NUEVAS ESTRATEGIAS EN EL MANEJO DE HEPATITIS C

Presentación del tema: "NUEVAS ESTRATEGIAS EN EL MANEJO DE HEPATITIS C"— Transcripción de la presentación:

1 NUEVAS ESTRATEGIAS EN EL MANEJO DE HEPATITIS C
24 Enero 2015 Dr. Javier de la Cabada Bauche Hotel Riu

2 Virus de Hepatitis C 1989 se identifica Virus Familia Flaviviridae
Virus muy heterogéneo con diversidad genética

3 Heterogéneo Virus 6 genotipos identificados:
Los mas comunes: 1a, 1b, 2a, and 2b GT 1 GT 3 GT 5 GT 6

4

5 Evaluación Pts con historia de exposición
Basal- Ac Anti-HCV, RNA VHC, transaminasas 4 semanas post exposición: RNA VHC y transaminasas 3 meses post exposición: Ac Anti-VHC, RNA VHC y Transaminasas 6 meses: Ac Anti-VHC

6 Salud Pública Méx 2011; Vol. 53(1):61-67
Incidencia La prevalencia es de 1.4%. Norte (2.0%) Sur (1.5%) y las entidades del centro (1.1%) del país. La incidencia se estima en nuevos casos por año 2005, la cirrosis hepática (complicación tardía de la hepatitis C) fue la tercera causa de mortalidad en hombres Salud Pública Méx 2011; Vol. 53(1):61-67

7 Metas en el Tratamiento Antiviral
Erradicar RNA VHC SVR (Respuesta Virológica Sostenida) 24 semanas post tx. SVR se asocia a % CV negativa= CURA 1-4% recaída en SVR

8

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10 Liang TJ, Ghany MG. N Engl J Med 2013; 368:

11 Liang TJ, Ghany MG. N Engl J Med 2013; 368:

12 Tratamiento para Hepatitis C
PI + PegIFN/RBV (6-12 m)[8-10] 100 70-75 80 PegIFN/ribavirin (6-12 m)[6,7] Interferon/ ribavirina (6-12 m)[3,4] 50-60 60 PegIFN monoterapia (6-12 m)[5,6] SVR (%) interferon estándar (12-18 )[2,3] 38-43 40 Standard interferon (6 m)[1] 25-30 15-20 20 8-12 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: Poynard T, et al. Lancet. 1998;352: McHutchison JG, et al. N Engl J Med. 1998;339: Lindsay KL, et al. Hepatology. 2001;34: Fried MW, et al. N Engl J Med. 2002;347: Manns MP, et al. Lancet. 2001;358: Poordad F, et al. N Engl J Med. 2011;364: Jacobson IM, et al. N Engl J Med. 2011;364: Sherman KE, et al. N Engl J Med. 2011;365:

13 Historia de Tratamiento
Interferon (1) Citocinas Alpha interferon (formerly known as leukocyte interferon) Interferon alfa-2b (pegilado= polietinelglicol) Interferon alfa-2a Beta interferon (formerly known as fibroblast interferon) Gamma interferon (formerly known as immune interferon) Therapy of hepatitis C: meta-analysis of interferon alfa- 2b trials. Hepatology. 1997;26(3 Suppl 1):83S. (1) Am J Gastroenterol. 1999;94(3):581.

14 Historia de Tratamiento
Ribavirina (Combo J Hepatol. 1995;23 Suppl 2:8. / Gastroenterology ;111(5):1307.) Análogo nucleosido con actividad antiviral amplio espectro Disminuye VHC dosis dependiente. Nature. 2004;432(7019):922.

15 Interferon GT 1 Fibrosis F3/F4 24% GT 1 Fibrosis F1/F2 44%
Poca respuesta en pacientes con cirrosis IDEAL pegINF alfa -2a vs alfa-2b Tasa curación: GT 1 Fibrosis F3/F4 24% GT 1 Fibrosis F1/F2 44% INF + RIB 44%

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20 Adaptado de Poordad y cols., 2011.
Tasa de RVS global en el estudio SPRINT-2 BOC+PegIFN+RBV en Pts sin tx previo Aumento de ~1.7 veces en la RVS TGR BOC 242/366 Poordad 2011, pp. 1200A, 1201A 242/366 233/368 Como se muestra en la diapositiva, las tasas de respuesta global fueron significativamente mayores en los pacientes que recibieron un esquema que contenía boceprevir en comparación con el grupo control. En general: 66% (242/366) de los pacientes que recibieron peginterferón alfa-2b y ribavirina + boceprevir durante 48 semanas (brazo de BOC/PR48) alcanzaron una RVS 63% (233/368) de los pacientes tratados con peginterferón alfa-2b y ribavirina + boceprevir de manera guiada por la respuesta (brazo de TGR BOC) alcanzaron una RVS y suspendieron todos el tratamiento en la semana 28 38% (137/363) de los pacientes que se les administró peginterferón alfa-2b y ribavirina durante 48 semanas (brazo de PR48) alcanzaron una RVS Las tasas de RVS en los brazos de boceprevir fueron aproximadamente 1.7 mayores que la tasa de RVS en el brazo control con PR48. La tasa de RVS en el brazo de TGR BOC fue 25% más alta que en el brazo control. La tasa de RVS en el brazo de BOC/PR48 fue 28% más alta que en el brazo control con PR48 control. Las tasas globales de RVS fueron similares en el brazo de TGR BOC y en el brazo de BOC/PR48, sugiriendo una eficacia equivalente. 137/363 Adaptado de Poordad y cols., 2011. 20

21 Tasas de RVS global en el estudio RESPOND-2 Pts en Recaída o Respondedores parciales
Aumento de ~3 veces en la RVS Bacon 2011, p. 1213A 107/161 95/162 Como se muestra en esta diapositiva, las tasas de RVS fueron significativamente mayores en los pacientes que recibieron boceprevir en combinación con peginterferón y ribavirina versus los pacientes tratados con el esquema de control. Las tasas de RVS global fueron: 21% en el brazo control de PR48, 59% en el brazo de TGR BOC y 66% en el brazo de BOC/PR48 Las tasas de RVS en los brazos de boceprevir fueron aproximadamente tres veces más alta que la tasa de RVS en el brazo control. La tasa de RVS en el brazo de TGR BOC fue 38% mayor que en el brazo control con PR48. La tasa de RVS en el brazo de BOC/PR48 fue 45% mayor que en el brazo control. Aunque hubo una RVS en 12 pacientes más en el brazo de BOC/PR48 que en el brazo de TGR BOC, las tasas en cada grupo no difirieron de manera significativa. Por lo tanto, no hubo ninguna diferencia entre el tratamiento estándar con boceprevir y el tratamiento guiado por la respuesta. 17/80 TGR BOC Bacon y cols., 2011. 21 21

22 SVR de acuerdo a respuesta previa
PROVIDE: Terapia triple con Boceprevir en pacientes tratados previamente SVR de acuerdo a respuesta previa En RESPOND-2 no incluyeron respondedores nulos. Un brazo único, multicentrico en pacientes bien caracterizados de estudios previos que recibieron el brazo pegIFN/RBV en estudios fase II/III con BOC Se incluyeron respondedores nulos deRESPOND-2 y SPRINT-2: < 2 log decline in HCV RNA después de12 semanas de tx con pegIFN/RBV (N = 52) 4-semanas de pegIFN/RBV lead-in seguido por 44 semanas con triple terapia 100 80 68 (53/78) 60 56 (5/9) Pacientes (%) 40 (19/47) 40 BOC, boceprevir; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. David R. Nelson, MD: The PROVIDE trial evaluating the efficacy of boceprevir-based therapy in treatment-experienced patients was an important study because the initial boceprevir registration trial for treatment-experienced patients did not include those with a previous null response, defined as a < 2 log10 IU/mL decline in HCV RNA after 12 weeks of peginterferon/ribavirin therapy.[1] Of note, the FDA incorporated recommendations for the use of boceprevir in previous null responders based on modeling analyses. To address the question of boceprevir efficacy in patients with previous null response, the PROVIDE trial enrolled well-characterized patients who experienced treatment failure, including null response, in the peginterferon/ribavirin control arms of phase II or III boceprevir studies. The patients were treated with a 4-week peginterferon/ribavirin lead-in followed by up to 44 weeks of boceprevir plus peginterferon/ribavirin. This study allowed investigators to prospectively assess responses to a boceprevir-based regimen in a well-defined group of patients who experienced previous treatment failure. The results were straightforward. The SVR rate in null responders was consistent with that predicted by the previous modeling analyses and similar to the rate observed in null responders treated with telaprevir-based therapy.[2] It is important to note that although the SVR rate was reported to be 40% in previous null responders, this was not an intent-to-treat analysis. If the analysis included 4 patients who dropped out during the peginterferon/ribavirin lead-in (3 with previous null response), the SVR rate in this subgroup was 38%. These findings suggest that previous null responders can be appropriately treated with boceprevir-based therapy, with an overall SVR rate similar to the rate achieved with telaprevir‑based treatment. Stefan Zeuzem, MD: Yes, the most important data from this trial are the findings in patients with previous null response. Physicians need to discuss the odds for achieving an SVR in previous null responders thoroughly with their patients and also consider alternative treatment options in clinical trials if available. Patients with previous treatment failure represent an area of substantial unmet need. There is something unique about patients with previous treatment failure, even when retreating with many of the direct-acting antiretroviral regimens, as will be discussed later in this presentation. For more information on this study, review the CCO Capsule Summary at: References 1. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364: 2. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364: 20 Nulos Parciales Recaída Respuesta previa Bronowicki J, et al. EASL Abstracto 11.

23 Respondedores Parciales
RVS en pacientes con tratamiento previo Recaída, Respondedores Parciales, Respondedores Nulos REALIZE: TVR + PegIFN/RBV en G1: Recaída, Respondedores Parciales/Nulos Se evaluó la terpapia de Inducción (Lead-in) pero no demostró influencia por lo que no se incluyo en la recomedación de la marca para TRV PR48 T12/PR48 LI T12/PR48 Recaídas Previas Respondedores Parciales Respondedores Nulos 100 88* 83* 80 59* 60 54* RVS(%) 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 *P < .001 vs PR48. Zeuzem S, et al. N Engl J Med. 2011;364:

24 REGLAS DE TRATAMIENTO CON BOCEPREVIR+ PegIFN+RIBA
TIPO DE PACIENTES TRATAMIENTO CIRROTICOS LEAD IN 4 SEMANAS TRIPLE TERAPIA 44 SEMANAS RESPONDEDORES NULOS EN TRATAMIENTO PREVIO PACIENTES VIRGENES CON DISMINUCION EL HCV RNA <1 LOG EN LA FASE DE INDUCCION

25 Problemas con inhibidores de proteasas de primera generacion
MULTIPLES EFECTOS COLATERALES : ANEMIA(BOC), COMPLICACIONES DERMATOLOGICAS (TPV) MULTIPLES DOSIS : DIFICULTAD EN EL APEGO, INGESTA CON ALIMENTOS MULTIPLES INTERACCIONES MEDICAMENTOSAS COMPLICACIONES GRAVES E INCREMENTO EN LA MORTALIDAD EN PACIENTES CON CIRROSIS HEPATICA DIFICULTAD PARA SER UTILIZADO EN OTROS GRUPOS DE RIESGO: PACIENTES TRASPLANTADOS DE HIGADO Y CON HIV.

26 CUPIC: Telaprevir or Boceprevir + P/R en cirróticos GT 1 previamente tratados
Experiencia Francesa de un programa de uso compasivo para acceso temprano de TVR y BOC antes de su aprovación. 100 Telaprevir + P/R Boceprevir + P/R 80 60 53 51 SVR12 (%) 40 41 40 40 32 29 BOC, boceprevir; GT, genotype; HCV, hepatitis C virus; P/R, peginterferon/ribavirin; SVR, sustained virologic response; TVR, telaprevir. Paul Y. Kwo, MD: This slide shows the final SVR rates for the CUPIC study of the French compassionate use program using triple therapy with either telaprevir or boceprevir plus peginterferon/ribavirin in treatment-experienced cirrhotics with genotype 1 HCV infection. The overall SVR rate between the 2 therapies was very similar: 40% for telaprevir plus peginterferon/ribavirin and 41% for boceprevir plus peginterferon/ribavirin. The same trend was seen as was observed in phase III trials, in that previous relapsers had the highest response rates, followed by partial responders, and then nulls responders. In addition, the SVR rates observed were somewhat lower than that seen in the registration trials, but these patients, in general, were somewhat sicker with more advanced liver disease than those who were treated in the nonresponder phase III trials (REALIZE and RESPOND-2).[1,2] Stefan Zeuzem, MD: I think the key message from the CUPIC study, which has been confirmed in many other trials, is that care must be taken in patients with platelets counts < 100,000/μL and those who have an albumin level < 3.5 g/dL. If they have both of these parameters—both lower albumin and portal hypertension as shown by thrombocytopenia—then the serious adverse event rate is close to 50%. In other words, 1 out of 2 such patients may have heavy complications and the risk:benefit ratio must be cautiously explored; only experienced treaters in experienced centers should manage those patients on treatment. These data also reconfirmed our previous experience with peginterferon/ribavirin in that, although the addition of these potent DAA agents improves the SVR rates, in cirrhotic populations, this is associated not only with decompensation but also infectious complications. Indeed, both an albumin level < 3.5 g/dL and thrombocytopenia (< 90,000 cells/µL) were associated with severe infectious complications in F3/F4 patients receiving triple therapy in a second study also reported at EASL. In a subset analysis, those with significant portal hypertension (hepatic venous pressure gradient > 10 mm Hg) were also at risk of infectious complications during triple therapy.[3] The CUPIC data set and other presentations suggest that the addition of DAA agents to peginterferon/ribavirin in a cirrhotic patient population must be considered carefully and—should you choose to treat these patients—collaboration with a transplantation center or an experienced treatment center is an important aspect of successful patient care. David R. Nelson, MD: It is important also to keep in mind that CUPIC was a very early access program that was launched well before we understood the potential utility of ribavirin dose reduction and before we had extensive experience on the use of telaprevir or boceprevir in cirrhotic patients. Overall, there is no doubt that caution needs to be exercised in cirrhotics, specifically, in cirrhotics with portal hypertension and with albumin levels < 3.5 g/dL. However, we must also keep sight of the fact that SVR rates were still fairly substantial, especially in interferon-responsive cirrhotics. As such, there is an appropriate use of these drugs in patients with easier-to-cure cirrhosis, defined as previous relapsers and potentially those who have the IL28B CC genotype. I think we can clearly select appropriate patients with cirrhosis for treatment even now while we wait for improved therapies. However, a 12-week regimen with sofosbuvir plus peginterferon/ribavirin will become a very appealing option for a shorter duration of treatment in patients with cirrhosis. References 1. De Meyer S, Dierynck I, Ghys A, et al. Characterization of telaprevir treatment outcomes and resistance in patients with prior treatment failure: results from the REALIZE trial. Hepatology. 2012;56: 2. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364: 3. Rutter K, Ferlitsch A, Maieron A, et al. Safety of triple therapy with telaprevir or boceprevir in hepatitis C patients with advanced liver disease—predictive factors for sepsis. Program and abstracts of the 48th Annual Meeting of the European Association for the Study of the Liver; April 24-28, 2013; Amsterdam, The Netherlands. Abstract 65. 20 11 118/ 295 79/ 190 61/ 116 43/ 85 43/ 135 32/ 80 8/ 28 n/N = 1/9 Todos los grupos Recaídas Respuestas parciales Respondedores nulos Respuesta previa a P/R Fontaine H, et al. EASL Abstract 60..

27 CUPIC: Seguridad del uso de TPV y BOC en cirróticos
Triple terapia con Boceprevir /TPV (n = 159) Eventos adversos serios 38.4 Abandono prematuro del tratamiento 23.9 Secundario a efectos adversos serios 7.4 Muerte Infecciòn broncopulmonar y sepsis Efectos adversos graves no hematológicos Infección 2.5 Rash Descompesación hepática 4.4 Efectos advesos hematológicos Anemia Grado 2 22.6 Grado 3/4 10.1 Uso de eritropoyetina 66.0 Transfusiones 10.7 Trombocitopenia 6.9 Uso de trombopoyetina 1.9 Neutropenia 5.0 Uso de filgastrim 3.8 Graham R. Foster, FRCP, PhD: This slide shows the safety results among patients treated with boceprevir, demonstrating much higher adverse event rates than the phase III trials. These data demonstrate that safety and tolerability of both agents is much more challenging when used in this patient population. David R. Nelson, MD: The safety results with both boceprevir and telaprevir are unfortunate because this population represents the group of patients we are most commonly treating now—those who cannot afford to wait for newer, improved therapies. However, despite the high incidence of adverse events, both drugs demonstrated potent antiviral efficacy. Some clinicians have doubted whether the protease inhibitors should be used in cirrhotics. However, it is clear that patients with cirrhosis have the greatest potential benefit from these therapies. The regimens are definitely associated with a high risk of toxicity, and patients must be very carefully monitored during treatment. But when rates of HCV RNA negativity at Week 12 are approaching 60% to 90%, it seems that there is also potential for benefit, albeit with a significant price in terms of tolerability. Stefan Zeuzem, MD: Yes, the overall message from this study is the considerable efficacy of these regimens but in conjunction with relatively severe toxicity profiles in patients with cirrhosis. No new adverse effects emerged, but the previously known events were more frequent and more severe than in noncirrhotic populations. Overall, 8 patients died during the study. This is indeed a challenging population to treat. Patients with HCV cirrhosis constitute a cohort whose only treatment options are liver transplantation or virus eradication. The preferred treatment approach depends on the availability of organ transplantation, with the choices being to defer treatment until after transplantation or to treat aggressively before transplantation. In the United Kingdom, a large proportion of patients who are on the liver transplantation waiting list die before receiving a transplant; therefore, we are considering treating all wait-listed patients who have genotype 1 infection with telaprevir- or boceprevir-based therapy to reduce the loss of organs after transplantation due to aggressive HCV recurrence. If patients have ready access to transplantation, immediate transplantation is not a bad choice. However, if patients are at a high risk of death while awaiting transplantation, then these regimens are a much better option. The data from the CUPIC study show encouraging rates of virologic response, albeit with a high incidence of adverse effects. It is important to note that the SVR data from this study are not yet available; therefore, the interpretation of efficacy outcomes may change if relapse rates are high. An important question is whether patients with cirrhosis are achieving higher drug concentrations, possibly because of portal hypertension shunting blood around the liver. Pharmacokinetic studies are needed in this population to answer that question. The findings of the current study are critical for providing more depth to the risk–benefit discussion with patients who have cirrhosis because these patients have not been evaluated in clinical trials of direct-acting antiviral agents. However, we await the final analysis. Of note, this is a selective data set and some patients have dropped out of the study. It is unfortunate that no factors predictive of poor tolerance to the regimens have yet been identified. It is also important to highlight that anemia is a very challenging problem in this population of patients with advanced cirrhosis and portal hypertension, and they appear to be poorly responsive to erythropoietin. Although we have discussed the importance of reducing the ribavirin dose as an initial anemia management strategy, it is more likely that growth factors will be required for successful treatment in this particular group of patients. Yes, the blood transfusion rates were very high in this study at 11% with boceprevir and 15% with telaprevir. For more information on this study, review the CCO Capsule Summary at: 50% de riesgo de complicaciones graves y sepsis cuando se utiliza triple terapia en pacientes con Plaquetas <100,000 Albúmina menor a 3.5 gr/dl Gradiente presión >10 mm/Hg Hezode C, et al. EASL Abstract 8.

28 Telaprevir y Boceprevir

29

30 phase III NEUTRINO trial reported the highest SVR rate (89%) for an IFN-containing regimen (sofosbuvir [400 mg daily]) in combination with PEG-IFN 2a (180 μg by subcutaneous injection weekly) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) in HCV genotype 1 infection and limited exposure to IFN to just 12 weeks, the safety and tolerability profile limits its usefulness in the setting of FDA-approved, highly efficacious oral DAA combinations. (Lawitz, 2013a)

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32 Tratamiento disponible VHC Genotipo 1, 4, 5, y 6

33 2013

34 Antiviral Therapies for Genotype 1 Currently Available
Regimen DAA Class PegIFN + RBV None PegIFN + RBV + boceprevir Protease inhibitor PegIFN + RBV + telaprevir PegIFN + RBV + simeprevir PegIFN+ RBV + sofosbuvir Nucleotide analogue NS5B polymerase inhibitor RBV + sofosbuvir* (Extended duration) Sofosbuvir + simeprevir NUC + PI (off-label) DAA, direct-acting antiviral; NUC, nucleotide analogue; PegIFN, peginterferon; PI, protease inhibitor; RBV, ribavirin. *Sofosbuvir + ribavirin for 24 wks can be considered in patients with genotype 1 HCV who are ineligible for interferon. AASLD/IDSA treatment recommendations. Available at: Accessed June 16, 2014.

35 Sofosbuvir + PegIFN/RBV: NEUTRINO Phase III Study Design
Wk 12 24 Sofosbuvir + PegIFN/RBV (N = 327) SVR12 Open label Sofosbuvir 400 mg QD + pegIFN alfa-2a 180 µg/wk + RBV mg/day for 12 wks (no response-guided therapy) Treatment-naive, genotype 1 89% , 4, 5, and 6 HCV-infected patients 17% of patients with cirrhosis HCV, hepatitis C virus; PegIFN, peginterferon; QD, every day; RBV, ribavirin; SVR sustained virologic response. Lawitz E, et al. N Engl J Med. 2013;368:

36 NEUTRINO Study: Virologic Response
Sofosbuvir + PegIFN/RBV x 12 Wks 100 90 89 80 80 60 SVR (%) 40 GT1, genotype 1; ITT, intent to treat; PegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. 20 ITT SVR12 GT1 Cirrhosis n = 327 n = Lawitz E, et al. N Engl J Med. 2013;368:

37 Sofosbuvir + Low-Dose RBV
NIH SPARE Study (No Interferon): Sofosbuvir + RBV in HCV GT1–Infected Pts 24 wks sofosbuvir + WB or low-dose (600 mg) RBV in treatment-naive subjects Primarily GT1a (70%), male (66%), black (83%), IL28B CT/TT (81%) Advanced liver disease 23% Part 1 (Stage F0-F2) Part 2 (All Stages) 100 96 90 90 EOT SVR24 88 80 68 60 48 Patients (%) BMI, body mass index; EOT, end of treatment; GT, genotype; HCV, hepatitis C virus; ITT, intent to treat; NIH, National Institute of Health; RBV, ribavirin; SVR, sustained virologic response; WB, weight-based. 40 20 Sofosbuvir + WB RBV Sofosbuvir + Low-Dose RBV Sofosbuvir + WB RBV N = 10 N = 50 Osinusi A, et al. JAMA. 2013;310:

38 FISSION: Sofosbuvir/RBV Noninferior to P/R in Tx-Naive GT 2/3 HCV Patients
PegIFN + RBV 99 99 99 100 92 80 67 60 HCV RNA < LLOQ (%) 40 GT, genotype; HCV, hepatitis C virus; LLOQ, lower limit of quantification; NA, not applicable; PegIFN, peginterferon alfa-2a; P/R, pegIFN + RBV; RBV, ribavirin; SVR, sustained virologic response; Tx, treatment. Stefan Zeuzem, MD: This slide shows the efficacy data for the FISSION trial. Both regimens achieved SVR rates of 67% 12 weeks after the end of treatment. This was somewhat surprising, given the 100% SVR rate with various sofosbuvir-based regimens in the phase II trial.[1] Reference 1. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368:34-44. 20 n/N = 249/250 158/236 242/244 207/224 NA 188/190 170/253 162/243 Semana 4 Semana 12 Semana 24 Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;368:34-44.

39 FISSION: SVR12 por Genotipo y Grado de Fibrosis
Sofosbuvir + RBV PegIFN + RBV 98 100 91 82 80 71 62 61 60 SVR12 (%) 40 34 30 GT, genotype; HCV, hepatitis C virus; PegIFN, peginterferon alfa-2a; RBV, ribavirin; SVR, sustained virologic response. Stefan Zeuzem, MD: This slide contains the key information from the FISSION study. First, these data highlight that noncirrhotic patients with genotype 2 HCV have a high likelihood of achieving SVR with sofosbuvir/ribavirin—even those with cirrhosis do well with this treatment regimen. Although there is a numeric difference in SVR for patients with genotype 2 HCV with vs without cirrhosis, more than 90% of cirrhotics achieved SVR with sofosbuvir/ribavirin. Sustained virologic response rates were considerably lower among genotype 2 cirrhotic or noncirrhotic patients treated with peginterferon and ribavirin. Second, these data also highlight that genotype 3 HCV will most likely be the most difficult-to-cure genotype for the future. Among noncirrhotic patients, the investigational arm performed reasonably well compared with the standard-of-care arm, but SVR rates were considerably lower for both treatment arms in genotype 3 HCV–infected cirrhotic patients. Therefore, there is now a debate on how to improve response rates for patients with genotype 3 HCV treated with sofosbuvir. Further data are awaited, in particular from the European VALENCE study, which includes an arm investigating 24 weeks of sofosbuvir plus weight-based ribavirin in patients infected with genotype 3 HCV, to determine whether treatment prolongation will improve SVR rates in this particular patient population. 20 n/N = 58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37 No Cirrosis Cirrosis No Cirrosis Cirrosis Genotipo 2 Genotipo 3 Gane E, et al. EASL Abstract 5. Reproduced with permission.

40 Resumen de estudios con SOFOSBUVIR
Pacientes n Regimen Duración semanas SVR12, % NEUTRINO[1] Tx-naive GT 1 292 SOF + P/R 12 89 Tx-naive GT 4 28 96 Tx-naive GT 5/6 7 100 FISSION[2] Tx-naive GT 2 70 SOF + RBV 97 Tx-naive GT 3 183 56 FUSION[3] Tx-previo GT 2 36 86 Tx-previo GT 3 64 30 32 16 94 63 62 POSITRON[4] IFN-UII GT 2 109 93 IFN-UII GT 3 98 61 GT, genotype; HCV, hepatitis C virus; IFN, interferon; LLOQ, lower limit of quantification; P/R, peginterferon/ribavirin; RBV, ribavirin; SOF, sofosbuvir; SVR, sustained virologic response; Tx, treatment; UII, Unwilling/Intolerant/Ineligible. Paul Y. Kwo, MD: To summarize our discussion of the phase III trials of sofosbuvir, the NEUTRINO study demonstrated high SVR rates with a 12-week regimen of sofosbuvir plus peginterferon/ribavirin in genotypes 1, 4, 5, and 6 HCV, and I think this will become the new gold standard for treatment-naive individuals with genotype 1 HCV infection when it is approved. Although many patients are reluctant to embark on interferon-based therapy, there are also many individuals who will not be daunted by a short 12-week course of peginterferon/ribavirin when combined with sofosbuvir, which has minimal additional adverse events. Moreover, if these patients fail, they will likely fail with virologic relapse, and it is encouraging that in this setting the likelihood of resistance associated variants will be minimal, if at all. Regarding genotypes 4, 5, and 6 HCV, there is a very high SVR rate, and it will be important to still explore this combination further in larger studies. There are not yet data in patients with genotypes 1, 4, 5, or 6 HCV infection who have previously failed interferon-based therapy, although I suspect that these areas will be explored once this combination is available. David R. Nelson, MD: All of the phase III studies suggest that sofosbuvir is a potent, safe treatment option, and consequently, sofosbuvir is likely to gain approval in the coming months, at least in North America, for patients infected with genotype 1 HCV in combination with peginterferon/ribavirin and for patients infected with genotypes 2 and 3 HCV as the first all-oral, interferon-free regimen. Stefan Zeuzem, MD: Once sofosbuvir is initially approved in combination with peginterferon/ribavirin, I will be curious to see how many patients infected with genotype 1 HCV will request to be treated with only sofosbuvir and ribavirin (without peginterferon). There is a very heterogeneous data set in the literature of small phase II studies with sofosbuvir and ribavirin. In some of these studies, although a small number of patients were included, genotype 1 HCV demonstrated SVR rates in the range of 70% or more.[1,2] I would not be surprised if some physicians and patients reviewing those data decide to attempt treatment with sofosbuvir and ribavirin dual therapy in genotype 1 HCV infection. There are certainly many patients who would rather not receive interferon-based treatment. Once simeprevir is also approved—which is discussed below—and physicians will have the opportunity to offer an off-label regimen such as sofosbuvir plus simeprevir; alternatively, some might consider an extended duration of sofosbuvir/ribavirin treatment, which has been evaluated in phase II trials.[2] However, I think that for patients with the IL28B CC genotype, peginterferon is a very potent drug and, for cost reasons and for the very short 12-week duration, peginterferon will continue to play a significant role. In our clinic, we certainly have patients who, for SVR rates approaching 90%, will be willing to undergo 12 weeks of treatment with peginterferon/ribavirin combined with sofosbuvir. I certainly recognize, however, that there is a strong desire to move away from peginterferon-based therapies, such that all individuals with hepatitis C will be candidates for all-oral therapy. I can also envision a hybrid model, in which one might encourage genotype 1 HCV–infected patients to start treatment with sofosbuvir plus peginterferon/ribavirin, since this offers the highest current SVR rates, but if patients have a difficult time tolerating peginterferon, one might discontinue peginterferon if necessary and continue therapy with an all-oral peginterferon-free regimen. References 1. Lawitz E, Ghalib R, Rodriguez-Torres M, et al. Suppression of viral load through 4 weeks post-treatment results of a once-daily regimen of simeprevir + sofosbuvir with or without ribavirin in hepatitis C virus GT 1 null responders. Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; Atlanta, Georgia; March 3-6, Abstract 155LB. 2. Osinusi A, Bon D, Herrmann E, et al. High efficacy of sofosbuvir with weight-based ribavirin for 24 weeks in difficult-to-treat patients. Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; Atlanta, Georgia; March 3-6, Abstract 157LB. 1. Lawitz E, et al. EASL Abstract Gane E, et al. EASL Abstract Nelson D, et al. EASL Abstract Jacobson I, et al. EASL Abstract 61.

41 Sofosbuvir + RBV ± PegIFN Post Trasplante hepático:
69% con RVS 4; 56% RVS12 2/36 recayeron 1/36 no respondieron 8/36 murieron 64% con mejoría de la descompensación 11% se estabilizaron 100 80 74 69 56 60 SVR4 (%) 40 HCV, hepatitis C virus; LT, liver transplantation; PegIFN, peginterferon; RBV, ribavirin; SOF, sofosbuvir; SVR4 or 12, sustained virologic response 4 or 12 weeks posttreatment. And what about sofosbuvir in the posttransplant setting? Well, this study shows sofosbuvir combined with ribavirin, with or without interferon, and that was at the discretion of the investigator in patients after liver transplant. And what you can see is that in these patients, many of whom had very severe recurrence of their HCV posttransplant, you can see that these regimens did quite well, with sofosbuvir and ribavirin alone leading to SVR in 74%, whereas 56% achieved SVR with sofosbuvir with peginterferon and ribavirin. But of course these were likely slightly harder patients to treat because the interferon was given at the discretion of the investigator. Importantly though, almost two thirds of these patients improved their decompensating events and an additional 11% showed stabilization. So this really looks like it seems to be a fairly effective therapy postliver transplant, and there have been studies, as well, showing, even in patients with less severe recurrence, that sofosbuvir and ribavirin alone is an effective regimen. 20 n/N = 25/36 20/27 5/9 Todos SOF + RBV SOF + PegIFN/RBV Forns X, et al. AASLD Abstract 1084.

42 CO-INFECTADOS TX CON SOFOSBUVIR Y RIBA
PHOTON-1[1] SOF + RBV efectivo con diferentes tratamamiento anti retrovirales Estudio piloto: 91% RVS con SOF + P/R por 12 semanas en HCV GT1-4[2] STARTverso4: FDV + P/R en GT1[3] Evaluatdo con múltiples dosis usando RGT en semanas SVR4 y EA SIMILARES a pts monoifectados con VHC tratados con FDV + P/R C212: SMV + P/R en GT1[4,5] SMV 150 mg QD + P/R por 12 semanas SVR and AEs similar a pts monoinfectedos EFECTOS ADVERSOS MUCHO MENORES QUE CON AVD DE PRIMERA GENERACION GT1: SOF+ RBV por 24 semanas GT2: SOF + RBV por 12 semanas GT3: SOF + RBV por 12 semanas 100 88 80 76 67 60 SVR12 (%) AE, adverse event; ART, antiretroviral therapy; DDI, drug-drug interaction; FDV, faldaprevir; GT, genotype; HCV, hepatitis C virus; PI, protease inhibitor; P/R, peginterferon/ribavirin; QD, once daily; RBV, ribavirin; RGT, response-guided therapy; SMV, simeprevir; SOF, sofosbuvir; SVR 4 or 12, sustained virologic response 4 or 12 weeks posttreatment. Now what about the HIV data? Just to summarize some overall principles: In coinfected patients, if we look at sofosbuvir combined with ribavirin for either 24 weeks in genotype 1 or 12 weeks in patients with genotypes 2 and 3, you see very high SVR rates, very similar to what was observed in patients with HCV monoinfection. And you can see that this regimen was effective across several genotypes, and, importantly with sofosbuvir, because of the very good drug interaction profile of this agent, patients were able to be suppressed on a variety of different antiretroviral regimens. In addition to sofosbuvir, the second-generation protease inhibitors faldaprevir and simeprevir have also both been studied in HIV coinfected patients and, interestingly, have yielded similar SVR rates to those found in monoinfected patients. Although there have been some issues with drug interactions, however, significantly fewer than seen with the first-generation PIs. And I think the overall conclusion from this is that the coinfected patients are starting to look a lot more like monoinfected patients. 40 20 87/ 114 23/ 26 28/ 42 n/N = 1. Sulkowski M, et al. AASLD Abstract Rodriguez-Torres M, et al. IDSA Abstract Rockstroh JK, et al. AASLD Abstract Dieterich D, et al. EACS Abstract LBPS9/5. 5. Jacobson I, et al. EASL Abstract 1425.

43 Response-Guided Treatment
Simeprevir + P/R in GT1, Tx-Naive Patients: QUEST-1/2 Phase III Trial Design Response-Guided Treatment SMV 150 mg QD + P/R P/R P/R N = 521* Placebo + P/R P/R P/R N = 264† Wk 12 24 48 72 RGT in simeprevir arm: if HCV RNA < 25 IU/mL at Wk 4 and undetectable at Wk 12, complete treatment at Wk 24; otherwise, continue treatment to Wk 48 Stopping rules If HCV RNA > 1000 IU/mL Wk 4, stop SMV/placebo If HCV RNA < 2 log10 IU/mL reduction at Wk 12, or confirmed > 25 IU/mL at Wk 24 or 36, stop all treatment GT, genotype; P/R, peginterferon alfa-2a 180 µg/wk + ribavirin mg/day; QD, every day; RGT, response-guided treatment; SMV, simeprevir; Tx, treatment. *QUEST-1: n = 264; QUEST-2: n = 257. †QUEST-1: n = 130; QUEST-2: n = 134. Jacobson I, et al. EASL Abstract Manns M, et al. EASL Abstract 1413.

44 Simeprevir + P/R: Phase III QUEST-1: Impact of Subtype & Fibrosis Stage in GT1
Overall GT1a GT1b F0-F F F4 100 90 100 83 80 78 80 71 80 58 60 60 52 60 50 49 SVR (%) 40 40 26 29 20 20 GT, genotype; P/R, peginterferon/ribavirin; SVR, sustained virologic response. Simeprevir P/R Simeprevir P/R SVR: GT1b > GT1a SVR is lowest for patients with GT1a and baseline Q80K mutation SVR: F0-F2 > F4 Jacobson I, et al. EASL Abstract 1425.

45 Simeprevir en pacientes previamente tratados Estudios fase II
SMV + P/R x 12 sem+ P/R 36 sem P/R x 48 sem 100 85 80 70 60 SVR24 (%) 45 37 40 FDA, US Food and Drug Administration; P/R, peginterferon/ribavirin; SMV, simeprevir; SVR24, sustained virologic response 24 weeks posttreatment. And finally, just showing you the data supporting the extension of therapy to treatment-experienced patients. You can see these are phase II results. Looking at prior relapsers, you can see that the SVR achieved was 85%—similar, in fact slightly better than treatment-naive patients, justifying lumping them together—whereas with prior partial responders or prior null responders, as with the first generation PIs, the SVR rate drops off and that’s why it’s recommended to extend therapy for a full 48 weeks. 3/ 16 19 20 9 45/ 53 10/ 27 32/ 46 2/23 15/ 33 Recaídas Respondedor Parcial Respondedor Nulo FDA incluyo la indicación para repondedores parciales y nulos Simeprevir FDA Hearing. October 24, 2013.

46 COSMOS: Simeprevir + Sofosbuvir ± RBV in GT1 HCV: Phase IIa Study Design
4 12 24 36 48 Wk Arm 1 SMV + SOF + RBV Posttreatment follow-up Arm 2 SMV + SOF Posttreatment follow-up Enrolment ratio 2:1:2:1 Arm 3 SMV + SOF + RBV Posttreatment follow-up Arm 4 SMV + SOF Posttreatment follow-up GT, genotype; HCV, hepatitis C virus; QD, every day; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir. Cohort 1: previous null responders (METAVIR F0-F2) Cohort 2: treatment naive and previous null responders (METAVIR F3-F4) SMV 150 mg QD + SOF 400 mg QD ± RBV 1000/1200 mg/day Jacobson I, et al. AASLD Abstract LB-3. Lawitz, et al. EASL Abstract 165.

47 Cohort 2 (F3-F4 vírgenes y nulos)*[2]
COSMOS: SVR12 en Cohortes 1 y 2 de acuerdo al subgenotipo de VHC y del polimorfismo basal Q80K SVR12 (%) GT1b GT1a sin Q80K GT1a con Q80K Cohort 1 (F0-F2 Nulos)*[1] Cohort 2 (F3-F4 vírgenes y nulos)*[2] 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 93 95 96 89 89 89 88 88 83 80 60 40 GT, genotype; HCV, hepatitis C virus; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR, sustained virologic response. 20 4/ 4 7/ 7 8/ 9 3/ 3 7/ 7 3/ 3 6/ 6 12/ 12 8/ 9 4/ 4 4/ 4 5/ 6 7/ 17 30/30 24/27 6/ 6 11/ 11 11/ 11 4/ 4 7/ 7 4/ 4 5/ 5 13/ 14 7/ 8 3/ 3 7/ 8 3/ 3 18/ 18 38/ 40 25/ 26 SMV/SOF + RBV SMV/SOF SMV/SOF+ RBV SMV/SOF SMV/SOF ± RBV SMV/SOF + RBV SMV/SOF SMV/SOF + RBV SMV/SOF SMV/SOF ± RBV 24 semanas 12 semanas Todos 24 semanas 12 semanas Todos *Excluyeron pacientes que suspendieron tratamiento por razones no virológicas. 1. Sulkowski M, et al. EASL Abstract O7. 2. Lawitz E, et al. EASL Abstract O165.

48 Adverse Effects of New Therapies
PegIFN/RBV: well-established AE profiles Sofosbuvir[1-3] Mild fatigue Mild headache Simeprevir[4,5] Mild, reversible hyperbilirubinemia Due to transporter inhibition and not associated with hepatotoxicity Mild photosensitivity AE, adverse effect; PegIFN/RBV, peginterferon/ribavirin. 1. Lawitz E, et al. N Engl J Med. 2013;368: Jacobson I, et al. AASLD Abstract LB Sofosbuvir [package insert]. 4. Fried MW, et al. Hepatology. 2013;58: Simeprevir [package insert].

49 Multiple Classes of Direct-Acting Antiviral Agents
5’UTR Core E1 E2 NS2 NS3 NS4B NS5A NS5B 3’UTR p7 Protease Polymerase Ribavirin NS3 Protease Inhibitors NS5A Replication Complex Inhibitors NS5B NUC Inhibitors NS5B Non-NUC Inhibitors Telaprevir Boceprevir Simeprevir Asunaprevir ABT-450 MK-5172 Faldaprevir Sovaprevir ACH-2684 Daclatasvir Ledipasvir Ombitasvir MK-8742 GS-5885 GS-5816 ACH-3102 PPI-668 GSK Samatasvir Sofosbuvir VX-135 IDX21437 ACH-3422 Dasabuvir BMS PPI-383 GS-9669 TMC647055 NUC, nucleotide analogue. *Representative list; may not be fully inclusive.

50 THE CURRENT COST OF A 12-WEEK
REGIMEN OF SOFOSBUVIR ALONE IS $84,000, OR $1,000 PER TABLET

51

52

53

54 2013 2014

55 Medicamentos Próximamente Disponibles Genotipes 1, 4, 5, and 6

56 HARVONI Ion-1-2 Viekira PakI Sapphire1-2 Turquoise

57 ION-2[3] Treatment-experienced HCV GT1; 20% cirrhotics (N = 440)
Phase III Studies of SOF/LDV(LEDIPASVIR) FDC ± RBV for 12 or 24 Wks in GT1 Patients Wk 12 Wk 24 SVR12, % 99 97 98 SOF/LDV (n = 214) ION-1[1,2] Treatment-naive HCV GT1; cirrhosis in 15% to 17% per arm (N = 865) SOF/LDV + RBV (n = 217) SOF/LDV (n = 217) SOF/LDV + RBV (n = 217) Wk 12 Wk 24 94 96 99 SOF/LDV (n = 109) ION-2[3] Treatment-experienced HCV GT1; 20% cirrhotics (N = 440) GT, genotype; FDC, fixed-dose combination; HCV, hepatitis C virus; RBV, ribavirin; SOF/LDV, sofosbuvir/ledipasvir; SVR, sustained virologic response. SOF/LDV + RBV (n = 111) SOF/LDV (n = 109) SOF/LDV + RBV (n = 111) ION-1,2: No difference in outcomes according to cirrhosis status, type of treatment failure 1. Mangia A, et al. EASL Abstract O Afdhal N, et al. N Engl J Med. 2014;370: Afdhal N, et al. N Engl J Med. 2014;370:

58 Treatment-naive, noncirrhotic pts with HCV GT1 (N = 647)
ION-3: Phase III Study of SOF/LDV FDC ± RBV for 8-12 Wks in Tx-Naive Noncirrhotic GT1 Patients Wk 8 Wk 12 SVR12, % SOF/LDV (n = 215) 94 93 95 Treatment-naive, noncirrhotic pts with HCV GT1 (N = 647) SOF/LDV + RBV (n = 216) SOF/LDV (n = 216) GT, genotype; FDC, fixed-dose combination; HCV, hepatitis C virus; RBV, ribavirin; SOF/LDV, sofosbuvir/ledipasvir; SVR, sustained virologic response; Tx, treatment. Kowdley KV, et al. N Engl J Med. 2014;

59 ION 1: efectos adversos Efectos adversos, n (%) 12 semanas 24 semanas
SOF/LDV (n = 214) SOF/LDV + RBV (n = 217) EA total 169 (79) 185 (85) 178 (82) 200 (92) Grado 3/4 4 (2) 14 (6) 21 (10) 12 (6) EA significativos 1 (< 1) 7 (3) 18 (8) EA que llevaron a DC tx 6 (3) Alteraciones lab 10 (5) 22 (10) 27 (12) Hemoglobina < 10 g/dL 20 (9) 16 (7) Hemoglobina < 8.5 g/dL AE, adverse event; LDV, ledipasvir; RBV, ribavirin; SOF, sofosbuvir. Mangia A, et al. EASL Abstract 164. Afdhal N, et al. N Engl J Med. 2014;[Epub ahead of print].

60 Pts co-infectados con HCV GT1 y HIV (N = 50)
ERADICATE: SOF/LDV en pacientes co-infectados HCV/HIV con/sin tx anti-retroviral Estudio fase II (Un brazo) ARV en 37 pts tratados ARV: efavirenz (41%), raltegravir (27%), rilpivirine (21%), rilpivirine and raltegravir (8%), efavirenz/raltegravir (3%). Cuenta basal de CD4: tratados con ARV 576 cells/mm3 ( ). Pacientes sin tx ARV 687 cells/mm3 ( ) SVR12 en pts tratados: 100% No se observaron cambios significativos en HIV-1 RNA o en cuenta de CD4+ SOF/LDV bien tolerado, no se suspendió tx en ningún paciente ni se observaros EA grado 4 AE AE, adverse event; ARV, antiretroviral; FDC, fixed-dose combination; GT, genotype; HCV, hepatitis C virus; LDV, ledipasvir; SOF, sofosbuvir; SVR, sustained virologic response. Semana 12 Pts co-infectados con HCV GT1 y HIV (N = 50) SOF/LDV FDC Sofosbuvir/ledipasvir 400/90 mg (una tableta diaria) Osinusi A, et al. EASL Abstract O14

61 Treatment-naive noncirrhotic pts with HCV GT1[1,2] (N = 631)
SAPPHIRE I & II: Phase III Studies of ABT-450/RTV/Ombitasvir (NS5A) + Dasabuvir (NNI) + RBV in Noncirrhotic GT1 Pts Wk 12 SVR12, % SAPPHIRE-I Treatment-naive noncirrhotic pts with HCV GT1[1,2] (N = 631) ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 473) 96 Placebo (n = 158)* SAPPHIRE-II Treatment-experienced noncirrhotic pts with HCV GT1[3,4] (N = 394) ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 297) Placebo (n = 97) GT, genotype; HCV, hepatitis C virus; NNI, nonnucleoside inhibitor; RBV, ribavirin; RTV, ritonavir; SVR, sustained virologic response. SAPPHIRE: no difference in outcomes according to 1a/1b subtype, type of treatment failure *Placebo recipients crossed over to active treatment regimen at Wk 12. 1. Feld JJ, et al. EASL Abstract O60. Reproduced with permission. 2. Feld JJ, et al. N Engl J Med. 2014;370: Zeuzem S, et al. EASL Abstract O1. 4. Zeuzem S, et al. N Engl J Med. 2014;370:

62 Viekira Pak  TURQUOISE II: Phase III Study of ABT-450/RTV/Ombitasvir (NS5A) + Dasabuvir (NNI) + RBV in Cirrhotic GT1 Patients Wk 12 Wk 24 SVR12, % ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 208) DAA-naive cirrhotic pts with HCV GT1; 58% of patients were treatment experienced, and 36% were previous null responders (N = 380) 92 96 ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 172) DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; NNI, non-nucleoside inhibitor; RBV, ribavirin; RTV, ritonavir; SVR, sustained virologic response. No significant difference in 12 vs 24 wks; high SVR in all subgroups analyzed ABT-450/RTV/ombitasvir 150/100/25 mg once daily; dasabuvir 250 mg twice daily; RBV mg/day. Poordad F, et al. N Engl J Med. 2014;370:

63 TURQUOISE II: RVS 12 3 AVD + RBV en Cirroticos
GT1a 12 Sem GT1b 93.3 100 100 100 92.9 92.2 92.9 24 Sem 100 100 100 100 85.7 100 100 100 100 100 80.0 80 80 60 60 SVR12 (%) 40 40 20 DAA, direct-acting antiviral; GT, genotype; HCV, hepatitis C virus; RBV, ribavirin; SVR, sustained virologic response. 20 59/64 52/56 14/15 13/ 13 11/11 10/10 40/50 39/42 22/22 18/18 25/25 20/20 6/7 3/3 14/14 10/10 Virgenes Recaída Parcial Nula Vírgenes Recaída Parcial Nula Falla Virológica en 17/380 (4.5%); recaídas más frecuentes en 12-sem vs 24-sem (12 vs 1 pt), 7/12 recaídas a las 12 sem fueron en respondedores nulos con GT1a Poordad F, et al. EASL Abstract 163

64

65 Ribavirin-Free Therapy in GT1b
Wk 12 SVR12, % PEARL-II[1] ABT450/RTV/Ombitasvir + Dasabuvir (n = 95) 100 GT1b Tx Experienced ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 91) 97 PEARL-III[2] ABT450/RTV/Ombitasvir + Dasabuvir (n = 209) 99 GT1b Tx Naive ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 210) 99 GT, genotype; RBV, ribavirin; RTV, ritonavir; SVR, sustained virologic response; Tx, treatment. PEARL-IV[2] ABT450/RTV/Ombitasvir + Dasabuvir (n = 205) 90 GT1a Tx Naive ABT450/RTV/Ombitasvir + Dasabuvir + RBV (n = 100) 97 1. Andreone P, et al. Gastroenterology. 2014;[Epub ahead of print]. 2. Ferenci P, et al. N Engl J Med ;370:

66 HALLMARK-DUAL: Daclatasvir + Asunaprevir in Pts con vhc GT1b HCV
AI : Estudio aleatorizado doble ciego fase III Semana 12 Semana 24 VHC GT1b Daclatasvir + Asunaprevir (n = 203) Vírgenes a tratamiento (N = 305) Placebo* (n = 102) Respondedores nulos o parciales (N = 205) Daclatasvir + Asunaprevir (n = 205) GT, genotype; HCV, hepatitis C virus. Intolerantes/no elegibles a Interferon(N = 235) Daclatasvir + Asunaprevir (n = 235) Daclatasvir 60 mg/día; asunaprevir 100 mg dos veces al día. *Pts en placebo recibierón tx en otro estudio después de 12 semanas. Manns M, et al. EASL Abstract O166.

67 HALLMARK-DUAL: RVS12 con Daclatasvir + Asunaprevir en VHC GT1b
SVR12, % (n/N) Daclatasvir + Asunaprevir Vírgenes a tratamiento 90 (182/203) Respondedores nulos 82 (98/119) Respondedores parciales 81 (68/84) Intolerantes/no elegibles a IFN (192/235) Fibrosis/cirrosis con trombocitopenia 73 (56/77) GT, genotype; HCV, hepatitis C virus; IFN, interferon; SVR, sustained virologic response. Resurgimiento viral: 9 (4%) en vírgenes a tx, 26 (13%) no respondedores, 20 (9%) Intolerantes/no elegibles a IFN Recaída: 5 (3%) en vírgenes 7 (4%) no respondedores, 12 (6%) Intolerantes/no elegibles a IFN RVS 12 en 28 / 73 patients con NS5A-L31 y/o variante Y93 al inicio de tx Manns M, et al. EASL Abstract O166.

68 FISSION, POSITRON, and VALENCE
FISSION, POSITRON, and VALENCE. (Lawitz, 2013a); (Jacobson, 2013c); (Zeuzem, 2013c) PROTON, ELECTRON

69

70 ALLY-3: SOF + DCV x 12 Wks in Tx-Naive and Tx-Experienced Pts With GT3 HCV
N = 152 pts with GT3 HCV 66% tx naive, 34% experienced 19% of tx-naive pts and 25% of tx-experienced pts had cirrhosis 61% of tx-experienced pts relapsed on previous therapy, 14% had null response 1 SAE, grade 3/4 lab abnormalities in 2% of pts No cirrhosis Cirrhosis 96 97 94 100 69 63 58 80 60 DCV, daclatasvir; GT, genotype; HCV, hepatitis C virus; SAE, serious adverse event; SOF, sofosbuvir; SVR, sustained virologic response; Tx, treatment. At AASLD this year, an alternative approach was taken to genotype 3. Here, sofosbuvir in combination with an NS5A inhibitor daclatasvir, which we spoke about earlier, for genotype 1, but also has potent activity against genotype 3 in vitro was used for 12 weeks without ribavirin in treatment-naive and treatment-experienced patients with genotype 3 hepatitis C. There were 152 patients in this study, of whom two thirds were naive and one third were experienced, 19% of the naive and 25% of the experienced patients had cirrhosis, and the majority of the experienced patients had relapsed on previous therapy but a few had, had a null response. The treatment was well tolerated and successful. How did it do? Well overall, the SVR rate in the noncirrhotic population was excellent. It didn’t matter whether you were treatment naive and treatment experienced; the treatment-naive patients had a 97% sustained response rate. However, when you look at the patients who had cirrhosis, we do not see such a good response. What we saw overall was a response in cirrhotic patients of 63% and low in both the treatment-naive and treatment-experienced group. I think we can look at this and say certainly sofosbuvir and daclatasvir for 12 weeks is very good in noncirrhotic genotype 3 patients but genotype 3 cirrhosis still represents a challenge. SVR12 (%) 40 20 Overall Tx Naive Tx Experienced Nelson DR, et al. AASLD Abstract LB-3.

71 C-WORTHY: MK-5172 + MK-8742 ± RBV in GT1 Patients With Cirrhosis and in Null Responders
Wk 12 Wk 18 SVR4/8, % MK MK RBV (n = 31) 90 97 94 91 100 Treatment-naive patients with GT1 HCV and cirrhosis (N = 123) MK MK-8742 (n = 29) MK MK RBV (n = 32) MK MK-8742 (n = 31) MK MK RBV (n = 31) GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. Patients with GT1 HCV and null response to pegIFN/RBV (N = 130) MK MK-8742 (n = 33) MK MK RBV (n = 33) MK MK-8742 (n = 32) MK mg once daily; MK mg once daily, RBV mg divided twice daily. Lawitz E, et al. EASL Abstract O61.

72 Requerimientos de una terapia ideal para virus de hepatitis C
RVS > 90% Baja toxicidad Tolerabilidad Debe de tener Corta duración Barrera alta a resistencias Helpful HCV, hepatitis C virus; SVR, sustained virologic response. To make an improvement on, this we need several specific requirements for HCV therapy moving forward. What we need, and must have, are SVR rates above 90% with limited and preferably no toxicity resulting in excellent tolerability. This is our number one goal—safe, effective and successful treatments. It would be helpful to have treatments of shorter duration, those that have a high barrier to resistance, so patients that fail do not fail with multidrug resistance. And it would be very nice to have a one-size-fits-all treatment, one that is so-called pan-genotypic and easy to administer. A nice bonus of treatment would be if there were no issues with drug–drug interactions and a low pill burden. But these are absolutely not essential. Tratamiento pangenotípico Sin interacción con otras drogas Pocas pastillas Nice bonus

73 Historically “Hard-to-Treat” Pts and Special Populations
Cirrhosis pts Compensated Decompensated Cirrhosis with HCC Treatment failure pts with GT3 HCV (pegIFN/RBV ± DAA) Posttransplant HCV HCV/HIV-coinfected individuals DAA, direct-acting antiviral; GT, genotype; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin. Let’s talk about these historically hard-to-treat patients. Really what we have seen is that cirrhosis patients in the past were difficult to treat, compensated cirrhosis was treated quite frequently in the interferon-based era, but many decompensation patients were actually not candidates for interferon-based therapy. We rarely ventured into the area of patients with cirrhosis and liver cancer. We have also seen recently that genotype 3 has become a more hard-to-treat patient. In particular, patients who are prior failures of pegylated interferon and ribavirin, where these patients are being retreated sometimes with, again, interferon-based therapy, but also with direct-acting antivirals and having some difficulty in achieving those sustained viral response rates we want, above 90%. Patients who are posttransplant have represented a challenge for 2 reasons: 1) the response rate in immunosuppressed patients has been lower than in patients with normal immune function, and 2) drug–drug interactions have made treatment and tolerability of drugs in this population quite difficult. Finally, historically, coinfected patients with both hepatitis C and HIV have also been difficult to treat.

74 Conclusiones Existen alternativas orales nuevas disponibles en los próximos meses (años) Esquemas duales o triples 90%+ RVS Dudas sobre papel de Ribavirina y duración tx en subtipos de VHC Duración de Tratamiento 12 semanas vs 8 sem. Bien tolerado. Poco efecto secundario. Beneficio población con cirrosis establecida COSMOS II DAA, direct-acting antiviral; IFN, interferon; PI, protease inhibitor; RBV, ribavirin; SVR, sustained virologic response.