Definition

Chronic hepatitis B infection is defined as positivity for hepatitis B surface antigen (HBsAg) for a period of at least six months.

Evaluation

The following guidelines are suggested for the evaluation of persons identified as chronic hepatitis B carriers. Initial testing includes: LFT (liver function tests); ALT, AST, and GGTP, AFP (alpha-fetoprotein), alkaline phosphatase, bilirubin, albumin, prothrombin time, CBC, glucose, ANA, hepatitis B E antigen (HBeAg), antibody to hepatitis E antigen (anti-HBe), HBV DNA quantitative level and hepatitis delta antibody.

Routine Follow-up of chronic Hepatitis B Carrier

1. Screen for hepatocellular carcinoma (HCC) with alpha-fetoprotein (AFP, a tumor marker) every 6 months. If AFP:
   
   1. Is elevated > 15, do a liver ultrasound (U/S) with AFP every 3 months as long as continues to rise.
   2. Remains > 15 but stable (no longer rising) with normal U/S, continue AFP with U/S every 6 months.
   3. Was elevated (with normal U/S) but then drops < 15, return to 6 months monitoring of AFP.
   4. Is elevated and person is pregnant, high levels may be due to the pregnancy, but AFP still needs repeating at the 6 week post partum check-up. (AFP should fall to normal by 6 weeks after birth.)

• Consider a Hepatitis Clinic consult with any AFP elevation > 15, especially if a new finding. Even when the U/S is normal, the patient is at high risk for HCC or may have cirrhosis and may need further studies including a liver CT.
   

2. Screen with liver transaminase (ALT, AST) every 6 to 12 months, evaluating all new elevations and elevations that were mild and suddenly rise to > 1 ½ times normal.
3. Test for HbsAg, HBeAg (antigen) and anti-HBe (antibody) every 6 months to 1-year as HBe antigen positivity is a measure of increased infectivity.

Vaccine Guidelines

1. Hepatitis A Vaccine, recommend 2 doses, 6-18 months apart to protect the liver in those with a negative HAV-Total (formerly anti-HAV IgG).
2. Hepatitis B Vaccine recommendations for infants born to hepatitis B carrier mothers,

• Give a dose of hepatitis B vaccine within 12 hours of birth.
  (This reduces the chance of Hepatitis B Carrier State in the child.)
• Complete the 3-dose vaccine series, and
• Draw anti-HBs level when the child is 12-15 months old to verify protection against Hep B.
   
• HBIG (Hyperimmune Hepatitis B Globulin) may also be given with the hepatitis B vaccine at birth if mom is HBeAg positive.

Evaluation for treatment with antiviral therapy

Based on studies in Alaska Natives, >70% of carriers who are HBeAg + will clear HBeAg and HBV DNA by quantitative assays within 10 years without antiviral therapy. However, based on follow-up studies in Alaska Natives, 10%-20% of these carriers with have one or more reversions back to HBeAg+ with concomitant exacerbation of liver disease that could lead to scarring. In addition, 10%-15% of persons who have cleared HBeAg will have high levels of HBV DNA and elevated liver transaminase levels, which may represent active, ongoing liver disease and some carriers with low levels of DNA will have exacerbation of hepatitis characterized by elevated ALT and HBV DNA level > 2,000 IU/ml (104 copies/ml). This is why all carriers need at least yearly testing for HBeAg and anti-HBeAg as well as 6-12 month testing of ALT and AST. Sera drawn in the bush if spun down in a couple of hours can be used for ALT/AST testing, as under these circumstances the enzymes are stable over time.

Candidates for Antiviral Therapy include all of the following:

1. HBV DNA > 20,000 IU/ml*
2. HBeAg or anti-HBe positive
3. Elevated ALT
4. Liver Biopsy showing moderate or severe hepatitis and moderate or severe fibrosis

*Some patients with HBV DNA between 2,000 and 20,000 IU/ml could have active hepatitis and need antiviral therapy

Persons with persistently elevated ALT levels, ALT levels changing from normal to elevated, and reversions from anti-HBe to HBeAg-positive should be evaluated as follows:

1. Complete liver function tests, CBC, PT.
2. Delta antibody and anti-HCV.
3. HBV DNA quantitative level.
4. If ALT elevation persists or is > 5X upper limit of normal (ULN), liver biopsy should be considered.

Current Available Licensed Antiviral Agents Approved for Treatment of Chronic Hepatitis B (CHB)

Approved for Adults:

1. Alfa 2 Interferon : Both Regular (2a and 2b) and Pegylated (2a)
2. Lamivudine
3. Adefovir
4. Entecavir

Approved for Children < 18 years:

1. Alfa 2 Interferon: Regular
2. Lamivudine

Currently Licensed Antiviral Agents not yet Approved for HBV but Effective:

1. Tenofovir DP
2. Emtricitabine
3. Combination Emtricitabine and Tenofovir DF (Truvada®)

Duration of Treatment:

1. HBeAg-positive CHB:
2. 1. 6-12 months pegylated Alfa 2a interferon or
   2. Nucleoside/Nucleotide analogue until 6 months after HBeAg clearance and appearance of anti-HBe occurs.

2. HBeAg-negative (anti-HBe positive) CHB.
3. 1. 1 year of pegylated Alfa 2a interferon (success rate only 20%-30%)
   2. Nucleoside/Nucleotide analogue indefinitely

Interferon Therapy

The best candidates for interferon therapy are those who meet the following criteria:

ALT of greater than 2.0 times the upper limits of normal.

HBeAg - positive.

Level of HBV DNA that is >100,000 copies/ml (20,000 IU/ml).

Biopsies showing moderate chronic active hepatitis (Hepatic Activity Index > 8) and moderate to severe fibrosis (Knodell 3,4 or Ishak 4-6).

Dose of IFN:

1. HBeAg-positive Chronic Hepatitis B
2. 1. Regular interferon 5 million units (mu) daily or 10 mu 3 times/week for 16 weeks or
   2. Pegylated alpha 2a 180 ug weekly for 1 year (preferred)

 

2. HBeAg-negative Chronic Hepatitis B
3. 1. Regular interferon 5 million units (mu) daily or 10 mu 3 times/week for 6 months to 1 year or
   2. Pegylated alpha 2a 180 ug weekly for 1 year (preferred)

 

Nucleoside/Nucleotide Analogue Antiviral Therapy

Lamivudine Therapy

Lamivudine: Approved for the treatment of Hepatitis B at a dose of 100mg/day is a potent inhibitor of HBV and in almost all patients treated there is an immediate and dramatic fall in HBV DNA. However some experts feel that 300 mg/ day is a more appropriate dose and costs the same. This drug has few side effects. Unfortunately, after a year of treatment it is effective at permanently clearing HBV DNA and HBeAg in only 20% of patients treated. In addition, 10%-20% of treated patients per year develop resistance to Lamivudine in the YMDD motif of the reverse transcriptase gene, similar to what is seen in HIV resistance. Resistance increases to 70% at 4 years. Emergence of the mutant virus may not initially cause a rise in ALT levels and, in some patients who develop resistance, stopping the drug results in an exacerbation of hepatitis that can occasionally be severe and even fatal. Thus it is often difficult to determine when to stop treatment. However, some patients with severe active hepatitis B, even with liver failure, have had dramatic turnarounds on this drug. Thus, candidates for this drug must be chosen carefully in consultation with a Hepatologist. Potential candidates would include:

1. HBsAg carriers who are anti-HBe-positive who have elevated transaminases and have moderate to severe disease with fibrosis on liver biopsy.
2. HBeAg-positive carriers with ALT levels >2.0 X ULN and a biopsy showing moderate hepatitis.

Adefovir Dipivoxil

Adefovir is active against HBV wild type and the Lamivudine YMDD mutant strain. It is 5 times as expensive, and less potent than lamivudine as 20%-30% of patients fail to respond to treatment. It can be used as first line therapy and in persons who develop Lamivudine resistance. A reversible rise in Creatinine or phosphorous occurs in 1%-2% of treated persons and must be monitored.

Other Medications Active against HBV

Two other medications are currently available but not approved for chronic hepatitis B: Tenofovir (a nucleoside antagonist licensed for HIV therapy) and Emtricitabine. Both have a relatively safe side effect profile. Tenofovir is a potent inhibitor of HBV DNA, but has not been tested widely in HBV. Emtricitabine is similar to Lamivudine but more potent. Other potent nucleoside analogues are currently undergoing clinical trials.

Management of Patients of Oral Nucleosides/Nucleotides

Patients on oral Nucleosides/Nucleotides should be followed periodically with HBV DNA levels and ALT/AST determinations. Every 3 to 4 months seems reasonable.

Lamivudine

1. ALT, AST and HBV DNA every 3 months. Suspect resistance to Lamivudine if:
2. 1. HBV DNA fails to fall > 2 logs 3 months after initiating therapy
   2. After initial fall of HBV DNA, subsequent level of HBV DNA rises > 1 log
   3. If resistance is suspected, send sera to ANMC molecular biology lab to test for YMDD resistance to Lamivudine.

2. If resistance occurs:
3. 1. Add adefovir and continue Lamivudine as combination. Both drugs should be continued indefinitely to prevent resistance from adefovir from occurring and because lamivudine is more potent against wild type HBV than adefovir which will reemerge if lamivudine is stopped.
   2. Or Switch to Entecavir
   3. Tenofovir may also be used as an alternative

Adefovir

1. ALT, AST, BUN, Creatinine, Phosphorous and HBV DNA every 3 months
2. 1. If HBV DNA levels fail to fall by at least 2 logs, suspect primary adefovir resistance and switch to another drug (entecavir)
   2. After initial fall of HBV DNA, if subsequent level of HBV DNA rises > 1 log, suspect adefovir resistance and send blood to ANMC for testing for adefovir resistance.
   3. If resistance has occurred, switch to either entecavir or Tenofovir
   4. If Serum Creatinine has risen > 0.5 X baseline or phosphorous has fallen below normal level, repeat these tests in one month and consider stopping adefovir and using another drug if abnormalities persist.

Treatment of HBV and HIV co-infection

Treatment of HBV Only

Pegylated Interferon or Entecavir

Treatment of HIV and HBV in Patients Naïve to Nucleoside/Nucleotide Analogues

Agents effective against both viruses should be selected*

Emtricitabine plus Tenofovir DF (Truvada®)

Lamivudine plus Tenofovir

Treatment of HIV and HBV in Patients with HBV resistance to Lamivudine or both Lamivudine and Adefovir

Resistant Lamivudine Only: Entecavir added to or Tenofovir DF included in HART regime Resistant to both drugs: Entecavir added to HART regime

* HIV infection should never be treated alone in co-infected patients without consideration for HBV therapy

The education and public health aspects of managing chronic HBsAg Positive Carriers

Household and sexual contacts of HBsAg-positive carriers should be screened for HBV markers and those persons who are seronegative should be offered hepatitis B vaccine.

HBsAg-positive carriers should be cautioned to practice barrier protection when having sexual intercourse with a person whose HBV status is unknown or who has not received hepatitis B vaccine.

HBsAg-positive carriers should be educated as to the lifetime risk of developing a hepatocellular carcinoma and urged to have appropriate screening for HCC at least biannually.

HBsAg-positive carriers should be given educational materials on the carrier state such as that supplied by the American Liver Foundation.

Revision 1.2006