New & Emerging Interferon‐ Free, Direct‐Acting Antiviral Regimens for the Treatment of Hepatitis C: An Expert Review of Recent Clinical Data Sponsored for CME credit by Rush University Medical Center Supported by independent educational grants from AbbVie, Boehringer Ingelheim and Janssen
72
Embed
New & Emerging Interferon ‐ Free, Direct ‐ Acting Antiviral Regimens for the Treatment of Hepatitis C: An Expert Review of Recent Clinical Data Sponsored.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
New & Emerging Interferon‐Free, Direct‐Acting Antiviral Regimens for the Treatment of Hepatitis C: An Expert Review of Recent Clinical Data
New & Emerging Interferon‐Free, Direct‐Acting Antiviral Regimens for the Treatment of Hepatitis C: An Expert Review of Recent Clinical Data
Sponsored for CME credit byRush University Medical Center
Supported by independent educational grants from AbbVie,
Boehringer Ingelheim and Janssen Therapeutics
2
Content Development FacultyContent Development Faculty
Paul Kwo, MDProfessor of Medicine
Medical Director, Liver TransplantationIndiana UniversityIndianapolis, IN
IntroductionIntroduction
4
Chronic HCV in the US:Underdiagnosed and UntreatedChronic HCV in the US:Underdiagnosed and Untreated
Estimated treatment rate is based on Q2 and Q4 2011 chart audits.Hepatitis C Monitor. Ipsos Healthcare.
0
500
1000
1500
2000
2500
3000
3500
4000
4500
Nu
mb
er (
in ‘
000s
)
Prevalence Diagnosed Treated
4.1 M
1.6 M
89,000
38%Diagnosed
5.5%Treated
Unaware of Infection
5
Chronic HCV Undetected by Risk-Based Screening in Primary CareChronic HCV Undetected by Risk-Based Screening in Primary Care
Cross-sectional study (2005-2010) of adult ( ≥18 years) patients in 4 large primary health care systems
Among 209,076 patients who attended at least 1 medical appointment:– 8.4% (17,464) had been tested for HCV, and 1115 cases were detected
Risk factors for HCV positivity among identified cases
Applying these risk factors to the entire cohort predicted that 6005 patients had HCV infection
Undetected cases (4890) accounted for 81% of HCV infections
Yartel AK, et al. Hepatology. 2013;58(suppl 1):219A. Abstract 24.
Predictors of HCV positivity Adjusted odds ratio*
Born 1945-1965Male genderBlackHispanicElevated ALTIntravenous drug use
Testing recommended at least once for persons born between 1945 and 1965
Others: Screen for risk factors and perform one-time testing if risk factors present
Annual HCV testing recommended for persons who inject drugs and for HIV-seropositive men who have unprotected sex with men
Periodic testing should be offered to other persons with ongoing risk factors for exposure to HCV
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version March 21, 2014
7
Risk Factors That Should Prompt One-Time or Periodic TestingRisk Factors That Should Prompt One-Time or Periodic Testing
Risk behaviors– Injection drug use (current or ever, including only once)– Intranasal illicit drug use
Risk exposures– Long-term hemodialysis (ever)– Getting a tattoo in an unregulated setting– Healthcare, emergency medical, and public safety workers after needle sticks, sharps, or
mucosal exposures to HCV-infected blood– Children born to HCV-infected women– Prior recipients of transfusions or organ transplants, including persons who:
• Were notified that they received blood from a donor who later tested positive for HCV infection• Received a transfusion of blood or blood components, or underwent an organ transplant before July 1992• Received clotting factor concentrates produced before 1987• Were ever incarcerated
Other medical conditions associated with risk– HIV infection– Unexplained chronic liver disease and chronic hepatitis including elevated alanine
aminotransferase levels
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version March 21, 2014
8
Preferred Treatment Recommendations: Initial Therapy or Relapsed after Prior PRAASLD-IDSA
Preferred Treatment Recommendations: Initial Therapy or Relapsed after Prior PRAASLD-IDSA
Genotype 1IFN eligible
IFN ineligible†
Sofosbuvir + PR 12 weeks
Sofosbuvir + simeprevir* ± RBV 12 weeks
Genotype 2 Sofosbuvir + RBV 12 weeks
Genotype 3 Sofosbuvir + RBV 24 weeks
Genotype 4IFN eligible
IFN ineligible
Sofosbuvir + PR 12 weeks
Sofosbuvir + RBV 24 weeks
Genotype 5 or 6 Sofosbuvir + PR 12 weeks
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version March 21, 2014
PR: Pegylated interferon + Ribavirin.
† Currently recommended only for patients who require immediate treatment.
*For genotype 1a, baseline resistance testing for the Q80K polymorphism should be performed and alternative treatments considered if this mutation is present.
Do not treat decompensated cirrhosis with PegIFN or simeprevir
9
Alternative Treatment Recommendations: Initial Therapy or Relapsed after Prior PRAASLD-IDSA
Alternative Treatment Recommendations: Initial Therapy or Relapsed after Prior PRAASLD-IDSA
Genotype 1IFN eligible
IFN ineligible†
Simeprevir* 12 weeks + PR 24 weeks
Sofosbuvir + RBV 24 weeks
Genotype 2 None
Genotype 3 Sofosbuvir + PR 12 weeks
Genotype 4IFN eligible
IFN ineligible
Simeprevir 12 weeks + PR 24-48 weeks
None
Genotype 5 or 6 PR 48 weeks
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version March 21, 2014
PR: Pegylated interferon + Ribavirin.
†Currently recommended only for patients who require immediate treatment.
*Acceptable alternative for genotype 1b patients, or genotype 1a patients in whom the Q80K polymorphism is not detected before treatment.
Do not treat decompensated cirrhosis with PegIFN or simeprevir
10
Not Recommended as Therapy for Treatment-Naïve PatientsAASLD-IDSA
Not Recommended as Therapy for Treatment-Naïve PatientsAASLD-IDSA
Genotype 1PR ± telaprevir or boceprevir for 24 or 48 weeksMonotherapy with PegIFN, RBV, or a DAA
Genotype 2PR for 24 weeksMonotherapy with PegIFN, RBV, or a DAATelaprevir-, boceprevir-, or simeprevir-based regimens
Genotype 3PR for 24 or 48 weeksMonotherapy with PegIFN, RBV, or a DAATelaprevir-, boceprevir-, or simeprevir-based regimens
Genotype 4PR for 24 or 48 weeksMonotherapy with PegIFN, RBV, or a DAATelaprevir-, boceprevir-, or simeprevir-based regimens
Genotype 5 or 6Monotherapy with PegIFN, RBV, or a DAATelaprevir- or boceprevir-based regimens
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version March 21, 2014
PR: Pegylated interferon + Ribavirin.
Do not treat decompensated cirrhosis with PegIFN or simeprevir
11
Preferred Treatment Recommendations: Partial or Null Response to Prior PR†
AASLD-IDSA
Preferred Treatment Recommendations: Partial or Null Response to Prior PR†
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version March 21, 2014
PR: Pegylated interferon + Ribavirin.
†Consideration should be given to postponing treatment, pending release of new drugs for patients with limited hepatic fibrosis (F 0-2).
*For genotype 1a, baseline resistance testing for Q80K should be performed and alternative treatments considered if this mutation is present.
Do not treat decompensated cirrhosis with PegIFN or simeprevir
13
Not Recommended as Therapy for Patients with Partial or Null Response to Prior PR† AASLD-IDSA
Not Recommended as Therapy for Patients with Partial or Null Response to Prior PR† AASLD-IDSA
Genotype 1PR ± telaprevir or boceprevir Monotherapy with PegIFN, RBV, or a DAA
Genotype 2PR ± telaprevir or boceprevir Monotherapy with PegIFN, RBV, or a DAA
Genotype 3PR ± any current protease inhibitorMonotherapy with PegIFN, RBV, or a DAA
Genotype 4PR ± any current HCV protease inhibitorMonotherapy with PegIFN, RBV, or a DAA
Genotype 5 or 6PR ± any current HCV protease inhibitorMonotherapy with PegIFN, RBV, or a DAA
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version March 21, 2014
PR: Pegylated interferon + Ribavirin.
Do not treat decompensated cirrhosis with PegIFN or simeprevir
IFN-Free Regimens for Chronic HCV InfectionIFN-Free Regimens for Chronic HCV Infection
15
Rationale for IFN-Free Direct-Acting Antiviral Therapy for HCVRationale for IFN-Free Direct-Acting Antiviral Therapy for HCV
Drawbacks of IFN-based Therapy– Challenging tolerability – High percentage of patients are ineligible for IFN– Long duration of therapy– Low SVR rates compared to modern all-oral regimens
• PR: ~40-50% in treatment-naïve patients
• Triple therapy PR + boceprevir or telaprevir: ~70%
– Many patient-specific and virus-specific factors affecting eligibility or treatment response (Race, IL28B, cirrhosis, prior treatment, etc)
– Development of resistance– Requires injection
16
Overview of DAAsOverview of DAAs
NS3/4A NS5A NS5B
Function Serine Protease Component of HCV Replication Complex
Sulkowski M, et al. EASL International Liver Congress, 2014. Abstract O63.
NS3/4A
NS5A
NS5BMK-5172 MK-8742 + RBV
0 12 24
HIV/HCV Co-infectedHCV Genotype 1Non-cirrhotic
Phase 2
SVR12
SVR12MK-5172 MK-8742 No RBV
Stable on raltegravir + two NRTIs for 8 weeks prior to enrollmentART dose modification not permitted during 8 weeks preceding enrollment unless dose modification due to tolerability failureCD4 >300 cells/mm3
Sulkowski M, et al. EASL International Liver Congress, 2014. Abstract O63.
NS3/4A
NS5A
NS5B
HC
V R
NA
< L
LQ
, %
pat
ien
ts
Week 4 Week 8 Week 12 SVR4
No RBV+ RBV
Interim Results
100 100 10097
100
90 90 90
0
20
40
60
80
100Phase 2
MK-5172 + MK-8742
29 30 29 30 29 30 29 29
69
Summary (1 of 4): Genotype 2/3 Chronic HCVSummary (1 of 4): Genotype 2/3 Chronic HCV
Sofosbuvir + RBV is approved and recommended for treatment of genotype 2/3 patients with chronic HCV and who are treatment-naïve or relapsed after prior PR– Genotype 2 chronic HCV (12 weeks of therapy)– Genotype 3 chronic HCV (24 weeks of therapy)
70
Summary (2 of 4): Genotype 1 Chronic HCVSummary (2 of 4): Genotype 1 Chronic HCV
Two regimens have demonstrated very high SVR12 rates (>90%) in phase III trials of treatment-naïve patients, and patients who failed prior therapy (relapsed, null response, partial response)– 3D +RBV (ABT-450 + ombitasvir + dasabuvir +RBV)– Ledipasvir + Sofosbuvir
Both regimens were studied in trials using 12-week duration of therapy– The ION-3 trial suggests that 8 weeks of therapy may be
sufficient for ledipasvir + sofosbuvir therapy (±RBV) in treatment-naïve patients without cirrhosis
71
Summary (3 of 4): Genotype 1 Chronic HCVSummary (3 of 4): Genotype 1 Chronic HCV
Other regimens showing high SVR12 rates in phase II trials include– Daclatasvir + asunaprevir + BMS-791325– MK-5172 + MK8742 ± RBV– Faldaprevir + Deleobuvir + PPI-668 ± RBV
Cirrhotic Patients– The phase III TURQUOISE-II trial enrolled only patients with
compensated cirrhosis and showed high SVR12 rates for 12 or 24 weeks of therapy with 3D + RBV (treatment-naïve and prior PR failures)
– The cirrhotic subgroups of other trials also showed high SVR12 rates for• Ledipasvir + sofosbuvir ± RBV (treatment-naïve patients)• Daclatasvir + asunaprevir (Gt1b patients)
72
Summary (4 of 4): Genotype 1 Chronic HCVSummary (4 of 4): Genotype 1 Chronic HCV
HIV Co-infected Patients– Phase II trials have found high SVR12 rates for treatment of HCV