HBV Journal Review
August 1, 2014, Vol 11, no 8
by Christine M. Kukka
Health Concerns Grow as Researchers Uncover the Risks of "Occult" Hepatitis B
Researchers studying the health effects of "occult" hepatitis B are finding that this infection that can "hide" from conventional lab tests carries a higher risk of liver cancer and poses a risk to the general population when undiagnosed.
This type of hepatitis B occurs when a mutation in the virus' outer coat, made up of the hepatitis B surface antigen (HBsAg), makes it impossible for common lab tests that look for that protein to identify an active HBV infection. The HBsAg lab test is commonly used to identify hepatitis B in patients and even blood supplies.
When lab tests fail to identity HBV infection, people can unknowingly spread the infection to their partners, family members and newborns. And when occult HBV infection goes untreated, a patient's risk of liver cancer is 3.7-fold higher than in patients with "regular" or non-occult hepatitis B, according to a recent report in the August issue of the Journal of Hepatology.
HBsAg has three proteins and in the case of occult HBV, the immune system attacks one of the three surface proteins–the same protein that lab tests look for when screening blood for HBsAg.
Most vaccines contain this exact same HBsAg protein in order to spur production of surface antibodies to fight off an actual infection. In most cases, the vaccine is very effective, but when occult hepatitis B occurs, the vaccine-induced antibodies are powerless against the remaining two surface proteins and viral reproduction and infection can continue.
This concern has grown recently as scientists find a number of children born to HBV-infected mothers, who were immunized at birth, have developed "occult" hepatitis B. Additionally, people with occult hepatitis B can transmit the mutated, "occult" version of HBV to partners and close contacts (even if they're vaccinated), adding to the spread of this hard-to-identify viral hepatitis infection.
Because of the unique genetic make-up of this mutated HBsAg and how it interacts with liver cells, this mutation appears to cause more rapid liver damage and cancer.
Scientists suggest that drug resistance, especially to the antiviral lamivudine (Epivir-HBV), may contribute to development of this mutation.
"Recent studies have reported that (surface mutations) tend to (emerge) with the drug resistance-associated mutations in lamivudine-treated patients, and that the (mutations) .... play a supportive role in the replication of lamivudine-resistant viruses," Italian researchers wrote in the report.
"Therefore it appears of the utmost importance that patients with chronic hepatitis B are screened for the presence of (surface antigen) mutant infection," they recommended. "The detection of these specific HBV variants may indeed be useful for the identification of those patients requiring a preventive and appropriate treatment and a more intensive follow-up strategy for early detection of liver cancer."
Are Current Hepatitis B Tests Missing Some Infections?
When do hepatitis B tests miss true infections?A number of confounding factors, ranging from "occult" hepatitis B increase (see above article), failure of lab tests to pick up extremely low levels of HBsAg, immunizations, and the rapidly changing progression of HBV infection can all conspire to mask the infection from conventional laboratory tests.
A recent study by the U.S. Centers for Disease Control and Prevention, published in the August issue of the Journal of Pediatrics, captures the complexities of hepatitis B testing in the general population. It examined what happened in pregnant women who initially tested positive for HBsAg and then weeks later tested negative for the infection.
All pregnant women in the U.S. are screened for hepatitis B so doctors can promptly immunize their newborns, within 12 hours of birth, to break the mother-to-child infection cycle and also so doctors can treat the liver disease in the pregnant women.
Usually these tests only look for HBsAg, but researchers suggest this can produce an incomplete and inaccurate picture in people.
- If someone has just been vaccinated with HBsAg, a blood test would show only the antigens and doctors would assume the patient was actively infected with HBV. It takes days or weeks for the immune system to respond to the vaccine and produce antibodies to get rid of the HBsAg circulating in the bloodstream. But if doctors tested for both HBsAg and the presence of hepatitis B core antibodies, which attack the "core" of the virus, they would know the HBsAg resulted from a chronic infection. The core antibody is present only when someone has actually been exposed to the real virus and infected.
- There can also be laboratory errors, though the failure rate of the six available commercial tests for HBsAg now on the market is not known.
- Occult hepatitis B, that does not produce the HBsAg that lab tests look for, can also mask an infection and produce a misleading result. Only if tests for the core antibody and HBV DNA were included with the HBsAg test would doctors get a 100% accurate snapshot of someone's infection status if they had occult hepatitis B. However, current medical guidelines only call for HBsAg testing in pregnant women.
In the CDC study, researchers examined 142 "discrepant" cases where pregnant women first tested positive for HBsAg and then tested negative.
- They found that more than half of the cases (75) were false positives, meaning the women were not actually infected. The second round of lab tests in the women, which included a core antibody test, found that 67 of them did not have the core antibody, and therefore they were not infected.
- In other cases of false positives, the women had recently been immunized and still had HBsAg circulating in them from the vaccine.
- In two cases, the false positives were the result of laboratory errors.
- In other cases, patients could have been newly infected with HBV, but when the second test occurred, they had resolved their infections and cleared HBsAg from their bodies.
- In addition to occult hepatitis B rendering inaccurate test results, if women have very low levels of HBsAg, the lab test often fails to identify the minute levels of HBsAg, according to the report.
"When results are in that so-called 'gray zone,' repeat testing of the same or subsequent specimens can result in discrepancies," CDC researchers noted. Researchers speculated that a lab could find HBsAg in a woman's first lab test but miss it the next time because of low HBsAg levels.
HBV genotypes or strains may also play a role in determining which women fall in this hazardous gray zone. In the CDC study, Asian-American women, who often have genotype B or C, were nearly all accurately screened because high viral loads and elevated HBsAg levels are hallmarks of both genotypes.
In contrast, Hispanic women in the study often had genotypes A or H. This genotype is associated with lower HBV DNA levels in women of child-bearing age. Most of the Hispanic women in the study were from Texas, which requires two HBV tests during pregnancy.
Researchers noted that the doubling up of HBV testing in pregnant women, as is now done in Texas, could benefit women by increasing the chance of identifying those with low viral loads who may have tested negative for HBsAg during the first test.
Also, adding a core antibody test to the current HBsAg screening would also produce far more accurate results, researchers noted. CDC experts suggest that to be on the safe side, immediate immunization of newborns should occur whenever there are discrepant results in the mother.
First Case of Tenofovir Resistance Found in Patient with Prior Entecavir Resistance
In the first study of its kind, Japanese researchers reported that a 51-year-old woman has developed drug resistance to the antiviral tenofovir (Viread.) This is the first reported case of drug resistance linked to tenofovir.
Tenofovir currently leads the list of "go to" antiviral drugs to treat hepatitis B. Numerous studies have shown that tenofovir causes no resistance, even after more than five years of treatment.
However, in this report published in the June issue of the journal of Drug Design, Development and Therapy, researchers reported that a woman with HBV genotype C who had developed resistance to the antiviral entecavir (Baraclude) months earlier also developed resistance to tenofovir.
For many months, she had been treated with just entecavir but when her viral load began to rise, doctors added tenofovir to her ongoing entecavir treatment. Her viral load decreased to less than 1,000 international units per milliliter (IU/mL) over 31 months while on the entecavir-tenofovir combination, but then it began to rise again.
When researchers examined the genetic make-up of her HBV, they found that it had mutated after the tenofovir was added. "Long-term therapy with tenofovir against the entecavir-resistant (HBV) has the potential to induce virologic breakthrough and resistance, and careful follow-up should be carried out," they wrote.
Even Specialists Fail to Treat Hepatitis in Patients Who Qualify for Treatment
The latest in a series of studies finds that primary care physicians–and even gastroenterologists who specialize in digestive diseases–fail to treat hepatitis B patients who qualify for treatment.
The latest study by Stanford University Medical Center researchers compared treatment rates in 1,976 hepatitis B patients seen by primary care clinics, gastroenterologists (these doctors specialize in digestive organs, including the liver) and hepatologists (gastroenterologists who specialize in liver diseases).
All three clinics served patients of similar age, gender and ethnicity. About 53% of patients treated at gastroenterology and hepatology clinics should have been treated based on current medical guidelines due to their liver damage.
However, hepatology clinics treated only 59% of eligible patients and gastroenterology clinics treated only 45% of them.
The reasons doctors gave for failing to render proper treatment included:
- They thought normal alanine aminotransferase (ALT) levels indicated there was no liver damage and no need for treatment. ALT levels rise above normal when liver cells are injured or die from the infection. Medical guidelines recommend treatment, even if ALT levels are slightly above normal, if patients are older, male and have elevated viral load depending on their hepatitis B "e" antigen status.
- Doctors also said they wanted more time to observe patients, and sometimes patients themselves refused treatment.
The reasons hepatologists gave for starting treatment was because of patients' older age, male gender (which increases risk of liver disease) and better knowledge of medical guidelines.
"Community gastroenterology and university liver clinics treated about one-half to two-thirds of eligible patients," researchers noted in their study (1) published in the July issue of the journal of Digestive Diseases and Sciences. Educating both providers and patients about the benefits of treatment in the prevention of liver disease and cancer should occur, they added. Providers should also be taught that treatment may be needed when patients' ALT levels are in the upper range of normal.
An unrelated study by the Pacific Health Foundation, published in the July issue of the Journal of Clinical Gastroenterolgy, came to a similar conclusion. It compared treatment rates by primary care providers and gastroenterologists over a six-month period.
Using current medical treatment guidelines, they found that specialists treated eligible patients far more than primary care providers (45% vs. 25%), but "...there are still a considerable number of patients from both settings who did not receive treatment despite being eligible." (2)
Source 1: www.ncbi.nlm.nih.gov/pubmed/25060778
Source 2: www.ncbi.nlm.nih.gov/pubmed/25014233
No Benefit Found from Antiviral Treatment after Liver Cancer Surgery
In a discouraging study, Taiwanese researchers found that hepatitis B patients who underwent surgery for liver cancer derived no benefit from antiviral treatment after surgery. In fact, according to the report published in the July issue of the journal PLoS One, treated patients fared worse than untreated patients.
Researchers followed 3,855 patients with HBV-related liver cancer between 2004 and 2009. About 12.7% (490) were treated with antivirals to suppress their HBV infection following liver cancer treatment. Those treated with antivirals tended to be younger, have earlier stage cancer and smaller tumors compared with untreated patients.
Despite their youth and early cancer diagnosis, the treated group experienced a faster recurrence of cancer and earlier deaths than untreated patients.
"This study found that adjuvant antiviral therapy did not reduce the risk of liver cancer progression or mortality in HBV-related liver cancer patients," researchers noted.
Another Study Confirms Success of Sequential Antiviral and Interferon Treatment
Another study in Italy confirms that adding pegylated interferon (Pegasys) to ongoing antiviral treatment may clear the hepatitis B surface antigen (HBsAg). In this case, the patient had hard-to-treat HBeAg-negative hepatitis B and eventually cleared HBsAg after the sequential treatment.
Recently, reports are emerging that this sequential approach, which adds interferon to ongoing antiviral treatment, appears to be highly successful in clearing the infection.
According to the latest report in the July issue of the World Journal of Gastroenterology, Italian researchers began treating a Caucasian male with HBV genotype D with lamivudine in 2002. Eventually the antiviral adefovir (Hepsera) was added to his treatment because of the development of lamivudine-resistance.
In 2011, because of his liver stiffness/fibrosis and his young age (44), doctors added the interferon to the ongoing antiviral treatment for three months. After three months of combination treatment, doctors stopped the antivirals and treated him with only interferon for three more months.
The patient's HBsAg levels began to decline one month after interferon was added, and he completely cleared HBsAg and achieved undetectable HBV DNA after treatment stopped. While he did not develop surface antibodies, the hallmark of clearing the infection entirely, the risk of liver damage greatly diminishes when HBsAg and HBV DNA disappear.
"HBsAg clearance by the addition of a short course of (pegylated interferon) represents an important result with clinical and pharmaco-economic implications, considering that (antiviral) therapy in HBeAg-negative chronic hepatitis B patients is considered a long-lasting/life-long treatment," they noted.
Snapshot of Hepatitis B in the United States
In the recently published Institute of Medicine's Committee on the Prevention and Control of Viral Hepatitis Infection's national strategy for prevention and control of hepatitis B and C book, experts included an overview of hepatitis B's impact on Americans' health.
- About 3.5% to 5.3% of people in the U.S. live with chronic hepatitis B or C, with up to 1.4 million infected with HBV.
- Viral hepatitis is 3- to 5-times more prevalent in the U.S. than HIV infection.
- About 65% of people infected with HBV are unaware of their infection.
- About 43,000 new acute hepatitis B infections occur each year, despite the availablity of a safe an effective vaccine.
- About 1,000 infants acquire HBV from their infected mothers each year, despite availability of immediate immunization to prevent mother-to-child infection.
- African-Americans have the highest rate of new HBV infections, with most occurring in the South, where immunization rates are lower.
- Immigrants from Asia and the Pacific Islands make up the largest foreign-born population at risk for chronic hepatitis B.
- Every year, an estimated 40,000 to 45,000 of HBV-infected people enter the United States legally.
Metformin Safe and Effective in Cirrhotic Patients with Diabetes Type 2
A study by Mayo Clinic researchers reverses a widely-held medical practice that discontinued the type 2 diabetes drug metformin in diabetic patients who developed cirrhosis (severe liver scarring).
Metformin is a very effective oral medication that helps liver cells absorb glucose. Historically, doctors discontinued this drug in diabetic patients once they developed cirrhosis in the mistaken belief that the medications might harm the vulnerable liver and cause lactic acidosis (which occurs when cells don't get the oxygen they need, and body tissue and blood has low pH).
The Mayo study, published in the June issue of Hepatology, found that continuing metformin in patients who had severe liver scarring actually benefited them and improved survival. This study is important because cirrhotic patients have higher rates of type 2 diabetes than the general public.
In the study, 172 cirrhotic, diabetic patients continued metformin while 78 discontinued the drug. Patients who continued metformin on average lived 11.8 years more, compared to those who discontinued the drug and lived only 5.6 more years. There was no diagnosis of lactic acidosis in any of the patients who continued to take metformin.
Continuation of metformin after cirrhosis diagnosis reduced the risk of death by 57%. Metformin should therefore be continued in diabetic patients with cirrhosis if there is no specific contraindication, researchers concluded.
140618163926.htm and http://onlinelibrary.wiley.com/doi/10.1002/
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