HBV Journal Review
July 1, 2013, Vol 10, no 7
by Christine M. Kukka
Experts Describe When to Treat Pregnant Women with Antivirals
Two U.S. hepatitis B experts have crafted guidelines for doctors to use when deciding when to treat pregnant women infected with the hepatitis B virus (HBV) with antivirals in order to safeguard the women's health and prevent infection of newborns.
More than half of new hepatitis B infections result from mother-to-child (vertical) transmission and despite immediate immunization and administration of HBIG (hepatitis antibodies), about 30% of infants born to women with high viral loads become infected. Additionally, women who want to become pregnant may already be treated with antivirals because of liver damage. There is little medical guidance on whether treatment is safe over the entire pregnancy.
Does pregnancy worsen hepatitis B? Generally it does not unless the woman has cirrhosis (severe liver scarring.) Studies show a pregnant woman's viral load generally does not increase over a pregnancy, but after the baby is born and the woman's hormone levels change (akin to a sudden decline in steroids), some women experience a "flare" and their alanine transaminase (ALT) levels may increase due to moderate liver cell damage. Because of these flares, doctors must monitor new mothers carefully for several weeks after childbirth.
When should pregnant women be treated? Starting in the second or third trimester of pregnancy, antiviral treatment is recommended when women have high viral loads—exceeding 1 million copies per milliliter or 200,000 international units per milliliter. However, if women are already receiving antiviral treatment when they become pregnant, treatment should probably continue over the pregnancy to prevent worsening liver disease.
Which antivirals are safe to use during pregnancy? The experts recommend tenofovir (Viread) in the event the woman continues to need antiviral treatment because this drug has a very low rate of drug resistance, or telbivudine (Tyzeka). Both have been shown to be safe and cause no birth defects when used in pregnant women infected with HIV or HBV.
What if women have elevated ALTs before becoming pregnant and have never been treated? The experts recommend these women should be treated with antivirals (not interferon), and if possible their viral load should be reduced through antiviral treatment before becoming pregnant. Their liver health should be monitored carefully during the pregnancy.
What about women with normal ALTs and high viral loads? Women in this immune-tolerant phase of infection should be monitored carefully during pregnancy and should be given antivirals during their second or third trimester if they:
- Continue to have viral loads exceeding 1 million copies per mL
- Have already had a child who became HBV-infected
- Or if they experience premature labor.
Is it safe to use antivirals during the entire pregnancy? If women have been using antivirals, or require treatment because of liver damage (ALT flares) during pregnancy, antivirals should be used to safeguard the women's health, according to the report published in the June issue of Seminars in Liver Disease. They recommend using tenofovir in this situation, because it is fast-acting, potent, and has no record of causing birth defects.
Monitoring after delivery: Because of the risk of hepatitis flares after delivery, and after treatment stops following delivery, the new mother should be monitored every four to six weeks for at least 12 weeks after antiviral treatment stops.
Can a woman taking antivirals breastfeed? Trace amounts of the antiviral have been found in breast milk, so experts do not recommend breastfeeding if antiviral treatment is ongoing.
Source: "Antiviral therapy for chronic hepatitis B in pregnancy" by Pan and Lee.Semin Liver Dis. 2013 May;33(2):138-46.
Half of Patients Treated Long-Term with Tenofovir Lose HBeAg
After more than five years of tenofovir treatment, 50% of patients lose the hepatitis B "e" antigen (HBeAg), 37% seroconvert and develop "e" antibodies, 11% lose the hepatitis B surface antigen (HBsAg), and 8% clear the infection and develop surface antibodies, according to a global study presented at the 23rd Conference of the Asian Pacific Association for the Study of the Liver held in early June.
This and several other studies on tenofovir presented at APASL provided strong proof that tenofovir appears to be highly effective in reducing viral replication with 96% of patients reporting reduced (or no worsening) fibrosis and all achieving undetectable viral load. Even 74% of patients with cirrhosis were no longer cirrhotic after five years of treatment.
Long-term antiviral use has been associated with bone loss and kidney damage, but neither symptom was evident among the patients over the lengthy study period.
In another APASL study, researchers monitored 280 patients who had developed drug resistance to the antiviral lamivudine (Epivir-HBV) to see if they developed resistance when treated with tenofovir (alone or in combination with emtricitabine).
After 96 weeks of treatment, researchers reported that all patients responded well and no drug resistance developed. Tenofovir was successful in stopping viral replication even among virus that had mutated and had been able to "resist" lamivudine.
Source 1: "Six years of treatment with tenofovir..." by Tsai, Buti, Gane et al. APASL Liver Week. Singapore, June 6-10, 2013
Source 2: No detectable tenofovir resistance..." by Gane, Corsa, Liu et al. APASL Liver Week. Singapore, June 6-10, 2013
Even Patients with High Viral Loads Lose HBeAg with Tenofovir
Half of 10 HBeAg-positive patients with extremely high HBV DNA (exceeding 1 million copies/mL) who were treated with tenofovir over five years (288 weeks) lost HBeAg, 40% developed “e” antibodies, and 72.7% achieved normal ALT levels.
This study is significant because current medical guidelines do not recommend treating patients in the “immune-tolerant” stage of infection—when viral load is high and ALT levels are only slightly elevated.
This study focused on younger Asian adults (average age 32), two-thirds of whom were male. Their results were compared with 172 patients with lower viral loads who were also treated with tenofovir over 288 weeks. The group with lower viral loads achieved undetectable HBV DNA faster (within 60 weeks) while patients with high viral loads took 88 weeks to achieve undetectable HBV DNA.
Tenofovir’s success in spurring HBeAg seroconversion in younger adults—which usually results in a permanent lowering of viral load—may force experts to reconsider whether to change practice guidelines and recommend treating this patient group.
However, the next challenge experts must tackle is how long to treat this younger patient group with antivirals in order to achieve a sustained, permanent HBeAg seroconversion.
Source: “Tenofovir Disoproxil Fumarate (TDF) in Asian…” by Fung, Gordon, Krastev et al. 23rd Conference of the Asian Pacific Association for the Study of the Liver, 6-9 June 2013, Singapore.
New Type of Interferon Effective in Phase 2 Hepatitis B Trial
A new type of pegylated interferon, called peginterferon Lambda, reduced viral load (HBV DNA) and hepatitis B surface antigen (HBsAg) levels faster than the standard pegylated interferon alfa-2a (Pegasys), according to results from a Phase 2 clinical trial presented at the APASL conference.
Eighty patients (most Asian and male) were given the weekly Lambda injections for 24 weeks in the ongoing study and 83 patients were treated with the standard interferon. The patients' ages ranged from 18 to 70 and half of the study participants had only moderately elevated ALT levels.
After the first 24 weeks covered by this study, both interferons appeared equally effective in spurring HBeAg loss. Surprisingly, the conventional interferon was better at reducing ALT levels to normal ranges (33.7% vs. 23.8% in the Lambda group.) There were no safety concerns or additional side effects resulting from Lambda treatment compared to the standard interferon.
Lambda interferon has proven effective in hepatitis C clinical trials, where it reportedly causes fewer flu-like side effects. The hepatitis B Lambda study is ongoing, with a goal of 48 total weeks of treatment followed by 164 weeks of follow-up.
Source: "Peginterferon Lambda for the Treatment of ..." by Chan, Ahn, et al.
APASL Liver Week. Singapore, June 6-10, 2013
Majority of Hepatitis B Patients Have Vitamin D Deficiency
Researchers know that people with hepatitis C and other types of liver disease have vitamin D deficiency, but little is known as to whether people with HBV infection also lack this vitamin, which is essential for strong bones and immune systems.
A group of global researchers measured vitamin D levels in 735 patients with active HBV infection just before they joined a clinical trial. They found that:
- Only 7% of the patients had healthy vitamin D levels
- 35% had relatively insufficient vitamin D levels
- And 58% were deficient (with less than 20 ng/mL of vitamin D in their systems.)
Vitamin D levels did rise in patients who were living in sunny, warm climates. Sunlight spurs the body to generate vitamin D.
Their findings mirror smaller studies that found hepatitis B patients with liver disease had lower vitamin D levels. This study was presented at APASL.
Source: "High Prevalence of Vitamin D Deficiency...." by Alkashab, Foster, Kim et al. APASL Liver Week. Singapore, June 6-10, 2013
Patients with Healthy Vitamin D Levels Are More Likely to Clear HBsAg
Israeli researchers found that hepatitis B patients who had healthy vitamin D levels were more likely to clear HBsAg and achieve "inactive" hepatitis B than those with vitamin D deficiency, according to a report published in the June issue of the World Journal of Hepatology.
They followed 53 patients who lost HBsAg between 2007 and 2012 and found that 83% of those who cleared the virus had normal vitamin D levels. Patients who lost HBsAg also had lower viral loads and were HBeAg-negative.
Source: “Normal Vitamin D Levels…” by Mahamid, Nseir, Elhija et al. World J Hepatol. 2013 Jun 27;5(6):328-331.
Activists Develop a National Plan to Eradicate Hepatitis B in the U.S.
An estimated 2 million Americans are infected with hepatitis B and two-thirds do not know it. Screening and treatment of those chronically-infected remains poor with fewer than 10% getting the treatment they need. To make matters worse, many of those infected are immigrants or first-generation Asian-Americans who face overwhelming cultural and financial barriers to getting diagnosed, immunized or treated.
To address this glaring health disparity, the Hepatitis B Foundation convened a team of experts and community activists from across the country to develop strategies to break down cultural barriers and educate medical providers and patients to address this challenge.
According to a report in the May issue of the Journal of Community Health, the summit generated the "Hep B United" Campaign with the following goals:
- Bolster and strengthen community groups and coalitions to raise awareness about hepatitis B and the benefits of testing and treatment and immunization as a key prevention strategy.
- Educate patients so they demand HBV testing, even when their medical providers are uninformed about the infection.
- Decrease community stigma and discrimination associated with hepatitis B.
To tackle provider ignorance and inaction, organizers urged government health care monitoring groups to evaluate doctors based on their hepatitis B screening, immunizing and treatment scores. They also encouraged use of electronic medical records to promote better provider adherence to current hepatitis B screening and treatment guidelines.
Educating providers and developing case management strategies so HBV-infected pregnant women had access to monitoring, treatment and other safeguards to prevent infection of their newborns was also recommended. Similar case management practices are now used when pregnant women are found to be HIV-infected to ensure treatment and prevention.
Striking down cultural barriers was also deemed essential, which requires more than simply translating English materials into new languages. The materials must be developed by native speakers, according to the group, who understand the nuances of culture and language of individual ethnic groups.
"Building upon the current national focus on prevention and treatment of viral hepatitis, the Hep B United community action plan is designed to be a national resource for local HBV coalitions across the country as they strive to meet the health needs of their communities and eliminate HBV-related health disparities," the coordinators wrote.
Source: "Eradication of Hepatitis B...," by Cohen, Caballero, Martin et al.
J Community Health. 2013 May 29.
New Guidelines Urge Britain's Doctors to Improve Hepatitis B Care
The National Institute for Health and Care Excellence (NICE), which develops medical practice guidelines for Britain's National Health Service, has found that its general practitioners are failing to adequately treat patients with hepatitis B, similar to what occurs in the United States.
A recent London audit found that one-third of people with chronic hepatitis B were not referred to specialists for monitoring and treatment. In June, NICE issued new hepatitis B treatment guidelines that detail what tests should be run, and when patients should be referred to specialists for treatment.
"With multiple treatment options that are efficacious and safe, the key questions are which patients need immediate treatment and what sequence and combination of drug regimens should be used, and which patients can be monitored and delay treatment," the guidelines note.
Interestingly, the guidelines promote treating pregnant women with high viral loads with tenofovir during their third trimester of pregnancy.
Hepatitis B (chronic): Diagnosis and management of chronic hepatitis B in children, young people and adults. Clinical Guideline 165. National Institute for Health and Care Excellence, Manchester. Great Britain
Measuring HBsAg Levels May Identify Fibrosis and Avoid Liver Biopsies
Chinese researchers have found that measuring HBsAg and the liver enzyme GGT (gamma-glutamyl transferase) can accurately identify if a person has fibrosis—and avoid the need for invasive liver biopsies.
The researchers performed liver biopsies—in which a small sliver of liver tissue was removed through a needle—on 197 HBeAg-positive patients (average age 31, most male). The doctors simultaneously measured HBsAg and GGT (a liver enzyme that is released when liver cells are damaged or die.)
The average HBsAg level in the patients was about 15,800 international units per milliliter. Researchers found significant fibrosis through their liver biopsies in 56.9% of patients with higher HBsAg levels.
They found that elevated levels of both HBsAg and GGT accurately indicated fibrosis (liver inflammation), according to the biopsies. They reported these two measurements accurately identified fibrosis in 78% of the patients, which means about 80% of liver biopsies could have been avoided in HBeAg-positive patients, according to their report published in the June issue of the Journal of Gastroenterology and Hepatology.
Source: "Serum HBsAg quantification ..." by Xun, Zang, Guo et al. J Gastroenterol Hepatol. 2013 Jun 25
HBsAg Levels May Also Predict Cancer Risk in HBeAg-negative Patients
In a large study of hepatitis patients, Taiwanese researchers were surprised to discover that higher levels of HBsAg increased these HBeAg-negative patients' liver cancer risk more than having high viral loads. The study was published in the May issue of the journal Gastroenterology.
Researchers followed 2,688 patients over 14 years and studied the link between HBsAg levels and liver cancer. While high viral load was a better indicator of which HBeAg-positive patients developed cancer (along with age, ALT, and gender), among HBeAg-negative patients with viral loads under 2,000 IU/mL, it was HBsAg levels that were the most important indicator.
"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 wrote.
Source: "High levels of hepatitis B..." by Tseng, Liu, Yang et al. Gastroenterology Vol. 142, Issue 5
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