HBV Journal Review
October 1, 2012, Vol 9, no 10
by Christine M. Kukka
Researchers Say Young, Immune-Tolerant Patients Should Be Treated
For years, scientists did not consider children, teens, and young adults in the "immune-tolerant" stage of hepatitis B infection—marked by high viral load and no apparent signs of liver damage—as candidates for treatment.
However, new findings published in the September issue of Gastroenterology has turned that thinking on its ear and may completely change current treatment guidelines. A multinational team of researchers suggests these young patients may benefit from early treatment, especially before their immune systems and fighter "T" cells become "ex-hausted" by years or decades of fighting a chronic hepatitis B virus (HBV) infection.
If confirmed by additional studies, these findings could represent a major sea change in hepatitis B treatment of younger patients.
These patients are nearly all infected at birth, have high viral loads (often in the millions of copies per milliliter) and are hepatitis B "e" antigen (HBeAg)-positive. Despite their high viral loads, these patients have normal alanine aminotransferase (ALT) levels, indicating a lack of liver damage. (ALT levels can rise when HBV-infected liver cells are attacked by the immune system's killer T cells.)
Because of the normal ALT levels, scientists assumed that their immune system was "tolerant" of the virus and therefore did not identify and attack the HBV-infected liver cells.
But new research suggests these young patients' immune systems are indeed capable of targeting HBV with distinct cytokines that help T cells identify and attack viruses.
And, they found that the longer a patient is left untreated, the less effective the cytokines and T cells become, so even if the patient is treated later in life with antivirals or interferon, the T cells have become exhausted and are not able to effectively fight the chronic infection.
The researchers argue that if treated early, these young patients' immune systems might produce a stronger offensive early enough to possibly clear the infection and avoid severe liver damage later in life.
"HBV infection in younger patients is not associated with an immune ... T-cell tolerance," they wrote. "On the contrary, children and young adults with chronic HBV infection have an HBV-specific immune profile that is less compromised than that observed in older patients."
An accompanying editorial noted that the research, "... counters the prevailing opinion that immune recognition of HBV is somehow completed averted in certain individuals."
The editorial noted that the findings raise more questions, including whether a different treatment strategy is needed during early infection to help the immune system fight the infection.
"Finally, young chronic hepatitis B patients who are most likely to go chronic but are least likely to be treated may now be considered more suitable for treatment," the editors concluded.
Antiviral-Induced HBeAg Loss in Young Patients May Not Last
Despite the findings suggested above, a separate study from Taiwan found that young people (under age 30) who lost the hepatitis B "e" antigen (HBeAg) and developed "e" antibodies (called seroconversion) during antiviral treatment were at higher risk of becoming HBeAg positive again, after they stopped treatment, compared to patients who seroconverted spontaneously without treatment.
According to the study reported in the September issue of the Journal of Infectious Diseases, researchers monitored 148 patients who lost HBeAg during antiviral treatment and compared them with a control group of 407 patients who spontaneously seroconverted.
They followed the untreated group for 1,652.8 person years and the antiviral-treated group for 465.2 person-years. Among the patients who seroconverted before they reached age 30, those treated with antivirals had higher rates of HBeAg return (called HBeAg seroreversion) within two years (12%) than those who spontaneously seroconverted (2.9%). Those who became HBeAg positive again also had a higher risk of reactivation of their infection, with elevated viral load and liver damage.
HBeAg seroconverters may not have a durable response after stopping therapy, researchers noted. "For patients achieving HBeAg seroconversion before 30 years of age, the risk of HBeAg seroreversion and HBV reactivation is higher in (antiviral)-induced seroconverters than spontaneous HBeAg seroconverters."
Interferon More Effective in Younger Patients, and When Extended to 72 Weeks
Pegylated interferon (Pegasys) works best in younger patients and if treatment is extended longer than 24 weeks, according to a report in a Chinese medical journal (Pubmed 22886227).
Fujian Medical University researchers explored which HBeAg-positive patients responded best to weekly 180 μg interferon injections, which boost the immune system to fight infection. They compared 37 patients who received 24 weeks of treatment and 37 patients who received about 72 weeks of interferon.
The HBeAg seroconversion rate was 54.5% in patients treated for 72 weeks compared to 29.7% in patients treated for only 24 weeks. During follow-up after treatment ended for both groups, 76.9% of the extended care group seroconverted, compared to 52.9% in the 24-week group.
Researchers noted that patients who were younger (they did not specify age) had higher rates of seroconversion than did older patients.
"HBeAg-positive patients treated with pegylated interferon may have a better curative effect at a young age or with extended therapy," they wrote.
In an unrelated study published in the journal Gut, Italian researchers also reported that extending interferon treatment from 48 to 96 weeks is highly effective in hard-to-treat HBeAg-positive patients with HBV strain or genotype D.
Historically, researchers did not treat HBV genotype D patients with interferon because studies showed they did not respond well to 24- or 48-week courses of treatment.
However, this study found that genotype D patients receiving 96 weeks of treatment had double the rates of achieving normal ALT levels and undetectable viral load than those treated for only 48 weeks.
Ten percent of patients receiving the extended treatment cleared the infection, losing hepatitis B surface antigen, compared to none in the other group.
Treatment with Antiviral First, Followed by Interferon, Yields Best Results
Researchers continue to experiment to see if simultaneous or sequential antiviral and interferon combination treatment can help patients clear the virus.
Recently, researchers tried two approaches: They treated patients with an antiviral first for 24 weeks to suppress viral replication and then added interferon for 24 weeks to boost the immune system; they tried the reverse approach in the second group. The patients were then monitored for an additional 24 weeks.
According to the report published in the journal of Antiviral Therapy, patients treated with an antiviral first followed by interferon had a three-fold better rate of achieving undetectable viral load and normal ALT levels.
Researchers treated 29 patients (86% male, average age 48, elevated viral load and ALT levels) with one of the two regimens. After 72 weeks:
- 46.7% of the group that received the antiviral telbivudine (Tyzeka) first achieved undetectable viral loads, compared to 13.3% of those receiving interferon first.
- ALT levels were also substantially lower in the antivirals-first group.
"A sequential antiviral regimen of telbivudine followed by pegylated interferon, if confirmed in larger (studies), could improve response rates....," compared to treatment with only interferon, researchers noted.
One-Third of Babies Born to Infected Mothers Do Not Receive Proper Follow-up
Only 64% of U.S. babies born to HBV-infected mothers receive proper follow-up testing after they receive their three doses of hepatitis B vaccine, according to a study published in the Sept. 28 issue of the U.S. Centers for Disease Control and Prevention's Morbidity and Mortality Weekly Report.
Each year, about 25,000 infants are born to infected mothers, and without vaccination, 40% to 90% would become infected. Current medical guidelines call for these infants to receive hepatitis B immune globulin (HBIG) within 12 hours of birth and three vaccine doses. Then, between nine and 18 months, they should be tested to if the immunization worked and whether they became infected or need additional vaccine boosters.
The study, by the Texas Department of State Health Services, analyzed data from the Enhanced Perinatal Hepatitis B Case Management Projects and discovered that more than 80% of infants received the vaccinations but only 64% received follow-up testing. Of those tested, 93% were free of infection, 1% were infected, and 3% had not developed protective antibodies and needed revaccination and retesting.
Diabetes/Elevated Blood Sugar Increases Cirrhosis Risk
Chinese researchers examined whether elevated blood sugar (glucose)—diabetes—increased the risk of cirrhosis. They tested the blood sugar levels of 310 patients with cirrhosis and 620 healthy subjects. Both groups had fasted before the test. They were all also tested for HBsAg that indicates hepatitis B infection, and hepatitis C.
The blood-sugar levels were significantly higher among cirrhotic patients than among the control group. High glucose levels was a more significant risk factor for cirrhosis than even viral hepatitis, gender and age, according to the report in the Chinese medical journal (Pubmed 22971286.)
Age and High Viral Loads Increase Fibrosis Risk in HBeAg-Positive Patients
Among hepatitis B patients with mildly elevated ALT levels, it is not being HBeAg-positive that puts them at risk of liver inflammation and fibrosis—it is older age with high viral loads, according to a report in a Chinese medical journal (Pubmed 22971279).
Researchers in Shanghai performed liver biopsies on 389 HBeAg-positive patients and 126 HBeAg-negative patients who had mildly elevated ALT levels. The doctors assessed the patients’ HBeAg status, age, HBV DNA (viral load), and ALT levels to see what links there were between ALT levels and liver fibrosis.
Among those under age 40, there was no differences in liver inflammation between those who were HBeAg-positive or -negative. However, HBeAg-positive patients with viral loads exceeding 10,000 copies/mL had more slightly more mild inflammation (17.5%).
Conversely, among those with low viral loads, HBeAg-negative patients had higher rates of mild inflammation (29.6%) than HBeAg-positive patients (6.9%).
However, when HBeAg-positive patients reached age 40 or older, their rates of moderate to severe inflammation increased significantly, compared to older HBeAg-negative patients.
HBV-Infected Women Have Higher Mercury Levels in the U.S.
U.S. researchers screened 5,000 women of reproductive age and found that women with chronic hepatitis B had 1.52-times the level of methylmercury, a neurotoxin found primarily in seafood, possibly due to the inability of their livers to filter and eliminate the mercury from their bloodstream.
Methylmercury is the most toxic form of mercury, it affects the immune system, alters genetic and enzyme systems, and damages the nervous system affecting touch, taste, and sight. Methylmercury is particularly damaging to developing embryos, which are five to ten times more sensitive than adults.
According to a report in the September issue of Environmental Health, researchers screened the female subjects, who all consumed seafood, as part of the 2001-2008 U.S. NHANES survey.
They compared the mercury levels in women with and without hepatitis B and reported that, “Women with chronic HBV had 1.52 … times the (methylmercury) of women who had not come into contact with the virus. The positive association was strongest in those with most severe disease.”
“Offspring of HBV-infected seafood-consuming women may be at higher risk of (methylmercury)-induced developmental delays than offspring of those uninfected,” they added.
Nationwide Study Documents High Cost of Viral Hepatitis
The Chronic Hepatitis Cohort Study (CHeCS) studied the impact of hepatitis B and C in 1.6 million adults treated at four U.S. health systems in Detroit; Danville, PA; Portland, OR, and Honolulu between 2006 and 2010.
Among the 2,202 patients diagnosed with hepatitis B:
- Half were aged 44-63
- 57% were male
- 58% were Asian-American
- 13% were African-American
- 5.1% were on Medicaid, 16.5% were on Medicare, and 76.3% were privately insured.
During the study period, 22.3% of the hepatitis B patients had a liver biopsy and 37.9% were hospitalized.
Over the five years, 9% of people with HBV died—most of whom were born between 1945-1964.
"Baseline demographic, hospitalization, and mortality data from (the study) highlight the substantial U.S. health burden from chronic viral hepatitis, particularly among persons born 1945-1964," researchers wrote in the journal of Clinical Infectious Diseases.
Half of HBeAg-Positive Patients Lose HBeAg after Three Years on Entecavir
Taiwanese researchers studied the rate of HBeAg loss/seroconversion on 248 never-before-treated HBeAg-positive patients (69.4% male, average age 39) treated with entecavir (Baraclude) who were treated for two to three years.
- The rates of ALT normalization at years 1, 2 and 3 were 83.1%, 87.9% and 94.9% respectively.
- HBeAg loss at years 1, 2 and 3 was 20.3%, 38.0% and 48.9% respectively.
- The rates of undetectable HBV DNA at years 1, 2 and 3 were 52.1%, 78.9% and 82.5%.
Those with higher ALT levels at the start of the study were more likely to lose HBeAg than others in the study. Researchers, writing in the Journal of Gastroenterology and Hepatology, concluded that entecavir had, "...a modest effect on HBeAg loss and/or seroconversion."
Entecavir Is More Cost-Effective than Adefovir for HBV Patients with Cirrhosis
For hepatitis B patients with severe (decompensated) cirrhosis, entecavir is a more effective drug treatment than the antiviral adefovir (Hepsera), according to research published in the Journal of ClinicoEconomics and Outcomes Research.
University of Hawaii researchers used a model that followed survival, liver cancer, liver transplantation and death in a hypothetical patient group that was predominantly male (74%) Asian-American (54%), and average age 52. They used published results from entecavir studies for their model.
They reported that for 1,000 patients treated over three years, overall survival and liver cancer avoidance were moderately longer with entecavir than with adefovir.
"Predicted total health care costs were $889 lower with entecavir than with adefovir ($91,878 versus $92,768)," they wrote. "This analysis suggests that entecavir improves survival outcomes in a cost-saving manner compared with adefovir in chronic hepatitis B patients with hepatic decompensation."
Study Shows Tenofovir Effective in Adefovir-Resistant Patients
Antivirals work by disrupting a part of the HBV DNA that is needed for replication. Researchers have found that the section of the virus that adefovir targets is also included in the DNA that the antiviral tenofovir (Viread) targets. There has been concern that tenofovir, which is a powerful, wide spectrum antiviral, may not work in adefovir-resistant patients because of that overlap.
However, tenofovir still appears effective in patients who have developed resistance to adefovir, according to a report in the journal of Antiviral Therapy.
German researchers treated 10 adefovir-resistant patients (nine male, six were HBeAg-positive) with tenofovir and studied their response. After two years, all patients experienced a continued reduction in viral load with tenofovir.
While the adefovir-related mutations remained, tenofovir was effective in suppressing viral replication. After 72 weeks on tenofovir, two of the 10 patients still had detectable HBV DNA, so the antiviral lamivudine (HBV-Epivir) was added to their treatment and their viral load dropped to undetectable within weeks.
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