Maitines septiembre de 2011 Francisco Jorquera Plaza

Bringing Into Focus: A Practical Guide to Using Virologic and Serologic Tests in the Management of Hepatitis B Maitines septiembre de 2011 Francisco Jorquera Plaza

2.000 millones de personas infectadas por el VHB en todo el mundo Casi la mitad de la población mundial vive en áreas con prevalencias elevadas de VHB 1 2.000 mill. de personas con evidencia de infección por VHB El 15 25% muere por cirrosis o cáncer de hígado Población mundial: 6.000 millomes 350 millones con infección crónica por VHB 1. Adaptado de Lavanchy D. J Viral Hepatitis 2004;11:97-107.

Geographic Distribution of Chronic HBV Infection 7.2% HBsAg Prevalence 8% (high) 2% to 7% (intermediate) < 2% (low) Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20. Liang X, Bi S, et al. Vaccine. 2009;27:6550-6557.

The HBV Iceberg Clinical populations are the tip of the iceberg Individuals in treatment are the tip of the tip Population-based studies allow us to look at the whole iceberg 2 million individuals in the US have chronic HBV infection 1.4 million are unaware of their chronic HBV infection 50,000 receive treatment 150,000 are diagnosed in care and meet treatment 300,000 are guidelines diagnosed in care 500,000 are potentially eligible for treatment 600,000 are aware of their chronic HBV infection Asia has been the place for these Cohen C, et al. J Viral Hepatitis. 2011;18:377-383. Graphic reproduced with permission.

Groups at High Risk for HBV Infection Who Should Be Screened Persons born in geographic regions with HBsAg prevalence of 2% US-born persons, not vaccinated as infants, whose parents were born in geographic regions with HBsAg prevalence of 8% Persons with chronically elevated aminotransferases Persons needing immunosuppressive therapy Men who have sex with men Persons with multiple sexual partners or history of sexually transmitted disease Inmates of correctional facilities Persons who have ever used injection drugs Dialysis patients HIV- or HCV-infected individuals Pregnant women Family members, household members, and sexual contacts of HBV-infected persons Lok AS, et al. Hepatology. 2009;50:661-662.

Assessing Patient History and Current Presentation Age Duration of disease Family history of HCC Alcohol use Smoking history Fatty liver disease, diabetes mellitus, metabolic syndrome Patient motivation, compliance, adherence Comorbidities: renal, bone Cost of testing and treatment/insurance

Hepatitis B Serology: First Phase Testing AASLD guidelines recommend HBsAg and anti-hbs testing for all patients HBsAg Protein on surface of HBV detected during acute or chronic HBV infection Presence indicates an individual is INFECTED OR INFECTIOUS Anti-HBs Presence indicates recovery and IMMUNITY from HBV infection Also develops following vaccination against hepatitis B Total anti-hbc can be used as alternative; those testing positive should be tested for HBsAg and anti-hbs Appears at the onset of symptoms in acute hepatitis and persists for life Presence indicates EXPOSURE (previous or ongoing infection with HBV) Lok AS, et al. Hepatology. 2009;50:661-662.

Why Do We Need to Do Anti-HBc Testing? Decide who needs HBV vaccine Patients testing negative for HBsAg but positive for anti-hbc in regions of high HBV prevalence have had exposure due to natural infection; therefore, no need to vaccinate* Chemoprophylaxis for HBV reactivation Immunocompromised patients can experience reactivation of HBV if anti-hbc is positive Assess risk of donor HBV transmission Recipients of livers from anti-hbc positive patients are at risk for HBV transmission *However, one of the possibilities for isolated HBcAb (total) is the possibility of false positive in low prevalence areas or in individuals with no risk factors for HBV, in which case they may need to be vaccinated.

Hepatitis B Serology: IgM anti-hbc IgM anti-hbc (IgM antibody to hepatitis B core antigen) [1] Presence indicates acute infection (negative in chronic infection) Positivity indicates recent infection with HBV ( 6 mos) Occasionally occurs in the presence of a severe flare of chronic HBV disease Small minority of pts with chronic HBV are IgM anti- HBc+, indicating higher risk for progression to cirrhosis or HCC [2] 1. CDC. Hepatitis B FAQs for health professionals. Available at: http://www.cdc.gov/hepatitis/ HBV/HBVfaq.htm. 2. Colloredo MG, et al. Arch Virol Suppl. 1993;8:203-211.

Interpretation of Serologic Results HBsAg Total Anti-HBc IgM Anti-HBc Anti-HBs Interpretation Negative Negative NA Negative Susceptible; offer vaccination Negative Positive NA Positive Immune due to natural infection Negative Negative NA Positive Immune due to hepatitis B vaccination Positive Positive Negative Negative Chronic HBV infection Positive Positive Positive Negative Acute HBV infection Negative Positive NA Negative Unclear; could be any one of the following: 1. Resolved infection (most common) 2. False-positive anti-hbc; susceptible 3. Low-level chronic infection 4. Resolving acute infection CDC. Hepatitis B FAQs for health professionals. Available at: http://www.cdc.gov/hepatitis/hbv/hbvfaq.htm.

Initial Testing in Patients Diagnosed With Chronic HBV Testing for Patients Who Are HBsAg Positive [1] Lab tests to assess liver disease: hepatic panel, and INR (prothrombin time) Tests for HBV replication: HBeAg/anti-HBe, HBV DNA Tests to rule out viral coinfections: anti-hcv, anti-hdv (in persons from countries where HDV infection is common and in those with history of injection drug use), and anti-hiv in those at risk Tests for screening and surveillance for HCC: AFP and ultrasound as appropriate Consider liver biopsy to grade and stage liver disease: for patients who meet criteria for chronic hepatitis Consider core and precore assays and testing for HBV genotype CDC guidelines recommend HIV testing in ALL chronic HBV patients [2] 1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

Hepatitis B Serology: Determining HBeAg Status in CHB Patients HBeAg Secreted coproduct of nucleocapsid gene of HBV found in serum during acute and chronic HBV with wild-type infection Presence indicates replicating natural variant virus and often associated with high HBV DNA levels Anti-HBe Produced by immune system temporarily during acute HBV infection or consistently during or after a burst in viral replication in setting of wild-type infection clearance Conversion from HBeAg positive to anti-hbe positive a predictor of Long-term clearance of HBV in patients undergoing antiviral therapy and indicates lower levels of HBV or Emergence of precore, mixed, or core promoter mutant infection and transition to HBeAg-negative disease

HBV Variants Wild type Unmutated HBeAg-positive hepatitis Mixed infection with Basal core promoter mutations (44% of US patients) [1,2] Precore mutations (27% of US patients) [2] Precore and core promoter mutations [3] Eventually abolishes HBeAg production (HBeAg-negative CHB) Genotypes Treatment-induced mutations 1. Buckwold VE, et al. J Virol. 1996;70:5845-5851. 2. Chu CJ, et al. Gastroenterology. 2003;125:444-451. 3. Hunt CM, et al. Hepatology. 2000; 31:1037-1044.

Natural History of HBV Infection Childhood > 95% Immune tolerance Adulthood < 5% HBeAg+ CHB HBeAg- CHB Inactive carrier Cirrhosis Chen DS, et al. J Gastroenterol Hepatol. 1993;8:470-475. Seeff L, et al. N Engl J Med. 1987;316:965-970.

High Risk of Cirrhosis in Asians & Patients With Vertically Transmitted Disease The lifetime risk of cirrhosis or cancer in a person who is HBsAg positive is 20% to 30% Risk is lower for women Risk is highest for men Fattovich G, et al. Am J Gastroenterol. 2002;97:2886-2895. Fattovich G, et al. Gastroenterology. 2004;11;27:S35-S50. McMahin BJ. Hepatology. 2009;49:S45-S55.

HBV Classified Into 10 Genotypes Genotype A B and C D E F G H I J Geographic distribution North America, northern Europe, India, and Africa Asia Southern Europe, Middle East, and India West Africa and South Africa Central and South America United States and Europe Central America and California Vietnam Japan Fung SK, et al. 2004;40:790-792. Norder H, et al. Intervirology. 2004;47:289-309. Tuan Huy TT, et al. J Virol. 2008;82:5657-5663. Tatematsu K, et al. J Virol. 2009;83:10538-10547.

Why Test for HBV Genotype? Differences in natural history and treatment responsiveness B is associated with less active disease, slower progression, and lower incidence of HCC than C C has higher risk of HCC and cirrhosis A and B respond better to IFN than C and D F is associated with fulminant liver disease; rare Current guidelines indicate that additional data are needed before testing for genotypes in clinical practice is recommended Lok AS, et al. Hepatology. 2009;50:661-662. EASL. J Hepatol. 2009;50:227-242.

Summary: Tests for Initial Evaluation and Diagnosis of HBV Clinical assessment for HBV disease is a multistep process History Physical exam Serologic tests Nucleic acid tests Liver biochemistries including liver synthetic tests HCC biomarkers Imaging

Parameters Used to Determine Candidates for Treatment of HBV ALT New normal or healthy ALT: < 30 U/L for men and < 19 U/L for women [1] Presence of 1 normal value does not exclude significant disease or subsequent complications HBV DNA Predicts development of cirrhosis and HCC [2,3] Interpret in conjunction with ALT and/or histology Liver biopsy Useful in situations where ALT or HBV DNA do not provide clear guidelines for treatment [1] 1. Lok AS et al. Hepatology. 2009;50:661-662. 2. Iloeje UH et al. Gastroenterology. 2006;130:678-686. 3. Chen CJ et al. JAMA. 2006;295:65-73.

Transmission of HBV Is Proportional to HBV DNA Level Horizontal Transmission Higher DNA, higher risk Vertical Transmission Infected person Recipient Mother > 10 6-8 IU/mL Child to child Contaminated needles Sexual Healthcare worker Transfusion Hemodialysis No clear risk factors in 20% to 30% of patients Infant Perinatal Common in regions with HBsAg prevalence of > 2% CDC. Hepatitis B Information for the Public. Fact sheet. http://www.cdc.gov/hepatitis/b/patientedub.htm. Lee WM. N Engl J Med. 1997;337:1733-1745. Lavanchy D. J Viral Hepat. 2004;11:97-107.

Natural History of HBV: Directly Related to HBV DNA Level 5% to 10% Liver cancer (HCC) Chronic infection 30% 10% to 15% in 5 yrs Cirrhosis 23% in 5 yrs Liver transplantation* Death Acute flare Liver failure *HBV is the 6th leading cause of liver transplantation in the United States. Fattovich G, et al. Gastroenterology. 2004;127:S35-S50. Seeff LB, et al. Hepatology. 2001;33:455-463. Torresi J, et al. Gastroenterology. 2000;118:S83-S103. Fattovich G, et al. Hepatology. 1995;21:77-82.

Treatment Criteria for Chronic Hepatitis B: Comparison of Guidelines Guidelines HBeAg Positive HBeAg Negative HBV DNA, IU/mL ALT HBV DNA, IU/mL EASL 2009 [1] > 2000 > ULN > 2000 > ULN APASL 2008 [2] 20,000 > 2 x ULN 2000 > 2 x ULN AASLD 2009 [3] > 20,000 NIH Consensus Conference > 20,000 2009 [4] US Algorithm 2008 [5] 20,000 > 2 x ULN or positive biopsy > 2 x ULN or positive biopsy > ULN or positive biopsy 20,000 20,000 2000 ALT 2 x ULN or positive biopsy 2 x ULN or positive biopsy > ULN or positive biopsy 1. EASL. J Hepatol. 2009;50:227-242. 2. Liaw YF, et al. Hepatol Int. 2008;3:263-283. 3. Lok AS, et al. Hepatology. 2009;50:661-662. 4. Degerekin B, et al. Hepatology. 2009;S129-S137. 5. Keefe EB. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

Clinical Profiles of Chronic HBV Infection Parameter Typical HBV DNA, IU/mL Immune Tolerance Immune Active/ HBeAg-Positive CHB Nonreplicative (Inactive Carrier) HBeAg- Negative CHB > 200,000 200,000-2 x 10 9 < 2000 2000-2 x 10 7 HBeAg Positive Positive Negative Negative ALT Other observations Treatment candidate? Normal Liver biopsy typically normal or minimal findings Elevated or fluctuating Active inflammation on liver biopsy Normal HBsAg may become undetectable Elevated or fluctuating Active inflammation on liver biopsy No Yes No Yes Lok AS, et al. Hepatology. 2009;50:661-662.

Noninvasive Serum-Based Tests for Detection of Fibrosis Test FibroTest FibroSpect II FibroSURE APRI Forns fibrosis index FIB-4 HepaScore Fibrometer Parameters Measured α2-macroglobulin, haptoglobin, GGT, total bilirubin, and apolipoprotein A1 α2-macroglobulin, hyaluronic acid, and tissue inhibitor of metalloproteinase-1 α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, GGT, ALT, AST, total cholesterol, triglycerides, and fasting AST-to-platelets glucose ratio index Age, platelet count, GGT, cholesterol Platelets, ALT, AST, and age α2-macroglobulin, GGT, hyaluronic acid, and total bilirubin Age, sex, α2-macroglobulin, hyaluronic acid, platelets, prothrombin index, AST, and urea No guidelines currently recommend routine clinical use of noninvasive methods for the detection of fibrosis

Transient Elastography: A Potential Noninvasive Alternative to Liver Biopsy Elastography Ultrasound transducer probe induces elastic wave through the liver Velocity of the wave is evaluated in a region located from 2.5-6.5 cm below the skin surface Whereas a liver biopsy is able to examine 1/50,000 of the liver, elastography is able to examine 1/500 of the liver Despite extensive research and progress, no guidelines recommend transient elastography as alternative to liver biopsy for CHB Effective at discriminating between severe and mild fibrosis but less effective at distinguishing intermediate levels of fibrosis [1-2] MRI and MR spectroscopy other potential noninvasive tests to detect cirrhosis [3] 1. Chan HL, et al. J Viral Hepat. 2009;16:36-44. 2. Marcellin P, et al. Liver Int. 2009;29:242-247. 3. Friedrich-Rust M, et al. J Clin Gastroenterol. 2010;44:58-65.