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18 Dicembre 2012Inibitori delle proteasi di HCV  di I generazione: sono una       reale innovazione?                Antoni...
Epidemiology of Hepatitis C in Europe                                                          Time trends incidence   • 9...
Map of estimated anti-HCV seroprevalence             by GBD region, 2005Hanafiah et al, Hepatology in press
Treatment of Hepatitis C: Evidence for    Effectiveness in SVR Patients     1. Durable HCV-RNA eradication achievable     ...
Accessibility to Peg-IFN antiviral therapy in                                        different European countries         ...
Effect of treatment strategy* according to fibrosisstage on HCV-related cirrhosis and deaths†                             ...
Milestones in Therapy of Genotype 1 HCV                                                                                  D...
Naive patients                       Increased SVR compared to Peg-IFN/RBV              Boceprevir                        ...
Treatment-experienced patients                          Increased SVR compared to Peg-IFN/RBV                Boceprevir   ...
Chance for Cure in HCV 1. The Impact of Triple Therapy                 A Systematic Review        Patients                ...
Number of Patients Ever Treated With PEG IFNs   per 100 Prevalent HCV Cases until End of 2005         Patients ever treate...
Treatment of HCV genotype 1 in Italy:               the current situation∀ ∼ 7000 patients HCV Gt 1 patients treated each ...
HCV-AIFA Italian study: RVR and SRV to P/R in        genotype 1 patients according to baseline factors                    ...
The balance of triple therapy with          boceprevir and telaprevir           Advantages                             Dis...
Addition of BOC or TVR to PegIFN/RBV  Improves SVR in Genotype 1 Patients          BOC and TVR each indicated in combinat...
Response-Guided Therapy
RGT Paradigm With BOC + PegIFN/RBV in Tx-Naive Patients  Indicated for all noncirrhotic treatment-naive patients         ...
Response-Guided Therapy Paradigm With BOC + PegIFN/RBV in Tx-Exp Patients  Indicated for noncirrhotic previous relapsers ...
RGT With TVR + PegIFN/RBV in Tx-Naive Patients and Previous Relapsers        Indicated for all noncirrhotic treatment-nai...
Futility Rules for BOC or TVR + PegIFN/RBV in Tx-Naive and Tx-Exp’d Pts  All therapy should be discontinued in patients w...
Use of HCV RNA Assays in ManagingPatients Receiving BOC or TVR A quantitative assay with an LLOQ of ≤ 25 IU/mL and an  LL...
Adverse Events
BOC Plus PegIFN alfa-2b/RBV: Adverse Events  Higher rates of anemia, neutropenia, and dysgeusia in   BOC arms vs control ...
TVR Plus PegIFN alfa-2a/RBV: Adverse Events  Higher rates of rash, anemia, and anorectal signs and   symptoms in TVR arms...
Cirrhotic Patients
Treatment regimen                                       Interim analysisPeg-IFN+ RBV                      BOC + Peg-IFN α-...
Telaprevir: baseline characteristics                                             Telaprevir                               ...
Telaprevir: baseline characteristics                                               Telaprevir                             ...
Telaprevir: week 16 safety findingsPatients, n (% patients with at least one event)                     Telaprevir        ...
Telaprevir: week 16 safety findingsPatients, n (% patients with at least one event)                    Telaprevir         ...
Boceprevir: baseline characteristics                                         Boceprevir                                   ...
Boceprevir: baseline characteristics                                              Boceprevir                              ...
Boceprevir: week 16 safety findingsPatients, n (% patients with at least one event)                      Boceprevir       ...
Boceprevir: week 16 safety findingsPatients, n (% patients with at least one event)                    Boceprevir         ...
Multivariate analysis: baseline predictors          of severe complications*Predictors                         OR         ...
Multivariate analysis: predictors of    anemia <8g/dL or blood transfusion *Predictors            OR      95%CI       p-va...
Telaprevir: week 16 efficacy data                                                                                         ...
Telaprevir: Week 16 efficacy according                       to prior treatment response (ITT)                            ...
Boceprevir: week 16 efficacy data                                                                                         ...
Boceprevir: Week 16 efficacy according   to prior treatment response (ITT)  80               P=0.001               69%  70...
Rationale for Prompt Treatment of HCV HCV is a progressive disease, associated with persistence  of viral replication and...
Indications for Treatment of ChronicHCV Infection All patients, regardless of the degree of fibrosis, are  potential cand...
Who Should Be Treated Now?Pts Who Want Tx           Pts Who Are                Pts Who AreWant to be cured of     Eligibl...
Severity of Disease Increases Need forHCV Therapy but Also Impairs Response May not need immediate  treatment            ...
What Are the Chances of Being Cured WithCurrent Therapy?  Black  Cirrhosis  Genotype 1                             Whi...
Limitations of Current Regimens andProspects for Future RegimensCurrent                                FutureMust be elig...
Challenging Patients for Whom TreatmentWith Current Options Less Than Optimal Cirrhosis (all genotypes)     Injection-dr...
Cumulative Incidence of Liver-Related Complications Following SVR in Cirrhosis                                            ...
SVR to Telaprevir in Treatment-Naive Pts   With GT1 HCV and Compensated   Cirrhosis          ADVANCE            ILLUMINATE...
CUPIC: Efficacy of TVR in Cirrhotics  ~ 80% of patients treated with TVR-based therapy had   undetectable HCV RNA at end ...
CUPIC: Efficacy of Boceprevir in Cirrhotics  ~ 60% of patients treated with BOC-based therapy had   undetectable HCV RNA ...
The First-Generation Protease Inhibitors:Where Are We Now? Telaprevir and boceprevir are harbingers of important treatmen...
Factors That InfluenceOutcomes With HCV Therapy
SPRINT-2: Influence of Baseline Patient     and Virus Factors on SVR With BOC                                             ...
ADVANCE: Influence of Baseline Patient    and Virus Factors on SVR With TVR     Data from TVR12 + pegIFN-α2a/RBV arm only...
IL28B Genotype Predicts Likelihood of Eligibility for Shortened Therapy                                      SPRINT-2: BOC...
IL28B Genotype Should Not Be Used to Exclude Patients From Therapy  If patients have favorable CC genotype      – Likelih...
Lead-in Strategies
Lead-in Strategy Can Help DetermineWhom to Treat 4 wks of pegIFN/RBV lead-in before BOC (or TVR)   – Lowers HCV RNA burde...
Early IFN Response (Lead-in) Further Defines Likelihood of SVR for Non-CC Pts                                             ...
Preparing for Treatment:    Possibilities ofDrug–Drug Interactions
Both BOC and TVR Have Potential forMany Drug–Drug Interactions BOC                              TVR   – Strong inhibitor...
Medicines That Are Contraindicated With BOC and TVR Drug Class*                            Contraindicated With BOC[1]    ...
Preparing for Treatment:Management of Adverse Events
Adverse Effect Management: Anemia  Recommendation: anemia should be managed initially by   reducing the RBV dose[1]  Do ...
EPO and RBV Dose Reduction for Anemia Lead to Similar SVR Rates in BOC Patients    Nested study within randomized trial o...
Predictive Value of Anemia for SVR With BOC or TVR           In phase III trials, anemia positive predictor of SVR with B...
Adverse Effect Management:Rash and Anorectal Symptoms Rash management   – Mild to moderate rash can be treated with oral ...
Managing Major Adverse Effects ofPegIFN Depression   – Assess mood, sleep, suicidal thoughts   – Consider SSRI to treat b...
Helping Patients Adhere to ComplexRegimens PegIFN/RBV + BOC or TVR = very complex regimen   – BOC 800 mg TID: 12 pills/da...
Optimizing Current HCV Therapy   With PIs Plus PegIFN/RBV
Strategies to Enhance Current Therapy With PegIFN/RBV Plus PI for GT1 Pts  Shorter therapy may be possible for certain pa...
NAIVES: RESULTS (SVR)Universal treatment   SVR %   ICER ( €)  • BOC-RGT            67.0    85,000  • TVR-RGT            74...
NAIVES: RESULTS (LYG)Universal treatment   LYG (yrs)   ICER ( €)  • BOC-RGT             3.75      13,400  • TVR-RGT       ...
ICER/LYG different clinical settingsICER = < 12.000 € triple therapy for naivesICER = 15.000 € Heart transplantationICER =...
Naives: key pointsTriple therapy with first-generation PIs in naïve Gt 1 CHC patients:• improves survival by about 4 years...
Re-treatment with P/R of treatment-experienced                   patients                                      FULL PAPERS...
Re-treatment with P/R plus a 1 st             generation PI   of treatment-experienced patientsPhase 3 RCTs (BOC: RESPOND-...
Cost-effectiveness of Boceprevir orTelaprevir for previously treated patients              with Gt 1 CHC      Competing st...
ICERs According to Profile of Previous                       Response and Severity of Liver Fibrosis               20000  ...
CAVEATS• Efficacy data from registration trials• Inconclusive data on cirrhosis• Aggregate rather than individual patient ...
Approval of triple therapy for reimbursement in Italy:   basic principles (presumably) followed by AIFA• Local disease epi...
Approval of triple therapy for reimbursement in Italy:   basic principles (presumably) followed by AIFA • IL28b status and...
Approval of triple therapy for reimbursement in Italy:        AIFA criteria for naive Gt 1 patients     Fibrosis     Tripl...
Approval of triple therapy for reimbursement in Italy:    AIFA criteria for treatment exp. Gt 1 patientsRR: relapsers; PR:...
Approval of triple therapy for reimbursement in Italy:                potential critical issue   • AIFA criteria are partl...
The Future of HCV Therapy
Investigational Agents for HCV                    Antiviral    Therapeutic      Host    Interferons                     ag...
Drugs in the HCV pipeline (November 2012)                                 Phase 2                                   Phase ...
Characteristics of HCV DAA classes Characteristic         Protease           Nucleos(t)ide      Non-nucleoside       NS5a ...
No cross resistance between classes:                 a combination of DAAs can eliminate RAVs                             ...
HCV therapy: hopes and hypes….• Interferon-free• >90% SVR• Once daily• High tolerability with low adverse event• Few drug-...
IL28B genotype has been associated with          viral kinetics during IFN-free therapyINFORM-1 : Mericitabine (NI) + dano...
Investigational HCV Regimens in Phase III Clinical Trials    •Regimens With 1 DAA                    •Regimens With 2 DAAs...
Interferon PlusDAA-Based Regimens
ASPIRE: Simeprevir (TMC435) 150 mg for 12, 24, 48 Wks + PR in Tx-Exp’d GT1 Pts  SVR24 rates according to previous respons...
ATOMIC: Sofosbuvir (GS-7977) Plus PR in Treatment-Naive GT1 Patients  Interim analysis of randomized, open-label phase II...
Interferon-Free Regimens
ELECTRON: Sofosbuvir and RBV in Naive and Experienced GT1 Patients                                                        ...
NIH SPARE: Interim Data on Sofosbuvir and RBV in Difficult-to-Treat GT1 Patients       Patients with poor prognostic indi...
Daclatasvir Plus Sofosbuvir ± RBV in Treatment-Naive GT1 or 2/3 Patients  No impact of RBV on viral response             ...
AVIATOR: IFN-Free Regimens With  ABT-450/RTV, ABT-267, ABT-333, and RBV  Phase II trial with 2 cohorts                    ...
Future Role of Interferon  What role may interferon play in future regimens?      – Preventing resistance?  For which se...
HCV: 2013-2020                0                      PEG/RBV                10                20                   PI+PEG+...
Inibitori delle proteasi di I generazione: sono una reale innovazione? - Gastrolearning®
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Inibitori delle proteasi di I generazione: sono una reale innovazione? - Prof. A. Craxì (Università di Palermo)
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  • DAA, direct-acting antiviral; HCV, hepatitis C virus; IFN, interferon; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response.
  • Milano Janssen 28 novembre 28.01.13
  • BOC, boceprevir; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir.
  • BOC, boceprevir; f/u, follow-up; pegIFN, peginterferon; PR, peginterferon/ribavirin; RBV, ribavirin; RGT, response-guided therapy; Tx, treatment.
  • BOC, boceprevir; f/u, follow-up; pegIFN, peginterferon; PR, peginterferon/ribavirin; RBV, ribavirin; RGT, response-guided therapy; Tx, treatment.
  • eRVR, early rapid virologic response; f/u, follow-up; pegIFN, peginterferon; PR, peginterferon/ribavirin; RBV, ribavirin; RGT, response-guided therapy; RVR, rapid virologic response; Tx, treatment.
  • BOC, boceprevir; pegIFN, peginterferon; RBV, ribavirin; TVR, telaprevir; Tx, treatment.
  • BOC, boceprevir; LLOD, lower limit of detection; LLOQ, lower limit of quantification; RGT, response-guided therapy; TVR, telaprevir.
  • BOC, boceprevir; PegIFN, peginterferon; PR, peginterferon/ribavirin; RBV, ribavirin; RGT response-guided therapy.
  • PegIFN, peginterferon; PR, peginterferon/ribavirin; RBV, ribavirin; RGT response-guided therapy; TVR, telaprevir.
  • HCV, hepatitis C virus; SVR, sustained virologic response.
  • HCV, hepatitis C virus; IFN, interferon.
  • pegIFN, peginterferon; RBV, ribavirin.
  • HCV, hepatitis C virus.
  • GT, genotype; IFN, interferon; pegIFN, peginterferon; PI, protease inhibitor; RBV, ribavirin; TID, 3 times daily.
  • HCV, hepatitis C virus; IV, intravenous; PI, protease inhibitor.
  • SVR, sustained virologic response.
  • eRVR, extended rapid virologic response; GT, genotype; SVR, sustained virologic response; PR, peginterferon/ribavirin; T, telaprevir.
  • HCV, hepatitis C virus; ITT, intent to treat; TVR, telaprevir.   For more information on this study, review the CCO Capsule Summary at: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Barcelona%202012/Tracks/Highlights%20From%20Barcelona/Capsules/8.aspx  
  • BOC, boceprevir; HCV, hepatitis C virus; ITT, intent to treat.   For more information on this study, review the CCO Capsule Summary at: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Barcelona%202012/Tracks/Highlights%20From%20Barcelona/Capsules/8.aspx  
  • SVR, sustained virologic response.
  • HCV, hepatitis C virus.
  • BOC, boceprevir; HCV, hepatitis C virus; p egIFN, peginterferon; RBV, ribavirin; RGT, response-guided therapy; SVR, sustained virologic response.
  • HCV, hepatitis C virus; p egIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir.
  • BOC, boceprevir; p egIFN, peginterferon; RBV, ribavirin; RGT, response-guided therapy; T, telaprevir.
  • p egIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir.
  • BOC, boceprevir; DAA, direct-acting antivirals; HCV, hepatitis C virus; IFN, interferon; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir.
  • BOC, boceprevir; IFN, interferon; p egIFN, peginterferon; RBV, ribavirin; RGT, response-guided therapy; SVR, sustained virologic response.
  • BOC, boceprevir; P-gp, P-glycoprotein; PI, protease inhibitor; TVR, telaprevir.
  • BOC, boceprevir; DRV, darunavir; EFV, efavirenz; FPV, fosamprenavir; GI, gastrointestinal; HTN, hypertension; LPV, lopinavir; N/A, not applicable; PI, protease inhibitor; RTV, ritonavir; TVR, telaprevir.
  • DAA, direct-acting antiviral; ESA, erythropoiesis-stimulating agents; Hb, hemoglobin; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin.
  • BOC, boceprevir; CI, confidence interval; DR, dose reduction; EPO, erythropoietin; HCV, hepatitis C virus; p egIFN, peginterferon; RBV, ribavirin; RGT, response-guided therapy; SVR, sustained virologic response.   For more information on this study, review the CCO Capsule Summary at: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Barcelona%202012/Tracks/Highlights%20From%20Barcelona/Capsules/1419.aspx    
  • BOC, boceprevir; DR, dose reduction; EOTR, end-of-treatment response; EPO, erythropoietin; Hb, hemoglobin; p egIFN, peginterferon; PR, peginterferon/ribavirin; RBV, ribavirin; RGT, response-guided therapy; SVR, sustained virologic response; T, telaprevir; TVR, telaprevir.
  • TVR, telaprevir.
  • CBC, complete blood count; GI, gastrointestinal; IFN, interferon; SSRI, selective serotonin reuptake inhibitor.  
  • BOC, boceprevir; EPO, erythropoietin; pegIFN, peginterferon; RBV, ribavirin; TID, 3 times daily; TVR, telaprevir.
  • HCV, hepatitis C virus; PegIFN, peginterferon; PI, protease inhibitor; RBV, ribavirin.
  • BID, twice daily; BOC, boceprevir; GT, genotype; PegIFN, peginterferon; PI, protease inhibitor; PR, peginterferon/ribavirin; RBV, ribavirin; T, telaprevir; TVR, telaprevir.
  • HCV, hepatitis C virus.
  • Cyp, cyclophilin; HCV, hepatitis C virus.
  • Key Point Cross-resistance does not occur between Peg-IFN/RBV and different classes of DAAs, and therefore combining multiple agents may provide an opportunity for elimination of DAA-resistant HCV variants. Notes Variants resistant to DAAs have shown to be susceptible to Peg-IFN/RBV, and combination therapy suppressed the emergence of variants in clinical trials. 1–9 Cross-resistance relates to mutations that confer resistance to more than one drug. Multiple DAAs are in development and can be classified according to which HCV moiety they bind to, and how/where they bind to it. Some examples include: NS3 protease inhibitors: macrocyclic (danoprevir, vaniprevir, TMC435, BI201335, and BMS-650032) or linear (telaprevir, boceprevir, ACH-1625 and GS 9256). NS5B polymerase inhibitors: Nucleoside (active site) inhibitors (RG7128, IDX184, INX-189 and PSI-7977) or non-nucleoside (allosteric) inhibitors. Non-nucleoside inhibitors: palm (ABT-333, ABT-072, GS 9190, ANA598 and IDX-375), thumb (VCH-759, VCH-916, VX-222, BI 207127 and filibuvir) or finger. NS5A inhibitors (BMS-790052, GS 5885 and PPI-461). Importantly, cross-resistance does not occur between DAA classes that have different mechanisms of action. Future HCV treatment regimens may include combinations of multiple classes of DAAs. References 1. Hézode C, et al. N Engl J Med 2009;360:1839–50. 2. Kwo P, et al. J Hepatol 2009;50(Suppl. 1):S4. 3. McHutchison JG, et al. N Engl J Med 2009;360:1827–38. 4. Sarrazin C, et al. J Hepatol 2009;50(Suppl. 1):S350. 5. Sarrazin C, et al. Gastroenterology 2007;132:1767–77. 6. Forestier N, et al. J Hepatol 2009;50(Suppl. 1):S35. 7. Manns MP, et al. Hepatology 2008;48(Suppl.):1133A. 8. Kieffer TL, et al. Hepatology 2007;46:631–9. 9. Forestier N, et al. Hepatology 2007;46:640–8.
  • BID, twice daily; Cyp, cyclophilin inhibitor; FDC, fixed-dose combination; NI, nucleoside NS5B inhibitor; NNI, nonnucleoside NS5B inhibitor; NS5A, replication complex inhibitor; pegIFN, peginterferon; PI, protease inhibitor; RBV, ribavirin; RTV, ritonavir; TVR, telaprevir.
  • DAA, direct-acting antiviral.
  • GT, genotype; pegIFN, peginterferon; PR, peginterferon/ribavirin; RBV, ribavirin; SVR, sustained virologic response; Tx, treatment.     For more information on this study, review the CCO Capsule Summary at: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Barcelona%202012/Tracks/Highlights%20From%20Barcelona/Capsules/2.aspx  
  • EOT, end of treatment; GT, genotype; HCV, hepatitis C virus; NA, not available; pegIFN, peginterferon; PR, peginterferon/ribavirin; QD, once daily; RBV, ribavirin; SVR, sustained virologic response.  
  • GT, genotype; IFN, interferon; RBV, ribavirin; SVR, sustained virologic response.
  • BMI, body mass index; EOT, end of treatment; GT, genotype; RBV, ribavirin; SVR, sustained virologic response.
  • GT, genotype; QD, once daily; RBV, ribavirin; SVR, sustained virologic response.
  • GT, genotype; HCV, hepatitis C virus; IFN, interferon; NR, not reported; RBV, ribavirin; RTV, ritonavir; SVR, sustained virologic response; Tx, treatment.
  • AE, adverse event; DAA, direct-acting antiviral; IFN, interferon; pegIFN, peginterferon.
  • Transcript of "Inibitori delle proteasi di I generazione: sono una reale innovazione? - Gastrolearning®"

    1. 1. 18 Dicembre 2012Inibitori delle proteasi di HCV di I generazione: sono una reale innovazione? Antonio Craxì Gastroenterologia & Epatologia, Di.Bi.M.I.S. Università di Palermo antonio.craxi@unipa.it
    2. 2. Epidemiology of Hepatitis C in Europe Time trends incidence • 9 million chronic carriers • 27,000 to 29,000 newly diagnosed cases per year • 86,000 deaths per year • Most affected age group: 25- 44 year, followed by 15-24 year • Clustered to sub-populationsVan de Laar, Hepatitis Summit Conference, Brussels 2010
    3. 3. Map of estimated anti-HCV seroprevalence by GBD region, 2005Hanafiah et al, Hepatology in press
    4. 4. Treatment of Hepatitis C: Evidence for Effectiveness in SVR Patients 1. Durable HCV-RNA eradication achievable 2. Histological reversal of cirrhosis documented 3. Reduced rates of decompensation and HCC 4. Reduced rates of liver-related mortality
    5. 5. Accessibility to Peg-IFN antiviral therapy in different European countries 4 16 HCV prevalence HCV prevalence rate (%) Treatment levels 14 Patients treated per 100 3 12 prevalent cases 10 2 8 6 1 4 2 0 0 Belgium France Germany Italy Spain UK There are substantial differences between European countries in terms of HCV prevalence and access to antiviral therapyPeg-IFN/RBV: peginterferon plus ribavirin Deuffic-Burban S, et al. Gastroenterology 2012;[ePub ahead of print]
    6. 6. Effect of treatment strategy* according to fibrosisstage on HCV-related cirrhosis and deaths† Cumulative HCV-related cirrhosis and deaths (95% CI) Treatment scenario Cirrhosis Deaths With treatment 330,700 282,300 (baseline scenario) (313,200–342,000) (268,600–294,200) Never treating patients 359,300 295,000 with F0/F1 (339,900–372,200) (280,700–307,700) Not treating F0/F1 332,200 282,700 until F2 is reached (314,600–343,600) (269,000–294,600) Not treating F0/F1 342,400 285,900 until F3 is reached (324,100–354,300) (272,100–298,000) • In comparison to the baseline scenario, delaying treatment in patients with F0/F1 is associated with an increase in HCV-related cirrhosis and deaths, regardless of the scenario • Delaying treatment until F2 is reached appears to be efficient in terms of mortality but will necessitate efficient diagnostic testing of fibrosis to detect progression from F0/F1 to F2*With Peg-IFN + RBV; †All genotypes Deuffic-Burban S, et al. Gastroenterology 2012 [Epub ahead of print]
    7. 7. Milestones in Therapy of Genotype 1 HCV Direct-acting antivirals 100 2011 Peginterferon 80 Ribavirin 2001 Standard 70+ interferon 1998 60 SVR (%) 55 1991 42 39 40 34 20 16 6 0 IFN IFN IFN/RBV IFN/RBV PegIFN PegIFN/ PegIFN/ RBV RBV/ 6 mos 12 mos 6 mos 12 mos 12 mos 12 mos DAAAdapted from US FDA Antiviral Drugs Advisory Committee Meeting; April 27-28, 2011; Silver Spring, MD.
    8. 8. Naive patients Increased SVR compared to Peg-IFN/RBV Boceprevir Telaprevir SVR increases from 38% to SVR increases from 44% to 63/66% 72/75% ( + 25-28%) (+ 28-31%) Sherman KE et al. Hepatology 2010; 52 (Suppl) : 401A.Poordad F et al. N Engl J Med 2011: 364: 1195-1206 Jacobson IM et al. Hepatology 2010; 52 (Suppl) : 427A.
    9. 9. Treatment-experienced patients Increased SVR compared to Peg-IFN/RBV Boceprevir Telaprevir Relapsers Relapsers SVR increases from 29% to 75% SVR increases from 24% to 83/88% Partial-Responders Partial-responders SVR increases from 7% to 52% SVR increases from 15% to 54-59% Null-responders SVR increases from 5% to 29/33%Bacon BR., et al. N Engl J Med 2011; 364:1207-1217. Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3
    10. 10. Chance for Cure in HCV 1. The Impact of Triple Therapy A Systematic Review Patients Dual Triple ∆ Pts # SVR Pts # SVRPreviously untreated 1545 39% 1634 <2-fold 68.5%Relapsers/Partial 539 26% 719 73% 3-foldResp.Nonresponders 255 7.5% 386 44% 6-foldJurchis AR et al. EASL 2012, Poster 1123 (S442)
    11. 11. Number of Patients Ever Treated With PEG IFNs per 100 Prevalent HCV Cases until End of 2005 Patients ever treated with Peg-IFNs per 100 prevalent casesLettmeier B et al, J Hepatol 2008;49:528-536
    12. 12. Treatment of HCV genotype 1 in Italy: the current situation∀ ∼ 7000 patients HCV Gt 1 patients treated each year (2008- 2011) with a 10% yearly trend to decrease (2010-2011): – Spontaneous change due to disease epidemiology – Warehousing effect (triple therapy  IFN-free)∀ ∼ ¼ of Gt 1 patients treated yearly (2008-2010) were re- treatments. This figure has decreased markedly in 2011 (warehousing for triple therapy)• Yearly expenditure (2011) for P/R: 165,000,000 Euros• Aging population of naives (mean age at tx 48 years) with 25- 30% of F3/F4 fibrosis• At least 20,000 patients with previous P/R failures (usually unclassified) with a mean age > 55 years and at least 40% of F3/F4 fibrosis
    13. 13. HCV-AIFA Italian study: RVR and SRV to P/R in genotype 1 patients according to baseline factors Variables N. of patients RVR SVR No favorable factors 21/179 (11.7%) 1/19 (5.2%) 3/21 (14.3%) 1 favorable factor 82/179 (45.8%) 17/80 (21.2%) 25/82 (30.5%)MALES 2 favorable factors 62/179 (34.6%) 25/58 (43.1%) 37/62 (59.6%) 3 favorable factors 14/179 (7.8%) 9/14 (64.3%) 12/14 (85.7%)Favorable factors: HCV-RNA < 400,000 UI/mlC/C genotype of rs12979860 SNPNo visceral obesity (VOB) Variables N. of patients RVR SVR No favorable factors 58/152 (38.1%) 8/57 (14.1%) 16/58 (27.6%) 1 favorable factor 75/152 (49.4%) 20/70 (28.6%) 26/75 (48.0%)FEMALES 2 favorable factors 19/152 (12.5%) 12/17 (70.1%) 16/19 (84.2%)Favorable factors: Age < 50 yearsC/C genotype of rs12979860 SNP
    14. 14. The balance of triple therapy with boceprevir and telaprevir Advantages Disadvantages  Not sufficiently tested in difficult First-generation protease inhibitors patients (cirrhosis) increase SVR rates in naive and  Modest potency with development treatment-experienced patients1,2 of resistance2,3 and may reduce liver-related morbidity and mortality in the long-  Genotype 1 restricted term1,2  Complex regimens, with risk of Potential for shorter poor adherence2 treatment duration1,2  Increased adverse reactions and toxicity burden2  Increased risk of DDIs2  Costs 1. Ghany MG, et al. Hepatology 2011; 54: 1433–44 2. Ferenci P & Reddy KR. Antivir Ther 2011; 16: 1187–1201 3. Pawlotsky J-M. Hepatology 2011; 53: 1742–51
    15. 15. Addition of BOC or TVR to PegIFN/RBV Improves SVR in Genotype 1 Patients  BOC and TVR each indicated in combination with pegIFN/RBV for genotype 1 HCV patients who are previously untreated or who have failed previous therapy 100 69-83 PegIFN + RBV 80 BOC/TVR + pegIFN* + RBV 63-75 40-59SVR (%) 60 38-44 29-40 40 24-29 20 7-15 5 0 Treatment Relapsers[3,4] Partial Null Naive[1,2] Responders[3,4] Responders[4,5] *BOC was administered with pegIFN-α2b; TVR was administered with pegIFN-α2a in these trials.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. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 4. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.5. Bronowicki JP, et al. EASL 2012. Abstract 11.
    16. 16. Response-Guided Therapy
    17. 17. RGT Paradigm With BOC + PegIFN/RBV in Tx-Naive Patients  Indicated for all noncirrhotic treatment-naive patients HCV RNA Undetectable < 100 IU/mL Undetectable PegIFN/ BOC + PegIFN/RBV Early response stop at Wk 28; f/u 24 wks RBV 0 4 8 12 24 28 36 48 HCV RNA Detectable < 100 IU/mL Undetectable Slow response extend triple therapy to Wk 36; PR to Wk 48; f/u 24 wks PegIFN/ BOC + PegIFN/RBV PegIFN/RBV RBV 0 4 8 12 24 28 36 48Boceprevir [US package insert]. July 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444.Boceprevir [EU package insert]. July 2012.
    18. 18. Response-Guided Therapy Paradigm With BOC + PegIFN/RBV in Tx-Exp Patients  Indicated for noncirrhotic previous relapsers or partial responders* [1,2] HCV RNA Undetectable < 100 IU/mL Undetectable PegIFN/ BOC + PegIFN/RBV Early response stop RBV at Wk 36; f/u 24 wks 0 4 8 12 24 28 36 48 HCV RNA Detectable < 100 IU/mL Undetectable Slow response PR to Wk 48; f/u 24 wks PegIFN/ BOC + PegIFN/RBV PegIFN/RBV RBV 0 4 8 12 24 28 36 48 *RGT for this group indicated in US only; European prescribing information indicates that noncirrhotic previous relapsers or partial responders should receive 4 wks of pegIFN/RBV followed by 32 wks of BOC + pegIFN/RBV and then 12 wks of pegIFN/RBV, regardless of early response. [3]1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Boceprevir [EU package insert]. July 2012.
    19. 19. RGT With TVR + PegIFN/RBV in Tx-Naive Patients and Previous Relapsers  Indicated for all noncirrhotic treatment-naive pts and previous relapsers*[1,3] HCV RNA Undetectable Undetectable Undetectable TVR + PegIFN/RBV PegIFN/RBV eRVR stop at Wk 24, f/u 24 wks 0 4 12 24 48 HCV RNA Detectable Undetectable or(≤ 1000 IU/mL) Undetectable detectable (≤ 1000 IU/mL) No eRVR extend pegIFN/ RBV to Wk 48; f/u 24 wks TVR + PegIFN/RBV PegIFN/RBV 0 4 12 24 48 *AASLD guidelines say RGT “may be considered” for previous partial responders but package inserts recommend [2] 48 wks of therapy.[1,3]1. Telaprevir [US package insert]. October 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Telaprevir [EU package insert]. March 2012.
    20. 20. Futility Rules for BOC or TVR + PegIFN/RBV in Tx-Naive and Tx-Exp’d Pts  All therapy should be discontinued in patients with the following: Boceprevir[1,2] Time Point Criteria* Action Wk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapy Wk 24 HCV RNA detectable Discontinue all therapy Telaprevir[2,3] Time Point Criteria* Action Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy Wk 24 HCV RNA detectable Discontinue pegIFN/RBV *Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA detection of approximately 10-15 IU/mL.1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Telaprevir [US package insert]. October 2012.
    21. 21. Use of HCV RNA Assays in ManagingPatients Receiving BOC or TVR A quantitative assay with an LLOQ of ≤ 25 IU/mL and an LLOD of approximately 10-15 IU/mL must be used HCV RNA undetectable* (“target not detected”) required to qualify for RGT – Detectable but < LLOQ is not equivalent to undetectable – Carefully read HCV RNA assay report to ensure HCV RNA was undetected or “target not detected” before truncating therapy*An assay with a LLOD of approximately 10-15 IU/mL must be used.
    22. 22. Adverse Events
    23. 23. BOC Plus PegIFN alfa-2b/RBV: Adverse Events  Higher rates of anemia, neutropenia, and dysgeusia in BOC arms vs control Adverse Event, % PR48 BOC + PR RGT/48* (n = 467) (n = 1225) Anemia* 30 50 Neutropenia 19 25 Dysgeusia 16 35 *Anemia was managed with RBV reduction and/or epoetin alfa (43% of BOC + PR and 24% of PR).Boceprevir [US package insert]. July 2012.
    24. 24. TVR Plus PegIFN alfa-2a/RBV: Adverse Events  Higher rates of rash, anemia, and anorectal signs and symptoms in TVR arms vs control Adverse Event, % PR48 TVR + PR RGT/48* (n = 493) (n = 1797) Rash 34 56 Anemia‡ 17 36 Anorectal events 7 29 *Pooled results from TVR arms. † Anemia was managed with RBV dose modification; epoetin alfa was not permitted.  In most subjects, rash was mild to moderate – Severe rash in 4%; discontinuation due to rash in 6% of subjectsTelaprevir [US package insert]. October 2012.
    25. 25. Cirrhotic Patients
    26. 26. Treatment regimen Interim analysisPeg-IFN+ RBV BOC + Peg-IFN α-2b + RBV Follow-up BOC: 800 mg/8h; Peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day TVR + Peg-IFN α-2a + RBV Peg-IFN α-2a + RBV Follow-up TVR: 750 mg/8h; Peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day0 4 8 12 16 36 48 72 Weeks SVR assessment http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdf http://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf
    27. 27. Telaprevir: baseline characteristics Telaprevir n=292Male, n (%) 197 (68)Mean age, range (years) 57.2 (27-83) 54Mean BMI, SD (kg/m2) 26.5 (4.1)Genotype 1b / 1a / other (%) 54 / 34 / 12HCV RNA >800,000 IU/mL, n (%) 181 (62)Mean Neutrophils, range (109/mm3) 3.3 (0.8-9.7)Mean Hemoglobin, range (g/dl) 14.6 (9.0-19.7) 15,6Mean Platelets, range (/mm3) 152,000 (18,000-604,000) 167000
    28. 28. Telaprevir: baseline characteristics Telaprevir n=292Mean Prothrombin Time, range (ratio) 86.3 (27-100)Mean Total Bilirubin, range (µmol/L) 15.4 (4.0-73.5)Mean Albumin, range (g/dL) 40.1 (20.7-52.0)Child-Pugh A / B (%) 98 / 2Mean MELD score, SD 8.1 (2.8)MELD score <10 / 10 - <13 / ≥13 (%) 81 / 13 / 6Esophageal varices (%) 33Realize / Respond-2 exclusion criteria (%) 33 / 46
    29. 29. Telaprevir: week 16 safety findingsPatients, n (% patients with at least one event) Telaprevir n=292Serious adverse events (SAEs)* 132 (45.2%)Premature discontinuation 66 (22.6%)Due to SAEs 43 (14.7%)Death 5 (2.6%)Septicemia, Septic shock, Pneumopathy, Endocarditis,Oesophageal varices Bleeding,Infection (Grade 3/4) 19 (6.5%)Hepatic decompensation (Grade 3/4) 6 (2.0%)Asthenia (Grade 3/4) 16 (5.5%)Rash Grade 3/SCAR 14 (4.8%)Renal failure 5 (1.7%)*334 SAEs in 132 patients; SCAR: severe cutaneous adverse reaction
    30. 30. Telaprevir: week 16 safety findingsPatients, n (% patients with at least one event) Telaprevir n=292Anemia Grade 2 (8.0 – <9.0 g/dL?) 55 (18.8%) Grade 3/4 (<8,0 g/dL) 34 (11.6%) EPO use 157 (53.8%) Blood transfusion 47 (16.1%) RBV dose reduction 38 (13.0%)Neutropenia Grade 3 (500 – <750/mm3) 6 (2.0%) Grade 4 (<500/mm3) 2 (0.7%) G-CSF use 7 (2.4%)Thrombopenia Grade 3 (20 000 – <50 000/mm3) 28 (9.6%) Grade 4 (<20 000/mm3) 9 (3.1%) Thrombopoïetin Use 4 (1.4%)EPO: Erythropoïetin; G-CSF: granulocyte-colony stimulating factor
    31. 31. Boceprevir: baseline characteristics Boceprevir n=205Male, n (%) 140 (68)Mean age, range (years) 56.9 (34-81)Mean BMI, SD (kg/m2) 26.2 (4.1)Genotype 1b / 1a / other (%) 50 / 40 / 10HCV RNA >800,000 IU/mL, n (%) 131 (64)Mean Neutrophils, range (109/mm3) 3.3 (0.5-8.5)Mean Hemoglobin, range (g/dl) 14.8 (9.7-18.4)Mean Platelets, range (/mm3) 146,000 (33,900-346,000)
    32. 32. Boceprevir: baseline characteristics Boceprevir n=205Mean Prothrombin Time, range (ratio) 87.3 (23-100)Mean Total Bilirubin, range (µmol/L) 15.0 (4.0-78.0)Mean Albumin, range (g/dL) 40.4 (27.0-50.3)Child-Pugh A / B (%) 99 / 1Mean MELD score, SD 8.1 (3.0)MELD score <10 / 10 - <13 / ≥13 (%) 83 / 12 / 5Esophageal varices (%) 40Realize / Respond-2 exclusion criteria (%) 29 / 40
    33. 33. Boceprevir: week 16 safety findingsPatients, n (% patients with at least one event) Boceprevir n=205Serious adverse events (SAEs)* 67 (32.7%)Premature discontinuation 54 (26.3%)Due to SAEs 15 (7.3%)Death 1 (0.5%)PneumopathyInfection (Grade 3/4) 5 (2.4%)Hepatic decompensation (Grade 3/4) 6 (2.9%)Asthenia (Grade 3/4) 12 (5.8%)Rash Grade 3/SCAR 0Renal failure 0 *159 SAEs in 67 patients; SCAR: severe cutaneous adverse reaction
    34. 34. Boceprevir: week 16 safety findingsPatients, n (% patients with at least one event) Boceprevir n=205Anemia Grade 2 (8.0 – <9.0 g/dL) 48 (23.4%) Grade 3/4 (<8,0 g/dL) 9 (4.4%) EPO use 95 (46.3%) Blood transfusion 13 (6.3%) RBV dose reduction 22 (10.7%)Neutropenia Grade 3 (500 – <750/mm3) 2 (1.0%) Grade 4 (<500/mm3) 7 (3.4%) G-CSF use 9 (4.4%)Thrombopenia Grade 3 (20 000 – <50 000/mm3) 10 (4.9%) Grade 4 (<20 000/mm3) 3 (1.5%) Thrombopoïetin Use 2 (1.0%)EPO: Erythropoïetin; G-CSF: granulocyte-colony stimulating factor
    35. 35. Multivariate analysis: baseline predictors of severe complications*Predictors OR 95%CI p-valueProthrombin Time 1.03 1.01-1.06 0.038(per unit decrease)Age 1.05 1.01-1.11 0.025(per year increase)Platelet count 3.19 1.32-7.73 0.0098≤100,000/ mm3Albumin level 4.95 2.04-12.01 0.0004<35 g/L * Death, severe infection and hepatic decompensation, n=32
    36. 36. Multivariate analysis: predictors of anemia <8g/dL or blood transfusion *Predictors OR 95%CI p-valueAge 1.06 1.026-1.09 0.0003(per year increase)Gender 2.32 1.10-4.35 0.023(Female)No lead-in phase 2.33 1.22-4.35 0.01Hemoglobin level 5.85 2.83-12.08 <0.0001≤12 g/dL for female≤13 g/dL for male * n=71
    37. 37. Telaprevir: week 16 efficacy data Per protocol ITT 100 92% 93% 92% 90Patients with undetectable HCV RNA (%) 80 80% 79% 70 67% 60 58% 55% 50 40 30 20 10 161/276 161/292 236/257 236/292 230/247 230/292 196/212 196/292 0 Week 4 Week 8 Week 12 Week 16
    38. 38. Telaprevir: Week 16 efficacy according to prior treatment response (ITT) 80 75%Patients with undetectable HCV RNA (%) P=0.005 70 66% 60 50 46% 40 30 20 10 11/24 90/136 92/123 0 Null Partial Relapse Response Response
    39. 39. Boceprevir: week 16 efficacy data Per protocol 90 ITTPatients with undetectable HCV RNA (%) 80 77% 70 64% 60 58% 55% 50 42% 40 38% 30 20 10 3% 2% 0 5/194 5/205 77/181 77/205 112/174 112/205 118/154 118/205 Week 4 Week 8 Week 12 Week 16
    40. 40. Boceprevir: Week 16 efficacy according to prior treatment response (ITT) 80 P=0.001 69% 70 60 50% 50 40 30 22% 20 10 2/9 45/90 69/100 0 Null Partial Relapse Response Response
    41. 41. Rationale for Prompt Treatment of HCV HCV is a progressive disease, associated with persistence of viral replication and ongoing necroinflammation and fibrosis Remission (SVR) is associated with loss of active viral replication and improvement in hepatic fibrosis Important questions – Does that equate to a need to treat all patients? – Can we avoid losing time for patients destined to progress? – How do we avoid unnecessary or detrimental treatment when there are improved treatments pending?
    42. 42. Indications for Treatment of ChronicHCV Infection All patients, regardless of the degree of fibrosis, are potential candidates for treatment IFN-based therapy is current standard of care Patients with mild disease may not require immediate treatment For those who require treatment – Patients should be fit for the regimen – Patients should have the ability to adhere to treatment goals and monitoring There is a complex ongoing debate regarding opportune timing for treatment given the therapeutic landscape
    43. 43. Who Should Be Treated Now?Pts Who Want Tx Pts Who Are Pts Who AreWant to be cured of Eligible for Tx Motivated anddisease Eligible for pegIFN/ RBV Understand . . .Personal or social Fit for regimen Likelihood of responsereasons No contraindications Risks/benefits ofPlans for pregnancy treatment Disease stageSocial support Risk of resistanceEligible for Possibility of shortenedreimbursement now therapy What is “coming down the line” for their genotype
    44. 44. Severity of Disease Increases Need forHCV Therapy but Also Impairs Response May not need immediate treatment  Greater need for treatment BUT  BUT  Easier to treat  Response may be impaired  High likelihood of  Perhaps more effective options in response future, but efficacy of some investigational agents may be unclear due to trial eligibility criteria Mild disease Advanced disease/ cirrhosis
    45. 45. What Are the Chances of Being Cured WithCurrent Therapy?  Black  Cirrhosis  Genotype 1  White  No fibrosis (1a worse than 1b)  IFN nonresponsive  Genotype 2/3  IFN responsive (eg,  IL28B TT RVR/EVR or response to lead-in)  Previous relapser  IL28B CC Less favorable Favorable prognostic factors prognostic factors
    46. 46. Limitations of Current Regimens andProspects for Future RegimensCurrent FutureMust be eligible for pegIFN/ RBV Perhaps IFN freeLarge pill burden, TID dosing of Lower pill burden, less than TIDPIs (at present); parenteral IFN dosing; perhaps all oralChallenging adverse events May be better toleratedHigh likelihood of resistance with May not generate resistancetreatment failure Pangenotypic or at least moreCurrent PIs only effective forgenotype 1 Higher barrier to resistance with some classesPossibility of resistance with pooradherence
    47. 47. Challenging Patients for Whom TreatmentWith Current Options Less Than Optimal Cirrhosis (all genotypes)  Injection-drug users Decompensated cirrhosis – Methadone substitution Null responders  Thalassemics Pretransplantation  Children Posttransplantation  IFN contraindicated Renal failure  IFN intolerant – Impaired renal function  Those on “edge” of society – Dialysis  Psychiatric comorbidity – Renal transplantation recipients
    48. 48. Cumulative Incidence of Liver-Related Complications Following SVR in Cirrhosis No SVR 100 SVR 80 Patients With Liver Complications (%) 60 40 20 0 0 24 48 72 96 120 144 168 Mos Pts at Risk, n 759 702 634 527 345 207 34 124 119 116 108 70 41 12Bruno S, et al. Hepatology. 2007;45:579-587.
    49. 49. SVR to Telaprevir in Treatment-Naive Pts With GT1 HCV and Compensated Cirrhosis ADVANCE ILLUMINATE All 100 92 92 Cirrhosis 90 79 80 74 71 66 61 60SVR (%) 50 51 46 40 38 20 n/N= 285/ 15/ 166/ 8/ 149/ 11/ 144/ 11/ 78/ 6/ 398/ 31/ 363 21 361 21 162 18 160 12 118 12 540 61 0 T12PR PR48 T12PR24 T12PR48 T12PR48 T12PR eRVR+* eRVR-* Overall *eRVR+ randomized: 60% (322/540); eRVR-: 22% (118/540).Kauffman RS, et al. HepDart 2011. Abstract 52.
    50. 50. CUPIC: Efficacy of TVR in Cirrhotics  ~ 80% of patients treated with TVR-based therapy had undetectable HCV RNA at end of 16 wks of triple therapy 100 Per protocol 85 86 86 ITT 79 Undetectable HCV RNA (%) 78 80 71 60 53 51 40 20 n/N = 145/ 145/ 224/ 224/ 219/ 219/ 177/ 177/ 276 285 265 282 254 281 205 251 0 Wk 4 Wk 8 Wk 12 Wk 16Hezode C, et al. AASLD 2012. Abstract 51.
    51. 51. CUPIC: Efficacy of Boceprevir in Cirrhotics  ~ 60% of patients treated with BOC-based therapy had undetectable HCV RNA at Wk 16 of ongoing therapy 100 Per protocol ITT Undetectable HCV RNA (%) 80 71 61 58 61 60 40 37 37 20 1 1 n/N = 2/ 2/ 55/ 55/ 88/ 88/ 89/ 89/ 155 155 149 150 144 151 126 146 0 Wk 4 Wk 8 Wk 12 Wk 16Hezode C, et al. AASLD 2012. Abstract 51.
    52. 52. The First-Generation Protease Inhibitors:Where Are We Now? Telaprevir and boceprevir are harbingers of important treatment advance Improved SVR rates in both naive and experienced patients Certain patients (advanced disease) require therapy imminently and should be treated now Others may be motivated to be treated now—opportunities for cure, candidates for shortened therapy, and/or personal reasons For many, the choice is not clear The advent of triple therapy changes the way treatment discussed with patients – Clinicians must educate and advocate for patients to choose the correct course of treatment
    53. 53. Factors That InfluenceOutcomes With HCV Therapy
    54. 54. SPRINT-2: Influence of Baseline Patient and Virus Factors on SVR With BOC BOC + pegIFN-α2b/RBV 48 wks BOC + pegIFN-α2b/RBV RGT 100 85 80 76 75 70 71 66 67 67 63 63 61 59 59SVR (%) 52 50 41 25 n/ 93/ 89/ 118/ 106/ 45/ 41/ 197/ 192/ 211/ 213/ 22/ 14/ 44/ 82/ 26/ N = 133 134 187 179 53 54 313 314 313 319 42 34 55 115 44 0 1b 1a ≤ 800,000 > 800,000 F0-2 F3/F4 CC CT TT Genotype [1] HCV RNA (IU/mL)[1] Fibrosis[1] IL28B[2] 1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Poordad F, et al. Gastroenterology. 2012;143:608-618.
    55. 55. ADVANCE: Influence of Baseline Patient and Virus Factors on SVR With TVR  Data from TVR12 + pegIFN-α2a/RBV arm only 100 90 79 78 78 71 74 71 73 75 62SVR (%) 50 25 n/ 118/ 152/ 64/ 207/ 226/ 45/ 45/ 48/ 16/ N = 149 213 82 281 290 73 50 68 22 0 1b 1a < 800,000 ≥ 800,000 F0-2 F3/F4 CC CT TT Genotype[1] HCV RNA (IU/mL)[1] Fibrosis[1] IL28B*[2] *IL28B testing was in whites only.1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.
    56. 56. IL28B Genotype Predicts Likelihood of Eligibility for Shortened Therapy SPRINT-2: BOC + ADVANCE: T12 + PegIFN-α2b/RBV [1] PegIFN-α2a/RBV *[2] 100 100 89 78 80 80 60 60 57 52 45 40 40 20 20 % T GRr o y ili b gl E % T GRr o y ili b gl E n/ 117/ 158/ n/ 39/ 39/ 10/ N= 132 304 N= 50 68 22 f t i i f t i i 0 0 CC CT/TT CC CT TT *IL28B testing in ADVANCE was in whites only.1. Poordad F, et al. Gastroenterology. 2012;143:608-618. 2. Jacobson IM, et al. EASL 2011. Abstract1369. ( (
    57. 57. IL28B Genotype Should Not Be Used to Exclude Patients From Therapy  If patients have favorable CC genotype – Likelihood of SVR is high with pegIFN/RBV alone, but triple therapy may allow shorter therapy and, in one TVR study, higher SVR rates[1]  If patients have unfavorable CT/TT genotype – Likelihood of SVR is higher with triple therapy than with pegIFN/RBV – 59% to 71% in SPRINT-2[2] – 71% to 73% in ADVANCE*[1]  Limited value of IL28B genotyping in treatment-experienced patients – Most have unfavorable TT or CT genotype *IL28B testing in ADVANCE was in white Americans only.1. Jacobson IM, et al. EASL 2011. Abstract 1369. 2. Poordad F, et al. Gastroenterology. 2012;143:608-618.
    58. 58. Lead-in Strategies
    59. 59. Lead-in Strategy Can Help DetermineWhom to Treat 4 wks of pegIFN/RBV lead-in before BOC (or TVR) – Lowers HCV RNA burden – May identify rapid responders who may not need DAA – Allows assessment of IFN responsiveness – Provides useful information regarding likelihood of SVR with addition of DAA – Provides insight into tolerability of pegIFN/RBV backbone – Elucidates hematologic response to pegIFN/RBV, especially in “marginal” patients; make needed dose adjustments before addition of DAA
    60. 60. Early IFN Response (Lead-in) Further Defines Likelihood of SVR for Non-CC Pts PegIFN-α2b/RBV*  A > 1 log10 decrease in HCV RNA at Wk 4 of therapy is the strongest BOC + pegIFN-α2b/RBV predictor of SVR RGT* SPRINT-2 and RESPOND-2 Combined BOC + pegIFN-α2b/RBV 100 48 wks* 81 81 82 82 80 75 75 76 67 60 SVR (%) 50 50 44 40 40 37 32 24 20 4 5 1/ 1/ n/N= 0/ 2/ 2/ 56/ 83/ 58/ 27 19/ 20/ 37/ 83/ 109/ 20 6/ 10/ 13/ 23/ 26/ 2 3 4 75 102 72 51 45 117 111 133 25 25 26 28 34 0 < 1 log ≥ 1 log < 1 log ≥ 1 log < 1 log ≥ 1 log CC CT TT *BOC was administered with pegIFN-α2b in these trials.Poordad F, et al. Gastroenterology. 2012;143:608-618.
    61. 61. Preparing for Treatment: Possibilities ofDrug–Drug Interactions
    62. 62. Both BOC and TVR Have Potential forMany Drug–Drug Interactions BOC  TVR – Strong inhibitor of – Substrate of CYP3A CYP3A4/5 – Inhibitor of CYP3A – Partly metabolized by CYP3A4/5 – Substrate and inhibitor of P-gp – Potential inhibitor of and substrate for P-gp Most drug–drug interactions can be overcome by careful survey of the patient’s medications and judicious substitutions during HCV therapy (or just during the period of PI-based triple therapy)
    63. 63. Medicines That Are Contraindicated With BOC and TVR Drug Class* Contraindicated With BOC[1] Contraindicated With TVR[2] Alpha 1-adrenoreceptor Alfuzosin Alfuzosin antagonist Anticonvulsants Carbamazepine, phenobarbital, N/A phenytoin Antimycobacterials Rifampin Rifampin Antiretrovirals EFV, all RTV-boosted PIs DRV/RTV, FPV/RTV, LPV/RTV Ergot derivatives Dihydroergotamine, ergonovine, Dihydroergotamine, ergonovine, ergotamine, methylergonovine ergotamine, methylergonovine GI motility agents Cisapride Cisapride Herbal products Hypericum perforatum (St John’s wort) Hypericum perforatum HMG CoA reductase Lovastatin, simvastatin Lovastatin, simvastatin inhibitors Oral contraceptives Drospirenone N/A Neuroleptic Pimozide Pimozide PDE5 inhibitor Sildenafil or tadalafil when used for Sildenafil or tadalafil when used for treatment of pulmonary arterial HTN treatment of pulmonary arterial HTN Sedatives/hypnotics Triazolam; orally administered Orally administered midazolam, midazolam triazolam *Studies of drug–drug interactions incomplete.1. Boceprevir [package insert]. July 2012. 2. Telaprevir [package insert]. October 2012.
    64. 64. Preparing for Treatment:Management of Adverse Events
    65. 65. Adverse Effect Management: Anemia  Recommendation: anemia should be managed initially by reducing the RBV dose[1]  Do not dose reduce DAA or stop and then restart  Do not discontinue pegIFN/RBV and continue DAA  Monitor closely if Hb falls < 10 g/dL  ESA agents are unlabeled for HCV anemia – May be effective as a secondary anemia management strategy1. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
    66. 66. EPO and RBV Dose Reduction for Anemia Lead to Similar SVR Rates in BOC Patients  Nested study within randomized trial of genotype 1 HCV therapy-naive patients receiving 4 wks of lead-in with pegIFN-α2b/RBV and then either 44 wks of triple therapy or RGT (24-44 wks) 100 ∆ -0.7% (95% CI: -8.6 to 7.2)* 80 71 71 SVR (%) 60 40 20 n/N = 178/249 178/251 0 RBV DR EPO *Stratum-adjusted difference in SVR rates, adjusted for stratification factors and protocol cohort.  82% of RBV dose reduction group vs 62% in EPO group did not require secondary anemia interventionPoordad F, et al. EASL 2012. Abstract 1419.
    67. 67. Predictive Value of Anemia for SVR With BOC or TVR  In phase III trials, anemia positive predictor of SVR with BOC[1] but not TVR[2]  EOTR, relapse, and SVR comparable between RBV DR and EPO arms in treatment-naive patients who developed anemia during BOC/PR therapy[1] SPRINT-2*[1] ADVANCE and ILLUMINATE†[2] 100 100 Hb ≥ 10 g/dL Hb < 10 g/dL 80 72 80 73 74 58 SVR (%) 60 60 40 40 20 20 0 n/N = 212/363 263/363 0 n/N = 384/524 267/361 *Data from BOC/48 and BOC RGT arms. † Data from T12/PR arm only.1. Sulkowski MS, et al. Hepatology. 2012;[Epub ahead of print]. 2. Poordad F, et al. DDW 2011. Abstract 626.
    68. 68. Adverse Effect Management:Rash and Anorectal Symptoms Rash management – Mild to moderate rash can be treated with oral antihistamines, topical steroids – Systemic steroids are not recommended – For severe rash, many practitioners will stop TVR alone and follow for 1 wk to see if the rash improves – If not, stop all 3 drugs – Important to have “go-to” dermatologist; vigilance with rash is key Anorectal symptom management – Fiber, loperamide, hydrocortisone, pramoxine topical cream, topical lidocaine
    69. 69. Managing Major Adverse Effects ofPegIFN Depression – Assess mood, sleep, suicidal thoughts – Consider SSRI to treat baseline or new depression – Refer to mental health services to follow high-risk patients during treatment Influenzalike symptoms – Acetaminophen, hydration – Reduce dose of IFN if necessary Neutropenia, thrombocytopenia: monitor CBC frequently Others: GI upset, hair loss, insomnia, injection-site reactions
    70. 70. Helping Patients Adhere to ComplexRegimens PegIFN/RBV + BOC or TVR = very complex regimen – BOC 800 mg TID: 12 pills/day with food – TVR 750 mg TID: 6 pills/day with high-fat meal – RBV (2-6 pills/day) and weekly pegIFN injection Adherence enhanced by a combination of – Patient education and motivation – Reducing pill burden when possible – Shortening therapy when appropriate – Prompt adverse effect management
    71. 71. Optimizing Current HCV Therapy With PIs Plus PegIFN/RBV
    72. 72. Strategies to Enhance Current Therapy With PegIFN/RBV Plus PI for GT1 Pts  Shorter therapy may be possible for certain patients – Investigational T12/PR12 regimens for IL28B CC patients  PR alone for IL28B CC patients? – Being evaluated in phase III trial vs BOC + pegIFN-α2a/RBV  Potential for BID dosing of TVR – OPTIMIZE[1]: TVR 1125 mg BID noninferior to TVR 750 mg every 8 hrs (both with pegIFN-α2a/RBV) in treatment-naive GT1 patients – SVR12 in 74% vs 72% of patients, respectively – No increase in adverse events1. Buti M, et al. AASLD 2012. Abstract LB-8.
    73. 73. NAIVES: RESULTS (SVR)Universal treatment SVR % ICER ( €) • BOC-RGT 67.0 85,000 • TVR-RGT 74.5 118,000Selective treatment • BOC-RVR 72.1 56,000 • TVR-IL28 79.0 74,000
    74. 74. NAIVES: RESULTS (LYG)Universal treatment LYG (yrs) ICER ( €) • BOC-RGT 3.75 13,400 • TVR-RGT 4.18 19,200Selective treatment • BOC-RVR 4.04 8,300 • TVR-IL28 4.42 11,400
    75. 75. ICER/LYG different clinical settingsICER = < 12.000 € triple therapy for naivesICER = 15.000 € Heart transplantationICER = 60.000 € erlotinib pancreatic cancerICER = 74.000 € sorafenib HCC
    76. 76. Naives: key pointsTriple therapy with first-generation PIs in naïve Gt 1 CHC patients:• improves survival by about 4 years• is cost-effective, with an ICER per LYG below € 12,000• is strongly influenced by the IL28B CC prevalence and theensuing likelihood of RVR and SVR, but also by the pricing ofBOC and TVR• is optimised by allocating patients according to IL28B and/or RVR based strategies- An individualized treatment strategy can avoid triple therapy in 25-33% of naive HCV G1 patients
    77. 77. Re-treatment with P/R of treatment-experienced patients FULL PAPERSOverall SVR rate after retreatment: 16.1% (CI 6-33%) EASL and AASLD Guidelines recommend that G1 HCV patients failing to eradicate HCV on P/R ABSTRACTS should not be retreated with P/R alone Cammà C, et al. J Hepatol. 2009 Oct;51(4):675-81.
    78. 78. Re-treatment with P/R plus a 1 st generation PI of treatment-experienced patientsPhase 3 RCTs (BOC: RESPOND-2, PROVIDE: TVR:REALIZE) show that TT achieves SVR in about 30%-75% ofexperienced G1 CHC patients, with SVR rates progressivelydecreasing from :• Relapse (RR)• Partial responders (PAR) (HCV-RNA drop >2 log at week 12, but never not detectable)• Null responders (NR) (HCV-RNA drop < 2 log at week 12).
    79. 79. Cost-effectiveness of Boceprevir orTelaprevir for previously treated patients with Gt 1 CHC Competing strategiesResponse to Response Strategyprevious P/R to lead-in • RR • BOC LEAD IN • BOC-POOR§ • PAR • TVR LEAD IN • BOC-GOOD* • NR • TVR NO LEAD IN • TVR-POOR § • TVR-GOOD* *>1Log drop at week 4 of DT §<1Log drop at week 4 of DT Cammà C, et al. J Hepatol, in press
    80. 80. ICERs According to Profile of Previous Response and Severity of Liver Fibrosis 20000 18000 16000 TVR 14000 BOC 12000ICER for LYG 10000 8000 6000 4000 2000 0 F3-F4 F3-F4 F3-F4 CHC CHC CHC CHC CHC RR PAR NR RR GOOD PAR POOR NR Cammà C, et al. J Hepatol, in press
    81. 81. CAVEATS• Efficacy data from registration trials• Inconclusive data on cirrhosis• Aggregate rather than individual patient data• Analysis limited to direct medical costs• Time horizon = 20 years
    82. 82. Approval of triple therapy for reimbursement in Italy: basic principles (presumably) followed by AIFA• Local disease epidemiology and cost issues do not allow universal use of triple therapy (TT) in Italy• Patients with F3/F4 fibrosis deserve priority for TT• Selected patients with F0/F2 fibrosis may benefit from TT• Some non-responders should not be retreated with currently available therapies• Boceprevir and telaprevir are equally effective• Only Centers who meet specific requirements are allowed to prescribe TT• HCV monoinfected and HCV/HIV coinfected patients should both receive access to TT• TT after OLT can only be used off-label (law 648/96)
    83. 83. Approval of triple therapy for reimbursement in Italy: basic principles (presumably) followed by AIFA • IL28b status and virological features (baseline viral load and HCV subtype) are weak predictors at the individual level of RVR and SVR and cannot be used to pre-assign to TT or P/R • Response to a lead-in phase (P/R alone for 4 weeks>1 log drop in HCV RNA from baseline) is the strongest predictor of SVR*, and its absence of appearance of RAVs, hence a lead-in period is enforced for both boceprevir and telaprevir to: – Rule-in naïve patients in need of TT – Rule-out treatment experienced patients with a low likelihood of response to TT * Proven for boceprevir, assumed for telaprevir
    84. 84. Approval of triple therapy for reimbursement in Italy: AIFA criteria for naive Gt 1 patients Fibrosis Triple therapy (P/R Dual therapy Comments stage with Boc or Tpv) (P/R) F0, F1, F2 RVR* negative RVR* positive Lead-in not needed for F3, F4 All patients None telaprevir * RVR: at least 1 log10 drop after 4 weeks of P/R
    85. 85. Approval of triple therapy for reimbursement in Italy: AIFA criteria for treatment exp. Gt 1 patientsRR: relapsers; PR: partial responders; NR: null responders; UK: unknown pattern Fibrosis stage Triple therapy (P/R with Dual Comments Boc or Tpv) therapy (P/R) RR: all PR: all F0, F1, F2 NR: only if RVR* positive None UK: only if RVR* positive Lead-in not F3, F4 All patients None needed for telaprevir * RVR: at least 1 log10 drop after 4 weeks of P/R
    86. 86. Approval of triple therapy for reimbursement in Italy: potential critical issue • AIFA criteria are partly hypothetical: • Lead-in largely unproven for telaprevir • No statements about indications for treatment (Do all patients with F0/F2 fibrosis deserve therapy? What policy for informed deferral)? • Assimilating an unknown response to null response may be unsound • Unclear diagnostic criteria for fibrosis • Efficacy in terms of cost reduction may be insufficient • 20% of naïve patients • 30-40% of treament experienced patients • Selection of Centers for treatment is delegated to regional Health Authorities, who are also empowered to impose further restrictions
    87. 87. The Future of HCV Therapy
    88. 88. Investigational Agents for HCV Antiviral Therapeutic Host Interferons agents vaccines target miRNA-122 Cyclophilin Entry Replication, polyprotein Cyp processing and/or assembly inhibitors NS5A NS5B NS3 replication polymerase protease complex inhibitors inhibitors inhibitors
    89. 89. Drugs in the HCV pipeline (November 2012) Phase 2 Phase 3 Approved Mericitabine4 X IDX-184 Sovaprevir1 X INX-189 ABT-267 miR-122 a-s* Simeprevir Peg-IFNα-2a* GS 9256 BI-207127 ALS 2200 BMS 824393 Silymarin (IV) * ABT-450/r Peg-IFNα-2B* GS 9451 GS-5885 CT-011 mAb* Asunaprevir7 ABT 072 RBV Danoprevir2 GSK 2336805 GS6624 mAb* Vaniprevir 8 BI 207127 IDX 719 Celgosivir Faldaprevir11 Boceprevir Narlaprevir3 BMS 791325 GS-9620 TLR7 Sofosbuvir Telaprevir Tegobuvir 5 GI-2005 ABT-333 GS-9669 Ad3NSmut* Daclatasvir9 GS-9254 IDX-375 Peg-IFNλ-3 * Alisporivir10 * Setrobuvir6 VX-222 Protease Inh (PI)Former IDs:1 ACH-1625 2. RG7227 (ITMN-191) 3 SH9005182 Polym Inh (nuc)4 RG-7128; RO5024048 5 GS-9190 6 RG7790 Polym Inh (nn)7 BMS-0032 8 MK-7009 9 BMS 790052 10 Deb025 NS5A (RCI) Inh11 BI-201335 Other (misc mechs)
    90. 90. Characteristics of HCV DAA classes Characteristic Protease Nucleos(t)ide Non-nucleoside NS5a inhibitors inhibitors polymerase polymerase inhibitors inhibitors Potency High, variable Moderate-high, Variable, variable High, multiple among HCV consistent across across HCV genotypes geno/subtypes geno/subtypes geno/subtypes Barrier to Low High Very low Low resistance 1a < 1b 1a = 1b 1a < 1b 1a < 1b DDI potential High Low Variable Low-moderate Toxicity Rash Mitochondrial Variable Variable Anemia nucleos(t)ide ↑ Bilirubin interactions (ART, RBV)Pharmacokinetics Variable: QD to QD Variable: QD to QD TID TID Comments 2nd generation Pis: Single target Allosteric Multiple mode of better barrier, active site inhibition, many action pangenotypic targets
    91. 91. No cross resistance between classes: a combination of DAAs can eliminate RAVs Kieffer T, et al. J Antimicrob Chemother 2010;65:202–12R: resistant (>4-fold increase in EC50) Gao M, et al. Nature 2010;465:96–100; Lagrace L, et al. Hepatology 2010;52(4 Suppl):1205AS: susceptible (<4-fold change in EC50) Lenz O, et al. Hepatology 2010;52(4 Suppl):709A; Zeuzem S, et al. Hepatology 2010;52(4 Suppl):400A
    92. 92. HCV therapy: hopes and hypes….• Interferon-free• >90% SVR• Once daily• High tolerability with low adverse event• Few drug-drug interactions• Short, fixed duration (12-24 weeks)• Pan-genotypic• High barrier to resistance or lack of cross resistance• Affordable
    93. 93. IL28B genotype has been associated with viral kinetics during IFN-free therapyINFORM-1 : Mericitabine (NI) + danoprevir (PI), 14 days, n = 15 Chu, Gastro , 2012
    94. 94. Investigational HCV Regimens in Phase III Clinical Trials •Regimens With 1 DAA •Regimens With 2 DAAs •IFN-Free Regimens + PegIFN alfa/RBV + PegIFN alfa/RBV  Faldaprevir* (BI 201335, PI)  Daclatasvir + asunaprevir*  Sofosbuvir + RBV  Daclatasvir* (BMS-790052,  Sofosbuvir + GS-5885 NS5A) (FDC) ± RBV •New Interferons  Daclatasvir + asunaprevir  Sofosbuvir* (GS-7977, NI)  Simeprevir* (TMC435, PI)  PegIFN lambda-1a + RBV  ABT-450/RTV + ABT-267 ± ABT-333 ± RBV  Alisporivir* (CYP) On Hold  PegIFN lambda-1a +  Vaniprevir (MK-7009, PI) daclatasvir + RBV •Alternative Dosing  TVR BID* (approved PI) *Studied with pegIFN-α2a. Studied with both pegIFN-α2a and pegIFN-α2b.ClinicalTrials.gov.
    95. 95. Interferon PlusDAA-Based Regimens
    96. 96. ASPIRE: Simeprevir (TMC435) 150 mg for 12, 24, 48 Wks + PR in Tx-Exp’d GT1 Pts  SVR24 rates according to previous response category[1] 100 Placebo + pegIFN-α2a/RBV 48 wks 85 Simeprevir 150 mg* + pegIFN-α2a/RBV 80 76 48 wks SVR24 (%) *Pooled. 60 51 40 37 19 20 9 n/ 10/ 67/ 52/ 3/ 26/ N = 27 79 2/23 69 16 51 0 Relapsers Partial Null Responders Responders  High rates of efficacy in patients with METAVIR F3/F4 fibrosis[2]1. Jacobson I, et al. IDSA 2012. Abstract 1287. 2. Poordad F, et al. AASLD 2012. Abstract 83. ̶ Relapsers: 65%; partial responders: 67%; null responders: 33%
    97. 97. ATOMIC: Sofosbuvir (GS-7977) Plus PR in Treatment-Naive GT1 Patients  Interim analysis of randomized, open-label phase II study Wk 12 Wk 24 SVR12,% Sofosbuvir + PegIFN-α2a/RBV 90 (n = 52) Treatment- 92 overall naive, Sofosbuvir + PegIFN-α2a/RBVnoncirrhotic (n = 125) 82 GT4 patients* (N = 332) 100 GT6 Sofosbuvir Sofosbuvir + (n = 75) PegIFN-α2a/RBV 91 (n = 155) Sofosbuvir + RBV (n = 75) *All infected with genotype 1 HCV, except for 16 patients with GT4 or 6 HCV who were eligible for 24-wk arm of sofosbuvir plus PR.Kowdley KV, et al. EASL 2012. Abstract 1. Hassanein T, et al. AASLD 2012. Abstract 230.
    98. 98. Interferon-Free Regimens
    99. 99. ELECTRON: Sofosbuvir and RBV in Naive and Experienced GT1 Patients Viral Response, % Wk 8 Wk 12 SVR4 SVR12 Sofosbuvir + RBV 1000/1200 mg (GT1; naive) (n = 25) 84 Sofosbuvir + RBV 1000/1200 mg (GT1; null responders) (n = 10) 10 Sofosbuvir + GS-5885 + RBV 1000/1200 mg (GT1; naive) (n = 25) 100 Sofosbuvir + GS-5885 + RBV 1000/1200 mg (GT1; nulls) (n = 9) 100* *Data reported for 3 pts only. Data collection ongoing.Gane EJ, et al. AASLD 2012. Abstract 229.
    100. 100. NIH SPARE: Interim Data on Sofosbuvir and RBV in Difficult-to-Treat GT1 Patients  Patients with poor prognostic indicators: GT1a (70%), male (63%), black (83%), IL28B CT/TT (80%), advanced liver disease (22%)  Median BMI: 28; median HCV RNA: 6.4 logs Viral Response, % Wk 24 Part 1 (early-stage fibrosis) EOT SVR4 SVR12 Sofosbuvir + RBV 1000/1200 mg (n = 10) 90* 90* 90* Part 2 (all stages of fibrosis) Sofosbuvir + RBV 600 mg (n = 25) 88† 56† Sofosbuvir + RBV 1000/1200 mg (n = 25) 96* 72* *1 dropout at Wk 3. † 3 dropouts by Wk 8.Osinusi A, et al. AASLD 2012. Abstract LB-4.
    101. 101. Daclatasvir Plus Sofosbuvir ± RBV in Treatment-Naive GT1 or 2/3 Patients  No impact of RBV on viral response SVR24, % Wk 1 Wk 24 GT1 GT2/3 Sofosbuvir Daclatasvir + SofosbuvirTreatment-naive, 93 88 noncirrhotic patients GT1a or 1b Daclatasvir + Sofosbuvir 100 100 (n = 44) GT2 or 3 (n = 44) Daclatasvir + Sofosbuvir + RBV 100 93 Sobosbuvir dosed 400 mg QD. Daclatasvir dosed 60 mg QD. RBV dosed by body weight for GT1 patients (1000-1200 mg/day); 800 mg/day for GT2/3 patients.Sulkowski MS, et al. AASLD 2012. Abstract LB-2.
    102. 102. AVIATOR: IFN-Free Regimens With ABT-450/RTV, ABT-267, ABT-333, and RBV Phase II trial with 2 cohorts SVR12, % ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV (n = 80) 87.5 ABT-450/RTV 100/100 mg + ABT-267 + Cohort 1: ABT-333 + RBV Treatment-naive (n = 79) 97.5 ABT-450/RTV 150/100 mg + ABT-267 + pts, GT1 HCV ABT-333 + RBV ABT-450/RTV 100/100 mg + ABT-267 + ABT-333 + RBV (n = 80) ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV NR ABT-450/RTV 100/100 mg + ABT-267 + ABT-333 + RBV Cohort 2: (n = 45) 93.3 ABT-450/RTV 150/100 mg + ABT-267 +Tx-exp’d pts, GT1 ABT-333 + RBVHCV, with previous null response ABT-450/RTV 100/100 mg + ABT-267 + ABT-333 + RBV (n = 43) NR ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV Wks 0 8 12 24 Kowdley KV, et al. AASLD 2012. Abstract LB-1.
    103. 103. Future Role of Interferon  What role may interferon play in future regimens? – Preventing resistance?  For which sets of patients may IFN play a role? – Patients with cirrhosis? – Treatment-experienced patients? – Patients with resistance to DAAs?  Will newer IFNs replace currently available agents? – EMERGE: IFN lambda may have comparable efficacy but fewer hematologic AEs vs pegIFN alfa[1]1. Muir AJ, et al. AASLD 2012. Abstract 214.
    104. 104. HCV: 2013-2020 0 PEG/RBV 10 20 PI+PEG+RBV PI2+PEG+RBV 30% of Patients 40 50 DAA1 + DAA2 + RBV (or) DAA1 + DAA2 + DAA3 + RBV 60 70 80 QUAD: PE G/RBV/DA A1/DAA2 90 (???) 100 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020
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