HBV Journal Review
May 1, 2012, Vol 9, no 5
by Christine M. Kukka
Hepatitis B plus a Family History of Liver Cancer Increases Cancer Risk 70-Fold
A family history of liver cancer increases the chance that a person infected with the hepatitis B virus (HBV) will develop liver cancer 70-fold, according to an article published in the May issue of the journal Hepatology.
Just a family history of liver cancer–even without hepatitis B or C infection–increases cancer risk, according to Italian researchers who compared family histories of liver cancer in 229 liver cancer patients and 431 cancer-free patients comprising the control group.
They found that 75% of liver cancer patients and 11% of the control group had hepatitis B or C infections. Compared to patients who had no family history of liver cancer and no hepatitis B or C, researchers found an odds ratio of 73 for those with both viral hepatitis and family history of cancer–resulting in a 70-fold increased risk of developing liver cancer.
"Our findings confirm that individuals with a positive family history of liver cancer have three-times higher risk of developing liver cancer," researchers noted. "Monitoring individuals with family history, particularly those with hepatitis markers (infection), could help to identify liver cancer at an earlier stage, and hence potentially reduce mortality from liver cancer."
New Blood Test Could Reveal Which Men Are at Risk of Liver Cancer
A new, inexpensive blood test could identify which people infected with HBV are at higher risk of liver cancer–prompting more aggressive monitoring and treatment.
People with significantly longer telomeres–the caps on the end of chromosomes that protect genetic data–were found to have an increased risk of getting liver cancer compared to those with shorter ones, according to research recently presented at the 2012 American Association for Cancer Research Annual Meeting.
The telomere length in those with HBV-related liver cancer was about 50% longer than in cancer-free HBV patients.
Researchers from the Department of Medical Oncology at Thomas Jefferson University and Jefferson's Kimmel Cancer Center examined telomeres' lengths in blood samples from more than 400 hepatitis B patients, including 140 with liver cancer and 280 without cancer. All participants were Korean-American in order to avoid the effects of ethnicity on telomere length. Most had been infected at birth or during childhood.
The difference in telomere length was only evident in males and in non-cirrhotic patients–possibly because cirrhosis itself can lead to liver cancer.
Kidney Problems Develop in 15% of Patients Treated Long-term with Adefovir or Tenofovir
A study by the National Institute of Diabetes and Digestive and Kidney Diseases found that kidney damage occurs in about 15% of patients treated for several years with the antivirals adefovir (Hepsera) or tenofovir (Viread). Antivirals, taken daily as pills, hinder the virus' ability to reproduce.
Researchers, prompted by reports of kidney problems resulting from long-term antiviral treatment, followed patients treated for an average 7.4 years with adefovir (42 patients), tenofovir (4), and with adefovir followed by tenofovir (5). Seven of these patients (14%) developed renal tubular acidosis (RTA), a medical condition that involves an accumulation of acid in the body due to a failure of the kidneys to filter urine.
RTA developed anywhere from 22 to 94 months (about 4 years on average) in 15% of the patients in the study over a 10-year period, according to the report in the April 2012 issue of the journal of Alimentary Pharmacology & Therapeutics.
Six of the patients with kidney problems were switched to the antiviral entecavir (Baraclude), and all experienced improvements in kidney function.
"Monitoring for serum phosphate, creatinine and urinalysis is prudent during long-term adefovir and tenofovir therapy," researchers noted, in order to identify development of RTA as soon as it occurs.
An unrelated study published in the journal of Clinical Gastroenterology and Hepatology would appear to contradict these findings. University of California at San Diego researchers reported that patients treated with tenofovir were no more likely to experience kidney damage than patients treated with entecavir. However, researchers did not note whether patients had been treated with the antivirals long-term.
Chemotherapy for Breast Cancer Appears Not to Exacerbate HBV Infection
Increasingly, doctors are becoming aware that chemotherapy used to treat various cancers can weaken the immune system and enable HBV infection to rebound–even in patients with inactive or resolved infection.
A recent Japanese study followed 32 HBV-infected women who were treated with chemotherapy for breast cancer. According to the report published in the April 2012 issue of Oncology, the current breast cancer chemotherapy did not result in liver damage or a resurgence of HBV DNA.
They measured alanine aminotransferase (ALT) levels, which increase when liver cells are damaged or die, and conducted other tests for liver damage in the women receiving chemotherapy over 378 cycles.
Among the 32 patients, three experienced moderate liver damage that required two chemotherapy treatment delays and one treatment revision. Nine patients experienced some red blood cell damage, which required treatment delays in two patients and treatment revisions in three.
Researchers concluded that hematotoxicities (causing damage to red blood cells or clotting problems) were not highly prevalent among breast cancer chemotherapy patients with hepatitis B and normal ALT levels at the start of treatment.
"Under careful monitoring, chemotherapy dosage or schedule adjustments may not be necessary in similar patients positive for HBV," they wrote.
Researchers Suggest Tears and Saliva May Transmit HBV Infection
Japanese researchers tested tears, saliva, urine and sweat from 39 HBV-infected children and eight adults to see if the samples contained HBV-DNA sufficient to transmit hepatitis B infection.
They found HBV DNA in:
- 73.7% (14 of 19) of urine samples
- 86.8% (33 of 38) of saliva samples
- 100% of tear samples
- And 100% of sweat samples.
The levels of HBV DNA levels were highest in tears. Also, the higher the viral loads in the children and adults tested, the higher the HBV DNA levels in the saliva and tears, according to the report published in the April edition of the Journal of Infectious Diseases.
The researchers then tried injecting the tears with HBV DNA into two engineered mice whose livers were similar to humans. One week after injection, both mice tested positive for HBV DNA.
In a separate study, published in the Compendium of Continuing Education in Dentistry, researchers screened the saliva of 35 HBV-infected patients for hepatitis B surface antigen (HBsAg). HBsAg was found in the saliva of 26 of the 35 patients.
The study's abstract did not suggest saliva alone could transmit HBsAg, but the authors suggested that saliva could be used as a non-invasive way to test large numbers of people for HBsAg.
To date, the U.S. Centers for Disease Control and Prevention (CDC) does not list saliva in tears as capable of transmitting hepatitis B infection.
REVEAL Study Shows Links between HBV DNA and Liver/Pancreatic Cancers
Researchers recently examined the latest results collected from the largest and longest study into HBV DNA and liver cancer worldwide to examine the links between HBV DNA and cancer in 3,653 patients.
The REVEAL-HBV Study (Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus) has followed participants (age 30-65) recruited from a community-based cancer screening program in Taiwan for more than 12 years. To date, there have been 164 cases of liver cancer and 436 deaths among those surveyed.
According to the overview published in the journal Liver International, HBV DNA levels are directly linked to the incidence of cirrhosis, liver cancer, and liver failure and death. Lowered or undetectable HBV DNA almost always predicts clearance of HBsAg.
HBV strains or genotypes and viral mutations, including those in the core or precore area of the virus, also increase the risk of liver cancer.
Even people with "inactive" hepatitis B–with HBsAg, low viral load, and normal ALT levels–still have an increased risk of liver compared to those who are HBsAg-negative.
"A somewhat provocative and novel finding from the REVEAL-HBV study is the association of chronic HBV infection (with) active replication with an increased pancreatic cancer risk especially in women less than 50 years old," researchers noted. "This finding will hopefully spur further research in this area seeking confirmatory evidence."
HBsAg Levels Predict Cancer Risk in HBeAg-Negative Patients with Low HBV DNA Levels
Usually, doctors use viral load to determine when patients who test negative for the hepatitis B "e" antigen (HBeAg) need treatment or are at high risk for liver cancer. But many HBeAg-negative patients have low viral loads, yet about 1% of them still develop liver damage each year. So what other indicators can doctors use to signal when treatment is needed?
Taiwanese researchers suggest they use HBsAg levels to determine when treatment is needed in a report published in the journal Gastroenterology.
HBsAg levels are increasingly being recognized as indicators of viral replication and how strong the patient's immune system is in controlling the infection. For example, a lower HBsAg level is associated with lower risk of liver damage.
In this study, researchers followed 2,688 HBV-infected patients age 28 and older with genotypes B or C, but no cirrhosis, over 15 years. According to the report, 191 patients developed liver cancer during the study period, about 4.8 cases per 1,000 person-years.
As expected, HBeAg positivity, higher levels of HBV DNA, and higher levels of ALT were all were associated with a higher rate of liver cancer, as was male gender, older age, and infection with genotype C.
But among the HBeAg-negative patients with low viral load, the risk for developing liver cancer was five-times higher in patients with HBsAg levels exceeding 1,000 international units per milliliter (IU/mL) or greater), compared to patients with lower HBsAg levels.
Researchers concluded that a combination of low viral load and low HBsAg levels may indicate that an HBeAg-negative patient may not require treatment, compared to patients with elevated HBsAg levels.
More Babies Born to HBV-Infected Mothers Are Getting Immunized in the U.S.
According to a report published in the March issue of Pediatrics, the number of babies born to HBV-infected mothers in the U.S. who received the immunization and hepatitis B antibodies within a day of birth increased from 92% to almost 97% between 1990 and 2008.
Additionally, the number of babies who developed hepatitis B, despite those preventive efforts, declined from 2% to less than 1% by 2008. Without same-day immunization, nearly all infants born to HBV-infected mothers would develop chronic hepatitis B.
Nationwide, between 1 and 2 million U.S. residents have chronic hepatitis B and CDC estimates that more than 40,000 become infected every year through exposure to body fluids through birth and sexual activity.
CDC guidelines require all pregnant women to be screened for HBV infection, and all newborns to be immunized against the virus within 12 hours of birth, followed by an additional two or three vaccine doses over the next year.
CDC estimates that from 1994 to 2008, the number of pregnant women who were found to be HBV-positive increased from about 19,000 to close to 26,000 due to better screening efforts. The number of HBV-exposed babies who got both hepatitis B antibodies and a vaccine within a day of birth increased from 92% to almost 97%.
On the down side, CDC was unable to track about half of the infants in its study to find out if they developed hepatitis B despite the vaccine, and the number of infants who received all three required vaccine doses decreased during the study period–from 86% to 78%.
Telbivudine Cuts Mother-to-Infant Hepatitis B Transmission to Zero
Telbivudine (Tyzeka) taken during the second or third trimester of pregnancy to reduce viral load in HBV-infected women cut mother-to-child infection to zero according to a study involving 88 women who had high viral loads and elevated ALT levels, published in the May issue of Clinical Gastroenterology and Hepatology.
In contrast, the infection transmission rate in newborns born to mothers who were not treated with antivirals was 9% despite administration of a vaccine and preventive hepatitis B antibodies, according to researchers at Mount Sinai Medical Center, who conducted the study in Nanjing, China.
The results support the use of antiviral drugs in pregnant women with high viral loads. This treatment has not yet been approved by the U.S. Food and Drug Administration, but clinical trials increasingly show the approach to be safe for both mothers and infants.
The 88 women with high viral loads were all given the choice to receive antiviral therapy (53 chose the treatment–a 600 mg telbivudine pill daily until 28 weeks after delivery) or not (35 women did not choose the antiviral, and they became the control group.)
Thirteen of the 52 treated mothers (29%) decided to discontinue the antiviral therapy during the first month after delivery (due to breast feeding), and the rest continued to take it until the study ended at 28 weeks after giving birth.
As expected, HBV DNA levels dropped to undetectable levels in 58% of the telbivudine-treated group and ALT levels normalized in 92% by the end of the study.
All the infants in the study received hepatitis B antibodies with the HBV vaccine within 6 hours of birth and completed all three HBV vaccine shots according to the vaccine schedule.
At birth, all infants were HBeAg-positive and two in the telbivudine group and eight in the control group were also HBsAg-positive. However by week 28, all infants in the telbivudine group tested negative for HBeAg, HBsAg, and HBV DNA.
There were no significant differences between the health of the infants or mothers in the two studies and all infants had normal development.
In an unrelated study, reported in the April issue of Gastroenterology, researchers suggested that women who were HBeAg-positive with high viral load should be prescribed antiviral treatment during the last two trimesters of pregnancy. They surveyed 583 infants born to HBeAg-positive mothers and 1,773 were born to HBeAg-negative mothers (with lower viral loads)–all of whom received the three doses of HBV vaccine.
They reported that 9.26% of children born to HBeAg-positive mothers became infected, compared with only 0.23% of children born to HBeAg-negative mothers.
These differences are so large that, "applying different preventive strategies (including antiviral treatment to women with high viral loads) can be justified," researchers noted.
Hepatitis B Foundation 2012 B Informed Parent Conference
A Outreach Program for Parents of Children Chronically Infected with HBV
Since 2001, the HBF patient conference has served as a beacon of hope for patients and families living with hepatitis B and, after eleven years, continues to be the only meeting of its kind. It provides a valuable forum for experts to share their knowledge and for attendees to share their stories in a relaxed and supportive environment. In 2012 we are concentrating on the unique health and personal issues and challenges of raising a child chronically infected with hepatitis B.
The HBF will partner with expert health care professionals to provide the latest medical information in a friendly supportive environment. Through presentations by experts in the field, workshops, and interactive Q&A sessions, parents will learn how to help their children as they grow, develop and mature.
B Informed Parent Conference on Hepatitis B
Saturday, May 19, 2012
9:00 am – 4:30 pm
Holiday Inn Express Midtown
1305 Walnut Street
Barbara Haber, MD, Pediatric Hepatologist, formerly of Children's Hospital of Philadelphia; Currently with Merck & Co.
Karen Murray, MD, Division Chief, Pediatric Gastroenterology/Hepatology, Seattle Children's Hospital
W. Thomas London, MD, HBF Medical Advisor and Board Member; Emeriti, Fox Chase Cancer Center
Click here to download program
Or contact the Hepatitis B Foundation
Tel: (215) 489-4900
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