HBV Journal Review
April 1, 2013, Vol 10, no 4
by Christine M. Kukka
Missing Your Daily Antiviral Pill Can Cause Resurgence in Infection
What impact does forgetting to take your daily antiviral pill have on hepatitis B virus (HBV) infection? It depends on what antiviral you take, according to a Japanese study published in the International Journal of Medical Sciences. Missing a few doses of entecavir (Baraclude) could result in an infection rebound.
Researchers followed 203 patients (135 treated with entecavir and 68 treated with lamivudine—Epivir HBV), and measured their alanine aminotransferase (ALT) levels and HBV DNA every three months to see what impact the medications had on liver health and viral load.
They discovered that patients who missed their daily entecavir pill more than 10% of the time had higher rates of a resurgence in viral load (called a breakthrough infection) than lamivudine-treated patients who missed their medications.
To assess the impact of missed doses, doctors asked patients how well they adhered to their daily medication regimen. Missing a daily antiviral dose more than 10% of the time is considered "poor adherence," resulting in ineffective treatment.
But researchers were surprised that missing entecavir doses caused more viral breakthrough than missing lamivudine doses. They found that three (42.8%) of seven entecavir patients who missed daily antiviral medications had viral breakthroughs. In contrast, only 3.1% of entecavir patients who took the antiviral regularly had viral breakthrough.
"Viral breakthrough associated with poor adherence could be a more important issue in the treatment with especially stronger (antivirals), such as entecavir," researchers noted.
Study Finds Telbivudine Effective in Spurring HBeAg Seroconversion
Telbivudine (Tyzeka) is a newer, potent antiviral that is more effective than lamivudine or adefovir (Hepsera), but it has been overshadowed by entecavir and tenofovir (Viread) which have lower rates of drug resistance.
However, new studies from China now suggest this drug may be more effective than other antivirals in causing patients to lose the hepatitis B "e" antigen (HBeAg) and develop "e" antibodies.
The reason for this high seroconversion rate (exceeding 50% after four years of treatment) may be that the antiviral disrupts viral reproduction and also acts like interferon—strengthening the immune system to fight the infection.
According to reports published in the April issue of the Journal of Viral Hepatitis, "telbivudine is associated with the highest HBeAg seroconversion rates, which are similar to those observed with pegylated interferon (Pegasys). Besides direct antiviral effect, modulation of the immune system may be an additional benefit for telbivudine-treated patients."
Researchers say there is evidence that telbivudine (600 mg daily pills) acts like interferon more than any other antiviral in its ability to spur HBeAg seroconversion resulting in declines in hepatitis B surface antigen (HBsAg) and viral load.
"The results described in this (study) suggest that the antiviral effect of telbivudine may be attributable not only to direct suppression of HBV, but also to immunoregulatory effects," they wrote.
HBeAg seroconversion rate 60% after interferon:
Another report on telbivudine, published in the same journal, found telbivudine to be highly effective in HBeAg-positive patients who had been treated with pegylated interferon for 48 weeks (administered through weekly injections.)
They compared the outcomes in patients who were treated with only interferon with those treated with telbivudine after stopping interferon.
After 48 weeks:
• Among 18 patients treated with only interferon, five patients (28%) experienced HBeAg seroconversion, nine patients (50%) had undetectable HBV DNA, and 11 patients (61%) achieved normal ALT levels.
• Among the 18 patients treated with telbivudine after stopping interferon, 11 patients (61%) experienced HBeAg seroconversion, and all patients achieved undetectable viral load and normal ALT levels.
This sequential treatment with telbivudine after interferon was highly effective and warrants additional research, scientists noted.
Seroconversion continues after treatment stops:
In the same journal, a report found that 82% of patients who stopped telbivudine after HBeAg seroconversion continued to test negative for HBeAg 111 weeks after treatment stopped. This is unusual because often the infection returns after antiviral treatment stops.
However, 10.6% of HBeAg-positive patients and 10% of HBeAg-negative patients developed drug resistance to entecavir after four years of continuous treatment.
Entecavir and Interferon Combo Treatment Effective, Except in HBV Genotype E
A combination of the antiviral entecavir (Baraclude) and pegylated interferon proved highly effective in spurring HBeAg seroconversion (which was sustained even after treatment ended) and undetectable viral load, except in patients with HBV genotype E, a viral strain found in Africa.
Italian researchers treated 20 patients with high viral loads and a variety of HBV genotypes with entecavir for 12 weeks, followed by pegylated interferon for 48 weeks. They compared the results to patients treated with just interferon for 48 weeks.
According to the report published in the Journal of Viral Hepatology, a sustained response—with no return of HBeAg or elevated viral load after treatment ended—was found in 60% of the combined drug group, compared to 10% in the interferon-only group.
HBeAg loss was reported in 76.9% of the combined treatment group compared to 15% of the interferon-only group. Twenty percent of the combination group produced "e" antibodies, compared to none in the other group.
Patients with genotype C had the best response to treatment, followed by genotype A, but those with genotype E had the worse response.
"These results show that a sequential approach (to treatment) is a promising strategy of treatment in patients with chronic hepatitis B and high viremia in comparison with interferon monotherapy," they wrote. "The E genotype seems to have the worse rate of response and requires other treatment strategies."
Study Shows Five Years of Entecavir Successful with No Drug Resistance
Chinese researchers treated 230 patients (113 HBeAg-positive, 117 HBeAg-negative) for up to five years with entecavir to see how effective the antiviral was and if drug resistance would develop after prolonged treatment.
The patients, who had never been treated previously, received 0.5 mg of entecavir daily. Forty-two patients remained in the study after four years and 11 remained in year five.
According to the report published in the International Journal of Medical Sciences, undetectable HBV DNA was achieved in 67%, 85%, 89.4%, 94.4%, 95.5%, 97.6%, and 100% of patients at month 3, month 6, 1 year, 2 years, 3 years, 4 years and 5 years.
Patients achieving normal ALT levels were 73.9%, 85.5%, 82.8%, 89.4%, 80.7%, 85.7%, and 100% over those time periods.
The rate of HBeAg seroconversion reached 21.4% and 15.4% at year 2 and 3 respectively; one patient cleared HBsAg after one year clearing the infection and developing surface antibodies at year 3.
One patient developed drug resistance to entecavir due to medication noncompliance.
Your Genes May Dictate If Interferon Treatment Succeeds
Hepatitis researchers have recently discovered that people who have a gene called IL28B Genotype may have an advantage in fighting viral hepatitis infection, especially when treated with interferon.
Historically, researchers thought HBV genotype (which is different from the IL28B Genotype) was the key factor in determining if interferon would be successful. But now, they are learning that your genetic make-up can also play a role.
For example, 50% to 80% of people who have a certain type of IL28B gene called CC genotype can more easily be cured of hepatitis C. This happens because the gene either naturally strengthens the immune system or responds well to interferon, which also jumpstarts the immune system.
An article in the March issue of the journal Current Opinion in Gastroenterology, suggests that hepatitis B patients who have the IL28B CC genotype may also fare better when treated with interferon than those without the gene.
"Sustained response rates to interferon may be influenced by the IL28B genotype and can be predicted by on-treatment monitoring HBsAg and HBV DNA," researchers from the University of Texas Southwestern Medical Center in Dallas wrote.
Monitoring HBsAg during interferon treatment can help doctors determine which IL28B genotype is present in the patient and help them personalize treatment for each patient.
35% of Veterans with Hepatitis C Have Been Exposed to Hepatitis B
In the largest study of its kind, researchers tested 168,239 patients enrolled in the National Veterans Affairs HCV Clinical Case Registry during 1997-2005 to identify how many hepatitis C-infected patients had also been infected with hepatitis B.
They reported in the March issue of the journal Hepatology that 58,415 (34.7%) patients had been exposed to HBV.
Among 102,971 patients with current HCV infection, 1,431 patients (1.4%) had HBV co-infection. Veterans with the HCV-HBV coinfections tended to be under age 50, male, HIV-positive or with a history of blood transfusions.
The HBV active infection rate was low, in part because hepatitis C tends to become the dominant liver infection and suppress hepatitis B.
Middle-Aged Men with New Sexual Partners Account for New HBV Cases
An urban hepatology clinic in Detroit tracked new (acute) hepatitis B cases to determine who in this era of immunization was becoming infected. They reported that among 32 patients with symptomatic, new hepatitis B infections, most were male, unemployed, unmarried, middle-aged, and 34% had contracted the infection from a new sexual partner.
According to the report published in the Journal of Clinical Gastroenterology, 15% of the patients reported no known risk factors.
Eight patients (25%) were given antivirals due to highly elevated ALT levels and liver damage. One diabetic patient underwent liver transplantation.
"These data reinforce the need for HBV vaccination of individuals at risk, including those not traditionally targeted," researchers noted.
Pregnant Women with HBV DNA Exceeding 1 Million May Infect Their Newborns
A Taiwanese study found that infants born to HBV-infected mothers whose viral load exceeded 10 million copies/milliliter were at far higher risk of HBV infection, despite immediate immunization and use of hepatitis B immune globulin (HBIG—hepatitis B antibodies) to prevent infection.
In contrast, mothers with lower viral loads, including those with HBV DNA in the thousands of copies/mL were less likely to transmit infection to their newborns.
Doctors screened 303 infants born to infected mothers for HBsAg between four and eight months and between one and three years of age, according to the study published in the Journal of Hepatology.
Eighty-one mothers (26.7%) were HBeAg-positive, and 10 infants born to mothers whose viral loads exceeded 100 million copies/mL became chronically infected despite immunization and use of HBIG. The rate of infection was:
• 6.6% when the mothers' viral load was 10 million copies/mL
• 14.6% when it was at 100 million copies/mL
• And 27.7% when the viral load exceeded 1 trillion copies/mL.
The study reinforced the need to lower viral load in pregnant women whose HBV DNA levels reached 1 million or more to prevent mother-to-child infection. To date, doctors have experimented with using antivirals late in the pregnancy to lower viral loads. However, medical guidelines currently do not recommend referring HBV-infected women with high viral loads to liver specialists who might treat them with antivirals.
Additionally, research into the impact of antiviral treatment on pregnant women and newborns is in its early stages and the U.S. Food and Drug Administration has not sanctioned any hepatitis B antiviral for use during pregnancy.
Currently, telbivudine and tenofovir are recommended for use during pregnancy because they have proven safe in HIV-infected women.
"Although current reports show no significant increase in birth defects and pregnancy complications," researchers noted, "more long-term safety data of antiviral therapy, continued epidemiological surveillance on HBsAg-positive mothers and their children, and cost-effectiveness analyses are needed to develop a safe and cost-effective preventive intervention strategy."
Telbivudine Treatment During the Entire Pregnancy Appears Safe
There are a growing number of studies following pregnant, HBV-infected women treated with antivirals during the last trimester of pregnancy to prevent mother-to-child infection. Now, one of the first studies to follow women treated during their entire pregnancy has been reported from China.
In the study, reported in the Journal of Viral Hepatitis, researchers monitored the health of 50 women who were treated with telbivudine during their entire pregnancies and their 52 infants. Presumably, the women were treated during their entire pregnancies because of elevated viral load and indications of liver damage from the infection.
The total rate of congenital abnormalities was 3.8%, apparently not above normal. None of the 38 infants followed for six months after birth developed hepatitis B infection, none of the mothers developed liver damage during pregnancy, and 86% maintained undetectable viral load.
"(Telbivudine) treatment is safe and effective in chronic HBV-infected pregnant mothers for the entire pregnancy," researchers reported.
Half of Children Achieve "Inactive" HBV Infection by Age 19
Canadian researchers followed 252 HBeAg-positive children between 1983 and 2008 and found that half had "inactive" hepatitis B (low viral load and no sign of liver damage) by the time they reached age 19.
The children were treated at Toronto's Hospital for Sick Children Liver Clinic over 25 years. About 60% were born to infected mothers, 77% were of Asian descent, and 33% were treated with interferon.
However, neither treatment, nor gender, nor how they were infected affected their health by the time they reached age 19. Doctors found 41.7% of the children lost HBeAg during the study period, "and this was not affected by transmission route, gender nor treatment," they wrote in the April issue of the Journal of Viral Hepatitis.
Additionally, 49% achieved "inactive" chronic infection by age 19, which included normal ALT levels, HBeAg loss, and low viral load.
Being non-Asian and having elevated ALT levels early in their diagnosis were linked to higher rates of HBeAg seroconversion and "inactive" infection by age 19.
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