Why make this statement?

Transcription

1 HCV Council clinical practice statements were evaluated by the Council A review of the available literature was conducted The level of support and level of evidence for the statements were discussed This activity will revisit the findings of the HCV Council from July 2014 and discuss how the field has changed over the last 4 months

2 Patients with cirrhosis have lower rates of SVR compared to patients who are non-cirrhotic and, thus, treatment efficacy remains suboptimal for this population. Why make this statement? Historical data suggests cirrhosis is the strongest baseline factor to predict treatment failure Patients with cirrhosis are felt to have higher SAE, dose modifications, and treatment discontinuation Compounded by prior treatment failure Trend blunted but not eliminated with SOF-PR and SMV-PR

3 Adjusted SVR4: SOF/SMV±RBV for 12 Weeks Impact of Cirrhosis Sulkowski MS, et al. Presented at AASLD: The Liver Meeting. November 7-11, Boston, Massachusetts. Poster 955.

4 SVR Effect of Cirrhosis Nearly Eliminated with Combination All-oral Therapy SVR 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% ION-1: Cirrhotic vs Non-cirrhotic SVR ION-2: Cirrhotic vs Non-cirrhotic SVR Cirrhotic Non-Cirrhotic Cirrhotic 100% 100% 100% 100% 100% 100% 97% 96% 100% 90% 80% 70% 60% 50% 95% 86% 82% Non-Cirrhotic 100% 100% 99% 100% 99% 40% 30% 20% 10% % wk-rbv 12 wk+rbv 24 wk-rbv 24 wk+rbv 12 wk-rbv 12 wk+rbv 24 wk-rbv 24 wk+rbv Ledipasvir/ sofosbuvir (LDV/SOF) ± RBV Afdhal N, et al. N Engl J Med. 2014;370: ; Afdhal N, et al. N Engl J Med. 2014;370:

5 SVR12, % Patients TURQUOISE-II (3D + RBV): ITT SVR12 by Prior Treatment Response 3D (Paritaprevir/r-ombitasvir and dasabuvir) + RBV 12-week arm 24-week arm 100.0% 92.2% 92.9% 93.3% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 85.7% 100.0% 100.0% 100.0% 80.0% 60.0% 40.0% 20.0% 0.0% 59/64 52/56 Naive 14/15 13/13 11/11 10/10 Prior Relapse Response Prior Relapse Response 22/22 18/18 Naive 25/25 20/20 Prior Relapse Response 6/7 3/3 14/14 10/10 Prior Relapse Response Prior Null Response G1a G1b Poordad F, et al. N Engl J Med. 2014;370:

6 Summary of Key Issues Cirrhosis is still a baseline factor that effects efficacy The impact can be blunted by other factors, such as favorable baseline characteristics (G1b) and the treatment regimen Patients continue to have lower rates of SVR, but the difference in SVR rate between non-cirrhotic and cirrhotic is now much smaller

7 Patients with easier to treat characteristics can be defined and treated for shorter duration. Why make this statement? PR data suggested that some populations may be able to shorten therapy Low-viral load IL28B CC Shorter therapy is desirable as treatment duration drives cost and compliance Efficacy higher when treatment is extended in certain populations with cirrhosis

8 SVR12 (%) SVR12 by Number of Negative Predictors Derived from Multivariate Analysis (combined dataset) > /9 70/70 181/ / /239 60/88 12/ *Prior treatment, sex, weight, IL28B, cirrhosis, and HCV RNA level. Phase 3 studies of sofosbuvir regimens Foster GR, et al. Abstract O66, EASL, 2014 Number of Negative Predictors*

9 SVR12 (%) ION-3: Ledipasvir/Sofosbuvir (LDV/SOF) ± RBV in HCV G1 Treatment-Naïve, Non-Cirrhotic Patients P = 0.52 P = 0.70 P = / / /216 LDV/SOF LDV/SOF + RBV LDV/SOF 8 Weeks 12 Weeks Kowdley, KV, et al. N Engl J Med. 2014;370(20):

10 SVR 12 (%) ION-3 (G1, Treatment-Naive, Non-Cirrhotic, Efficacy in Subjects with Baseline HCV RNA < 6 Million IU/mL LDV/SOF ± RBV x 8 or 12 weeks) Efficacy in Subjects with Baseline HCV RNA < 6 Million IU/mL % 96% Relapse Rates by Baseline Viral Load 0 119/ /131 LDV/SOF 8 Weeks LDV/SOF 8 weeks LDV/SOF 12 Weeks LDV/SOF 12 weeks HCV RNA < 6M IU/mL 2% (2/123) 2% (2/131) 8 weeks of LDV/SOF was non-inferior to 12 weeks for patients with HCV RNA < 6M IU/ml and in the overall population Ledipasvir and sofosbuvir prescribing information. Gilead Sciences, Inc

11 Summary of Key Issues Next-wave DAA trials confirm that shortening therapy for easier-to-treat patients is plausible Especially treatment-naïve without cirrhosis Even within difficult populations, cohorts of patients can be identified for shorter duration therapy Treatment experienced genotype 1b with cirrhosis and treatment experienced genotype 1a (without prior null response) can shorten to 12 weeks with 3D regimen (Paritaprevir/r-ombitasvir and dasabuvir)

12 C-SWIFT: MK-5172+MK-8742+Sofosbuvir in Treatment-naïve Patients with HCV G1 With or without cirrhosis for durations of 4, 6, or 8 weeks SVR 4/8 (n) Non-cirrhotic Cirrhotic 4 Weeks 6 Weeks 6 Weeks 8 Weeks 39% (31) 87% (30) 80% (20) 95% (19) Optimized regimen of PI + NS5A + NUC Non-cirrhotics: 4-6 weeks; Cirrhotics: 6-8 weeks Treatment failure due exclusively to relapse Lawitz, et al. Presented at AASLD: The Liver Meeting. November 7-11, Boston, Massachusetts. LB-33.

13 The preferred approach to treatment for all subgroups of patients with genotype 3 is sofosbuvir and ribavirin for 24 weeks. Why make this statement? G3 continues to have lower efficacy despite longer duration of therapy The impact of the next wave of therapy remains controversial

14 SVR 12 (%) Sofosbuvir + Ribavirin for Genotype VALENCE: 24 weeks, n= /92 2/13 87/100 28/45 No cirrhosis Cirrhosis No cirrhosis Cirrhosis Naïve Treatment-experienced Zeuzem S, et al. N Engl J Med. 2014;370:

15 SVR12 (%) Retreatment of Genotype 3: Sofosbuvir + RBV Failures PR + SOF 12 Wks SOF + RBV 24 Wks /14 17/23 7/8 7/15 No cirrhosis Cirrhosis Esteban R, et al. EASL 2014, Abstract O8.

16 All-oral 12-week Combination of Daclatasvir and Sofosbuvir in Patients with Genotype 3: ALLY-3 ALLY-3 0 Weeks EOT SVR Treatment Naïve 19% with cirrhosis N=101 Daclatasvir + Sofosbuvir 99% 90% Prior Treatment 25% with cirrhosis N=51 Daclatasvir + Sofosbuvir 100% 86% SVR F0-F3 = 96% (105/19) SVR F4 = 63% (20/32) Nelson DR, et al. Presented at AASLD: The Liver Meeting. November 7-11, Boston, Massachusetts. LB-3.

17 Summary of Key Issues 24 weeks of SOF + RBV highly effective in G3 AEs are those of RBV No virologic price to pay for failure PEG + RBV + SOF may be more effective in certain populations (eg, treatment-experienced cirrhotics) Drugs in development may increase the number of options

18 Due to the high costs of medications, only patients with advanced fibrosis should be offered treatment with all oral regimens for HCV. Why make this statement? To treat entire US HCV population would cost > $250 billion, thus need to prioritize access Based on the premise that patients with advanced fibrosis have the most at risk and most to gain with therapy, while those with mild disease can wait Current access issue: Many payors restricting care to only those with disease severity and/or high risk for disease progression Advanced fibrosis Extrahepatic manifestations Cryoglobulins with renal disease

19 % Patients After 5 Years Effects of SVR on Risk of Liver Transplant, Hepatocellular Carcinoma, Death, and Re-infection SVR No SVR 5-Year All Cause Mortality 10.5% 11.3% % 3.6% 2 0 General: 18 Studies n=29,269 Cirrhotic: 9 Studies n=2,734 Meta-analysis of 129 studies; RR substantially reduced for all groups with SVR Adapted from Saleem, et al. Presented at AASLD: The Liver Meeting. November 7-11, Boston, Massachusetts. Abstract 44.

20 Adjusted Hazard Ratio for Mortality Adjusted Hazard Ratio for Mortality Adjusted Hazard Ratio for Mortality SVR Reduces All-cause Mortality Even in the Absence of Cirrhosis 1.2 Genotype 1 (n=12,166) SVR rate: 35% 1.2 Genotype 2 (n=2904) SVR rate: 72% 1.2 Genotype 3 (n=1794) SVR rate: 62% ( ) (P=0.0003) 0.72 ( ) (P=0.001) ( ) (P=0.005) 0.69 ( ) (P=0.049) ( ) (P=0.0002) 0.40 ( ) (P=0.0001) Overall SVR Group SVR With No Baseline Cirrhosis 0 Overall SVR Group SVR With No Baseline Cirrhosis 0 Overall SVR Group SVR With No Baseline Cirrhosis Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:

21 Impact of IFN-free Regimens on Clinical and Cost Outcomes Triple Therapy Staging Treat all Oral Therapy Staging Treat all Life expectancy (yr) Progression to: Cirrhosis (%) Decompensation (%) HCC (%) Decomp or HCC Transplant (%) Strategy Oral staging Oral treat-all Cost ($) 77,133 90,681 Effectiveness (QALYs) ICER ($/QALY) 15,709 HCC: hepatocellular carcinoma; QALY: quality adjusted life years; ICER: incremental cost effectiveness analysis Younossi ZM, et al. J Hepatol. 2014;60:

22 Summary of Key Issues HCV has significant effect on morbidity and mortality Highest in patients with cirrhosis, but also impacts patients without cirrhosis HCV cure reduces morbidity and mortality Effect seen in both patients with and without cirrhosis Cirrhosis has a negative impact on SVR, especially in treatment-experienced population Requires longer duration and more expensive therapy Treating all patients infected with HCV, without using fibrosis screening based intervention has the greatest impact on morbidity/mortality and is the most costeffective strategy

23 Patients Meeting "Highest" or High" Priority for HCV Treatment in Chronic Hepatitis C Cohort Study (CHeCS) Treatment recommendations have suggested prioritizing patients for treatment based on disease severity, risks of progression, co-morbidities, and extrahepatic manifestations Priority status N=8504 HIGHEST PRIORITY 32.9% HIGH PRIORITY 28.9% NOT MEETING HIGHEST or HIGH PRIORITY 38.2% This study determined treatment priority status in a large, multicenter patient cohort. Cryoglobulinemia and Debilitating fatigue not evaluated Xu, et al. Presented at AASLD: The Liver Meeting. November 7-11, Boston, Massachusetts. LB-29.

24 Patients co-infected with HIV/HCV should no longer be considered a special population. Why make this statement? Patients infected with HIV/HCV have been historically more difficult to treat Poorer response to IFN-based therapy Increased risk of toxicities and adverse events Fewer options due to drug-drug interactions Recent data suggest IFN-free therapies may be equally effective in patients who are HIV negative or positive Special designation delays therapy to this group EASL guidelines has already proclaimed patients with HIV/HCV non-special

25 NIAID ERADICATE: Sofosbuvir/Ledipasvir for the Treatment of HCV G1 in Patients Co-infected with HIV HCV, GT1, treatment-naïve subjects treated with SOF/LDV x 12 weeks GT1a= 74% African American = 84% Mild fibrosis = 78% Arm A (n=13): ARV-naïve Arm B (n=37): ARV-treated ARV combination Tenofovir/FTC with Efavirenz, Rilpivirine, or Raltegrevir ARV-naïve ARV-treated EOT 100% 100% SVR12 100% 97% No change in CD4 or HIV RNA No SAE and no early discontinuations due to AE Townsend KS, et al. Presented at AASLD: The Liver Meeting. November 7-11, Boston, Massachusetts. Abstract 84.

26 TURQUOISE-I: Paritaprevir/r/Ombitasvir, Dasabuvir + RBV SVR12 in HCV/HIV Co-infected Patients Randomized to 12 or 24 weeks of 3-drug regimen + RBV 3D = Paritaprevir/r (PI) + Ombitasvir (NS5A) + Dasabuvir (NNI) Treatment-naïve (65%) or Experienced (35%) Cirrhotic ~20% (CP-A) HIV ART Regimen: Atazanavir (44%) or Raltegrevir (56%) 0 Weeks SVR HCV/HIV Co-infected N=31 3D + RBV 94% N=32 3D+ RBV 91% AE: Mild fatigue, nausea, insomnia; No SAE Wyles DL, et al. Presented at AASLD: The Liver Meeting. November 7-11, Boston, Massachusetts. Abstract 1939.

27 Summary of Key Issues Efficacy with newer agents now comparable to HCV monoinfection, raising possibility that HIV/HCV co-infection no longer is a special population Need expansion to larger and more diverse populations High viral loads may remain an important factor Drug-drug interactions require ongoing evaluation but are reduced for selected agents and combinations Earlier access to new therapies likely for co-infected population