Emerging Challenges In Primary Care: 2015 Chronic Hepatitis B: Guidelines for Screening, Clinical Management, Whether to Follow or Treat, 1 Faculty 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 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 1
Disclosures Christopher O'Brien, MD, AGAF, FRCMI Research Gilead, BMS Research Grant Gilead, Abbott (Abbvie), Janssen, BMS Eugene R. Schiff, MD, MACP, FRCP, MACG, AGAF, FAASLD Consultant Gilead, Merck Scientific Advisory Board Bristol Myers Squibb, Gilead, Janssen Pharma, Acorda Data Monitoring Board Bristol Myers Squibb, Salix, Pfizer, Arrowhead Grant/Research Abbott, Bristol Myers Squibb, Gilead, Merck, Orasure Technologies, Roche Molecular, Janssen Pharma, Discovery Life Sciences, Beckman Coulter, Siemens, MedMira, Conatus Elliot Wortzel, MD, FACG, FACP No relationships to disclose 3 Pre-test Question 1 On a scale of 1 to 5: Please rate how confident you would be treating a patient with Chronic Hepatitis B: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 4 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 2
Pre-test Question 2 Case 47-yr-old woman, born in Viet Nam No symptoms Only medical problem: mild hypertension Her husband and 2 sons, aged 20 and 25 yrs, have never been tested for HBV 5 Pre-test Question 2 You decide to screen this patient for Hepatitis B. Which laboratory test confirms the diagnosis of chronic hepatitis B? 1. A positive hepatitis B surface antibody 2. A positive hepatitis B surface antigen and hepatitis B core antibody IgM 3. A positive hepatitis B surface antigen of greater than six months duration. 4. A positive hepatitis B core antigen. 6 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 3
The Screening (and More) Results Hepatitis serologies HBsAg positive, HBcAb positive, HBsAb negative HBeAg negative, anti-hbe positive CBC WBC 4200 cells/mm 3, Hb 13 g/dl, platelets 182,000 cells/mm 3 Liver Tests AST 12 IU/L, ALT 16 IU/L 7 Pre-test Question 3 Which of the following is not essential for determining further management of patients newly diagnosed with chronic hepatitis B? 1. Ask about family history 2. Order a Fibroscan or an equivalent test 3. Order an abdominal ultrasound 4. Order a liver biopsy 8 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 4
Results Fibroscan shows no fibrosis Ultrasound of the abdomen is normal Family history is negative for liver cancer HBV DNA 145 IU/mL 9 Pre-test Question 4 Does the Patient Require Treatment or Only Medical Monitoring? 1. Treatment 2. Medical monitoring only with repeat labs every 6 months and abdominal ultrasound screening 10 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 5
Family Member Screening for HBV On screening of the family members for HBV Both sons have been vaccinated and are HBsAb (+) Husband, however, is found to be HBsAg (+), HBcAb (+), HBsAb (-) HBeAg (-) HBV DNA 79,000 IU/mL A Fibroscan shows moderate fibrosis A screening abdominal US is negative 11 Pre-test Question 5 What would be an appropriate treatment for the patient s husband? 1. Tenofovir 300 mg oral daily 2. Ledipasvir 90 mg oral daily 3. Simeprevir 150 mg oral daily 4. Sofosbuvir 400 mg oral daily 12 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 6
Learning Objectives 1. Identify patients who should be screened and appropriate testing for those patients 2. Discuss evidence-based strategy for the overall medical management of patients with chronic hepatitis B 3. Determine which patients require medication for chronic hepatitis B and which should be monitored clinically 4. Discuss the medications available for treating chronic hepatitis B and associated resistance issues 13 Geographic Prevalence of Chronic Hepatitis B May Be Impacted by Migration Identify patients who should be and appropriate testing for those patients Discuss evidence-based strategy for the overall medical management of patients with chronic hepatitis B Determine which patients require medication for chronic hepatitis B and which should be monitored clinically Discuss the medications available for treating chronic hepatitis B and associated resistance issues 14 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 7
Geographic Prevalence of Chronic Hepatitis B May Be Impacted by Migration ~2 million Asians ~400,000 South Americans ~930, 000 Europeans HBsAg Prevalence 8% - High 2-7% - Intermediate <2% - Low ~350,000 Africans Immigration numbers summed by continent from 1996-2002 HBV: A Global Problem HBV is 50-100 times more infectious than HIV 2 billion people worldwide have been infected with HBV ~ 350 million chronic carriers Leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide 30% to 50% of HCC associated with HBV in the absence of cirrhosis Second only to tobacco in causing the most cancer deaths 16 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 8
Candidates for HBV Screening Persons born in high and intermediate endemic areas ( 2% prevalence) US-born children of immigrants from high endemic areas ( 8%; only if not vaccinated as infants in the US) Household and sexual contacts of HBV carriers Persons who have injected drugs Persons with multiple sexual partners or history of STDs Men who have sex with men Inmates of correctional facilities Individuals with chronically elevated ALT/AST Individuals infected with HIV or HCV Patients undergoing dialysis Patients undergoing immunosuppressive therapy All pregnant women Infants born to HBV carrier mothers HBV Screening Algorithm Assess HBsAg Positive Negative CHB* Assess anti-hbs Negative (no antibodies) Positive (antibodies present) Evaluate for treatment Vaccinate Immune to HBV *Time from positive HBsAg test to diagnosis of CHB is 6 mos. NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 9
Outline Identify patients who should be and appropriate testing for those patients Discuss evidence-based strategy for the overall medical management of patients with chronic hepatitis B Determine which patients require medication for chronic hepatitis B and which should be monitored clinically Discuss the medications available for treating chronic hepatitis B and associated resistance issues 19 Natural History of HBV Infection Childhood >95% Immune Tolerance Adulthood <5% HBeAg+ CHB HBeAg- CHB Inac6ve carrier <15-30% of HCC associated with HBV occurs in the absence of cirrhosis or advanced fibrosis HCC 20 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 10
Assessment of Hepatic Fibrosis Is liver biopsy necessary for all HBV-infected 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 21 Cirrhosis Defined by Morphologic and Functional Changes of the Liver Normal Cirrhosis 22 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 11
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 23 Fibroscan 24 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 12
Fibroscan Propagation Speed Examples Low Speed 4 kpa High Speed 36 kpa 25 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 26 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 13
Medical Management of Cirrhosis Routine assessment for the presence of Fluid retention (ascites) Cognitive impairment (hepatic encephalopathy) Yearly endoscopy (as indicated) Screening for varices Routine HCC screening By ultrasound every 6 months 27 Hepatocellular Carcinoma Screening Screening with Ultrasound recommended at 6 month intervals in all individuals with cirrhosis HCC detected after the onset of symptoms has 0-10% survival at 5 years Early recognition may give a 5-year disease-free survival of greater than 50% 28 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 14
HCC Diagnostic Algorithm Liver nodule < 1 cm > 1 cm Repeat US at 3 months CT or MRI with HCC tumor protocol Growing/changing character Stable Arterial hypervascularity AND venous or delayed phase washout Yes Other contrast Enhanced study (CT or MRI) No Investigate according to size HCC Arterial hypervascularity AND venous or delayed phase washout Biopsy Yes No 29 Outline Identify patients who should be and appropriate testing for those patients Discuss evidence-based strategy for the overall medical management of patients with chronic hepatitis B Determine which patients require medication for chronic hepatitis B and which should be monitored clinically Discuss the medications available for treating chronic hepatitis B and associated resistance issues 30 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 15
Course of Chronic HBV Infection is Characterized by Remissions and Relapses 31 HBV Patient Categories HBeAg-positive: Active viral replication Active or inactive liver disease HBeAg-negative: Low-level or no detectable replication Inactive liver disease HBeAg-negative: Active viral replication Active or inactive liver disease 32 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 16
Information Needed to Determine HBV Treatment HBeAg status ALT HBV DNA level Degree of liver fibrosis Family history 33 Chronic Hepatitis B Disease Types HBeAg positive Also known as wild type Often, HBV DNA > 20,000 IU/mL HBeAg negative Also known as precore mutant HBV DNA variable 34 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 17
New Definition for Elevated ALT Levels Standard reference ranges for ALT vary 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 treatment-initiation decisions 30 IU/L for men 19 IU/L for women 35 FDA-Approved Therapies First-Line Therapy Peginterferon alfa-2a PEGASYS Roche Laboratories 2005 Entecavir BARACLUDETM Bristol-Myers Squibb 2005 Tenofovir VIREAD Gilead Sciences 2008 Second-Line Therapy Adefovir dipivoxil HEPSERA Gilead Sciences 2002 Telbivudine TYZEKA Idenix and Novartis 2006 Third-Line Therapy Lamivudine EPIVIR-HBV GlaxoSmithKline 1998 36 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 18
2009 AASLD Guidelines: Treatment Candidacy for HBeAg-Positive Patients HBsAg positive HBeAg positive ALT < 1 x ULN HBV DNA < 20,000 IU/mL ALT 1-2 x ULN HBV DNA > 20,000 IU/mL Monitor if not cirrhotic every 6 months Treat 37 2009 AASLD Guidelines: Treatment Candidacy for HBeAg-Negative Patients HBsAg positive HBeAg negative ALT < 1 x ULN HBV DNA < 2000 IU/mL ALT ULN HBV DNA 2,000 IU/mL q3 mos ALT x 3, then q6-12 mos if ALT still < 1 x ULN Treat Lok AS, et al. Hepatology. 2009;50:661-662. 38 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 19
Algorithm for HBV Management During Pregnancy Previous child HBV (+) No Yes HBV DNA <10 8 10 9 copies/ml HBV DNA >10 8 10 9 copies/ml HBV DNA >10 6 copies/ml HBV DNA <10 6 copies/ml Monitor Consider treatment with lamivudine, Tenofovir, or telbivudine at 32 weeks Infant receives HBIG vaccine at birth 39 Prevention of Reactivation During Immunosuppression Prevention is more effective than treatment after HBV-related hepatitis is diagnosed Screen for HBV before start of immunosuppressive therapy Prophylactic antiviral therapy to high + moderate risk patients 40 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 20
HBV Treatment in HBV/HIV Coinfected Patients HBV coinfection complicates disease course and management of HIV patients HBV coinfection does not substantially affect the course of HIV infection HIV coinfection significantly alters the course of HBV disease All patients with active HBV infection should be treated with ART containing emtricitabine/tenofovir DF Entecavir may be useful in patients with active replication despite tenofovir or in persons with contraindications to tenofovir in both infections 41 Immunosuppressive Therapies Associated with HBV Reactivation Corticosteroids Anti-tumor necrosis factor Others: methotrexate, molecular target agents Cancer chemotherapy Rituximab anti-cd20 monoclonal antibody 42 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 21
Outline Identify patients who should be and appropriate testing for those patients Discuss evidence-based strategy for the overall medical management of patients with chronic hepatitis B Determine which patients require medication for chronic hepatitis B and which should be monitored clinically Discuss the medications available for treating chronic hepatitis B and associated resistance issues 43 Manifestations of Antiviral Resistance 8 Antiviral Treatment HBV DNA (Log 10 IU/mL) ALT (IU/mL) 6 4 2 ULN Virologic Breakthrough Genotypic Resistance Virologic Rebound Hepatitis Flare Biochemical Breakthrough 0 0 1 2 3 Years 44 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 22
HBV DNA Testing Indicates chronic hepatitis when still positive 6 mos after diagnosis of acute HBV infection Can differentiate chronic, inactive carrier (< 2000 IU/mL) vs. resolved HBV infection (undetectable) HBV DNA level correlates with disease progression Change in HBV DNA level used to monitor response to therapy Increasing HBV DNA level during antiviral therapy indicates emergence of resistant variants 45 5-Yr Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients Cumulative Resistance Rate (%) 100 80 60 40 20 0 70 29 17 1.2 0 Lamivudine Adefovir Telbivudine Entecavir Tenofovir 46 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 23
Selection of Entecavir vs Tenofovir: Either Is an Excellent Choice Response at Wk 48-52 (%) 25 20 15 10 5 0 21 21 HBeAg seroconversion 2 3 HBsAg loss Entecavir Tenofovir < 1 0 HBsAg loss Parameter Entecavir Tenofovir Log HBV DNA at Wk 48-52 HBeAg positive 6.9 6.2 HBeAg negative 5.0 4.6 Genotypic resistance, % NA naive 1.2 (Yr 5) 0 (Yr 3) Lamivudine experienced 51 (Yr 5) NR Pregnancy rating Class C Class B AEs None Renal toxicity; BMD HBeAg Positive HBeAg Negative 47 Entecavir or Tenofovir Dosage and Administration Entecavir: oral administration Patients naive to lamivudine therapy: 0.5 mg QD Patients who are refractory/resistant to lamivudine: 1.0 mg QD Dose adjustment needed if egfr < 50 ml/min Tenofovir: oral administration 300 mg QD Dose adjustment needed if egfr < 50 ml/min 48 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 24
Entecavir or Tenofovir Duration of Therapy Duration, based on clinical endpoints HBeAg positive: Treat until HBV DNA undetectable and HBeAg seroconversion achieved; Continue for 6 mos after anti-hbe appearance Close monitoring for relapse required after treatment discontinuation HBeAg negative: Continue treatment until HBsAg clearance 49 Case Presentation 55 y.o. woman scheduled for treatment of rheumatoid arthritis with Rituximab P.E. positive for arthritic signs consistent with rheumatoid arthritis CBC and CMP WNL Negative viral serologies for hepatitis A and C and HIV Abdominal ultrasound without any significant abnormalities No family history of liver disease No tobacco use; EtOH: 3-4 drinks/wk (wine) 50 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 25
*ARS Question What Initial Testing Would You Recommend for This Patient? 1. Schedule a liver biopsy 2. Check her hepatitis B serologies 3. Observe, repeat labs every 6 months 4. Order an ultrasound of the abdomen 51 Testing Results HBsAg (-), HBcAb (+), HBsAb (-) Liver tests are normal CBC is normal 52 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 26
Additional Testing Blood fibrosis test shows no fibrosis and the ultrasound of the abdomen is normal HBV DNA 145 IU/mL 53 *ARS Question Does Your Patient Require Treatment or Medical Management? 1. Refer to specialist to be seen 2. Ask the best approach from a friend 3. Start treatment 4. Observe, repeat labs every 6 months 54 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 27
*ARS Question Which treatment would you recommend? 1. Sofosbuvir 400 mg oral daily 2. Entecavir 0.5 mg oral daily 3. Simeprevir 150 mg oral daily 4. Ledipasvir 90 mg oral daily 55 Post-Test Questions 56 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 28
Post-test Question 1 On a scale of 1 to 5: Please rate how confident you would be treating a patient with Chronic Hepatitis B: 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 57 Post-test Question 2 Case 47-yr-old woman, born in Viet Nam No symptoms Only medical problem: mild hypertension Her husband and 2 sons, aged 20 and 25 yrs, have never been tested for HBV 58 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 29
Post-test Question 2 You decide to screen this patient for Hepatitis B. Which laboratory test confirms the diagnosis of chronic hepatitis B? 1. A positive hepatitis B surface antibody 2. A positive hepatitis B surface antigen and hepatitis B core antibody IgM 3. A positive hepatitis B surface antigen of greater than six months duration. 4. A positive hepatitis B core antigen. 59 The Screening (and More) Results Hepatitis serologies HBsAg positive, HBcAb positive, HBsAb negative HBeAg negative, anti-hbe positive CBC WBC 4200 cells/mm 3, Hb 13 g/dl, platelets 182,000 cells/mm 3 Liver Tests AST 12 IU/L, ALT 16 IU/L 60 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 30
Post-test Question 3 Which of the following is not essential for determining further management of patients newly diagnosed with chronic hepatitis B? 1. Ask about family history 2. Order a Fibroscan or an equivalent test 3. Order an abdominal ultrasound 4. Order a liver biopsy 61 Results Fibroscan shows no fibrosis Ultrasound of the abdomen is normal Family history is negative for liver cancer HBV DNA 145 IU/mL 62 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 31
Post-test Question 4 Does the Patient Require Treatment or Only Medical Monitoring? 1. Treatment 2. Medical monitoring only with repeat labs every 6 months and abdominal ultrasound screening 63 Family Member Screening for HBV On screening of the family members for HBV Both sons have been vaccinated and are HBsAb (+) Husband, however, is found to be HBsAg (+), HBcAb (+), HBsAb (-) HBeAg (-) HBV DNA 79,000 IU/mL A Fibroscan shows moderate fibrosis A screening abdominal US is negative 64 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 32
Post-test Question 5 What would is appropriate treatment? 1. Tenofovir 300 mg oral daily 2. Ledipasvir 90 mg oral daily 3. Simeprevir 150 mg oral daily 4. Sofosbuvir 400 mg oral daily 65 Post-test Question 6 Which of the statements below describes your approach to treating Chronic Hepatitis B? 1. I do not treat patients with Chronic Hepatitis B, nor do I plan to this year. 2. I did not treat patients with Chronic Hepatitis B, but as a result of attending this course I m thinking of doing this now. 3. I do treat patients with Chronic Hepatitis B and this course helped me change my methods. 4. I do treat patients with Chronic Hepatitis B and this course confirmed that I don t need to change my methods 66 NACE - Emerging Challenges in Primary Care: 2015 Chronic Hepatitis B - 33