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Management of Hepatitis B 2000

Summary of NIH Recommendations for Chronic HBV

"The Management of Hepatitis B: 2000" was the first-ever workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) in Bethesda, MD, September 8 - 10, 2000. The 3-day workshop was held almost ten years after the first drug was approved for chronic hepatitis B.

According to Anna Lok, M.D., meeting co-chair, "the workshop was held because new advances in diagnostic tests and treatment have created controversies about their utilization, so summary recommendations were needed."
 
The NIH Workshop recommendations attempt to standardize (and reform) terminologies describing HBV infected individuals and identify general criteria regarding monitoring and antiviral drug treatment. The degree of controversy over these matters remains to be seen, but most of the suggestions should not be surprising to those in this field.

A full report is available in "Management of Hepatitis B: 2000 - Summary of a Workshop", written by Drs. Anna S. Lok, E. Jenny Heathcote, and Jay H. Hoofnagle and published in Gastroenterology, June 2001; 120:1828-1853.

The Hepatitis B Foundation organized the workshop report in an outline format to make it easier to read. Our summary is not intended to be used as personal medical advice. Please talk to your physician about your own situation.

MANAGEMENT OF HBV: SUMMARY RECOMMENDATIONS

  1. Standardization of Nomenclature & Terminology
    1. The Disease
      1. Should refer to the disease as "chronic hepatitis B" with the following attributes:
        1. Virologic - HBeAg + or -; with or without detectable HBV DNA.
        2. Biochemical - with or without ALT elevations.
        3. Histologic status - activity and degree of fibrosis.
      2. Avoid terms such as "asymptomatic" or "healthy carrier state".
      3. "Inactive carrier state" refers to a patient who is HBsAg+, HBeAg-, normal ALT and HBV DNA <100,000 copies/mL.
      4. Resolved HBV should include normal ALT, absence of HBsAg, presence of anti-HBc(with or without anti-HBs) in serum.
    2. Responses to Therapy
      1. Responses can be classified using the following criteria:
        1. Virologic - decrease in HBV DNA to <100,000 copies/mL; loss of HBeAg in those who were initially positive.
        2. Biochemical - normal ALT levels.
        3. Histologic - decrease in inflammation and necrosis.
      2. Responses should also be designated either as:
        1. Initial - occurring within first 6 months.
        2. End-of-Treatment - at the time of stopping therapy.
        3. Maintained - at the time of last evaluation during long-term therapy.
        4. Sustained - within 6 to 12 months after stopping therapy.
        5. Combined - meets virologic, biochemical, and histologic criteria.
        6. Complete - sustained loss of HBsAg.
    3. The Virus and Variants
      1. Mutants and variants should be defined based on protein region, nucleotide changes or amino acid changes.
  2. Evaluation and Monitoring
    1. Baseline Evaluation
      1. An initial evaluation should include routine liver tests, virologic assays for anti-HDV, HBeAg, anti-HBe and HBV DNA levels, as well as abdominal ultrasound.
      2. Baseline information affects eventual recommendations for management.
        1. Patients with elevated ALT should be considered for therapy, therefore, a liver biopsy is warranted.
        2. Patients with normal ALT do not require a liver biopsy unless there is evidence of other significant or underlying liver disease.
    2. Monitoring Chronic HBV
      1. All patients with chronic HBV should be monitored regularly. Frequency will be determined by the progression of liver disease and/or the decision to start therapy.
      2. Minimal level of monitoring recommended for chronic HBV includes:
        1. Visits at 6-month intervals with repeat aminotransferase levels.
        2. Serial HBV DNA testing is not necessary, and repeat liver biopsy is not needed unless therapy is being considered.
      3. At present, routine surveillance for HCC (liver cancer) at defined intervals should be reserved for those at moderately-high risk, which include:
        1. Patients with cirrhosis or family history of liver cancer.
        2. Patients older than 40 years from endemic areas of the world.
        3. Those infected as infants or children.
      4. AFP testing and liver ultrasound exams every 6 months is an acceptable approach to HCC surveillance.
  3. Therapy
    1. Making the Treatment Decision
      1. The decision should be based on a combination of:
        1. Serum liver tests (ALT elevations)
        2. Virologic assays (HBeAg+ and HBV DNA > 100,000 copies/mL)
        3. Liver histology (moderate disease activity and fibrosis)
        4. Tests that exclude concurrent HCV, HDV, and HIV infections
      2. In patients with "inactive" or mild disease, it is appropriate to monitor ALT levels and defer therapy until advances have been made that allow for sustained benefit.
      3. However, the key question is what criteria should be used to define "moderate-to-severe" disease and subsequent treatment recommendations?
    2. ALT Levels and Response Rates
      1. Retrospective analyses suggest that ALT levels can be used as a basis for recommending therapy, at least in those with HBeAg+ chronic HBV.
      2. Response rates to lamivudine and interferon strongly correlate to ALT levels:
        1. More than 50 % of patients with ALT levels greater than 5 times the upper limits of normal responded to therapy. Therefore, therapy can be readily recommended for these patients if there is no evidence of spontaneous loss of HBeAg after a 2-3 month observation.
        2. Only 20 -35% of patients with ALT levels in the range of 2-5 times the upper limit of normal responded to therapy. Factors such as liver histology, age, and other health issues should be considered in the treatment decision.
        3. Response rates are low in patients with normal or minimally elevated ALT levels (<2 times the upper limit of normal). In these patients, therapy is best deferred.
    3. Monotherapy or Combination Therapy?
      1. Interferon alpha
        1. Advantages - given for a limited time, no antiviral resistance develops, and quality and durability of long-term response are excellent. 
        2. Disadvantages - expensive, significant side effects.
        3. Not recommended for patients with decompensated cirrhosis.
      2. Lamivudine
        1. Advantages - easy to administer and monitor; few, if any, side effects.
        2. Disadvantages - long-term durability of responses appears to be less than with interferon, and prolonged therapy is often needed, which is associated with a high rate of viral resistance.
        3. Lamivudine monotherapy should be reserved presently for patients with moderate-to-severe disease.
        4. Long-term therapy is recommended for patients with advanced or decompensated chronic HBV, regardless of HBeAg status. However, therapy should be coordinated with a liver transplant team, because timing of lamivudine may be critical.
      3. Combination of Interferon and Lamivudine has not been proven to be significantly more effective than either drug alone and therefore, cannot be recommended outside of clinical trials.
  4. Future Research
    1. Development of Safe and More Effective Treatments
      1. Major contribution of new agents in the pipeline is likely to be in combination with each other or with lamivudine.
    2. Key "Surrogate" Endpoints for Combination Trials
      1. Maintain suppression of HBV DNA
      2. Prevention of viral resistance
    3. Reliable and Standardized HBV DNA Tests
    4. Clinical Studies in "Problem Populations" with HBV
      1. Studies of new therapies are needed in patients with renal failure, organ transplantation, HIV coinfection, substance or alcohol abuse, hemophilia, and advanced liver disease.


Source: "Management of Hepatitis B: 2000 - Summary of a Workshop" was written by Drs. Anna S. Lok, E. Jenny Heathcote, and Jay H. Hoofnagle and published in Gastroenterology, June 2001; 120:1828-1853.

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