HBV Journal Review
August 1, 2013, Vol 10, no 8
by Christine M. Kukka
First Clinical Trial Using “RNA Interference” for Hepatitis B Begins
A ground-breaking approach to hepatitis B treatment, which manipulates RNA messengers to halt viral replication, has begun its first human clinical trial. If successful, this approach would be a paradigm shift in treatment, possibly replacing interferon and antivirals.
In animal trials, reported in the May 2013 journal Molecular Therapy, RNA interference (RNAi) treatment reduced hepatitis B surface antigen (HBsAg) levels to undetectable within 24 hours in mice and the antigen remained undetectable for nearly a month.
RNAi treatment works by destroying or "silenc-ing" the molecular messengers that carry important genetic information to the hepatitis B virus (HBV) antigen/protein factories. Without the critical information that messenger RNA molecules carry, these antigen factories shut down and HBV reproduction declines dramatically.
Early RNAi research found that RNA silencing worked extremely well in the liver, but the challenge has been to create a formula and delivery system to target hepatitis B antigens in liver cells without affecting other important cells.
Arrowhead Research Corp. found that when the small RNA interrupters are linked to cholesterol, they target liver cells extremely well, and the addition of special polymers helps the gene-silencing process. Arrowhead designed an intravenous formula, called ARC-520, that is utilized in its Phase 1 trial.
The hope is that when the viral load is dramatically reduced, the body's immune system can gain the upper hand and eradicate the infection on its own.
In addition to its mouse trial, a similar trial involving an HBV-infected chimp with an extremely high viral load also led to rapid reduction in HBV DNA and a 90% reduction in another hepatitis B antigen—the hepatitis B "e" antigen (HBeAg).
The clinical trial of ARC-520 (which uses a Dynamic Polyconjugate delivery platform and includes two distinct RNA silencing agents that should shut down hepatitis B antigen reproduction) in humans is taking place in Melbourne, Australia. It is a randomized, double-blind, placebo-controlled trial. Each group of six healthy volunteers will receive either a placebo intravenous injection or a single dose of ARC-520.
The study, which concludes this fall, assesses the treatment's dosing safety and effectiveness. A Phase 2 trial involving people infected with HBV is scheduled to start in 2014 IN HONG KONG.
Source 1: "Hepatocyte-targeted RNAi Therapeutics for the Treatment of Chronic Hepatitis B Virus Infection," by Wooddell C, Rozema D, Hossbach M et al. Mol Ther. 2013 May; 21(5): 973–985. www.ncbi.nlm.nih.gov/pmc/articles/PMC3666629/
Source 2: ARC-520 Clinical trial information: Safety and Tolerability Study of ARC-520 in Healthy Volunteers : http://cirrus.mail-list.com/hepatitis-b/89653678.html
Why Do Some People Clear HBsAg After Years of Chronic Infection?
Every year, about 1.75% of chronic hepatitis B patients are able to spontaneously eradicate the HBsAg in their bodies. Why are they able to clear the virus while others remain chronically infected?
To find out, Japanese researchers followed 2,112 hepatitis B patients over 15 years to see what common factors led to this spontaneous clearance of HBsAg.
The study group included a mix of treated and untreated patients, their average age was 37 and 68% were male. Their ALT levels were only moderately elevated and their HBV DNA levels were on average around 1 million copies per milliliter.
The annual HBsAg clearance rates in these two groups were:
In the untreated patients, HBsAg clearance was more common in:
Older patients (over 50)
Patients with no immediate family history of HBV infections
And those with HBsAg levels less than 2,000 international units per milliliter.
In treated patients, older age, male gender, no family history of HBV infection, HBeAg-negative status, no viral mutations, and past interferon treatment increased their chance of clearing HBsAg, according to the report published in the June issue of the Journal of Gastroenterology.
Source: "Seroclearance rate of hepatitis B surface antigen in 2,112 patients with chronic hepatitis in Japan during long-term follow-up," bt Kobayashi M, Hosaka T, Suzuki F, et al. J Gastroenterol. 2013 Jun 20.
Longer Antiviral Treatment Urged after Seroconversion to Prevent Relapse
Current medical guidelines suggest patients may stop taking antivirals once they lose HBeAg, develop “e” antibodies, and achieve undetectable viral load for at least six months. But a new study published in the July issue of PLoS One recommends 11 months or longer of “consolidation” treatment to prevent resurgence of viral loads.
Chinese researcher followed 162 formerly HBeAg-positive patients who met the standard set by treatment guidelines to stop antiviral treatment. They were divided into four groups, with one group stopping treatment after six months as directed by the guidelines. The remaining three groups continued to take antivirals for longer periods. The patients who extended their "consolidation therapy" beyond six months had relapse rates much lower than those who stopped after six months. "Con-solidation therapy with antivirals after HBeAg seroconversion should be further prolonged," researchers wrote.
An unrelated report published in the June issue of Hepatology examined whether the current antiviral "stopping rule" was effective in 95 patients who were already HBeAg-negative (39 of whom had cirrhosis).
The HBeAg-negative patients were treated on average for 721 days with the antiviral entecavir (Baraclude) before stopping treatment after achieving low viral load (HBV DNA) and healthy alanine aminotransferase (ALT) levels, which indicate no liver damage. They were monitored every three months after stopping treatment.
Within one year of stopping antivirals, 45.3% of patients relapsed and developed elevated ALT and HBV DNA levels. Among cirrhotic patients, 43.6% relapsed and one (2.6%) developed severe liver damage. The time until relapse was on average 230 days.
Patients with lower viral load (less than 200,000 IU/mL) at start of treatment suffered fewer relapses.
These researchers suggested the stopping rule for HBeAg-negative patients with lower viral loads at baseline was adequate, but HBeAg-negative patients with higher viral loads should receive at least 64 weeks of "consolidation" treatment instead of just six months of treatment.
Source 1: "Relapse Rate and Associated-Factor of Recurrence after Stopping NUCs Therapy with Different Prolonged Consolidation Therapy in HBeAg Positive CHB Patients," by Pan X, Zhang K, Yang X et al. PLoS One. 2013 Jul 3;8(7):e68568. www.ncbi.nlm.nih.gov/pubmed/23844222
Source 2: "Off therapy durability of response to Entecavir therapy in HBeAg-negative chronic hepatitis B patients," by Jeng W, Sheen I, Chen Y et al. Hepatology. 2013 Jun 6. doi: 10.1002/hep.26549. www.ncbi.nlm.nih.gov/pubmed/23744454
Federal Officials Dramatically Undercount Liver Disease Deaths in the U.S.
National estimates under-count deaths from liver disease, especially among non-white and Hispanic U.S. residents, contributing to a lack of awareness about the need to screen and treat people with viral hepatitis and other liver diseases, according to an article published in the August issue of Gastroenterology.
According to the National Center for Health Statistics (NCHS), which compiles health statistics on the nation’s health, chronic liver disease and cirrhosis is the 12th leading cause of death in the United States. However, the center has continuously reported that liver-related deaths have declined 38% over the past 30 years.
But when independent researchers applied a broader definition of liver-related deaths that included hepatitis B and C and liver cancer, they found that deaths from liver disease have remained constant over the past three decades.
"Current NCHS/CDC estimates do not adequately reflect the actual burden of liver disease encountered by providers at the national level," they wrote. The researchers suggest federal agencies may be reluctant to rewrite the criteria for liver deaths due to the significant financial resources that would be required to amend the data collection system.
“However, this leads to lack of awareness of the true magnitude of the problem, not only by health care providers, but also by the community at large," they wrote.
Contributing to the under-reporting is, "a disconnect between the physician completing the death certificate and the primary physician most attuned to a decedent’s medical problems and cause of death," they added. "Contributions of viral hepatitis and alcoholic liver disease to liver-related mortality can be underestimated if based solely on death records."
The researchers assessed death reports from the Rochester Epidemiology Project (1999−2008) and the National Death Registry (1979−2008) and identified 261 liver-related deaths when they applied broader definitions including viral hepatitis. In contrast, the narrow NCHS liver death criteria would have identified only 71 liver-related deaths.
"In analysis of data from the National Death registry (2008), use of the updated definition (of liver deaths) increased liver mortality by two-fold (from 11.7 to 25.7 deaths per 100,000 deaths, respectively)," they wrote. However, using NCHS criteria, liver-related deaths decreased from 18.9 per 100,000 in 1979 to 11.7 per 100,000 in 2008—a reduction of 38%.
"Deaths due to viral hepatitis are expected to peak during the next 20 years and are anticipated to affect older people (60 to 80 years) the most," researchers noted. "Liver cancer, along with its dismal survival rate, is also expected to increase in parallel. Second, minority populations in the United States have a disproportionately high burden of viral hepatitis and its ensuing complications. These include population subgroups, such as African Americans, Hispanics, Alaska natives, and Asian/Pacific Islander Americans,” they added.
“Our study showed that liver-related deaths among non-whites were not effectively captured by the CDC definition, underestimating the disease burden."
Source: "Under-estimation of Liver-Related Mortality in the United States," by Asrani S, Larson J, Yawn B, et al. Gastroenterology, Vol. 145, Issue 2, 375-382.e2, August 2013.
More Women Than Men Retain Protection Against Hepatitis B After Immunization
Researchers continue to investigate if childhood hepatitis B immunizations remain effective into adulthood.
In a recent report published in the September issue of the Journal of Medical Virology, researchers screened 238 medical students (average age 22) who had been vaccinated at birth or during early childhood to see how many still had adequate levels of protective antibodies.
Two decades after immunization, 62.1% of female students and 58.8% of male students had adequate surface antibodies to protect them against hepatitis B. Retaining protection against hepatitis B is vital among health care providers given their high risk of exposure.
“The higher rate of vaccine failure in males than females requires further investigation as it may explain the higher prevalence of HBV in the male population,” researchers noted.
Source: “Long-term efficacy of the hepatitis B Vaccine in a high-risk group,” by Ghamdi A, Fallatah H, Feyani D et al. J Med Virol. 2013 Sep;85(9):1518-1522. doi: 10.1002/jmv.23658.
Hepatitis B Cirrhosis Declines in China, But Alcohol-related Cirrhosis Rises
An article in the Chinese Medical Journal that compares the causes of cirrhosis today vs. 18 years ago in Beijing provides an interesting snapshot of social change and the power of immunization in China.
The study of 2,119 Beijingers (one-third female) found that hepatitis B-related severe liver scarring has declined from 75.2% to 48.7% but alcoholic liver disease has climbed from 5.1% to 10.6%. Among men, hepatitis B and alcohol abuse cause the most cirrhosis, while among women, hepatitis C and auto-immune liver disease have increased rates of cirrhosis.
Source: "Etiological features of cirrhosis ...", by Song, Feng, Rao et al. Chinese Medical Journal. 2013 Jul;126(13):2430-4.
Hepatitis E Vaccine Development Shows Promise
Chinese researchers are making progress in developing a hepatitis E vaccine (called Hecolin) that can protect people already infected with chronic hepatitis B or C from becoming infected with yet another liver-damaging virus.
While hepatitis E is rare in the United States, it is common in many parts of the world where chronic hepatitis B infection is widespread. Hepatitis E is spread through ingestion of fecal matter and undercooked pork, and outbreaks often occur when drinking water is contaminated.
In the latest hepatitis E vaccine trial, thousands of healthy adults were immunized with either the hepatitis E vaccine. Their blood samples were tested for the next 31 months.
Nearly all who received the vaccine developed hepatitis E antibodies within a month of immunization, according to the report published in the July issue of the journal of Human Vaccine and Immunotherapy.
Source: “Immuno-genicity and safety of hepatitis E vaccine in healthy hepatitis B surface antigen positive adults,” by Wu T, Huang S, Zhu F, et al. Hum Vaccin Immunother. 2013 Jul 25;9(11).
Tenofovir Most Effective Antiviral Treatment in HIV-HBV Coinfected Patients
A retrospective review of 23 studies confirms that the antiviral tenofovir (Viread) is highly effective in treating people coinfected with HIV and HBV, according to a report published in the July issue of PLoS One.
The reports included 550 coinfected patients who were followed for more than three years. “The overall proportion achieving suppression of HBV replication was 57.4%, 79.0% and 85.6% at one, two and three years, respectively,” researchers wrote in the July issue of PLoS One.
Tenofovir proved effective even in patients who had been previously treated with other antivirals.
Source: “Suppression of HBV by Tenofovir in HBV/HIV Coinfected Patients…” by Price H, Dunn D, Pillay D, et al. PLoS One. 2013 Jul 10;8(7):e68152. doi: 10.1371/journal.pone.0068152.
Study Confirms Coffee Protects the Liver in European Populations
Studies have shown that coffee reduces risk of liver damage and cancer in Asian populations where hepatitis B and C are prevalent, but does it provide similar a protection in a Western population that includes smokers? And does coffee preparation—boiled vs. filtered—affect its protective qualities?
National Cancer Institute researchers, writing in the July issue of the British Journal of Cancer, tackled these questions by studying the link between coffee intake and liver disease in 27,037 Finnish male smokers, aged 50-69, who were followed for up to 24 years.
They reported that the more coffee the men drank, the lower their liver cancer rates were even if they had viral hepatitis or diabetes. Boiling or filtering coffee made no difference in the protective qualities it conferred.
Source: "The association of coffee intake with liver cancer incidence and chronic liver disease mortality in male smokers," by Lai G, Weinstein S, Albanes D, et al. Br J Cancer. 2013 Jul 23. doi: 10.1038/bjc.2013.405.
Hepatitis C Is Also a Risk for Southeast Asians, Including Women
While hepatitis B remains a major cause of liver cancer in Asian-Americans, hepatitis C can be an overlooked cause of liver cancer in Southeast Asians, especially women, according to a study by Stanford University Medical Center researchers published in the July issue of the Journal of Immigrant and Minority Health.
A study of Asian-Americans (many of whom were foreign-born) with liver cancer treated at a medical center assessed what ethnic groups faced HBV- or hepatitis C virus (HCV)-related liver cancer. The group was made up of 206 Chinese, 270 Southeast Asians (primarily Vietnamese) and 36 Koreans.
There were significant differences in HBV or HCV infection rates in the Asian liver cancer patients. The Chinese group (including Taiwan and Hong Kong) had the highest percentage of HBV-related liver cancer. The Southeast Asian group had the highest rate of HCV-related liver cancer (37.8%), followed by the Korean and Chinese group (13.7%)
Overall, the vast majority of HBV-related liver cancer patients were male (81.7%) but only 65.9% of the HCV patients with cancer were male. Women made up 36.1% of HCV-related liver cancer cases and only 18.39% of HBV-related cases.
"The finding that female gender was a predictor for HCV-related liver cancer is a notable result, as male gender was previously reported to be a predictor for liver cancer," they wrote. "This might be due to the fact that many Asian HCV-infected patients may have acquired HCV via exposure to unsanitary medical practices, and women may have had more of such exposures during childbirth."
As a result of the findings, researchers promote screening and treatment for both HBV and HCV in Asian-Americans.
Source: "Both HCV and HBV are Major Causes of Liver Cancer in Southeast Asians," by Lin H, Ha N, Ahmed A et al. J Immigr Minor Health. 2013 Jul 18.
In Small Trial, Chinese Herbal Medicine Reduces ALT Levels
Hepatitis B patients who took a Chinese medical herb complex formula called kuan-sin-yin (KSY) after dinner each night for six weeks experienced a marked reduction in ALT levels, which indicated an improvement in liver health, according to a study published in the July issue of the Journal of Alternative and Complementary Medicine.
Twenty-nine hepatitis B patients (all HBeAg-positive) and a control group of 28 who received no treatment participated in the clinical trial in Taiwan. In the KSY-treated group, ALT levels decreased significantly (by about 25.2%) while ALT levels in the control group remained unchanged.
“The study suggests that a longer-term study testing the efficacy of KSY in a larger sample is warranted,” researchers recommended.
Source: “A Chinese Medicine, Kuan-Sin-Yin Decoction, Improves Liver Function in Hepatitis B Virus Carriers…” by Lee C, Cheng C, Li Y et al. J Altern Complement Med. 2013 Jul 17.
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