Treatment Guideline Chart

Hepatitis B is transmitted through perinatal, percutaneous, sexual, and close person-to-person contact, ie by open cuts and sores.

Human hepatitis B virus belongs to the family of Hepadnaviridae of small, enveloped, primarily hepatotropic DNA viruses. The virus replicates in the host and assembles exclusively in the hepatocytes and virions are released non-cytopathically through the cellular secretory pathway.

Chronic hepatitis B is defined as a chronic necroinflammatory liver disease due to persistent hepatitis B virus infection.

Hepatitis D infection is found only in patients with hepatitis B as it requires the hepatitis B outer coat. It is transmitted through sexual and percutaneous (especially IV drug use) routes.

Hepatitis B and D both have an incubation period of 30-180 days.

Hepatitis%20b Treatment

Hepatitis B - Pharmacological Therapy

Severe Acute Hepatitis B

  • Characterized by coagulopathy, persistent jaundice for >4 weeks or signs of acute hepatic failure
  • >95% of immunocompetent individuals with symptomatic acute hepatitis B would recover spontaneously without antiviral therapy 
  • Antiviral therapy is given only to patients with acute liver failure or with a protracted severe course, ie total bilirubin >3 mg/dL, INR >1.5, presence of ascites or encephalopathy
  • Entecavir, Tenofovir alafenamide or Tenofovir disoproxil fumarate may be used
    • Peginterferon is contraindicated
  • Observational data have shown that early nucleos(t)ide analogue treatment can reduce rates of chronicity if treatment is initiated within 8 weeks of acute hepatitis B
  • Continue treatment until HBsAg is cleared or indefinitely if to undergo liver transplantation

Chronic Hepatitis B

Preferred Agents


  • Considered first-line agent for treatment of chronic HBV infection 
  • Approved for treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in ALT or AST or histologically active disease
  • Use is based on histologic, virologic, biochemical and serologic responses after 1 year of treatment in nucleoside-treatment-naive and Lamivudine-resistant adult patients with HBeAg-positive or HBeAg-negative chronic HBV infection with compensated liver disease
  • Appears to be superior to Lamivudine based on histologic improvement, reduction in viral load and ALT normalization
  • Effective in the treatment of Adefovir and Tenofovir resistance
  • Inhibits the following HBV polymerase activities: Base priming, reverse transcription of the negative strand from the pregenomic messenger RNA, and synthesis of the positive strand of HBV DNA

Other Considerations

  • Studies in rodents exposed to high doses (ie 3-40x that given to humans) of Entecavir showed increased incidence of lung adenomas, brain gliomas and hepatocellular carcinoma

Tenofovir alafenamide

  • Used as a first-line agent for treatment of immune-active chronic HBV infection in adults with compensated liver disease 
  • It is equally effective as Tenofovir disoproxil fumarate but uses a lower dose, thus less systemic adverse effects 
  • Considered in patients with or at risk of bone disease or renal dysfunction 
  • Approved for use in patients with HIV in combination with Emtricitabine with or without other HIV drugs
  • Clinical trials with follow-up at 2 years reported no resistance with Tenofovir alafenamide therapy
  • Action: A phosphonamidite prodrug of Tenofovir which inhibits HBV replication through incorporation into the viral DNA by HBV reverse transcriptase resulting to DNA chain termination 

Other Considerations

  • Potential significant side effect includes lactic acidosis 
  • Perform HIV testing prior to initiating therapy and monitor lactic acid levels

Tenofovir disoproxil fumarate

  • Used as a first-line agent for treatment of chronic HBV infection and as an alternative agent in patients with suspected or confirmed resistance to Adefovir, Entecavir, Lamivudine and Telbivudine
  • An effective antiviral agent for hepatitis B (chronic HBeAg positive or HBeAg negative) that so far has no resistance detected
  • May be given to pregnant women who require treatment 
    • Preferred antiviral agent in the third trimester which significantly reduces perinatal transmission of HBV
  • Action: A prodrug of Tenofovir, it inhibits HBV polymerase resulting in inhibition of viral replication  

Other Considerations

  • Potential significant side effects include lactic acidosis, nephropathy, Fanconi syndrome and osteomalacia 
  • Perform HIV testing prior to initiating therapy and monitor renal function at baseline, within the first 4 weeks of treatment, after 3 months of treatment, and every 3-6 months thereafter, bone density at baseline and during treatment, and lactic acid levels if with clinical concern

Peginterferon alfa

  • Approved in a number of countries as first-line agent for chronic hepatitis B for both HBeAg-positive and HBeAg-negative chronic hepatitis in adult patients with compensated liver disease, evidence of viral replication and liver inflammation
    • In many countries in Asia, Peginterferon alfa 2b is approved for use in the treatment of chronic hepatitis B
  • Appears to have superior efficacy compared to nucleos(t)ide analogues based on HBeAg seroconversion, HBV DNA suppression and HBsAg seroconversion
    • Longer half-life compared to Interferon alfa and appears to impart a clinical benefit over conventional Interferon alfa
  • Treatment with Peginterferon is more likely to achieve loss of HBeAg and HBsAg in genotypes A and B than in other genotypes 
  • Action: Inert Polyethylene glycol is added to Interferon, decreases the drug’s renal clearance and increases its half life
    • Provides sustained viral suppression with efficacy similar to or better than standard Interferon alfa
  • Finite duration of therapy, no reported resistance

Other Considerations

  • Contraindicated in patients with decompensated cirrhosis, autoimmune disease, uncontrolled epilepsy, severe infection, retinal disease, heart failure, chronic obstructive pulmonary diseases, pregnancy, history of mental illness, and other underlying diseases
  • Side effects include mood swings and depression; patient’s mental health should be closely monitored by the clinician

Other Agents

Adefovir dipivoxil

  • Used as an alternative treatment in patients with HBeAg-positive chronic hepatitis B infection
  • May be a preferred agent for patients with negative HBeAg, HBV DNA >105 copies/mL and elevated ALT
  • Inhibits reverse transcriptase and DNA polymerase activity and is incorporated into HBV DNA causing chain termination; however, it has a low barrier to resistance that can lead to drug resistance
  • Effective as an add-on agent in suppressing Lamivudine-resistant HBV; resulted in HBV DNA suppression of 82-87% and lower risk of Adefovir resistance of 4-8% in 3-4 years
    • 10-mg dose has a more favorable risk-benefit profile compared to 30-mg dose
  • HBeAg-positive chronic hepatitis patients may discontinue therapy after 1 year and confirmed HBeAg seroconversion but durability of response is unknown
    • Therapy may be continued in those who did not achieve HBeAg seroconversion but safety and efficacy have not been established
  • HBeAg-negative chronic hepatitis may need extended treatment (>1 year) to maintain response
    • Further studies are needed to determine optimal duration of therapy

Other Considerations

  • Renal function and bone profile must be monitored every 3 months for patients with predisposition to renal insufficiency and for patients on Adefovir dipivoxil for >1 year


  • Daily dose of 30 mg for 24 weeks has been shown in 2 randomized, double-blind, placebo-controlled studies to be associated with serum HBV DNA levels of <300 copies/mL in the Amplicor PCR assay in 59% of HBeAg-positive patients and in 92% of HBeAg-negative patients
  • Monitor for muscle symptoms and muscle weakness during therapy
  • Discontinued in some countries due to cases of serious myopathy leading to myonecrosis

Interferon alfa

  • Interferons have antiviral, antiproliferative and immunomodulatory effects
  • May be a preferred agent in the treatment of HBeAg-negative chronic hepatitis B and HBeAg-positive chronic hepatitis with elevated ALT
  • Suppresses HBV replication and induces remission of liver disease
  • Efficacy is limited to a small percentage of highly selected patients
    • Relapse is a major problem in HBeAg-negative chronic hepatitis B
  • For HBeAg-positive chronic hepatitis B, important predictors of response to therapy are high pretreatment ALT and lower levels of serum HBV DNA
  • Finite duration of therapy

Other Considerations

  • Prednisone priming prior to Interferon alfa therapy is not recommended
  • Contraindicated in patients with decompensated cirrhosis and coexisting autoimmune diseases
  • Not recommended for patients with compensated cirrhosis because of risk of hepatic decompensation associated with Interferon alfa-related flares of hepatitis
  • Side effects include mood swings and depression; patient’s mental health should be closely monitored by the clinician
  • Pregnancy is discouraged during Interferon therapy
    • If patient becomes pregnant during therapy, Interferon should be replaced with another drug


  • Used for HBeAg-positive chronic hepatitis with elevated ALT but has a high rate of drug resistance during long-term treatment
  • Recommended in viremic patients (HBeAg-positive and HBeAg-negative patients) with ALT >5x upper limit of normal (ULN) especially if there is concern regarding decompensation
  • Good safety profile and 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 and reduction in rate of development of hepatic fibrosis
  • Effects:
    • Pretreatment ALT is the most important predictor of response
    • Response is greatest in patients with an ALT 2-5x the normal value
  • Treatment may be discontinued in patients who have completed 1 year of treatment and have persistent HBeAg seroconversion to anti-HBe and undetectable HBV DNA by PCR assay
  • Treatment may be continued in patients who have not achieved HBeAg seroconversion and have no evidence of breakthrough infection because HBeAg seroconversion may occur with continued treatment

Other Considerations

  • While on therapy, monitor LFTs, HBeAg and anti-HBe every 3 months
  • Test for HBV DNA at 3 and 6 months of therapy and every 3-6 months thereafter

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
  • Benefits of continued treatment must be balanced against the risk of resistant mutants


  • Orally bioavailable with potent and specific anti-HBV activity
  • Clinical trials show that Telbivudine gave more potent HBV suppression than Lamivudine or Adefovir in both HBeAg-positive and negative patients and showed equal potency to Entecavir in HBV suppression in HBeAb-positive patients but has a high rate of resistance
  • Action: Competitively inhibits viral reverse transcriptase blocking DNA polymerase activity
  • Monitor for muscle symptoms and muscle weakness during therapy

Drug Resistance to Current Therapy

Entecavir Resistance

  • Switch to or add Tenofovir*  
  • Add Adefovir (if Tenofovir is not available) or alternative Emtricitabine-Tenofovir   

Tenofovir* Resistance

  • Has not been detected to date; no experience yet
  • Add Entecavir, Telbivudine, Lamivudine or Emtricitabine, if Tenofovir resistance is confirmed  
  • Switch to Entecavir if Lamivudine-naive or add Entecavir if Lamivudine-resistant

Adefovir Resistance

  • Switch to Entecavir or Tenofovir* if nucleoside analogue-naive  
  • Add Entecavir  
  • If with prior Lamivudine resistance, switch to Tenofovir and add nucleoside analogue

Lamivudine Resistance

  • Switch to or add Tenofovir*  
  • Add Adefovir (if Tenofovir is not available) or alternative Emtricitabine-Tenofovir

Telbivudine Resistance

  • Switch to or add Tenofovir*  
  • Add Adefovir (if Tenofovir is not available)

Multi-Drug Resistance

  • Switch to Tenofovir  
  • Add combined Tenofovir* and Entecavir 

*Tenofovir alafenamide or Tenofovir disoproxil fumarate

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