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

Entecavir

• Considered 1st-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 1st-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 1st-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 3rd 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 1st-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

Clevudine

• 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

Lamivudine

• 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

Telbivudine

• 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

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