HBV Journal Review
May 1, 2015, Vol 12, no 5
by Christine M. Kukka  PDF (download)
New Treatments Targeting Hepatitis B Start Clinical Trials Soon
A Pennsylvania firm will soon start clinical trials of a unique drug called birinapant that helps liver cells infected with the hepatitis B virus (HBV) self-destruct, according to two reports published in the April edition of the Proceedings of the National Academy of Sciences.
The treatment, which employs tiny molecules to force the infected liver cells to die while leaving normal liver cells intact, has eradicated hepatitis B infection in mice, according to TetraLogic Pharmaceuticals Corp. officials and their partner researchers at the University of Melbourne in Australia.
The current treatment evolved from cancer research that developed ways to make abnormal cancer cells die–a process called apoptosis. The human body uses apoptosis every day to clear away abnormal or unwanted cells, but cancer cells and HBV-infected liver cells have unique proteins that prevent apoptosis, which allows tumors and HBV infection to spread. (1)
TetraLogic developed a molecule called Smac that counteracts these apoptosis-stopping proteins in HBV-infected liver cells. In their mouse models, birinapant treatment with the SMAC molecule resulted in the complete eradication of all HBV-infected liver cells. When birinapant was used along with the antiviral entecavir (Baraclude), HBV infection disappeared even faster from the liver. (2)
Researchers report that birinapant treatment in mice, "resulted in loss of HBV-DNA, loss of the hepatitis B surface antigen (HBsAg) and the appearance of hepatitis B surface antibodies," which signal the infection has been cleared from the body.
Phase I clinical trials, which will begin in Australia and expand to the U.S., will involve HBV-infected adults who are currently treated with either entecavir or the antiviral tenofovir (Viread). Participants will receive either a placebo or varying levels of birinapant intravenously to test safety and determine what dose is most effective.
Another new hepatitis B drug scheduled to start human clinical trials this year is the immunotherapy drug TG1050, developed by the French company Transgene SA and presented to The International Liver Congress 2015 in Vienna in late April.
According to their report, TG1050 spurs the body's immune system to fight the infection. In animal experiments, the drug significantly reduced HBV DNA and HBsAg, leading to production of surface antibodies, an indication that the infection has been eradicated.
Transgene officials said they expect to enroll patients in clinical trials in mid-2015. It will assess the effectiveness of the drug alone or possibly with antivirals. (3)
Source 1:www.pnas.org/content/early/2015/04/15
/1502390112.full.pdf?sid=683e56b9-6a97-4370-9add-7a3df97f2f5d
Source 2: www.pnas.org/content/early/2015/04/15
/1502400112.full.pdf?sid=683e56b9-6a97-4370-9add-7a3df97f2f5d
Source 3: www.transgene.fr/wp-content/uploads
/2015/04/20150423-US-EASL2015-TG10501.pdf
Experts Urge Doctors to Screen Pregnant Women for Both Hepatitis B and High Viral Loads
An editorial in the April issue of Pediatrics calls for doctors to not only test all pregnant women for hepatitis B infection, but to also measure viral loads in women found to be infected so they can be treated with antivirals to lower their risk of infecting their newborns.
Current medical guidelines call for all pregnant women to be tested for HBsAg, the antigen that indicates an existing hepatitis B infection. This universal screening helps identify women with previously undiagnosed infections and it alerts doctors to immediately immunize and administer HBIG to newborns to stop mother-to-child infection. Without those preventive interventions, about 90% of babies born to HBV-infected mothers become chronically infected with hepatitis B.
Despite immunization and HBIG, many infants born to hepatitis B "e" antigen (HBeAg)-positive women who have high viral loads (exceeding 1 million copies per milliliter) will still become infected. However, if women with high viral loads are treated with antivirals during their pregnancy to reduce viral load, the risk of infecting the newborn is dramatically reduced.
But current mandated screening focuses only on determining a woman's hepatitis B infection status. Doctors are currently not required to perform any additional screenings to determine if a woman is HBeAg-positive or has a high viral load and needs antiviral treatment to prevent mother-to-child infection.
"A program like this has already been implemented with some success in northern California," Dr. Ravi Jhaveri wrote in the editorial. "It is clear that we have come a long way in preventing (mother-to-child transmission of HBV). It is also clear that it is time to take the next step. We have the tools available, we just need to have the will."
Source: www.ncbi.nlm.nih.gov/pubmed/25896838 , based on companion report at www.ncbi.nlm.nih.gov/pubmed/25896839
Using Antivirals Early in a Pregnancy Reduces Infection of Newborns
A study of 82 women with high viral loads treated with the antiviral telbivudine (Tyzeka) during their pregnancy found that starting treatment early in the pregnancy reduced the risk of infecting newborns better than waiting until the third trimester of pregnancy.
The findings, published in the April issue of Hepatology Research, followed pregnant women with high viral loads who received 600 mg of telbivudine daily.
- 17 started the antiviral before they became pregnant
- 9 started during their first trimester
- 24 started during their second trimester
- And 32 started during their third trimester.
One year after birth, researchers found that none of the infants born to women who took telbivudine before or during the first two trimesters of pregnancy became infected. However, 3.1% of children born to women who started antivirals during their third trimester of pregnancy became infected with HBV.
"The earlier application of telbivudine during pregnancy, the better preventive effects it offered on mother-to-child-transmission (of HBV)," researchers wrote.
Source: www.ncbi.nlm.nih.gov/pubmed/25869545
Some Pregnant Women in U.S. Still Not Getting Screened for HBV and STIs
A team of researchers reviewed insurance claims for nearly 365,000 pregnant women in the U.S. to see how many were being properly screened for hepatitis B and sexually-transmitted infections, as recommended by medical guidelines. They found room for improvement.
According to the report published in the April issue of the journal of Obstetrics & Gynecology, researchers scoured insurance claims from 98,709 Medicaid-insured patients and 266,012 commercially-insured women between 2009 and 2010 to see if doctors performed the required screenings for syphilis, hepatitis B, HIV, chlamydia and gonorrhea.
- Among Medicaid-insured pregnant women: 96.3% were screened for syphilis, 96.3% for hepatitis B, 82.4% for HIV, 83.1% for chlamydia, and 74.8% for gonorrhea.
- Among commercially insured women, 97.8% were screened for syphilis, 96.8% for hepatitis B, 85.4% for HIV, 70.3% for chlamydia, and 68.6% for gonorrhea.
"Prenatal screening for syphilis and hepatitis B was nearly universal among Medicaid- and commercially-insured women; HIV screening rates were much lower and varied by insurance type and demographic characteristics," researchers noted. "Chlamydia screening was suboptimal and most often occurred with Pap testing."
Source: http://journals.lww.com/greenjournal
/Abstract/publishahead/Screening_for_
Human_Immunodeficiency _Virus_and.99116.aspx
High Viral Loads in Men Increase the Amount of HBV DNA in Their Sperm
Researchers working with HBV-infected men at fertility clinics examined these patients' HBV DNA levels in blood and their HBeAg and HBsAg status to see what impact these factors had on the quantity of HBV DNA in the men's sperm.
According to their findings published in the April issue of Andrology, 43% of the men who had detectable HBV DNA in their blood also had detectable HBV DNA in their sperm.
As expected, the higher the men's HBV DNA levels in their blood, the higher the HBV DNA levels in their sperm. Men who had high viral loads and were HBeAg-positive had the highest viral load in their semen.
Source: www.ncbi.nlm.nih.gov/pubmed/25873521
Despite Vaccine, Rural States See Rise in Hepatitis B Due to Heroin Use
A Centers for Disease Control and Prevention study of hepatitis B in seven regions of the country between 2006 and 2011 found a 19% overall decline in new (acute) hepatitis B infections, but Tennessee saw a 90% rise in new infections, most resulting from injecting drug use.
Similar spikes in hepatitis B have been documented in rural regions of the country plagued by heroin use, including neighboring Kentucky. Most of the new cases in Tennessee involved men between the ages of 30 and 49 who used injecting drugs.
Researchers, who reported their findings in the April issue of the journal of Clinical Infectious Diseases, gathered data on new HBV infections from health departments in Colorado, Connecticut, Minnesota, Oregon, Tennessee, 34 counties in New York state, and New York City.
Reported cases of acute hepatitis B represent a small percentage of actual infections–hepatitis B usually causes no symptoms and about 70% of people with hepatitis B are unaware of their infections.
"Despite an overall decline in HBV infection, attributable to successful vaccination programs, a rise in incident HBV infection related to drug use is an increasing concern in some localities," researchers concluded.
Source: www.ncbi.nlm.nih.gov/pubmed/25904365
More Than Half of Young Drug Users Are Not Vaccinated Against Hepatitis A and B
A joint study by the Centers for Disease Control and Prevention and the University of California San Diego School of Medicine found that half of young people who inject drugs have not been immunized against hepatitis A and B, despite national guidelines that recommend these immunizations for all youth and all drug users.
Researchers screened blood from 519 injecting drug users between the ages of 18 and 40 to see how many had antibodies that proved they had been immunized against the two liver infections. About 72% of the group was male, 49% was White, 7% was African-American and 27% was Hispanic.
The tests revealed:
- 47% had not been immunized against hepatitis B, though many more reported they been immunized,
- And 63% had not been immunized against hepatitis A, despite claims by participants that they had already been immunized.
- Of those screened, 1% were infected with hepatitis B,
- And 26% had been exposed to hepatitis C.
Programs serving this population should vaccinate young people who inject drugs against hepatitis A and B and not rely on "self-reports" that they were vaccinated, researchers concluded in the April issue of the medical journal Vaccine.
Source: www.ncbi.nlm.nih.gov/pubmed/25889161
Shorter Vaccination Schedule Works to Prevent Infection Among Drug Users
Administering the three hepatitis B vaccine doses over two months, instead of the standard six-month period, appears to be equally effective in protecting injecting drug users against the blood-borne infectious disease.
Researchers, reporting in the April issue of the American Journal of Public Health, compared hepatitis B infection rates in drug users who were given the three doses over a two-month period (at baseline and then every 30 days for the next two months) against a group who were given the vaccine at baseline, one month later and then five months later.
The second, longer immunization schedule is unwieldy and many patients fail to show up for the third dose five months later.
Researchers followed 707 drug users over a five-year period and found the accelerated vaccination schedule worked better and was as effective as the longer, conventional schedule.
"To overcome the disadvantages of a standard vaccination schedule, an accelerated vaccination schedule should be considered in drug users with low adherence (failure to show for medical appointments)," they wrote. "Our study should be repeated in different cohorts to validate our findings and establish the role of an accelerated schedule in hepatitis B vaccination guidelines for drug users.
Source: http://www.ncbi.nlm.nih.gov/pubmed
/25880946
Generic Entecavir Could Treat All Patients Worldwide for $36 a Year
Ramping up global production of a generic, reformulated version of the antiviral entecavir (Baraclude) could reduce the cost of hepatitis B treatment to $36 per patient each year around the world, according to a study published in the April edition of the Journal of Virus Eradication.
Researchers extrapolate that a year's supply of entecavir, if priced at $36 per patient, could provide treatment to millions of people around the world, preventing liver damage, cancer and premature deaths, especially in Asia and Africa.
Medical experts and the World Health Organization recommend either entecavir or tenofovir as first-line treatment for patients because of the drugs' potency and low rate of drug resistance. The patent on entecavir has already expired in several countries, including the U.S., while the patent on tenofovir (Viread) does not expire for another two years.
Experts hope treatment with a generic entecavir pill, reformulated to reduce its cost, would amount to $36 per patient, per year. Currently, a year's supply of generic entecavir costs about $427 in the U.S. and $7,000 in Europe, where it is still under patent protection.
Source: www.researchgate.net/publication
/274734796_ Analysis_of_minimum_target_prices
_for_production_of_ entecavir_to_treat_hepatitis_B
_in_high-_and_low-income_countries
Reformulated Tenofovir Appears Better at Fighting Infection in Liver Cells
A different formulation of the antiviral tenofovir–called tenofovir alafenamide (TAF)–appears to be more effective and last longer in the body than the current formulation of tenofovir.
This is good news for both HIV and hepatitis B patients; even without the improvement the current form of tenofovir is considered one of the best for treating hepatitis B because of its potency and lack of drug resistance.
TAF, a "prodrug" of tenofovir, is now in clinical evaluation in preparation for human trials. A prodrug by itself is inactive, it must be metabolized in the body in order to be effective. But the metabolic process helps TAF reach its target–in this case the liver–and stay active longer.
According to a report published in the April issue of the journal of Antimicrobial Agents and Chemotherapy, TAF was highly effective in laboratory experiments and now appears headed to human clinical trials. "These results support clinical testing of once-daily, low-dose TAF for the treatment of HBV infection," researchers wrote.
Source: www.ncbi.nlm.nih.gov/pubmed/25870059
Another Report Calls for Doctors to Screen All Patients for HBV Before Starting Chemotherapy
Another medical journal has called for all cancer patients to be screened for hepatitis B before immune-suppressing chemotherapy treatment begins. Why? Because studies consistently show that despite medical recommendations, doctors still aren't testing patients who may be at high risk for hepatitis B before starting chemotherapy.
When patients with active or even inactive HBV infections are treated with chemotherapy, their liver infection often reactivates when no longer held in check by a strong immune system. The patients face the double-whammy of liver damage on top of cancer unless they are treated with antivirals during chemotherapy to prevent HBV reactivation.
Researchers, writing in the April issue of the highly respected medical journal PLoS One, reviewed the medical records of 140 rheumatology patients, 79 cancer patients and 53 blood cancer (lymphoma) patients worldwide and found that their doctors considered 81%, 11% and 81% respectively were at high risk of possible HBV infection and reactivation. However, only 27%, 6% and 62% of the patients were actually screened for HBV infection before chemotherapy began.
In this study, 81 patients were screened for HBsAg and two were found to be infected. Of the 33 patients screened for the hepatitis B core antibody (indicating a past infection), 30% were found to be positive and could still be at risk of reactivation.
Clearly, doctors who prescribe immune-suppressing drugs for cancer and rheumatology patients failed to properly screen patients for hepatitis B before treatment, researchers noted, "...largely due to poor identification of those at risk for infection. Risk-based screening strategies are unlikely to be effective and should be replaced by universal screening."
Source: www.ncbi.nlm.nih.gov/pubmed/25875198
Study Confirms Aflatoxins Increase Liver Cancer in Hepatitis B Patients
A report published in the April issue of the Journal of Viral Hepatology confirms that people with hepatitis B who eat grains, dried fruit or vegetables contaminated with aflatoxins face high rates of liver cancer.
Aflatoxins are fungi produced by molds that grow in wet grain, fruit and other agricultural products including corn, rice, wheat and peanuts. They can cause liver cancer, especially in people with hepatitis B.
Turkish researchers screened hepatitis B patients for aflatoxin concentrations in their bloodstream. They found aflatoxin levels in hepatitis B patients with liver cancer were significantly higher than in non-cancerous HBV-infected patients.
"These results suggest that patients with chronic hepatitis B who are exposed to aflatoxins are at increased risk for developing liver cancer, which might be prevented by reducing consumption of contaminated foods."
Source: www.ncbi.nlm.nih.gov/pubmed/25894298
|
发表于 2015-5-5 08:11