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Seventh Annual
B Informed Patient Conference
June 8-9, 2007
Philadelphia, Pennsylvania

 

Highlights from the Parent Session
June 8, 2007

Management and Treatment of Children with Hepatitis B
Maureen Jonas, M.D.
Children’s Hospital Boston and Harvard Medical School

Children with HBV Slides

HBV Genotypes

  • HBV genotype testing in kids should take place possibly when interferon treatment is being considered, to check on their possible response to interferon – or, when someone has advanced liver disease or when the question of drug resistance is brought up. In the near future, genotype testing may play more of a clinical role for patients.

Viral Load

  • Viral load (or HBV DNA) is important to measure when looking at treatment response (before and during interferon), during treatment to find resistance to a medication (if viral load goes up one log during treatment, it is called clinical resistance).
  • Viral load does not predict severity of liver disease and does not predict response to treatment with the currently approved nucleoside/nucleotide analogues (i.e. oral drugs).
  • Dr. Jonas only tests for HBV DNA if a child’s ALT is abnormal. Since she won’t treat a child with a normal ALT (even if the viral DNA levels are high), there is no reason to put a child through another needle stick.

Immune Tolerance Phase

  • Most children and young adults are in the immune tolerance phase, with high viral loads and normal ALT. The high level of virus at this stage is usually not an indicator of more serious liver disease or liver cancer.
  • The current medications are not effective during the immune tolerance phase, and should be avoided to prevent the development of possible drug resistance which can cause problems later on when a child really may need treatment.
  • Resistance decreases a patient’s treatment options, so it is important to only start treatment when there are signs of “active liver disease” (usually represented by high ALT levels).
  • When the immune clearance stage lasts 6 months or longer, there is more liver damage – the longer it lasts, the more liver damage occurs (which can set the stage for developing fibrosis or cirrhosis). 
  • Usually at the end of this stage there is e-antigen seroconversion (loss of HBeAg+ to HBeAg-). It is rare for patients to lose the surface antigen (s-antigen seroconversion or HBsAg- and HBsAb+). 
  • About 20% of people will come out of the low/non-replicative phase into a reactivation phase, maybe as a response to mutation – this is a late stage HBV infection, and patient is HBeAg-.  This can also lead to liver damage/cirrhosis.

Management Issues

  • Regular monitoring is very important! Dr. Jonas sees children with HBV beginning at age 2 years and tests ALT every 6 months, and HBeAg/HBeAb and AFP once a year.
  • There are no clear recommendations for ultrasound in children. In adults, ultrasound imaging is generally recommended every 6 months.
  • There is no need to measure HBV DNA during immune tolerance phase because the test result will not change the course of management. Dr. Jonas bases treatment decisions on whether a child has a high ALT, not a high DNA level.
  • If the ALT is elevated, have it tested monthly to see if it is persistent or a fluke. Rule out other possible causes for an abnormal ALT.  If it continues to be 2x normal for more than several months, then consider treatment.
  • After seroconversion, about 2/3 of people will remain in remission, and about 24% will have HBeAg negative re-activation.
  • Monitoring after eAg seroconversion – yearly ALT and AFP, HBeAg/HBeAb, HBsAg and HBsAb.  Ultrasound is also needed, and how often is based on the person’s history and family history (i.e. if there is a family history of cirrhosis or liver cancer, then more frequent ultrasounds may be ordered). DNA is only tested if ALT goes back up (to look and see if it is either seroconversion or emergence of HBV mutation such as e-antigen negative HBV).

Liver Cancer Screening

  • Although the optimal age for screening children for hepatocellular carcinoma (HCC or primary liver cancer due to chronic HBV infections) is unknown, the risk for HCC increases with age. Dr. Jonas always starts screening adolescents, if not sooner.
  • All HBsAg+ patients have a 0.4% chance of developing HCC annually. Family history, duration of active disease, heavy alcohol use, and co-infections with immune suppressive diseases (i.e. HIV) are factors linked with the increased risk of developing cirrhosis and HCC.

Liver Biopsies

  • A liver biopsy is important to know what is actually happening in the liver. There is some risk because the liver is a highly vascular organ (lots of blood vessels).
  • A liver biopsy is helpful in deciding whether to treat, to provide a baseline value before starting treatment, and to help determine prognosis.
  • Dr. Jonas does not do a biopsy with normal ALT because even if she finds liver damage, there are no therapies that will work, and if she started treatment with normal ALT, she could reduce the effectiveness of the drugs at a later time when their ALTs may go up.
  • Although a biopsy only takes tissues from one area of the liver, the risk of “sampling error” is generally not much more than a one stage difference. So it is generally considered a good representation of what is going on in the entire liver.

Treatment

  • Goal of treatment: to reduce the risk of long-term complications and improve long-term outcomes by suppressing viral replication that will hopefully lead to seroconversion (e-antigen or the ultimate, surface antigen seroconversion).
  • HBV fibrosis and cirrhosis can improve with response to treatment (in adults and kids).
  • Treatment is indicated for children and adults with “active liver disease” (i.e. high ALT) and:

HBeAg+ and HBV DNA >105
HBeAg- and HBV DNA >104
A liver biopsy is indicated if high ALT and DNA <104

  • Treatment can be considered to shorten the immune clearance phase or during the re-activation phase.
  • Viral breakthrough during treatment happens when DNA increases more than one log after initial suppression.
  • If there is viral breakthrough and there is a documented virus mutation, then this is considered “resistance”.
  • If the DNA never goes below 5 log during therapy, then this is considered “treatment failure”.

 

Approved Drug Therapies

  • Only two approved drugs for children with HBV: interferon alpha (IFN) and lamivudine (LAM).
  • IFN meta-analysis in children (n=240):

DNA decrease in 28.6%
HBeAg- in 23%
Normal ALT in 38%

  • Interferon treatment – seroconversion from eAg to eAb can occur during treatment or within the year after treatment.
  • In children, the interferon dose for HBV is double than that of HCV.
  • The higher the ALT, the better the response for interferon and lamivudine.
  • Lamivudine is used only in children with ALT at least twice normal.
  • Begin to check on lamivudine for HBeAg seroconversion at around the 1 year mark.
  • Children are kept on LAM for at least one year – and must be continued for at least 6 months after documented HBeAg seroconversion.
  • Children who do not seroconvert can continue LAM until the DNA increases by one log (which indicates resistance since DNA should decrease on treatment). 
  • Children must be monitored after stopping LAM for a potential ALT flare.
  • Children who received LAM for 3 years: 64% developed resistance.
  • Interferon works best with high ALT, lower viral load – so, does pre-treatment with LAM work?  Not as shown in the larger studies, even though it seems to make sense.

 

Pediatric HBV Clinical Trials

  • Early results of Adefovir in children are disappointing – adolescents responded similarly to adults, but there was lower efficacy in younger children.
  • Entecavir pediatric trials are beginning (approved for adults in 2005).
  • Pediatric trial are being considered for Telbivudine (approved in adults 2006), but it has cross resistance with LAM.
  • Adding lamivudine and adefovir in children with a partial response to adefovir is useful to prevent the development of resistance to adefovir.
  • No data yet for tenofovir
  • Good website for pediatric clinical trials - www.researchchildren.org

Additional Issues

  • Tylenol – children with mild liver disease should not be restricted from any medication they may need.
  • Corticosteroids – Although the viral DNA level will increase with corticosteroids, with short-term use (i.e. in asthma), there is no evidence that it will cause lasting damage. Long-term use must be evaluated on an individual basis.
  • Alcohol – it is not known how much alcohol is safe and the recommendation is generally to avoid it or use it very sparingly. Must certainly discourage binge drinking or continuous heavy drinking. 

BIOGRAPHY
Maureen Jonas, M.D .

Dr. Jonas’ research focuses on liver disease in children with an emphasis on viral hepatitis. Her recent work includes investigations of the transmission and prevention of HBV and HCV in newborns.  She is a principal investigator in the pediatric trials of Pegylated Interferon (with and without Ribavirin), Adefovir Dipivoxil in children and adolescents, and the “Pediatric Acute Liver Failure Study Group.”

Dr. Jonas received her medical degree from the University of  Miami School of Medicine.  She completed her internship, residency, and fellowship at Children’s Hospital Boston.  Dr. Jonas is a member of the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases.  She is also on the editorial board of Gastroenterology & Hepatology and is the author of many journal articles and monographs.

 

DISCLAIMER:
Please know that the Hepatitis B Foundation provides these summaries for information purposes only, not as personal medical advice. Be sure to consult your own health care provider with any questions or concerns you may have about your management and/or treatment.


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