6/2/2015. Interactive Case-Based Presentations and Audience Discussion

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1 6/2/215 Interactive Case-Based Presentations and Audience Discussion Andrew Aronsohn, MD Assistant Professor of Medicine University of Chicago Medical Center Chicago, Illinois Formatted: Washington, DC: May 12, 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 HCV Identify important side effects of HCV therapy Slide 2 of 33 Which patient would be among those who should be the highest priority to receive immediate therapy? 1. Patient with compensated cirrhosis 2. Patient with stage 2 fibrosis (F2) 3. Patient who is unable to tolerate interferon alfa 4. Patient with ALT consistently between 1 and 15 U/mL 5. Patient with HCV infection >25 years 9% 1% % % % Slide 3 of 33 1

2 6/2/215 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 Result Lab/Test Result INR 1.1 HCV RNA 8,, IU/mL Creatinine.9 mg/dl HCV genotype WBC Hemoglobin Slide 4 of 33 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 Total bilirubin.3 AST ALT Alkaline phosphatase Albumin U/L 68 U/L 111 U/L FIB-4 score 1.94 APRI.73 Case 1 An appropriate regimen for this patient is: A. Telaprevir + Simeprevir x 12 B. Sofosbuvir + ledipasvir x 8 C. Sofosbuvir + ledipasvir x 24 D. Paritaprevir/r/ombitasvir/ dasabuvir x 12 E. Paritaprevir/r/ombitasvir/ dasabuvir/ribavirin x 12 35% 29% 18% 12% 6% A. B. C. D. E. Slide 6 of 33 Slide 7 of 33 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 2

3 1-year cumulative occurrence rate (%) 6/2/215 Slide 8 of 33 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 9 of 33 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 Slide 1 of 33 Persons Whose Risk of HCV Transmission is Elevated 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 HCV-infected healthcare workers who perform exposure-prone procedures 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 3

4 6/2/215 Structure of HCV Genome: Protease Inhibitors Slide 11 of 33 Nucleoside/tide Polymerase Inhibitors Mechanism of Action Slide 12 of 33 Nucleoside/tide Inhibitor (NI) Chain-terminator Primer strand 5 G C C A NI RNA chain cannot be elongated 3 C G G U G A C G 5 Template strand Slide 13 of 33 HCV NS5a Replication Complex: Another Therapeutic Target Structure of NS5A domain associated with endoplasmic reticulum (ER) Large phosphoprotein Associates at least as a dimer Binds RNA Amphipathic helix (H) at amino terminus promotes membrane association Essential component of HCV RNA ER-membrane associated replication complex Modulates cellular systems involved in IFN resistance Tellinghuisen TL, et. al. Nature. 25;435(74): Love RA, et al. J Virol. 29;83(9):

5 SVR12 (%) SVR12 (%) 6/2/215 Currently Available DAAs for Genotype 1 DAA Class Sofosbuvir Ledipasvir Paritaprevir/r Ombitasvir Dasabuvir Sofosbuvir Simeprevir Protease Inhibitor X X Slide 14 of 33 NS5A inhibitor X X Nucleoside Polymerase Inhibitor X X Non-Nucleoside Polymerase Inhibitor Ribavirin X X Slide courtesy of Donald Jensen MD Slide 15 of 33 SMV + SOF: HCV Monoinfection, 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 33 Studies of Sofosbuvir + Ledipasvir ± RBV in GT1 HCV Trial Population Treatment Regimen ION-1 ION-2 ION-3 HCV Monoinfection, Treatment-naïve HCV Monoinfection, Treatment-experienced HCV Monoinfection, Treatment-naïve 12 + RBV 24 + RBV 12 + RBV 24 + RBV 8 + RBV 12 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 5

6 SVR12 (%) Relapse (%) 6/2/215 Slide 17 of 33 Studies of Sofosbuvir + Ledipasvir ± RBV in GT1 HCV 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 18 of 33 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, Tx-exp GT1, HIV/HCV, GT1, HIV/HCV, Tx-exp Tx-exp 3D+RBV x 12 RBV+: 99.5% RBV-: 99% 3D+RBV x 12 RBV+: 97% RBV-: 9% 3D+RBV x 12 96% 3D+RBV x 12 96% 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 19 of 33 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:

7 6/2/215 Slide 2 of 33 Treatment of HCV: USA No cirrhosis Cirrhosis Geno Regimen TN TE Regimen TN TE 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 Slide 21 of 33 Case 2 55 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 Result Lab/Test HCV RNA HCV genotype WBC Hemoglobin Result 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 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 22 of 33 You obtain a liver biopsy. He has METAVIR F2 disease. Which of the following is the appropriate regimen? 1. No treatment 2. Sofosbuvir + ledipasvir x Sofosbuvir + ledipasvir x 8 4. Paritaprevir/r/ombitasvir/dasabuvir x Paritaprevir/r/ombitasvir/dasabuvir 6% /ribavirin x 12 19% 44% 19% 13%

8 6/2/215 Slide 23 of 33 Studies of Sofosbuvir + Ledipasvir ± RBV in GT1 HCV Trial Population Treatment Regimen SVR12 (%) ION-1 ION-2 ION-3 HCV Monoinfection, Treatment-naïve HCV Monoinfection, Treatmentexperienced HCV Monoinfection, Treatment-naïve 12 + RBV 24 + RBV 12 + RBV 24 + RBV 8 + RBV 12 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 Abbvie Trial Population Treatment Regimen SVR12 Slide 24 of 33 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, Tx-exp GT1, HIV/HCV, GT1, HIV/HCV, Tx-exp Tx-exp 3D+RBV x 12 RBV+: 99.5% RBV-: 99% 3D+RBV x 12 RBV+: 97% RBV-: 9% 3D+RBV x 12 96% 3D+RBV x 12 96% 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 25 of 33 Treatment of HCV: USA No cirrhosis Cirrhosis Geno Regimen TN TE Regimen TN TE 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

9 6/2/215 Case 3 55 y.o. man with positive HCV antibody. He has never had a liver biopsy and is HCV treatmentexperienced, to pegylated IFN/RBV and boceprevir, stopping after 8 because of nonresponse. No known history of other liver disease. Physical examination unremarkable You obtain the following tests: Lab/Test HCV RNA HCV genotype WBC Hemoglobin Result 5,, 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 4.1 Result.9 mg/dl 48 U/L 68 U/L 111 U/L FIB-4 score 1.94 APRI.73 Slide 26 of 33 Slide 27 of 33 New Agents for PI Nonresponse (avoid retreatment with PI) Polymerase inhibitor (sofosbuvir) + NS5A inhibitor (ledipasvir) Genotype 1 Treatment: Treatment Experienced Slide 28 of 33 AASLD/IDSA/IAS USA Recommendations for Testing, Managing, and Treating Hepatitis C, 215 9

10 SVR12 (%) 6/2/215 SOF/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 29 of /43 LDV/SOF Afdhal N, et al. N Engl J Med. 214;37: /66 45/47 62/64 LDV/SOF + RBV 58/58 49/5 58/59 51/51 LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Slide 3 of 33 Adverse Effects of HCV Therapies Sofosbuvir Mild fatigue Mild headache Not recommended in renal failure CrCl <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 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 C-WORTHY Studies ESRD!! Grazoprevir- next generation NS3 PI Enhanced pangenotypic activity Higher resistance barrier Elbasvir- NS5A inhibitor Potent, pangenotypic activity GZP 1mg + ELB 5mg +/- RBV Non-cirrhotic: 8 wks vs 12 wks 59% male, 88% white, 73% 1a, 8% F3 Included HIV co-infected subjects Null and/or cirrhosis: 12 wks vs 18 wks Slide 31 of 33 Sulkowski MS. Lancet 214. Lawitz E. Lancet

11 SVR12 (%) 6/2/215 C-WORTHY Non-cirrhotic Slide 32 of All 1a 1b wks + R 12wks 12wks + R 4% virologic failure rate in 12-week arms (7/188). Sulkowski MS. Lancet 214. Which patient would be among those who should be the highest priority to receive immediate therapy? 1. Patient with compensated cirrhosis 2. Patient with stage 2 fibrosis (F2) 3. Patient who is unable to tolerate interferon alfa 4. Patient with ALT consistently between 1 and 15 U/mL 5. Patient with HCV infection >25 years 1% % % % % Slide 33 of 33 Which patient would be among those who should be the highest priority to receive immediate therapy? Patient with compensated cirrhosis 9% 1% Patient with stage 2 fibrosis (F2) % % Patient who is unable to tolerate interferon alfa Patient with ALT consistently between 1 and 15 U/mL % % % % Patient with HCV infection >25 years % 1% Slide 34 of 33 First Slide Second Slide 11

12 6/2/215 Interactive Case-Based Presentations and Audience Discussion Andrew Aronsohn, MD Assistant Professor of Medicine University of Chicago Medical Center Chicago, Illinois Formatted: Washington, DC: May 12, 215 (INTRODUCTORY) 12