Simply Speaking Hepatitis February 7 2014

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  • Slide: New and Emerging Strategies to Simplify the Cure of Chronic Hepatitis C Infection
  • Slide: New Sign-In Process
  • Slide: CME Disclosure and Slide Handouts
  • Slide: Educator
  • Slide: Accreditation and Designation
  • Slide: Faculty
  • Slide: Faculty Disclosures
  • Slide: Faculty Disclosures
  • Slide: Opinions and Off-Label Discussions
  • Slide: New Electronic Evaluation Process
  • Slide: Learning Objectives (CME/CNE and CPE)
  • Slide: Chronic HCV Therapy (Genotype 1): Advances in Raising Cure Rates
    Since the use of standard interferon for the treatment of chronic HCV, SVR rates have increased slowly first with the introduction of ribavirin and then peginterferon. The recent addition of direct antiviral agents to the HCV armamentarium have resulted in a significant increase in HCV cure rates.1-3
    References
    Schaefer EA, Chung RT. Anti-hepatitis C virus drugs in development. Gastroenterology. 2012;142:1340-1350.
    Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-1374.
    Ghany MG, Nelson DR, Strader DB, et al. An update on the treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guidelines by the American association for the Study of Liver Diseases. Hepatology. 2011;54:1433-1444.
  • Slide: SVR Rates in Treatment-Naïve, Genotype 1 HCV: Telaprevir and Boceprevir
    The ADVANCE study was a prospective, randomized phase 3 study assessing the safety and efficacy of telaprevir 750 mg q8h given either for 8 or 12 weeks in combination with peginterferon alfa-2a + ribavirin in patients with chronic HCV (genotype 1).1
    The rate of sustained virologic response was 44% in the PR48 group, as compared with 75% in the T12/PR group (P<0.0001), 69% in the T8/PR group (P<0.0001). There was no significant difference between the two telaprevir groups.
    Overall relapse occurred in 9% in both telaprevir groups compared with 28% in the PR 48 group.
    The SPRINT-2 study was a prospective, randomized phase 3 study assessing the safety and efficacy of boceprevir administered for either 24 or 44 weeks versus peginterferon alfa-2a + ribavirin in treatment-naïve patients with chronic HCV (genotype 1).2
    The rate of sustained virologic response in the nonblack group was 40% in the PR48 group compared with 68% in the LI/B44/PR group (P<0.001) and 67% in the LI/B24/PR44 group (P<0.001). A similar trend was seen among the Black patients, however the response rates were lower that those in the nonblack group.
    Relapse occurred in 8% and 9% of nonblack patients in the LI/B44/PR and LI/B24/PR groups respectively, compared with 23% in the PR48 group. In contrast, the response rates in the black patients were higher than those in the nonblack patients and there were similar among the 3 treatment groups.
    References
    Jacobson IM, McHutchison JG, Dusheiko GM, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.
    Poordad F, McCone J, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.
  • Slide: Toxicities Impacting Completion of Telaprevir and Boceprevir Based Therapy
    The most common adverse events limiting the administration of telaprevir or boceprevir include rash and anemia.1,2
    References
    Jacobson IM, McHutchison JG, Dusheiko GM, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.
    Poordad F, McCone J, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.
  • Slide: Variation in SVR Rates: Previously Treated, HCV Genotype 1 Patients (REALIZE Study)
    Although SVR rates with boceprevir and telaprevir represent a significant advance of that achieved with peginterferon + ribavirin, there are subgroups of patients who remain harder to treat. For example, in the REALIZE study, sustained virologic response rates were higher in patients receiving telaprevir-based regimens compared with pegIFN + ribavirin regardless of prior response category or baseline liver disease. In prior relapsers, sustained virologic response rates in the telaprevir arm were similar despite the level of baseline liver disease. Lower sustained virologic response rates with telaprevir, relative to prior relapsers, were achieved in prior partial responders and null responders.1
    Reference
    Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.
  • Slide: Treatment of Chronic HCV: Recent Successes
    Within the last year, the landscape of therapy for genotype 1 chronic HCV has changed dramatically as telaprevir and boceprevir became available for use. These agents when used in combination with pegIFN + RBV offer patients an improved chance of cure and the opportunity for a shorter duration of therapy. SVR rates have been reported in up to 75% or treatment-naïve patients, 88% in prior relapsers and partial responders, and 41% in null responders.1
    The potential for yet another quantum leap in the field is underscored by the recent proof of concept studies demonstrating the capacity to eradicate HCV without interferon, including genotypes 2, 3, 4, 5, and 6.1-3
    References
    Fox AN, Jacobson IM. Recent successes and noteworthy future prospects in the treatment of chronic hepatitis C. Clin Infect Dis. 2012;55(suppl 1):S16-S24.
    Lawitz E, Wyles D, Davis M, et al. Sofosbuvir + peginterferon + ribavirin for 12 weeks achieves 90% SVR12 in genotype 1, 4, 5, or 6 HCV infected patients: the NEUTRINO study. J. Hepatol. 2013;58(suppl 1):S567. Abstract 1411.
    Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887.
  • Slide: Telaprevir or Boceprevir + PegIFN + RBV: Shortcomings of the Current Standard of Care
    Although these drugs represent a major advance in HCV treatment, there are short comings that continue to spur new research and drug development.
    These agents require administration with peginterferon + ribavirin.
    Cirrhotics not eligible for response-guided therapy with either drug.
    Therapy telaprevir and boceprevir reduce hemoglobin levels by 1.0 to 1.5 g/dL more than peginterferon + ribavirin alone. Telaprevir-specific adverse events include rash and anorectal discomfort, whereas boceprevir therapy is associated with dysgeusia and neutropenia (although the clinical significance is unknown).
    Both agents have a low barrier to resistance and the emergence of resistant variants. More than 50% of patients who fail to achieve a SVR with telaprevir or boceprevir-based regimens have detectable variants (wane in frequency over time off-therapy). To minimize the emergence of resistance, stopping rules have been defined.
    Both agents have a high potential for drug-drug interactions due to their CYP4A3 involvement.
    Reference
    Fox AN, Jacobson IM. Recent successes and noteworthy future prospects in the treatment of chronic hepatitis C. Clin Infect Dis. 2012;55(suppl 1):S16-S24.
  • Slide: Chronic HCV Infection: Targets for Direct-Acting Antiviral Agents
    This slide shows a schematic diagram of the HCV life cycle and potential drug targets for direct-acting antiviral agents.1
    Prevent viral entry: polyclonal and monoclonal antibodies
    Prevent translation of viral RNA: NS3/4 protease inhibitors and NS3-NS4A inhibitors.
    Inhibit HCV-RNA polymerase: nucleoside analogue NS5B polymerase inhibitors, non-nucleoside analogue NS5B polymerase inhibitors, NS5A inhibitor, and cyclophilin B inhibitors.
    Viral assembly/release: glucosidase inhibitor.
    Reference
    Pereira AA, Jacobson IM. New and experimental therapies for HCV. Nat Rev Gastroenterol Hepatol. 2009;6:403-411.
  • Slide: Selected Characteristics of Direct-Acting Antiviral Agents for Chronic HCV Infection
    This slides lists selected characteristics associated with direct-acting antiviral agents for chronic HCV infection. The clinical development of drugs with different mechanisms of action is expected to provide clinicians with more therapeutic options to achieve a cure while minimizing toxicities and emerging resistant variants.1
    Reference
    Schaefer EA, Chung RT. Anti-hepatitis C virus drugs in development. Gastroenterology. 2012;142:1340-1350.
  • Slide: Combination Therapy: Potential for Preventing the Emergence of Resistant Variants
    HCV drugs with different mechanisms of action have different patterns of resistance, underscoring the potential for combining direct acting antiviral agents to further minimize emergence of resistant variants.1
    Reference
    HCV DrAG ResisSS. 2012;1.2. Available at http://www.hivforum.org.
  • Slide: Program Overview
  • Slide: DAA + PegIFN + Ribavirin in Late Stage Clinical Development
    Listed on this slide are the phase 2b studies with DAA + peginterferon + ribavirin for which results have been reported.
  • Slide: ATOMIC Trial: Sofosbuvir + PR
    The ATOMIC study is an ongoing prospective, randomized phase 2b study assessing the safety and efficacy of the uridine nucleotide analog sofosbuvir 400 mg qd + peginterferon + ribavirin for 12 or 24 weeks versus peginterferon alfa-2a + ribavirin in treatment-naïve patients with chronic HCV genotype 1.1
    Reference
    Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. 2013;Mar 14. [Epub ahead of print].
  • Slide: ATOMIC Trial: Treatment Outcomes
    There was a rapid reduction in HCV RNA in first 2 weeks of therapy regardless of IL28B status. The SVR12 and 24 rates were comparable between sofosbuvir regimens of 12 and 24 week duration.1
    Virologic relapse was rare to date. Sequence data was available for 4 patients and found no S282T mutation (population sequencing). Deep sequencing results are pending for all patients with relapse.1
    Reference
    Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. 2013;Mar 14. [Epub ahead of print].
  • Slide: ATOMIC Trial: Safety and Tolerability
    Overall, sofosbuvir was generally well tolerated with no reports of serious adverse events. There was a low rate of treatment discontinuation due to adverse events associated with sofosbuvir (<5%).
    Adverse events reported are consistent with those associated with peginterferon + ribavirin treatment, which included constitutional symptoms, influenza-like symptoms, rash, anemia.1
    Reference
    Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. 2013;Mar 14. [Epub ahead of print].
  • Slide: NEUTRINO Study: Sofosbuvir + PR in Treatment-Naïve, HCV Genotype 1, 4, 5, and 6
    The NEUTRINO trial was a single-group, open-label study of sofosbuvir 400 mg qd + peginterferon alfa-2a + ribavirin for 12 weeks in 327 patients infected with HCV genotype 1, 4, 5, or 6. Ribavirin was administered orally as a divided dose according to body weight (1000 mg daily in patients with a body weight of <75 kg and 1200 mg daily in patients with a body weight of >75 kg).1,2
    There was no upper limit to age or BMI for study inclusion and opioid substitution permitted. Patients were to have a platelet >90,000/mm3 (cirrhotic: 17% enrolled).1,2
    The primary efficacy endpoint was SVR12 in comparison to a prespecified historical SVR12 control of 60%.1,2
    References
    Lawitz E, Wyles D, Davis M, et al. Sofosbuvir + peginterferon + ribavirin for 12 weeks achieves 90% SVR12 in genotype 1, 4, 5, or 6 HCV infected patients: the NEUTRINO study. J. Hepatol. 2013;58(suppl 1):S567. Abstract 1411.
    Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887.
  • Slide: NEUTRINO Study: SVR12 Rates by Prespecified Subgroups
    Sofosbuvir + PR resulted in a SVR12 of 90%, which was significantly higher than the historical control of 60% (P<0.001).1,2
    There were no substantial differences in SVR12 rates on the basis of HCV genotype, HCV RNA level, presence of cirrhosis, or IL28B genotype.1,2
    References
    Lawitz E, Wyles D, Davis M, et al. Sofosbuvir + peginterferon + ribavirin for 12 weeks achieves 90% SVR12 in genotype 1, 4, 5, or 6 HCV infected patients: the NEUTRINO study. J. Hepatol. 2013;58(suppl 1):S567. Abstract 1411.
    Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887.
  • Slide: NEUTRINO Study: Resistance and Safety
    No resistance was detected in the sofosbuvir + PR virologic failures. One relapse patient had discontinued therapy (HCV RNA >1000 IU/mL).1,2
    The safety of sofosbuvir + PR was well tolerated, with no additive effects of the addition of sofosbuvir to PR. There was a low rate of discontinuations due to adverse events (2%). The most common adverse events included fatigue (59%), headache (36%), nausea (34%), insomnia (25%), anemia (21%), and rash (18%).1,2
    Safety profile of sofosbuvir + PR was consistent with ribavirin with regard to anemia: hemoglobin <10 g/dL (23%) and hemoglobin <8.5 g/dL (2%).1,2
    References
    Lawitz E, Wyles D, Davis M, et al. Sofosbuvir + peginterferon + ribavirin for 12 weeks achieves 90% SVR12 in genotype 1, 4, 5, or 6 HCV infected patients: the NEUTRINO study. J. Hepatol. 2013;58(suppl 1):S567. Abstract 1411.
    Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887.
  • Slide: COMMAND-1 Study: Daclatasvir + PR
    Hezode and colleagues conducted a phase 2b, randomized study in treatment-naïve, genotype 1 or 4 patients (n=395) to evaluate the safety and efficacy of daclatasvir 20 or 60 mg qd + pegIFN RBV for 48 weeks. At week 12 patients were re-randomized to either another 12 weeks (24 weeks total) of triple therapy or 12 weeks of pegIFN + RBV if HCV RNA was <LOQ at week 4 and undetectable at week 10. The comparator arm was pegIFN + RBV for 48 weeks.1
    Reference
    Hezode C, Hirschfield GM, Ghesquiere W, et al. Daclatasvir, an NS5A replication complex inhibitor, combined with peginterferon alfa-2a and ribavirin in treatment-naïve HCV-genotype 1 or 4 subjects: phase 2b COMMAND study. Hepatology. 2012;56(suppl 4):553A. Abstract 755.
  • Slide: COMMAND-1 Study (ITT): SVR12 Rates (All PDR)
    Patients receiving daclatasvir-based triple therapy had higher SVR rates compared with pegIFN +RBV among genotypes 1 or 4, and among those with genotype 1a and 1b. Higher SVR rates tended to be in the 60 mg qd daclatasvir arm.1
    Reference
    Hezode C, Hirschfield GM, Ghesquiere W, et al. Daclatasvir, an NS5A replication complex inhibitor, combined with peginterferon alfa-2a and ribavirin in treatment-naïve HCV-genotype 1 or 4 subjects: phase 2b COMMAND study. Hepatology. 2012;56(suppl 4):553A. Abstract 755.
  • Slide: COMMAND-1 Study: SVR12 Rates by IL28B (All PDR)
    Overall, patients with IL28B CC genotype had higher SVR12 rates compared with non-CC genotypes. Higher SVR12 rates were seen in patients receiving daclatasvir-based triple therapy compared with PR.1
    Reference
    Hezode C, Hirschfield GM, Ghesquiere W, et al. Daclatasvir, an NS5A replication complex inhibitor, combined with peginterferon alfa-2a and ribavirin in treatment-naïve HCV-genotype 1 or 4 subjects: phase 2b COMMAND study. Hepatology. 2012;56(suppl 4):553A. Abstract 755.
  • Slide: COMMAND-1 Study: Daclatasvir + PR
    Overall, treatment failure was seen in 35% and 64% of patients receiving daclatasvir + PR and PR only, respectively. Treatment failure rates were lower in daclatasvir-treated patients who achieved PDR (11%-24%).1
    Both treatment arms had similar adverse event profiles, with discontinuations due to adverse events being <5%. Changes in laboratory parameters were consistent across all treatment arms.1
    Future clinical trials will be with genotype 1b patients only.1
    Reference
    Hezode C, Hirschfield GM, Ghesquiere W, et al. Daclatasvir, an NS5A replication complex inhibitor, combined with peginterferon alfa-2a and ribavirin in treatment-naïve HCV-genotype 1 or 4 subjects: phase 2b COMMAND study. Hepatology. 2012;56(suppl 4):553A. Abstract 755.
  • Slide: COMMAND-2 Study: Daclatasvir + PR
    Dore and colleagues conducted a phase 2b, randomized study in treatment-naïve, genotype 2 or 3 patients (n=351) to evaluate the safety and efficacy of 12 or 16 weeks of daclatasvir 60 mg qd + pegIFN RBV for 16 or 48 weeks. At week 12 patients were re-randomized to either another 12 weeks (24 weeks total) of triple therapy or 12 weeks of pegIFN + RBV if HCV RNA was <LOQ at week 4 and undetectable at week 10. The comparator arm was pegIFN + RBV for 48 weeks.1
    Reference
    Dore GJ, Lawitz E, Hezode C, et al. Daclatasvir combined with peginterferon alfa-2a and ribavirin for 12 or 16 weeks in patients with HCV genotype 2 or 3 infection: COMMAND GT2/3 study. J. Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1418.
  • Slide: COMMAND-2 Study (ITT): SVR24 Rates
    Patients receiving daclatasvir-based triple therapy had higher SVR rates compared with pegIFN +RBV among genotypes 2 or 3, and among those with genotype 2 IL28B CC and non-CC genotype, and genotype 3 with IL28B non-CC genotype.1
    Reference
    Dore GJ, Lawitz E, Hezode C, et al. Daclatasvir combined with peginterferon alfa-2a and ribavirin for 12 or 16 weeks in patients with HCV genotype 2 or 3 infection: COMMAND GT2/3 study. J. Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1418.
  • Slide: COMMAND-2 Study: Treatment Failure and Safety in Genotype 2/3
    Treatment failure (daclatasvir versus PR) was more common in genotype 3 patients. Factors associated with relapse in genotype 3 included:1
    With versus without baseline NS5A Y93 and/or A30 polymorphisms (50% versus 19%).
    Cirrhotics versus non-cirrhotics (36% versus 21%)
    No apparent effect of IL28B genotype or baseline HCV RNA on relapse
    The safety and tolerability profiles were similar across all arms. Approximately 7% of daclatasvir-treated patients discontinued due to adverse events compared with 4% in the PR arm.1
    Changes in laboratory parameters were consistent across all treatment arms.1
    Further evaluation of daclatasvir + PR in HCV genotype 2/3 patients is planned.1
    Reference
    Dore GJ, Lawitz E, Hezode C, et al. Daclatasvir combined with peginterferon alfa-2a and ribavirin for 12 or 16 weeks in patients with HCV genotype 2 or 3 infection: COMMAND GT2/3 study. J. Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1418.
  • Slide: DAUPHINE Study: Danoprevir/r + PR
    The DAUPHINE study was a phase 2b, randomized, open-label study in treatment-naïve, genotype 1 or 4 patients (n=421) evaluating the safety and efficacy of various doses of danoprevir/r + pegIFN + RBV (200/100 mg bid, 24 weeks; 100/100 mg bid, 24 weeks; 50/100 mg bid, 24 weeks; 100/100 mg bid, 12/24 weeks response-guided therapy) plus pegIFN + RBV compared with pegIFN + RBV only.1
    Reference
    Everson GT, Cooper C, Hezode C, et al. High SVR24 rates with ritonavir-boosted danoprevir plus pegIFN alfa-2a (40KD)/RBV in HCV genotype 1 or 4 patients in the DAUPHINE study. Hepatology. 2012;56(suppl 4):552A. Abstract 754.
  • Slide: DAUPHINE Study: SVR24 Rates
    SVR24 rates with ritonavir-boosted danoprevir were dose related (SVR24 for pegIFN + RBV not reported and not shown). The SVR24 dose-response relationship to danoprevir/r was seen in harder-to-treat patients (genotype 1a, IL-28B non-CC).1
    Overall danoprevir/r was well tolerated with low rates of withdrawals due to adverse events (4% to 9%). There was no significant dose-dependent increases in anemia, neutropenia, or rash.1
    Reference
    Everson GT, Cooper C, Hezode C, et al. High SVR24 rates with ritonavir-boosted danoprevir plus pegIFN alfa-2a (40KD)/RBV in HCV genotype 1 or 4 patients in the DAUPHINE study. Hepatology. 2012;56(suppl 4):552A. Abstract 754.
  • Slide: DAUPHINE Safety and Tolerability
    Overall, 17.5% of patients experienced treatment failure and 11% had relapse (predominately genotype 1a and non-CC IL28G genotype).1
    - Resistance was uniquely associated with the NS3 R155K substitution.
    Both treatment arms had similar adverse event profiles, with 5% of patients discontinuing treatment due to adverse events.1
    Laboratory abnormalities were not dose related.1
    Anemia (hemoglobin <8.9 g/dL or any decrease >4.5 g/dL): 7%.
    Reference
    Everson GT, Cooper C, Hezode C, et al. High SVR24 rates with ritonavir-boosted danoprevir plus pegIFN alfa-2a (40KD)/RBV in HCV genotype 1 or 4 patients in the DAUPHINE study. Hepatology. 2012;56(suppl 4):552A. Abstract 754.
  • Slide: QUEST-1 and -2 Trials: Simeprevir + PR in Treatment-Naïve, HCV Genotype 1
    QUEST-1 and -2 were phase 3 trials of similar design in treatment-naïve, genotype 1 HCV. Patients were randomized to receive either simeprevir + PR for 12 weeks followed by PR alone for 12 or 36 weeks or PR alone for 48 weeks.1,2
    Patients were to have an HCV RNA >10,000 IU/mL at enrollment. Patients were stratified by HCV subtype and IL28B genotype.
    Response-guided therapy criteria: HCV RNA <25 IU/mL at week 4 and undetectable at week 12.1,2
    The distribution of patients with a METAVIR score of F0-F1 and >F2 was approximately 50% and 50%, respectively.1,2
    Primary efficacy endpoint: SVR12.1,2
    References
    Jacobson I, Dore GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naive patients: results from QUEST-1, a phase III trial. J. Hepatol. 2013;58(suppl 1):S574. Abstract 1425.
    Manns M, Marcellin P, Poordad F, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-2, a phase III trial. J. Hepatol. 2013;58(suppl 1):S568. Abstract 1413.
  • Slide: QUEST-1 and 2 Trials: Overall SVR12 Rates by Genotype 1 Subgroup
    Patients receiving simeprevir + PR had significantly higher SVR rates compared with PR alone regardless baseline HCV genotyp (P<0.01).1,2
    References
    Jacobson I, Dore GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naive patients: results from QUEST-1, a phase III trial. J. Hepatol. 2013;58(suppl 1):S574. Abstract 1425.
    Manns M, Marcellin P, Poordad F, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-2, a phase III trial. J. Hepatol. 2013;58(suppl 1):S568. Abstract 1413.
  • Slide: QUEST-1 and -2 Trials: SVR12 Rates by Prespecified Subgroups
    Patients receiving simeprevir + PR had significantly higher SVR rates compared with PR alone regardless baseline IL28B genotype or METAVIR score (P<0.01).1,2
    References
    Jacobson I, Dore GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naive patients: results from QUEST-1, a phase III trial. J. Hepatol. 2013;58(suppl 1):S574. Abstract 1425.
    Manns M, Marcellin P, Poordad F, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-2, a phase III trial. J. Hepatol. 2013;58(suppl 1):S568. Abstract 1413.
  • Slide: QUEST-1 and -2 Trials: Resistance and Safety
    Among patients who failed simeprevir + PR, 98% had NS3 PI mutations at the of failure.1,2
    Genotype 1: mainly R155 alone.
    Genotype 1b: mainly D168V or Q80R + D168E.
    Overall, simeprevir + PR was well tolerated, with a low incidence of treatment discontinuations due to adverse events.1,2
    The adverse event profile of simeprevir + PR was similar to the PR arm, with the most frequent adverse events being headache, pyrexia, fatigue, influenza-like illness, rash, anemia, and pruritus.1,2
    References
    Jacobson I, Dore GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naive patients: results from QUEST-1, a phase III trial. J. Hepatol. 2013;58(suppl 1):S574. Abstract 1425.
    Manns M, Marcellin P, Poordad F, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-2, a phase III trial. J. Hepatol. 2013;58(suppl 1):S568. Abstract 1413.
  • Slide: ASPIRE Trial: Simeprevir + PR
    The ASPIRE trial is an ongoing prospective, randomized phase 2b study assessing the safety and efficacy of the NS3/4A protease inhibitor simeprevir (100 or 150 mg qd) for either 12, 24, or 48 weeks versus peginterferon alfa-2a + ribavirin in nonresponders to previous pegIFN + ribavirin therapy (HCV genotype 1).1
    The primary outcome was a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy).1
    Reference
    Zeuzem S, Berg T, Gane E, et al. TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon/ribavirin treatment: final SVR24 results of the ASPIRE Trial. J. Hepatol. 2012;56(suppl 2):S1. Abstract 2.
  • Slide: ASPIRE Trial: SVR24 Rates With Simeprevir + PR
    Patients in the simeprevir arms achieved higher SVR24 rates compared with peginterferon + ribavirin, with the highest rates achieved in patients who were prior relapsers to peginterferon + ribavirin therapy.1
    Reference
    Zeuzem S, Berg T, Gane E, et al. TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon/ribavirin treatment: final SVR24 results of the ASPIRE Trial. J. Hepatol. 2012;56(suppl 2):S1. Abstract 2.
  • Slide: ASPIRE Trial: Resistance and Safety and Tolerability
    In the ASPIRE trial, viral breakthrough/relapse was usually associated with emerging mutations to simeprevir.1,2
    Q80K at baseline did not alter SVR24 rates in the simeprevir 150 mg treatment arms.
    Both treatment arms were well tolerated, with 7% of patients discontinuing therapy due to adverse events.1,2
    Hematologic abnormalities were similar across all treatment arms.
    Mild and reversible increases in bilirubin were seen in the simeprevir arms.
    No other liver changes
    References
    Lenz O, Fevery B, Vigen L, et al. TMC435 in patients infected with HCV genotype 1 who have failed previous pegylated interferon/ribavirin treatment: virologic analysis of the ASPIRE trial. J. Hepatol. 2012;56(suppl 2):S5. Abstract 9.
    Zeuzem S, Berg T, Gane E, et al. TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon/ribavirin treatment: final SVR24 results of the ASPIRE Trial. J. Hepatol. 2012;56(suppl 2):S1. Abstract 2.
  • Slide: STARTVerso1 Trial: Faldaprevir + PR in Treatment-Naïve, Genotype 1
    The STARTVerso1 trial was a phase 3 study in treatment-naïve, HCV genotype 1 patients. Patients were randomized to receive either 1) faldaprevir 120 mg qd for 12 or 24 weeks (response guided); 2) faldaprevir 240 mg qd for 12 weeks; or 3) 24 weeks PR.1
    Patients with early treatment success (ETS, HCV RNA < 25 IU/mL at Week 4 and undetectable at Week 8) stopped all treatment at Week 24.
    Patients without ETS received PR for 48 weeks.
    Randomization was stratified by HCV genotype-1 subtype and race.1
    The primary endpoint was SVR12 after planned end of treatment.1
    Reference
    Ferenci P, Asselah T, Foster GR, et al. Faldaprevir plus pegylated interferon alfa-2a and ribavirin in chronic HCV genotype-1 treatment-naïve patients: final results from STARTVERSO1, a randomised, double-blind, placebo-controlled phase III trial. J. Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416.
  • Slide: STARTVerso1 Trial: Faldaprevir + PR in Treatment-Naïve, Genotype 1
    Patients in the faldaprevir-based arms had significantly higher SVR12 rates compared with PR (79% and 80% versus 52%; P<0.0001). Higher SVR12 rates were achieved with faldaprevir + PR regardless of baseline genotype 1 subtype, and IL28B genotype.1
    Reference
    Ferenci P, Asselah T, Foster GR, et al. Faldaprevir plus pegylated interferon alfa-2a and ribavirin in chronic HCV genotype-1 treatment-naïve patients: final results from STARTVERSO1, a randomised, double-blind, placebo-controlled phase III trial. J. Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416.
  • Slide: STARTVerso1 Trial: Resistance and Safety
    There was no significant effect of Q80K on SVR12 in genotype 1a patients (Note: the Q80K mutation is associated with a decreased susceptibility to some NS3/4A protease inhibitors).1
    Faldaprevir + PR was well tolerated with a low incidence of discontinuations due to adverse events (4%).1
    The adverse event profile of faldaprevir + PR was similar to the PR arm, with the most common adverse events of at least moderate severity were rash (8%) and anemia (12%).1
    The elevations in total bilirubin (>2.6 x ULN) seen in the faldaprevir + PR treatment arms were benign and transient (120 mg qd: 12%; 240 mg qd: 53%).1
    Reference
    Ferenci P, Asselah T, Foster GR, et al. Faldaprevir plus pegylated interferon alfa-2a and ribavirin in chronic HCV genotype-1 treatment-naïve patients: final results from STARTVERSO1, a randomised, double-blind, placebo-controlled phase III trial. J. Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416.
  • Slide: SILEN-C2 Study: Faldaprevir + PR (Non-Responders)
    The SILEN-C2 trial was phase 2b study of the NS3/4A protease inhibitor faldaprevir in genotype 1 patients who were nonresponsive to previous pegIFN + ribavirin therapy (relapsers excluded) (C2).1
    LI/240 mg bid/PR: peginterferon alfa-2a and ribavirin daily for 3 days, followed by peginterferon alfa-2b, ribavirin, and faldaprevir 240 mg bid for 20 weeks, then 24 weeks of peginterferon alfa-2a and ribavirin.
    Faldaprevir (240 mg qd) + peginterferon alfa-2a and ribavirin for 24 weeks, then peginterferon alfa-2a and ribavirin another 24 weeks.
    LI/240 mg qd/PR: peginterferon alfa-2a and ribavirin daily for 3 days, followed by peginterferon alfa-2a, ribavirin, and faldaprevir 240 mg qd for 20 weeks, then either 24 weeks of peginterferon alfa-2a and ribavirin or follow-up depending on whether eRVR is achieved.
    The primary outcome was a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy).1
    Reference
    Sulkowski MS, Bourliere M, Bronowicki J-P, et al. SILEN-C2: sustained virologic response (SVR) and safety of BI1201335 combined with peginterferon alfa-2a and ribavirin (P/R) in chronic HCV genotype 1 patients with non-response to P/R. J Hepatol. 2011;54(suppl 1):S30. Abstract 66.
  • Slide: SILEN-C2 Study: SVR and Overall Relapse With Faldaprevir
    The rate of sustained virologic response was 27%, 41%, and 31% in the LI/240 mg qd, 240 mg qd, and LI240 mg bid group, respectively.1
    Overall relapse occurred in 25%, 9%, and 19% in the LI/240 mg qd, 240 mg qd, and LI240 mg bid group, respectively.1
    Reference
    Sulkowski MS, Bourliere M, Bronowicki J-P, et al. SILEN-C2: sustained virologic response (SVR) and safety of BI1201335 combined with peginterferon alfa-2a and ribavirin (P/R) in chronic HCV genotype 1 patients with non-response to P/R. J Hepatol. 2011;54(suppl 1):S30. Abstract 66.
  • Slide: SILEN-C2 Study: Virologic Failure, Discontinuations, and Adverse Events
    The virologic failure rates were similar across all treatment arms, although they tended to be higher in the 240 mg qd arms .1
    Overall, discontinuations due to adverse events were higher in the faldaprevir LI/240 mg bid arm and similar among the 2 groups.1
    The most common adverse events were nausea, diarrhea, and rash, and were higher in the faldaprevir LI/240 mg qd arm. None of the cases of jaundice were severe.1
    Reference
    Sulkowski MS, Bourliere M, Bronowicki J-P, et al. SILEN-C2: sustained virologic response (SVR) and safety of BI1201335 combined with peginterferon alfa-2a and ribavirin (P/R) in chronic HCV genotype 1 patients with non-response to P/R. J Hepatol. 2011;54(suppl 1):S30. Abstract 66.
  • Slide: Program Overview
  • Slide: Multiple DAA + PegIFN + Ribavirin in Late Stage Clinical Development
    Listed on this slide are the phase 2 studies with multiple DAA + peginterferon + ribavirin for which results have been reported.
  • Slide: MATTERHORN Study: Danoprevir/r + Mericitabine + PR
    The MATTERHORN is a multicenter, randomized, open-label, parallel phase II trial evaluating the safety of danoprevir/r + mericitabine + RBV with or without pegIFN.1
    The study included both prior partial responders and prior null responders to pegIFN + RBV.1
    Reference
    Feld JJ, Jacobson IM, Jensen DM, et al. Up to 100% SVR4 rates with ritonavir-boosted danoprevir (DNVr), mericitabine (MCB), and ribavirin (R) ± peginterferon alfa-2a (40KD) (P) in HCV genotype 1-infected partial and null responders: results from the MATTERHORN study. Hepatology. 2012;56(suppl 4):231A-232A. Abstract 81.
  • Slide: MATTERHORN Study: Treatment Outcomes
    The highest overall SVR12 rates were seen in the QUAD arm and the lowest SVR12 rates were in the IFN-free arm. In addition, higher SVR rates were seen in genotype 1b patients (91% to 100%). In genotype 1a patients, the addition of mericitabine increased SVR12 from 30% to 75%.1
    Virologic breakthrough was associated with the emergence of danoprevir/r resistance (R155K D168E/T), but not mericitabine resistance.1
    All regimens were safe and well tolerated and the addition of mericitabine did not change the safety profile of danoprevir/r + pegIFN + RBV.1
    Reference
    Feld JJ, Jacobson IM, Jensen DM, et al. Up to 100% SVR4 rates with ritonavir-boosted danoprevir (DNVr), mericitabine (MCB), and ribavirin (R) ± peginterferon alfa-2a (40KD) (P) in HCV genotype 1-infected partial and null responders: results from the MATTERHORN study. Hepatology. 2012;56(suppl 4):231A-232A. Abstract 81.
  • Slide: Study 011 (Expansion Cohort): Daclatasvir + Asunaprevir + PR
    Lok and colleagues reported on the results from Study 011, which was randomized, open-label phase 2a study on the safety of daclatasvir + asunaprevir with or without pegIFN + RBV in genotype 1 null responders.1
    - Two difference doses of asunaprevir were also evaluated in this study.
    Reference
    Lok AS, Gardiner DF, Hezode C, et al. Sustained virologic response in chronic HCV genotype (GT)-1-infected null responders with combination of daclatasvir (DCV; NS5A inhibitor) and asunaprevir (ASV; NS3 inhibitor) with or without peginterferon alfa-2a/ribavirin (PEG/RBV). Hepatology. 2012;56(suppl 4):230A. Abstract 79.
  • Slide: Study 011: Treatment Outcomes
    Patients receiving the QUAD regimen achieved higher SVR12 rates compared with those receiving the dual regimen. However, 56% of patients experienced viral breakthrough in the triple regimen (without pegIFN).1
    The overall safety and tolerability of all 3 regimens was well tolerated, with no discontinuations due to adverse events. The most common adverse events were headache, diarrhea, fatigue, and insomnia. No deaths were reported during the study.1
    Reference
    Lok AS, Gardiner DF, Hezode C, et al. Sustained virologic response in chronic HCV genotype (GT)-1-infected null responders with combination of daclatasvir (DCV; NS5A inhibitor) and asunaprevir (ASV; NS3 inhibitor) with or without peginterferon alfa-2a/ribavirin (PEG/RBV). Hepatology. 2012;56(suppl 4):230A. Abstract 79.
  • Slide: Program Overview
  • Slide: Interferon-Free Regimens in Late Stage Clinical Development
    Listed on this slide are the phase 2 studies with interferon-free regimens for which results have been reported.
  • Slide: FISSION Trial: Sofosbuvir + RBV in Treatment-Naïve, HCV Genotype 2 or 3
    The FISSION trial was a phase 3, open-label study in treatment-naïve, genotype 2 or 3 HCV patients who received either 12 weeks of sofosbuvir 400 mg qd + ribavirin 1000-1200 mg/day (n=256) or 24 weeks of peginterferon alfa 2a + ribavirin 800 mg/day (n=243).1,2
    There was no upper limit to age or BMI for study inclusion and opioid substitution permitted. Patients were to have a platelet >75,000/mm3 (cirrhotic: 20% maximum).1,2
    Patients were stratified by genotype, HCV RNA, and cirrhosis.1,2
    The primary efficacy endpoint: SVR12 (non-inferiority margin: 15%).1,2
    References
    Gane E, Lawitz E, Rodriquez-Torres M, et al. Phase 3 randomized controlled trial of all-oral treatment with sofosbuvir+ribavirin for 12 weeks compared to 24 weeks of peg+ribavirin in treatment-naïve Gt2/3 HCV-infected patients (FISSION). J. Hepatol. 2013;58(suppl 1):S3. Abstract 5.
    Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887.
  • Slide: FISSION Trial: SVR12 Rates by Prespecified Subgroups
    Sofosbuvir–ribavirin was shown to be non-inferior to peginterferon + ribavirin with respect to the primary end point. At 12 weeks, the rates of SVR for patients receiving 12 weeks of sofosbuvir + ribavirin and those receiving 24 weeks of peginterferon + ribavirin were each 67%.1,2
    A SVR occurred in 97% of patients with genotype 2 and in 56% of those with genotype 3 in the group receiving sofosbuvir + ribavirin, as compared with response rates of 78% and 63%, respectively, in the group receiving peginterferon + ribavirin.1,2
    SVR rates based on baseline HCV RNA levels were similar between the two treatment arms.1,2
    Among patients with cirrhosis at baseline, 47% of those receiving sofosbuvir + ribavirin had a SVR, as compared with 38% of those receiving peginterferon + ribavirin. SVR rates in those without cirrhosis were higher at 72% and 74%, respectively.1,2
    SVR rates among male and females were similar between the 2 treatment arms, with females achieving numerically higher SVR rates compared with males.1,2
    References
    Gane E, Lawitz E, Rodriquez-Torres M, et al. Phase 3 randomized controlled trial of all-oral treatment with sofosbuvir+ribavirin for 12 weeks compared to 24 weeks of peg+ribavirin in treatment-naïve Gt2/3 HCV-infected patients (FISSION). J. Hepatol. 2013;58(suppl 1):S3. Abstract 5.
    Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887.
  • Slide: FISSION Trial: SVR12 Rates by Genotype and Cirrhosis
    Among patients receiving sofosbuvir + ribavirin, genotype 2 infection and an absence of cirrhosis were strongly associated with high SVR rates compared with genotype 3 patients and patients receiving peginterferon + ribavirin.1,2
    References
    Gane E, Lawitz E, Rodriquez-Torres M, et al. Phase 3 randomized controlled trial of all-oral treatment with sofosbuvir+ribavirin for 12 weeks compared to 24 weeks of peg+ribavirin in treatment-naïve Gt2/3 HCV-infected patients (FISSION). J. Hepatol. 2013;58(suppl 1):S3. Abstract 5.
    Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887.
  • Slide: FISSION Trial: Resistance and Safety
    No resistance was detected among the sofosbuvir + RBV virologic failures, with relapse accounting for all but 1 virologic failure (nonadherence).1
    The safety of sofosbuvir + ribavirin was well tolerated with few adverse events. The most common adverse events included fatigue (36%), headache (25%), nausea (18%), and insomnia (12%). The overall safety profile was consistent with ribavirin therapy.1
    References
    Gane E, Lawitz E, Rodriquez-Torres M, et al. Phase 3 randomized controlled trial of all-oral treatment with sofosbuvir+ribavirin for 12 weeks compared to 24 weeks of peg+ribavirin in treatment-naïve Gt2/3 HCV-infected patients (FISSION). J. Hepatol. 2013;58(suppl 1):S3. Abstract 5.
    Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887.
  • Slide: FUSION Trial: Sofosbuvir + RBV for 12 Versus 16 Weeks in HCV Genotype 2/3, Previously Failed PR Therapy
    The FUSION trial was a phase 3, open-label study in patients who failed previous peginterferon + ribavirin therapy who were genotype 2 or 3 HCV patients. Patients received either 12 or 16 weeks of sofosbuvir 400 mg qd + ribavirin 1000-1200 mg/day.1,2
    There was no upper limit to age or BMI for study inclusion and opioid substitution permitted. Patients were to have a platelet >50,000/mm3, with no neutrophil minimum. Approximately 34% were cirrhotic at baseline and 34% were prior relapsers to peginterferon + ribavirin therapy.1,2
    Patients were stratified by genotype and cirrhosis.1,2
    The primary efficacy endpoint: SVR12.1,2
    References
    Nelson DR, Feld J, Kowdley KV, et al. All oral therapy with sofosbuvir+ribavirin for 12 or 16 weeks in treatment experienced Gt2/3 HCV-infected patients: results of the phase 3 FUSION trial. J. Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6.
    Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867-1877.
  • Slide: FUSION Trial: SVR12 Rates by Prespecified Subgroups
    Patients treated with sofosbuvir + ribavirin in the population of patients with prior treatment were superior to the historical control rate of 25%, with rates of 50% and 73% in the 12- and 16-week groups, respectively. The SVR rate in the 16-week arm was significantly higher compared with the 12-week arm (P<0.001).1,2
    Overall, 16-weeks of sofosbuvir + ribavirin produced significantly higher SVR rates relative to the 12-week arm regardless of baseline genotype, HCV RNA, presence of cirrhosis, and gender.1,2
    References
    Nelson DR, Feld J, Kowdley KV, et al. All oral therapy with sofosbuvir+ribavirin for 12 or 16 weeks in treatment experienced Gt2/3 HCV-infected patients: results of the phase 3 FUSION trial. J. Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6.
    Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867-1877.
  • Slide: FUSION Trial: SVR12 Rates by Genotype and Cirrhosis
    SVR rates were decreased among those with cirrhosis at baseline relative the absence of cirrhosis. The SVR rate among patients with cirrhosis in the 12-week arm was 31% (60% with HCV genotype 2 infection and 19% with HCV genotype 3 infection), as compared with 61% among patients without cirrhosis (96% with HCV genotype 2 infection and 37% with HCV genotype 3 infection).1,2
    Among patients with cirrhosis in the 16-week arm, the SVR rate was 66% (78% with HCV genotype 2 infection and 61% with HCV genotype 3 infection) as compared with 76% among patients without cirrhosis (100% with HCV genotype 2 infection and 63% with HCV genotype 3 infectionn.1,2
    References
    Nelson DR, Feld J, Kowdley KV, et al. All oral therapy with sofosbuvir+ribavirin for 12 or 16 weeks in treatment experienced Gt2/3 HCV-infected patients: results of the phase 3 FUSION trial. J. Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6.
    Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867-1877.
  • Slide: FUSION Trial: Resistance and Safety
    No resistance was detected in among virologic failures in the sofosbuvir + ribavirin arm.1,2
    The safety of sofosbuvir + ribavirin was well tolerated, with few adverse events. There were no discontinuations due to adverse events. The most common adverse events included fatigue (46%), headache (27%), nausea (21%), and insomnia (24%).1,2
    The safety profile of both regimens was consistent with ribavirin relative to anemia: hemoglobin <10 g/dL (7.5%) and hemoglobin <8.5 g/dL (1%).1,2
    References
    Nelson DR, Feld J, Kowdley KV, et al. All oral therapy with sofosbuvir+ribavirin for 12 or 16 weeks in treatment experienced Gt2/3 HCV-infected patients: results of the phase 3 FUSION trial. J. Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6.
    Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867-1877.
  • Slide: POSITRON Trial: Sofosbuvir + RBV in HCV Genotype 2 or 3 With Limited Options
    The POSITRON trial was a blinded, placebo-controlled study that compared 12-weeks sofosbuvir + ribavirin with placebo in patients who had previously discontinued interferon therapy owing to unacceptable adverse events, who had a concurrent medical condition precluding therapy with an interferon-containing regimen, or who had decided against treatment with an interferon-containing regimen.
    There was no upper limit to age or BMI for study inclusion and opioid substitution permitted. There was no lower limit of platelet or neutrophil count (cirrhotic: 16% at baseline).1,2
    Patients were stratified by presence or absence of cirrhosis.1,2
    The primary efficacy endpoint: SVR12.1,2
    References
    Jacobson IM, Yoshida EM, Sulkowski MS, et al. Treatment with sofosbuvir+ribavirin for 12 weeks achieves SVR12 of 78% in GT2/3 interferon-ineligible, -intolerant, or -unwilling patients: results of the phase 3 POSITRON trial. J. Hepatol. 2013;58(suppl 1):S28. Abstract 61.
    Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867-1877.
  • Slide: POSITRON Trial: SVR12 Rates With Sofosbuvir + RBV by Prespecified Subgroups
    The SVR12 was 78% among patients receiving sofosbuvir + ribavirin, as compared with 0% among those receiving placebo (P<0.001).1,2
    Among patients who received sofosbuvir + ribavirin, 93% of patients with HCV genotype 2 infection had a SVR compared with 61% of those with HCV genotype 3 infection.1,2
    There was no difference in the SVR12 rate baed on baseline HCV RNA level.1,2
    81% of patients without cirrhosis had a SVR compared with 61% of patients with cirrhosis.1,2
    References
    Jacobson IM, Yoshida EM, Sulkowski MS, et al. Treatment with sofosbuvir+ribavirin for 12 weeks achieves SVR12 of 78% in GT2/3 interferon-ineligible, -intolerant, or -unwilling patients: results of the phase 3 POSITRON trial. J. Hepatol. 2013;58(suppl 1):S28. Abstract 61.
    Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867-1877.
  • Slide: POSITRON Trial: SVR12 Rates With Sofosbuvir + RBV by Genotype and Cirrhosis
    Among patients without cirrhosis, 92% with HCV genotype 2 infection and 68% with HCV genotype 3 infection had a SVR compared with 94% of HCV genotype 2 and 21% of HCV genotype 3 with cirrhosis.1,2
    References
    Jacobson IM, Yoshida EM, Sulkowski MS, et al. Treatment with sofosbuvir+ribavirin for 12 weeks achieves SVR12 of 78% in GT2/3 interferon-ineligible, -intolerant, or -unwilling patients: results of the phase 3 POSITRON trial. J. Hepatol. 2013;58(suppl 1):S28. Abstract 61.
    Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867-1877.
  • Slide: POSITRON Trial: Resistance and Safety
    No resistance detected in patients who failed sofosbuvir + ribavirin therapy.1,2
    The safety of sofosbuvir + ribavirin was well tolerated with few adverse events. Treatment discontinuations due to adverse events was seen in 2% of patients.1,2
    The most common adverse events included fatigue (44%), headache (21%), nausea (22%), and insomnia (19%).1,2
    The safety profile was consistent with ribavirin therapy relative to anemia: hemoglobin <10 g/dL (7%) and hemoglobin <8.5 g/dL (1%).1,2
    References
    Jacobson IM, Yoshida EM, Sulkowski MS, et al. Treatment with sofosbuvir+ribavirin for 12 weeks achieves SVR12 of 78% in GT2/3 interferon-ineligible, -intolerant, or -unwilling patients: results of the phase 3 POSITRON trial. J. Hepatol. 2013;58(suppl 1):S28. Abstract 61.
    Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867-1877.
  • Slide: ELECTRON Study: Sofosbuvir + Ribavirin
    ELECTRON was a phase 2b study in treatment-naïve patients with HCV genotype 2 or 3 infection to determine the shortest duration of peginterferon administration with sofosbuvir + ribavirin. Patients with cirrhosis were excluded from study participation.1
    Reference
    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.
  • Slide: ELECTRON Study: SVR Rates in HCV Geneotype 2/3 and 1
    All genotype 2 or 3 patients achieved a week 12 and 24 SVR who received sofosbuvir + ribavirin for 8 weeks.1
    Low SVR12 rates were achieved in genotype 1 null responders receiving sofosbuvir + ribavirin. A 84% SVR12 rate was achieved among genotype 1 treatment-naïve patients and 68% genotype 2, 3 treatment experienced patients.1
    Reference
    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.
  • Slide: ELECTRON Study: Sofosbuvir + RBV + Either Ledipasvir (NS5A Inhibitor) or GS-9669 (NS5B Non-Nucleoside Inhibitor)
    ELECTRON was a phase 2b study in treatment-naïve and treatment-experienced patients with HCV genotype 1 infection to determine the safety and efficacy of sofosbuvir 400 mg qd + ledipasvir + ribavirin (1000-1200 mg/day). Patients with cirrhosis were excluded from study participation.1
    Reference
    Gane EJ, Stedman CA, Hyland RH, et al. All-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV infection: the ELECTRON study. J. Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14.
  • Slide: ELECTRON Study (Genotype 1 Cohort): Interim Analysis of SVR12 Rates
    In the genotype 1 cohort, an SVR12 was achieved in 84%, 100%, and 92% of patients receiving sofosbuvir + ribavirin, sofosbuvir + ledipasvir + ribavirin, and sofosbuvir + GS-9669 + ribavirin, respectively. The SVR12 rates in prior null responders were 10%, 100%, and 100%, respectively (Note: the small number of patients in each arm).1
    Reference
    Gane EJ, Stedman CA, Hyland RH, et al. All-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV infection: the ELECTRON study. J. Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14.
  • Slide: ELECTRON Study (Genotype 1 Cohort): Safety
    The addition of ledipasvir to sofosbuvir + ribavirin or GS-9669 to sofosbuvir + ribavirin resulted in no additional safety or tolerability issues.
    A fix-dose combination of sofosbuvir/ledipasvir is undergoing phase 3 trial in patients with and without cirrhosis. Additional studies exploring shorter duration of therapy are planned.1
    Reference
    Gane EJ, Stedman CA, Hyland RH, et al. All-oral sofosbuvir-based 12-week regimens for the treatment of chronic HCV infection: the ELECTRON study. J. Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14.
  • Slide: Study 040: Sofosbuvir + Daclatasvir + Ribavirin
    Sulkowski and colleagues conducted a phase 2s study to evaluate the virologic response with all oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naïve patients chronically infected with HCV genotype 1, 2, or 3.1
    Reference
    Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. High-rate of sustained virologic response with all oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naïve patients chronically infected with HCV genotype 1, 2, or 3. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
  • Slide: Study 040: (24-Week Treatment): SVR12 and SVR24 Rates
    In this phase 2a study, all genotype 2/3 and 1 patients receiving sofosbuvir + daclatasvir achieved an SVR24. the addition of lead-in treatment with sofosbuvir or ribavirin did not improve SVR rates.1
    Reference
    Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. High-rate of sustained virologic response with all oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naïve patients chronically infected with HCV genotype 1, 2, or 3. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
  • Slide: Study 040: (24-Week Treatment): Safety and Tolerability
    Sofosbuvir + daclatasvir + RBV was well tolerated, with only 3% of patients receiving 24-week therapy discontinuing therapy due to adverse events. The most common adverse events were fatigue (36%), headache (27%), and nausea (26%).
    There were no grade 3/4 elevations in ALT, AST, or total bilirubin; and only 7% of patients had anemia (hemoglobin <9 g/dL) (all in the RBV-containing arms).1
    Reference
    Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. High-rate of sustained virologic response with all oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naïve patients chronically infected with HCV genotype 1, 2, or 3. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
  • Slide: Study 040: (12-Week Treatment): SVR4 Rate and Safety
    In genotype 1 patients receiving 12-weeks of sofosbuvir + ribavirin, there were no virologic failures.1
    A SVR12 of 100% was achieved in 68 of the 82 patients with evaluable dat at this time point.1
    No treatment discontinuations occurred due to adverse events. There was also no grade 3/4 anemia in patients not receiving ribavirin.1
    Reference
    Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. High-rate of sustained virologic response with all oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naïve patients chronically infected with HCV genotype 1, 2, or 3. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
  • Slide: Study 040: Sofosbuvir + Daclatasvir + RBV in Previous Telaprevir or Boceprevir Failures
    Sulkowski and colleagues conducted a phase 2a study to evaluate the virologic response with all oral combination of daclatasvir (NS5A inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in patients who were prior non-responders, relapse, or breakthrough with telaprevir or boceprevir based triple therapy in genotype 1 HCV patients.1
    Patients were to have a baseline HCV RNA >105 IU/mL, with no upper limit to age or BMI. Baseline METAVIR scores: F0-F1 (12%) and >F2 (88%).1
    NS3 polymorphisms conferring resistance to boceprevir or telaprevir as baseline were detected in 46% at baseline. NS5A polymorphisms conferring resistance to daclatasvir was seen in 7% at baseline.1
    Not included in the study were patients who discontinued telaprevir or boceprevir based triple therapy due to an adverse event.1
    The primary efficacy endpoint was SVR12.1
    Reference
    Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Sustained virologic response with daclatasvir plus sofosbuvir ± ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC). J. Hepatol. 2013;58(suppl 1):S570. Abstract 1417.
  • Slide: Study 040: (24-Week Treatment): SVR4 and SVR12 Rates
    All of the patients in the sofosbuvir + daclatasvir arm achieved an SVR 4 and SVR12. Similarly, all patients achieved an SVR4 in the sofosbuvir + daclatasvir + ribavirin arm. One patient was missing at post-treatment 12 weeks (thus the SVR12 rate), but the patient was HCV RNA undetectable at post-treatment week 24 (preliminary).1
    There were no virologic failures and neither baseline NS3 PI resistance nor use of RBV influenced response.1
    Overall, sofosbuvir + daclatasvir with or without ribavirin was well tolerated, with no discontinuations due to adverse events.1
    The most common adverse events (without ribavirin) included fatigue (29%), headache (33%), and arthralgia (14%). There were no grade 3/4 elevations in ALT, AST, or total bilirubin. Anemia (hemoglobin <9 g/dL) was not detected in any patient.1
    Reference
    Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Sustained virologic response with daclatasvir plus sofosbuvir ± ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC). J. Hepatol. 2013;58(suppl 1):S570. Abstract 1417.
  • Slide: Study 014: Asunaprevir + Daclatasvir + BMS-791325
    Everson and colleagues conducted a phase 2a, open-label study in treatment-naïve, HCV genotype 1 patients (n=32) to assess the safety and efficacy of daclatasvir, asunaprevir, and BMS-791325.1
    Non-cirrhotic.
    HCV RNA 6.3 log10 IU/mL.
    Genotype 1b (75%).
    IL28B CC genotype: 28%.
    Asunaprevir + daclatasvir + BMS-791325 75 mg was administered for 24 or 12 weeks. In this interim analysis, an SVR4 (24 and 12-week arms) was achieved in 94% of patients. An SVR12 (12-week arm only) was achieved in 94% of patients.1
    Reference
    Everson GT, Sims KD, Rodriguez-Torres M, et al. An interferon-free, ribavirin-free 12-week regimen of daclatasvir, asunaprevir, and BMS-791325 yielded SVR4 of 94% in treatment-naïve patients with genotype 1 chronic hepatitis C virus infection. Hepatology. 2012;56:1517A-1518A. Abstract LB-3.
  • Slide: SOUND-C2 Study: Faldaprevir + BI 207127 + Ribavirin
    SOUND-C is a phase 2b study on the efficacy and safety of interferon-free combination regimens of faldaprevir and BI 207127 with or without ribavirin for up to 40 weeks in patients with genotype 1 HCV infection.1
    Reference
    Zeuzem S, Soriano V, Asselah T, et al. Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor BI 201335 and the non-nucleoside NS5B inhibitor BI 207127 ± ribavirin (R): final results of SOUND-C2 and predictors of response. Hepatology. 2012;56(suppl 4):308A-309A. Abstract 232.
  • Slide: SOUND-C2 Study: Final SVR12 Results
    The highest SVR rates were achieved in patients receiving the BID regimen and among those with genotype 1b who received the BID regimen.1
    Reference
    Zeuzem S, Soriano V, Asselah T, et al. Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor BI 201335 and the non-nucleoside NS5B inhibitor BI 207127 ± ribavirin (R): final results of SOUND-C2 and predictors of response. Hepatology. 2012;56(suppl 4):308A-309A. Abstract 232.
  • Slide: SOUND-C2 Study: SVR12 by Genotype Subtype and METAVIR Score
    There were no significant differences in SVR12 rates between patients with mild or moderate fibrosis and those with advanced fibrosis/cirrhosis within each treatment arm and within genotype subtypes.1
    Reference
    Zeuzem S, Soriano V, Asselah T, et al. An analysis of response rates by fibrosis stage in patients treated with faldaprevir, BI 207127 and ribavirin in the SOUND-C2 study. J Hepatol. 2013;58(suppl 1):S498. Abstract 1227.
  • Slide: SOUND-C2 Study: Virologic Failure and Baseline Predictors of SVR12
    Virologic failure (twice daily, 28-week treatment arm):
    Genotype 1a versus 1b: 47% versus 8%.
    Genotype-1a patients had a higher rate of resistance compared with genotype-1b patients
    Baseline predictors of SVR12 (multivariate odds ratio):
    Gender (female:male): 3.99 (P<0001).
    HCV subtype (1a:1b): 7.11 (P<0.0001).
    IL28B genotype (CC:non-CC): 4.94 (P<0.0001).
    GGT (>ULN:normal): 2.08 (P=016).
    Reference
    Zeuzem S, Soriano V, Asselah T, et al. Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor BI 201335 and the non-nucleoside NS5B inhibitor BI 207127 ± ribavirin (R): final results of SOUND-C2 and predictors of response. Hepatology. 2012;56(suppl 4):308A-309A. Abstract 232.
  • Slide: SOUND-C2 Study: Safety and Tolerability
    The BID28W arm had the most favorable safety and tolerability profile.1
    Grade 3/4 bilirubin increase: 39% of patients.
    Grade 3/4 hemoglobin decrease: 2% of patients.
    No effects on white blood cell and platelet counts.
    Data from this interim analysis shows that combination of faldaprevir with ribavirin remains necessary.1
    Phase 3 studies planned for faldaprevir 120 mg bid + BI207600 600 mg bid + RBV in genotype 1b patients.1
    Reference
    Zeuzem S, Soriano V, Asselah T, et al. Interferon (IFN)-free combination treatment with the HCV NS3/4A protease inhibitor BI 201335 and the non-nucleoside NS5B inhibitor BI 207127 ± ribavirin (R): final results of SOUND-C2 and predictors of response. Hepatology. 2012;56(suppl 4):308A-309A. Abstract 232.
  • Slide: AVIATOR Study: ABT-450/r –Based Therapy (Treatment-Naïve Cohort)
    AVIATOR was a multicenter, randomized, open-label phase II study evaluating various doses of ritonavir-boosted ABT-450/r + ABT-267 + ABT-333 + ribavirin in treatment-naïve and null responders. Kowdley and colleagues presented the SVR24 data.1
    Reference
    Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 + ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
  • Slide: AVIATOR Study (ITT): SVR24 Rates (Treatment-Naïve Cohort)
    The highest SVR12 and 24 results were seen among the arms comprising all 3 direct-acting antivirals + ribavirin.1
    Reference
    Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 + ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
  • Slide: AVIATOR Study: SVR24 by Baseline Subgroups (Treatment-Naïve Cohort)
    The SVR24 rates for the 3 drug combination plus ribavirin arms were similar when analyzed by baseline subgroups.1
    Reference
    Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 + ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
  • Slide: AVIATOR Study: ABT-450/r –Based Therapy (Null Responders Cohort)
    AVIATOR was a multicenter, randomized, open-label phase II study evaluating various doses of ritonavir-boosted ABT-450/r + ABT-267 + ABT-333 + RBV in treatment-naïve and null responders. Kowdley and colleagues presented the SVR24 data.1
    Reference
    Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 + ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
  • Slide: AVIATOR Study (ITT): SVR Rates (Null Responders Cohort)
    All 3 treatment arms produced high SVR12 and 24 results in this difficult-to-treat patient population.1
    Reference
    Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 + ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
  • Slide: AVIATOR Study: SVR24 by Baseline Subgroups (Null Responders Cohort)
    The SVR24 rates for the 3 drug plus ribavirin arms were similar among the baseline subgroups.1
    Reference
    Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 + ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
  • Slide: AVIATOR Study: Virologic Relapse and Safety
    The virologic relapse rate in the 8-, 12-, and 24-week arms were 12.5%, 6.3%, and 2.5%, respectively.1
    There were few discontinuations due to adverse events in the 12- and 24-week arms (2.4%).1
    The most common adverse events were headache (31%), fatigue (30%), nausea (23%), insomnia (20%), diarrhea (15%).1
    Bilirubin increase: 2.4%.
    Anemia (hemoglobin 6.5 to <8 g/dL): 2.4%.
    Reference
    Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 + ribavirin in patients with chronic HCV GT1 infection: results from the AVIATOR study. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.
  • Slide: New and Emerging Strategies: Clinical Considerations
    Recent recommendations from the CDC emphasize the importance to screen and early diagnosis of HCV infection.
    Newly diagnosed patients with chronic HCV infection still require comprehensive counseling.
    For patients who are candidates for therapy:
    Initiate treatment with currently available therapy.
    Defer treatment until availability of new antiviral agents with the potential for increased efficacy, decreased adverse events, and shorter duration of therapy over existing regimens.
  • Slide: New and Emerging Strategies: Conclusions
    Results from phase 2 trials for all oral agents are excellent, with well tolerated regimens and high SVR rates.
    High SVR rates with interferon-free regimens are possible in a variety of patient populations, including difficult-to-treat patient populations (prior null responders and cirrhotics). Ribavirin and IL28B status remain important for some regimens.
    Non-CC and genotype 1a status remain important for DAA + peginterferon + ribavirin regimens.
    Further study is needed for DAAs in special patient populations (ie, cirrhosis, HIV coinfection, liver transplant recipients).
  • Slide: New Electronic Evaluation Process
  • Slide: Outcomes Measurement Reminder
  • Simply Speaking Hepatitis February 7 2014

    1. 1. New and Emerging Strategies to Simplify the Cure of Chronic Hepatitis C Infection Sponsored for CME credit by Rush University Medical Center Supported by an independent educational grant from Gilead Sciences Medical Affairs
    2. 2. 2 New Sign-In ProcessNew Sign-In Process We Are Eliminating Hard Copy Evaluations!• Please clearly print all information on the sign-in sheet • You must indicate your NAME, DEGREE, MAILINGNAME, DEGREE, MAILING ADDRESS, EMAIL and SIGNATUREADDRESS, EMAIL and SIGNATURE (NAPB # pharmacists only) in order to attend this lecture • Completion is required for all healthcare providers • Failure to provide complete information will result in removal from attending future lectures
    3. 3. 3 CME Disclosure and Slide HandoutsCME Disclosure and Slide Handouts We Are Eliminating Hard Copy Evaluations!● CME DisclosureCME Disclosure - These slides may not be videotaped, published, posted online, and/or presented for Continuing Medical Education credit without written permission from Rush University Medical Center and Practice Point Communications ● Disclosure InformationDisclosure Information - It is the policy of the Rush University Office of Interprofessional Continuing Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME - Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months - If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Interprofessional Continuing Education prior to the participation of the faculty member in the development or presentation of course content ● Slide HandoutsSlide Handouts - The enclosed slide handouts are provided for reference purposes only - The faculty presenter may have customized the slides through reordering or deleting and thus the handouts may not exactly match the presentation
    4. 4. 4 EducatorEducator We Are Eliminating Hard Copy Evaluations! ● Disclosures - Grants/Research Support: list here - Consultant: list here - Speakers’ Bureau: list here - Stock Shareholder: list here - Other Financial or Material Support: list here Educator Title, Degree Affiliation City, State EDUCATOR TO COMPLETE
    5. 5. 5 Accreditation and DesignationAccreditation and Designation Supported by an independent educational grant from Gilead Sciences Medical Affairs. Rush University (OH-390, 8/25/2014) is an approved provider of continuing education by the Ohio Nurses Association (OBN-001-91), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. Rush University designates this live activity for one (1) Continuing Nursing Education credit. Rush University Medical Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Rush University Medical Center designates this live activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only credit commensurate with the extent of their participation in the activity. The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (UAN #0012-9999-13-013-L01-P). This activity is accredited for 1 hour of continuing pharmacy education (CPE) credit. The University of Florida College of Pharmacy will report all credit to CPE Monitor within 30 working days after receiving evidence of successful completion of the course. Successful completion means that you must attend the entire program and complete an evaluation form.
    6. 6. 6 FacultyFaculty CME Course DirectorCME Course Director Harold A. Kessler, MD rofessor of Medicine and Immunology/Microbiology Associate Director, Section of Infectious Diseases Rush University Medical Center Chicago, Illinois Content Development and TrainingContent Development and Training Mark S. Sulkowski, MD Professor of Medicine Medical Director, Viral Hepatitis Center Johns Hopkins Medical Institution Baltimore, Maryland Program ChairProgram Chair S. Martin Cohen, MD Medical Director, Hepatology Professor of Medicine University Hospitals/Case Medical Center Cleveland, Ohio CME ReviewerCME Reviewer David M. Simon, MD, PhD Associate Professor of Medicine Section of Infectious Diseases Rush University Medical Center Chicago, Illinois
    7. 7. 7 Faculty DisclosuresFaculty Disclosures CME Course Director: Harold A. Kessler, MD Program Chair: S. Martin Cohen, MD Content Development and Training: Mark S. Sulkowski, MD Grants/research support None None Anadys, BIPI, Genentech, Gilead Sciences, Merck, Tibotec, Vertex Consultant None Bristol-Myers Squibb, Gilead Sciences, Vertex AbbVie, Anadys, BIPI, Genentech, Gilead Sciences, Merck, Tibotec, Vertex Speakers’ bureau None Bristol-Myers Squibb, Genentech, Gilead Sciences, Vertex None Stock shareholder AbbVie, GlaxoSmithKline, Merck None None Other financial or material support None None None
    8. 8. 8 Faculty DisclosuresFaculty Disclosures CME Reviewer: David M. Simon, MD, PhD Medical Editor: Peter Pinkowish Grants/research support None None Consultant None None Speakers’ bureau None None Stock shareholder None None Other financial or material support None None
    9. 9. 9 Opinions and Off-Label DiscussionsOpinions and Off-Label Discussions The opinions or views expressed in this educational program are those of the participants and do not necessarily reflect the opinions or recommendations of Gilead Sciences Medical Affairs, Rush University Medical Center, Rush University College of Nursing, or the University of Florida College of Pharmacy The faculty may have included discussion on unlabeled uses of a commercial product or an investigational use of a product not yet approved for this purpose Please consult the full prescribing information before usingPlease consult the full prescribing information before using any medication mentioned in this programany medication mentioned in this program
    10. 10. 10 New Electronic Evaluation ProcessNew Electronic Evaluation Process We Are Eliminating Hard Copy Evaluations!• You will receive an electronic evaluation to the email address provided within 1 business day • Reminder email communications will be sent up to 5 days post lecture until the evaluation is completed • Completion Is Required for CME/CNE/CPE credit and future attendance • Incomplete evaluations will preclude attendees from receiving their CME/CNE/CPE certificate & future communications about lectures in your area
    11. 11. 11 Learning ObjectivesLearning Objectives (CME/CNE and CPE)(CME/CNE and CPE) We Are Eliminating Hard Copy Evaluations! ● Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine: - Assess my hepatitis C (HCV)-infected patients on their chances of achieving a successful outcome after failing to respond to either PI-based therapy of a peginterferon-based initial regimen - Appropriately select specifically targeted antiviral HCV therapies agents for my HCV-infected patients who are not responding to current standard of care, as they become available - Appropriately select targeted antiviral HCV therapies agents for my HCV- infected patients who are not candidates for initial therapy with PI- based therapy of peginterferon + ribavirin, as they become available CME/CNECME/CNE ● Upon completion of this activity, the pharmacist should be able to: - Assess my hepatitis C (HCV)-infected patients on their chances of achieving a successful outcome after failing to respond to either PI-based therapy of a peginterferon-based initial regimen - Review and discuss specifically targeted antiviral HCV therapies agents for my HCV-infected patients who are not responding to current standard of care, as they become available - Review and discuss targeted antiviral HCV therapies agents for my HCV- infected patients who are not candidates for initial therapy with PI- based therapy of peginterferon + ribavirin, as they become available CPECPE
    12. 12. 12 Chronic HCV Therapy (Genotype 1): Advances in Raising Cure Rates SVR(%) 16% 44% ~70% 35%1991 1998 2001 2011 IFN IFN/RBV PegIFN/RBV Telaprevir or Boceprevir + PegIFN/RBV >90% >2013 2nd Generation DAAs PegIFN-Free Regimens Schaefer EA, et al. Gastroenterology. 2012;142:1340-1350. Ghany MG, et al. Hepatology. 2009;49:1335-1374. Ghany MG, et al. Hepatology. 2011;54:1433-1444.
    13. 13. 13 SVR Rates in Treatment-Naïve, Genotype 1 HCV: Telaprevir and Boceprevir Patients(%) T12/PR (n=363) 75%* 69%* 44% T8/PR (n=364) PR48 (n=361) Patients(%) 68%* 67%* 40% LI/B24/PR (n=350) LI/B44/PR (n=354) PR48 (n=344) ADVANCE (Telaprevir + PR) SPRINT-2 (LI-PR, Boceprevir + PR) *P<0.001 versus PR48. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. *P<0.0001 versus PR48. T:telaprevir 750 mg tid; B:boceprevir 800 mg tid; PR: pegIFN + RBV.
    14. 14. 14 Toxicities Impacting Completion of Telaprevir and Boceprevir Based Therapy Patients(%) Discontinuations 10% 7% 36% Hemoglobin (g/dL) ADVANCE (Telaprevir + PR) SPRINT-2 (LI-PR, Boceprevir + PR) Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Telaprevir 12/PR (n=363) PR48 (n=361) LI:lead-in; PR: pegIFN + RBV. AEs Rash <10 <8.5 Patients(%) Discontinuations Hemoglobin (g/dL) AEs Rash <10 <8.5 Pooled boceprevir (n=804) PR48 (n=344) 7% 1% 14% 9% 2% 12% N/A 16% 29% 6% 3% 49%
    15. 15. 15 Variation in SVR Rates: Previously Treated, HCV Genotype 1 Patients (REALIZE Study) Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. Patients(%) Prior Relapsers 32% 86% 85% F2-3 (n=62/15) F0-1 (n=167/38) F4 (n=57/15) T:telaprevir 750 mg q8h; PR: pegIFN + RBV. METAVIR: F0-1 (no, minimal, or portal fibrosis); F2-3 (bridging fibrosis); F4 (cirrhosis). Patients(%) Prior Partial Responders Null Responders 13% 13% 84% Pooled T12/PR PR48 Pooled T12/PR PR48 Pooled T12/PR PR48 72% 56% 34% 18% 0% 20% F2-3 (n=18/5) F0-1 (n=47/17) F4 (n=32/5) F2-3 (n=38/9) F0-1 (n=59/18) F4 (n=50/10) 41% 39% 14% 6% 0% 10% Patients(%)
    16. 16. 16 Treatment of Chronic HCV: Recent Successes ● Telaprevir or boceprevir + PR - Offer patients an improved chance of cure and the opportunity for a shorter duration of therapy - SVR rates • Treatment-naïve patients: 68%-75% • Prior relapsers, partial responders: 59%-88% • Null responders: 40%-41% ● Potential for yet another quantum leap in the field - Recent proof of concept studies demonstrating the capacity to eradicate HCV without interferon - PegIFN-free regimens for genotypes 1-6 Fox AN, et al. Clin Infect Dis. 2012;55(suppl 1):S16-S24. Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Updated Slide
    17. 17. 17 Telaprevir or Boceprevir + PR: Shortcomings of the Current Standard of Care ● Only effective in HCV genotype 1 patients ● Require PR therapy ● Thrice-daily dosing ● Cirrhotics not eligible for response-guided therapy ● Side effects - Both agents: hemoglobin decline (1.0-1.5 g/dL >PR) - Telaprevir: rash, anorectal discomfort - Boceprevir: dysgeusia, neutropenia ● Low barrier to resistance, emergence of resistant variants - >50% who fail to achieve an SVR have detectable variants (wane in frequency over time off-therapy) - Stopping rules designed to minimize resistance ● Potential for drug-drug interactions - CYP3A4 inhibition Fox AN, et al. Clin Infect Dis. 2012;55(suppl 1):S16-S24. Updated Slide
    18. 18. 18 Chronic HCV Infection: Targets for Direct-Acting Antiviral Agents ● Prevent viral entry - Polyclonal and monoclonal antibodies ● Prevent translation of viral RNA - NS3/4 protease inhibitors ● Inhibit HCV-RNA polymerase - Nucleoside analogue NS5B polymerase inhibitors - Non-nucleoside analogue NS5B polymerase inhibitors - Replication complex inhibitor - Cyclophilin B inhibitors ● Viral assembly/release - Glucosidase inhibitor Pereira AA, et al. Nat Rev Gastroenterol Hepatol. 2009;6:403-411.
    19. 19. 19 Selected Characteristics of Direct-Acting Antiviral Agents for Chronic HCV Infection Protease Inhibitors Nucleos(t)ide Polymerase Inhibitors Non-Nucleoside Polymerase Inhibitors NS5A Inhibitors Potency High (varies by HCV genotype) Moderate-to-high (consistent across HCV genotypes, subtype) Variable (HCV genotypes) High (multiple HCV genotypes) Barrier to resistance Low (1a<1b) High (1a=1b) Very low (1a<1b) Low (1a<1b) Potential for drug interactions High Low Variable Low-to- moderate Toxicity Rash, anemia, ↑ Bilirubin Mitochondrial, NRTI interactions (ART, RBV) Variable Variable Dosing qd to tid qd to bid qd to tid qd Comments 2nd generation PIs (higher barrier to resistance, pan-genotype) Single target Active site Allosteric Many targets Multiple antiviral MOA Schaefer EA, et al. Gastroenterology. 2012;142:1340-1350.
    20. 20. 20 Combination Therapy: Potential for Preventing the Emergence of Resistant Variants Variant NS3 Linear NS3 Macrocytic NS5A Inhibitor NS5B Nuc NS5B Palm NS5B Thumb NS5B Finger IFN RBV NS3 PI V36M R S S S S S S S S T54A R S S S S S S S S R155K R R S S S S S S S A156T R R S S S S S S S D168V S R S S S S S S S NS5A L28V S S R S S S S S S Y93H S S R S S S S S S NS5B S282T S S S R S S S S S C316Y S S S S R S S S S M414T S S S S R S S S S R422K S S S S S R S S S M423T S S S S S R S S S P495S S S S S S S R S S HCV DrAG ResisSS. 2012;1.2. Available at http://www.hivforum.org. S: susceptible and R: resistant based on arbitrary <4 and >4 fold shift in HCV replicon EC50, respectively.
    21. 21. 21 Program Overview ● DAA + pegIFN + ribavirin ● Multiple DAAs + pegIFN + ribavirin ● Interferon-free regimens
    22. 22. 22 DAA + PegIFN + Ribavirin in Late Stage Clinical Development NS3/4A Protease Inhibitors Nucleotide NS5B Polymerase Inhibitors Non- Nucleoside NS5B Polymerase Inhibitors NS5A Replication Complex Inhibitors PegIFN RBV Sofosbuvir (genotypes 1-6) PegIFN RBV Daclatasvir (genotypes 1-3) PegIFN RBV Danoprevir* PegIFN RBV Simeprevir* PegIFN RBV Faldaprevir* PegIFN RBV *Genotype 1. Updated Slide
    23. 23. 23 ATOMIC Trial: Sofosbuvir + PR HCV RNA >50,000 IU/mL, no cirrhosis. BMI: >18 kg/m2 . Non-CC IL28B: 72.4%; genotype 1a: 71.4%. Week 0 12 24 48 PR: pegIFN + RBV (weight-based dosing: 1000 or 1200 mg). Follow-Up Sofosbuvir (400 mg) + PR Stratified by IL28B (CC versus non-CC) and by HCV RNA (<800K and >800K IU/mL). Kowdley KV, et al. Lancet. 2013;Mar 14. [Epub ahead of print]. G1 (n=52) G1,4,6 (n=125) GT 1 (n=155) Sofosbuvir (400 mg) + PegIFN + RBV Sofosbuvir (400 mg) + PR Sofosbuvir (n=75) Sofosbuvir + RBV (n=75) Follow-Up Follow-Up Phase 2b Treatment-naïve Updated Slide
    24. 24. 24 ATOMIC Trial: Treatment Outcomes ● SVR12 and SVR24 - Similar among sofosbuvir regimens (12 and 24 weeks) - Genotype 4 (n=11) • SVR12/SVR24: 82%/82% - Genotype 6 (n=5) • SVR12/SVR24: 100%/100% ● Sequence data from 4 patients who relapsed showed no S282T mutation (population sequencing) - Deep sequencing for all patients with relapse is ongoing SVR12 and SVR24 (ITT) Patients(%) 90%89% 93% 12 Sofosbuvir + PR (weeks) SVR12 SVR24 91% 24 12 + 12 89% 87% PR: pegIFN + RBV (weight-based dosing: 1000 or 1200 mg). Kowdley KV, et al. Lancet. 2013;Mar 14. [Epub ahead of print]. Updated Slide
    25. 25. 25 ATOMIC Trial: Relapse and Safety and Tolerability ● Relapse: 3% - No S282T mutation detected (phenotypic data generated in 10/11 relapse patients) - No change in susceptibility to sofosbuvir ● Safety and tolerability - Well tolerated up to 24 weeks, with no serious adverse events • Discontinuation due to adverse events: <5% ● Most common adverse events - Consistent with those associated with PR • Constitutional symptoms, influenza-like symptoms, rash, anemia Updated Slide Kowdley KV, et al. Lancet. 2013;Mar 14. [Epub ahead of print].
    26. 26. 26 NEUTRINO Study: Sofosbuvir + PR in Treatment-Naïve, HCV Genotype 1, 4, 5, and 6 Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Phase 3 Open-label Treatment-Naïve Genotype 1, 4, 5, and 6 Week 0 12 24 36 Sofosbuvir (nucleotide NS5B polymerase Inhibitor). No upper limit to age or BMI. Opioid substitution permitted. Platelets >90,000/mm3 , neutrophils >1500/mm3 or 1000/mm3 (blacks). Cirrhosis permitted (17% enrolled). Primary efficacy endpoint: SVR12. Prespecified comparison to historical SVR control rate of 60%. Follow-UpSofosbuvir 400 mg qd + PR (n=327) New Slide
    27. 27. 27 NEUTRINO Study: SVR12 Rates by Prespecified Subgroups Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Patients(%) 82% 90%* 96% 92% Overall (n=327) 100% 96% 89% 92% 80% 98% 1a (n=255) 1b (n=66) <6 (n=71) >6 (n=256) No (n=273) Yes (n=54) Genotype Baseline HCV RNA (log) Cirrhosis CC (n=98) Non-CC (n=232) IL28B 87% 4 (n=28) 5/6 (n=7) *P<0.001 versus historical SVR rate of 60%. Sofosbuvir 400 mg qd + PR (12 weeks) New Slide
    28. 28. 28 NEUTRINO Study: Resistance and Safety ● No resistance detected in sofosbuvir + PR virologic failures and 1 relapse patient who discontinued therapy (HCV RNA >1000 IU/mL) ● Safety of sofosbuvir + PR - Well tolerated and no additive effects of the addition of sofosbuvir to PR • Discontinuations due to adverse events: 2% - Most common adverse events • Fatigue (59%), headache (36%), nausea (34%), insomnia (25%), anemia (21%), rash (18%) - Safety profile consistent with ribavirin • Hemoglobin <10 g/dL: 23% • Hemoglobin <8.5 g/dL: 2% Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. New Slide
    29. 29. 29 COMMAND-1 Study: Daclatasvir + PR PR: pegIFN + RBV. All daclatasvir patients not achieving a protocol-defined response at week 12 (HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks. HCV RNA: 6.5 log10 IU/mL. Compensated cirrhosis: 7.3%. BMI: >18 kg/m2 . Non-CC IL28B: 69%; genotype 1a: 70%; genotype 4: 8%. Week 0 12 24 48 Follow-UpDaclatasvir (20 mg) + PR (n=159) PR (n=78) Daclatasvir 60 mg + PR (n=158) Daclatasvir + PR Follow-Up Phase 2b Treatment-naïve Genotype 1 or 4 Hezode C, et al. Hepatology. 2012;56(suppl 4):553A. Abstract 755. PR Daclatasvir + PR PR PR (n=78)
    30. 30. 30 COMMAND-1 Study (ITT): SVR12 Rates (All PDR) Patients(%) Genotype 67%65% 36% 100% Genotype 1 (n=147/146/72) 64% 50% DCV 20 mg + PR DCV 60 mg + PR PR Genotype 4 (n=12/12/6) Hezode C, et al. Hepatology. 2012;56(suppl 4):553A. Abstract 755. Patients(%) Genotype 1 Subgroup 78% 59% 38% 87% Genotype 1a (n=106/113/56) 58% 31% DCV 20 mg + PR DCV 60 mg + PR PR Genotype 1b (n=41/31/16) PDR: week-12 protocol-defined response (HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks). PR: pegIFN + RBV.
    31. 31. 31 COMMAND-1 Study: SVR12 Rates by IL28B (All PDR) Patients(%) Genotype 1a 51% 85% 45% 31% CC (n=41/36/18) 61% 36% CT (n=51/61/26) Hezode C, et al. Hepatology. 2012;56(suppl 4):553A. Abstract 755. Patients(%) Genotype 1b DCV 20 mg + PR PR DCV 60 mg + PR PDR: week-12 protocol-defined response (HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks). PR: pegIFN + RBV. TT (n=11/14/9) 78% 22% CC (n=11/7/4) CT (n=24/20/10) TT (n=6/4/2) 71% 40% 85% 67% 0% 75% 100% 25% DCV 20 mg + PR PR DCV 60 mg + PR
    32. 32. 32 COMMAND-1 Study: Treatment Failure and Safety and Tolerability ● Treatment failure - Overall (daclatasvir versus PR): 35% versus 64% • Treatment failure rates were lower in daclatasvir-treated patients who achieved PDR (11%-24%) ● Safety and tolerability - Similar adverse event profile between the daclatasvir + PR and PR treatment arms • Discontinuation due to adverse events: <5% - Changes in laboratory parameters were consistent across all treatment arms ● Future clinical trials will be with genotype 1b patients only Hezode C, et al. Hepatology. 2012;56(suppl 4):553A. Abstract 755. PR: pegIFN + RBV. PDR: week-12 protocol-defined response.
    33. 33. 33 COMMAND-2 Study: Daclatasvir + PR PR: pegIFN + RBV. All daclatasvir patients not achieving a protocol-defined response at week 12 (HCV RNA <LLOQ at week 4 and undetectable [<10 IU/mL] at week 10) received PR for 24 weeks. HCV RNA: 6.5 log10 IU/mL. Compensated cirrhosis: 7.3%. BMI: >18 kg/m2 . Non-CC IL28B: 69%; genotype 1a: 70%; genotype 4: 8%. Week 0 12 16 24 48 Follow-Up Daclatasvir 60 mg qd + PR (n=50) Daclatasvir 60 mg qd + PR (n=50) Follow-Up Follow-Up Phase 2b Treatment-naïve Genotype 2, 3 Dore GJ, et al. J Hepatol. 2013;58(suppl 1):S570-S571. Abstract 1418. PR Daclatasvir + PR PR PR (n=51) Follow-Up Follow-Up (36 weeks) New Slide
    34. 34. 34 COMMAND-2 Study (ITT): SVR24 Rates (ITT) Patients(%) Genotype 69% 83% 63% 67% Genotype 2 (n=24/23/24) 83% 59% DCV + PR (12 weeks) DCV + PR (16 weeks) PR Genotype 3 (n=26/27/27) Patients(%) IL28B Genotypes 50% 80% 85% 75% CC 83% 64% Dore GJ, et al. J Hepatol. 2013;58(suppl 1):S570-S571. Abstract 1418. 100% Non-CC Genotype 2 CC Non-CC Genotype 3 75% 56% 81% 64% 56% DCV + PR (12 weeks) DCV + PR (16 weeks) PR New Slide
    35. 35. 35 COMMAND-2 Study: Treatment Failure and Safety in Genotype 2/3 ● Treatment failure (daclatasvir versus PR) - Genotype 2: 5% versus 5% - Genotype 3: 25% verus 14% • With versus without baseline NS5A Y93 and/or A30 polymorphisms (50% versus 19%) • Cirrhotics versus non-cirrhotics (36% versus 21%) • No apparent effect of IL28B genotype or baseline HCV RNA on relapse ● Safety and tolerability - Similar adverse event profile across all arms • Discontinuation due to adverse events (daclatasvir versus PR): 7% versus 4%) - Changes in laboratory parameters were consistent across all treatment arms ● Further evaluation of daclatasvir + PR in HCV genotype 2/3 patients is planned PR: pegIFN + RBV. New Slide Dore GJ, et al. J Hepatol. 2013;58(suppl 1):S570-S571. Abstract 1418.
    36. 36. 36 DAUPHINE Study: Danoprevir/r + PR *RGT (response-guided therapy): week 12 all drugs stopped if eRVR [HCV RNA <15 IU/L achieved during weeks 2-10, if not then continue to week 24. PR: pegIFN + RBV. HCV RNA: >50,000 IU/Ml; fibrosis score: F0-F2; non-CC IL28B: 70%; genotype 1a: 60%; genotype 4: 8%. Week 0 12 24 48 Follow-UpDanoprevir/r 200/100 mg + PR (n=94) PR (n=46) Follow-Up Phase 2b Treatment-naïve Genotype 1 or 4 Danoprevir/r 100/100 mg + PR (n=94)* Follow-Up Danoprevir + PR Danoprevir/r 100/100 mg + PR (n=93) Danoprevir/r 50/100 mg + PR (n=94) Follow-Up eRVR: Follow-Up Everson GT, et al. Hepatology. 2012;56(suppl 4):552A. Abstract 754.
    37. 37. 37 DAUPHINE Study: SVR24 Rates ● Dose-dependent increases in SVR24 - Highest SRV24 rates achieved in the danoprevir/r 200/100 mg treatment arm ● Dose-response relationship seen in a harder-to-treat subgroup (genotype 1a, IL28B non-CC) - 200/100 mg: 88% - 100/100 mg: 70% - 50/100 mg: 58% ● Genotype 1b/IL28B CC and genotype 4 patients - All achieved SVR24 in <12 weeks Everson GT, et al. Hepatology. 2012;56(suppl 4):552A. Abstract 754. SVR24 (ITT) Patients(%) 1a (n=56/56/58/49) 4 (n=8/8/7/7) 1b (n=29/29/26/37) 84% 60% 70% 97% 93% 100% 88% 73% 100% 200/100 mg 50/100 mg 100/100 mg 100/100 mg RGT Genotype RGT: response-guided therapy. Danoprevir/r was administered with PR (pegIFN + RBV). 59% 78%
    38. 38. 38 DAUPHINE Study: Treatment Failure and Safety and Tolerability ● Treatment failure: 17.5% - Relapse: 11% • Predominately genotype 1a and non-CC IL28G genotype - Resistance uniquely associated with the NS3 R155K substitution ● Safety and tolerability - Similar adverse event profile between the danoprevir/r + PR and PR treatment arms • Discontinuation of danoprevir/r due to adverse events: 5% - Laboratory abnormalities were not dose related - Anemia (hemoglobin <8.9 g/dL or any decrease >4.5 g/dL): 7% Le Pogam, et al. Hepatology. 2012;56(suppl 4):571A-572A. Abstract 782. Everson GT, et al. Hepatology. 2012;56(suppl 4):552A. Abstract 754.
    39. 39. 39 QUEST-1 and -2 Trials: Simeprevir + PR in Treatment-Naïve, HCV Genotype 1 Jacobson I, et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425. Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413. Week 0 12 24 48 72 Simeprevir (NS3/4A protease inhibitor). HCV RNA >10,000 IU/mL. PR: pegIFN (alpha 2a or 2b) + RBV (weight-based dosing: 1000-1200 mg). Patients stratified by HCV subtype and IL28B genotype. Response-guided therapy criteria: HCV RNA <25 IU/mL at week 4 and undetectable at week 12. METAVIR score: F0-F1 (~50%); >F2 (~50%). Primary efficacy endpoint: SVR12. Simeprevir 150 mg qd + PR Follow-Up Follow-Up Phase 3 Treatment-naïve Genotype 1 PR PR PR (n=134) Follow-Up New Slide
    40. 40. 40 QUEST-1 and -2 Trials: Overall SVR12 Rates by Genotype 1 Subgroup Patients(%) 49% 80%* 71%* 90%* 50% Overall (n=264/130) 52% Simeprevir + PR PR 1a (n=147/74) 1b (n=117/56) Genotype *P<0.01 versus PR. New Slide Jacobson I, et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425. Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413. QUEST 1 Patients(%) 46% 81%* 80%* 82%* 50% Overall (n=257/134) 53% Simeprevir + PR PR 1a (n=107/57) 1b (n=150/77) Genotype QUEST 2 *P<0.01 versus PR.
    41. 41. 41 QUEST-1 and -2 Trials: SVR12 Rates by Prespecified Subgroups Patients(%) 42% 94%* 76%* 65%* 78% 24% Simeprevir + PR PR 83%* 60% CC (n=77/37) CT (n=150/76) TT (n=37/17) F0-F2 (n=183/90) IL28B Genotype METAVIR Score F3 (n=46/23) F4 (n=37/17) 58%* 29% 78%* 26% *P<0.01 versus PR. New Slide Patients(%) 41% 96%* 80%* 58%* 81% 19% Simeprevir + PR PR 85%* 51% CC (n=75/42) CT (n=142/71) TT (n=40/21) F0-F2 (n=195/102) IL28B Genotype METAVIR Score F3 (n=37/17) F4 (n=17/15) 65%* 40% 67%* 53% *P<0.01 versus PR. QUEST 1 QUEST 2 Jacobson I, et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425. Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413.
    42. 42. 42 QUEST-1 and -2 Trials: Resistance and Safety ● NS3 PI mutations were detected in the time of failure for the majority (>90%) of simeprevir-treated patients not achieving an SVR - Genotype 1: mainly R155 alone - Genotype 1b: mainly D168V or Q80R + D168E ● Simeprevir + PR was well tolerated - Simeprevir treatment discontinuations due to adverse events • QUEST-1: 3% • QUEST-2: 1.6% ● Adverse event profile of simeprevir + PR was similar to the PR arm - Headache, pyrexia, fatigue, influenza-like illness, rash, anemia, pruritus New Slide Jacobson I, et al. J Hepatol. 2013;58(suppl 1):S574. Abstract 1425. Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413.
    43. 43. 43 ASPIRE Study: Simeprevir + PR Week 0 12 24 48 72 SMV 100 mg 12/PR (n=66) HCV RNA >10,000 IU/mL. PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg). Follow-Up Phase 2b Previously failed Genotype 1 PR SMV (150 mg qd) + PR Follow-Up PRSMV 150 mg 12/PR (n=66) SMV 100 mg 24/PR (n=65) SMV (100 mg qd) + PR Follow-Up PR SMV (150 mg qd) + PR Follow-Up PRSMV 150 mg 24/PR (n=66) Follow-Up SMV (100 mg qd) + PR PR SMV (100 mg qd) + PR SMV (150 mg qd) + PR Follow-Up Follow-Up Zeuzem S, et al. J Hepatol. 2012;54(suppl 2):S1. Abstract 2. PR48 (n=66) SMV 100 mg 48/PR (n=66) SMV 150 mg 48/PR (n=65)
    44. 44. 44 ASPIRE Trial: SVR24 Rates With Simeprevir + PR Patients(%) Prior Relapsers 85% 85% 100 mg (n=79) 150 mg (n=79) PR48 (n=27) *Duration pooled. PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg). Patients(%) Prior Partial Responders Null Responders 37% 75% 57% 9% 51% 46% 19% Patients(%) Zeuzem S, et al. J Hepatol. 2012;54(suppl 2):S1. Abstract 2. Simeprevir + PR48 100 mg (n=68) 150 mg (n=69) PR48 (n=23) Simeprevir + PR48 100 mg (n=68) 150 mg (n=69) PR48 (n=23) Simeprevir + PR48
    45. 45. 45 ASPIRE Trial: Resistance and Safety and Tolerability ● Viral breakthrough/relapse was usually associated with emerging mutations to simeprevir - Q80K at baseline did not alter SVR24 rates in the simeprevir 150 mg treatment arms ● Safety and tolerability - Well tolerated, treatment discontinuations due to adverse events: 7%) - Hematologic abnormalities were similar across all treatment arms - Mild and reversible increases in bilirubin were seen in the simeprevir arms • No other liver changes Lenz O, et al. J Hepatol. 2012;54(suppl 2):S5. Abstract 9. Zeuzem S, et al. J Hepatol. 2012;54(suppl 2):S1. Abstract 2.
    46. 46. 46 STARTVerso1 Trial: Faldaprevir + PR in Treatment-Naïve, Genotype 1 Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416. Week 0 12 24 48 72 ETS, Follow-Up Follow-Up Faldaprevir 120 mg qd + PR (n=261) PR Faldaprevir 240 mg qd + PR (n=262) PR ETS, Follow-Up PR Follow-Up Faldaprevir (NS3/4A protease inhibitor). Platelets >90,000 cells/mm3 . No HBV or HIV coinfection. Fibrosis stage >F3: 17% ETS: early treatment success (HCV RNA <25 IU/mL at week 4 and undetectable at week 8. Primary efficacy endpoint: SVR12 Phase 3 Treatment-Naïve Genotype 1 PR Follow-Up PRFaldaprevir + PR No ETS No ETS New Slide
    47. 47. 47 STARTVerso1 Trial: SVR12 Rates by Prespecified Subgroups Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416. Patients(%) 36% 69% 84%83% 76% Overall (n=259/261/132) 60% 70% 90% 63% 69% 95% 51% Faldaprevir 120 mg qd + PR Faldaprevir 240 mg qd + PR PR 76% 1a (n=87/90/45) 1b (171/171/86) CC (n=75/42) CT (n=142/71) TT (n=40/21) Genotype IL28B Genotype ETS Patients (n=225/232) 86% 89% 79% 28% *P<0.0001 versus PR. 79%*80%* 52% New Slide
    48. 48. 48 STARTVerso1 Trial: Resistance and Safety ● No significant effect of Q80K on SVR12 in genotype 1a patients ● Faldaprevir + PR was well tolerated - Discontinuations due to adverse events: 4% ● Adverse event profile of faldaprevir + PR was similar to the PR arm - Most common adverse events of at least moderate severity • Rash (8%), anemia (12%) ● Total bilirubin elevations >2.6 x ULN with faldaprevir + PR were benign and transient - 120 mg qd: 12% - 240 mg qd: 53% Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416. The Q80K mutation is associated with a decreased susceptibility to some NS3/4A protease inhibitors. New Slide
    49. 49. 49 SILEN-C2 Study: Faldaprevir + PR (Non-Responders) Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S30. Abstract 66. Week 0 24 48 72 LI/240 mg qd/PR (n=142) 240 mg qd/PR (n=76) eRVR, Follow-Up Follow-Up LI/120 mg qd/PR (n=70) Faldaprevir 240 mg qd + PR LI* PR Faldaprevir 240 mg qd + PR PR Follow-Up Faldaprevir 120 mg qd + PR LI* PR Follow-Up *LI: 3-day lead-in with PR. Relapsers excluded. HCV RNA >100,000 IU/mL, no cirrhosis. PR: pegIFN + RBV (weight-based ribavirin: 1000-1200 mg). Phase 2b Non-responders Genotype 1
    50. 50. 50 SILEN-C2 Study: SVR and Overall Relapse With Faldaprevir Patients(%) LI/240 mg qd/PR (n=142) Sustained Virologic Response 27% 41% 31% Relapse: rebound from undetectable at end of all treatment. 240 mg qd/PR (n=76) LI/240 mg bid/PR (n=70) Patients(%) Overall Relapse 25% 9% 19% LI/240 mg qd/PR (n=142) 240 mg qd/PR (n=76) LI/240 mg bid/PR (n=70) Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S30. Abstract 66.
    51. 51. 51 SILEN-C2 Study: Virologic Failure, Discontinuations, and Adverse Events LI/240 mg qd/PR (n=142) 240 mg qd/PR (n=76) LI/240 mg bid/PR (n=70) Virologic failure (%) During faldaprevir During PR phase 25 5 28 7 17 6 Discontinuation (%) Adverse events 6 4 23 Adverse events (%) Rash Jaundice Nausea Diarrhea Vomiting 34 19 48 32 17 28 21 53 32 22 42 41 64 39 32 Sulkowski MS, et al. J Hepatol. 2011;54(suppl 1):S30. Abstract 66.
    52. 52. 52 Program Overview ● DAA + pegIFN + ribavirin ● Multiple DAAs + pegIFN + ribavirin ● Interferon-free regimens
    53. 53. 53 Multiple DAA + PegIFN + Ribavirin in Late Stage Clinical Development NS3/4A Protease Inhibitors Nucleotide NS5B Polymerase Inhibitors Non- Nucleoside NS5B Polymerase Inhibitors NS5A Replication Complex Inhibitors PegIFN RBV Danoprevir Mericitabine PegIFN RBV Asunaprevir Daclatasvir PegIFN RBV
    54. 54. 54 Phase 2a Genotype 1 Prior Partial Responders Prior Null Responders MATTERHORN Study: Danoprevir/r + Mericitabine + PR Week 0 24 48 72 Danoprevir/r + Mericitabine + PR (n=50) Danoprevir/r + PR (n=49) QUAD Danoprevir/r + Mericitabine + RBV (n=52) IFN Free Feld JJ, et al. Hepatology. 2012;56(suppl 4):231A-232A. Abstract 81. Triple Danoprevir/r + Mericitabine + PR (n=77) Danoprevir/r + PR (n=77) Danoprevir/r + Mericitabine + RBV (n=74) QUADPR HCV RNA >50,000 IU/mL. Absence of cirrhosis. Mericitabine dosed bid. PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg). QUAD IFN Free
    55. 55. 55 MATTERHORN Study: Treatment Outcomes ● QUAD regimen produced the highest overall SVR12 rates - Genotype 1b patients (91% to 100%) - Genotype 1a • Adding mericitabine increased SVR12 from 30% to 75% ● Virologic breakthrough was associated with resistance to danoprevir (R155K, D168E/T) ● QUAD, triple, and IFN-free regimens were safe and well tolerated - Addition of mericitabine did not change the safety profile of danoprevir/r + pegIFN + RBV Patients(%) SVR12 84%86% 39% N/A Prior Partial Responders (n=50/48/23) 56% 55% QUAD IFN free Triple Prior Null Responders (n=74/31) Feld JJ, et al. Hepatology. 2012;56(suppl 4):231A-232A. Abstract 81.
    56. 56. 56 Study 011 (Expansion Cohort): Daclatasvir + Asunaprevir + PR Week 0 24 36 48 Dual-1 (n=18) Daclatasvir 60 mg qd + Asunaprevir 200 mg bid (Genotype 1b only) Follow-Up Lok AS, et al. Hepatology. 2012;56(suppl 4):230A. Abstract 79. SVR12 Primary Endpoint Dual-2 (n=20) QUAD-1 (n=20) QUAD-2 (n=21) Triple (n=22) Phase 2a Genotype 1 Prior null responders Daclatasvir 60 mg qd + Asunaprevir 200 mg qd (Genotype 1b only) Daclatasvir 60 mg qd + Asunaprevir 200 mg bid + PR (Genotype 1a/1b) Daclatasvir 60 mg qd + Asunaprevir 200 mg qd + PR (Genotype 1a/1b) Daclatasvir 60 mg qd + Asunaprevir 200 mg bid + RBV (Genotype 1a/1b) Follow-Up Follow-Up Follow-Up Follow-Up Non-cirrhotic PR: pegIFN + RBV (weight-based dosing: 1000-1200 mg).
    57. 57. 57 Study 011: Treatment Outcomes ● SVR12 rates higher in the QUAD arm compared with the dual arm ● Virologic breakthrough - IFN-free arm: 56% ● QUAD, triple, and IFN-free regimens were well tolerated - Discontinuations due to adverse events: 0% ● Most common adverse events - Headache, diarrhea, fatigue, and insomnia SVR12 Rate Patients(%) Dual-1 (n=78) Dual-2 (n=65) 78% 97% 90% 65% QUAD-1 (n=20) QUAD-2 (n=21) Lok AS, et al. Hepatology. 2012;56(suppl 4):230A. Abstract 79.
    58. 58. 58 Program Overview ● DAA + pegIFN + ribavirin ● Multiple DAAs + pegIFN + ribavirin ● Interferon-free regimens
    59. 59. 59 Interferon-Free Regimens in Late Stage Clinical Development NS3/4A Protease Inhibitors Nucleotide NS5B Polymerase Inhibitors Non-Nucleoside NS5B Polymerase Inhibitors NS5A Replication Complex Inhibitors PegIFN RBV Sofosbuvir Sofosbuvir RBV Sofosbuvir Daclatasvir Sofosbuvir Daclatasvir RBV Faldaprevir BI 207127 Faldaprevir BI 207127 RBV Faldaprevir PegIFN RBV ABT-450/r ABT-333 ABT-267 RBV ABT-450/r ABT-333 RBV ABT-450/r ABT-267 RBV ABT-450/r ABT-333 ABT-267
    60. 60. 60 FISSION Trial: Sofosbuvir + RBV in Treatment-Naïve, HCV Genotype 2 or 3 Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Phase 3 Open-label Treatment-Naïve Genotype 2 or 3 Week 0 12 24 36 Sofosbuvir (nucleotide NS5B polymerase inhibitor). No upper limit to age or BMI. Opioid substitution permitted. Platelet >75,000/mm3 (cirrhotic: 20% maximum). Stratified by genotype, HCV RNA, and cirrhosis. Primary efficacy endpoint: SVR12 (non-inferiority margin: 15%). Follow-UpSofosbuvir 400 mg qd + RBV 1000-1200 mg/day (n=256) PegIFN + RBV (800 mg/day) (n=243) Follow-Up New Slide
    61. 61. 61 FISSION Trial: SVR12 Rates by Prespecified Subgroups Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Patients(%) 78% 67% 97% 56% 67% Overall* (n=253/243) 63% 66% 75% 62% 72% 67% 74% Sofosbuvir + RBV PR 47% 38% 2 (n=70/67) 3 (n=183/176) <6 (n=107/106) >6 (n=146/137) No (n=204/193) Yes (n=49/50) Genotype Baseline HCV RNA (log) Cirrhosis Male (n=168/156) Female (n=85/87) Gender 79%76% 61% 62% *Non-inferiority criteria met. New Slide
    62. 62. 62 FISSION Trial: SVR12 Rates by Genotype and Cirrhosis Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. Patients(%) Genotype 2 98% 91% 82% 62% No Cirrhosis (n=59/54) Cirrhosis (n=11/13) Patients(%) Genotype 3 61% 71% 34% 30% No Cirrhosis (n=145/139) Cirrhosis (n=38/37) Sofosbuvir + RBV PR Sofosbuvir + RBV PR New Slide
    63. 63. 63 FISSION Trial: Resistance and Safety ● No resistance detected in sofosbuvir + RBV virologic failures - Relapse accounted for all but 1 virologic failure (nonadherence) ● Safety of sofosbuvir + RBV - Well tolerated and few adverse events - Most common adverse events • Fatigue (36%), headache (25%), nausea (18%), insomnia (12%) - Safety profile consistent with ribavirin Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5. Lawitz E, et al. N Engl J Med. 2013;368:1878-1887. New Slide
    64. 64. 64 FUSION Trial: Sofosbuvir + RBV for 12 Versus 16 Weeks in HCV Genotype 2/3, Previously Failed PR Therapy Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. Phase 3 Double-blind Failed Prior PegIFN-Based Therapy Genotype 2 or 3 Sofosbuvir (nucleotide NS5B polymerase inhibitor). No upper limit to age or BMI. Opioid substitution permitted. Platelet >50,000/mm3 , no neutrophil minimum. Cirrhosis at baseline (34%). Prior relapsers (76%). Stratified by genotype and cirrhosis. Primary efficacy endpoint: SVR12. Follow-UpSofosbuvir 400 mg qd + RBV 1000-1200 mg/day (n=103) Week 0 12 16 24 Placebo Sofosbuvir 400 mg qd + RBV 1000-1200 mg/day (n=98) Follow-Up New Slide
    65. 65. 65 FUSION Trial: SVR12 Rates by Prespecified Subgroups Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. Patients(%) 94% 50% 86% 30% 73%* Overall (n=100/95) 62%* 77% 50% 50% 61%62% 76% Sofosbuvir + RBV 12 weeks 16 weeks 31% 66% 2 (n=36/32) 3 (n=64/63) <6 (n=26/29) >6 (n=74/66) No (n=64/63) Yes (n=36/32) Genotype Baseline HCV RNA (log) Cirrhosis Male (n=71/64) Female (n=29/31) Gender 69% 87% 42% 66% *P<0.001 versus 12 weeks of active therapy. New Slide
    66. 66. 66 FUSION Trial: SVR12 Rates by Genotype and Cirrhosis Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. Patients(%) Genotype 2 96% 60% 100% 78% No Cirrhosis (n=26/23) Cirrhosis (n=10/9) Patients(%) Genotype 3 37% 63% 19% 61% No Cirrhosis (n=38/40) Cirrhosis (n=26/23) Sofosbuvir + RBV 12 weeks 16 weeks Sofosbuvir + RBV 12 weeks 16 weeks New Slide
    67. 67. 67 FUSION Trial: Resistance and Safety ● No resistance detected in sofosbuvir + RBV virologic failures ● Safety of sofosbuvir + RBV - Well tolerated and few adverse events • No discontinuations due to adverse events - Most common adverse events • Fatigue (46%), headache (27%), nausea (21%), insomnia (24%) - Safety profile consistent with ribavirin • Hemoglobin <10 g/dL: 7.5% • Hemoglobin <8.5 g/dL: 1% Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. New Slide
    68. 68. 68 POSITRON Trial: Sofosbuvir + RBV in HCV Genotype 2 or 3 With Limited Options Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. Phase 3 Double-blind, placebo-controlled Interferon-Ineligible, Intolerant, or unwilling Genotype 2 or 3 Sofosbuvir (nucleotide NS5B polymerase inhibitor). No upper limit to age or BMI. Opioid substitution permitted. No lower limit to platelet or neutrophil count. Cirrhosis at baseline (16%). Prior relapsers (76%). Stratified by presence or absence of cirrhosis. Primary efficacy endpoint: SVR12. Follow-UpSofosbuvir 400 mg qd + RBV 1000-1200 mg/day (n=207) Week 0 12 24 Placebo (n=71) Follow-Up New Slide
    69. 69. 69 POSITRON Trial: SVR12 Rates With Sofosbuvir + RBV by Prespecified Subgroups Patients(%) 93% 78% Overall (n=207) 61% 79%76% 81% 61% 2 (n=109) 3 (n=98) <6 (n=67) >6 (n=140) No (n=176) Yes (n=31) Genotype Baseline HCV RNA (log) Cirrhosis Male (n=117) Female (n=90) Gender 84% 73% SVR12 rate was 0% in the placebo arm. Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. New Slide
    70. 70. 70 POSITRON Trial: SVR12 Rates With Sofosbuvir + RBV by Genotype and Cirrhosis Patients(%) Genotype 2 92% 94% No Cirrhosis (n=92) Cirrhosis (n=17) Patients(%) Genotype 3 68% 21% No Cirrhosis (n=84) Cirrhosis (n=14) SVR12 rate was 0% in the placebo arm. Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. New Slide
    71. 71. 71 POSITRON Trial: Resistance and Safety ● No resistance detected in sofosbuvir + RBV virologic failures ● Safety of sofosbuvir + RBV - Well tolerated and few adverse events • Treatment discontinuations due to adverse events: 2% - Most common adverse events • Fatigue (44%), headache (21%), nausea (22%), insomnia (19%) - Safety profile consistent with ribavirin • Hemoglobin <10 g/dL: 7% • Hemoglobin <8.5 g/dL: 1% Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877. New Slide
    72. 72. 72 ELECTRON Study: Sofosbuvir + Ribavirin Week 0 4 8 12 24 Follow-Up Treatment-Naïve Genotype 2, 3 (n=10) Sofosbuvir (nucleotide NS5B polymerase Inhibitor). PR: pegIFN + RBV. HCV RNA >50,000 IU/mL. No cirrhosis. Weight-based ribavirin dosing (800-1200 mg). Sofosbuvir 400 mg qd + PR Follow-Up Sofosbuvir 400 mg qd + RBV Null Responders Genotype 1 (n=10) Sofosbuvir 400 mg qd + RBV Follow-Up Treatment-Naïve Genotype 1 (n=25) Sofosbuvir 400 mg qd + RBV Follow-Up Treatment-Experienced Genotype 2, 3 (n=25) Gane EJ, et al. N Engl J Med. 2013;368:34-44. Phase 2b
    73. 73. 73 ELECTRON Study: SVR Rates in HCV Genotype 2/3 and 1 Patients(%) Genotype 2/3 SVR12 SVR24 100% 68% 100% NR PR: pegIFN + RBV; NR: not reported. Treatment-Naïve Sofosbuvir + PR 8 weeks (n=10) Treatment-Experienced Sofosbuvir + RBV 12 weeks (n=25) Patients(%) Genotype 1 SVR12 SVR24 84% 10% NR NR Null Responders Sofosbuvir + RBV 12 weeks (n=10) Treatment-Naïve Sofosbuvir + RBV 12 weeks (n=25) Gane EJ, et al. N Engl J Med. 2013;368:34-44.
    74. 74. 74 ELECTRON Study: Sofosbuvir + RBV + Either Ledipasvir (NS5A Inhibitor) or GS-9669 (NS5B Non-Nucleoside Inhibitor) Week 0 4 8 12 24 Follow-Up Treatment-Naïve (n=25) Sofosbuvir (nucleotide NS5B polymerase Inhibitor). No cirrhosis. Weight-based ribavirin dosing (1000-1200 mg). Sofosbuvir 400 mg qd + RBV Sofosbuvir 400 mg qd + RBV Null Responders (n=10) Sofosbuvir 400 mg qd + Ledipasvir + RBV Follow-Up Treatment-Naïve (n=25) Sofosbuvir 400 mg qd + Ledipasvir + RBV Follow-Up Null Responders (n=9) Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14. Phase 2b Genotype 1 Follow-Up Sofosbuvir 400 mg qd + GS-9669 + RBV Follow-Up Treatment-Naïve (n=25) Sofosbuvir 400 mg qd + GS-9669 + RBV Follow-Up Null Responders (n=9) New Slide
    75. 75. 75 ELECTRON Study (Genotype 1 Cohort): Interim Analysis of SVR12 Rates Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14. Patients(%) Treatment-Naive 84% 92% Sofosbuvir + RBV (n=25) Null Responders 100% Sofosbuvir + Ledipasvir + RBV (n=25) Sofosbuvir + GS-9669 + RBV (n=25) Patients(%) 10% 100% Sofosbuvir + RBV (n=10) 100% Sofosbuvir + Ledipasvir + RBV (n=9) Sofosbuvir + GS-9669 + RBV (n=3) New Slide
    76. 76. 76 ELECTRON Study (Genotype 1 Cohort): Safety ● Adding ledipasvir to sofosbuvir + RBV - No additional safety or tolerability issues ● Adding GS-9669 to sofosbuvir + RBV - No additional safety or tolerability issues ● Fix-dose combination of sofosbuvir/ledipasvir - Undergoing phase 3 trial in patients with and without cirrhosis - Additional studies exploring shorter duration of therapy Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14. New Slide
    77. 77. 77 Phase 2a Treatment-naïve Genotype 2/3 Genotype 1 Study 040: Sofosbuvir + Daclatasvir + Ribavirin Week 0 12 24 48 Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=16) Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2. Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=14) Follow-Up Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd + RBV (n=14) *LI: 7-day lead-in with sofosbuvir 400 mg qd. HCV RNA >50K IU/mL, no cirrhosis. Primary outcome: SVR12. LI* Follow-Up Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=15) Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=14) Follow-Up Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd + RBV (n=15) LI* Follow-Up Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=14) Follow-Up Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd + RBV (n=15) Follow-Up
    78. 78. 78 Study 040 (24-Week Treatment): SVR12 and SVR24 Rates Patients(%) Genotype 2/3 SVR12 SVR24 88% 86% 93% 93% LI/SOF/ DCV (n=16) Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2. 100% SOF/DCV (n=14) SOF/DCV + RBV (n=14) LI: 7-day lead-in with sofosbuvir 400 mg qd. Patients(%) Genotype 1 SVR12 SVR24 100% 93% 100% LI/SOF/ DCV (n=15) 100% SOF/DCV (n=14) SOF/DCV + RBV (n=15)
    79. 79. 79 Study 040 (24-Week Treatment): Safety and Tolerability ● Sofosbuvir + daclatasvir + RBV was well tolerated - Discontinuations due to adverse events: 3% ● Most common adverse events - Fatigue (36%) - Headache (27%) - Nausea (26%) ● No grade 3/4 elevations in ALT, AST, or total bilirubin ● Anemia (hemoglobin <9 g/dL): 7% • All in the RBV-containing arms Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2.
    80. 80. 80 Study 040 (12-Week Treatment): SVR4 Rate and Safety Sulkowski MS, et al. Hepatology. 2012;56:1516A-1517A. Abstract LB-2. Patients(%) Genotype 1: SVR4 98% 95% SOF/DCV (n=41) SOF/DCV + RBV (n=41) ● No virologic failure reported ● SVR12 evaluable for 68 of 82 patients: 100% ● Safety - No discontinuations due to adverse events - Hemoglobin <9 g/dL • Without ribavirin: 0% • With ribavirin: 12%
    81. 81. 81 Phase 2a Prior Nonresponse, Relapse, or Breakthrough with Telaprevir or Boceprevir With PR Genotype 1 Study 040: Sofosbuvir + Daclatasvir + RBV in Previous Telaprevir or Boceprevir Failures Week 0 12 24 48 Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd (n=21) Sofosbuvir 400 mg qd + Daclatasvir 60 mg qd + RBV (n=20) Follow-Up Follow-Up Sulkowski MS, et al. J Hepatol. 2013;58(suppl 1):S570. Abstract 1417. Sofosbuvir (nucleotide NS5B polymerase inhibitor). Daclatasvir (NS5A replication complex inhibitor). HCV RNA >105 IU/mL. No upper limit to age or BMI. METAVIR score: F0-F1 (12%), >F2 (88%). NS3 polymorphisms conferring resistance to boceprevir or telaprevir as baseline: 46% NS5A polymorphisms conferring resistance to daclatasvir: 7% Excluded: patients who discontinued telaprevir or boceprevir due to an adverse event. Primary efficacy endpoint: SVR12. New Slide
    82. 82. 82 Study 040 (24-Week Treatment): SVR4 and SVR12 Rates ● No virologic failures ● Neither baseline NS3 PI resistance nor use of RBV influenced response ● Sofosbuvir + daclatasvir + RBV was well tolerated - No discontinuations due to adverse events ● Most common adverse events (without RBV) - Fatigue (29%), headache (33%), arthralgia (14%) ● No grade 3/4 elevations in ALT, AST, or total bilirubin ● Anemia (hemoglobin <9 g/dL): 0% Sulkowski MS, et al. J Hepatol. 2013;58(suppl 1):S570. Abstract 1417. Patients(%) Genotype 1 SVR4 SVR12 100% 100% 95%* Sofosbuvir + Daclatasvir (n=21) 100% Sofosbuvir + Daclatasvir + RBV (n=20) *1 patient missing at post-treatment 12 weeks, HCV RNA undetectable at post-treatment week 24 (preliminary). New Slide
    83. 83. 83 Study 014: Asunaprevir + Daclatasvir + BMS-791325 ● Phase 2a, open-label study in treatment-naïve, HCV genotype 1 patients (n=32) - Non-cirrhotic - HCV RNA 6.3 log10 IU/mL - Genotype 1b (75%) - IL28B CC genotype: 28% ● Asunaprevir + daclatasvir + BMS- 791325 75 mg - 24 or 12 weeks of therapy ● Primary outcome: SVR12 - Interim analysis • SVR4: 24 and 12-week arms • SVR12: 12-week arm only) 24-Week Treatment (n=16) 12-Week Treatment (n=16) SVR4 (%) Overall Genotype 1a 94 92 94 100 SVR12 (%) N/A 94 Safety (%) Discontinuations due to adverse events Grade 3/4 laboratory abnormalities Headache Diarrhea Asthenia 0 0 25 13 13 0 6 38 38 19 Interim Outcomes Everson GT, et al. Hepatology. 2012;56:1517A-1518A. Abstract LB-3.
    84. 84. 84 SOUND-C2 Study: Faldaprevir + BI 207127 + Ribavirin Week 0 16 28 40 TID16W (n=81) Follow-Up TID28W No RBV (n=46) TID28W (n=80) Follow-Up Faldaprevir + BI 207127 TID + RBV Follow-UpTID40W (n=77) BID28W (n=78) Zeuzem S, et al. Hepatology. 2012;54(suppl 4):308A-309A. Abstract 232. Faldaprevir + BI 207127 TID + RBV Faldaprevir + BI 207127 BID + RBV Follow-Up Follow-Up Faldaprevir + BI 207127 TID HCV RNA >100K IU/mL, cirrhotic patients permitted. Faldaprevir (NS3/4A inhibitor), BI 207127 (non-nucleoside NS5B inhibitor). Phase 2b Treatment-naïve Genotype 1 Faldaprevir + BI 207127 TID + RBV
    85. 85. 85 SOUND-C2 Study: Final SVR12 Results Patients(%) Overall 69% 59% 52% 39% 59% Patients(%) Genotype 1 Subtypes Genotype 1a Genotype 1b TID16W (n=81) TID28W No RBV (n=46) TID28W (n=80) TID40W (n=77) BID28W (n=78) TID16W (n=34/47) TID28W No RBV (n=18/28) TID28W (n=32/48) TID40W (n=34/43) BID28W (n=30/48) Zeuzem S, et al. Hepatology. 2012;54(suppl 4):308A-309A. Abstract 232. 38% 75% 44% 68% 47% 56% 43% 85% 11% 57%
    86. 86. 86 SOUND-C2 Study: SVR12 by Genotype Subtype and METAVIR Score Patients(%) Genotype 1a METAVIR Score F0-F2 F3-F4 TID16W (n=27/7) TID28W No RBV (n=16/2) TID28W (n=26/6) TID40W (n=29/5) BID28W (n=25/5) Zeuzem S, et al. J Hepatol. 2013;58(suppl 1):S498. Abstract 1227. 44% 14% 40% 67% 45% 60% 44% 40% 13% 0% Patients(%) Genotype 1b METAVIR Score F0-F2 F3-F4 TID16W (n=36/10) TID28W No RBV (n=19/9) TID28W (n=33/15) TID40W (n=33/10) BID28W (n=32/16) 78% 70% 64% 80% 52% 70% 91% 75% 63% 44% New Slide
    87. 87. 87 SOUND-C2 Study: Virologic Failure and Baseline Predictors of SVR12 ● Virologic failure (twice daily, 28-week treatment arm) - Genotype 1a versus 1b: 47% versus 8% - Genotype-1a patients had a higher rate of resistance compared with genotype-1b patients ● Baseline predictors of SVR12 (multivariate odds ratio) - Gender (female:male): 3.99 (P<0001) - HCV subtype (1b:1a): 7.11 (P<0.0001) - IL28B genotype (CC:non-CC): 4.94 (P<0.0001) - GGT (normal:>ULN): 2.08 (P=016) Zeuzem S, et al. Hepatology. 2012;54(suppl 4):308A-309A. Abstract 232.
    88. 88. 88 SOUND-C2 Study: Safety and Tolerability ● Twice daily, 28-week treatment arm - Most favorable safety and tolerability profile • Grade 3/4 bilirubin increase: 39% • Grade 3/4 hemoglobin decrease: 2% • No adverse hematologic effects ● The inclusion of ribavirin remains necessary component of treatment ● Future phase 3 studies (genotype 1b only) - Faldaprevir 120 mg bid + BI 207600 600 mg bid + RBV Zeuzem S, et al. Hepatology. 2012;54(suppl 4):308A-309A. Abstract 232.
    89. 89. 89 Phase 2 Treatment-naïve Genotype 1 AVIATOR Study: ABT-450/r-Based Therapy (Treatment-Naïve Cohort) Week 0 8 12 24 ABT-450/r 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=80) Follow-Up ABT-450/r 150/100 mg qd + ABT-333 + RBV (n=41) Follow-Up ABT-450/r 100/100 or 200/100 mg qd + ABT-267 + RBV (n=79) ABT-450 (NS3/4A protease inhibitor); ABT-267 (NS5A replication complex inhibitor); ABT-333 (non-nucleoside NS5B polymerase inhibitor). HCV RNA >50K IU/mL, absence of cirrhosis, no HIV or HBV. ABT-267 25 mg qd; ABT-333 400 mg bid. Ribavirin 1000-1200 mg divided bid. Primary outcome: SVR24. Follow-Up ABT-450/r 150/100 mg qd + ABT-267 + ABT-333 (n=79) Follow-Up ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=79) Follow-Up ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=80) Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. New Slide
    90. 90. 90 AVIATOR Study (ITT): Overall SVR Rates (Treatment-Naïve Cohort) Patients(%) 83% 89% 85% 91%88% ABT-450/r ABT-267 ABT-333 RBV (n=80) 8 Weeks 12 Weeks ABT-450/r -- ABT-333 RBV (n=41) ABT-450/r ABT-267 -- RBV (n=79) ABT-450/r ABT-267 ABT-333 -- (n=79) ABT-450/r ABT-267 ABT-333 RBV (n=79) Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. 89% 96% 90% 99% 93% 87% 90% ABT-450/r ABT-267 ABT-333 RBV (n=80) 24 Weeks SVR12 SVR24 New Slide
    91. 91. 91 AVIATOR Study: SVR24 by Baseline Subgroups (Treatment-Naïve Cohort) Patients(%) 98% 92% 91% 94% Male (n=78) Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. 89% 91% 94% 94% 95% 89% ABT-450r + ABT-267 + ABT-333 + RBV (12- and 24-Week Arms Combined) Female (n=81) 1a (n=108) 1b (n=50) >7 (n=35) <7 (n=124) F0-F1 (n=113) F2-F3 (n=42) Non-CC (n=115) CC (n=44) Genotype HCV RNA (log) Fibrosis Stage IL28B Genotype New Slide
    92. 92. 92 Phase 2 Null Responders Genotype 1 AVIATOR Study: ABT-450/r-Based Therapy (Null Responders Cohort) Week 0 8 12 24 Received at least 12 weeks of pegIFN + RBV and failed to achieve >2 log10 IU/mL HCV RNA decrease. HCV RNA >50K IU/mL, absence of cirrhosis, no HIV or HBV. IL28B CC genotype (~3%). ABT-267 25 mg qd; ABT-333 400 mg bid. Ribavirin 1000-1200 mg divided bid. Primary outcome: SVR24. Follow-Up Follow-Up ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=43) Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. ABT-450/r 100/100 or 200/100 mg qd + ABT-267 + RBV (n=45) ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=45) New Slide
    93. 93. 93 AVIATOR Study (ITT): Overall SVR Rates (Null Responders Cohort) Patients(%) 89% 89% 12 Weeks ABT-450/r ABT-267 -- RBV (n=45) ABT-450/r ABT-267 ABT-333 RBV (n=45) Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. ABT-450/r ABT-267 ABT-333 RBV (n=43) 24 Weeks SVR12 SVR24 93% 93% 98% 95% New Slide
    94. 94. 94 AVIATOR Study: SVR24 by Baseline Subgroups (Null Responders Cohort) Patients(%) 97% 93% 93% 97% Male (n=55) Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. 91% 93% 96% 95% 94% 100% ABT-450r + ABT-267 + ABT-333 + RBV (12- and 24-Week Arms Combined) Female (n=53) 1a (n=55) 1b (n=33) >7 (n=22) <7 (n=66) F0-F1 (n=41) F2-F3 (n=45) Non-CC (n=85) CC (n=3) Genotype HCV RNA (log) Fibrosis Stage IL28B Genotype New Slide
    95. 95. 95 AVIATOR Study: Virologic Relapse and Safety ● Virologic relapse in prior null responders - 8-, 12-, and 24-week arms: 12.5%, 6.3%, 2.5% ● Discontinuations due to adverse events in the 12- and 24-week arms: 2.4% - Considered related to treatment (n=4/6): hepatitis cholestatic, feeling jittery, homicidal ideation, decreased creatinine clearance ● Most common adverse events - Headache (31%), fatigue (30%), nausea (23%), insomnia (20%), diarrhea (15%) - Bilirubin increase: 2.4% - Anemia (hemoglobin 6.5 to <8 g/dL): 2.4% Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3. New Slide
    96. 96. 96 New and Emerging Strategies: Clinical Considerations ● Recent recommendations from the CDC emphasize the importance to screen and early diagnosis of HCV infection ● Newly diagnosed patients with chronic HCV infection still require comprehensive counseling ● For patients who are candidates for therapy - Initiate treatment with currently available therapy - Defer treatment until availability of new antiviral agents with the potential for increased efficacy, decreased adverse events, and shorter duration of therapy over existing regimens
    97. 97. 97 New and Emerging Strategies: Conclusions ● Results from phase 2 trials for all oral agents are excellent, with well tolerated regimens and high SVR rates ● High SVR rates with interferon-free regimens are possible in a variety of patient populations, including difficult-to-treat patient populations (prior null responders and cirrhotics) - Ribavirin and IL28B status remain important for some regimens ● Non-CC and genotype 1a status remain important for DAA + peginterferon + ribavirin regimens ● Further study is needed for DAAs in special patient populations - Cirrhosis - HIV coinfection - Liver transplant recipients
    98. 98. 98 New Electronic Evaluation ProcessNew Electronic Evaluation Process We Are Eliminating Hard Copy Evaluations!• You will receive an electronic evaluation to the email address provided within 1 business day • Reminder email communications will be sent up to 5 days post lecture until the evaluation is completed • Completion Is Required for CME/CNE/CPE credit and future attendance • Incomplete evaluations will preclude attendees from receiving their CME/CNE/CPE certificate & future communications about lectures in your area
    99. 99. 99 Outcomes Measurement ReminderOutcomes Measurement Reminder • We are required to assess “changes in learners’ competence, performance or patient outcomes achieved as a result of their participation in a CME/CNE/CPE sponsored educational activity” • As a result of this requirement you will receive a short survey via email 8 to 12 weeks after completing this course • We consider the survey to be an additional component of your overall participation in this educational activity and would urge you to reflect on what you learned in the activity and then complete this survey

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