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HBV Journal Review

HBV Journal Review
December 1, 2012, Vol 9, no 12
by Christine M. Kukka

PDF PDF (download)

Vaccination May Not Protect Against HBV with Surface Antigen Mutation

In a disturbing development, researchers have documented the first case of infection with a mutated hepatitis B virus (HBV) that was able to infect a vaccinated man.

“The possibility of an infection with HBV despite an effective vaccination may pose a major health issue, requiring a change in routine diagnostic and screening programs,” German researchers wrote in the Journal of the International AIDS Society 2012.

The hepatitis B vaccine contains only the hepatitis B surface antigen (HBsAg) in order to trigger the immune system to create surface antibodies that are primed to attack if there was exposure to the real virus.

Recently, researchers have found patients with mutated HBsAg that are able to avoid the vaccine-induced or antiviral treatment-induced surface antibodies. They call these mutated viral proteins “vaccine escape” surface antigens because they can survive despite immunization.

However, this is the first documented case where “vaccine escape” HBV infected a previously-vaccinated person. According to the report, a young man who had sex with men was treated for a newly-diagnosed HIV infection. Because his alanine aminotransferase (ALT) levels were above normal–indicating liver damage–he was tested for hepatitis B. He tested negative for HBsAg and was found to have high levels of surface antibodies, probably due to his immunization.

But three months later, he was retested and this time he tested positive for HBsAg; his surface antibodies had vanished, and his HBV DNA load was high. When his HBV was analyzed, he was found to have HBV genotype F with the "vaccine escape" mutation in the surface antigen.

“Despite a fairly high CD4 count (indicating a strong immune system), the transmission may have been promoted by a loss of immunity through an acute HIV infection,” researchers noted. “Clinicians need to be aware of the possibility of HBV infections with mutant viruses.”

HBV-Infected Fathers Appear Not to Pose Infection Risk to Fetuses

Men infected with HBV can safely have sex with their pregnant partners without posing an infection risk to the fetus, according to a report in the November issue of the International Journal of Infectious Diseases.

Chinese researchers followed 164 couples where the father was the only one infected with HBV. In all cases the wives had been immunized against hepatitis B. The doctors sampled the amniotic and cord fluid for HBV, and screened all infants for infection for one year after birth. All babies had been treated with hepatitis B immune globulin and immunized at birth.

None of the offspring of the HBV-infected fathers became infected. “The infection of fetuses with HBV from the spermatozoa of carrier fathers seems unlikely, especially in an area where pre-conception hepatitis B vaccination is routinely provided,” researchers concluded.

Genotype B Prone to Chronic Infection, and Genotype D Prone to Liver Cancer Despite Treatment

HBV genotypes or strains developed and evolved over thousands of years in specific regions of the world. Today, researchers are discovering that each genotype may be unique when it comes to disease progression and severity.

Two recent reports from the 2012 American Association for the Study of Liver Diseases (AASLD) suggest:

  • HBV genotype B, found in Asia and Oceania, may be more prone to cause chronic hepatitis B infection–lasting for more than six months–than genotypes A or C.

  • And genotype D, found in the Middle East, Mediterranean Basin and Central Asia, can lead to liver cancer despite treatment with antivirals.

Japanese researchers followed 215 Japanese adult patients who were newly infected with HBV–52.5% had genotype A, 12% had genotype B, and 34% had genotype C. Only six (2.8%) patients–five of whom had genotype B–failed to clear the infection within 12 months.

The second study from Italy found that many patients with hepatitis B "e" antigen-negative hepatitis B still developed liver cancer, despite treatment with antivirals. In other genotypes, antivirals have been found to lower the risk of liver cancer.

Researchers measured liver cancer rates in 235 antiviral-treated patients, all with genotype D, who had been treated for about 18 months. Over a seven-year observation period, cancer developed in:

  • 15 of 120 patients treated with entecavir (Baraclude) (12.5%)

  • 7 of 27 treated with tenofovir (Viread) (13.4%)

  • 6 of 7 treated with lamivudine (Epivir-HBV) (85.7%)

  • 4 of 18 (22.2%) treated with adefovir (Hepsera) plus lamivudine

  • And in no patients treated with telbivudine (Tyzeka) (2 patients).

As might be expected, liver cancer was higher in patients with cirrhosis than in those without the severe liver scarring (35% vs. 2.5%). What surprised researchers was the high rate of liver cancer, despite the long-term antiviral treatment, suggesting genotype D carries a higher risk of cancer.

Lamivudine Results Raising Concern Among Researchers

As noted in the previous report, lamivudine failed to prevent liver cancer in six of seven cirrhotic patients with genotype D treated with the antiviral. Other reports presented at AASLD also raised concerns about this antiviral, which was the first antiviral approved to treat hepatitis B, but later found to have a high rate of drug resistance.

Increased cancer risk in older men: In a unique study, researchers compared liver cancer risk in patients who had been successfully treated with antivirals and achieved low viral loads. Despite the low viral loads, which should have lowered cancer risk, a small group of older, male patients developed liver cancer. Seventy-seven percent of those developing liver cancer had been treated with lamivudine.

"The association with lamivudine exposure raises the possibility of drug-induced mutations associated with an increased risk of liver cancer development–this possibility is currently under investigation," researchers noted.

Avoid lamivudine when treating cancer patients: To prevent reactivation of hepatitis B in patients treated with chemotherapy, doctors often use lamivudine to prevent reactivation in patients with inactive or resolved hepatitis B.

Chemotherapy weakens the immune system and can contribute to life-threatening reactivation of hepatitis B. Because of this, physicians often prescribe antivirals to prevent reactivation during chemotherapy treatment for other cancers.

One study described two men, both HBeAg-negative, who were treated with chemotherapy for lymphoma. They were both given lamivudine during treatment to suppress any viral resurgence. However, several months after chemotherapy ended, both men died from liver failure despite their continued lamivudine treatment.

"Lamivudine should not be used for prophylaxis of patients with chronic hepatitis B with detectable HBV DNA undergoing chemotherapy with R-CHOP, even if they have never had exposure to lamivudine in the past," researchers wrote. "In this setting, lamivudine failure due to resistance can develop quickly leading to liver failure that cannot be salvaged with (the antiviral) tenofovir."

In another study, researchers compared the effectiveness of the antivirals lamivudine, telbivudine and entecavir in preventing HBV reactivation after chemotherapy for a variety of cancers. They found lamivudine to be the least effective.

HBeAg Seroconversion Rate Lower with Entecavir Than Earlier Reported

Is entecavir as good as early studies touted, resulting in HBeAg serconversion (loss of HBeAg and development of "e" antibodies) within 12 months in 21% of those treated? Newer studies found lower seroconversion rates, so Stanford University researchers followed 136 HBeAg-positive patients treated with 0.5 mg of entecavir daily for three years to assess the accurate HBeAg seroconversion rate. About 61% of patients were male and average age was 39.

According to their report published in the November issue of the European Journal of Gastroenterology and Hepatology, at months 12, 24, and 36, undetectable HBV DNA was achieved in 41%, 66%, and 85% of those treated.

However, the HBeAg seroconversion rates were much lower than early reports indicated–4.8% at 12 months, 20% at 24 months, and 30% at 36 months.

"In clinical settings, entecavir is highly tolerable and potent at suppressing hepatitis B viremia," researchers wrote, "however, the rates of HBeAg seroconversion appear to be much lower than those reported, highlighting the importance of appropriate counseling and planning for long-term therapy."

Environmental Toxin Dramatically Increases Liver Cancer in Asia and Africa

According to a report in Hepatology Monthly, aflatoxin is partially to blame for the high rate of liver cancer in Asia and sub-Saharan Africa, where hepatitis B is prevalent.

Aflatoxin is a toxic poison produced by a fungus found in soil and decaying plant matter. It contaminates more than 25% of maize and groundnut crops produced in some African countries and also affects rice. Aflatoxin causes liver cancer, suppresses the immune system, and slows the growth and development of children.

U.S. researchers evaluated various studies of aflatoxins and reported, "... the data suggest that dietary exposure to aflatoxins is an important contributor to the high incidence of liver cancer in Asia and sub-Saharan Africa, where almost 82% of the cases occur."

Antivirals Reduce Liver Cancer Risk in Some–But Not All

A number of studies unveiled at the AASLD conference and published this month in the Journal of the American Medical Association (JAMA) find that antivirals are effective in some cases in lowering liver cancer rates in some hepatitis B patients.

But some patients–including those with cirrhosis–appear to remain at high risk of cancer despite treatment.

A Taiwanese study published in JAMA revealed that people treated with antivirals after a liver transplant had lower rates of cancer recurrence than those not treated with antivirals after surgery (20.5% vs. 43.6%) and lower death rates (10.6% vs. 28.3%). This was true even in transplant patients who had cirrhosis.

However several AASLD studies found that antiviral treatment did not substantially decrease liver cancer risk. A Danish review of numerous studies found, "In patients with chronic hepatitis B, antiviral treatment decreases the incidence of liver cancer in a subgroup of patients with established cirrhosis, but not in patients without cirrhosis. The absolute risk reduction is modest and especially in cirrhosis, liver cancer (monitoring) surveillance is still essential."

Contradicting this finding, a Chinese study found cirrhosis to increase liver cancer risk despite antiviral treatment. The researchers followed 531 patients treated with antivirals and found 22 to have developed liver cancer–all of whom had cirrhosis when treatment began.

"Cirrhosis status before antiviral treatment (begins) is an independent risk factor of liver cancer....And in the first or second years after antiviral therapy, even (when patients' viral load decrease and liver damage diminishes), the risk of liver cancer was not significantly reduced," they wrote.

Because It Can Be Reversed, New Terminology Needed to Describe Cirrhosis

As recently as five to 10 years ago, cirrhosis was considered the final swan song of liver disease–usually terminal and never reversible.

But recent discoveries show that antiviral treatment can stop and even reverse cirrhosis. Because of this, experts writing in the journal Alimentary Pharmacology & Therapeutics, are calling for different terms and vocabulary in how doctors diagnose and treat cirrhosis.

Recent developments in the understanding of how the liver responds to HBV infection–including the evolution of fibrosis and development of severe scarring or cirrhosis–"...have revealed that the process is a dynamic one and a capacity for recovery from any degree of fibrosis including those associated with cirrhosis is plausible," they wrote.

They reviewed recent studies that show the remarkable ability of livers–even cirrhotic ones–to recover and create healthy liver tissue with treatment.

"There is abundant clinical evidence in support of the idea of the reversibility of cirrhosis in patients with ... advanced hepatic disease including viral, autoimmune and metabolic/infiltrative liver disease," they noted. "The concept of cirrhosis has changed from being a form of static and irreversible entity to a dynamic and reversible disease stage."

Instead of describing livers as having either fibrosis or cirrhosis, the writers call for a more nuanced approach that utilize several stages to identify fibrosis or cirrhosis that can still be reversed through treatment.

Depression During Interferon More Severe in Hepatitis C Than Hepatitis B Patients

A study of 73 hepatitis B and 85 hepatitis C Asian patients treated with interferon found that those with hepatitis C and/or prior depression experienced more depression during treatment than those with hepatitis B, according to the report in the journal of Antiviral Therapy.

Historically, there have been more reports of depression in white males with hepatitis C treated with interferon than among Asians with hepatitis B treated with the same dose of interferon. This has led some to speculate that race, gender and/or type of viral infection could play a role in dictating the severity of depressive side effects during interferon treatment.

Taiwanese researchers screened for depression before treatment began and then biweekly until treatment ended. They found depression was heightened for all patients between treatment weeks 2-10 and between weeks 16-36.

They found, however, that hepatitis C patients and those with pre-existing depression had more severe symptoms. "Depression ... should be early and actively assessed especially in patients with chronic hepatitis C or pre-existing depression," they recommended.

Nearly Half of HBV-Infected Children Eventually Lose HBeAg–With or Without Treatment

A team of Canadian researchers followed 252 HBeAg-positive children for 25 years into adulthood to see how the infection progressed, how many lost HBeAg and how many achieved inactive infection without liver damage.

Among the children in the study, 59.9% had HBV-infected mothers, 77% were of Asian descent, and 33 (13%) had been treated with interferon.

About 41.7% lost HBeAg over an average 19 years of follow-up. HBeAg seroconversion was not affected by how the children became infected, their gender, or whether they were treated. By age 19, about half of the children had achieved "inactive" hepatitis B, with no apparent liver damage and low viral load, according to the report in the Journal of Viral Hepatitis.

Those who were not Asian and who had moderate liver damage during childhood had higher rates of HBeAg serconversion and inactive disease later in life.

Researchers Identify the Protein Doorway That Allows HBV to Infect Liver Cells

Chinese researchers have found the protein "receptor" or doorway that allows HBV to attach itself to and infect liver cells. They scoured thousands of proteins and RNA in tree shrew cells (the only mammal in addition to humans and chimpanzees that can be infected with HBV), to find sodium taurocholate cotransporting polypeptide or NTCP–the protein that HBV target to infect liver cells.

According to the report published in eLife, both hepatitis B and D viruses target this receptor. After researchers tried silencing the gene that controls NTCP, they found that HBV had difficulty attaching to and replicating in liver cells without the NTCP.

This discovery means researchers can use this gene to develop treatments that might shut down this receptor and halt HBV replication in liver cells.

Tenofovir Used to Treat Many Newly-Infected with Multi-Drug Resistant HBV

Italian doctors treated a man who contracted a severe hepatitis B infection with HBV that was reportedly already resistant to lamivudine and telbivudine. Doctors quickly treated him successfully with tenofovir, which proved to be effective against the drug-resistant HBV.

The patient, according to the report in the November issue of the Journal of Medical Virology, cleared the infection, and developed surface antibodies. He had contracted the infection with the drug-resistant HBV in Thailand.

Researchers stressed that in cases of life-threatening acute hepatitis B cases, doctors should screen for drug resistance so the most effective antiviral–in most cases broad spectrum tenofovir–can be used to suppress the infection.

Another Study Links Hepatitis B and Diabetes

A study of nearly 8,000 Korean men and women (average age 49) confirmed earlier studies that show adults with hepatitis B are one and a-half times more likely to also have diabetes or some kind of insulin sensitivity, according to a study published in the World Journal of Gastroenterology.

"For subjects identified with insulin resistance, the odds ratio of an accompanying diagnosis of chronic hepatitis B was 1.534 after adjustment for age, gender, body mass index and amount of alcohol consumption," they reported. They suggested that all adults with chronic hepatitis B also be monitored for insulin resistance and/or diabetes.



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