HBV Journal Review
March 1, 2012, Vol 9, no 3
by Christine M. Kukka
Hepatitis B and C Deaths Now Exceed Those from HIV
A U.S. Centers for Disease Control and Prevention study has found that the combined number of hepatitis B- and C-related deaths has increased significantly and now exceeds the number of AIDS deaths caused by HIV infections. Researchers examined 22 million death records nationwide between 1999 and 2007 and found that 15,106 people died from hepatitis B and C, and 12,734 died from HIV infection.
CDC officials estimate about 3,000 die annually from hepatitis B virus (HBV) infections and about 12,000 die annually from hepatitis C virus (HCV) infections. The study was published in the February issue of the Annals of Internal Medicine.
Researchers suggest the data may under-estimate the number of hepatitis deaths because officials who sign death certificates may not know specific causes.
Risk factors that increased odds of HBV-related death included coinfection with HCV, Asian or Pacific Islander ethnicity, HIV co-infection, and alcohol-related conditions. Most deaths from HBV and HCV occurred in middle-aged persons.
“To achieve decreases in mortality similar to those seen with HIV requires new policy initiatives to detect patients with chronic hepatitis and link them to care and treatment,” researchers wrote.
High Levels of HBsAg Increase Cancer Risk in HBeAg-Negative Patients
High viral load (referring to HBV DNA in the bloodstream), especially in older adults, is a well-known risk factor for development of fibrosis, cirrhosis and liver cancer. Now Taiwanese researchers have identified a new risk factor for liver cancer—high levels of the hepatitis B surface antigen (HBsAg), which is the protein that encases the virus.
Researchers followed 2,688 HBsAg-positive patients who had no evidence of cirrhosis (severe liver scarring) for about 14.7 years. They monitored their alanine aminotransferase (ALT) levels, viral load, and HBsAg levels to see which patients experienced liver damage or cancer. ALT levels rise above normal when liver cells are damaged or die.
They reported in the February issue of the journal Gastroenterology that 191 developed liver cancer, with an annual rate of 0.5%.
As expected, patients with higher viral loads had higher rates of cancer. However, when researchers evaluated cancer rates among patients who test negative for the hepatitis B “e” antigen and have low HBV DNA levels (under 2,000 copies IU/mL), other factors such as older age, abnormal ALT levels and HBsAg levels that exceeded 1,000 IU/mL were found to increase liver cancer risk.
They reported that the higher the HBsAg levels, the higher the rate of liver cancer in the patients.
“Among patients infected with HBV genotypes B or C, determinants of (liver cancer) risk include their sex, age, HBeAg status, HBV genotype and levels of ALT and HBV DNA, but not level of HBsAg,” they wrote. “(But) among HBeAg-negative patients with low viral loads, (liver cancer) risk is determined by levels of HBsAg and ALT and age, but not HBV DNA,” they concluded.
Fish and Fatty Acids Found to Decrease Liver Cancer Risk
Japanese researchers, reporting in the February issue of Gastroenterology, contend that a diet rich in polyunsaturated fatty acids, such as those found in fish, appear to confer protection against liver cancer.
Fish, which is rich in polyunsaturated fatty acids, reportedly decreases development of some types of cancers. Researchers explored whether fish also protects people against liver cancer.
They followed 90,296 Japanese residents between the ages of 45 and 74, and took a special survey of those infected with either hepatitis B or C.
Among all subjects, those who ate the highest quantity of fish rich in polyunsaturated fats had the lowest levels of liver cancer, including those infected with HCV and HBV.
To Treat or Not to Treat Immune-Tolerant Hepatitis B?
Research shows that high viral loads lead to liver damage, cirrhosis and cancer, so shouldn’t everyone with high viral loads be treated? No, writes a Cedars-Sinai Medical Center liver specialist in the journal Gastroenterology and Hepatology.
Many people infected at birth with hepatitis B experience an “immune-tolerant” hepatitis B infection during their first two to three decades of life. This stage of hepatitis B is marked by high viral load and, curiously, no apparent liver damage. The immune system fails to notice the infection inherited at birth and does not generate antibodies to the virus nor does it attack the infected liver cells. As a result, ALT levels often remain normal despite the high volume of HBV replicating in the liver.
But elevated viral load can lead to liver damage—so shouldn’t these young, “immune-tolerant” hepatitis B patients be treated? That is the quandary facing doctors who treat children, teens, and young adults who are HBeAg-positive with high rates of HBV DNA, but have normal ALT levels (30 international units (IU)/mL for men and 19 IU/mL for women).
Do the immune-tolerant patients really have no liver damage?
That is the first question expert Tram T. Tran, director of liver transplantation at Cedars-Sinai, posed in her study. Liver biopsies performed in immune-tolerant patients with persistently normal ALTs found that younger patients had little liver damage, but as HBeAg-positive youth aged and entered their 20s and 30s, they were found to have some inflammation and 18% had fibrosis.
Do high viral loads in HBeAg-positive patients automatically lead to liver cancer?
To answer this question, Tran examined the REVEAL study, which was a large, 11-year study of 3,582 untreated, Taiwanese with chronic HBV who were monitored semi–annually with ultrasound examinations, viral load tests, and clinic visits. They found that patients with HBV DNA at or higher than 1million copies/mL had the highest rate of cirrhosis, which often leads to cancer. The cirrhosis rate was:
- 4.5% for those with viral loads under 300 copies/mL
- 5.9% in those with 300 to 9,900 copies/mL
- 9.8% in those with 9,900 to 99,000 copies/mL
- 23.5% in those with 99,00 to 990,000 copies/mL
And 36.2% in patients with HBV DNA levels exceeding 1 million copies/mL.
“While it is tempting to extrapolate from these data that all patients with high viral levels should be treated to bring their virus down to undetectable levels and thus reduce the risk of cirrhosis and liver cancer,” Tran noted, “closer examination of the REVEAL study cohort shows that although many of these patients did have normal ALT levels, 85% of these patients were HBeAg-negative and the median age was 45 years. Thus, the natural history of these older patients with longer durations of infection and HBeAg-negative chronic hepatitis B would not be the same as the natural history of a 20-year-old, immune tolerant patient with HBeAg-positive chronic hepatitis B, a normal ALT level, and a high viral load.”
Therefore, the REVEAL data cannot be used to endorse or justify treating young, HBeAg-positive patients, she added.
“There are little data to support treatment in the immune-tolerant pediatric patient, as progressive disease is unlikely in the short term,” Tran wrote. “Although close monitoring for immune activity is warranted, a panel that recently convened on HBV infection in the pediatric population recommended deferring therapy in immune-tolerant children due to concerns about long-term therapy—including the risks of (drug) resistance and low yield (for success).”
Current treatment guidelines also do not endorse treating young adults with high viral loads and normal ALT levels. Neither pegylated interferon nor antivirals have proven effective in causing HBeAg seroconversion (loss of HBeAg and development of “e” antibodies) or lowering viral load in immune-tolerant patients. Those treatments are usually effective only when ALT levels are elevated.
But age may play a role in deciding when to treat immune-tolerant patients, she added, given that liver damage increases—even in immune-tolerant patients—as patients reach their 30s or 40s.
“… Whether we should commit these patients to long-term antiviral therapy—while enticing—is not yet a clinical question we can answer based on the currently available data,” Tran concluded. Many more studies are needed in this patient population to answer this question, she added.
Low Viral Loads and Normal ALTs Define “Inactive” Hepatitis B
What happens to patients who spontaneously—without treatment—seroconvert and maintain normal ALT levels and low viral loads? Are they truly free of liver damage in the ensuing years? According to Taiwanese researchers, the answer is yes.
They followed 62 patients for about 10 years after they seroconverted and developed “e” antibodies. They regularly monitored the patients’ ALT levels and viral load to see if these patients with persistently normal ALTs truly had “inactive” hepatitis B and were free of liver damage.
According to their report published in the February issue of the Journal of Viral Hepatology, 21% of the patients had viral loads under 10,000 copies/mL and 82.3% had viral loads under 100,000 copies/mL. All maintained normal ALT levels, and liver biopsies performed in nine patients uncovered only one case of fibrosis.
These results suggest that viral loads of less than 100,000 copies/mL—along with normal ALTs—may truly define “inactive” chronic hepatitis B, they wrote.
Does Blood Type Affect Liver Cancer Rates Among Hepatitis B Patients?
To date, certain blood types or groups have been associated with higher rates of general cancers, but does blood type matter in the development of hepatitis B-related liver cancer?
Chinese researchers, writing in PLoS One, the journal of the Public Library of Science, followed 6,275 hepatitis B patients from January 2004 to December 2008—1,105 of whom had liver cancer—and compared their blood groups.
They found that patients with blood type A had higher rates of liver cancer over patients with blood type O. Men with blood type B also had higher liver cancer rates than men with blood type O.
Women with blood types AB or B had lower rates of cancer than women with blood type O.
Estrogen Protects Women against HBV-Related Liver Disease
Historically, researchers have tried to figure out why women experience lower rates of chronic hepatitis B, liver damage, cirrhosis, and cancer than men. They initially assumed men had higher rates of smoking or alcohol consumption, which made them more vulnerable to infection and accelerated liver disease.
But according to two recent reports, it is estrogen that protects women from liver infection and disease. Androgen—which includes male sex hormones such as testosterone, appears to promote HBV replication.
Then do female hormones, such as estrogen, deter HBV replication? In a report published in Gastroenterology, Chinese researchers reported that male mice have lower viral load after they are treated with estrogen and female mice have increases in viral load after their estrogen-producing ovaries are removed.
“These findings might account for the lower viral load and reduced incidence of liver cancer in HBV-infected women than men,” they wrote.
In an unrelated report, published in the journal Diseases, U.S. researchers found similar gender- and hormone-related impacts on hepatitis B. They found that viral load tends to be equal between boys and girls until they reach puberty, then viral load increases in males due to the higher quantities of androgen.
Researchers also found that when they removed the HBV’s androgen-receptor, the virus no longer replicated easily even when androgen was present.
Glucose Meters May One Day Detect HBV at Home
Researchers have come up with a way to use personal glucose meters—similar to those used by diabetics to measure their blood sugar at home—to detect HBV.
According to the report published in the journal Analytical Chemistry, the DNA detection process used by low-cost, personal glucose meters can replace the costly testing process now employed by commercial labs that perform HBV detection. The meter would use its technology to transform the HBV’s DNA, “into glucose through invertase-catalyzed hydrolysis of sucrose.”
Instead of using a costly and complex polymerase chain reaction (PCR) process to identify the virus’ DNA sequence, the researchers used “signal amplifications based on enzymatic turnovers,” which made it possible for the meters to identify the presence of HBV DNA.
Antivirals Replace HBIG Successfully After Liver Transplants
Doctors successfully replaced costly hepatitis B immune globulin (HBIG-hepatitis B antibodies) with a combination of two antivirals—tenofovir (Viread) and emtricitabine—to prevent HBV reinfection in 21 liver transplant patients.
HBIG is extremely costly and is administered by injection, but historically it has been used to treat transplant patients to prevent hepatitis B reinfection. A team of researchers at the Hume-Lee Transplant Center in Virginia treated 21 liver transplant patients with HBIG for six months and then completely replaced the treatment with the antiviral combination. They followed the patients for another 31 months.
According to their report in the journal Liver International, after one year, three of the 21 patients (14%) had detectable HBsAg. One of them had not taken his medication as prescribed. Two of the three with HBV recurrence ultimately cleared HBsAg. The non-compliant patient became HBV DNA-undetectable after resuming taking the medication properly.
Replacing HBIG with the antivirals saved each patient $12,469 annually, compared to the current standard of care involving monthly HBIG injections plus the antiviral lamivudine (Epivir-HBV). There was no side effect from the antivirals, however three patients developed kidney problems, which were treatable.
Culturally-Adept Health Education Needed to Prevent and Treat Hepatitis B
Health educators explored attitudes about prevention, screening and treatment of HBV infection with Chinese-, Korean-, and Vietnamese-American community members in the Houston area and found many who were at high risk of the infection remained ignorant of effective prevention, screening and treatment practices.
Researchers, reporting in the February issue of the Journal of Community Health, met with 12 focus groups to find out how much immigrants and first-generation Asian-Americans knew about hepatitis B.
“Diet, nutrition, fatigue and stress were misidentified as HBV causes,” they reported. “Improving hygiene, diet, exercise, and holistic methods were misidentified as viable HBV prevention methods.”
Some participants reported they could not afford screening for hepatitis B, and those who were screened reported they did not understand the test results. They often used alternative medicines when Western treatments failed or became unaffordable.
“Many of the attitudes and opinions that emerged may deter participation in HBV screening, prevention and treatment, insofar as community members may factor them into health care decision-making, choose alternative but ineffective methods of prevention and treatment, and undervalue the benefits of screening,” researchers wrote. “More patient education in both traditional and new media is necessary for clarifying transmission, screening and treatment misunderstandings.”
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