/HCV Long-Term Term Outcome Rate (per 100 person/years) GESIDA 3603 Cohort 4.33 (3.16,5.8) Achieved SVR Did not achieve SVR 3.12 (2.16,4.37) 1.65 (0.98,2.16) 1.02 0.83 0.93 (0.50,1.82) (0.44,1.70) (0.38,1.58) 0.46* (0.06,1.65) 0.23† (0.01,1.27)) (0.01,1.27 0.23‡ 0 0§ (0.01,1.27) (0,0.84) (0,0.84) Liver Overall Liver-Related Mortality Mortality Decompensation 0.23 (0.01,1.27) HepatoLiver carcinoma Transplantation New AIDS Conditions *P=0.003, †P=0.028, ‡P<0.001, and §P=0.034 versus not attaining a sustained virologic response. n=711 HIV/HCV-coinfected patients receiving interferon (peg or conventional) + ribavirin. Berenguer J. et al. Hepatology 2009. Erradicação da Hepatite C Reduz Descompensação Hepática Progressão do HIV e Morte em Coinfectados HIV/HCV com Fibrose Hepática não Avançada J. Berenguer1, F. X. Zamora2, C. Díez1, M. Crespo3, M. A. Von Wichmann4, J. López-Aldeguer5, M. J. Galindo6, I. Santos 7, H. Esteban8, C. Barros9, J. J. Jusdado10, C. Tural11, T. Aldámiz1, J. M. Bellón1, and J. González-García2, for the GESIDA HIV/HCV Cohort Study Group 53rd ICAAC 2013 September 10-13, Denver, CO Superioridade do Peg IFNIFN-Ribavirina (Resposta Virológica Sustentada Sustentada)) Tipo IFN n. IFN IFN /RBV PEG IFN IFN/RBV ACTG 2a 133 12% 27% APRICOT 2a 868 12% 40% RIBAVIC 2b 400 19% 27% Laguno 2b 95 21% 44% Crespo 2b 121 26% 55% Berenguer 2a/2b 315/242 33% 31% Laguno 2a/2b 96/86 46% 42% Superioridade do Peg IFNIFN-Ribavirina (RVS) em Pacientes Genótipo 1 IFN IFN /RBV PEG IFN IFN/RBV ACTG G1 (78%) 6% 14% APRICOT G1 (60%) 7% 29% RIBAVIC G1 (65%) 6% 17%* Laguno G1 (63%) 7% 38%** Crespo G1 (48%) 18% 46%** Laguno G1 (45%) 28% (2b) 32% (2a) # Berenguer G1 (50%) 31% (2b) 33% (2a) ¥ *p<0.01; **p<0.002 # p=0.677 Desenho do Estudo e Randomização Randomiza ção dos Pacientes PRESCO 0 Peg-IFN IFN alfa alfa-2a + RBV 1000-1200 1200 mg/dia n=389 G1,4 Follow-up N=192 G1,4 G2,3 Follow-up G2,3 12 24 Follow-up N=45 N=96 Follow-up 60 48 36 Semanas de Estudo N=56 72 84 96 Somente pacientes que obtiveram RVP ( >2 log no HCV-RNA na sem. 12) continuaram tratamento PRESCO APRICOT (RVS Global 40%) PRESCO FRIED (RVS Global 50%) (RVS Global 56%) 76% 72% 62% Pacientes (%) 50 46% 40 36% 30 29% 20 10 0 Geno 1 n=176 Geno 3 n=95 Geno 1 Geno 3 Geno 1 Geno 3 n=191 n=152 n=298 n=140 48 semanas de terapia 24, 48 ou 72 semanas terapia 48 semanas terapia HIV + dose RBV HIV + dose RBV baseada PC HIV - dose RBV baseada PC n=180 0 Desenho do Estudo e Randomização Randomiza ção dos Pacientes Peg-IFN IFN alfa alfa-2a + RBV 1000-1200 1200 mg/dia ML18473 G1 N=90 Follow-up Follow-up G1 12 24 60 48 36 Semanas de Estudo 72 84 N=90 96 Desenho do Estudo Estudo de fase IV, aberto, randomizado (1:1), multicêntrico (17 centros, todos no Brasil), de grupos paralelos Grupo 48 semanas: n=90 Alfapeginterferona-2a (40KD) 180 µg/semana + ribavirina* Seguimento Grupo 72 semanas: n=90 Alfapeginterferona-2a (40KD) 180 µg/semana + ribavirina* 0 48 Semanas * Dose de ribavirina: 1.000 mg/dia (<75 kg de peso ) ou 1.200 mg/dia (≥75 kg de peso) Seguimento 72 96 Características Basais (ITT) Grupo 48 semanas (n=80) Grupo 72 semanas (n=85) 42 42 49 (61) 59 (69) Caucasiano/Branco 28 (35) 35 (41) Outros 52 (65) 50 (59) Média de peso, kg 68 69 Média do HCV RNA, log10 UI/mL 6.6 6.6 HCV RNA ≥800 000 UI/mL, n (%) 60 (77) 61(73) Cirróticos (F3/F4), n (%) 11 (14) 16 (20) Razão de ALT, n (%) >1–2 >2–5 39 (51) 19 (25) 38 (48) 22 (28) 1 (1) 2 (3) HIV-RNA indetectável, n (%) 64 (79) 60 (70) CD4 >350 cels/mm3, n (%) 61 (78) 57 (70) TARV na linha de base, n (%) 69 (86) 63 (74) Média de idade Masculino, n (%) Raça, n (%) >5 Características Basais – Estudo Co-infecção ML18743 Características Idade (Anos) Sexo (masculino/feminino) (%) Pêso Corporal Droga intra venosa n (%) 48 Semanas (N=80) 42.3 49/31 (61) 68.0 34 (42.5) 72 Semanas (n= 85) 42.2 59/26 (69) 68.7 28 (32.9) Raça: Caucasiana (branca) (%) 28 (35) 35 (41) 60 (77) 61 (73) Carga Viral > 800 000 IU/ml. (%) Quociente de ALT n (%) > 11- 2 39 (51) 38 (48) > 22- 5 19 (25) 22 (27.8) > 55- 10 1 (1.3) 2 (2.5) 11 (13.9) 16 (19.7) Contagem CD4 (> 350 cel.mm3) 61(78.2%) 57(70.3%) HIV RNA < 50 cópias/mL n (%) 64 (79) 60 (69.7) Tratamento antiretroviral n (%) 69 (86.2) 63 (74%) Cirrose n (%) Taxa de resposta virológica (HCV RNA <50 UI/mL) 24 semanas após o final do tratamento (RVS) População ITT População Por Protocolo Diferença entre tratamentos: 16% (IC 95%: 0.00–28.9); p=0.0374 Diferença entre tratamentos: 10% (IC 95% : 0.01–26.6); p=0.0536 50 33 40 30 23 20 10 0 n=18/80 48 semanas n=28/85 72 semanas % Pacientes com RVS* % Pacientes com RVS* 50 39 40 30 23 20 10 0 n=18/77 48 semanas n=31/79 72 semanas *RVS = resposta virológica sustentada, definida com HCV RNA indetectável (<50 IU/mL) conforme medido pelo Teste Roche COBAS AMPLICOR HCV 24 semanas após completar o período de tratamento. Cheinquer, AASLD, 2010 ML18473: Taxas de Recidiva Pacientes com HCVHCV-RNA Indetectável (< 50 UI/ml) no Final de Tratamento sem RVS – Análise por ITT • Pacientes com Genótipo 1 (n=165) 48 sem. n=38 (50.7%) Com RVS: n=18 47.4% Sem RVS: n=20 RNA-HCV indetectável no Final de Tratamento N= 75 72 sem. (52.6%) n=37 (49.3%) Com RVS: n=28 (75.7%) Sem RVS: n=09 24.3% Brandão-Mello, et al. Hepatology, 2010 ML18473: Taxas de Recidiva Pacientes com HCVHCV-RNA Indetectável (< 50 UI/ml) no Final de Tratamento sem RVS – Análise por PP • Pacientes com Genótipo 1 (n=156) 48 sem. n=37 (50.7%) Com RVS: n=18 48.6% Sem RVS: n=19 RNA-HCV indetectável no Final de Tratamento N= 73 72 sem. (51.4%) n=36 (49.3%) Com RVS: n=28 (77.8%) Sem RVS: n=08 22.2% Brandão-Mello, et al., Hepatology, 2010 Tratamento da CoCo-infecção HCVHCV-HIV Novo algoritmo S4 S12 G2/3 HCV-RNA neg S48 S24 24 semanas terapia * G1/4 > 2 log no HCV-RNA HCV-RNA pos HCV-RNA neg HCV-RNA pos < 2 log no HCV-RNA S72 G2/3 G1/4 48 semanas terapia 72 semanas terapia Parar Parar * Pacientes com baixa carga viral basal e fibrose hepática minima. APRICOT: semana 4 – genótipo 1 RNA--HCV indetectável RNA • Pacientes com Genótipo 1 (n=176) Sim n=22 (13%) Com RVS: n=18 VPP=82% Sem RVS: n=4 (18%) RNA-HCV indetectável Não n=154 (87%) Com RVS: n=33 (21%) Sem RVS: n=121 VPN=79% Torriani F, et al. 45th ICAAC 2005; Abstract 1024 Taxa de RVS (%) Tipo IL28B é preditivo de RVS na co-infecção HCV-HIV 100 p<0.0001 p=0.68 P=0.001 86% 80 75% 81% 65% 60 40 38% 38 30% 20 CT/TT CC 0 CT/TT CC Todos HCV-1 N=164 N=95 CT/TT CC HCV - 3 N=51 Rallon et al., AIDS, 2010 AIDS 2010 SVR 86% 81% p<0.0001 75% p=0.684 p=0.001 p=0.087 65% 67% 38% 30% 25% CC CT/TT CC CT/TT CC CT/TT CC CT/TT 75 89 34 61 HCV-1 35 16 HCV-3 6 12 HCV-4 95 51 18 All 164 IL28B-CC (rs 12979860) é potente fator preditivo pré-tratamento de RVS na co-infecção HCV-HIV Odds Ratio 95% Confidence Interval p-value CC IL28B vs não-CC 3.7 1.6 8.4 <0.002 VL ≤ 600,000 IU/mL 11.9 3.8 37.4 <0.001 METAVIR F0- F2 3.5 1.4 8.9 <0.0009 GENÓTIPO 3 8.0 3.1 21.0 <0.001 Rallon et al., AIDS, 2010 Futuro II: Novas Drogas antianti- HCV 33 O Futuro - Novas drogas: ANTIVIRAIS Ribozymes Nucleotideos anti-sense Inibidores de Entrada Inibidores de protease - Inibidores de Polimerase Inibidores de Glucosidase Adaptado de: Pawlotsky et al., Antivir Ther 2006 Ação da protease Quebra P7 NS2 NS3/4A Protease NS4B E2 NS5A E1 NS5B C 35 Kwong A, et al. Beyond interferon and ribavirin: Antiviral therapies for hepatitis C virus. Drug Discovery Today: Therapeutic Strategies. 2006;3:211-220. 35 Futuro: novos antivirais contra o HCV STAT-C - Specifically Targeted Antiviral Therapies for Hepatitis C Poliproteína do HCV capsid C envelope proteins E1 E2 p7 protease/helicase NS2 NS3 Structural Proteins NS3 protease NS4A NS4B NS5B NS5A Nonstructural Proteins NS3 helicase Full-length NS3 ... Asvir … PREVIR Telaprevir, Boceprevir Telaprevir, Simeprevir,, Faldaprevir Simeprevir Asunaprevir,, Vaniprevir Asunaprevir polymerase NS5A Daclatasvir Ledipasvir, Ombitasvir NS5B RNA polymerase ... Buvir Sofosbuvir Deleobuvir Tegobuvir Resposta virológica sustentada Terapia Tripla : Taxas de RVS Elevadas em pacientes experimentados 100 REALIZE RESPOND-2/PROVIDE* (+/- Lead-in) TVR 12 sem. + PEG2a + Riba 48 semanas Lead-in (+/-RGT) BOC + PEG2b + Riba 36 / 48 semanas 100 86% 80 80 57% 60 40 40 15% 20 52% 60 31% 24% 75% 36%* 29% 20 7% 5% 0 TVR SOC REL TVR SOC P-Não R TVR SOC NULL 0 BOC SOC REL BOC SOC P-NR NULL Relapser (REL): negativo ao final do tratamento mas recidiva após Parcial Não-Respondedor (P-NR): ≥2log sem.12 mas HCV RNA positivo sem. 24 Null-Responder (NULL): <2log sem. 12 Zeuzem et al., NEJM 2011 Bacon et al., NEJM 2011 *PROVIDE study, Vierling et al., AASLD 2011 Terapia Tripla : Taxas de RVS 24 Elevadas (61% – 75%) HCV RNA negativo sem. 24 Co-infecção HIV-HCV Genótipo 1, naive Boceprevir (n=98) Telaprevir (n=60) 100 86% 12 TVR Tripla + 36 sem. SOC 75% 80 60 75% 67% 71% 80 60 50% 40 Lead-in - BOC Tripla 48 sem. 100 38% 33% 20 15% 20 BOC 0 TVR SOC Sem HAART 34% 40 TVR SOC TVR HAART SOC HAART EFV/TDF/FTC ATVr/TDF/FTC eRVR global 63% vs. 5% Elevação de Bilirubinas com ATVr TVR 1125mg TID em combinação com EFV Sulkowski et al., AASLD 2011 SOC BOC SOC 0 Semana 8 Semana 24 HAART: PI Sem booster, Raltegravir, CCR-5 antagonistas, sem NNRTI, NRTI sem ATZ, d4T, ddI Sulkowski et al., AASLD 2011 Novas Drogas antianti-HCV a DAAs de 1 Geração Inibidores da NS3 Boceprevir Telaprevir 39 Resposta virológica sustentada Terapia Tripla : Taxas de RVS Elevadas (Naïve) 80 75% ADVANCE SPRINT-2 RGT, TVR 12 vs. 8 sem. Lead-in(LI), RGT vs. não-RGT 69% 80 70 70 60 44% 50 60 40 30 30 20 20 10 10 TVR TVR Resposta Resposta guiada guiada TVR 12 sem TVR 8 sem + PEG2a + PEG2a + Riba + Riba SOC PEG2a + Riba (48sem.) Jacobson et al. NEJM 2011 38% 50 40 0 63% 66% 0 BOC Resposta guiada LI BOC + PEG2b + Riba BOC LI BOC + PEG2b + Riba (48 sem.) SOC PEG2b + Riba (48sem.) Poordad et al. NEJM 2011 Desenho do Estudo Boceprevir Weeks 72PEG2b Arm 1 Arm 2 +RBV 4 sem. PEG2b +RBV 4 sem. 12 24 28 Placebo + PEG2b + RBV 44 semanas 48 Follow-up SVR-24 sem Boceprevir + PEG2b + RBV Follow-up 44 semanas SVR-24 sem Futility Rules • • • Two-arm study, doubleTwodouble-blinded for BOC, openopen-label for PEG2b/RBV – 2:1 randomization (experimental: control) – Boceprevir dose 800 mg TID 4-week leadlead-in with PEG2b/RBV for all patients – PEG PEG--2b 1.5 µg/kg QW; RBV 600600-1400 mg/day divided BID Control arm patients with HCVHCV-RNA ≥ LLOQ at TW 24 were offered open--label PEG2b/RBV+BOC via a crossover arm open Características Demográficas PR B/PR (N=34) (N=64) Idade (anos), mediana (SD) 45 (9.8) 43 (8.3) Masculino, n (%) 22 (65) 46 (72) 28 (82) 6 (18) 52 (81) 12 (19) Indice de Massa Corpórea, mediana (SD) 26 (4) 25 (4) Cirrose n (%) 1 (3) 4 (6) 22 (65) 10 (29) 42 (66) 15 (23) HCV RNA carga >800,000 IU/mL, n (%) 30 (88) 56 (88) HIV RNA <50 cópias/mL, n (%) 33 (97) 62 (97) 586 (187-1258) 577 (230-1539) Raça, n (%) Branca Não-branca HCV genotipo e subtipo, n (%)* 1a 1b CD4 contagem cels/mm3), mediana (variação) % HCV RNA Indetectável Resposta Virológica ao Longo do Tempo† 100 PR B/PR 80 73.4 65.6 60.7 59.4 60 42.2 40 32.4 23.5 20 0 29.4 14.7 8.8 4.7 3/34 3/64 4 5/34 27/64 8 8/34 38/64 12 11/34 47/64 10/34 42/64 24 EOT Treatment Week † 26.5 Three patients undetectable at FW4 have not yet reached FW12 and were not included in SVR12 analysis. 9/34 37/61 SVR12 Taxas de RVS 12 Com BOC + P/R vs Peg-IFN/R em Coinfectados HCV-HIV RVS12 (%) RVS 12 de acordo com TARV % BOC + PegIFN/RBV (n = 61) PegIFN/ RBV (n = 34) 100 ATV/RTV 67 62 80 LPV/RTV 67 0 DRV/RTV 67 0 Outros PI/RTV* 57 0 Raltegravir 43 33 Outros† 0 0 60.7 60 40 26.5 20 0 n/N = 9/34 P/R 37/61 BOC + P/R *SQV, FPV, TPV., †MVC, EFV. Rebote virológico do HIV-1 RNA observado em 7 pacientes – BOC + P/R: n = 3 (todos com Pis + RTV) – Placebo + P/R: n = 4 Dados preliminares (3 pacs pacs.. no braço braço BOC ainda não chegaram na semana FU 12) Sumário de Segurança PR (N=34) B/PR (N=64) 34 (100) 63 (98) 7 (21) 11 (17) 0 0 34 (100) 61 (95) Descontinuação do Estudo devido à EAs 3 (9) 13 (20) Qualquer Modificação de Droga devido à EAs 8 (24) 18 (28) Qualquer Evento Adverso (EA) EA Sério Morte EAs relacionados ao tratamento . Eventos Adversos Hematológicos PR B/PR (N=34) (n=64) Anemia Eventos Adversos Sérios (EAS) 6% 3% EAS conduzindo a descontinuação 3% 2% WHO, Grau 1-4 (<11.0 g/dL) 53% 63% 3% 5% Uso de Eritropoietina 21% 38% Transfusão 6% 6% 74% 86% 12% 27% Grau 3-4 (<8.0 g/dL) Neutropenia WHO, Grau 1-4 (≤1.5x109/L) Grau 3-4 (<0.75x109/L) Rebote Virológico do HIV em Grupos B/PR No geral, 7 pacientes tiveram rebote virológico do HIV (>50 cópias HIV-RNA em 2 visitas consecutivas): 3/64 randomizados para B/PR e 4/34 para PR HIV RNA (cópias/mL) Regime BL TW4 TW12 TW24 TW36 EOT ATV/r <50 <50 --- 659 --- 53 2990 †LPV/r <50 <50 <50 55 59 67 68 ATV/r <50 <50 <50 <50 243 --- 7870 ATV/r, atazanavir/ritonavir; LPV/r, lopinavir/ritonavir †The only subject to change ART. LPV/r changed to ATV/r at TW42; ATV/r to DRV/r at FW24. FW4 Dados Preliminares em coinfectados HIV/HCV Genótipo 1 Tratados com Telaprevir Wk 12 Part A: No Current ART HIV/HCV-coinfected patients; CD4+ ≥ 500 cells/mm³; HIV-1 RNA ≤ 100,000 c/mL (N = 13) Part B: Stable ART HIV/HCV-coinfected patients on stable ART, EFV/TDF/FTC or TDF + (FTC or 3TC) + ATV/RTV; CD4+ ≥ 300 cells/mm³; HIV-1 RNA ≤ 50 c/mL (N = 47) Telaprevir 750 mg q8h + PR† (n = 7) Current Analysis: Wk 24 Wk 48 Wk 72 PR† (n = 7) Follow-up Placebo + PR† (n = 6) PR† (n = 6) Telaprevir* 750 mg q8h + PR† (n = 31) PR† (n = 31) Follow-up Placebo + PR† (n = 16) PR† (n = 16) *Telaprevir dose increased to 1125 mg q8h with efavirenz. alfa-2a 180 μg/wk; RBV 800 mg/day or weight based in France and Germany (1000 mg/day if weight < 75 kg; 1200 mg/day if weight ≥ 75 kg). †PegIFN Sherman KE, et al. AASLD 2011. Abstract LB-8. Study 110: Interim Data on Telaprevir in HIV/HCV Genotype 1– 1–Coinfected Patients Wk 12 Part A: No Current ART HIV/HCV-coinfected patients; CD4+ ≥ 500 cells/mm³; HIV-1 RNA ≤ 100,000 c/mL (N = 13) Part B: Stable ART HIV/HCV-coinfected patients on stable ART, EFV/TDF/FTC or TDF + (FTC or 3TC) + ATV/RTV; CD4+ ≥ 300 cells/mm³; HIV-1 RNA ≤ 50 c/mL (N = 47) Telaprevir 750 mg q8h + PR† (n = 7) Current Analysis: Wk 24 Wk 48 Wk 72 PR† (n = 7) Follow-up Placebo + PR† (n = 6) PR† (n = 6) Telaprevir* 750 mg q8h + PR† (n = 31) PR† (n = 31) Follow-up Placebo + PR† (n = 16) PR† (n = 16) *Telaprevir dose increased to 1125 mg q8h with efavirenz. alfa-2a 180 μg/wk; RBV 800 mg/day or weight based in France and Germany (1000 mg/day if weight < 75 kg; 1200 mg/day if weight ≥ 75 kg). †PegIFN Sherman KE, et al. AASLD 2011. Abstract LB-8. Resposta Virológica durante o tratamento com Telaprevir em coinfectados HCV HCV--HIV • • Higher response rates with TVRTVR-based triple therapy vs pegIFN pegIFN/RBV /RBV through Wk 24 Bilirubin adverse events more common in patients receiving ATV/RTVATV/RTV-based antiretroviral therapy with TVR + pegIFN pegIFN/RBV /RBV (27%; 4/15) vs pegIFN pegIFN/RBV /RBV (0%; 0/8) – – • Hyperbilirubinemia related to ATV exposure, primarily unconjugated in nature 3 discontinuations due to AEs, all in patients receiving TVR + ATV/RTV Pharmacokinetic interactions with ATV or EFV not clinically significant Undetectable HCV RNA, Wk 24 (ITT) Patients (%) 100 86 75 80 75 71 67 60 55 50 33 40 20 0 n/N= Telaprevir + PR 6/7 11/16 10/15 27/38 Sherman KE, et al. AASLD 2011. Abstract LB-8. PR 2/6 4/8 6/8 12/22 No antiretroviral therapy EFV/TDF/FTC ATV/RTV + TDF/FTC Total Taxas de RVS12 Com Telaprevir + P/R vs Peg-IFN/R em Coinfectados HIV/HCV Sem Terapia ARV Pacientes com RVS12 (%) 100 Terapia ARV baseada em EFV 80 80 71 Terapia ARV baseada em ATZ 69 60 40 50 50 4/8 4/8 33 20 n/N = 5/7 11/16 12/15 2/6 0 TVR + P/R Placebo + P/R Rebote do HIV-RNA não foi observado em qualquer paciente Dieterich DT, et al. CROI 2012. Abstract 46. Efeitos Farmacocinéticos do BOC e TVR sobre os IPs do HIV com booster de RTV ATV/RTV Mudança na Concentração HIV PI Cmin,% (90% CI) 100 LPV/RTV DRV/RTV TVR[2] 85 (40 to 144) 80 60 40 14 (-4 to 36) 20 0 -20 -40 -60 -80 -49 (-39 to -56) BOC[1] -43 (-35 to -51) -42 (-37 to -48) -59 (-55 to -62) -100 1. Hulskotte EGJ, et al. CROI 2012. Abstract 771LB. 2. van Heeswijk R, et al. CROI 2011. Abstract 119. Efeitos Farmacocinéticos dos Inibidores de Protease do HIV+RTV sobre BOC e TVR Similar reductions in BOC and TVR exposures observed with coadministration of ATV/RTV, DRV/RTV, and LPV/RTV Prescribing information for TVR does not recommend coadministering TVR with DRV/RTV, FPV/RTV, or LPV/RTV; prescribing information for BOC does not recommend coadministering BOC with any HIV PI Mudança na Concentração HCV PI Cmin, % (90% CI) BOC[1] TVR[2] 0 -20 -40 -60 -15 (-2 to -25) -18 (-2 to -32) -35 (-24 to -44) -57 (-47 to -64) ATV/RTV DRV/RTV LPV/RTV -32 (-26 to -37) -52 (-44 to -60) -80 -100 1. Hulskotte EGJ, et al. CROI 2012. Abstract 771LB. 2. van Heeswijk R, et al. CROI 2011. Abstract 119. Estudo Insight – Telaprevir + PR para coinfectados HCV-HIV- Montes, ML et al., AASLD, 2013 Estudo Insight – Telaprevir + PR para coinfectados HCV-HIV Estudo Insight – Telaprevir + PR para coinfectados HCV-HIV Estudo Insight – Telaprevir + PR para coinfectados HCV-HIV Estudo Mono versus Coinfectados Características dos Pacientes Co-infected (N = 33) Monoinfected (N = 117) P-value Median age (IQR) 57 (52-59) 56 (51-61) 0.82* Male (% of total) 26 (78.8%) 79 (67.5%) 0.21§ Race (% of total) White Black Other Prior treatment response (% of total) Naive Relapser Non responder/Intolerant 16 (48.5%) 14 (42.4%) 3 (9.1%) 65 (55.6%) 19 (16.2%) 34 (28.2%) <0.01§ 0.02§ 3 (9.1%) 5 (15.2%) 25 (75.8%) 36 (30.8%) 23 (19.7%) 58 (49.6%) Bridging fibrosis/cirrhosis (% of total) 16 (48.5%) 40/113 (35.4%) 0.17§ Baseline HCV viral load log10 IU/mL (IQR) 6.46 (5.92-7.00) 6.46 (5.91-6.73) 0.42† Sulkowski & Dieterich, 2014 Resposta Virológica Terapia Tripla em Mono versus Coinfectado HCVHCV-HIV Trend for better virologic responses in co-infected patient is potentially explained by a selection bias Novas Drogas antianti-HCV a DAAs de 2 Geração Inibidores da NS3 Simeprevir 60 QUEST-1: Resposta Virológica ao Tratamento com Simeprevir + P/R RVS12 por RGT Desfechos Virológicos SMV + P/R P/R 85% dos pcs no braço SMV atingiram critérios RGT 80 100 80 60 50 40 20 0 91 80 80 n/ 202/ N = 254 12 Sem. 4 RVS12 (%) HCV RNA Indetectavel (%) 100 60 40 21 20 210/ 65/ 264 130 RVS12 Jacobson I, et al. EASL 2013. Abstract 1425. 0 n/ N= 203/224 6/28 24 Sem 48 Sem Braço SMV : Duração do RGT QUEST-1: RVS12 por Nível de Fibrose, Subtipo e Resistência 100 100 SMV + P/R P/R 82 80 RVS12 (%) RVS12 (%) 80 60 90 58 53 40 29 71 60 52 49 40 20 20 n/N = 188/229 60/113 18/31 5/17 105/147 36/74 105/117 29/56 0 0 Sem Cirrose GT 1a Cirrose GT 1b Differences in SVR12 by Subgroup (95% CIs) SMV (n) Pbo (n) 147 74 GT 1a/other HCV 28.2 (13.4-42.9) 60 74 - With baseline Q80K vs Pbo 4.7 (-14.6 to 24.1) 86 74 - Without baseline Q80K vs Pbo 40.3 (25.8-54.8) 117 56 GT 1b HCV 42.1 (26.5-57.6) -100 Jacobson I, et al. EASL 2013. Abstract 1425. -50 Favors Placebo 0 50 Favors SMV 100 QUEST-2: Resposta Virológica ao Tratamento com Simeprevir + P/R SMV + P/R P/R 100 81 86 RVS12 (%) 80 60 91% dos pcs no braço SMV atingiram critérios de RGT 50 40 32 20 n/N = 209/257 67/134 202/235 7/22 0 Global 24 sem 48 sem Braço SMV: Duração da RGT Manns M, et al. EASL 2013. Abstract 1413 QUEST-2: RVS12 por Subtipo e Grau de Fibrose Altas taxas de RVS12 com SMV, independente do genótipo HCV ou cirrose Mutação Q80K (Baseline) não foi preditiva de resposta ( do QUEST-1) SMV + P/R P/R 100 RVS12 (%) 80 82 82 80 65 60 46 53 51 40 40 20 n/N = 0 86/ 107 26/ 57 GT 1a Manns M, et al. EASL 2013. Abstract 1413. 123/ 41/ 150 77 GT 1b 189/ 61/ 231 119 Sem Cirrose 11/ 17 6/ 15 Cirrose C212 study design: Phase III, openopen-label, singlesingle-arm, international trial 24 12 36 Primary analysis 60 48 72 Week SMV • HCV treatment-naïve • Prior relapse+ RGT* 150 mg/PR SMV 150 mg/PR • Partial response • Null response • Cirrhotic patients (F4) SMV 150 mg/PR PR Follow-up PR Follow-up PR Follow-up Primary endpoints: SVR12, safety and tolerability Secondary endpoints: virologic response at other time points, meeting RGT criteria* for shortened treatment to 24 weeks, onon-treatment failure and relapse rates Primary analysis: All patients included in the analysis (N=106) had completed 24 weeks of treatment, or had reached the time point of the primary efficacy endpoint SVR12 (Week 60), or discontinued prior to that point (for those on 48 weeks of treatment) PR, peginterferon-α2a + ribavirin; RGT, response-guided treatment; SMV, simeprevir; SVR12, sustained virologic response 12 weeks’ after end of treatment +After PR treatment; *RGT criteria: HCV RNA <25 IU/mL (detectable or undetectable) at Week 4 and undetectable at Week 12 (measured using Roche COBAS TaqMan HCV/HPS assay, v.2) C212: SMP + PR - RVS12 de acôrdo com o tipo de resposta prévia ao tratamento Altas taxas de RVS12 com SMV + PR, independente do tipo de resposta. 87% dos pacs. virgens e relapsers atingiram critérios para RGT por 24 sem. Em TARV: 99% com NRTI, 87% Raltegravir e 15% com Rilpivirina 100 74 79 87 70 RVS12 (%) 80 57 60 40 20 n/N = 78/106 42/53 Global Virgens 13/15 7/10 Relapsers Parcial 16/28 0 Dieterich et al. 2013. EACS. Nulo SVR12 (%) C212: RVS12 ― Endpoint Primário 78/106 42/53 13/15 SVR12, sustained virologic response 12 weeks’ after end of treatment 7/10 16/28 C212: RVS12 por Subtipo do Genótipo 1 e presença de Polimorfismo da NS3 Q80K Altas taxas de RVS12 com SMV, independente do genótipo HCV ou mutação Q80K (Baseline) 87% dos pacs. virgens e relapsers atingiram critérios para RGT por 24 sem. 100 89 RVS12 (%) 80 72 71 67 60 40 20 n/N = 16/18 62/88 GT 1b GT 1a 20/30 42/58 0 Dieterich et al. 2013. EACS. G 1a c/ Q80K G 1a s/ Q80K C212: RVS12 por Escore de Fibrose METAVIR Proportion of patients, % (n/N) METAVIR score Overall Naïve Relapser Partial Null F0–F2 80 (36/45) 89 (24/27) 78 (7/9) 50 (1/2) 57 (4/7) F3–F4 64 (14/22) 57 (4/7) 100 (2/2) 67 (2/3) 60 (6/10) SVR12, sustained virologic response 12 weeks’ after end of treatment Introduction to faldaprevir • Faldaprevir is a potent and selective inhibitor of the HCV NS3/A4 protease – The pharmacokinetics of FDV allow oral once daily administration • Phase IIb data demonstrated potent antiviral activity against HCV GTGT-1 for: – Faldaprevir combined with pegIFN/RBV – An IFNIFN-free combination of faldaprevir Faldaprevir: Interaction with NS3/4A protease Green = hydrophobic Blue = mildly polar Purple = H bonding GT, genotype; HCV, hepatitis C virus; IFN, interferon alpha; RBV, ribavirin; BI 207127, a non-nucleoside inhibitor of HCV RNA polymerase with BI 207127 and RBV • Phase III trials are ongoing for the iFree and iBased faldaprevir clinical development programs Llinàs-Brunet M, et al. J Med Chem 2010;53:6466–6476; Lemke CT, et al. J Biol Chem 2011;286:11434–11443; Sulkowski MS, et al. Hepatology 2013 Jan 28 [Epub ahead of print]; Zeuzem S, et al. AASLD Congress November 9–13, 2012 [Abstract No. 232]. STARTVerso1: RVS12 de acordo com ETS, Genótipo e Grau de Fibrose FDV 120 mg 100 87 89 84 80 SVR12 (%) Pacientes (%) 60 40 Placebo 100 86 89 80 69 67 60 60 40 81 56 36 20 20 0 FDV 240 mg n/ 226/ 233/ N = 259 261 194/ 208/ 226 233 Alcançaram ETS RVS12 in pcs ETS 0 60/ 16/ 87 45 143/ 52/ 171 86 172/ 212 30/ 45 9/ 16 GT 1a GT 1b < F3 ≥ F3 F4 ETS definido como HCV RNA < 25 IU/mL na sem. 4 e HCV RNA < 25 IU/mL, TND na sem.8. 23% dos pcs com GT 1a HCV tinham mutação Q80K (baseline); não preditiva de RVS12 Ferenci P, et al. EASL 2013. Abstract 1416. STARTVerso 4: High rates of early virologic response in HCV genotype 1/HIV1/HIV-co co--infected patients treated with faldaprevir plus pegIFN and RBV • Douglas Dieterich, Dieterich,1 Vicente Soriano,2 Mark Nelson,3 Jürgen Kurt Rockstroh,4 Keikawus Arastéh,5 Sanjay Bhagani,6 Andrew Talal,7 Cristina Tural,8 Richard Vinisko,9 and Jens Kort 9 1Mount Sinai School of Medicine, New York, NY, USA; 2Hospital Carlos III, Madrid, Spain; 3Chelsea and Westminster Hospital, London, UK; 4University of Bonn, Bonn, Germany; 5EPIMED, Vivantes Auguste-Viktoria Hospital, Berlin, Germany; 6Royal Free Hospital, London, UK; 7State University of New York, Buffalo, NY, USA; 8Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; 9Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA 20th Conference on Retroviruses and Opportunistic Infections, March 3–6, 2013 STARTVerso 4: Study design (1) Phase III open-label, sponsor-blinded study in treatment-naïve and relapser patients with chronic HCV GT-1 and HIV infection Interim data Primary endpoint: SVR12 Faldaprevir 240 mg QD + pegIFN/RBV Faldaprevir 240 mg QD + pegIFN/RBV pegIFN/RBV pegIFN/RBV Randomization 1:1 pegIFN/RBV Faldaprevir 120 mg QD + pegIFN/RBV Day 1 Week 12 Week 24 Week 48 Patients with HCV RNA below LLoQ, at Week 4, and HCV RNA below LLoQ target not detected at Week 8 (=ETS) will be re-randomized 1:1 at week 24 to stop treatment or continue pegIFN/RBV through week 48 Patients who did not achieve ETS will continue pegIFN/RBV through week 48 LLoQ, lower limit of quantification <25 IU/mL HCV RNA; pegIFN: pegylated interferon alfa-2a 180 µg once weekly; QD, once daily; SVR, sustained virologic response at 12 weeks after end of treatment.; ETS, early treatment success RBV: ribavirin 1000 or 1200 mg daily dose for body weight <75 kg or ≥75 kg, respectively STARTVerso 4: Baseline characteristics Treatment-naïve (N=239) Relapser (N=69) Total (N=308) 47 47 47 184 (77) 64 (93) 80 179 (75) 39 (16) 21 (9) 63 (91) 2 (3) 4 (6) 79 13 8 67 (28) 60 (25) 105 (44) 7 (3) 17 (25) 7 (10) 41 (59) 4 (6) 84 (27) 67 (22) 146 (47) 11 (4) Mean baseline CD4+ T cell count, cells/µL 544 549 545 Baseline HCV RNA ≥800 000 IU/mL, n (%) 197 (82) 49 (71) 246 (80) HCV Genotype-1a, n (%) 184 (77) 55 (80) 239 (78) Cirrhosis F4 or FibroScan >13 kPa, n (%) 40 (17) 11 (16) 51 (17) Age, years (mean) Male, n (%) Race, n (%) White Black or African American Othera ART, n (%) EFV-based ATZ/r- or DRV/r-based Ral-based and otherb No ART (ARV-naïve), n (%) aIncludes bIncludes Asian, Native Hawaiian or other Pacific Islander, American Indian or Alaska Native, and missing data. 1 patient taking maraviroc plus emtricitabine/tenofovir disoproxil fumarate, 1 patient taking emtricitabine/tenofovir disoproxil fumarate only. Ral, raltegravir STARTVerso 4: Patient disposition (Week 12 interim data) Screened (N=453) Screen failure (N=143) Allocated/ Randomized (N=153/N=157) HCV treatmentnaïve (N=239) Faldaprevir (120 or 240 mg QD) + pegIFN/RBV (N=308) Not available (N=18) Discontinued (N=45) 15 Due to AE 12 Lack of efficacya 18 Other reasonb Completed 12 weeks of treatment (N=176) aIncludes: Not treated (N=2) Relapser (N=69) Not available (N=4) Discontinued (N=7) 3 Due to AE 1 Lack of efficacya 3 Other reasonb Completed 12 weeks of treatment (N=58) viral rebound ≥1 log10 HCV RNA from previous undetected level; lack of HCV RNA reduction from baseline by ≥ 2 log10 at Week 12; lack of viral response at Week 24. bIncludes: protocol violation, withdrawal by subject, or other reasons AE, adverse event; ATZ, atazanavir; DRV, darunavir; EFV, efavirenz; r, ritonavir Early virologic response in HIV/HCV co-infected patients: comparison with HCV mono-infected patients Treatment-naïve <LLoQ TND Relapser <LLoQ Relapser <LLoQ TND Proportion of patients (%) Treatment-naïve <LLoQ Treatment-naïve <LLoQ TND * 191/ 239 143/ 239 63/ 69 51/ 69 Week 4 aSILEN-C1 Mono-infected patients, SILEN-C1 study: 108/ 142 206/ 239 195/ 239 64/ 69 63/ 69 132/ 142 Week 12 study arm of 240mg QD FDV plus pegIFN/RBV in HCV GT1 treatment-naïve monoinfected patients without cirrhosis; data on file Response guided therapy criteria (ETS) in STARTVerso 4 Relapser Proportion of patients (%) Treatment-naïve aData missing for 4 patients. ETS, early treatment success ETS criteria: Wk 4 HCV RNA <LLoQ, + Wk 8 <LLOQ, TND a YES 184/ 239 61/ 69 50% Stop treatment at week 24 50% continue with pegIFN/RBV through week 48 Proportion of patients with SVR4 (%) RVS4 Global 89/123 66/84 72/86 140/185 a aIncludes additional patients from 240 mg treatment group who discontinued prior to week 12. 229/308 StartVerso 4 : RVS 12 de acordo com HCV Genótipo, IL28B e Presença ou não de cirrose e tipo de resposta prévia HCV/HIV tratados com FDV+ PegIFN + RBV x 24 semanas 100 89 HCV RNA <LLOQ (%) 74 77 90 74 80 67 67 70 60 50 40 30 20 10 178/242 51/66 89/100 101/151 34/51 229/308 GT 1a GT 1b IL28 CC IL28 CT IL 28 TT Global SVR12 (%) 0 100 90 80 70 60 50 40 30 20 10 0 Rockstroh et al. EACS 2013; AASLD, 2013 87 74 76 71 194/261 34/45 169/239 60/69 Virgens Relapser s/ Cirrose c/ Cirrose Acknowledgments • Patients, and study investigators and site staff at 67 study centers: Brazil Hans Jäger Arastéh Keikawus Josep Mallolas Chloe Orkin Alison Uriel Carlos Eduardo Brandão Juan Antonio Pineda Mello United States Raymundo Ferreira Filho Hartwig Klinker Daniel Podzamczer Paulo Ferreira Jürgen Kurt Rockstroh Cristina Tural John Baxter Italy Juvencio Furtado Jorge Vergas Maurizio Bonacini Switzerland Beatriz Grinsztejn Giacchino Angarano, Cynthia Brinson Jose Madruga France Marc Bourliere Laurent Cotte Pierre-Marie Girard Andrea Antinori Giovanni Di Perri Gaetano Filice Francesco Mazzotta Paola Nasta Manuel Battegay Enos Bernasconi Jan Fehr Andri Rauch United Kingdom Caroline Lascoux-Combe Marc-Antoine Valantin Germany Massimo Puoti Spain Kosh Agarwal Sanjay Bhagani Martin Fisher Ranjababu Kulasegaram Clifford Leen Mark Nelson • Johannes Bogner Francisco Blanco Manuel Crespo, Christian Hoffmann Patrick Ingiliz Josep Guardiola Juan Carlos Lopez Marina Nunez Gerald Pierone Michael Saag Michael Somero Richard Sterling Mark Sulkowski Douglas Dieterich Andrew Talal Richard Elion Kristen Marks Jerome Ernst Douglas G. Fish Federico Hinestrosa Mamta Jain Anthony LaMarca Eric Lawitz Cheryl McDonald Karam Mounzer Ronald Nahass Boehringer Ingelheim for sponsoring the study and the Boehringer Ingelheim 1220.19 team The external Data Monitoring Committee Novas Drogas antianti-HCV Inibidores da NS5a e NS5b Sofosbuvir 81 Study Design & Duration Wk 4 Wk 24 Wk 12 DCV + P/R Wk 48 Wk 72 Follow Up Yes VR (4 & 12) No P/R Follow Up Response Guided Treatment (RGT) • Subjects who achieve Virologic Response (VR) at Wks 4 and 12 will complete 24 weeks of triple therapy – 48 weeks follow up after treatment • Subjects not achieving VR at Wks 4 and 12 will receive 48 weeks total duration of therapy (additional 24 weeks P/R) 24 weeks follow up after treatment – Therefore, the maximum duration of study for any subject completing treatment will be 72w 82 Study Overview Single-arm study Population 500 Subjects Enrolled Sites Countries DCV plus P/R Previously untreated genotype 1 HCV coinfected with HIV • 300 treated (at least 40% screen fail projected) ~250 subjects on highly active antiretroviral therapy (HAART) – Up to 50 subjects not on HAART – ~ 90 sites in 12 countries • • • • Argentina Australia Belgium Brazil • • • • Canada France Germany Italy • • • • Russia Spain UK US Topline Summary of Sofosbuvir Trials Trial NEUTRINO[1] FISSION[2] FUSION[3] POSITRON[4] Patient Population n Regimen Duration, Wks SVR12, % Tx-naive GT 1 292 SOF + P/R 12 89 Tx-naive GT 4 28 SOF + P/R 12 96 Tx-naive GT 5/6 7 SOF + P/R 12 100 Tx-naive GT 2 70 SOF + RBV 12 97 Tx-naive GT 3 183 SOF + RBV 12 56 Tx-experienced GT 2 36 SOF + RBV 12 86 Tx-experienced GT 3 64 SOF + RBV 12 30 Tx-experienced GT 2 32 SOF + RBV 16 94 Tx-experienced GT 3 63 SOF + RBV 16 62 IFN-UII GT 2 109 SOF + RBV 12 93 IFN-UII GT 3 98 SOF + RBV 12 61 1. Lawitz E, et al. EASL 2013. Abstract 1411. 2. Gane E, et al. EASL 2013. Abstract 5. 3. Nelson D, et al. EASL 2013. Abstract 6. 4. Jacobson I, et al. EASL 2013. Abstract 61. Study 1910 Virologic Response and SVR12 Pacientes com HCV RNA <LLOQ (%) Treatment--Naïve HCV/HIV CoTreatment Co-infected Patients SOF + PegIFN + RBV x 12 weeks 10 0 100 100 91 90 80 70 60 50 40 30 20 10 23/23 23/23 21/23 Week 4 EOT SVR12 0 There was no on-treatment HCV or HIV virologic breakthrough Relapse occurred in 1 patient and accounted for the only virologic failure Two patients discontinued treatment early due to adverse events • one patient discontinued at week 6 and was lost to follow-up • one patient achieved SVR12 after 8 weeks of SOF + RBV therapy Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714 SVR in HCV Mono-infected and HCV/HIV Co-infected Short Duration of SOF + PegIFN + RBV x 12 Weeks 100 91 91 SVR12 (%) 80 60 40 20 296/327 21/23 0 NEUTRINO (HCV Mono-infected) Study 1910 (HIV/HCV Co-infected) Similar response rates in HCV/HIV co-infected patients compared to HCV mono-infected patients Lawitz E, et al. APASL 2013. Singapore. Oral #LB-02 Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714 Phase 2 Study 1910 Design Treatment-Naïve HCV/HIV Co-infected Patients SOF + PegIFN + RBV x 12 weeks • Open-label trial in treatmentOpentreatment-naïve, nonnon-cirrhotic chronic HCV patients cocoinfected with HIV 0 Week 12 16 24 36 SVR4 SVR12 Primary endpoint SVR24 HCV GT 1–4 Treatment-naïve, on stable HIV ARV N=23 SOF 400 mg + PegIFN + RBV 1000‒1200 mg No response guided therapy • Primary endpoints – Efficacy: proportion of patients with SVR12 – Safety and tolerability of treatment, including effects on HIV RNA and CD4 TT-cell % Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714 Study 1910 SVR12 According to HCV GT and HIV ARV Treatment--Naïve HCV/HIV CoTreatment Co-infected Patients SOF + PegIFN + RBV x 12 weeks 100 100 100 100 89 87 17/19 13/15 4/4 1/1 2/2 1/1 GT 1 GT 1a GT 1b GT 2 GT 3 GT 4 90 HCV RNA <LLOQ (%) 100 80 70 60 50 40 30 20 10 SVR12 (%) 0 100 90 80 70 60 50 40 30 20 10 0 100 89 88 8/9 7/8 6/6 FTC/TDF + Protease Inhibitor FTC/TDF + NNRTI FTC/TDF + Raltegravir Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714 NNRTI, non-nucleoside reverse transcriptase inhibitor Sofosbuvir and Peginterferon AlfaAlfa-2a/Ribavirin for TreatmentTreatment-Naïve Genotype 11-4 HCVHCVInfected Patients Who Are Coinfected With HIV Maribel Rodriguez-Torres,1 Jose Rodriguez-Orengo,2 Anuj Gaggar,3 Gong Shen,3 Bill Symonds,3 John McHutchison,3 Milagros Gonzalez1 IDWeek 2013, October 2-6, 2013, San Francisco, CA Phase 3 PHOTON-1 Study Design All-Oral Therapy of SOF + RBV in HCV/HIV Co-infection GT 1 TN n=114 SOF 400mg + RBV 1000-1200 mg GT 2,3 TN n=68 SOF 400mg + RBV 1000-1200mg GT 2,3 TE n=41 SOF 400mg + RBV 1000-1200 mg Study Week 0 SVR12 SVR12 SVR12 12 24 No response guided therapy Broad inclusion criteria – Cirrhosis permitted with no platelet cutoff – Hemoglobin: ≥12 mg/dL (males); ≥11 mg/dL (females) Wide range of ART regimens allowed – Undetectable HIV RNA for >8 weeks on stable ART regimen Baseline CD4 count – ART treated: CD4 T-cell count >200 cells/mm3 and HIV RNA < 50 c/mL – ART untreated: CD4 T-cell count >500 cells/mm3 Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212 36 PHOTON-1 Baseline Characteristics PHOTONGT 1, 2, 3 HCV TreatmentTreatment-Naïve, HCV/HIV CoCo-infection GT 1 TN SOF + RBV 24 Weeks (n=114) GT 2 TN SOF + RBV 12 Weeks (n=26) GT 3 TN SOF + RBV 12 Weeks (n=42) 49 (24-71) 48 (28-71) 48 (25-70) Male, n (%) 93 (82) 21 (81) 34 (81) Black, n (%) 37 (33) 6 (23) 2 (5) Hispanic, n (%) 25 (22) 8 (31) 11 (26) 27 (19-46) 27 (21-32) 28 (20-44) 30 (27) 10 (39) 15 (36) 6.6 (1.4-7.7) 6.5 (5.0-7.3) 6.2 (5.0-7.4) Cirrhosis, n (%) 5 (4) 1 (4) 6 (14) On ART, n (%) 112 (98) 22 (85) 39 (93) 636 (251) 627 (278) 559 (224) Mean age, y (range) Mean BMI, kg/m2 (range) IL28B CC, n (%) Mean baseline HCV RNA, log10 IU/mL (range) CD4 T-cell count (cells/μL), mean (SD) Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212 HCV RNA < 25 IU/mL (%) PHOTON-1 SVR12 All-Oral Therapy of SOF + RBV in GT1, 2, 3 HCV Treatment-Naive and GT 3 Treatment-Experienced/HIV Co-infection 100 90 80 70 60 50 40 30 20 10 0 SOF + RBV x24 weeks GT1 TN1 100 SOF + RBV x12 weeks GT2 TN1 100 SOF + RBV x12 weeks GT3 TN1 100 SOF + RBV x24 weeks GT3 TE2 92 88 80 76 67 60 60 60 40 40 40 20 20 23/26 87/114 0 20 28/42 87/114 SVR12 80 80 0 SVR12 12/13 0 SVR12 SVR12 An all-oral regimen of SOF + RBV for 12–24 weeks resulted in high SVR12 rates in TN GT 1, 2 and 3 and TE GT 3 CHC with HIV coinfection – with SVR12 rates similar to mono-infection No HCV resistance (S282T) was observed in virologic failures via deep sequencing Two patients had HCV breakthrough; both had documented non-adherence to SOF Two other patients had transient HIV breakthrough; both had documented non-adherence to ART 1. Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212; 2. SOVALDI™ [PI]. Gilead Sciences, Inc. Foster City, CA December 2013 ‡ SVR in HCV Mono-infected and HCV/HIV Co-infected All-Oral SOF+RBV x 12 or 24 weeks GT 2 SOF + RBV 12 weeks 100 100 60 40 0 100 60 40 87/114 SPARE1 HCV PHOTON-12 HCV/HIV 0 85 60 56 40 68/73 VALENCE3 HCV 23/26 PHOTON-12 HCV/HIV 0 92 80 67 20 20 17/25 100 80 80 20 GT 3 SOF + RBV 24 weeks 88 SVR12 (%) 68 76 SVR12 (%) SVR12 (%) 80 93 GT 3 SOF + RBV 12 weeks SVR12 (%) GT 1 SOF + RBV 24 weeks 60 40 20 102/183 FISSION4 HCV 28/42 PHOTON-12 HCV/HIV 0 212/250 12/13 VALENCE3 PHOTON-15 HCV HCV/HIV Similar response rates in HCV/HIV coinfected patients compared to HCV monoinfected patients 1. Osinusi A, et al. JAMA. 2013;310(8):804-811. 2. Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212. 3. Zeuzem S, et al. AASLD 2013. Washington, DC. #1085. 4. Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87. 5. SOVALDI™ [PI]. Gilead Sciences, Inc. Foster City, CA December 2013 Drug Interactions with GSGS-7977 and HIV Antiretrovirals in Healthy Volunteers Effect of Co-Administration of GS-7977 on HIV ARVs AUC tau Cmax Ctau GMR% (90% CI) Combination/Alone 200 150 143% 100 70% 50 Kirby B, et al. AASLD 2012; Boston. #1877. L A R TV R V R D PV R V EF C FT TF V 0 Novas Drogas antianti-HCV DAAs de 2a Geração Inibidores da NS3/4, NS5a e NS5b (IFN Free) MK5172 + MK 7842 Sofosbuvir +Ledipasvir 96 RVS 12 com regimes de DAAs IFN Free em Coinfectados Virgens e Experimentados HCV/HIV 100 100 92 97 92 88 HCV RNA <LLOQ (%) 90 80 76 67 70 60 50 naive 42 40 30 experimentado 20 10 114 24 37 59 26 17 0 Photon 1 Sofo +RBV Sofo + Ledi GT 1 C-Worthy MK5172 + MK8742 RBV Photon 1 GT 3 Photon 1 GT 2 Sofo +RBV Sulkowski, M et al. AASLD, 2013; Osinuzi, A. et al. EASL 2014, Sulkowski, M et al. EASL 2014 Taxas de RVS com os Novos Agentes DAAs para pacientes virgens de tratamento mono e coinfectados HCV-HIV Estudos de Fase II/III - DAAs PegIFN/RBV Not head-to-head comparisons > 90 100 71-75 RVS (%) 80 68-85 65-85 75-80 61-84 > 95 > 95 42-83 63-75 60 40 20 0 BOC or TVR [1,2] 1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 3. Sulkowski M, et al. EASL 2011. Abstract 60. 4. Terrault N, et al. AASLD 2011. Abstract 79. 5. Vierling JM, et al. AASLD 2011. Abstract LB-17. 6. Fried M, et al. AASLD 2011. Abstract LB-5. 7. Manns MP, et al. AASLD 2010. Abstract 82. 8. Jacobson I, et al. EASL 2010. Abstract 2088. 9. Lawitz E, et al. EASL 2011. Abstract 445. 10. Pol S. ICAAC 2011. Abstract HI-376. 11. Flisiak R, et al. EASL 2011. Abstract 4. Progression of SVR in HCV treatment in HIV Fixed dose ribavirin Weight-based ribavirin Direct-acting antiviral agents AASLD & IDSA Guidelines GT 1, 2, 3 TreatmentTreatment-Naïve, Experienced HCV/HIV CoCo-infection GT 1 GT 2 Treatment Naïve and Prior PR relapsers IFN eligible SOF + PegIFN/RBV 12 Weeks SOF + RBV 12 Weeks Treatment Naïve and Prior PR relapsers IFN ineligible SOF + RBV 24 Weeks SOF + RBV 12 Weeks SOF + RBV 24 weeks Treatment Naïve and Prior PR relapsers IFN ineligible (alternative) SOF + SMP RBV 12 Weeks SOF + RBV 12 weeks SOF + DCL* RBV 12/24 weeks Treatment experienced and PR non-response SOF + SMP RBV 12 Weeks SOF + RBV 12 Weeks 16 weeks for cirrhotic SOF + RBV 24 Weeks 24 weeks for cirrhotic Treatment experienced and TPV/BOC nonresponse SOF x 12 weeks + PegIFN/RBV 12/24 Weeks NA NA AASLD & IDSA Guidelines, 2014 GT 3 SOF + RBV 24 weeks * EASL Guidelines & Recommendations April 2014 Interação Medicamentosa entre DAAS e TARV Droga Telaprevir Boceprevir Simeprevir Faldaprevir Daclatasvir Sofosbuvir Atazanavir Monitorar bilirrubinemia Individualizar Não recomendada Recomendada 120 mg/dia Recomendada 30 mg/dia Recomendada Darunavir Não recomendada Não recomendada Não recomendada Recomendada 120 mg/dia NA Recomendada Efavirenz 1125 mg 3 x/dia Não recomendada Não recomendada Recomendada 240 mg/dia Recomendada 90 mg/dia Recomendada Rilpivirina Cautela com intervalo QT Recomendada Recomendada NA NA Recomendada Etravirina Recomendada Individualizar NA NA NA NA Raltegravir Recomendada Recomendada Recomendada Recomendada NA Recomendada Adaptado de Bhagani, EASL, 2014 Hepatite C - HIV - Resumo • Ocorre em 25 25--30 30% % dos pacientes com infecção pelo HIV HIV.. • Mais freqüente em usuários de drogas ilícitas e hemofíicos hemofíicos.. • Hepatite C é importante causa de morbi morbi--mortalidade em doentes HIV HIV.. • Terapia com Peg Peg--interferon e Ribavirina com eficácia de 27 – 55 55% % (Geral), de 14 – 46 46% % nos pacientes com Gen Gen.. 1 e 43 – 73 73% % Gen Gen.. 2-3. • Terapia combinada de Peg Peg--interferon e Ribavirina e 1ª geração de DAAs (Telaprevir e Boceprevir Boceprevir)) com taxas de RVS 61 61% % a 75 75% %. • Terapia combinada de 2ª geração de DAAs (Simeprevir Simeprevir,, Faldaprevir Faldaprevir)) e de inibidores da NS NS5 5a/NS a/NS5 5b IFN IFN--Free com taxas de RVS 80 80--90 90% %. • Atenção a interação medicamentosa entre os novos DAAs e a TARV TARV.. Recomendações Tratamento de Escolha Escolha:: Peg Peg--Interferon + Ribavirina com doses otimizadas (1000 1000--1200 mg mg)) e DAA (inibidores de Protease) Protease).. Aguarda Aguarda--se os resultados dos ensaios com novas moléculas (Boehringer Boehringer,, Bristol)) Bristol para pacientes virgens e para os recidivantes e não não--respondedores Independente do genótipo a duração deve ser de 48 semanas semanas.. Avaliar resposta virológica rápida (na 4a) e precoce (12a) semana.. Valor preditivo positivo (> semana (>80 80% %) e negativo altos (98 98% %) Atenção com a interação do esquema HAART e DAA (IP) (IP).. OBRIGADO... Phase I Gilead Vertex Phase II SCY635 (Scynexis) ANA598 (Anadys) HTAs DAA: NS5A inhibitor DAA: Nucpolymerase inhibitors Phase III MK7009 (MSD) RG7128 (Roche/ Pharmasset) PSI-7977 (Pharmasset) Filed BMS650032 (BSM) DAA: Protease inhibitors DAA: Non nucpolymerase inhibitors (BI Pharma) Alisporivir (Novartis) BMS-791325 (Nuc/non-nuc BMS) Boceprevir Telaprevir (MSD) (J&J/Vertex) BI201335 (BI) GS9256 & GS9451 (Gilead) Tegobuvir (Gilead) IDX-184 (Idenix) IDX-375 (Idenix) BMS790052 (BMS) VX-222 (Vertex) ACH-0141625 (Achillion) BI207127 (BI) TMC435 (Tibotec/Medivir) RG7128 (Genentech/ Pharmasset) ABT-333 & ABT-072 (Abbott) ITMN-191/RG7227 (Roche/Interume) NS=non-structural; nuc=nucleoside; HTA=host-targeting antiviral; DAA=direct-acting antiviral ABT-450 (Abbott) Data correct as of March 2011
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3. Kamal SM, et al. Hepatology. 2007;46:1732-1740. 4. Khuroo MS, et al. Aliment Pharmacol Ther. 2004;20:931-938. 5. Conjeevaram H, et al. Gastroenterology. 2006;131:470-477.
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