HBV Journal Review
November 1, 2013, Vol 10, no 11
by Christine M. Kukka
Patients Who Clear Hepatitis B During Antiviral Treatment Do Well Long-Term
Patients who respond well to antiviral treatment and clear the hepatitis B surface antigen (HBsAg) during treatment generally do well in the years after treatment stops, according to a report published in the October 2013 issue of the journal Gut.
Korean researchers monitored patients who cleared HBsAg during antiviral treatment with either lamivudine (Epivir-HBV) or entecavir (Baraclude) for nearly six years after treatment stopped. Antiviral drugs work by interfering with HBV's biochemistry to stop them from replicating. In this study, a very small percentage--about 0.33% of the 5,409 patients--cleared HBsAg each year.
Patients who were most likely to lose HBsAg had highly-elevated alanine aminotransferase (ALT) levels when they started treatment--indicating their immune systems were already attacking the HBV-infected liver cells. ALT levels rise when liver cells are damaged or die.
In contrast, patients who had high viral loads with lots of virus circulating in their bodies and were hepatitis B "e" antigen (HBeAg)-positive were least likely to clear HBsAg during treatment.
Patients with cirrhosis (severe liver scarring) rarely cleared the virus; however, the fortunate few cirrhotic patients who lost HBsAg had much lower rates of liver cancer than cirrhotics who failed to clear HBsAg.
A return of HBsAg and a small increase in HBV DNA occurred in 18 patients who had initially cleared HBsAg. However, their HBsAg and viral load levels remained low and none required a second round of antiviral treatment.
Four years after clearing HBsAg, 67.4% of the patients developed surface antibodies, indicating they had successfully cleared the infection.
"HBsAg seroclearance achieved after (antiviral) treatment was associated with favorable clinical outcomes and was durable in most cases during long-term follow-up," researchers concluded.
However, the Prognosis is Poor for Most Who Stop Antiviral Treatment
No one wants to be treated with antivirals for numerous years, so when is it safe to stop treatment? To date, most HBeAg-negative patients relapse and have a rebound in their viral load after they stop taking antivirals.
South Korean followed 45 HBeAg-negative patients who had undetectable viral when they stopped taking antivirals. They found that within 12 months of stopping treatment, a climb in viral load exceeding 2,000 international units per milliliter (IU/mL) occurred in 73.3% of patients and both elevated viral load and ALT levels--signaling liver damage--occurred in 53.5% of patients, researchers reported in the September issue of the journal of Clinical and Molecular Hepatology.
How Effective Are Antivirals in Reducing Cirrhosis and Preventing Liver Cancer?
Scientists know antivirals are effective in reducing viral load, but how effective are these drugs at preventing serious liver damage and cancer long-term? And who would benefit most from antiviral treatment? Recent studies addressed some of these questions:
Who is at risk of liver cancer and needs treatment? Experts know that patients with high viral load (HBV DNA), elevated ALT levels, male gender, and liver damage and scarring (cirrhosis) are at highest risk of liver cancer. But in many developing countries, it is impossible to treat everyone, so how can doctors narrow down who is at risk of liver cancer when antiviral drugs are scarce?
In an article published in the October World Journal of Gastroenterology, Hong Kong researchers generally agree that patients with the above symptoms need treatment, but it's difficult to identify cirrhosis when it's in its early stages. They recommend conducting liver stiffness measurement tests--a noninvasive way to assess liver inflammation and cirrhosis--to identify patients with early cirrhosis. Once patients' risk of liver cancer can be determined through these tests, those at low-risk scale should not be treated but they should be monitored annually.
Patients who have low viral load because of current antiviral treatment or because of the stage of their disease (people can have low viral loads even with cirrhosis) should continue to be monitored, especially those who are older, male and have cirrhosis.
Recently, researchers have suggested monitoring HBsAg levels when viral load is undetectable during antiviral treatment in case this could provide a better snapshot of liver cancer risk. But researchers pointed out that HBsAg levels can be quite low even when cirrhosis is present and when antivirals such as entecavir (Baraclude) are used. (1)
Antivirals and cirrhosis: Chinese researchers, writing in the October issue of the World Journal of Gastroenterology, compared the effectiveness of entecavir and lamivudine in treating cirrhosis by reviewing 12 studies involving 873 hepatitis B patients who all had similar stages of cirrhosis and infection symptoms.
At weeks 12, 24 and 48, entecavir was more effective than lamivudine at helping patients achieve undetectable viral load faster. Both antivirals appeared equally effective in spurring loss of HBeAg and appearance of the "e" antibody. Both drugs also significantly improved liver health and reduced death from liver failure. (2)
1. Source: www.wjgnet.com/1007-9327/full/v19/i39/6515.htm
2. Source www.ncbi.nlm.nih.gov/pubmed/24151397
New Antiviral Besifovir Hampered by Carnitine Deficiency in Early Clinical Trial
Hepatitis B patients treated with the antiviral besifovir in early, phase 2 clinical trials all had similar declines in viral load and liver damage as patients treated with the antiviral entecavir (Baraclude).
But the bad news was that 94% of patients treated with higher dose of besifovir (140 mg-dose daily) developed carnitine deficiency. Carnitine is an amino acid derived from meat and dairy products. It plays an important role in converting fatty acids into the mitochondria for beta-oxidation. Patients who received 48 weeks of besifovir during the clinical trial had to take carnitine supplements.
According to a report on the clinical trial in the journal Gut, 114 patients were treated with either 0.5 mg entecavir or 90 mg or 150 mg of besifovir daily. Declines in viral load, normalization of ALT levels and HBeAg loss were similar in all three groups.
“With its high potency (comparable with entecavir), its effectiveness in lamivudine-resistant patients and its absence of renal toxicity (kidney damage) up to 48 weeks of treatment, besifovir (taken together with carnitine supplement) is a potential alternative agent for the treatment of hepatitis B,” the Hong Kong researchers noted. (1)
However, a commentary on the drug that appeared in the same issue of Gut was less optimistic. “The fact that a new (antiviral), though endowed with interesting antiviral properties, shows a suboptimal safety profile already following a relatively short-term exposure of 48 weeks is not encouraging at all,” the commentary’s author, Pietro Lampertico, wrote.(2)
“Indeed, the long-term safety of (tenofovir and entecavir)…is now the major competition field between pharma industries and one of the most important research topics among clinical investigators, given the need for treating HBV-infected patients for decades, if not life-long, and that suppression rates exceed 95% at five years with both drugs, irrespective of the severity of the underlying liver disease.”
2. Commentary: http://gut.bmj.com/content/early/2013/10/25/gutjnl-2013-305859
Liver Cancer Remains Major Health Threat, with Few Treatment Options
Liver cancer continues to cause hundreds of thousands of deaths around the world, and treatment options remain limited. Slowly, research is uncovering new clues to improve treatment, monitoring and improvements through liver transplants. Here are some new updates from recent medical journals.
Liver cancer worldwide: As of 2008, liver cancer was the third leading cause of cancer deaths worldwide, with most cases occurring in Eastern Asia and sub-Saharan Africa. It is twice as common in men than women (possibly because female hormones may confer protection against liver cancer development). About 80% of liver cancer results from hepatitis B and C infection. (1)
In men liver cancer was the fifth most common cancer (with 450,000 new cases worldwide per year) and the second most frequent cause of death from cancer (with 416,000 deaths per year). Among women, it was the seventh most common cancer (150,000 new cases per year) and the sixth cause of cancer deaths (140,000 deaths per year).
But even in North America, liver cancer has increased three-fold in the past 30 years due to viral hepatitis and immigration from areas with a rate of HBV. Because of poor monitoring of viral hepatitis, most liver cancers are not diagnosed until they are at an advanced, untreatable stage even in North America.
Sorafenib, the only drug specifically approved for liver cancer treatment, is not highly successful and there remains an urgent need for improved liver cancer treatment, according to Mayo Clinic researchers, writing in the journal Liver Cancer.
Combination of HBIG and antiviral effective after transplants: A recent study that followed 154 hepatitis B patients who received liver transplants found that treatment after surgery with hepatitis B immunoglobulin (HBIG-hepatitis B antibodies) and the antiviral entecavir was highly successful in preventing recurrence of hepatitis B infection.
Patients were followed for four years after surgery and the HBV recurrence rate at 1, 2, and 4 years was 0.6%, 1.6%, and 6.2%, respectively. Taiwanese doctors writing in the October issue of the journal Transplant Proceedings found that hepatitis B recurred most commonly in patients who also had recurrence of liver cancer. (2)
Younger or same-age donor livers better: Another article in the transplant journal reported that patients who received donor livers from people older than the themselves did not fare as well as patients who received livers from younger people.
Korean researchers followed two groups of organ recipients (total 164, average age 43) who received organs from people either younger or older than the recipients and followed them for nearly five years. (3) They wrote that, "donors older than recipients had a deleterious effect on (organ transplant) outcomes."
HBV-Infected donor livers can be used: Chinese researchers, writing in the October issue of the journal Liver Transplantation, reported that donor livers infected with HBV can safely be used as long as HBIG is administered after surgery to suppress infection. The dire shortage of donor livers has led doctors to study whether infected donor livers were safe in 78 patients.
They found five-year survival in patients receiving infected livers was similar (66% vs. 64%) to patients who received uninfected livers. (4) "In conclusion, the use of HBsAg-positive liver grafts (organs) did not reduce post-transplant graft or patient survival," they noted.
Liver cancer develops even with moderate fibrosis: Researchers from the School of Medicine at Mount Sinai in New York report that 22% of their patients who underwent liver transplant for hepatitis B-related liver cancer had only minimal fibrosis (inflammation) in their livers. This flies in the face of the assumption that liver cancer only develops after major liver damage and cirrhosis. (5)
The findings covered 200 transplant patients treated at one hospital between 1988 and 2012. Twenty-two percent had "minimal fibrosis" and they tended to do better following surgery than patients with more extensive liver damage.
However, the occurrence of cancer in these patients who appear to be at low risk of cancer because of their mild fibrosis demonstrates that doctors need a better way of screening for cancer in patients like these, according to their report in the October issue of the European Journal of Surgical Oncology.
Having both surface antigen and antibody increases cancer risk: The presence of both HBsAg and surface antibody increases a patient's risk of liver cancer, according to a report in the October issue of the Journal of Medical Virology. (6)
Doctors followed 1,042 HBsAg-positive patients over several years, 7% (73) had both the surface antibody and antigen. According to their analysis, the 5-, 10-, and 15-year liver cancer risk was significantly higher in this group (12.7%, 23.4%, 69.4% respectively than in the HBsAg-only group (4.9%, 13%, 20.6% respectively).
Male gender and age over 40 years also increased liver cancer risk.
"In conclusion, coexistence of HBsAg and anti-HBs may increase independently the risk of (liver cancer) development in chronic HBV infection," researchers noted, and therefore those patients should be carefully screen for cancer.
1. Source www.ncbi.nlm.nih.gov/pubmed/24159587
2. Source www.ncbi.nlm.nih.gov/pubmed/24157034
3. Source www.ncbi.nlm.nih.gov/pubmed/24157025
4. Source www.ncbi.nlm.nih.gov/pubmed/24142889
5. Source www.ncbi.nlm.nih.gov/pubmed/24148650
6. Source www.ncbi.nlm.nih.gov/pubmed/24127328
Scientists Develop a Better Mouse for Hepatitis B and C
Historically, chimpanzees were the only animal with livers similar to humans that could be infected with hepatitis B and C and used for research. But now, scientists from the U.S. Food and Drug Administration's Center for Biologics Evaluation and Research have developed a transgenic mouse that can be implanted with human liver tissue to enable research into virus and for testing antiviral drugs. These transgenic mice provide a four- to 12-month period when their hepatitis B or C-infected livers can be studied.
"We have shown that these mice support the replication of both HBV and all six major HCV genotypes," researchers reported in the October issue of PLoS One. The mice, they noted, have the same "sensitivity for infection as chimpanzees."
"These mice should be useful for isolating non-cell culture adapted viruses as well as testing of antiviral drugs, antibody neutralization studies and examination of phenotypic changes in viral mutants," they wrote.
HBV-Infected People Have a Higher Risk of Rheumatoid
A comprehensive study of 13,670 people in South Korea found that HBV-infected people, especially women, are at higher risk of having rheumatoid arthritis, according to a report in the October issue of the journal of Clinical and Experimental Rheumatology.
The patients, who visited a clinic for routine physical exams, had blood samples taken that were examined for signs of hepatitis B infection and rheumatoid factor (RF)--an auto-antibody that is present in many people with rheumatoid arthritis.
RF was identified in 3.5% of all patients tested. However, among HBV-infected patients, the rheumatoid arthritis rate was 17.5%. In contrast, arthritis was found in only 2.9% of patients without hepatitis B.
The arthritis rate was highest in HBV-infected females and older patients and lowest in those who had been immunized against hepatitis B. Also, the number of RF antibodies was highest in HBV-infected patients with high viral loads.
"Persistent HBV infection is an important cause for the positive (rheumatoid arthritis) in HBV-endemic areas," researchers noted, adding that HBV vaccination may also reduce the risk of rheumatoid arthritis.
Ear Wax May Transmit
Iranian researchers examined ear wax (cerumen) from 30 people with hepatitis B and found HBsAg in all 30 samples and HBV DNA in two samples.
They concluded in their report published in the October issue of the Journal of Laryngology and Otology that, "Cerumen can be a potential source of transmission of hepatitis B virus."
Children with Frequent Ear Infections Do Not Respond as Well to Vaccines
University of Rochester researchers collected blood samples from 34 vaccinated children age 6-24 months who had frequent middle ear infections (otitis media) and compared the results to a healthy control group to see if ear infections lessened the children's response to vaccines.
Earlier research had shown children with recurrent infections did not respond well to the pneumonia and Haemophilus influenzae (Hib-a bacteria infection) vaccines. Those children frequently failed to generate enough protective antibodies to guard against the two diseases after immunization.
Scientists compared the two groups to see if the group with frequent ear infections also failed to respond appropriate to other vaccines, including the hepatitis B immunization.
They found the group plagued by ear infections generated few protective antibodies after immunization for diphtheria, whooping cough and hepatitis B.
Even after vaccine boosters were administered, the children still remained poorly protected against the infections, based on the report in the November issue of the Pediatric Infectious disease journal.
Clean-Shave Haircuts Leave Traces of Virus on the Scalp
According to a report in the October issue of the journal Dermatology, about one-quarter of men who get a clean-shave haircut (leaving them bald) have residual, invisible bleeding on their scalps that may transmit viral infections.
University of Cape Town researchers examined the scalps using swabs on 16 men after professional haircuts. Six were found to have identifiable blood on their scalp that could transmit blood-borne infections such as HIV or hepatitis B. However, no HIV was found in the samples although at least one man was HIV-positive.
"This study confirms ... haircut-associated bleeding but goes further to show for the first time that invisible bleeding from clean-shave haircuts is also common," they wrote. "Future investigations for potential HIV and hepatitis B transmission through clean-shave haircuts are warranted but should not delay public education for disease prevention."
Back to News Review