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Hepatitis B Treatment

Alnylam Discloses HBV Program, Shows 2 Log HBSAG Knockdown with Research-Grade SNALP Tech

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HepatitisBVirus-1

Harnessing the Power of RNAi Gene Silencing in Quest of a Cure for Chronic Hepatitis B, and the HBV KnockDown blog written by Dirk Haussecker, who believes it’s about time everyone got serious about a functional cure for hepatitis B. 

Following cryptic remarks during a conference call earlier this year, Alnylam today officially announced its entry into the cure-HBV race.  In impressive data presented at the ongoing TIDES meeting, the company showed that up to 0.5mg/kg SNALP-siRNA was able to knock down HBsAg by ~2 log (99% knockdown) in infected chimpanzees.  The data had been generated by Merck from which Alnylam acquired the RNAi assets in January.  The goal is now to apply some of the learnings generated with Merck’s research-grade SNALP LNP technology and come up with a new candidate based on Alnylam’s GalNAc delivery platform (IND to be filed end of 2015).
In addition to the impressive HBsAg knockdowns, 3-4log knockdowns of viral DNA in serum were seen in the 4 chimpanzees.  In the most viremic chimp, the 4log lowering of viral load was able to normalize liver enzyme (ALT) levels that had been elevated by ~5x ULN.  Intriguingly, in 2 chimps with normal ALTs at the time of treatment, liver enzymes started to increase after dosing had finished (ruling out SNALP LNP as the culprit) and in 1 case also well after viral DNA had started to recover following cessation of RNAi dosing.
Intriguingly, while viral DNA recovered in this short study involving the administration of 3 doses (for every chimp 0.125mg/kg, then 0.25mg/kg, then 0.5mg/kg) over a span of 40 days, there were indications of a desired immunological response similar to that seen withARC520 in the chimp study, most notably an elevation of interferon gamma accompanied by ~2x increases in ALT in 2 of the chimps.
The competition
 
With Tekmira, ISIS/GSK and now Alnylam (and possibly more to come) following on the heels of Arrowhead Research and ARC520, the competitive landscape is starting to look quite complex.  How it will play out will likely depend on the degree of HBsAg knockdown required (in relative and absolute terms) and who will run the right combination studies with other HBV agents, especially immune boosters such as interferon and possibly RT inhibitors (note: Alnylam speculates that RT inhibitor co-treatment will be beneficial and thereby justified its use of a single RNAi trigger).
If a deep multi-log HBsAg knockdown were required, it would favor Tekmira’s candidate which will be based on a 3rd gen SNALP LNP which can be considered superior to what came out of Merck’s copy-cat efforts subject of today’s presentation.  If lesser knockdowns were able to achieve comparable cure rates, then the power would shift to the subcutaneous versions by Alnylam and ISIS/GSK (esp. the likely GalNAc-based follow-up version).
For ARC520, especially at 2mg/kg and Tekmira probably just 6 months behind, the competition may prove too much, not least because in the 2-dose study in the chimpanzee, the HBsAg knockdown was less than a log (80%).  Granted it was an extremely viremic chimp and one of the RNAi triggers was a mismatch, but still.  If Arrowhead and/or Tekmira demonstrate increased cure rates in 2015, Arrowhead should waste no time and push a single-molecule DPC into development to potentially once again take the lead.
The big question is how far along the way to clinical translation is single-molecule DPC?  Tomorrow may provide an answer.

Hepatitis B Prevention, Liver Cancer

Do You Know Your Hepatitis Facts from Fiction?

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Hepatitis-Awareness-Month(2)
May is Hepatitis Awareness Month!

In recognition of May as Hepatitis Awareness Month, Liver Cancer Connect reviews some important facts and dangerous fiction about chronic hepatitis B and C- the world’s leading causes of liver cancer.  Continue reading "Do You Know Your Hepatitis Facts from Fiction?" →

Hepatitis B Treatment, Living with Hepatitis B

HBV Journal Review – May 2014

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ChrisKHBF is pleased to connect our blog readers to Christine Kukka’s monthly HBV Journal Review that she writes for the HBV Advocate. The journal presents the
 latest in hepatitis B research, treatment, and prevention from recent academic and medical journals. This month, the following topics are explored:

  • Adding Interferon to Ongoing Antiviral Treatment Is Highly Successful
  • Vitamin E Helps HBV-Infected Children Lose HBeAg, Reducing Liver Damage
  • Common Chinese Toad May Hold the Key to Preventing and Treating Liver Cancer
  • Even at Top Hospitals, Doctors Fail to Treat Hepatitis B Patients Properly
  • Study Finds Doctors More Likely to Treat Hepatitis B in Men Than Women
  • Study Confirms Doctors Frequently Fail to Screen and Vaccinate Those at Risk
  • Antiviral Treatment Dramatically Improves Liver Cancer Test Accuracy
  • $50 Cash Incentive Increases HBV Immunization 12-Fold
  • Hepatitis B and C Cause Ten-Times More Deaths Than HIV in Europe

HBV Journal Review
May 1, 2014
Volume 11, Issue 5
by Christine M. Kukka

Adding Interferon to Ongoing Antiviral Treatment Is Highly Successful 

Adding pegylated interferon to ongoing antiviral treatment produced remarkable rates of hepatitis B “e” antigen (HBeAg) loss and even hepatitis B surface antigen (HBsAg) loss, according to a study presented at the International Liver Congress held in London in April.

Eighty-three HBeAg-positive patients in China, who had been on antivirals for more than two years, had 48 weeks of interferon treatment added to their treatment regimen. A control group continued on only antivirals:

  • 60% of the group treated with add-on interferon lost HBeAg and their viral loads dropped below 2,000 IU/mL. In contrast, only 13.8% of patients treated with only antivirals achieved those benchmarks.
  • 27.7% of patients in the combination treatment group lost HBsAg. No one in the antiviral group lost HBsAg.
  • All patients who had low HBsAg levels (less than 1,000 IU/mL) at the start of interferon treatment achieved HBeAg loss and 91% cleared HBsAg.

” Sequential combination therapy of (antivirals) and pegylated interferon effectively resulted in high rates of complete response and HBsAg loss in patients with prior long-term exposure to (antivirals),” researchers wrote. (Abstract 0117)

Another study exploring the benefits of sequential antiviral and interferon treatment found that HBeAg-positive patients who had been on antivirals for three years or longer also experienced high rates of HBeAg loss and development of “e” antibodies (HBeAg seroconversion) when their antivirals were replaced with pegylated interferon.

At week 48, the HBeAg seroconversion rate in the interferon-treated group was 66.67% compared to 2.5% in the antiviral group. (Abstract P1071)

A third study from India also found notable improvements when pegylated interferon was added to ongoing tenofovir treatment. Sixty patients were treated with tenofovir for 12 weeks (300 mg daily), then:

  • One group had pegylated interferon added to the ongoing tenofovir regimen for 24 weeks, and then were followed for another 28 weeks.
  • The other half continued their tenofovir treatment for 52 weeks.

Sixty percent of the interferon-plus-tenofovir group achieved healthy liver health, with normal alanine aminotransferase (ALT) levels, compared to 30% in the tenofovir-only group. The combination-treatment group also experienced greater viral load (HBV DNA) declines and HBeAg seroconversion (53.3% vs. 23.3% in the antiviral-only group).

“Sequential therapy using tenofovir and pegylated interferon may provide rapid and high biochemical and virological response in selected HBeAg-positive patients,” researchers noted. “Long-term clinical trials are needed to assess (the) sustained durable response.” (Abstract P1092)

Source: www.hbvadvocate.org/EASL_2014_
Abstracts.pdf

Vitamin E Helps HBV-Infected Children Lose HBeAg, Reducing Liver Damage

A small study, presented at the 2014 Liver Congress found that HBeAg-positive children who were treated with vitamin E (15 mg/kg/daily) for 12 months achieved higher rates of HBeAg conversion, lower viral loads and normal ALT levels than did untreated children.

Continue reading the HBV Journal Review… 

 

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U.S. Residents Only: Reporting Discriminatory Behavior Due to Chronic HBV Infection

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Unknown-1An important message from the U.S. Department of Justice (DOJ) which pertains only to U.S. Residents:

If you or someone you know is dismissed or barred from a program due to chronic hepatitis B infection, report the incident to the Department of Justice, whether the complaint is against a State or local agency, a school or any private entity that serves the public.

As a friend, advocate or colleague, you have the right to file a complaint to report discriminatory behavior.  Fill in and submit the Americans with Disabilities Act (ADA) Complaint Form (www.ada.gov/t2cmpfrm.htm).

Kindly return the form to the following address:
U.S. Department of Justice
Civil Rights Division
950 Pennsylvania Avenue, NW
Disability Rights – NYAV
Washington, D.C. 20530

Or you may print and send the report via fax to the following number: (202) 307-1197.

Please note: you must be a U.S. resident in order to file a complaint with the U.S. Department of Justice

Hepatitis B Treatment

Three New Studies Help Clarify Optimal Use of Combination Therapy in Chronic Hepatitis B Patients

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EASLThree new studies presented today at the International Liver Congress 2014 have helped clarify the optimal use of combination therapy with peginterferon and nucleoside analogues (NUCs) to achieve the best treatment outcomes in patients with chronic hepatitis B (CHB).

“Together these ground-breaking data will go a long way to influencing future CHB  guidelines,” said EASL’s Educational Councillor Professor Cihan Yurdaydin from the Department of Gastroenterology, University of Ankara, Turkey.

In the first study , CHB patients who had failed on prior long-term exposure to one of the nucleoside analogue (NUC) antivirals demonstrated high rates of complete response and HBsAg loss when prescribed a sequential combination of peginterferon and NUC.

In the second study , adding peginterferon to the nucleoside analogue entecavir was shown to enhance response rates and viral decline in HBeAg-positive CHB patients with compensated liver-disease, was generally safe and well tolerated, and may facilitate the discontinuation of entecavir.

Finally, data from a third study suggested that adding on a NUC for six weeks to PegIFNalfa-2a does not enhance treatment response, with no increase in HBeAg seroconversion rates beyond that achieved by PegIFNα-2a alone after 24 weeks follow-up.

Continue reading more…

Hepatitis B Treatment, Liver Cancer, Living with Hepatitis B

HBV Journal Review – April 2014

ChrisKHBF is pleased to connect our blog readers to Christine Kukka’s monthly HBV Journal Review that she writes for the HBV Advocate. The journal presents the
latest in hepatitis B research, treatment, and prevention from recent academic and medical journals. This month, the following topics are explored:

  • Despite Antiviral Treatment, Liver Cancer Risk Persists
  • Vitamin D Appears to Help Prevent Liver Cancer
  • Dandelions May Be the Next Best Herbal Treatment for Hepatitis B
  • Kidney Problems Are Prevalent with Hepatitis B Even Before Treatment Starts
  • HBV Genotype H Appears to Cause Immediate Chronic Infection in Adults
  • HBV Genotype E Has the Worst Response to Pegylated Interferon
  • Cancer-Causing YMDD Mutations Found Frequently in HBV Genotype C
  • High Iron Levels Found in Patients with Liver Failure
  • Vietnamese-Americans at High Risk of Undiagnosed Hepatitis B and C
  • Entecavir Performance Is Mediocre in Lamivudine-Resistant Patients
  • A Simple Platelet Count Test Could Be Best Indicator of Fibrosis

HBV Journal Review
April 1, 2014
Volume 11, no 4
by Christine M. Kukka

Despite Antiviral Treatment, Liver Cancer Risk Persists
Researchers have hoped that treating hepatitis B patients with antivirals would reduce both their viral loads and their liver cancer risk. However, a new study that followed 1,378 treated and 1,014 untreated patients over five years found antivirals did not reduce liver cancer rates as hoped.

The study tracked new liver cancer cases among patients infected with the hepatitis B virus (HBV) (average age 47, 65% male) who had been treated primarily with entecavir (Baraclude) for their high viral loads and liver damage. They compared that group’s liver cancer occurrence to those of patients whose “inactive” HBV infection did not require treatment.

Among the treated group, 70 patients (6.2%) developed liver cancer during the study period compared to only 11 (1.1%) in the untreated group. Notwithstanding  the ability of antivirals to reduce viral load, a life-long history of HBV infection and liver damage appeared to increase cancer risk, despite the reduction in viral load later in life.

What is especially disappointing is that liver cancer developed even in treated patients who had no history of cirrhosis (severe liver scarring) which increases cancer risk. Among the antiviral-treated patients:

  • • 20 of 223 HBeAg-negative patients who had cirrhosis at the start of treatment developed liver cancer.
  • • 15 of 316 HBeAg-negative patients who had no cirrhosis also developed liver cancer.
  • • Among the treated patients who developed liver cancer, 30 were positive for the hepatitis B “e” antigen (HBeAg) and 30 were HBeAg-negative.

How well the antiviral worked in patients also determined who remained cancer-free. Of the 246 patients who failed to achieve low or undetectable viral loads as a result of treatment, 36 (18.8%) patients developed liver cancer over the five-year study.

The risk of cancer was increased overall by male gender, underlying cirrhosis and older age in the treated group. Curiously, having high viral loads (HBV DNA) at the start of treatment did not appear to increase liver cancer risk.

The key message for doctors is that liver cancer risk remains despite a dramatic reduction in viral load, researchers noted. “…Patients on (antiviral) treatment that effectively suppressed viral replication are still at higher risk of liver cancer compared with patients with inactive stage chronic hepatitis B,” they concluded in the study published in the March issue of the journal Gut.

Persistent liver damage before the start of antiviral treatment, evidenced by elevated alanine aminotransferase (ALT) levels, may predispose patients to liver cancer, they also noted.

“The inactive group may have more intact immune response to HBV and therefore may also have entered the inactive stage early in life, with a shorter period of high viral replication and active hepatitis,” they wrote.

Source: www.ncbi.nlm.nih.gov/pubmed/24615378

Vitamin D Appears to Help Prevent Liver Cancer
Recent studies show a diet rich in vitamin D can improve liver health in patients with hepatitis B. A new study from Emory University in Atlanta finds that people with high vitamin D levels have lower rates of liver cancer.

The researchers examined vitamin D levels and liver cancer risk among 520,000 participants in the European Prospective Investigation into Cancer and Nutrition between 1992 and 2010.

Continue reading this review and additional HBV related reviews for March

Hepatitis B Advocacy, Living with Hepatitis B

Viral Hepatitis Action Alert!

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red-phoneRepresentatives Mike Honda, Hank Johnson, and Judy Chu are asking all House Representatives to sign an important letter supporting increased funding for viral hepatitis programs in the Fiscal Year 2015 appropriations bill (see text of letter below)

Please take a few minutes before March 25th to call your House Representative’s office in Washington, DC and ask/him to sign this letter.

You can reach your Representative through the Congressional Switchboard at (202) 224-3121. Ask to be connected to your Representative. Once you are connected to the office, ask to speak to the staff person who handles health care issues. Whether you speak to that person live or leave a voicemail, tell them (1) your name, (2) where you live and that you are a constituent, (3) that you would like the Representative to sign the “Dear Colleague” letter from Representatives Honda, Johnson, and Chu supporting increased funding for viral hepatitis and (4) a brief message why this issue is important to you. Tell them they can sign the letter by contacting Kelly Honda in Representative Honda’s office, Scott Goldstein in Representative Johnson’s office, or Linda Shim in Representative Chu’s office. The deadline for Representatives to sign is March 25th.

Text of “Dear Colleague” letter from Representatives Honda, Johnson, and Chu:

Support Funding for Viral Hepatitis

March XX, 2014

The Honorable Jack Kingston
Chairman
Subcommittee on Labor, Health and Human Services
United States House
Washington, D.C., 20515

The Honorable Rosa DeLauro
Ranking Member
Subcommittee on Labor, Health and Human Services
United States House
Washington, D.C., 20515

Dear Chairman Kingston and Ranking Member DeLauro:

As you begin deliberations on the Fiscal Year 2015 Labor, Health and Human Services, Education, and Related Agencies Appropriations bill, we would like to respectfully request that you allocate $47.8 million for the Division of Viral Hepatitis (DVH) at the Centers for Disease Control and Prevention (CDC), an increase of $16.4 million over the FY2014 level.

The CDC’s 2010 professional judgment (PJ) budget recommended $90.8 million each year from FY2011-FY2013, $170.3 million annually from FY2014-FY2017, and $306.3 million annually from FY2018-FY2020 for DVH in order to comprehensively address the viral hepatitis epidemic. While past increases have been helpful, these have only been small steps toward building a more comprehensive response to viral hepatitis. Our recommendation of $47.8 million is in line with the needs determined by the PJ and the goals of the Viral Hepatitis Action Plan, but pales in comparison to the CDC’s PJ.

The need to enhance and expand these prevention efforts is growing more urgent. Viral hepatitis is the leading cause of liver cancer – one of the most lethal, expensive and fastest growing cancers in America. More than 5.3 million people in the U.S. are living with hepatitis B (HBV) and/or hepatitis C (HCV) and 65-75% of them are undiagnosed. Without an adequate, comprehensive surveillance system, these estimates are only the tip of the iceberg. Viral hepatitis kills 15,000 people each year and is the leading non-AIDS cause of death in people living with HIV – nearly 25 percent of HIV-positive persons are also infected with HCV and nearly 10 percent with HBV.

The epidemic is particularly alarming because of the rising rates of new infections and high rates of chronic infection among disproportionately impacted racial and ethnic populations, and presents a dramatic public health inequity. For example, HCV is twice as prevalent among African Americans as among Caucasians. Asian Americans comprise more than half of the known hepatitis B population in the United States and, consequently, maintain the highest rate of liver cancer among all ethnic groups. Additionally, African American and Latino patients are less likely to be tested for HCV in the presence of a known risk factor, less likely to be referred to treatment for subspecialty care and treatment, and less likely to receive antiviral treatment. Recent alarming epidemiologic reports indicate a rise in HCV infection among young people throughout the country. Some jurisdictions have noted that the number of people ages 15 to 29 being diagnosed with HCV infection now exceeds the number of people diagnosed in all other age groups combined.

Further, the baby boomer population (those born 1945-1965) currently accounts for two out of every three cases of chronic HCV. As these Americans continue to age, they are likely to develop complications from HCV and require costly medical interventions that can be avoided if they are tested earlier and provided with treatment options. It is estimated that this epidemic will increase costs to private insurers and public systems of health such as Medicare and Medicaid from $30 billion in 2009 to over $85 billion in 2024, and also account for additional billions lost due to decreased productivity from the millions of workers suffering from chronic HBV and HCV.Over the last two years, CDC and the U.S. Preventive Services Task Force (USPSTF) have begun to align their recommendations for hepatitis screening, recommending one-time testing of baby boomers and screening vulnerable groups for HCV.

We appreciate the Committee’s support for viral hepatitis prevention, in particular the increased support to prioritize the identification of HBV and HCV-positive individuals who are unaware of their status. We strongly encourage you to sustain your commitment this year. We have the tools to prevent the major causes of viral hepatitis and liver cancer – a hepatitis B vaccine and effective treatments that reduce disease progression, new diagnostics for HCV and treatments that increase cure rates over 90%, and even more medical advances in the research pipeline. Making this relatively modest investment in the prevention and detection of viral hepatitis represents a key component in addressing a vital public health inequity and will get more Americans into care, strengthen our public health infrastructure and combat the devastating and expensive complications caused by viral hepatitis.

Sincerely,

XXX

Hepatitis B Treatment, Living with Hepatitis B

HBV Journal Review – February 2014

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ChrisKHBF is pleased to connect our blog readers to Christine Kukka’s monthly HBV Journal Review that she writes for the HBV Advocate. The journal presents the
latest in hepatitis B research, treatment, and prevention from recent academic and medical journals. This month, the following topics are explored:

  • Tests for Antigens and Drug-Resistant Virus Emerge as Valuable Diagnostic Tools
  • Experts Issue a Report Card on Side Effects from Antivirals
  • Experts Weigh in on Why They Prefer Either Antivirals or Interferon
  • Doctors Explain Which Medical Guidelines They Follow, Or Ignore
  • Truvada Effective in Lowering Viral Load in Young Adults with High Viral Load
  • Hepatitis B Causes Most Liver Cancer Deaths in China
  • Smoking Shortens Survival after Liver Cancer Surgery

 HBV Journal Review

February 1, 2014
Vol 11, no 2
by Christine M. Kukka

Tests for Antigens and Drug-Resistant Virus Emerge as Valuable Diagnostic Tools

Measuring the amount of hepatitis B surface antigen (HBsAg) in your bloodstream or conducting quick tests for drug-resistant hepatitis B virus (HBV) may soon be part of your office visit in the brave new molecular world of hepatitis B treatment.

Doctors increasingly are measuring HBsAg levels to determine if treatment is needed or if current medications are working. HBsAg tests—along with measuring alanine aminotransferase (ALT) for signs of liver damage and HBV DNA for viral load—may become essential tools to assess hepatitis B progression or remission.

HBsAg is the protein that makes up the outer covering of HBV. When a patient has a high viral load (and is positive for the hepatitis B “e” antigen—HBeAg), there are often large quantities of HBsAg circulating in the blood stream. When viral replication slows and HBeAg disappears, there can be lower quantities of HBsAg.

But experts are learning that high HBsAg levels can increase cancer risk, even in HBeAg-negative patients, according to a study published in the journal Annales de Biologie Clinique. (1) As a result, there is heightened attention on HBsAg as a key indicator of a patient’s health. For example:

  • In HBeAg-negative patients, HBsAg levels less than 1,000 international units per milliliter (IU/mL) along with low viral load (HBV DNA) under 2,000 IU/mL indicate the patient is an “inactive” patient.
  • When patients are treated with pegylated interferon, doctors can tell if the treatment is working if there is a decline in HBsAg levels within 12 weeks. This early indicator can save money if the drug isn’t working and help to avoid uncomfortable side effects. Doctors recommend patients with genotypes B and C should stop interferon at week 12 if their HBsAg levels remain at 20,000 UI/mL or higher.

Another team of French researchers, also exploring the implications of HBsAg in an article published in the February 2014 issue of the journal Liver International, suggest that as HBsAg levels decline, so does the risk of liver cancer.

They also suggest that during antiviral treatment, a rapid decline in HBsAg may indicate which patients will eventually clear HBsAg. A 100-fold decline or more of HBsAg over six months of treatment, “… could be a marker of a sustained response after treatment cessation,” they wrote.(2)

In another diagnostic breakthrough, researchers writing in the December journal of Clinical Molecular Hepatology promoted the value of a HepB Typer-Entecavir kit that can precisely detect HBV that have viral mutations that can “resist” the antiviral drug entecavir (Baraclude). This diagnostic tool allows doctors to select the most effective antiviral for each individual patient based on the molecular makeup of their HBV.(3)

1. Source: www.ncbi.nlm.nih.gov/pubmed/24235324  
2. Source: www.ncbi.nlm.nih.gov/pubmed/24373085  
3. Source: www.ncbi.nlm.nih.gov/pubmed/24459645

Experts Issue a Report Card on Side Effects from Antivirals
Hong Kong researchers evaluated the side effects of commonly-used antivirals in the December 2013 issue of the Journal of Gastroenterology and Hepatology. Antivirals disrupt the genetic make-up of HBV, making it difficult for the virus to replicate. While generally safe, patients must take antiviral pills daily over several years and side effects include damage to the mitochondria of the body’s cells (called mitochondria toxicity.)

Continue reading this and additional studies for Februrary

Hepatitis B Prevention, Hepatitis B Treatment, Living with Hepatitis B

HBV Journal Review – January 2014

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HBF is pleased to connect our blog readers to Christine Kukka’s monthly HBV Journal Review that she writes for the HBV Advocate. The journal presents the
 latest in hepatitis B research, treatment, and prevention from recent academic and medical journals. This month, the following topics are explored: Continue reading "HBV Journal Review – January 2014" →

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Re-energized in Our Mission … A Message from Joan Block of HBF

Historic ruling now officially recognizes HBV infection as a protected disability under the Americans with Disabilities Act.

What a difference two years make. In 2011 the Hepatitis B Foundation celebrated its 20th anniversary and we were ready to rest awhile on our laurels after working so hard. But instead, we rallied for new challenges and now we have a lot to celebrate in 2013! Continue reading "Re-energized in Our Mission … A Message from Joan Block of HBF" →

Baruch S. Blumberg Institute