HBV Journal Review
June 1, 2014, Vol 11, no 6
by Christine M. Kukka
Belatedly, National Panel Recommends Screening At-Risk Patients for Hepatitis B
Ten years after it recommended against screening the "general population" for hepatitis B, an independent national task force that creates prevention guidelines for primary care providers has finally recognized that certain high risk groups in the U.S. should be screened for hepatitis B.
Their recommendations, recently published in the Annals of Internal Medicine, come after numerous studies faulted primary care providers for failing to screen patients for hepatitis B and missing opportunities to treat patients for liver disease and immunize family members against hepatitis B virus (HBV) infections.
Other health care organizations, including the U.S. Centers for Disease Control and Prevention (CDC), the Institute of Medicine, and the American Association for the Study of Liver Disease, have been recommending for years that primary care doctors screen high-risk patients for hepatitis B, which has infected up to 2.2 million Americans.
The U.S. Preventive Services Task Force (USPSTF) recently issued clinical guidelines recommending that doctors screen the following patients for hepatitis B:
- People from countries that have hepatitis B rates exceeding 2% (which includes Asia, Africa, Central Europe and parts of Central and South America).
- U.S.-born people whose parents immigrated from countries with high rates of HBV infection.
- HIV-positive people, injecting drug users, men who have sex with men, and
- Household contacts of people infected with HBV.
The task force's guidelines suggest that because an effective vaccine to protect against the infection and effective treatments for hepatitis B are now available, they decided to issue these recommendations. However, both the vaccine and effective treatments have been available for more than a decade.
"In the 2004 recommendation, the USPSTF focused only on the general population," the authors wrote in the recommendations. "In the current recommendation, the USPSTF focused on high-risk populations as it considered new evidence on the benefits and harms of antiviral treatment, the benefits of education or behavior change counseling, and the association between improvements in intermediate and clinical outcomes after antiviral treatment.” The task force noted that it, "...found inadequate evidence that education or behavior change counseling reduces disease transmission."
Genotypes and Mutations Define the Course of Hepatitis B Infection
Researchers are increasingly finding that HBV genotypes or strains—and the mutations that they generate—can determine the severity of a patient's infection.
Each of the world's 10 genotypes and their mutations have different characteristics that can increase risk of cirrhosis and liver cancer, determine whether an infection becomes chronic, and basically determine a patient's destiny, according to a recent study, published in the May issue of the World Journal of Hepatology.
For example, those infected with genotype A are more likely to develop a chronic infection, while those with genotype C have higher rates of viral mutations that promote cirrhosis and cancer. Both chronic infection and cancer-causing mutations frequently occur with genotypes D.
Increasingly, researchers noted, genotype, subgenotypes, and mutations will guide doctors' decisions in selecting treatment and frequency of monitoring patients for liver disease.(1)
The impact of mutations: In an unrelated article in the May issue of PLOS One, Chinese researchers examined the molecular make-up of HBV from 2,387 HBV untreated male patients to find out what role mutations in the pre-S and S gene region (the hepatitis B surface antigen—HBsAg—the outer protein coat of the virus) played in promoting liver cancer.
Mutations in the surface antigen give HBV a distinct advantage in evading the immune system's hepatitis B surface antibodies. Researchers examined the S gene in 96 patients who developed liver cancer, and compared it to HBV patients who were cancer-free.
They found patients with S and pre-S mutations had higher rates of liver cancer. Curiously, these mutations were not present when patients were young, they emerged over time as the patients' immune systems failed to eradicate these mutated antigens.
"In conclusion, our present study showed that HBV pre-S deletions, especially pre-S2 deletions, were associated with the development of liver cancer, irrespective of age, HBeAg status, and HBV genotype. Further prospective studies are needed to confirm the role of these mutations in the development of HCC," they wrote. (2)
Another mutation, this one in the microRNAs that can either enhance or suppress cancer tumors, also appears to affect the risk of hepatitis B-related liver cancer.
Chinese researchers studied the rate of mutations in microRNAs (called miR-499 rs3746444 and miR-423 rs6505162) in 984 cancer patients and compared them to people without liver cancer. They found liver cancer risk—including development of large liver tumors—was higher in patients with the miR-499 rs3746444 mutation.
Writing in the May issue of the journal Genetic Testing and Molecular Biomarkers, researchers suggest screening of all hepatitis B patients for this mutation. (3)
Source 1: www.ncbi.nlm.nih.gov/pubmed/24833873
Source 2: www.plosone.org/article/info%3Adoi%2F10.1371%2F
Source 3: www.ncbi.nlm.nih.gov/pubmed/24854593
Older Patients Who Lose HBeAg After Treatment May Relapse
Patients age 40 and older who lose the hepatitis B "e" antigen (HBeAg) as a result of antiviral treatment face a high risk of its return, compared to people who lose it spontaneously (without treatment), or who lose it during treatment when they're younger.
Researchers, writing in a report published in the May journal of Digestive Diseases and Sciences, compared 135 patients with antiviral-induced HBeAg seroconversion (loss of HBeAg and development of "e" antibodies) with 251 patients who experienced HBeAg seroconversion spontaneously.
When patients spontaneously seroconverted, various factors played roles in whether they relapsed, such as age at HBeAg seroconversion, male gender, HBV DNA levels before HBeAg seroconversion, HBV genotype C, and the presence of mutations in HBsAg (pre-S deletions).
However, in patients with antiviral-induced HBeAg seroconversion, the only risk factor for a return of HBeAg was older age at time of seroconversion. These researchers found that antiviral-treated patients who seroconverted after age 40 had higher rates of HBeAg returning than treated patients who seroconverted in their 20s and 30s. (1)
An unrelated study published in the May issue of Liver International followed 228 patients after they spontaneously cleared HBeAg and found that those who continued to have elevated viral loads were most at risk of relapse (including liver damage and increased viral load.)
Hepatitis B flares occurred in 76 (33.3%) patients over the five-year study period, and the patients who experienced a resurgence of infection were older, had higher HBV DNA levels at the time they lost HBeAg, and were male (42.7% vs 23.4% female). (2)
Source 1: www.ncbi.nlm.nih.gov/pubmed/24846794
Source 2: www.ncbi.nlm.nih.gov/pubmed/24840542
Tenofovir Proves Ineffective in Patient with Multiple Drug Resistance
The antiviral tenofovir (Viread) is considered the most powerful antiviral currently on the market with the lowest rate of drug resistance, even after five years of use.
But tenofovir may have met its match in a patient who had already developed resistance to the antivirals lamivudine (HBV-Epivir), adefovir (Hepsera) and entecavir (Baraclude) before trying tenofovir.
According to a report by Korean researchers published in the April issue of the Journal of Clinical Virology, the 54-year-old man with HBeAg-positive hepatitis B was treated with tenofovir after unsuccessful treatment with lamivudine, followed by entecavir, and then a combination of adefovir and lamivudine.
The man developed various mutations in his HBV that were able to evade these antivirals that target certain areas of the virus to stop replication. When he finally tried tenofovir, the various mutations he had developed were enough to render even tenofovir ineffective.
"Tenofovir resistance may emerge due to multi-site polymerase (multiple) mutations rather than (a) single-site polymerase mutation," the researchers wrote.
Nearly All HBeAg-Negative Patients Relapse After Antiviral Treatment Stops
Is it possible to stop antiviral treatment once patients with HBeAg-negative hepatitis B reach undetectable viral load? No, according to a study published in the May issue of the medical journal Gut.
Chinese researchers stopped entecavir treatment in 184 patients (average age 54, 67.9% male), after they had gone for more than two years with undetectable viral load while on treatment. Their viral loads and HBsAg were monitored every six to 12 weeks for 48 weeks after treatment ended.
The results were disheartening, after 24 weeks 74.2% of the patients had a resurgence of HBV DNA exceeding 2,000 IU/mL and after 48 weeks ,91.4% of patients had relapsed with elevated viral loads.
Notably, the doctors had stopped the entecavir treatment in accordance with the Asia-Pacific Association for the Study of the Liver guidelines, which call for halting antivirals if patients maintain an undetectable viral load over 18 months.
"Entecavir cessation in Asian HBeAg-negative (patients) resulted in high rates of virologic relapse, suggesting (antiviral) therapy should be continued indefinitely until ... HBsAg seroclearance," they wrote.
Studies Find Hepatitis Infection Does Not Increase Pancreatic Cancer Risk
Two studies published in different medical journals both conclude that HBV infection does not increase a patient's risk for pancreatic cancer. Both studies were undertaken because prior reports suggest a link between hepatitis B and this cancer.
Researchers, reporting in a study published in the May issue of the Journal of Gastrointestinal Cancer, scoured all recent studies that examined hepatitis B and pancreatic cancer (also called pancreatic adenocarcinoma.) Their analysis found a, "nonsignificant increased risk of cancer" in patients who had been or were currently infected with HBV. However they did encourage more research into any possible linkage. (1)
The second report, published in the May issue of the World Journal of Gastroenterology compared hepatitis B and C infection rates in 585 Taiwanese patients with pancreatic cancer with a group of healthy 1,716 people of similar age and gender.
Both groups were screened for hepatitis C virus (HCV) antibodies, hepatitis B surface antigens and antibodies, and hepatitis B core antibodies, which indicate a prior hepatitis B infection.
HBsAg, indicating a current hepatitis B infection, was present in 73 cases in the pancreatic cancer group (12.5%) and in 213 of the control group (12.4%).
Hepatitis C infection was positive in 22 pancreatic cancer cases (3.8%) and in 45 of the control group (2.6%).
Surface antibodies, indicating a resolved hepatitis B infection or immunization, was present in 338 cancer cases (57.8%) and 1,047 of the control group (61%).
The similar rates of viral hepatitis infection in the cancer and the control group show there was no increased rate of pancreatic cancer from hepatitis infection, the researchers concluded. However, older age, male gender, diabetes and smoking did increase pancreatic cancer risk.(2)
Source 1: www.ncbi.nlm.nih.gov/pubmed/24788082
Source 2: www.ncbi.nlm.nih.gov/pubmed/24803819
Screening Pregnant Women for High Viral Loads Is Cost Effective
A study by the U.S. Centers for Disease Control and Prevention finds undisputedly that it is cost effective to screen HBV-infected pregnant women for HBeAg and HBV DNA to determine if antiviral treatment is needed during pregnancy to tamp down viral load and prevent mother-to-child (vertical) infection.
While immunization immediately after birth reduces infection of newborns in more than 90% of cases, pregnant women with high viral loads can still infect newborns despite immunization and treatment with HBIG (HBV antibodies).
However, when women with high viral loads are treated with antivirals during pregnancy, the risk of vertical infection declines markedly and future infections and their associated health care costs are avoided. But is this testing for high viral loads cost effective?
Researchers analyzed the cost benefits of screening HBV-infected women for either HBeAg and viral loads (both reveal high viral loads) against continuing with the current policy of just treating newborns.
The benefits were measured in quality-adjusted life-years (QALYs) and all costs were in 2010 U.S. dollars
"The HBeAg testing strategy saved $3.3 million and 3,080 QALYs and prevented 486 chronic HBV infections compared with the current recommendation," researchers wrote in the May issue of the journal of Obstetrics and Gynecology.
"Testing HBsAg-positive pregnant women for HBeAg or HBV load followed by maternal antiviral prophylaxis if HBeAg-positive or high viral load to reduce (vertical) hepatitis B transmission in the United States is cost-effective," they concluded.
Hepatitis B Appears to Impede Fertility
Hepatitis B infection in either men or women makes it more difficult to create a pregnancy through in vitro fertilization, according to a study published online, ahead of print, in the July issue of the Journal of Medical Virology.
Chinese researchers examined the impact of hepatitis B in 224 couples involved in the various steps of in vitro fertilization. Their assessment included sperm health, ovarian stimulation, and embryo transfer. In all couples, either one partner (77 women, 136 male) or both (11) were HBV-infected.
Their in vitro success was compared with 448 uninfected couples who served as controls. Couples with HBV infection had a longer history of infertility than uninfected couples. HBV-infected men had higher numbers of abnormal sperm than men in the control group (11.9% vs.19%).
Couples with HBV-infected female partners had fewer "top-quality embryos" than the control group, and fertilization rates among HBV-infected couples were significantly lower than in the control group.
"These results suggest that chronic HBV infection is likely to represent a significant cause of infertility," researchers wrote.
Despite Low Viral Load, Infected People Can Still Infect Family Members
Despite low viral loads and inactive infections, HBV-infected people can still infect family members, according to a 10-year study from Turkey, published in the journal of Clinical Molecular Hepatology.
Researchers studied HBV status of 438 inactive HBsAg carriers and their families. The HBsAg-positive rate was 34.6% in 625 family members of 334 patients. Surprisingly, infection rates were higher in family members of hepatitis B patients with undetectable HBV DNA than among family members of patients with detectable HBV DNA.
"The HBsAg positivity rate was higher in family members of inactive HBsAg carriers than in the general population, " researchers wrote. "... these family members therefore have a higher risk of HBV transmission. Furthermore, despite negative HBV DNA levels, transmission risk was not reduced in these patients, and horizontal transmission seems to be independent of the HBV DNA value."
Good News: HBV Infection Rates Lower Than Expected Among Korean-Americans
A community screening program conducted in Korean churches in southern California uncovered good news: only 3% of 973 first-generation Korean-Americans screened were infected with HBV. That rate is far below the estimated 10% infection rate among many Asian immigrant groups.
The bad news is that many of those screened had not been immunized and many had been infected in the past, but managed to clear the virus.
The screening occurred in San Bernardino and Riverside counties, home to 4 million residents, including many Asian-Americans. Participants, whose average age was 52, were surveyed about hepatitis B, and asked if they had ever been infected or immunized against the virus.
About 25% said they had been vaccinated against hepatitis B. But their blood tests revealed:
- 3% were infected with HBV
- 35.7% had been infected at some point but had cleared the infection.
- 20% had not been immunized and were susceptible to infection
- And 40.3% had been immunized against hepatitis B.
Men had a higher infection prevalence (4.9% vs. 1.7%) than women and a lower vaccination rate (34.6% vs. 44.0%). About 35.1% of participants incorrectly reported their immunization status.
"This large screening study in first-generation Koreans in Southern California demonstrates: 1) a lower than expected HBV prevalence (3%), 2) a continued need for vaccination, and 3) a need for screening despite a reported history of vaccination," researchers reported in the journal BMC Infectious Diseases.
Green Tea May Be an Effective Antiviral
An experiment in a laboratory setting found that an extract from green tea was an effective antiviral, stopping HBV from producing HBsAg and HBeAg.
Researchers from Beijing, writing in the Journal of Zhejiang University Science, reported they used epigallocatechin-3-gallate (EGCG, a compound found in green tea) and found it effectively suppressed the secretion of HBsAg and HBeAg.
The extract proved to be more powerful than the antiviral lamivudine in suppressing the virus. Researchers suggest this substance may emerge as an effective antiviral, which would not carry the side effects of current antivirals.
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