4/30/2015. Interactive Case-Based Presentations and Audience Discussion. Debika Bhattacharya, MD, MSc. Learning Objectives

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1 4/3/215 Interactive Case-Based Presentations and Audience Discussion Debika Bhattacharya, MD, MSc Assistant Clinical Professor University of California Los Angeles Los Angeles, California Formatted: Los Angeles, CA: April 28, 215 (INTRODUCTORY) Learning Objectives After attending this presentation, participants will be able to: Recognize when and in whom to initiate hepatitis C virus (HCV) treatment Identify current treatment options for patients with genotype 1 and 4 HCV Identify important side effects of HCV therapy Slide 2 of 53 Case 1 55 y.o. man with positive HCV antibody, diagnosed on routine screening He had never had a liver biopsy and is HCV treatment naïve No known history of other liver disease Physical examination unremarkable You obtain the following tests: Lab/Test HCV RNA HCV genotype WBC Hemoglobin 8,, IU/mL 1a 4.58 x 1 3 /ul 14 g/dl Platelets 165, HIV-1 Ab US: NR increased echogenicity c/w chronic liver disease or fatty infiltration Lab INR 1.1 Creatinine Total bilirubin.3 AST ALT Alkaline phosphatase Albumin mg/dl 48 U/L 68 U/L 111 U/L FIB-4 score 1.94 APRI.73 Slide 4 of 53 1

2 1-year cumulative occurrence rate (%) 4/3/215 Slide 5 of 53 Reduce Burden of HCV Morbidity and Mortality Among Persons Born Between Prevalence 5.3 times higher than other ages (3.29% vs.55%) 1 Represents 81% of all U.S. adult chronic HCV infections Represents 73% of all HCVassociated mortality % do not report a risk for infection on national surveys Smith, et al. Ann Intern Med. 212; Armstrong, et al. Ann Int Med. 26; Kramer Et al., Hepatology Ly, et al. Ann Int Med. 212.Boomers Slide 8 of 53 SVR Decreases All-cause Mortality 53 patients followed for a median of 8.4 years All with advanced fibrosis SVR 36% SVR patients 26. All-cause mortality Liver-related mortality or liver transplant Non-SVR patients HCC 2.1 Liver failure Baseline factors significantly associated with all-cause mortality: Older age GT 3 (2-fold increase in mortality and HCC) Higher Ishak fibrosis score Diabetes Severe alcohol use van der Meer AJ. JAMA 212. Slide 1 of 53 When and in Whom to Initiate HCV Therapy Highest Priority for Treatment Owing to Highest Risk for Severe Complications Advanced fibrosis (Metavir F3) or compensated cirrhosis (F4) Organ Transplant Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations (e.g. vasculitis) Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis Rating: Class I, Level A Rating: Class I, Level B Rating: Class I, Level B Rating: Class IIa, Level B High Priority for Treatment Owing to High Risk for Complications Fibrosis (Metavir F2) HIV-1 Coinfection Hepatitis B Virus (HBV) Coinfection Other coexistent liver disease (e.g. NASH) Debilitating fatigue Type II Diabetes mellitus (insulin resistant) Porphyria cutanea tarda Rating: Class I, Level B Rating: Class I, Level B Rating: Class IIa, Level C Rating: Class IIa, Level C Rating: Class IIa, Level B Rating: Class IIa, Level B Rating: Class IIb, Level C AASLD/IDSA/IAS USA Recommendations for Testing, Managing, and Treating Hepatitis C, 215 2

3 SVR12 (%) SVR12 (%) 4/3/215 Slide 11 of 53 Persons Whose Risk of HCV Transmission is High and in Whom HCV Treatment May Yield Transmission Reduction Benefits High HCV Transmission Risk* Men who have sex with men (MSM) with high-risk sexual practices Active injection drug users Incarcerated persons Persons on long-term hemodialysis HCV-infected women of child-bearing potential wishing to get pregnant Rating: Class IIa, Level C *Patients at high risk of transmitting HCV should be counseled on ways to decrease transmission and minimize the risk of reinfection AASLD/IDSA/IAS USA Recommendations for Testing, Managing, and Treating Hepatitis C, 215 Slide 14 of 53 SMV + SOF: Genotype 1, and experienced Cohort 1 (F-F2 Nulls): SVR12 (N = 8, all arms) Cohort 2 (F3-F4 Naives/Nulls): SVR12 (N = 87, all arms) SMV + SOF + RBV SMV + SOF /27 13/14 19/24 14/15 28/3 13/14 25/27 16/16 12-Wk Arm 24-Wk Arm 12-Wk Arm 24-Wk Arm study (OPTIMIST) EASL 215, no data in HIV infection COSMOS: Lawitz E et al, Lancet 214;146: COSMOS. Slide 16 of 53 Studies of Sofosbuvir + Trial Population Treatment Regimen ION-1 ION-2 ION-3 Treatment-experienced 8 weeks + RBV 12 weeks w/o RBV SVR12 (%) RBV+: 97 RBV-: 99 RBV+: 99 RBV-: 98 RBV+: 96 RBV-: 94 RBV+: 99 RBV-: 99 RBV+: 93 RBV-: 94 RBV-: 95 3

4 SVR12 (%) Relapse (%) 4/3/215 Slide 17 of 53 Studies of Sofosbuvir + ION-3: GT1 treatment-naive pts: SOF/LDV FDC ± RBV for 8 or 12 wks SOF/LDV FDC SOF/LDV FDC + RBV HCV RNA < 6 million IU/mL HCV RNA > 6 million IU/mL n/n = 5 22/ 21/ 26/ n/n = Wks 12 Wks ION-3: Kowdley K et al, NEJM 214;37: HARVONI [package insert] 2 2/213 9/92 SOF/LDV 8 Wks 2 1 2/131 1/85 SOF/LDV 12 Wks Abbvie Trial Population Treatment Regimen SVR12 Slide 19 of 53 PEARL-III 1 PEARL-IV 1 SAPPHIRE-I 2 SAPPHIRE-II 3 TURQUOISE-I 4 Phase II/III TURQUOISE- II 5 GT1b, Monoinfected, GT1a, Monoinfected, GT1, Monoinfected, GT1, Monoinfected, Tx-exp GT1, HIV/HCV, GT1, HIV/HCV, Tx-exp GT1, Monoinfected, GT1, Monoinfected, Tx-exp 3D+RBV x 12 weeks RBV+: 99.5% RBV-: 99% 3D+RBV x 12 weeks RBV+: 97% RBV-: 9% 3D+RBV x 12 weeks 96% 3D+RBV x 12 weeks 96% 3D+RBV x 12/24 weeks 3D+RBV x 12/24 weeks 3D+RBV x 12/24 weeks 3D+RBV x 12/24 weeks 12 wks: 95% 24 wks: 91% 12 wks: 91% 24 wks: 9% 12 wks: 94% 24 wks: 95% 12 wks: 9% 24 wks: 97% 1. Ferenci P NEJM 214; 2. Feld JJ NEJM 214; 3. Zeuzem S NEJM 214; 4. Sulkowski MS JAMA 215; 5. Poordad F NEJM 214. Slide 2 of 53 Paritaprevir/r-Ombitasvir + Dasabuvir ± RBV HCV G1a, No Cirrhosis, Naïve, 12 Weeks (PEARL-4) SVR12 (%) RBV No RBV Ribavirin Needed in 1a Ferenci P, et al. N Engl J Med.214;37:

5 4/3/215 Slide 22 of 53 Treatment of HCV: USA No cirrhosis Cirrhosis Gen Regimen TN TE Regimen TN TE o 1a SOF+LDV (<6M) 12 (8) 12 SOF+LDV SOF+LDV +RBV 12 3D +RBV D +RBV SMV +SOF±RBV SMV +SOF±RBV b SOF+LDV (<6M) 12 (8) 12 SOF+LDV SOF+LDV +RBV 12 3D D +RBV SMV +SOF±RBV SMV +SOF±RBV Case 2 Slide 23 of y.o. man with positive HCV antibody He has never had a liver biopsy and is HCV treatment-experienced, having had a null response to pegylated IFN/RBV No known history of other liver disease Physical examination unremarkable You obtain the following tests: Lab/Test HCV RNA HCV genotype WBC Hemoglobin 5,, IU/mL 1b 4.58 x 1 3 /ul 14 g/dl Platelets 165, HIV-1 Ab US: NR increased echogenicity c/w chronic liver disease or fatty infiltration Lab INR 1.1 Creatinine Total bilirubin.3 AST ALT Alkaline phosphatase Albumin mg/dl 48 U/L 68 U/L 111 U/L FIB-4 score 1.94 APRI.73 Slide 26 of 53 Studies of Sofosbuvir + Trial Population Treatment Regimen SVR12 (%) ION-1 ION-2 ION-3 Treatmentexperienced 8 weeks + RBV 12 weeks w/o RBV RBV+: 97 RBV-: 99 RBV+: 99 RBV-: 98 RBV+: 96 RBV-: 94 RBV+: 99 RBV-: 99 RBV+: 93 RBV-: 94 RBV-: 95 5

6 SVR12 (%) SVR12 (%) 4/3/215 Slide 27 of 53 Studies of Sofosbuvir ION-2: GT1 treatment-experienced pts (2% cirrhotic): SOF/LDV FDC ± RBV x 12/24 wk SOF/LDV FDC SOF/LDV FDC + RBV No Cirrhosis Cirrhosis n/n = 2 12/ 17/ 18/ 11/ Wks 24 Wks n/n = 2 83/ 19/ 85/ 22/ Wks 24 Wks ION-2: Afdhal N et al, NEJM 214;37: HARVONI [package insert] Slide 3 of 53 Treatment of HCV: USA No cirrhosis Cirrhosis Genotype Regimen wk Regimen TN TE 1a SOF+LDV (<6M) 12 (8) SOF+LDV SOF+LDV +RBV 12 3D +RBV 12 3D +RBV SMV +SOF±RBV 12 SMV +SOF±RBV b SOF+LDV (<6M) 12 (8) SOF+LDV SOF+LDV +RBV 12 3D 12 3D +RBV SMV +SOF±RBV 12 SMV +SOF±RBV Case 3 Slide 32 of y.o. man with positive HCV antibody. He has never had a liver biopsy and is HCV treatment-experienced, to pegylated IFN/RBV and boceprevir, stopping after 8 weeks because of nonresponse. No known history of other liver disease. Physical examination unremarkable You obtain the following tests: Lab/Test HCV RNA 5,, IU/mL HCV genotype 1a WBC 4.58 x 1 3 /ul Hemoglobin 14 g/dl Platelets 165, HIV-1 Ab NR US: increased echogenicity c/w chronic liver disease or fatty infiltration Lab INR 1.1 Creatinine Total bilirubin.3 AST ALT Alkaline phosphatase Albumin mg/dl 48 U/L 68 U/L 111 U/L FIB-4 score 1.94 APRI.73 6

7 SVR12 (%) 4/3/215 Genotype 1 Treatment: Treatment Experienced Slide 34 of 53 AASLD/IDSA/IAS USA Recommendations for Testing, Managing, and Treating Hepatitis C, 215 Slide 35 of 53 Studies of Sofosbuvir + Trial Population Treatment Regimen SVR12 (%) ION-1 ION-2 ION-3 Treatmentexperienced 8 weeks + RBV 12 weeks w/o RBV RBV+: 211/217 (97) RBV-: 211/214 (99) RBV+: 215/217 (99) RBV-: 212/217 (98) RBV+: 17/111 (96) RBV-: 12/19 (94) RBV+: 11/111 (99) RBV-: 18/19 (99) RBV+: 21/216 (93) RBV-: 22/215 (94) RBV-: 26/216 (95) S OF LDV:SVR12 in PEG-IFN+RBV vs. PI+PEG-IFN+RBV Failures: ION-2 1 Failed PEG-IFN+RBV Failed Protease Inhibitor + PEG- IFN+RBV Slide 36 of /43 62/66 45/47 62/64 58/58 49/5 58/59 51/51 LDV/SOF Afdhal N, et al. N Engl J Med. 214;37: LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks 7

8 4/3/215 Slide 38 of 53 Adverse Reactions for Par/r/OMB/DBV+RBV Skin Reactions: - 7-9% without RBV, 1-16% with ribavirin. Higher in HIV coinfected Anemia/decreased hemoglobin Mean change from BL in.5 mg/dl without RBV vs 2.4 mg/dl with RBV Effect of RBV Dose Reductions on SVR12 7% (11/1551) of subjects underwent a RBV dose reduction due to a decrease in hemoglobin; of these 98% achieved SVR12 Serum Bilirubin Elevations Elevations in bilirubin >2xULN: 2% in patients treated without RBV vs. 15% in those treated with RBV Not associated with serum ALT elevations Serum ALT Elevations Pooled analyses of clinical trials: Approximately 1% patients experienced serum ALT levels >5xULN after starting treatment Not associated with bilirubin elevations and cirrhosis was not a risk factor for elevated ALT ALT elevations in 25% among women on ethinyl estradiol or estradiol-containing medication Slide 39 of 53 Adverse Effects of HCV Therapies Sofosbuvir Mild fatigue Mild headache Not recommended in renal failure Cr Cl <3 ml/min Bradycardia Simeprevir Mild, reversible hyperbilirubinemia Due to transporter inhibition and not associated with hepatotoxicity Mild photosensitivity Paritaprevir/ritonavir/ombitasvir + dasabuvir Nausea, pruritus, and insomnia Increased risk of ALT elevations 1% of all subjects during clinical trials Occurred during first 4 weeks of treatment Discontinue ethinyl estradiol-containing medications prior to starting PegIFN/RBV: well known Lawitz E, et al. N Engl J Med. 213;368: Sofosbuvir [package insert]. 4. Fried MW, et al. Hepatology. 213;58: Simeprevir [package insert]. 6. Viekiera Package Insert Investigational Agents Slide 4 of 53 8

9 4/3/215 Slide 41 of 53 Some options in pipeline for genotype 1 daclatasvir sofosbuvir ABT-493 ABT-53 GS-5816 sofosbuvir Grazoprevir elbasvir Asunaprevir daclatasvir beclabuvir Ng et al. Role CROI 214; of clinicaltrials.gov RBV not search clear* performed 2/2/15, NCT , NCT , NCT , NCT