February 12, 2012

Antiviral strategies in hepatitis C virus infection

J Hepatol. 2012;56 Suppl:S88-S100.

Sarrazin C, Hézode C, Zeuzem S, Pawlotsky JM.

Klinikum der J.W. Goethe-Universität, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.

Abstract

Resolution of the three-dimensional structures of several hepatitis C virus (HCV) proteins, together with the development of replicative cell culture systems, has led to the identification of a number of potential targets for direct-acting antiviral (DAA) agents. Numerous families of drugs that potently inhibit the HCV lifecycle in vitro have been identified, and some of these molecules have reached early to late clinical development. Two NS3/4A protease inhibitors, telaprevir and boceprevir, were approved in Europe and the United States in 2011 in combination with pegylated interferon (IFN)-α and ribavirin for the treatment of chronic hepatitis C related to HCV genotype 1, in both treatment-naïve and treatment-experienced patients. Sustained virological response rates in the range of 6675% and 5966% (2988% if the response to the first course of therapy is taken into account) have been achieved in these two patient populations, respectively, with treatment durations of 24 to 48 weeks. A number of other DAAs are at the clinical developmental stage in combination with pegylated IFN-α and ribavirin or with other DAAs in IFN-free regimens, with or without ribavirin. They include second-wave, first-generation, and second-generation NS3/4A protease inhibitors, nucleoside/nucleotide analogue inhibitors and non-nucleoside inhibitorsof HCVRNA-dependent RNA polymerase, inhibitors of nonstructural protein 5A (NS5A) and host-targeted compounds, such as cyclophilin inhibitors and silibinin. The proof of concept that IFN-free regimens may lead to HCV eradication has recently been brought. However, new drugs may be associated with troublesome side effects and drugdrug interactions, and the ideal IFN-free DAA combination remains to be found.

Source

J Hepatol. 2012 Feb 4. [Epub ahead of print]

Lawitz EJ, Gruener D, Hill JM, Marbury T, Moorehead L, Mathias A, Cheng G, Link JO, Wong KA, Mo H, McHutchison JG, Brainard DM.

Alamo Medical Research, San Antonio, Texas.

Abstract
BACKGROUND & AIMS: GS-5885 is an inhibitor of the hepatitis C virus (HCV) NS5A protein and exhibits potent suppression of genotype 1 HCV replicons. The safety, tolerability, pharmacokinetics, antiviral activity, and resistance profile of once-daily GS-5885 doses of 1-90 mg were evaluated in patients with chronic genotype 1 HCV.

METHODS: Genotype 1 HCV-infected patients were randomized to 3 days of once-daily (QD) dosing with placebo (n=12) or GS-5885 1 mg (n=10), 3 mg (n=10), 10 mg (n=20), 30 mg (n=10), or 90 mg (n=10). Plasma samples for pharmacokinetics, HCV RNA, and NS5A sequencing were collected through Day 14.

RESULTS: GS-5885 was well tolerated and resulted in median maximal reductions in HCV RNA ranging from 2.3 log(10) IU/mL (1 mg QD) to 3.3 log(10) IU/mL (10 mg QD in genotype 1b and 30 mg QD). E(max) modeling indicated GS-5885 30 mg was associated with >95% of maximal antiviral response to HCV genotype 1a. HCV RNA reductions were generally more sustained among patients with genotype 1b versus 1a. Three of 60 patients had a reduced response and harbored NS5A-resistant virus at baseline. NS5A sequencing identified residues 30 and 31 in genotype 1a, and 93 in genotype 1b as the predominant sites of mutation following GS-5885 dosing. Plasma pharmacokinetics were consistent with QD dosing.

CONCLUSIONS: During 3 days of monotherapy, low doses of GS-5885 demonstrated significant antiviral activity in genotype 1a and 1b HCV-infected patients. GS-5885 is currently being evaluated in combination direct antiviral regimens with and without peginterferon.

Source

New research reveals how protein protects cells from HIV infection

Public release date: 12-Feb-2012

Contact: Jessica Guenzel
jessica.guenzel@nyumc.org
212-404-3591
NYU Langone Medical Center / New York University School of Medicine

Finding offers potential new drug targets aimed at slowing progression of disease

NEW YORK -- A novel discovery by researchers at NYU Langone Medical Center and colleagues reveals a mechanism by which the immune system tries to halt the spread of HIV. Harnessing this mechanism may open up new paths for therapeutic research aimed at slowing the virus' progression to AIDS. The study appears online ahead of print today in Nature Immunology.

"A lot of research on viruses, especially HIV, is aimed at trying to understand what the body's mechanisms of resistance are and then to understand how the virus has gotten around these mechanisms," said co-lead investigator Nathaniel R. Landau, PhD, a professor of microbiology at the Joan and Joel Smilow Research Center at NYU School of Medicine.

The research focused on a protein called SAMHD1. Recent studies have found that immune cells, called dendritic cells, containing the protein are resistant to infection by HIV. Since the discovery, scientists have sought to understand how SAMHD1 works to protect these cells, with hopes that science might find a way to synthetically apply that protection to other cells.

Dr. Landau and his team are now able to provide an answer:

When a virus, like HIV, infects a cell, it hijacks the cell's molecular material to replicate. That molecular material is in the form of deoxynucleotide triphosphates (dNTPs), which are the building blocks for DNA. Once the virus replicates, the resulting DNA molecule contains all the genes of the virus and instructs the cell to make more virus.

Researchers wanted to understand how cells containing the SAMHD1 protein are protected from such hijacking. They found that SAMHD1 protects the cell from viruses by destroying the pool of dNTPs, leaving the virus without any building blocks to make its genetic information – a process researchers call nucleotide pool depletion. "SAMHD1 essentially starves the virus," Dr. Landau said. "The virus enters the cell and then nothing happens. It has nothing to build and replicate with, so no DNA is made."

As a result, the most common form of HIV does not readily infect these cells. Instead, the virus has evolved to replicate mainly in a different kind of cell, called CD4 T-cells, which do not contain SAMHD1 and therefore have a healthy pool of dNTPs. Dr. Landau explained that the virus has evolved in such a way that it may deliberately avoid trying to infect immune cells with SAMHD1 to avoid alerting the greater immune system to activate a variety of antiviral mechanisms to attack the virus. Viruses that are related to HIV, like HIV-2 and SIV, have developed a protein called viral protein X (VPX) that directly attacks SAMHD1. This allows the virus to infect dendritic cells, an important type of immune cell.

"Viruses are remarkably clever about evading our immune defenses," Dr. Landau said. "They can evolve quickly and have developed ways to get around the systems we naturally have in place to protect us. It's a bit of evolutionary warfare and the viruses, unfortunately, usually win. We want to understand how the enemy fights so that we can outsmart it in the end."

Understanding the mechanism by which SAMHD1 provides protection to cells may provide a new idea about how to stop or slow the virus' ability to spread, Dr. Landau explained. Potential future research efforts, for example, might focus on finding a way to increase the amount of SAMHD1 in cells where it does not exist, or to reduce the amount of dNTPs in cells vulnerable to infection.

"Over the past few years, a number of these natural resistance mechanisms have been identified, specifically in HIV, but some have potential applications to other viruses, as well," he said. "This is a very exciting time in HIV research. Many of the virus' secrets are being revealed through molecular biology, and we're learning a tremendous amount about how our immune system works through the study of HIV."

###

Funded in part by the National Institutes of Health and the American Foundation for AIDS Research, the study was conducted in collaboration with researchers at several institutions, including the University of Rochester Medical Center and The Cochin Institute, in Paris.

About NYU School of Medicine:

NYU School of Medicine is one of the nation's preeminent academic institutions dedicated to achieving world class medical educational excellence. For 170 years, NYU School of Medicine has trained thousands of physicians and scientists who have helped to shape the course of medical history and enrich the lives of countless people. An integral part of NYU Langone Medical Center, the School of Medicine at its core is committed to improving the human condition through medical education, scientific research and direct patient care. The School also maintains academic affiliations with area hospitals, including Bellevue Hospital, one of the nation's finest municipal hospitals where its students, residents and faculty provide the clinical and emergency care to New York City's diverse population, which enhances the scope and quality of their medical education and training. Additional information about the NYU School of Medicine is available at http://school.med.nyu.edu/

Source

Management of treatment failure in chronic hepatitis B

J Hepatol. 2012;56 Suppl:S112-22.

Zoulim F, Locarnini S.

INSERM, U1052, Cancer Research Center of Lyon, 69003 Lyon, France; Université de Lyon, 69003 Lyon, France; Hospices Civils de Lyon, Hepatology Department, 69004 Lyon, France; Institut Universitaire de France.

Abstract

Antiviral therapy of chronic hepatitis B remains a clinical challenge. The primary goal of therapy is to prevent liver disease progression. Because of the mechanism of viral persistence in infected hepatocytes, long-term antiviral therapy is needed in the majority of patients. Incomplete viral suppression and emergence of drug resistance is a major concern. The correct choice of a first-line potent therapy to achieve sustained long-term suppression of viral replication provides the best chance of preventing treatment failure and drug resistance. Clinical studies have demonstrated that drugs with a high barrier to resistance, such as entecavir and tenofovir, have significantly lower rates of resistance when compared with those with a low barrier to resistance such as lamivudine, adefovir, or telbivudine. Management of treatment failure requires a precise clinical and accurate virologic monitoring as well as an early treatment intervention with appropriate complementary drugs with respect to their cross-resistance profile. Long-term surveillance for treatment efficacy and possible emergence of drug resistance is necessary for those patients who have been sequentially treated with multiple antivirals. Finally, the identification of novel treatment targets remains a major research challenge to improve the efficacy of current antiviral therapy.

Source

Interferon and Ribavirin Control HCV Genotype 6

From Reuters Health Information

By David Douglas

NEW YORK (Reuters Health) Feb 08 - Pegylated interferon and ribavirin are effective against chronic infection with hepatitis C virus (HCV) genotype 6, a recent study shows.

"This large randomized study provides new information on treatment of genotype 6 patients, particularly on shortening duration of therapy in select patients (and) thus limiting costs of an expensive treatment," said Dr. K. Rajender Reddy of the University of Pennsylvania, Philadelphia in an email to Reuters Health.

Genotype 6 (which now includes genotypes 7, 8 and 9) is endemic in Southeast Asia, where it accounts for up to 47% of HCV infections. Once problematic mainly in that part of the world, "in the changing era of increasing migration of populations, it has been recently reported in the United States, as well as in China, Taiwan, and Hong Kong," Dr. Reddy and colleagues wrote in a paper online January 17 in the Journal of Hepatology.

The interferon/ribavirin combination is the standard treatment for HCV, but genotype is considered to be a strong predictor of sustained virological response (SVR) and little is known about response and optimal treatment duration with genotype 6, the investigators say.

The new trial included 105 treatment-na�ve HCV genotype 6 patients in Vietnam who were randomized to 24 or 48 weeks of treatment with pegylated interferon alfa-2a 180 mcg per week and ribavirin 15 mg/kg per day.

The study was not funded, and the patients had to pay for their care. Six dropped out for economic reasons and another seven were lost to follow-up.

Even so, on intention-to-treat analysis the SVR was 60% in the 24-week group and 71% in the 48-week group. The difference was not significant. Corresponding biochemical responses were 63% and 77%.

Rates of virological relapse were 7% with the shorter course of treatment and 5% with the longer course.

Overall, SVR was most likely in those with a rapid virological response. In the 24-week group, 75% of such patients achieved SVR. In the 48-week group, the proportion was 86%.

Rates of hematologic and general adverse events were similar between the two groups, except the rate of anemia was lower with shorter treatment (31% vs 57%).

According to the paper, "24 weeks of therapy in younger patients, with low viral load and rapid virological response appeared equally effective as 48 weeks of therapy and this is likely to have a major economic impact on HCV therapy, in such subpopulations."

In fact, Dr. Reddy noted that the efficacy of shorter-duration therapy is scientifically worth pursuing in larger trials, but given the lack of support for the current study, "challenges are in funding."

"While new drugs are being developed for non-genotype 6 hepatitis C infections," he concluded, "pegylated interferon and ribavirin will remain the standard of care for the foreseeable future for genotype 6 infections."

Source: http://bit.ly/zJBkoU

J Hepatol 2012.

Source

PR-Logo-Businesswire

PRESS RELEASE

Feb. 10, 2012, 5:00 p.m. EST

AIDS advocates call on public with e-letter campaign and call for Valentine boycott of Hershey chocolates over Milton Hershey School's rejection of a 13-year-old boy due to his HIV-positive status

LOS ANGELES, Feb 10, 2012 (BUSINESS WIRE) -- --Advocates for the "Hershey: A Day without Kisses" demand that Hershey -- which funds the school -- denounce the discrimination and permit the boy's enrollment

AIDS Healthcare Foundation (AHF) announced today that it is spearheading a nationwide 'Hershey: A Day without Kisses' Valentine Day's boycott of the Hershey Company over the Milton Hershey School's AIDS discrimination. The Milton Hershey School -- a prestigious boarding school for low-income scholarship students funded by the Hershey Company -- recently rejected a 13-year-old boy for admission citing his HIV-positive status as the reason, misguidedly calling him a "direct threat to the health and safety of others." The group formally launched its action via Facebook, Twitter and other online media today as part of its ongoing 'No Kisses for Hershey' campaign. AHF and AIDS advocates are now calling on the public to forgo buying all Hershey candy and chocolates this Valentine's Day.

On Tuesday, February 14th, AHF and AIDS advocates in Los Angeles will also host a press conference and teleconference about its call on the public to forgo buying Hershey candy and chocolates this Valentine's Day. The group formally launched its action via Facebook, Twitter and other online media today as part of its ongoing 'No Kisses for Hershey' campaign.

The group previously launched the website www.EndHIVStigma.org where the public can learn more about the case, learn the facts about HIV/AIDS and send e-letters to three Hershey Company board members who also sit on the board of the Milton Hershey School Trust, urging them to denounce the discrimination and facilitate the boy's admission into the school.

"We are asking the public to join us in telling Hershey that this Valentine's Day will be 'A Day without Kisses' for them as Hershey continues on its path of discrimination and ignorance as displayed by the Hershey School's recent rejection of an otherwise qualified student due to his HIV-positive status," said Michael Weinstein, President of AIDS Healthcare Foundation in a statement from Africa. "Ultimately, it is the Hershey Company itself, as the main funder of the school, that must answer for the decision not to admit the boy -- a decision fueled by prejudice and fear. Hershey must denounce this illegal and repugnant discrimination and enroll the boy at the school. In the meanwhile, we plan to use the power of pocketbook to shame Hershey by asking fair-minded members of the chocolate-buying public not to buy Hershey this Valentine's Day."

Shortly after news broke just before World AIDS Day, December 1, 2011, about the school's rejection of the HIV-positive boy, AIDS Healthcare Foundation hosted a press conference in Washington, D.C., to announce the launch of a campaign against HIV/AIDS discrimination at Hershey School in Pennsylvania and in support of the federal discrimination lawsuit filed on behalf of a 13-year-old boy who was rejected for admission at Hershey explicitly due to his HIV-positive status. At the event, AHF announced its willingness to contribute up to $50,000 to support a lawsuit filed by AIDS Law Project of Pennsylvania on behalf of the boy and expressed its moral outrage at the case.

According to the Associated Press (claim:Hershey School Rejects HIV-Positive Pa. Boy)(claim:By Peter Jackson)(claim:12/1/11): "A private boarding school connected with the Hershey chocolate company says it was trying to protect other students when it denied admission to a Philadelphia-area teenager because he is HIV-positive. The AIDS Law Project of Pennsylvania filed a lawsuit on behalf of the unidentified boy in U.S. District Court in Philadelphia on Wednesday, claiming the Milton Hershey School for disadvantaged students violated the Americans with Disabilities Act. School officials acknowledged that the 13-year-old boy was denied admission because of his medical condition. They said they believed it was necessary to protect the health and safety of the 1,850 others enrolled in the residential institution, which serves children in pre-kindergarten to 12th grade and where students live in homes with 10 to 12 others."

"The ignorance displayed by the Hershey School's leadership is unacceptable and demonstrates just how much work there is still to be done to dismantle the fear and misinformation that still surrounds this disease more than 25 years after Ryan White," added AHF's Weinstein.

Ryan White was an American teenager from Kokomo, Indiana who, in the mid-1980s, was expelled from middle school because he was HIV-positive. A lengthy legal battle with the school ensued and White became a galvanizing force in educating the country about HIV & AIDS at a time when misinformation about the disease was widespread. After his death in 1990, the U.S. Congress passed a major piece of legislation named in his honor, the Ryan White CARE Act, which provides funding for HIV/AIDS programs for low-income American.

"It is unfortunate that Hershey has shown such a shocking lack of knowledge of basic facts about HIV and how it is spread, and are instead reacting with ignorance and prejudice," said Tom Myers, General Counsel and Chief of Public Affairs for AIDS Healthcare Foundation. "This is an excellent opportunity to educate the public about HIV, including the fact that people who are living with HIV/AIDS do not pose a significant risk to others and generally do not require any special medical attention that cannot be obtained through normal medical visits."

He/she added: "In addition, people should know that recent studies have shown that people with HIV on treatment are up to 96% non-infectious. Because of this, those on treatment are not a threat to health and safety of others. The young man in question does not pose a 'direct threat' to anyone and Hershey should admit him into the school to begin the education that he desires -- and deserves."

AIDS Healthcare Foundation (AHF), the largest global AIDS organization, currently provides medical care and/or services to more than 125,000 individuals in 26 countries worldwide in the US, Africa, Latin America/Caribbean, the Asia/Pacific Region and Eastern Europe. To learn more about AHF, please visit our website: www.aidshealth.org , find us on Facebook: www.facebook.com/aidshealth and follow us on Twitter: @aidshealthcare.

        
WHAT: PRESS CONFERENCE -- update on HERSHEY COMPANY VALENTINE BOYCOTT targets AIDS discrimination at Milton Hershey School


WHEN:    Tuesday, February 14th, 10:00 a.m(Pacific)


WHERE:   AIDS Healthcare Foundation Headquarters
6255 Sunset Blvd., Suite 2100 (cross street:Argyle) Hollywood, CA 90028

www.EndHIVStigma.org


NOTE:    TELECON to follow 10:30 a.m. -- Dial in +1-877-411-9748 participant code #7931503

February 10, 2012

By J. Nadine Gracia, MD, MSCE, Acting Director, Office of Minority Health, U.S. Department of Health and Human Services

J. Nadine Gracia

Dr. J. Nadine Gracia

During February’s observance of African American History Month, please join us in working to end the unfortunate history of viral hepatitis’ disproportionate impact on the African American community. This Administration is working hard to reduce and eliminate health disparities and achieve health equity.

Unfortunately, viral hepatitis is a health problem that is often overlooked by the public as well as healthcare providers. This, despite the fact that viral hepatitis is a leading infectious cause of death, claiming the lives of 12,000–15,000 Americans each year. As many as 5.3 million Americans are living with viral hepatitis, though most do not know that they are infected. This places them at greater risk for severe, even fatal, complications from the disease and increases the likelihood that they will spread the virus to others.

What Is Hepatitis?
“Hepatitis” means inflammation of the liver. It is most often caused by a virus. In the U.S., the most common types are hepatitis A, hepatitis B, and hepatitis C. All of these viruses cause acute, or short-term, viral hepatitis. But the hepatitis B and C viruses (HBV and HCV) can also cause chronic hepatitis, in which the infection is prolonged, sometimes lifelong. Chronic hepatitis can lead to cirrhosis, liver failure, and liver cancer. In fact, viral hepatitis is the leading cause of liver cancer and the most common reason for liver transplantation.

Viral Hepatitis Disparities
Within the African American community, significant hepatitis-related health disparities exist. For example:

Hepatitis B

  • Hepatitis B can be prevented by a vaccine; however, African American children have lower HBV vaccination rates than non-Hispanic white children.
  • Since 2004, rates of hepatitis B have remained steady among all racial/ethnic populations. However, new infections of hepatitis B remain the highest among African Americans, with 2.3 cases per 100,000 people.

Hepatitis C

  • African Americans are twice as likely to be infected with hepatitis C when compared with the general U.S. population and chronic liver disease, often hepatitis C-related, is a leading cause of death among African Americans ages 45-64.
  • While African Americans represent only 12% of the U.S. population, they make up about 22% of the chronic hepatitis C cases. In fact, African Americans have a substantially higher rate of chronic hepatitis C infection than do Caucasians and other ethnic groups.

Viral Hepatitis Action Plan
My Federal colleagues and I are committed to ensuring that new cases of viral hepatitis are prevented and that persons who are already infected are tested; informed about their infection; and provided with counseling, care, and treatment. In fact, last year we issued Combating the Silent Epidemic of Viral Hepatitis: Action Plan for the Prevention, Care & Treatment of Viral Hepatitis (PDF 672KB), which outlined robust and dynamic steps that are now underway across the government to increase viral hepatitis awareness and knowledge among health care providers and communities, and improve access to quality prevention, care, and treatment services for viral hepatitis. (Read more about the Action Plan.)

In addition, the Viral Hepatitis Action Plan is both supported by and complements several other initiatives unfolding within HHS and across the Federal government, including the:

Your Help Is Essential
These are all part of our response to the silent epidemic of viral hepatitis. But we need your help, too. So, during African American History Month, please help by learning more about viral hepatitis, educating family and friends about this silent killer in the African American community, and encouraging conversations with healthcare providers about vaccinations for hepatitis A and B and screening for hepatitis C for those who may have been exposed.

Together, we can make viral hepatitis history.

Source

Tenofovir: Q&A for Patients and Providers

February 10, 2012

Scientists at the San Francisco VA Medical Center and the University of California, San Francisco have published a study showing that one of the most effective and commonly prescribed antiretroviral medications for HIV/AIDS, tenofovir, is associated with a significant risk of kidney damage and chronic kidney disease that increases over time. See accompanying news release, Tenofovir, Leading HIV Medication, Linked with Risk of Kidney Damage.

What is the new finding about HIV/AIDS drugs and associated kidney problems?

Tenofovir, an anti-retroviral drug used to treat HIV, was associated with an increased risk of kidney disease in an observational study of 10,841 HIV-infected veterans who were new users of antiretroviral therapy between 1997 and 2007. The study found that tenofovir is associated with an elevated risk of kidney disease, even in persons without pre-existing risk factors for kidney disease, and that this toxicity to the kidney may not be reversible.

The study showed that for each year that a person uses tenofovir, there is a 34 percent higher risk of developing protein in the urine, which is an important sign of kidney damage; an 11% higher risk of rapidly declining kidney function, and a 33% higher risk of developing chronic kidney disease. These risks are all independent of the other factors that cause kidney disease, such as age, diabetes, hypertension, smoking, hepatitis C infection and HIV-related factors.

How much extra risk is this?

Overall in the study, the differences in risk between users and non-users of tenofovir each year were: 13% vs. 8% for protein in urine, which is an important marker of kidney damage 9% vs. 5% for rapidly declining kidney function; and 2% vs. 1% for developing chronic kidney disease. However, these numbers are based on the average risks in the study population, and patients with more risk factors for kidney disease would be put at proportionately higher risk when they use tenofovir.

Which drugs are we talking about?

In the study, the risk appeared to be unique to tenofovir. Other antiretroviral drugs showed weaker or inconsistent associations with kidney disease events, and none was associated with higher risk for even two of these three adverse kidney disease outcomes.

Should I stop taking these drugs if I am already taking them now?

This decision should be made on an individual basis, in consultation with your physician. The decision should involve weighing the risks/benefits and discussion of alternative treatment options. Tenofovir is an important component of effective antiretroviral therapy that you may need to control your viral load. If you remain on tenofovir, you may need more frequent monitoring of your kidney function and your level of urine protein. You are likely at increased risk of kidney disease if you have diabetes, high blood pressure, cardiovascular disease or hepatitis C. African Americans, Hispanics, Pacific Islanders, Native Americans and older adults are also at increased risk.

What are the symptoms of kidney problems? Should I be taking tests to monitor my kidney function?

Most people do not have any symptoms until their kidney disease is advanced. So, kidney disease is typically detected by screening tests of blood and urine.

Moving forward, what questions should I ask my doctors?

You should ask your doctor about whether you need routine monitoring of blood and urine samples to measure the following: serum creatinine, proteinuria, and microalbuminuria. You should also ask your doctor to calculate your estimated glomerular filtration rate (eGFR). You may want to have a discussion about alternative treatment options.

What about the prophylactic use of these drugs to prevent HIV progression and transmission?

A study of HIV pre-exposure prophylaxis (PrEP) using once-daily oral tenofovir was presented at the XVIII International Conference on AIDS (AIDS 2010), which included 323 men. This study found no indication of significant safety issues, including kidney problems or bone loss. However, this study may not have been large enough to detect increases in risk for kidney disease.

Where can I get more information?

You may get more information from HIV/AIDS websites such as Project Inform or HIV InSite. You can also contact your doctor if you have additional questions about your anti-retroviral medications or risk for kidney disease.

Source

How Reliable is Hepatitis B Vaccination in People Celiac Disease?

vaccine

By Jefferson Adams Published 02/10/2012

Celiac.com 02/10/2012 - The HBV vaccine is usually effective against common hepatitis B virus (HBV) infection, with just 4-10% of vaccine recipients failing to respond to standard immunization. Some studies suggest that people with celiac disease may have high levels of resistance to the HBV vaccine, compared to the general population.

A team of researchers recently took a look at the issue of HBV vaccine reliability in people with celiac disease.

The study team included Mohammad Rostami Nejad, Kamran Rostami, and Mohammad Reza Zali. They are variously affiliated with the Research Center for Gastroenterology and Liver Disease at Shahid Beheshti University of Medical Sciences in Tehran, Iran, and with Acute Medicine at Dudley Group of Hospital in Dudley, UK. Together, they reviewed data from previous studies.

The ability to respond to recombinant HBV vaccine is associated with certain gene sites. At those sites, certain HLA haplotypes, such as B8, DR3, and DQ2 are common genetic markers among non-responders.

Since HLA genotypes play an important role in unresponsiveness to the HBV vaccine, and since 90-95% of people with celiac disease have HLA-DQ2, celiac disease may be a factor in this failure to respond to the HBV vaccine.

For one study, Ertekin et al., a research team gave HBV vaccinations, according to a standard immunization schedule, to 52 children with celiac disease, and another twenty matched for age and sex.

The average age of the celiac disease patients was 10.7 ± 4 years (range, 4-18 years). Anti-HBs titers were positive in 32 (61.5%) patients and negative in 20 (38.5%) patients, while they were positive in 18 (90%) of the children in the control group (P < 0.05).

The review team found statistically significant differences between negative anti-HBs titers, clinical presentation of CD, and dietary compliance in patients with CD (P < 0.05).
In all, 32 of the 52 children with celiac disease responded favorably to HBV vaccination. This was a substantially lower percentage that the 18 of 20 control subjects responded (P < 0.05).

Ertekin et al. concluded that a significantly higher percentage of children with celiac disease failed to respond to hepatitis B vaccination, as compared with the control group.

They concluded that response to the HBV vaccine in children with celiac disease should be investigated, and a different immunization schedule should be developed for them. They suggested that celiac children who follow a gluten-free diet may have a better immune response to the HBV vaccine.

The data fits with previous studies that confirm the findings that children with celiac disease fail to respond to the HBV vaccine at significantly higher rates than do healthy children.

In fact, the researchers point out a similar study on adults, Noh et al., revealed that, of 23 adults with celiac disease who had completed a full course of HBV vaccination, 19 tested positive for HBsAb and 13 failed to acquire proper long-term immunity.

Another study, by Stachowski et al., further cemented this connection between HLA and non-responsiveness to HBV vaccine. In that study, 34 out of 153 patients with end-stage renal disease failed to respond to HBV vaccine, and HLA-DQ2 was found almost exclusively in the non-responder group.

Long stretches of time between vaccination and antibody testing might be one reason even celiac disease patients who follow a gluten-free diet have significantly reduced post-vaccination levels of HBV antibody. Therefore, current guidelines recommend revaccinating celiac patients once they have established a reliable gluten-free diet.

This study was not designed to assess the presence of HLA-DQ2 and HLA-DQ8 in the groups. Therefore, future studies assessing HLA haplotypes in celiac disease should seek to describe the role of HLA typing in response to HBV vaccination.

The evidence indicates that early diagnosis of celiac disease, and treatment with a gluten-free diet may increase the overall percentage of patients responding favorably to the HBV vaccine.

Treatment of celiac disease with a strict, gluten-free diet seems to play a positive role in the development of antibody memory.

The review team points out that the high prevalence of celiac disease in the general population and a lack of response to HBV vaccine in untreated patients, invites routine assessment in patients with celiac disease receiving the HBV vaccine.

Lastly, the review team notes that non-responsiveness to HBV vaccine may indicate undiagnosed celiac disease or noncompliance with gluten-free diet.

SOURCE:
Hepat Mon. 2011 August 1; 11(8): 597–598.
doi: 10.5812/kowsar.1735143X.761

Source

New Molecule Has Potential to Help Treat Genetic Diseases and HIV

snake-271x300

Chemists at The University of Texas at Austin have synthesized a molecule that can entangle itself in a specific sequence of DNA and stay attached for 16 days, longer than any other molecule reported.

Feb. 10, 2012

AUSTIN, Texas — Chemists at The University of Texas at Austin have created a molecule that's so good at tangling itself inside the double helix of a DNA sequence that it can stay there for up to 16 days before the DNA liberates itself, much longer than any other molecule reported.

It's an important step along the path to someday creating drugs that can go after rogue DNA directly. Such drugs would be revolutionary in the treatment of genetic diseases, cancer or retroviruses such as HIV, which incorporate viral DNA directly into the body's DNA.

"If you think of DNA as a spiral staircase," says Brent Iverson, professor of chemistry and chair of the department of chemistry and biochemistry, "imagine sliding something between the steps. That's what our molecule does. It can be visualized as binding to DNA in the same way a snake might climb a ladder. It goes back and forth through the central staircase with sections of it between the steps. Once in, it takes a long time to get loose."

Iverson says the goal is to be able to directly turn on or off a particular sequence of genes.

"Take HIV, for example," he says. "We want to be able to track it to wherever it is in the chromosome and just sit on it and keep it quiet. Right now we treat HIV at a much later stage with drugs such as the protease inhibitors, but at the end of the day, the HIV DNA is still there. This would be a way to silence that stuff at its source."

Iverson, whose results were published in September in Nature Chemistry, strongly cautions that there are numerous obstacles to overcome before such treatments could become available.

The hypothetical drug would have to be able to get into cells and hunt down a long and specific DNA sequence in the right region of our genome. It would have to be able to bind to that sequence and stay there long enough to be therapeutically meaningful.

"Those are the big hurdles, but we jumped over two of them," says Iverson. "I'll give presentations in which I begin by asking: Can DNA be a highly specific drug target? When I start, a lot of the scientists in the audience think it's a ridiculous question. By the time I'm done, and I've shown them what we can do, it's not so ridiculous anymore."

In order to synthesize their binding molecule, Iverson and his colleagues begin with the base molecule naphthalenetetracarboxylic diimide (NDI). It's a molecule that Iverson's lab has been studying for more than a decade.

They then piece NDI units together like a chain of tinker toys.

"It's pretty simple for us to make," says Amy Rhoden Smith, a doctoral student in Iverson's lab and co-author on the paper. "We are able to grow the chain of NDIs from special resin beads. We run reactions right on the beads, attach pieces in the proper order and keep growing the molecules until we are ready to cleave them off. It's mostly automated at this point."

Rhoden Smith says that the modular nature of these NDI chains, and the ease of assembly, should help enormously as they work toward developing molecules that bind to longer and more biologically significant DNA sequences.

"The larger molecule is composed of little pieces that bind to short segments of DNA, kind of like the way Legos fit together," she says. "The little pieces can bind different sequences, and we can put them together in different ways. We can put the Legos in a different arrangement. Then we scan for sequences that they'll bind."

Iverson and Rhoden Smith's co-authors on the paper were Maha Zewail-Foote, a visiting scientist in Iverson's lab who's now an associate professor and chairman of chemistry at Southwestern University in Georgetown; Garen Holman, another former doctoral student of Iverson's who did most of the experimental work before obtaining his Ph.D.; and Kenneth Johnson, the Roger J. Williams Centennial Professor in Biochemistry at The University of Texas at Austin.

For more information, contact: Daniel Oppenheimer, College of Natural Sciences, 512 232 0682; Brent Iverson, 512-471-5053

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