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Hepatitis B Virus Overview

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									Hepatitis B Virus: Overview
        Overview Objectives
   History
   Epidemiology
   Molecular Biology
   Pathogenesis
   Diagnostic Markers
   Therapeutic Interventions
Disease Progression of
      Hepatitis B
 NATURAL HISTORY OF HBV
 INFECTION
                                             HBeAg+                      Anti-HBe+
Caucasian
(Adult-acquired)
                        HBV DNA




                            ALT
                                                                                         Age(yrs)
                                         Replicative phase         Low replicative
                                                                   phase
                                             HBeAg+                Anti-HBe+
Chinese                                  HBeAg+                        Anti-HBg+
(Perinatal acquired)
                       HBV DNA



                           ALT
      HBV DNA                                                                            Age(yrs)
                                     Immune           Immune           Low replicative
      ALT                            tolerance        clearance        phase
                                     phase            phase
                                 0               20               40                      Lok 1999
            Why is HBV Important?
   Infectious or transmissible disease

   Asymptomatic Disease in the majority:
     – Acute
     – Chronic 400 M carriers in the world
     – US: 2 M HBsAg+

   Persistent carriers of HBV have a high risk of developing cirrhosis and
    hepatocellular carcinoma
     – 7-30%

   Long-term, expensive treatment
     –   IFN: 15-25,000$
     –   Oral therapies 3600-8,000$ /year
     –   liver transplantation 150,000$
     –   Death 150,000$

   Death
     – 30% life time risk
     – 9th leading cause of death according to WHO in the world
             History of HBV
   Viral hepatitis
    – since antiquity
    – Talmud - 5th century Babylonia
    – Hippocrates (460-375 B.C.)
    – Phylogenetic analysis dates HBV @
      200,000 years in East Africa
                         History of HBV
   1883 - Bremen Shipyard
      – first recognized outbreak
   1947 - MacCallum
      – termed “hepatitis B”
      – adopted by WHO in 1973
   1965 - Blumberg
      – characterized Australian antigen (HBsAg)


Lok, A.(2000) J of Hepatology: 32(1):89-97
              Epidemiology of HBV
   Global health problem
      – causes 80% of of all liver cancer
               second most important carcinogen behind
                tobacco
      – carrier rates range from 0.1% in Western
        countries to 15% is some Asian & African
        nations
      – HBV is 100 times more contagious than
        HIV

Lok, A.(2000) J of Hepatology: 32(1):89-97; Hilleman, M.(2001) Vaccine 19: 1837-1848
     Epidemiology - Worldwide
   2 Billion People
     – have serologic evidence of past or present
       HBV infection
   350 Million Carriers
     – are chronically infected with HBV
   1 Million People or more
     – die each year from HBV-related Chronic
       Liver Diseases

Alter, M.; CDC Atlanta, GA, 2002
    Geographic Patterns of HBV
          Transmission
   High Endemicity
        8% HBsAg (+)
       70-90% of the pop’n have evidence of HBV infection


   Intermediate Endemicity
       2-7% HBsAg (+)
       10 - 60% of the pop’n have evidence of HBV infection


   Low Endemicity
       < 2% HBsAg (+)
       5-7% overall infection rate
Geographic Distribution of Chronic HBV
              Infection




              HBsAg Prevalence
                  8% - High
                  2-7% - Intermediate
                  <2% - Low
CDC 2002
Epidemiology - United States
   100,000 - 130,000 HBV infections/year
     – vaccination has been key
   8,000 - 32,000 chronic infections/year
   5,000 - 6,000 deaths/year
   1 - 1.25 to 2 Million Americans with
    Chronic HBV infection
     – 7% of adult acquired and 15 to 25% of
       childhood acquired chronically infected
       patients will die from CLD

CDC and HIVandHepatitis.com, 2002
                               Estimated Incidence of Acute Hepatitis B
                                      United States, 1978-1995
                                80                            HBsAg screening
                                                                of pregnant      Infant
Cases per 100,000 Population



                                            Vaccine               women       immunization
                                70          licensed           recommended recommended

                                60
                                                                               OSHA Rule
                                50                                              enacted
                                                                                           Adolescent
                                40                                                        immunization
                                                                                         recommended
                                30

                                20
                                                            Decline
                                10                          among
                                                          homosexual
                                                                       Decline among
                                                                         injecting
                                                                        drug users
                                                                                                *
                                                          men & HCWs
                                 0
                                     78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95
                                                              Year
                               CDC 2002
       Modes of Transmission
   Percutaneous Exposures
    – IV drug use, blood transfusions,
      contaminated equipment, needle sticks,
      tatooing/accupuncture


   Mucous Membrane Exposures
    – perinatal, sexual transmission and saliva


   HBV is stable on surfaces for  7 days
              Key Problem
   Most persons with chronic HBV are
    unaware they are infected
    – asymptomatic acute phase
    – long incubation time
    – over 90% of childhood HBV infections are
      asymptomatic
    – 5 % of adults become persistent carriers
      following primary infection
                        Outcome of HBV infection by
                        100        Age            100

                                                                                          80
Chronic Infection (%)




                        80




                                                                                                Symptomatic Infection (%)
                        60                                                               60
                                                         Chronic Infection

                        40                                                               40


                        20                                                               20

                                     Symptomatic Infection
                         0                                                                0
                             Birth   1-6 months   7-12 months      1-4 years   Older Children
                                                                                 and Adults
                        CDC 2002              Age at Infection
    Molecular Biology of HBV
   Hepadnaviridae
   lipoprotein envelope
   nucleocapsid
   circular genome (3200 base pairs)
    – dsDNA and ssRNA
    – 4 overlapping ORF
          encode for the polymerase, surface proteins,
           core proteins and X proteins
      Molecular Biology of HBV
   Dane Particle
    – infectious form of HBV
    – spherical (42 nm in diameter)
    – outer envelope with HBsAg protein
    – nucleocapsid with HBcAg and genome
   Infected cells also produce non-infectious
    spheres and filaments
    – HBsAg and host cell lipids
    – highly immunogenic
    – may bind neutralizing antibodies = decoys
                    Hepatitis B Virus




CDC Web Site 2002
 HBV Particles and Filaments




Stannard, L.M. 1995, Cape Town
       HBV with Exposed Cores




Stannard, L.M. 1995, Cape Town
           HBV Replication
   Dane particle binds to a receptor on
    hepatocyte
    – fusion of viral and host membranes
   HBV nucleocapsid is transported to the
    nucleus
   Circular viral DNA is converted to
    covalently closed circular DNA (cccDNA)
               HBV Replication
   cccDNA = template for viral RNA synthesis
    – messenger RNA for envelope proteins
    – pregenomic RNA:
        template for reverse transcription of first (-) strand
         of HBV DNA
        serves as mRNA for nucleocapsid and polymerase
         proteins
   Virus proteins and genome form Dane
    particles
   Dane particles are secreted from the liver
    cell
      Molecular Biology of HBV
   Classified into 7 genotypes: A thru G
     – 10 - 15% sequence divergence
   A = NW Europe, N. America, C. Africa
   B & C = Southeast Asia, China, Japan
   D = S. Europe, Middle east, India
   E = West Africa
   F = American natives, Polynesia, C. & S. America
   G = United States, France
   H = Various

Chu and Lok (2002) Hepatology; 35(5); 1274-76.
             HBV Variants
   HBV genome is replicated via reverse
    transcription of an RNA intermediate
    – prone to mutations
    – no proof-reading mechanism


   but most mutations are not tolerated
    – due to compact size of HBV genome
               HBV Variants
   Variants
    – offer a selective advantage over wild-type
        evade host immune response
        enhanced viral replication




   Mutations can occur throughout the
    HBV genome
               HBV Variants
   Pre-Core Mutant A1986 (GA)
    – premature termination of the pre-core protein
    – prevents production of HBeAg
    – observed in patients infected with HBV
      genotypes B,C,D & E
    – HBeAg (-) patients are becoming more common
    – increased viral production, enhanced disease
      and treatment difficulties
    Immune Response to HBV
   Acute Infection
    – Strong B-cell response with Antibodies to
      pre-S and S proteins
    – Vigorous T-cell response


   Chronic Infection
    – CTL response is weak and limited
    – CD4+T-helper cell response is also weak
    – antibodies are generated
    Immune Response to HBV
   Immune Tolerance
    – if HBV is acquired perinatally
    – high rate of chronicity (>90%)
    – lack of disease activity despite high HBV
      titers
    – low rates of HBeAg seroconversion
    – mechanisms unknown
          HBV Pathogenesis
   HBV is not considered to be directly
    cytopathic
   greatest damage to the host is self-
    inflicted
    – immune response
   if enhance immune clearance of HBV -
    may result in increasing damage to the
    liver
    – fulminant hepatitis
          HBV Pathogenesis
   Primary HBV infection can generate a
    spectrum of clinical symptoms
    – asymptomatic infection to fulminant
      disease resulting in death within a few
      days
   Typical course of illness:
    – Asymptomatic Hepatitis
    – Acute Hepatitis
    – Atypical Acute Hepatitis
            HBV Pathogenesis
   Asymptomatic Hepatitis
    – most frequent response to HBV infection
    – difficult to detect
    – HbsAg and HBeAg are present transiently
    – antibodies to HBsAg and HBcAg develop quickly
    – liver enzymes may or may not be elevated
    – may lead to lasting immunity or chronic carrier
      state
                HBV Pathogenesis
   Acute Hepatitis
    – follows a long asymptomatic period (4-26 weeks)
    – may be icteric or anicteric hepatitis
    – flu-like symptoms are common
    – if icteric - most observe brown urine first
    – 90-95% of patients resolve infection within 4
      months
    – Liver enzymes (ALT and AST) may be elevated
          if liver enzymes remain elevated 6-12 months after
           acute illness - suggests chronicity
                            Normal Liver




FSU, College of Medicine, 2002
      Normal Liver Architecture




Virginia Commonwealth University, Dept. of Pathology, 2002
  Hepatitis B with Hepatocyte
         Degeneration




FSU, College of Medicine, 2002
                   Acute Hepatitis B




FSU, College of Medicine, 2002
                        Acute Hepatitis




Virginia Commonwealth University, Dept. of Pathology, 2002
            HBV Pathogenesis
   Atypical Acute Hepatitis
    – Prolonged Hepatitis
    – Relapsing Hepatitis
    – Fulminant Hepatitis
              Atypical Hepatitis
   Prolonged Hepatitis
    – illness lasts more than 4 months
    – includes chronic lobular hepatitis
    – not usually jaundice
    – fatigue
    – self-limited disease
    – cirrhosis does not develop
             Atypical Hepatitis
   Relapsing Hepatitis
    – original symptoms recur on several occasions
    – within 6 months of the original illness
    – incidence of relapse = 1.5 to 18%
    – self-limited disease
    – cirrhosis does not develop
              Atypical Hepatitis
   Fulminant Hepatitis
    – life threatening
    – may result in liver failure
    – massive necrosis of the liver
    – symptoms may present rapidly or slowly
    – strength of the immune response has been
      implicated
    – if survive - may develop chronic hepatitis leading
      to cirrhosis or HCC
         HBV Pathogenesis
   Outcomes of HBV Infection
    – Carrier State
    – Chronic Persistent Hepatitis
    – Chronic Active Hepatitis
    – Cirrhosis
    – Hepatocellular Carcinoma (HCC)
            HBV Pathogenesis
   Carrier State
    – HBsAg (+) for more than 6 months after acute
      infection
    – 5-10% of Adults
    – most carriers had asymptomatic infection or
      were infected early in life
    – may remain infectious for years
    – may go on to develop chronic liver diseases
      including cirrhosis and HCC
            HBV Pathogenesis
   Chronic Persistent Hepatitis (CPH)
    – chronic infection having a benign course and
      good prognosis
    – 1/3 of all chronic hepatitis cases
    – HBsAg and anti-HBc markers are present
    – diagnosed by long-term fluctuations of liver
      enzymes
    – most symptoms are very mild or inapparent
    – may not progress to more serious disease
    – Progression to Chronic Active Hepatitis is rare
            HBV Pathogenesis
   Chronic Active Hepatitis (CAH)
    – serious, destructive liver disease
    – 2/3 of chronic HBV infections
    – chronic necrosis and fibrosis
    – a variety of clinical symptoms ranging from
      asymptomatic disease to fulminant icteric
      hepatitis
    – liver enzymes elevated
    – may advance to cirrhosis or HCC
    – 5 year mortality = 25 to 50%
            HBV Pathogenesis
   Cirrhosis
    – irreversible chronic injury to the liver
    – extensive fibrosis
    – impaired liver function
    – portal hypertension, edema, jaundice are
      common
    – 5 year survival rates are shorter than CAH
      without cirrhosis
              Cirrhosis of the Liver




FSU, College of Medicine, 2002
              Cirrhosis of the Liver




FSU, College of Medicine, 2002
              Cirrhosis of the Liver




Virginia Commonwealth University, Dept. of Pathology, 2002
            HBV Pathogenesis
   Hepatocellular Carcinoma (HCC)
    – associated with HBV and HCV infections
    – HBV DNA integrated into HCC cell genome
    – usually requires decades to develop
    – more common in patients who acquired HBV in
      childhood
    – Two Theories:
       Direct or Viral Integration theory
       Indirect or Nodular Cirrhosis Theory
     Hepatocellular Carcinoma




FSU, College of Medicine, 2002
      Hepatocellular Carcinoma




Virginia Commonwealth University, Dept. of Pathology, 2002
          Diagnosis of HBV
   Serological Assays

   Biochemical Assays

   Molecular Diagnostics
    Key Serological Markers for
               HBV
   Hepatitis B Surface Antigen (HBsAg)
   =INFECTION
    –   earliest viral marker to be detected
    –   appears before symptoms
    –   after elevated liver enzymes
    –   indicator of active HBV infection
    –   disappears in 2-6 months
    –   if persistent for > 6 months without generation of
        anti-HBsAg antibody indicates a chronic carrier
        state
    Key Serological Markers for
               HBV
   Hepatitis B e Antigen (HBeAg)
   =WILD TYPE INFECTION
    – appears after HBsAg but before symptoms
    – limited presence (3-6 weeks)
    – indicates viral replication in the liver and high
      infectivity
    – sera containing HBsAg and HBeAg is 3-5 times
      more infectious than HBsAg alone
    – lack of HBeAg does not mean there is no
      circulating HBV
          pre-core or HBeAg (-) mutants
      Key Serological Markers for
                 HBV
   Hepatitis B e Antibody (anti-HBe)
   =LOW HBV DNA OR CORE MUTANT
    – detectable shortly after declination of HBeAg
    – implies HBV no longer replicating & disease is
      resolving
         indicates risk of infection is reduced
    – if no anti-HBe seroconversion - increased
      disease activity and progression
    – Patients with pre-core mutants but are anti-HBe
      (+) can still progress to HCC and cirrhosis
        Key Serological Markers for
                   HBV
   IgM Hepatitis Core Antibody (IgM anti-HBc)
   =ACUTE HBV
    –   before onset of symptoms
    –   same time as elevated liver enzymes
    –   after HBeAg
    –   persists for months to years
    –   marker of an acute HBV infection
    –   usually replaced by IgG anti-HBc
    –   Occasionally seen in patient with CHB (flare or very
        active disease)
      Key Serological Markers for
                 HBV
   Hepatitis B Surface Antibody (anti-HBs)
    – not evident until acute disease subsides
    – weeks to months after HBsAg disappears
    – persists for life
    – used to document recovery and/or immunity to
      HBV infection
    – individuals who have responded to the vaccine
      will have anti-HBs antibodies
  Typical Serologic Profile for
     Acute HBV Infection
                        Symptoms
                    HBeAg                anti-HBe


                                         Total anti-HBc
HBV
Titer
            HBsAg                  IgM anti-HBc            anti-HBs




            0   4   8   12 16 20 24 28 32 36          52      100

 CDC 2002               Weeks after Exposure
 Typical Serologic Profile for
   Chronic HBV Infection
                     Acute                     Chronic
                  (6 months)                   (Years)
                                HBeAg                      anti-HBe
                                        HBsAg
                                        Total anti-HBc
HBV
Tite
r
                               IgM anti-HBc




           0 4 8 12 16 20 24 28 32 36     52             Years
CDC 2002
                    Weeks after
         Serological Assays
   HBsAg Immunoassay
    – most widely used diagnostic test for HBV
    – detect 100-200 pg of HBsAg per mL
    – equivalent to 3 x 107 viral particles/mL


   HBeAg Immunoassay
      Interpretation of Serological
            Markers for HBV
HBsAg   HBeAg   Anti-HBe   Anti-HBc   Anti-HBc   Anti-HBs       Interpretation
                             IgM        IgG
  +       +        -          -          -          -       Incubation period
  +       +        -          +          +          -       Acute Hepatitis B or
                                                            Persistent carrier state
  +       +        -          -          +          -       Persistent carrier state
  +       -        +                    +          -       Persistent carrier state
  -       -        +                    +          +       Convalescence
  -       -        -          -          +          +       Recovery
  -       -        -          +          -          -       HBV infection without
                                                            detectable HBsAg
  -       -        -          -          +          -       Recovery with loss of
                                                            detectable anti-HBs
                                                            Immunization without
  -       -        -          -          -          +       or recovery from
                                                            infection with loss of
                                                            detectable anti-HBc
            Biochemical Assays
   Evaluate liver inflammation and function
   Do not determine the cause of dysfunction
   Three common liver tests: (function)
    – Serum Bilirubin - 0.2 to 1.2 mg/dL
    – INR
    – Albumin

   Elevated liver enzymes levels reflect level of liver
    damage
    – Alanine Aminotransferase (ALT) - 6-34 IU/L
    – Aspartate Aminotransferase (AST) - 9-34 IU/L
   Levels effected by a number of disorders
         Molecular Diagnostics
   Technologies to detect and quantify levels of
    HBV DNA in sera
    – for monitoring HBV during treatment
   Presence indicates active HBV replication
   HBV DNA is detectable prior to biochemical
    evidence of hepatitis
   HBV DNA persists through both acute and
    chronic disease
   More accurate than HBeAg especially with
    escape mutants
           Molecular Diagnostics

   Amplicor PCR techniques
    – Roche Cobas RT Taqman - 20 - 108 IU/mL

         Note: HBV viremia can be as high as 1012 IU/mL
             Molecular Diagnostics
   Utility and Clinical Application of quant HBV
    DNA
    – when serological markers for HBV are (-)
          post-transfusional HBV infections from HBsAg (-) blood
    – confirmation of acute viremia in patients with
      chronic hepatitis
          HBs-mutants = appear negative by HBsAg serology
    – HBeAg mutants
          anti-HBe (+) and HBeAg (-) but HBV DNA (+)
    – confirmation of infection when antibodies but no
      HBV antigens are present
    Practical Use of HBV DNA Detection
   Screening of Blood Donations
    – HBV DNA appears 3 weeks before HBsAg
   Prognosis of HBV Infection is driven by HBV
    DNA quantification
    – more useful for disease status*
          if <103 IU/mL = ?inactive carrier state
          if >103 IU/mL = clinically significant

   Assessment of Disease Severity & Prognosis
    – active HBV replication = greater risk of
      progression to chronic HBV complications
     *Lok, AS (2001) Gastroenterology; 120: 1828-1853
     Treatment of HBV Infection
   Main objective is to suppress HBV
    replication before there is irreversible liver
    damage

   Viral Eradication
    – Not possible (difficult) due to cccDNA and
      extrahepatic reservoirs
    – not be necessary to prevent (decrease)
      progression to cirrhosis and HCC
                   Evolution of CHB guidelines with
                   introduction of new information
                                                                                                                                             • Asian-
                                                                                                                                               Pacific
                                     • EASL                              • Asian-Pacific            • Asian-             • AASLD               update
                                     • Asia-Pacific                        update                     Pacific            • HBV               • Dutch
                                       Consensus                                                      alert                Roadmap           • Egyptian
                                                                                                    • HBV                • Belgian           • Italian
 • NIH                                                     • HBV                                      algorithm          • German            • Polish
   workshop                                                  algorithm                                update             • Swedish             EASL
 • AASLD                                                   • AASLD                                                       • Turkish


   2001                 2002                 2003                2004                2005                   2006                2007          2008
                        ADV                                                          ETV                    LdT
                                                                                    PegIFN
                                                                                                                  Revised (lower) definitions
  Treatment threshold              Development of more sensitive
                                                                                                                  of normal ALT (men: 30 U/l;
    set at HBV DNA               PCR-based assays (eg Taqman assay)1
                                                                                                                       women: 19 U/l)5,6
     >20,000 IU/ml1
                                              Liver disease & increased                         HBV DNA indicator
     Publication of guidelines               mortality linked with normal/                     of long-term outcome
     Drug launched
                                                                                                                                    NIH AASLD MEETING WASH
                                               slightly elevated ALT2,3                           (cirrhosis/HCC)4                            DC
     Advances in HBV management
                                                                                                                                            PENDING
1. Weiss J, et al. J Clin Virol. 2004;30:86-93; 2. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-62; 3. Kim HC, et al.
Br Med J. 2004;328:983; 4. ACT-HBV Asia-Pacific Steering Committee Members. Liver Int. 2006;26:47-58; 5. Liaw Y-F, Suh
DJ, Omata M. Available at: www.apasl.info/guidelinesHBV.html; 6. Cornberg M, et al. Z Gastroenterol. 2007;45:1281-328
      CPMC Roadmap to manage or prevent
      resistance in Treatment-Naive Patients
Available treatment   LAM     ADV         TDF         ETV        Telbivudine
      options


  Response and           Measure HBV DNA with sensitive assays;
   Resistance           monitor virologic changes every 3-6 months;
   Monitoring           monitor for breakthrough, and compliance etc


                                                       “Suboptimal
                                                        response”:
                                                        4-12w Lam
                       No resistance                      6m: LdT
                         identified                     1 year ADF
                         with viral     Resistance     3+years ETV/
     Outcome                                               ?TDF
                        negativity       identified



    Therapeutic        Continue with   Swtich/Add
                                                        add second
                         planned        second
       Plan                                             medication
                        medication     medication
       Treatment of HBV Infection
   PEG Interferon Alpha (5-10 MU, SQ for 16-32 weeks)
    – first evaluated in the 1970’s for HBV treatment
    – only 14-17% of patients respond to IFN
    – administered to patients who are HBV DNA (<108),
      HBeAg (+/-) with elevated liver enzymes over 90 IU/mL
    – loss of HBsAg, an indication of HBV eradication, only
      occurs in 10-20% of patients and may take >4 years
    – multiple side effects
    – can exacerbate advanced liver disease
      Treatment of HBV Infection
   Lamivudine (100mg orally for 48 weeks or longer)
    – 3rd line therapy
    – nucleoside analog
    – inhibits HBV DNA synthesis
    – effective in patients that failed IFN treatment
    – does not exacerbate advanced liver disease
    – well-tolerated
    – relapse common with cessation of treatment
    – limited by drug resistant HBV mutants
     End-Points of Treatment
   Seroconversion HBeAg+ > (-)
   Undetectable serum HBV DNA
    – usually accompanied by remission of liver
      disease
    – HBV DNA may still be detectable in
      sustained responders
   Undetectable HBsAg
    – considered a cure
      Role of HBV DNA Assays in
      Treatment of HBV Infection*
   Decision to treat
    – no precise clinically relevant HBV DNA levels are
      known
    – require trials
   Selection of Optimal Therapy

   Treatment Monitoring
   Assessment of HBV resistance

    Pawlotsky, JM(2002) Gastroenterology 122:1554-1568
            HBV Resistance
   Require:
    – new antiviral strategies
    – genotyping assays
    – highly sensitive viral quantitation assays
   for optimal monitoring of antiviral therapy
    of chronic HBV
 Significant Progression in Liver Disease
    Can Occur in Less Than One Year
                     40%
                                                                 36.0%


                     30%

  % of Patients on
   Placebo with
                                  21.0%
   Worsening of      20%
   Fibrosis at 48
      Weeks*


                     10%



                     0%
                                 HBeAg +                       HBeAg -
                                  n=338                         n=184
* Defined as > 1 point improvement or worsening in Ishak Fibrosis Score
                             Long Term Beneficial Effect of INF in Chronic HBV
Cumulative Incidence (%)   100                                                          Treated Group



                            75                                                     P = 0.018


                                                                             Control Group
                           50



                            25
                                                                             Control Group
                                                                  P = 0.013
                                                                                     Treated Group
                             0
                                 0   2     4        6      8           10            12
                                            Year of Follow-up
                                                                Lin et al et al; Hepatology 1999 Vol 29, No.3,
    Univariate Analysis of Factors Affecting HBV Virologic
                           Response
                                   Responders       Non-Responders               P
                                     (n=58)             (n=58)
Pretreatment ALT (> 4 x ULN, %)*      57%                  27%                .001
HBV DNA < 100/>100 pg/mL              50%/22%              50%/78%            .001
Flare**
          No flare                    19(22%)              66(78%)
          Mild flare                  9 (37%)              16 (65%)           NS
          Moderarte flare             16 (55%)             13 (45%)           .002
          Severe flare                14 (58%)             10 (42%)           .002
Treatment
        Untreated control             10 (24%)             32
          Low dose                    11 (27%)             30                 NS
          High dose                   18 (47%)             20                 .03
          Prednisone                  19 (46%)             23                 .05

                                       Nair et al, Hepatology, Vol 34, No.5, 2001;1021-1026
              Chronic HBV:
    Effects of Interferon on Cirrhosis
                        Annual      Exacerbation
                 No.   incidence   ALT*>1000U/L    Bil*>2mg/dl    PT*>3’        Ref.

YMDD mutants      32      27%           23%            30%         23%          25
Natural course
HBeAg(+)         358      27%           27%              3%          3%         29
HBeAg(-)         279      11%           27%              0%          0%




                                         Sobesky R, et al, Gasteroenterology,
                                         1999; 116-378
                             Chronic HBV:
            Comparison Between Patients with or without a Flare
                           During Treatment
                                    Flare( n = 78)   No Flare( n = 85)               P
Pretreatment ALT IU/L (range)        145 (60-544)        136 (54-605)               NS

Pretreatment ALT (< 4 x ULN)         44%                 32%                        NS

Pretreatment HBV DNA pg/mL
(range)                              101 (2.3-777)       101 (47-532)               NS

Sustained Loss of HBV DNA (%)        50                  22                         .0001

Loss of HBeAg/HBV DNA (%)            40                  15                         .001

Loss of HBSAg/ (%)                   10                  2                          .049

Treatment
 Untreated control (n =42)           11 (26%)            31 (74%)
 Low dose (n =41)                    15 (49%)            26 (51%)                   .04
 High dose (n =38)                   14 (45%)            24 (55%)                   NS
 Prednisone + interferon (n = 42)    25 (71`%)           17 (29`%)                  .0001
                                            Nair et al, Hepatology, Vol 34, No.5, 2001;1021-1026
Disease Known to be Transmitted via Blood or Blood
    Components Include, but are not Limited to,
                  the Following:
                           Estimated Risk
       Hepatitis B Virus     1:137,000
       Hepatitis C Virus     1:237,000-1:1,000,000
       HIV                   1:1,326,300-1:1,930,000
       HTLV                  1:641,000
       Malaria               < 1:1 million
       Babesiosis            < 1:1 million
       Long-term FU after INF therapy for HBV
The Demographic Data of the IFN--Treated Group and the Control Group
                                                    IFN--Treated                     Control
                                                       Group                           Group
Number of patients                                           208                               203
Male-Female                                                  148:60*                   116:87*
Median age in years (range)                                27 (1-46)              28 (0.5-44)
Medium ALT (IU/L)(range)                               46 (4-1,020)             38 (5-1,240)
Number of Patients with ALT                                           75                         56
Medium follow-up in months(range) 107 94-191)                                    108 (3-221)
             Note: ALT, elevated pretreatment ALT (more than 1.5 times upper limit of normal)

* P = .004                                                  Yuen, et al, Hepatology. July. 2001, pg.140

								
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