Ponni V. Perumalswami, MD, MCR Associate Professor of Medicine Recanati Miller Transplant Institute Icahn School of Medicine at Mount Sinai

Transcription

1 Ponni V. Perumalswami, MD, MCR Associate Professor of Medicine Recanati Miller Transplant Institute Icahn School of Medicine at Mount Sinai

2 DISCLOSURES ALL FACULTY, COURSE DIRECTORS, PLANNING COMMITTEE, CONTENT REVIEWERS AND OTHERS INVOLVED IN CONTENT DEVELOPMENT ARE REQUIRED TO DISCLOSE ANY FINANCIAL RELATIONSHIPS WITH COMMERCIAL INTERESTS. ANY POTENTIAL CONFLICTS WERE RESOLVED DURING THE CONTENT REVIEW, PRIOR TO THE BEGINNING OF THE ACTIVITY The following individuals have a relevant financial relationship with a commercial interest(s): Faculty Commercial Interest Name What Was Received For What Role For what Clinical Area/Disease State Kalyan Ram Bhamidimarri, MD, MPH Gilead AbbVie Alexion Honorarium Honorarium Honorarium Advisory board Advisory board Speaking HBV, HCV HCV LALD/fatty liver No other planner/faculty member has any relevant financial relationships to report. There will be no references to unlabeled or unapproved uses of drugs or products.

3 EDUCATIONAL OBJECTIVES Identify USPSTF-defined HBV endemic areas to more effectively identify first- and second-generation immigrant populations who should be screened for HBV. Develop effective plans to overcome culture-specific barriers to screening your patient populations. Evaluate patient cases to identify when to screen patients and how to refer to specialist care for treatment. Describe current treatment guidelines and newly available HBV therapies. Discuss the importance of early screening and treatment in specific patient populations, including pregnant and postpartum women.

4 WHO AND HOW TO SCREEN

5 THE BURDEN OF HBV INFECTION Global Burden Over 300 million persons living with chronic HBV infection Over 780,000 deaths attributed to HBV-related causes annually Most common viral hepatitis infection worldwide US Burden Between 700,000 and 2.2 million persons living with chronic HBV infection 50% or more have not yet received HBV diagnoses Estimated 38,000 new cases of infection in 2009 Estimated 3,000 deaths attributed to hepatitis-associated chronic liver disease, or hepatocellular carcinoma (HCC), annually WHO website. Accessed Sept , last updated July 2015 CDC website.

6 GEOGRAPHIC DISTRIBUTION OF CHRONIC HBV INFECTION HBsAg Prevalence* 8% (high) 2% to 7% (intermediate) < 2% (low) Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. *HBsAg, Hepatitis B surface antigen

7 IMMIGRATION HAS A HIGH IMPACT ON US HBV PREVALENCE Immigration Numbers by Continent: ~ 3.6 million Asians ~ 1.3 million Europeans HBsAg Prevalence 2 8% (high) 2% to 7% (intermediate) < 2% (low) ~ 875,000 South Americans ~ 804,000 Africans >60% of the ~28 million immigrants who entered the US between 1974 and 2008 were born in countries where HBsAg >2%* 1. US Department of Homeland Security. Yearbook of Immigration Statistics: Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

8 ESTIMATED NUMBER AND PERCENTAGE OF HBSAG POSITIVE PERSONS US, 2006 Population segment 2006 population (millions) HBsAg prevalence (%) HBsAg-positive persons No. (thousands) (%) US born, noninstitutionalized ( ) (30-50) * Foreign-born (47-70) Correctional (3-5) institutions Other group living (2-3) quarters ** Total ,405 *Source: 2006 American Community Survey, US Census Bureau. HBsAg prevalence estimates were derived from NHANES (CDC, unpublished data, 2008). Sources: 2006 American Community Survey, U.S. Census Bureau. Prevalence range represents estimates from the National Health and Nutrition Examination Survey (1%) (CDC, unpublished data, 2008) and country-specific HBsAg estimates reported in the medical literature (2.6%) (CDC, unpublished data, 2008), applied to the estimated population by country of origin. Sources: Sabol WJ, Minton TD, Harrison PM. Prison and jail inmates at midyear Washington, DC: U.S. Department of Justice, Bureau of Justice Statistics, Office of Justice Programs; Available at CDC. Prevention and control of infections with hepatitis viruses in correctional settings. MMWR 2003;52(No. RR-1). ** Includes college dormitories, military quarters, nursing homes, group homes, and long-term care hospitals, as well as homeless persons. Source: 2006 American Community Survey, U.S. Census Bureau.

9 USPSTF SCREENING RECOMMENDATIONS FOR HBV INFECTION IN HIGH-RISK INDIVIDUALS HBsAg prevalence 2% 8% HBV SCREENING People born in regions with prevalence of HBV infection of 2% 1 US-born people not vaccinated as infants whose parents were born in regions with HBV infection prevalence of 8% 1 Figure adapted from Table 1 in LeFevre ML 1 and Figure 3 in CDC LeFevre ML; USPSTF. Ann Intern Med. 2014;161: CDC. Morb Mortal Wkly Rep. 2008;57:1-20.

10 USPSTF SCREENING RECOMMENDATIONS FOR HBV INFECTION IN HIGH-RISK INDIVIDUALS USPSTF screening recommendations for HBV infection in individuals with high-risk factors Household and sexual contacts 1 People whose household members or sexual contacts have HBV infection People infected with HIV 1 Injection drug users 1 Men who have sex with men 1 People with certain medical conditions 2,a Immunosuppressed Undergoing hemodialysis The new USPSTF recommendations currently align with those from the CDC and AASLD 1-4 a Part of screening recommendations from the USPSTF Consumer Fact Sheet. 2 AASLD=American Association for the Study of Liver Diseases; CDC=Centers for Disease Control and Prevention. For a complete list of screening recommendations, please see: 1. LeFevre ML; USPSTF. Ann Intern Med. 2014;161: USPSTF. Consumer Fact Sheet. May Accessed August 3, Lok ASF, McMahon BJ. Hepatology. 2009;50(3): CDC. Morb Mortal Wkly Rep. 2008;57:1-20.

11 HBV SCREENING IN PREGNANT WOMEN HBV screening should be performed on all pregnant women Knowing the HBV status is important to reducing the risk of vertical transmission to newborns Mother HBeAg HBsAg No Vaccination Infant Vaccination + HBIG Immunoprophylaxis + + > 90% risk for chronic HBV 10%-15% risk for chronic HBV - + < 5% risk for chronic HBV; some risk for fulminant and/or acute hepatitis < 1% risk for chronic HBV; some risk for fulminant and/ or acute hepatitis Institute of Medicine. Hepatitis and Liver Cancer Report

12 POTENTIAL CONSEQUENCES OF CHRONIC HBV Cirrhosis End-stage liver disease Hepatocellular carcinoma (HCC) HBV causes ~50% of liver cancer cases worldwide. HBV is a carcinogen that is second only to smoking tobacco in causing cancer deaths worldwide. Cirrhotic liver HCC Llovet J. Nature Reviews Volume

13 HBV IS A SILENT KILLER Chronic HBV infection usually asymptomatic, even with liver cancer and well-compensated cirrhosis Liver panel may be normal As many as 2 of 3 chronically infected persons are unaware of HBV infection Institute of Medicine. Hepatitis and Liver Cancer Report

14 OUTCOME OF HBV INFECTION BY AGE OF TRANSMISSION Chronic Infection (%) % Predominantly neonatal infection in Asia Chronic infection Symptomatic infection 25-30% Predominantly adult infection in Western countries <5% Symptomatic Infection (%) 0 0 Birth 1-6 mos 7-12 mos 1-4 yrs Asian Liver Center Physicians Guide to Hepatitis B: A Silent Killer. Older Children and Adults

15 HBV: MODES OF TRANSMISSION Endemic Countries Mother to baby at time of birth (~50% of cases, most common among Asians) Horizontal within household during early childhood (Virus can survive at least 7 days outside body) Nonendemic Countries Adult sexual activity (~54% of cases, most common) IV drug use (~20% of cases) Health care (Re-use of non-sterilized needles and syringes in resource-poor areas, contaminated blood products) Traditional medicine (Acupuncture, coining, cupping, scarification, etc.) Shepard, CW et al. Epidemiol Rev. 2006;28: Leung N. Hepatol Int. Dec 2009;3 Suppl 1: WHO Dept. Communicable Diseases Surveillance and Response. Hepatitis B. Accessed March 4, 2011.

16 HBV SEROLOGY 101 HBsAg: hepatitis B surface antigen Marker of active infection Chronic HBV: HBsAg positive for at least 6 months Anti-HBs (or HBsAb): antibody to HBsAg Marker of immunity to hepatitis B Anti-HB core antibody (IgG) Previous exposure If HBsAg is positive, additional testing is needed: HBeAg: hepatitis B e antigen Surrogate marker of high viral load Anti-HBe: antibody to HBeAg Precore mutation: associated with lower viral load Inactive carrier state HBV DNA: active viral replication Adapted from McMahon, BJ, Peters, M. Accessed March 12, 2010.

17 INTERPRETATION OF HBV SEROLOGIES

18 INTERPRETATION OF HBV SEROLOGIES Refer patient to specialist

19 CLINICIAN BARRIERS TO HBV SCREENING Too many things to keep track of and accomplish in too short a time at primary care visit HBV serological results are confusing HBV guidelines are conflicting and/or confusing No reminders built into clinic system (electronic health records, etc.)

20 POSSIBLE SOLUTIONS FOR CLINICIAN BARRIERS TO HBV SCREENING Make HBV risk assessment and appropriate screening routine parts of care Understand HBV screening guidelines to identify at-risk persons Identify effective ways to engage patients in HBV screening Learn how to effectively screen for HBV and interpret serologies Identify opportunities for prevention through HBV vaccination Understand when/how to refer patients to specialists for HBV care

21 INDICATIONS FOR REFERRAL AND WHEN TO TREAT HBV? Referral to specialist based on PCP s comfort level All HBsAg-positive patients need to be managed for HBV HBV treatment should be considered in (AASLD guidelines 1 ): Immune-active CHB (HBeAg negative or HBeAg positive) to decrease the risk of liver-related complications Patients who are not on treatment - monitor regularly with blood work every 3-6 months and liver cancer screening with US every 6 months if criteria are met 1. Terrault N. AASLD guidelines for treatment of chronic hepatitis B. Nov 2015

22 INITIAL EVALUATION OF HBSAG-POSITIVE PATIENT Historical/Physical Examination Routine Laboratory Tests Serology/Virology Imaging/Staging Studies All patients Symptoms/signs of cirrhosis Alcohol and metabolic risk factors Family history of HCC Vaccination status CBC including platelet count, AST, ALT, total bilirubin, alkaline phosphatase, albumin, INR HBeAg/anti-HBe HBV DNA quantitation Anti-HAV to determine need for vaccination Abdominal ultrasound Vibration-controlled transient elastography or serum fibrosis panel (APRI, FIB-4, or FibroTest) Select patients Tests to rule out other causes of chronic liver diseases if elevated liver test(s) AFR, GGT HBV genotype Anti-HDV Anti-HCV Liver biopsy AASLD guidelines for treatment of chronic hepatitis B. Nov 2015 Anti-HIV in those who have not undergone one-time screening (ages 13-64) Evaluate for co-infection with HCV, HIV and/or delta virus Abbreviations: INR, international normalized ratio; GGT gamma-glutamyl transpeptidase.

23 MODELING HBV SCREENING CONVERSATIONS

24 PATIENT BARRIERS (LUIS) Identify endemic areas for screening Lack of understanding (screening, mother to child transmission) Cultural shame Privacy Address culture barriers to screening Value of testing/treatment Asymptomatic

25 PATIENT BARRIERS (YU-WEN) Stigma (sexual promiscuity) Lack of understanding (screening, mother to child transmission) Modeling effective conversations around screening Destigmatizing HBV Identifying and addressing cultural barriers to screening Value of screening/potential treatment Discussing prenatal and postpartum management Asymptomatic

26 HAVING THE CONVERSATION

27 EFFECTIVE WAYS TO ENGAGE PATIENTS Provide a context for why HBV screening is important Elicit a family history to identify risk factors Discuss the risk of coinfection (HIV, HCV, and delta virus) Obtain alcohol use and sexual history and counsel cessation/abstinence Explain what it means to have HBV infection Discuss liver cancer risk in HBV-positive persons (early screening) Highlight ways in which HBV infection is transmitted and can be prevented Emphasize that HBV can be prevented through a highly effective vaccine Highlight that there are highly effective HBV treatments to prevent bad long-term outcomes

28 POSSIBLE SOLUTIONS FOR PATIENT BARRIERS No insurance: Local community health centers and sometimes public health departments provide free HBV screening and vaccination and can refer to appropriate specialist Provide appropriate patient education materials in waiting rooms, examination rooms Materials translated into multiple languages available by CDC and others online testingchronic.htm#section2 SCALE HBV app Provides clinicians an easy way to link local HBV specialists based on patients city, state, or ZIP code Counseling tips, CDC screening recommendations, links to additional patient education Available in App Store, Google Play, and Amazon

29 DETERMINING INITIAL TREATMENT AND INDIVIDUALIZING THERAPY

30 SHARED DECISION-MAKING Management and treatment options should be discussed in detail with patients infected with HBV AASLD practice guidelines can be used to help guide the discussion regarding risk of progression Patients opinions should be factored into decisions regarding management and treatment Shared decision-making will make for a better providerpatient relationship

31 HBV LIFE CYCLE Unlike HCV, HBV incorporates DNA in host No current curative therapy for HBV Adapted from Shuping Tong, Peter Revil ljournal of Hepatology, Volume 64, Issue 1, Supplement, 2016, S4 S16

32 HBV TREATMENT RECOMMENDATIONS APASL (2015) EASL (2017) AASLD (2016) HBV DNA threshold (IU/L) -HBeAg positive -HBeAg negative 20, , ALT: Normal range - - 2X ULN (M: 30 U/L; F: 19 U/L) When to treat: key factors HBV DNA and ALT HBV DNA and ALT HBV DNA and ALT Biopsy Consider in certain groups Consider in certain groups Consider in certain groups Lok AS, et al. Hepatology 63.1 (2016): EASL. J Hepatol vol. 57 j Liaw Y-F, et al. Hepatol Int. 2008;2: Terrault, Norah A., et al. Hepatology 63.1 (2016):

33 DRUGS WITH ANTI-HBV ACTIVITY Nucleoside Analogs: Lamivudine 1 Entecavir 2 (first line) Telbivudine Emtricitabine 1,3 Nucleotide Analogs Adefovir dipivoxil Tenofovir disoproxil fumarate 1,3 (first line) Tenofovir alofenamide (first line) Immune Modulator/Antiviral Interferon alfa Pegylated interferon alfa (first line) 1. Active against and approved for HIV 2. Possible activity against HIV 3. FDA-approved for treatment of HBV August 2008

34 GOALS OF CURRENTLY APPROVED TREATMENTS FOR CHRONIC HBV Prevent adverse clinical outcomes Markers of treatment response: suppression of HBV DNA Improvements in liver histology Suppression of HBV DNA Decrease or normalization of serum ALT Induction of HBeAg loss or seroconversion Not a goal for HBeAg-negative patients at diagnosis Induction of HBsAg loss or seroconversion HBV prophylaxis in immunosuppressed patients Prevention of mother to child transmission for select patients Lok ASF. Hepatology. 2004;39: Keeffe EB. Clin Gastroenterol Hepatol 2006;4:

35 THERAPIES FOR HBV-HIV COINFECTION Treatment of HBV needs to be coordinated with HIV therapy given that several HBV drugs have anti-hiv activity tenofovir entecavir lamivudine +/- emtricitabine telbivudine Most HIV-infected patients with chronic HBV will be treated for their HIV and HBV, regardless of the stage of liver disease or their level of immunosuppression

36 HBV-HIV COINFECTION TREATMENT Most HIV-infected patients with HBV will be treated with an antiretroviral regimen that typically includes a tenofoviremtricitabine containing backbone Considered first-line treatment Ultimate choice depends on the patient s prior treatment history of HIV and/or HBV as well as their kidney function Presence of delta virus may also influence treatment decisions Prior exposure to lamivudine for HIV treatment should be considered A baseline HBV resistance panel is sometimes obtained in patients with prior exposure to lamivudine-containing regimens to determine effectiveness of entecavir-based treatment

37 RECENTLY APPROVED NEW THERAPIES (TAF) TAF = orally bioavailable phosphoramidate prodrug of tenofovir (TDF) Compared with tenofovir, TAF enables enhanced delivery of the parent nucleotide and its active diphosphate metabolite into lymphoid cells and hepatocytes. This is attributed to an improved plasma stability and differential intracellular activation mechanism for TAF relative to TDF NH 2 NH 2 NH 2 N N N N N N P O HO OH O N N O O O O O P O O O N N O O O P N H O O N N O O EC 50 HIV-1 Tenofovir Tenofovir Disoproxil TAF (PBMCs) 1.2 µm µm µm

38 TAF: SIMILAR EFFICACY, BETTER SAFETY PROFILE HBV DNA <29 IU/mL (%) Log 10 HBV DNA Change Proportion of Patients (95% Cl). % TAF TDF Log 10 HBV DNA Mean Change (95% Cl). IU/mL Week Improved renal safety profile Improved bone turnover parameters Week

39 EMERGING HBV THERAPIES: HOW TO ACHIEVE A CURE? HBV DNA suppresses immune response by: Shock and Awe overwhelming antigens Control viral replication Cripple the virus Reactivate the host immune response Release immune tolerance Clear cccdna

40 HBV CURE: THE DRUG DISCOVERY LANDSCAPE Immune modulation Toll-like receptors agonists, Gilead, Roche Anti-PD-1 mab, BMS, Merck Vaccine therapy Transgene, Gilead, Roche Inovio, M Medimmune, ITS, TeTekmira RNA interference, Arrowhead, Tekmira, Alnylam, GSK HBx Targeting HBsAg mab, Gilead Release, Replicor, Tekmira Surface proteins Polymerase Core pgrna Polymerase inhibitors Nucleoside analogues, eg, Gilead, BMS Non-nucleoside, eg, LB80380 cccdna rcdna Entry inhibitors Lipopeptides, eg, myrcludex B Endosome Targeting cccdna Tekmira Inhibition of nucleocapsid assembly, Novira, Assembly Biosciences, Gilead, Janssen, Roche, Tekmira Zoulim F, et al. Antiviral Res 2012;96(2):256 9; HBF Drug Watch, Available at: hbf_drug_watch.htm.

41 RECOMMENDED HBV VACCINE DOSAGES AND SCHEDULES FOR ADULTS Vaccine Dosage Dosing and Route Hepatitis B Vaccines Engerix-B Recombivax HB Combined Hepatitis A and B Vaccines 20 mcg 3-dose schedule: 1 ml given IM at 0, 1, and 6-12 months 100 mcg 3-dose schedule: 1 ml given IM at 0, 1, and 6-12 months Standard 3-dose schedule: 1 ml given IM at 0, 1, and 6 months Twinrix HAV: 720 EL.U plus HBsAg: 20 mcg or Accelerated 4-dose schedule: 1 ml given IM on days 0, 7, and 21-30, followed by a booster dose at month 12

42 KEY TAKEAWAYS HBV represents a major public health problem and is underdiagnosed in the US, which disproportionately affects foreign-born persons HBV screening is vital in specific populations, including pregnant and postpartum women Effective specific cultural/stigma conversations can lead to increased patient acceptance of HBV screening Vaccines and therapies for HBV are highly effective New therapies for HBV infection that offer a cure are on the horizon