AIDS virus changes in semen make it different than in blood

Scanning electron micrograph of HIV-1 budding from cultured lymphocyte. Image source: Centers for Disease Control & Prevention.

The new findings are significant because the nature of the virus in the male genital tract is of central importance to understanding the transmission process and the selective pressures that may impact the transmitted virus.

Media contacts: Leslie Lang (919) 966-9366, llang@med.unc.edu or Tom Hughes (919) 966-6047 or tahughes@unch.unc.edu

Embargoed until 5 p.m. EDT Thursday, August 19, 2010

CHAPEL HILL – The virus that causes AIDS may undergo changes in the genital tract that make HIV-1 in semen different than what it is in the blood, according to a study led by researchers from the University of North Carolina at Chapel Hill.

Worldwide much of the transmission of HIV-1 is through sexual contact, men being the transmitting partner in a majority of cases. The new findings are significant because the nature of the virus in the male genital tract is of central importance to understanding the transmission process and the selective pressures that may impact the transmitted virus. Ultimately it is the transmitted virus that must be blocked by a vaccine or microbicide.

“If everything we know about HIV is based on the virus that is in the blood, when in fact the virus in the semen can evolve to be different, it may be that we have an incomplete view of what is going on in the transmission of the virus,” said senior study author Ronald Swanstrom, PhD, professor of biochemistry and biophysics and of microbiology and immunology at the UNC School of Medicine.

The results of his research appear August 19, 2010 in the online journal PLoS Pathogens.

In the study, Swanstrom and his colleagues compared viral populations in blood and semen samples collected from 16 men with chronic HIV-1 infection. Using an expensive and labor-intensive laboratory technique called single genome sequencing, they analyzed the gene coding for the major surface protein of the virus -- called envelope or Env – in the samples. The differences between the viruses from the two sources were striking.

“The sequence differences between the blood and the semen were like a flashing red light, it was a big hint about the biology of virus in the seminal tract” said Swanstrom. “When we looked at sequences in the blood, we hardly found any that were the same, it was a very complex and diverse population. But when we looked in the semen, suddenly we were getting the same sequence over and over again.”

They found two mechanisms that significantly altered the viral population in the semen, which they called clonal amplification and compartmentalization. In the first, one to several viruses are rapidly expanded over a short period of time such that the viral population is relatively homogeneous (compared to the complex population in the blood). In the second, the virus replicates in T cells in the seminal tract over a long period of time, creating a separate population of virus that is both complex and distinct from the virus in the blood.

To begin to answer why these mechanisms are at play, the researchers measured the levels of 19 cytokines and chemokines in the blood and semen samples. They discovered a significant concentration of these immune system modulators in the semen relative to the blood, which could boost viral replication by creating an environment where target cells are kept in an activated state.

Swanstrom’s laboratory is now exploring whether evolutionary selection for some special property of the virus is occurring in the seminal tract that does not happen in the blood. Knowing how the virus in the semen is different is an important part of understanding the HIV transmission puzzle.

The UNC research was funded by the National Institutes of Health in the context of the Center for HIV/AIDS Immunology (CHAVI). Study co-authors include Jeffrey A. Anderson, Li-Hua Ping, Oliver Dibben, Cassandra Jibara, Leslie Arney, Laura Kinser, Yuyang Tang, Marcia Hobbs, Irving Hoffman, Peter Kazembe, Corbin D. Jones, Persephone Borrow, Susan Fiscus and Myron S. Cohen. Volunteers participating in this study were attending the Kamuzu Central Hospital and the UNC Project in Lilongwe, Malawi.
 
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Researchers Identify Two FDA Approved Drugs That May Fight HIV

ScienceDaily (Aug. 20, 2010) — Researchers at the University of Minnesota Academic Health Center have identified two drugs that, when combined, may serve as an effective treatment for HIV.

The two drugs, decitabine and gemcitabine -- both FDA approved and currently used in pre-cancer and cancer therapy -- were found to eliminate HIV infection in the mouse model by causing the virus to mutate itself to death -- an outcome researchers dubbed "lethal mutagenesis."

This is a landmark finding in HIV research because it is the first time this novel approach has been used to attack the deadly virus without causing toxic side effects. Because decitabine and gemcitabine are already FDA approved, researchers believe that if their research is effective in large animal models, it will be much easier to expedite the development of the drugs for human use.

The study is a collaboration between molecular virologists Louis Mansky, Ph.D., and Christine Clouser, Ph.D., of the Institute for Molecular Virology and School of Dentistry, as well as medicinal chemist Steven Patterson, Ph.D., from the Center for Drug Design. The findings were recently published online in the Journal of Virology.

"The findings provide hope that such an approach will someday help the 33 million people worldwide who currently live with HIV," Mansky said.

Lethal mutagenesis

HIV mutates and evolves quickly. Rather than inhibiting virus growth and replication like current HIV drugs, this new drug combination forces the virus to do just the opposite -- evolve beyond control, to the point of extinction.

"HIV's ability to mutate makes it difficult to target and treat," Mansky said. "We wanted to take advantage of this behavior by stimulating HIV's mutation rate, essentially using the virus as a weapon against itself."

Drug repositioning

One way to decrease cost and expedite the development of novel drugs is by the use of drug repositioning, the process of taking a drug that is used to treat one medical condition, and using it to treat a different illness.

By examining drugs that are already approved by the Food and Drug Administration, the researchers hope to expedite the development of this drug combination because the safety profiles of the two drugs are known.

U of M researchers found that the drug concentrations needed to eliminate HIV infection cause no measureable cell toxicity and were effective against HIV cultures at concentrations well below the current levels used for cancer treatment.

The path ahead

Gemcitabine and decitabine have been administered in pre-clinical trials with mice. Initial findings confirm that the drugs are an effective antiviral therapy for HIV.

The researchers are now in the process of modifying the drugs to forms that can be absorbed by the human body when taken orally.

The study was funded by the Center for Drug Design, Academic Health Center and the National Institutes of Health.

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Cells' demise provides clues about cancer

Derek Parker From: The Australian
August 21, 2010

APOPTOSIS may sound like an unfortunate malady.

In fact, it may be the secret to understanding the development of cancer and devising better cancer therapies.

Ultimately, it may provide an alternative to invasive surgery or debilitating chemotherapy.

Research into apoptosis is taking place worldwide, with several large drug companies pouring money into the area, but critical work is being undertaken in Australia.

"The key is to look at how cancer cells differ from healthy cells," says Andreas Strasser, of the molecular genetics of cancer division at Melbourne's Walter and Eliza Hall Institute.

"We need to understand how cells function and, even more importantly, how they die.

"Apoptosis is the study of programmed cell death and it is taking us into very promising areas of research, including towards a whole new generation of anti-cancer drugs."

All healthy cells in the body have genes that can cause or program them to die. Cell suicide and replenishment are crucial to all living organisms and play critical roles in the body's development even before birth.

But many cancer cells can override or ignore their programmed death machinery. They grow, mutate and multiply at a rate enabling them to take over and eventually destroy their host.

There's also good evidence that subversion of the cell death machinery is necessary for the transformation of normal cells into cancer cells.

Although the principle of apoptosis was recognised in the 19th century, much of the fundamental work in translating the idea into possible therapies can be traced to a 1988 paper published by WEHI researchers David Vaux, Suzanne Cory and Jerry Adams.

They showed that a cancer-causing gene, Bcl-2, inhibits apoptosis. The finding was the critical breakthrough in the field.

Little wonder that as a postdoctoral researcher Strasser was excited by the opportunity to continue the work. And followed up the research in a 1990 paper he co-authored with Alan Harris and Cory. It demonstrated that blocking apoptosis in mice could cause cancer. It also revealed that combined abnormalities in cell death and the control of cell division co-operated in tumour development.

"The field of cancer biology has come to the realisation that a cancer is caused by a string of abnormalities, maybe five or six, in critical cellular processes, including a lack of cell death," he says. "If we can reliably overcome or restore one or even several of the processes in that string, it would be a major advance for cancer therapy."

Strasser's WEHI team recently announced findings that could lead to a new class of anti-cancer drugs.

"Until now, everybody believed that a failure of damaged cells to undergo suicide allowed mutated cells to proliferate, which contributes to tumour development," he says. "That's certainly true, but we discovered that, in certain settings, the opposite can also hold, that the body's natural cell-suicide program can fuel tumour development."

Specifically, their experiments with mice showed this could happen if cellular DNA was damaged, say, by repeated exposure to low doses of radiation. When the body attempts to replace the damaged tissue it drives tumour development because the damaged cells will divide quickly, promoting tumour development.

The critical issue, Strasser notes, is whether a gene called Puma is present. His group found that if mice with the Puma gene were given a low dose of radiation it destroyed about 80 per cent of the mature white blood cells.

This means stem cells in the bone marrow must work extra hard to replace the white cells, many of which may themselves be damaged. The result: leukaemia, cancer of the blood or bone marrow.

"The surprise was that mice that don't carry the Puma gene are fully protected from this type of tumour development," says Strasser. "Puma is essential for the death of cells that have damaged DNA. If mice don't have the Puma gene when they receive low doses of radiation the white blood cells aren't destroyed, so they don't force stem cells to become activated to replenish the blood system."

This suggests the risk of cancer is increased in people who experience cycles of tissue destruction followed by tissue repopulation by stem cells. Such a process may account for the liver cancers frequently associated with viral infections, such as hepatitis C, or alcohol-related liver damage.

The finding also helps explain why secondary cancers sometimes arise in patients who were cured of their primary cancer. The secondary cancer was triggered by the DNA damaged from the original life-saving chemotherapy.

To transform its research into therapeutic products, WEHI has entered into a collaborative agreement with US medical giants Genentech and Abbott. The agreement involves funding support for WEHI, as well as data sharing between the parties.

The present focus of research is to develop drugs targeted at a specific protein that would activate the suicide process in existing cancer cells or in other cells likely to become cancerous if genetic activity overrode their programmed cell death.

Early phase clinical trials with people are under way in several places across the world using a compound called ABT-263, which is showing promising signs.

Apoptosis is also revealing other strategies for dealing with cancer, according to Paul Ekert of the Children's Cancer Centre at the Murdoch Childrens Research Institute in Melbourne.

"Building on the basic work from WEHI, we've been looking at how the apoptosis pathways are activated, or how activation fails in response to signals that originate from outside the cell," he explains. "We want to understand the biochemical processes [that] underpin how signals originate and are transmitted."

In particular, this research is examining the role of a family of genes called the Hox genes, which appears to regulate critical aspects of the apoptosis pathway.

"Originally we were simply using the Hox gene to create large numbers of cells for experimentation purposes," Ekert says. "But then we began to think about how it could be manipulated for possible therapeutic purposes."

According to Ekert, the idea is to inhibit the division of some cells while not affecting others.

This could be especially relevant to treating leukaemia-type cancers, although the applications could be broad.

"The way signals from the outside of the cells regulate apoptosis pathways is still something of a black box, where you can see things going in and things coming out, but you don't know much about what happens inside," Ekert says. "We are starting to lift the lid."

He is collecting proof-of-principle data as the basis for early-stage testing.

Another area of apoptosis research focuses on the nature of the suicide trigger.

"There are cells [that] require constant signals to stay alive and they die when those signals cease," says John Silke of the biology department at La Trobe University, where he heads a team looking at apoptosis-related proteins.

"There are others [that] require a particular signal to activate the suicide trigger," says Silke.

"Understanding those processes would go a long way to understanding not just cancer but a whole gamut of cell-related diseases."

This research has already led to a drug, at present in phase one trials in the US, he says. The drug mimics a natural protein that activates apoptosis, amplifying the signal so cells commit suicide.

"There's still a long way to go, but there is the potential to focus on specific types of cells, avoiding the system damage generated by approaches like chemotherapy," Silke says.

"It would be like using a sniper rifle rather than a hand grenade."

For his part, Strasser underlines the importance of fighting cancer at the fundamental level: "It's a matter of understanding your enemy."

As he notes, cancer cells are an excellent example of so-called generational evolution.

"Our medium-term goal is to be able to disrupt that process, to give the body of a person with cancer a good fighting chance."

His long-term goal?

"To fight cancer at the time in the early stages of its development, hopefully preventing it from becoming a danger in the first place."

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HBV DNA Decline at 24 Weeks Predicts Sustained Response to Pegylated Interferon for Chronic Hepatitis B

SUMMARY: Patients who experience a significant decrease in hepatitis B virus (HBV) DNA, or viral load, during the first 24 weeks of treatment with pegylated interferon were more likely to achieve a long-term response, according to a study described in the July 2010 Journal of Medical Virology. If HBV DNA does not decline by at least 100-fold during this period, however, treatment is unlikely to be successful and should be discontinued, the researchers recommended.
By Liz Highleyman

Bettina Hansen from Erasmus University Medical Center in Rotterdam and colleagues aimed to develop a model that could better predict at baseline which chronic hepatitis B patients would respond to pegylated interferon, and to establish an early indicator for when treatment should be halted.

Pegylated interferon leads to virological response (undetectable HBV DNA) and hepatitis B "e" antigen (HBeAg) loss in only a minority of patients with HBeAg positive chronic hepatitis B. The treatment is expensive and can cause difficult side effects, so clinicians want to know when to stop therapy that is unlikely to produce a favorable outcome.

Known baseline predictors of response to pegylated interferon include HBV genotype (B responds better than D), pre-treatment HBV viral load, and alanine aminotransferase (ALT) level. The investigators looked at whether viral load reduction early in treatment also has predictive value.

This analysis included 136 chronic hepatitis B patients treated with pegylated interferon. Response was defined as HBV DNA < 10,000 copies/mL and HBeAg loss 26 weeks after completion of treatment. The researchers used logistic regression analysis to develop a dynamic prediction model using HBV DNA during the first 32 weeks of therapy.

Results

• The researchers identified an early clinically useful rule for continuation or discontinuation of treatment, with a grid of cut-off values for HBV DNA decline during treatment.
• Adding HBV DNA decline at weeks 4, 12, and 24 to baseline factors improved predictions of sustained response.
• HBV DNA decline of at least 2?log(10), or 100-fold, within 24 weeks of starting therapy was strongly associated with response when added to baseline predictors. 

These findings led the study authors to conclude, "A dynamic model including HBV DNA decline during treatment provides more accurate predictions of response to pegylated interferon."

"The model strongly supports individual decision making on treatment (dis)continuation in patients with HBeAg positive chronic hepatitis B," they continued. "It is recommended that pegylated interferon treatment is stopped by 24 weeks if HBV DNA declined < 2?log(10)."

Investigator affiliations: Departments of Gastroenterology & Hepatology, Biostatistics, and Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Department of L-Biostat, Catholic University of Leuven, Leuven, Belgium.

8/20/10

Reference
BE Hansen, EHCJ Buster, EW Steyerberg, and others. Prediction of the response to peg-interferon-alfa in patients with HBeAg positive chronic hepatitis B using decline of HBV DNA during treatment. Journal of Medical Virology 82(7): 1135-1142 (Abstract). July 2010.

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Silymarin Milk Thistle Extract May Inhibit Hepatitis C Virus Entry into Cells

SUMMARY: Silymarin, an extract from the milk thistle plant, has an inhibitory effect on the hepatitis C virus (HCV) polymerase in laboratory studies, but its anti-HCV action also appears to include blocking HCV from entering cells and preventing cell-to-cell transmission, according to research described in the June 2010 issue of Hepatology.

Milk thistle (Silybum marianum) has an extensive history of use as a remedy for liver problems in both Eastern and Western traditional medicine. Silymarin is a flavonoid comprised of a mix of milk thistle components including silibinin. Most silymarin studies have looked at its effect on liver fibrosis, but in recent years researchers have studied its direct activity against HCV in the laboratory and in vivo.

A survey of participants in the HALT-C trial -- which evaluated the benefits of long-term pegylated interferon for patients who did not respond to standard treatment with pegylated interferon plus ribavirin -- found that participants who said they used silymarin did not have lower HCV viral load on average than non-users. Another recent study, however, showed that silymarin inhibited activity of the HCV polymerase, which copies viral genetic material as part of replication.

In the present study, Jessica Wagoner from the University of Washington in Seattle and colleagues further characterized the antiviral action of silymarin in the laboratory.

Results

• Silymarin had antiviral effects against HCV in cell cultures, including inhibition of virus entry into cells, HCV RNA and protein expression, and production of infectious virus particles.
• Silymarin did not block HCV binding to cells, but did inhibit entry of viral pseudoparticles and fusion of HCV pseudoparticles with liposomes, or fat bubbles.
• Silymarin -- but not silibinin -- inhibited activity of the HCV genotype 2a NS5B RNA-dependent RNA polymerase at concentrations 5-10 times higher than required for an anti-HCV effect in cell culture.
• Silymarin had only minimal activity against genotype 1b isolate BK and 4 genotype 1b polymerases derived from HCV-infected patients, however.
• Silymarin did not inhibit HCV replication in 5 independent genotype 1a, 1b, and 2a replicon model cell lines that did not produce infectious virus.
• Silymarin inhibited microsomal triglyceride transfer protein activity, apolipoprotein B secretion, and infectious virion production in cell culture medium.
• Silymarin also blocked cell-to-cell spread of HCV. 

Based on these findings, the study authors concluded, "Although inhibition of in vitro NS5B polymerase activity is demonstrable, the mechanisms of silymarin's antiviral action appear to include blocking of virus entry and transmission, possibly by targeting the host cell."

Investigator affiliations: Departments of Laboratory Medicine, Microbiology, and Global Health, University of Washington, Seattle, WA; Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA; Department of Pediatrics, University of Texas Medical Branch, Galveston, TX; School of Medicine, University of Texas Southwestern Medical Center, Dallas, TX; Hepatitis C Virus Research Group, Institute of Biomedical Research, University of Birmingham, Birmingham, UK; Institut de Biologie et Chimie des Protéines, Université Lyon 1, IFR128 Lyon Biosciences Gerland, CNRS-Universite Claude Bernard, Lyon, France; Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC; Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO.

8/20/10

Reference
J Wagoner, A Negash, OJ Kane, and others. Multiple effects of silymarin on the hepatitis C virus lifecycle. Hepatology 51(6): 1912-1921 (Abstract). June 2010.

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Acute Hepatitis C as a Sexually Transmitted Infection in HIV Positive Men

SUMMARY: Sexual transmission of hepatitis C virus (HCV) among HIV positive men who have sex with men has now been recognized for a decade, occurring in cities in Europe, North America, and Australia. Since acute HCV outbreaks occur almost exclusively among men with HIV, being HIV positive probably plays a critical role, according to the authors of a review article in the July 31, 2010 issue of AIDS.
By Liz Highleyman

Thijs van de Laar from the Amsterdam Public Health Service and colleagues presented an overview of acute HCV infection among gay/bisexual men with HIV, including epidemiology, risk factors, natural history, disease progression, and challenges of management. The review was based on published studies identified through a MEDLINE search and relevant conference abstracts.

HCV Transmission

HCV is usually transmitted through direct blood contact, for example, via shared needles for injection drug use (IDU) or blood transfusions before donated blood was screened. Due to common transmission routes, an estimated 4-5 million people -- or approximately one-third of people with HIV -- are HIV/HCV coinfected.

Sexual transmission of HCV was traditionally thought to be uncommon (less than 1%) based on studies of monogamous heterosexual couples. Early cross-sectional studies found a relatively high HCV prevalence rate among men who have sex with men (MSM), but these often did not take into account injection drug use.

Since 2000, however, several outbreaks of acute hepatitis C among HIV positive gay and bisexual men who denied injection drug use have been reported, first in the U.K., then in other large cities in France, Germany, and the Netherlands, followed by Australia, the U.S., and Canada.

ACUTE HEPATITIS C

"Given the burden of liver disease, in particular HCV, on the morbidity and mortality in HIV patients in the era of combination antiretroviral therapy, the rapid and significant rise in the incidence of HCV in the HIV-infected MSM population in high-income countries is alarming," the review authors wrote. "This relates to a significant change in the epidemiology of HCV that has occurred, with HCV emerging as a sexually transmitted infection within this population."

In the Netherlands, for example, a biannual survey among sexually transmitted infection (STI) clinic attendees showed an increase in HCV prevalence among HIV positive MSM from 1%-4% before 2000 to 15% in 2007 and 21% in 2008. HCV prevalence among HIV negative gay/bisexual men, however, remains comparable to that of the general population.

Most cases of acute hepatitis C among MSM in Europe involve hard-to-treat HCV genotypes 1a and 4d, the latter of which is otherwise uncommon in Europe and the U.S. Genetic sequencing has revealed closely related virus strains coinciding with sexual networks.

Evolutionary analysis "suggests multiple independent introductions of HCV into the MSM community, some as early as the 1980s," the authors surmised. "Most likely, these strains were introduced from the IDU population." They noted that the recent increase in HCV sexual transmission coincides with a rise in sexual risk behavior and increased STI rates in the era of effective combination ART, some of which is due to serosorting, or HIV positive men have unprotected sex with other positive men.

Research to date indicates that HCV transmission is associated with a variety of sexual practices -- including fisting, unprotected anal intercourse, use of shared sex toys, group sex, and sex while on drugs -- though specific activities vary from study to study. Other risk factors include non-injection drug use and presence of other sexually transmitted diseases.

These studies show that "most MSM with HCV report a combination of various, potentially high-risk, sexual and drug practices," the authors wrote. "The interaction between sex and drugs is complex, and many of these factors are highly correlated and difficult to disentangle."

"Given this occurs almost exclusively in HIV-infected MSM, HIV probably has a critical role mediated either through behavioral and/or biological factors," they stated. "It is not yet known whether lower CD4 cell count increases the risk of acquiring HCV, but the fact that many MSM with acute HCV have relatively preserved CD4 cell counts suggests this may not be a critical factor."

Disease Progression and Treatment

Turning to hepatitis C disease progression in this population, they wrote, "The natural history of HCV is determined by host-viral interactions, which are perturbed in HIV coinfection, resulting in accelerated liver fibrosis, higher HCV loads, and poorer responses to interferon-based therapy when compared with HCV monoinfection."

While about 25% of HIV negative individuals spontaneously clear HCV without treatment, this is less likely among people with HIV -- as low as 5% in one study -- perhaps due to reduced T-cell responses. HIV/HCV coinfection is associated with more rapid liver fibrosis. Some studies indicate that progression is especially fast among people who already have HIV at the time of HCV infection, but other data are conflicting.

Hepatitis C treatment using pegylated interferon (with or without ribavirin) is quite successful during acute HCV infection. Because they receive regular liver function tests to monitor drug toxicity, people with HIV are more likely to have HCV infection diagnosed during the acute stage. Acute hepatitis C cure rates among HIV positive people are around 60%-80% in most studies.

Optimal timing and duration of therapy for acute HCV infection is not well defined, but most experts recommend waiting 12 weeks to see if spontaneous clearance will occur. Most favor combination therapy over pegylated interferon monotherapy and a treatment duration of 24 weeks for coinfected patients.

"Targeted prevention such as raising awareness, regular screening and treatment of acute and chronic infections are needed to stop the further spread among MSM," the review authors concluded. "It is clear that a message of 'safe sex' through condom use during anal intercourse could be provided, but given the practice of negotiated unprotected sex among HIV-infected MSM might not be accepted. In addition, it may not cover practices that increase risk of blood-to-blood contact (e.g. fisting). Furthermore, MSM population needs to be informed that reinfection is an ongoing risk, given the recent reports of HCV reinfection following successful treatment and documented clearance of HCV."

Cluster of Infectious Diseases, Public Health Service, Amsterdam, Netherlands; Viral Hepatitis Clinical Research Program, National Centre for HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; Department of Internal Medicine, Centre for Infection and Immunity Amsterdam, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands; St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.

8/20/10

Reference
TJ van de Laar, GV Matthews, M Prins, and M Danta. Acute hepatitis C in HIV-infected men who have sex with men: an emerging sexually transmitted infection. AIDS 24(12): 1799-1812 (Abstract). July 31, 2010.

Source

Adoptive transfer of splenocytes to study cell-mediated immune responses in hepatitis C infection using HCV transgenic mice

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and a health problem affecting over 170 million people around the world. We previously studied transgenic mice that express HCV Core, Envelope 1 and Envelope 2 proteins predominantly in the liver, resulting in steatosis, liver and lymphoid tumors, and hepatocellular carcinoma.

Herein, the immune-mediated cell response to hepatitis C antigens was evaluated by adoptive transfers of carboxyfluorescein succinimidyl ester (CFSE) labelled splenocytes from HCV immunized mice into HCV transgenic mice.

Results: In comparison to non-transgenic mice, there was a significant decrease in the percentage of CFSE-labeled CD4+ and CD8+ T cells in transgenic mouse peripheral blood receiving adoptive transfers from immunized donors. Moreover, the percentage of CFSE-labeled CD4+ and CD8+ T cells were significantly higher in the spleen of transgenic and non-transgenic mice when they received splenocytes from non-immunized than from immunized mice.

On the other hand, the percentages of CD4+ and CD8+ T cells in the non-transgenic recipient mouse lymph nodes were significantly higher than the transgenic mice when they received the adoptive transfer from immunized donors. Interestingly, livers of transgenic mice that received transfers from immunized mice had a significantly higher percentage of CFSE labeled T cells than livers of non-transgenic mice receiving non-immunized transfers.

Conclusions: These results suggest that the T cells from HCV immunized mice recognize the HCV proteins in the liver of the transgenic mouse model and homed to the HCV antigen expression sites.

We propose using this model system to study active T cell responses in HCV infection.

Author: Turaya NaasMasoud GhorbaniCatalina SoareNicole SherlingRudy MullerPeyman GhorbaniFrancisco Diaz-Mitoma

Credits/Source: Comparative Hepatology 2010, 9:7

Published on: 2010-08-20

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Achillion to Raise $50M in Stock Offering for HCV Studies

By Catherine Hollingsworth
Staff Writer

Achillion Pharmaceuticals Inc. plans to raise about $50 million through the sale of stock and warrants to a select group of investors, money that would be used to advance the company's early stage pipeline of drug candidates for hepatitis C virus (HCV).

At the end of June, the New Haven, Conn.-based company had $20 million in cash resources. With the added funds from the financing, which is expected to close Aug. 20, Achillion hopes to extend its cash through most of 2012.

The financing is intended to take the company's ACH-1625 protease inhibitor to the completion of Phase IIa testing, explained Mary Kay Fenton, Achillion's vice president and chief financial officer.

The Phase II study, which is expected to get under way next month, will have a 28-day segment that is targeted to report data in March 2011 and a 12-week segment that is slated to report results at the end of next year.

"We believe this financing will get us through both of those milestones," Fenton told BioWorld Today.

In addition, Achillion hopes to move its preclinical candidates, ACH-2684, a pan-genotypic protease inhibitor, and ACH 2928, an NS5A inhibitor, through Phase I testing in 2011. The company also plans to put those candidates in combination studies in 2012 with other HCV assets in development, Fenton said.

ACH-1625, while it has shown promising data in Phase Ib studies, is far behind the front runners in the crowded HCV space. Both Vertex Pharmaceuticals Inc. and Merck & Co. Inc. have their own HCV candidates in Phase III, protease inhibitors telaprevir and boceprevir, respectively. Analysts view both drugs as approvable.

The current standard therapy for HCV is a combination of ribavirin and a pegylated interferon. There are no protease inhibitors currently approved for the infection.

Achillion believes its protease inhibitor, though still in early testing, may stand apart from the others because of its safety and tolerability and sustained viral suppression.

"Based on the early Phase Ib data, we view ACH-1625 as a very promising HCV protease inhibitor in early development," Cowen & Co. analyst Phil Nadeau stated in a research note. He added, "We believe the risk/reward of owning ACHN shares at current levels is highly favorable."

In several dosing cohorts, study patients infected with HCV were dosed for five days and showed a mean maximum drop in viral load of between 3.63 and 4.25 logs. All dosing cohorts also showed a sustained viral suppression in HCV-infected subjects, even after dosing was completed.

"This observation could be an important distinguishing feature and competitive advantage for our compound in comparison to other HCV therapies," Elizabeth Olek, vice president and chief medical officer, said in a Thursday conference call.

A select group of investors, namely venture firms Domain Associates, Clarus ventures, Quaker BioVentures and Pappas Ventures, have agreed to purchase Achillion's stock and warrants in the private placement offering.

While the company's focus is HCV, it also has an HIV candidate elvucitabine, an L-cytosine nucleoside analogue reverse transcriptase inhibitor. Earlier this year, Achillion reported 96-week data showing that the drug had a substantial antiviral effect similar to 3TC (lamivudine, GlaxoSmithKline plc), with 95 percent of patients in the elvucitabine-treated group achieving undetectable viral load compared with 93 percent in the 3TC group.

Achillion is offering 19,755, 101 shares of common stock at a price of $2.49 per share, its consolidated closing bid price reported by NASDAQ Aug. 17.

The warrants to purchase 0.35 shares of common stock for each share of common stock are priced at $0. 125 per warrant share. The warrants, which have a seven-year term from the date of issuance, represent the right to acquire an aggregate of 6,921,285 shares of common stock and will be exercisable at a price of $3. 1125 per share.

Shares in Achillion (NASDAQ:ACHN) lost 1 cent, closing at $2.60 Thursday.

In other financing news:

• Complete Genomics Inc., of Mountain View, Calif., which recently filed to take the company public, raised $39 million in its Series E financing. New investor Sands Capital led the round and was joined by existing investors Essex Woodlands, OVP Venture Partners, Prospect Venture Partners, OrbiMed Advisors, Highland Capital Management and Enterprise Partners. Complete Genomics also reported that it is evaluating a lawsuit alleging patent infringement filed against it by Illumina Inc., of San Diego, and Solexa Inc. (acquired by Illumina), in the U.S. District Court in Delaware. The lawsuit claims that the Complete Genomics Analysis Platform infringes three patents owned by the plaintiffs. The company said it believes it has "substantial and meritorious defenses to the claims."
• Corcept Therapeutics Inc., of Menlo Park, Calif., has filed a shelf registration statement to sell, from time to time, up to $100 million in equity, debt and other offerings. Specific terms will be disclosed at the time of any financing. Proceeds will be used for research, development and commercial activities, working capital and other general purposes. The company is developing drugs to treat severe metabolic and psychiatric disorders that are associated with steroid hormone cortisol. Lead product Corlux is a Phase III drug candidate for Cushing's syndrome and psychotic depression.

• Jennerex Inc., of San Francisco, completed a fully subscribed private placement financing with aggregate gross proceeds of about $8.6 million. The money will allow the company to complete the ongoing Phase II trials of JX-594 in patients with liver cancer and colorectal cancer. Existing stockholders as well as a number of new investors participated in the financing.

• MannKind Corp., of Valencia, Calif., said that it has entered a previously announced stock lending agreement in which it will lend 9 million shares of its common stock to Bank of America NA. It also entered an underwriting agreement with Bank of America affiliate Merrill Lynch, Pierce, Fenner & Smith Inc., in which Merrill Lynch will sell the shares at an offering price of $5.55 per share. MannKind will not receive any proceeds from the common stock offering but will receive a nominal one-time lending fee. And Bank of America will be required to return the borrowed shares under the terms of the share lending agreement. Bank of America will use the short position resulting from the loan and sale of the shares of MannKind's common stock to facilitate the establishment of hedge positions by investors in a concurrent private offering of $100 million aggregate principal amount of MannKind's senior convertible notes due 2015. The notes, which will mature on Aug. 15, carry an approximate conversion price of $6.80 per share. An additional $10 million aggregate principal amount of the notes could be purchased to cover any overallotments. The closing of the common stock offering is expected to take place Aug. 24.

• Silence Therapeutics Plc, of London, a company focused on RNAi therapeutics, said that it anticipates future milestones of more than $65 million stemming from a siRNA deal that partner Quark Pharmaceuticals Inc., of Fremont Calif., recently entered with Novartis AG, of Basel Switzerland. Privately held Quark would receive a potential $680 million, including $10 million up front, under the deal, which grants the Swiss drugmaker an option to obtain an exclusive worldwide license to develop and commercialize QPI-1002. The investigational p53 temporary inhibitor which incorporates Silence Therapeutics' AtuRNAi technology. (See BioWorld Today, Aug. 19, 2010.)

Published August 20, 2010

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A Cure for HIV Could Be All in the 'Mix'

ScienceDaily (Aug. 18, 2010) — Current HIV treatments do not eradicate HIV from host cells but rather inhibit virus replication and delay the onset of AIDS. However, a new research study published in BioMed Central's open access journal, AIDS Research & Therapy describes an innovative approach to eliminate HIV in host by targeted killing of only HIV infected cells. This approach if successful could lead into an anti-HIV therapy that will eradicate the virus.

On infection, HIV spreads through the human body after the viral DNA is incorporated into the genome of host cells. Highly Active Anti-Retroviral Therapy (HAART) works by blocking HIV replication at various steps but does not eliminate the infected cells.

Professors Abraham Loyter, Assaf Friedler and their colleagues at Hebrew University, Jerusalem, focussed on the elimination of infected cells. Prof. Loyter contends that while HIV integrates its DNA into the human genome, it only inserts enough DNA to replicate yet avoids host genome instability leading to programmed death of the infected cells (apoptosis).

Dr. Loyter and his team sought to induce increased integration of HIV DNA into human genome that could lead to apoptosis. Toward that goal, they developed peptides (called "mix") that can penetrate into infected cells and stimulate the activity of the viral integrase. The stimulation of the viral integrase resulted in an increase in the number of the viral DNA molecules integrated into the infected cells that lead the infected cells into "panic mode," causing self-destruction.

Dr Loyter said: "Whilst this research is promising, a major caveat with these studies is that they are preliminary. So far these experiments have only been shown to 'cure' HIV from small dishes of cultured cells in the authors' laboratory, but the findings are an exciting development in the quest to eradicate this devastating global pandemic."

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Rutgers-Camden’s Freezable Fruit Fly Could Extend Organ Donor Shelf Life

August 19, 2010
 
CAMDEN – When kitchens become infiltrated with fruit flies, especially during the dog days of summer, homeowners might wish that the flying pests would just turn to ice.
 
The fruit fly Drosophila melanogaster does boast a powerful genetic system making it an ideal organism to test a cool new discovery: how an enzyme regulates body energy levels. Shutting off this molecular thermostat could result in a newfound cold tolerance that has multiple applications, including extending the 24-hour window donated organs now have for optimum use.

Thanks to a $385,419 grant from the National Institute of Health, a team of Rutgers–Camden biologists is working to engineer cold tolerant fruit flies and ultimately human cells within the next three years.

This research breakthrough can be credited to Daniel Shain, a professor of biology at Rutgers–Camden, who has traveled the globe seeking knowledge on how ice worms don’t just survive in glaciers, but thrive. When Shain identified a key enzyme that helps ice worms do this – AMP phosphatase – he tapped Nir Yakoby, an expert Drosophila geneticist and assistant professor of biology at Rutgers–Camden, to create this cold-tolerant fruit fly.

“The goal is to make human cells survive on ice. Twenty-four hours on ice is pushing it and many people die waiting,” says Shain, who is scheduled to travel to Tibet next year to observe ice worms in the vicinity. “We’re lucky to have an expert Drosophila geneticist on campus to test this genetic switch.”

Not just the ice worm lives on ice; the Rutgers–Camden research team, which includes undergraduate and graduate students, observed how other organisms, like bacteria, fungi, and algae, also are breaking through their internal thermostats.

“Shain accomplished this switch in mono-cell organisms and now we are going further up into the evolutionary tree to a more complex species,” offers Yakoby, who joined the Rutgers­–Camden faculty last year after conducting postdoctoral research at Princeton University’s Lewis Sigler Institute for Integrative Genomics. “If we can get these human cells to survive on ice, we should expect organs to do the same. Organs are just a collection of cells.”

A graduate of the University of New Hampshire, where he earned both his bachelor’s and master’s degrees, Shain earned his doctorate from Colorado State University and held a postdoctoral fellowship through the national Institute of Health at the University of California-Berkeley.

Yakoby, who earned his undergraduate and doctoral degrees from Hebrew University in Israel, teaches genetics at Rutgers–Camden. Both Shain and Yakoby are active members of the Rutgers–Camden Center for Computational and Integrative Biology, which offers doctoral and graduate programs and strives to determine the quantitative organizational principles of complex biological systems, using a combination of theoretical and experimental approaches.

Media Contact: Cathy K. Donovan
(856) 225-6627
E-mail: catkarm@camden.rutgers.edu

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Can serum hyaluronic acid replace simple non-invasive indexes to predict liver fibrosis in HIV/Hepatitis C coinfected patients?

Published on: 2010-08-19

Hyaluronic acid (HA) serum levels correlate with the histological stages of liver fibrosis in hepatitis C virus (HCV) monoinfected patients, and HA alone has shown very good diagnostic accuracy as a non-invasive assessment of fibrosis and cirrhosis. The aim of this study was to evaluate serum HA levels as a simple non-invasive diagnostic test to predict hepatic fibrosis in HIV/HCV-coinfected patients and to compare its diagnostic performance with other previously published simple non-invasive indexes consisting of routine parameters (HGM-1, HGM-2, Forns, APRI, and FIB-4).

Methods: We carried out a cross-sectional study on 201 patients who all underwent liver biopsies and had not previously received interferon therapy.

Liver fibrosis was determined via METAVIR score. The diagnostic accuracy of HA was assessed by are under the receiver operating characteristic curves (AUROCs).

Results: The distribution of liver fibrosis in our cohort was 58.2% with significant fibrosis (F[greater than or equal to]2), 31.8% with advanced fibrosis (F[greater than or equal to]3), and 11.4% with cirrhosis (F4).

Values for the AUROC of HA levels corresponding to significant fibrosis (F[greater than or equal to]2), advanced fibrosis (F[greater than or equal to]3) and cirrhosis (F4) were 0.676, 0.772, and 0.863, respectively. The AUROC values for HA were similar to those for HGM-1, HGM-2, FIB-4, APRI, and Forns indexes.

The best diagnostic accuracy of HA was found for the diagnosis of cirrhosis (F4): the value of HA at the low cut-off (1182 ng/mL) excluded cirrhosis (F4) with a negative predictive value of 99% and at the high cut-off (2400 ng/mL) confirmed cirrhosis (F4) with a positive predictive value of 55%. By utilizing these low and high cut-off points for cirrhosis, biopsies could have theoretically been avoided in 52.2% (111/201) of the patients.

Conclusions: The diagnostic accuracy of serum HA levels increases gradually with the hepatic fibrosis stage.

However, HA is better than other simple non-invasive indexes using parameters easily available in routine clinical practice only for the diagnosing of cirrhosis.

Author: Salvador ResinoJose BellonCristina AsensioDariela MicheloudPilar MirallesAna VargasPilar CatalanJuan LopezEmilio AlvarezJaime CosinRaquel LorenteMaria Munoz-FernandezJuan Berenguer

Credits/Source: BMC Infectious Diseases 2010, 10:244

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Testing for disease with paper the size of a postage stamp

Diagnostics For All device

By Christina Hernandez
Aug 19, 2010

It’s postage stamp-sized technology with global implications for healthcare. With a mission to provide diagnostics for the developing world that are cheap, portable and easy to use, the nonprofit Diagnostics For All has developed a testing technology made from paper.

Founded in 2007 on the work of George Whitesides, a chemistry professor at Harvard University, the Massachusetts-based Diagnostics For All is preparing to begin field testing its device next year. I spoke last week with CEO Una Ryan about the implications of this technology in the developing world — and in the United States.

Your diagnostic tool is made from patterned paper. How does that work?

Instead of trying to re-engineer some of the big, expensive devices we have in the U.S., [we thought] about the problem and what would be the cheapest, most convenient way to address it. The cheapest and most ubiquitous substance that’s available worldwide is paper. We have printed micro-fluidic channels onto the paper. If you take a biological fluid, like blood or urine or tears, it will move down that pathway and interact with chemicals we put in those reservoirs. You get a color reaction that you can easily read by eye. For a more permanent record, you can take a cell phone picture of it. Since everything we do is telemedicine compatible, it gives us the opportunity to make some amazing databases tracking worldwide health trends.

Which medical conditions can the technology detect?

Ultimately we want it to be for everything, so patients can monitor their health and populations can be monitored. You can’t begin to manage healthcare until you know what you’re dealing with. That’s why we started with diagnosis. [But] you need to be able to monitor the course of the disease. If somebody is lucky enough to have medication for that disease, sometimes they cause side effects.

One of the [tests] we started with was liver function. Patients who have HIV or [tuberculosis] and get drugs are at risk of getting liver damage from those drugs. In the U.S., for example, the incidence of liver damage is 2 percent. In the developing world, it’s 25 percent. That’s because people aren’t checked. We wanted tests [with] a very easy, inexpensive action. We wanted tests where it’s just a finger prick or a urine specimen, you get the answer immediately, you could be given the drug and counseling and you’re on your way.

There are many ways our tests can be used. Since they’re paper and the size of a postage stamp, they’re very portable. We could mail them. A healthcare worker in a rural area can carry them in a satchel. Our tests [don't] require electricity. They don’t require water. They don’t require a doctor. It’s game changing.

What’s the status of the liver function test? When will it be put into use?

We have about 10 we’ve tested. Liver function is the most advanced, largely because we have funding from the [Bill and Melinda] Gates Foundation. Now, we’re testing our test with discarded blood from one of the Boston hospitals. We’re finding a nice correlation between our results and [the hospital's]. When we’ve completed that lab-level testing, we want to be in the field. We hope to start field testing at the beginning of 2011. We will probably be testing in Africa.

What are the other conditions you could expand testing to?

Diabetes, cholesterol. We could also [test for] heavy metals in water. We can test for iron imbalances in sweat. We haven’t yet developed them into a product, [but some have been tested at the lab level].

We talked about these tests in the context of the developing world. Do you also see uses for this technology in the U.S.?

Absolutely. We’re already getting an enormous amount of corporate interest from companies here. Medicine is moving more toward the patient. We all want to be empowered to manage our own health. But patients need to be compliant with their drugs. If you have a way of testing yourself, you can very quickly see if you’re not eating well, not taking your medicines. It gives you a sense of control.

Since we take just a small prick of blood, this will be very useful for pediatrics. We think it will be useful on ambulances. We think it will be directly applicable to consumers, [such as] runners in the Boston Marathon who want to check their sweat. We think about this for the military. The uses for the developed world are huge. We can teach the U.S. a thing or two about the cost of healthcare.

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Live organ donation: Lifesaving but risky

Ryan Arnold, 34, who was healthy when he donated 60 percent of his liver to his brother, died four days after the surgery.

By Elizabeth Cohen, CNN Senior Medical Correspondent
August 19, 2010 11:41 a.m. EDT

STORY HIGHLIGHTS

--More than 6,000 living donations take place each year
--Many live donors giving to family, friends, make decisions out of emotion

--Advocates: Make sure you know all risks before donating a kidney or part of liver

 

(CNN) -- Chad Arnold clearly remembers the day he received the call from his older brother, Ryan, telling him they were a perfect match for a liver transplant.

"You feel a lot of things at that point. Relief, gratefulness to God and to Ryan," says Chad, who suffers from an incurable liver disease called primary sclerosing cholangitis.

Chad told his story to Ginger Delgado, a reporter for KDVR in Denver, Colorado.

"After that, you wrestle with a lot of guilt, like I really don't want to bring him through this," Chad added. "But he shut me up pretty fast, and said, 'Well, you would do it for me, wouldn't you?'"

The Arnold family had invited KDVR to be with them the day of the surgery when it took an unexpected and devastating turn. Ryan Arnold, 34, who was completely healthy when he went in to donate 60 percent of his liver to his brother, died four days after the surgery. He is survived by a wife and three young sons.

In a statement, the University of Colorado says, "Despite the risks, Ryan selflessly made the decision to give part of his liver to his brother, Chad. We will learn everything we can from this to keep making the phenomenal gift of transplant safe for donors as well as recipients. We will continue working to improve this vital, life-changing program, which pioneered liver transplants 40 years ago. Ryan's passing will not be in vain."

"This is a story about a man who is deeply convicted by his faith and because of that, what he did for me was just sort of a normal thing that he did for people," Chad, 38, told KDVR after his brother's death. "Ryan is the hero in this."

Advocates for living donors say one should seriously weigh all the risks before deciding to donate a kidney or section of the liver.

Nationally, two out of every 1,000 liver donors die as a result of the surgery , according to OrganDonor.gov, a part of the federal Department of Health and Human Services. From 1996 to 2006, there were 3,016 living liver transplants in the United States.

Between October 1999 and December 2007, 14 people died within a month after donating a kidney, according to a study commissioned by the National Kidney Foundation. During that time, 51,153 people donated a kidney.

Cristy Wright said she didn't do much research before donating a kidney to her sister, Mary Edington.

"Normally I'm a big research hound -- an info junkie," says Wright, 39, a freelance writer who lives in Copley, Ohio. "But with the transplant, I made the decision emotionally. It was pretty impulsive. It was about loyalty. I love my sister and wanted to help her."

Since donating her kidney, Wright started a website, LivingDonor101.com, to help get information to other donors.

Wright says she recovered well physically from losing a kidney but suffered anxiety, anger and depression when the organ failed to function in her sister.

"They had to bring her into surgery and remove the kidney," Wright says. "I was a crying mess. I called up the living donor coordinator at the hospital and she gave me all sorts of platitudes and said she'd call me back, but she never did."

The kidney was removed a week after the donation. A year later, she says, her sister received a kidney from a friend, which did work.

Wright says the consent form she signed at the Cleveland Clinic was "generic" and didn't mention all the specific risks of kidney donation.

"Nobody ever apologized to me," Wright says. "I felt abandoned and betrayed by the surgeons and the transplant center."

Cleveland Clinic offered this response to CNN: "We are committed to ensuring that patients undergoing treatment at our hospitals understand the risks and benefits of procedures. Conversations with patients are thoroughly documented in the patient's medical records. Patients meet with their physician and surgeon, patient educators, donor coordinators, social workers, donor advocates and others if needed for special circumstances. We regret that our patient's experience did not meet her expectations."

"The literature shows most people make the decision to donate without doing research," says Donna Luebke, a nurse practitioner who donated a kidney to her sister in 1994, and a former board member of the Organ Procurement Transplantation Network and the United Network for Organ Sharing.

"You need to be informed about the outcomes for your surgeon and your hospital. Educate yourself."

Luebke says you should ask many questions, including how many transplants of the type you're having the surgeon does per year, and what the short and long-term outcomes have been.

More than 6,000 living donations take place each year, according to HHS, usually among family members or close friends, and the transplants have saved hundreds of thousands of lives. Before becoming a living donor, here are some resources to check:

This sample consent form from the U.S. Department of Health and Human Services includes information on the risks of donating a lobe of your liver.

The National Kidney Foundation has information about the risks of donating a kidney.

The federal government keeps statistics on how many transplants have been done at individual hospitals,, so you can see how experienced a hospital is in a particular procedure.

From livingdonorsonline.org, you can find advice on how to prepare to become a living donor, an online message board to talk to more than 4,000 people who've donated an organ or are considering it and links to read other donors' experiences.

The United Network for Organ Sharing also has information for potential living donors.

The National Living Donor Assistance Center offers videos that feature kidney and liver donors and expert advice on what to expect when donating an organ.

Livingdonor101 has a list of questions you should ask before becoming a living organ donor from someone who herself has donated an organ.

CNN's Sabriya Rice contributed to this report.

Source
 
Also See:

• Donor dies after liver transplant at CU Hospital
• Pioneering hospital halts live liver transplants

Multi-centre Phase II Trial Reports Safety and Clinical Benefits of Radioactive Microspheres in Patients with Colorectal Cancer Liver Metastases who have Failed Chemotherapy

Aug. 19, 2010, 9:36 a.m. EDT

ROME, August 19, 2010 /PRNewswire via COMTEX/ -- Radioactive yttrium-90 labelled resin microspheres (SIR-Spheres; Sirtex Medical, Sydney, Australia) appear to be a safe and effective treatment for patients with colorectal cancer liver metastases who have failed available chemotherapy options, according to the final results of a prospective clinical multi-centre phase II trial conducted by the Italian Society of Locoregional Therapies in Oncology (SITILO) and published in the British Journal of Cancer.[1]

The results of the 52-patient study revealed that the liver tumours completely disappeared in one patient (2%), and 11 (22%) patients had a partial response involving at least a 30% reduction in tumour size, which met the pre-determined criteria for significance (P = 0.05). A further 12 (24%) patients had stable disease. The liver tumours shrank sufficiently in two patients (4%) to enable potentially curative surgery to be performed. The median overall survival was 12.6 months for all patients in the trial, with significantly longer survival in the 24 (48%) patients that responded to SIR-Spheres or who had stable disease compared to non-responders (median 16 months versus 8 months; P = 0.0006), and 40% of the responders remaining alive at two years compared to none of the non-responders. Mild-to-moderate side effects consisting mostly of fever and pain were reported in 16% of patients in the first 48 hours and 22% in days 3 to 30.

"These results reveal that radioembolisation using SIR-Spheres is a promising therapy for patients with colorectal cancer liver metastases who have failed chemotherapy," said Prof. Maurizio Cosimelli, Professor of Surgery at the Regina Elena National Cancer Institute in Rome, and co-ordinator of the study. "The prolonged 12.6-month median survival and encouraging tumour response reported in the SITILO study compares favourably with the clinical trial results of second- or third-line chemotherapy, even though three-quarters of our patients had previously received at least four different combinations of chemotherapy drugs and therefore had a poor prognosis with no other treatment options available."

"At a minimum, patients with liver-only or liver-dominant colorectal cancer who are failing chemotherapy and who remain fit should be considered for radioembolisation using SIR-Spheres," said Prof. Cosimelli. "However, SITILO will be conducting a multi-centre randomised trial using SIR-Spheres in combination with chemotherapy at an earlier line of treatment since we believe that this may further improve the prognosis for patients with colorectal liver metastases. Above all, it will be possible to clarify the potential of SIRT together with chemotherapy to increase the rate of surgical resections in patients that were previously unresectable."

Patients in the SITILO study had to have liver metastases from colorectal cancer that could not be removed by surgery and which had progressed despite modern chemotherapy regimens containing oxaliplatin and irinotecan. The presence of metastases outside the liver did not exclude the patients from treatment as long as these were limited in number, size and in the same organ. All patients were heavily pre-treated, having received at least 3 previous chemotherapy regimens: 24% had received 3 different lines or courses of chemotherapy, 50% had received 4 lines and 26% had received 5 lines.

The SITILO study used a single-arm design since this group of patients had no other treatment options available. Patients were reviewed by a multidisciplinary team of cancer specialists prior to recruitment into the study. The median survival of metastatic colorectal cancer treated in clinical studies using modern chemotherapy regimens such as cetuximab plus irinotecan at second-line and panitumumab at third-line treatment has been reported to be 8.6 to 10.7 months[2-5] and 6.3 to 9.3 months[6-9] respectively.

Each year, more than 145,000 Americans and 307,000 Europeans are diagnosed with colorectal cancer. Around half of these patients will develop metastases that have spread from the original site of the disease, predominately to the liver. Up to 90% of these patients ultimately die from liver failure due to the spread of the disease. Selective Internal Radiation Therapy (SIRT) using 90Y microsphere therapy is a novel approach to treating liver metastases. The microspheres are implanted by interventional radiologists to selectively target the tumors with radiation while sparing the much-needed healthy liver tissue.

The SITILO study was conducted by a multidisciplinary team of interventional radiologists, nuclear medicine physicians, medical oncologists, surgeons and other specialists at the Regina Elena National Cancer Institute in Rome, the University of Bologna, the University of Udine and the Cancer Institute of Naples in Italy. SIR-Spheres was developed by, and is manufactured by, Sirtex Medical, and is the only FDA-approved microsphere therapy for colorectal cancer liver metastases.

SITILO is the only Italian multidisciplinary oncology society. Different specialties work together within SITILO to design prospective clinical trials on loco-regional therapies in the field of liver metastases and primary carcinoma, melanoma, soft tissue sarcoma, and other cancers. Each protocol includes a biological component aimed at identifying predictive factors in serum and tissue.

The SITILO trial was conducted at the following hospitals:

- Regina Elena Cancer Institute, Rome, Italy
- University of Bologna, Bologna, Italy
- University of Udine, Udine, Italy
- Fondazione Pascale Cancer Institute, Naples, Italy

References

1. Cosimelli M, Golfieri R, Cagol PP et al. Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases. British Journal of Cancer 2010; 103: 324-331.

2. Sobrero AF et al. EPIC: Phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. Journal of Clinical Oncology 2008; 26: 2311-2319.

3. de Cerqueira Mathias et al. Front cetuximab plus irinotecan in patients (pts) with metastatic colorectal cancer (mCRC) progressing on or after prior irinotecan therapy: final results of the LABEL study. ECCO meeting, European Journal of Cancer Supplements 2007; 5: Abs. P3055.

4. Wilke H et al. Cetuximab plus irinotecan in heavily pretreated metastatic colorectal cancer progressing on irinotecan: MABEL study. Journal of Clinical Oncology 2008; 26: 5335-5343.

5. Cunningham D et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. New England Journal of Medicine 2004; 351: 337-345.

6. Hecht JR et al. Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer. Cancer 2007; 110: 980-988.

7. Van Cutsem E et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. Journal of Clinical Oncology 2007; 25: 1658-1664.

8. Van Cutsem E et al. An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy. Annals of Oncology 2008; 19: 92-98.

9. Yoshino T et al. Phase II study of panitumumab (Pmab) monotherapy in Japanese patients (pts) with metastatic colorectal cancer (mCRC) after the failure of fluoropyrimidine, irinotecan (CPT-11), and oxaliplatin (OHP) chemotherapy. ASCO GI Symposium 2008; Abs. 366.

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Hispanics and Asians less likely to receive liver transplants

Public release date: 19-Aug-2010

Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell

Study links locale to diminished access to organs

Researchers at the University of Michigan and Arbor Research Collaborative for Health, both in Ann Arbor, have identified geographic variation as a key factor accounting for disparities in access to liver transplantation among racial and ethnic groups. Full details appear in the September issue of Liver Transplantation, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases (AASLD).

Organ allocation in the U.S. is designed for equitable distribution of deceased donor organs. Patients are prioritized to receive organs for liver transplantation (LT) based on their Model for End-stage Liver Disease (MELD) score, an objective assessment of their risk of dying on the waitlist. Hence, two candidates with similar MELD scores should have an equal chance of receiving a transplant regardless of race, gender, geography, or economics. However, there are multiple patient-specific as well as healthcare-specific barriers to LT that potentially compromise this system. Some of these variables include inadequate access to healthcare, lack of recognition of the need for transplant, access to a transplant center, and inequities in the transplant evaluation process.

While racial and ethnic disparities are evident throughout this entire process, the researchers found that the locale where candidates seek care for their liver disease modifies the effect of race/ethnicity on access to liver transplantation. Organ availability differs by region, and even within a region, the likelihood of LT varies among donor service areas (DSA). Local organ availability and center specific transplant practices may also play a role.

Amit K. Mathur, M.D., M.S., and colleagues propose that racial/ethnic disparity in access to transplantation at the DSA level must be evaluated because previous studies fail to acknowledge that organ availability is highly variable across DSAs, only evaluate African-Americans as a minority, and fail to account for changes in the severity of liver disease over time while candidates are waitlisted.

The authors conducted a Scientific Registry of Transplant Recipients analysis of data submitted to the Organ Procurement and Transplantation Network (OPTN). They considered 39,114 adult chronic end-stage liver disease candidates on the waitlist between 2002 and 2007. The primary variable of interest was candidate race (74.1% Caucasian, 13.9% Hispanic, 7.3% African-American and 3% Asian) and the primary outcome of interest was transplant rates by race/ethnicity, stratified by DSA and MELD score.

The analysis reveals that without adjustment by DSA, African-Americans appeared to have a 10% lower rate of receipt of LT as compared to Caucasians. After adjustment by DSA the deficit in this rate decreased to 2% and was no longer significant, , suggesting a direct link to DSA as the source of racial disparity and that African Americans are likely over represented in DSAs with organ shortage.

In contrast, Hispanics had an 8% lower LT rate than Caucasians even after adjustment for DSA. Stratified by DSA, this difference was pronounced at a MELD score < 20 (15% lower transplant rate) but the difference was no longer present at higher MELD scores. The persistently lower rates of transplant for Hispanics even after consideration of DSA may indicate Hispanics are over represented at centers that transplant candidates at higher MELD scores. Prior studies also suggest that Hispanics are overrepresented in DSAs with longer median waiting times for LT.

Asians experienced no significant difference in liver transplant rates compared to Caucasians. On analysis of MELD subgroups, however, Asian candidates with lower MELD scores (6-14) had a 24% higher transplant rate relative to Caucasians but a lower transplant rate (15-46%) was observed at MELD scores >15, possibly due to a combination of center effect as well as donor issues such as body size. However, the overall rates of transplant were similar among Caucasians and Asians.

"Geographic variation is being increasingly recognized as a threat to optimizing the use of donated organs, and in our study had a clear effect on the measured differences in transplant rates between minorities and Whites," concluded Dr. Mathur. "We observed significantly lower liver transplant rates for minority candidates compared to their White counterparts, particularly among Hispanic candidates and Asians with high MELD scores. Importantly, these lower relative transplant rates were not accompanied by higher rates of death, removal for non-transplant reasons, and inactivation."

In an editorial also published this month, Patrick Kamath, M.D., from the Mayo Clinic concurred, "Geographic incongruence serves to undermine an organ allocation scheme based on equity and needs to be addressed to make complex path to LT less cumbersome for persons with chronic liver disease, regardless of race, gender, payer or any other status."

###

This study is published in Liver Transplantation. Media wishing to receive a PDF of this article may contact healthnews@wiley.com

Full Citations: "Racial and Ethnic Disparities in Access to Liver Transplantation." Amit K. Mathur, Douglas E. Schaubel, Qi Gong, Mary K. Guidinger, Robert M. Merion. Liver Transplantation; Published Online: May 20, 2010 (DOI: 10.1002/lt.22108); Print Issue Date: September 2010. http://onlinelibrary.wiley.com/doi/10.1002/lt.22108/abstract.

Editorial: "Race and Receipt of Liver Transplantation: Location Matters." Sumeet K. Asrani, W. Ray Kim, Patrick S. Kamath. Liver Transplantation; Published Online: June 30, 2010 (DOI 10.1002/lt.22123); Print Issue Date: September 2010. http://onlinelibrary.wiley.com/doi/10.1002/lt.22123/abstract.

Liver Transplantation is published on behalf of The American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Since the first application of liver transplantation in a clinical situation was reported more than twenty years ago, there has been a great deal of growth in this field and more is anticipated. As an official publication of the AASLD and the ILTS, Liver Transplantation delivers current, peer-reviewed articles on surgical techniques, clinical investigations and drug research — the information necessary to keep abreast of this evolving specialty. For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-6473.

Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit http://www.wileyblackwell.com/ or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

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Genes may play a role in liver disease

Updated: 2010-08-18 20:15:28 CST

A family history of liver disease may predict the necessity of liver testing. A new study has found that variations of a particular gene that can be passed from generation to generation may be a contributor to liver conditions such as nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis.

Researchers from the National Institutes of Health Medical Center performed genetic testing on individuals who had one such liver disease or exhibited its early stages. They found that a significant number of patients had a particular gene that is uncommon in healthy individuals.

"Our findings suggest that the allele may predispose patients to fat accumulation in the liver, but that other factors, environmental or hereditary, may be required for the development of inflammation, cellular injury and fibrosis," said T. Jake Liang, who led the study. "However, once patients develop NASH, the allele predisposes them to more severe injury."

A total of 20 to 30 percent of the population has nonalcoholic fatty liver disease, a precursor to more severe liver conditions. The findings could give physicians a better idea of which patients will benefit from liver testing by including family history as a risk factor.

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Alcohol Use Before Liver Tx Key to Use Afterward

Crystal Phend, Senior Staff Writer, MedPage Today Published: August 19, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

Problem drinking after liver transplantation for alcoholic liver disease can be predicted by looking at just a few factors, a prospective study showed.

Return to alcohol use was predicted by a shorter length of sobriety before transplantation, a positive family history of alcoholism, and a diagnosis of alcohol dependence, Andrea DiMartini, MD, of the University of Pittsburgh Medical Center in Pittsburgh, and colleagues found.

Fully 46% of those in the cohort study started drinking again at some point, with moderate to heavy consumption in 42% of those, the researchers reported online in the American Journal of Transplantation.

The predictors may allow physicians to target their preventive and interventional treatment resources to at-risk individuals at the right time, DiMartini's group suggested.

The study included detailed prospectively-collected data on alcohol consumption from 208 patients who had a liver transplant for a primary or secondary diagnosis of alcoholic liver disease (78% of all such cases treated) at a single center over a six-year period.

Patients were counseled at every follow-up office visit to abstain completely from alcohol. Those who reported drinking got further counseling from the transplant psychiatrist and referral for professional alcohol counseling as needed.

Although therefore not a natural history study, this standard of care is followed at most transplant programs, the researchers noted.

Several patterns emerged for return to alcohol use among the 95 patients who didn't stay on the wagon:

•55 drank low amounts infrequently
•13 started drinking moderate amounts right away but cut down over time
•15 resumed moderate drinking later on and increased the amount over time
•12 immediately started drinking heavy amounts and increased the amount over time

This suggested that problem drinking may not start right away and thus "clinical monitoring should extend well beyond the early years post-liver transplantation," the researchers recommended in the paper.

Early moderate to heavy drinking patterns were predicted by:

•Poorer health after transplantation than in the year prior
•More bodily pain
•More fatigue
•More perceived stress
•A pretransplantation history of other substance use
•Not feeling confident that they would get another liver if needed

One explanation may be that patients felt ineffectual, feeling worse and not sure anything could make it better, the researchers suggested.

Or, alcohol use may have been how they handled stress, including the difficulties of the early post-liver transplantation phase, they added.

"Early identification and treatment of stress especially as it relates to early post-liver transplantation recovery, attention to complaints of pain and fatigue, as well as resumption of addiction counseling may aid in the stabilization of these patients," DiMartini's group wrote in the paper.

By contrast, those who drank minimally and consistently in the early period after transplantation reported better health and more vitality afterward, were less stressed, less likely to be in pain, did not regret their decision, and felt more confident they would get another liver if needed.

A possible explanation for their return to drinking could have been complacency about their overall health and the health of their liver leading to the feeling that occasional drinking early on would not be a problem, the researchers speculated.

They cautioned that the study was limited by the small size of the different trajectory groups and that participation in the study may have affected behavior of those in it.

The authors also noted that they had just begun to collect outcome data, which will be the subject of a later report.

The study was funded by grants from the National Institute of Alcohol Abuse and Alcoholism and the National Institute of Digestive Disorders and Kidney Diseases.

The researchers reported having no conflicts of interest to disclose.

Primary source: American Journal of Transplantation

Source reference:
DiMartini A, et al "Trajectories of alcohol consumption following liver transplantation" Am J Transplant 2010; 10.

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Eleven hospitals join hands to assess the impact of liver disease and hepatitis C in the health sector

India Infoline News Service / 10:07 , Aug 19, 2010

Bristol-Myers Squibb Foundation Delivering Hope Program has committed US$ 2,223,295 to support efforts to combat Hepatitis B and C in India

Liver Foundation, West Bengal is coordinating a first of its kind collaboration among public health facilities to assess the impact of liver disease and in particular hepatitis C on Indian health care system, the organization announced today in New Delhi.

HCV: The Indian Face and Action is a two year operational research project that is first serious attempt to assess the impact of liver disease and hepatitis C in order to be able to advocate for robust viral hepatitis awareness, prevention and educational programs. The project, launched early this year is supported by Bristol-Myers Squibb Foundation (BMSF) Delivering Hope Program through a grant of about Rs19.5mn [US$415857] also aims improve diagnosis skills for 500 blood bank and laboratory technicians while enhancing prevention efforts among high risk groups.

“WHO estimates that it cost between one and three US dollars to prevent Hepatitis B through vaccination but we know it costs about US$5000 to treat a person with hepatitis B infection. For hepatitis C, there is no vaccine but it is curable and therefore awareness and prevention efforts should be paired with early detection, hence our training of laboratory technicians,” says Dr. Abhijit Chowdhury, Secretary-Liver Foundation West Bengal who is leading this consortium.

“Through this initiative we aim to inform public health policy regarding the significance and impact that a liver disease has, HCV in particular, in the general population. Additionally, we would work to foster coordinated HCV prevention and awareness activities through action targeted at key risk populations in awareness or scientific understanding and transmission”, he added.

BMSF Delivering Hope has committed an amount of about Rs105mn [US$2,223,000] to eight non-profit organizations partners across India since 2007. In the year 2010, BMSF would support ‘Americares India Foundation’ in Mumbai, ‘Baptist Christian Hospital’ in Tezpur in addition to HCV: The Indian Face and Action to enhance awareness on Hepatitis in the country. Institute of Development Studies, Kolkata has taken an endeavor to assess the impact of the intervention conducted by Liver foundation, West Bengal which has been also supported by BMSF.

“The Bristol-Myers Squibb Foundation has a long track record of harnessing expert resources and community support to bring measurable advances in the response to public health threats such as Hepatitis and HIV around the world.” said John Damonti, President, Bristol-Myers Squibb Foundation. “Our Delivering Hope Program builds on our expertise and commitment in addressing health disparities to help coordinate the response to hepatitis in countries where the need is the greatest.”

The project aims to determine the footfall in hospitals due to liver diseases and also map the healthcare resource utilization patterns in liver diseases in India. Initiatives will be undertaken to spread awareness on HCV prevention and care through action targeted at key risk populations.

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From one arm to another: the journey of donated blood

An ordinary student has the potential to save three lives every two months

By Jessica Neville, Science & Tech Editor

Published: Thursday, August 19, 2010
Updated: Thursday, August 19, 2010

Donated blood goes through many treatments before being distributed to hospitals for patient use. Saving lives isn’t just a job reserved for firefighters and soldiers. In fact, an ordinary University student has the potential to save three lives every two months. How? It’s as easy as giving blood.

This Friday the University, led by the Center for Student Leadership, Ethics and Public Service, has set a goal to collect 500 units of blood, which would be a personal record.

According to Michael Giancola, Director of CSLEPS, 687 people had signed up as of Wednesday at 2 p.m.

“We estimate that we need at least 660 people to sign up to reach the goal of 500, due to the possibility that some people will not come or will not be able to give blood when they arrive,” Giancola said.

Once the goal has been met, what happens to the donated blood? It turns out the blood isn’t shipped directly to a hospital to be transfused into a patient’s arm; there is actually a much longer process blood must go through to make the cut. From collection to treatment to distribution, find out how a blood donation can turn into a saved life.

Step 1: Donation

When a blood donor candidate arrives at a blood drive, the donor registers and completes a health history and mini physical. If everything checks out, about one pint of blood will be collected from the donor along with several small test tubes that can be used for further testing. An identical bar code label is placed on the bag, test tubes and the donor record to keep track of the donation, and the donation is stored in ice coolers until it is transported to a Red Cross processing center.

Kirsten Kruhm, senior blood donor recruiter with the American Red Cross, has worked with the University on multiple blood drives, including Friday’s record-setting drive.

“Last year, N.C. State gave 1,820 pints of blood on campus through 37 unique blood drives,” Kruhm said. “Most people have 10 to 12 pints of blood in their bodies, and donors usually give one pint at blood drives.”

Step 2: Processing

After the blood is donated, the barcode numbers are scanned into a computer database. The blood is sent to a Red Cross processing facility, where the blood is spun in centrifuges to separate it into its sub-components.

Dave Miller, director of testing at the Charlotte Red Cross Treatment Center, said the usable components of blood are the red blood cells, platelets and plasma. According to Miller, red cells are given to patients when their tissues need oxygen, platelets are used for clotting, particularly of capillaries, and plasma is used for clotting, especially for patients with hemophilia.

“The blood is also leuko-reduced, or white-reduced, meaning the blood is filtered to remove the white blood cells,” Miller said.

Primary components can be further manufactured into components such as cryoprecipitate, which is a harvested precipitate of plasma that contains fibrinogen. The test tubes collected from the initial blood donation are sent for testing at this time.

Step 3: Testing

The test tubes donated this Friday will be received at the Charlotte Red Cross National Testing Laboratory, one of five laboratories nationwide. The blood samples then undergo a dozen tests to make sure the blood doesn’t contain any infectious diseases and to establish the blood type. If the blood tests positive for any infectious diseases, the unit is discarded and the donor is notified.

“About one percent of the blood we collect has to be thrown away because it is contaminated,” Miller said. “50 percent of this is due to Hepatitis B, followed by Hepatitis C.”

Miller said blood type refers to the antigens present on the red blood cells. Antigens are substances that can produce an immune response if they are foreign to the body. Blood type A possesses A antigens, blood type B contains B antigens, blood type AB contains AB antigens, and blood type O has no antigens.

There are very specific ways blood types can be matched based on the antigens the patient’s red blood cells possess.

Step 4: Storage

After processing and testing, components of blood that are suitable for transfusion are labeled and stored. Red blood cells are stored in refrigerators at six degrees Celsius for up to 42 days, platelets are stored at room temperature in agitators for up to five days, and plasma and cyroprecipiate are stored in freezers for up to one year.

Miller said platelets are the hardest to maintain blood component because they can only be used for five days and have to stay at room temperature. People undergoing chemotherapy need a constant supply of platelets, according to Miller.

“We constantly need blood donated-not just a large amount at one time,” Miller said.

Step 5: Distribution

The blood is finally available to be distributed! Red Cross blood is available to be shipped to hospitals seven days a week, 24 hours a day.

Kruhm said the Red Cross divides areas of the United States into blood regions. North Carolina, South Carolina and Georgia comprise a common blood region where blood is generally maintained, according to Kruhm.

“In the Carolina blood region we need 1500 pints of blood every day to meet all the local patient needs,” Kruhm said.

Although blood donated in Raleigh will probably stay within the Carolina blood region, Kruhm said there are situations where the blood could be transported to another part of the U.S.

“If there’s a hurricane in another part of the country, we can send blood there to help them if necessary,” Kruhm said. “But we have some of the largest blood-using hospitals in the nation in RDU, such as Duke Medical, WakeMed, and REX, so much of the blood donated on Friday will go to those hospitals.”

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