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
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
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