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HBV Journal Review

HBV Journal Review
February 1, 2013, Vol 10, no 2
by Christine M. Kukka

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Chances Are Low Patients Will Lose the “e” Antigen During Antiviral Treatment

A recent study shows that the chance of losing the hepatitis B “e” antigen (HBeAg) and developing “e” antibodies during antiviral treatment remains far lower than early studies suggested.

The U.S. study followed 333 HBeAg-positive patients, most Asian-American. One-quarter received lamivudine (Epivir-HBV), 16% received adefovir (Hepsera), 51% received entecavir (Baraclude) and 8% were treated with tenofovir (Viread).

HBeAg seroconversion (losing “e” antigen and developing “e” antibodies) after 12 months of treatment averaged 8.2%—far lower than clinical trials initially found.

“The HBeAg seroconversion rate … appears much lower than those reported in pivotal trials, especially in those with lower alanine amino-transferase (ALT) and higher HBV DNA levels,” researchers wrote in the Journal of Gastroenterology and Hepatology. ALT levels rise when liver cells are damaged or die.

“HBeAg-positive patients should be counseled about the high possibility of the long treatment duration required to achieve recommended treatment endpoints,” they wrote.

Interferon Effective in HBeAg-Positive Patients after Lamivudine Fails to Work

Treating patients chronically infected with the hepatitis B virus (HBV) who did not lose HBeAg after antiviral treatment with pegylated interferon (Pegasys) can be very effective, according to a study published in the January issue of the Virology Journal.

Researchers treated 50 patients, who had not lost HBeAg after 96 weeks of treatment with lamivudine, with 48 weeks of pegylated interferon after they stopped taking lamivudine. Interferon is administered as a weekly injection.

After 48 weeks of interferon treatment, 51.2% achieved undetectable viral load (HBV DNA) and lost HBeAg, and 20.9% lost the hepatitis B surface antigen (HBsAg), indicating they were on the way to clearing the infection.

Twenty-four weeks after treatment ended, 44.2% patients remained HBV DNA undetectable and HBeAg-negative, and 18.6% remained HBsAg-negative.

The patients who did best had HBsAg levels under 20,000 IU/mL and lower viral loads.

“Retreatment with pegylated interferon was effective and safe for patients without HBeAg loss after the withdrawal of long-term lamivudine therapy,” researchers wrote. Lowered HBsAg and HBV DNA levels at 12 and 24 weeks into treatment can help predict which patients will succeed on interferon.

Doctors Debate Pros and Cons of Antivirals vs. Interferon for HBeAg-Negative Patients

Two doctors, writing in the journal Liver International, presented their arguments for either pegylated interferon or antivirals when treating HBeAg-negative patients.

The argument for antivirals:
George Papatheodoridis, hepatologist and associate professor of medicine and gastroenterology at the Medical School of Athens University, made the case for antivirals.

“They can be prescribed to all chronic HBV patients, even those with contraindications to interferon and even interferon candidates are usually treated with (antivirals) because of their advantages,” he wrote. “Administration of (antivirals) is easier (one tablet per day compared with weekly interferon injections), tolerance is excellent and the safety profile is good.” In contrast, interferon may cause side effects such as depression and flu-like symptoms that impact a patient's quality of life.

“The current first-line antivirals (entecavir and tenofovir) have minimal or no risk of long-term resistance,” he added. They almost always cause a decline in viral load. “The need for long-term, perhaps indefinite, treatment is the main limitation of antivirals....“However, at most 25% of interferon-treated patients achieve a sustained off-treatment response and therefore more than 75% of them will eventually receive antivirals, even if they start with interferon,” he added.

He admitted there will be concerns about family planning issues with antivirals, and cautioned they should be used carefully in young patients with mild liver disease.

The argument for pegylated interferon:
A team of researchers from the Center for the Study of Liver Disease in Milan made the case for interferon.

“Although antivirals may ensure persistent viral suppression by preventing disease progression in most patients, they require lifelong administration with the hypothetical disadvantages of cost, lack of long-term safety data and, most important, the (zero) null rates of HBsAg seroclearance,” they wrote.

“On the other hand, one year of pegylated interferon has the advantage of providing an immune-mediated control of HBV infection, with the possibility of achieving a sustained off-treatment response in 20% of the patients, ultimately leading to HBsAg loss in approximately 50% of them.”

These success rates can be boosted if doctors carefully select candidates who have elevated ALT levels, lower HBV DNA levels, and HBV genotypes that respond well to interferon. Also, extended treatment beyond the currently-recommended 48 weeks also boosts success.

“Overall, (interferon) is an ideal treatment strategy in selected patients with HBeAg-negative hepatitis B, because of its well-recognized and predictable safety profile and a unique mechanism of antiviral activity leading to long-lasting immune control,” they wrote.

New treatments using a combination of interferon and antivirals such as entecavir and tenofovir, “are ongoing to further increase the rates of HBsAg seroclearance, which remains the 'ideal end-point' in all HBeAg-negative chronic hepatitis B subjects,” they wrote.

Hepatitis B Infections Found Primarily in Middle-aged, Asian-Americans

In January, the journal of Clinical Infectious Diseases published previously-released data that found that half of all chronic hepatitis B infections in the U.S. are found in people aged 44 to 63. Chronic Hepatitis Cohort Study researchers reviewed medical records of more than 1.6 million adults treated between 2006 to 2010. Among them were 2,202 people infected with HBV.

Among those surveyed, 57.8% were Asian-Americans, 28.3% were white and 13.3% were African-American. Most patients (76.3%) had private insurance, 16.5% were covered by Medicare and 5.1% were covered by Medicaid.

Between 2001 to 2010, 22.3% of HBV-infected patients had a liver biopsy, 37.9% were hospitalized at least once, and 2.1% underwent liver transplant for end-stage liver disease. The death rate was 21.6 per 1,000 person-years.

Entecavir and Tenofovir Are Both Cost-Effective, First Treatments

Spanish researchers analyzed recent studies on the cost effectiveness of the antivirals tenofovir and entecavir to determine which was the most economic treatment for patients receiving treatment for the first time.

Their report, published in the journal Parmacoeconomics, evaluated five high-quality studies that performed a cost-effectiveness analysis of the two highly-rated antivirals. It concluded that tenofovir had a slight edge over entecavir in its value and effectiveness.

“In countries where both alternatives are available, it appears that tenofovir dominates entecavir,” they wrote. “These results could help decision-makers and clinicians to understand economic issues regarding the available drugs for first-line treatment of hepatitis B.”

Tenofovir Effective in Patients Who Develop Resistance to Multiple Antivirals

Korean researchers studied how effective tenofovir was in 29 patients who had developed resistance to a combination of antivirals, including entecavir, lamivudine and/or adefovir.

Patients were treated with tenofovir alone (13), or in combination with lamivudine (12) or entecavir (4) for 16 months on average.

Eighteen patients had previously been treated with all three above-mentioned antivirals and 27 were HBeAg-positive with high viral loads.

After 12 months of treatment, 86.2% of the tenofovir-treated patients achieved undetectable viral load and 96.6% achieved it after 24 months. The one patient who did not clear HBV DNA still experienced a three-fold reduction in his viral load, and was close to being undetectable. No patients in this study showed any signs of drug resistance to tenofovir.

HBeAg clearance was 7.4%, 12%, and 27% after 6, 12, and 18 months of treatment.

Researchers, writing in the World Journal of Gastroenterology, concluded that tenofovir was effective in patients with multiple drug resistance.

Travel Clinics Could Be Important Venues to Screen Immigrants for Hepatitis B

Many immigrants and their offspring have never been screened for hepatitis B, even though they have come from countries with high rates of HBV infection. In an innovative approach to screen this at-risk group, the Travel Medicine Center in Cambridge, Mass., screened travelers who came in for pre-travel immunizations for hepatitis B before traveling to their (or their parents’) birth country.

According to their report in the Journal of Travel Medicine, of 13,732 travelers screened between 2008 and 2010, 16% (2,134) were born in countries with high hepatitis B prevalence. Of this group, 230 were tested for hepatitis B.

They found that 3.3% were HBV-infected, 43.6% had already been vaccinated, 59.2% were susceptible and needed vaccination, and 5.5% had resolved hepatitis B infections.

“The travel clinic offers an opportunity to capture, identify, and educate infected persons unaware of their infection, educate those with known results, and initiate preventive action (such as vaccination) for those still susceptible,” researchers noted.

NIH Scientists Study Role of the “e” Antigen in Chronic Hepatitis B

Scientists from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health, and Britain have uncovered the structure and function of the “e” antigen. Their findings, reported in the journal Structure, could lead to new treatments.

HBV has three major antigens (proteins): the hepatitis B surface antigen (HBsAg—also used to safely vaccinate people), the core antigen (HBcAg), and the “e” antigen (HBeAg).

The core and “e” antigens are basically two versions of the same protein, but the core antigen is important for virus production, while the “e” antigen is not. The “e” antigen apparently plays a role in tricking the body’s immune system into “tolerating” the antigens and not generating antibodies to vanquish the infection.

The core antigen generates the shell (capsid) that houses the genetic blueprint of the virus, while the “e” antigen is secreted freely into the bloodstream. The relationship between the e-antigen and the core antigen has been a mystery for the past three decades.

In the new study, researchers developed a unique antibody that was able to bind to the “e” antigen and allowed the antigen to be studied.

They discovered that unlike the core antigen, the “e” antigen splits into two subunits with a unique rotation between the subunits. The rotation stops the protein from assembling and transforms its character. Understanding this unique structure provides a framework for future studies that can uncover the “e” antigen’s role in chronic hepatitis B and possibly lead to a way to prevent hepatitis B from becoming chronic.

More Frequent Screening for Liver Cancer Does Not Yield Benefits

Taiwanese researchers followed 744 adult patients with hepatitis B and thrombocytopenia (low platelet counts in the blood that causes slow blood clotting, possibly due to liver damage) who were screened either every four months or every 12 months for new liver cancer.

Over a three-year period, the group that was screened every four months had a cancer rate of 11.7% and the less-frequently screened group had a rate of 9.7%. Male gender, cirrhosis, and having low platelet counts increased the risk of liver cancer.

However, researchers found no added advantage or survival among patients who were screened every four months during the four-year follow-up period. The only advantage was that smaller tumors were detected with more frequent screening.

“There was no difference in the detection rate of liver cancer between 4- and 12-month U.S. surveillance intervals for patients with chronic viral hepatitis and thrombocytopenia,” the researchers concluded in their report in the American Journal of Gastroenterology.

Immunization Combined with Reducing Aflatoxin Exposure Cuts Liver Cancer

A program in Qidong City in China found that a combination of hepatitis B immunization of newborns and reducing exposure to aflatoxin (a toxic fungus that affects grains) reduced liver cancer rates in young adults 14-fold.

Historically, Qidong City had extremely high rates of HBV infection and exposure to aflatoxin, which affected the corn that the region depended on for food. Both HBV infection and aflatoxin exposure separately cause liver damage and cancer, and when combined they cause dramatic increases in liver cancer.

In 1980, scientists began a program to reduce aflatoxin risk by shifting the 1.1 million residents' diet away from moldy corn (containing aflatoxin) to fresh rice. Economic reforms in China also helped improve access to healthier foods.

Additionally, universal immunization against hepatitis B was offered to all newborns in a trial beginning in 1983.

Liver cancer rates in 2005-2008 (compared to the 1980-1983 period) dropped dramatically as improved diet and immunization occurred in the region. Liver cancer rates declined:

  • 14-fold in ages 20-24
  • 9-fold in ages 30-34
  • And 1.5-fold in ages 35-39.

However, during this period liver cancer continued to increase among the unvaccinated, HBV-infected older adults as long-term hepatitis B infections and past aflatoxin exposure took their toll on the elderly.

The 14-fold cancer reduction in younger adults may reflect the combined effect of reduced aflatoxin exposure and HBV vaccination, scientists reported in the January issue of the journal Carcinogenesis. The decreased cancer in unvaccinated adults age 25 to 39, “... could mainly be attributable to rapid aflatoxin reduction.”

HBV Genotype C Linked to Higher Liver Cancer Rates than Other Genotypes

Hong Kong researchers studied 43 relevant reports published between 1950 and 2012 to see if some HBV strains or genotypes caused higher rates of liver cancer than others.

The reports involved 14,545 patients (average age 43), of whom 71% were male and 17% had cirrhosis. In 33 studies, liver cancer was found in 25% of those with genotype C compared to 12% of those with genotype B.

No difference in liver cancer risk was found between those with genotype A compared to those with genotype D. In 10 other studies, liver cancer risk was higher among genotype C patients than genotypes A and D.

Researchers, writing in the journal Alimentary Pharmacology & Therapeutics, reported, "Genotype C hepatitis B virus is associated with a higher risk of (liver cancer) than other major hepatitis B virus genotypes."

Another Study Casts Doubt on the Long-Term Protection from Immunization

A new study published in Hepatology finds that infants vaccinated against HBV may lose protection against infection during adolescence. This is the third study published in the past two months that questions the longevity of protection from immunization during infancy.

In this study, Taiwanese researchers tested 8,733 high school students born between 1987 and 1991 for surface antigen, and surface antibodies, which shows the vaccine is still doing its job. Most had been immunized before age 3, including 381 who received hepatitis B immunoglobulin (HBIG) as added protection, probably because their mothers were HBV-infected.

They found 1.9% of the students were HBV-infected and only 48.3% had detectable, protective surface antibodies.

Students who received one to two doses of the vaccine—instead of the recommended three doses—were more likely to be infected, as were student who did not receive HBIG (15.4% vs. 1.3%).

Not surprisingly, students born to infected mothers with high viral load themselves had higher infection rates. Interestingly, students with infectious mothers who had been immunized immediately after birth had lower infection rates than those who were immunized the day after birth (14.9% vs. 29.0%).

Researchers administered a booster vaccination to students with undetectable antibodies, and the number of students who achieved protective antibodies after the shot increased from 48.3% to 84.3%.

“A significant proportion of adolescents who had received primary infantile vaccination may have lost their immunological memories against HBsAg,” researchers wrote. “Booster vaccination in subjects aged 15 years or (older) should be considered, especially in subjects born to HBsAg-positive mothers or who have a high risk of HBV exposure.”


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