March 27, 2012

steve-weinman

Steven Weinman M.D., Ph.D

March 26, 2012

By Alissa Poh

As diseases go, hepatitis C should be highly treatable, even curable. Like other viruses, it speedily replicates inside the cells of its host and dodges drugs by frequently mutating. One crucial difference, however, is that hepatitis C doesn't stay dormant in the body.

"If you can turn hepatitis C's replication off completely for three or more months, you're rid of it," says Steven Weinman, M.D., Ph.D., a professor of Internal Medicine and director of translational research at the University of Kansas Medical Center's Liver Center.

An estimated 3.2 million Americans, including roughly one in 33 baby boomers, are infected with hepatitis C. According to the Centers for Disease Control and Prevention, more Americans die from this infection each year than from HIV-related causes. So the fact that hepatitis C is potentially curable should be good news.

But there's a paradox. "The current drug regimen for hepatitis C is a difficult ordeal that many patients struggle to tolerate," Weinman says.

Hepatitis C patients typically undergo a year-long course of interferon and ribavirin; both boost the immune system but have major side effects. "With interferon, you feel lousy the entire time; you're weak and you have no appetite," Weinman explains. "It can cause personality changes and depression, or make pre-existing depression worse." Both interferon and ribavirin also lower a patient's blood counts, increasing the risk of other infections and causing anemia.

Two new drugs, telaprevir and boceprevir, were approved by the FDA last May. But they're only effective alongside interferon and ribavirin. Their own side effects — including a nasty rash and severe bone marrow suppression — compound the misery of the original therapy. They also need to be taken three times daily at exact eight-hour intervals and, in telaprevir's case, with a high-fat diet so it's properly absorbed.

"The ordeal's now even worse, but the new drugs do bring a cure rate that had been below 50 percent closer to 70 percent, and that's huge," Weinman says.

Hepatitis C is all the more difficult to treat because the blood-borne virus spreads most commonly through intravenous drug use, so many patients already have a history of psychiatric problems that are aggravated by the grim course of treatment. "We occasionally get patients who aren't greatly affected by therapy," Weinman says. "But many with hepatitis C are already struggling to cope with their disease before treatment, and the side effects of interferon alone could send them over the edge. That's why we need better treatments."

Targeting the virus

Different proteins — 10 of them, in the case of hepatitis C — make up a virus's structure. By working on HIV, scientists have learned that combinations of drugs, each aimed at a particular protein, are necessary to cut off a virus's survival strategies.

"It's a general principle of treating viruses — if you attack them at multiple sites, they can't mutate away from therapy," Weinman says. "We need potent combinations of new drugs that patients can tolerate long enough to rid themselves completely of hepatitis C."

Boceprevir and telaprevir target a class of viral proteins called proteases. Pharmaceutical companies are also busy developing and testing 20 to 30 different drugs — mostly against other parts of the virus, including its polymerase proteins.

There are additional hepatitis C viral proteins for which drugs could be developed. Weinman is studying one of these lesser-known possibilities, a protein called p7.

"It has similar properties to a protein in the influenza virus, for which the drug amantadine has worked pretty well," he says. "That's what got me interested."

Without p7, the hepatitis C virus is crippled: It can still replicate, but it can't create the packaging material needed to assemble brand-new viruses.

"For a long time, though, nobody knew p7's exact role, only that the virus could not do without it," Weinman says. He and his graduate student, Ann Wozniak, were the first to figure out what p7 actually does: it makes the interior of hepatitis C-infected cells less acid, which is necessary for the virus to function. They published their findings in the journal PLoS Pathogens in September 2010.

Weinman and Wozniak worked with researchers at the University of Leeds in the United Kingdom to deduce p7's function, and are continuing to collaborate to figure out how it could be stifled. In another paper in the journal Hepatology last summer, they described two classes of p7 inhibitors — adamantanes and alkylated imino-sugars — that attack p7 in different ways.

"Most of the current drugs target hepatitis C's early stages of replication," Weinman says. "We're trying instead to prevent replicated viral parts from being assembled." While p7 inhibitors have yet to advance to clinical trials, he reckons it's just a matter of time.

Alcohol's clout

Hepatitis C is most often caught early in people who undergo a health screening as part of a rehabilitation program — or if an observant person notes nondescript symptoms such as fatigue and mild liver tenderness. Most infected people, though, take decades to realize that they have the disease. This is because cirrhosis, or scarring, of the liver, is a stealthy process.

With cirrhosis comes the risk of cancer. Hepatitis C is, in fact, the main cause of liver cancer in Americans.

Besides working on new ways to target the virus with drugs, Weinman wants to better understand hepatitis C's long-term effects on the liver — particularly how alcohol consumption makes hepatitis C run a more aggressive course.

"In the U.S., alcoholism is actually a minor component of liver scarring — 85 percent of people who drink heavily and regularly never get cirrhosis," Weinman says. "That's a pretty surprising statistic, and it indicates that there are natural protective mechanisms against alcohol injury."

Weinman is investigating the potential role of a protein called FOXO3 in shielding the liver from alcohol. "It's a protective factor that gets activated when we either infect laboratory-cultured liver cells with hepatitis C or treat those cells with alcohol," he says. However, feeding alcohol to mice with hepatitis C results in exacerbated liver injury, and under these conditions, FOXO3's activity is significantly diminished.

Like most proteins, FOXO3's surface gets different "tags" added or removed, depending on its cellular environment. These tags alter the protein's function. Weinman and his postdoctoral fellow Irina Tikhanovich have found that in the presence of hepatitis C, FOXO3 is tagged in particular ways that engage its ability to prevent liver inflammation. Alcohol, however, interferes with this process and subverts FOXO's protective function.

Weinman was recently awarded a grant from the National Institutes of Health to continue dissecting the negative impact of alcohol on hepatitis C's progression. He's using some of this funding to explore another conundrum: while FOXO3 protects the liver against hepatitis C or alcohol, it also behaves abnormally in liver cancer.

"FOXO3 normally has another role as a tumor suppressor, but it goes haywire and loses this function in the majority of liver cancer cases," he explains. "It may be that hepatitis C eventually interferes with FOXO3's ability to suppress tumor growth, but we don't know for sure."

Weinman would like to figure out how to manipulate FOXO3 so it both protects the liver from cirrhosis and functions fully as a tumor suppressor. Current chemotherapy drugs produce a slew of harsh side effects and are only marginally effective against liver cancer.

"Chemoprevention is not as sexy; you can't point to Mrs. Jones over there and say you got rid of her liver cancer and saved her life," he says. "But I'm more interested in preventing cancer from ever occurring in patients with cirrhosis than treating cancer that's already developed. I think we'll save more lives this way."

A different approach, and hope for a cure

Through its active liver transplant practice, the KU Medical Center has acquired more than 2,000 tissue samples from the liver biopsies of more than 1,000 patients. These samples allow KU researchers to rapidly test ideas in ways that wouldn't be possible without the multi-year specimen repository, Weinman says.

Several other Liver Center researchers are also using these samples, along with patient histories, to investigate alcohol's influence on hepatitis C. In December 2011, they published a paper in Hepatology showing that alcohol may mask the effects or impair the expression of several nuclear receptor genes which, among other things, regulate the formation of scar tissue that eventually leads to liver cirrhosis, which happens much faster in alcoholics with hepatitis C.

"We haven't determined if there's a direct association between alcohol's effect on nuclear receptors and the progression of hepatitis C," says Richard Gilroy, M.D., a liver transplant specialist at KU Medical Center and one of the paper's authors. "However, it's a likely reason why this disease is more aggressive in alcoholics."

Weinman, who did not contribute to this paper, considers it a good example of how hepatitis C and alcohol might individually alter gene expression in the liver, with each influencing the other's effects.

"I think it's a nice proof-of-principle that the interaction of alcohol and hepatitis C is not the sum of two parts — instead, alcohol is modifying what hepatitis C does," he says.

Ultimately, Weinman and his colleagues are looking forward to greatly improved drugs for hepatitis C, especially the dawning era of interferon-free therapy.

"It's as certain as anything can be in medicine that we're on the cusp of curing this disease in 90 to 95 percent of patients," he says.

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4 hours ago

Posted in News, Sharps Safety, PPE & Standard Precautions, Bloodborne Pathogens

Every day, 5.6 million healthcare personnel in the U.S. are put at risk of occupational exposure to HIV, hepatitis C and other life-threatening blood-borne diseases via transmission modes such as needlestick injuries.

Safe in Common, a non-profit organization of healthcare safety advocates is launching a nationwide campaign to unite 100,000 U.S. healthcare personnel who believe current Federal standards for needlestick prevention to be largely inadequate, and that safer devices and other measures are needed to maximize protection to those at risk of harm.

Dr. Mary Foley, Chairperson of Safe in Common, notes, “As president of the American Nursing Association during the adoption of the federal Needlestick Prevention Act in 2000, I was honored to have helped our industry take a vital first step towards protecting healthcare personnel at risk of injury. But we must now come together again to help finish the job. I firmly believe that every needlestick injury is preventable with the right equipment, the right procedures and the right culture. I encourage all U.S. healthcare personnel to join me in the signing of the Safe in Common Pledge.”

Each year, nurses, physicians and other healthcare workers suffer an estimated 800,000 accidental needlestick injuries in U. S. hospitals. More than 1,000 of them become infected with HIV/AIDS or hepatitis B and C and other deadly blood-borne diseases

Safe in Common is a non-profit organization established to enhance and save the lives of U.S. healthcare personnel at risk of harm from needlestick injuries. It is led by Chairperson Mary Foley, PhD, RN, former president of the American Nursing Association and a U.S. leader for needlestick prevention, Healthcare Safety Advocate Nancy Purcell-Holmes, RN, and other industry leaders.

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Like many Millennials who self-identify as "AIDS activists", I learned about the organization ACT-UP (the AIDS Coalition to Unleash Power) during high school, when I first became interested in HIV/AIDS activism. I read a few articles, saw some photos of protest, but struggled to navigate their website -- my generation's medium du jour -- and thus I never had a sense of why they were considered so legendary.

It was not until this past Saturday night that I first saw the faces and heard the voices of ACT UP's founders via archived video footage, at a screening of How To Survive A Plague, a new documentary about the history of AIDS activism in America.

The film's timing was impeccable, as this weekend marks 25 years since ACT-UP's first protest; the kind of clever civil disobedience that brought AIDS into America's moral discourse by targeting political, scientific and religious leaders in the quest for a cure. The timing was also poignant for me, a 25-year-old whose AIDS activism developed in a world where HIV treatment has always existed.

ACT UP fought to survive and survive they did, so that by the time I was a teenager in 2000, life-saving HIV medications existed and were, for the most part, affordable and accessible in America. And now the "AIDS problem" my generation has taken up is no longer how to survive a plague, but how to end one. Research suggests that people successfully on HIV treatment become virtually unable to pass the virus on -- meaning that if everyone in the world with HIV had access to these drugs, there would be no further HIV transmission and no more AIDS deaths. There are, of course, political and systemic and behavioral challenges that come with getting 14.2 million people on a daily regimen.

Watching How To Survive cast a guiding light on my thoughts about solving those problems. ACT UP was comprised of people who suffered from a disease they could not WebMD or Wikipedia for a solution, and who communicated to the masses without platforms of YouTube, Twitter and Facebook. Would Millennials -- who, by contrast, oftentimes ditch protests and instead sign online petitions, 'like' pages, share viral videos and write blog posts -- have survived as activists under those circumstances?

I don't mean to get down on my generation. In fact, I think many of us wisely avoid traditional activism in favor of practivism -- practical activism. Rather than protesting at the offices of the Global Fund or the World Bank to galvanize more funds for AIDS treatment, we just fundraise for a clinic in a highly affected are and make treatment happen directly. Online tools can raise thousands in a matter of hours. A well-made viral video can circulate to millions in a single day.

There are many ways in which our digitized world has allowed us to raise awareness like never before, but the film's presentation of ACT UP's legacy reminded me of how the Internet gives us the easy way out in some ways:
  1. ACT UP members earned the title of experts in a pre-Google era. They sought out, befriended and studied under leading scientists so that when they stormed FDA and NIH offices, they blew away decision-makers with their detailed knowledge on the topic of HIV drug research. They didn't just raise their fists, they studied, analyzed, created and convinced experts to adopt a new concept of 'humane' clinical trials. I wonder: In a world with endless information easily available online for all (even entire college courses like MIT OpenCourseware), rather than being empowered, do we end up inundated and perhaps less likely to talk to and learn from one another?

  2. ACT UP members fought for their lives and the lives of their neighbors. "You are my murderer, in your suit and tie," one member shouted directly at a pharmaceutical company executive. "These are the people who know what's going on because they're dealing with it everyday!" yelled another ACT UP activist about her peers. While it's quite beautiful that the Internet lets us learn, and thus care, about people millions of miles away, will strangers always be a significant degree less committed to a solution than sufferers and their immediate circles?

  3. ACT UP members worked together on a united agenda. Sure, there was in-fighting and internal politics and debated priorities. But there was a central struggle -- to find a way to survive AIDS -- and it was fought for with maniacal focus and determination. As we fight now to end AIDS (and poverty and global warming and warlords), does our culture -- a culture that facilitates instantaneous creation of brand new websites, campaigns and social media accounts -- also make us less likely to reform, consolidate and coordinate the actions of the actors already in existence?
Millennials have technological tools at our fingertips that ACT UP members never had. But unless we use them correctly and strategically we may end up with an even greater challenge than our activist predecessors.

How To Survive A Plague was a powerful reminder to think more critically about activism and public service, and a motivating force to keep presenting Everyday Ambassador, to continue asking audiences to seek out more in-person interaction -- especially with people whose opinions challenge their own -- and continue asking people to not only cross country lines, but also comfort zones. Because ACT UP's legacy teaches us that surviving a plague means facing opposition relentlessly, strategically, respectfully and, most importantly, in-person.

ACT UP's Peter Staley recently wrote on his POZ magazine blog, "It's my sincere hope that this small flood of AIDS docs will teach younger generations about those remarkable and surreal early years, and inspire future activists for all the work that still needs doing."

Until you get a chance to watch the film for yourself, remember that we live in an era of enormous potential. If you want to end AIDS, you can start by joining the remarkable movement "ACT V". Poverty? Begin with ONE. But whatever your cause, strive to meet more experts face to face. Form alliances. Keep people affected by the issue in your closest social circles. Share a story over dinner, on the train, at a party -- not just on your Facebook wall. We must recognize that ending any problem means, above all, staying human.

And that's a whole new challenge we will need to overcome as activists raised in a digital age.

Source


Hepatitis B program helps cut infant infections

Genevra Pittman

Reuters

4:16 p.m. CDT, March 27, 2012

NEW YORK (Reuters Health) - A program to prevent chronic hepatitis B infection in newborns seems to be working, according to a new study from researchers at the Centers for Disease Control and Prevention.

They found that more babies exposed to hepatitis B through their moms have gotten vaccinated right away, and fewer have ended up with chronic infections, since the program started in 1990.

That's important because the virus can be passed between mother and child during birth, and over the long run chronic infection increases the risk of liver failure and cancer.

"The findings were very encouraging -- they showed that most infants completed the (vaccination) series," said Emily Smith, the lead researcher on the study.
"For the infants that were followed... they had great results and outcomes," she told Reuters Health.

Still, Smith emphasized that there's work to be done in making sure all new moms with hepatitis B are reported to the CDC's program so that babies can receive the proper care to prevent infection.

40,000 NEW INFECTIONS PER YEAR

About one million people living in the United States have chronic hepatitis B infection, and an additional 40,000 are infected every year though bodily fluids such as blood and semen -- as well as during birth.

The CDC's vaccine program calls for screening all pregnant women for hepatitis B and giving exposed babies antibodies and a vaccine against the virus within 12 hours of birth, followed by an additional two or three vaccine doses over the next year or so. Individual cities and states submit reports to the CDC on the number of hepatitis B cases identified in women and how their infants were managed, and those numbers are used to make nationwide estimates.

Based on those reports, the researchers calculated that from 1994 to 2008, the number of women who screened positive for hepatitis B each year increased from about 19,000 to close to 26,000. And health care workers seemed to get better at making sure their babies were protect against the virus.

Over the study period, the number of exposed babies who got both hepatitis B antibodies and a vaccine within a day of birth increased from 92 percent to almost 97 percent.

Along with that, tracked infants who ended up with chronic hepatitis B infection fell from two percent to less than one percent by 2008, the researchers reported in Pediatrics.

LONGER FOLLOW-UP NEEDED

Still, they were only able to follow about half of babies out to one year. And the number of infants who'd had all of their hepatitis B vaccines by that point actually decreased during the study period -- from 86 percent to 78 percent -- with at least some of that due to more families refusing vaccines.

"The program is certainly working -- they're vaccinating more infants successfully," said Dr. Maya Gambarin-Gelwan, who has studied hepatitis B at Weill Cornell Medical College in New York but wasn't involved in the new research.

"But half of the infants who are born to those mothers are slipping through the system essentially," she told Reuters Health. "It's also bothersome that there's this growing percentage of infants who are not completing vaccination or that we don't have a follow-up on."

Smith agreed that not being able to follow infants over time is a problem.

"Women need to receive hepatitis B screening and positive results need to be reported to (the program), to make sure that the infants receive vaccination and care and testing," she said.

Gambarin-Gelwan added that it's important to get the message out that hepatitis B programs really do work when babies get all of their recommended vaccines, especially to communities with high virus rates, such as among Asian-Americans.

Dr. Tram Tran from Cedars-Sinai Medical Center in Los Angeles told Reuters Health that while doctors are really good at screening women early in pregnancy when they're already in the health care system, there's still a big gap for other women, such immigrants and illicit drug users.

And even if those women do get screened, she said, they may not have the resources to bring their babies back for the multiple hepatitis B shots necessary for protection.

"It's a completely preventable disease, that's the thing that's frustrating," said Tran, a hepatitis researcher who wasn't part of the study team.

"We have a vaccine that works really well. It's just getting to these high-risk pockets and these high-risk groups where there's still a lot of opportunity."

SOURCE: http://bit.ly/GRqwAP Pediatrics, online March 26, 2012.

Source

Also See: Hepatitis B Vaccinations Increasing for At-Risk Infants

New Antiviral Agents for Hepatitis C

Jean-Michel Pawlotsky1,2

1. National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Henri Mondor Hospital, University of Paris-Est, France
2. INSERM U955; 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France

Corresponding author

F1000 Biol Reports2012, 4:5 (doi: 10.3410/B4-5)

Published: 01 Mar 2012

© 2012 Faculty of 1000 Ltd

The electronic version of this article is the complete one and can be found at: http://f1000.com/reports/b/4/5

The PDF of this article can be found at: http://f1000.com/reports/b/4/5/pdf

Abstract

Approximately 120-130 million individuals are chronically infected with hepatitis C virus (HCV) worldwide, although it is curable by therapy. Until recently, treatment of chronic hepatitis C was based on the combination of pegylated interferon-α and ribavirin. A number of models have been developed to study the HCV lifecycle and screen for potential HCV inhibitors. They led to the development of antiviral agents that specifically target a viral function (direct acting antivirals), and host-targeted agents that inhibit HCV replication. Direct acting antivirals in clinical development include NS3-4A protease inhibitors (two of which, telaprevir and boceprevir, have recently been approved for treatment of HCV genotype 1 infection in combination with pegylated interferon-α and ribavirin), nucleoside/nucleotide analogue and non-nucleoside inhibitors of HCV RNA-dependent RNA polymerase, and NS5A inhibitors. Host-targeted agents include cyclophilin inhibitors. This article describes the direct acting antivirals and host-targeted agents that have recently been approved or have been tested in HCV-infected patients and discusses their two current paths of clinical development: with or without interferon-α.

Introduction

Hepatitis C virus (HCV) was discovered in 1989 [1]. It was found to be responsible for the vast majority of so-called chronic non-A, non-B hepatitis and cryptogenetic liver diseases [2-4]. In adults, acute HCV infection leads to chronic infection in approximately 80% of cases. Chronic HCV infection is responsible for chronic hepatitis, which is complicated by cirrhosis in approximately 20% of cases. Patients with cirrhosis are exposed to life-threatening complications, including end-stage liver disease, esophageal varices hemorrhage and the development of hepatocellular carcinoma, which occurs at an incidence of 4%-5% per year in these patients [5]. Approximately 120-130 million individuals are chronically infected with HCV worldwide [6]. Chronic HCV infection has become the leading cause of hepatocellular carcinoma (primary liver cancer) and the first indication of liver transplantation in industrialized countries [5]. Six genotypes (1 to 6) and a number of subtypes have been described. Genotype 1 (subtypes 1a and 1b) is by far the most frequent genotype worldwide [7].

Unlike other known chronic viral infections, HCV infection is curable by therapy. Cure of infection is characterized by the “sustained virological response”, defined as undetectable HCV RNA in peripheral blood by means of sensitive molecular biology-based techniques. Until recently, treatment of chronic hepatitis C was based on the combination of a pegylated form of interferon (IFN)-α (pegylation improves the pharmacokinetic and pharmacodynamic properties and enhances the antiviral potency of IFN) and ribavirin [8-10]. This combination cures approximately 80% of infections in patients infected with HCV genotypes 2 or 3, but only 40%-50% in patients infected with genotypes 1 or 4. This emphasizes the need for more efficient antiviral strategies.

Over the past 10 years, a number of models have been developed to study the HCV lifecycle and screen for potential HCV inhibitors [11]. These models include cell-free enzyme assays for the HCV NS3-4A protease and RNA-dependent RNA polymerase, hepatoma cell lines harboring subgenomic and genomic replicons (nucleic acids capable of autonomous replication), an infectious cell culture system (limited to genotype 2a), and humanized mouse models infectable by HCV. They led to the development of antiviral agents that specifically target a viral function, now collectively termed “direct acting antivirals”. In addition, “host-targeted agents” that inhibit HCV replication are also in development. This article describes the direct acting antivirals that have recently been approved and direct acting antivirals and host-targeted agents that have been tested in HCV-infected patients and discusses their current paths of clinical development: with or without IFN-α.

New HCV drugs in development

In principle, every step of the HCV lifecycle, including receptor binding, endocytosis, fusion, uncoating, translation, polyprotein processing, RNA replication, virion assembly, maturation, transport and release, can be a target for new anti-HCV drugs [12]. Thus far, drugs targeting two major steps of the HCV lifecycle have reached clinical development. They include inhibitors of the HCV NS3-4A protease that block polyprotein processing and several drug families that block viral replication, including nucleoside/nucleotide inhibitors of the HCV RNA-dependent RNA polymerase, non-nucleoside inhibitors of the HCV RNA-dependent RNA polymerase, and inhibitors of the NS5A viral protein which plays a regulatory role in replication. Host-targeted agents that inhibit the host cell protein cyclophilin A, a protein required to interact with the replication complex for efficient viral genome production, are also in clinical development. Table 1 summarizes the drugs that have been tested in clinical trials and for which results have been published or presented at medical meetings as of November 2011.

Table 1. New drugs that have reached clinical development for treating chronic hepatitis C (/r means boosted by ritonavir)

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Barrier to resistance of HCV drugs

Like antiretroviral drugs, HCV direct acting antivirals have been shown to select drug-resistant viral variants, the outgrowth of which is responsible for virological breakthrough and disease progression [13]. In vivo, the “barrier to resistance” of an HCV drug is influenced by three parameters: (a) the “genetic barrier to resistance” of the drug, defined as the number of amino acid substitutions needed for a viral variant to acquire full resistance to the drug in question (if a single substitution is sufficient to confer high-level resistance, the drug is considered to have a low genetic barrier to resistance, while the need for three or more substitutions represents a high genetic barrier); (b) the “in vivo fitness” of the resistant viral variant population, defined as its ability to survive and grow in the replicative environment; and (c) drug exposure, defined as the drug concentration achieved in vivo relative to the 50% and 90% inhibitory concentrations (in enzyme assays) and efficient concentrations (in cellular assays) [13]. HCV drugs in development can be split into two groups according to their barrier to resistance, including drugs with a low barrier to resistance, and drugs with a high barrier to resistance.

HCV drugs with a low barrier to resistance

HCV drugs with a low barrier to resistance include the following direct acting antivirals: first-generation NS3-4A protease inhibitors, non-nucleoside inhibitors of HCV RNA-dependent RNA polymerase and NS5A inhibitors.

A large number of NS3-4A protease inhibitors have reached clinical development, including two drugs, telaprevir and boceprevir (Table 1), that have recently been approved for use in combination with pegylated IFN-α and ribavirin in patients infected with genotype 1. NS3-4A protease inhibitors have closely related chemical structures. They inhibit viral replication by 3.5 to 4.5 Log international units (IU)/mL when administered alone for a few days (one log reduction means that the viral level has been divided by 10, 2 log by 100, etc). Telaprevir and boceprevir are active against genotypes 1 and 2 only, whereas other protease inhibitors have broader genotype coverage; however, none of the first-generation NS3-4A protease inhibitors are active against genotype 3. A large number of amino acid substitutions conferring resistance to protease inhibitors have been shown to pre-exist at generally low levels in infected patients and are selected within a few days to weeks on drug monotherapy [13]. Different resistance profiles have been reported for subtypes 1a and 1b. Second-generation NS3-4A protease inhibitors, such as MK-5172 or ACH-2684 (Table 1), are expected to have broader genotypic coverage and higher barriers to resistance.

In contrast to protease inhibitors, non-nucleoside inhibitors of HCV RNA-dependent RNA polymerase are a heterogeneous group of drug families targeting one of four allosteric sites at the surface of the viral enzyme (Table 1). Their antiviral action is thus far restricted to HCV genotype 1. Different non-nucleoside inhibitors may have different antiviral potencies and select amino acid substitutions conferring resistance that is generally, but not always, located in close vicinity to their target site. Extensive cross-resistance has been reported between drugs targeting the same site, and cross-resistance can also occur between drugs targeting different sites.

NS5A inhibitors are potent antiviral drugs that block the function of the NS5A protein through an, as yet, unclear mechanism (Table 1). They have broad genotypic coverage, but a low barrier to resistance, with the highest levels of resistance conferred by single amino acid substitutions in subtype 1a.

New HCV drugs with a high barrier to resistance

HCV drugs with a high barrier to resistance include nucleoside/nucleotide analogues and host-targeted agents, such as cyclophilin inhibitors. Nucleoside/nucleotide analogues target the catalytic site of the RNA-dependent RNA polymerase. Several nucleoside and nucleotide analogues have reached clinical development, including purine and pyrimidine analogues. They are effective on all known genotypes and subtypes. Although these drugs have a low “genetic barrier” to resistance (as one single amino acid substitution is sufficient to confer resistance to the drug), these amino acid substitutions alter the conformation of the enzyme catalytic site. Thus, resistant variants exhibit low fitness and are not clinically meaningful. In this respect, nucleoside/nucleotide analogues have a high “barrier” to resistance in vivo, as resistant viral populations on single drug administration grow very slowly with virological breakthrough eventually occurring after months of treatment.

Cyclophilin A plays an important role in the HCV replication cycle by binding to both NS5A and the RNA-dependent RNA polymerase within the viral replication complex. Blocking cyclophilin peptidyl-prolyl cis-trans isomerase enzyme activity results in a significant inhibition of HCV replication both in vitro and in vivo, through molecular mechanisms that remain unclear. Because their target is a host protein, cyclophilin inhibitors have broad genotypic coverage and a favorable resistance profile. Amino acid substitutions in the NS5A protein can be selected by these drugs, but they confer low-level resistance and the corresponding variants exhibit low fitness.

Newly approved NS3-4A protease inhibitors

The first available direct acting antivirals for clinical development in patients infected with HCV genotype 1 were the NS3-4A protease inhibitors telaprevir and boceprevir. Due to their low barrier to resistance, it soon appeared that they could not be used alone and should be combined with other compounds with potent antiviral properties and no cross-resistance with the protease inhibitors. Only pegylated IFN-α and ribavirin were available for combination in Phase II and III clinical trials. It soon became apparent that ribavirin was also needed to improve the cure rates in combination with pegylated IFN-α and a protease inhibitor [14]. In 2011, the results of several Phase III trials have led to the approval of both telaprevir (Incivek, Vertex Pharmaceuticals, in the US; Incivo, Janssen, in Europe) and boceprevir (Victrelis, Merck) in combination with pegylated IFN-α and ribavirin [15-18]. Complex treatment algorithms have been issued in the US Food and Drug Administration and European Medicines Agency labels, which substantially differ between the two protease inhibitors (Tables 2 and 3). Treatment duration must be tailored to the severity of liver disease, prior virological response to pegylated IFN-α and ribavirin in previously treated patients, and the virological response during therapy (response-guided therapy). Sustained virological response rates in the range of 66% to 75% have been achieved in treatment-naïve patients in Phase III trials, significantly higher than with pegylated IFN-α and ribavirin alone [16,18]. In previously treated patients, the results strongly depended on the prior response to pegylated IFN-α and ribavirin, with sustained virological response rates of the order of 30% in prior null responders and up to approximately 85% in prior responder-relapsers [15,17].

Table 2. Telaprevir label (US and Europe)

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Table 3. Boceprevir labels (US and Europe)

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In addition to the complexity of the approved treatment regimens, the new triple combination therapies raise a number of issues.

  1. They are restricted to HCV genotype 1.
  2. The addition of a third drug to pegylated IFN-α and ribavirin is associated with additional, and eventually severe, side effects. The principal adverse reactions associated with telaprevir are anemia, pruritus and rash [17,18]. Rash is observed in approximately half of cases. It is generally benign and responds well to topical corticosteroids; however, severe cases have been reported in clinical trials, including occasional cases of Stevens-Johnson syndrome and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome. These complications can be life-threatening and impose rapid treatment interruption. Therefore, telaprevir therapy requires strict adherence to the rash management plan, in close collaboration with experienced dermatologists. Boceprevir administration is associated with anemia that aggravates hemolytic anemia due to ribavirin and dysgueusia [15,16].
  3. Selection of viral variants that are resistant to the protease inhibitor is an inevitable consequence of treatment failure, i.e. the failure to eradicate the virus on triple combination therapy. Such failure is due to an inadequate response to pegylated IFN-α and ribavirin, which does not prevent outgrowth of resistant variants selected by the protease inhibitor [13]. After treatment cessation, resistant viral populations progressively decrease in proportion and are no longer detectable with population sequencing after a period of a few months to two years [19-21]. Selection of resistant HCV variants does not appear to have a negative impact on the outcome of liver disease. Theoretically, it should not compromise the chance for a subsequent cure with another drug regimen.
  4. The addition of a protease inhibitor substantially increases the cost of therapy, raising issues regarding screening policies and access to care.
Two paths of clinical development of HCV direct acting antivirals

Issues raised by the recent approval of telaprevir and boceprevir in combination with pegylated IFN-α and ribavirin emphasize the need for alternative therapeutic strategies that ensure broader genotypic coverage, better efficacy, better tolerance and limited selection of resistant HCV variants. The clinical development of new HCV drugs currently follows two paths, according to whether or not pegylated IFN-α is included in the drug combination.

IFN-based regimens

Most of the new direct acting antivirals and host-targeted agents in development are currently tested as part of triple combinations with pegylated IFN-α and ribavirin. The results of Phase II trials have been encouraging with other NS3-4A protease inhibitors, such as TMC435 or BI201335 (currently in Phase III evaluation), the NS5A inhibitor daclatasvir (BMS-790052), or the cyclophilin inhibitor alisporivir (DEBIO-025, currently in Phase III evaluation), with sustained virological response rates of the same order as those with telaprevir and boceprevir [22-25]. Results of trials with two non-nucleoside inhibitors, filibuvir and tegobuvir, have been disappointing. However, this result cannot be generalized to the wider group of non-nucleoside inhibitors of HCV RNA-dependent RNA polymerase, as it seems to be essentially the result of the modest antiviral efficacy of the two individual compounds. Results are awaited with other drugs, tested in ongoing clinical trials. As with telaprevir and boceprevir, the response to IFN and ribavirin is a key determinant of the final outcome of therapy. It is too early to say whether the effect of IFN responsiveness will be attenuated when drugs with a high barrier to resistance are used in combination with pegylated IFN-α and ribavirin.

Interest was recently raised about quadruple combination treatment regimens that combine pegylated IFN-α, ribavirin, and two direct acting antivirals belonging to different drug classes without cross-resistance. In a study in patients who previously experienced a null response to pegylated IFN-α and ribavirin, 10 out of 10 patients receiving a quadruple combination including both daclatasvir (an NS5A inhibitor) and asunaprevir (an NS3-4A protease inhibitor) showed a sustained virological response [26]. The number of patients in this study was too small to draw firm conclusions, and it also remains to be established whether two drugs with a low barrier to resistance do better in combination with pegylated IFN-α and ribavirin than one drug with a high barrier to resistance, or whether quadruple combinations may be further improved by including at least one drug with a high barrier to resistance.

All-oral, IFN-free regimens

Enthusiasm about IFN-free regimens has recently risen dramatically with reports of sustained virological response rates of the order of 100% in small groups of patients treated with one or two direct acting antivirals alone, with or without ribavirin. What is known about IFN-free regimens can be summarized as follows: (a) the combination of two oral drugs with a low barrier to resistance results in early virological breakthroughs due to the selection of viral populations that are resistant to both drugs [26-28]; (b) ribavirin accelerates HCV clearance in combination with direct acting antivirals in the absence of IFN and is useful for shortening treatment duration and preventing post-treatment relapses [27]; (c) the use of a nucleotide analogue (PSI-7977) with ribavirin in patients infected with HCV genotypes 2 and 3 [29], or of a combination of an NS3-4A protease inhibitor (asunaprevir) and an NS5A inhibitor (daclatasvir) in patients infected with genotype 1b [30], a population in which daclatasvir has a reasonably high barrier to resistance, yielded 100% sustained virological response rates in small groups of patients.

Overall, these results provide a proof-of-concept that HCV infection can be cured by an all-oral IFN-free treatment regimen within 12 to 24 weeks and that very high sustained virological response rates can be achieved with drugs or drug combinations that have a high barrier to resistance. They strongly suggest that the IFN era is coming to an end in hepatitis C therapy, although this end cannot yet be precisely dated. Further results are awaited that will allow the establishment of an ideal all-oral IFN treatment regimen for patients with chronic HCV infection.

Conclusion

A new standard-of-care is now available for patients infected with HCV genotype 1, based on the triple combination of pegylated IFN-α, ribavirin, and either telaprevir or boceprevir. However, these new therapies are associated with increased costs, additional side effects and more complex treatment strategies, whereas pegylated IFN-α and ribavirin remain the standard treatment for all other genotypes, as well as in resource-limited settings where the cost of these new therapies cannot be afforded. A universal, cost-effective, well-tolerated all-oral first-line treatment regimen is needed and will most likely be available within a few years, when more is known about the ideal combination of drugs and the optimal doses and duration. Nevertheless, antiviral therapy is not the solution to definitively eradicate HCV infection, most of the 120-130 million chronic carriers live in areas where screening, cost and access to care preclude the use of these novel therapies. An efficient prophylactic vaccine is still urgently needed. This will be the next, and probably last, challenge of the HCV story.

Abbreviations

HCV, hepatitis C virus; IFN, interferon.

Competing Interests

The author has received research grants from Gilead and Roche/Genentech. He has served as an advisor for Abbott, Achillion, Anadys, Biotica, Boehringer-Ingelheim, Bristol-Myers Squibb, DebioPharm, Gen-Probe, Gilead, Glaxo-SmithKline, Idenix, Inhibitex, Janssen-Cilag, Madaus-Rottapharm, Sanofi-Aventis, Schering-Plough/Merck, Novartis, Pfizer, Roche/Genentech, Vertex and Virco.

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Hepatitis B Vaccinations Increasing for At-Risk Infants

From Medscape Medical News

Jenni Laidman

March 26, 2012 — A greater percentage of infants at risk for hepatitis B are being successfully vaccinated against the virus, but almost half of all at-risk infants slip through the healthcare system unnoticed. This puts them at risk for chronic liver disease and premature death, according to an article published online March 26 in Pediatrics.

Despite a 33% increase in the number of infants at risk for hepatitis B (from 19,208 in 1994 to 25,600 in 2008; P < .001) the percentage of infants managed for hepatitis B risk increased even more (from 40.8% to 50.5%; P < .001) in those years.

Emily A. Smith, MPH, from the Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, and colleagues examined data from 1994 to 2008 to determine the success of the National Perinatal Hepatitis B Prevention Program (PHBPP), established in 1990 by the CDC to decrease perinatal hepatitis B virus (HBV) transmission.

Although CDC guidelines call for hepatitis B (HepB) vaccination before hospital discharge for all newborns, infants born to mothers who test positive for the hepatitis B surface antigen (HBsAG) are to receive HepB, as well as hepatitis B immune globulin (HBIG), within 12 hours of birth, followed by 2 to 3 more HepB doses during infancy, with a goal of 90% series completion by 6 to 8 months of age. PHBPP protocol calls for these at-risk infants to be tested for the infection after the vaccination series is complete.

At-risk infants who fail to complete the vaccine series or who delay completion have a significantly higher risk for chronic HBV. In a study of 426 children at risk for HBV, incomplete vaccination increased risk for chronic infection almost 8-fold. Another study showed that receiving HBIG more than 12 hours after birth was associated with increased risk for HBV infection among at-risk infants.

The new analysis covered 49 states (excluding Alaska), as well as Chicago, Illinois; Houston, Texas; New York City; Philadelphia, Pennsylvania; San Antonio, Texas; and Washington, DC. "The PHBPP achieved substantial progress in preventing perinatal hepatitis B virus infection in the United States," the authors note.

Among the case-managed infants, 94.4% received HepB and HBIG within a day of birth, and a smaller proportion of children completed the vaccine series within a year, falling from 86.0% to 77.7% (P = .004). However, testing for HBV increased among children who completed the vaccination series, rising from 25.1% to 56.0% (P < .001). This testing showed a decline in chronic HBV infections, from 2.1% in 1999 to 0.8% in 2008 (P = .001).

However, the authors acknowledge, "Significant gaps remain in identifying HBsAG-positive pregnant women, and completing management and assessment of their infants to ensure prevention of perinatal hepatitis B virus transformation."

Children born to mothers with the hepatitis B surface antigen have a 90% risk of developing chronic hepatitis, which could lead to liver failure or liver cancer. However, proper prophylaxis prevents 85% to 95% of infections.

Although fewer infants were lost to follow-up in 2008 (13.0%) than in 2004 (26.4%), the difference was not significant (P = .126) The most common reason for lack of follow-up was failure to locate the child, at 33.1%, followed by "moved out of country," at 24.4%. Family refusal was a growing reason children did not complete testing, rising from 10.8% in 2005 to 17.9% in 2008 (P = .020). The authors termed this "problematic."

Even with timely vaccines, risks remain for some portion of at-risk children. An estimated 1% to 10% of infants born to hepatitis-positive mothers develop chronic or breakthrough hepatitis infection. Breakthrough infection is strongly associated with the mother's viral load, with transmission rates as high as 32% for mothers with HBV DNA concentrations greater than 108 copies/mL.

The authors have disclosed no relevant financial relationships.

Pediatrics. 2012;129:609-616.

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Posted On: March 27, 2012 - 3:00pm

A late stage liver condition, known as minimal hepatic encephalopathy (MHE), is associated with impaired driving skills and greater risk of motor vehicle accidents. Cost analysis of management strategies for detection and treatment of MHE are published in the April issue of Hepatology, a journal of the American Association for the Study of Liver Diseases. Findings report that MHE diagnosis using the inhibitory control test followed by treatment with lactulose was the most cost-effective approach--preventing the most car accidents and reducing societal cost by up to $3.6 million over a 5-year period.

In cirrhosis, as the liver fails, the build-up of toxic substances normally removed by the liver can lead to MHE—a reversible condition that causes cognitive impairment and loss of consciousness. Medical evidence reports that MHE is present in 55% of cirrhotic patients tested, and is associated with higher risk of motor vehicle collisions due to attention and visuomotor coordination deficits. The Inhibitory control test measures an individual's attention and experts suggest it could be cost-effective in diagnosing MHE and correlates with driving impairments.

Previous research estimates vehicular accidents cost more than $200 billion per year in the U.S. in terms of lost productivity, medical costs, automobile damage, and insurance expenses. "Detection and treatment of MHE has potential to reduce costs and morbidity related to car accidents," explains lead study author Dr. Jasmohan Bajaj with McGuire VA Medical Center and Associate Professor at Virginia Commonwealth University School of Medicine. "Our study analyzes the cost-effectiveness of various strategies for diagnosing and treating MHE to reduce vehicular accidents and the societal cost burden."

Researchers compared five strategies for managing MHE that included presumptive treatment of all cirrhotic patients; diagnosis by neuropsychological exam with therapy; psychometric diagnostic testing with treatment; diagnosis using inhibitory control test with treatment; and no MHE diagnostics or treatment. Analysis was conducted on a simulated group of 1,000 cirrhotic patients treated for MHE with lactulose or rifaximin, and followed for 5 years. Researchers estimated the societal cost of a single car accident to be $42,100.

Results show the cost per motor vehicle accident prevented by diagnosing MHE with the inhibitory control test was $24,454; standard psychometric tests was $25,470; with presumptive treatment it was $30,469; and with neuropsychological exam the cost was $33,742. "Our findings provide strong evidence that detection of MHE, particularly the inhibitory control test, and subsequent treatment with lactulose reduces societal costs by preventing motor vehicle accidents in patients with MHE," concludes Dr. Bajaj.

The authors of a related editorial also published in this month's issue cite previous research that reports driving errors account for 71% to 98% of all motor vehicle accidents. They suggest that the high percentage of traffic accidents involving driver error makes the assessment of driving abilities crucial for patients with MHE. The study by Bajaj et al. provides evidence which may encourage further real-life effect of MHE on accident rates, and according to the authors, raise awareness of the implications for patients with liver disease and the whole of society.

Source: Wiley-Blackwell

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Public release date: 27-Mar-2012

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

 

70,000 deaths and 3,000 stillbirths caused by infections

New research funded by the World Health Organization (WHO) estimates that 20.1 million individuals were infected with hepatitis E virus (HEV) genotypes 1 and 2 across 9 world regions in 2005. According to findings available in the April issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases, there were 3.4 million symptomatic cases, 70,000 deaths, and 3,000 stillbirths from HEV that year in countries throughout Asia and Africa.

Unlike hepatitis virus B and C strains that lead to chronic disease states, HEV causes acute illness. Previous studies show HEV genotypes 1 and 2 specifically infect humans, and are associated with large outbreaks in developing countries where sanitation conditions are poor. There is evidence that HEV increases mortality risk among pregnant women. While a safe and effective HEV vaccine has been developed, it has not been widely implemented.

"Our study represents the first attempt to estimate the annual global impact of hepatitis E," said lead author Dr. David Rein of the social science research organization NORC at the University of Chicago. Estimates were created by modeling the disease burden of HEV genotypes 1 and 2 in the 9 regions, representing 71% of the world's population. Based on published evidence the team—a collaboration between researchers from NORC, WHO and RTI International—also estimated annual incidence of infection to determine symptomatic, asymptomatic, and mortality cases.

The team determined that the prevalence pattern of HEV was consistent across the regions, with the largest incident increase occurring in those between the ages of 5 and 20 years. The average age of infection was 17 years with the lowest age of infection in North Africa (8 years) and highest in East Asia (21 years).

Of the more than 20 million people infected with HEV, 61% of the cases occurred in East and South Asia, two regions which also accounted for 65% of deaths from HEV. Researchers also noted that North Africa accounted for 14% of all global HEV infections, but only 8.3% of symptomatic cases and 8% of deaths, which the authors attribute to the younger average age of infection in that region.

The authors caution there are limitations to the study which only estimated incidence of HEV genotypes 1 and 2, leaving out genotype 3 that prevalently occurs in Europe and the U.S., and genotype 4. "Future HEV estimates should include genotypes 3 and 4 to provide a complete picture of the global burden of HEV," concludes Dr. Rein.

###

Full Citation: "The Global Burden of Hepatitis E Virus Genotypes 1 and 2 in 2005." David B. Rein, Gretchen Stevens, Jordan Theaker, John S. Wittenborn and Steven T. Wiersma. Hepatology; Published Online: November 26, 2011 (DOI: 10.1002/hep.25505); Print Issue Date: April 2012. http://onlinelibrary.wiley.com/doi/10.1002/hep.25505/abstract.

Author Contact: To arrange an interview with Dr. Rein, please contact Raymond Boyer at raymondcboyer@gmail.com or at 312-330-6433.

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

About the Journal

Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Hepatology's current impact factor is 10.885.Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350 .

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From Medscape Medical News

Megan Brooks

March 27, 2012 (New York, New York) — Scaling up prevention and treatment programs will help control and possibly eliminate the transmission of HIV and hepatitis C virus (HCV) among people who inject drugs, according to a poster abstract presented here at the International Conference on Viral Hepatitis 2012.

"With prevention efforts like syringe exchange, drug dependence treatment, and treatment for hepatitis C and HIV, we really have the potential to either eliminate transmission of those viruses among people who inject drugs or get it down to close to trivial levels," study author Don C. Des Jarlais, PhD, noted in an interview with Medscape Medical News. Dr. Des Jarlais is director of research at the Rothschild Chemical Dependency Institute, Beth Israel Medical Center, in New York City.

"People who inject drugs are at very high risk of infection with HIV and hepatitis C," Dr. Des Jarlais explained. "Is it going to be possible to eliminate HIV and HCV in people who inject drugs? We did a literature review and meta-analysis looking specifically at combined prevention and treatment and concluded that yes, it is certainly conceivable to eliminate transmission of those viruses among people who inject drugs," he said.

Moving in the Right Direction

Current estimates put the number of injection drug users at 16 million. Of these, 10 million are HCV-seropositive and 3 million are HIV-seropositive. Most live in low/middle-income countries; however, there has been a recent increase in new injectors in the United States, the researchers report. The estimated incidence of HCV infection ranges from 10 to 40 per 100 person-years; for HIV, it ranges from approximately 0.5 to 10.0 per 100 person-years.

On the basis of their analysis, Dr. Des Jarlais and colleagues estimate that combined prevention programs — particularly needle-exchange programs, drug dependence treatment, counseling, and testing — should be able to reduce HIV incidence to less than 0.5 per 100 person-years.

If this were the case, it would be "providing effective control," he said. The same programs applied to HCV could reduce incidence to 2.5 to 5.0 per 100 person-years, they report.

They also say that treatment for HCV infection, including new direct-acting antivirals, "might substantially reduce HCV transmission below these levels, but would be required on a large-scale basis, with 70% or more of currently infected persons treated."

"It's going to take prevention efforts like syringe exchange, pharmacy sales of syringes, and providing treatment for drug dependence," Dr. Des Jarlais said. "We are moving in that direction; certainly the new direct-acting antivirals are a huge advance. Without them, one wouldn't really consider the likelihood of treating large numbers of people who are infected with hepatitis C because the old treatments were really not that good," he told Medscape Medical News.

He also noted that although "many more people are getting screened, there are still a lot of gaps in getting someone screened, evaluated, and successfully treated. There is a big fall off at each of those steps."

Dr. Des Jarlais has disclosed no relevant financial relationships.

International Conference on Viral Hepatitis (ICVH) 2012: Poster abstract 79359. Presented March 26, 2012.

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Northwestern trials involve manipulation of donor stem cells to trick recipient's immune system

By Steven Ross Johnson, Special to the Tribune

March 28, 2012

Since she was first diagnosed with polycystic kidney disease at age 19, Lindsay Porter, now 47, has had to face the reality that she would someday need a kidney transplant.

"It really didn't affect me very much at all until my early 30s, when I developed high blood pressure," said Porter, who lives on Chicago's Northwest Side. "In my 40s, I started feeling really tired, and my abdomen just started growing huge by leaps and bounds. Eventually, my function declined to the point where I knew I was going to have to have a transplant."

Scheduled for June 2010, Porter's surgery was delayed until July, which she said turned out to be a stroke of good fortune.

"I knew that Northwestern (Memorial Hospital) was doing these trials. But at the time that (a friend) offered to donate the kidney, the trial wasn't open," Porter said. "The trial opened again on July 1, and I ended up being the first person in the trial."

The trial Porter referred to was the testing of a new kidney transplant method that has the potential to someday allow organ recipients to live a life free of anti-rejection medication.

The method, published this month in the journal Science Translational Medicine, suggested that through the manipulation of donor stem cells, the recipient's immune system might be tricked into accepting the new organ as a natural part of the body, thereby eventually eliminating the need for immunosuppressant drugs.

Study co-author Dr. Joseph Leventhal said the procedure has marked the first success at making a recipient's immune system accept a mismatched organ — one with a high rate of rejection — or from those donors who are unrelated, which made up the majority of the roughly 28,000 organ transplants conducted in the U.S. last year.

"We think this approach has very broad applicability to the larger number of patients receiving a solid organ transplant by virtue of the fact that it has been successful in mismatched, unrelated individuals, which is the usual scenario when you're doing a solid organ transplant," said Leventhal, a transplant surgeon at Northwestern Memorial Hospital.

Transplant recipients often must take a number of medications for the rest of their lives in order to prevent the body's immune system from rejecting their new organ.

As a result, the immune system is left susceptible to viruses and bacteria that it could easily fight off prior to surgery, which in turn requires the need to take a number of anti-viral drugs along with immunosuppressants.

But prolonged exposure to such drugs can have serious side effects, including high blood pressure, diabetes, cancer and damage to the new organ. That damage often requires the patient to eventually undergo another transplant.

On average, kidneys that are transplanted from living donors can last up to 15 to 20 years, with kidneys from deceased donors lasting anywhere from 5 to 10 years, Leventhal said. He felt the new procedure could prolong the life span of the new organ, eliminating the need for additional transplants.

"Many of the individuals who are coming onto the transplant waiting list — be it for a kidney, or for a heart, or for a liver — are people who have received a previous transplant and that transplant is failing," Leventhal said. "By achieving better control of the immune system without the need for drugs that can have negative side effects, we think that this is going to further prolong how the organs will last."

Dr. Suzanne Ildstad, a co-author of the study, said the process, which she called immune system tolerance, requires the kidney donor to also donate part of his or her immune system. The bone marrow stem cells that are collected are then enriched for "facilitating cells," which is believed to help transplants succeed.

During the monthlong process, the recipient undergoes radiation and chemotherapy to suppress his or her own bone marrow in order to provide enough space for the donor's stem cells to grow once they have been transplanted, said Ildstad, who is director of the University of Louisville's Institute of Cellular Therapeutics.

Conditioning of the stem cells takes about two days, which makes it possible to use only kidneys that come from living donors because bone marrow taken out of the body has already begun to degrade after such time, Ildstad said.

Ildstad and Leventhal said they hope the new transplant procedure might become a standard alternative in three to five years. For now, additional trials were needed to see whether the process could be used to treat patients who receive organs from deceased donors.

For physicians such as Dr. Dorry Segev, an associate professor of surgery at Johns Hopkins University School of Medicine, such a discovery has been what many in his field have waited to become a reality for years.

"Organ transplantation without anti-rejection medication is the holy grail that transplant folks have been dreaming about for decades," Segev said. "So if this can work, this would be a major breakthrough in our field."

Now two years removed from her surgery, Porter has remained drug-free and said living free of medications has vastly improved her quality of life.

"I feel great, I feel fantastic," Porter said. "I kind of feel like I got into a time machine, and it suddenly took me back about 10 or 15 years."

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How Much Aspirin Is Too Much of a Good Thing?

March 26, 2012, 6:20 pm

By RONI CARYN RABIN, Reporter

More than 40 million American adults already take an aspirin a day to prevent heart disease. Now many more are weighing the pros and cons of daily aspirin use in light of new studies finding that it also may reduce the risk of many cancers and stop the spread of tumors.

Six months ago Vanessa Brannan, a 31-year-old Seattle mother of two, learned she had colon cancer and Lynch syndrome, an inherited condition that increases risk of the disease and other cancers. Some of the best data on aspirin’s effectiveness against cancer has been found in patients like Mrs. Brannan. In one British study, patients with Lynch syndrome who took aspirin for two years cut their risk of colon cancer in half.

Yet doctors still don’t know how much aspirin these patients — or anyone else — should take. So Mrs. Brannan is taking 325 milligrams daily, though patients in the British study received nearly twice that amount. Her oncologist, though, recommended just an 81-milligram baby aspirin. “We kind of decided to split the difference and get as much aspirin into me as we can, knowing that higher amounts have been proven to work,” she said.

She is not the only cancer patient grappling with uncertainty. The science about daily aspirin and its effect on cancer is still in its infancy. In research studies, subjects have received doses ranging from 75 milligrams a day to 1,200 milligrams a day.

Now some scientists think low doses may work if they’re taken every day; American clinical trials of every-other-day aspirin had no effect on cancer rates at all.

Renewed interest in aspirin was set off by studies by researchers at Oxford, published last week in The Lancet, that found that after just three years of daily aspirin use, the risk of developing cancer was reduced by almost 25 percent when compared with a control group not taking aspirin.

Over six and a half years on average, daily aspirin reduced the risk of metastatic cancer by 36 percent and the risk of adenocarcinomas — common solid cancers including colon and prostate cancer — by 46 percent.

The studies found large reductions in colon and esophageal cancers, and hinted at benefits for the prevention of breast, uterine, ovarian and pancreatic cancers and lung cancer in smokers. The mechanism is believed to be aspirin’s suppression of inflammation, which is believed to play a role in cancer, and its inhibition of COX-2, an enzyme that helps tumors grow.

Critics say the new analyses may not be reliable because they are based on data from studies that were designed to assess aspirin’s effect on vascular disease, not cancer.

“The data with regard to breast cancer is interesting, but it is not actionable — period,” said Dr. Clifford A. Hudis, chief of the breast cancer medicine service at Memorial Sloan-Kettering Cancer CenterinNew York City.

But he does not dismiss aspirin altogether, saying it may help a specific subgroup of people at high risk for breast cancer because of changes related to obesityand inflammation. “That is far different than saying everybody should take it,” he said.

Public health experts worry about widespread use of aspirin, because the drug increases the risk of gastrointestinal bleeding, ulcers and hemorrhagic strokes that can be fatal. An analysis in Archives of Internal Medicine in January found that for every 162 people who took aspirin, the drug prevented one nonfatal heart attack but caused about two serious bleeding episodes.

Aspirin may be a household staple, but it is also a potentially toxic drug, said Dr. Khosrow Kashfi, an associate medical professor at the City College of New York, who is working to develop a safer but more potent form of aspirin. “If you are telling healthy people that they should take a drug for a long period of time, for years — at what dose we don’t even know, but for a long time — then safety becomes of paramount importance,” he said.

It may be necessary to treat as many as 2,000 patients with daily aspirin to prevent a single case of colon cancer a year, said Dr. Alfred Neugut, a professor of cancer research, medicine and epidemiology at Columbia University. “The question is: what does aspirin do on a daily basis to 2,000 people?” If 20 or more of those patients suffer bleeding episodes, then taking aspirin to prevent cancer isn’t worthwhile, he added.

But if research were to uncover significant reductions in other common cancers, “you could start to argue, for general cancer prevention, the cumulative benefit may make it worthwhile.”

Other researchers are more enthusiastic about aspirin’s prospects as a cancer treatment.

“These studies may not be perfect, but do we say, ‘Wait, and we’ll do a 15-year study to answer this’?” said Dr. Scott Kopetz, who treats gastrointestinal cancers at M.D. Anderson Cancer Center in Houston. “Or do we say, ‘This is really good, compelling data, and we need to start taking this into consideration for the individual who may be at cancer risk’?”

So what’s a consumer to do? The best evidence on aspirin’s potential as a cancer preventive has been found in clinical trials of patients at increased risk for colon cancer because of a strong familial or personal history of colon cancer.

“In that case, the benefit of long-term aspirin is likely to outweigh the risks,” said Dr. Peter M. Rothwell, the Oxford professor who led the recent Lancet studies. Dr. Rothwell said research indicates that a low 75-milligram dose of aspirin a day mitigates risk, but he urged patients to seek individualized guidance from a physician.

Those who use blood thinners or have stomach ulcers, blood clot disorders, liver or kidney disease, uncontrolled blood pressure or risks for hemorrhagic stroke should not take aspirin, said Dr. Asad Umar, chief of the gastrointestinal cancers research group in the National Cancer Institute’s Division of Cancer Prevention.

If you already take aspirin, don’t stop suddenly without telling your physician. Don’t take it on an empty stomach, and avoid alcohol and other anti-inflammatory drugs.

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Public release date: 26-Mar-2012

Contact: Karen N. Peart
karen.peart@yale.edu
203-432-1326
Yale University

Obese youths with particular genetic variants may be more prone to fatty liver disease, a leading cause of chronic liver disease in children and adolescents in industrialized countries, according to new findings by Yale School of Medicine researchers.

The study, which focused on three ethnic groups, is published in the March issue of the journal Hepatology.

Led by Nicola Santoro, M.D., associate research scientist in the Department of Pediatrics at Yale School of Medicine, the authors measured the hepatic, or liver, fat content of children using magnetic resonance imaging. The study included 181 Caucasian, 139 African-American and 135 Hispanic children who were, on average, age 13.

"We observed that a common genetic variant known as Patatin-like phospholipase domain containing protein-3 (PNPLA3) working with a regulatory protein called glucokinase (GCKR), was associated with increased triglycerides, very low-density lipoproteins levels, and fatty liver," said Santoro.

Santoro explained that his observations could help unravel the genetic mechanisms that contribute to liver fat metabolism. "This may drive the decisions about future drug targets to treat hypertriglyceridemia and non-alcoholic fatty liver disease," he said.

Childhood obesity is a global health concern. Experts say nonalcoholic fatty liver disease is now the leading cause of chronic liver disease in children and adolescents in industrialized countries.

"Our findings confirm that obese youths with genetic variants in the GCKR and PNPLA3 genes may be more susceptible to fatty liver disease," said Santoro, who is cautious about automatically extending this observation to the overall population.

"Our data refer to a population of obese children and adolescents," he said. "I think that further studies in a larger sample size involving lean subjects and adults may help to further define in more details these associations."

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Other authors on the study included Clarence K. Zhang, Hongyu Zhao, Andrew J. Pakstis, Grace Kim, Romy Kursawe, Daniel J. Dykas, Allen E. Bale, Cosimo Giannini, Bridget Pierpont, Melissa M. Shaw, Leif Groop, and Sonia Caprio.

The work was also funded, in part, by the Yale Clinical and Translational Science Award grant from the National Center for Research Resources at the National Institutes of Health.

Citation: Hepatology Vol. 55, No. 3 (March 2012)
http://onlinelibrary.wiley.com/doi/10.1002/hep.24806/abstract.

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