Emerging Challenges In Primary Care: 2015

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Care Se'ng Emerging Challenges In Primary Care: 2015 Chronic Hepatitis C: Update on Screening, Diagnosis, Management, and Promising New 1 Faculty Kalyan R.

Transplant Institute Miami, FL Christopher O'Brien, MD, AGAF, FRCMI Professor of Clinical Medicine Center for Liver Diseases Medical Director, Liver and GI Transplantation Miami Transplant Institute

Nasser Ibrahim Al-Rashid Chair Director, Schiff Center for Liver Diseases Director, Hepatology Research Laboratory University of Miami Miller School of Medicine Miami, FL Elliot Wortzel, MD, FACG,

1 Care Se'ng Emerging Challenges In Primary Care: 2015 Chronic Hepatitis C: Update on Screening, Diagnosis, Management, and Promising New 1 Faculty Kalyan R. Bhamidimarri, MD, MPH Assistant Professor of Clinical Medicine University of Miami Miller School of Medicine Transplant Hepatology/ Medical Director of Small Bowel & MultiVisceral Transplant Miami Transplant Institute Miami, FL Christopher O'Brien, MD, AGAF, FRCMI Professor of Clinical Medicine Center for Liver Diseases Medical Director, Liver and GI Transplantation Miami Transplant Institute University of Miami School of Medicine Miami, FL Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF, FAASLD Leonard Miller Professor of Medicine Dr. Nasser Ibrahim Al-Rashid Chair Director, Schiff Center for Liver Diseases Director, Hepatology Research Laboratory University of Miami Miller School of Medicine Miami, FL Elliot Wortzel, MD, FACG, FACP Gastroenterology Weston, FL 2 Disclosures Kalyan R. Bhamidimarri, MD, MPH is a member of the scientific advisory board for Bristol Myers Squibb, Gilead Sciences, Janssen Therapeutics, AbbVie, Genentech. Dr. Bhamidimarri also receives research/grant support from Bristol Myers Squibb, Gilead Sciences, AbbVie, Vital Therapies Inc., Biotest Pharmaceuticals, Ocera Therapeutics Inc., Salix Pharmaceuticals, and Synageva. Christopher O'Brien, MD, AGAF, FRCMI conducts research for and receives research grants from Gilead, BMS, Abbott (Abbvie), and Janssen. Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF, FAASLD is a consultant for Gilead and Merck. He serves on the scientific advisory boards of Bristol Myers Squibb, Gilead, Janssen Pharma, and Acorda; and he serves on the data monitoring boards of Bristol Myers Squibb, Salix, Pfizer, and Arrowhead. Dr. Schiff receives grant/research support from Abbott, Bristol Myers Squibb, Gilead, Merck, Orasure Technologies, Roche Molecular, Janssen Pharma, Discovery Life Sciences, Beckman Coulter, Siemens, MedMira, and Conatus. Elliot Wortzel, MD, FACG, FACP has no relationships to disclose. 3 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 1

2 Learning Objectives After participating in the proposed educational activities, clinicians should be better able to: 1. Identify patients at risk for hepatitis C and explain the approach to screening and confirmation of the diagnosis in these patients 2. Discuss guidelines for the overall medical management of patients with hepatitis C 3. Discuss patient and viral factors that determine the appropriate drug treatment for patients with chronic HC infection 4. Distinguish patients who may be treated in the primary care setting from those who require specialty referral 4 PRE-TEST QUESTIONS 5 Pre-test Question 1 On a scale of 1 to 5, please rate how confident you would be treating a patient with Chronic Hepatitis C:! 1. Not at all confident " " 2. Slightly confident " " " 3. Moderately confident " "" 4. Pretty much confident " " 5. Very confident" " 6 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 2

3 Pre-test Question 2 Case A 55 year old Caucasian female presents with an upper GI bleed Endoscopy demonstrated esophageal varices that were banded to obliteration Routine labs revealed HCV Ab+ On further discussion she states that she: Drinks wine daily Has drastically reduced her work productivity due to debilitating fatigue 7 Pre-test ARS Question 2 How would you confirm the diagnosis of Hepatitis C in this patient? 1. HCV DNA 2. HCV RNA 3. HCV Ag 4. HCV Ab 8 Initial Testing Results HCV RNA 6.1 million IU/mL Genotype 1 AST; ALT 204 IU/L; 79 IU/L Platelets 99,000 cells/mm3 Ultrasound Nodular surface consistent with cirrhosis 9 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 3

4 Pre-test ARS Question 3 What factor below is not required to qualify the patient for drug treatment? 1. HCV genotype 1 2. on ultrasound 3. Elevated AST and ALT 4. HCV RNA (+) 10 Pre-test Question 4 Pre-test ARS Question 4 You have decided to offer this patient treatment for HCV Type 1. Which treatment is not FDA approved for HCV Genotype 1? 1. Entecavir and ribavirin (Baraclude) 2. Ledipasvir and sofosbuvir (Harvoni) 3. Ombitasvir/paritaprevir/r + dasabuvir + ribavirin (Viekira Pak) 11 Pre-test ARS Question 5 All of the following strategies are required to monitor patients that have failed treatment for Hepatitis C except: 1. Monitor hepatic function panel and CBC every 6- months 2. Routine evaluation for cancer with CEA and AFP every 6 months 3. Liver US every 6 months in patients with advanced fibrosis and cirrhosis 4. Endoscopic surveillance for esophageal varices if cirrhotic NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 4

5 Outline Identify patients at risk for hepatitis C and explain the approach to screening and confirmation of the diagnosis in these patients Discuss patient and viral factors that determine the appropriate drug treatment for patients with chronic HC infection Recognize appropriate treatment options for patients with Hepatitis C Discuss guidelines for the overall medical management of patients with hepatitis C 13" Worldwide Prevalence of HCV Infection ~180 Million With HCV Infection Prevalence of Infection >10% 2.5%-10% 1%-5% N/A 14 CDC Recommendations for HCV Screening Regardless of risk factors, one-time testing for HCV of adults born between Testing of persons of all ages at risk for HCV infection CDC also recommends for those identified with HCV infection Brief alcohol screening and intervention as clinically indicated Referral to appropriate care and treatment services for HCV infection and related conditions 15" NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 5

6 Deaths From HCV Have Surpassed Those From HIV Change in Mortality Rates From 1999 to 2007 Rate per 100,000 People HIV 15,106,734 Hepatitis C Hepatitis B 1, Year 16" Liver Transplant Projection From 2013 to 2043 Potential Transplant Need: Treatment of all candidates and SVR of 90% will still require 22,000 transplants/year in , , , , ,747 Number of Persons 140,000 6,296 0, ,000 91,310 80,000 60,000 49,013 40,000 20,000 25,573 27,175 26,207 24,258 18,193 21, Year in Model No treatment 25% treated 50% treated 75% treated All treated 17 HCV-Infected Persons in the US: Estimated Rates of Detection, Referral to Care and Cure CDC & USPSTF recommend 1-time testing of baby boomers (born ) X1000 persons % 32-38% 20-23% % 5-6% 0 Infected Diagnosed Referred HCV RNA Treated Cure to care test 18" NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 6

7 Natural History of HCV Infection Leading to Liver Transplant Acute Infection (often asymptomatic) Progression to chronic infection (54%-86%) ( 25% of chronic cases currently) ( 37% of chronic cases by 2020) Decompensated cirrhosis 11.7% of cirrhotics (5-year survival = 50%) Hepatocellular carcinoma (risk = 1%-5%/year) 18% in year after first decompensation Liver Transplant Death 19 Outline Identify patients at risk for hepatitis C and explain the approach to screening and confirmation of the diagnosis in these patients Discuss patient and viral factors that determine the appropriate drug treatment for patients with chronic HC infection Distinguish patients who may be treated in the primary care setting from those who require specialty referral Discuss guidelines for the overall medical management of patients with hepatitis C 20" What Is an Elevated ALT Level? Reference ranges for ALT vary between 2 most widely used commercial laboratories Men: 4-60 IU/L; women: 6-40 IU/L Men: 0-55 IU/L; women: 0-40 IU/L Both AASLD and US treatment algorithms recommend lower ULN levels for ALT when making treatmentinitiation decisions 30 IU/L for men 19 IU/L for women 21" NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 7

Pretreatment Tests For Patients Who Will Start Treatment Assessment of hepatic fibrosis Assessment of potential drug:drug interactions HCV genotype and quantitative HCV viral load within weeks of

8 Pretreatment Tests For Patients Who Will Start Treatment Assessment of hepatic fibrosis Assessment of potential drug:drug interactions HCV genotype and quantitative HCV viral load within weeks of treatment start Other lab tests within 6 weeks of start of treatment CMP CBC INR 22" Global Distribution and Prevalence of HCV Genotypes: US Focus on GT 1 23" Baseline Viral Load Is Important If considering shorter duration (8 week) treatment for Genotype 1 patients, question(s) to ask: Has the patient been previously treated? If yes, baseline viral load does not matter If no and the patient is cirrhotic, baseline viral load does not matter If no and the patient is not cirrhotic, baseline 24 viral load matters NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 8

GT 1 Treatment Naïve, Non-Cirrhotics: Baseline HCV RNA GuidesTreatment Duration LDV/SOF 8 Weeks (N=215) LDV/SOF Weeks (N=216) SVR 94% (202/215) 96%

GT 1, treatment-naïve, Non-cirrhotic patients Baseline viral load < 6 million IU/mL 2% (2/131) 1% (1/85) 25" Assessment of Hepatic Fibrosis Is liver

aphy (FibroScan) Non-invasive assays (e.g., FibroTest, APRI, FIB-4) If a subset of patients should be biopsied, who are they?

9 GT 1 Treatment Naïve, Non-Cirrhotics: Baseline HCV RNA GuidesTreatment Duration LDV/SOF 8 Weeks (N=215) LDV/SOF Weeks (N=216) SVR 94% (202/215) 96% (208/216) Relapse Rates Overall 5% (11/215) 1% (3/216) <6 M IU/mL >6 M IU/mL 2% (2/3) 10% (9/92) 8 week LDV/SOF regimen should only be considered in GT 1, treatment-naïve, Non-cirrhotic patients Baseline viral load < 6 million IU/mL 2% (2/131) 1% (1/85) 25" Assessment of Hepatic Fibrosis Is liver biopsy necessary for all HCVinfected patients before treatment? Alternatives to biopsy Transient elastography (FibroScan) Non-invasive assays (e.g., FibroTest, APRI, FIB-4) If a subset of patients should be biopsied, who are they? Important to identify patients with cirrhosis in order to define treatment duration 26 Defined by Morphologic and Functional Changes of the Liver Normal 27" NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 9

10 Indirect Markers of Fibrosis FibroTest/FibroSure Alpha-2 globulin Alpha-2 macroglobulin Gamma globulin Apoliprotein A1 GGT ActiTest Fibrotest +ALT Forns index APRI FIB-4 AST/ALT ratio AST/ALT with plts 28 Fibroscan 29 Fibroscan Propagation Speed Examples Low Speed 4 kpa High Speed 36 kpa 30" NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 10

Role of Liver Biopsy Needed less frequently Non-invasive tests improving Less essential for decisions regarding timing of treatment Worth considering if Non-invasive tests conflicting and need info

11 Role of Liver Biopsy Needed less frequently Non-invasive tests improving Less essential for decisions regarding timing of treatment Worth considering if Non-invasive tests conflicting and need info to make treatment decision Suspect second disease: e.g. NASH Deferring treatment and concern for advanced disease 31" Outline Identify patients at risk for hepatitis C and explain the approach to screening and confirmation of the diagnosis in these patients Discuss patient and viral factors that determine the appropriate drug treatment for patients with chronic HC infection Recognize appropriate treatment options for patients with Hepatitis C Discuss guidelines for the overall medical management of patients with hepatitis C 32" Rising Cure Rates for Chronic HCV Telaprevir or Boceprevir + PegIFN/RBV 2 nd Gen DAAs IFN- Free Regimens 3 rd Gen DAAs IFN- Free Regimens Cure Rate* IFN IFN/RBV PegIFN/RBV Year 33" NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 11

12 When and in Whom to Initiate HCV Therapy: Highest Priority Advanced fibrosis (Metavir F3) or compensated cirrhosis (Metavir F4) Organ transplant; Rating Type 2 or 3 essential mixed cryoglobulinemia with endorgan manifestations (eg, vasculitis) Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis 34" When and in Whom to Initiate HCV Therapy: High Priority Fibrosis (Metavir F2) HIV-1 coinfection HBV coinfection Other coexistent liver disease (eg, NASH) Debilitating fatigue; Rating Type 2 Diabetes mellitus (insulin resistant) Porphyria cutanea tarda;rating 35" Common Minimal Prior Authorization Requirements HCV RNA within 3 months Genotype Staging of fibrosis Documented lack of abuse of alcohol or illicit drugs If simeprevir containing regimen, Q80K status May also require CBC, ALT, INR 36" NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C -

13 Each Drug Class Has Unique Features NS3/4A Protease Inhibitors! High efficacy" Low genetic barrier to resistance" Macrocyclic or linear" Simeprevir" Paritaprevir" NS5A Inhibitors!! NS5A has role in assembly of replication complex" Mechanism of inhibition under study" Ledipasvir" Ombitasvir" NS5B Polymerase Inhibitors! Nucleos(t)ide Analogue! Mimic natural substrates of the polymerase" Incorporated into RNA chain causing chain termination" Broad genotypic coverage" High genetic barrier to resistance" Sofosbuvir" Nonnucleos(t)ide! Bind to several different allosteric enzyme sites; results in conformational change" Resistance more frequent than nucs" Dasabuvir " " 37" Recommended HCV Regimens for Treatment-Naïve Patients (Genotype 1) Genotype 1a No Duration of Therapy (weeks) With Genotype 1b No With Ledipasvir/sofosbuvir (90/400 mg qd) Sofosbuvir 400 mg + simeprevir 150 mg qd + RBV Ombitasvir/paritaprevir/r (25/150/100 mg qd) + dasabuvir 250 mg bid + RBV (with RBV) 24 (with RBV) (no RBV) (with RBV) 38" Recommended HCV Regimens for Treatment-Naïve Patients (Genotype 2, 3, 4, 5, 6) Genotype 2 Sofosbuvir + RBV for weeks (16 weeks is recommended for cirrhotics) Genotype 3 Sofosbuvir + RBV for 24 weeks Genotype 4 Genotype 5 Ledipasvir/sofosbuvir (90/400 mg qd) for weeks Sofosbuvir + RBV for 24 weeks Ombitasvir/paritaprevir/r (25/150/100 mg qd) + dasabuvir 250 mg bid + RBV for weeks Sofosbuvir + PR for weeks Genotype 6 Ledipasvir/sofosbuvir (90/400 mg qd) for weeks 39" NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 13

14 On Treatment Monitoring CMP and CBC count Every 4 weeks More frequently for drug-related toxic effects (eg, CDC count for patients receiving RBV) Quantitative HCV viral load After 4 weeks of therapy At the end of treatment weeks following completion of therapy 40" Recommended HCV Regimens for Prior PegIFN + RBV Failure (Genotype 1) Duration of Therapy (weeks) Ledipasvir/sofosbuvir (90/400 mg qd) + RBV Sofosbuvir 400 mg + simeprevir 150 mg qd + RBV * Genotype 1a No (no RBV) With (with RBV) 24 (no RBV) Genotype 1b No (no RBV) With (with RBV) 24 (no RBV) Ombitasvir/paritaprevir/r (25/150/100 mg qd) + dasabuvir 250 mg bid + RBV (with RBV) 24 (with RBV) (no RBV) (with RBV) 41" Standard of Care for Treatment of Chronic HCV Infection (2015) Genotype! Regimen! Duration! Considerations! GT 2 " Sofosbuvir 400 mg QD + RBV 1000 or 00 mg/day in 2 divided doses BID " weeks" FDA approved" " GT 3 " " GT 1 " " Sofosbuvir 400 mg QD + RBV 1000 or 00 mg/day in 2 divided doses BID " 24 weeks" Data to support addition of PegIFN along with SOF + RBV for weeks" Sofosbuvir 400 mg QD weeks" FDA approved" Ledipasvir 90 mg QD (FDC) " [Paritaprevir/r + Ombitasvir] weeks " FDA approved" Dasabuvir BID ± RBV BID " 42" NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 14

15 Outline Identify patients at risk for hepatitis C and explain the approach to screening and confirmation of the diagnosis in these patients Distinguish patients who may be treated in the primary care setting from those who require specialty referral Recognize appropriate treatment options for patients with Hepatitis C Discuss guidelines for the overall medical management of patients with hepatitis C 43" Post-Treatment Monitoring in Patients In Whom Treatment Failed To Achieve An SVR Disease progression assessment every 6- months with a hepatic function panel, CBC count and INR Surveillance for HCC with ultrasound testing every 6 months in those with advanced fibrosis / cirrhosis Endoscopic surveillance for esophageal varices if cirrhotic Evaluation for retreatment is recommended as alternative treatments become available 44" Post-Treatment Follow-up in Patients Who Achieve An SVR F0-F2 Same as if they were never infected with HCV F3-F4 Surveillance for HCC with twice yearly ultrasound testing Baseline endoscopy to screen for varices if cirrhosis present (if found, treat and follow up as indicated) 45" NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 15

16 Prevalence of The prevalence of cirrhosis, both worldwide and in the US, is difficult to know is an outcome of a variety of causes; underlying cause is commonly used for surveillance purposes Compensated cirrhosis often goes undetected for prolonged periods of time Experts estimate that 5.5 million people in the United States have cirrhosis 46" Progressive Increase in Incidence of HCV-Related and HCC in US Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected Veterans 20% 5% C i r r h o s i s a n d D e c o m p e n s a t e d C i r r h o s i s 18% 16% 14% % 10% 8% 6% Decompensated HCC 4% 3% 2% 1% H e p a t o c e l l u l a r C a n c e r ( H C C ) 4% % 47" Summary Active HCV infections with a detectable viral load are at increased risk of death due to hepatic and extrahepatic diseases Chronic HCV patients with active infection may benefit from antiviral treatment, once diagnosed, to reduce overall mortality Approval of newer, direct-acting, oral agents have high HCV cure rates, fewer adverse events, and negligible resistance compared with the first generation HCV protease inhibitors PegIFN & ribavirin based regimens are no longer recommended for treatment-naïve genotypes 1, 2, 3, 4, and 6s 48" NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 16

17 POST-TEST QUESTIONS 49 Pre-test Question 2 Case A 55 year old Caucasian female presents with an upper GI bleed Endoscopy demonstrated esophageal varices that were banded to obliteration Routine labs revealed HCV Ab+ On further discussion she states that she: Drinks wine daily Has drastically reduced her work productivity due to debilitating fatigue 50 Post-test ARS Question 1 How would you confirm the diagnosis of Hepatitis C in this patient? 1. HCV DNA 2. HCV RNA 3. HCV Ag 4. HCV Ab 51 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 17

18 Initial Testing Results HCV RNA 6.1 million IU/mL Genotype 1 AST; ALT 204 IU/L; 79 IU/L Platelets 99,000 cells/mm3 Ultrasound Nodular surface consistent with cirrhosis 52 Post-test ARS Question 2 What factor below is not required to qualify the patient for drug treatment? 1. HCV genotype 1 2. on ultrasound 3. Elevated AST and ALT 4. HCV RNA (+) 53 Pre-test Question 4 Post-test ARS Question 3 You have decided to offer this patient treatment for HCV Type 1. Which treatment is not FDA approved for HCV Genotype 1? 1. Entecavir and ribavirin (Baraclude) 2. Ledipasvir and sofosbuvir (Harvoni) 3. Ombitasvir/paritaprevir/r + dasabuvir + ribavirin (Viekira Pak) 54 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 18

19 Post-test ARS Question 4 All of the following strategies are required to monitor patients that have failed treatment for Hepatitis C except: 1. Monitor hepatic function panel and CBC every 6- months 2. Routine evaluation for cancer with CEA and AFP every 6 months 3. Liver US every 6 months in patients with advanced fibrosis and cirrhosis 4. Endoscopic surveillance for esophageal varices if cirrhotic 55 Post-test Question 5 On a scale of 1 to 5, please rate how confident you would be treating a patient with Chronic Hepatitis C:! 1. Not at all confident " " 2. Slightly confident " " " 3. Moderately confident " "" 4. Pretty much confident " " 5. Very confident" " 56 Post-test Question 6 Which of the statements below describes your approach to treating Chronic Hepatitis C? 1. I do not treat patients with Chronic Hepatitis C, nor do I plan to this year. 2. I did not treat patients with Chronic Hepatitis C, but as a result of attending this course I m thinking of doing this now. 3. I do treat patients with Chronic Hepatitis C and this course helped me change my methods. 4. I do treat patients with Chronic Hepatitis C and this course confirmed that I don t need to change my methods 57 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis C - 19

Emerging Challenges In Primary Care: 2015

Care Se'ng Emerging Challenges In Primary Care: 2015 Chronic Hepatitis C: Update on Screening, Diagnosis, Management, and Promising New Treatments 1 Faculty Kalyan R. Bhamidimarri, MD, MPH Assistant Professor