Hepatitis B Diagnosis and Management Marion Peters University of California San Francisco
COI Spouse works for Hoffmann-La Roche
HBV is a life long, dynamic disease Changes over time Risk of end stage liver disease and cancer increases with ongoing inflammation and viremia in adults Fibrosis can be reversible Drugs can decrease fibrosis progression HBV can be controlled but not cured Reactivation can occur even in those who have lost HBsAg
Prevalence of HBV in HIV-Positive and negative patients Estimated Number of Persons Infected Worldwide, in Millions About 5% to 10% of anti-hcvantibody positive patients are HBsAg-positive Hepatitis C superinfection of chronic HBsAg carriers is common in HBV endemic regions, such as Southeast Asia HCV ~140 Not to scale. HCV/HBV 15 HIV/HCV/HBV 0.5 HIV 35 HBV 350 Fernandez-Montero JV, Soriano V. Best Pract Res Clin Gastroenterol. 2012;26:517-530.
Geographic Distribution of HBV Genotypes Ae, Bj, C, D, F B,C,A,D G F 1 &, H B, A/Bj H Greenland: A, B, D Ae G D E D A D B 3 Ba B Bj C F 2 Aa B C D
HBV HBsAg DNA HBsAg cag HBeAg Dane Particle Infectious virion Subviral particles
Hepatitis B Virus
HBV Serologic Markers HBsAg Acute or chronic infection First serologic marker to appear Infection considered chronic if persistent for > 6 months HBeAg Indicates active replication of virus Absent if inactive or mutations develop Anti-HBc total (HBcAb total) Present in infection (IgM in acute infection) Present in past exposure to HBV May occur alone when anti-hbs wanes Anti-HBs Recovery from HBV with anti-hbc Detectable alone after immunity conferred by HBV vaccination Occasionally seen in chronic carriers with HBsAg & anti-hbc Anti-HBe Generally indicates virus is no longer replicating Present in those with HBeAg mutations who have active disease Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87-106.
What to do with results? HBsAg HBsAb HBcAb Management + - + refer to care - + + past infection* - - - vaccinate - + - immune (vaccinated) * latent infection important if immune compromised or chemo BRM
HBV Control Inflammatory: normalize serum ALT, biopsy Virologic: decrease HBV DNA Immune: seroconversion HBeAg to anti-hbe HBsAg to anti-hbs HBV as of 2018 not cured but controlled
Who to treat Those with inflammation and fibrosis Elevated ALT and Elevated HBV DNA If not clear Liver biopsy
EASL Guidelines 2017 HBeAg positive Chronic infection Chronic hepatitis HBsAg High High/intermediate HBeAg Positive Positive HBV DNA >10 7 IU/ml 10 4-10 7 IU/ml ALT Normal Elevated Liver disease None/minimal Moderate/severe Old terminology Immune tolerant Immune reactive HBeAg positive J Hep 2017
EASL Guidelines 2017 Chronic infection HBeAg negative Chronic hepatitis HBsAg Low Intermediate HBeAg Negative Negative HBV DNA <2,000 IU/ml >2,000 IU/ml ALT Normal Elevated Liver disease None Moderate/severe Old terminology J Hep 2017 Inactive carrier HBeAg negative chronic hepatitis
Monitoring HBV monoinfection Serum ALT- check every 3 months at first If normal for one year, follow labs every 6 months (normal ALT <20 for women, <=30 for men) Older patients may have cirrhosis with normal serum ALT HBV DNA If low monitor If elevated consider need for therapy Over age 40 or family history monitor for HCC
Who should be treated Chronic hepatitis (elevated ALT and HBV DNA) Cirrhotics- any level ALT, detectable DNA HCC HIV On Chemotherapy or biologics Pregnancy 3 rd trimester if HBV DNA >200,000 IU/mL
Approved HBV treatments 2018 Interferon alfa-2b 1991 Lamivudine 1998 Adefovir 2002 Entecavir 2005 Peginterferon alfa-2a 2005 Telbivudine 2006 Tenofovir Dipivoxil 2008 Tenofovir alafenamide- 2017
Patients (%) Long-term Entecavir Treatment Improves 100 80 60 Liver Histology and Fibrosis 73 96 88 Wk 48 Long-term biopsy >3y 40 32 20 0 n = 41 55 158 50 Histologic improvement Coprimary Endpoints Chang TT, et al. Hepatology. 2010;52:886-893 CCO Hepatitis. Fibrosis improvement
Undetectable HBV DNA (%) Undetectable HBV DNA Over Time in HBeAg Negative Patients Not head-to-head trials; different patient populations and trial designs Extended Treatment With Nucleos(t)ide Analogues vs 1 Yr Peginterferon Treatment 100 80 60 40 20 0 *Single center study. 90 93 96 100* 91 87 63 15 16 NA 1 Yr 2 Yrs 3 Yrs Entecavir Tenofovir Peginterferon Lok AS, et al. Hepatology. 2009;50:661-662. Marcellin P, et al. AASLD 2008. Abstract 146. Marcellin P, et al. AASLD 2009. Abstract 481. Marcellin P, et al. Gastroenterology. 2009;136:2169-2179. Baqai S, et al. AASLD 2009. Abstract 476. Lai CL, et al. Hong Kong International Liver Congress 2006.
HBsAg Loss (%) HBsAg Loss Over Time in HBeAg Positive Patients Not head-to-head trials; different patient populations and trial designs 100 80 60 40 Extended Treatment With Nucleos(t)ide Analogues* vs 1 Yr Peginterferon Treatment 20 2 3 5 5 6 6 8 8 NA 0 1.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs *With sustained undetectable HBV DNA. Entecavir Tenofovir Peginterferon TDF +PEG 1y 9.3% 37.5% geno A Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology. 2008;135;459-467. Gish R, et al. Gastroenterology. 2007;133:1437-1444. Heathcote J. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483. Janssen HL, et al. Lancet. 2005;365:123-129; Marcellin Gastro 2016
Patients (%) HBsAg Loss Over Time in HBeAg Negative Patients Not head-to-head trials; different patient populations and trial designs 100 80 60 40 Extended Treatment With Nucleos(t)ide Analogues* Vs 1 Yr Peginterferon Treatment 20 4 7 9 < 1 0 < 1 0 NA 0 0 1.0 Yr 1.5-2.0 Yrs 3.0-4.0 Yrs *With sustained undetectable HBV DNA. Entecavir Tenofovir Peginterferon TDF +PEG 1y 5% 33% geno A Lai CL, et al. N Engl J Med. 2006;354:1011-1020. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Marcellin P, et al. AASLD 2008. Abstract 146. Shouval D, et al. J Hepatol. 2009;50:289-295. Marcellin P, et al. AASLD 2009. Abstract 481. Brunetto M, et al. EASL 2008. Abstract 683.Marcellin Gastro 2016
Types of HBV cure Functional Cure- clinical resolution Sustained, off drug: No inflammation: ALT and liver biopsy HBsAg loss Anti-HBs gain Complete cure- virological cure All of above plus Loss of cccdna in liver Inactive state -an interim goal? No inflammation: ALT and liver biopsy HBV DNA low or u/d HBsAg positive
Viral Life Cycle HBsAg pos Entry ER Budding Nucleus Repair Recycling cccdna Plus strand synthesis Minus strand synthesis S, C, P,e synthesis Reverse transcriptase P protein pregenomic RNA Transcription Host RNA pol Translation RNA packaging (encapsidation)
Viral Life Cycle- latent or recovered HBV Immune system considers this recovered BUT cccdna is template for viral replication ER HBsAg neg Anti-HBs Anti-HBc cccdna Nucleus
Patients on Immunosuppressive Therapy There is a high rate of HBV reactivation in immunosuppressed patients: During chemotherapy In HIV patients after immune reconstitution After organ transplant and stem cell transplant With biologic response modifiers: Rituximab (anti-cd20), TNF-α inhibitors Rituximab/ stem cell transplant the most potent reactivator of HBV Prophylax if anti-hbc without HBsAg All patients should be tested prior to chemotherapy for: HBsAg, anti-hbs and anti-hbc Loomba R, et al. Ann Intern Med. 2008;148:519-528; Dong J. Clin Virol. 2013.
Patients on Immunosuppressive Therapy All patients who are to receive immunosuppressive therapy should be tested for HBsAg and anti-hbc and anti-hbs If HBsAg positive, initiate antiviral therapy before IS If anti-hbc positive but HBsAg negative: Anti-HBV therapy should be administered preemptively for rituximab or stem cell transplant Consider preemptive anti-hbv therapy for other forms of chemotherapy or close monitoring of HBV DNA if anti-hbv therapy not given Loomba R, et al. Gastro 2017
HCC and HBV Increased risk of progression/hcc shown in: male sex younger age of infection Excess alcohol consumption, NAFLD High hepatitis B DNA levels (over age 40 years) Co-infections with HIV, HCV and HDV Hepatitis B virus genotype C, Aa Screen with 6 monthly ultrasound and AFP If lesion CT or MRI to determine if HCC McMahon Hep 2009; MMWR Recomm. Rep. 2005;54:1-31Lancet. 2014;384:2053-2063.
HCC - RADIOLOGIC CHARACTERISTICS QUAD-PHASE CT OF THE ABDOMEN Arterial Phase Enhancement Portal Venous phase washout
Cumulative incidence of HCC (%) 16 14 12 10 8 6 4 2 0 Baseline HBV DNA and HCC REVEAL study cohort 3,582 HBV DNA (copies/ml) 10 6 10 5 <10 6 10 4 <10 5 300 <10 4 <300 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Chen et al. JAMA 2006 Age 45, Male 61%, ALT>45 6%, HBeAg-positive 15% Relative Risk (95% CI) Year of follow-up 14.89% 12.17% 3.57% 1.37% 1.30% 10.7 (5.7 20.1) 8.9 (4.6 17.5) 2.7 (1.3 5.6) 1.0 (0.5 2.2) 1.0 (ref pink)
HCC and HIV survival: 6 monthly AFP and ultrasound 2 yr survival HIV + HIV- p value Puoti (R 41) 11% 41% 0.01 Brau (R 63) 16% 18% 0.6 Berretta (R 104) 69% 72% 0.048 Lim (P 23-TB) 44% 60% 0.2 All note younger age in HIV+ but other factors not common AIDS 2004; J Hepatol 2007; oncol 2011; JAIDS 2012
HBV and HIV HIV increases HBV chronicity HBV increases antiretroviral-related hepatotoxicity HIV/HBV coinfection increases the risk of end stage liver disease compared to HBV alone HIV HBV coinfected patients have poorer hospital outcomes, more progression to cirrhosis, HCC and death than either HIV or HBV monoinfected patients Thio CL, et al. Lancet. 2002: Koziel NEJM 2007; Rajbhandari J Viral Hepat 2016
HBV-HIV Summary Immune response predicts HBV outcome Flares in HBV/HIV patients are common Many HIV medications are hepatotoxic Other causes of ALT elevations in HBV/HIV should be sought Less common causes of flares now are ART without HBV therapy and stopping ART Atypical serologies may occur in HIV patients during ART Reverse seroconversion occurs All HBV HIV patients require screening for HCC
Terrault Hepatology 2016; Zhang. Hepatology. 2014. Treatment of HBV in Pregnancy
Summary Treat if elevated ALT and HBV DNA (and special considerations) Comorbidities occur in patients with HBV Check HIV, HCV, HDV, HAV, MS HBV patients should report to their primary care provider of any new diagnoses or planned therapies so that considerations for HBV antiviral therapy can be made, particularly If receiving high-dose steroids, chemotherapy, or rituximab If pregnant or wishing to become pregnant Screen for HCC with 6 monthly imaging and ALF
Strategies to Eradicate HBV Virologic approaches Entry inhibitors Block cccdna Transcription inhibitors RNA interference HBV capsid inhibitor polymerase inhibitors Secretion inhibitors Host immune approaches Interferons TLR-7 PD-1/ PDL-1 IL-7 Therapeutic vaccines Immune complex vaccines Nasal HBV (NASVAC) vaccines DNA vaccines T cell vaccines Adenovirus based vaccines (TG1050) Yeast based vaccines
TRANSCRIPTION HBeAg (P14-17) spherical HBsAg subviral particles Mature HBV virion ASSEMBLY AND SECRETION NUCLEAR TRANSPORT DNA Repair Precore mrna cccdna Pregenomic RNA HBx mrna Precore Protein (p25) Pre-S1 mrna Pre-S2/S mrna Smc 5/6 HBx HBsAg proteins: Core + pg RNA + Polymerase LHBsAg MHBsAg SHBsAg Immature Nucleocapsid ENCAPSIDATION Intracellular Conversion Pathway RT Mature Nucleocapsid RC-DNA