hepatitis%20-%20viral%20(pediatric)
HEPATITIS - VIRAL (PEDIATRIC)
The majority of acute viral hepatitis infections are asymptomatic or they can cause an anicteric illness that may not be diagnosed as hepatitis.
Hepatitis A generally causes minor illness in childhood with >80% of infections being asymptomatic. Jaundice and intestinal symptoms usually resolve 2-3 weeks after onset. A patient is infectious 1-2 weeks prior to the clinical illness.
Hepatitis B, C, & D may be symptomatic depending on the mode and time of transmission.
Hepatitis A is predominantly transmitted through oral-fecal by person-person direct transmission and contaminated material or food.
Hepatitis B is transmitted perinatal, horizontal spread, percutaneous, sexual, close person-to-person contact.
Majority of hepatitis C infections are identified in children with repeated exposure to blood products.
Hepatitis D is route of transmission is through sexual, percutaneous especially IV drug use.
Hepatitis E is transmitted primarily through contaminated drinking water and oral-fecal transmission.

Principles of Therapy

Hepatitis B

  • Children at high risk for disease progression or HCC development should be identified early so that therapy can be started, reducing the risk for antiviral resistance 
  • Initiate treatment in patients with chronic hepatitis B with evidence of fibrosis or alanine aminotransferase (ALT) ≥30 IU/L for boys & ≥19 IU/L for girls obtained from 2 consecutive tests conducted 3 months apart

Hepatitis C

  • Antiviral therapy should be given to HCV-infected patients aged 3-17 years
  • The benefits of treatment need to be weighed against the risk of side effects for children who have mild or no liver disease & are asymptomatic
  • Treatment should start between 3 & 6 months of diagnosis, if the infection has not resolved spontaneously

Consequences of HCV Infection

  • More likely to resolve spontaneously in children
  • Slower rate of progression to end-stage liver disease
  • 50% of cases of HCV infection becomes chronic
    • 70% of transfusion acquired infections persist for >6 months
  • 5-20% of these patients may develop cirrhosis over the next 20-25 years
    • HCV-related cirrhosis is associated with risk of developing end-stage liver disease (30% risk over 10 years) as well as hepatocellular carcinoma (HCC)
  • HCV-infected children should be monitored to determine the minority who are at risk of progressive fibrosis during childhood & who may be candidates for treatment
  • In patients with persistent infection, the evolution to cirrhosis is the primary concern
    • Usually occurs ≥20 years after initial infection & occurs more often in patients at older ages (especially in men), those who drink >50 g of alcohol/day, those who are obese or have substantial hepatic steatosis & in those with HIV infection

Hepatitis B

Patients For Whom Treatment is Not Recommended

  • Negative HBeAg, positive anti-HBe, HBV DNA <105 copies/mL, normal ALT (inactive HBV infection)
  • Positive HBeAg, HBV DNA >105 copies/mL & normal ALT

Patients For Whom Treatment is Recommended

  • Positive HBeAg, HBV DNA >105 copies/mL, persistent or intermittent elevations of ALT
  • Negative HBeAg, HBV DNA >104 copies/mL, elevated ALT

Goals of Treatment

  • Continued viral suppression is necessary to reduce or prevent hepatic disease & disease progression
  • Primary goal of treatment is to permanently suppress HBV or to eliminate it
    • Short-term goal is the sustained suppression of HBV DNA, ALT normalization, to prevent decompensation & to decrease hepatic necroinflammation & fibrosis during & after therapy
    • Long-term goal of therapy is to avoid hepatic decompensation, reduce or prevent progression to cirrhosis &/or HCC & to prolong survival
  • Endpoints used to assess response:
    • Biological response: Normalization of serum ALT
    • Virological response: Undetectable HBV DNA, loss of HBeAg in those initially HBeAg positive
    • Histological response: Decrease in histology activity compared to pretreatment liver biopsy
    • Complete response: Fulfill criteria of biochemical & virological response & loss of HBsAg
    • Anti-HBs positive on 2 consecutive annual tests
  • Current treatments of chronic hepatitis B have limited long-term efficacy

Considerations Prior to Initiation of Treatment

  • Age of patient
  • Severity of liver disease
  • Likelihood of response
  • Potential adverse events & complications
  • HBeAg positive chronic HBV patients with elevated ALT levels & compensated liver disease should be observed for 3-6 months for spontaneous seroconversion from HBeAg to anti-HBe prior to initiation of treatment; initiation of therapy may be delayed
  • Choice of therapy will depend on availability, cost of medication, necessary number of clinic visits, expected duration of treatment & patient/parent/guardian clinician preference
  • Different genotypes may have different prognoses but currently do not imply difference in therapeutic management compared to hepatitis C

Other Considerations

  • In children with high viremia, delay the treatment until viremia decreases
  • Consider Interferon alfa in case of cirrhosis due to chronic HBV in children with Child-Turcotte-Pugh class A & persistent HBe antigenemia
  • Contraindicated in patients with decompensated cirrhosis, coexisting autoimmune diseases & in children with organ transplant, renal or cardiac failure, neurological diseases & severe function disturbances
  • Not recommended for patients with compensated cirrhosis because of risk of hepatic decompensation
  • Prednisone priming prior to Interferon alfa therapy is not recommended
  • Discontinue treatment when HBV DNA levels reach <2 log10 IU/ml &/or HBsAg >20,000 IU/ml
  • Monitor HBV DNA levels, quantitative HBsAg, HBeAg levels at 12, 24, & 48 weeks after initiation of therapy, & every 6 months thereafter
    Test for HBV DNA every 12 weeks in HBeAg-negative patients on Lamivudine treatment for ≥5 years

Hepatitis C

  • Peginterferon/Ribavirin combination therapy with either Telaprevir or Boceprevir is the treatment of choice for chronic hepatitis C genotype 1
  • Peginterferon alfa/Ribavirin combination therapy is the treatment of choice for chronic hepatitis C genotype 2, 3, 4, 5 & 6
  • Assess liver disease severity prior to therapy

Goals of Treatment

  • Prevent complications of HCV infection by eradication of the infection
  • Treatment responses are usually characterized by HCV RNA testing (<15 IU/ml at 12 & 24 weeks post-treatment
  • Eradication of infection is considered when there is sustained virologic response (SVR)
    • SVR is defined as the absence of HCV RNA in serum by a sensitive test at the end of treatment & 6 months later
  • Early virologic response is defined as 2-log drop or loss of HCV RNA 12 weeks into therapy
  • End of treatment response is defined as continued absence of detectable virus at end of treatment
  • Relapse is considered when HCV RNA becomes undetectable on treatment but is detected after discontinuation of therapy
  • Patients in whom HCV RNA levels remain stable while on treatment are considered non-responders while those HCV RNA levels decline but never become undetectable are referred to as partial responders

Individualize treatment based on the following:

  • Severity of liver disease
  • Potential of serious side effects
  • Likelihood of treatment response
  • Presence of comorbid conditions

Pharmacotherapy

Hepatitis B
Interferon alfa

  • Interferons have antiviral, antiproliferative & immunomodulatory effects
  • Therapy of choice for pediatric patients >1 year old with chronic hepatitis B & compensated liver disease
  • May be a preferred agent, in the treatment of HBeAg negative chronic hepatitis B & may be used as initial therapy for HBeAg positive chronic hepatitis with elevated alanine aminotransferase (ALT)
  • Action: Suppresses hepatitis B virus (HBV) replication & induces remission of liver disease
  • Effects:
    • Efficacy is similar for adults & children
    • Relapse is a major problem in HBeAg negative chronic hepatitis B
    • Accelerates HBV DNA clearance & HBeAg/anti-HBe conversion
  • Consensus guidelines on optimal selection for Interferon alfa treatment:
    • HBeAg & HBV DNA positive
    • Age >3 years
    • Elevated ALT levels (at least 2x the normal or higher)
    • Intermediate & low levels of HBV DNA in serum (<1000 pg/mL)
  • For HBeAg positive chronic hepatitis B, important predictors of response to therapy are high pretreatment ALT & lower levels of serum HBV DNA
  • Obtain baseline complete blood count (CBC), liver function tests (LFTs) [bilirubin, albumin, ALT], renal function tests (urea, electrolytes), thyroid function test, weight, height, prior to & during therapy
  • Finite duration of therapy associated with Interferon alfa related flares of hepatitis
  • Side effects include mood swings & depression; patient’s mental health should be closely monitored by the clinician
  • Peginterferon, the pegylated form of Interferon, is currently being studied for the treatment of chronic hepatitis B infection in children

Nucleoside/Nucleotide Analogues

  • Eg Adefovir, Entecavir, Lamivudine, Tenofovir
  • Given to HBV DNA-positive pediatric patients unresponsive to Interferon alfa-48 weeks treatment course
  • Obtain baseline CBC, LFTs, renal function tests (with urine protein/creatinine ratio), blood clotting, HBV DNA & HBeAg levels in patients with compensated liver disease prior to & weekly after initiation of Lamivudine or Entecavir therapy
    • Add phosphate level measurement in patients with compensated liver disease who are to be given Tenofovir
  • Adefovir
    • Alternative treatment for HBeAg-positive children >12 years of age with persistently elevated LFTs
    • Studies showed that seroconversion can be achieved after a few years of continuous Adefovir therapy
    • Action: Inhibits DNA synthesis through competitive reverse transcriptase inhibition & viral DNA incorporation
  • Entecavir
    • Treatment option for HBeAg-positive HBV patients >16 year of age with compensated liver disease intolerant or unresponsive to treatment with Interferon alfa or Tenofovir
      • May also be given if HBV DNA is still detectable despite a 96-weeks treatment with Tenofovir & Lamivudine
      • Alternative treatment to Tenofovir in HBeAg-negative HBV patients with compensated liver disease & with detectable HBV DNA even at 48 weeks treatment duration
    • Alternative treatment for HBsAg-negative HBV patients with compensated liver disease previously given Interferon alfa with HBV <2 log IU/ml & HBsAg remains the same
    • Consider in HBV patients with possible HCV coinfection & without history of Lamivudine resistance
  • Lamivudine
    • May be used as initial therapy for HBeAg positive chronic hepatitis with elevated ALT
    • Recommended in viremic patients (HBeAg positive & HBeAg negative patients) aged >2-3 years with ALT >5x ULN especially if there is concern regarding decompensation
    • Good safety profile & ease of administration are its advantages over Interferon alfa
    • Action: Premature termination of viral DNA chain termination thereby inhibiting HBV DNA synthesis
      • Induces histologic improvement & reduction in rate of development of hepatic fibrosis
    • Effects:
      • Pretreatment ALT & active histological disease are the most important predictors of response
      • Response is greatest in patients with an ALT twice the normal value
      • Treatment may be discontinued in patients who have completed 1 year of treatment & have persistent HBeAg seroconversion to anti-HBe
      • Treatment may be continued in patients who have not achieved HBeAg seroconversion & have no evidence of breakthrough infection, because HBeAg seroconversion may occur with continued treatment
    • Lamivudine-resistant HBV
      • Emergence of Lamivudine-resistant HBV is increasingly common with prolonged treatment, together with a decreasing rate of remission
      • Associated with development of Lamivudine-resistant YMDD viral mutants, which appear to be less virulent than wild-type HBV, but have been associated with rapidly progressive liver disease in some patients
      • Lamivudine resistance is usually manifested as breakthrough infection, with reappearance of HBV DNA in serum
      • Factors that may correlate with the emergence of Lamivudine resistance: High pre-treatment HBV DNA levels, high pre-treatment ALT levels, male gender, high body mass index (BMI)
  • Tenofovir
    • Drug of choice for HBeAg-positive HBV patients unresponsive or intolerant to Interferon alfa treatment
    • Alternative treatment for HBsAg-negative HBV patients with compensated liver disease previously given Interferon alfa with HBV <2 log IU/ml & HBsAg remains the same
    • Lamivudine may be added if HBV DNA is still detectable at 96 weeks of treatment
    • Test for HBV DNA, quantitative HBsAg & HBeAg levels prior to, at 12, 24, & 48 weeks during, & every 6 months after initiation of treatment
    • May help evaluate patient’s response & adherence to Tenofovir

Hepatitis C
Boceprevir

  • Addition to Interferon alfa/Ribavirin combination yields higher sustained virological response (SVR) rates
  • Recommended triple therapy regimen for the following:
    • Patients with detectable HCV RNA at weeks 8 & 24: stop treatment at 28 weeks
    • Patients with detectable HCV RNA within 8-24 weeks of therapy: stop Boceprevir at week 36 of treatment, then continue Interferon alfa & Ribavirin regimen up to 48 weeks

Interferon alfa with or without Ribavirin

  • The use of Interferon alfa-2b combined with Ribavirin may be considered in patients with HCV infection

Peginterferon alfa-2a with Ribavirin

  • Treatment of choice for treatment-naive chronic HCV patients aged 3-17 years with genotype 2 or 3, & genotype 1 & 4 & high viral load

Ribavirin

  • Assess HCV genotype prior to initiation of treatment

Telaprevir

  • Added to Interferon alfa/Ribavirin regimen for patients with undetectable HCV RNA at week 4 & 12 of therapy

Hepatitis D

  • Interferon alfa may have a role
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