HBV Journal Review
December 1, 2013, Vol 10, no 12
by Christine M. Kukka
Studies Find Hepatitis B Virus Can Mutate and Infect Even Immunized People
A growing number of studies are finding that the hepatitis B virus (HBV) is so adept at mutating that in some cases it is able to infect people who have been immunized against hepatitis B.
The hepatitis B vaccine contains only one particle (antigen) of the virus—the hepatitis B surface antigen (HBsAg)—which makes up the outer layer of the virus. When immunized with this antigen, the body's immune system creates the hepatitis B surface antibody to specifically target and eradicate HBsAg if a person comes in contact with the virus. To date, the vaccine has effectively protected millions against hepatitis B.
However, researchers are finding some people who were immunized and then exposed to the virus are now infected with HBV that is able to replicate without HBsAg. Scientists say these vaccinated people have "occult" or a "vaccine escape" version of the infection. They have HBV DNA in their bodies, but they test negative for normal HBsAg.
A new study published in the November issue of the Journal of Virology finds that the number of vaccinated Chinese children with mutated HBV has increased from 6.5% in 1992 to 15% in 2005.(1) And, as these vaccinated children age and become adults, the rate of mutations increases. Researchers also fear these mutated virus may cause more severe liver disease in patients than regular HBV.
"The vaccine has been successful in protecting millions of children from HBV, but there is concern that use of the vaccine puts selective pressure on the virus to develop 'breakout' mutations that could render the vaccine less effective," wrote M. J. Friedrich in an editorial citing the study, entitled, "Hepatitis B vaccination spurs virus mutation rise," in the November issue of the Journal of the American Medical Association.(2)
In the investigation, researchers from the U.S. and China compared blood samples taken from vaccinated children and unvaccinated adults before and after universal HBV immunization began in China in 1992. "They found that the prevalence of HBV mutants in children increased from 6.5% in 1992 to almost 15% in 2005, whereas in the adults, little difference was seen in HBV mutation prevalence from 1992 to 2005—as would be expected because the adults did not receive vaccines.
"Although the vaccine remains effective, this study indicates that HBV mutations should be monitored so that additional vaccination strategies can be implemented when necessary," Friedrich cautioned.
In another study, published in the November issue of the Journal of Viral Hepatitis, researchers compared outcomes in babies born to HBV-infected mothers who were given only the vaccine or a combination of the vaccine and HBIG, which is composed of hepatitis B surface antibodies derived from humans. They found occult hepatitis B, with HBsAg mutations, in 42% of 222 babies two years after their births.(3) The occult infection rate was higher in infants treated with both the vaccine and HBIG, and whose mothers had high rates of HBV DNA when they were born.
1. Source: www.ncbi.nlm.nih.gov/pubmed/24006443
2. Source: http://jama.jamanetwork.com/data/Journals/JAMA/929168/jwm130041.pdf.gif
3. Source: www.ncbi.nlm.nih.gov/pubmed/24168259
Hepatitis B Patients Appear to Be At Risk of Other Diseases
Several new studies report that people with chronic hepatitis B appear to be at higher risk of heart disease, eye problems and fibromyalgia.
Abnormally High Rates of Heart Disease Found in Hepatitis B Patients: Japanese researchers screened 47 hepatitis B patients, who had no overt signs of cardiac problems, for heart disease using a variety of tests.
Myocardial perfusion defects (injury to heart muscle and restriction of blood flow) were found in 47% of the hepatitis B patients (far higher than in an uninfected control group) and abnormal electrocardiography results were found in 9% of the patients, according, according to a report in the November issue of the Journal of Gastroenterology and Hepatology.
The severity of the heart disease was then monitored during and after interferon treatment in 10 patients—and researchers found that heart disease markers declined in those patients who responded well to the interferon treatment.
"Myocardial perfusion defects were found in 47% of the patients with chronic hepatitis B, and improved along with (viral load) reduction with interferon administration," they reported. (1)
Higher risk of macular degeneration reported in older, HBV-infected patients:
An article in the November issue of the journal of Investigative Ophthalmology and Visual Science reports that hepatitis B infection, in addition to other risk factors, increases risk of macular degeneration, which is a major cause of partial-blindness in people 50 and older.
The study surveyed 7,899 Koreans age 40 and older. The overall rate of early-onset age-related macular degeneration—which is a major cause of partial-blindness in people 50 and older—was estimated at 6.7% and that of late macular degeneration at 0.7%.
Significant risk factors for macular degeneration, according to researchers, included older age, high cholesterol, high blood pressure, and HBV infection.(2)
Fibromyalgia syndrome found in 22% of hepatitis B patients in small study: A Turkish study has found that 22% of 77 hepatitis B patients suffered from fibromyalgia—a syndrome with widespread fatigue, muscle pain, morning stiffness and sleep disturbance.
It made no difference if the patients had "active" hepatitis B with liver damage or high viral load. The syndrome affected both types of chronic hepatitis B patients, according to the report published in the September issue of the International Journal of Clinical and Experimental Medicine.
"Recognition and management of fibromyalgia in HBsAg-positive patients will aid in improvement of quality-of-life," researchers wrote. "We fully accept that our preliminary results require confirmation in (larger) studies... More work is needed to ... understand the role played by, and the relevance of, infections (including HBV) in fibromyalgia syndrome pathogenesis."(3)
1. Source: www.ncbi.nlm.nih.gov/pubmed/24224614
2. Source www.ncbi.nlm.nih.gov/pubmed/24204048
3. Source: www.ncbi.nlm.nih.gov/pubmed/24179575
Experts: Do Not Rush to Treat HBV-Infected Children
Experts reviewed studies on the pros and cons of treating children infected with HBV and found few reasons to rush to treat infected children, especially with antivirals, according to their commentary published in the November issue of the Journal of Antiviral Therapy.
To date, the most common treatment children have received has been interferon, which has not been highly successful. Most children achieve HBeAg serocoversion (losing HBeAg and developing "e" antibodies) on their own without treatment.
Doctors are hesitant to use antivirals in children, because once started it is difficult to stop them. Children risk developing drug resistance with long-term use and a dangerous resurgence of infection once antiviral treatment stops.
"... It is still unknown whether (drug-induced) earlier (HBeAg) seroconversion can modify the natural history of the disease, considering that two-thirds of cirrhosis-related complications and (liver cancers) in Asian patients with hepatitis B occur after HBeAg seroconversion," they wrote.
There have been few studies with a sufficiently long follow-up period to even, "accurately assess the risk of progression towards serious liver disease in children with chronic hepatitis B."
Although (HBeAg) seroconversion (either spontaneous or drug-induced) appears to improve children's health, there have been reports of liver cancer in children even after they seroconverted.
"There is no accurate standard for treatment of chronic hepatitis B in childhood: the age to undergo treatment is not defined; the cut-off value for HBV DNA and for (ALT) in children has not yet been established. When therapy is indicated, the preferred choice of therapeutic agent is still not clear."
Finally, studies into hepatitis B management in children are limited and little is known how children respond to the different available treatments.
"To date, it remains (un)clear in which conditions children should be treated or not," they wrote. "Thus, careful understanding of the natural history of HBV infection and consideration of likelihood of response and potential adverse events and the possibility of favorable spontaneous viral clearance is needed before considering treatment of infected children."
Primary Care Doctors Essential in Treating Immigrants at Risk of Liver Cancer
Liver cancer is the ninth-leading cause of cancer deaths in the U.S. and hepatitis B or C causes nearly 80 % of these cancers. Immigrants are at particularly high risk and one New York-based study found that 40% of immigrants who tested positive for viral hepatitis never returned for additional care, leaving them at high risk of liver cancer.
Researchers reviewed this data, mined from Hepatitis Outreach Network program, and surveyed 20 of these patients' primary care doctors to find out why.
The doctors primarily served Korean, Chinese, Egyptian, and Russian immigrant patients. The barriers to proper care for these immigrants included busy work schedules and limited English proficiency. Doctors said if they could be more involved in patient care and have better connections to the patients’ cultural communities that follow-up efforts would be more successful.
"Providers perceived that they are gatekeepers to specialty care for their patients and therefore key persons to engage in viral hepatitis evaluation and management by specialists," researchers wrote in the November issue of the Journal of Cancer Education. "This initial study suggests that re-focusing energy into primary care physicians might offer promise for improved care for individuals from immigrant communities who have viral hepatitis to help them engage in care and thereby reduce the burden of liver cancer."
Relapse Rate Low in Those Who Respond Well to Entecavir
A study in Argentina finds that patients who respond well to the antiviral entecavir (Baraclude) and lose HBeAg and the surface antigen tend to do well one year after treatment ends.
Doctors treated 169 patients for an average 181 weeks (about 3.5 years). When treatment started, 61% were HBeAg-positive, 23% had cirrhosis, and average HBV DNA levels were high. After 3.5 years of treatment:
92% achieved undetectable HBV DNA
71% lost HBeAg and 68% developed "e" antibodies (seroconversion)
14% lost HBsAg
And 13% developed surface antibodies, indicating they had cleared the infection.
Thirty-five patients (20%) who responded well to entecavir and ended treatment were re-evaluated 69 weeks (1.3 years) later. Thirty-three had seroconverted and 18 had lost HBsAg and developed surface antibodies.
Nine patients (26%) relapsed with a reappearance of HBeAg in three cases and high viral loads after 48 weeks off-treatment.
However, no patient who lost HBsAg or who developed surface antibodies had a relapse after treatment, according to the report in the November issue of the Journal of Viral Hepatitis.
"After entecavir discontinuation, HBsAg seroconversion was maintained in 100% of the patients, HBeAg seroconversion (was) maintained in 90%, and (the) virological relapse rate was 24%," researchers wrote.
Only 64% of U.S. Health Care Providers Are Immunized Against Hepatitis B
A disturbing report in the November issue of Public Health Reports by the U.S. Centers for Disease Control and Prevention finds that only 64% of U.S. health care providers have been immunized against hepatitis B, despite current medical recommendations for these at-risk workers.
The CDC researchers compared self-reported hepatitis B vaccinations with immunization rates in the general population using the 2010 National Health Interview Survey (NHIS) data. Those surveys were asked if they had received one or more or all three required vaccine doses.
They found 69.5% reported receiving at least one vaccine dose and 63.4% reported receiving all three doses.
Among health care workers who had direct patient contact, 80.7% had received at least one dose and 74% had all three doses.
Those who had all three doses tended to have more than a high school education, had been vaccinated against the flu in the past year, and had been tested for HIV at some point. These 2010 immunizations rates were similar to those reported for health care workers in 2004.
"The 2010 ... vaccine coverage estimate among health care personnel remained well below the Healthy People 2010 goal of 90%," CDC researchers wrote. "Efforts to target unvaccinated health care personnel for pre-exposure hepatitis B protection should be encouraged."
Studies Reveal Important Information about Hepatitis B in Women
Because men appear to suffer more liver damage from hepatitis B infection, and are therefore more frequently treated, enrolled in clinical trials and studied, there has been scant information on how HBV infection progresses in women and what role ethnicity or HBV strain or genotype play. This information is vital, considering that many new infections occur when infected mothers transmit the virus to their newborns.
Asian women with genotypes B or C remain HBeAg-positive longer: An international research team, led by Cedars-Sinai Medical Center doctors, assessed 355 HBV-infected women for race (Asian vs. non-Asian), age, alanine aminotransferase (ALT), and HBeAg status.
The average age was 41, most had moderately elevated ALT levels (indicating some liver damage), high HBV DNA levels, and 44.4% were HBeAg-positive. About 40% were Asian and 49.6% were Caucasian. HBV genotypes were available for about half of the study participants.
Researchers at the 64th annual American Association for the Study of Liver Diseases (AASLD) conference in Washington D.C. in November reported:
"In this large cohort of HBV patients, women under 35 had a significantly higher likelihood of HBeAg positivity and high HBV viral load," they wrote. "Asian women and those with genotypes B/C are also more likely to be HBeAg-positive... These results suggest higher risk of HBV perinatal (mother-to-child) transmission in these groups."
One-fifth of women experience ALT flares after giving birth: Australian researchers followed 126 HBV-infected women after they gave birth and discovered that 21% experienced an ALT flare (indicating liver damage) in the weeks after giving birth. Those who had flares were more likely to be younger, HBeAg-positive, and in their first pregnancy.
"Clinicians need to be aware of this phenomenon so women at the highest risk can be appropriately identified for close monitoring in the post-natal period," they wrote.
Source 1. AASLD Control ID: 1735475. HBeAg status, race and DNA levels in women with chronic hepatitis B infection.
Source 2: AASLD Control ID: 1732687. Clinical and virological factors that predict post partum flares in pregnant women with chronic HBV
Hepatitis B Risk in African Immigrants and African-Americans Studied
While Africans who have recently emigrated to the U.S. have high rates of hepatitis B, there has been little research into how their disease with its various genotypes progress. Two studies from Minnesota, presented at the AASLD conference, explore hepatitis B in east and west African immigrant communities.
In one study, University of Minnesota researchers followed 400 Asian and African immigrant adults who were treated for hepatitis B at outpatient clinics between 2007 and 2010—the average age was 41, 58% were males and 42% were female.
About 26% were Southeast Asian, 38% East African, 13% East Asian, 12% US-born, and 7% West African. Patients from Asia had higher rates of HBeAg-positivity, while only 8% of East Africans and 4% of West African were HBeAg-positive. Patients from Africa tended to have lower viral loads than those from Asia, and lower (healthier) ALT levels, indicating less liver damage.
"From this retrospective study, we found that ... (patients) from Southeast Asia were more likely to have active hepatitis B, more advanced liver disease at presentation, and an increased risk of developing liver cancer, while patients from East Africa were less likely to receive adequate screening and follow up," researchers reported.
Study compares hepatitis B in African-Americans and African immigrants: A second study, led by the Mayo Clinic College of Medicine, compared hepatitis B progression in 56 African-Americans and 163 African immigrants. While genotype A was most common in both groups, a substantial proportion of African immigrants had genotypes E or D, neither of which were found in African-Americans.
West Africans were more likely to have abnormal ALT levels, indicating current liver damage, and high viral loads than East Africans. The predominant genotype among West Africans was E (60%), whereas genotypes A (67%) and D (23%) were common in East Africans.
African-Americans were more likely to be HBeAg-positive and have higher HBV DNA levels compared to African immigrants, who were more likely to be "inactive carriers."
"Significant clinical and virological differences were found between (African immigrants and African-Americans)..., which may be attributable to differences in HBV epidemiology as well as genotype," researchers noted. They urged more studies to be done so those at higher risk of liver damage (African-Americans and West Africans) could be monitored and treated adequately.
Source 1. AASLD Control ID: 1730673. Comparison of demographic, virologic, and outcome characteristics of people with chronic hepatitis B in a major US urban center.
Source 2. AASLD Control ID 1731291. Differences in epidemiological and clinical characteristics in US- versus foreign-born Americans of African descent with chronic hepatitis B Enrolled in the HBRN Cohort.
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