Viral Hepatitis

    .

    Source: MKSAP 16

     

     

     

     

    Introduction

     

     

     

    Hepatitis Liver Failure Chronic? Diagnosis Vaccine? Treatment Complications

    Hepatitis A

    - non-enveloped

     ssRNA

    RARE

    NO Anti-HCV IgM YES

    PEP: HAV vaccine or IVIG

    Self-limited illness.

     

    Hepatitis B

     

    COMMON YES

    Complex

    Serology

    YES

    PEP (newborns): 

      HBV vaccine + HBV Ig

    Supportive

    Antivirals for chronic

      active HBV or SEVERE acute

    - MPGN

    - Polyarteritis Nodosa

    - HCC (if cirrhosis or perinatal)

    Hepatitis C COMMON Yes (80%) Anti-HCV Ab NO

    GT 1: PegInterferon + Ribavirin

       + Boceprevir OR telaprevir 

    GT 2 or 3: PegInterferon +

          Ribavirin

    (Significant S/E of Tx)

    - Mixed cryoglobinemia

    - MPGN

    Hepatitis D

    (Requires HBV

    to replicate)

        Anti-HDV IgM

    NO

    (Vaccinate

    for HBV)

    - Treat HBV

      HDV will resolve

     

    Hepatitis E

    RARE NO

    Anti-HEV IgM

    (Reference Labs)

    NO

    - Supportive.

    - Hand hygeine to prevent tsm.

     

    Hepatitis A

    • Virus:
      • Non-enveloped ssRNA virus.
      • Infected patients are contageous during incubation period and x1week after onset of jaundice.
      • Transmission: Fecal-Oral (handwashing is crutial!!)
      • Vaccine available! - Vaccinate patients with risk factors.
    • Risk Factors:
      • Travel to endemic areas
      • Men-Sex-With-Men (MSM)
    • Symptoms:
      • 2-6w post-exposure: malaise, fatigue, nausea, RUQ pain  (more severe in adults, can be silent in children)
      • 1-2w after symtoms: Jaundice and cholestasis
      • 3mo: Clinical recovery
    • Clinical Course:
      • Overt liver failure is RARE.
      • Chronic hepatitis does not occur.
    • Diagnosis
      • Serum Anti-HAV IgM antibodies
    • Management:
      • Self-limited, rarely causes liver failure.
      • Prompt vaccination of patients exposed to HAV can prevent acute infection.
      • If vaccine unreliable (Immunocompromised), give IVIG for post-exposure prophylaxis.

     

    Hepatitis B

    • For more information: PHAC HepB Management Guidelines
    • Virus:
      • 350 million worldwide and 1.25m in US carry HepB.
      • Can cause acute and chronic hepatitis.
      • Transmission:  (Blood)
        • Blood (needles, transfusions, etc..)
        • Mucocutaneous [sexual]
        • Perinatal exposure
    • Symptoms:
      • Similar to HepA --> malaise, fatigue, nauea, RUQ pain
      • Incubation: 4-16w
    • Diagnosis:
      • Many tests including HBV antigens and direct DNA assays.
      • Principles:
        • Surface Antigen --> exposure to surface antigen happens via vaccine or natural infection. 
        • Core Antigen --> exposure to core antigen happens via natural infection (NOT vaccine).
        • HBe Antigen --> 
        • Test Meaning
          HBsAg (HB Sufrace Antigen) Presence of HB particles
          HBsAb (HB Surface Antibody) Immunity to surface antibody (artificially or naturally immunized)
          HBc IgM (HB Core IgM) Naturally immunized (Core) and NEW! (IgM)
          HBc IgG (HB Core IgG) Naturally Immunized (Core) and OLD! (IgG)
          HBeAg (HBE Antigen)

          Secreted by infected liver cells, marker of high viral levels and 

          infectivity (high!)

          HBeAb (HBE Antibody)

          Produced in response to previous HBeAg, positive in patients

          who "recovered" from active disease.

     

    • Interpretation of Hepatitis B Virus Serologic Studies

      Condition

      HBsAg

      HBsAb

      HBc IgM

      HBc IgG

      HBeAg

      HBeAb

      HBV DNA

      AST, ALT

      Acute HBV

      +

      +

      +

      +

      ↑↑

      Chronic active HBV

      +

      +

      + or –

      + or –

      High

      Inactive HBV carrier

      +

      +

      + or –

      Low

      Normal

      Immune-tolerant HBV

      +

      +

      + or –

      + or –

      High

      Normal

      Resolved HBV

      +

      +

      +

      Normal

      Previously immunized

      +

      Normal

      ALT = alanine aminotransferase; AST = aspartate aminotransferase; HBc IgG = IgG antibody to hepatitis B core antigen; HBc IgM = IgM antibody to hepatitis B core antigen; HBeAb = antibody to hepatitis B e antigen; HBeAg = hepatitis B e antigen; HBsAb = antibody to hepatitis B surface antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus.


       
    • Types of infection:
      • Exposure as adult = usually acute infection + resolution.
      • Exposure during childhood = usually chronic infection.
      • Exposure perinatally = immunetolerant --> high levels of HBV DNA, but no hepatitis.
        • High risk of conversion to active.
      • Inactive Carriers  = Lowlevels of HBV DNA, and low risk of hepatitis (no need to start treatment)
      • Immunetolerant + Inactive Carriers = Maintain risk of reactivation, must monitor for active hepatitis.
    • Management:
      • APPROACH: (information you need to decide treatment)
        • 1. ALT level (remember normal values)
        • 2. HBV DNA
        • 3. E-Antigen Status
        • 4. Cirrhosis
      •  
      • Reduce progression and reduce complications (Hepatocellular carcinoma).
      • Infection Management
        Acute HBV

        - Supportive care, usually self-limited.

        - Antivirals ONLY for those with liver failure.

        - May require transplant if fulminant hepatic failure

        Chronic Active HBV

        (Elevated liver enzymes

        OR

        Inflammation on liver Bx)

        - Antivirals indicated!

         (Clinical outcomes improve with viral suppression)

        • Target: HBsAg clearance or viral suppression.  
          (HBeAg seroconversion or HBsAg if HBeAg negative to start)
        Immune-Tolerant HBV

        - Do not benefit from antivirals

        - Screen periodically for active conversion.

        Inactive Carriers - Do not benefit from antivirals
        • Counsel on lifestyle factors to prevent spread of HBV
          • Vertical transmission can be minimized by prompt vaccniation and HBV Ig to newborns immediately after delivery.

     

    Medicat ions:

    • Note potency and resistance.

    • Goal is to convert HBsAg to negative!

      • More common goal is to suppress the virus (may not be entirely cleared).

    • Inactive carriers and immunetolerant pts do not benefit from antiviral therapy.

    Medical Therapy for Hepatitis B Virus Infection

     

    Medication

    Duration of Therapy

    Expense

    Potency

    Resistance

    Peginterferon

    (Most expensive)

    1 year

    - Considered with elevated enzymes >2x ULN and low HBV DNA lvls.

    - If no elevated liver enzymes, and high HBV DNA = unlikely to respond.

    ↑↑↑

     

    None

    Lamivudine

    6 months after HBeAg seroconversion, or loss of HBsAg if HBeAg negative to start

    High

    High

    Telbivudine

    6 months after HBeAg seroconversion, or loss of HBsAg if HBeAg negative to start

    ↑↑

    High

    High

    Adefovir

    6 months after HBeAg seroconversion, or loss of HBsAg if HBeAg negative to start

    ↑↑

    Moderate

    Moderate

    Tenofovir

    (Common)

    6 months after HBeAg seroconversion, or loss of HBsAg if HBeAg negative to start

    ↑↑

    High

    Low

    Entecavir

    (Common)

    6 months after HBeAg seroconversion, or loss of HBsAg if HBeAg negative to start

    ↑↑

    High

    Low

    HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen.

    • Targets of Treatment:
      • If HBE positive --> treat to negative
      • If HBE negative ---> treat until clear surface antigen. (surface ab positive)
    • Types of treatment:
      • Interferon: more side effects, but finite treatment duration and more seroconversion
      • Direct acting anti-virals: Low side effects, lower seroconversion rate, so will need 
    • Pregnancy:
      • If E antigen positive and HBV DNA > 200,000 IU/mL --> antivirals to decrease transmission around birth.
        • Use Tenofovir (also lamivudine, and telbivudine)
        • Baby also needs post-exposure prophylaxis (vaccination after birth)
      • Breastfeeding is OK on antivirals
      • C-section is not necessary. 

     

     

    • Complications
      • Mediated by circulating immune complexes:
        • Polyarteritis nodosa
        • Renal failure (Membranous Glomerulonephritis)
      • Risk of Hepatocellular Carcinoma:

        • HBV-related cirrhosis
          AND
        • Perinatal acquisition of HBV
    • Vaccine
      • Given as 3 doses (1st and 2nd 4w apart, and 3rd is 5mo later)
      • If 2nd dose is missed, give it as soon as remember, and 3rd dose 2 months later.
      • If 3rd dose is missed, just give the 3rd dose.
      • If Immunity not attached, repeat the series
      • (From "The Little ICU Book" by Paul Marino)

    Hepatitis C

    • Virus
      • 4-5million ppl in US.
      • Risk Factors:
        • Percutaneous exposure
        • IVDU
        • Blood transfusion prior to 1992
      • Most acute HCV are asymptomatic.
      • Chronic infection develops in 85% of pts with Anti-HCV ab.
      • Can result in cirrhosis after 30y of infection in 25% of chronic infections.
    • All patients with chronically elevated aminotransferases or with risk factors (above) need screening.
    • Risk factors for progression to cirrhosis:
      • Males
      • Obesity
      • EtOH
      • Daily marijuana use (perhaps surrogate for other exposures).
    • Symptoms:
      • Chronic: Fatigue, arthralgia, and mild RUQ abdo discomfort.
    • Diagnosis:
      • Anti-HCV antibodies (high positive predictive value if risk factors and elevated transaminases
      • The recombinant immunoblot assay (RIBA) or HCV RNA by PCR confirms HCV infection.
      • Liver biopsy not necessary, but helpful if deciding therapy (minimal fibrosis = can observe)
      • Approach to a patient with HepC:
        • Bloodwork: Exclude other causes of cirrhosis (workup everything: ceruloplasmin, A1AT, AMA, ANA, etc..)
        • Liver function/enzymes
        • HepC genotype & viral load
        • FibroScan (or bloodwork FibroTest)  [Biopsies are no longer done for this]
        • Deciding Treatment:
          • In Ontario: treatment is only covered for Stage 2 or more fibrosis.  Otherwise treatment costs $60,000-80,000
          • Generally patients with low-stage disease can be followed.
          • 20% progress in 20 years, so patients may live lifetime without progression.

     

    • Treatment:
      • If minimal fibrosis on biopsy -> can observe. (discuss risks of therapy)
      • If fibrosis present --> treat!
      • Peg Interferon and Ribavirin are gold standard.
      • NS3/4A recently developed against HCV Genotype 1 (hardest to treat), combined with PegInt and Ribavirin.
        • Boceprevir OR telaprevir 
        • Combine with Peg Interferon and Ribavirin for Genotype I (80% success).
      • Side Effects are are significant, weigh risks/benefits.
        • Drug   Side Effects
          Peg Interferon
          • Influenza-like symptoms, fatigue
          • Psychiatric (worsens depression/insomnia/irritability)
          • Cytopenias (any/all cell lines), 
          • autoimmune thyroiditis
          Ribavirin
          • Hyperuricemia
          • Rash
          • Hemolytic anemia
          • Teratogenic

          NS 3/4A Protease 

          Inhibitors

          Boceprevir

          Telaprevir

          • Rash
          • Anemia
      • Contraindications to Peg-Interferon + Ribavirin:

              1.  Decompensated liver disease

              2.  Severe psychiatric disease (candidate if well treated)

              3.  Severe pre-existing cytopenias

              4.  Pregnancy

      • Goal of therapy: Obtain a complete sustained virological response (SVR)
        • SVR defined by: Undetectable HCV viral level by PCR 6 months after completion of antivirals.
      • Responses to Peg-Int and Ribavirin different:
        • Genotype 1: Peg-Int + Ribavirin + NS 3/4A --> (80% SVR, 20-40% without NS3/4A)
        • Genotype2 and 3: Peg-Int + Ribavirin alone --> >80% SVR
      • Monitor viral load
        • To check response to treatment.
        • If undetectable:
          • in 4w --> rapid virologic response (Good)
          • in 12w --> early virologic response (Good)
          • If not decreased by 2-log at 12w --> considered failure --> treatment stopped.
    • Complications:

     

    • Mixed cryoglobulinemia
    • Membranoproliferative GN
    • Porphyria cutanea tarda
    • Non-Hoghkin's Lymphoma

     

    HepC + HIV Coinfection

    • Similar risk factors.
    • All patients with HIV should be checked for HCV.
    • Progress to cirrhosis faster than HCV alone.
    • Treatment can be offered at earlier stages of fibrosis.
    • Rates of SVR are lower than HCV by itself.
    • If CD4 < 500 => should treat ART prior to HCV treatment. --> better treatment outcomes after raising CD4.

     

     

    Hepatitis D

    • Incomplete virus.
    • Requires presence of HBV to replicate.
    • Co-infection or superinfection (if already has HBV) causes severe acute hepatitis.
    • Diagnosis:
      • Anti-HDV antibodies in serum.
    • Co-infection HDV vs. HBV does not have clinical differences than HBV alone.
    • Resolution of HBV will resolve HDV as well.

     

    Hepatitis E

    • Similar to Hepatitis A.
    • Transmitted enterically
    • Causes acute hepatitis, but not chronic liver disease.
    • High incidence in:
      • Asia
      • Africa
      • Central-America
    • Fulminant HEV is RARE.
    • Incubation: 2w-2mo.
    • Mortality: LOW, but pregnant women in 3rd trimester has 25% risk of death.
    • Diagnosis:
      • Anti-HEV Antibodies, but not commercially available (must send to reference labs).
    • Treatment:
      • No prophylaxis (no vaccines or PEP).
      • Good hand hygeine, avoid contaminated substances (drinking water, poorly cooked food in edemic areas)
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